Advances of Novel Formulations in Drug Delivery 1394166435, 9781394166435

ADVANCES in NOVEL FORMULATIONS for DRUG DELIVERY The 27 chapters describe novel strategies for drug/nutraceutical delive

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Advances of Novel Formulations in Drug Delivery
 1394166435, 9781394166435

Table of contents :
Cover
Title Page
Copyright Page
Contents
Preface
Part I: Novel Drug Carriers and Therapeutics
Chapter 1 Nanoarchitectured Materials: Their Applications and Present Scenarios in Drug Delivery
1.1 Introduction
1.2 Liposomes
1.3 Nanoparticles
1.3.1 Nanoparticles in Drug Delivery
1.4 Nanoemulsions
1.4.1 Advantages and Shortcomings of Nanoemulsions
1.4.2 Application of Nanoemulsion in Drug Delivery
1.5 Dendrimers
1.5.1 Synthesis of Dendrimers
1.5.2 Advantages of Dendrimers
1.5.3 Applications of Dendrimers in Drug Delivery
1.6 Aquasomes
1.6.1 Properties of Aquasomes
1.6.2 Application of Aquasomes in Drug Delivery
1.7 Nanogel
1.7.1 Properties of Nanogels
1.7.2 Nanogels in Drug Delivery
1.8 Quantum Dots
1.8.1 Applications of Quantum Dots in Drug Delivery
1.9 Carbon Nanotubes
1.9.1 Features of Carbon Nanotubes
1.9.2 Carbon Nanotubes in Drug Delivery
References
Chapter 2 Nanopharmaceuticals for Drug Delivery
2.1 Introduction
2.2 What Are Nanopharmaceuticals and What Do They Do?
2.3 Nanopharmaceuticals Importance
2.4 Nanotechnology
2.5 Pharmaceutical Companies and Nanotechnology
2.6 Applications and Advantages of Nanopharmaceuticals as Drug Carriers
2.7 Characteristics of Nanoparticles in Nanopharmaceuticals
2.7.1 Particle Size
2.7.2 Surface Properties of Nanoparticles
2.7.3 Drug Loading
2.7.4 Drug Release
2.8 Targeted Drug Delivery
2.9 Types of Nanoparticles
2.10 Nanoparticle Preparation Methods
2.11 Evaluation of Nanoparticles
2.12 Efficiency of Drug Entrapment
2.13 Particle Shape
2.14 Size of the Particles
2.15 Zeta Potential
2.16 Rise of Nanopharmaceuticals
2.17 Nanopharmaceuticals Approval Regulations (FDA Rules & Regulations)
2.18 Conclusions and Prospects for the Future
References
Chapter 3 Applications and Prospects of Nanopharmaceuticals Delivery
3.1 Introduction
3.2 Nanopharmaceuticals
3.3 Development of Nanopharmaceuticals
3.3.1 From Lab to the Marketplace
3.3.2 Techniques
3.3.3 Cost
3.3.4 Ethics
3.3.5 Nanopharmaceuticals Approval Regulations (FDA Rules & Regulations)
3.4 Clinical Applications of Nanotechnology
3.4.1 Diagnostic Applications
3.4.1.1 Detection
3.4.1.2 Protein Chips
3.4.1.3 Individual Target Probes
3.4.1.4 Nanotechnology as a Tool in Imaging
3.4.1.5 Sparse Cell Detection
3.4.2 Therapeutic Applications
3.4.2.1 Surfaces
3.4.2.2 Gene Delivery
3.4.2.3 Drug Delivery
3.4.2.4 Liposomes
3.4.2.5 Nanotechnology in Orthopedic Applications
3.4.2.6 Nanotechnology in Cardiac Therapy
3.4.2.7 Nanotechnology in Dental Care
3.4.2.8 Biomolecular Engineering
3.4.2.9 Biopharmaceuticals
3.5 Nanopharmaceuticals Delivery—Recent Applications
3.5.1 Nanoparticulate Systems for Vaccine
3.5.1.1 Polyanhydride-Based NPs
3.5.1.2 Biodegradable Synthetic PLGA NPs
3.5.1.3 Liposome-Based NPs
3.5.1.4 Polysaccharide-Based NPs
3.5.2 Chemotherapy
3.5.2.1 Increasing the Concentration of Chemotherapeutic Agents in Tumor Tissue
3.5.3 Drug/Gene Delivery
3.5.3.1 Nanoparticles Used in Drug Delivery System
3.5.3.2 Cellulose
3.6 Nanotechnology in Neurodegenerative Disorders Treatment
3.7 Future Perspective
3.8 Issues with Current Nanopharmaceutical Concepts
3.8.1 Large-Scale Manufacturing
3.8.2 Biological Challenges
3.8.3 Intellectual Property (IP)
3.8.4 Biocompatibility and Safety
3.8.5 Government Regulations
3.9 Conclusion
References
Chapter 4 Nanomedicine Regulation and Future Prospects
4.1 Introduction
4.2 Importance of Regulation of Nanomedicine
4.3 Regulatory Challenges Faced by Nanomaterial in Medicine
4.3.1 Performing Various Functions
4.3.2 Nanomedicine Classification Issues
4.3.3 Variation in Size of the Particle
4.3.4 Manufacturing Process
4.3.5 Difficulties to Create CQA
4.3.6 Nanotoxicology and Cellular Response
4.3.7 Administering Right Doses
4.3.8 Pharmacokinetics
4.3.9 Developing Guidelines
4.4 Nanomedicine Future Aspects
4.5 Challenges that Threaten the Future of Nanomedicine
4.5.1 Financial Crisis
4.5.2 Lack of Confidence
4.5.3 Potential Dangers
4.5.4 Unsuccessful Patenting
4.5.5 Breakdowns in the Pharmaceuticals and Financial Markets
4.5.6 Limited Regulation
4.6 Future Prospects for Nanomedicine
4.6.1 Emerging Nanomaterials
4.6.2 Personalized Nanomedicine
4.6.3 Nanorobots and Nanodevices
4.6.4 Orthopedic Augmentations and Cytocompatibility
4.6.5 Cardiology and Nanotechnology
4.6.6 Cancer and Nanotechnology
4.6.7 NAPT
4.6.8 Gene, Protein, Lab-on-a-Chip Devices
4.6.9 Polymeric Nanoparticles in Medicine
References
Chapter 5 Nanotechnology Application in Drug Delivery for Medicinal Plants
5.1 Introduction
5.1.1 Nanodrug Delivery Systems (NDDS)
5.2 Nanoherbals
5.2.1 Cucuma longa (Cucurmin)
5.2.2 Gingko biloba
5.2.3 Artemisia
5.2.4 Silybum marianum—Silymarin
5.2.5 Salvia miltiorrhiza (Danshen)
5.2.6 Glycyrrhiza glabra (L.)
5.2.7 Camellia sinensis (Green tea)
5.2.8 Camptotheca acuminata
5.2.9 Leea indica
5.2.10 Ziziphus mauritiana (Malay apple)
5.2.11 Cuscuta chinensis
5.3 Conclusion
References
Chapter 6 Nanosystems Trends in Nutraceutical Delivery
6.1 Introduction
6.2 Classification of Nutraceuticals
6.3 Biopharmaceutical Issues Associated with Nutraceuticals
6.4 Nanosystems for Delivery of Nutraceuticals
6.4.1 Nanoemulsions
6.4.2 Self-Emulsifying Systems
6.4.3 Solid Lipid Nanoparticles and Nanostructured Lipid Carriers
6.4.4 Liposomes
6.4.5 Polymeric Nanoparticles
6.4.6 Inorganic Nanoparticles
6.5 Challenges
6.6 Market Potential
6.7 Conclusion and Perspective
References
Chapter 7 Nanoencapsulated Systems for Delivery of Phytopharmaceuticals
7.1 Introduction
7.1.1 Nanoencapsulation Techniques in Phytopharmaceuticals
7.1.1.1 Physical-Chemical Techniques
7.1.1.2 Chemicals Techniques
7.1.1.3 Mechanical Techniques
7.1.2 Characterization of Nanoencapsulates
7.1.2.1 Morphological Characterization
7.1.2.2 Physicochemical Characterization
7.1.3 Nanoencapsulated Systems for Free Delivery of Phytopharmaceuticals
7.1.4 Studies to Evaluate Phytopharmaceuticals Nanoencapsulates
7.2 Conclusions
References
Chapter 8 Topical Drug Delivery Using Liposomes and Liquid Crystalline Phases for Skin Cancer Therapy
8.1 Introduction
8.2 Liposomes for Topical Application
8.2.1 Development of Liposomal Nanoparticles
8.3 Liquid Crystals and Liquid Crystalline Nanodispersions for Topical Application
8.3.1 Characterization Techniques
8.4 Physical Methods Applied to Nanoparticles Delivery
8.4.1 Sonophoresis
8.4.2 Microneedles
8.5 Conclusions and Perspectives
Acknowledgements
References
Chapter 9 Vesicular Drug Delivery in Arthritis Treatment
9.1 Introduction
9.2 Skin Penetration Pathways
9.2.1 Intercellular Pathway
9.2.2 Transcellular Pathway
9.2.3 Appendgeal Pathway
9.3 Principles of Drug Permeation Through Skin
9.4 Problems Associated with Conventional Dosage Forms
9.5 Novel Treatment Strategies for Arthritis
9.5.1 Traditional Liposomes as Skin Drug Delivery Systems
9.5.2 Transferosomes (Ultradeformable Liposomes) as Skin Drug Delivery Systems
9.5.3 Ethosomes as Skin Drug Delivery Systems
9.5.4 Niosomes as Skin Drug Delivery Systems
9.6 Conclusion and Future Perspectives
References
Chapter 10 Perspectives of Novel Drug Delivery in Mycoses
10.1 Introduction
10.2 Role of Conventional Drugs in Antifungal Therapy
10.3 Mechanism of Action of Conventional Antifungals
10.4 Summary of Nanoparticles and Their Role in Antifungal Therapy
10.4.1 Lipid Nanoparticles
10.4.2 Liposome
10.4.3 Transfersomes
10.4.4 Transethosomes
10.4.5 Solid Lipid Nanoparticles (SLN)
10.4.6 Nanostructured Lipid Carriers (NLC)
10.4.7 Polymer Lipid Hybrid Nanoparticles (PLN)
10.4.8 Polymeric Nanoparticles
10.4.9 Microsponge and Nanosponge Systems
10.4.10 Polymeric Micelles
10.4.11 Polymersomes
10.4.12 Dendrimers
10.4.13 Metallic Nanoparticles
10.5 Other Drug Delivery Systems
10.5.1 Niosomes
10.5.2 Spanlastics
10.5.3 Microemulsions and Nanoemulsions
10.5.4 Silicon Dioxide Nanoparticles
10.6 Conclusion
References
Chapter 11 Nano-Based Drug Delivery in Eliminating Tuberculosis
11.1 Introduction
11.1.1 Latent and Active Tuberculosis
11.1.2 Multidrug-Resistant Tuberculosis (MDR-TB)
11.1.3 Extensively Drug-Resistant TB
11.2 Antitubercular Therapy
11.3 Therapies Based on Nanotechnology
11.3.1 Nanoparticles for Anti-TB Therapy
11.3.2 Advantages and Disadvantages of Nanoparticles
11.3.3 Types of Nanoparticles and Their Characteristics
11.3.3.1 TB Dendrimers
11.3.3.2 Cyclodextrins
11.3.3.3 Polymeric Micelles
11.3.3.4 Liposomes
11.3.3.5 Nanoemulsions
11.3.3.6 Solid Lipid Nanoparticles
11.3.3.7 Niosomes
11.3.3.8 Polymeric Nanoparticles
11.4 Routes of Administration of Nanoparticles
11.4.1 Oral Administration of Nanoparticles
11.4.2 Inhalational Administration of Nanoparticles
11.4.3 Intravenous Administration of Nanoparticles
11.4.4 Other Routes of Administration
11.5 Conclusion
References
Chapter 12 Promising Approaches in Drug Delivery Against Resistant Bacteria
12.1 Introduction
12.2 Drug Delivery Systems
12.2.1 Microneedles
12.2.2 Nanoparticles
12.2.2.1 Inorganic Nanoparticles
12.2.2.2 Polymer-Based Nanomedicines
12.2.3 Lipid-Based Nanoformulations
12.2.4 Stimuli-Responsive Nanocarriers
12.2.4.1 Endogenous Stimuli
12.2.4.2 Exogeneous Stimuli
12.2.5 Nanogels
12.2.6 Nanofibers
12.2.7 Biomedical Implants
12.2.8 Wound Dressing
12.3 Biofilm Disruption
12.4 Conclusion
References
Chapter 13 Emulgels: A Novel Approach for Enhanced Topical Drug Delivery Systems
13.1 Introduction
13.2 Approaches Used for Topical Drug Delivery
13.3 Factors Affecting Topical Absorption of Drug
13.4 Drug Delivery Across the Skin
13.5 Emulgels
13.5.1 Types of Emulgels
13.5.2 Advantages of Emulgel
13.5.3 Rationale of Emulgel as a Topical Drug Delivery System
13.5.4 Formulation Considerations
13.5.5 Excipients Used in the Formulation of Emulgel
13.5.5.1 Vehicle
13.5.5.2 Emulsifying Agents
13.5.5.3 Gelling Agent
13.5.5.4 Penetration Enhancers
13.5.5.5 Preservatives
13.5.5.6 Antioxidants
13.5.5.7 Humectant
13.5.6 Formulation Methods
13.5.7 Routes of Administration for Emulgel Formulation
13.5.8 Evaluation of Emulgels
13.5.8.1 Physical Appearance
13.5.8.2 Spreading Coefficient
13.5.8.3 Rheological Studies
13.5.8.4 Globule Size and its Distribution in Emulgel
13.5.8.5 Swelling Index
13.5.8.6 Extrudability Study of Topical Emulgel (Tube Test)
13.5.8.7 Skin Irritation Test (Patch Test)
13.5.8.8 Drug Content Determination
13.5.8.9 In Vitro Release/Permeation Studies
13.5.8.10 Ex Vivo Bioadhesive Strength Measurement of Topical Emulgel (Mice Shaven Skin)
13.5.8.11 Microbiological Assay
13.5.8.12 Drug Release Kinetic Study
13.5.8.13 Stability Studies
13.5.9 Marketed Preparations
13.5.10 Future Prospective of Emulgel as Topical Drug Delivery
13.5.11 Therapeutic Profile of Emulgel
13.6 Conclusions
References
Chapter 14 Electrospun Nanofibers in Drug Delivery
14.1 Introduction
14.2 Electrospinning Setup
14.3 Polymers Used to Produce Electrospun Nanofibers
14.4 Drug Release
14.5 Matrix Type NFs
14.5.1 Monolithic
14.5.2 Blended NFs
14.6 Core-Shell Nanofibers
14.6.1 Multimatrix Core-Shell NFs
14.6.2 Reservoir Type Core-Shell NFs
14.7 Electrospun Nanofiber for Drug Delivery Applications
14.7.1 Nucleic Acid Delivery Using NFs
14.7.2 Antibiotics Delivery Using NFs
14.7.3 Vaginal Drug Delivery Using NFs
14.7.4 Ocular Drug Delivery Using NFs
14.7.5 Other Drug Delivery Using NFs
14.8 Conclusion
References
Part II: Drug Carriers in Drug Delivery
Chapter 15 Role of Nanotechnology-Based Materials in Drug Delivery
15.1 Introduction
15.2 Nano-Based Drug Delivery Systems
15.3 Types of Nanoparticles
15.3.1 Polymeric Nanoparticles (PNPs)
15.3.2 Dendrimers
15.3.3 Polymeric Micelles
15.3.4 Liposomes
15.3.5 Quantum Dots (QDs)
15.3.6 Nanocrystals
15.3.7 Gold Nanoparticles
15.3.8 Carbon Nanoparticles
15.3.8.1 CNTs
15.3.8.2 CNH
15.3.8.3 Fullerenes
15.3.9 Magnetic Nanoparticles (MNPs)
15.4 Advantages of Nanoparticles
15.5 Toxicity of Nanoparticles
15.6 Conclusion
References
Chapter 16 Nanomedicine Drug Delivery System
16.1 Introduction
16.2 Background
16.3 Five Overlapping Subthemes of Nanomedicine
16.4 How Nanomedicine Work?
16.5 Nanomedicine for Screening of Individuals with Serious Diseases
16.6 Objectives of Nanomedicine
16.7 Advantages of Nanomedicine
16.8 Physiological Principles for Nanomedicines
16.9 Nanotoxicology from Nanomedicines
16.9.1 Health and Safety Issues
16.9.2 Cell Death and Altered Gene Expression
16.9.3 Cell Death and Gene Therapy
16.9.4 Pseudoallergy and Idiosyncratic Reactions
16.9.5 Cytotoxicity
16.9.6 Implications for Nanotoxicology from Nonmedical Nanoparticles
16.10 Nanomedicine Applications
16.10.1 Analytical and Diagnostic Tools
16.10.1.1 In Vitro Diagnostic Devices
16.10.1.2 In Vivo Imaging
16.10.2 Drug Delivery
16.10.2.1 Micelles
16.10.2.2 Nanoemulsions
16.10.2.3 Solid Nanoparticles
16.10.3 Regenerative Medicine
16.11 Toxicological and Ethical Issues in Nanomedicine
16.11.1 Toxicity Issues
16.11.2 Ethical Issues
16.12 Conclusions
References
Chapter 17 Nanocarriers-Based Topical Formulations for Acne Treatment
17.1 Introduction
17.2 Acne Therapeutics
17.2.1 Nanocarriers Toward Topical Acne Therapy
17.3 Efficacy and Safety of Nanotechnology-Based Acne Therapeutics
17.3.1 Ex Vivo and In Vitro Assays
17.3.2 Animal Assays
17.3.3 Clinical Assays
17.4 Improvement of Acne Therapy by Nanocarrier-Based Formulations
17.4.1 Conventional Drugs in Nanocarriers
17.4.2 Alternatives Drugs in Nanocarriers
17.5 Conclusion
References
Chapter 18 Emerging Trends of Ocular Drug Delivery
18.1 Introduction
18.2 Barriers to Ocular Drug Delivery
18.3 Classical Drug Delivery Technology
18.3.1 Anterior Segment
18.3.2 Posterior Segment
18.4 Novel Interventions for Ocular Drug Delivery
18.4.1 Ocular Implants
18.4.2 Punctum Plugs
18.4.3 Drug-Eluting Contact Lenses
18.4.4 Ocular Iontophoresis
18.4.5 Intravitreal Implants
18.4.6 Ocular Vaccination
18.5 Applied Nanotechnology for Ocular Drug Delivery
18.5.1 Nanomicelle
18.5.2 Liposomes
18.5.3 Chitosan-Based Nanoparticles
18.5.4 Niosomes
18.5.5 Nanospheres
18.5.6 Nanocapsules
18.5.7 Dendrimers
18.5.8 Nanowafers
18.5.9 Micronanosurgery for Ocular Drug Delivery
18.6 Conclusion
References
Chapter 19 Microspheres: An Overview on Recent Advances in Novel Drug Delivery System
19.1 Introduction
19.2 Advantages of Novel Drug Delivery System
19.3 Classification of Novel Drug Delivery System
19.3.1 Microspheres
19.3.1.1 Types of Microspheres
19.3.2 Ideal Properties of Microparticulate Carriers
19.3.3 Polymers Used in Preparation of Microspheres
19.3.4 Advantages of Microspheres
19.3.5 Disadvantages of Microspheres
19.3.6 Classification of Microspheres
19.3.6.1 Bioadhesive Microspheres
19.3.6.2 Magnetic Microspheres
19.3.6.3 Floating Microspheres
19.3.6.4 Radioactive Microspheres
19.3.6.5 Polymeric Microspheres
19.3.7 Method of Preparation of Microspheres
19.3.7.1 Single Emulsion Technique
19.3.7.2 Double Emulsion Method
19.3.7.3 Polymerization Technique
19.3.7.4 Phase Separation Coacervation Technique
19.3.7.5 Spray Drying and Spray Congealing Method
19.3.7.6 Solvent Evaporation Method
19.3.8 Evaluation Parameters of Microspheres
19.3.8.1 Particle Size and Shape
19.3.8.2 Chemical Analysis by Electron Spectroscopy
19.3.8.3 FTIR Spectroscopy
19.3.8.4 Determination of Density
19.3.8.5 Isoelectric Point Determination
19.3.8.6 Entrapment Efficiency
19.3.8.7 Angle of Contact
19.3.8.8 Swelling Index
19.3.8.9 Production Yield
19.3.8.10 In Vitro Drug Release Study
19.3.8.11 Drug Release Kinetics
19.3.8.12 Stability Studies
19.3.9 Applications of Microspheres
References
Chapter 20 Drug Delivery Systems and Oral Biofilm
20.1 Introduction
20.2 Oral Biofilm
20.2.1 Biofilm Related Infections in The Oral Cavity
20.2.1.1 Oral Biofilm and Periodontal Disease
20.2.1.2 Oral Biofilm and Endodontic Infections
20.2.1.3 Oral Biofilm and Dental Caries
20.3 Drug Delivery Systems
20.3.1 Nanoparticles
20.3.2 Hydrogels
20.3.3 Dendrimers
20.4 Applications of Drug Delivery Systems for Treatment of Oral Biofilm Infection
20.4.1 DDS and Dental Caries
20.4.2 DDS and Periodontal Disease
20.4.3 DDS and Other Oral Pathologies
20.5 Conclusion
References
Chapter 21 Oral Drug Delivery System: An Overview on Recent Advances in Novel Drug Delivery System
21.1 Introduction
21.1.1 Oral Route
21.1.2 Oral Health
21.1.3 Oral Hygiene
21.2 Oral Drug Administration Sites
21.2.1 Oral Mucosal Drug Delivery System
21.2.1.1 Physiology of Oral Mucosa
21.2.1.2 Importance of Saliva and Mucin
21.2.2 Buccal and Sublingual Drug Absorption
21.3 Factors Affecting Drug Absorption
21.3.1 Lipid Solubility, pH, and Degree of Ionization
21.3.2 Molecule Weight and Size of Drug
21.3.3 Formulation Physiochemical Properties Related Factors
21.3.4 Permeability Enhancer
21.4 Drug Delivery for Periodontitis
21.4.1 Periodontal Pocket
21.4.1.1 Classification of Periodontal Pockets According to their Morphology
21.4.1.2 Classification of Periodontal Pocket According to the Involvement of Tooth Surfaces
21.5 Oral Periodontitis Drug Delivery System
21.5.1 Antibacterial DDS for Periodontitis
21.5.2 Remineralizing DDS
21.5.3 Inflammation Modulating and Alveolar Bone Repairing DDS for Periodontitis
21.5.3.1 DDS for Peri-Implantitis
21.6 Teeth Treatments
21.7 Periodontal Local Drug Delivery
21.8 Carriers of Oral and Periodontitis Drug Delivery System
21.8.1 Hydrogel
21.8.2 Dendrimers
21.8.3 Chewing Gum
21.8.4 Lozenges
21.8.5 Tablets
21.9 Mucoadhesive Drug Delivery System/Buccal Adhesive Drug Delivery System
21.9.1 Patches and Films
21.9.2 Oral Suspension
21.9.3 Spray
21.9.4 Liposome
21.9.5 Nanoparticles
21.9.6 Laminated Film
21.9.7 Injectable Gels
21.9.8 Fibers
21.9.9 Strips and Compacts
References
Chapter 22 Cancer Nanotheranostics: A Review
22.1 Introduction
22.1.1 Lipid and Polymer-Based Nanosystems
22.1.2 Magnetic Nanoparticles
22.1.3 Quantum Dots (QD)
22.1.4 Other Metal-Derived Nanoparticles
22.2 Conclusion
References
Chapter 23 Nanomedicine in Lung Cancer Therapy
23.1 Introduction
23.2 Nanotechnology
23.3 Nanomedicines for Lung Cancer Therapy
23.3.1 Nanoparticles
23.3.1.1 Gold and Silver Nanoparticles
23.3.1.2 Solid Lipid Nanoparticles
23.3.1.3 Inhalable Nanoparticles
23.3.2 Micelles
23.3.3 Dendrimers
23.3.4 Liposome
23.3.5 Carbon Nanotubes
23.3.6 Quantum Dots
23.3.7 Nanofibers
23.3.8 Nanoshells
23.4 Evaluation of Nanoformulations
23.5 Application of Nanoformulations
23.6 Marketed Therapies
23.7 Challenges
23.8 Potential
23.9 Future Scope
23.10 Conclusion
References
Chapter 24 Delivering Herbal Drugs Using Nanotechnology
24.1 Introduction
24.2 Methods of Preparation of Nanoparticles
24.3 Novel Drug Delivery Systems (NDDS) for Herbal Drugs
24.3.1 Liposomes
24.3.2 Phytosomes
24.3.3 Transferosome
24.3.4 Niosomes
24.3.5 Ethosomes
24.3.6 Dendrimers
24.3.7 Self-Nanoemulsifying Drug Delivery System (SNEDDS)
24.3.8 Self-Micro Emulsifying Drug Delivery System (SMEDDS)
24.4 Conclusion
References
Chapter 25 Nanoherbals Drug Delivery System for Treatment of Chronic Asthma
25.1 Introduction
25.2 Mechanism of Asthma Physiopathology
25.3 Asthma Etiology
25.4 Severity of Asthma
25.5 Asthma Phenotypes
25.6 Asthma Epidemiology
25.7 Asthma Treatment
25.7.1 Adverse Effects of Current Treatment Techniques
25.8 Need of Natural Products as Alternative
25.9 Selected Medicinal Plants in Asthma Treatment
25.9.1 Piper betel Linn
25.9.2 Bacopa monnieri L.
25.9.3 Momordica charantia
25.9.4 Ficus bengalensis (Linn.)
25.9.5 Clerodendrum serratum (Linn.) Moon
25.10 Potentials of Nanotechnology in Asthma Drug Delivery
25.11 Nanoherbals as Asthma Drug Delivery System
25.12 Future Prospectus of Nanoherbal Drug Delivery
25.13 Conclusion
References
Chapter 26 Nutrients Delivery for Management and Prevention of Diseases
26.1 Introduction
26.2 Nutrients in Management and Prevention of Disease
26.2.1 Herbal Nutrients
26.2.2 FDA Regulations on Herbal Drugs
26.3 Phenolic Nutraceuticals
26.3.1 Polyphenols and Neurodegeneration
26.3.2 Polyphenols and Brain Tumors
26.3.3 Phenols and Other Cancer Treatments
26.3.4 Phenols and Hepatotoxicity
26.3.5 Clinical Trials
26.3.6 Curcumin
26.4 Routes for Nutrients Delivery
26.4.1 Oral Route
26.4.2 Intranasal Delivery
26.4.3 Transdermal Route
26.5 Nanoparticle-Based Nutrients Delivery System
26.5.1 Nanostructured Lipid Carriers (NLCs)
26.5.2 Solid Lipid Nanoparticles (SLNs)
26.5.3 Liposomes
26.5.4 Nanocrystals
26.5.5 α-Lactalbumin
26.5.6 Carbon Nanotubes
26.5.7 Nanocochleates
26.5.8 Nanosized Self-Assembled Liquid Structures
26.5.9 Polysaccharide-Based Nanoscale Delivery of Nutrients
26.5.10 Chitosan
26.5.11 Alginate
26.5.12 Pectin
26.5.13 Gum Arabic
26.5.14 Cashew Gum
26.6 Protein-Based Nanoscale Delivery of Nutrients
26.6.1 Zein
26.6.2 Gliadin
26.6.3 Soy Protein Isolates (SPI)
26.6.4 Whey Protein
26.6.5 Casein
26.6.6 Other Proteins
26.7 Micelles
26.8 Advantages of Nanomaterials in Nutraceuticals
26.9 Safety and Toxicity of Nanostructures Applied in Food Systems
26.10 Conclusion
References
Chapter 27 Nanonutraceuticals for Drug Delivery
27.1 Introduction
27.2 Approaches to Enhance Oral Bioavailability of Nutraceuticals
27.2.1 Protection of Labile Compounds
27.2.2 Extension of Gastric Retention Time
27.2.3 Intonation of Metabolic Activities
27.3 Carriers for Nutraceutical Delivery
27.3.1 Nanoparticles for Nutraceuticals Delivery
27.3.2 Solid Lipid Nanoparticles (SLNs) for Nutraceutical Delivery
27.3.3 Niosomes
27.3.4 Nanospheres
27.3.5 Nanoliposomes
27.3.6 Nanofibers
27.3.7 Nanoemulsion
27.4 Nanotechnology in Food Sector
27.4.1 Nanotechnology in Nutraceuticals
27.4.2 Nanotechnology in Medications
27.4.3 Commercial Nanonutraceuticals
27.4.4 Nanosized Self-Assembled Structured Liquids
27.5 Delivery of Nutraceuticals
27.5.1 In-Feed or Oral Nanodelivery
27.5.2 Dermal Delivery
27.5.3 Ophthalmic Delivery
27.6 Constraints in Nanodrug Delivery Systems
27.7 Conclusion
Acknowledgments
References
Index
EULA

Citation preview

Advances in Novel Formulations for Drug Delivery

Scrivener Publishing 100 Cummings Center, Suite 541J Beverly, MA 01915-6106 Publishers at Scrivener Martin Scrivener ([email protected]) Phillip Carmical ([email protected])

Advances in Novel Formulations for Drug Delivery

Edited by

Raj K. Keservani

Faculty of B. Pharmacy, CSM Group of Institutions, Prayagraj, India

Rajesh Kumar Kesharwani

Department of Computer Application, Nehru Gram Bharati (Deemed to be University), Prayagraj, India

and

Anil K. Sharma

School of Medical and Allied Sciences, GD Goenka University, Gurugram, India

This edition first published 2023 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA © 2023 Scrivener Publishing LLC For more information about Scrivener publications please visit www.scrivenerpublishing.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. Wiley Global Headquarters 111 River Street, Hoboken, NJ 07030, USA For details of our global editorial offices, customer services, and more information about Wiley products visit us at www. wiley.com. Limit of Liability/Disclaimer of Warranty While the publisher and authors have used their best efforts in preparing this work, they make no rep­resentations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchant-­ability or fitness for a particular purpose. No warranty may be created or extended by sales representa­tives, written sales materials, or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further informa­tion does not mean that the publisher and authors endorse the information or services the organiza­tion, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Library of Congress Cataloging-in-Publication Data ISBN 978-1-394-16643-5 Cover image: Pixabay.Com Cover design by Russell Richardson Set in size of 11pt and Minion Pro by Manila Typesetting Company, Makati, Philippines Printed in the USA 10 9 8 7 6 5 4 3 2 1

Contents Preface xxiii

Part I: Novel Drug Carriers and Therapeutics 1 Nanoarchitectured Materials: Their Applications and Present Scenarios in Drug Delivery Moreshwar P. Patil and Lalita S. Nemade 1.1 Introduction 1.2 Liposomes 1.3 Nanoparticles 1.3.1 Nanoparticles in Drug Delivery 1.4 Nanoemulsions 1.4.1 Advantages and Shortcomings of Nanoemulsions 1.4.2 Application of Nanoemulsion in Drug Delivery 1.5 Dendrimers 1.5.1 Synthesis of Dendrimers 1.5.2 Advantages of Dendrimers 1.5.3 Applications of Dendrimers in Drug Delivery 1.6 Aquasomes 1.6.1 Properties of Aquasomes 1.6.2 Application of Aquasomes in Drug Delivery 1.7 Nanogel 1.7.1 Properties of Nanogels 1.7.2 Nanogels in Drug Delivery 1.8 Quantum Dots 1.8.1 Applications of Quantum Dots in Drug Delivery 1.9 Carbon Nanotubes 1.9.1 Features of Carbon Nanotubes 1.9.2 Carbon Nanotubes in Drug Delivery References 2 Nanopharmaceuticals for Drug Delivery Swapnali Ashish Patil, Akshadha Atul Bakliwal, Vijay Sharad Chudiwal and Swati Gokul Talele 2.1 Introduction 2.2 What Are Nanopharmaceuticals and What Do They Do? 2.3 Nanopharmaceuticals Importance

1 3 3 4 8 9 10 10 10 11 12 12 12 15 15 16 16 17 17 18 19 19 19 20 20 29 29 30 30 v

vi  Contents 2.4 Nanotechnology 2.5 Pharmaceutical Companies and Nanotechnology 2.6 Applications and Advantages of Nanopharmaceuticals as Drug Carriers 2.7 Characteristics of Nanoparticles in Nanopharmaceuticals 2.7.1 Particle Size 2.7.2 Surface Properties of Nanoparticles 2.7.3 Drug Loading 2.7.4 Drug Release 2.8 Targeted Drug Delivery 2.9 Types of Nanoparticles 2.10 Nanoparticle Preparation Methods 2.11 Evaluation of Nanoparticles 2.12 Efficiency of Drug Entrapment 2.13 Particle Shape 2.14 Size of the Particles 2.15 Zeta Potential 2.16 Rise of Nanopharmaceuticals 2.17 Nanopharmaceuticals Approval Regulations (FDA Rules & Regulations) 2.18 Conclusions and Prospects for the Future References 3 Applications and Prospects of Nanopharmaceuticals Delivery Hemant K. S. Yadav, Fejer Al mohammedawi and Rawan J. I. Abujarad 3.1 Introduction 3.2 Nanopharmaceuticals 3.3 Development of Nanopharmaceuticals 3.3.1 From Lab to the Marketplace 3.3.2 Techniques 3.3.3 Cost 3.3.4 Ethics 3.3.5 Nanopharmaceuticals Approval Regulations (FDA Rules & Regulations) 3.4 Clinical Applications of Nanotechnology 3.4.1 Diagnostic Applications 3.4.1.1 Detection 3.4.1.2 Protein Chips 3.4.1.3 Individual Target Probes 3.4.1.4 Nanotechnology as a Tool in Imaging 3.4.1.5 Sparse Cell Detection 3.4.2 Therapeutic Applications 3.4.2.1 Surfaces 3.4.2.2 Gene Delivery 3.4.2.3 Drug Delivery 3.4.2.4 Liposomes 3.4.2.5 Nanotechnology in Orthopedic Applications 3.4.2.6 Nanotechnology in Cardiac Therapy

30 31 32 32 32 33 33 34 34 34 35 35 37 37 37 37 38 39 40 41 45 45 46 46 46 47 47 48 48 49 49 50 50 50 51 51 51 51 51 52 52 52 53

Contents  vii 3.4.2.7 Nanotechnology in Dental Care 3.4.2.8 Biomolecular Engineering 3.4.2.9 Biopharmaceuticals 3.5 Nanopharmaceuticals Delivery—Recent Applications 3.5.1 Nanoparticulate Systems for Vaccine 3.5.1.1 Polyanhydride-Based NPs 3.5.1.2 Biodegradable Synthetic PLGA NPs 3.5.1.3 Liposome-Based NPs 3.5.1.4 Polysaccharide-Based NPs 3.5.2 Chemotherapy 3.5.2.1 Increasing the Concentration of Chemotherapeutic Agents in Tumor Tissue 3.5.3 Drug/Gene Delivery 3.5.3.1 Nanoparticles Used in Drug Delivery System 3.5.3.2 Cellulose 3.6 Nanotechnology in Neurodegenerative Disorders Treatment 3.7 Future Perspective 3.8 Issues with Current Nanopharmaceutical Concepts 3.8.1 Large-Scale Manufacturing 3.8.2 Biological Challenges 3.8.3 Intellectual Property (IP) 3.8.4 Biocompatibility and Safety 3.8.5 Government Regulations 3.9 Conclusion References 4 Nanomedicine Regulation and Future Prospects Md Anwar Nawaz R., Darul Raiyaan G. I., Sivakumar K. and Kantha D. Arunachalam 4.1 Introduction 4.2 Importance of Regulation of Nanomedicine 4.3 Regulatory Challenges Faced by Nanomaterial in Medicine 4.3.1 Performing Various Functions 4.3.2 Nanomedicine Classification Issues 4.3.3 Variation in Size of the Particle 4.3.4 Manufacturing Process 4.3.5 Difficulties to Create CQA 4.3.6 Nanotoxicology and Cellular Response 4.3.7 Administering Right Doses 4.3.8 Pharmacokinetics 4.3.9 Developing Guidelines 4.4 Nanomedicine Future Aspects 4.5 Challenges that Threaten the Future of Nanomedicine 4.5.1 Financial Crisis 4.5.2 Lack of Confidence 4.5.3 Potential Dangers

53 53 53 54 54 54 54 55 55 55 56 57 58 59 59 59 60 60 62 62 63 63 64 64 67 67 68 68 69 69 69 69 70 70 71 71 71 71 72 72 72 72

viii  Contents 4.5.4 Unsuccessful Patenting 4.5.5 Breakdowns in the Pharmaceuticals and Financial Markets 4.5.6 Limited Regulation 4.6 Future Prospects for Nanomedicine 4.6.1 Emerging Nanomaterials 4.6.2 Personalized Nanomedicine 4.6.3 Nanorobots and Nanodevices 4.6.4 Orthopedic Augmentations and Cytocompatibility 4.6.5 Cardiology and Nanotechnology 4.6.6 Cancer and Nanotechnology 4.6.7 NAPT 4.6.8 Gene, Protein, Lab-on-a-Chip Devices 4.6.9 Polymeric Nanoparticles in Medicine References

73 73 74 74 75 75 75 76 76 77 77 78 78 79

5 Nanotechnology Application in Drug Delivery for Medicinal Plants 81 Bui Thanh Tung, Duong Van Thanh and Nguyen Phuong Thanh 5.1 Introduction 81 5.1.1 Nanodrug Delivery Systems (NDDS) 81 5.2 Nanoherbals 83 5.2.1 Cucuma longa (Cucurmin) 83 5.2.2 Gingko biloba 84 5.2.3 Artemisia 85 5.2.4 Silybum marianum—Silymarin 85 5.2.5 Salvia miltiorrhiza (Danshen) 88 5.2.6 Glycyrrhiza glabra (L.) 88 5.2.7 Camellia sinensis (Green tea) 88 5.2.8 Camptotheca acuminata 91 5.2.9 Leea indica 91 5.2.10 Ziziphus mauritiana (Malay apple) 91 5.2.11 Cuscuta chinensis 91 5.3 Conclusion 92 References 92 6 Nanosystems Trends in Nutraceutical Delivery Aristote Buya 6.1 Introduction 6.2 Classification of Nutraceuticals 6.3 Biopharmaceutical Issues Associated with Nutraceuticals 6.4 Nanosystems for Delivery of Nutraceuticals 6.4.1 Nanoemulsions 6.4.2 Self-Emulsifying Systems 6.4.3 Solid Lipid Nanoparticles and Nanostructured Lipid Carriers 6.4.4 Liposomes 6.4.5 Polymeric Nanoparticles 6.4.6 Inorganic Nanoparticles

97 97 98 101 101 101 105 105 106 107 107

Contents  ix 6.5 Challenges 6.6 Market Potential 6.7 Conclusion and Perspective References

108 110 111 111

7 Nanoencapsulated Systems for Delivery of Phytopharmaceuticals 127 Jacqueline Renovato-Núñez, Luis Enrique Cobos-Puc, Ezequiel Viveros-Valdez, Anna Iliná, Elda Patricia Segura-Ceniceros, Raúl Rodríguez-Herrera and Sonia Yesenia Silva-Belmares 7.1 Introduction 127 7.1.1 Nanoencapsulation Techniques in Phytopharmaceuticals 128 7.1.1.1 Physical-Chemical Techniques 129 7.1.1.2 Chemicals Techniques 130 7.1.1.3 Mechanical Techniques 131 7.1.2 Characterization of Nanoencapsulates 132 7.1.2.1 Morphological Characterization 132 7.1.2.2 Physicochemical Characterization 134 7.1.3 Nanoencapsulated Systems for Free Delivery of Phytopharmaceuticals 137 7.1.4 Studies to Evaluate Phytopharmaceuticals Nanoencapsulates 141 7.2 Conclusions 144 References 145 8 Topical Drug Delivery Using Liposomes and Liquid Crystalline Phases for Skin Cancer Therapy Karina Alexandre Barros Nogueira, Jéssica Roberta Pereira Martins, Thayane Soares Lima, Jose Willams Bandeira Alves Junior, Alanna Letícia do Carmo Aquino, Lorena Maria Ferreira de Lima, Josimar O. Eloy and Raquel Petrilli 8.1 Introduction 8.2 Liposomes for Topical Application 8.2.1 Development of Liposomal Nanoparticles 8.3 Liquid Crystals and Liquid Crystalline Nanodispersions for Topical Application 8.3.1 Characterization Techniques 8.4 Physical Methods Applied to Nanoparticles Delivery 8.4.1 Sonophoresis 8.4.2 Microneedles 8.5 Conclusions and Perspectives Acknowledgements References 9 Vesicular Drug Delivery in Arthritis Treatment Nilesh Gorde, Sandeep O. Waghulde, Ajay Kharche and Mohan Kale 9.1 Introduction 9.2 Skin Penetration Pathways 9.2.1 Intercellular Pathway 9.2.2 Transcellular Pathway

153

153 156 156 162 164 165 167 168 169 169 169 177 177 178 179 179

x  Contents 9.2.3 Appendgeal Pathway 9.3 Principles of Drug Permeation Through Skin 9.4 Problems Associated with Conventional Dosage Forms 9.5 Novel Treatment Strategies for Arthritis 9.5.1 Traditional Liposomes as Skin Drug Delivery Systems 9.5.2 Transferosomes (Ultradeformable Liposomes) as Skin Drug Delivery Systems 9.5.3 Ethosomes as Skin Drug Delivery Systems 9.5.4 Niosomes as Skin Drug Delivery Systems 9.6 Conclusion and Future Perspectives References

179 180 180 182 183 183 184 185 187 187

10 Perspectives of Novel Drug Delivery in Mycoses D. Maheswary, Kakithakara Vajravelu Leela and Sujith Ravi 10.1 Introduction 10.2 Role of Conventional Drugs in Antifungal Therapy 10.3 Mechanism of Action of Conventional Antifungals 10.4 Summary of Nanoparticles and Their Role in Antifungal Therapy 10.4.1 Lipid Nanoparticles 10.4.2 Liposome 10.4.3 Transfersomes 10.4.4 Transethosomes 10.4.5 Solid Lipid Nanoparticles (SLN) 10.4.6 Nanostructured Lipid Carriers (NLC) 10.4.7 Polymer Lipid Hybrid Nanoparticles (PLN) 10.4.8 Polymeric Nanoparticles 10.4.9 Microsponge and Nanosponge Systems 10.4.10 Polymeric Micelles 10.4.11 Polymersomes 10.4.12 Dendrimers 10.4.13 Metallic Nanoparticles 10.5 Other Drug Delivery Systems 10.5.1 Niosomes 10.5.2 Spanlastics 10.5.3 Microemulsions and Nanoemulsions 10.5.4 Silicon Dioxide Nanoparticles 10.6 Conclusion References

197

11 Nano-Based Drug Delivery in Eliminating Tuberculosis Anusha Gopinathan, Shweta Sagar Naik, Leela K.V. and Sujith Ravi 11.1 Introduction 11.1.1 Latent and Active Tuberculosis 11.1.2 Multidrug-Resistant Tuberculosis (MDR-TB) 11.1.3 Extensively Drug-Resistant TB 11.2 Antitubercular Therapy

207

197 198 198 199 199 200 200 200 200 200 200 201 201 201 201 202 202 202 202 202 202 203 203 203

208 208 209 209 209

Contents  xi 11.3 Therapies Based on Nanotechnology 11.3.1 Nanoparticles for Anti-TB Therapy 11.3.2 Advantages and Disadvantages of Nanoparticles 11.3.3 Types of Nanoparticles and Their Characteristics 11.3.3.1 TB Dendrimers 11.3.3.2 Cyclodextrins 11.3.3.3 Polymeric Micelles 11.3.3.4 Liposomes 11.3.3.5 Nanoemulsions 11.3.3.6 Solid Lipid Nanoparticles 11.3.3.7 Niosomes 11.3.3.8 Polymeric Nanoparticles 11.4 Routes of Administration of Nanoparticles 11.4.1 Oral Administration of Nanoparticles 11.4.2 Inhalational Administration of Nanoparticles 11.4.3 Intravenous Administration of Nanoparticles 11.4.4 Other Routes of Administration 11.5 Conclusion References

211 211 211 212 212 213 213 213 214 214 214 214 215 215 215 215 216 216 216

12 Promising Approaches in Drug Delivery Against Resistant Bacteria Shweta Sagar Naik, Anusha G., KakithakaraVajravelu Leela and Sujith Ravi 12.1 Introduction 12.2 Drug Delivery Systems 12.2.1 Microneedles 12.2.2 Nanoparticles 12.2.2.1 Inorganic Nanoparticles 12.2.2.2 Polymer-Based Nanomedicines 12.2.3 Lipid-Based Nanoformulations 12.2.4 Stimuli-Responsive Nanocarriers 12.2.4.1 Endogenous Stimuli 12.2.4.2 Exogeneous Stimuli 12.2.5 Nanogels 12.2.6 Nanofibers 12.2.7 Biomedical Implants 12.2.8 Wound Dressing 12.3 Biofilm Disruption 12.4 Conclusion References

219

13 Emulgels: A Novel Approach for Enhanced Topical Drug Delivery Systems Shanti Bhushan Mishra, Shradhanjali Singh, Amit Kumar Singh, Anil Kumar Singh and Divya Rani Sharma 13.1 Introduction 13.2 Approaches Used for Topical Drug Delivery 13.3 Factors Affecting Topical Absorption of Drug

231

219 220 220 221 222 222 223 224 224 225 226 226 226 227 227 227 228

231 232 233

xii  Contents 13.4 Drug Delivery Across the Skin 13.5 Emulgels 13.5.1 Types of Emulgels 13.5.2 Advantages of Emulgel 13.5.3 Rationale of Emulgel as a Topical Drug Delivery System 13.5.4 Formulation Considerations 13.5.5 Excipients Used in the Formulation of Emulgel 13.5.5.1 Vehicle 13.5.5.2 Emulsifying Agents 13.5.5.3 Gelling Agent 13.5.5.4 Penetration Enhancers 13.5.5.5 Preservatives 13.5.5.6 Antioxidants 13.5.5.7 Humectant 13.5.6 Formulation Methods 13.5.7 Routes of Administration for Emulgel Formulation 13.5.8 Evaluation of Emulgels 13.5.8.1 Physical Appearance 13.5.8.2 Spreading Coefficient 13.5.8.3 Rheological Studies 13.5.8.4 Globule Size and its Distribution in Emulgel 13.5.8.5 Swelling Index 13.5.8.6 Extrudability Study of Topical Emulgel (Tube Test) 13.5.8.7 Skin Irritation Test (Patch Test) 13.5.8.8 Drug Content Determination 13.5.8.9 In Vitro Release/Permeation Studies 13.5.8.10 Ex Vivo Bioadhesive Strength Measurement of Topical Emulgel (Mice Shaven Skin) 13.5.8.11 Microbiological Assay 13.5.8.12 Drug Release Kinetic Study 13.5.8.13 Stability Studies 13.5.9 Marketed Preparations 13.5.10 Future Prospective of Emulgel as Topical Drug Delivery 13.5.11 Therapeutic Profile of Emulgel 13.6 Conclusions References 14 Electrospun Nanofibers in Drug Delivery Sathish Kumar Karuppannan, Saravannan Mani, Jayandra Bushion, Mohammed Junaid Hussain Dowlath and Kantha Deivi Arunachalam 14.1 Introduction 14.2 Electrospinning Setup 14.3 Polymers Used to Produce Electrospun Nanofibers 14.4 Drug Release 14.5 Matrix Type NFs 14.5.1 Monolithic

233 234 234 235 236 237 238 238 238 242 244 245 245 246 246 248 248 252 252 252 252 252 253 253 253 253 254 254 254 255 255 256 258 258 258 263 263 264 264 265 266 266

Contents  xiii 14.5.2 Blended NFs 14.6 Core-Shell Nanofibers 14.6.1 Multimatrix Core-Shell NFs 14.6.2 Reservoir Type Core-Shell NFs 14.7 Electrospun Nanofiber for Drug Delivery Applications 14.7.1 Nucleic Acid Delivery Using NFs 14.7.2 Antibiotics Delivery Using NFs 14.7.3 Vaginal Drug Delivery Using NFs 14.7.4 Ocular Drug Delivery Using NFs 14.7.5 Other Drug Delivery Using NFs 14.8 Conclusion References

Part II: Drug Carriers in Drug Delivery

266 266 267 267 267 267 268 269 269 270 271 272

279

15 Role of Nanotechnology-Based Materials in Drug Delivery Manasa R. and Mahesh Shivananjappa 15.1 Introduction 15.2 Nano-Based Drug Delivery Systems 15.3 Types of Nanoparticles 15.3.1 Polymeric Nanoparticles (PNPs) 15.3.2 Dendrimers 15.3.3 Polymeric Micelles 15.3.4 Liposomes 15.3.5 Quantum Dots (QDs) 15.3.6 Nanocrystals 15.3.7 Gold Nanoparticles 15.3.8 Carbon Nanoparticles 15.3.8.1 CNTs 15.3.8.2 CNH 15.3.8.3 Fullerenes 15.3.9 Magnetic Nanoparticles (MNPs) 15.4 Advantages of Nanoparticles 15.5 Toxicity of Nanoparticles 15.6 Conclusion References

281

16 Nanomedicine Drug Delivery System Akshada Atul Bakliwal, Swapnali Ashish Patil, Vijay Sharad Chudiwal, Swati Gokul Talele, Gokul Shravan Talele and Anil Govindrao Jadhav 16.1 Introduction 16.2 Background 16.3 Five Overlapping Subthemes of Nanomedicine 16.4 How Nanomedicine Work? 16.5 Nanomedicine for Screening of Individuals with Serious Diseases 16.6 Objectives of Nanomedicine 16.7 Advantages of Nanomedicine

309

281 282 282 282 284 286 288 290 291 291 294 294 295 295 296 298 299 299 299

309 312 312 313 313 313 314

xiv  Contents 16.8 Physiological Principles for Nanomedicines 16.9 Nanotoxicology from Nanomedicines 16.9.1 Health and Safety Issues 16.9.2 Cell Death and Altered Gene Expression 16.9.3 Cell Death and Gene Therapy 16.9.4 Pseudoallergy and Idiosyncratic Reactions 16.9.5 Cytotoxicity 16.9.6 Implications for Nanotoxicology from Nonmedical Nanoparticles 16.10 Nanomedicine Applications 16.10.1 Analytical and Diagnostic Tools 16.10.1.1 In Vitro Diagnostic Devices 16.10.1.2 In Vivo Imaging 16.10.2 Drug Delivery 16.10.2.1 Micelles 16.10.2.2 Nanoemulsions 16.10.2.3 Solid Nanoparticles 16.10.3 Regenerative Medicine 16.11 Toxicological and Ethical Issues in Nanomedicine 16.11.1 Toxicity Issues 16.11.2 Ethical Issues 16.12 Conclusions References

315 315 316 316 316 317 318 318 318 318 319 320 320 321 321 321 321 322 322 323 323 324

17 Nanocarriers-Based Topical Formulations for Acne Treatment Júlia Scherer Santos 17.1 Introduction 17.2 Acne Therapeutics 17.2.1 Nanocarriers Toward Topical Acne Therapy 17.3 Efficacy and Safety of Nanotechnology-Based Acne Therapeutics 17.3.1 Ex Vivo and In Vitro Assays 17.3.2 Animal Assays 17.3.3 Clinical Assays 17.4 Improvement of Acne Therapy by Nanocarrier-Based Formulations 17.4.1 Conventional Drugs in Nanocarriers 17.4.2 Alternatives Drugs in Nanocarriers 17.5 Conclusion References

327

18 Emerging Trends of Ocular Drug Delivery Sora Yasri and Viroj Wiwanitkit 18.1 Introduction 18.2 Barriers to Ocular Drug Delivery 18.3 Classical Drug Delivery Technology 18.3.1 Anterior Segment 18.3.2 Posterior Segment 18.4 Novel Interventions for Ocular Drug Delivery

341

327 328 329 330 331 332 332 332 334 335 336 336

341 342 342 343 343 343

Contents  xv 18.4.1 Ocular Implants 343 18.4.2 Punctum Plugs 344 18.4.3 Drug-Eluting Contact Lenses 344 18.4.4 Ocular Iontophoresis 345 18.4.5 Intravitreal Implants 345 18.4.6 Ocular Vaccination 346 18.5 Applied Nanotechnology for Ocular Drug Delivery 346 18.5.1 Nanomicelle 346 18.5.2 Liposomes 347 18.5.3 Chitosan-Based Nanoparticles 347 18.5.4 Niosomes 347 18.5.5 Nanospheres 347 18.5.6 Nanocapsules 347 18.5.7 Dendrimers 348 18.5.8 Nanowafers 348 18.5.9 Micronanosurgery for Ocular Drug Delivery 348 18.6 Conclusion 348 References 349 19 Microspheres: An Overview on Recent Advances in Novel Drug Delivery System Sarang Kumar Jain, Swati Saxena and Raj K. Keservani 19.1 Introduction 19.2 Advantages of Novel Drug Delivery System 19.3 Classification of Novel Drug Delivery System 19.3.1 Microspheres 19.3.1.1 Types of Microspheres 19.3.2 Ideal Properties of Microparticulate Carriers 19.3.3 Polymers Used in Preparation of Microspheres 19.3.4 Advantages of Microspheres 19.3.5 Disadvantages of Microspheres 19.3.6 Classification of Microspheres 19.3.6.1 Bioadhesive Microspheres 19.3.6.2 Magnetic Microspheres 19.3.6.3 Floating Microspheres 19.3.6.4 Radioactive Microspheres 19.3.6.5 Polymeric Microspheres 19.3.7 Method of Preparation of Microspheres 19.3.7.1 Single Emulsion Technique 19.3.7.2 Double Emulsion Method 19.3.7.3 Polymerization Technique 19.3.7.4 Phase Separation Coacervation Technique 19.3.7.5 Spray Drying and Spray Congealing Method 19.3.7.6 Solvent Evaporation Method 19.3.8 Evaluation Parameters of Microspheres 19.3.8.1 Particle Size and Shape

355 355 356 356 356 356 357 358 359 359 359 359 359 360 360 360 360 361 361 362 362 363 363 364 364

xvi  Contents 19.3.8.2 Chemical Analysis by Electron Spectroscopy 19.3.8.3 FTIR Spectroscopy 19.3.8.4 Determination of Density 19.3.8.5 Isoelectric Point Determination 19.3.8.6 Entrapment Efficiency 19.3.8.7 Angle of Contact 19.3.8.8 Swelling Index 19.3.8.9 Production Yield 19.3.8.10 In Vitro Drug Release Study 19.3.8.11 Drug Release Kinetics 19.3.8.12 Stability Studies 19.3.9 Applications of Microspheres References 20 Drug Delivery Systems and Oral Biofilm Elda Patricia Segura Ceniceros, Luis Méndez González, Reginaldo Tijerina, Eduardo Osorio Ramos, Francisco Javier Mendoza González, Verónica Leticia Rodríguez Contreras, Alejandra Isabel Vargas Segura and Luis Antonio Vázquez Olvera 20.1 Introduction 20.2 Oral Biofilm 20.2.1 Biofilm Related Infections in The Oral Cavity 20.2.1.1 Oral Biofilm and Periodontal Disease 20.2.1.2 Oral Biofilm and Endodontic Infections 20.2.1.3 Oral Biofilm and Dental Caries 20.3 Drug Delivery Systems 20.3.1 Nanoparticles 20.3.2 Hydrogels 20.3.3 Dendrimers 20.4 Applications of Drug Delivery Systems for Treatment of Oral Biofilm Infection 20.4.1 DDS and Dental Caries 20.4.2 DDS and Periodontal Disease 20.4.3 DDS and Other Oral Pathologies 20.5 Conclusion References 21 Oral Drug Delivery System: An Overview on Recent Advances in Novel Drug Delivery System Sarang Kumar Jain, Ankita Sahu and Raj K. Keservani 21.1 Introduction 21.1.1 Oral Route 21.1.2 Oral Health 21.1.3 Oral Hygiene 21.2 Oral Drug Administration Sites 21.2.1 Oral Mucosal Drug Delivery System

364 364 364 364 364 364 365 365 365 365 365 365 366 367

368 369 371 371 373 373 374 375 375 376 376 377 378 378 379 379 383 383 383 385 386 387 387

Contents  xvii 21.2.1.1 Physiology of Oral Mucosa 21.2.1.2 Importance of Saliva and Mucin 21.2.2 Buccal and Sublingual Drug Absorption 21.3 Factors Affecting Drug Absorption 21.3.1 Lipid Solubility, pH, and Degree of Ionization 21.3.2 Molecule Weight and Size of Drug 21.3.3 Formulation Physiochemical Properties Related Factors 21.3.4 Permeability Enhancer 21.4 Drug Delivery for Periodontitis 21.4.1 Periodontal Pocket 21.4.1.1 Classification of Periodontal Pockets According to their Morphology 21.4.1.2 Classification of Periodontal Pocket According to the Involvement of Tooth Surfaces 21.5 Oral Periodontitis Drug Delivery System 21.5.1 Antibacterial DDS for Periodontitis 21.5.2 Remineralizing DDS 21.5.3 Inflammation Modulating and Alveolar Bone Repairing DDS for Periodontitis 21.5.3.1 DDS for Peri-Implantitis 21.6 Teeth Treatments 21.7 Periodontal Local Drug Delivery 21.8 Carriers of Oral and Periodontitis Drug Delivery System 21.8.1 Hydrogel 21.8.2 Dendrimers 21.8.3 Chewing Gum 21.8.4 Lozenges 21.8.5 Tablets 21.9 Mucoadhesive Drug Delivery System/Buccal Adhesive Drug Delivery System 21.9.1 Patches and Films 21.9.2 Oral Suspension 21.9.3 Spray 21.9.4 Liposome 21.9.5 Nanoparticles 21.9.6 Laminated Film 21.9.7 Injectable Gels 21.9.8 Fibers 21.9.9 Strips and Compacts References 22 Cancer Nanotheranostics: A Review Ozge Esim and Canan Hascikek 22.1 Introduction 22.1.1 Lipid and Polymer-Based Nanosystems

388 388 389 389 390 390 390 390 391 391 391 392 393 393 393 394 394 394 395 395 396 396 396 397 397 397 398 398 398 398 399 399 399 399 399 400 401 401 403

xviii  Contents 22.1.2 Magnetic Nanoparticles 22.1.3 Quantum Dots (QD) 22.1.4 Other Metal-Derived Nanoparticles 22.2 Conclusion References

413 418 421 425 425

23 Nanomedicine in Lung Cancer Therapy 433 Jagdale Swati C., HableAsawaree A. and ChabukswarAnuruddha R. 23.1 Introduction 433 23.2 Nanotechnology 434 23.3 Nanomedicines for Lung Cancer Therapy 435 23.3.1 Nanoparticles 436 23.3.1.1 Gold and Silver Nanoparticles 436 23.3.1.2 Solid Lipid Nanoparticles 437 23.3.1.3 Inhalable Nanoparticles 437 23.3.2 Micelles 437 23.3.3 Dendrimers 439 23.3.4 Liposome 439 23.3.5 Carbon Nanotubes 440 23.3.6 Quantum Dots 441 23.3.7 Nanofibers 442 23.3.8 Nanoshells 442 23.4 Evaluation of Nanoformulations 442 23.5 Application of Nanoformulations 443 23.6 Marketed Therapies 444 23.7 Challenges 445 23.8 Potential 445 23.9 Future Scope 446 23.10 Conclusion 446 References 446 24 Delivering Herbal Drugs Using Nanotechnology Manasa R. and Mahesh Shivananjappa 24.1 Introduction 24.2 Methods of Preparation of Nanoparticles 24.3 Novel Drug Delivery Systems (NDDS) for Herbal Drugs 24.3.1 Liposomes 24.3.2 Phytosomes 24.3.3 Transferosome 24.3.4 Niosomes 24.3.5 Ethosomes 24.3.6 Dendrimers 24.3.7 Self-Nanoemulsifying Drug Delivery System (SNEDDS) 24.3.8 Self-Micro Emulsifying Drug Delivery System (SMEDDS) 24.4 Conclusion References

449 449 450 451 451 454 457 458 459 459 462 463 464 464

Contents  xix 25 Nanoherbals Drug Delivery System for Treatment of Chronic Asthma 473 Harsh Yadav, Satish Dubey, Naureen Shaba Khan and Ashwini Kumar Dixit 25.1 Introduction 474 25.2 Mechanism of Asthma Physiopathology 474 25.3 Asthma Etiology 475 25.4 Severity of Asthma 475 25.5 Asthma Phenotypes 475 25.6 Asthma Epidemiology 476 25.7 Asthma Treatment 476 25.7.1 Adverse Effects of Current Treatment Techniques 477 25.8 Need of Natural Products as Alternative 477 25.9 Selected Medicinal Plants in Asthma Treatment 478 25.9.1 Piper betel Linn 478 25.9.2 Bacopa monnieri L. 479 25.9.3 Momordica charantia 479 25.9.4 Ficus bengalensis (Linn.) 479 25.9.5 Clerodendrum serratum (Linn.) Moon 479 25.10 Potentials of Nanotechnology in Asthma Drug Delivery 479 25.11 Nanoherbals as Asthma Drug Delivery System 482 25.12 Future Prospectus of Nanoherbal Drug Delivery 483 25.13 Conclusion 484 References 484 26 Nutrients Delivery for Management and Prevention of Diseases Darul Raiyaan G. I., Sameera Khathoon A. and Kantha D. Arunachalam 26.1 Introduction 26.2 Nutrients in Management and Prevention of Disease 26.2.1 Herbal Nutrients 26.2.2 FDA Regulations on Herbal Drugs 26.3 Phenolic Nutraceuticals 26.3.1 Polyphenols and Neurodegeneration 26.3.2 Polyphenols and Brain Tumors 26.3.3 Phenols and Other Cancer Treatments 26.3.4 Phenols and Hepatotoxicity 26.3.5 Clinical Trials 26.3.6 Curcumin 26.4 Routes for Nutrients Delivery 26.4.1 Oral Route 26.4.2 Intranasal Delivery 26.4.3 Transdermal Route 26.5 Nanoparticle-Based Nutrients Delivery System 26.5.1 Nanostructured Lipid Carriers (NLCs) 26.5.2 Solid Lipid Nanoparticles (SLNs) 26.5.3 Liposomes 26.5.4 Nanocrystals

491 491 492 492 493 493 494 494 494 495 496 496 497 497 497 497 498 498 499 499 499

xx  Contents 26.5.5 α-Lactalbumin 500 26.5.6 Carbon Nanotubes 500 26.5.7 Nanocochleates 500 26.5.8 Nanosized Self-Assembled Liquid Structures 500 26.5.9 Polysaccharide-Based Nanoscale Delivery of Nutrients 500 26.5.10 Chitosan 501 26.5.11 Alginate 501 26.5.12 Pectin 502 26.5.13 Gum Arabic 502 26.5.14 Cashew Gum 503 26.6 Protein-Based Nanoscale Delivery of Nutrients 503 26.6.1 Zein 503 26.6.2 Gliadin 503 26.6.3 Soy Protein Isolates (SPI) 504 26.6.4 Whey Protein 504 26.6.5 Casein 505 26.6.6 Other Proteins 505 26.7 Micelles 505 26.8 Advantages of Nanomaterials in Nutraceuticals 507 26.9 Safety and Toxicity of Nanostructures Applied in Food Systems 509 26.10 Conclusion 509 References 509 27 Nanonutraceuticals for Drug Delivery Charu Gupta and Dhan Prakash 27.1 Introduction 27.2 Approaches to Enhance Oral Bioavailability of Nutraceuticals 27.2.1 Protection of Labile Compounds 27.2.2 Extension of Gastric Retention Time 27.2.3 Intonation of Metabolic Activities 27.3 Carriers for Nutraceutical Delivery 27.3.1 Nanoparticles for Nutraceuticals Delivery 27.3.2 Solid Lipid Nanoparticles (SLNs) for Nutraceutical Delivery 27.3.3 Niosomes 27.3.4 Nanospheres 27.3.5 Nanoliposomes 27.3.6 Nanofibers 27.3.7 Nanoemulsion 27.4 Nanotechnology in Food Sector 27.4.1 Nanotechnology in Nutraceuticals 27.4.2 Nanotechnology in Medications 27.4.3 Commercial Nanonutraceuticals 27.4.4 Nanosized Self-Assembled Structured Liquids 27.5 Delivery of Nutraceuticals

521 521 522 523 523 523 523 524 524 525 525 525 526 526 527 527 528 533 534 536

Contents  xxi 27.5.1 In-Feed or Oral Nanodelivery 27.5.2 Dermal Delivery 27.5.3 Ophthalmic Delivery 27.6 Constraints in Nanodrug Delivery Systems 27.7 Conclusion Acknowledgments References

536 537 537 537 537 538 538

Index 541

Preface Drug delivery technology has witnessed a number of advancements purported to cater to the customized needs of its ultimate beneficiaries—the patients. Nowadays, dosage forms are not confined to conventional tablets, capsules or injectables, but have evolved to cover novel drug carriers such as particulates, vesicles and many others. Nanotechnological advancements have played a major role in this paradigm shift in ways of delivering active pharmaceutical ingredients; as researchers across the globe continue striving to provide site-specific (targeted) drug in the treatment of diseases. A new dimension in the use of food as medicine has also gained prominence in recent years. A portmanteau of nutrition and pharmaceuticals is “nutraceuticals,” also known as functional foods and dietary supplements. The technologies which were earlier included in drug delivery parlance have been attempted for delivery of nutraceuticals as well. Herbal actives have received increased attention due to their low risk to benefit ratio. The health of an individual should allow the performance of routine roles/responsibilities in a smooth manner. Any physiological disease/disorder may lead to impairment of the normal functioning of the human body. Since the beginning of human civilization, humans have acquired knowledge about medicines derived from mother nature, and researchers across the globe have served mankind by developing a number of natural and synthetic/ semi-synthetic medicines. Nowadays, food is also considered as a medicine, which has opened several avenues of possibilities in the domain of nutraceuticals, functional foods and dietary supplements. The field of drug delivery is quite dynamic in nature, as witnessed by its evolution from conventional dosage forms to nanotechnology-assisted drug products. A variety of formulations via different drug delivery routes have been developed with the objective to treat/cure/mitigate diseases or disorders. This book is a compilation of information relevant to drug delivery systems with an emphasis on products based on nanotechnology. The contributors are from a diverse pool of academic and industrial researchers from different geographical locations across the globe. The 27 chapters described below compile novel strategies for drug delivery and embrace the development of formulations with herbal ingredients. Several chapters also highlight disease therapeutics. –– Chapter 1 gives an overview of nanotechnology-based drug delivery systems. Several nanomaterials, such as liposomes, nanoparticles, aquasomes, nanogels, nanoemulsions, nanotubes, quantum dots, etc., are described that were found to have important roles in drug delivery to humans and animals. The general features, types and applications in drug delivery have been mentioned where applicable. xxiii

xxiv  Preface –– Chapter 2 discusses the incorporation of nanotechnology into the medical profession, which has resulted in the emergence of new multidisciplinary fields of nanomedicine such as nanopharmaceuticals. The formulation and evaluation of nanopharmaceuticals are addressed from a regulatory perspective for market authorization of the same. –– Chapter 3 discusses current and future scenarios of nanopharmaceuticals. Potential challenges in commercialization of nanotechnology-based products are listed; and therapeutic applications of nanopharmaceuticals with site-specific drug delivery are also mentioned. –– Chapter 4 offers a detailed description of the regulatory status of nanomedicines. It delineates the threats and opportunities for successful licensing in different markets. Newer approaches, such as personalized medicines, nanorobots and devices, lab-on-a-chip technologies and gene/protein delivery, are also mentioned in the latter half of the chapter. –– Chapter 5 discusses several highly effective herbal pharmaceuticals produced at nanoscale level with improved bioavailability, in-vitro, in-vivo, and clinical efficacy. Phytoconstituents with pharmacological activity are also discussed in detail. –– Chapter 6 describes the use of nanotechnology as a tool to deliver nutraceuticals. It also focuses on the drawbacks associated with nutraceuticals and presents different nanosystems (lipid, polymeric or inorganic) that have been used to improve their biopharmaceutical and health properties. –– Chapter 7 offers relevant information on herbal actives confined in nanosystems. The types, preparation and applications for improved bioavailability and reduction in toxicity are discussed. –– Chapter 8 entails topical drug delivery approaches for treatment of skin cancer. In particular, the chapter describes liposomes and liquid crystals as topical formulations which are derived using nanotechnology. –– Chapter 9 presents an overview of vesicular carriers for control of arthritis. Vesicular systems are particularly significant for targeted delivery of drugs due to their ability to carry the drug to a particular site or organ of action, thus lowering its concentration in other sites of the body. Various pharmaceutical carriers, such as particulate systems, polymeric micelles, and macro- and micromolecules, are presented in the form of a novel drug delivery system. –– Chapter 10 is about the use of novel drug delivery systems for fungal infestations. Nanotechnology in drug delivery has opened new paths in antifungal therapy, especially in the immunocompromised population, where drug toxicity has been a major concern. –– Chapter 11 outlines various nanotechnology-based therapeutic approaches against tuberculosis (TB) and the challenges to their implementation. The chapter begins with an introduction to TB, its etiology and traditional therapeutic regimen. Subsequent text deliberates on nanotechnology in the treatment/­control of TB. –– Chapter 12 addresses the issue of drug-resistant bacterial infections via nanotechnological interventions. It includes recent advances in stimuli-­ responsive antibiotic-loaded nanoparticles which deliver targeted therapy

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by recognizing the presence of bacteria. Surface engineering the nanoparticles enables customizing the biological and physical properties of nanoparticles as well as attaching specific ligands. Chapter 13 details the use of emulgels as a topical delivery system for treatment of different ailments. Emulgel is one of the innovative formulations commonly utilized for fungal infections, acne, psoriasis and other topical diseases. The chapter begins with an introduction to emulgels and then discusses the types, formulation aspects, evaluation and applications. Chapter 14 is about a special nanotechnological advancement known as electrospun nanofibers. Electrospinning is a versatile technique for fabricating native tissue-like nanofibrous scaffolds. The chapter introduces this nanocarrier along with the types, polymers used for its formulation and therapeutic applications. Chapter 15 contains basic information on nanotechnology, the need for emerging nanotechnologies, and the classifications of nanoparticles. The authors discuss different types of nanotechnology-based materials used in drug delivery, such as liposomes, dendrimers and micelles, and their properties and applications. The chapter also discusses the merits of nanoparticles over traditional drug carriers and the toxicity potential of these nanometric artefacts. Chapter 16 describes nanomedicines and covers various aspects concerning their historical progress, rationale and mechanism of action, applications, toxicity and ethical concerns. It presents a concise audit of nanomedicines that accentuates different viewpoints related, for example, to presentation, foundation, objective, physiological standards of nanomedicine, etc. The chapter also delves into the concept of nanotoxicology from nanomedicines and non-clinical nanoparticles. Chapter 17 entails the topical applications of nanocarriers in treatment of acne. The chapter begins with an introduction to acne therapeutics and then moves on to nanocarriers. Afterwards, a toxicity profile based on animal and clinicals studies as evaluation criteria is given. A vis-a-via comparison of conventional and nanocarrier-based dosage forms is presented in subsequent sections of the chapter. Chapter 18 offers an overview of ocular drug delivery incorporating nanotechnology principles. The authors provide information on the anatomy of the eye with prevailing drug delivery systems. The successive text is relevant to applications of various nanotechnology-based drug carriers for treatment of ocular diseases. Chapter 19 discusses microparticulate drug carriers in detail. Following their introduction to microspheres, the authors present an exhaustive overview of their advantages, types, evaluation characteristics and applications. Chapter 20 focuses on drug carriers in oral biofilm infectious diseases. The authors discuss the role of biofilms in oral cavity infections. Furthermore, novel drug carriers are mentioned in relation to their utility in countering oral biofilm infections. The information provided will be helpful in identifying

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the most effective treatment using drug delivery systems, which has definitely become a trend in dentistry and the oral health sector. Chapter 21 discusses oral drug delivery in a detailed fashion. The authors describe the inherent physicochemical properties of oral biomembranes and drug molecules, which are in fact vital variables in the success of any delivery system. Thereafter, the chapter discusses different drug delivery systems purported to address health concerns of the oral cavity. This is followed by specific information on muco/bioadhesive drug delivery systems. Chapter 22 endeavours to inform the reader about recent advances in the field of cancer diagnostics and therapeutics. It reviews various polymeric/ non-polymeric theranostic nanosized systems and the opportunities they provide for the treatment of cancer. Chapter 23 covers the applications and scope of nanomedicines in the treatment of pulmonary tumor (lung cancer). The nanotechnology-based interventions and applications used for cancer treatment are elaborated on. In addition, the existing marketed formulations are also mentioned. Chapter 24 elaborates on nanotechnology-derived herbal formulations. It summarizes information on various novel techniques used for improving the safety and efficacy of phytomedicines, type of active ingredients, biological activity and application of novel formulation of herbal drugs to achieve a better therapeutic response. Chapter 25 focuses on herbal nano-formulations meant for curing asthma. It discusses the current scenario in the treatment of asthma, the mechanism involved in asthma physiopathology and epidemiology, the use of herbal nano-formulations in asthma drug delivery system, their delivery route and efficiency. It is suggested that herbal-based nano-drug delivery is effective in the treatment of asthma with easier dissolution without any toxicity or incompatibility. Chapter 26 highlights the role of nutrients in the prevention and treatment of diseases. The chapter describes beneficial plant constituents, such as polyphenols, curcumin, proteins and carbohydrates, as medicines to combat diseases like cancer and nervous disorders. The nanometric carriers having these phytoconstituents are also described. In addition, regulatory perspectives on the clinical trials of herbals are also mentioned. Chapter 27 reviews a variety of nutraceuticals for possible use in formulating nanocarriers. The chapter focuses on the benefits and new dimensions provided by nanomaterials and nanotechnology in the food and health sectors by improving treatment strategies and quality of life. In addition, a general introduction to nanocarriers for nutraceuticals is presented, which includes a list of approaches for bioavailability enhancement and barriers to the scale-up of nanomedicine as commercial products. The Editors December 2022

Part I NOVEL DRUG CARRIERS AND THERAPEUTICS

1 Nanoarchitectured Materials: Their Applications and Present Scenarios in Drug Delivery Moreshwar P. Patil1 and Lalita S. Nemade1,2* Department of Pharmaceutics, MET institute of Pharmacy, Adgaon, University of Pune, Nashik, India 2 Department of Pharmaceutics, Govindrao Nikam College of Pharmacy, University of Mumbai, Sawarde, India 1

Abstract

Nanotechnology is proposed to make a fundamental difference in drug production in the imminent years and will have a huge demeanor on life sciences, encircling drug delivery, diagnostics, nutraceuticals, and production of nanomaterials. The use of nanotechnology in medicine and, more specifically, drug delivery is bound to expand quickly. Engineered nanoparticles (NP) ( 100%) and bioavailability (> 80%) in the presence of nicotinamide. The fact that NPs are prospective carriers of insulin via the sublingual route was proven in the streptozotocin-induced diabetic mouse model, with a pharmacological high potential of 20.2% and bioavailability of 24.1% when compared to subcutaneous injection at 1 IU/kg [37].

3.5.3.1.3 Xanthan Gum

Xanthomonas campestris generates xanthan gum (XG), a heteropolysaccharide with a high molecular weight. It is a bioadhesive polyanionic polysaccharide with excellent bioadhesion. Because it is nontoxic and nonirritating, xanthan gum is often used as a pharmaceutical excipient. The mucoadhesion of the grafted polymer is 1.7 times that of thiolated xanthan and 2.5 times that of native xanthan. Furthermore, the frequency of ciliary beating in nasal epithelial cells remained unaltered by the polymer and was only reversible after it was withdrawn from the mucosa [38].

3.5.3.1.4 Dendrimers

Dendrimers are highly bifurcated, monodisperse, and well-defined three-dimensional structures. They have a globular shape and can be easily functionalized in a controlled way, making them ideal drug delivery options. Dendrimers have limited therapeutic utility due to the presence of amine groups. These groups are harmful because they are positively charged or cationic, and dendrimers are regularly altered to reduce or eliminate their toxicity. To load medicines into dendrimers, the following processes are used: simple encapsulation, covalent conjugation, and electrostatic contact [39].

Current and Future Trends in Nanopharmaceuticals  59

3.5.3.1.5 Nanocrystals

Pure solid pharmaceutical particles with a dimension of less than 1000 nanometers are known as nanocrystals. These are pure pharmaceuticals that are stabilized by polymeric steric stabilizers or surfactants and do not include any carrier molecules. The use of a surfactant agent known as nanosuspension typically improves the suspension of nanocrystals in a thin liquid media. Water or any other aqueous or nonaqueous media, such as liquid polyethylene glycol and oils, serves as the dispersion medium in this case. Nanocrystals have special qualities that enable them to overcome obstacles such as increased saturation solubility, faster dissolution, and better surface adhesion [40].

3.5.3.2 Cellulose Cellulose and its derivatives are commonly employed in drug delivery systems to change the solubility and gelation of medications, allowing for more precise control over their release patterns. Because of the hydrogen bonds created between the cellulose nanocrystals and the drug, the drug’s release was extended, and as a result, the nanoparticles made with oxidized cellulose nanocrystals had a lower release than those made with native cellulose nanocrystals. Any of the cellulose derivatives had no effect on the tissues and cells of the nasal mucosa [41].

3.6 Nanotechnology in Neurodegenerative Disorders Treatment Nanoparticles have the potential to revolutionize the treatment of neurological disorders including Alzheimer’s, Parkinson’s, and strokes. Nanotechnologies have considerable potential in brain therapy because they preserve therapeutic agents and enable for longterm release; nanoparticles may also be utilized to carry genes. Neurotrophic factors have the ability to influence neuronal survival and synaptic connection, making them a prospective treatment option for many neurodegenerative illnesses. However, long-term administration in the brain is problematic owing to the tight blood brain barrier (BBB). Drug distribution to the brain remains a severe challenge for the treatment of all neurodegenerative illnesses due to the various protective barriers that surround the central nervous system (CNS). New drugs with the capacity to pierce the BBB are badly needed to treat these illnesses. Nanotechnology has recently patented novel formulations as a possible therapy for brain disorders, particularly neurodegenerative diseases, where genetically modified cells may be used to provide specific growth factors to target cells [42].

3.7 Future Perspective The growing expense of healthcare has been a source of concern for most industrialized and developing countries in recent years. Governments must have a better grasp of the cost-­ effectiveness of nanopharmaceuticals in order to optimize cost efficiency. The first stage in building this market is to conduct a standardized cost-effectiveness assessment to determine whether the enhanced health advantages of nanopharmaceuticals above traditional

60  Advances in Novel Formulations for Drug Delivery formulations are worth the extra expense. Governments will be free to set clear instructions and examine the financial benefits of establishing this sector as a result of this [43]. The current lack of such fundamental knowledge is not the only roadblock to effective nanomedicine commercialization. The viability of this market is totally dependent on patient, citizen, and physician confidence in the commercial success and safety of nanomedicines. To meet this issue, the futures market will require a greater public understanding of the advantages, hazards, and safety concerns associated with nanopharmaceuticals [44]. To persuade investors of the value of nanopharmaceuticals and to improve society’s overall health and welfare, intellectual property and regulatory agencies must adjust their procedures to meet the particular needs of nanomedicines and minimize the time it takes for them to gain regulatory clearance. However, when it comes to nanodrugs, it is especially very important to consider the health and environmental risks. In some cases, it may be necessary to take a step back and reevaluate the situation in order to be better prepared for long-term rational planning for the future, rather than being focused just on the short-term benefits. Another key reason that has drawn the attention of researchers and businesses is the rising importance of cancer in global mortality and morbidity statistics. For example, five of the FDA-approved medications in September 2016 were cancer-related. This, together with the large number of other cancer-related medications authorized in recent years, illustrates not just patients’ urgent need for new cancer therapies, but also the huge market for cancer therapy. Chemotherapy combined with photothermal or photodynamic treatment has also shown promising results.

3.8 Issues with Current Nanopharmaceutical Concepts Nanopharmaceutical-based treatments for noncancer disorders have become increasingly popular in recent years. Nanopharmaceuticals were developed specifically to meet the therapeutic challenge of successfully treating inflammatory diseases by using the underlying biology of these diseases. Noncancerous inflammatory disorders, such as rheumatoid arthritis, inflammatory bowel disease, asthma, multiple sclerosis, diabetes, and neurodegenerative illnesses, have all been examined with nanopharmaceuticals. Nanopharmaceutical clinical translation is a time-consuming and costly process. Standard formulation procedures, which utilize free drug dispersion in a base, are frequently more sophisticated than nanopharmaceuticals technology [45]. Different type of challenges, important factors to consider, and current barriers that can be seen in nanopharmaceuticals concept (as seen in Table 3.1).

3.8.1 Large-Scale Manufacturing The formulation’s structural and physicochemical complexity is one of the major issues leading to the delayed pace of clinical translation of nanopharmaceuticals. Platforms that involve sophisticated and/or time-consuming synthesis techniques have limited clinical translation potential since they might be difficult to produce pharmaceutically on a big scale. Potential difficulties include the following: I inadequate quality control; (ii) scaling challenges; (iii) incomplete contamination purification; (iv) excessive material and/or manufacturing costs; and (v) low production yield [46].

Current and Future Trends in Nanopharmaceuticals  61 Table 3.1  Various challenges of nanopharmaceuticals. Challenges Challenge type

Important factors to consider

Current barriers

Nanophar­maceutical design

Administration route Formulation design complexity should be reduced. For human usage, the final dose form Biodegradability and biocompatibility Stability of pharmaceuticals (physical and chemical)

Manufacture on a wide scale in accordance with GMP guidelines Reproducibility, infrastructure, methodologies, knowledge, and cost are only a few examples. Characterization quality control assays for example, Size and polydispersity, morphology, charge, encapsulation, surface changes, purity, and stability are all factors to consider.

Preclinical evaluation

In-depth knowledge of in vivo behavior, including cellular and molecular relationships Pharmacodynamics is the study of how drugs interact with one another (intracellular trafficking, functionality, toxicity and degradation) Pharmacokinetics is the study of how drugs work in the body (absorption, distribution, metabolism and excretion) For early identification of toxicity, there is a need for validated and standardized tests. Animal models of sickness that are ideal for testing

NNM has adequate structural stability after in vivo injection. More specific toxicological studies for nanopharmaceutical are being developed. Nanopharmaceutical only accumulate to a limited extent in target organs/ tissues/cells. Having a good grasp of how NNM interacts with tissues and cells.

Clinical evaluation for commercia­lization

Clinical trial design that is most effective. To save time and money, development methods from discovery to commercialization have been simplified. Patients’ therapy effectiveness is assessed. In humans, safety and toxicity are assessed (acute and chronic).

The biological interaction of NNM with the biological environment (including the target location) in the body of patients is poorly understood. There are no clear regulatory criteria for NNMS. NNM patents and IP have a high level of complexity.

62  Advances in Novel Formulations for Drug Delivery

3.8.2 Biological Challenges Surprisingly, cancer is the focus of the vast majority of nanopharmaceutical formulations in research and clinical trials, accounting for more than 80% of nanopharmaceutical publications in only the last two decades. Despite the large number of publications, there has been a dearth of translational research into medicinal uses. The EPR effect has been exploited to target nanopharmaceuticals for cancer, despite the fact that EPR-mediated accumulation has only been demonstrated for a few tumor types. Tumors, like other clinical illnesses, can vary greatly from patient to patient, with substantial interpatient and intrapatient variabilities as the disease progresses. As a result, a one-size-fits-all approach to nanopharmaceutical-based treatment is unlikely to yield clinically useful outcomes [47]. 

3.8.3 Intellectual Property (IP) Given the difficulties of bringing nanopharmaceuticals into biomedical and clinical applications, more specific criteria of what constitutes innovative nanopharmaceuticals IP are required. Nanopharmaceuticals are complicated because they contain a large number of changeable components and serve as a link between medicine and medical devices. In general, controlling an NNM product necessitates an IP position on I the enclosed cargo; (ii) the carrier technology; and (iii) the drug and carrier’s combined properties. Although this definition is simple, it raises a number of issues with the way patents have been issued in the past. NNMs that combine current medications with novel carrier technology, or NNMs that combine existing pharmaceuticals with existing carrier technology for a new biological or disease use, are examples. With increasingly complicated drug delivery systems, such as those that integrate commercially available targeting ligands (e.g., antibodies) or coatings (e.g., Eudragit®) that are owned by other businesses, the IP position becomes even more perplexing. Multiple patents are likely to be connected with any particular technology, necessitating cross-licensing arrangements. As a result, new IP processes and standards are required to simplify the journey from invention to commercialization, as well as to bring down the time and expense of negotiating, collaboration and licensing agreements. Patent review delays, patent thickets, and the issuance of invalid patents are some of the other major issues that have arisen as a result of the significant increase in the number of nanotechnology patent applications over the last few decades. A popular nanonomenclature for nanostructures or nanomaterials that are comparable or equivalent, as well as more. More precise search techniques and commercial databases, as well as more precise search methods and commercial databases, are necessary to avoid multiple nanopatents on the same subject. The PTO’s databases must be able to search through nanotech-related prior art in scientific journals all over the world, including earlier works that predate the advent of internet publishing databases. Patent examiners must also be well versed in the rapidly evolving fields of nanotechnology and nanomedicine. The complexities of nanotechnology have resulted in so-called “patent thickets,” which can lead to costly litigation and stymie commercialization efforts. As a result, more clarity on intellectual property and patenting in the context of nanotechnology in health and medicine, as well as the adoption of universal legislation and regulations unique to this commercialization sector, are critical [48].

Current and Future Trends in Nanopharmaceuticals  63

3.8.4 Biocompatibility and Safety Pharmaceutical regulatory authorities often motivate sponsors to evaluate any changes in the drug ingredient, manufacturing method, or drug product formulation at any stage of clinical development to see if the changes can directly or indirectly influence the product’s safety. If any changes are noticed, strict procedures are there to ensure that appropriate comparison testing of the drug substance and/or drug product produced using the previous manufacturing process with that produced using the new manufacturing process to determine product equivalency, quality, and safety is conducted. The reason being, circulation half-lives and drug retention durations are often extended by nanoencapsulation, special toxicological studies in animal models are required to determine both shortand long-term toxicities. To anticipate toxicological reactions to nanopharmaceuticals, a full understanding of the absorption, distribution, metabolism, and excretion of developing nanomaterials in vivo is required. Appropriate assessment protocols are required to monitor various aspects of the nanopharmaceuticals drug delivery process, including pharmacokinetics, biodistribution, target site accumulation, local distribution at the target site, localization in healthy tissues, drug release kinetics, and therapeutic efficacy. Biocompatibility, immunotoxicological potential, and inflammatory potential should all be assessed, with functional outcomes tied to tissue absorption and clearance systems [49].

3.8.5 Government Regulations Although nanopharmaceuticals have the potential to accelerate pharmaceutical industry growth and improve health outcomes, the current scientific and regulatory gap for nanomedicines is large and difficult to close. Commercialization of nanopharmaceuticals is heavily reliant on a range of government-mandated regulatory concerns in the areas of manufacturing practice, quality control, safety, and patent protection. The lack of clear regulatory and safety requirements has impeded nanopharmaceutical product development, preventing them from reaching the clinic on time and effectively. Due to the increasing number of unique polymeric materials and difficult polymeric-based nanopharmaceuticals formulations, an acceptable regulatory framework is urgently needed to aid in the evaluation of innovative polymeric materials and complex polymeric-based nanopharmaceuticals formulations. Nanopharmaceuticals are currently regulated under the traditional regulatory system, which is overseen by each country’s primary regulatory authority. Global regulatory criteria for nanopharmaceuticals should be developed in collaboration with significant nations with vested interests. Despite the significant progress made in the previous 5 years, more cooperation between regulatory authorities, academia, research, and business is required. These methodologies will change depending on the nanomaterials and nanostructures in question. As a result, regulatory authorities should work together to establish the testing techniques and standardized processes for toxicity studies and regulatory requirements that will be necessary to ensure the efficacy and safety of current and future NNMs [50].

64  Advances in Novel Formulations for Drug Delivery

3.9 Conclusion As a conclusion, in recent years nanotechnology has progressively become a part of our daily life. This groundbreaking technology may now be found in a range of industries thanks to an integrated approach. There are an increasing number of products and applications that employ nanoparticles or claim to be nano-based. There is no exception in the field of pharmaceutical research. Nanopharmaceuticals have grown in popularity as a consequence of their capacity to encapsulate drugs or bind therapeutic chemicals to nanostructures and transport them to target tissues with greater precision and control. The US Food and Drug Administration (FDA) has already approved a large number of nanopharmaceuticals, with many more in various stages of clinical trials. Disease detection, target-specific medicine delivery, and molecular imaging are among the clinical applications of nanotechnology now being investigated.

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66  Advances in Novel Formulations for Drug Delivery 36. Silva, M.M., Calado, R., Marto, J., Bettencourt, A., Almeida, A.J., Gonçalves, L., Chitosan nanoparticles as a mucoadhesive drug delivery system for ocular administration. Mar. Drugs, 15, 370, 2017. 37. Patil, N.H. and Devarajan, P.V., Insulin-loaded alginic acid nanoparticles for sublingual delivery. Drug Deliv., 23, 429–36, 2016. 38. Goswami, S. and Naik, S., Natural gums and its pharmaceutical application. J. Sci. Innov. Res., 3, 112–21, 2014. 39. Zhu, J. and Shi, X., Dendrimer-based nanodevices for targeted drug delivery applications. J. Mater. Chem. B, 1, 4199–211, 2013. 40. Junyaprasert, V.B. and Morakul, B., Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J. Pharm. Sci., 10, 13–23, 2015. 41. Elseoud, W.S.A., Hassan, M.L., Sabaa, M.W., Basha, M., Hassan, E.A., Fadel, S.M., Chitosan nanoparticles/cellulose nanocrystals nanocomposites as a carrier system for the controlled release of repaglinide. Int. J. Biol. Macromol., 111, 604–13, 2018. 42. Spuch, C., Saida, O., Navarro, C., Advances in the treatment of neurodegenerative disorders employing nanoparticles. Recent Pat. on Drug Deliv. and Formul., 6, 12–18, 2012. 43. Liang, X.-J., Nanopharmaceutics: The Potential Application of Nanomaterials, World Scientific Publishing Co., Pte Ltd, Toh Tuck Link, Singapore, 2013. 44. Shah, R.B. and Khan, M.A., Nanopharmaceuticals: Challenges and regulatory perspective, in: Nanotechnology in Drug Delivery, M.M. de Villiers, P. Aramwit, G.S. Kwon, (Eds.), Springer, NY, USA, 2009. 45. Hare, J., II, Lammers, T., Ashford, M.B., Puri, S., Storm, G., Barry, S.T., Challenges and strategies in anti-cancer nanomedicine development: An industry perspective. Adv. Drug Deliv. Rev., 108, 25–38, 2017. 46. Barz, M., Luxenhofer, R., Schillmeier, M., Quo vadis nanomedicine? Nanomedicine, 10, 3089– 3091, 2015. 47. Park, K., The drug delivery field at the inflection point: Time to fight its way out of the egg. J. Control. Release, 267, 2–14, 2017. doi: 10.1016/j.jconrel.2017.07.030. 48. Satalkar, P., Elger, B.S., Shaw, D.M., Defining nano, nanotechnology and nanomedicine: Why should it matter? Sci. Eng. Ethics, 22, 1255–1276, 2015. doi: 10.1007/s11948-015-9705-6. 49. Accomasso, L., Cristallini, C., Giachino, C., Risk assessment and risk minimization in nanomedicine: A need for predictive, alternative, and 3Rs strategies. Front. Pharmacol., 9, 228, 2018. doi: 10.3389/fphar.2018.00228. 50. Tinkle, S., McNeil, S.E., Muhlebach, S., Bawa, R., Borchard, G., Barenholz, Y.C. et al., Nanomedicines: Addressing the scientific and regulatory gap. Ann. N. Y. Acad. Sci., 1313, 35–56, 2014. doi: 10.1111/nyas.12403.

4 Nanomedicine Regulation and Future Prospects Md Anwar Nawaz R.1, Darul Raiyaan G. I.2, Sivakumar K.1 and Kantha D. Arunachalam2* Department of Biomedical Engineering, Karpaga Vinayaga College of Engineering and Technology, Chengalpattu, Tamil Nadu, India 2 Center for Environmental Nuclear Research, DRVE, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India

1

Abstract

The application of nanotechnology knowledge and techniques to disease prevention and treatment is known as nanomedicine. The use of nanomaterials in biomedicine has increased over the last decade, with several different nanoparticle systems now being used in clinical settings. Several nanomedicines function by interacting directly with genetic materials or biomolecules that are required for proper genome function and cell division, both of which can cause genotoxicity and mutagenicity. There are currently no global regulatory standards in place for nanotherapeutic clinical translation. Difficulties in the classification of nanomedicine, performing a variety of functions, particle size variation, manufacturing process, administering appropriate doses, and pharmacokinetics are some of the regulatory challenges faced by nanomedicines. Lack of financial profitability, consumer distrust, ineffective regulation of new and generic products, weak patent protection, and insurance market failure all adversely impact the future of nanomedicines. Despite the challenges that nanomaterials face, nanotechnology provides extraordinary opportunities for not only improving materials and medical devices but also for developing new smart devices and technologies in areas where existing and more traditional technologies may have reached their limits. Keywords:  Nanomedicine, nanomedicine regulation, regulatory challenges, future aspects, nanotechnology, nanobots

4.1 Introduction Nanomedicine is the application of nanotechnology knowledge and techniques to disease prevention and treatment. It is the use of nanoscale materials, such as biocompatible nanoparticles and nanorobots, in a living organism for diagnosis, delivery, sensing, or actuation [1]. In general, nanomedicine encompasses any application of nanomaterials for medical purposes, from diagnostic to therapeutic [2]. The use of nanomaterials in medicine has grown over the last decade, with several different nanoparticle systems being used in clinical settings. Despite limited growing success in clinical investigations, polymeric, metallic, *Corresponding author: [email protected] Raj K. Keservani, Rajesh Kumar Kesharwani and Anil K. Sharma (eds.) Advances in Novel Formulations for Drug Delivery, (67–80) © 2023 Scrivener Publishing LLC

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68  Advances in Novel Formulations for Drug Delivery and lipid-based nanoparticles have all found a place in medicine, with these frequent higher pharmacological efficacies or therapeutic benefits compared to standard medication therapy. Although we know very little about the pharmacokinetics, pharmacodynamics, and toxicity of many nanomaterials in humans, there may be some benefits to adopting such technology. The topic of nanomedicine and its impact on the pharmaceutical business continues to elicit excitement; nevertheless, regulatory guidance in this area is urgently needed to offer legal clarity to producers, legislators, healthcare professionals, and the general public.

4.2 Importance of Regulation of Nanomedicine Most nanomedicines work by directly interacting with genetic materials or biomolecules required for proper genome function and cell division, both of which can cause genotoxicity and mutagenicity [3]. The inflammatory response of neutrophils and macrophages induces oxidative and nitrosative stress, which is mediated by neutrophil and macrophage production of reactive oxygen and nitrogen species [4]. The accumulation of such free radicals can be extremely harmful to the body. Inducing oxidative DNA damage, which leads to strand breakage, protein denaturation and lipid peroxidation, which leads to cancer, damaging mitochondrial membranes, which leads to cell death and necrosis, and transcription of genes involved in carcinogenesis and fibrosis, are just a few examples of how this damage can occur. There is evidence that these particles accumulate inside the liver and move to areas such as the central nervous, cardiovascular, and renal systems when administered intravenously [5]. There are too many unknowns that might provide possible threats to safety for particles that cannot be traced after ingestion. Many nanomedicines’ unique interactions with biological systems are not yet fully understood, making understanding, recognizing, and drawing conclusions about the physicochemical and toxicological properties of nanomedicines difficult. However, given the absence of standardized regulatory advice, little is expected to change in this area. It must also be acknowledged that in this process, one size does not fit all, as the unique properties observed at the nanoscale are highly dependent on nanoparticle type, surface properties, administration route, and, most importantly, nanoparticle morphology, which can be diverse, a factor that is stymieing the regulatory process [6]. The regulatory agencies are justified to be cautious; in the past, market approval was given for nanoparticles used in medical imaging, only to be revoked when unforeseen patient events occurred after injection. Significant adverse responses involving muscular discomfort, particularly in the lower back, as well as allergic reactions that resulted in one death, were among the concerns. Therefore, it was concluded that the risks connected with this specific nanomolecule exceeded any possible benefits, and marketing authorization was rejected [7–9].

4.3 Regulatory Challenges Faced by Nanomaterial in Medicine A barrier to the development of nanotherapeutics is the lack of regulation and standards in manufacturing practices, quality control, safety, and efficacy evaluation. There are currently no global regulatory standards for nanotherapeutic clinical translation. Regulatory agencies, such as the FDA and the European Medicines Agency (EMA), have only issued

Nanomedicine Regulation and Future Prospects  69 preliminary guidance documents for nanotechnology products. Some of the common challenges for the regulation of nanomaterials in medicine are listed below.

4.3.1 Performing Various Functions The fact that regulatory authorities like the FDA use safety data based on bulk materials, which do not have the same pharmacologic and pharmacokinetic action as nanomedicines, is likely the most important barrier to nanomedicine regulation. This means that data generated on safety and efficacy will not be typical of what might happen when the nanomedicine is utilized in clinical settings once it has received marketing approval. This complicates the development of laws governing the safety and efficacy criteria of nanomedicines because a non-nanoversion may meet regulatory standards but a nanomedicine may not [10].

4.3.2 Nanomedicine Classification Issues Another significant problem has been encountered in the categorization of nanomedicine. They could be categorized as medications or medical devices, and global regulators are not always consistent in their classification. As a result, nanomedicine may be classified as a medicine in one nation and a medical device in another and the rules that must be followed will differ depending on its classification. As a result, the specific safety and efficacy standards it must meet to be placed on the market may vary, and some countries will be able to use a nanomedicine that may not have passed regulatory standards in another country [11].

4.3.3 Variation in Size of the Particle Rannard and Owen [6] told that when it comes to nanomedicine, one size does not fit all, based on clinical need, application route, and physiology, but current regulatory frameworks have largely ignored this. Nanomedicines are difficult to characterize due to their complexity in terms of structure, form, size, and therapeutic use. Dynamic light scattering, for example, can be used to estimate hydrodynamic size; however, because this technique equates light-scattering particles to spherical shapes, it is not an accurate metrology technique for rod-shaped materials. Furthermore, some commonly used size measurement techniques may depict the nanomaterial in a different light than how it would appear in the human body. One example is transmission electron microscopy. Here, samples are dried, which may change their shape or size when compared to their solution phase. Protein coronas have been extensively observed to occur after nanomaterials are injected into the bloodstream, therefore, in the physiological environment, all size reports may vastly underestimate ultimate size. Even in the literature, there is no consensus on the best nanometrology or characterization standards. Preclinical nanomedicine development characterization will remain unchanged until there is rigorous clinical regulatory guidance or intervention [12, 13].

4.3.4 Manufacturing Process For nanomaterial and nanomedicine stability, scaling up and manufacturing processes are frequently hit or miss. As a result, approval requires stringent protocols and assurances. Nanomaterials are manufactured in two ways in the pharmaceutical industry: top-down

70  Advances in Novel Formulations for Drug Delivery and bottom-up. The top-down process entails the mechanical or chemical breakdown of a bulk substance into a smaller one or smaller bits. The bottom-up approach, on the other hand, begins with atomic or molecular species, enabling precursor particles to grow in size through a chemical reaction. These two production processes are responsible for the formation of primary particles, aggregates, and agglomerates. A particle is a small piece of matter with defined physical boundaries. An aggregate is a particle made up of strongly bound or fused particles whose external surface area is smaller than the sum of the individual particles surface areas. Agglomerate is a collection of weakly bound particles or aggregates whose external surface area is similar to the sum of the individual components’ surface areas. It is easy to see why aggregates and agglomerates are included in the definition. They may retain the characteristics of unbound particles and have the ability to degrade to the nanoscale [14]. Nanomaterials utilized in nanomedicine are assemblies of nanomaterials that interact with one another in weak or strong ways. To account for these various interactions, nanomaterial assemblies were classified as either firmly bound or fused nanomaterials (aggregates) or weakly bound nanomaterials (agglomerates) [15].

4.3.5 Difficulties to Create CQA To increase knowledge of the nanomedicine manufacturing idea, Critical Quality Attributes (CQA) must be developed. At important stages in the manufacturing process, it is necessary to identify and regulate the process. It is challenging to build a solid and consistent manufacturing process that defines the quality, effectiveness, stability, and safety of nanomedicines due to their complicated architectures and features. A comprehensive description of CQA would entail the discovery and study of nanomedicine qualities in the small-scale manufacturing process, which would improve comprehension of the large-scale manufacturing process. Regarding such issues, consortiums and government agencies all over the world, such as the US and EU Nanotechnology Characterization Laboratories, have been formed to provide researchers with semiregulatory testing facilities. However, such resources are commonly inaccessible to researchers until much later in the development pipeline, after preclinical testing [14, 16, 17].

4.3.6 Nanotoxicology and Cellular Response Nanotoxicology and cellular response are two more challenges that regulators encounter. Numerous recommendations for feasible ways of detecting nanotoxicity have been made. When applied to the evaluation of nanotoxicity, traditional toxicity measures, such as large-scale animal testing for tiny medicinal compounds in the past have been lowered and declared unethical, extremely expensive, and impracticable. In vitro toxicity approaches are utilized as a preliminary step in analyzing nanoparticles. When compared to animal testing, it is a less expensive and time-consuming approach that provides for better control over trial circumstances. Furthermore, there is mounting evidence that the traditional assays used for in vitro testing of small compounds are unsuitable for nanomaterials. Many nanoparticles interact with in vitro assay reagents or disrupt the detection mechanism, resulting in false positives or invalid data. Nanomaterials with high adsorption capacity, optical properties, catalytic activity, acidity or alkalinity, magnetic properties, and dissolution are all likely to interact with in vitro testing reagents or measurements [9, 18, 19].

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4.3.7 Administering Right Doses Before developing nanomedicines for clinical use, extensive preclinical safety data, including adverse impact data, is required. A high medication dosage in nanoform could cause cell or organ toxicity (which could be fatal in people with chronic renal disease or diabetes) or the development of antibiotic resistance. Furthermore, because small particles travel faster than larger particles, they may put patients at risk. This enables them to pass through the blood-brain barrier, possibly affecting brain function or causing edema in the long term. This is perhaps one of the most important factors, and a lack of data to convincingly demonstrate that the new form of medicine is safe can result in approvals that are later revoked [9, 20].

4.3.8 Pharmacokinetics Defining the pharmacokinetics of nanomedicines presents a significant challenge in their regulation. This is because they deviate from the typical and expected path of small drug molecules. As a result, they are bioavailable for an extended period, posing a high health hazard to the general public if nanomedicine products are ever used over the counter. Regulatory bodies must evaluate whether a given nanomedicine should be available as an over-the-counter product or enter the market under strict supervision. However, due to a lack of toxicity information and data currently available, it is incredibly hard to provide even a conclusive answer on this particular topic [9, 21].

4.3.9 Developing Guidelines Another issue concerning the regulation of nanomedicines is the question of who should be in charge of developing nanomedicine guidelines. A consultative process involving many stakeholders, including academics and clinicians, resulted in this decision. In this regard, regulatory, high-caliber laboratories, as well as risk assessments of personnel, guidelines, and technical standards, are all urgently needed at the federal level. Key bodies frequently lack scientific expertise on the subject due to the newness of the technology and the diversity of nanomedicines’ modes of action. It is difficult to create adequate regulations when there is limited knowledge of nanomedicines, and any regulations that are created may not be suitable to maintain patient safety and regulate the use of nanomedicines in a clinical setting. With strong national consortiums and national characterization laboratories, this infrastructure is already in place in many ways; however, the translation of information and guidance recommendations from these bodies has not yet been integrated into regulatory frameworks [21].

4.4 Nanomedicine Future Aspects The future of nanomedicines is jeopardized by a lack of financial profitability, consumer distrust, ineffective regulation of new and generic products, weak patent protection, and insurance market failure. Its economic recovery is dependent on a series of protective measures and actions. More investment prompted by cost-effectiveness analyses and business

72  Advances in Novel Formulations for Drug Delivery plans based on clinical data, public education based on nanotoxicology studies, smart regulatory reform in testing, market entry, and liability, effective and strategic patenting, patent dispute prevention and resolution, and innovative insurance policies are all required for success.

4.5 Challenges that Threaten the Future of Nanomedicine Several factors can delay or prevent the clinical translation of nanomedicines, regardless of whether they are therapeutically beneficial or not. Some of the common challenges, which threaten the future of nanomedicine, are listed below.

4.5.1 Financial Crisis Despite high R&D costs, start-ups and small- and medium-sized enterprises (SMEs) are driving the development of nanomedicines. Regrettably, the majority of them lack the financial means to fully exploit and market their inventions. Nanotechnology-based therapeutics is rarely commercialized by SMEs, according to evidence. As a result, collaboration with larger pharmaceutical companies is critical. However, investing in new alternative nanotherapeutics puts a large number of their traditional blockbuster drugs at risk. As a result, there is almost no commercial incentive for large corporations to switch. The scenario is comparable to that of fossil-fuel engines and electric vehicles. Despite the need for environmental reform, there is little commercial need to shift technologies. Similarly, nanotherapeutics may improve efficacy and reduce treatment-related side effects, but the commercial need to switch remains modest. Furthermore, profitability is jeopardized by diseconomies of scale that result in high patient acquisition costs [22, 23].

4.5.2 Lack of Confidence Despite its enormous potential health advantages, the general public is mostly unaware of nanotechnology. Even among knowledgeable populations, opinions differ greatly, resulting in a multitude of visions and creating concerns about toxicity, environmental harm, and long-term impacts. Inadequate communication and a lack of knowledge breed uncertainty, suspicion, and even dread. This may result in the cancellation of a single nanomedical project, but it also jeopardizes the future of nanotechnology as a whole, because successful commercialization is based on customer trust [23].

4.5.3 Potential Dangers The biological activity and biokinetics of nanomaterials are determined by their size, shape, chemistry, and surface characteristics. These factors are expected to alter responses and cell interactions, as well as to cause toxicity. Phagocytes, for example, remove germs, foreign particles, and dead or dying cells in the circulation. Phagocytosis is a biological activity that occurs as part of the human immune system. To survive and prolong their circulation time, therapeutic nanoparticles must attempt to deceive the phagocytes. Surface modification with polyethylene glycol is commonly used to achieve this (PEG). Particles 20–50 nm in

Nanomedicine Regulation and Future Prospects  73 size can reach healthy cells and the CNS; particles less than 70 nm can penetrate the pulmonary interstitium because macrophages on the alveolar surfaces of the lungs have difficulty identifying them. Inhaled nanoparticles can travel through the respiratory tract, circulation, and lymph nodes to reach the bone marrow, heart, and spleen. Furthermore, nanoparticles as big as 1 mm in diameter can pass through the skin. Finally, some particles enter cells via the gastrointestinal system, while others collect in the liver. Translocation across epithelia from the portal of the entrance to other organs and tissues is also influenced by shape and surface qualities (chemistry, area, porosity, and charge). Because of the harmful side effects of nanomedicine, public acceptance may suffer. Nanoparticles can cause major health and environmental problems if they are not carefully confined. Because nanoparticles, for example, are easily aerosolized, the harm to human health is more likely to reveal itself over time and is not restricted to the patients undergoing treatment but may affect the entire population. The impact of nanosizing on live beings and the environment, on the other hand, is unknown. Particle stability is a subject about which little is understood. Nanoparticles have the potential to create modest alterations in plant and animal tissues, with unknown cascading implications. This lack of information is a huge concern for those marketing nanoparticles and attempting to acquire the public’s trust and confidence [23].

4.5.4 Unsuccessful Patenting The development of nanomedicines is dependent on the protection of intellectual property rights through patents. A patent grants the exclusive right to create, use, and sell an invention for a specific length of time. It is a critical motivator for commercialization. As a result, corporations and research organizations are devoting an increasing portion of their expenditures to acquiring and defending patents. This is especially true for new businesses. Patents also bring credibility to the stakeholders of the company. Unpatented technology, on the other hand, will have a difficult time attracting investment. When patents expire, rivals get unrestricted access to the technology. In general, generic products are priced 30–40% lower than brand products in the first year, and up to 80% lower two years following expiration. Because they do not pay R&D or marketing expenditures, generic producers may sell their goods at reduced rates. Because of the lengthy development time of nanomedicines, most patents are in danger of expiration soon after commercialization. As a result, the present patent structure does not take into account the lengthy R&D operations. As a result, the number of years required to recover development expenditures and produce a decent profit (which is required to drive additional research in this specific sector) is just too short. A well-designed patent system, in theory, produces successful patents that communicate both safety and medical efficacy into the market. As a result, it serves as a trust-enhancing filter. However, if the patenting system is dysfunctional, for example, by requiring overly lengthy procedures, the dissemination of nanomedicines may be hampered. Furthermore, firms may face overlapping patents owned by others. As a result, the current patent policy represents a significant impediment to future innovation [23].

4.5.5 Breakdowns in the Pharmaceuticals and Financial Markets Apart from the expense, there is no difference between generic and brand goods in principle. However, certain generics, particularly those produced in underdeveloped nations, are

74  Advances in Novel Formulations for Drug Delivery made from low-quality components. There is also a major danger of counterfeiting, and false test reports or compliance certifications can mislead regulatory agencies. Consequently, generic drug marketing needs a minimal demonstration of bioequivalence in healthy persons, implying equal clinical effectiveness and tolerance in the patient population. The above, however, is not a proven reality. Cheap, low-quality items can result in many negative outcomes, including death. Besides repaying merely, the cheapest products, insurance companies and other third-party payers tend to support and stimulate the manufacturing of generics. They seldom fund the expenses of experimental medications, no matter how safe and beneficial they are. Current health insurance coverage does not cover the price of “unproven” technologies. Although this is a concern with pharmaceuticals in general, these policies have a greater impact on nanomedicines. Nanotherapeutics is frequently beneficial in treating disorders that are not indicated on the prescription label. There is a huge risk of losing remedies for life-threatening diseases if they are not included because they are not covered by insurance coverage. Nonetheless, the quick rise of the drug sector is being driven by low-cost generics rather than creative items. The generics market is predicted to rise by 10–15%, while the entire pharmaceutical industry is expected to grow by 7–9%. Finally, generics may cause market loss. In other words, a thriving market may result in increased sales and profits, but just minor extra medical advantages for patients [23].

4.5.6 Limited Regulation Regardless of how promising nanomedicines are, their benefits must be balanced against the risks they may pose. The latter’s necessary regulation is hampered by a lack of nanotoxicology studies. Because drugs, medical devices, and biological agents are currently regulated differently, it is unclear how nanotherapeutics should and will be evaluated. Nanoparticles are made up of various materials and have unique surface properties, as well as increased reactivity. For the time being, the tripartite nature of nanoparticle-based therapeutics presents a challenge to the three regulatory bodies, as there are no specific and integrated requirements in place to test the health and safety impacts of nanomedicines. As a result, current regulations for nanomedicines are inappropriately based on those developed for bulk materials. The behavior and functionality of nanoscale materials, on the other hand, differ significantly from their parent form. As a result, advisory organizations and regulatory authorities take a case-by-case approach. The multifunctional nature of nanomedicines necessitates regulatory approval for each of its three components, as well as approval for the combined therapy. As a result, the entire process takes a significant amount of time. A more integrated regulatory approach would undoubtedly reduce approval time. Investors will be hesitant to invest in this new technology as long as the regulatory process is not tailored to the specific needs of nanomedicine [23, 24].

4.6 Future Prospects for Nanomedicine Nanotechnology offers extraordinary opportunities not only to improve materials and medical devices but also to develop new smart devices and technologies in areas where existing and more traditional technologies may have reached their limits. Some of the promising development of nanomedicine is listed below.

Nanomedicine Regulation and Future Prospects  75

4.6.1 Emerging Nanomaterials Block copolymer micelles, polymers, carbon nanotubes, quantum dots, and dendrimers are examples of emerging nanomaterials that can help distribute or target medications more effectively. Carbon nanotubes are made up of hexagonally bonded carbon atoms that form a hollow tube. They are being studied for use in therapy, particularly cancer treatment, as well as the development of new diagnostic agents and nanosensors. Carbon nanotubes can be utilized to deliver drugs to specific locations. Quantum dots are semiconductor nanocrystals with an inorganic core as well as a metallic shell around them. They can serve as drug carriers or fluorescent markers for other drug carriers like liposomes. They can support the creation of treatments for cancer, for example, by coupling molecular imaging for diagnostics with therapy. Toxicology is a major worry for both carbon nanotubes and quantum dots, and researchers are working to find ways to make these materials less harmful before using them in medical applications. Dendrimers are molecules with a tree-like structure that is regular and extremely branching. They have a hydrophobic interior chamber that can be filled with hydrophobic compounds, such as anticancer medicines, and measure between 1 and 10 nanometers in diameter. Dendrimers are mechanically more stable than other drug carriers like liposomes; however, they can only carry a limited amount of the drug [25].

4.6.2 Personalized Nanomedicine Personalized medicine is a therapeutic method that is personalized to a patient’s distinct attributes through techniques like molecular profiling. Nanotechnology may one day allow us to obtain customized treatments. Newly developed nanomedicines include theranostics, which are multicomponent systems that can comprise both therapeutic and diagnostic compounds. The resulting nanosystem will enable drug delivery, diagnostics, and monitoring of the medicine’s effects. The development of such systems could aid in the pursuit of personalized remedies for a variety of conditions [25].

4.6.3 Nanorobots and Nanodevices Respirocyte is a hypothetical nanomachine that can act like a human red blood cell. It could be used to supplement or completely replace our red blood cells as oxygen and carbon dioxide carriers in the bloodstream. The potential capacity for oxygen in these artificial red blood cells is 2366 times greater than hemoglobin, the body’s oxygen transport protein. The primary medical applications of respirocytes would be blood transfusion, partial treatment for anemia, lung disorders, enhancement of cardiovascular/neurovascular procedures, tumor therapies and diagnostics, prevention of asphyxia, artificial breathing, and a variety of sports, veterinary, and battlefield applications [26]. Microbivores are microscopic artificial mechanical phagocytes whose primary function is to digest and discharge microbiological pathogens found in the human bloodstream [27]. Microbivores are projected to be up to 1000 times quicker than unassisted either natural or antibiotic-assisted biologic phagocytic defenses and to be capable of expanding the physician’s therapeutic competence to include locally dense illnesses. Medical nanorobots may also be

76  Advances in Novel Formulations for Drug Delivery capable of performing cellular cytosurgery in vivo. The nucleus, particularly the chromosomes, is the most likely location of pathogenic activity in the cell. A physician-controlled nanorobot would extract existing chromosomes from a specific injured cell and implant new ones in their place, in that same cell, in one straightforward cytosurgical treatment known as chromosome replacement therapy. If the patient desires inherited faulty genes can be replaced with nondefective basepair sequences, permanently curing a genetic ailment. Engineered bacterial biobots (synthetic microorganisms) can be programmed to produce vitamins, hormones, enzymes, or cytokines that a patient’s body is deficient in, or to selectively absorb and metabolize harmful compounds such as poisons and toxins into harmless end products [23].

4.6.4 Orthopedic Augmentations and Cytocompatibility Biomaterials, which are used in orthopaedic implants and as scaffolds for tissue-created products, are a significant field of application for nanotechnology in medicine. For example, if a hip implant is designed at the nanoscale, it may be possible to create an implant that closely resembles the mechanical properties of human bone, eliminating stress shielding and the resulting loss of surrounding bone tissue. The extracellular matrix (ECM) is a three-dimensional network of intricate nanofibers that both supports and instructs cells on how to behave. It manifests itself in a variety of ways in various tissues and at various stages of development within the same tissue. Nanostructuring of materials is a powerful tool for promoting and controlling cell behavior, from cell adhesion to gene expression, and thus increasing biocompatibility by dictating the desired interactions between cells and materials [28].

4.6.5 Cardiology and Nanotechnology Scientists are working toward minimally invasive treatments for heart disease, diabetes, and other diseases, and thanks to nanotechnology, there is hope. Cardiovascular gene therapy would necessarily involve the following steps: identifying a protein whose presence causes blood vessels to form, producing and packaging strands of DNA containing the gene for making the protein, and delivering the DNA to the heart muscle. The last of those steps is the most difficult. Another use of nanotechnology is the development of muscle-powered nanoparticles capable of transferring information into cells, with the potential to restore missing biological processes in numerous tissues, such as the sinoatrial node. This effect has the potential to lead to the treatment of diseases that would otherwise be fatal or difficult to treat in humans, such as Coronary Artery Disease (CAD), by improving the biocompatibility of intracoronary stents and using nanoparticles to regulate the main limit factors for Percutaneous Transluminal Coronary Angioplasty (PTCA) [28]. Another application of recent nanotechnology advancements in the diagnosis of cardiovascular diseases. For noninvasive detection of atherosclerotic lesions, myocardial necrosis, cerebral infarction, and various tumors, a variety of monoclonal antibodies, peptides, and carbohydrates can be used. The detection of the complementary DNA strand, which is based on the discovery of complexes of single-walled Carbon nanotubes with single-stranded DNA, is another application of nanotechnology in cardiology. When

Nanomedicine Regulation and Future Prospects  77 a single nucleotide changes, the link between the carbon nanotube and the corresponding DNA strand changes, allowing ­single-nucleotide polymorphisms to be identified (SNPs). SNPs are single-base variants in the human genome that cause people to have different DNA sequences. Minor variations in DNA sequences can have a significant impact on whether or not a person develops a disease, as well as how they respond to drug regimens [28, 29].

4.6.6 Cancer and Nanotechnology Nanotechnology has the potential to impact key challenges in cancer diagnosis and treatment. Diagnosis, treatment, and monitoring the progress of therapy for each type of cancer has long been a goal for oncologists, and it has become a reality thanks to parallel revolutions in genomics, proteomics, and cell biology. The ability to combine multiple functions may be nanotechnology’s most significant advantage over traditional therapies [30]. The major areas in which nanomedicine is being developed in cancer are: a) Early detection of tumors by creating smart collection platforms for simultaneous analysis of cancer-associated markers and designing contrast agents that improve the resolution of tumor area compared to nearby normal tissues and b) Cancer treatment by creating nanodevices that can release chemotherapeutic agents. Tumor diagnostics and prevention are the best cancer therapies, but in the absence of such, early detection will significantly improve survival prospects, on the logical assumption that an in situ tumor will be easier to eradicate than a metastasized tumor. Nanodevices, particularly nanowires, can detect cancer-related compounds, assisting in tumor detection early on. Nanowires with unique selectivity and specificity can be developed to identify molecular markers of malignant cells. They sit on top of a microfluidic channel, allowing cells or particles to pass through. A probe, such as an antibody or an oligonucleotide, a short stretch of DNA that can detect specific RNA sequences, can be coated on nanowires. Proteins that bind to antibodies alter the nanowire’s electrical conductance, which can be measured using a detector. As a result, proteins produced by cancer cells can be identified, allowing for earlier tumor identification [28, 30].

4.6.7 NAPT Nanoshell-assisted photothermal therapy is a noninvasive method of targeted photothermal tumor elimination. It is based on nanoshells that absorb light in the near-infrared (NIR) range, which is the most effective wavelength for penetrating tissues. A silica core is coated with a metallic coating, usually gold, in these nanoshells. The absorbed light is efficiently converted to heat by the metal shell. Antigens that are specifically targeted by cancer cells can be added to the nanoshells to increase specificity. When a laser emits near-infrared light, the particles produce heat, which causes the tumor to die. The temperature of the nanoshell-treated tumors increased by around 40 degrees Celsius, compared to a 10 degree

78  Advances in Novel Formulations for Drug Delivery Celsius increase in tissues treated with NIR light alone. The advantage of thermal therapies is that most methods are noninvasive and offer the ability to treat tumors that cannot be treated surgically [28].

4.6.8 Gene, Protein, Lab-on-a-Chip Devices Medical devices used for in vitro diagnostics, such as gene-, protein-, or lab-on-a-chip technologies, do not pose the same safety risks as nanoparticles put into the body. Some numerous devices and techniques may be used to sequence single molecules of DNA. Nanopores are being used as a novel nanoscale technology for cancer detection, allowing for ultrafast and real-time DNA sequencers. Protein-chip and lab-on-a-chip device development are generally more difficult than gene-chip development. These devices are expected to play a key role in future medicine since they will be personalized and will combine diagnostics and therapies into a new emergent medical speciality known as “theranostics” [28, 31].

4.6.9 Polymeric Nanoparticles in Medicine One of the most studied organic nanomedicine methods is polymeric nanoparticles (NPs). Many researchers are intrigued by the potential of polymeric NPs to change modern medicine. Particle size, morphology, material selection, and processing procedures are all research topics that are being investigated to find the ideal nanosystem for more effective and precisely targeted therapeutic delivery. Drug delivery strategies like conjugation and drug entrapment, prodrugs, stimuli-responsive systems, imaging modalities, and theranostics all use polymeric NPs. Cancer, neurological illnesses, and cardiovascular diseases are all affected by NP technologies, which push scientific frontiers to the forefront of transformative nanomedicine developments. One of the most significant biomedical applications of biodegradable polymeric nanoparticles is in medication delivery [32]. Polymeric nanomaterials have several advantages, including the ability to: • Provides controlled release from the matrix structure into a targeted part of the body • Encapsulates labile molecules (e.g., DNA, RNA, and proteins) and prevent degradation • The ability to modify surfaces with ligands and • It has a greater standard of in vitro and in vivo stabilities. Polymeric micelles in cancer therapy provide new tools for loading poorly water-soluble anticancer medicines and increasing the lifespan of the molecules to develop novel therapeutic entities. Stimuli-responsive polymeric NPs exhibit exceptional regulated release profiles, resulting in more effective anticancer effects in vitro and in vivo. Polymeric NPs provide good contrast enhancement for practically all medical imaging modalities, allowing tumor activity to be monitored by following NP dynamics. NPs can also be used in MI theranostics. If there is a large concentration of NPs in tumors, a burst release of the medicine happens by introducing a physical source to the NPs, which might be NIR lasers, external heat, or lighting photosensitive components. The future of nanomedicine, particularly

Nanomedicine Regulation and Future Prospects  79 through polymeric NPs, will improve and facilitate traditional therapeutics to help humans on both an individual and global scale. Continuous preclinical and clinical research on polymeric NPs will profoundly modify and improve illness diagnosis, therapy, and prevention [28, 32].

References 1. Nature, Nature. https://www.nature.com/subjects/nanomedicine. 2. Tinkle, S., Mcneil, S.E., Mühlebach, S. et al., Nanomedicines: Addressing the scientific and regulatory gap. Ann. N. Y. Acad. Sci., 1313, 1, 35–56, 2014. 3. Singh, N., Manshian, B., Jenkins, G.J.S. et al., NanoGenotoxicology: The DNA damaging potential of engineered nanomaterials. Biomaterials, 30, 23–24, 3891–3914, 2009. 4. Smolkova, B., Dusinska, M., Gabelova, A., Nanomedicine and epigenome. Possible health risks. Food Chem. Toxicol., 109, 780–796, 2017. 5. Manke, A., Wang, L., Rojanasakul, Y., Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed. Res. Int., 2013, 2013. 6. Rannard, S. and Owen, A., Nanomedicine: Not a case of “One size fits all.” Nano Today, 4, 5, 382–384, 2009. 7. Falkner, R. and Jaspers, N., Regulating nanotechnologies: Risk, uncertainty and the global governance gap. Glob. Environ. Polit., 12, 1, 30–55, 2012. 8. Kermanizadeh, A., Balharry, D., Wallin, H., Loft, S., Moller, P., Nanomaterial translocation-the biokinetics, tissue accumulation, toxicity and fate of materials in secondary organs-a review. Crit. Rev. Toxicol., 45, 10, 837–872, 2015. 9. Foulkes, R., Man, E., Thind, J., Yeung, S., Joy, A., Hoskins, C., The regulation of nanomaterials and nanomedicines for clinical application: Current and future perspectives. Biomater Sci., 8, 17, 4653–4664, 2020. 10. Bawa, R., Regulating nanomedicine–can the FDA handle it. Curr. Drug Deliv., 8, 3, 227–234, 2011. 11. Kelly, B., Nanomedicines: Regulatory challenges and risks ahead. Regul. Aff. Medtech., 10, 14–17, 2010. 12. Leong, H.S., Butler, K.S., Brinker, C.J. et al., On the issue of transparency and reproducibility in nanomedicine. Nat. Nanotechnol., 14, 7, 629–635, 2019. 13. Oh, J.Y., Kim, H.S., Palanikumar, L. et al., Cloaking nanoparticles with protein corona shield for targeted drug delivery. Nat. Commun., 9, 1, 1–9, 2018. 14. Soares, S., Sousa, J., Pais, A., Vitorino, C., Nanomedicine: Principles, properties, and regulatory issues. Front. Chem., 6, 1–15, Aug. 2018. 15. Alphandéry, E., A discussion on existing nanomedicine regulation: Progress and pitfalls. Appl. Mater. Today, 17, 193–205, 2019. 16. Sainz, V., Conniot, J., Matos, A.I. et al., Regulatory aspects on nanomedicines. Biochem. Biophys. Res. Commun., 468, 3, 504–510, 2015. 17. Mühlebach, S., Regulatory challenges of nanomedicines and their follow-on versions: A generic or similar approach? Adv. Drug Deliv. Rev., 131, 122–131, 2018. 18. Paradise, J., Regulating nanomedicine at the food and drug administration. AMA J. Ethics, 21, 4, 347–355, 2019. 19. Siegrist, S., Cörek, E., Detampel, P., Sandström, J., Wick, P., Huwyler, J., Preclinical hazard evaluation strategy for nanomedicines. Nanotoxicology, 13, 1, 73–99, 2019.

80  Advances in Novel Formulations for Drug Delivery 20. Sharma, H.S., Hussain, S., Schlager, J., Ali, S.F., Sharma, A., Influence of nanoparticles on blood-brain barrier permeability and brain edema formation in rats. Acta Neurochir. Suppl., 106, 359–364, 2009. 21. Agrahari, V. and Hiremath, P., Challenges associated and approaches for successful translation of nanomedicines into commercial products. Nanomedicine, 12, 8, 819–823, 2017. 22. Wagner, V., Dullaart, A., Bock, A.K., Zweck, A., The emerging nanomedicine landscape. Nat. Biotechnol., 24, 10, 1211–1217, 2006. 23. Bosetti, R. and Vereeck, L., Future of nanomedicine: Obstacles and remedies. Nanomedicine, 6, 4, 747–755, 2011. 24. Meredith, P., Bioequivalence and other unresolved issues in generic drug substitution. Clin. Ther., 25, 11, 2875–2890, 2003. 25. Future of nanomedicines. https://euon.echa.europa.eu/future-of-nanomedicines. 26. Malasala, S., Sai, S.M., Karlapudi, S., Sreekanth, N., Baburao, C., Respirocytes: Mechanical artificial red blood cells. Int. J. Biol. Pharm. Res., 4, 4, 297–301, 2013. 27. Deepthi, M.S., Microbivores: Artificial mechanical phagocytes using digest and discharge protocol. Pharm. Regul. Affairs, 1, 4, 200, 2012. https://www.hilarispublisher.com/proceedings/ microbivores-artificial-mechanical-phagocytes-using-digest-and-discharge-protocol-845. html. 28. Abeer, S., Future medicine: Nanomedicine. J. Int. Med. Sci. Acad., 25, 3, 187–192, 2012. 29. Kane, J.P., Aouizerat, B.E., Luke, M.M. et al., Novel genetic markers for structural coronary artery disease, myocardial infarction, and familial combined hyperlipidemia: Candidate and genome scans of functional SNPs. Int. Congr. Ser., 1262, C, 309–312, 2004. 30. Yih, T.C. and Wei, C., Nanomedicine in cancer treatment. Nanomed. Nanotechnol. Biol. Med., 1, 2, 191–192, 2005. 31. Zandonella, C., The tiny toolkit. Nature, 423, 6935, 10–12, 2003. 32. Banik, B.L., Fattahi, P., Brown, J.L., Polymeric nanoparticles: The future of nanomedicine. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 8, 2, 271–299, 2016.

5 Nanotechnology Application in Drug Delivery for Medicinal Plants Bui Thanh Tung*, Duong Van Thanh and Nguyen Phuong Thanh Department of Pharmacology, VNU University of Medicine and Pharmacy, Vietnam National University Ha Noi, Ha Noi, Vietnam

Abstract

In recent years, there has been a considerable increase in the usage of herbal medicines for medicinal purposes. Concurrently, developments in phytochemical and phytopharmacological studies have assisted in the discovery of medicinal plant bioactive components. Flavonoids and tannins, for example, account for the majority of bioactive components found in plant extracts. These substances have a high water solubility but low absorption due to the difficulties of penetrating cellular lipid membranes, too large a molecular size, or poor absorption, resulting in bioavailability and efficacy loss or reduction. As a result of these obstacles, certain extracts are not being used therapeutically. In order to reduce these drawbacks, scientists have suggested combining herbs with nanotechnology in order to improve the activity of the extracts and perhaps improve the treatment outcomes and decrease the adverse effects and dose necessary. This chapter discusses several highly effective pharmaceuticals produced in nanoscale, including improved bioavailability, in vitro, in vivo, and clinical efficacy. Keywords:  Herbal medicines, nanotechnology, bioavailability, in vitro, in vivo, and clinical efficacy

5.1 Introduction 5.1.1 Nanodrug Delivery Systems (NDDS) In recent years, thanks to scientific advances that combine the extraordinary advantages of nanomaterials, nanotechnology is becoming mainstream in disease diagnosis, medical development, and other disciplines. NDDS is a wonderful nanomedical method that is constantly evolving. In NDDS, small molecule drugs or biotherapeutics are chemically enclosed or bound to the nanoparticles. Unlike conventional pharmaceuticals, NDDSs have material physicochemical properties that relate to the properties of drug delivery after administration. NDDS increases the solubility and bioavailability of a drug, as well as absorption, accurate delivery of the target dose, and overcoming drug resistance and reducing immunogenicity and toxicity, thereby improving the pharmacological and *Corresponding author: [email protected] Raj K. Keservani, Rajesh Kumar Kesharwani and Anil K. Sharma (eds.) Advances in Novel Formulations for Drug Delivery, (81–96) © 2023 Scrivener Publishing LLC

81

82  Advances in Novel Formulations for Drug Delivery pharmaceutical properties of parent drugs [42]. Herbal medicine has been famous for its excellent therapeutic effects, widely applied in traditional medicines in many countries. However, these effects are limited by drug solubility, poor bioavailability and lack of selectivity. These limitations and drawbackscan be deal with by controlling drug delivery. One of the most effective drug delivery systems is nanodrug delivery system. There are several nanodrug delivery systems used to improve the bioactive of herbals, such as: –– Liposomes, the first drug carriers to be researched and developed. Liposomes, usually with 80 to 300 nm size range, are spherical vesicles included phospholipids and steroids (e.g., cholesterol), bilayers or other surfactants and form spontaneously when certain lipids are dispersed in aqueous media where liposomes can be prepared, e.g., by sonication [34]. The combination of drugs and liposomes can increase the solubility of drugs and improve the pharmacokinetic properties, such as the therapeutic index of chemotherapeutic agents, rapid metabolism, reduction of harmful side effects [31]. –– Solid lipid nanoparticles (SNL), nanostructured lipid carriers (NLC), and lipid drug conjugates (LDC) belong to nanoparticles based on solid lipids. SNL is prepared by solid lipids (such as triglycerides), using various surfactants to stabilize the complex glyceride mixtures or waxes [17]. The effects of SNL include good physical stability, protection of incorporated drugs from degradation, controlled drug release, and good tolerability; but SNL also has some drawbacks, such as low loading capacity, drug expulsion after crystallization and relatively high water content of the dispersions [25]. Therefore, NLC and LDC were developed to improve those drawbacks [41]. –– Polymeric nanoparticles are made up of synthetic polymers, such as poly-e-caprolactone, polyacrylamide and polyacrylate, natural polymers like albumin, DNA, chitosan, gelatin [45]. This nanoform improved aqueous stability and photostability of a drug. Nonionic surfactants were used to cover polymeric nanoparticles to reduce immunological interactions [8, 40]. –– Silica materials used in controlled drug delivery systems are classified as xerogels and mesoporous silica nanoparticles (MSMs). There are several advantages of these nanoparticles, such as carrier systems, including biocompatibility, highly porous framework, and ease in terms of functionalization [3]. –– Magnetic nanoparticles are promising carriers for drug delivery because of the advantages such as easy handling with the aid of an external magnetic field, the possibility of using passive and active drug delivery strategies, the ability of visualization (visualization MNPs are used in MRI), and enhanced uptake by the target tissue resulting in effective treatment at the therapeutically optimal doses [4]. Besides these attributes, magnetic nanoparticles have appeared some drawbacks like the mismatch of the magnetic nanoparticle and the drug or magnetic molecule is not enough to connect [26]. Using magnetic nanoparticles also bases on many factors including magnetic properties and size of particles, the strength of magnetic field drug loading capacity, the place of accessibility of target tissue or the rate of blood flow [8].

Drug Delivery for Medicinal Plants  83

5.2 Nanoherbals 5.2.1 Cucuma longa (Cucurmin) Turmeric (Curcuma longa) belonging to the Zingiberaceae family is a famous spice plant in South-East Asia. Rhizome of this plant has also been used as a safe remedy against many ailments in many countries, principally in China, India and Vietnam [38]. Table 5.1 summarizes some research on the impacts of Curcuma longa nanocompounds. In 2009, Takahashi et al. published a study on the bioavailability of LiposomeEncapsulated curcumin (LEC). Accordingly, LEC was produced by combining SPL-WHITE or SPL-PC70 with 2.5 g of curcumin. SPL-PC70 showed significantly better encapsulation efficiency than SPL-WHITE (68% and less than 10%, respectively). Then, this LEC was

Table 5.1  Effect of Curcuma longa nanocompounds. Study

Active ingredients

Formulations

Biological activity

Ref

In vivo (male SpragueDawley rats)

(5% SPL-PC70 & 2.5% curcumin) with 100 mg curcumin/kg body weight

Liposome

- Faster rate and better absorption. - Tmax and Cmaxare shorter. - Better antioxidant activity

[39]

In vitro

ApoE3 mediated Polybutylcyanoacrylate (PBCA)

PBCA nanoparticles (25–800 nM curcumin/ well)

- Enhanced the activity of curcumin and cell uptake. - Sustained drug release effect

[24]

In vivo

Encapsulated curcuminnanoparticles

PLGA poly(lactideco-glycolide)

- Oral bioavailability increased at least 9-fold.

[33]

In vitro (Plasmodium yoelii infected mice)

Curcumin loaded chitosan nanoparticles 1 mg/day during 7 days

Chitosan nanoparticles

- Enhanced bioavailability and increased stability of CUR against P. yoelii

[2]

In vivo

Water-soluble albuminbound curcumin nanoparticles

CUR – loaded human serum albumin nanoparticles (CCM-HSANPs) 10 or 20 mg/kg

- Enhanced water solubility - Increased accumulation in tumors - Ability to traverse vascular endothelial cells.

[16]

84  Advances in Novel Formulations for Drug Delivery tested for bioavailability on male Sprague-Dawley rats at a dose of 100mg curcumin/kg. The results showed that the bioavailability of LEC was better than that of curcumin as evidenced by higher serum concentrations of curcumin, higher Cmax, Tmax and 4.96 times higher AUC than conventional curcumin [39]. Another nanoparticles of curcumin also studied is PBCA. Mulik et al. prepared ApoE3-mediated poly(butyl) cyanoacrylate nanoparticles containing curcumin (ApoE3-C-PBCA) and then tested it against beta-amyloid–induced cytotoxicity using SH-SY5Y cells. The results showed that ApoE3-C-PBCA enhanced the activity of curcumin, cell uptake and a sustained drug release effect. ApoE3 also has a synergistic effect with curcumin to increase the antioxidant effect and offer a great advantage in the treatment of beta-amyloid–induced cytotoxicity in Alzheimer’s disease [24]. Shaikh et al. encapsulated curcumin into nanoparticles by emulsion technique, the products were spherical in shape with particle size of 264 nm and 76.9% entrapment at 15% loading. The in vivo pharmacokinetics of these curcumin nanoparticles demonstrate at least a 9-fold increase in oral bioavailability compare to curcumin [33]. Akhtar et al. made nanoparticles of curcumin by bounded curcumin to chitosan nanoparticles. This combination not only enhanced bioavailability and chemical stability of curcumin in mouse plasma but also treated for the mice induced by Plasmodium yoelii [2]. Besides, water-soluble albumin-bound curcumin nanoparticles were studied by Kim et al. in 2011. The test result on xenograft HCT116 models without inducing toxicity showed that CCM-HSA-NPs (10 or 20 mg/kg) had a greater therapeutic effect (50% or 66% tumor growth inhibition vsPBStreated controls) than CCM (18% inhibition vscontrols) [16].

5.2.2 Gingko biloba Gingko biloba is one of the most sold medicinal plants in the world. It has been used as early as 2800BC. The main bioactive compounds in G. biloba are terpene trilactones and flavonoid glycosides [35]. Han et al. prepared PELGE nanoparticles of four active components (ginkgolides A, B, C and bilobalide) in G. biloba extract, created an injectable nanoparticulate system. The products had an encapsulation efficiency of about 78.84% with a loading dose of 11.9mg/150mg PELGE. The half-life time of the four terpenoid compounds was also significantly improved by incorporation into PELGE nanoparticles. The results indicate that a PELGE nanoparticle is a promising carrier system for the sustained and synchronized release of herbal medicines containing multiple components [14]. Table 5.2 includes studies on the effects of Gingko biloba nanocompounds. Aslam et al. prepared a nanoform of G. biloba using sodium lauryl sulfate as a stabiliser by antisolvent precipitation method. The product is 139.5nm in size polydispersity index is 0.258 and the zeta potential is 58.7 mV. In the in vitro drug release study, nanosuspension dissolute 2.5 times better than coarse extract. The pharmacokinetics in rats of nanoform are also better than coarse extract, the concentration of quercetin was found greater in nanosuspension administrated rats [5]. In another study, Haghighi et al. demonstrated that SNLs loaded with Ginkgo biloba showed acceptable particle size and shape, suitable loading of active substance and sustained release profile, as well as appropriate antimicrobial effects without any significant skin toxicity [13].

Drug Delivery for Medicinal Plants  85 Table 5.2  Effect of Gingko biloba nanocompounds. Study

Active ingredients

Formulations

Biological activity

Ref

In vitro + in vivo

Gingko terpen

MPEG-PLGAmPEG (PELGE) nanoparticles

- Sustained and synchronized release of the four components from PELGE

[14]

In vitro + in vivo

Extract of G. biloba

Surfactant stabilized nanosuspension

- Greater in vitro dissolution - Increased plasma concentration of quercetin - No toxic effect of nanoformulation

[5]

In vitro

G. biloba extract

Solid lipid nanoparticles (SLNs)

- Improved antibacterial - Sustained manner and no initial rapid release - Don’t have any skin toxicity

[13]

5.2.3 Artemisia Artemisia (Artemisia annua L., Asteraceae) is an annual plant native to Asia, possibly China, and many other countries, including Argentina, Bulgaria, France, Hungary, Italy, and the United States. Artemisinin, the main bioactive component of the plant, was isolated and structurally correct in China in 1972 as a sesquiterpene lactone with an endoperoxide bridge. Artemisinin is currently used in China and Vietnam as an effective antimalarial drug against treatment-resistant strains of Plasmodium [48]. Despite its potent antimalarial action, artemisinin is chemically unstable, has low water solubility, a short half-life, and has poor pharmacokinetic characteristics. According to Satyavati et al., nano-coated Artemisinin pellets were created by employing a polyelectrolyte self-assembly method on natural drug crystals that are well distributed in an aqueous solution. Furthermore, the hydrophilicity of artemisinin crystals is enhanced [32]. Some research on the impacts of Artemisia nanocompounds is shown in Table 5.3. Mughees studies together with proteome analysis suggest that extract loaded NPs effectively inhibits cell proliferation and induce apoptosis and cell cycle arrest in both the breast cancer cell lines [23]. Furthermore, according to Mahdieh et al., when A. ciniformis extract is encapsulated in nanogels, it can suppress AGS cell-cell proliferation and block the G0/G1 phase cell cycle. When treated with alginate nanogel, apoptosis was induced in a time- and dose-dependent manner [27].

5.2.4 Silybum marianum—Silymarin For almost 200 years, Silybummarianum derivatives have been utilized as herbal remedies. Silybin is a powerful and important component of silymarin, a milk thistle extract. Silybin has several effects, including antioxidation and anticancer, that promote health. However, its exceedingly weak water solubility reduces the benefits. Therefore, silybin is limited in

86  Advances in Novel Formulations for Drug Delivery Table 5.3  Effect of Artemisia nanocompounds. Study

Active ingredients

Review of Indian council of medical research

Formulations

Biological activity

Ref

Artemisinin (Artemisia annua L.)

Nano-coated artemisinin by self-assembly procedure using polyelectrolyte on natural drug crystals

↑ distribution in aqueous solution improvement the hydrophilicity of artemisinin crystals

[32]

In vivo (the breast cancer cell lines MCF-7 & MDA MB-231 cell, MTT, and LDH assay)

A. absinthium extract

extract A.absinthium loaded polymeric nanoparticles (NPs)

Anti-breast cancer

[23]

In vivo (AGS cell line)

Artemisinin

Nanogel encapsulating A. ciniformis

Anticancer agent against AGS gastric cancer cells

[27]

its bioavailability and therapeutic effectiveness [46]. Two studies using nanoformulation of Silybum on beagle dogs are summarized in Table 5.4. Wang et al. tested liver tissue and blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (Tbil) following CCl4 poisoning on 18 random beagle dogs. According to the findings, silybin nanosuspensions (SN-A for intravenous treatment and SN-B for oral administration) protect hepatic cells against CCl4-induced acute liver damage [43]. The cold homogenisation process was used to produce solid lipid silymarin-­loaded nanoparticles (SLNSly). Trial beagle dogs found SLN to be an appropriate carrier for improving the oral bioavailability of silymarin [15]. In addition, Wang’s article reviews nearly all of the nanotechnology used in silybin delivery, including Table 5.4  Effect of Silybum marianum nanocompounds. Study

Active ingredients

Formulations

Biological activity

Ref

In vitro (beagle dogs)

Silybin

Solid lipid silymarinloaded nanoparticles (SLNSly)

Improve the oral bioavailability

[15]

In vitro (beagle dogs)

silymarin (Silybin)

Silybin nanosuspensions (for intravenous andoral administration)

Protect the hepatic cells against CCl4 induced acute liver injured

[43]

Drug Delivery for Medicinal Plants  87 nanodistributions, phosphatidylcholine complexes, NLCs, micelles, beta-cyclodextrin, SEDDS, MSNs, PAMAM dendrimers, solid and microdispersible formulations, and demonstrated the benefits and drawbacks of each formulation in terms of improving bioavailability, loading, and dissolution rates (see Table 5.5) [44]. Table 5.5  Biological effects of silymarin nanostructures. Formulations

Biological activity

Nanosuspensions

Increase the solubility, permeability, and bioavailability

Phosphatidylcholine complexes

- Improve the cisplatin antitumor activity (A silybin– phosphatidylcholine complex with a molar ratio of 1:1) - A dose of 13 g oral silybin–phytosome daily, divided into three doses, was shown to be well tolerated by patients with advanced prostate cancer. - Delay the spontaneous mammary tumor development, reduce the number and size of mammary tumor masses, and diminish lung metastasis in HER-2/neu transgenic mice. - Increase bioavailability, improve liver damage in cirrhosis, HCV chronic liver disease, nonalcoholic fatty liver.

Micelles

- Using the parenteral method to deliver micelles resulted in a prolonged drug circulation time (In vivo—micelles loaded with silybin–phosphatidylcholine complex.). - Silybin-polymeric micelles with a liver-targeted delivery capacity based on lactobionic acid (LA)-conjugated Pluronic P105

Beta-cyclodextrin (135 mg/d silybins per oz)

- Oral treatment of silybinbeta-cyclodextrin reduces plasma glucose and lipid levels significantly in patients with compensated chronic alcoholic liver disease and non-insulin-dependent diabetic mellitus (T2DM).

Self-emulsifying drug delivery systems (SEDDS)

- In vivo studies indicated that AUC0-12 h increased nearly threefold compared with conventional self-emulsifying formulations at a drug dose of 533 mg/kg, in the absence of HPMC. - Improve oral bioavailability.

Mesoporous silica nanoparticles (MSNs)

- Improved the bioavailability of silybin (Dissolution rate tests and animal experiments). - According to IVIVC, MSN in 0.08 M Na2CO3 solution has a value of R2 correlation coefficient of 0.9931, while MSN in artificial gastric juice and artificial intestinal juice is only 0.9287 and 0.7689 respectively.

Polyamidoamine (PAMAM) dendrimers

- Increase the water solubility of silybin. - Improved oral bioavailability (in vivo pharmacokinetic study, silybin-G2 PAMAM complex)

Solid dispersion

- Improve formulation permeability, increase solubility, increase the bioavailability of silybin (Silybin solid dispersion and PEG 6000)

Micronization

- Increased specific surface area to improve dissolution rate (spherical and rod-shaped silybin)

88  Advances in Novel Formulations for Drug Delivery

5.2.5 Salvia miltiorrhiza (Danshen) Salvia miltiorrhiza is said to have originated in China, and it has been and continues to be studied for a variety of therapeutic purposes, including increasing blood circulation, heart and blood vessel health, and cancer prevention. Je-Ruei Liu et al. studied the effects of S. miltiorrhiza root conventional and nanoproduct particles. According to the comparative results, Danshen powder produced with nanotechnology has greater antioxidant activity. Specifically, studies demonstrate an increase in DPPH radical scavenging capability and ferrous ion chelation [20]. According to Su’s research, coating Salviamiltiorrhiza nanoparticles with gelatin and CMC-Na improved bioavailability, dissolution rate, and drug release [36].

5.2.6 Glycyrrhiza glabra (L.) Glycyrrhiza glabra, also known aslicorice or sweetwood or Mulaithi belongs to Fabaceae, native to parts of Asia and Europe. G. glabra contains beta-glycyrrhetinic acid, which processes immunomodulatory properties and affects the level of component C2 [6]. G. glabra also contains glycyrrhizin, a compound that has antihyperglycemic effects [29]. Glycyrrhizin is a triterpene glycoside, a major active constituent obtained from the plant G. glabra. Rani et al. prepared glycyrrhizin-loaded nanoparticles via the ionotropic gelation method using the biocompatible polymers chitosan and gum arabic. These nanoparticles were tested in in vitro and in vivo models. The results show that in vitro release of glycyrrhizin nanoformulation was slow and sustained; the body weight and blood glucose levels of diabetic rats decreased significantly after 21 days using nanoformulation of glycyrrhizin [29]. G. glabra contains glabridin, an active constituent against both yeast and filamentous fungi [11]. In vitro studies of Roque et al. showed that the extract of G. glabra (the ethanol extract which is against Candida albicans the most) incorporated into mucoadhesive nanoparticles (PLA, PLGA, and alginate), the mean size of nanoparticles among 100 to 900 nm and the process was successed with high encapsulation efficiency [30].

5.2.7 Camellia sinensis (Green tea) Camellia sinensis is often prepared by steeping in hot water into a drink. They are common in China, Japan, and India [1]. Green tea is a good source of antioxidant polyphenols, in particular catechins, which constitute 30% of tea leaves’ dry weight. Green tea leaf extract can be utilized as a reducing agent in the anticancer and antibacterial production of Ag nanoparticles and Ag/GO compounds [10]. Furthermore, Table 5.6 also shows a number of the impacts of green tea leaf extract nanocompositions. Hidayat Sulistyo et al. have demonstrated that the effects of green-tea nanoparticles have similar effects to deferoxamine—a medication that helps to eliminate the excess iron from the body in thalassemia in a study in the ionized rat model. Green tea nanoparticles were created in the study using chitosan-coated magnetite at a dose of 3 mg/kg/day. Green tea nanoparticles may be coupled with an iron chelator without losing their iron chelation capacity. This combination has the potential to increase the efficacy and minimize the toxicity of iron chelation [37]. Five individuals were chosen at random to collect overnight developed biofilms from their teeth with sterile toothbrushes in the morning. The nanoparticles exhibited a stronger antibacterial impact on the oral cavity, according to fluorescence imaging [12].

Drug Delivery for Medicinal Plants  89

Table 5.6  Summary of the effects of other plant nanoformulations. Plant

Study

Active ingredients

Formulations

Biological activity

Ref

Salvia miltiorrhiza (Danshen)

Comparative study

Radix S. miltiorrhiza (acid salvianolic B) 

Danshen powder prepared by nanotechnology

- ↑ antioxidant bioactivity - ↑ DPPH radical scavenging power - ↑ ferrous ion chelation

[20]

In vitro

Radix S. miltiorrhiza

Encapsulated withgelatin and CMC-Na

- Improve the bioavailability and the dissolution rate. - Regulate drug release

[36]

In vivo (mice induced by nicotinamide and streptozocin) + in vitro drug release study

Glycyrrhizin-loaded nanoparticles

Chitosan nanoparticles (in vivo 20 and 40 mg/kg)

- Slow and sustained release

[29]

In vitro

Extract of G. glabra

Mucoadhesive nanoparticles (PLA, PLGA and alginate)

- Against Candida albicans

[30]

In vitro (Rattus norvegicusfemales, ironized mouse model)

Polyphenol (catechin) epigallocatechin gallate

Chitosan-coated magnetite. (3 mg/kg/ day, oral for 66 days)

- Depleting the state of hemosiderosis - Effect comparable to deferoxamine

[37]

Clinical (5 healthy volunteers)

Green tea extracts

Nano-sized particles

- ↑ oral antibacterial

[12]

In vitro (male Wistar)

2.5 mg CPT eq./ kg 3 days

CPT-loaded nanoparticles (using PLA/ (PEG-PPG-PEG)

- ↑ water solubility, ↑ dose retention in body

[18]

Glycyrrhiza glabra (L.)

Camellia sinensis (green tea)

Camptotheca acuminata

In vivo (Sarcoma 180 cells)

(Continued)

90  Advances in Novel Formulations for Drug Delivery

Table 5.6  Summary of the effects of other plant nanoformulations. (Continued) Plant

Study

Active ingredients

Formulations

Biological activity

Ref

Leea indica

In vitro

Acid gallic

PLGA nanoparticles

- ↓ cytotoxicity, ↑ pharmacodynamics

[21]

Ziziphus mauritiana

In vitro (Swiss albino mice with reduced immune systems)

Leaf extract

Chitosan nanoparticles, 3 mg/day, 21 days

The immune response is much stronger than when using only plant extracts.

[7]

Cuscuta chinensis

In vivo (male Wistaralbino rats induced by acetaminophen

C. chinensis ethanolic extract

C. chinensis ethanolic extract nanoparticles

- ↑ solubility& activity

[47]

Drug Delivery for Medicinal Plants  91

5.2.8 Camptotheca acuminata Camptotheca acuminata, a member of the Nyssaceae family, is endemic to China. It has a long history of usage as a decorative and medicinal plant. C. acuminata has recently gained prominence due to its high amount of camptothecins (CPT), a natural secondary metabolite that has demonstrated exceptional benefits in anti-tumor, immune-deficient disease resistance, in its various sections [19]. However, it has low aqueous solubility and is acute toxicity. According to Ryotaro Kunii., using poly(dl-lactic acid) and poly(ethylene glycol)-blockpoly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG) and by means of the self-assembly methods, CPT-loaded nanoparticles were made. These nano-loaded CPTs have greater solubility in water, a larger body dosage retention capacity, as well as working at lower levels [18].

5.2.9 Leea indica Leea indica, an evergreen large shrub that belongs to Leeaceae family, is locally known as Kukur jiwa, Achila gach or Arengi. They grow in disturbed areas of lowland and upland rain forest in Asia Pacific islands, especially in Bangladesh [28]. L. indica contains gallic acid which has antiacanthamoebic potential. Gallic acid (100 µg/ml) inhibited 83% trophozoites and 69% cysts. This component was successfully loaded within poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles with 82.86% encapsulation efficiency. These PLGA nanoparticles inhibited against 90% trophozoites and the cytotoxicity toward MRC-5 also reduced [21].

5.2.10 Ziziphus mauritiana (Malay apple) Ziziphus mauritiana is a medicinally valuable fruit that is extensively spread in India. The root is used to treat cough and headaches while acne and dysentery are treated with bark according to eastern medicine. The leaves cool, while the fruit is used to aid digestion and treat tuberculosis. The seeds are used to treat eye disorders, leukaemia, and as a tonic for the heart and brain. The seeds also contribute to calming hunger, have hypnotic and sedative properties, and are useful for insomnia, weaknesses, pains, and rheumatism [22]. In a recent study, chitosan was utilized as an eco-friendly nanocarrier to transport Z. mauritiana leaf extract containing different medicinal components. The leaf of Z. mauritiana has been shown to modulate immunological response. To assess the restorative activity of this phytochemical, chitosan nanocapsules containing Z. mauritiana leaf extract were administered to previously hydrocortisone-treated Swiss albino mice with reduced immune systems. The findings revealed a substantial improvement in the host’s immune response following oral administration of the developed medication [7].

5.2.11 Cuscuta chinensis Cuscuta chinensis Lam also known as Chinese dodder is a parasitic plant belonging to Convolvulaceae. It has been widely used in China, Korea, Pakistan, Vietnam, India, and Thailand as a traditional medicine because of its anti-aging effect, anti-inflammatory effect, pain reliever and aphrodisiac effects [9, 47]. C. chinensis is also famous for nourishing the

92  Advances in Novel Formulations for Drug Delivery liver and kidney, but this effect is limited by the poor solubility of major constituents, such as flavonoids and lignans. Therefore, Yen et al. used the nanosuspension method to prepare C. chinensis ethanolic extract nanoparticles. The nanoparticles. The test was conducted on mice with liver damage caused by acetaminophen, one group was treated with nanoparticles with a dose of 50 mg C. chinensis extract, the other group was used an ethanolic extract of C. chinensis at a dose of 125 mg/kg. The results show that the hepatoprotective and antioxidant of the nanoparticles group was more effectively better than the other one, superoxide dismutase, catalase, glutathione peroxidase increased significantly and malondialdehyde reduced. The authors claim that the nanoparticles system can be applied to overcome other water poorly soluble herbal medicines and to decrease the treatment dosage [47].

5.3 Conclusion Nanosized drug delivery systems for herbal drugs have the potential to improve biological activity while overcoming issues associated with plant medicines. Formulating herbal drugs in nanocarriers would be a viable guide for the progression of the core cure and a promising suggestion for many pathological diseases. There are, however, significant hurdles to the deployment of clinically effective therapies in this sector, and more extensive research is necessary to respond quickly to pathological therapeutic demands.

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Drug Delivery for Medicinal Plants  93 9. Donnapee, S., Li, J., Yang, X., Ge, A., Donkor, P.O., Gao, X., Chang, Y., Cuscuta chinensis Lam.: A systematic review on ethnopharmacology, phytochemistry and pharmacology of an important traditional herbal medicine. J. Ethnopharmacol., 157, 292–308, 2014. https://doi. org/10.1016/j.jep.2014.09.032. 10. Jeronsia, J.E., Ragu, R., Sowmya, R., Mary, A.J., Das, S.J., Comparative investigation on Camellia Sinensis mediated green synthesis of Ag and Ag/GO nanocomposites for its anticancer and antibacterial efficacy. Surf. Interfaces, 21, 100787, 2020. https://doi.org/10.1016/j. surfin.2020.100787. 11. Fatima, A., Gupta, V.K., Luqman, S., Negi, A.S., Kumar, J.K., Shanker, K., Khanuja, S.P., Antifungal activity of Glycyrrhiza glabra extracts and its active constituent glabridin. Phytother. Res., 23, 8, 1190–1193, 2009. 12. Gopal, J., Muthu, M., Paul, D., Kim, D.-H., Chun, S., Bactericidal activity of green tea extracts: The importance of catechin containing nano particles. Sci. Rep., 6, 19710, 2016. 13. Haghighi, P., Ghaffari, S., Bidgoli, S.A., Qomi, M., Haghighat, S., Preparation, characterization and evaluation of Ginkgo biloba solid lipid nanoparticles. Nanomed. Res. J., 3, 2, 71–78, 2018. 14. Han, L., Fu, Y., Cole, A.J., Liu, J., Wang, J., Co-encapsulation and sustained-release of four components in ginkgo terpenes from injectable PELGE nanoparticles. Fitoterapia, 83, 4, 721–731, 2012. 15. He, J., Feng, J.F., Zhang, L.L., Lu, W.G., Hou, S.X., [Freeze-drying of silymarin-loaded solid lipid nanoparticles (SM-SLN)]. Zhongguo Zhong Yao Za Zhi, 30, 2, 110–112, 2005. 16. Kim, T.H., Jiang, H.H., Youn, Y.S., Park, C.W., Tak, K.K., Lee, S., Lee, K.C., Preparation and characterization of water-soluble albumin-bound curcumin nanoparticles with improved antitumor activity. Int. J. Pharm., 403, 1, 285–291, 2011. https://doi.org/10.1016/j.ijpharm.2010.10.041. 17. Kovacevic, A., Savic, S., Vuleta, G., Müller, R.H., Keck, C.M., Polyhydroxy surfactants for the formulation of lipid nanoparticles (SLN and NLC): Effects on size, physical stability and particle matrix structure. Int. J. Pharm., 406, 1, 163–172, 2011. 18. Kunii, R., Onishi, H., Machida, Y., Preparation and antitumor characteristics of PLA/(PEGPPG-PEG) nanoparticles loaded with camptothecin. Eur. J. Pharm. Biopharm., 67, 1, 9–17, 2007. 19. Li, S., Yi, Y., Wang, Y., Zhang, Z., Beasley, R.S., Camptothecin accumulation and variations in camptotheca. Planta Med., 68, 11, 1010–1016, 2002. 20. Liu, J.R., Chen, G.F., Shih, H.N., Kuo, P.C., Enhanced antioxidant bioactivity of Salvia miltiorrhiza (Danshen) products prepared using nanotechnology. Phytomedicine, 15, 1–2, 23–30, 2008. 21. Mahboob, T., Nawaz, M., de Lourdes Pereira, M., Tan, T.-C., Samudi, C., Sekaran, S.D., Nissapatorn, V., PLGA nanoparticles loaded with Gallic acid-a constituent of Leea indica against Acanthamoeba triangularis. Sci. Rep., 10, 1, 8954, 2020. 22. Mishra, T., Paice, A.G., Bhatia, A., Chapter 87-Use of seeds of malay apple (Ziziphus mauritiana) and related species in health and disease, in: Nuts and Seeds in Health and Disease Prevention, V.R. Preedy, R.R. Watson, V.B. Patel (Eds.), pp. 733–739, Academic Press, San Diego, 2011. 23. Mughees, M. and Wajid, S., Artemisia absinthium nanoparticles induce apoptosis in breast cancer cells via inhibiting vesicular trafficking related proteins. Ann. Oncol., 30, vii9, 2019. 24. Mulik, R.S., Monkkonen, J., Juvonen, R.O., Mahadik, K.R., Paradkar, A.R., ApoE3 mediated poly(butyl) cyanoacrylate nanoparticles containing curcumin: Study of enhanced activity of curcumin against beta amyloid induced cytotoxicity using in vitro cell culture model. Mol. Pharm., 7, 3, 815–825, 2010. 25. Müller, R.H., Radtke, M., Wissing, S.A., Nanostructured lipid matrices for improved microencapsulation of drugs. Int. J. Pharm., 242, 1, 121–128, 2002. https://doi.org/10.1016/ S0378-5173(02)00180-1.

94  Advances in Novel Formulations for Drug Delivery 26. Neuberger, T., Schöpf, B., Hofmann, H., Hofmann, M., von Rechenberg, B., Superparamagnetic nanoparticles for biomedical applications: Possibilities and limitations of a new drug delivery system. J. Magn. Magn. Mater., 293, 1, 483–496, 2005. 27. Rahimivand, M., Tafvizi, F., Noorbazargan, H., Synthesis and characterization of alginate nanocarrier encapsulating Artemisia ciniformis extract and evaluation of the cytotoxicity and apoptosis induction in AGS cell line. Int. J. Biol. Macromol., 158, 338–357, 2020. 28. Rahman, M.A., Imran, T.B., Islam, S., Antioxidative, antimicrobial and cytotoxic effects of the phenolics of Leea indica leaf extract. Saudi J. Biol. Sci., 20, 3, 213–225, 2013. 29. Rani, R., Dahiya, S., Dhingra, D., Dilbaghi, N., Kim, K.-H., Kumar, S., Evaluation of anti-­ diabetic activity of glycyrrhizin-loaded nanoparticles in nicotinamide-streptozotocin-induced diabetic rats. Eur. J. Pharm. Sci., 106, 220–230, 2017. https://doi.org/10.1016/j.ejps.2017.05.068. 30. Roque, L., Duarte, N., Bronze, M.R., Garcia, C., Alopaeus, J., Molpeceres, J., Reis, C., Development of a bioadhesive nanoformulation with Glycyrrhiza glabra L. extract against Candida albicans. Biofouling, 34, 8, 880–892, 2018. 31. dos Santos Giuberti, C., de Oliveira Reis, E.C., Rocha, T.G.R., Leite, E.A., Lacerda, R.G., Ramaldes, G.A., de Oliveira, M.C., Study of the pilot production process of long-circulating and pH-sensitive liposomes containing cisplatin. J. Liposome Res., 21, 1, 60–69, 2011. 32. Satyavati, G.V., Raina, M.K., Sharma, M., Medicinal Plants of India (Vol. 2), Indian Council of Medical Research, 1987. 33. Shaikh, J., Ankola, D.D., Beniwal, V., Singh, D., Kumar, M.N.V.R., Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer. Eur. J. Pharm. Sci., 37, 3, 223–230, 2009. https://doi.org/10.1016/j.ejps.2009.02.019. 34. Silva, R., Ferreira, H., Cavaco-Paulo, A., Sonoproduction of liposomes and protein particles as templates for delivery purposes. Biomacromolecules, 12, 10, 3353–3368, 2011. 35. Singh, B., Kaur, P., Gopichand, R.D.S., Ahuja, P.S., Biology and chemistry of Ginkgo biloba. Fitoterapia, 79, 6, 401–418, 2008. https://doi.org/10.1016/j.fitote.2008.05.007. 36. Su, Y., Wang, H., Zhang, J., Wang, W., Wang, H., Wang, Y., Zhang, Q., Microencapsulation of Radix salvia miltiorrhiza nanoparticles by spray-drying. Powder Technol., 184, 114–121, 2008. 37. Sulistyo, H., Kurniawan, D.W., Rujito, L., Biochemical and histopathological effects of green tea nanoparticles in ironized mouse model. Res. Pharm. Sci., 12, 2, 99–106, 2017. 38. Sun, M., Su, X., Ding, B., He, X., Liu, X., Yu, A., Zhai, G., Advances in nanotechnology-based delivery systems for curcumin. Nanomedicine, 7, 7, 1085–1100, 2012. 39. Takahashi, M., Uechi, S., Takara, K., Asikin, Y., Wada, K., Evaluation of an oral carrier system in rats: Bioavailability and antioxidant properties of liposome-encapsulated curcumin. J. Agric. Food Chem., 57, 19, 9141–9146, 2009. 40. Torchilin, V., Multifunctional pharmaceutical nanocarriers: Development of the concept, in: Multifunctional Pharmaceutical Nanocarriers, pp. 1–32, Springer, 2008. 41. Uner, M. and Yener, G., Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int. J. Nanomedicine, 2, 3, 289–300, 2007. 42. Wang, T., Zhang, D., Sun, D., Gu, J., Current status of in vivo bioanalysis of nanodrug delivery systems. J. Pharm. Anal., 10, 3, 221–232, 2020. https://doi.org/10.1016/j.jpha.2020.05.002. 43. Wang, Y., Wang, L., Liu, Z., Zhang, D., Zhang, Q., In vivo evaluation of silybin nanosuspensions targeting liver. J. Biomed. Nanotechnol., 8, 5, 760–769, 2012. 44. Wang, Y., Zhang, L., Wang, Q., Zhang, D., Recent advances in the nanotechnology-based drug delivery of Silybin. J. Biomed. Nanotechnol., 10, 4, 543–558, 2014. 45. Wilczewska, A.Z., Niemirowicz, K., Markiewicz, K.H., Car, H., Nanoparticles as drug delivery systems. Pharmacol. Rep., 64, 5, 1020–1037, 2012.

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6 Nanosystems Trends in Nutraceutical Delivery Aristote Buya

*

University of Kinshasa, Faculty of Pharmaceutical Sciences, Pharmaceutics and Phytopharmaceutical Drug Development Research Group, BP 212 Kinshasa XI, Democratic Republic of the Congo

Abstract

Nutraceuticals have been widely studied for their potential to improve health outcomes and prevent various diseases. Although having shown several health benefits and functions, most nutraceuticals are poorly water-soluble, unstable in the gastrointestinal environment, and have low oral bioavailability. Recent advances in the food industry have incorporated nanosystems to overcome the drawbacks associated with nutraceuticals. Nanosystems are gaining more and more attention in enhancing the health benefits of nutraceuticals. Due to the reduction in particle size, nanosystems have shown significant potential to improve the aqueous solubility, gastrointestinal stability, and oral bioavailability of nutraceuticals. This chapter focuses on the drawbacks associated with nutraceuticals and presents different nanosystems (lipid, polymeric, or inorganic) that have been used to improve their biopharmaceutical and health properties. Keywords:  Nutraceuticals, foods, nanosystems, nanoformulations, drug delivery, aqueous solubility, oral bioavailability

6.1 Introduction The change in lifestyle has led to an upsurge in diseases such cardiovascular diseases and type 2 diabetes [1]. Simultaneously, people awareness of the intimate link between these diseases and dietary habits has grown. Consumers are increasingly aware of the quality of the food they consume and are interested in meals that can improve their health and prevent the onset of dangerous diseases. As a result, there is an increase in nutraceutical consumption due to their ability to reduce the risk of many diseases. All of these aspects have prompted researchers to deepen their knowledge on the health benefits of nutraceuticals and food industry is encouraged to produce new products that would attract the attention of customers [2]. Nutraceuticals (a term that combines “nutrition” and “pharmaceutical”) are foods or their extracts that have been shown to improve human health and prevent diseases [3]. They are required compounds in addition to the basic nutrients that we get from our regular Email: [email protected]

*

Raj K. Keservani, Rajesh Kumar Kesharwani and Anil K. Sharma (eds.) Advances in Novel Formulations for Drug Delivery, (97–126) © 2023 Scrivener Publishing LLC

97

98  Advances in Novel Formulations for Drug Delivery meals. They can contain food supplements, plant-based products, nutrients extracted from mixtures, genetically modified foods, and processed meals, such as cereals, beverages, cereals, and soups [4]. Nutraceuticals also include concentrated substances of various groups, such as fibers, amino acids, minerals, fats, and probiotics [5]. All these substances have an effect on different organs and systems of the human body, either directly (by replenishing required or missing compounds) or indirectly (by interacting with cells and tissues) [6–9]. They are mostly used to prevent diseases or as supplements for nutrients that are difficult to acquire from regular meals. Currently, the market offers a wide range of nutraceuticals, ranging from low cost everyday products to high cost combinations indicated for specific diseases. People are spending more money on healthy food, which is increasing the global nutraceutical market [10]. According to a report published by Transparency Market Research in September 2015, the global market of nutraceuticals was US $ 165.62 billion in 2014, with a compound annual growth rate (CAGR) of 7.3% from 2015 to 2021, and is expected to reach US $ 278.96 billion by the end of 2021 [11]. However, the majority nutraceuticals suffer from insufficient in vivo efficacy due to their low aqueous solubility and oral bioavailability [12, 13]. Furthermore, most of them exhibit poor gastrointestinal stability and hepatic first-pass metabolism [14, 15]. Nowadays, several innovative techniques have been developed to improve the biopharmaceutical properties of nutraceuticals. Among them, nanosystems are gaining a lot of attention in improving the health benefits of nutraceuticals. Nanosystems can provide numerous benefits, such as increased aqueous solubility and oral bioavailability, controlled-release and targeted delivery of encapsulated bioactive compounds, which result in increased biological efficacy [16]. Most of nanosystems are cost-effective and made of nontoxic biodegradable components, which are desirable characteristics for the food industry [17]. Therefore, the present chapter aims to review different types of nanosystems that have recently been used to improve the benefits of nutraceuticals, with an emphasis on how nanotechnology can improve their effects.

6.2 Classification of Nutraceuticals Nutraceuticals are classified according to food source, chemical nature and mechanism of action. Commonly studied nutraceuticals are presented in Table 6.1, and their main categories are described below. (i) Natural nutraceuticals: they are acquired directly from nature and are used in their original form (e.g., lycopene in tomatoes and omega-3 fatty acids present in cod liver oil). They can be subdivided into four subgroups: nutrients, phytochemicals, probiotic microorganisms and minerals. –– Nutrients: this subgroup contains vitamins, amino acids and fatty acids that play key roles in metabolic reactions. The main sources of nutrients are fruits, vegetables, eggs, milk, cheeses, meats and oils. Nutrients are involved in many physiological functions and their deficiency can lead to several diseases. For example, vitamin C is necessary for collagen synthesis, therefore its

Nanosystems Trends in Nutraceutical Delivery  99 Table 6.1  Common nutraceuticals and their health benefits. Nutraceutical

Health benefits/application

Reference

Silymarin

Antioxidant, hepatoprotective, free radical scavenger

[40, 41]

Omega-3

Antioxidant, lowers risk of heart diseases

[42, 43]

β-carotene and α-carotene

Antiaging, antioxidant, prevents heart diseases

[44, 45]

Quercetin

Antioxidant, anti-inflammatory, decreases blood lipids

[46, 47]

Naringenin

Antioxidant, hepatoprotective, anti-inflammatory

[48, 49]

Puerarin

Antioxidant, bone formation, reduces cholesterol levels

[50, 51]

Curcumin

Anticancer, anti-inflammatory, prevents neurological and heart diseases

[52, 53]

Epigallocatechin gallate

Prostate cancer, pancreatic cancer, atherosclerosis

[54, 55]

Capsaicin

Anti-inflammatory, breast cancer, colon cancer, leukemia

[56, 57]

Lutein

Antioxidant, improves vision

[58, 59]

Lycopene

Antioxidant, anti-inflammatory, prostate cancer

[60, 61]

Coenzyme Q10

Antioxidant, prevents heart diseases

[62, 63]

Resveratrol

Antioxidant, anticancer, lowers LDL and increases HDL

[64, 65]

β-lapachone

Antioxidant, colon cancer, breast cancer

[66, 67]

Eugenol

Anti-inflammatory, liver cancer

[68, 69]

Ellagic acid

Bladder cancer, colorectal cancer, melanoma

[70, 71]

Dihydroartemisinin

Breast cancer, ovarian cancer, malaria

[72, 73]

Daidzein

Breast cancer, cardiovascular diseases

[74, 75]

Thymoquinone

Leukemia, glioblastoma, osteosarcoma

[76, 77]

Genistein

Lung cancer, cervical cancer, prostate cancer

[78, 79]

Retinol (vitamin A)

Anti-inflammatory, improves vision, increases immunity

[80, 81]

Triptolide

Breast cancer, pancreatic cancer

[82, 83]

Cholecalciferol (vitamin D)

Calcium metabolism, absorption of phosphorus

[84, 85]

Honokiol

Liver cancer, breast cancer

[86, 87]

Tocopherol (vitamin E)

Antioxidant, reduces risk of breast and prostate cancer

[88, 89]

Ursolic acid

Bladder carcinoma, melanoma, lung cancer

[90, 91]

Phytonadione (vitamin K)

Blood clotting, regulates calcium levels

[92, 93]

Myricetin

Antioxidant, anticarcinogen, antiartherosclerotic

[94, 95]

100  Advances in Novel Formulations for Drug Delivery deficiency can cause increased bleeding and reduced strength of the fibrous apparatus of the tooth (oscillation, loss of teeth) [17]. Omega-3 fatty acids improve the immune system, have an anti-inflammatory effect and a positive effect on the development of the central nervous system [18, 19]. –– Phytochemicals: they are secondary metabolites of plants that have been clinically proven to prevent diseases like diabetes, heart and kidney problems. The most studied phytochemicals include carotenoids [20, 21], flavonoids [22, 23], alkaloids [24, 25], terpenoïds [26, 27], tannins [28, 29] and saponins [30, 31]. For example, carotenoids found in legumes like chickpeas and soybeans can lower cholesterol levels and have the potential to kill cancer cells [32]. They also increase the immune system [32]. The tannin content of lavender (Lavandula angustifolia) shows the ability to reduce stress, lower blood pressure, and treat lung diseases such as asthma [13]. –– Probiotic microorganisms: they play a vital role in the gut when it comes to processes like absorption and metabolism, because they make the intestine more conductive to these activities. Probiotics work by eradicating the toxic flora that lodges inside the intestine. Human diseases can be cured by a variety of probiotic products available on the market, as they contain enough nutrients to restore physiological balance. For example, the helpful consumption of Bacillus bulgaricus in infection diseases [33]. Probiotics make the epithelial cells more anchored in the gut, helping food and bioactive compounds to cling better, which is important for their absorption. They are also useful for people who are lactose intolerant, as they provide β-galactosidase, which hydrolyzes lactose into its sugar components [34]. –– Minerals: they are elements found on the earth and in food that our bodies require to develop and function normally. The needed minerals are known as essential minerals. Essential minerals are divided into major minerals and trace elements. Major minerals include sodium, chloride, potassium, calcium, phosphorus, magnesium and sulfur while trace elements include iron, zinc, iodine, selenium, copper, manganese, fluoride, chromium, and molybdenum [35]. These two categories of minerals are equally important, although trace elements are required in lesser quantities than the major minerals. The quantity required in the body is not indicative of their importance. (ii) Nonnatural nutraceuticals: these are modified foods or crops that have a much higher nutrient content than ordinary foods. They can be classified as follows: –– Fortified nutraceuticals: compatible nutrients are added to the primary ingredients such as milk fortified with cholecalciferol in order to treat deficiency of vitamin D, flour fortified with calcium, minerals added to cereals [36]. –– Recombinant nutraceuticals: these are foods (e.g., cheese, bread) that are biotechnologically modified to develop products containing recombinant compounds and proteins that would make them more beneficial to health [37]. For example, golden kiwifruit contains a recombinant gene that increases levels of carotenoid, lutein, and ascorbic acid to improve immune function. In addition, it is considered a source of potassium, vitamins, and fiber [38, 39].

Nanosystems Trends in Nutraceutical Delivery  101

6.3 Biopharmaceutical Issues Associated with Nutraceuticals Nutraceuticals can only affect biological processes if they can reach systemic circulation. The common problems associated with them are low aqueous solubility and oral bioavailability. It is a known fact that the fate of bioactive substances ingested orally relies on their solubilization in the gastrointestinal fluid. As the gastrointestinal fluid consists primarily of water, oral administration of a poorly water-soluble nutraceuticals is questionable. In fact, the majority of nutraceuticals are classified as Biopharmaceutics Classification System (BCS) II and IV, indicating low aqueous solubility and membrane permeability [96]. The literature reports that the aqueous solubility of a bioactive is directly related to gastrointestinal dissolution, which in turn correlates with the oral bioavailability [97]. Further, the oral delivery of nutraceuticals can also be associated with precipitation, food and drug interactions, susceptibility to degradation, and first-pass metabolism, leading to low oral bioavailability [97]. Many nutraceuticals, such as curcumin, silymarin, lycopene, rutin, quercetin, and resveratrol, are unable to show their full therapeutic potential due to their low aqueous solubility; in vivo stability issues and poor oral bioavailability [98, 99]. Thus, the development of innovative formulations that provide the desired biopharmaceutical properties to nutraceuticals remains important.

6.4 Nanosystems for Delivery of Nutraceuticals Nanosystems for drug delivery are products of nanotechnology with particle size ranging from 100 to 300 nm [100, 101]. The advancement of pharmaceutical nanotechnology has led to a novel class of nanosystems known as nanonutraceuticals, which are defined as nanosystems loaded with nutraceuticals [102]. Due to reduction in particle size, nanonutraceuticals have showed a significant potential in improving the aqueous solubility, stability and oral bioavailability of nutraceuticals. Nanosystems (lipid or polymeric) that have been studied for the delivery of nutraceuticals are described below and Table 6.2 and Figure 6.1 summarize them.

6.4.1 Nanoemulsions Nanoemulsions are nanosystems composed of an oily and aqueous phase, stabilized by a surfactant and a cosurfactant or cosolvent [103]. The particle size of a nanoemulsion is less than 200 nm. Water-in-oil (w/o) and oil-in-water (o/w) nanoemulsions are suitable carriers for nutraceuticals, as they can improve the efficacy of both hydrophilic and hydrophobic food compounds [104–106]. Quagliariello et al. used nanoemulsion for the delivery Coenzyme Q10, a nutraceutical acting as antioxidant, anti-inflammatory with cardioprotective properties. The study aimed to protect cardiomyocytes and hepatocytes from the toxic effects of doxorubicin, a strong antineoplastic agent. The formulated nanoemulsions showed high drug loading, good stability, and increased cell viability in both cardiomyocytes and hepatocytes during anticancer treatment [107].

102  Advances in Novel Formulations for Drug Delivery Table 6.2  Nanosystems for improved nutraceutical properties. Nanosystem

Nutraceutical

Research finding

Reference

Nanoemulsions

Vitamin A, D, E, K

Improved oral absorption

[159]

Berberine

Improved oral bioavailability and efficacy

[160]

Polymethoxyflavones

Improved oral absorption

[161]

Fish oil

Enhanced intestinal absorption

[162]

Puerarin

Improved nasal absorption

[163]

Coenzyme Q10

Enhanced pharmacokinetics

[164]

Capsaicin

Improved oral absorption

[165]

Lycopene

Improved aqueous solubility

[166]

Resveratrol

Enhanced oral absorption

[167]

Silymarin

Improved solubility and oral bioavailability

[168]

α-tocopherol

Enhanced oral bioavailability

[169]

β-carotene

Enhanced oral bioavailability

[170]

Rutin

Improved solubility and mucus permeability

[171]

Ferulic acid

Improved oral bioavailability

[172]

β-carotene

Improved intestinal permeation

[173]

Resveratrol

Enhanced dissolution and hypolipidemic activity

[174]

Curcumin

Enhanced intestinal permeation

[175]

Quercetin

Improved bioavailability and antioxidant activity

[176]

Genistein

Enhanced dissolution and intestinal permeation

[177]

Dihydromyricetin

Better in vitro release

[178]

Carvedilol

Enhanced oral bioavailability and activity

[179]

6-shogaol

Enhanced oral bioavailability

[180]

Papain

Improved mucolytic effect

[181]

SEDDS

(Continued)

Nanosystems Trends in Nutraceutical Delivery  103 Table 6.2  Nanosystems for improved nutraceutical properties. (Continued) Nanosystem

Nutraceutical

Research finding

Reference

SLNs

Resveratrol

Improved oral absorption

[125]

Lycopene

Improved stability

[182]

β-carotene

Improved stability

[183]

Camptothecin

Improved biodistribution

[184]

Curcumin

Improved permeability

[185]

Fish oil

Improved stability

[186]

Lutein

Improved solubility and stability

[187]

Curcumin

Enhanced bioavailability and anxiolytic activity

[188]

Carotenoids

Improved bioaccessibility

[189]

Melatonin

Improved bioavailability

[190]

Quercetin

Enhanced stability and permeability

[191]

Curcumin

Improved bioavailability and antioxidant activity

[192]

(+)- Catechin

Improved bioavailability and brain distribution

[193]

Docosahexaenoic acid

Improved activity

[194]

Resveratrol

Improved stability and provided sustained release

[195]

β-carotene

Provided sustained release

[196]

Lutein

Improved solubility and cell uptake

[197]

Naringenin

Improved hepatoprotective effects

[198]

Coenzyme Q10

Improved stability and antioxidant activity

[199]

Cascuta chinensis

Improved efficacy

[200]

Betulinic acid

Extended the blood circulation

[201]

NLCs

Liposomes

Polymeric nanoparticles

(Continued)

104  Advances in Novel Formulations for Drug Delivery Table 6.2  Nanosystems for improved nutraceutical properties. (Continued) Nanosystem

Inorganic nanoparticles

Nutraceutical

Research finding

Reference

Emodin

Provided sustained release

[202]

Curcumin

Improved activity

[203]

Ursolic acid

Enhanced in vitro cytotoxicity

[204]

Thymoquinone

Enhanced in vitro cytotoxicity

[205]

Simvastatin

Enhanced in vivo activity

[206]

Resveratrol

Enhanced anticancer activity

[207]

Quercetin

Enhanced in vitro cytotoxicity

[208]

Honokiol

Enhanced in vitro cytotoxicity

[209]

Apigenin

Enhanced activity

[210]

Gambogenic acid

Enhanced in vitro cytotoxicity

[211]

Epigallocatechin-3gallate

Enhanced selectivity towards cancer cells

[212]

Plumbagin

Enhanced activity

[213]

Sulforaphane

Enhanced in vitro cytotoxicity

[214]

Foods

H Nutraceuticals

CH2

CH

NH2

OH

H

CH

CH

HO

HO

NH + 3

OH

OH

Nanosystems NE/SEDDS

SLN

NlC

Liposome

PNP

INP

Figure 6.1  Food source and nanosystems for nutraceuticals delivery. NE, nanoemulsion; PNP, polymeric nanoparticle; INP, inorganic nanoparticle. Figure created with Biorender.

Nanosystems Trends in Nutraceutical Delivery  105 The oral bioavailability of astaxanthin, a carotenoid with several health benefits, was improved when encapsulated in nanoemulsions. Three long chain triglycerides: olive oil, corn oil, and flaxseed oil were used for the formulation. The authors demonstrated how the nanoemulsions, especially those containing olive oil increased the oral bioavailability of astaxanthin [108]. Curcumin, a yellow chemical compound found in the rhizomes of turmeric plant, needs a carrier to reach and efficiently affect organs and other areas of the body. Nanoemulsions of curcumin were formulated and evaluated in mice. Those nanoemulsions significantly increase the oral bioavailability of curcumin [109]. Recently, Chang et al. used ultra-high-pressure homogenization technique to prepare a nanoemulsion of the oil extracted from the pulp of sea buckthorn. The formulation was stabilized with sodium caseinate and whey protein isolates. The in vitro test showed a high antioxidant activity and good stability of the encapsulated oil [110].

6.4.2 Self-Emulsifying Systems Although nanoemulsions are stable systems, their applications are limited due to problems such as poor palatability and drug hydrolysis during the storage [97, 111]. The introduction of self-emulsifying systems (SEDDS) alleviated the problems associated with nanoemulsions. They are defined as isotropic mixtures of oils, surfactants, and cosurfactants or cosolvents that spontaneously form an nanoemulsion with droplet size of 200 nm or less when exposed to gastrointestinal fluids [112]. SEDDS have shown several benefits in the delivery of nutraceuticals, including high drug loading, better absorption, and reduced dose variability [113]. Ogino et al. used SEDDS to enhance the oral bioavailability of ginger extract. The formulated SEDDS improved the dissolution and relative bioavailability of 6-gingerol and 8-gingerol compared to the pure extract. In addition, the formulations provided a hepatoprotective effect in a rat model [114]. (R)-α-lipoic acid (RLA) was encapsulated in SEDDS to improve its physicochemical and nutraceutical properties. The in vivo studies in rats demonstrated an increased (seven-fold) in systemic exposure compared to the free RLA. Improvement in systemic exposure has been attributed to an improved gastric dissolution and stability [115]. Onoue et al. developed solid SEDDS to increase the photostability and oral bioavailability of coenzyme Q10. The authors demonstrated that the formulated SEDDS was less photoreactive and increased the oral bioavailability of coenzyme Q10 compared to crystalline form [116].

6.4.3 Solid Lipid Nanoparticles and Nanostructured Lipid Carriers Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are two lipid-­ based nanosystems that have found considerable use in the food and nutraceutical industries [117, 118]. SLNs usually have mean particle size in the range of 50 to 100 nm and are composed of solid lipids, which are stabilized by a surfactant [119]. SLNs have many advantages, including high loading capacity for lipophilic drugs, high drug stability and good ability to control the release of drugs [120]. In the presence of melted lipids; however, drug loading capacity can be reduced, leading to lipid core ejection during phase transition.

106  Advances in Novel Formulations for Drug Delivery Thus, the components of SLNs must be chosen according to their physicochemical properties and the nature of the nutraceutical to be encapsulated. Mehrad et al. have demonstrated that the effectiveness of SLNs in nutraceutical delivery is strongly dependent on their excipients [121]. NLCs were developed to address the instability issues associated with SLNs. Compared to SLNs, they are made of a mixture of solid and liquid lipids, have a solid matrix at room temperature, and have a high loading capacity [122, 123]. The use of SLNs and NLCs in the administration of nutraceuticals has been extensively investigated. To improve the stability and oral bioavailability of curcumin, Ramalingam and Ko have developed chitosan coated SLNs. The formulated SLNs have been encapsulated with curcumin, and allow targeting brain tissue. SLNs improved the stability at room temperature (20°C) and the oral bioavailability of curcumin compared to the commercial suspension [124]. Resveratrol is a poorly water-soluble nutraceutical with many properties, including antioxidant, anti-inflammatory, cardioprotective, and neuroprotective. To improve its aqueous solubility and oral bioavailability, Pandita et al. formulated resveratrol SLN using stearic acid as lipid phase. The encapsulation efficiency of 88.9 % was achieved and the formulation prolongs the release of resveratrol up to 120 hours. The in vivo studies showed a significant improvement (eight-fold) of resveratrol oral bioavailability compared to the suspension [125]. Similar studies were also carried out to enhance the stability and the oral bioavailability of β-carotene [126, 127]. NLC loaded with vitamin A was formulated to improve its stability. Different amount of poloxamer were used to stabilize the formulation. The optimized formulation contained 6% (w/v) of poloxamer and was stable up to 2 months [128]. Fang et al. prepared curcumin loaded NLC for intragastric administration. They showed an enhanced oral bioavailability, and curcumin was detected in liver, spleen, kidney, lungs heart, and brain during distribution studies [129]. To improve the oral bioavailability of quercetin, a quercetin-loaded cationic NLC was formulated and evaluated for its in vivo distribution. The formulated NLC showed higher Cmax and AUC value in liver, kidney, and lung compared with control group [130]. The literature reports many other studies using NLCs to improve the properties of nutraceuticals [131–134].

6.4.4 Liposomes Liposomes are spherical vesicles composed of natural or synthetic phospholipids and cholesterol to improve the in vitro/vivo stability [135]. Upon aqueous dispersion, phospholipids spontaneously form a bilayer, with the polar head facing the aqueous phase and nonpolar tails facing towards each other. The polar head incorporates hydrophilic molecules, while hydrophobic molecules are encapsulated in the lipid bilayer. Liposomes are the most investigated nanosystems for the delivery of bioactive compounds [136–139], including nutraceuticals [140]. Trans-retinoic acid (TRA) is a nutraceutical widely studied for its anticancer properties. Encapsulation of TRA in liposomes prevents photodegradation, which could compromise

Nanosystems Trends in Nutraceutical Delivery  107 its pharmacological activity. TRA-loaded liposome enhanced cellular uptake and anticancer activity of TRA on thyroid carcinoma cells [141]. Tyrosol, hydroxytyrosol, and oleuropein, tree antioxidants extracted from Olea europaea, have been encapsulated in liposomes to improve their availability in human chondrocyte cells. The results showed the safety of the formulations and an improved cell permeation [142, 143]. Flavonoids are easily metabolized due to their sensitivity to environmental conditions. Quercetin, kaempferol, and luteolin have been encapsulated in liposomes, which protect them from degradation and enhance their antioxidant properties [144].

6.4.5 Polymeric Nanoparticles Polymeric nanoparticles developed from biocompatible and biodegradable polymers are attractive options for controlling the delivery of nutraceuticals. They are solid colloidal having particles size less than 100 nm [145]. These nanoparticles have the potential to protect therapeutic compounds from degradation while modifying their pharmacokinetics [13]. The most commonly used polymers to encapsulate nutraceuticals include hydroxypropyl methylcellulose (HPMC), poly (d, l)-lactic-coglycolide (PLGA), starch, pectin, chitosan and dextran [146]. Nutraceuticals are dispersed within the polymeric matrix or conjugated to them and are released by diffusion or erosion of the particles [147]. These polymeric nanosystems have many advantages, including pH-dependent controlled release, and ease of surface modification for targeting. Xie et al. used solvent evaporation method to prepare curcumin-loaded nanoparticles with PLGA as polymer. Compared to pure curcumin, the solubility and oral bioavailability of nanoscale curcumin were improved by 640- and 5.6-fold, respectively [148]. Resveratrol was encapsulated in PLGA nanoparticles to improve its oral bioavailability. The authors formulated different nanoparticles by varying the amount PLGA and surfactant. The release studies showed that resveratrol was released over 12 days, and the nanoparticles were stable for at least 6 months. The in vivo results revealed the increase in absorption (seven-folds) and area under the curve (10-fold) of resveratrol loaded PLGA nanoparticles compared with the marketed product [149]. Lutein polymeric nanoparticles were formulated using chitosan. It was observed that lutein solubility and oral bioavailability was significantly improved compare to conventional formulations [150]. In another study, Quiñones et al. used chitosan to improve the vitamin A release profile in animals [151].

6.4.6 Inorganic Nanoparticles Inorganic nanoparticles are emerging due to their attractive physicochemical properties, such as size, shape, higher surface to volume ratio, chemical composition, and surface modification ability [152, 153]. They include gold nanoparticles, carbon nanotubes, magnetic nanomaterials, quantum dots and nanosilica particles. However, gold nanoparticles have been widely studied for the delivery of nutraceuticals due to their ease of synthesis, well-­ defined surface chemistry, and excellent biocompatibility [154]. In a recent study, gold nanoparticles of apigenin were formulated, and their biocompatibility toward normal epidermoid cells was shown using cytotoxicity study. The nanoparticles

108  Advances in Novel Formulations for Drug Delivery demonstrated in vitro activity on human cervical squamous carcinoma cells and epidermoid squamous carcinoma [155]. In another study, gold nanoparticles conjugated to green tea and (-) epigallocatechin-3-gallate were also developed and were shown to be selectively toxic to MCF-7 cells and Ehrlich ascites carcinoma, while not demonstrating any toxicity on normal mouse primary hepatocytes due to their antioxidant properties [156]. Shafiei et al. have developed Ca / Al-NO3 double-layer hydroxide nanoparticles for the delivery of epigallocatechin-3-gallate to a prostate cancer cell line. An in vitro cytotoxicity study showed an increase (five-fold) in cytotoxicity compared to pure epigallocatechin-3-gallate [157]. Recently, curcumin has been encapsulated in magnetic nanoparticles to improve its bioavailability and effectiveness. The results demonstrated an improvement (2.5 times) in bioavailability compared to pure curcumin. In addition, the formulated nanoparticles retarded tumor growth, which improved mouse survival and suppressed the growth of pancreatic tumors in an HPAF-II xenograft mouse model [158].

6.5 Challenges The potential of nanonutraceuticals as dietary supplements has been widely documented in the literature; however, despite the fact that they are mostly made of safe components, some nanosystems can have harmful side effects after ingestion. In general, the toxicity has been linked to their composition, size and shape, as these characteristics could contribute to the penetration of the nanosystems into nontarget areas. Additionally, depending on their size, they can cause oxidative stress, inflammation or DNA damage, leading to cell death. Due to increased cell contact and internalization, these systems especially positively charged ones can produce higher toxicity [215, 216]. Consequently, toxicological studies are required. However, long-term toxicity of nanosystems cannot be quickly and completely understood from in vivo studies. A thorough physicochemical characterization of nanosystems is essential to speculate on their potential application in nutraceutical delivery. The size, shape, surface charge, and pH-dependent stability are important factors in assessing nanosystems as they can contribute to the toxicity. Several in vitro and in vivo studies are recommended to investigate the acute toxicity of nansosystems. The in vitro studies aim to assess cell viability and oxidative stress following the contact between the tested formulation and cellular models, and to investigate any harmful effect that could occur using nanosystems [217]. Choosing the right test is the limiting step in obtaining a correct toxicity result. The choice of a test should be based on its performance, reliability, and cost. Further in vivo studies are important to overcome the limitations associated with the closed environment of cultured cell lines. Animal model studies are performed on the whole organism rather than on isolated cells or tissues. Rats and mice are the most commonly used animal models for in vivo toxicity studies of nanonutraceuticals, as they can predict absorption, biodistribution, metabolism, and excretion (ADME), as well as acute and chronic dose–response [218]. Dose-dependent effects should be investigated prior considering a new nanosystem for nutraceutical delivery. It should be noted that certain changes may occur during gastrointestinal absorption which may result in changes in the pharmacokinetic profile of the administered nutraceutical [219]. Most of nanonutraceuticals contain enhancers

Nanosystems Trends in Nutraceutical Delivery  109 (surfactants, cosurfactants) that increase the permeability of the encapsulated compound. However, these enhancers could also improve in no specific way the gastrointestinal permeability of dangerous agents such allergens, bacteria and toxins [220]. For this reason, deeper investigations on barrier repair process are required to ensure the reversibility of the damage [221]. It is also important to assess the potential immunotoxicity induced by certain components of nansosystems that could act as antigens [222]. To date, the lack of standardized guidelines and protocols for the preclinical and clinical evaluation of nanopharmaceuticals still make it difficult to draw a conclusion from the in vitro and in vivo results. Nanonutraceuticals and all dietary supplements are regulated in the market without evidence of safety, which is major concern [223]. Regulatory agencies are unable to address the issue of potential risk that emerge throughout the nanotechnology processing cycle. Due to several considerations formulated, the FDA has redesigned its food additive safety offices to provide support for the approval of nanonutraceuticals and nutrients. Several regulators are setting up specialized governance structures to control the entire manufacturing cycle of nanonutraceuticals in order to minimize the risk. For the safe regulation of nanonutraceuticals, many recommendations have been implemented, including: firstly, strict manufacturing rules on food supplements containing nanoparticles, secondly, a classification of nanonutraceuticals based on the information found on the label and thirdly, the application of the directive for the regulation of nanonutraceuticals [224]. In the coming years, in-depth research should be integrated in the field of nanonutraceuticals, in particular preclinical and clinical trials to confirm the safety and efficacy of Table 6.3  Commercially available nanonutraceuticals. Product

Nutraceutical

Manufacturer

Nano C®

Vitamin C, quercetin, α-lipoic acid

Neurvana

Nano Resveratrol®

Resveratrol

Neurvana

Nano Curcumin®

Curcumin

Neurvana

LifePak®

Vitamins, minerals, fatty acids

Pharmanex

NanoCoQ10®

Coenzyme Q10

Pharmanex

ACZnano®

Zeolite

Vitality Products Co., Inc. USA

Navasol® ADEK-Q10

Vitamin A, D, E, K, coenzyme Q10

Aquanova

Nanoceuticals® Artichoke Nanoclusters

Artichoke

RBC Lifesciences

Nanotea®

Antioxydant, selenium

Qinhuangdao Taiji Ring Nano product Company Ltd

OilFresh®

Oil

OilFresh Corporation, USA

Canola active oil

Phytosterols

Shemen Industries

110  Advances in Novel Formulations for Drug Delivery nanonutraceuticals in animals and humans. The appropriate composition and correct dosage of nutraceuticals must be established and regulated. Studies at the molecular level are needed to identify physiological effects in the human body in order to provide scientific validation. This should include researchers from various fields such as statistics, biology, chemistry and market research.

6.6 Market Potential Current advances in food industry and nanotechnology have given rise to innovative applications in nutraceuticals. However, the use of nanotechnology in nutraceuticals delivery is still in the early stages of application. Various leading food companies, such as Neurvana, GlaxoSmithKline, Hershey, Unilever, Nestlé, and Heinz are working hard to bring more nanonutraceuticals into the market. Currently, many nanonutraceuticals are commercially available with improved solubility and bioavailability (Table 6.3), and some are undergoing clinical trials (Table 6.4). This illustrates how nutraceuticals can successfully pass clinical evaluation and result in better healthcare products. Obviously, the future holds great potential in the application of nanosystems to deliver nutraceuticals and new manufacturing technologies and regulatory rules are expected.

Table 6.4  Clinical trials on nanonutraceuticals. Nanosytem

Nutraceutical

Aim

Condition

Reference

SEDDS

EPA, DHA

Pharmacokinetics of EPA and DHA loaded SEDDS

Healthy volunteers under poor diet

[225]

Coenzyme Q10

Pharmacokinetics of Coenzyme Q10-loaded SEDDS

Healthy volunteers

[226]

Curcumin

Evaluation of bioavailability, safety and tolerability of curcumin loaded liposomes

Healthy volunteers, patients with long-term chest drain

NCT01403545 (ClinicalTrials. gov), NCT03­ 530436 (Clinical­ Trials.gov), ACTRN126­ 20001216909 (ANZCTR.­org.au)

Coenzyme Q10

Evaluation of bioavailability of Coenzyme Q10 loaded liposomes

Patients with mild to moderate heart disease

ACTRN1261­ 6001527459 (ANZCTR.­org.au)

Liposomes

Nanosystems Trends in Nutraceutical Delivery  111

6.7 Conclusion and Perspective The growing demand for healthy food products has pushed industries to develop nutraceuticals that are able to prevent and/or treat different pathologies. Many nutraceuticals showed low aqueous solubility and oral bioavailability, which limits their wide application. The use of nanosystems has enabled to overcome the solubility and pharmacokinetics limitations of nutraceuticals. Most of components used to formulate nanosystems are generally recognized as safe (GRAS) by FDA and EMA. The success of these nanosystems can be attested by the approval of certain nanonutraceuticals such Nanotea® and NanoCoQ10®. Literature suggests that nanotechnology will provide the next generation of food products that can adjust their nutrient content, flavor or color to meet individual preferences or health requirements. However, some details, such as the specific mechanism by which certain nanosystems might enhance the benefits of nutraceuticals and the possible health risk/ toxicity of these nanosystems are still unknown. Further studies will be needed to clarify the mechanism of action of nutraceuticals and their toxicological profile. In addition, future research should be based on the industrial application of nutraceuticals in order to increase their viability.

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7 Nanoencapsulated Systems for Delivery of Phytopharmaceuticals Jacqueline Renovato-Núñez1, Luis Enrique Cobos-Puc1, Ezequiel Viveros-Valdez2, Anna Iliná1, Elda Patricia Segura-Ceniceros1, Raúl Rodríguez-Herrera1 and Sonia Yesenia Silva-Belmares1* Food Research Department, School of Chemical Sciences, Autonomous University of Coahuila, Saltillo, Coahuila, Mexico 2 Chemistry Department, School of Biological Sciences, Autonomous University of Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico

1

Abstract

Plants have been used to treat diseases since ancient times, but their active principles are regu­ larly degraded in physiological conditions, such as that which occurs in the gastrointestinal tract. Therefore, the pharmaceutical industry focuses on designing new phytopharmaceutical forms to ensure that the active principle reaches the site of action without modifications. Therefore, nanocap­ sules are used to transport phytopharmaceuticals. In addition, they improve its pharmacokinetics, biodistribution, solubility, stability, and reduce its toxicity. However, its use in medicine is affected by its physical and chemical properties, so its characterization and biological evaluation are essential for its development. Consequently, for years, nanoparticles of solid lipids, polyethylene glycol, nano­ liposomes, and chitosan have been synthesized to biodirect the release of phytopharmaceuticals to the site of action. The main applications of these nanoparticles are cytotoxic, antiproliferative, anti­ cancer, cardiovascular, and antimicrobial. These nanoparticles have sizes and charges ranging from 111 to 210 nm and -10.5 to +26 mV and are frequently used to deliver active ingredients directly to a specific target. Currently, different nanoencapsulation techniques are used to protect and deliver bioactive compounds in a controlled way. Therefore, natural or synthetic active ingredients can be added safely and with better bioavailability. Keywords:  Nanoencapsulation, nanocapsules, phytopharmaceuticals, characterization, free delivery

7.1 Introduction Today, phytotherapeutic medicine focuses on designing new pharmaceutical forms to deliver active principles and guarantee efficacy and safety in human health [1]. However, one of the main drawbacks is ensuring that the active ingredient is intact at the site of action. Therefore, researchers are currently focused on developing drug and herbal medicine *Corresponding author: [email protected] Raj K. Keservani, Rajesh Kumar Kesharwani and Anil K. Sharma (eds.) Advances in Novel Formulations for Drug Delivery, (127–152) © 2023 Scrivener Publishing LLC

127

128  Advances in Novel Formulations for Drug Delivery administration systems using nanotechnology [2] since it has allowed great advances in the development of pharmaceutical and nutraceutical forms. Nanoparticles are a great option to improve conventional therapies and overcome bio­ logical barriers (systemic, microenvironmental, and cellular) present in the human body [3]. Since nanoencapsulation systems for drugs or phytopharmaceuticals use particles of less than 100 nm as nanocarriers. In addition, all carriers focus on improving pharmaco­ kinetics, biodistribution, solubility, stability, and reducing toxicity [4]. However, the use of nanoparticles in medicine is affected by their physical and chemical properties since circulation, absorption, and specific delivery of phytopharmaceutical must be guaranteed. Therefore, the size and charge of the nanoparticles play a key [5] since the charge interacts directly with the cell membrane of many cells and tissues and directs the delivery of the active principle. Additionally, the properties improve the response of the phytopharmaceu­ tical to the conditions of acidity, ionization, solubility, or increase the affinity to a specific target, consequently, they are selective [6–7]. Accordingly, the solid lipid nanoparticles, polyethylene glycol, nanoliposome, and chi­ tosan are the most used to biodirect phytopharmaceuticals. These nanoparticles are used to evaluate phytopharmaceuticals cytotoxic, antiproliferative, anticancer, cardiovascular, and antimicrobial protection [8–12]. Additionally, the sizes and charges frequently used to direct the active principles to the site of action range from 111 to 210 nm and -10.5 to +26 mV. Currently, different nanoencapsulation techniques are used to protect and deliver bioac­ tive compounds in a controlled way. Therefore, natural or synthetic active principles can be added safely and with better bioavailability [13].

7.1.1 Nanoencapsulation Techniques in Phytopharmaceuticals Nanotechnology is defined as the technology developed from new materials, systems, and processes that operate at a scale of fewer than 100 nanometers (nm). Therefore, the develop­ ment of nanomaterials produces a change in their properties compared to those of a larger dimension but the same composition [14]. The size of the nanoparticles gives them greater reactivity by increasing their biological activity, so they have better access to cells [7]. These properties offer new applications in biosciences. Therefore, nanomaterials represent a solid basis for innovating bioactive nat­ ural products since their size allows them to be incorporated as food additives in different product formulations. The development of nanocapsules filled with essential oils, extracts, and isolated medicines from plants are some examples [6, 15–17]. Additionally, nanoen­ capsulation maintains a sustained, controlled release and enhances the biological effect of the active ingredients. Nanoparticles smaller than 300 nm are an example since they can be absorbed by the cell until reaching its nucleus [18–19]. Nanoparticles can vary in shape, charge and size, which modifies absorption, distribu­ tion, metabolism, excretion, and toxicity. Therefore, its properties are considered to carry out the formulation of more effective phytopharmaceuticals. Given that the properties of the nanoparticles improve the response of the active ingredients to acidity, ionization, and solubility conditions, or else, they increase the affinity to a specific target, and with it its selectivity [6–7].

Nanoencapsulated Systems for Delivery of Phytopharmaceuticals  129 Polymeric matrix

Polymeric membrane

Drug

Oil or aqueous core Drug Nanocapsules

Nanosphere

Figure 7.1  Nanoparticle type: noncapsular and nanospheres.

For this reason, the nanoencapsulation of natural ingredients is a current trend to formu­ late better phytopharmaceuticals. Consequently, its design focuses on releasing the active principle under previously established physicochemical conditions. Then, nanoparticles are obtained by coating or trapping material or a mixture (encapsulated material) in another material that can be a polymer, macromolecule, or lipid (encapsulating material) [20]. Nanospheres and nanocapsules are the groups of nanoparticles used most frequently for encapsulation. Both differ in their constitution the nanospheres is formed of a dense poly­ meric matrix, while the nanocapsules is composed of a polymeric membrane that covers an oily liquid center [21], as presented in Figure 7.1. The material used during the formation of nanoparticles must be biodegradable and intertwine with the active ingredient or encapsulated extracts and remain inert during the storage of the nanoparticles. Additionally, the material used for nanoencapsulation must be a GRAS type substance capable of protecting the encapsulated material or facilitating its handling under standard conditions. Carbohydrates, lipids, proteins, and polymeric compounds are most often used to form nanoparticles. Maltodextrin, chitosan, alginate, cyclodextrin, gums, and agar are some examples of carbohydrates. Waxes, paraffin and fats are examples of lipids. Casein, gelatins, and albumins are examples of proteins. Polycaprolactone, polyvinyl alcohol, polylactic acid, and polyglycolic acid are examples of polymeric compounds [22]. On the other hand, the techniques used to form “nanophytopharmaceuticals” can be divided into physical-chemical, chemical, and mechanical procedures. Physicochemical pro­ cedures include coacervation and emulsion-evaporation/emulsion-extraction. Chemicals include polycondensation, complexation, and gelling. Mechanicals include spray drying, supercritical emulsion extraction, and electrospinning or electrospinning. The basics of some techniques physical-chemical, chemical, and mechanical are described below.

7.1.1.1 Physical-Chemical Techniques Coacervation It is a method that involves the electrostatic attraction between a polymeric solute separated into small droplets and a nonpolymer phase called the equilibrium solution. There are two

130  Advances in Novel Formulations for Drug Delivery types of coacervation, the simple and the complex. The simple contains a single polymer, while in the complex, two colloids interact [23]. The method is simple, inexpensive, and results in the formation of capsules by gelation once the coacervate is deposited around insoluble particles dispersed in a liquid. Emulsion Evaporation/Emulsion Extraction The most used techniques to encapsulate hydrophilic active principles are single and double emulsion by evaporation or solvent diffusion since it represents an easy and reproducible method that provides uniformity in particle size. This method gives rise to the formation of particles in four stages that are described below. 1) Primary emulsification is carried out by emulsifying an aqueous solution of the active compound in an organic solution containing the polymer. 2) Reemulsification obtained by incorporating the previous emulsion in an aqueous phase containing a surfactant to give rise to a double emulsion. 3) Purification of the formulation to remove the organic solvent by evaporation or extraction, which induces the solidification of the particles. 4) Separation and purification of the microparticles by centrifugation or filtra­ tion to collect the polymeric particles [24].

7.1.1.2 Chemicals Techniques Interfacial Polycondensation Interfacial polymerization is a nanoencapsulation process that occurs through the interac­ tion of two reactive agents or monomers. During the process, all the monomers dissolve in the phases known as continuous and dispersed then the reaction takes place at the interface of both liquids [25]. Additionally, they participate simultaneously in the condensation reac­ tions that are formed. The most common technique is polycondensation and consists of forming an emulsion from polymer solutions prepared in organic solvents subsequently evaporated. The evap­ oration of the solvent allows the formation of nanoparticles that remain in suspension. Finally, the nanoparticles are obtained by centrifugation [26]. However, the “Salting-Out” technique has recently been used and does not use surfactants or solvents. The technique consists of a polymeric emulsion from a water-miscible solvent using the Ouzo effect [27]. Consequently, the aqueous phase contains a high concentration of salt or sucrose to achieve a strong saline displacement effect in the aqueous phase [28]. Gelling and Complexation Gelation is a procedure commonly used to synthesize nanoparticles. First, a dilute solu­ tion of a polysaccharide is prepared in an aqueous medium at acidic pH. Nanoparticles are formed by mixing this solution with an aqueous solution of a low molecular weight polyan­ ion under magnetic stirring that produces a complexation between the opposite charges. Then the polysaccharide undergoes ionic gelation and forms nanocapsules that are finally separated by centrifugation [29].

Nanoencapsulated Systems for Delivery of Phytopharmaceuticals  131 Complexation is similar to gelation. However, polyanions of a macromolecular nature are used to form the nanoparticles. The most commonly used polyanion is pentasodium tripolyphosphate. Additionally, complexation produces reactions that give rise to particles with positive or negative charges on their external surface. However, this depends on the polyelectrolyte solution dripping onto the other. As well, the technique allows the construc­ tion of nanocapsules with a variable number of layers [30]. These methods have advantages compared to others since they avoid the use of high temperatures and organic solvents.

7.1.1.3 Mechanical Techniques Supercritical Emulsion Extraction The most used mechanical encapsulation techniques as spray drying, fluidized bed coating, high-temperature evaporation, and reduced pressure. However, produce larger particles than nanocapsules or microcapsules [31]. Additionally, they have difficulty in forming par­ ticles with homogeneous morphology [31]. On the other hand, some techniques use heat to remove the solvent, risking the integ­ rity of the encapsulated compound or extract. Added to these limitations is the high cost of its implementation on an industrial scale. Therefore, supercritical emulsion extraction represents an alternative because supercritical CO2 extracts solvents from an emulsion con­ taining the active principle. Consequently, when removing the solvent, the particles precip­ itate, remaining suspended in water. If the active compound is soluble in water, it starts with double emulsions [32]. Electrospun or Electrospun Yarn Electrohydrodynamic techniques are based on the dynamics of electrically charged fluids and represent an alternative to nanoencapsulation of phytopharmaceuticals. These tech­ niques do not require high temperatures or expensive equipment. Therefore, they maintain the integrity of heat-sensitive compounds to process them successfully and avoid organic solvents. Electrospinning is known as “electrostatic spinning” and is a cost-effective, highly flex­ ible and robust technique. This technique uses an uniform electrohydrodynamic force to generate fine threads of a polymeric matrix in which the active principle is incorporated through electrostatic interactions [33]. The electrospray equipment has four components that are described below [34]. The technique will be implemented horizontally or vertically as required. 1)  A reservoir of solution or molten material that connects to a tube. 2) An infusion pump connected to a syringe that delivers a constant and deter­ mined flow. 3)  A high voltage source. 4)  A grounded metal plate to collect electrospun material. Table 7.1 presents some nanoencapsulated compounds using the physicochemical, chemical, and mechanical techniques previously described.

132  Advances in Novel Formulations for Drug Delivery Table 7.1  Frequently used techniques to nanoencapsulation plant compounds or extracts. Encapsulated natural compounds or extracts

Techniques Physical-chemical

Chemical

Mechanical

Reference

Coacervation

Anthocyanins, tea polyphenols, Echium seeds and beta-sitosterol

[35–37]

Double emulsion/ solvent evaporation

Chamomile and Aloe vera extracts

[38–39]

Interfacial polycondensation

Paclitaxel and curcuminoids

[40–41]

Gelling and complexation

Indigoferaintricata extracts, essential oils, polyphenols from Camellia sinesis and mint infusions

[38–39]

Supercritical Emulsion Extraction (ESE)

Lavender essential oil, querticin, oils rich in omega 3, flavone and 3-hydroxyflavone

[42–45]

Electrospun or electro spun yarn

Nutraceuticals, paclitaxel and artemisinin

[46–48]

7.1.2 Characterization of Nanoencapsulates The characterization of polymeric nanoparticles is a fundamental aspect that must be evaluated to control and ensure their manufacturing process. Therefore, the estimation of the particle size and zeta potential are the most used methods for its morphological characterization. However, particle size can be estimated by zeta potential, transmission electron microscopy, atomic force microscopy, and scanning electron microscopy are also used. Additionally, FTIR, thermogravimetric analysis and encapsulation efficiency evaluation is used for physicochemical characterization. These techniques are focused on determining the integrity and encapsulation efficiency of the active principle (Table 7.2). Currently, research on the characterization of nanocapsules loaded with phytophar­ maceuticals is scarce. However, the characterization techniques described below could be employed.

7.1.2.1 Morphological Characterization Particle Size Estimation of the size of the nanoparticles and their distribution is essential because they can affect the characteristics of the final product in which they are to be incorpo­ rated [49]. After all, its parameters are the result of the method used for the formation

Nanoencapsulated Systems for Delivery of Phytopharmaceuticals  133 of nanocapsules. Therefore, its selection must be established according to the applica­ tion and properties of the active ingredient. Additionally, the nanoparticles size values​ (100–1000 nm) must be taken into account, in accordance to established in the FDA regulations [49]. On the other hand, the size, porosity and surface area of nanoparticles are parameters that can affect the bioavailability and efficacy of drugs. Consequently, their detection is essential for the pharmaceutical industry. The powder used in nasal inhalers is one example, as it allows the medication to travel and be delivered to the site of action. For this reason, the appropriate size of nanocapsules loaded with phytopharmaceuticals must be estimated since its incorporation frequently increases the size of the nanocapsules. However, the concentration of material used to form the nanocapsule can also modify its size. Chitosan nanocapsules loaded with capsaicin to deliver wtCFTR-mRNA are an exam­ ple. Because those lacking active ingredients measure 100 to 150 nm, and those loaded with capsaicin measure 200 to 250 nm [50]. Nevertheless, the gum arabic nanocapsules loaded with α-tocopherol have an average size that increases with increasing concentration of gum Arabic [51]. Additionally, it should be noted that the smaller nanosizes present better solubility and bioavailability; but may show the Ostwald ripening phenomenon and lack solution stability [51]. Zeta Potential The zeta potential expresses the potential difference between the dispersion medium and the stationary layer of fluid adhered to the dispersed particle [5]. When the zeta potential is high (positive or negative), the particles repel each other and resist aggregation, there­ fore, the solution is stable. Additionally, the Z potential is used to evaluate the stability of nanoparticles during their long-term storage because its decrease causes instability of the nanocapsule [52]. Prelyophilized honokiol-loaded pegylated PLGA nanocapsules are one example. Since when resuspended in an aqueous solution, their potential z decreased, which demonstrated the loss of their stability [52]. On the other hand, the detection of the z potential of the nanoparticles is decisive to know their surface charge since it plays a fundamental role in the administration of drugs and phytopharmaceuticals in an organism [53]. Additionally, the charge allows the union of the nanoparticles to the cell membrane. Therefore, variation in surface charge can define binding to a tissue or cell compartment in vivo or in vitro, improving delivery at the site of action [5]. The zeta potential is calculated using theoretical models. The z-potential of natural nano­ capsules such as gum Arabic loaded with α-tocopherol is measured by the Doppler laser velocity technique. The technique measures electrophoretic mobility, and the potential z is estimated using the Smoluchowski equation from the detected velocity values [51]. However, the z-potential of capsaicin-loaded chitosan nanocapsules is measured by Henry’s equation. Detection is performed by laser Doppler microelectrophoresis and phase anal­ ysis light scattering. The technique is used to measure the increase in the hydrodynamic diameter Z of chitosan nanocapsules loaded with capsaicin. Additionally, it detects the relationship between nanometric size and polydispersity because the polydispersity index decreases as the nanocapsules increase in nanometric size [50].

134  Advances in Novel Formulations for Drug Delivery Transmission Electron Microscopy Transmission electron microscopy is a widely used method to analyze the shape and size of nanoencapsulated containing active plant compounds. The method has been used to demonstrate the morphology of nanoparticles of chitosan loaded with capsaicin to deliver WTCFTR-mRNA in a cystic fibrosis cell line. Therefore, heterogeneous nanoencapsulated not completely spherical and slightly elliptical were detected [50]. Additionally, transmission electron microscopy analysis is used to demonstrate the spherical shape and nanosize of nanocapsules loaded with Nerolidol used to treat zymosan-­ induced arthritis in mice [54]. The technique is employed to demonstrate the encapsulation of thyme essential oil in halloysite nanocapsules [55]. Atomic Force Microscopy This technique uses a microscope to evaluate the morphology of the nanoparticles and offers results similar to those of transmission electron microscopy. This technique makes it possible to study the morphology of nanocapsules such as chitosan-poly (ε-caprolac­ tone) core-shell loaded with tea tree oil. Since these nanocapsules have spherical shapes and nanometric sizes [56]. Scanning Electron Microscopy The technique uses an instrument to measure particle size and shape distribution at the nanoscale using images. Furthermore, it can provide evidence on crosslinking in nanoma­ terials. Chitosan-alginate-oleoresin-tripolyphosphate (TTP) particles are an example since their matrices have irregular shapes with scaly surfaces and a crosslinking between chi­ tosan, oleoresin, and TTP [57].

7.1.2.2 Physicochemical Characterization FTIR Analysis The FTIR technique detects the absorbance signals attributed to the vibrations of the func­ tional groups of the active compounds [57]. Therefore, it is used to demonstrate crosslink­ ing in a nanocapsule. Chitosan nanocapsules loaded with linalool are one example. These nanocapsules produce different absorption than nanocapsules without active ingredients in the infrared spectrum, which happens by crosslinking of chitosan with linalool [58]. Additionally, the technique is used to demonstrate the encapsulation of active principles, such as resveratrol, whose signals disappear when the compound is improperly encapsu­ lated [59]. Thermogravimetric Analysis The technique is part of the characterization of nanoparticles. However, it focuses on detecting decomposition, thermal stability, oxidation, and dehydration of the active prin­ ciples. It also detects the content of volatile compounds. The technique has been used to analyze the decomposition of chitosan nanocapsules loaded with linalool. Linalool had complete decomposition at 200°C, blank and charged nanocapsules show around 72% to 77% decomposition at 400°C. Therefore, thermogravimetric analysis shows that encapsula­ tion retains linalool at high temperatures, preventing its release [58].

Nanoencapsulated Systems for Delivery of Phytopharmaceuticals  135

Table 7.2  Parameters detected by nanocapsule characterization techniques. Nanocapsules matriz/active ingredient

Technique for characterization

Shape

Size (nm)

Z potential (mV)

Encapsulation (%)

Chitosan-poly (ε-caprolactone) coreshell/tea tree oil

Reference

AFM, dynamic light scattering, Zetasizer

Spherical

100–500

+ 31.0

94.9

[56]

ε-caprolactonenanocapsules/ Nerolidol

TEM, dynamic light scattering, Electrophoretic mobility Zetas nanoZs

Spherical

219

−20.3

71.2

[54]

PEGylated PLGA/Honokiol

TEM, dynamic light scattering, Laser Doppler Anemometry

Smooth spherical

125

−6.21

94

[52]

Halloysite/Thyme Essential Oil

FE-SEM, SEM

Nanotubes

300–500, diameters 40–60

UD

UD

[55]

Gum Arabic/α-tocopherol

Dynamic light scattering in Zetasizer, electrophoretic mobility

UD

171.2

−47.8

UD

[51]

Chitosan/Linalool

SEM, dynamic light scattering Zetasizer nano Zs

Nearly spherical

352

UD

15.17

[58]

(Continued)

136  Advances in Novel Formulations for Drug Delivery

Table 7.2  Parameters detected by nanocapsule characterization techniques. (Continued) Nanocapsules matriz/active ingredient

Technique for characterization

Shape

Size (nm)

Z potential (mV)

Encapsulation (%)

Reference

Chitosan/Cyanidin-3-O glucoside

TEM, Zetasizer

Nearly spherical

180

−19

53.88

[61]

Chitosan/Oleoresin

SEM

Flake-like surfaces, not spherical, irregular

UD

UD

69–79

[57]

Carboxymethyl chitosan/ resveratrol

SEM, dynamic light scattering, dynamic light scattering

Spherical

155.3

−10.28

44.5

[59]

UD: undetermined; TEM: transmission electron microscopy; SEM: Scanning electron microscopy; AFM: atomic force microscopy.

Nanoencapsulated Systems for Delivery of Phytopharmaceuticals  137 Encapsulation Efficiency The encapsulation efficiency (EE%) is defined as the relationship between the content of the active principle retained in the nanocapsule and the initial content used in the formulation. The active ingredient could be a drug or phytopharmaceutical [60]. The encapsulation efficiency depends on the chemical interactions between the active compound and the encapsulation matrix. The encapsulation of cyanidin-3-O-glucoside (C3G) in matrices of chitosan (CS), chitosan oligosaccharides (CO), and carboxymethyl chitosan (CMC) and an ionic crosslinking agent ϒ-polyglutamic acid or calcium chloride is an example. Given that, the C3G-CMC-CaCl2 nanoparticles have high encapsulation effi­ ciency due to the charge-charge interactions of the matrix, the C3G functional group and the surface charge interactions between them [61]. As well, the ionic crosslinking of the matrices used to synthesize nanocapsules plays a fundamental role since the ionic concen­ tration directly affects the formation of the complex. Carboxymethylchitosan nanoparticles (CMNPs) are an example given that by increasing the CaCl2 content during their formula­ tion, the efficiency of resveratrol encapsulation increases, reaching up to 44.3% [59].

7.1.3 Nanoencapsulated Systems for Free Delivery of Phytopharmaceuticals Nanotechnology includes several disciplines that study and manipulate matter at the nanoscale level. Nanomedicine is one of the most important areas that focus on the design of nanosystems for the controlled transport and release of drugs to treat various diseases. Since traditional medicine is based on the direct dosage of the phytopharmaceuticals, which can present problems, such as its incorrect biodistribution, low specificity, low stability, or solubility, causing high toxicity of the treatments, since higher doses are used to achieve the effect wanted. On the other hand, nanoparticles and nanomaterials have different structural and bio­ logical properties, which can be modified depending on the polymers, solutions and addi­ tives used for their synthesis. Therefore, they offer greater advantages as the possibility of carrying out an external control and diagnosis of the treatment. In addition, they offer multiple treatments using different active ingredients simultaneously and controlled doses. Therefore, they allow short-, medium-, and long-term treatments. Additionally, they can be administered orally, topically, parenterally and mucosa. Consequently, have great ver­ satility. The nanoparticles used in the administration of drugs for therapy or diagnosis are colloidal solids that vary in size from 2 nm to 1000 nm [62]. The small size and the use of biodegradable materials used to synthesize the nanoparti­ cles represent an advantage for the administration of drugs and phytopharmaceuticals. The size of the nanoparticles allows them to reach the sites of action such as inflammation of the endothelium, the epithelium (of the intestinal tract and liver), tumors, or it allows them to penetrate microcapillaries. In addition, nanoparticles can be administered intravenously since their size and diameter are smaller than that of capillaries. Therefore, they prevent the formation of aggregates and ensure that emboli or thrombi do not form. Nanoparticles designed to administer drugs or phytopharmaceuticals are classified into five groups [63]: 1. nanoparticles based on the use of lipids, 2. nanoparticles composed of emulsions,

138  Advances in Novel Formulations for Drug Delivery 3. nanoparticles composed of vesicles, 4. nanoparticles composed of diverse structures, 5. nanofibers. The materials and technologies with which nanosystems for prolonged release of drugs or phytopharmaceuticals are built are diverse but are classified into two groups [64]. A. Organic nanostructures: polymeric materials with which nanospheres, nanocapsules, micelles, liposomes, dendrimers and polymer-drug conju­ gates are synthesized. B. Inorganic nanostructures: metal oxide nanoparticles, mesoporous silica nanoparticles and carbon nanotubes. As described, nanotechnology is a multidisciplinary area and is defined as science and technology on a nanometric scale in which nanopharmacy has a place. Nanopharmacy synthesizes nanoparticles that contain the active ingredient and a nano­ pharmaceuticals agent. The active principle can be a drug or a phytopharmaceutical. These nanostructures can dose the active ingredients without causing collateral damage. The active principle and the nano pharmaceutical agent must have low toxicity, optimal trans­ port property, and a long half-life. Bionanotechnology is an area derived from nanotechnology, which in turn includes nanomedicines. Nanomedicines include components that are described below. 1. Additives to improve the solubility and bioavailability of very poorly soluble active ingredients, 2. Phytopharmaceuticals delivery vehicles for developing circulatory per­ sistence and site-specific delivery to particular cells, 3. Conveyors to promote their controlled release, 4. Adjuvants for vaccines, 5. Diagnostic aids and drug delivery devices. In nanopharmacy, the effectiveness of the active principles depends on their intrinsic physical and chemical properties and their correct administration in the body because it seeks to overcome the limitations of therapeutics and minimize toxic side effects to carry out good drug administration. The development of mechanisms that allow increasing the half-life of the active principle in plasma, increasing the stability or maximizing its thera­ peutic activity is some strategies to improve the administration of phytopharmaceuticals. Nanostructured materials based on a ceramic matrix are considered the new nanophar­ maceuticals agents. Since can evade the immune system and cross the blood-brain and the wall of the gastrointestinal tract. Therefore, they prevent the penetration of foreign or undesirable substances. Ceramic nanoparticles have physicochemical and structural prop­ erties that make them ideal as nanopharmaceuticals agents. These nanoparticles have a size smaller than 50 nm, a high specific surface and a porous nature that does not show changes with pH or swelling. Therefore, these nanoparticles selectively protect the active principles avoiding denaturation induced by changes in pH and high temperature SiO2, TiO2, ZrO2 are the most common ceramic materials and are compatible with biological systems due to their inert nature.

Nanoencapsulated Systems for Delivery of Phytopharmaceuticals  139 Additionally, they have high chemical and mechanical stability, are relatively easy to pre­ pare and are inexpensive. Also, its surface structure can be modified with the inclusion of functional groups that allow the anchoring of active principles [65]. There are different types of nanoparticles used to release drugs or phytopharmaceuticals. These nanoparticles have various applications and are described below [66]. 1. Liposomes: Encapsulate hydrophobic active ingredients for prolonged release and protect the active principles from degradation by light and water. 2. Micelles: Solubilizing agents in pharmaceutical formulations gradually release active ingredients that are poorly soluble in water. 3. Dendrimers: Encapsulate organic molecules within their nucleus or attach them to the surface. 4. Quantum dots: Transport of therapeutic agents, drug delivery, in vivo imag­ ing and application in tissue engineering. The design of nanomaterials and nanoparticles in pharmaceutical products represents a challenge due to the need to control the release of the active principle and the intrinsic toxicity of the carrier material. The search for vehicles to release active ingredients has focused on nanostructured ceramic-type materials in recent years. Since offers properties such as morphology control and biocompatibility. These materials are essential to pharmacology and medicine since they do not harm compared to other materials. On the other hand, they have various benefits for human health and have no restric­ tions on their use in different therapies. These materials are used as genetic vectors and pharmaceutical vehicles to administer different active principles, such as antibiotics, anti-­ inflammatories, and anticancer agents. Nanoparticles for phytopharmaceutical use are solid colloidal particles ranging in size from 1 to 1000 nm. They are composed of macromolecular materials in which the active principle dissolves, encompasses, encapsulates, adsorbs or binds in different ways. The use of nanoparticles is essential to investigate drug delivery. Since they allow a wide variety of molecules to be directed to different tissues, releasing them in a sustained way over time. Here are some advantages of the use of nanoparticles in the release of drugs or phytophar­ maceuticals [67]. Pharmaceuticals 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Modulate drug release Control absorption Modify the deletion Favorable pharmacodynamics Less degradation of the active ingredient Longer elimination half-life Less toxic effects Higher bioavailability Longer circulation time of the drug in the body Higher dissolution speed Deep tissue penetration of the drug

140  Advances in Novel Formulations for Drug Delivery 12. Encapsulation of hydrophilic and hydrophobic substances 13. More biologically active formulas. Technological 1. 2. 3. 4. 5.

Provide solid characteristics to products of a liquid nature Protection of the drug from atmospheric agents Avoid or reduce volatility Avoid incompatibilities Protection of handling personnel.

Nanotechnology has various applications, among which medicine stands out [68]. Therefore, natural and synthetic polymers are widely used as encapsulating materials for a wide variety of bioactive compounds. Polymers are macromolecules formed by the covalent union of numerous monomers [69]. Synthetic polymers are classified as polyesters, polyethers, poloxamers, and polymers based on recombinant proteins. Natural polymers are subdivided into polysaccharides and proteins [70]. Encapsulation is the process in which a coating material known as a matrix is used to wrap or trap an active compound [71]. Therefore, nanoencapsulation is used to wrap biological or chemical molecules in a matrix to form nano-sized capsules [72]. Alginate and gelatin are natural polymers used to nanoencapsulation curcumin and jasmine essential oil. Both have nutraceutical and pharmaceutical applications [73–74]. Accordingly, the phar­ maceutical industry is interested in the encapsulation of active principles to protect their integrity from extreme environments. On the other hand, nanoencapsulation depends on the characteristics of the active prin­ ciples. Therefore, its inclusion during the formation of the nanostructures constitutes a solution since they are formed by natural lipid material, emulsifiers, coemulsifiers, water, and phytopharmaceuticals. Nanostructured lipid carriers have imperfect crystallization given that formed from mixtures of unsaturated fatty acids. Therefore, its imperfect structure produces voids in the fillings by a wide range of lipophilic active compounds [75–76]. These structures carry the active ingredients through the digestive system and are absorbed into the bloodstream. Therefore, they must present melting temperatures above 37°C to avoid adverse health effects [77–78]. Hence, the structures protect the integrity of various active compounds, such as carotenoids, flavonoids, tocopherols, and polyphenols. In addition, they improve the penetration and release of the active principles in the tissues [79–80]. Additionally, they are more stable, and safe since they do not present toxicity. Consequently, the FDA considers them GRAS [81], and the encapsulation percentages of the bioactive compounds are higher because the active compound is previously dissolved in the excipient and favors the encapsulation process [82]. As well, nanostructured lipid carriers promote greater skin hydration and better penetration of bioactive compounds such as resveratrol [83]. Efficacy in dermal and transdermal drug delivery and their absence of toxicity have also been demonstrated and the use of nanostructured systems is known to be an alternative for the treatment of breast cancer [84]. Alternatively, surfactant species known as polymeric micelles are used to encapsu­ late active principles of phytopharmaceutical importance [85–86]. Micellar systems have

Nanoencapsulated Systems for Delivery of Phytopharmaceuticals  141 recently been developed to encapsulate active principles of phytopharmaceutical impor­ tance. Polydiacetylene micelles (sub-30 nm) and hydroxypropylated and debranched starch micelles (80–200 nm) are examples. Its formation uses a polymeric surfactant to encap­ sulate and release camptothecin in ovarian cancer cells and improve curcumin solubility, respectively [87–88]. On the other hand, colloid science enhanced the development of nanostructured com­ pounds, such as micelles. The techniques most used to make nanoemulsions are high-­ energy since they generate rapid phase dispersion and reduce the size of the droplets. The most used methods are ultrasound, piston hole homogenizer, and microfluidizer [89]. However, emulsifiers influence the dispersion of nanoparticles because nanocarriers trans­ port and release the molecules of interest. Sodium caseinate, Tween (polysorbate), deca­ glycerol monolaurate, and detergents are some examples [90–91]. Nanoemulsions, unlike microemulsions and micellar dispersions, present better stability and solubility due to their configuration, size, and conformation. Given that water-soluble and fat-soluble bioactives mix simultaneously and provide kinetic stability [92]. As well, nanoemulsions have various applications in the medical and pharmaceutical industries because they can be matrices or controlled release vehicles of active compounds as phy­ topharmaceuticals [93–94]. The release of the active principle occurs in two phases. First, the bioactive molecules are released from the oil phase to the fraction where they are in the area of the surfactant. Afterward, they pass to the aqueous phase and are nanoprecipitated to generate a bioactive surface with dissolution that favors the release in a controlled way [89–95]. It should be noted that nanoemulsions can be made with various natural compounds or GRAS, which reduces toxicity without affecting the stability of the components. Accordingly, human health is not affected. Mixtures are widely used to direct drug admin­ istration where the active ingredient is loaded into oil droplets, released and absorbed in the body through different routes [96–97]. Consequently, this strategy could be applied to administer phytopharmaceuticals. The most widely used surfactants are peptides, serum proteins, phospholipids, poly­ saccharides, and small-structure nonionic surfactants. Egg or vegetable lecithin, such as soy, are examples of phospholipids. Food starches, such as avocado seeds, acacia gum, caseinate, are examples of polysaccharides. Tween is an example of a nonionic surfactant [91, 97–100]. Active compounds added to nanoemulsions have better bioavailability and are easier to load. In addition, they protect themselves from chemical and enzymatic damage caused by the body’s metabolism [96–97, 101]. Lycopene is an active principle that can be eas­ ily incorporated into nanoemulsions. This compound presents antioxidant, anticancer and cardioprotective properties [94, 102]. Therefore, it forms 100- to 200-nm nanoparticles with antioxidant property demonstrated by reducing free radicals in vitro, with adequate stability and high bioavailability [91, 100].

7.1.4 Studies to Evaluate Phytopharmaceuticals Nanoencapsulates The effect of various active compounds with phytopharmaceutical properties has been studied worldwide by various research groups. Most of the active principles derived from plant extracts are flavonoids, tannins, and terpenoids. However, one of the drawbacks is

142  Advances in Novel Formulations for Drug Delivery preserving the integrity of the active compound until it reaches its site of action. Given that, some are water-soluble or have high molecular weight and hardly cross the lipid mem­ branes. Therefore, they lose efficacy in their bioavailability. Therefore, nanoencapsulated systems loaded with phytopharmaceuticals represent a great tool for their administration [2]. For this reason, in recent years, different nanotechnological strategies have been pro­ posed to break this barrier. The use of polymeric nanoparticles, liposomes, microemulsions, liquid crystal systems, solid lipid nanoparticles, and liquid crystal precursor systems are some examples. These strategies have been implemented to use substances with different properties in the same formulation, change their properties or the behavior of a substance in a biological environ­ ment. Some strategies are focused on increasing selectivity, efficiency, and controlling the release of phytopharmaceuticals [103–106]. The biological models used to evaluate the release of phytopharmaceuticals loaded in nanocapsules are scarce. However, some research groups in the world have developed strat­ egies to evaluate its behavior in cell lines and some tissues. For this reason, a small number of phytopharmaceuticals have been evaluated, among which compounds with antioxidant properties stand out. Therefore, polyphenolic com­ pounds as gallic acid, ellagic acid, curcumin and epigallocatechin-3-gallate are the most evaluated. Since they are directly related to the anticancer effect, they are used as chemo­ preventive agents [107]. However, the efficacy and bioavailability of natural antioxidants are limited by their poor absorption through cell membranes and their degradation. Therefore, some antioxidants have been covalently linked in a nanogel, encapsulated in nanoparticles and hollow particles to provide better stability, gradual and sustained release [108]. Additionally, it has been shown that solid lipid nanoparticles loaded with epigallocate­ chin gallate increase toxicity in cancer cell lines. On the other hand, nanoparticles loaded with phytopharmaceutical undergo a modification in the size, PI and ZP [8]. Curcumin is a phytopharmaceutical of turmeric and has an anticancer effect. But curcumin-loaded nanocapsules improve antiproliferative efficacy without encapsulating even at low concen­ trations. Furthermore, curcumin nanocapsules exhibit antioxidant and cytotoxic [109]. Furthermore, the extract of Phytolaccadecandra encapsulated in poly (lactide-co-­ glycolide) has an effect against A549 cells in vitro. But improve the chemopreventive effect on lung cancer in mice than the extract without encapsulation. As well, the nanoencapsu­ lation of the extract increases the bioavailability of the drug. Chemopreventive effects were detected by cell viability, comet tail length, and DNA fragmentation. The physicochemical studies used to evaluate its morphology were dynamic light scattering, scanning electron microscopy and atomic force microscopy. In addition, a triterpenoid, a derivative of betu­ linic acid, was identified as the active principle by FTIR and (1) H NMR and the drug-DNA interaction by circular dichroism and fusion temperature spectra in DNA [9]. In addition, nanocapsules loaded with phytopharmaceuticals have been tested in tumor tissues. Given that improve the biocompatibility, bioavailability, and therapeutic efficacy of the drug. Encapsulation of the antitumor allows a limited final concentration to be used that prevents its activity in the bloodstream. Therefore, its therapeutic efficacy is improved [110]. Paclitaxel is a phytopharmaceutical widely used to treat breast cancer. However, some research groups have focused on nanoencapsulation together with ibuprofen to deliver it to

Nanoencapsulated Systems for Delivery of Phytopharmaceuticals  143 the CD44 receptor of breast cancer cells. Nanocapsules loaded with the phytopharmaceuti­ cal improved apoptosis and cell uptake compared to the free drug cocktail [12]. Sanguinarine is used to treat skin neoplasms, and its indiscriminate application causes extensive tissue necrosis. However, it has selective cytotoxic and antiproliferative activity against human/murine melanoma when applied in a controlled manner. Therefore, a directed system is required since the compound acts by various mechanisms. Since at 2 hours, sang-np kills B16 melanoma cells by apoptosis similar to free sanguinarine administered for 24 hours. Therefore, confirms the controlled release of sanguinarine from sang-NPs [111]. Polyphenols play a therapeutic role in cardiovascular diseases associated with ­metabolic syndrome such as diabetes. However, they suffer from poor bioavailability problems through their metabolism, which makes their applicability difficult. Consequently, its nanoencapsu­ lation improves the controlled release, solubility, chemical protection and scope of its sites of action. Since nanoencapsulated polyphenols loaded in food-grade polymers or lipids are safe. Therefore, they gain enteric resistance and improve their intestinal absorption and mucoadhesiveness, which ensures greater uptake. Additionally, nanocapsules confer a gradual release of polyphenols, longer half-life and permanence both at the cellular level and in the body, which improves their effectiveness Table 7.3  Biological evaluation of nanoencapsulates loaded with phytopharmaceuticals. Nanoencapsule/ active ingredient

Physicochemical characteristics (size = nm; PDI; ZP = mV)

Biological effect

Reference

SLN/epigallocatechin gallate

~144; ~0.160; ~ + 26 mV

Antiproliferative cell line SV-80

[8]

Poly (lactideco-glycolide)/ Phytolaccadecandra extract

111 nm ± 5, 0.327 ± 0.025 17.5 mV ± 2.1

Antiproliferative cell line A549 (lung cancer), anticancer Lung cancer model in mice induced with benzo [α] pyrene and sodium arsenite.

[9]

PEG-cholesterol NLs/ resveratrol

200 nm, ≤0.1, −35 mV

Protection of the cardiovascular system, relieve oxidative stress and control blood glucose. TC cells, antidiabetic effect, GSH-Px, and SOD enzyme activities.

[10]

(SLN/Chi/Eu)/ Oxfloxacin

210.1 ± 5.9, 0.418 ± 0.033, 15.47 ± 0.21

Antibacterial, cytotoxic, antibiotic

[11]

SLN-HA/ibuprofen + paclitaxel

169.3 ± 0.55 nm, 0.285 ± 0.004, -10.5 ± 0.15 mV).

Breast cancer

[12]

SLN, solid lipid nanoparticles; PEG, polyethylene glicol; NLs, nanoliposomes; Chi, chitosan; Eu, Eugenol; HA, Hyaluronic acid.

144  Advances in Novel Formulations for Drug Delivery [112]. Given that nanoliposomal formulations loaded with resveratrol have antidiabetic and antioxidant effects. Also, they improve the decrease in insulin levels and reduce the increase in glucose levels. Therefore, they can be effective against type II diabetes mellitus and oxidative stress, which improves cardiovascular health [10]. Furthermore, curcumin nanocapsules exhibit antiviral effects against the hepati­ tis C virus and antibacterial effects against methicillin-resistant Staphylococcus aureus. Therefore, it improves wound healing by reducing the bacterial load [109]. While hybrid solid lipid nanoparticles synthesized by incorporating chitosan and eugenol into a lipid matrix released encapsulated ofloxacin for 24 hours in a sustainable way. MIC decreased 6.1 to 16.1 times from 1.0 µg/mL. Furthermore, the fluorescence-labeled nanoparticles were observed to interact with the bacterial cell membrane. However, they showed selective tox­ icity of 0.3-30.0 µg/mL of ofloxacin in human cell models (A549 and Wi-38) at 24 and 48 hours. But, the inhalation administration of dry powder in mice reached therapeutic levels in the lungs [11]. Polyethylene glycol liposomes loaded with artemisinin-curcumin have an immediate antimalarial effect against Plasmodium berghei NK-65 compared to free phytopharmaceuti­ cal. Since artemisinin plus curcumin cured all malaria-infected mice at the same time after inoculation [113]. The biological evaluation of nanoencapsulates loaded with phytophar­ maceuticals is presented in Table 7.3.

7.2 Conclusions Nanotechnology has enormous potential to improve the delivery of bioactive compounds to improve health. Emulsification, polycondensation, coacervation, complexation, and sol­ vent evaporation by supercritical fluids are used for nanoencapsulation phytopharmaceuti­ cals. However, these techniques depend on drying to produce nanoencapsulated powders, making the final product significantly more expensive. Therefore, new and novel nanoen­ capsulation techniques are emerging with better advantages than conventional techniques. Electrospun or electrospun yarn is an example, but it takes time to consolidate. Most of the nanoencapsulated have good bioavailability and enhancement of the therapeutic effect. However, the health risks until a few years ago were unknown or poorly addressed. Therefore, national and international organizations focus on imple­ menting strategies to control, manage, and promote the safe use of nanoencapsulated phytopharmaceuticals. Currently, nanoparticles are developed to modify the pharmacokinetics of drugs or phytopharmaceuticals; therefore, it seeks to improve its efficiency, stability, solubility, and bioavailability. In addition, to reduce its toxicity and improve the specificity of the site of action. For this reason, characterizing the nanoparticles loaded with phytopharmaceuticals is essential to gather the information that allows the development of a stable product with desired effects. However, to get to this point, it is necessary to evaluate its biological effect and the safety of the final product. Therefore, the experimental design to develop a nano­ encapsulated phytopharmaceutical must have physical, chemical, biological, and safety aspects that intervene until its final destination. Accordingly, the research of nanocapsules is focused on the evaluation with various models of human pathology. But they must have scientific evidence on the interactions

Nanoencapsulated Systems for Delivery of Phytopharmaceuticals  145 between their structures and mechanisms with a wide range of molecular targets. Examples are transcription factors, growth factors, receptors, cytokines, enzymes, and genes that reg­ ulate cell proliferation. So far, research has shown that particle size and Z potential are related to cell interactions. Therefore, characterization is essential to direct the release of the phytopharmaceutical to the site of action, which represents a great advance in the delivery of phytopharmaceuticals.

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8 Topical Drug Delivery Using Liposomes and Liquid Crystalline Phases for Skin Cancer Therapy Karina Alexandre Barros Nogueira1, Jéssica Roberta Pereira Martins2, Thayane Soares Lima3, Jose Willams Bandeira Alves Junior4, Alanna Letícia do Carmo Aquino4, Lorena Maria Ferreira de Lima4, Josimar O. Eloy3 and Raquel Petrilli4* Federal University of Ceará, Center of Technology, Department of Chemical Engineering, Fortaleza, Brazil 2 Northeast Network in Biotechnology – Renorbio, Federal University of Ceará, Fortaleza, Brazil ³Federal University of Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Pharmacy, Fortaleza, Brazil 4 University of International Integration of the Afro-Brazilian Lusophony, Institute of Health Sciences, Redenção, Brazil 1

Abstract

Skin and basal squamous cell carcinomas and keratinocyte cancer are classified as a less aggressive skin cancer but with a high incidence of occurrence. Melanoma, on the other hand, presents itself as an aggressive form that is generally resistant to conventional treatments. One approach that can be used to overcome the biological barriers of the skin through topical administration and drug delivery is nanotechnology. Liposomes are lipid nanocarriers composed of one or more phospholipid bilayers concentrically oriented around an aqueous compartment and liquid crystals are in the state between liquid and solid and can appear in different forms: cubic, hexagonal, and lamellar. These nanoparticles provide drug release and retention in a controlled manner in addition to the reduction of side effects and toxicities. The combination of the use of nanoparticulate formulations and physical methods, such as sonophoresis, iontophoresis and microneedling can bring additional advantages by increasing the penetration of the drug into the skin. In this chapter, we will present an overview of skin cancer and the use of nanotechnology and physical methods for improving the topical therapy. Keywords:  Liposomes, liquid crystals, skin cancer, topical delivery, drug delivery, nanotechnology

8.1 Introduction Skin cancer is the most common type of cancer. They are classified as melanoma and the non-melanoma forms, such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which represent the highest and second highest prevalence, respectively [1, 2]. *Corresponding author: [email protected] Raj K. Keservani, Rajesh Kumar Kesharwani and Anil K. Sharma (eds.) Advances in Novel Formulations for Drug Delivery, (153–176) © 2023 Scrivener Publishing LLC

153

154  Advances in Novel Formulations for Drug Delivery BCC  is the most prevalent skin cancer and manifests itself in the basal cells of the epithelium that usually occurs by the development of mutations in the p53 or PTCH1 genes, detected in 60% or 70% of cases, respectively. SCC is present in squamous cells of the epidermis and mucous membranes, in addition to being biologically more aggressive than basal cell carcinoma of the skin, with metastatic characteristics in approximately 3% to 7% of cases. Melanoma-type cancer comprises less than 2% of skin lesions and is characterized as a brownish or blackish lesion that may bleed and is usually found in sun-exposed areas [3–6]. Treatment for skin cancer is primarily through surgery. The main purpose of a surgical excision is to remove the tumor partially or completely, resulting in scarring or loss of tissue function. When surgical treatment is not possible, radiotherapy can be used as an option, mainly in BCC, achieving high cure rates. However, side effects, such as necrosis and tissue atrophy, have been reported [7]. Another method of treatment is through cryotherapy, in which the tumor is destroyed with the use of liquid nitrogen, however it is more favorable when used in less developed tumors and can cause adverse reactions at the application site, such as edema, redness of the skin, blisters and alopecia. In addition to these, chemotherapy agents are administered intravenously, with high bioavailability, however, its use tends to be painful for the patient, with many side effects, high cost and requires health professionals experienced in administering the drugs [8]. In this sense, the topical treatment appears as an alternative for the delivery of drugs. Topical therapies are generally used when the area to be treated is large, with the presence of multiple injuries or injuries that take a longer time to heal. The skin plays a protective role for the organism, preventing the entry of exogenous molecules and microorganisms, maintaining homeostasis. Its structure is divided into three layers: epidermis, which consists of the outermost layer; dermis, an intermediate layer composed of interstitial (collagen fibers and elastic tissue); and cellular elements, such as lymphocytes, fibroblasts, histiocytes; and the hypodermis, which is the innermost layer presenting adipose cells. In addition, the skin has important adnexal structures, such as hair follicles, sebaceous and sweat glands [9]. The stratum corneum (SC) is in the outermost layer and is formed by cells that have lost their nuclei plasma and organelles and are called corneocytes, constituting the main barrier of the skin and one of the main factors that regulate penetration of drugs through the topical route [9, 10]. This stratum acts as a barrier, preventing the loss of excess water, in addition to limiting the entry of substances that could be harmful both locally and systemically. The transport of drugs through the cutaneous route is limited by the fact that corneocytes hinder the permeation of more hydrophilic substances and those that present high molecular weight, such as peptides and polysaccharides, since their lipid structure and their distinct structural organization reduce permeability [11, 12]. In this context, the drug needs pathways so that it can cross the stratum corneum. These pathways are known as intercellular, transcellular and transappendix routes [13]. The transappendix pathway is characterized by drug permeation by sweat glands and hair follicles, being an important mediator of passage of compounds that have slow diffusion and very high molecular weight substances, such as nanoparticles, however, hair follicles correspond to only about 0.1% of the skin surface [14]. The intercellular pathway is described by penetration through intercellular lipids which lie between corneocytes, while the transcellular pathway is characterized by penetration through corneocytes. In experimental studies the predominant route of penetration appears to be the intercellular pathway [15, 16].

Topical Drug Delivery in Skin Cancer Therapy  155 For a given drug to exert its effect, the molecule needs to go beyond the stratum corneum barrier and reach its site of action, thus commonly absorption promoters are used in the development of formulations for topical therapy [17]. These absorption promoters can be chemical, physical, and nanotechnology methods. Chemical methods play an important role in increasing drug solubility, which is related to improving the drug’s partition coefficient through the association of the chemical promoter with SC, creating a favorable microenvironment for its free diffusion, promoting disruption of the overly organized structure of lipids located in the stratum corneum, in addition to interacting with intercellular proteins [18–21]. One of the first and most widely studied chemical absorption promoters is dimethyl sulfoxide (DMSO), whose use is related to lipids extraction, making the stratum corneum more permeable by the formation of aqueous channels; however, its toxicity can cause erythema, stratum corneum papules, in addition to the ability to denature some proteins [21, 22]. Another approach that can be used to improve the permeability of drugs through the skin are physical methods that promote improved drug delivery using an external driving force able to break the skin barrier or help the permeability of the drug [23, 24]. Thus, some physical methods can be highlighted, such as iontophoresis, sonophoresis and micro­ needling. Iontophoresis is a method that promotes an interesting enhancing effect on molecules with hydrophilic activity with molecular weight below 15 kDa [11]. In this method, the membranes or biological tissues, such as the skin, receive an application of an electric current with low intensity, so that the delivery of molecules with therapeutic activity is carried out, aiming at a topical or transdermal effect. This process is based on the sum of electromigration, characterized by an orderly movement of ions in the presence of an electric current, and electroosmosis, which refers to the flow of a volume of solvent, in addition to a movement of charges arising from an electrical potential difference when applied to the skin [24]. Sonophoresis is characterized by the use of an ultrasound that promotes an increase in the percutaneous permeability of a drug [25]. In addition, it is generally classified into two categories: low-frequency sonophoresis (LFS), which has frequencies in the 20- to 100-kHz range, and high-frequency sonophoresis (HFS), which has frequencies in the range of 0.7 to 16 MHz, with the most used band being the 1.3 MHz frequency [26]. Another important method is microneedling, which consists of the application of m ­ icrometer-sized needles that break the skin layer, thus creating micropores that allow more molecules to pass through the SC layer, thus improving permeability and effectiveness [27]. Compared to conventional formulations, the development of nanocarriers as drug delivery systems for the topical route increases its stability avoiding incompatibilities, protecting the drug from the body where it could be degraded and even improving its physicochemical characteristics (such as increased solubility and bioavailability). As a result, there is an improvement in therapeutic efficacy and a decrease in side effects [28]. Given the above, the development of lipid-based nanoparticles, such as liposomes, which are lipid-based round bilayer vesicles, and liquid crystals, which are a unique state of condensed matter that has a crystalline order of solids and fluidity like liquids , become advantageous when it is necessary to optimize drug delivery, reduce toxicity, in addition to topical application for delivery to the superficial layers of the skin [29, 30]. This chapter will cover the concepts and applications of liposomes and liquid crystals as topical drug delivery systems in the treatment of skin cancer, as well as some techniques for

156  Advances in Novel Formulations for Drug Delivery obtaining and characterizing these nanocarriers. Also, physical methods associated to these nanocarriers will be presented herein.

8.2 Liposomes for Topical Application Nanometric drug delivery systems have benefits, such as greater diffusion in several types of biological media and their surface properties, have great potential to target particular cell types. Different types of nanoparticles with therapeutic potential have been studied and in many cases improved therapeutic efficacy was found [4, 31, 32]. Among the various types of nanoparticles used, liposomes have gained highlight because they are non-toxic, biocompatible and biodegradable, which explains their wide applicability as drug nanocarriers [33, 34]. Basically, liposomes are relatively small vesicles composed of lipid aggregates formed by one or more layers. Its structure is organized in a spherical shape with bilayers separated by an aqueous compartment in which it is possible to encapsulate substances with hydrophobic, lipophilic, or amphiphilic character. In the preparation of liposomes, the phospholipids used present cylinder-shaped structure, with a hydrophilic portion or head and two nonpolar tails (hydrophobic portion). The organization in aqueous medium of these molecules takes place on two sides of an imaginary plane in which the hydrophobic portions interact with each other and are directed toward the interior of the system, and the hydrophilic portions are oriented toward the outside, interacting with the water [34, 35]. The use of liposomes to encapsulate drugs provides a prominent controlled release mechanism, as it is possible to direct the liposomes to the location where cells have been affected with pathologies, such as skin cancer, reducing the harmful effects on healthy cells and optimizing the therapeutic effect [36, 37]. Liposomes are formed by a single lipid bilayer or numerous bilayers around the internal aqueous compartment; thus, they can be classified as unilamellar and multilamellar vesicles (MLVs), respectively. MLVs are essentially multiple concentric bilayers separated by aqueous compartments. For the production of unilamellar vesicles, several methods have been developed, generating vesicles of different sizes, such as giant unilamellar vesicles (GUVs; ˃ 1 μm); large unilamellar vesicles (LUVs; ~ 100–500 nm) and small unilamellar vesicles (SUVs; ~ 30–50 nm) [34]. Furthermore, we can also classify liposomes according to their charge in cationic (positive charge), anionic (negative charge), and neutral (uncharged) liposomes [38, 39]. The physical properties obtained for these nanometric systems can be controlled by adjusting the lipid composition during liposome preparation and under physiological conditions are related to the physicochemical characteristics of the hydrophobic fatty acid tails and hydrophilic heads of their composition. Thus, lipid hydrophilic groups influence the molecular structure and charge of the liposome, whereas lipid hydrophobic groups determine liposome particle size and flexibility due to relative differences in fatty acid type, hydrocarbon chain length, and number of double bonds [40].

8.2.1 Development of Liposomal Nanoparticles To obtain liposomes, different lipids can be used, including phosphatidylcholine (PC), either natural mixtures obtained from egg yolk or soy, or hydrogenated derivatives. Initially

Topical Drug Delivery in Skin Cancer Therapy  157 described by Bangham in 1964, the researchers observed that dry lipids spontaneously reorganize if placed in contact with a sufficient amount of water, so that liposomes may be synthesized by different methods. Among them, the lipid film hydration is based on the solubilization of lipids and amphiphilic molecules in organic solvent. In a round bottom glassware, the organic solvent of the resulting mixture is subjected to evaporation under vacuum in a rotary evaporator. At the end of this step, the thin lipid layer adhered to the flask walls is hydrated with an aqueous solution that may or may not contain hydrophilic molecules for encapsulation. In order to adjust the size and lamellarity of the obtained lipid vesicles, the formulation can be subjected to extrusion, high pressure homogenization or sonication processes, for example [38, 39, 41]. Another technique to obtain these nanoparticles is using solvent dispersion including the ethanol injection method in which vesicular lamellae with small size may be prepared without sonication offering reproducibility, simplicity, rapid implementation and also avoiding lipid degradation or oxidative changes. The ethanol injection method was first reported by Batzri and Korn (1973) as an alternative for the preparation of small unilamellar vesicles (SUVs) without sonication. Thus, an ethanol lipid solution is quickly injected in the aqueous phase by a fine needle under rapid agitation, considering the excess buffer in this process. The lipid molecules precipitate due a dilution of ethanol in the aqueous phase generate bilayer fragments, which will form vesicles with the encapsulated aqueous phase. In this method, population heterogeneity varies widely (30 to 110 nm), liposomes are very diluted and it is tough to remove all the ethanol as it forms an azeotrope with water. Also, several biologically active macromolecules can be inactivated even in the presence of a small amounts of ethanol [42–44]. Microfluidization or lab-on-a-chip technology enables the production of liposomes of controlled size considering fluid dynamics, the surfaces or interfaces and the structure of the devices. Thus, there are two types of devices used to produce liposomes, a chip-based device and a capillary-based device [45]. Liposome production using chip-based device is shown in Figure 8.1. A lipid solution dissolved in organic solvent and a buffer solution are introduced into the microfluidic device, where the process consists of dispersing lipids that are added to the device and pumped through a 1-5 µm channel under high pressure. Microchannels are responsible for dispersion that is divided into streams and then returns and meet to collide at high speed. The liquid is collected, and the process is performed again until a uniform dispersion is obtained. This technique can produce liposomes with a diameter of 50 to 500 nm and diameter can be controlled by adjusting the pressure applied by the device [34]. Also, to obtain liposomes, reverse phase evaporation method can be carried out. It was first described by Szoka and Papahadjopoulos and the procedure initially occurs with the dissolution of the phospholipids in an organic solvent followed by the addition of the aqueous phase to the organic phase obtained to form inverse micelles. At this point, two non-miscible phases are formed, the phospholipids are located at the interface of the two phases and after the sonication process, a water and oil emulsion (W/O) is formed, which is subjected to evaporation in order to remove the solvent resulting from the formation of a gel. Liposomal vesicles are then formed under high agitation and addition of aqueous solution through self-association of the phospholipids in bilayers. encapsulated. This method produces large unilamellar vesicles with a large aqueous core, capable of encapsulating large amounts of hydrophilic drugs. Due to the conditions used in the method, such as exposure

158  Advances in Novel Formulations for Drug Delivery Lipid phase

Aqueous phase

Aqueous phase

Phospholipids bilayer fragments

Small Unilamellar Liposomes

Figure 8.1  Schematic illustration of liposome production by lipid phase injection method in chip type of microfluidic device.

to organic solvent and sonication, biologically active molecules, such as enzymes, proteins and RNA-like molecules can suffer DNA strand breakage, conformational changes or protein denaturation [34, 46–48]. Dispersion of MLVs can occur by different methods, using mechanical, electrostatic or chemical processes. Mechanical processes include the use of a homogenizer/microfluidizer as described above and sonication, which is a high-energy cavitation-based process using a sonicator to produce SUVs. There are two ultrasound processing techniques: probe ultrasound in which the tip of the sonicator rod is placed in direct contact with the liposome

Topical Drug Delivery in Skin Cancer Therapy  159 dispersion, resulting in high energy input generating heat, so the container containing the liposome must be immersed in a bath of ice/water. In the ultrasound bath, the liposome dispersion is placed in a bath so that the temperature of the lipid dispersion is easily controlled in this method. Among the disadvantages of this method, limited processing capacity, possible degradation of phospholipids and compounds that are encapsulated, overheating during the process, metal contamination of the probe tip have been described [34, 43, 49]. According to Batista (2007), physical instability occurs mainly due to aggregation, fusion of vesicles and encapsulated drug leakage. Thus, a small amount of charged lipids can be incorporated during preparation to create electrostatic repulsion between vesicles, thus reducing aggregation and fusion. Incorporation of cholesterol and sphingomyelin into the preparation reduces drug permeability and extravasation by reducing membrane fluidity and may increase the phase transition temperature. In this way, an ideal formulation must have maximum encapsulation efficiency and limited extravasation during storage, thus the incorporation of high-temperature transition lipids and/or cholesterol may be considered [35]. Likewise, Calvagno et al. 2007, evaluating the lipid composition of liposomes A , B and C, which contained fixed amount of 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (DPPC) and varied between oleic acid compositions, 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine monohydrate (DPPS), and 1,2-distearol-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-MPEG) respectively, has found wide range of particle size (0.55 to 7 μm) and polydispersity (0.4 to 1), depending on the composition and preparation technique. Thus, oleic acid has the characteristic of increasing the fluidity of the liposomal bilayer, thus being similar to an edge activator, while DPPS can influence the packaging of the lipid bilayer structure as a function of the environment, providing fusogenic properties. The influence of oleic acid and DPPS on the liposome structure can generate the formation of multivesicular aggregates, which can cause higher mean size values. The liposome C obtained in the work had a smaller average size (0.55 µm) and a reduced polydispersity index of 0.4, which are characterized by a rigid bilayer structure and colloidal stability due to the presence of cholesterol and DSPE-MPEG. The method applied was extrusion, which consists of passing multilamellar vesicles through a small orifice of small-sized polycarbonate membranes under high pressure [43, 48]. The use of oleic acid in the extrusion process could not effectively reduce the size because the fluidity of the bilayer causes the vesicles to deform as they pass through the 400 nm and 200 nm pores of the membrane. On the other hand, formulations containing DPPS and DSPE-MPEG were effectively reduced by membranes with pore diameters of 200 nm and 100 nm [50]. Recent works have applied liposomes in the treatment of nonmelanoma and melanoma skin cancers to expand the therapeutic profile and reduce the incidence of toxic effects associated with anticancer drugs [4, 51, 52]. Liposomes are efficient transporters in the skin of bioactive molecules because the hydrophobic characteristics of the lipid layer. Since liposomes are similar to the cell membrane, they can interact and cross the cell, allowing them to act as a reservoir until reaching the site of action and gradually releasing its contents [33, 53]. However, for the liposome to reach satisfactory efficacy in the penetration of skin layers, it is important to consider that the stratum corneum layer is the limiting factor to promote skin penetration. Thus, a requirement for lipid vesicles to penetrate the skin layers is flexibility, that is, the ability to pass through spaces in the intercellular lipid layers and that the

160  Advances in Novel Formulations for Drug Delivery driving force of this phenomenon is not eliminated by occlusion of the skin surface where the lipid nanocarrier is applied. The main types of liposomes developed for administration through the skin have phospholipids in their composition, they may or may not contain cholesterol and other components that allow them to increase their elasticity or change their shape. Elastic liposomes can be classified in transferosomes, ethosomes, and niosomes. Transfersomes are ultra-deformable as they contain, in addition to phospholipids, substances in their membranes that increase the deformability of bilayers, such as Span 60, 65, or 80. Ethosomes have between 20% and 50% ethanol in their composition, which can increase drug transport under non-occlusive conditions. Finally, niosomes are composed of non-ionic surfactants and in the absence of phospholipids thus, the presence of surfactant can modify the structure of the stratum corneum to become more permeable [10, 33, 53]. In a study conducted by Calienni 2019, a topical drug delivery system was developed, where Vismodegib (Vis) was incorporated into ultra-deformable liposomes, in order to decrease systemic distribution and thus side effects for treatment of a specific target of viable epidermis where basal cell carcinoma can develop. For the evaluation and characterization of the system, skin penetration studies were performed with human skin and 60 μg of Vis encapsulated in liposome or DMSO solution were applied to skin discs, and incubated without occlusion. After 8 hours, 5.4 μg of Vis was recovered from the viable epidermis and dermis. As the volume of the cutaneous disc is 0.64 cm3, the Vis concentration in the viable epidermis and dermis equal to 8.4 μg/mL was found. Thus, the developed system delivers a concentration approximately three times greater than the dose required for the treatment of basal cell carcinoma [54]. Other studies using liposomes for treatment of skin cancer are shown in Table 8.1. Table 8.1  Liposome formulations application in skin cancer. Nanoparticles/ drug Liposome/ niclosamide

Composition Hydrogenated Soy Phosphatidyl­ choline (HSPC), DSPEMPEG and chol

Model (in vitro and/or in vivo) B16F10 melanoma cells

Main findings

Reference

The results indicate that the nanoparticle produced is homogeneous and stable with a diameter of 108 nm. Free niclosamide showed cytotoxic effects at IC50 values of 4.4 μM, whereas the liposome resulted in IC50 value of 0.8 μM, showing better cytotoxicity to B16F10 melanoma cells.

[55]

(Continued)

Topical Drug Delivery in Skin Cancer Therapy  161 Table 8.1  Liposome formulations application in skin cancer. (Continued) Nanoparticles/ drug

Composition

Model (in vitro and/or in vivo)

Main findings

Reference

Liposome/ Avicequinone-­B

Lysolecithin; Cosphaderm® E145V), pluronic F-68

Squamous cell carcinoma HSC-1 Cells

Liposomal formulations of Avicequinone-B showed high encapsulation efficiency, around 95%. It was possible to observe a significant cytotoxic effect on HSC-1 cells through increased cleaved caspase 8, reduced mitochondrial membrane potential, inducing apoptosis.

[56]

Curcumin-Loaded Cationic Liposome siRNA Complex

1, 2-Dioleoyl3-trimethyl­ ammonium propane (DOTAP), 1, 2-dioleoylsn-glycero3-phosphoethanolamine DOPE, C6 ceramide, and sodium cholate

Excised porcine ear skin, B16F10 melanoma cells and Female C57BL/6 mice

Cytotoxicity studies presented cell growth inhibition for the developed nanoparticle. The liposomes after application of iontophoresis reached a depth of 160 µm in the skin. Tumor progression was observed in animals with suppression of STAT3 protein.

[57]

Liposome gold nanoparticles for curcumin (Au-Lipos Cur NPs)

Hydrogenated Soy Phos­ phatidyl Choline (SPC-3)

B16F10 melanoma cells

Curcumin was loaded into Liposome gold nanoparticle with an encapsulation efficiency of 70%. The gold nanoparticle allow by surface plasma resonance (SPR) generation of heat from light energy. In the B16F10 cell line, the nanoparticles showed increased uptake and cytotoxicity when compared to free curcumin.

[52]

162  Advances in Novel Formulations for Drug Delivery

8.3 Liquid Crystals and Liquid Crystalline Nanodispersions for Topical Application Liquid crystals (LCs) are defined as the fourth state of matter formed between solid and liquid states [58]. Under these two conditions, a distinct phase of condensed material is formed thus, liquid crystals share characteristics of a crystal and a liquid, that is, with partial order/disorder of atomic species [59]. Friedrich Reinitzer, a botanist, discovered the properties of LCs in 1888. In his studies, it was observed that cholesterol-derived acetate and cholesterol benzoate had no optical axis between the isotropic liquid and crystalline solid states. This revelation was interpreted by the existence of two melting points of the crystalline solid, in which the first made the transition to a milky-looking fluid and the second to a transparent liquid fluid. It was found that, with white light deflected from the plane, a peculiar color phenomenon occurs before solidification [60]. Lyotropic liquid crystals (LLC) are amphiphilic systems, which contain a hydrophilic main group and a region of the hydrophobic hydrocarbon chain that self-organize after the addition of water to form long-range ordered structures [61]. An example of this are the LLCs described by Bitancherbakovsky (2011), which are based on monoglycerides, and are self-organized in a wide variety of morphologies [62]. LLCs are strongly birefringent and their formation depends on hydrophilic or lipophilic substances. Among the LLC mesophases, the most observed are the lamellar (neat phase), hexagonal (middle phase) and the cubic phase, these systems are shown in (Figure 8.2). The hexagonal shape has a more rigid appearance compared to the lamellar shape, these liquid crystal nanoparticles are produced from simple amphiphilic combinations that have high propensities to form inverse non-lamellar liquid crystalline phases at room and body temperature [63–65]. Additionally, both lamellar and hexagonal phases feature a variety of textures that can be easily identified using polarized light microscopy. For example, the hexagonal phase features the characteristic fan like texture. Furthermore, the phase transition in hexagonal and inverse hexagonal depends mainly on the polarity of the solvating agent and due to the molecule itself [66]. Regarding cubic liquid crystals, they are more rigid than other mesophases, therefore, they do not flow like lamellar and hexagonal liquid crystals [30]. Some lipids in aqueous solution are part of the formation of liquid crystals. This can be done by simply mixing the lipids and aqueous phase by stirring to form hexagonal or cubic liquid crystals, depending on the type of lipid used. Regarding the phase transition between cubic and hexagonal phases, many factors can influence this process, such as the molecular structures of lipids, pressure, temperature, salt concentration, pH and also the addition of a third substance [67]. In addition to being multifunctional and versatile tools in drug delivery due to their structural characteristics, LCs are less toxic, have improved permeation capacity and provide protection of unstable substances, such as proteins and peptides for example [68, 69]. LLC can be formed by mixing an oil phase with an aqueous phase. The oil phase may include lipids and surfactants. However, the preparation of the dispersed form, liquid crystalline nanoparticles (LCNPs) is more complex, the dispersions of the cubic phase, for example, offer greater protection to the encapsulated drug, preventing it from being degradation, biocompatibility and better solubility and absorption [70].

Topical Drug Delivery in Skin Cancer Therapy  163

Lamerllar phrase

Cubic phase

Liposomes Phospholipid

Normal hexagonal phase

Reverse hexagonal phase

Figure 8.2  Schematically depicted polymorphism of phospholipid aggregates.

Two approaches used for the production of LCNPs have been reported: a bottom-up approach and a top-down approach [71]. The most common method to prepare LCNPs is the top-down approach. In this approach, dispersions are formed from a liquid-crystal phase. However, some disadvantages are related to this method, as small-scale production and the high heat rates required by shear techniques can limit the preparation of formulations with labile compounds [61]. The second, bottom-up approach, also known as the hydrotropic or solvent dilution method, was developed for the production of cubic LCNPs, as first reported by Spicer et al. [72]. As a result of this method, most amphiphilic substances can form LLC phases. In addition, LCNPs prepared from this approach have longterm stability, which can be attributed to homodispersed stabilizers on the surface of the particles [73]. The application of drugs to the skin is a challenge precisely because of its role as a biological barrier, which inhibits the entry of substances into the body, including drugs [73]. LC have strong bioadhesive properties and improve the fluidity and permeability of the lamellar membrane, transforming the gelled crystalline packing of the stratum corneum into liquid-crystalline lipid packing [74].

164  Advances in Novel Formulations for Drug Delivery In recent years, a number of studies have shown the potential of liquid crystal nanodispersions for improving skin permeation [30]. In a recent study, a new liquid dispersion of polymer-free cubosomes was developed [75]. Polymer-free cubosomes composed of monoolein and phospholipids and propylene glycol were evaluated as hydrotrope. Through the analysis of backscattering, it was possible to obtain an assessment of the kinetic stability aiming to obtain a more stable formulation as a potential vehicle of photosensitizers for photodynamic therapy (PDT) of cutaneous melanoma skin cells. It was observed that upon propylene glycol addition to the cubosomes greater stability was found. The potential of the cubosomes obtained for the diagnosis of skin cancer was confirmed by bioimaging that revealed the cytoplasmic localization in melanoma fibroblast cells (MeWo) and cutaneous melanoma lymph node metastases (Me45). In addition, the biocompatibility and photodynamic activity of chlorin e6 was demonstrated by the reduction of more than 90% of the viability of melanoma cells after irradiation [75]. Hexosomes are nanoparticles formed by inverted discontinuous hexagonal liquid crystalline phases (HII) that offer exceptional physicochemical characteristics for drug encapsulation and targeted drug delivery [76]. The hexagonal phase formed by lipids and water is the most common nonlamellar phase [73, 77]. The normal and reversed hexagonal phase have been described (Figure 8.2). In the normal phase, long cylindrical micelles are separated by water in which the non-polar region of the amphiphilic molecules is contained within the cylinder part. The reverse phase consists of long cylindrical water nuclei arranged in a hexagonal network in which the polar region of the molecule is in the inner part [78]. Furthermore, these hexagonal structures can be arranged in a hexagonally closed layer of water covered by a single layer of surfactant, called the intermediate phase [79]. The colloidal dispersion of bicontinuous cubic liquid crystalline structures in water using surfactants results in “cubosomes,” nanostructured systems from 100 to 300 nm. They have a larger surface area but with the same 3D structure as the parent phase [80, 81]. Cubic and hexagonal liquid-crystalline phases are composed of a lipid as the main structural compound. Among the advantages, their bioadhesive characteristics can be highlighted. Furthermore, they are able to incorporate water-soluble and fat-soluble compounds, which prevent their chemical and enzymatic degradation. Another advantage is the ability to control the release of incorporated compounds [78, 82–84].

8.3.1 Characterization Techniques Once LLCs are prepared for drug loading, their characterization can be performed using a variety of techniques used in soft matter physics. The identification of lyotropic phases involves several techniques, such as polarized light microscopy, transmission electron microscope (TEM), and small/wide angle X-ray diffraction, well-known techniques used to identify the phases of liquid crystals [30, 85]. Furthermore, liquid crystals and liquid crystalline nanodispersions are evaluated regarding appearance, pH, viscosity, particle size and zeta potential [86]. In the polarized light microscopy, all liquid crystals can be distinguished, excluding the cubic mesophase. Using polarized light will cause these other liquid crystals to have double refraction. Light that is polarized can pass through the second polarizer in anisotropic materials, but it cannot pass through a polarizer that is placed below an isotropic object. The “fan-shaped” pattern is indicative of the hexagonal liquid crystal, while the “maltese

Topical Drug Delivery in Skin Cancer Therapy  165 cross” pattern is demonstrated by lamellar liquid crystals. These specific maltese crosses are derived from “confocal domains,” which are defects that uprise from the layers which make them cross-shaped under polarized light. Thermotropic liquid crystals show various textures, but most of them are fan-shaped, like hexagonal liquid crystals [30, 86]. Petrilli et al. [87] used the same technique, in the study the characterization of samples was performed by polarized light microscopy. The authors showed the morphology of the liquid-crystalline phases before dispersion, at an observation temperature of 25°C with an optical microscope equipped with a polarizing filter and coupled to a digital camera. This technique can also be seen in a variety of reports in the literature, where lamellar and cubic phase gels were examined under a polarized light microscope to characterize their liquid crystal structure [67]. According to Rapalli et al. [30], in transmission electron microscopy high energy electrons affect the structure of LCNPs, a result of the fragile and dynamic environment of structural observations at the NP level. The most commonly used sample preparation techniques include thin-film dip freezing, glass-section cryo-TEM (cryofixation), and freeze-fracture TEM. In a study carried out by Yaghmur et al. [88] and collaborators non-lamellar liquid crystalline nanocarriers containing thymoquinone (TQ) were investigated. The effect of TQ loading on the structure and morphological characteristics of glycerol monooleate (GMO) and vitamin E liquid crystalline nanoparticles were studied. Cryo-TEM showed nanovesicles, lamellar and non-lamellar liquid crystal structures. Another characterization method is small-angle X-ray diffraction (SAXRD), which also confirms the arrangement of an LCNP structure, based on the Bragg equation, 2d sinθ = nʎ, which measures the spacing between the planes of the lattice [89]. For instance, Petrilli et al. [87] in their work on lyotropic liquid crystal nanoparticles loaded with a chlorine derivative developed for use in photodynamic therapy (PDT), demonstrated by SAXRD that the preparations remained in the hexagonal-type liquid crystalline phase. after drug loading, this was proven through the analysis performed (FWHM) which proved the presence of the drug accommodated in the extructure of the hexagonal phase.

8.4 Physical Methods Applied to Nanoparticles Delivery Physical methods are important tools for drug delivery by increasing the permeation of the SC layer, allowing for higher drug concentrations in the innermost layers of the skin, also improving drug distribution, increasing drug accumulation and release [24, 90]. Thus, research on transdermal and topical drug administration using physical methods has gained prominence over the years in the area of p ​ harmaceutical nanotechnology. Among the methods used, the most widely studied are iontophoresis, sonophoresis and microneedling, shown in Figure 8.3. Iontophoresis is a physical method that promotes drug delivery through the use of a low electrical current of 0.1 to 0.5 mA/cm² that is applied on a drug or nanoparticles reservoir in order to improve delivery and enhance drug transport across biological barriers adjacent to target tissues and organs in a simple and noninvasive way [91–93]. It can be defined as the movement of soluble salt ions across a biological membrane upon applied potential difference [94]. This system consists of a power supply and two electrodes: the anode and the cathode. The anode is characterized as a negative electrode and the cathode as a positive one.

166  Advances in Novel Formulations for Drug Delivery Microneedles

Iontophoresis

Sonophoresis

Iontophoresis device Anode

Catode

Stratum corneum

Electromigration

Electroosmosis

Viable epidermis

Dermis

Figure 8.3  Schematic representation of physical methods application in the skin: microneedling, sonophoresis and iontophoresis.

With this, the drug should be preferably ionized and is placed in a compartment that must be in contact with the electrode that presents equal polarity, that is, the cationic drugs are inserted in the anode compartment, while the anionics are inserted into the cathode. This process is important because the electric current applied to the skin results in the migration of cations toward the cathode and the migration of anions toward the anode. Thus, there is an increase in the transport of drugs through the skin through the facilitated migration of ionized substances [24]. Furthermore, iontophoretic transport occurs through two main transport mechanisms, namely electromigration or otherwise known as electrorepulsion and electroosmosis. In the electromigration mechanism, a vehicle solution or nanoparticles in which a positively or negatively charged drug is dissolved, which is positioned under the positive electrode (anode) and negative electrode (cathode), respectively, so that the electrorepulsive forces drive drug molecules or nanoparticles away from the electrodes. In electroosmosis, drug molecules are transported through the convective flow of solvent that is generated by the potential difference induced on the surface of charged tissues [93, 95]. The main parameters of iontophoresis are current density and drug concentration, the pH of the medium becomes crucial, however, because of its influence on drug ionization and tissue ionization, the former contributing to electromigration, while tissue ionization aids in electroosmosis [96]. Iontophoresis efficiency depends on the polarity, valence, and ionic mobility of the drug, as well as the composition and distribution of the drug [97]. Its influence on increased penetration usually occurs via a transappendix pathway that includes sweat glands and hair follicles because the ions tend to follow the path of least resistance or another pathway, such as transcellular and intercellular pathways [98, 99].

Topical Drug Delivery in Skin Cancer Therapy  167 For instance, liposomes have been studied for drug delivery associated to iontophoresis. Petrilli and collaborators [4] combined the use of topical liposomes and physical methods. For this, 5-FU liposomes and immunoliposomes were evaluated in vitro in porcine ear skin and in vivo in xenograft model. The results showed that, in vitro, the penetration of 5-FU into the viable epidermis was approximately 4.5 times greater than that observed in passive diffusion. In vivo, the mean tumor size after 22 days with iontophoresis application was approximately half the mean tumor size compared to subcutaneous treatment for the same period. Jose et al. [57] investigated the delivery of curcumin encapsulated in cationic liposomes and complexed with STAT3 siRNA in combination with iontophoresis for the treatment of cancer. The results showed that the delivery of curcumin together with siRNA STAT3 in liposomes significantly inhibited mouse melanoma cells (B16F10) compared to treatment without liposomes. Anodic iontophoresis at 0.47 mA/cm² was applied for 4 hours in excised porcine skin, resulting in increased penetration into the skin for liposome-siRNA loaded curcumin. Thus, the authors concluded that liposomes have the ability to be used with iontophoresis to favor the delivery of curcumin and siRNA to the skin to treat skin cancer.

8.4.1 Sonophoresis Sonophoresis refers to the application of ultrasound for the transport of drugs or nanoparticles into or through the skin [24]. The use of ultrasound waves in the range of 20 kHz to 1 MHz to increase the percutaneous absorption of a drug, in addition to soft tissue, it is known as sonophoresis [25, 100]. The frequency used regulates skin penetration or permeation, since it was observed that low frequency is more effective in the transdermal administration of large molecular weight drugs, such as proteins and the high frequency increases drug transport through the structural alteration of the skin and by increasing permeability [101]. The mechanism varies according to the frequency of each sonophoresis and is basically classified into thermal effects, which are defined by ultrasound energy absorption and cavitation effects, the latter being the most significant mechanism for permeation. The thermal effect on the skin may increase drug permeability due to an increase in diffusivity; however, it can be avoided by the replacement of the coupling medium. Cavitation can be basically divided into two types, namely: stable and transient cavitation. The pulsation of cavitation bubbles when in a process of several cycles at an acoustic pressure without collapse is known as stable cavitation; however, transient cavitation is characterized by bubbles in a faster growth over several cycles that normally form smaller bubbles, which is the main mechanism of low-frequency sonophoresis (LFS). This mechanism promotes the formation of micro-jets that appear when a flat solid surface causes the bubble to shrink and develop a high-speed liquid micro-jet that can reach speeds of hundreds of meters per second toward the solid surface, favoring increased permeability of the skin through structural changes occurred by high-pressure shock [26, 102, 103]. To the best of our knowledge, to date, the studies have focused on the effects of ultrasound in skin penetration of anticancer drugs but it was not found, studies addressed drugs loaded into liposomes or liquid crystalline nanodispersions and sonophoresis for topical treatment. Ma et al. [104] investigated sonophoresis-enhanced transdermal delivery of cisplatin in a nude BALB/c mouse cervical cancer xenograft tumor model. The results showed

168  Advances in Novel Formulations for Drug Delivery that sonophoresis favored the transdermal delivery of cisplatin under pulsed ultrasound which had an intensity of 2.0 W/cm2, in addition to a frequency of 1.0 MHz for a period of 60 minutes. Thus, the authors concluded that although there was no significant inhibition of tumor growth due to the short time, sonophoresis brought about an important increase in the concentration of cisplatin in the tumor and promoted the response of induction of apoptosis and inflammatory response. In another study, Pereira et al. [105] investigated whether low-frequency ultrasound (LFU) would have the ability to increase porcine ear skin permeability together with the use of hydrogels, in order to investigate its contribution to heterogeneous localized transport regions (LTRs) through coupling to LFU, in addition to investigating the importance of hydrogels for the penetration of calcein and doxorubicin. The results showed that treatment with LFU plus hydrogel increased the areas of LTRs and showed possible targeting of ionized drugs to specific skin layers; however; this depends on the zeta potential of the coupling medium.

8.4.2 Microneedles Microneedles (MNs) are three-dimensional structures formed by small projections with a variety of shapes and lengths. MN have a technology based on the formation of small micrometer-sized channels in the SC, promoting an increase in release and diffusivity of drugs across the skin barrier. In addition, this physical method can be advantageous because it is minimally invasive and painless. These properties become fundamental for patient compliance, in addition to allowing skin penetration into deep skin layers or targeting of molecules of molecules that can range from small hydrophilic drugs to macromolecules [24, 106, 107]. MNs are made of a variety of materials, such as metals, silicon, glass, non-degradable polymers, and carbohydrates [108, 109]. Regarding the types of MN, five types can generally be highlighted, namely solid microneedles, hollow microneedles, coated microneedles, dissolvable microneedles, and hydrogel-forming microneedles [108]. The use of solid MNs involves creating microchannels after application onto the skin. Afterward, the MNs are removed, and the drugs or nanoparticles are layered on the surface of the skin so that they can diffuse. Hollow MNs have hollow channels capable of injecting the drug or nanoparticles into the skin after its insertion. In addition, they provide easy dose control based on the patient’s need; however, skin compaction can limit the delivery rate and volume of the drug solution. Therefore, if the molecules are of high molecular weight, they can be rapidly delivered to the skin as a bolus using coated MNs. Coated MNs are obtained from solid MNs. These MNs have many advantages, including the long-term stability of solid phase microneedle with coated drugs. In this sense, because of advances in polymer chemistry and its favoring control over the physicochemical properties of polymers, the development of soluble MNs that have control over the drug delivery rate occurred. Soluble MNs are characterized by their biodegradable capacity and absence of active ingredients in their manufacture. Furthermore, the drug is loaded into the microneedle matrices, which makes a two-step administration process unnecessary. By the time MNs are applied onto the skin, they are dissolved and can release the drug from the needle, thus avoiding the need for a two-step drug delivery process as seen with solid MNs. Finally, hydrogel-forming MNs have also been reported. These microneedles are formed from hydrogel polymers, and this allows them to absorb

Topical Drug Delivery in Skin Cancer Therapy  169 interstitial fluid after insertion into the skin, which causes the hydrogel to swell. This forms channels that favor the passage of the drug through the skin [108, 110]. Thus, a couple of studies were successful in the topical delivery of chemotherapeutic agents when applying the microneedling technique in association with liposomes. Qiu et al. [111] reported the superiority of cutaneous penetration of docetaxel encapsulated into elastic liposomes by adding a step of pretreatment of microneedles in porcine skin in vitro. This resulted in increased transdermal flux (1.3–1.4 μg/cm2/h), and the latency time obtained after application was decreased by almost 70% compared to that obtained from conventional liposomes. Ahmed et al. [112] applied this method in a liposomal gel co-loaded with doxorubicin (DOX) and celecoxib, resulting in an approximately two-fold increase in skin penetration of DOX compared to passive delivery.

8.5 Conclusions and Perspectives Here, some main concepts about the cutaneous administration of drugs were a type of therapy for cancer and type of nanotechnology as liposomes and liquid crystals were presented and discussed. We briefly describe the skin layer and routes for administer drugs and some of the main subtypes of these nanocarriers and their importance given the advantages that these systems provide for application in skin cancer, as well as different methods of preparation and characterization were described. Studies of topical application in vitro and in vivo of liposomes and crystal liquid were also described and shown the increase of cutaneous absorption of drugs in the skin and decrease tumor volume in cancer studies. In addition, physical methods were highlighted as an important strategy to overcome the stratum corneum that constitutes an effective barrier of the skin.

Acknowledgements This work was supported by the National Council for Scientific and Technological Development (CNPq) (grants # 409352/2018-7; #409362/ 2018-2). We also thank Cearense Foundation for Scientific and Technological Development Support (FUNCAP) and PIBIC/ UNILAB for scholarships.

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174  Advances in Novel Formulations for Drug Delivery 71. Guo, C., Wang, J., Cao, F., Lee, R.J., Zhai, G., Lyotropic liquid crystal systems in drug delivery. Drug Discov. Today, 15, 1032–40, 2010. 72. Spicer, P.T., Hayden, K.L., Chester, W., Lynch, M.L., Ofori-Boateng, A., Burns, J.L., Novel process for producing cubic liquid crystalline nanoparticles (cubosomes). Langmuir, 17, 5748–56, 2001. 73. Silvestrini, A.V.P., Caron, A.L., Viegas, J., Praca, F.G., Bentley, M.V.L.B., Advances in lyotropic liquid crystal systems for skin drug delivery. Expert Opin. Drug Deliv., 17, 1781–805, 2020. 74. Seo, S., Chen, M., Wang, H., Sil, M., Leong, K.W., Kim, H., Extra-and intra-cellular fate of nanocarriers under dynamic interactions with biology. Nano Today, 14, 84–99, 2017. 75. Bazylinska, U., Kulbacka, J., Schmidt, J., Talmon, Y., Murgia, S., Polymer-free cubosomes for simultaneous bioimaging and photodynamic action of photosensitizers in melanoma skin cancer cells. J. Colloid Interface Sci., 522, 163–173, 2018. [Internet] Available from: https://doi. org/10.1016/j.jcis.2018.03.063. 76. Helvig, S.Y., Andersen, H., Antopolsky, M., Airaksinen, A.J., Urtti, A., Yaghmur, A. et al., Hexosome engineering for targeting of regional lymph nodes. Materialia, 11, 100705, May 2020. [Internet] Available from: https://doi.org/10.1016/j.mtla.2020.100705. 77. Praça, F.S.G., Medina, W.S.G., Petrilli, R., Bentley, M.V.L.B., Liquid crystal nanodispersions enable the cutaneous delivery of photosensitizer for topical PDT: Fluorescence microscopy study of skin penetration. Curr. Nanosci., 8, 535–540, 2012. 78. Lara, M.G., Vit, M., Bentley, L.B., Collett, J.H., In vitro drug release mechanism and drug loading studies of cubic phase gels. Int. J. Pharm., 293, 241–50, 2005. 79. Singhvi, G., Banerjee, S., Khosa, A., Chapter 11 Lyotropic liquid crystal nanoparticles: A novel improved lipidic drug delivery system, in: Organic Materials as Smart Nanocarriers for Drug Delivery, pp. 471–518, Elsevier Inc, Cambridge, 2018, [Internet] Available from: http://dx.doi. org/10.1016/B978-0-12-813663-8.00011-7. 80. Pan, X., Han, K., Peng, X., Yang, Z., Qin, L., Zhu, C. et al., Nanostructed cubosomes as advanced drug delivery dystem. Curr. Pharm. Des., 19, 6290–7, 2013. 81. Rarokar, N.R., Saoji, S.D., Raut, N.A., Taksande, J.B., Khedekar, P.B., Dave, V.S., Nanostructured cubosomes in a thermoresponsive depot system: An alternative approach for the controlled delivery of docetaxel. AAPS PharmSciTech, 17, 13, 436–445, 2015. https://doi.org/10.1208/ s12249-015-0369-y. 82. Lee, J. and Kellaway, I.W., Combined effect of oleic acid and polyethylene glycol 200 cubic phase of glyceryl monooleate. International Journal of Pharmaceutics, 204, 137–44, 2000. 83. Borné, J., Nylander, T., Khan, A., Phase behavior and aggregate formation for the aqueous monoolein system mixed with sodium oleate and oleic acid. Langmuir, 17, 7742–7751, 2001. 84. Shah, J.C., Sadhale, Y., Chilukuri, D.M., Cubic phase gels as drug delivery systems. Adv. Drug Deliv. Rev., 47, 2–3, 229–50, 2001. 85. Hong, S.H., Verduzco, R., Williams, J.C., Twieg, R.J., Dimasi, E., Pindak, R. et al., Short-range smectic order in bent-core nematic liquid crystals. Soft Matter, 6, 19, 4819–27, 2010. 86. Wang, X., Zhang, Y., Gui, S., Huang, J., Cao, J., Li, Z., Characterization of lipid-based lyotropic liquid crystal and effects of guest molecules on its microstructure: A systematic review. AAPS PharmSciTech, 19, 2023–2040, 2018. 87. Petrilli, R., Praca, F.S.G., Carollo, A.R.H., Medina, W.S.G., De Oliviera, K.T., Iamamoto, Y. et al., Nanoparticles of lyotropic liquid crystals: A novel strategy for the topical delivery of a chlorin derivative for photodynamic therapy of skin cancer. Curr. Nanosci., 9, 1–8, 2013. 88. Yaghmur, A., Tran, B.V., Moghimi, S.M., Non-lamellar liquid crystalline nanocarriers for thymoquinone encapsulation. Molecules, 25, 1, 1–14, 2020.

Topical Drug Delivery in Skin Cancer Therapy  175 89. Kim, D., Lim, S., Shim, J., Song, J.E., Chang, J.S., Jin, K.S., Cho, E.C., A simple evaporation method for the large scale production of liquid crystalline lipid nanoparticles with various internal structures. ACS Appl. Mater. Interfaces, 7, 20438–20446, 2015. 90. Sun, T., Dasgupta, A., Zhao, Z., Nurunnabi, M., Mitragotri, S., Physical triggering strategies for drug delivery. Adv. Drug Deliv. Rev., 158, 36–62, 2020. 91. Byrne, J.D., Yeh, J.J., DeSimone, J.M., Use of iontophoresis for the treatment of cancer. J. Control. Release, 284, 144–51, April 2018. 92. Gómez, C., Benito, M., Teijón, J.M., Blanco, M.D., Novel methods and devices to enhance transdermal drug delivery: The importance of laser radiation in transdermal drug delivery. Ther. Deliv., 3, 373–88, 2012. 93. Helmy, A.M., Overview of recent advancements in the iontophoretic drug delivery to various tissues and organs. J. Drug Deliv. Sci. Technol., 61, 102332, 2021. 94. Takmaz, E.A. and Yener, G., Effective factors on iontophoretic transdermal delivery of memantine and donepezil as model drugs. J. Drug Deliv. Sci. Technol., 63, 102438, 2021. 95. Tesselaar, E. and Sjöberg, F., Transdermal iontophoresis as an in-vivo technique for studying microvascular physiology. Microvasc. Res., 81, 1, 88–96, 2011. 96. Ciach, T. and Moscicka-Studzinska, A., Buccal iontophoresis: An opportunity for drug delivery and metabolite monitoring. Drug Discov. Today, 16, 7–8, 361–6, 2011. 97. Long, L., Zhang, J., Yang, Z., Guo, Y., Hu, X., Wang, Y., Transdermal delivery of peptide and protein drugs: Strategies, advantages and disadvantages. J. Drug Deliv. Sci. Technol. Elsevier B.V., 60, 102007, 2020. 98. Panchagnula, R., Pillai, O., Nair, V.B., Ramarao, P., Transdermal iontophoresis, in: Current Technologies to Increase the Transdermal Delivery of Drugs, pp. 41–52, 2010. 99. Wang, Y., Thakur, R., Fan, Q., Michniak, B., Transdermal iontophoresis: Combination strategies to improve transdermal iontophoretic drug delivery. Eur. J. Pharm. Biopharm., 60, 2, 179–91, 2005. 100. Joshi, A. and Raje, J., Sonicated transdermal drug transport. J. Control. Release, 83, 13–22, 2002. 101. Wong, T.W., Electrical, magnetic, photomechanical and cavitational waves to overcome skin barrier for transdermal drug delivery. J. Control. Release, 193, 257–69, 2014. 102. Park, D., Park, H., Seo, J., Lee, S., Sonophoresis in transdermal drug deliverys. Ultrasonics Elsevier B.V., 54, 56–65, 2014. 103. Wolloch, L. and Kost, J., The importance of microjet vs shock wave formation in sonophoresis. J. Control. Release, 148, 2, 204–11, 2010. 104. Ma, S., Liu, C., Li, B., Zhang, T., Jiang, L., Wang, R., Sonophoresis enhanced transdermal delivery of cisplatin in the xenografted tumor model of cervical cancer. Onco Targets Ther., 13, 889– 902, 2020. 105. Pereira, T.A., Ramos, D.N., Lopez, R.F.V., Hydrogel increases localized transport regions and skin permeability during low frequency ultrasound treatment. Nat. Publ. Gr., 7, 1–10, March 2017. 106. Gomaa, Y.A., Garland, M.J., McInnes, F.J., Donnelly, R.F., El-Khordagui, L.K., Wilson, C.G., Microneedle/nanoencapsulation-mediated transdermal delivery: Mechanistic insights. Eur. J. Pharm. Biopharm., 86, 2, 145–55, 2014. 107. Yamada, M. and Prow, T.W., Physical drug delivery enhancement for aged skin, UV damaged skin and skin cancer: Translation and commercialization. Adv. Drug Deliv. Rev. Elsevier B.V., 153, 2–17, 2020. 108. Sabri, A.H., Ogilvie, J., Abdulhamid, K., Shpadaruk, V., McKenna, J., Segal, J. et al., Expanding the applications of microneedles in dermatology. Eur. J. Pharm. Biopharm. Elsevier, 140, 121–40, 2019. 109. Khan, S., Hasan, A., Attar, F., Babadaei, M.M.N., Zeinabad, H.A., Salehi, M. et al., Diagnostic and drug release systems based on microneedle arrays in breast cancer therapy. J. Control. Release, 338, 341–57, August 2021.

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9 Vesicular Drug Delivery in Arthritis Treatment Nilesh Gorde, Sandeep O. Waghulde*, Ajay Kharche and Mohan Kale Konkan Gyanpeeth Rahul Dharkar College of Pharmacy & Research Institute, Dahivali, Parade Vengaon Road, Maharashtra, India

Abstract

Osteoarthritis could be a chronic disease of the joint cartilage and bone, usually thought to result from wear and tear on a joint, though there are several causes like congenital defects, trauma, and metabolic disorders. Cartilage is the slippery tissue that is available at the ends of bones in a joint, and in an inflammatory osteoarthritis, the cartilage in joints breakdown. In current era majority of the drugs are either poorly soluble and thus have bioavailability issues. Various methods are utilized and assessed to overcome these issues; however, none of these methods has covered the entire problems encountered in delivering the drug. Shortcomings, like poor efficacy, higher doses, low responsiveness, frequent administration, higher cost, and serious side effects, are associated with the conventional dosage forms for OA treatment. Vesicular systems are particularly significant for targeted delivery of drugs as of their ability to carry the drug to a particular site or organ of action and thus lowering its concentration to other sites in body. Various pharmaceutical carriers, such as particulate systems, polymeric micelles, macro, and micro molecules are presented in the form of novel drug delivery system. These drugs loaded nanocarriers may enhance the solubility of poorly water-soluble drugs, improve the bioavailability, afford targetability, and may improve the therapeutic activity. Nanomedicines are recently gaining more attention toward the treatment of OA, and researchers were also concentrating toward the development of variety of anti-inflammatory drugloaded nanoformulations with an aid to both actively/passively targeting the inflamed site to afford an effective treatment regimen for OA. Keywords:  Arthritis, vesicular carriers, topical drug delivery, bioavailability, nanocarriers, novel strategies

9.1 Introduction Arthritis is a major reason of disability and morbidity, particularly in older individuals. The symptoms and signs of arthritis and related conditions include pain, stiffness, swelling, muscle weakness, and limitation of movement of the joints [1]. The currently available oral dosage forms of NSAIDs, like tablet, capsules, etc., are more likely to produce adverse effects like GI toxicity, peptic ulcer, renal toxicity, and anaphylactic *Corresponding author: [email protected] Raj K. Keservani, Rajesh Kumar Kesharwani and Anil K. Sharma (eds.) Advances in Novel Formulations for Drug Delivery, (177–196) © 2023 Scrivener Publishing LLC

177

178  Advances in Novel Formulations for Drug Delivery reactions of these drugs. The intravenous administration of these drugs leads to distribution throughout the whole body and rapid clearance; thus, a high and frequent dosing is necessary to achieve an effective concentration of drug at inflamed target sites. Moreover, the activities of drug in many different tissues increase the risk of adverse effects in patients. However, oral steroids and rubefacients, such as capsaicin and intra-articular hyaluronan injections are not recommended for the treatment of OA due to their modest benefit and high rate of side effects [2–4]. Topical delivery of drugs can be a suitable option and is associated with advantages such as avoidance of hepatic first-pass metabolism, improved patient compliance and ease of access, provides a means to quickly terminate dosing, sustained therapeutic drug levels, possible self-administration, noninvasive, avoids food-related interaction, reduction of doses as compared to oral dosage forms and intravenous therapy and most important is avoidance of gastrointestinal adverse effects [4]. The topical drug delivery also suffers from some shortcomings such as poor permeability through skin, unpredictable drug release and skin irritation. These shortcomings can be overcome if we develop a transdermal drug delivery system in nanoscaled drug carriers, with enhanced localization to the target site and sustained drug release [5, 6]. Different types of pharmaceutical carriers, such as polymeric micelles, particulate systems, and macromolecules and micromolecules, are presented in the form of novel drug delivery system for targeted delivery of drugs. Particulate type carrier, also known as colloidal carrier system, includes lipid particles, microparticles and nanoparticles, microspheres and nanospheres, polymeric micelles, and vesicular systems like liposomes, sphingosomes, niosomes, transferosomes, aquasomes, ufasomes, and so forth. Vesicular systems offer a delivery means of drug in controlled manner to enhance bioavailability and get therapeutic effect over a longer period of time. Vesicular systems are lamellar structures made up of amphiphilic molecules surrounded by an aqueous compartment. Vesicular systems are useful for the delivery of both hydrophilic and hydrophobic drugs, which are encapsulated in interior hydrophilic compartment and outer lipid layer, respectively [7–10].

9.2 Skin Penetration Pathways Percutaneous absorption is defined as penetration of substances into various layers of skin and permeation across the skin into the systemic circulations [11–13]. Skin as an optimum route of administration offers various advantages but its barrier nature results in limited permeation [14]. As skin acts as a functional barrier between our body and surroundings so it allows the penetration of some compounds only, whereas repel the others. The obstructive nature of skin resides in its outermost layer, the stratum corneum. It prevents the entry of some molecules from outside to penetrate directly into the skin whereas allow penetration of liposoluble compounds easily. Further, nonionized molecules penetrate more rapidly as compared to ionized molecules [15–18]. Thus, it has been concluded that upper layer of the skin, the stratum corneum acts as a limiting barrier to the penetration. Thus, various attempts have been made to search several compounds or to develop the system that can enhance permeation to the circulatory system. Therefore, there are three major routes of penetration [19, 20].

Vesicular Drug Delivery in Arthritis Treatment  179

9.2.1 Intercellular Pathway The intercellular pathway by which most of the compounds thought to be penetrated is the penetration between corneocytes present in the stratum corneum [21, 22]. This route is a significant obstacle for two reasons. First, “bricks and mortar” model of the stratum corneum consists of 10- to 15-µm-thick matrixes of corneocytes, which is in contrast to the relatively direct path of the transcellular route. Second, the intercellular domain is a region of alternating structured bilayers. Accordingly, a drug must sequentially partition into, and diffuse through repeated aqueous and lipid domains. This route is generally accepted as the most common path for small uncharged molecules penetrating the skin [23, 24]. Various skin penetration enhancers also act by affecting the intercellular lipid bilayer, which constitutes this route. Skin penetration accelerators, such as diethyl sulphoxide, laurocapram (azone), glycols, and surfactants, act via enhancing the infiltration by decreasing the diffusional resistance of its intercellular lipid bilayers reversibly. These enhancers in spite of acting as solvents by solubilizing the intercellular lipids affect intercellular desmosomal connections or interfere with the metabolic activity, i.e., necessary for creating an intact barrier [25].

9.2.2 Transcellular Pathway Drugs entering the skin by directly passing through both the phospholipid membranes and the cytoplasm of the dead keratinocytes that constitute the stratum corneum. While this is the path of shortest distance, the drugs encounter significant resistance to permeation. This is because the drugs must cross the lipophilic membrane of each cell, then the hydrophilic cellular contents containing keratin, and then the phospholipid bilayer of the cell one more time method [26, 27]. Thus, the diffusion pathway for a drug via the transcellular route requires a number of partitioning and diffusion steps. These steps are repeated numerous times to traverse the full thickness of the stratum corneum. Very few drugs have the properties to cross via this. The transcellular pathway is, however, thought to be the predominant pathway for highly hydrophilic drugs during steady-state flux [28, 29].

9.2.3 Appendgeal Pathway Various scientists reported this pathway as less important pathway of drug. Hair follicles pass through the stratum corneum, allowing more direct access to the dermal microcirculation. However, hair follicles occupy only 1/1,000 of the entire skin surface area, therefore limiting the area available for direct contact of the applied drug formulation [30]. Understanding of the follicle distribution in the body is essential to study this route as a possible route for penetration. Sweat ducts are either empty or actively secreting an aqueous salt solution. Although an aqueous pathway across the skin is considered desirable for many drugs, permeation may be limited as sweat is travelling against the diffusion pathway of the permeant. Sebaceous glands are filled with a lipid-rich sebum, which may present a barrier to hydrophilic drugs [31, 32]. It was also reported that higher penetration rate was observed into the skin containing high density of follicles in comparison to the skin occupied with or without low density of follicles. Follicular penetration was observed for the topical delivery of DNA, nanoparticles, microspheres, and organic dyes in vivo and in vitro on human skin [33, 34].

180  Advances in Novel Formulations for Drug Delivery

9.3 Principles of Drug Permeation Through Skin In the initial transient diffusion stage, drugs molecules may penetrate the skin along the hair follicles or sweat ducts and then be absorbed through the follicular epithelium and sebaceous glands. When the steady state has been reached, diffusion through stratum corneum becomes the dominant pathway. The rate of drug penetration is expressed as the flux (J), i.e., the amount of drug penetrated per unit area, per unit time (usually µg cm−2 h−1). The flux can be determined by (a) the permeability of the skin to the permeant and (b) the concentration gradient (∆C) of the permeant across the skin (usually µg mL−1), according to Eq. 9.1:



J = Kp · ∆C

(9.1)

In Eq. 9.1, skin permeability is represented by the permeability coefficient, Kp (usually cm h−1. The permeability coefficient is a combined measure of the partition coefficient (P, which represent how readily the drug partitions from the formulation into the skin), the diffusion coefficient (D, which measures how readily the drug diffuses through the skin) and the diffusional path length (h), according to Eq. 9.2:



Kp = P · D h

(9.2)

The progression in partitioning and diffusion (and thus skin permeability, according to Eq. 9.2) is highly dependent on the physicochemical properties of the drug, such as molecular mass and hydrophilicity. As a general rule, molecules that penetrate the skin most readily have a molecular mass of < 500 Da and are moderately hydrophilic, with an octanol-water partitioned coefficient of 1 to 3. The quantitative relationship between skin permeability (Kp), molecular mass (MW), and hydrophilicity is widely described using Eq. 9.3:



Log Kp = 0.71· log Poctanol-water −0.0061·MW−2.74

(9.3)

Other measures that may influence skin permeation include hydrogen bond activity, melting point, molecular volume, and solubility. Other mathematical models have been devised to relate the role of these parameters to skin permeation [35–41].

9.4 Problems Associated with Conventional Dosage Forms Oral Conventional dosage forms for the treatment of arthritis like tablets and capsules are most widely used drug delivery system but both dosage forms face problem of gastric drug/ enzyme instability due to hepatic metabolism. Various problems are arising during taking pills; hence, problems are being faced during treatment. Sometimes, patients become noncompliant [42–44]. Transdermal patches are topical drug delivery system, which delivers medication through the skin in a noninvasive manner. The major drawbacks associated with the conventional dosage forms for the treatment of arthritis were short half-life, low bioavailability, and poor solubility, which may be improved by modified novel dosage

Vesicular Drug Delivery in Arthritis Treatment  181 Table 9.1  Conventional dosage forms for the treatment of rheumatoid arthritis.

Sr. no.

Therapeutic drugs with antirheumatic properties

Route of administration

1

Paracetamol

Mouth

2

Brand name

Side effect

Reference

Tylenol, Calpol

Liver damage, skin reactions, asthma

[49]

Naproxen

Synflex, Aleve, Accord

Heartburn, constipation, diarrhea, myocardial infarctions and strokes

[50]

3

Diclofenac

Voltaren

Ulceration, vascular and coronary risk, acute kidney failure

[51]

4

Celecoxib

Celebrex

Ulceration, bleeding, myocardial infarction

[52]

5

Indomethacin

Indocin

Peptic ulcer, dyspepsia, heartburn

[53]

6

Tramadol

Ultram

Nausea, dizziness, dry mouth, indigestion

[54]

7

Piroxicam

Feldene Gel

Headache, dizziness, nervousness, depression

[55]

8

Ketoprofen

Ketoprofen Fastum Gel

Erythema, eczema, pruritus

[56]

9

Capsaicin

CapzacineHP Gel

Intense tearing, pain, conjunctivitis,

[57]

10

Teriflunomide

Aubagio

Skin rashes

[58]

Topical

182  Advances in Novel Formulations for Drug Delivery forms [45]. Lipid and nonlipid vesicular systems available for arthritis treatments includes liposome, noisome, transferosome, and ethosome have been suggested to overcome the problems related to conventional topical formulations [46–48]. The conventional dosage forms available for the treatment of arthritis are displayed in Table 9.1.

9.5 Novel Treatment Strategies for Arthritis Novel vesicular drug delivery systems design to deliver the drug at per need of body during the period of treatment, and direct the active entity to the site of action. A number of novel vesicular drug delivery systems have been emerged encompassing various routes of administration, to achieve targeted and controlled drug delivery [59, 60]. The use of vesicular nanostructures in transdermal drug delivery is being extensively studied with authors reporting different findings depending on the composition and specifications of the vesicular system. Early studies recorded localizing effect for vesicles in which the amount of drug deposited in the skin was increased after loading into liposomes [61]. Liposomes still faces major deficiencies including lack of control over drug release rate, insufficient loading of drugs for which pH and ion gradients do not apply and lack of means to override biological barriers. Surface modification of conventional liposomes by the addition of hydrophilic components (e.g., carbohydrates, glycolipids or polymers) form long-circulating liposomes that cause changes in its pharmacokinetic pattern. The advancement in the field introduced new vesicular systems (transferosomes) capable of penetrating the intact skin delivering therapeutic amounts of drugs to the systemic circulation [62–64]. The biologic origin of lipidic vesicles was first reported by Bingham in 1965 and hence was named as Bingham Bodies. Vesicular systems are usually important for targeted delivery of drugs because of their ability to localize the activity of drug at the site or organ of action thereby lowering its concentration at the other sites in body [65]. The first-generation lipid-based vesicular carrier was called liposomes. Mezei and Gulasekharam first reported the publication in this field in 1980. However, the success of liposomal delivery was mainly limited by its vesicular size (typically 200–800 nm) and rigidity, which can impede skin permeation [66–68]. In 1992, Cevc and Blume introduced the second-generation vesicular carriers named ultradeformable liposomes or transferosomes, which possess smaller vesicular size (typically