This book comprehensively reviews the recent developments of natural polymers for drug delivery systems in various lung
233 126 11MB
English Pages 482  Year 2023
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Table of contents :
Editors and Contributors
1: Introduction to Lung Disease
1.2 Overview of Lung Disease
1.2.1 Chronic Obstructive Pulmonary Disease
22.214.171.124 The Genetic Origins
126.96.36.199 MicroRNAs´ Origins
188.8.131.52 Epidemiology (Hernandez-Gonzalez et al. 2021; Hoffman 2021)
1.2.5 Cystic Fibrosis
1.2.6 Lung Cancer
2: Natural Polymers for Drugs Delivery
2.2 Polysaccharide-Based Drug Delivery Systems
2.2.1 Alginate-Based Drug Delivery Systems
2.2.2 Cyclodextrin-Based Drug Delivery Systems
2.2.3 Chitosan-Based Drug Delivery Systems
2.2.4 Dextran-Based Drug Delivery Systems
2.2.5 Agarose-Based Drug Delivery Systems
2.2.6 Hyaluronic Acid-Based Drug Delivery Systems
2.2.7 Starch-Based Drug Delivery Systems
2.2.8 Cellulose-Based Drug Delivery Systems
2.3 Protein-Based Drug Delivery Systems
2.3.1 Collagen-Based DDS
2.3.2 Albumin and Gelatin-Based Drug Delivery Systems
2.4 Summary and Conclusion
3: Drug Delivery Systems Based on Various Natural Polymers for Lung Diseases
3.2 Merits of Natural Polymers
3.3 Demerits of Natural Polymers
3.4 Natural Polymer-Based Drug Delivery Systems for Lung Disease
3.4.1 Polymeric Nanoparticles
3.4.3 Polymeric Microparticles
3.4.4 Pulsatile Microcapsules
3.4.8 Polymeric Solutions
3.5 Devices for Delivery of Drugs
3.5.1 Dry Powder Inhalers
3.5.3 Metered Dose Inhalers
3.6 Advantages of Natural Polymers in Developing Drug Delivery System for Lung Diseases
Part I: Plant-Derived Natural Polymers Employed in Respiratory Diseases
4: Cellulose-Based Drug Delivery Systems in Lung Disorders
4.2 Characteristics of Cellulose
4.3 Global Production of Cellulose
4.4 Application of Cellulose and its Derivatives in Lung Diseases
4.4.1 Cellulose and Lung Cancer
4.4.2 Cellulose and Lung Infections
4.4.3 Cellulose and Influenza
4.4.4 Cellulose and Tuberculosis
4.4.5 Cellulose and Lung Tissue Engineering
4.4.6 Cellulose and Chronic Obstructive Pulmonary Disease
4.4.7 Cellulose and Asthma
4.4.8 Cellulose-Based Aerogels in Pulmonary Disease
5: Pectin-Derived Drug Delivery Systems in Respiratory Diseases
5.1.1 Preparation of Pectin
5.2 Applications of Pectin in Respiratory Diseases
5.2.1 Treating Lung Cancer
5.2.2 Treating Acute Exacerbations of Lungs
5.2.3 Inhibition and Prevention of Viral Infection
5.2.4 Treatment of Chronic Rhino-Sinusitis
5.2.5 A Sealant in Pleural Injury
5.2.6 As Efficient Microbial Agent
5.2.7 Nose-to-Brain Targeting
5.2.8 In Treating the Pain Episodes
5.2.9 Treating Asthma and Pulmonary Diseases and Respiratory Symptoms
5.2.10 In Preventing Tuberculosis in Macrophage Culture
6: Starch-Based Drug Delivery Systems in Lung Disorders
6.2 Sources and Characteristics
6.3 Overview of Starch Market
6.5 Application of Starch in Lung Disease
6.5.1 Starch and Asthma
6.5.2 Starch and Pulmonary Arterial Hypertension
6.5.3 Starch and Lung Cancer
6.5.4 Starch and Tuberculosis
7: Cyclodextrin-Derived Drug Delivery Systems in Respiratory Diseases
7.2 Sources and Physicochemical Properties of Different CD Derivatives
184.108.40.206 CDs from Natural Sources
220.127.116.11 CD Derivatives
7.2.2 Physicochemical Properties of Different CDs Derivatives
18.104.22.168 Alpha-Cyclodextrin (α-CD)
22.214.171.124 Beta-Cyclodextrin (beta-CD)
126.96.36.199 Gama-Cyclodextrin (gamma-CD)
7.3 Application of Various Cyclodextrin-Based Drug Delivery Systems for Respiratory Diseases
7.3.1 Chronic Obstructive Pulmonary Disease
7.3.3 Bacterial Pneumonia
7.3.4 Pulmonary Fibrosis
7.3.5 Lung Cancer
7.3.6 Severe Acute Respiratory Syndrome Coronavirus 2
7.4 Clinical Pertinency
8: Gum-Based Drug Delivery Systems
8.4 Classification of Gums
8.5 Characterization of Gums
8.6 Miscellaneous Pharmaceutical Applications of Gums
8.6.1 Tablet Formulations
8.6.2 Gums in Microencapsulation
8.6.3 Gums as Coating Agent
8.6.4 Gums as Gelling Agent
8.6.5 Gums as Emulsifying and Suspending Agent
8.6.6 Gums in Sustained Drug Delivery
8.6.7 Natural Gums in Intelligent Drug Delivery
8.6.8 Utilization of Gums as Film Formers
8.6.9 Normal Polymers for Theranostics
8.6.10 Normal Polymers for BioMEMS
8.7 Gums Used in Respiratory Diseases
8.7.1 Tamarind Gum
188.8.131.52 Chemical Composition
184.108.40.206 Physical Properties
220.127.116.11 Pharmaceutical Applications of Tamarind Seed Polysaccharide
In Sustained Drug Delivery
8.7.2 Almond Gum
18.104.22.168 Chemical Composition
22.214.171.124 Pharmaceutical Applications
8.7.3 Cashew Gum
126.96.36.199 Chemical Composition
188.8.131.52 Pharmaceutical Applications
8.7.4 Albizia Gum
184.108.40.206 Chemical Composition
220.127.116.11 Pharmaceutical Applications
8.7.5 Abelmoschus Gum
18.104.22.168 Chemical Composition
22.214.171.124 Pharmaceutical Applications
8.7.6 Ferula Gum
126.96.36.199 Chemical Composition
188.8.131.52 Pharmaceutical Applications
8.7.7 Cordia Mucilage
184.108.40.206 Chemical Composition
220.127.116.11 Pharmaceutical Applications
8.8 Physical Appearance and Chemical Structures of the Gums
9: Emergence of Glucomannan and Xyloglucan for Respirable Delivery
9.2.1 Konjac Glucomannan
18.104.22.168 Physicochemical Properties
22.214.171.124 Drug Delivery to Respiratory System
9.2.2 Bletilla Striata GM
126.96.36.199 Physicochemical Properties
188.8.131.52 Drug Delivery to Respiratory System
9.3.1 Physicochemical Properties
9.3.4 Drug Delivery to Respiratory System
10: Arabinogalactan-Based Drug Delivery Systems
10.1.1 Physical Characteristics
10.1.2 Chemical Nature
10.2 Pharmaceutical/Medical Applications of Arabinogalactan
10.3 Arabinogalactan in Pulmonary Drug Delivery
10.3.1 Arabinogalactan as a Complexing Agent
10.3.2 Arabinogalactan as an Immune-Modulating Agent
10.3.3 Arabinogalactan as Chemopreventive Agent
10.3.4 Arabinogalactan as Mucoadhesive Agent
10.3.5 Arabinogalactan as a Functional Excipient
Part II: Animal-Derived Natural Polymers Employed in Respiratory Diseases
11: Chitosan-Based Drug Delivery Systems for Respiratory Diseases
11.1.1 Modifications of Chitosan
11.2 Chitosan in Novel Drug Delivery Systems
11.2.1 Chitosan Nanoparticles (CNPs)
11.2.2 Chitosan Microspheres
11.2.3 Chitosan Microcapsules
11.2.4 Chitosan-Coated Liposomes
11.2.5 Chitosan Hydrogels
11.3 Chitosan-Based Vaccine Delivery
11.4 Limitations of Chitosan
12: Albumin for Application in Drug Delivery System for Lung Diseases
12.1.1 Treatment of Lung Diseases
12.1.2 Challenges in Lung Delivery
12.2 Novel Carriers for Lung Delivery
12.2.1 Albumin Drug Delivery Systems in the Treatment of COPD
12.2.2 Albumin as a Drug Delivery System in the Treatment of Lung Cancer
12.2.3 Applications of Albumin in the Treatment of Pulmonary Tuberculosis
12.2.4 Applications of Albumin in the Treatment of Asthma
13: Gelatin in Drug Delivery System for Treatment of Lung Diseases
13.2 Advantages of Gelatin as a Drug Delivery Carrier
13.3 Modification of Gelatin
13.3.1 Stealth Delivery
13.3.2 Targeted Drug Delivery
13.4 Mechanism for Drug Release
13.5 Applications of Gelatin as Drug Delivery Carrier in Lung Disorders
14: Hyaluronan and Chondroitin Sulphate-Based Drug Delivery Systems
14.2 Advantages of CS and HA as a Drug Delivery Carrier
14.3 Clinical Need to Develop a Safe and Effective Delivery System for Lung Disorders
14.4 Physiological Role of CS and HA
14.5 Applications of HA and CS as Drug Delivery Carrier in Lung Targeting
14.6 Products with HA and CS as Active Components
14.7 Conclusion and Future Prospects
15: Insulin-Based Drug Delivery Systems
15.2 Types and Analogues of Insulin Polymer
15.2.1 Various Types of Insulins Derived from Animals
15.2.2 Insulin Analogues
184.108.40.206 Fast-Acting Insulin Analogues
220.127.116.11 Delayed-Action Insulin Analogues
18.104.22.168 Porcine and Bovine Insulins
15.3 Novel Drug Delivery Systems Targeting Pulmonary Diseases
15.3.1 Mechanisms of Pulmonary Drug Administration
15.3.2 Strategic Criteria for Particle-Based Pulmonary Delivery Systems
15.3.3 General Pulmonary Drug Delivery Devices
15.3.4 Particle-Based Pulmonary Systems
15.4 Polymeric Nanomaterials: Characteristics and Uses in Insulin Delivery
15.4.1 Natural Polymers
15.4.2 Synthetic Polymers
15.5 Role of Insulin in Respiratory Mechanisms
15.5.1 Insulin and Lung
15.5.2 Insulin and Airway Smooth Muscle
15.5.3 Insulin and PI3K/Akt Signaling
15.5.4 Insulin, Wnt/beta-Catenin Signaling, and Airway Remodeling
15.6 Nano Platforms and Their Properties for Nano-Insulin Delivery
15.7 Future Perspective for Insulin Nano Therapeutics
Part III: Microorganisms Derived Natural Polymers Employed in Respiratory Diseases
16: Xanthan Gum-Based Drug Delivery Systems for Respiratory Diseases
16.2 Xanthan Gum
16.2.1 Rationale for Selection of Xanthan Gum
16.2.2 Modified Xanthan Gum Materials
22.214.171.124 Modification with Carboxymethylation
126.96.36.199 Esterified Xanthan Gum
188.8.131.52 Acetylated Xanthan Gum
184.108.40.206 Oxidized Xanthan Gum
220.127.116.11 Physically Modified Xanthan Gum
16.3 Xanthan Gum-Based Pulmonary Drug Delivery Systems
16.3.3 Matrix System
16.4 Clinical Trials
16.5 Xanthan Gum Functionalized Nanoparticles for Gene Therapy in Pulmonary Vascular Diseases
17: Dextran for Application in DDS for Lung Diseases
17.2 Dextran: The Physicochemical Alterations
17.2.1 Esters of Dextran
17.2.2 Ethers of Dextran
17.2.3 Dialdehyde Derivative of Dextran
17.2.4 Acetylated Derivative of Dextran
17.3 Dextran and Its Potential Derivatives for Drug Delivery Systems
17.3.1 Critical Attributes of Dextran
17.4 Multifaceted Role of Dextran in Drug Delivery System
17.4.1 Self-assembly of Dextran as Micelles
17.4.2 Dextran as Stabilizer in Nano-Emulsions
17.4.3 Coating with Dextran by Coprecipitation
17.4.4 Dextran as Cross-linking Agents
17.4.5 Dextran as Co-excipient in Spray-Dried Formulations
17.5 Dextrans in Drug Delivery: Perspectives and Prospects
17.6 Dextran-Based Novel Drug Delivery Systems in Respiratory Disorders: The Prior Art
17.6.1 Nanoparticulate Carriers
17.6.2 Microparticulate Carriers
17.6.3 Instillation Delivery System
17.6.4 Other Delivery Systems
17.7 Other Therapeutic Applications of Dextran
18: Pullulan in Drug Delivery System for the Treatment of Lung Disorders
18.1.1 Pullulan Biosynthesis
18.1.2 Strains Producing the Pullulan
18.1.3 Pullulan Derivatives
18.2 Beneficial Attributes of Pullulan
18.3 Pullulan-Based Drug Delivery System for the Treatment of Lung´s Disease
18.3.1 Pullulan-Based Nanogel for the Delivery of Drugs for Respiratory Ailments
18.3.2 Pullulan-Based Nanoparticles for the Treatment of the Respiratory Disease
18.3.3 Pullulan-Based Microparticles for the Treatment of Various Respiratory Disorders
18.3.4 Pullulan-Based Liposomes for the Treatment of Various Respiratory Diseases
18.4 Other Biomedical Applications of Pullulan
18.4.1 Gene Delivery at Specific Place in Human Body
18.4.2 Tissue Engineering
18.4.3 Film-Forming Agents
18.4.4 Molecular Chaperons
18.4.5 Plasma Expander
18.4.6 Medical Imaging
18.5 Limitations of Pullulan-Based DDS
Part IV: Algae Derived Natural Polymers Employed in Respiratory Diseases
19: Alginate-Based Drug Delivery Systems for Respiratory Disease
19.1.1 General Properties
19.1.2 Gelling Properties
19.1.3 Gel Formation
19.1.4 Gel Power
19.1.7 Structure and Characterization
19.1.8 Derivatives of Alginates
19.2 Application of Alginate and Its Derivatives in Lung Diseases
19.2.1 Alginate and Lung Cancer
19.2.2 Alginate and Lung Infection
19.2.3 Alginate and COPD
19.2.4 Alginate and Tuberculosis
19.3 Alginate-Based Drug Delivery Systems for Antifungal Drugs
20: Carrageenan-Based Drug Delivery Systems for Respiratory Disease
20.2 Classification of Carrageenan Polymers
20.2.1 Kappa (kappa)-Carrageenan
20.2.2 Iota (iota)-Carrageenan
20.2.3 Lambda (lambda)-Carrageenan
20.2.4 Mu (mu)-Carrageenan, Nu(nu)-Carrageenan, and Theta (theta)-Carrageenan
20.3 Carrageenan Polymer in Designing Diverse Drug Delivery Systems for the Management of Respiratory Disease
20.4 Applications of Carrageenan and Its Derivatives for the Treatment of Various Respiration/Lung Diseases
20.4.1 Role of CG in Respiratory Disorders Caused Due to Influenza Virus
20.4.2 Role of CG in Respiratory Disorders Caused Due to Bacteria
20.4.3 Role of CG in Respiratory Disorders Caused Due to SARS-Cov Virus
20.4.4 Role of CG in Respiratory Disorders Caused Due to HRV
20.4.5 Role of CG in the Treatment of Tuberculosis
20.5 Safety and Toxicology of Carrageenan
21: Agar-Based Drug Delivery Systems for Respiratory Disease
21.1 Introduction of Agar Polymers in Drug Delivery Systems
21.2 Classification of Agar Polymers
21.3 Physiological Barriers to Agar-Based Drug Delivery Systems
21.4 Application of Agar Polymer in Diverse Dosage Forms Which Can Be Used for Respiratory and Lung Disorders
21.4.1 Embedding of Bacteria
21.4.2 Agar-Based Microparticles
21.4.3 Agar as a Polymer for the Development of Films
21.4.4 Agar in a Form of Aerosols
21.4.5 Agar-Based Nanoparticles
21.4.6 Agar Used in the Formulation of Gels
21.4.7 Agar in the Preparation of Tablets
21.4.8 Use of Agarose as a Potential Polymer
22: Clinical Trials and Regulatory Issues of Natural Polymers Employed in Respiratory Disease
22.2 Preclinical Model Study
22.3 Regulatory Aspects of Natural Polymers in Pharmaceuticals
23: Elucidating the Molecular Mechanisms of Toxicity of Natural Polymer-Based Drug Delivery Systems Used in Various Pulmonary ...
23.2 Pulmonary Toxicity of Natural Polymer-Based Drug Delivery Systems
23.2.1 Oxidative Stress
23.2.4 Other Toxicities of Natural Polymers (Neurotoxicity, Nephrotoxicity, Hepatotoxicity, and Cardiotoxicity)
24: Compelling Impacts of Natural Polymer-Centered Drug Delivery Systems as Prophylactic and Therapeutic Approaches in Various...
24.2 Prevalent Pulmonary Disorders and the Current Therapeutic Approaches
24.2.1 Pulmonary Hypertension
24.2.2 Cystic Fibrosis
24.2.4 Chronic Obstructive Pulmonary Disorder (COPD)
24.2.6 Chronic Bronchitis
24.2.7 Lung Cancer
24.3 Natural Polymer-Centered Drug Delivery Systems
24.3.2 Alginates (Sodium Alginates)
24.3.5 Hyaluronic Acid
24.4 Advantages of Using a Natural Polymer-Centered Drug Delivery System for Lung Pathologies
25: Future Prospects of Natural Polymer-Based Drug Delivery Systems in Combating Lung Diseases
25.2 Natural Polymer-Based Drug Delivery for Lung Diseases
25.2.1 Polysaccharide NPs
18.104.22.168 Chitosan NPs
22.214.171.124 Alginate NPs
25.2.2 Gelatin NPs
25.3 Advantages and Disadvantages of Natural Polymer-Based Drug Delivery Systems in Lung Diseases
25.4 Future Aspect of Nature Polymer-Based Drug Delivery Systems in Lung Diseases
Harish Dureja · Jon Adams · Raimar Löbenberg · Terezinha de Jesus Andreoli Pinto · Kamal Dua Editors
Natural Polymeric Materials based Drug Delivery Systems in Lung Diseases
Natural Polymeric Materials based Drug Delivery Systems in Lung Diseases
Harish Dureja • Jon Adams • Raimar Löbenberg • Terezinha de Jesus Andreoli Pinto • Kamal Dua Editors
Natural Polymeric Materials based Drug Delivery Systems in Lung Diseases
Editors Harish Dureja Department of Pharmaceutical Sciences Maharshi Dayanand University Rohtak, Haryana, India
Jon Adams School of Public Health University of Technology Sydney Ultimo, NSW, Australia
Raimar Löbenberg Drug Development and Innovation Centre University of Alberta Edmonton, AB, Canada
Terezinha de Jesus Andreoli Pinto School of Pharmaceutical Sciences Universidade de São Paulo São Paulo, Brazil
Kamal Dua Discipline of Pharmacy, Graduate School of Health University of Technology Sydney Ultimo, NSW, Australia
ISBN 978-981-19-7656-8 ISBN 978-981-19-7655-1 https://doi.org/10.1007/978-981-19-7656-8
# The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, speciﬁcally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microﬁlms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a speciﬁc statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional afﬁliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore
Lung diseases are the biggest cause of death throughout the world. In recent years, natural polymers have attracted attention in the ﬁeld of pharmaceutical delivery. Pulmonary drug delivery with natural polymers is an exciting area of research that requires contributions from a variety of disciplines, including phytochemistry, pharmaceutical and medical sciences, drug delivery and aerosol physics. Biodegradable and bioreducible polymers are a fantastic option for a variety of innovative medication delivery systems due to their intended locations in a safe and effective manner. Several biodegradable natural polymeric carriers derived from various sources, such as plants (e.g., starch, cellulose, and pectin), animals (e.g., chitosan, albumin, and gelatin), microorganisms (e.g., xanthan gum, dextran, and pullulan), and algae (e.g. alginate) are used/investigated in various lung diseases. Animals, plants, and bacteria provide the majority of them. Natural polymers have less toxicity than synthetic polymers. Nanotechnology based on natural polymers may soon give considerable beneﬁts to humans in the management and treatment of fatal diseases, particularly lung ailments. The main objective of the book, Natural Polymeric Materials based Drug Delivery Systems in Lung Diseases, is to comprehensively provide an overview of natural polymers employed in respiratory diseases. The book adequately highlights a myriad of natural polymers obtained from plants, animals, microorganisms or algae for the drug delivery approaches for lung diseases. This book could be immensely informative for readers who are interested in recent developments in polymers-based drug delivery for lung diseases that could be targeted therapeutically, as well as the innovative drug delivery systems that may become mainstream in coming years for effectively treating the lung regions/cells/pathways that demonstrate associated pathology. The book rightly begins with an elaborate introduction to lung diseases, natural polymers for drug delivery and the drug delivery systems based on these natural polymers. Further, this book expands into four parts covering the various natural polymers for drug delivery systems for respiratory disorders. Part I of the book encompasses detailed chapters covering the plant-derived natural polymers employed for respiratory diseases. Thereafter, the book contains comprehensive chapters on animal-derived natural polymers as Part II; Part III consists of chapters on microorganisms-derived natural polymers, and algae-derived natural polymers v
employed in respiratory diseases are covered in Part IV. This section is followed by chapters comprising discussions on clinical trials and regulatory issues of natural polymers, elucidation of molecular mechanisms of toxicity of natural polymers and compelling impacts of natural polymers-centred drug delivery systems for various lung diseases. The ﬁnal section of the book exclusively summarises the future prospects of natural polymers-based drug delivery in combating lung diseases. The chapters in the book have extensive visual illustrations that make it easier for readers to understand the complex disease mechanisms. The editors believe that this book will be a valuable resource for academicians, researchers and industry-engaged working in the ﬁeld of natural polymers and drug delivery systems for treating lung disorders. It is also a valuable resource for translational researchers, graduates and postgraduates (master’s, PhD and postdoctoral researchers) of various disciplines including pharmaceutical and polymer sciences, biotechnology, immunology and medical & health sciences. The editorial team has extensive research experience in the ﬁeld of respiratory diseases and its associated drug delivery systems. The editors of this book would like to express their sincere gratitude to all the authors for their time and valuable contributions to the production of this book. Rohtak, Haryana, India Ultimo, NSW, Australia Edmonton, AB, Canada São Paulo, Brazil Ultimo, NSW, Australia
Harish Dureja Jon Adams Raimar Löbenberg Terezinha de Jesus Andreoli Pinto Kamal Dua
Introduction to Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sarita Rawat, Karuna Dhaundhiyal, Ishwar Singh Dhramshaktu, B. Tazneem, Roshan Salﬁ, Dinesh Kumar Chellappan, Harish Dureja, Sachin Kumar Singh, Kamal Dua, and Gaurav Gupta
Natural Polymers for Drugs Delivery . . . . . . . . . . . . . . . . . . . . . . . Manjit and Brahmeshwar Mishra
Drug Delivery Systems Based on Various Natural Polymers for Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sumita Singh, Kunal Arora, Kamal Dua, and Lubhan Singh
Plant-Derived Natural Polymers Employed in Respiratory Diseases
Cellulose-Based Drug Delivery Systems in Lung Disorders . . . . . . . Divya Suares, Srishti Shetty, and Saritha Shetty
Pectin-Derived Drug Delivery Systems in Respiratory Diseases . . . . 103 Himanshu Jain, Viney Chawla, and Pooja A. Chawla
Starch-Based Drug Delivery Systems in Lung Disorders . . . . . . . . . 115 Srishti Shetty, Divya Suares, and Saritha Shetty
Cyclodextrin-Derived Drug Delivery Systems in Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Vineet Kumar Rai, Jitu Halder, Tushar Kanti Rajwar, Goutam Rath Viney Chawla, and Pooja A. Chawla
Gum-Based Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . 147 A. Umamaheswari, M. Vijayalakshmi, S. Barath Raj, Dinesh Kumar Chellappan, and S. Lakshmana Prabu
Emergence of Glucomannan and Xyloglucan for Respirable Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 Megha Joshi and Bharti Sapra
Arabinogalactan-Based Drug Delivery Systems . . . . . . . . . . . . . . . . 183 Foziyah Zakir, Mamta Bishnoi, and Geeta Aggarwal
Animal-Derived Natural Polymers Employed in Respiratory Diseases
Chitosan-Based Drug Delivery Systems for Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 C. Sarath Chandran, Krishnameera Sajayan, Shijina Kappally, M. Gowtham, Alan Raj, and K. K. Swathy
Albumin for Application in Drug Delivery System for Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 Ritika Puri, Abhishek Sharma, Sanjay Sharma, and Vimal Arora
Gelatin in Drug Delivery System for Treatment of Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Shubham Thakur, Navid Reza Shahtaghi, Manjot Kaur, Riya Shivgotra, and Subheet Kumar Jain
Hyaluronan and Chondroitin Sulphate-Based Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 Manjot Kaur, Riya Shivgotra, Shubham Thakur, Navid Reza Shahtaghi, and Subheet Kumar Jain
Insulin-Based Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . 259 S. Lakshmana Prabu, N. Tamilselvan, S. N. Jegasubramaniam, A. Puratchikody, and A. Umamaheswari
Microorganisms Derived Natural Polymers Employed in Respiratory Diseases
Xanthan Gum-Based Drug Delivery Systems for Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Tarun Virmani, Girish Kumar, Reshu Virmani, Ashwani Sharma, and Kamla Pathak
Dextran for Application in DDS for Lung Diseases . . . . . . . . . . . . . 297 Sanyam Sharma, Subh Naman, Jayesh Dwivedi, and Ashish Baldi
Pullulan in Drug Delivery System for the Treatment of Lung Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Subh Naman, Sanyam Sharma, Jayesh Dwivedi, and Ashish Baldi
Algae Derived Natural Polymers Employed in Respiratory Diseases
Alginate-Based Drug Delivery Systems for Respiratory Disease . . . 361 Rishabh Gupta, Deblina Dan, Aanchal Singh, and Nimisha
Carrageenan-Based Drug Delivery Systems for Respiratory Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381 N. Vishal Gupta, Souvik Chakraborty, Balamuralidhara Veeranna, Riyaz Ali M. Osmani, Afrasim Moin, K. Trideva Sastri, M. Sharadha, and A. Ramkishan
Agar-Based Drug Delivery Systems for Respiratory Disease . . . . . . 397 N. Vishal Gupta, Souvik Chakraborty, K. Trideva Sastri, M. Sharadha, Balamuralidhara Veeranna, and A. Ramkishan
Clinical Trials and Regulatory Issues of Natural Polymers Employed in Respiratory Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 407 Tarif Hussian, Swagat Tripathy, Kamal Dua, and Harish Dureja
Elucidating the Molecular Mechanisms of Toxicity of Natural Polymer-Based Drug Delivery Systems Used in Various Pulmonary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425 Suhrud Pathak, Kruthi Gopal, Jack Deruiter, Rishi M. Nadar, Satyanarayana Pondugula, Sindhu Ramesh, Kamal Dua, Harish Dureja, Randall Clark, Timothy Moore, and Muralikrishnan Dhanasekaran
Compelling Impacts of Natural Polymer-Centered Drug Delivery Systems as Prophylactic and Therapeutic Approaches in Various Pulmonary Disorders/Lung Diseases . . . . . . . . . . . . . . . . . 445 Kruthi Gopal, Suhrud Pathak, Jack Deruiter, Rishi M. Nadar, Sindhu Ramesh, R. Jayachandra Babu, Courtney Suzanne Watts Alexander, Kamal Dua, Randall Clark, Timothy Moore, and Muralikrishnan Dhanasekaran
Future Prospects of Natural Polymer-Based Drug Delivery Systems in Combating Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . 465 Saman Yasamineh, Omid Gholizadeh, Hesam Ghafouri Kalajahi, Pooneh Yasamineh, Akram Firouzi-Amandi, and Mehdi Dadashpour
Editors and Contributors
About the Editors Harish Dureja is Professor and Head, Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak. Dr. Dureja is also the Director, Centre for IPR Studies and Director, Professional Consultancy Cell. Dr. Dureja has more than 22 years of teaching experience. He also holds 18 years’ research experience in the ﬁeld of nanoparticulate drug delivery, regulatory affairs and in silico ADME modelling. Dr. Dureja has been awarded with Gold-Medal for the best PhD thesis and research projects worth 1.2 Crore from various funding agencies. He has ﬁled an Indian patent and authored three books and more than 25 book chapters. He has published more than 200 research articles in various international and national journals of repute. He worked as Chairman-Scientiﬁc Services Committee (LOC) during 69th IPC at Chitkara University, Rajpura. He also worked as content writer for e-Pathashala program of Ministry of Human Resources Development for Post Graduate course of Pharmaceutical Sciences for the paper novel drug delivery system. He has delivered more than 180 invited Lectures in various conferences, seminars and symposiums and has guided 60 PG scholars and 11 students for doctoral work. He has been awarded the MDU Best Researcher Award–2020, Gold-Medal for Best PhD Thesis, Best Paper Award—Prof. M.L. Khorana Memorial Prize Award–2005 and Dr. R.L. Nicore award–2018. He has published six special issues as a Guest Editor for the Journals published by Bentham Science Publishers, and one issue published by Frontiers, Switzerland. He is currently also serving as President, Association of Pharmaceutical Teachers of India (APTI) Haryana State Branch. Jon Adams is Distinguished Professor of Public Health, Founder and Director of the Australian Research Centre in Complementary and Integrative Medicine (ARCCIM), and Deputy Head of School (Research), School of Public Health, University of Technology Sydney. Prof. Adams has attracted over $20M in external grant funding, and his work has involved interdisciplinary collaborations across many clinical, practice and project design areas. Jon has authored over 580 peerreviewed academic publications and is Chief Editor of 8 international research books and author of over 70 book chapters. Jon is the only Australian researcher ever to have attracted three consecutive Government Fellowships (NHMRC and ARC) xi
Editors and Contributors
focused upon complementary and integrative health care, and he was recently awarded a prestigious Fulbright Senior Scholarship (2019) to examine complementary and integrative medicine for vulnerable communities in Boston, US. Jon holds leadership roles at both the Public Health Association of Australia (PHAA) and the American Public Health Association (APHA), and his research has been commissioned by and/or partnered with the World Health Organization (WHO) and various Ministries of Health. Raimar Löbenberg holds a BS in pharmacy from the Johannes GutenbergUniversity in Mainz, Germany. He received his PhD in Pharmaceutics from the Johann Wolfgang Goethe-University in Frankfurt in 1996 for his work in drug delivery using nanoparticles. He joined the University of Alberta in the year 2000. His research interests are in Biopharmaceutics to predict the oral performance of drugs and botanicals and inhalable nanoparticles to treat lung diseases like lung cancer, tuberculosis or leishmaniasis. He is founder and director of the Drug Development and Innovation Centre at the University of Alberta. He was president of the Canadian Society for Pharmaceutical Sciences 2014–2015. He is the member of the United States Pharmacopeia Dietary Supplement Expert Committee. He is vice chair of the Specialty Committee of Traditional Chinese Medicine in Pharmaceutics of the World Foundation of Chinese Medicine Science. He is member of the Health Canada Scientiﬁc Advisory Committee on Pharmaceutical Sciences and Clinical Pharmacology. Dr. Löbenberg is also the member of the Health Canada Scientiﬁc Advisory Committee on Opiate Abuse. Terezinha de Jesus Andreoli Pinto educational background is in Pharmaceutical Sciences (Bachelor’s, Master’s and PhD). Her career is more than 40 years of sound experience in Academia, being currently Full Professor in one of the most prestigious Universities in Brazil: University of São Paulo. Dr. Andreoli Pinto develops and run researches on Dosage Forms, focusing on Parenterals (formulation, analytical, microbiological and performance methods) and Medical Devices. Under her supervision, out of 50 researchers concluded their scientiﬁc investigations, and she has authored 180 articles in scientiﬁc journals, over 12 book chapters. She also has two commercial patents to her name and have taken the management roles in the University, such as being Dean of School of Pharmacy for two mandates (2004–2008 and 2012–2016) and also being Chair of Deliberative Board of FURP—a pharmaceutical industry that manufactures products from the WHO Essential Medicines List and is run by Sao Paulo State Government. Strong scientiﬁc skills allied to leadership and management allowed her to establish agreements with internationally prestigious institutions (Universities of Alberta, Lisbon and Bath) as well as some important national scientiﬁc and educational institutions. Kamal Dua Senior Lecturer, Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney (UTS) has a research experience of over 12 years working in the ﬁeld of drug delivery targeting inﬂammatory diseases. Dr. Dua is also a Node Leader of Drug Delivery Research in the Centre for Inﬂammation at
Editors and Contributors
Centenary Institute/UTS and Senior Research Fellow, the Australian Research Centre in Complementary and Integrative Medicine (ARCCIM), where the targets identiﬁed from the research projects are pursued to develop novel formulations as the ﬁrst step towards translation into clinics. Dr. Dua researches in two complementary areas: drug delivery and immunology, speciﬁcally addressing how these disciplines can advance one another helping the community to live longer and healthier. This is evidenced by his extensive publication record in reputed journals. Dr. Dua’s research interests focus on harnessing the pharmaceutical potential of modulating critical regulators such as Interleukins and microRNAs and developing new and effective drug delivery formulations for the management of inﬂammation in chronic airway diseases and cancer.
Contributors Geeta Aggarwal Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi, India Courtney Suzanne Watts Alexander Department of Pharmacy Practice, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA Kunal Arora Kharvel Subharti College of Pharmacy, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India Vimal Arora University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, Punjab, India R. Jayachandra Babu Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA Ashish Baldi Pharma innovation Lab, Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India Mamta Bishnoi Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi, India Souvik Chakraborty Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, India Goutam Rath Viney Chawla School of Pharmaceutical Science, Sikhsa ‘O’ Anusandhan University, Bhubaneswar, Odisha, India University Institute of Pharmaceutical Sciences and Research, Baba Farid University of Health Sciences, Faridkot, Punjab, India
Editors and Contributors
Pooja A. Chawla Department of Pharmaceutical Chemistry and Analysis, ISF College of Pharmacy, Moga, Punjab, India Viney Chawla University Institute of Pharmaceutical Sciences and Research, Baba Farid University of Health Sciences, Faridkot, Punjab, India Dinesh Kumar Chellappan Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia Randall Clark Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA Mehdi Dadashpour Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran Deblina Dan Amity Institute of Pharmacy, Lucknow, Uttar Pradesh, India Amity University Uttar Pradesh, Noida, Uttar Pradesh, India Jack Deruiter Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA Muralikrishnan Dhanasekaran Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA Karuna Dhaundhiyal Amrapali Group of Institute, Haldwani, Uttarakhand, India Ishwar Singh Dhramshaktu Dr. Sushila Tiwari Medical College and Hospital, Haldwani, Uttarakhand, India Kamal Dua Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, Australia Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, Australia Priority Research Centre for Healthy Lungs, University of Newcastle & Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia Harish Dureja Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, India Jayesh Dwivedi Paciﬁc Academy of Higher Education and Research University, Udaipur, Rajasthan, India Akram Firouzi-Amandi Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Omid Gholizadeh Department of Bacteriology and Virology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Kruthi Gopal Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA M. Gowtham Department of Pharmaceutics, Sanjivani College of Pharmaceutical Education and Research, Kopargaon, Maharashtra, India
Editors and Contributors
Gaurav Gupta School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, India Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India N. Vishal Gupta Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, India Rishabh Gupta Future Group of Institutions, Bareilly, Uttar Pradesh, India Jitu Halder School of Pharmaceutical Science, Sikhsa ‘O’ Anusandhan University, Bhubaneswar, Odisha, India Tarif Hussian Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, India Himanshu Jain University Institute of Pharmaceutical Sciences and Research, Baba Farid University of Health Sciences, Faridkot, Punjab, India Subheet Kumar Jain Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India Centre for Basic and Translational Research in Health Sciences, Guru Nanak Dev University, Amritsar, India S. N. Jegasubramaniam Department of Pharmaceutical Technology, University College of Engineering (BIT Campus), Anna University, Tiruchirappalli, India Megha Joshi Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India Hesam Ghafouri Kalajahi Department of Biotechnology, Uskudar University, Istanbul, Turkey Shijina Kappally College of Pharmacy, Sharjah University, Sharjah, UAE Manjot Kaur Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India Girish Kumar School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, India Manjit Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, India Brahmeshwar Mishra Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, India Afrasim Moin Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail, Saudi Arabia
Editors and Contributors
Timothy Moore Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA Rishi M. Nadar Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA Subh Naman Pharma innovation Lab, Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India Nimisha Amity Institute of Pharmacy, Lucknow, Uttar Pradesh, India Amity University Uttar Pradesh, Noida, Uttar Pradesh, India Riyaz Ali M. Osmani Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, India Kamla Pathak Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Saifai, Etawah, Uttar Pradesh, India Suhrud Pathak Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA Satyanarayana Pondugula Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA S. Lakshmana Prabu Department of Pharmaceutical Technology, University College of Engineering (BIT Campus), Anna University, Tiruchirappalli, Tamil Nadu, India A. Puratchikody Department of Pharmaceutical Technology, University College of Engineering (BIT Campus), Anna University, Tiruchirappalli, India Ritika Puri University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, Punjab, India Vineet Kumar Rai School of Pharmaceutical Science, Sikhsa ‘O’ Anusandhan University, Bhubaneswar, Odisha, India Alan Raj Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India S. Barath Raj Department of Pharmaceutical Technology, University College of Engineering (BIT Campus), Anna University, Tiruchirappalli, Tamil Nadu, India Tushar Kanti Rajwar School of Pharmaceutical Science, Sikhsa ‘O’ Anusandhan University, Bhubaneswar, Odisha, India Sindhu Ramesh Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA
Editors and Contributors
A. Ramkishan Deputy Drugs Controller (India), Central Drugs Standard Control Organization, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, New Delhi, India Sarita Rawat Amrapali Group of Institute, Haldwani, Uttarakhand, India Krishnameera Sajayan College of Pharmaceutical Sciences, Govt. Medical College Kannur, Kannur, Kerala, India Roshan Salﬁ Deccan School of Pharmacy, Darussalam, Aghapura, Hyderabad, Telangana, India Bharti Sapra Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India C. Sarath Chandran College of Pharmaceutical Sciences, Govt. Medical College Kannur, Kannur, Kerala, India K. Trideva Sastri Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, India Navid Reza Shahtaghi Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India M. Sharadha Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, India Abhishek Sharma University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, Punjab, India Ashwani Sharma School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, India Sanjay Sharma Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India Sanyam Sharma Pharma innovation Lab, Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India Paciﬁc Academy of Higher Education and Research University, Udaipur, Rajasthan, India Saritha Shetty Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India Srishti Shetty Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India Riya Shivgotra Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
Editors and Contributors
Aanchal Singh Amity Institute of Pharmacy, Lucknow, Uttar Pradesh, India Amity University Uttar Pradesh, Noida, Uttar Pradesh, India Lubhan Singh Kharvel Subharti College of Pharmacy, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India Sachin Kumar Singh School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, Australia Sumita Singh Kharvel Subharti College of Pharmacy, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India Divya Suares Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India K. K. Swathy Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India N. Tamilselvan Department of Pharmaceutical Technology, University College of Engineering (BIT Campus), Anna University, Tiruchirappalli, India B. Tazneem Deccan School of Pharmacy, Darussalam, Aghapura, Hyderabad, Telangana, India Shubham Thakur Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India Swagat Tripathy Biocon Biologics, Bengaluru, Karnataka, India A. Umamaheswari Department of Pharmaceutical Technology, University College of Engineering (BIT Campus), Anna University, Tiruchirappalli, Tamil Nadu, India Balamuralidhara Veeranna Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, India M. Vijayalakshmi Department of Pharmaceutical Technology, University College of Engineering (BIT Campus), Anna University, Tiruchirappalli, Tamil Nadu, India Reshu Virmani School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, India Tarun Virmani School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, India Pooneh Yasamineh Cellular and Molecular Research Center, Research Institute for Cellular and Molecular Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
Editors and Contributors
Saman Yasamineh Department of Medical Biotechnology, Faculty of Advanced Science and Technology, Tabriz Medical Sciences, Tabriz, Iran Foziyah Zakir Department of B.Pharm (Ayurveda), School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
Introduction to Lung Disease Sarita Rawat, Karuna Dhaundhiyal, Ishwar Singh Dhramshaktu, B. Tazneem, Roshan Salfi, Dinesh Kumar Chellappan, Harish Dureja, Sachin Kumar Singh, Kamal Dua, and Gaurav Gupta
S. Rawat · K. Dhaundhiyal Amrapali Group of Institute, Haldwani, Uttarakhand, India I. S. Dhramshaktu Dr. Sushila Tiwari Medical College and Hospital, Haldwani, Uttarakhand, India B. Tazneem · R. Salﬁ Deccan School of Pharmacy, Darussalam Aghapura, Hyderabad, Telangana, India D. K. Chellappan Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia H. Dureja Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India S. K. Singh School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, Australia K. Dua Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, Australia Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, Australia G. Gupta (✉) School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, India Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 H. Dureja et al. (eds.), Natural Polymeric Materials based Drug Delivery Systems in Lung Diseases, https://doi.org/10.1007/978-981-19-7656-8_1
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Lung disease, which affects both adults and children, is on the rise worldwide. The following chapter provides a brief overview of some of the respiratory disorders currently affecting millions of people worldwide. The source of respiratory disease mortality and morbidity is uncertain; according to recent studies by the World Health Organization (WHO) and other agencies, nearly 400 million people worldwide suffer from mild to severe asthma and chronic obstructive lung disease (COPD) only. The pathophysiology of major lung diseases such as COPD, asthma, pneumonia, lung cancer, tuberculosis, and cystic ﬁbrosis is discussed in this chapter, with their limitations on existing treatment approaches. Keywords
Lung disease · COPD · Tuberculosis · Asthma · Lung cancer · Cystic ﬁbrosis · Pneumonia
The human respiratory system is divided into two main groups: the upper respiratory tract (URT) and the lower respiratory tract (LRT). The nose/nostrils, mouth, and the ﬁrst segment of the trachea make up the URT. The trachea is part of the LRT, which divides into bronchi, bronchioles, and alveoli, functional components. Lungs are the primary organs of the human respiratory system, allowing gaseous exchange from the outside atmosphere into circulation. Gas exchange into the pulmonary capillaries occurs typically through the lungs’ single membranes of the pulmonary alveoli (Agarwal and Neujahr 2021; Akiyama and Kaneko 2022). Inhalation, or the air intake into the lungs, mainly occurs by chest volume expansion, and the absorbed air then passes through the progressively narrower “conductive” airways; similarly, exhalation, or the expulsion of air from the lungs, occurs primarily through the chest volume contraction. Pulmonary mechanics comprises efﬁcient gas exchange, which involves a set of features and several indicators routinely used to check the lungs’ appropriate functioning. Spirometry is a safe, practical, and systematic ideal breathing test used in almost all clinical laboratories to examine lung ventilatory capacity and function (Amati et al. 2022; Ang et al. 2021). The standard lung volumes that are monitored include tidal volume (TV), inspiratory reserve volume (IRV), residual volume (RV), expiratory reserve volume (ERV), and other standard lung functions that are frequently tested include inspiratory capacity (IC), functional residual capacity (FRC), total lung capacity (TLC), and vital capacity (VC) (ArangoDíaz et al. 2021; Avci et al. 2022; Valluri et al. 2021; Vyas et al. 2017). The rising population and a transformation in lifestyle in the twenty-ﬁrst century have laid the groundwork for one of the many diseases that are now affecting human life beyond boundaries. The most common diseases were respiratory infections, affecting large populations in both middle- and low-income countries worldwide
Introduction to Lung Disease
Fig. 1.1 Difference in healthy and diseased lung. (a) Healthy lungs with normal alveoli and normal bronchiole. (b) Inﬂamed lung with inﬂamed alveoli and inﬂamed bronchiole
(Baker 2021; Bennet et al. 2021). The human lungs, one of the principal organs in the human body, are frequently exposed to various allergens and atmospheric contaminants, such as organic, inorganic, and biological toxins. These are the most common cause of lung disease (Fig. 1.1) (Bertolizio et al. 2022; Boechat et al. 2021; Mathur and Vyas 2013; Muchakayala et al. 2022).
Overview of Lung Disease
In the following chapter, we have covered some of the respiratory lung disorders currently affecting millions of people worldwide.
Chronic Obstructive Pulmonary Disease
Chronic Obstructive Pulmonary Disease is generally described as a curable and controllable illness with certain major extrapulmonary effects that might contribute to the seriousness in particular patients. Its respiratory component is distinguished by a limitation of airﬂow that is irreversible. Frequently, the airﬂow limitation is progressive and associated with an abnormal inﬂammatory response of the lungs to irritating particles or gases (Brown et al. 2021; Burgess and Harmsen 2022; Gobinath et al. 2021). COPD is deﬁned by the British Thoracic Society (BTS) as a moderately progressing illness indicated by airﬂow restriction that does not change
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signiﬁcantly during several months of monitoring. It is a common condition affecting 10% of the world’s population, drastically diminishing people’s quality of life and life duration. The World Health Organization predicts that COPD will be the third leading cause of death by 2030. COPD is expected to become more common in the next years due to continued contact with risk elements such as cigarette smoke and an older community. The Global Initiative for Chronic Obstructive Lung Disease requires three criteria to diagnose the chronic obstructive pulmonary disease (Caldeira et al. 2021a; Caldeira et al. 2021b): 1. Ratio of Forced expiratory volume (FEV1) to forced vital capacity (FVC) of less than 70% postbronchodilator. 2. “Relevant symptoms”, like dyspnea, sputum formation, prolonged cough, or wheezing. 3. “Frequent exposures to unpleasant environmental triggers”. There are at least three phenotypes of this disease: emphysema, prolonged bronchitis, minor lung remodeling and obstruction, and environmental and genetic variables that have a role in the disease’s origin and progression. The extent of airﬂow restriction, primarily FEV1, or composite measures that represent respiratory disorder and diagnosis, such as the body mass index (BMI), air ﬂow blockage, dyspnea, and exercise capability and age, dyspnea, and obstruction (ADO) index, have typically been used to decide COPD serious nature (Table 1.1) (Canan et al. 2021; Chen 2021; Churg 2022).
126.96.36.199 Etiology COPD is most typically triggered by cigarette smoking, although other hazardous particles, such as smoke from biomass sources, can also cause lung inﬂammation. The primary well-known risk factor for the development of COPD is smoking cigarettes. COPD often arises in lifetime nonsmokers, whereas less than 50% of regular smokers develop Chronic Obstructive Pulmonary Disease. After hitting adequate peak lung performance in young adulthood, several patients acquire Chronic Obstructive Pulmonary Disease due to speedy lung function decline, which is assumed to be induced by toxic particle inhalation. Another cause of long-lasting air ﬂow restriction is poor lung growth and development, which leads to characteristic lung function deterioration as individuals age (Canan et al. 2021; Chen 2021; Churg 2022). 188.8.131.52 The Genetic Origins For some patients, COPD and impaired lung function (FEV1, FEV1/FVC) may be diagnosed before birth. COPD family history reveals 18.6% of the populationrelated risk, with more severe illnesses, worse quality of life, and more recurrent exacerbations, according to independent family aggregation. Furthermore, asthma with family aggregation is an indirect threat factor for COPD (Collaco et al. 2021; Criner et al. 2021).
Introduction to Lung Disease
Table 1.1 Various stages of COPD Stages of COPD Treatment at this stage can include quitting Stage 1: Mild May have no symptoms smoking, taking particular medications, and Winded with moderate continuing pulmonary rehabilitation. exercise or walking upstairs Airﬂow = 80% of normal Stage 2: Frequent stop to catch a Medication, such as bronchodilators, antiModerate breath inﬂammatory drugs, and antibiotics are some Complain of coughing or treatment options for continued pulmonary wheezing, and breathlessness rehabilitation. Airﬂow = 50% to 79% of normal Inhalers, bronchodilators, oxygen treatment, Stage 3: Shortness of breath is and ongoing pulmonary rehabilitation are Severe worsened, used to treat stage 3 COPD. worsening symptoms Frequent ﬂare-ups or exacerbations that lead to hospitalization Airﬂow = 30% to 50% of normal At stage 4, bronchoscopy lung volume Stage 4: Oxygen levels Very severe Shortness of breath regularly reduction (BLVR) or lung transplant, in addition to the other treatments described in Flare-ups or exacerbations the early stages, are feasible therapy choices. can be life-threatening Airﬂow = less than 30% of normal Alpha-1 antitrypsin deﬁciency (AATD) is a genetic/family history condition. Risk factors Long-term exposure to second-hand smoking and other lung irritants, such as for COPD pollution, chemical fumes, and dust, may cause damage to pulmonary tissue. include
184.108.40.206 MicroRNAs’ Origins MicroRNAs (miRNAs) have been shown to perform a fundamental regulatory function in various biological procedures, considering cellular propagation, variation, and apoptosis, in a growing number of human/animal models and cell investigations. In addition, miRNAs are important in lung formation and respiratory disorders like COPD (Fig. 1.2) (D’Andrea et al. 2006; Danopoulos et al. 2021). 220.127.116.11 Pathophysiology COPD is distinguished by a limitation of airﬂow that is irreversible. The lack of elastic recoil due to emphysematous degradation of the parenchyma results in a steady drop in FEV1, insufﬁcient lung emptying on expiration, and subsequent static and dynamic hyperinﬂation. Inﬂammatory cells inﬁltrate the mucosa, submucosa, and glandular tissue after contact with smoking on a pathological scale. Cigarette smoke directly damages airway epithelial cells, releasing endogenous intracellular compounds or hazardous molecular sequences (Dietrich et al. 2021; Ding et al. 2021). These signals are recognized by pattern-recognition receptors on epithelial cells, such as Toll-like receptors 4 and 2, resulting in a nonspeciﬁc inﬂammatory response. When early cytokines (tumor necrosis factor and interleukins 1 and 8) are
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Fig. 1.2 Etiology of lung diseases. (a) Common triggers of COPD exacerbations. (b) Clinical and pathophysiologic effects of COPD
generated, they drive the innate immune response by attracting macrophages, neutrophils, and dendritic cells to the infection site. Additional ways could aid the inﬂammatory cycle. The immunological response of regulatory T cells is tapered, which protects against uncontrolled infection, and lower concentrations of these cells have been found in the lungs of COPD patients (Effendi and Nagano 2021; Eskind et al. 2021).
18.104.22.168 Treatment Bronchodilators and corticosteroids are among the inhaled drugs used to treat COPD. Dyspnea is treated mainly with as-needed bronchodilators, either β2 agonists or anticholinergics. In stages 3 and 4, doctors frequently recommend oxygen treatment to return blood oxygen levels to normal; however, this is only temporary. Once the oxygen supply is disrupted, the patient’s health quickly worsens back to its original state. Lifestyle modiﬁcations, such as stopping smoking, minimizing pollutants, and eating a more restricted diet, can help slow down the development (Espinosa and Raja 2022; Fazeli et al. 2021).
Introduction to Lung Disease
Asthma is a severe inﬂammatory illness of the lungs in which numerous different cells and cellular components are involved. Chronic inﬂammation causes lung hyper-responsiveness, which causes frequent attacks of breathlessness, dyspnea, chest stiffness, and coughing, especially at night or in the morning. Numerous cells and biological elements perform a role in the inﬂammation of the airways in asthma, including mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils, and epithelial cells. Such occurrences are typically characterized by severe but varying airway blockage, usually curable, either gradually or through therapy (Fernandez et al. 2021; Franquet et al. 2021). Severe asthma is still a global issue with a lack of knowledge of its mechanism. It is deﬁned by signiﬁcant treatment requirements to partially or control intense and frequent symptoms and massive use of hospital resources. Therefore, more effective asthma treatment is urgently required. Asthma was once considered a single diagnosis with the standard therapies for all patients; yet, it is presently recognized as a heterogeneous, complicated disorder incorporating several hereditary and environmental components, with specialized medicines enhancing asthma management. The most prevalent type of asthma is immunoglobulin E (IgE) mediated or allergic asthma, accounting for about 80% of chronic asthma episodes (Gersten et al. 2021; Gille and Laveneziana 2021). It can strike anyone at any age, but it is most common in children between four and forty. Patients with more clinically visible allergic asthma are those whose asthma ﬂuctuates according to seasons, locales, or exposures. Some patients with allergic asthma, on the other hand, are more challenging to detect. Asthma that is not caused by allergies is known as nonallergic asthma. There is no evidence of allergenspeciﬁc IgE and no correlation between allergen exposure and symptoms. Inﬂammations of the upper respiratory tract or sinuses are common causes of nonallergic asthma. (1) Atopic asthma usually develops throughout childhood or puberty and is linked to speciﬁc triggers that cause wheezing. Atopic asthma is frequently linked to a family background of allergic illnesses and atopy symptoms, including eczema and rhinitis. However, the most prevalent cause of the disease is an allergic reaction to speciﬁc allergens such as house dust particles, grass and tree spores, and hair from domestic pets. When atopic people are exposed to an allergen, their B lymphocytes generate an excessive amount of Immunoglobulin E (IgE). IgE attaches to cells associated with inﬂammation, causing inﬂammatory mediators to be released, causing bronchoconstriction and inﬂammation of the lungs. (2) Nonatopic Asthma, since the atopic disease is not responsible for all occurrences of asthma, other variables must be considered. Nonatopic asthma is a type of asthma that develops in adults as a result of viral respiratory infections. With few evident triggers other than infection, this type of asthma can be more chronic. Therefore, IgE is not required for nonatopic asthma (Gillett et al. 2021; Haine et al. 2021; Haque et al. 2021).
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22.214.171.124 Etiology Though no etiology for asthma has been detected, risk markers have been identiﬁed, and gene-environment interactions are essential. Asthma has a heritability of around 35 and 95 percent. Thus, genetics are recognized to play a part. Hundreds of genetic variants associated with an increased risk of asthma have been identiﬁed via extensive genomic research. Respiratory infections, especially viral infections in children, increase the likelihood of asthma, mainly if the symptoms are severe. Tobacco smoking, pollution, and ozone are examples of airborne contaminants that increase the risk of asthma. Asthma is associated with atopic illnesses and inhalant allergen sensitivity. It is believed that the microbiota, vitamin-D, chemical exposure, dietary changes, stress, and metabolites all have a role in the advancement of asthma (Harrison et al. 2021; He et al. 2021). 126.96.36.199 Epidemiology (Hernandez-Gonzalez et al. 2021; Hoffman 2021) From 2001 to 2009, the number of persons treated for asthma climbed by 4.3 million. As a result, the expense of asthma in the United States grew by about 6 percent between 2002 and 2007, from $53 billion to $56 billion. According to a 2012 National Center for Health Statistics data brief, the incidence rate increased from 7.3% in 2001 to 8.4% in 2010. From 2001 to 2009, the number of persons diagnosed with asthma grew by 4.3 million. Between 2002 and 2007, asthma expenses in the United States increased by about 6 percent, from $53 billion to $56 billion. In 2010, asthma was predicted to affect around 25.7 million individuals, including 18.7 million adults and 17.0 million children (aged 0 to 17). In addition, asthma death appears to be higher in females and adults. Between 2007 and 2009, the asthma death rate per 1000 asthmatics was 0.15. Females had more than 30 percent higher asthma death rates than males, blacks had 75 percent higher asthma death rates than whites, and adults had about seven times higher asthma death rates than children (Hou et al. 2021; Hu and Keat 2021). 188.8.131.52 Pathophysiology Asthma affects breathing by disrupting the trachea, bronchi, and bronchioles, all components of the lower respiratory tract. Bronchoconstriction, or abnormal constriction of the airways, is caused by epithelial damage, increased mucus production, bronchospasm, and muscle damage. Injuries to the epithelium - In asthma, the epithelium (a layer of cells covering the lungs) may be damaged and peel off. In some ways, epithelial shedding may produce airway hyper-reactivity, including the loss of barrier function, which may allow allergens to enter (Huang et al. 2021; Jain 2021). Airway Remodeling- Airway remodeling refers to a series of progressive anatomical changes in the airways. Changes in structural cells and tissues of the lower respiratory tract may result in airway remodeling and chronic ﬁbrotic damage in poorly managed or untreated asthma. These variations are most likely the outcome of recurrent events of inﬂammation in which inﬂammatory cells produce matrix
Introduction to Lung Disease
proteins and growth elements. It is also probable that repeated epithelial injury, followed by repair, results in airway remodeling. Due to diminished ﬂexibility, increased muscle mass, and mucosal edema, airways that have undergone considerable remodeling may not act as bronchodilators (Johannson et al. 2021). Airway Inﬂammation- In asthma patients, the severity, intensity, and duration of illness are determined by the level of inﬂammation. In sensitive people, introducing pathogenic substances initiates an immune reaction, resulting in an inﬂammatory cycle with varying degrees of airway blockage. In asthmatic airways, there are various inﬂammatory cells, most of which are in higher numbers. Among them are lymphocytes, mast cells, eosinophils, neutrophils, dendritic cells, and macrophages. All these things produce mediators that lead to inﬂammation, which is at the base of disease development. Mucus hypersecretion- As a consequence of asthma, the mucus-secreting cells in the airways proliferate, and the mucous glands swell. Increased mucus production leads to ﬂuid mucus clots that may clog the airways (Jukema et al. 2021; Kadura and Raghu 2021a).
184.108.40.206 Treatment An appropriate diagnosis of the type of asthma (allergic vs. nonallergic) and its intensity is necessary for effective asthma treatment. If asthma control is poor, further regulators such as inhaled long-acting beta 2 agonists (LABA), montelukast, and theophylline are given as the primary treatment. In addition, steroids are effective anti-inﬂammatory that has been utilized for the therapy of asthma. They are commonly given orally as prednisolone; however, inhalation treatment with modiﬁed spacing devices is also used (Kadura and Raghu 2021b).
Pneumonia is one of the primary causes of illness and mortality worldwide. Pneumonia is an inﬂammatory disease caused by bacteria penetrating and overgrowing in the lung parenchyma, breaking down barriers, and causing intra-alveolar secretions. For pneumonia to occur, the causative agent must reach the alveoli, and the host’s barriers must be overwhelmed by the microbe’s virulence or the volume of the inoculum. The risk of pneumonia has been associated with the nasal cavity, oropharyngeal, bioﬁlm, and respiratory tract colonies, primarily in delayed pneumonia. The following are some of the most common types of pneumonia: • Community-acquired pneumonia (CAP): illness obtained outside of a hospital environment. • Hospital-acquired pneumonia (HAP) is an illness that arises after a minimum of 48 h in the hospital. Immune resistance and tissue resilience are two factors determining pneumonia’s severity. Immune resistance is a word that refers to host processes that reduce the number of live microorganisms that cause illness by killing or eliminating them. The
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word “tissue resilience” refers to the mechanisms that allow the host to tolerate the stress of a pathogenic attack. Resilience mechanisms reduce pathophysiology by minimizing the harm caused by infections or immune resistance pathways rather than modifying microbial loads (Kapnadak and Raghu 2021; Karampitsakos et al. 2021).
220.127.116.11 Etiology The challenge in acquiring appropriate samples for culture and distinguishing infection from colonization and an absence of accurate diagnostic methodology make recognizing the etiologic agents responsible for pneumonia difﬁcult. Since the isolation of the causative organism does not exist in half of the cases, it is impossible to estimate the occurrence of the various bacteria responsible for pneumonia entirely and effectively. Yet factors such as age, underlying illness, and environment signiﬁcantly impact pneumonia’s microbiological etiology (Kershaw et al. 2021; Khanna et al. 2022). S. pneumoniae is one of the most common pathogenic sources of pneumonia disease and mortality in young kids, individuals with underlying chronic systemic disorders, and the elderly around the world. Staphylococcus aureus gram-positive microorganisms are amongst the most widely accepted isolates. 18.104.22.168 Epidemiology Pneumonia is still a major factor of illness and mortality around the world. Pneumonia was the eighth largest cause of mortality in the US in 2015, the fourth biggest reason of mortality globally, and the top cause of death in minimal-income nations. In addition, pneumonia has a high morbidity and death rate in the elderly. A current prospective investigation looked at 150 cases of pneumonia over 10 years in a Spanish LTCF (Khedoe et al. 2021). 22.214.171.124 Pathophysiology If the typical host defense systems operate regularly, pneumonia may not develop. Normal functions include nasopharyngeal air ﬁltration; laryngeal protection of the respiratory system from an oral and gastric ﬂuid; mucociliary clearance of particulate and pathogens from the upper and lower airways; normal cough reﬂexes and coughing strength; anatomically normal, unobstructed airway drainage; normal humoral and cellular immune function; and average innate biochemical and redoxbased host defense. The respiratory system ﬁlters dangerous infections inhaled. Bypassing the upper airway, artiﬁcial airways such as tracheostomy and endotracheal tubes allow unﬁltered air to enter the respiratory system (Khor et al. 2021; Kifjak et al. 2022). Cough-impairing disorders, such as neurologic disorders and even pharmaceutical cough restriction, might affect the lung’s potential to remove pathogenic particles. Infectious droplets might enter the proximal airways through the airways or the circulation. The affected region’s inﬂammatory response typically takes 1–2 weeks to organize, with enzymatic destruction of the collected white blood cells. These breakdown products are swallowed, coughed up, or reabsorbed by macrophages. The lungs stiffen and become less distensible due to acute infection
Introduction to Lung Disease
and edema. The patient’s breathing frequency will accelerate. Nutritional deﬁciencies and chronic conditions such as diabetes and renal failure make people more prone to pneumonia (Kochergin-Nikitsky et al. 2021; Kondoh et al. 2020).
126.96.36.199 Treatment Adequate antibiotic medication and supportive treatment, especially with oxygen in extreme cases, are necessary for efﬁcient pneumonia management. Cotrimoxazole or amoxicillin are used as ﬁrst-line treatments.
In immune-competent individuals with chronic tuberculosis, the lung is the most typically damaged organ, with predictions of lung participation ranging from 79 to 87%. Airﬂow blockage can occur in patients with pulmonary tuberculosis during either the active or post-treatment stage of the disease. Constitutional and pulmonary symptoms are the two types of symptoms. Whether the patient has primary tuberculosis or recurrence tuberculosis, the frequency of these symptoms varies. Primary tuberculosis patients are far more likely to be asymptomatic or only mildly unwell. The incidence of pulmonary TB airﬂow obstruction varies depending on the investigation, the deﬁnition of airﬂow restriction, and the geographic region. Six months after being diagnosed with TB, patients with pulmonary tuberculosis often have the largest decline in lung function, which stabilizes 18 months after treatment is completed. In pulmonary TB, the frequency and severity of airﬂow limitation are determined by the number of tuberculosis episodes (Lai et al. 2021; Lee et al. 2021; Liu et al. 2021a).
188.8.131.52 Etiology Mycobacterium tuberculosis, a rod-shaped, aerobic bacteria that may indeed produce spores, causes tuberculosis. Mycobacteria are acid-fast bacteria having a distinctive cell wall structure that is vital for survival. Acid-fast bacilli are bacteria that measure 0.5 m by 3 m in size. A substantial quantity of mycolic acid is covalently connected to the underlying peptidoglycan-bound polysaccharide arabinogalactan in the well-developed cell membrane, resulting in an excellent lipid barrier. Many of tuberculosis’s medically problematic physiological properties, such as drug resistance and host defense systems, are due to this barrier. The pathogenicity and growth speed of bacteria are inﬂuenced by the composition and amount of cell wall components. Mycobacteria depend on their cell walls to survive (Liu et al. 2021b; López-Cervantes et al. 2021). 184.108.40.206 Epidemiology The threat of tuberculosis to public health has resurfaced. Every year, TB claims the lives of over two million people, while an additional nine million get sick. Although the national TB case count was over 14,000 in 2006, down by about 3.2 percentage points from 2005, 20 states and the District of Columbia still had higher rates.
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One-third of the world’s population is infected with mycobacteria (Lu et al. 2021; Luppi et al. 2022).
220.127.116.11 Pathophysiology The contaminated droplets eventually settle around the airways after being inhaled. Upper airway goblet cells secrete mucus and capture the airborne bacilli’s bulk. Mucus acts as a trap for invading particles, and the cilia on the cell surface continually propel the mucus and its cargo upward and out of the cell. This procedure provides early physical resistance to infection in most persons who are vulnerable to TB. Drops of bacteria that escape the mucociliary system and reach the alveoli are quickly surrounded and ingested by alveolar macrophages, the most numerous immune response cells in these areas. Among these mechanisms is the involvement of macrophage receptors in the absorption of mycobacteria (Ma et al. 2021; Machado et al. 2021). Phagocytosis of bacteria also involves the complement system. C3 is a cell wall-attaching complement protein that aids macrophages in recognizing mycobacteria. Mycobacteria proliferate slowly after being swallowed by macrophages, with each generation of bacteria taking between 25 and 32 hours. Cell-mediated immunity is activated when cytokines are released, drawing T lymphocytes to the site of infection. When cell-mediated immunity is functional, granulomas develop around M tuberculosis organisms, marking the following line of defense. The lesions progress to primary advanced TB in persons with compromised immune systems. Depending on the patient’s immune system, tuberculosis may develop differently in each individual (Marčetić et al. 2021; McPherson et al. 2022). 18.104.22.168 Treatment In aspects of therapy, individuals with drug-susceptible pulmonary Tuberculosis must take four medications for 2 months, including isoniazid, rifampicin, pyrazinamide, and ethambutol, continued by isoniazid and rifampicin for another 4 months, as per WHO. However, multidrug-resistant Tuberculosis requires a more extended treatment period, with the WHO-recommended standard treatment comprising a thorough 8-month treatment stage involving at least four effective second-line tuberculosis drugs and pyrazinamide, accompanied by a follow-up stage involving at least three potent second-line antituberculosis drugs (McQuiston et al. 2021; Milad and Morissette 2021).
Mutations in the gene for the protein that controls ion transport across epithelial membranes cause the autosomal-dominant disease known as cystic ﬁbrosis (CF). Epithelial dehydration affects many organs, but the respiratory system, pancreas, reproductive system, and sweat glands are particularly vulnerable. First, the respiratory system is disrupted because of a thickening of the mucus around the airways caused by an osmotically driven drop in airway surface liquid levels, which reduces mucociliary clearance and promotes pathogenic organism colonization. Pathogens
Introduction to Lung Disease
such as bacteria, viruses, and fungi thrive in the thickened mucus of the conducting airways, setting off a vicious cycle of inﬂammation and infection (Milito et al. 2021; Mitra et al. 2021). Inﬂammation and infection set off a chain reaction that eventually leads to respiratory failure due to bronchiectasis and ﬁbrosis of the airways. A large number of CF-causing mutations have been discovered. However, only 22 mutations that occur in at least 0.1% of all known alleles have been reported. Many of the remaining modiﬁcations only manifest themselves in a single individual. Airways and submucosal (Mleczko et al. 2022; Neacşu et al. 2021) glands are often the ﬁrst to be affected by CF, with the interstitium and alveolar spaces remaining relatively untouched until late in the course of the disease.
22.214.171.124 Etiology S. aureus and H. inﬂuenzae, which can also be seen in other young children with chronic diseases and adults with non-CF bronchiectasis, are the most common causes of early infections in CF airways. S. aureus is frequently the ﬁrst pathogen grown in a young child with CF and respiratory tract (Nombel et al. 2021; Hemrajani et al. 2022; Paudel et al. 2022). 126.96.36.199 Epidemiology Cystic ﬁbrosis affects about 30,000 persons in North America, with 49.1 percent of them being adults aged 18 or older and a median survival time of 41.1 years, according to statistics collected in 2012 by the Cystic Fibrosis Foundation. Since the newborn screening was implemented in all 50 states by 2010, there have been around 1000 annual instances recorded, with 70 percent of infected babies discovered before the age of two. Predicted rates of occurrence range from 1 in 3200 in whites to 1 in 15,000 in individuals of African heritage, 1 in 35,000 in people of Asian descent, and 1 in 9200 to 1 in 13,500 in Hispanics (Nowak et al. 2021; O’Callaghan et al. 2021). 188.8.131.52 Pathophysiology Mutations in the CFTR gene (7q31.2) refer to the cystic ﬁbrosis transmembrane conductance regulator (CFTR), a protein that operates as an apical epithelial Cl channel. Ionic movement in tissue is affected by this channel’s dysfunction, which modiﬁes mucus features and affects the inﬂammatory cycle and body defenses. Recently, over 1900 mutations have been found and classiﬁed into six categories that indicate CFTR production, structure, and function problems. Due to lack or faulty protein biosynthesis, Class I mutations lead to the synthesis of no functional CFTR protein. Protein variations poorly digested or delivered to the apical cell membrane result from Class II mutations. Class III mutations impair CFTR activation and chloride transport across cell surface channels (Okwara and Chan 2021; Pathak et al. 2021). Class IV mutations generate problems that cause an average or reduced amount of CFTR and impair CFTR function at the apical epithelial cell membrane. Reduced quantities of fully functioning CFTR cause Class V mutations. The VI mutation class is indicated by decreased cell surface steadiness of a fully synthesized and functional CFTR, frequently resulting in CFTR reduction toward
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the carboxyl terminus. Cystic Fibrosis is caused by two CFTR mutations, which do not have to be from the same class. Class I, II, and III mutations are the most common types. Initial participation of respiratory and digestive signs (i.e., persistent cough, recurrent sinopulmonary infections, and exocrine pancreatic dysfunction) is generally associated with Class I, II, and III mutations. Class IV and V mutations are linked to exocrine pancreatic adequacy and lesser or later-onset lung disease. Secretion thickening, chronic obstructive lung disease, high Cl-levels in sweat, and exocrine and endocrine pancreas disorders are all symptoms of CFTR Cl-channel disruption (Peñaloza et al. 2021; Ptasinski et al. 2021; Gupta et al. 2018a; Gupta et al. 2020a).
184.108.40.206 Treatment A range of treatments can be utilized depending on the disease’s complexity and duration. Several patients receive conservative therapy, such as respiratory therapies, yearly inﬂuenza immunizations, and symptomatic breathing therapy as basic therapy. Nebulized hypertonic saline improves mucociliary clearance and enables the respiratory tract to be hydrated. Ibuprofen, as per the recent guidelines announced in 2013, can minimize lung performance decline in children under 18. In addition, ibuprofen is the only anti-inﬂammatory medicine approved for long-term usage in CF patients (Qiu et al. 2021; Raevens et al. 2021).
In the United States, lung cancer is among the most diagnosed cancers. It is also one of the easiest to eliminate. Lung cancer, like all malignancies, has the best chance of being cured if diagnosed early in the disease’s progression. Many persons with lung cancer, on the other hand, are detected at advanced stages, which are often deadly. Radiation treatment and chemotherapy are essential for these patients. Some symptoms noticed in lung cancer patients can also be found in persons who smoke or have other illnesses, such as upper respiratory tract infections (Rahman et al. 2022; Ravaglia and Poletti 2022; Gupta et al. 2014; Gupta et al. 2020b). The size and location of the primary tumor and the existence of metastatic disease inﬂuence the signs and symptoms. Cough, hemoptysis, wheezing, and dyspnea are common symptoms, yet a lesion identiﬁed by chest radiography in an asymptomatic patient is not uncommon. As the lesions grow larger and spread, other symptoms may occur. Coughing and wheezing are common symptoms of bronchus growth (Renzoni et al. 2021; Ruiz et al. 2021).
220.127.116.11 Etiology Lung cancer is caused primarily by smoking. About 75–80 percent of lung cancer deaths are reported to be caused by smoking. According to a 1995 study, 47 million adults in the United States smoke. Men (27 percent) are more likely than women to smoke (23 percent). The number of cigarettes smoked each day and years spent
Introduction to Lung Disease
smoking raise the risk of developing cancer. When a person stops smoking, the risk steadily decreases (Saab et al. 2021).
18.104.22.168 Epidemiology In most countries, lung cancer is the extremely common malignant neoplasm among men and the leading reason of cancer death in both men and women, taking into account an estimated 27 percent of all cancer deaths in the United States in 2015 and 20 percent in the European Union in 2016. The smoking intensity and lifetime length have proportional effects on risk—a large percentage of female lung cancer among nonsmokers in East and South Asia. As per GLOBOCAN, lung cancer caused approximately 1,242,000 new cases in males in 2012, accounting for 17 percent of all cancer cases omitting nonmelanoma skin cancer, and 583,000 (9 percent) in women. Lung cancer is also responsible for 19 percent of all cancer deaths. As a result, the drop in men’s lung cancer mortality rates has maintained in current years and is expected to continue in the near future (Table 1.2) (Samarelli et al. 2021; Sayani et al. 2021; Gupta et al. 2020c; Gupta et al. 2013). 22.214.171.124 Pathophysiology Small-cell carcinomas and nonsmall-cell carcinomas are the two types of lung cancer that can be found. Squamous cell carcinomas, adenocarcinomas, and large-cell carcinomas are the three types of nonsmall-cell carcinomas. Lung malignancies with squamous-cell carcinomas make up about 30% of all cancers. One of two types of tumors is most typically linked to smoking, the other being small-cell carcinoma. Squamous-cell tumors are most commonly detected in the chest’s middle region and develop slowly, doubling in size every 88 days. Squamous cell carcinomas are the ones that are more likely to stay in the center. Nonsmokers and women are more likely to get adenocarcinomas than smokers (Schreiber et al. 1946; Selman and Pardo 2021; Gupta et al. 2018b; Gupta et al. 2020d; Gupta et al. 2018c). Adenocarcinomas account for 30–40% of lung cancers. They expand toward the lung’s periphery and double in size every 161 days. Large-cell carcinomas are the least prevalent category of lung cancer, representing 10–15 percent of all cases. These tumors grow at a rate equivalent to squamous-cell malignancies in a peripheral location, multiplying in 86 days. Lung cancer, that is, small-cell carcinomas, accounts for 20–25 percent of all lung cancer. They like to develop in central regions and evolve quickly, with a doubling time of about 29 days. At the time of diagnosis, most patients with small cell carcinomas have advanced metastatic illness (Fig. 1.3). 126.96.36.199 Treatment The only possibly curative treatment for lung cancer is operative removal. However, because about 2/third to 3/fourth of patients with lung cancer may arrive with progressed and probably unresectable illness, it can only be provided to a small percentage of patients. Surgery can be offered to individuals presenting with stage IA to stage IIIA disease who can tolerate surgery. Chemotherapy, radiation treatment, or chemoradiotherapy are options for patients with more severe stages of cancer.
Large cell carcinoma
Accounts for about 10% of NSCLC cases
Lung cancer subtypes Prevalence (Annual number of people affected by the disease) Squamous cell Accounts for carcinoma About 25% of NSCLC cases Adenocarcinoma Accounts for about 40% of NSCLC cases
Table 1.2 Various types of lung cancer
Incidence (Average number of new cases per year) Decreasing
Central or peripheral location
The focus is usually peripheral, but it can sometimes be multifocal.
Location Usually central
Nonsmokers have the most common type. Atypical alveolar hyperplasia is a precursor to this condition.
Risk factors Highly correlated with smoking
Diagnosis of exclusion (i.e., no signs or symptoms of adenocarcinoma or squamous cell cancer)
Cancer of the alveolar surface epithelium or the bronchial mucosa (glandular) tissue. Cancer mimics glandular patterns.
Histological features Cancer of squamous epithelial cells
Squamous cell has a faster doubling time Often early metastasize Usually has a poorer prognosis than squamous cell carcinoma Can cavitate Metastasizes early (often to the Gl tract) The prognosis is identical to adenocarcinoma
Prognosis Slow-growing tumor
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Bronchoalveolar *variant of adenocarcinoma
About 3% of all lung cancer patients have this condition.
Increasing (corresponds to increase in adenocarcinoma)
Patients who are younger, female, and do not smoke are more prone to be affected. Cancer of type 2 pneumocytes Grows along alveolar septa (“lepidic” or scalelike growth)
Often radio and chemo-resistant In comparison to other NSCLC types, lymph node metastasis is limited. Better prognosis than non-BAC Adenocarcinoma
1 Introduction to Lung Disease 17
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Small cell carcinaoma
Squamous cell carcinoma
Large cell undifferentiated carcinoma
Fig. 1.3 Different type of lung cancer. (a) Small cell cancer (SCLC): early widespread metastasis, most common in heavy smokers. (b) Nonsmall cell lung cancer (NSCLC): affects smokers and people who do not smoke and mainly arises in bronchi and peripheral lung tissue
Lung infection has a major global burden and is becoming increasingly common in an older population, because of modern life style and a lack of adequate strategies to decrease the risk factors that promote the emergence, spread, and progression of these lung diseases. Despite extensive research into the etiology and epidemiology of several viral and noninfectious lung diseases, the discovery of more therapies is still in the initial stages. COVID-19, a recent outbreak triggered by the unique coronavirus family, is an excellent example of how a lack of natural immunity to neonatal mutants can seriously threaten global health. Even with more research and development of new CRD treatments, work needs to be done to ensure that treatment options are given to the pathological site, which involves the airway epithelium, parenchyma, and bronchioles. Treatments should also aim at particular cell types that may have played a signiﬁcant role in the disease’s progression.
Introduction to Lung Disease
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Natural Polymers for Drugs Delivery Manjit and Brahmeshwar Mishra
Drug delivery systems are often termed pharmaceutical formulations meant for the delivery of the therapeutic agents. The pharmacodynamic and pharmacokinetic behaviours of therapeutics agents in our body are directly linked with their physicochemical properties, i.e. Log P, solubility and plasma-protein interaction. So, these parameters need to be considered during formulation development process. The polymers help formulation scientists in maintaining or modifying the physicochemical properties of the therapeutics agent to get desired therapeutic response with minimal toxicity. The polymers are natural or synthetic large molecular weight macromolecules composed of repeating monomer units. Natural polymers are often termed biopolymers which are derived from the life cycle of the plant, bacteria, algae and animals. Towards the delivery of the active pharmaceutical ingredients, natural polymers played a major role. Natural polymers have inherent biocompatibility and biodegradability properties with ease of availability at an economical cost. That is why natural polymers always got special attention by the formulation scientists during the development of effective formulation. The signiﬁcance of natural polymers is such that they are not only used in traditional medicine but also play an attractive role in the development of novel delivery systems. In this chapter, we provided an overview of different natural polymers and elaborated about their role in formulation development.
Manjit · B. Mishra (✉) Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 H. Dureja et al. (eds.), Natural Polymeric Materials based Drug Delivery Systems in Lung Diseases, https://doi.org/10.1007/978-981-19-7656-8_2
Manjit and B. Mishra
Polymers · Natural · Polysaccharides · Drug delivery · Pharmaceutical
Polymers are macromolecular moieties formed by the repeated chemical bonding of monomer units. The number of the monomeric units, polymeric chain arrangement, the nature of the chemical bonds and the kind of monomer units mainly affect the property of the polymers. Polymers can be classiﬁed into different classes; on the basis of their origin, on basis of their application and on the basis of the fate of polymers in the living systems. Generally, we categorize polymers based on their origin as natural polymers, synthetic polymers and semi-synthetic polymers. Natural polymers are extracted from living sources and used after further puriﬁcation, i.e. Chitosan, Alginate, Gelatin, Cellulose, etc. Semi-synthetic polymers are prepared from the alteration in the monomer unit of the natural polymer, which modify the properties of the natural polymers, i.e. Hydroxy propyl methyl cellulose. Synthetic polymers are polymers whose monomer chains are tailored in the laboratory by polymerization and condensation reactions for speciﬁc purposes, i.e. Poly (Lactide-co-glycolic acid) (PLGA), Polycaprolactone (PCL) and Poly (Lactide-cocaprolactone) (PLCL), etc. (Qi et al. 2019). In pharmacy, polymers play a dynamic role in the design and development of different pharmaceutical formulations for speciﬁc purposes. Polymers used in the pharmaceutical speciﬁcally used as a suspending agent, emulsifying agents, binding agents, ﬂocculating agents, adhesives, coating materials and release modiﬁers. Although polymers from all origins have contributed to the development of formulations, but natural polymers due to their excellent biocompatibility, economical price, controlled enzymatic degradation, superior biological activity and easy procurement always attract the formulation scientist to use them for the development of the formulations. Natural polymers such as chitosan have the inherently antibacterial property. Hyaluronic acid is one of the important basic components of our body structure (Tibbitt et al. 2016). In comparison to the synthetic polymers, the natural polymer has high biocompatibility, ease of modiﬁcation and economical in nature. The natural polymer is also used in combination with other polymers to modulate the properties of formulation, i.e. use of gelatin in the polycaprolactone nanoﬁbre increases the hydrophilicity of the nanoﬁbre. Natural polymers modiﬁed with stimuli-sensitive groups provide stimuli-sensitive release of the therapeutics agents, i.e. Chitosan alone or in modiﬁcation provides the pH-sensitive release of the medicaments (Li et al. 2015).
Natural Polymers for Drugs Delivery
Polysaccharide-Based Drug Delivery Systems
Polysaccharides are generally composed of the monomer of D-glucose, D-fructose, Dmannose, D-xylose, L-galactose and L-arabinose, which combine together to form speciﬁc polymers. Polysaccharides are mainly derived from living systems such as alginate derived from the algae (alginic acid of the algae), pectin and guar gum from plants and dextran and xanthan gum from microbes and chitosan and chondroitin from an animal. These materials not just have excellent biocompatibility with the living physiology, but also they are biodegradable in nature. Polysaccharides’ properties can be modulated by grafting, conjugation or nano formulation techniques. In conjugation and grafting, polysaccharide chains are chemically linked with suitable polymeric chains or drug molecules to get the desired response. In nano formulation, we use the concept of nanotechnology and polysaccharide polymeric chains self-organize in such a way they form the drug encapsulate nanoparticles. In some cases, the polysaccharides form hydrogel and encapsulate the drug within its bulk chains. So, polysaccharides have a dynamic role in drug delivery applications. In, this section we will discuss the type of polysaccharides’ polymer and their role in drug delivery applications.
Alginate-Based Drug Delivery Systems
Alginates are extracted from the alkaline extracts of the brown seaweed Phaeophyceae. It is extracted in the form of alginic acid later which is converted into alginate which is the salt of the alginic acid. It consists of alternate repeating units of D-mannuronic acid and L-guluronic acid (Sahoo and Biswal 2021). Depending on the procurement, source alginate can have different proportions of mannuronic acid and guluronic acid. This ratio is responsible for different properties such as transmittance, swelling and viscoelasticity of the alginate gel. Alginate has excellent water solubility, biodegradability, biocompatibility, non-toxicity, bioadhesive and gel-forming ability, that is why it is widely used as a carrier in different micro or nano formulations (Bennacef et al. 2021). Alginate-based delivery system helps in the improvement of the pharmacokinetics and dynamics properties of the therapeutic molecules as shown in Table 2.2. Scolari et al. developed the chitosan-coated alginate nanoparticles of the rifampicin and ascorbic acid co-delivery for the treatment of the mycobacterium tuberculosis. The resultant formulation shows signiﬁcant antimicrobial activity against tuberculosis in several stains (Scolari et al. 2019). Banks et al. developed methods for the alginate modiﬁcations; the ﬁrst method involves amide bond formation between the alginate and 4-(2-aminoethyl) benzoic acid and the second method involves the reductive amination of the oxidized alginate for controlling the degradation rate of the alginate-based hydrogels for control release applications (Banks et al. 2019). Ahmed et al. working on alginate-based delivery systems developed the ciproﬂoxacin-loaded alginate-based wafers for diabetic foot ulcer applications. The ciproﬂoxacin-loaded alginate wafer shows a better release proﬁle and higher water
Manjit and B. Mishra
holding capacity. The porous structure of the lyophilized wafer results in optimal moisture condition around the wound which is essential for faster wound healing in diabetic feet (Ahmed et al. 2018). Zhang et al. developed the pH-sensitive ovalbumin-conjugated PLGA nanoparticle coated with chitosan and alginate to enhance response in ulcerative colitis. The developed nanoparticles show encapsulation efﬁcacy of 87.26% and a histological study of the colon tissue indicates that the formulation group shows a better response and results in tissue morphology similar to healthy tissue. But other groups show the signature of epithelial destruction. The efﬁcient adherence and mucous membrane penetration due to alginate and chitosan coating are the primary reasons behind this potential therapeutics response; which proves that the chitosan and alginate-coated resveratrol PLGA nanoparticle shows good therapeutic potential (Zhang et al. 2017).
Cyclodextrin-Based Drug Delivery Systems
Cyclodextrin is glucopyranosides ring conﬁgurations of 5–10 glucopyranosides units, which bind together with α-1, 4 glycosidic bonds to form different types of cyclodextrin. The arrangement of glucopyranosides units in cyclodextrin is such that it forms a truncated cone conﬁguration with multiple hydroxyl groups at each end which makes the inner pocket of the cyclodextrin hydrophobic without losing the hydrophilicity of the upper surface (Tian et al. 2021). Cyclodextrin was ﬁrst discovered as Cellulosine by Antoine Villers in 1891 and Schrodinger categorizes them as alpha (α), beta (β) and gamma (γ) cyclodextrin in 1901 (Table 2.1) (Poulson et al. 2021). Cyclodextrin such as α, β and γ cyclodextrin contains 6, 7 and 8 glucose units, respectively and prepared through enzymatic treatment of the starch. Cyclodextrin has various excellent properties and employed in numerous applications, i.e. drug delivery, dye-sensitized solar cells, supercapacitors, food technology and other environmental applications. Cyclodextrin also has numerous synthetic derivatives prepared through the substitution of glycosyl residue. For example, propyl, methyl and sulphonyl ether derivatives of α, β and γ cyclodextrin are some of the popular derivatives widely used in drug delivery. Cyclodextrin inclusion complexation with Table 2.1 An overview of the different derivatives of cyclodextrin (Poulson et al. 2021) Name α-Cyclodextrin β-Cyclodextrin 2-hydroxyl propylβ-Cyclodextrin Randomly methylated β-cyclodextrin γ-cyclodextrin 2Hydroxypropyl-γ-cyclodextrin
Degree of substitution – – 0.65
Molecular weight (Dalton) 972 1135 1400
Solubility in water (mg/mL) 145 18.5 >600
Natural Polymers for Drugs Delivery
speciﬁc molecules improves the solubility, stability, odour and taste of the guest molecules as described in Table 2.2. Jia et al. prepared the graphene quantum dot embedded γ-cyclodextrin complex, modiﬁed through poly (ethylene glycol) di-methacrylate for pH-responsive delivery of the doxorubicin. The in vivo antitumour experiment on MCF-7 bearing nude mice reveals that the drug-only and a saline group of the experiment show the 4.935*104 and 5.670*104 ﬂuorescent photon count as compared to the developed formulation which shows the 2.535*105 photon count which clearly indicates the increased accumulation rate and better targeting ability mediated through AS1411 receptor-ligand interaction (Jia et al. 2019). Das et al. prepared the stimuli-responsive nano β-cyclodextrin-based theranostic system. The β-cyclodextrin conjugated with maleic anhydride and N, N’ Methylene bisacrylamide provides a stimuli-sensitive response and ferric oxide conjugation provides hyperthermia-induced killing of the cells. The in vivo hepatocellular carcinoma study on the BALBc mice shows that the Doxorubicin-loaded modiﬁed β-cyclodextrin shows fewer signs of hepatic carcinoma in the formulation treatment group as compared to the doxorubicin-only group (Das et al. 2019). Another research group of Singh et al. develop the β-cyclodextrin grafted hyaluronic acid supermolecular polymer for the delivery of the doxorubicin and rhodamine. The resultant formulation shows the higher CD44 targeting in the HeLa cervical cancertargeting mediated through hyaluronic acid (Singh et al. 2021). The biosimilar product provided very excellent results in the recent decades, but the problem associated with the delivery of the biological molecules such as high molecular weight, fragile 3D structure and poor permeation ability limits their production. That is why biosimilar product and their delivery patents are major revenue sources for pharma giants in developed countries. To take advantage of this opportunity pharma giants across the globe, researching these problems and developing safer and more effective delivery of the biological molecules. Appleton et al. developed the β-cyclodextrin cross-linked Nano sponge for the intestinal delivery of insulin, the in vitro drug release of the formulation shows that the insulin-loaded nanosponge provides 25% of insulin release at pH 6.8 in comparison to the only 2.5% drug release in the 3 hours at pH 1.2. Also, the in vitro Caco-2 intestinal absorption in the nanosponge is three times more than free insulin (Appleton et al. 2020). Another researcher developed the cyclodextrin-based nanoparticles for the enhancement of the pharmacokinetic and stability properties of insulin. The study concluded that β-cyclodextrin insulin glulisine nanoparticles show a better stability proﬁle as compared to the insulin glulisine solution, the insulin glulisine solution degrades completely post-treatment proteolytic enzymes but the insulin incorporated in the nanoparticle shows no degradation after post-proteolytic action. The in situ glucose reductions’ study proves that intestinal administration of the β-cyclodextrin insulin complex shows good glucose reduction (within 60 min) for a time duration of up to 4 h as compared to the free insulin glulisine solution subcutaneous administration which shows a relatively faster dip in the glucose reduction for a relatively short time. So, the resultant behaviour of the insulin nanoparticles in comparison to the free insulin deﬁnitely provides a better response due to the improvement of the pharmacokinetics of the insulin (Presas et al. 2018).
Nanoparticles Nanoparticles Nanoparticles
Chitosan Chitosan Chitosan
2 3 4
Hydrogel Inhalation Microparticles Nanoparticles
Inclusion complex Inclusion complex Inclusion complex Hydrogel
Curcumin and crysin Quercetin –
Acute lung Injury Chronic obstructive pulmonary disease Lung cancer
(Huang et al. 2022)
(Vaghasiya et al. 2021a) (Abbasalizadeh et al. 2022) (Chen et al. 2022) (Prestisya et al. 2022)
(Kanagaki et al. 2021)
Pulmonary ﬁbrosis Alveolar disorder
(Togami et al. 2022)
(Jin et al. 2021) (Ding et al. 2022) (Dhayanandamoorthy et al. 2020) (Prasher et al. 2022)
(Gulati et al. 2021)
(Amar-Lewis et al. 2021) (Pandolﬁ et al. 2021)
Acute lung injury Lung injury Asthma
Hesperidin Glucocorticoids Ferulic acid
Hyaluronic acid modiﬁcation –
Hyaluronic acid modiﬁcation – Erythrocyte-hitchhiking Hyaluronic acid modiﬁcation Stearylamine grafting
Inhalable Nano micellar cluster –
S. No Polymer For Lung Disorders 1 Chitosan
Table 2.2 Applications of polysaccharides-based natural polymer in drug delivery
30 Manjit and B. Mishra
Dextran Dextran Cyclodextrin 2hydroxypropyl-γ-cyclodextrin
9 10 11 12
Insulin Doxorubicin Naringenin Dexamethasone
Cationic β-cyclodextrin –
Acryloyl modiﬁcation Cystamine modiﬁcation Chitosan modiﬁcation PLGA nanosphere
– Nanoparticles – Nano sphere
siRNA/ Paclitaxel –
Dextran coating on ferric oxide nanoparticles PEG modiﬁcations Methacrylate
Doxorubicin Paclitaxel, Silybin Doxorubicin
Microparticles Nanoparticles Poly(ε-caprolactone)
Succinate conjugation Succinic anhydride
16 Dextran For cancer and other diseases 1 Dextran 2 Dextran
Alginate-Fe3O4 modiﬁcation –
Lymph node imaging Dressing materials Antibioﬁlm in bacterial infection Insulin oral delivery Cancer Ocular delivery Increase entrapment for ocular delivery Oral delivery of insulin Antifungal activity
Colon cancer treatment Solid tumour treatment Cancer treatment
Pulmonary nodule diagnosis Tuberculosis
Natural Polymers for Drugs Delivery (continued)
(Gao et al. 2021)
(Zhang et al. 2010)
(Jamwal et al. 2019) (Yu et al. 2020) (Zhang et al. 2016) (Moya-Ortega et al. 2013)
(Tehrani et al. 2016) (Hu et al. 2021)
(Predescu et al. 2018)
(Wang et al. 2020)
(Jin et al. 2017)
(Delorme et al. 2020)
(Wang et al. 2019a) (Huo et al. 2020)
(Kadota et al. 2019)
(Zhang et al. 2022)
Alpha and β-Cyclodextrin
Formulation Inclusion complex Inclusion complex Nanoparticles
S. No 15
Table 2.2 (continued)
Silibinin Quercetin and Curcumin Ciproﬂoxacin Cefazolin/ ceftriaxone
Bovine serum albumin
Poly (N-isopropyl acrylamide) and benzimidazole terminated poly (ε-caprolactone) Poly (2-(dimethylamino) ethyl methacrylate) Poly (ethylene glycol) monomethyl ether Mesoporous silica particles
Colorectal carcinoma Oral cancer treatment Brain tumour Epidermoid carcinoma Antibiotic sustain delivery Sustain release
Stimuli-sensitive Chemotherapeutics delivery Breast cancer
Application Stimuli-sensitive anti-cancer therapy Stimuli-sensitive anticancer therapy Chemotherapeutics purpose
(Lohiya and Katti 2022) (Shahiwala et al. 2018) (Shariﬁ-Rad et al. 2021) (Alipour et al. 2020) (Agotegaray et al. 2017) (Manimekalai et al. 2017) (Manuja et al. 2018; Jamil et al. 2015)
(Liu et al. 2018)
(Wang et al. 2019b)
(Zhou et al. 2018b)
(Zhou et al. 2018a)
(Dai and Zhang 2018)
Reference (Bai et al. 2018)
32 Manjit and B. Mishra
Pluronic 85 modiﬁcation
Iron oxide particles with HA coating
Metronidazole and Salicylic acid Doxorubicin
Curcumin and Resveratrol Bismuth sulphide Vancomycin
Vascular endothelial growth factor (VEGF) Amphotericin B
Quinapyramine Sulphate siRNA and Doxorubicin Arg-Gly-Asp (RGD) peptides Indomethacin
Better cancer cellular uptake and endocytosis Inhibit multiple drug resistance in cancer
Photo thermal effect in cancer Control delivery of antibiotics pH-sensitive drug delivery Smart organogels
Visceral leishmaniosis Prostate cancer
Sustain release of poorly soluble drugs. Injectable implants
(Cho et al. 2011)
(Thomas et al. 2015)
(Sagiri et al. 2014)
(Kang et al. 2019)
(Unagolla et al. 2018)
(Saralkar and Dash 2017) (Zou et al. 2016)
(Gupta et al. 2015)
(DeVolder et al. 2013)
(Zhu et al. 2017)
(Han et al. 2010)
(Man et al. 2010)
(Manuja et al. 2018)
Natural Polymers for Drugs Delivery
Polymer Hyaluronic acid
S. No 41
Table 2.2 (continued)
DOTAP/ DOPE Liposomes
Citric acid modiﬁcation
S -Trityl-L-cysteine or cystamine Tyramine modiﬁcation
Surface conjugation of the HA on liposome
Modiﬁcation/conjugations Cisplatin conjugate
siRNA and Doxorubicin Doxorubicin
Stimuli-sensitive treatment Photo responsive treatment Increase cellular adhesion in cervical cell Flexible wearable medical devices Super absorbent
Application Reduce renal toxicity of the Cisplatin and Increase therapeutics and reduce toxicity in melanoma cells. Breast cancer treatment Melanoma
(Sangseethong et al. 2018)
(Zhang et al. 2021c)
(Bagheri et al. 2021)
(Hu et al. 2018)
(Zhang et al. 2021b)
(Fan et al. 2013)
(Park et al. 2014)
(Taetz et al. 2009)
Reference (Fan et al. 2015)
34 Manjit and B. Mishra
Natural Polymers for Drugs Delivery
Chitosan-Based Drug Delivery Systems
Chitosan is a polycationic biopolymer produced from the alkali deacetylation of chitin. It is available in powder, ﬁbres, and sponge form. It is a macromolecular polymer with various physicochemical and pharmacological properties, i.e. biodegradability, bioadhesive, biocompatible and antibacterial, antioxidant, hypoglycaemic effect, cholesterol and triglyceride trapping pharmacological effects. Chitosan is formed from the β-1,4 linkage of the glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (Kou, and Gabriel), Peters LM, Mucalo MR. 2021). Chitosan physiochemical characteristics depend on the degree of the acetylation and molecular weight of the polymeric chain. Chitosan has various applications from drug delivery to the green environment chemistry for treatment of the pollutants. Normally it is insoluble in water and soluble in weak acidic conditions (most suitable in 0.1% acetic acid solutions); but other factors such as molecular weight, degree of acetylation, ionic concentration, pH and distribution of the acetyl groups also affect the solubility of the chitosan. The chitosan is majorly used to improve the bioadhesion, surface wettability and pharmacokinetics’ characteristics of the therapeutic agents as shown in Table 2.2. Xie and Liu developed the pH-responsive carboxyl methyl chitosan-modiﬁed doxorubicin nanoparticle. The principle behind this development is to form a pH-sensitive polymer produced through poly (2-(diisopropylamine) ethyl methacrylate) chains grafting on the backbone of the carboxymethyl cellulose to provide pH-sensitive release of the doxorubicin. The resultant nanoparticles show the release of the approx. ~81% in the tumoursimulated environment, and drug leakage in the simulated normal physiological environment is approx. ~8 percent in 57 h which is much lower than other approaches (Xie and Liu 2020). Similar development by Wang et al. developed the galactosylated chitosan and graphene oxide nanoparticles loaded with doxorubicin. The nanoparticles demonstrate a higher tumour suppression efﬁcacy, as the nanoparticles show a tumour volume of 1385 ± 70 mm3, compared to the doxorubicin alone and saline group which have a tumour volume of 2603 ± 39 mm3 and 3797 ± 82 mm3 which clearly show that the nanoparticle encapsulated doxorubicin shows much better antitumour response in comparison to the control group (Wang et al. 2018a). Another research group developed the chitosan-modiﬁed composite that provides the controlled release of the vancomycin to improve the therapeutic potential of the vancomycin and prevent bioﬁlm production in osteomyelitis as shown in SEM image (Fig. 2.1) of Staphylococcus aureus reduction at pH 5.8 and 7.4 on chitosan biocomposite (Karakeçili et al. 2019).
Dextran-Based Drug Delivery Systems
Dextran-based drug delivery systems show decent biocompatibility, biodegradability and non-immunogenic response which provide this polymer an extra edge in comparison to other polymers. Chemically it is made up of glucan branched together with each other through glycosidic linkage and branched through α-1,2, α-1,3, α-1,4
Manjit and B. Mishra
Fig. 2.1 S. aureus attachment on Zeolitic imidazolate (ZIF)/chitosan scaffolds with different concentrations of vancomycin after 96 h of incubation in MH broth at (a) pH: 5.4 and (b) pH: 7.4. (Reprinted with permission from (Karakeçili et al. 2019))
linkage. Commercially it is produced through fermentation of the sucrose in the presence of the Leuconostoc mesenteroides NRRL B512 F strain and through the chemical ring-opening reaction of the levoglucosan (Díaz-Montes et al. 2021). Dextran molecular weight ranges from 107 to 108 Dalton, under acid condition hydrolytic cleavage of the chains, reduces the molecular weight of the dextran polymer. It is optically active and shows a speciﬁc rotation in the range of +199° to +235° (Hu et al. 2021). Dextran grades are divided on the basis of molecular
Natural Polymers for Drugs Delivery
weight and degrees of branching which ultimately depend on the time duration and process used for the production of the dextran. Dextran has many uses, its aqueous solutions in 6–10% medically used as blood plasma substitutes. Dextran (40 kD) improves blood ﬂow by reducing erythrocyte aggregation, Dextran (60 kD) is used as a blood volume expander, and dextran (70 kD) is medically prescribed for ophthalmic application. Dextran in drug delivery is used for the preparation of nano emulsions, micelles and nanoparticles or microparticles. Zhang et al. developed the pH-sensitive dextran doxorubicin micelles whose animal study on nude Balb/c mice 4T1 xenograft model shows the tumour growth volume of 296 mm3 in the formulation group as compared to the free doxorubicin which tumour growth volume of 627.21 mm3 and PBS only group show the growth volume up to 1376.35 mm3 which clearly indicate that the dextran doxorubicin micelles highly efﬁcient in treatment of the breast cancer (Zhang et al. 2020). Another research group developed the novel dextran and dextran aldehyde-coated silica aerogels for enzyme triggered 5-ﬂuorouracil release in the colorectal cancer. In this system, the dextran helps in enzyme-triggered release of the 5-ﬂurouracil. The 5-ﬂuorouracil solution provides 75–80% of cumulative percentage release in 2 h. The silicon oxide aerogel modiﬁed with dextran at intestinal 6.8 pH shows 3–4 percentage release in the absence of dextranase enzymes and up to 7–8 percent in the presence of enzyme in 24 h. But at collateral tumour pH 5.8, it shows the 30 percent of drug release in the presence of dextranase enzyme. The result clearly indicates that dextran-modiﬁed silica aerogel shows pH and enzyme-assisted prolonged release of the 5-ﬂurouracil (Tiryaki et al. 2020). Similar research on vascular delivery of protein components with dextran and poly l-arginine multilayer-coated calcium carbonate calcium nanoparticles provides uniform release of the protein component (bovine serum albumin) and increases formulation stability (Ferrari et al. 2021).
Agarose-Based Drug Delivery Systems
Agarose is a natural polysaccharide which contains repetitive units of agarobiose, a disaccharide of D-galactose and 3, 6 anhydro-L-Galactopyranose. It is obtained from the marine red algae, as agarose and through agaropectin (two major components of agar are agarose and agaropectin) extraction from agar. It has an average molecular weight of 100 kD with a melting point of 80–90 °C and possesses a slow degradation rate. It is soluble in hot water, Dimethyl sulphoxide and Dimethyl formamide, and after solubilization it forms a thermosensitive hydrogel (Guastaferro et al. 2021). It is biocompatible and widely used in microﬂuidics, electrophoresis, drug delivery, biosensor, gold separation and tissue engineering applications. Wang et al. developed the agarose-based gelatin and chitosan-modiﬁed nanoparticle for the delivery of the Stromal cell-derived factor 1 (SDF-1) and bone morphogenetic protein 2 (BMP-2). The SDF-1 and BMP-2 play a critical role in the development of the tissue development, but the delivery of SDF-1 and BMP-2 is limited due to the short half-life as it undergoes rapid degradation under in vivo conditions. The agarosebased nanoparticle provides protection from degradation under in vivo conditions
Manjit and B. Mishra
and prolongs the half-life. The in vitro drug release result reports that the SDF-1 and BMP-2-loaded nanoparticles provide initial burst release of the SDF-1 for 72 h followed by slow release up to 80% in 380 h and BMP-2 shows a release proﬁle similar to zero-order kinetics. This result clearly indicates that the modiﬁed nanoparticles have a sustained release effect (Wang et al. 2018b). Another researcher Zhang et al. developed the advanced agarose-based wound healing dressing material. The author concludes that agarose-based dressing reduces the total bleeding to 0.19 ± 0.03 g and haemostasis time up to 10 s, which ultimately proves that the agarose-based dressing is better dressing as compared to the regular gauze treatment (Zhang et al. 2018). Similarly, the use of agarose shows wide opportunity in the development of smart biomaterial for cartilage tissue engineering. Literature ﬁnding supports that the health of the cartilage diminishes with time under reduced oxygen and nutrient supply (Guaccio et al. 2008). But suitable biomaterial such as agarose can impact the metabolic performance of the cartilage as the agarose have two times higher oxygen utilization level than collagen. So, agarose-based biomaterials increase the oxygen level for the cartilage tissue and improve cartilage tissue function (Guaccio et al. 2008). Another researcher group modiﬁed the agarose gel with cyclodextrin for the controlled release of the doxorubicin. Kim et al. report that conventional agarose has a high gelling temperature which can be modulated with the functionalization of the agarose with cyclodextrin. The ﬁnal result of the study shows that the cyclodextrin-modiﬁed agarose shows an initial gelation temperature of 25 °C as compared to the agarose alone which has an initial gelation temperature of about 60 °C (Kim et al. 2019).
Hyaluronic Acid-Based Drug Delivery Systems
Hyaluronic acid is an essential component of our body, average adults have an approximately 15 g of hyaluronic acid, majorly present in the bones, joints, skin and eyes of their body. It is a component of the extracellular matrix and performs cell proliferation, migration and morphogenesis and controls the tissue macro and microenvironment. It is a non-sulphonated GAG and composed of repeated units of D-Glucuronic acid and N-acetyl-D-glucosamine linked through β-1, 3 glucuronides bonds. Hyaluronic acid molecular weight ranges from 20 to 200 kD with excellent solubility in the water (Ashraﬁzadeh et al. 2021; Zhang et al. 2021a). Hyaluronic acid has excellent application in drug delivery. Lu et al. developed the hyaluronic acid-based mesoporous silica nanoparticle loaded with doxorubicin. The Doxorubicin loaded in the pores of the mesoporous silica nanoparticles which later bonder with β-CD-grafted hyaluronic acid acts as a gatekeeper. At the low pH in the cancer tissue, the cleavage of the disulphide bond by GSH provides pH-sensitive doxorubicin release for cytotoxic effect. The in vitro cytotoxicity study on the 4T1 and 293T cell line shows excellent CD44-mediated cellular uptake of the nanoparticles. Hyaluronic acid helps in the CD44 mediating targeting of cancer and the TSH-sensitive release of the doxorubicin further improves the cytotoxicity (Lu et al. 2020). A similar approach was used by Miyazaki et al. to develop the
Natural Polymers for Drugs Delivery
hyaluronic acid-based pH-sensitive polymer-modiﬁed liposome for the intracellular release of the doxorubicin. The result reports that the 2-carboxycyclohexane-1carboxylated (Ch2)-conjugated hyaluronic acid unit shows the liposomes’ lipid membrane destruction under acidic pH, and 3-methyl glutarylated (3Gy)-associated hyaluronic acid-modiﬁed liposomes show the higher binding to CD44 receptor, as compared to the unmodiﬁed liposomes (Miyazaki et al. 2018). Batool et al. developed the papain-grafted hyaluronic acid-based mucoadhesives self-emulsifying drug delivery system of tamoxifen, the in vitro release study of the formulation shows that >80% of the drug release in 48 h and ex vivo permeation study reports 7.11 folds higher permeation of tamoxifen as compared to the pure tamoxifen (Batool et al. 2020). Another research developed the imidazole metal-organic frameworks coated with hyaluronic acid that produce the smart delivery of the tocopherol. The Hyaluronic acid smart coating provides the tumour environment-speciﬁc delivery of the medicament in the tumour’s acidic pH. The in vivo cytotoxicity and pharmacokinetic study of the nanoparticles on female Kunming mice show that the negative charge found on the nanoparticle surface provides a high circulation time. The histology study of the U14 xenograft model shows that the tumour volume of the formulation treatment group has a minimum growth which clearly indicates the efﬁcacy of the hyaluronic acid-modiﬁed metal-organic frameworks (Sun et al. 2019).
Starch-Based Drug Delivery Systems
Starch is composed of polysaccharide amylose which forms the linear backbone and amylopectin which forms the branched part. Amylose and amylopectin are made up of D-glucose units linked through α-1,4 linkage in amylose and α-1,4 linkage and α-1,6 linkage in amylopectin. Starch is a tasteless and odourless ﬂuffy powder which is insoluble in an aqueous system (Lemos et al. 2021). It is mainly obtained from the plant source, i.e. wheat, corn, potato, etc. As most plants store energy in the form of starch granules by changing the excess glucose into the starch. In the human body, excess glucose is stored in the form of glycogen. The reason behind storing glucose in the form of starch is the insoluble nature of the starch does not affect osmotically as compared to glucose when stored in excess amount (Chen et al. 2021). In pharmaceutical development, starch is used widely as an excipient in the manufacturing of tablets. Starch is a stable, cheap and easily available diluent. A simple corn starch pastes with a concentration of 10–20% are used as a binder for tablets and its different derivatives are used in the tablet-making process as binder disintegrant, diluent or to improve the properties of the APIs. The Sta-Rx-1500 is a popular starch-based diluent, binder and disintegrant which is used in the directly compressible tablets, another derivative of starch, i.e. Emdex and Cellutab, are widely acceptable diluents used in the Chewable table (Arhewoh et al. 2016). In the novel, drug delivery starch is a widely used polymer, Mariadoss et al. prepared the Helianthus tuberosus-loaded starch-based copper oxide nanoparticles conjugated with folic acid for the treatment of breast cancer. The in vitro cytotoxicity activity on
Manjit and B. Mishra
the MDA-MB-231 and cell line show that the nanoparticle produces good cytotoxicity as compared to the Helianthus tuberosus (Mariadoss et al. 2020).
Cellulose-Based Drug Delivery Systems
Cellulose is composed of D-glucose unit’s β-1,4 linkage, its molecular weight ranges from 104 to 105. Cellulose is the most abundant natural polymer on the earth. In cotton, approximately 90% of cellulose is present, and in wood approximately 40–50% cellulose present. It is used in a variety of applications but the timber industry and pharmaceutical industry have most predominately applications of cellulose (Nagarajan et al. 2021; Seddiqi et al. 2021). In drug delivery, the use of carboxymethyl cellulose is widely used for the synthesis of the hydrogel’s polymer due to its biocompatibility, ease in tailored chemical modiﬁcations and economical cost. Lee et al. prepared the CMC and PEG-Tetranorbornene hydrogels for the delivery of the protein drugs (Lee et al. 2016). Another research group developed the CMC- based injectable hydrogels to crosslink carboxymethyl cellulose with Schiff base reaction to provide rapid drug release at low pH (Shen et al. 2016). A similar development in the gastric ﬂoating delivery system uses starch /cellulose for the delivery of medicaments, Xu et al. developed the microcrystalline cellulose and gelose 50-based ranitidine gastroretentive system. The optimized formulation shows the ﬂoating behaviour in the stomach environment within the 5 min of the administration and lasts up to 36 h, and the ranitidine tablet shows the release of 62.16%, 97.27% and 99.55% in 0.5 h, 1.5 h and 2 h respectively, but the cellulose-modiﬁed ranitidine ﬂoating drug delivery system shows an initial rapid release of the medicament in initial one hour followed by sustain release (Xu et al. 2019). Another use of the cellulose derivatives is the development of the nanoﬁbre for different applications. Liakos et al developed the rosemary and oregano oil incorporated cellulose acetate-based nanoﬁbre drug delivery systems, which show the excellent antimicrobial against the S. aureus, E. coli and C. albicans and prevent bioﬁlms formation (Liakos et al. n.d.). Another researcher developed the cellulose-based nanoﬁbre for antiviral therapy. Huang et al., cellulose acetate phthalate nanoﬁbre (CAP) loaded with tenofovir shows the effective neutralization of the CD4 TZmbl cells with no toxicity on the vaginal epithelial cell (Huang et al. 2012).
Protein-Based Drug Delivery Systems
Collagen is one of the main structural proteins of our human body found majorly in connective tissues. It is made up of a group of amino acids bound together to form the triple helical structure. Approximately 30 types of collagens have been identiﬁed so far (Ricard-Blum 2011). But 80–90% of the human body majorly consists of Type I, II and III collagen. Collagen plays a structural protein role in the body; it is
Natural Polymers for Drugs Delivery
present in different parts and depending on the degree of mineralization it can be hard to soften. As in the bone and teeth, it is in the hardest form and in the cartilage and muscles, it is present in the much softer form. Commercial collagen is extracted from the bones and skin of bovine, porcine, ship, human placenta and marine sources. Nowadays recombinant human collagen from transgenic animals is also available in the market. Collagen has a variety of applications in the pharmaceutical which include the development of sponges for burns and wounds, protein delivery and control release formulations, collagen also has major use in the development of surgical dressing for faster wound healing. Copes et al. prepared the scaffold of the bovine collagen Type I to support the capillary formation and vascularization animal model (Copes et al. 2019). Different research across the globe reported that the loading proangiogenic growth factors in the collagen matrices help in release control for wound healing and tissue engineering applications. Wissink et al developed the heparin cross-linked collagen matrix for the delivery of the basic ﬁbroblast growth factor (bFGF) to improve the endothelialization of the vascular grafts (Wissink et al. 2000). Macaya et al. prepared the collagen-based injectable hydrogel containing ﬁbroblast growth factor-2 (FGF-2) for astrocyte inﬁltration in spinal cord injury and the published result reports that collagen hydrogel has astrocyte migration up to 2 mm in FGF-2/collagen hydrogel (Fig. 2.2) and provides better spinal cord treatment (Macaya et al. 2013).
Albumin and Gelatin-Based Drug Delivery Systems
Albumin is the most abundant plasma protein that serves as a transportation carrier for a variety of endogenous and exogenous components. Albumin has multiple hydrophobic binding sites for the attachment of different macromolecules (i.e. Fats and steroids) and small molecules. Albumin has a blood serum concentration of 35–50 g/L with a molecular weight of 66.5 kD. It is mainly produced in the liver and an average of 10–15 g of albumin is produced and cleared in the vascular space daily. It can have a blood circulation of ~19 days. Albumin consists of the three homologues’ domains and its 3D single-crystal X-ray crystallography image appears as a heart shape. Due to the multiple binding sites of the albumin, researcher across the globe developed numerous albumin-based drug delivery systems that are just limited to the laboratory bench but helping patients at the bedside. Currently, multiple Albumin-based formulations are already marketed by pharma giants and numerous are under the clinical trial for potential clinical beneﬁts (Table 2.3). Abraxane®, an albumin-bound paclitaxel formulation got approval for clinical use in 2005 for the treatment of breast, pancreatic and non-small cell lung cancer. The advantage of the album-bound paclitaxel is its lack of hypersensitivity as shown by the taxol another paclitaxel formulation, also the conjugation of the albumin to the Paclitaxel improves the pharmacokinetic properties of the paclitaxel resulting in better treatment. Another clinical molecule ABI-009 which is Albumin-bound docetaxel is under the clinical trial IIIrd for the treatment of hormone-refractory prostate cancer (Clinical Trial Number NCT00477529). On the laboratory level,
Manjit and B. Mishra
Fig. 2.2 Representation of ﬂuorescence microscopy image of the calcein-stained astrocyte migration into collagen hydrogel containing ﬁbroblast growth factor-2 (FGF-2), genpin (Gen) and lipid microtubules (LMT). The dotted line shows the interface of the hydrogel and astrocyte seeded cell (Image reprinted with permission from (Macaya et al. 2013))
MTX-HSA Aldoxorubicin CJC-1134 Eperzan
4 5 6 7
Abraxane® ABI-008 ABI-009 99mTcAlbures Albuferon®
8 9 10 11
S. No 1
Glucagon-like peptide-3 Methotrexate Doxorubicin Exendin-4 Glucagon-like peptide-1 Paclitaxel Docetaxel Rapamycin Technetium-99
Drug Insulin detemir
Disease Diabetes I and II Rheumatoid arthritis Diabetics type 2 Cancer Cancer Diabetics 2 Diabetes type 2 Cancer Cancer Cancer Diagnostic purpose Hepatitis C Phase III completed under human genome sciences in collaboration with Novartis
Marketed by Celgene Phase I/II by Celgene Phase I/IInd by Celgene Marketed by GE healthcare
Under Phase IInd by Access Pharmaceuticals Phase I completed by CytRx. Inc Phase IInd by ConjuChem Marketed by Glaxo Smith Kline
Marketed by Novo Nordisk
Clinical Phase IIIrd
Status Marketed by Novo Nordisk
Table 2.3 Albumin-bound formulation currently marketed or under clinical trial
(Larsen et al. 2016; Anonymous n.d.)
(Larsen et al. 2016) Clinical Trial No. NCT00477529 Clinical Trial No. NCT02009332 (Larsen et al. 2016)
(Bolling et al. 2006) (Kratz 2014) Clinical Trial no. NCT01706835 (Poole and Nowlan 2014)
(Elsadek and Kratz 2012)
Reference (Elsadek and Kratz 2012; Home and Kurtzhals 2006) (Larsen et al. 2016)
2 Natural Polymers for Drugs Delivery 43
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Choi et al. developed the albumin-bound doxorubicin nanoparticles for the selective delivery to the Broncho alveolar region (Choi et al. 2015). Gelatin is a natural polymer made up of the alkaline or alkali hydrolytic cleavage of collagen. It is made up of 18 different types of amino acids with a major proportion belonging to glycine, proline and hydroxyproline. All these amino acids bind together to form two types of polypeptide chains α, β & γ. The molecular weight of α, β & γ chains ranges from 9*104 g/mol, 18*104 g/mol and 30*104 g/mol respectively. Gelatin has a very rich application in the drug delivery application as described in Table 2.4. Cheng et al. developed the Chitosan and Gelatin-modiﬁed thermosensitive gel for the dual drug delivery in glaucoma; the resultant formulation gives the release of curcumin and latanoprost in a sustained manner. Also, the formulation maintains the concentration of the medicament below 20 μM which prevents toxicity to the healthy cells (Cheng et al. 2019). Another research developed the biodegradable Gelatin-based Nano sphere for the pH-sensitive release of the diclofenac sodium which shows the initial burst release for 3 h and then sustained release for 27 h (Curcio et al. 2013). The chemical structures of various natural polymers are illustrated in Fig. 2.3.
Summary and Conclusion
Natural polymers play a vital role in maintaining and modifying the physicochemical properties of the therapeutic agents. Natural polymers originated from a natural source, i.e. plant, animal or marine source and used in raw form after puriﬁcation from the principal source. On the basis of the monomeric unit, natural polymers are further classiﬁed into polysaccharides-based natural polymers and protein-based polymers. The Polysaccharides-based natural polymers generally have D-glucose, D-fructose, D-mannose, D-xylose, L-galactose and L-arabinose as repeated monomeric units and protein-based polymers have the amino acid as a monomer unit. The natural polymers are widely employed in formulation development due to their excellent biodegradability, biocompatibility, and also providing control release proﬁle with improved bioavailability. Alginates are biopolymers that originate from marine seaweed, carry excellent swelling, viscoelastic and possess bioadhesive properties and majorly employed in the preparation of control release nanoparticle or hydrogel formulations. Cyclodextrin previously termed Cellulosine consists 5–10 glucopyranosides units, which are arranged in such a way that it forms a cavity inside its chemical structure. This host-guest complexation of cyclodextrin provides unique physiochemical properties to the guest molecule. The cyclodextrin inclusion complexes are widely used in drug delivery for the improvement of solubility, stability, taste and pharmacokinetics of the therapeutic agents. Chitosan, a polycationic polymer produces from the deacetylation of the chitin. It not just provides the excellent biodegradability, bioadhesive, biocompatible and pH-sensitive release to the therapeutic agents but inheritably have antibacterial, antioxidant, antidiabetic, cholesterol trapping and other pharmacological activity. It is used widely in the preparation of stimuli-sensitive nano formulation preparation
10 Albumin Nanoparticles For cancer and other diseases 1 Gelatin Nanoparticles
Bovine serum albumin as a model drug Doxorubicin
Gelatin cross-linked nanoparticles Gelatin iron oxide nanoparticles –
Collagen-modiﬁed gold nanoparticles Collagen/chitosanmodiﬁed gold nanoparticles –
Basic ﬁbroblast growth factor
Gelatin-coated silica nanoparticles –
Human bladder cancer
pH-responsive drug delivery
Metastasis lung cancer
Pulmonary lung disease
Angiotensin-converting enzyme 2 receptor-binding domain - 62 Pirfenidone
(Ding et al. 2012) (Madan et al. 2011)
(Wen et al. 2021) (Luo et al. 2021)
(Hongsa et al. 2022)
(Zhang et al. 2021d) (Otsuki et al. 2022) (Vaghasiya et al. 2021b) (Moin et al. 2021) (Anwar et al. 2022) (Yu et al. 2021)
(Li et al. 2022)
Table 2.4 Applications of protein-based natural polymer in drug delivery
Natural Polymers for Drugs Delivery
S. No Polymer For lung disorders 1 Gelatin
Table 2.4 (continued)
Tannic acid and lignin modiﬁed
PEG- Gelatin hydrogel loaded with liposomes Liposome loaded hydrogels PLGA modiﬁed
Vascular endothelial growth factor (VEGF) Isoniazid and Rifampicin
Control release of medicament
Smart of control release
Improved release rate
Control release of the biological agents Prevent drug resistance in tuberculosis treatment Lesser toxicity and higher duration of actin Storage and transportation of propolis Excellent antibacterial activity against Pseudomonas aeruginosa Imaging
(Won and Kim 2008) (Anandhakumar et al. 2017) (Pourjavadi and Doroudian 2015) (Choi et al. 2016)
(Fuchs et al. 2010) (Magadala and Amiji 2008) (Bhavsar et al. 2006)
References (Saxena et al. 2005) (Jătariu (Cadinoiu et al. 2012) (Kaul and Amiji 2005) (Xu et al. 2012)
46 Manjit and B. Mishra
Bovine Serum Albumin Albumin
Bioconjugation with sodium alkyl sulphate Polysorbate 80 stabilization N-(2-hydroxypropyl) methacrylamide
Albumin microsphere containing liposomes
BMP-2 (Bone morphogenetic protein) Vancomycin
Diazepam and Paclitaxel
Fludarabine and Epirubicin
Liposome encapsulated Silk modiﬁcation
Improve drug loading capacity
Increasing the bioavailability
Topical treatment in cancer
Local delivery of medicament
(Benkő et al. 2015) (Taneja and Singh 2018) (Smith et al. 2016)
(De Jesús et al. 2016)
(Teodora Tihan et al. 2015) (Tihan et al. 2016) (Voicu et al. 2016) (Okamoto et al. 2018) (Sun et al. 2017)
2 Natural Polymers for Drugs Delivery 47
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Fig. 2.3 Representation of chemical stricture of different natural polymers used in drug delivery
either alone or as an adjuvant with other polymers. Dextran obtained through sucrose bacterial fermentation and chemical ring-opening reaction of the levoglucosan have decent biocompatibility, biodegradability and non-immunogenic. In drug delivery, it is used in the preparation of micro and nanoparticles to improve the pharmacokinetic properties of the therapeutic agents. Dextran in the concentration of 6–10% aqueous solution is medically used as blood plasma substitute. Agarose, a red algae extract has good biocompatibility and very slow degradation kinetics widely used with other polymers to improve the pharmacokinetics and self-life of formulation. The popularity of agarose is such that it is not just used in drug delivery but also have application in microﬂuidics, electrophoresis, biosensor, gold separation and tissue
Natural Polymers for Drugs Delivery
engineering. Starch and cellulose due to their inert nature and biocompatibility with the living system, are widely used in tablet production as diluent, binder and disintegrant agents. Hyaluronic acid is an essential component of our body bones, skin and eyes. Hyaluronic acid is widely used to improve the biocompatibility of the therapeutic agents. Albumin is one of the important plasma proteins that helps in improving the pharmacokinetic properties of many molecules and currently has many marketed albumin-bound formulations, i.e. Ambraxane®. Gelatin and collagen are widely used in the preparation of nanoparticles, the coating of the gelatin or collagen on nanoparticles improves the cellular adhesion of the nanoparticles and provides control release of the therapeutic agents. So, we can conclude that contribution of the natural polymer in drug delivery is irreplaceable and we cannot imagine the formulation development without them.
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Zhang Z, Lv L, Shi A, Li Y, Wang T, Guo Y, Hu B, Yan X, Fu J, Ma F, Wang H, Lv Y, Zhang Y (2022) Implementation of sodium alginate-Fe3O4 to localize undiagnosed small pulmonary nodules for surgical management in a preclinical rabbit model. Sci Rep 12:9979. https://doi.org/ 10.1038/s41598-022-13884-w Zhou Z, Li G, Wang N, Guo F, Guo L, Liu X (2018a) Synthesis of temperature/pH dual-sensitive supramolecular micelles from β-cyclodextrin-poly(N-isopropylacrylamide) star polymer for drug delivery. Colloids Surf B Biointerfaces 172:136–142. https://doi.org/10.1016/j.colsurfb. 2018.08.031 Zhou Z, Guo F, Wang N, Meng M, Li G (2018b) Dual pH-sensitive supramolecular micelles from star-shaped PDMAEMA based on β-cyclodextrin for drug release. Int J Biol Macromol 116: 911–919. https://doi.org/10.1016/j.ijbiomac.2018.05.092 Zhu L, Ge F, Yang L, Li W, Wei S, Tao Y, Du G (2017) Alginate particles with ovalbumin (OVA) peptide can serve as a carrier and adjuvant for immune therapy in B16-OVA cancer model. Med Sci Monit Basic Res 23:166–172. https://doi.org/10.12659/msmbr.901576 Zou L, Zhang Z, Zhang R, Liu W et al (2016) Encapsulation of protein nanoparticles within alginate microparticles: impact of pH and ionic strength on functional performance. J Food Eng 178:81– 89. https://doi.org/10.1016/j.jfoodeng.2016.01.010
Drug Delivery Systems Based on Various Natural Polymers for Lung Diseases Sumita Singh, Kunal Arora, Kamal Dua, and Lubhan Singh
Pulmonary diseases have affected millions of people globally, and continuous steps have been taken by the formulation scientists in developing different drug delivery systems which are entirely based on natural polymeric systems. Efforts have been made to diminish the occurrence and management of associated diseases with the pulmonary system like asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, tuberculosis, and lung cancer by development of the drug delivery systems which are based on natural polymers. The natural sources like plants, animals, and microbes are all involved in the creation of natural polymers. As these are derived from natural sources, these are biocompatible as well as biodegradable and these possess lesser toxicity when compared with the synthetic polymers. The signiﬁcant natural polymers which have been exploited in the development of advanced drug delivery systems in curing the pulmonary diseases are chitosan, hyaluronic acid, cellulose, starch, carrageenan, alginates, etc. In the present scenario, a lot of novel drug delivery systems has been formulated which comprises of natural polymeric systems which could enhance the efﬁcacy as well as efﬁciency of the therapeutic agent by achievement of controlled or sustained release to the targeted site. In this chapter, an emphasis has been given to various advanced drug delivery systems like nanoparticles, S. Singh · K. Arora · L. Singh (✉) Kharvel Subharti College of Pharmacy, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India K. Dua Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, Australia Priority Research Centre for Healthy Lungs, University of Newcastle & Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 H. Dureja et al. (eds.), Natural Polymeric Materials based Drug Delivery Systems in Lung Diseases, https://doi.org/10.1007/978-981-19-7656-8_3
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nanospheres, microparticles, microspheres, solid lipid nanocarriers, liposomes, and nanoﬁbers and the devices which are being utilized to deliver the drugs to the respiratory system have also been listed for a better understanding. Keywords
Chronic obstructive pulmonary disease · Natural polymer
Delivery of any drug for the management of pulmonary disorders is a concern of patient compliance and efﬁcacy of that delivery system. While developing a formulation, various excipients are used to improvise the quality attributes of a therapeutic product. Polymers are the most widely used excipients for their enormous beneﬁting properties which are necessary for the formulation of a drug delivery system. Synthetic polymers have been the polymer of choice from a long time due to easy availability and cost affectivity despite their various drawbacks. In the present scenario, the research scientists, product processor, and even patients also prefer the natural polymer-based formulations over synthetic ones. These polymers are derived from natural sources like plants, animals, and microbes. Any issue which affects the normal functioning of lungs can be considered as a lung disease. These problems can be associated with airways, lung tissues, and lung circulation. If airway of the lungs is being affected, that may lead to various diseases like asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis. Pulmonary ﬁbrosis and sarcoidosis affect the structure and functioning of lung tissues. Sometimes the blood vessels of lung get affected due to enormous reasons like clotting, scarring, inﬂammation and as these conditions may also affect the functioning of heart and could lead to pulmonary hypertension. Targeting of lungs for respiratory diseases has various beneﬁts in comparison with the rest of the route of drug administrations. One of the important advantages associated with the inhalation therapy includes local deposition of the drug which leads to the site-speciﬁc treatment of the respiratory disease. To reduce the dosing frequency and associated compliance of inhalation formulations, a controlled release formulation with aerosolizing capability could be developed (Labiris and Dolovich 2003). The synthetic and natural polymers with the inclusion of excipients have been employed from a long time in the formulation of controlled or sustained release formulations for lung disorders. The past researches in the ﬁeld of pulmonary diseases have proved that the medicines meant for inhalational purpose have been in constant use for minimizing the diseases associated with lungs and their effects from the very existence of these diseases. This therapy is a well-established and accepted form of drug delivery in many forms of respiratory disorders (Stein and Thiel 2017).
Drug Delivery Systems Based on Various Natural Polymers for Lung Diseases
The natural polymers possess many superior characteristics as compared with the synthetic ones in being biocompatible with the human tissues and they are biodegradable also with an absence of toxicity (Vinjamuri et al. 2021). A thorough knowledge of physicochemical properties of the natural polymers is required by the formulator in improvising their clinical outcomes in treating respiratory diseases (Liu et al. 2020). These natural polymers are basically delivery tools which are required in the designing of pulmonary drug delivery system which could further help in distributing the drug molecule in a precise way as well as to make the drug available within the targeted tissues in a required concentration (Sowjanya et al. 2017).
Merits of Natural Polymers
Natural polymers have been great choice while selecting a polymer due to the following merits associated with them and these are depicted in Fig. 3.1 below: • Natural polymers are derived from natural sources and considered to be biocompatible, i.e., compatible with living tissues or cells. These polymers do not produce any toxin or immunological responses if exposed to living cells and body ﬂuids. Hence, they can be safely employed for delivery of drugs for therapeutic purposes. • Natural polymers are biodegradable in nature and get decomposed or degraded by living organism. The rate of degradation of these polymers is based upon the location of the body. Human body has different pH at different body locations. Some polymers get affected by changes in pH so they can be used accordingly to deliver a drug at speciﬁc site to minimize drug-associated side effects. Enzymatic
Fig. 3.1 Merits of polymer derived from natural sources
• • •
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degradation of polymers is also helpful in the development of site-speciﬁc drug delivery systems. Polymers have been everywhere in the nature since the very beginning in the form of cellulose, starch, natural rubber, chitin, etc. Natural polymer is widely available and can be obtained from different part of animals, plants, and microbes (Namazi 2017). Being biocompatible, naturally occurring polymers are not toxic or very less toxic in nature. This becomes an important factor behind the selection of these natural polymers by the formulation scientists in developing an efﬁcient drug delivery system. As these polymers are obtained directly from the nature, they do not pose any harm to the environment in contrary to synthetic polymers. These polymers are also eco-friendly in nature. Natural polymers are renewable in nature. Due to the property of replacement of these renewable polymers with some other newer ones, they prove to be quite superior. Natural polymers are biofunctional and show response to host living cell signaling. They can bind to the host tissues and assist in site-speciﬁc delivery of drugs.
Demerits of Natural Polymers
Although natural polymers exhibit many advantages, some disadvantages are also associated with these polymers which are represented in Fig. 3.2. These polymers show high variability when these have been especially derived from animal sources. Plant and microbial sources also show variability but the extent of variation is much lesser than animal sources. The natural polymers are structurally more complexed than synthetic polymers. As these polymers are present in nature,
Fig. 3.2 Demerits of Natural polymers
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their extraction process is quite exhaustive and thus it becomes a noneconomical process.
Natural Polymer-Based Drug Delivery Systems for Lung Disease
Natural polymers are biodegradable and bioabsorbable in nature. After exposure to biological environment, these polymers endure transformations by means of phagocytosis and other cellular activities. The frequently utilized natural polymers which are recognized in the formulation of drug delivery systems for the cure of pulmonary diseases are chitosan, dextran, hyaluronic acid, albumin, and gelatin (Coelho et al. 2010). Albumin and gelatin both are proteinaceous in nature, and thus, they become signiﬁcant in the development of drug delivery systems. About 50% of total mass of the human blood plasma is made up of album protein. From the past literatures, it has been established that gelatin protein is generated with the thermal denaturation of animal collagen (Nair and Laurencin 2007, 2006). Polysaccharides can be obtained from different origins, i.e., plants (e.g., cellulose, pectin, and guar gum) and animals (e.g., chitosan, hyaluronic acid, chondroitin, and heparin), and have some different origins also such as the algal origin (e.g., alginate and carrageenan) (Naidu and Paulson 2011). Hyaluronic acid (HA) is an anionic and nonsulfated linear polysaccharide that is related to the glycosaminoglycan family and it exists extensively throughout connective, epithelial, and neural tissues (Malafaya et al. 2007). Depending on its molecular weight, HA has a capability to control the various physiological activities. High molecular weight HA hampers the process of cell proliferation as well as the migration of cells and possesses some anti-inﬂammatory properties also. Some reports suggest that HA expresses immunosuppressive properties also. Low molecular weight HA involves in proangiogenic activities like cell proliferation and hence used in tissue culture and tissue engineering. Development of formulations like nanoparticles and microparticles employs use of polymers to sustain and control the release of drug from delivery system. Advantages of using natural polymers have been discussed earlier in this chapter. Controlled and sustained release of drug from polymeric system depends upon three key mechanisms which could be altered by the properties of drug–polymer system. Fig. 3.3 represents the basic mechanisms involved in the polymeric-based release of drug, i.e., drug diffusion, polymer swelling followed by drug diffusion, and polymer degradation. In diffusion mechanism of drug release, drug passes through the matrix formed by polymer to the surrounding biological system. The polymer which exhibits this mechanism is stable in physiological conditions, i.e., no swelling and degradation take place. As diffusion is a phenomenon of concentration gradient, hence rate of diffusion is decelerated with time. The amount of drug release is managed by concentration and solubility performance of the therapeutic agent (Brannon-Peppas
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Fig. 3.3 Polymeric systems and the associated mechanisms of drug delivery. (a) Diffusion, (b) matrix swelling, (c) erosion and/or degradation (Comparative concentration of drug is represented by color)
1997). Type of polymer and porosity of the matrix formed is also few accountable factors to achieve controlled drug release systems. Another mechanism involves swelling of polymeric matrix. The swelled-up matrix enables the diffusion of drug from the matrix. In this mechanism, matrixforming polymer absorbs ﬂuid from the surrounding and swelling happens. Diffusion of drug through swelled matrix is preferred by the amount of ﬂuid present around the delivery system, i.e., existence of additional ﬂuid promotes the pore size of the matrix, hence an improved diffusion rate predominantly in the case of hydrophilic drugs (Louey and Garcia-Contreras 2004). The change in pH, temperature, pKa can activate the swelling of polymers. Degradation mechanism of drug release usually happens via hydrolysis or erosion process. Erosion and hydrolysis lead to the decline of molecular mass of the polymer which favors dissolution process. In this particular event, the rate of drug release is governed by coating of drug by slow solubilizing material or by mixing such material with the matrix. Degradation of polymeric matrix can happen in two ways one is bulk erosion and another is surface erosion. As the name suggests, in bulk degradation, dilapidation of drug delivery system occurs in an even manner all over the matrix and in surface erosion decay of polymers occurs only at the solventexposed surface. Natural polymeric drug delivery systems for the treatment of pulmonary or lung diseases are being summarized below:
Drug Delivery Systems Based on Various Natural Polymers for Lung Diseases
Nanoparticles are tiny colloidal particles in which the size ranges from 1 to 1000 nm. This tiny particle size favors the dissolution rate and bioavailability of lipophilic drugs. Polymeric nanoparticles can be used as targeted drug delivery system, controlled release, and sustained release of encapsulation of drug molecules. Commonly employed natural polymers in the development of nanoparticles are chitosan, alginate, albumin, and gelatin (Mishra and Singh 2020; Deacon et al. 2015). Polymeric nanoparticles are broadly divided into two types. (a) Nanocapsules: The drug is encapsulated inside the polymeric nanocapsules. (b) Nanospheres: The drug is dispersed throughout the polymeric matrix.
Nanocrystals are successful drug delivery systems especially for the upgrading of solubility of those drugs which have poor water solubility. Nanocrystals are crystals in the dimensions of less than 1 mm in diameter. They are constructed of noncarrier drug molecules and further supported by polymeric systems. Homogenization and sonication of nanocrystals are frequently used approach to achieve a nanomaterial of diminished size range for reduced nucleation and aggregation (Rofeal et al. 2022). Natural polymers including proteins and polysaccharides help in advancement of a targeted drug delivery system. Nanocrystals have been incorporated for the treatment of pulmonary diseases like lung cancer as these possess certain properties like improved stability, drug release in a sustained manner, increased aerosolization, good distribution of particle size, enhanced penetration, and a minimum number of excipients used. A selective cellular internalization along with minimum clearance rate and a higher drug deposition rate makes it ideal for pulmonary delivery of drug. It has also proved to deliver the drug into the cancer cells present in lungs (Goyal et al. 2015).
Polymeric microparticles developed through natural polymers like chitosan and guar gum have resulted into an extended residence time at the site of delivery of the therapeutic moieties, thus reducing the systemic toxicity. These delivery systems have potential applications if site-speciﬁc targeting is required. Polymeric microparticles have also been developed to deliver antitubercular drugs in an improvised manner which results in the decrease of systemic toxicity and bacterial resistance because they are selectively taken up by the alveolar macrophages (Zaru et al. 2009).
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When the pathophysiology of few important pulmonary diseases like bronchial asthma is observed, then it is seen that these possess circadian rhythms and their mitigation involves the employment of a Pulsatile drug delivery system in which the drug is released at a very fast rate and a complete release of drug is achieved after a particular lag time of drug release (Mastiholimath et al. 2007). The pulsatile microcapsules are being used in the management of nocturnal asthma also. For the management of chronic asthma, theophylline formulation has been developed in the form of a pulsatile release formulation. The employment of a hard gelatin capsule was done and it was used as an outer layer, and on the other hand, drug mixed with a different polymer was taken which was sealed by a hydrogel plug at the end. To overcome the variability in gastric emptying time, this device was coated with an enteric coated material. The optimized formulation was developed in such a way that colon-speciﬁc drug release could be accomplished. This formulation was developed to treat nocturnal asthmatic attack.
Liposomes are bilayer vesicular structures composed of phospholipids and are appropriate for hydrophilic and lipophilic drugs together, thus forming an important delivery in the treatment of Pulmonary disorders. Liposomes are typically composed of phospholipids which are arranged as bilayer vesicles (Zaru et al. 2009). Liposomes which were coated with chitosan were developed to deliver rifampicin for pulmonary delivery by nebulization technique. Chitosan-coated liposomes showed improved encapsulation efﬁciency and mucoadhesive capacity.
Certain type of lung diseases could be treated with the inclusion of microspheres because the design of microspheres involves an enhanced retention of drug in the lungs and results into a sustained manner of drug release. Further, with the use of these microspheres, the targeted drug delivery could also be achieved and the absorption of the drug candidate can be improved signiﬁcantly. These have also resulted to lower the frequency of dosing and still maintaining the efﬁcacy of drug with minimal side effects. Albumin is natural polymer of animal origin and commonly found in egg white and blood serum. The microsphere loaded with drug in the form of an inhalation formulation was developed. This formulation development included bovine serum albumin which was further used to deliver the therapeutic agent via pulmonary route. A modiﬁcation in the release of drug was achieved by treating microspheres thermally. After extended heat treatment, water solubility of the microspheres was diminished and in vitro enzymatic degradation time was
Drug Delivery Systems Based on Various Natural Polymers for Lung Diseases
extended. So, polymeric microspheres can be used for controlled and extended delivery of drugs to treat pulmonary ailments (Li et al. 2001).
This type of drug delivery system possesses a spherical structure and the size is less than one micron. These systems, when prepared from natural polymers, show excellent results in delivering site-speciﬁc drugs to the lungs as these could easily pass through the smallest size of the capillary vessels due to their very small size. A formulation consisting of natural polymer-based nanospheres was developed. A nanosphere delivery system based on chitosan was developed and a comparison was made through in vitro investigations with respect to the particular interaction and acceptance by human lung adenocarcinoma cell. Further studies reﬂect that these nanospheres show lower cytotoxicity than a formulation without chitosan (Tahara et al. 2009).
Carrageenans are natural polymers and obtained from certain species of red seaweed. Kappa, iota, and lambda are three classes of carrageenan, which are commercially available in the market. A controlled release of drug was depicted from a solution of drug with carrageenan. It has been emphasized that one percent of iota carrageenan formulation have resulted into a prolonged time period in attainment of maximum plasma drug concentration with twofold surge in area under curve of drug plasma concentration–time graph. This gave an evidence that this polymer could be used to modify the drug release proﬁle of drug (Yamada et al. 2005). This becomes important to mention here that different classes work differently with different type of drugs while developing a modiﬁed drug release formulation. In the case of pulmonary diseases, the dosing frequency could be drastically reduced by preparing a polymeric solution as a dosage form which results into an enhanced therapeutic effect of drug.
Nanoﬁbers are ﬁne ﬁbers of width of about one nanometer. The method of nanoﬁber development as well as the polymers used in its development directly impacts the size of nanoﬁbers produced. The main advantage of nanoﬁbers over microﬁbers is increased surface area to volume ratio. Other merits include signiﬁcant mechanical strength, porosity, and ﬂexibility of the nanoﬁber over microﬁbers. Few natural polymers like alginate, silk, keratin, gelatin, cellulose, and collagens are extensively used in the development of nanoﬁbers (Sivan et al. 2022). These types of ﬁbers can be used to deliver a number of drug moieties. Nanoﬁbers can be developed for
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site-speciﬁc delivery of a drug. Nanoﬁbers are believed to be smaller in size when compared with other nanoparticles when they are employed in the treatment of pulmonary hypertension and their size range is between 6 and 19 nm (Marulanda et al. 2021). The studies have proved that nanoﬁbers have a higher localization capacity in affected lungs as compared with healthy lungs.
Devices for Delivery of Drugs
For the transport of drugs in the management of pulmonary diseases, there are three main delivery devices which include the dry powder inhalers, nebulizers, and metered dose inhalers.
Dry Powder Inhalers
Dry powder inhalers consist of loose powders of micronized drug particles or carrierbased (e.g., lactose) mixture of micronized drugs. Carrier-based mixture contains some polymers which are bio-adhesive in nature (e.g., Chitosan). Such systems help in controlling and prolonging the release of drug and proves to deliver an efﬁcient treatment in case of pulmonary diseases (Smyth and Hickey 2011). Dry powders are commonly employed in the noninvasive drug delivery systems.
Nebulizers are usually being utilized at the time of emergency conditions. These devices passively administer the therapeutic agents to patients (Telko and Hickey 2005; Ali 2010). A spacer is used to deliver aerosolized drug formulations to the lungs. The basic nebulizers are of two types: (a) Air jet nebulizers (compressed air is used for aerosolization). (b) Ultrasonic nebulizers (piezoelectric crystals are used for aerosolization).
Metered Dose Inhalers
In metered dose inhalers, drug formulation is present in a pressurized canister in a plastic case with a mouthpiece and a valve to control mist delivery. In this system, drugs are being dissolved or dispersed with help of propellants (Mullen 2018). There is a holding chamber that includes plastic tubes with mouth piece, a valve, and a sealed end for holding this device. Though it is a portable and convenient device, the drawback associated with it is that only 10-30% of the drug delivered from device reaches to lung and remaining of the drug is transported into the oropharynx (Muhamad et al. 2014).
Drug Delivery Systems Based on Various Natural Polymers for Lung Diseases
Advantages of Natural Polymers in Developing Drug Delivery System for Lung Diseases
Lung diseases are prominent in the global population from the very earliest time and form an integral reason in increasing the mortality rates among such type of patients who are suffering from different lung diseases. A lot of efforts have been made in the past to treat such kind of diseases from the contributions and efforts of the pharmaceutical scientists and researchers to develop drug delivery systems for lung diseases which are entirely based on the concept of natural polymers. From the time of existence of this human life, the nature and earth have been only using the natural polymers in sustaining the life (Bangar et al. 2014). Natural polymers are basically derived from the living sources such as animals and plants and one of its important attributes of not causing any harmful effect on the environment and other living systems make them fairly unique from other classes of polymers. When structurally viewed, a polymer consists of a long chain of monomers which could be branched or unbranched. A two- or three-dimensional monomeric network could also be present in the structure of polymer. The commonly used natural polymers utilized in the expansion of drug delivery systems for lung diseases that have been extensively used in the past are albumin, gelatin, chitosan, carrageenan, and hyaluronic acid (Muralidharan et al. 2014). The prime advantages of employing the natural polymers in developing the drug delivery system for lung diseases could be appreciated and efforts are being made to summarize them below (Labiris and Dolovich 2003; Suzuki and Yamaguchi 1993; Bakhshayesh et al. 2018; Lim et al. 2016; Liang et al. 2015; Guo et al. 2021): • The natural polymers are very much biocompatible with the human system which makes them a great choice in formulation development. • The polymers which are naturally derived are quite superior in bearing the property of biodegradability which makes them much safer than the synthetic polymers. • They have been reported to cause a minimal immunogenic effect, thus rendering them to be a very suitable polymer without resulting to any adverse event. • They possess the property of bioadhesion, and thus, they have been found to be very effective in getting attached to the mucous membrane of the lung, thus helping the drug to get delivered at the site at a constant rate. • One of the important natural polymers, which is the hyaluronic acid, bears an excellent therapeutic activity of diminished macrophage phagocytosis, rendering it an ideal polymer for pulmonary administration. • Toxicity is also a matter of concern and becomes very vital especially in the design of drug delivery systems for pulmonary diseases. The natural polymers possess a very less rate of toxicity when compared to other polymeric systems and thus make them again a very suitable choice. • Chitosan is a suitable choice in the development of such delivery systems due to its property of mucoadhesion which results into the improvisation of drug absorption and also controls the release of drug in an effective manner.
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Table 3.1 Some important natural polymers and their advantages S. No. 1
Natural polymer Chitosan
Hyaluronic acid Carrageenan
Advantages Excellent biocompatibility, biodegradability, antimicrobial activity, and no immunogenic effect Biocompatibility biodegradability, optimum hydrophilic nature, elevated porosity, and could be combined with additional polymers. Immediate gelation property, superior biocompatibility, and biodegradability Possession of good mechanical strength, biocompatibility, and biodegradability are much higher than other polymers. Nontoxic property, inert in nature, and can be regenerated for further use. Widely available and not costly, renewable polymer with both the properties of biocompatibility and biodegradability. Superior property of getting blended with other polymers, biocompatible, and biodegradable. Nontoxic, biocompatibility, and biodegradability properties.
• The formulation scientist prefers to use such polymers in the design of a drug delivery system which are easily available. The natural polymers, being associated with the nature, could be easily procured, thus making them a ﬁne choice. • The chemical modiﬁcation is believed to be possible in natural polymers, and thus, it becomes effortless by the formulation scientists to modify them accordingly depending upon the formulation which certainly makes them superior. • The natural polymers have an attribute in breaking themselves into smaller units on reaching in human body, and further, these smaller units or molecules are easily accepted by the inner environment of body. They are also excreted from the body conveniently by various metabolic pathways, thus making them again a suitable choice. • The natural materials or polymers used have the biochemical properties which result into improvisation of their biocompatibility and the possession of a structure which is similar to the extracellular matrix of the surrounding tissues which makes them much advantageous in the design of drug delivery systems. The advantages of few natural polymers are being depicted in Table 3.1 below: The drug delivery systems based on natural polymers have been developed for the mitigation of various respiratory diseases and the following table appreciates these delivery systems (Table 3.2):
Natural Polymer Gelatin, chitosan, and alginate Chitosan
Drug delivery system Nanoparticles (NPs)
To prolong the retention time of drug and to bypass P-glycoprotein drug efﬂux pumps. To produce inhalable microspheres and to promote high drug loading via ionotropic crosslinking. Assessment of absorption in the developed formulation containing positively and negatively charged gelatin To load dry powders for inhalation in bronchial diseases.
To develop nanoparticles with biphasic drug release proﬁle
To develop a controlled and targeted drug delivery with controlled deposition of drug in the lung To develop a formulation with increased drug speciﬁcity and reduced side effect
To develop a polymeric system to induce lung cancer cell’s death
Objective of using natural polymer Site-speciﬁc delivery of protein and DNA to lung
Table 3.2 Natural polymers-based drug delivery systems for lung diseases
Positively charged gelatin possesses more pharmacological availability of drug than the negatively charged gelatin. 2.2- and 4.9-fold increase in the mean residence time as well as absorption time was achieved.
Inference NPs containing gelatin proved to be a promising carrier to deliver protein and DNA to lungs Selective killing of cancerous cells via polymeric system loaded with siRNA to check MAD2 (an important component for mitotic division) Controlled release as well as a satisfactory deposition of nanoparticles in dimensional range of 1-5 μm was achieved. A colloidal polymeric nanocarrier-mediated effectiveness in immunotherapy was observed. A zero order and sustained release for 10 h and 72 h, respectively, in developed nanoparticles with a cumulative drug release of 99%. End product with prolonged circulation time with signiﬁcant accumulation in the lungs. Enhanced drug loading by using alginate and sodium CMC in the ratio of 1:1
Drug Delivery Systems Based on Various Natural Polymers for Lung Diseases (continued)
Yamamoto et al. (1997)
Morimoto et al. (2000)
Liu et al. (2017) Shahin et al. (2019)
Huang et al. (2016)
Klier et al. (2012)
Rytting et al. (2008)
Nascimento et al. (2014)
References Menon et al. (2014)
Natural Polymer Dextran
Drug delivery system Microparticles
Solid lipid nanoparticles (SLN) Liposomes
Table 3.2 (continued)
To develop a delivery system with rapid absorption, little irritation with controlled release of drug. To develop a nebulizable mucoadhesive drug delivery system.
To enhance the mean residence time of the drug in lungs after pulmonary delivery. To achieve site-speciﬁc targeting, that is, alveolar cell of macrophage to treat tuberculosis.
To develop an inhalation formulation with increased concentration of drug at the site of infection and to minimize systemic side effects. To improve the delivery rate of drug in the treatment of lung cancer.
To develop inhalable chitosan microparticles containing isoniazid and rifabutin for the treatment of pulmonary tuberculosis. To develop a sustained release dry powder formulation.
Objective of using natural polymer To develop the rifampicin-loaded dextran formulations by using spray-drying and to enhance the drug encapsulation.
Extended exposure of paclitaxel on mucosal membrane of lungs and decrease in the systemic delivery of drug. An increase in mean residence time of up to 3-4 times in lungs was observed. The formulation showed excellent entrapment efﬁciency, drug release of 78% up to 24 h, and improved recovery of drugs from the target site. Superior absorption rate, controlled drug release, and improvised bioavailability with less irritation in developed system. Better mucoadhesive property after administered through nebulization was achieved.
Inference Enhancement of drug encapsulation with increased concentration of dextran resulting into ﬁner particle fractions with superior inhalational properties. Chitosan-based microparticles as a potential drug delivery system for inhalable lung tuberculosis therapy. Absence of burst release and an inhalation formulation with sustained release was developed. Enhancement of bioavailability of drug in comparison with oral route and drug exhibited a sustained effect.
Zaru et al. (2009)
Willis et al. (2012)
Zhang et al. (2008) Bhardwaj et al. (2013)
Rosiere et al. (2018)
Patil et al. (2015)
Cook et al. (2005)
Cunha et al. (2019)
References Kadota et al. (2019)
74 S. Singh et al.
Alginate and chitosan
Gellan and carrageenan
To develop a formulation which combat the issues associated with mucus present in the pulmonary environment. To produce a nasal spray formulation which can prevent SARS-CoV-2 infections.
Improved interaction with cystic ﬁbrosis mucus leading to better efﬁcacy of the therapeutic candidate. A suppression of SARS-CoV-2 virus by trapping in the sprayed layer followed by natural pathways was achieved. Moakes et al. (2021)
Hill et al. (2019)
3 Drug Delivery Systems Based on Various Natural Polymers for Lung Diseases 75
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Lung diseases have been widely spread in all portions of the world from decades and affected millions of people. Drug delivery system based on natural polymers has been widely accepted in the present era and these polymers are being used in the design of such delivery systems due to superior characters. These natural polymers have excellent properties like biocompatibility and biodegradability with absence of any side effect. These polymers are employed in development of controlled drug delivery systems in the management of pulmonary diseases. The targeted drug delivery to the lungs and various respiratory organs could also be achieved by using these polymers. Pulmonary drug delivery systems, based on natural polymers like polymeric nanoparticles, polymeric microparticles, pulsatile microcapsules, liposomes, microspheres, nanospheres, and polymeric solutions are being studied for the treatment of pulmonary diseases. Controlled drug delivery devices have been considered important, and efforts are put in their design and applicability. The prime devices used for pulmonary drug delivery system are dry powder inhalers, nebulizers, and the metered dose inhalers. These devices are capable of delivering a measured dose of drug at the target site. An ease in procurement and rapid gelation property are some of the attributes of natural polymers and have been used by the designers and formulators. The nontoxic nature of these natural polymers makes them far way better than the synthetic polymers. These drug delivery systems built on natural polymers are used in drug targeting to the lungs. The physicochemical properties of these natural polymers must be studied and understood thoroughly by the formulation scientists so that their applicability could be expanded in accomplishing clinical results.
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Sivan M, Madheswaran D, Valtera J, Kostakova EK, Lukas D (2022) Alternating current electrospinning: the impacts of various high-voltage signal shapes and frequencies on the spinnability and productivity of polycaprolactone nanoﬁbers. Mater Des 213:110308. https:// doi.org/10.1016/j.matdes.2021.110308 Smyth HD, Hickey AJ (2011) Controlled pulmonary drug delivery. Springer Sowjanya M, Debnath S, Lavanya P, Thejovathi R, Babu MN (2017) Polymers used in the designing of controlled drug delivery system. Res J Pharm Tech 10:903–912. https://doi.org/ 10.5958/0974-360X.2017.00168.8 Stein SW, Thiel CG (2017) The history of therapeutic aerosols: a chronological review. J Aerosol Med Pulm Drug Delivery 30:20–41. https://doi.org/10.1089/jamp.2016.1297 Suzuki Y, Yamaguchi T (1993) Effects of hyaluronic acid on macrophage phagocytosis and active oxygen release. Agents Actions 38:32–37 Tahara K, Sakai T, Yamamoto H, Takeuchi H, Hirashima N, Kawashima Y (2009) Improved cellular update of chitosan-modiﬁed PLGA nanospheres by A549 cells. Int J Pharm 382:198– 204 Telko MJ, Hickey AJ (2005) Dry powder inhaler formulation. Respir Care 50:1209–1227 Vinjamuri PB, Kotha AK, Kolte A, Haware RV, Chougule MB. Polymer applications in pulmonary drug delivery. In Applications of polymers in drug delivery. Misra A, Shahiwala A. 2nd ed. Elsevier; 2021.p.333-354 Willis L, Hayes D, Mansour HM (2012) Therapeutic liposomal dry powder inhalation aerosol for targeted lung delivery. Lung 190:251–262. https://doi.org/10.1007/s00408-011-9360-x Yamada K, Kamada N, Odomi M, Okada N, Nabe T, Fujita T, Kohno S, Yamamoto A (2005) Carrageenans can regulate the pulmonary absorption of antiasthmatic drugs and their retention in the rat lung tissues without any membrane damage. Int J Pharm 293:63–72. https://doi.org/10. 1016/j.ijpharm.2004.12.008 Yamamoto D, Takahashi K, Matsuo T, Maeda M, Kondo S (1997) A Ras target canoe is enriched in the apical membrane and is required for notch and wingless signaling in drosophila. Dev Biol 186:280 Zaru M, Manca ML, Fadda AM, Antimisiaris SG (2009) Chitosan-coated liposomes for delivery to lungs by nebulisation. Colloids Surf B Biointerfaces 71:88–95. https://doi.org/10.1016/j. colsurfb.2009.01.010 Zhang LJ, Xing B, Wu J, Xu B, Fang XL (2008) Biodistribution in mice and severity of damage in rat lungs following pulmonary delivery of 9-nitrocamptothecin liposomes. Pulm Pharmacol Ther 21:239–246. https://doi.org/10.1016/j.pupt.2007.04.002
Part I Plant-Derived Natural Polymers Employed in Respiratory Diseases
Cellulose-Based Drug Delivery Systems in Lung Disorders Divya Suares, Srishti Shetty, and Saritha Shetty
Polymer-based drug delivery strategies have drawn a lot of attention over the past two decades. Recent years have seen a rise in research related to natural biopolymer-based drug delivery techniques. However, functionalization seems to be challenging due to their intricate network structure and intramolecular interactions. Respiratory disease is a leading cause of death with a serious danger to one’s quality of life and life expectancy. Respiratory disorders like tuberculosis, asthma, bronchitis, cystic ﬁbrosis, and chronic obstructive pulmonary disease require proper management and treatment. Natural polymers are particularly promising in the ﬁeld of drug delivery systems due to their biological characteristics, such as sustainability and chemical ﬂexibility. Cellulose is a natural polymer that is affordable, renewable, and available from a variety of sources. Literature cites unique qualities of cellulose and cellulose-based derivatives being explored for various drug delivery applications. Natural cellulose has intrinsic repeating glucose subunits and hydrogen bonds within the ﬁbrillar structure that contribute to its high mechanical strength, crystallinity, and biocompatibility. Several cellulose-based systems with variable mechanical characteristics and compositions are also explored for lung disorders. This chapter will discuss the progress and future possibilities of cellulose and its derivativebased drug delivery in respiratory illnesses. Keywords
Polysaccharide · Fibers · Cellulose · Respiratory · Nanoformulations · Inhalers D. Suares · S. Shetty · S. Shetty (✉) Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 H. Dureja et al. (eds.), Natural Polymeric Materials based Drug Delivery Systems in Lung Diseases, https://doi.org/10.1007/978-981-19-7656-8_4
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Cellulose, a polysaccharide, is an organic substance present in the cell wall of plants that can be derived from a range of plant sources, such as wood (Salehudin et al. 2012), seed ﬁbers (cotton, coir, etc.), ﬁbers (ﬂax, hemp, jute, etc.), and grass (bagasse, bamboo, etc.). It can also be derived from non-plant sources such as marine animals (tunicate) (Jonoobi et al. 2015), algae (Valonia, Oocystis apiculate, Chaetomorpha), fungi, invertebrates, and bacteria (Acanthamoeba, Achromobacter, Gluconacetobacter xylinus) (Nechyporchuk et al. 2016). In about mid-nineteenth century, chemical composition of cellulose (C6H12O5)n was derived (where n = degree of polymerization of glucose) (Kamide 2005). Cellulose structure is made up of repeating units of glucose monomers linked in unbranched chains by β-1,4-glycosidic bonds. Through inter- and intramolecular hydrogen bonds, they have a propensity to align into crystalline structures (Sai and Fujita 2020). One primary and two secondary hydroxyl functional groups attached to each anhydroglucose unit give the molecule a hydrophilic character. When two glucose molecules are connected through a 1,4 β-ether linkage, it results in a disaccharide, cellobiose unit (Oprea and Voicu 2020). Nevertheless, the structure of cellulose would vary depending on the source. Cellulose is available in several polymorphic forms. Native cellulose, also known as cellulose I, co-exists in varying ratios in two different crystalline forms, designated as Iα (exhibiting triclinic unit cells) and Iβ (exhibiting monoclinic type of unit cells). Cellulose II, seldom found in nature, but found in marine algae Halicystis, can also be synthesized from cellulose I via regeneration or mercerization. Contrary to cellulose I, this polymorphic form has antiparallel glucan chains and is thermodynamically more stable. Cellulose III and cellulose IV are two more allomorphs of cellulose (Khalil et al. 2012). Due to differences in particle size, shape, and degree of crystallinity, cellulose can be found in a variety of forms (i.e., ﬁbrous or agglomerated). One of the most thoroughly investigated celluloses for diverse drug delivery applications is microcrystalline cellulose (MCC), a reﬁned form of pure cellulose. To enhance the characteristics of the material, siliciﬁed grades of MCC have also been developed by co-processing cellulose with other compounds. Other forms of pure cellulose that are available include powdered cellulose (PC) and low crystallinity powdered cellulose (LCPC) (Shokri and Adibkia 2013). During the early twentieth century, studies on cellulose and its derivatives as macromolecules expanded. Although the application of cellulose was very well established in industries such as textiles, wood, paper, leather, paints, plastic, food, beverages to name a few, there was a need to further expand the usage of cellulose in biomedical industry. Thus, the cellulose derivatives were produced by carrying out chemical modiﬁcations and complexations. The degree of chemical modiﬁcation had a signiﬁcant impact on the characteristics of cellulose (Seddiqi et al. 2021). Alkyl or substituted alkyl groups replaced the hydrogen atoms from the hydroxyl groups in cellulose anhydroglucose units to form high molecular weight compounds, i.e., cellulose ether derivatives. Few examples of cellulose ethers include
Cellulose-Based Drug Delivery Systems in Lung Disorders
methylcellulose (MC), carboxymethyl cellulose (CMC), ethylcellulose (EC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC). Esteriﬁcation of cellulose generated cellulose ester derivatives, which were either organic or inorganic. Organic cellulose esters include cellulose acetate (CA), cellulose acetate phthalate (CAP), cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), and hydroxypropyl methylcellulose phthalate (HPMCP), while cellulose nitrate and cellulose sulfate are few inorganic cellulose esters (Shokri and Adibkia 2013). Table 4.1 displays the characteristics of various cellulose and its derivatives utilized in pharmaceutical applications. Cellulosic ﬁbers refer to natural ﬁbers that originate from plants, where water attaches to the hydrophilic surface of cellulose ﬁbers resulting in sponge-like structures that can absorb water (Salehudin et al. 2012). In the plant source, such as wood, enzyme cellulose synthase polymerizes single glucan chain, which assembles and crystallizes to form orderly patterns of single cellulose microﬁbrils with a diameter of 3.5 nm. Nonetheless, it is reported that they form fringed-ﬁbrillar systems with irregular patterns of amorphous and crystalline areas (Klemm et al. 2005). During acid hydrolysis, the glucan chains are cut in the amorphous areas, forming whiskers or microﬁbril fragments that are slender and rod-like. Furthermore, the single microﬁbrils pack themselves into larger bundles, held together by the matrix substances such as hemicellulose, lignin, and pectin. The mechanical properties of cellulose are dependent on the orientation of these microﬁbrils. Microﬁbrils having low angles and oriented parallel to the ﬁber axis exhibit greater elastic modulus, while microﬁbrils with large angles demonstrate higher elongation at break. Thus, cellulose comprising of desirable ﬁbrillar structure and higher amounts of hydrogen bonds have higher tensile strength (Klemm et al. 2005). As mentioned earlier, cellulose ﬁber has a unique packing arrangement in which the nanoﬁbers assemble themselves within a diameter range of 2-20 nm and more than a few micrometers in length (Khalil et al. 2012). Unique cellulosic structures are isolated from plant cells, either mechanically or chemically, employing top-down techniques. These primary ﬁbers have a diameter of around 5 nm and hence are referred to as nanocellulose or cellulose nanoﬁbers (Ng et al. 2015). According to the literature, nanocellulose is found to be a promising choice for membrane fabrication, owing to its favorable physicochemical features such as high tensile strength, increased surface area, and ability to incorporate high degree of functionalization (Vatanpour et al. 2021). On the other hand, bacterial cellulose, synthesized from microbes, possesses several hydroxyl surface groups, granting the material higher degree of hydrophilicity, biodegradability, and possibility of chemical modiﬁcation. Additionally, the bacterial cellulose shows higher percent purity due to the absence of plant-based matrices. Bacterial cellulose demonstrates several features, namely unique nanostructure, higher capacity to hold water, suitable degree of polymerization, superior mechanical strength, and good crystallinity (Esa et al. 2014; Moniri et al. 2017). According to published research, nanocellulose can be categorized into the following types, namely, (a) bacterial nanocellulose (BNC), (b) nano-ﬁbrillated cellulose (NFC), and (c) cellulose nanocrystals (CNC) (Klemm et al. 2018). Among these, NFCs and CNCs are prepared by purifying cellulose ﬁbers and then using
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Table 4.1 Properties of Cellulose and Its Derivatives Sources Wood
Cellulose derivatives Microcrystalline cellulose (MCC)
Carboxymethyl cellulose (CMC)
Ethyl cellulose (EC)
Hydroxy ethyl cellulose (HEC)
Hydroxy propyl cellulose (HPC)
Cellulose acetate (CA)
Properties Biologically degradable carbohydrates like cellulose, hemicellulose, and lignin make up the wood ﬁber. Wood cellulose is packed into nanoﬁbrils that are joined by lignin and hemicellulose (Seddiqi et al. 2021). The ﬁbers exhibit more chemical reactivity, and their curled shape contributes to their bulky and porous nature. Cellulose derivatives provide transparent, light-resistant, and colorless high viscosity solutions (Heinze et al. 2018). Compared to other forms of cellulose, BC is an extremely pure form of cellulose with a ribbon-shaped network that gives greater mechanical strength. Their distinctive qualities, such as high crystallinity, larger water capacity, and higher polymerization, set them apart from plant sources. Since BC is highly hydrated, no additional chemical treatment is required (Jonoobi et al. 2015). Acid catalysis of cellulose using hydrochloric acid, sulfur dioxide, and sulfuric acid produces MCC. MCC is extremely pure, slightly viscous, and used for laboratory-scale derivatization. MCC is employed as an opaciﬁer in the pharmaceutical, cosmetic, food, and beverage sectors (Heinze et al. 2018). Methyl cellulose is a simple alkyl ether that is used as an emulsifying agent and has thermogelling properties. Methyl cellulose is effectively used in drug delivery systems (Seddiqi et al. 2021). Water solubility, hydrophilicity, and good chemical stability are the characteristics of CMC. CMC is effectively used as a viscosity-increasing agent, binder, and a ﬁlm-forming agent (Seddiqi et al. 2021). EC has excellent ﬁlm-forming, water resistance, and barrierforming qualities and is naturally biodegradable (Seddiqi et al. 2021). HEC is soluble in a wide range of organic solvents and thus an excellent choice for a variety of biological applications. HEC permits higher drug loading and is non-toxic in nature. When combined with HEC, cellulose becomes more compatible with less polar matrices (Seddiqi et al. 2021). The hydroxyl group in the structure of cellulose can be partially or entirely replaced to create the water-soluble thermoplastic polymer HPC. The secondary groups can be further modiﬁed to allow HPC to be employed in various drug delivery systems and tissue engineering techniques (Seddiqi et al. 2021). CA is a thermoplastic biodegradable polymer obtained by esteriﬁcation of cellulose. It is inexpensive and its preparation does not require additional procedures. Its biomedical applications include drug delivery, tissue engineering, and wound healing (Seddiqi et al. 2021). (continued)
Cellulose-Based Drug Delivery Systems in Lung Disorders
Table 4.1 (continued) Sources Cellulose acetate phthalate (CAP)
Cellulose acetate butyrate (CAB)
Cellulose acetate trimellitate (CAT)
Hydroxypropyl methylcellulose phthalate (HPMCP)
Cellulose nitrate (CN)
Cellulose sulfate (CS)
Properties CAP application in the formulation of enteric ﬁlms has increased due to its propensity to maintain its integrity in an acidic environment and to dissolve only at higher pH levels (Roxin et al. 1998). The number of substitutions connected through anhydroglucopyranose unit and the acetyl and phthaloyl groups governs its pH-dependent solubility (Dobos et al. 2012). CAB shows lesser water absorption and has lower density compared to its parent molecule and hence preferred to cellulose acetate (Yang et al. 2010). It is a rigid, thermoplastic polymer with a high glass transition temperature (Xing et al. 2013). CAB is widely used in coating and has certain pharmaceutical applications (Yang et al. 2010). CAT has a carboxylic group attached to its aromatic ring. It displays a pH-dependent solubility, ensuring the disintegration of the enteric coat at pH 5.5. CAT resembles a dissolution proﬁle very similar to that of CAP in organic solvents (Kapoor et al. 2019). HPMCP is a cellulose ether derivative. It is colorless, odorless, and a non-toxic powder. It is widely used as ﬁlm forming polymer and has good mechanical qualities. HPMCP is used as a polymer in oral drug delivery as well as a coating material to aid in the controlled release of the drug (Shi 2021). CN is obtained by replacing the hydroxyl groups in cellulose with nitrate groups. The features of cellulose nitrate depend on the degree of nitration. CN is a versatile polymer and can be employed as a plasticizer by lowering the nitration level (Seddiqi et al. 2021). CS exhibits antiviral, antibacterial, and anticoagulant properties. Its biological properties are due to the presence of sulfate groups, which allow for a wide range of substitution. CS has high ﬁlm-forming ability and is biocompatible in nature (Seddiqi et al. 2021).
them as reinforcing components in polymer composites. Due to the crystalline structure of CNC, they are known to have better strength, stiffness, and an ideal load-bearing capacity. Flexible ﬁbrils make up NFCs, which can be easily coupled to create stiff web-like networks, providing additional strength to the composite (Ng et al. 2015). Cellulose nanoﬁbers serve as a replacement for a wide range of non-renewable polymers (Salehudin et al. 2012).
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Characteristics of Cellulose
Cellulose plays a vital role in human food chain, veterinary food supplies, wood and paper, textile, cosmetic, pharmaceutical industries, etc. (Shokri and Adibkia 2013). A large pool of different varieties of cellulose are available worldwide (Jonoobi et al. 2015). It is obtained from natural sources; it is renewable and can be modiﬁed to cater to the needs of its application. Due to its distinctive properties, such as high glass transition temperature, good chemical stability, good mechanical strength, high reactive surface area, low density, low cost (Jonoobi et al. 2015), higher shelf-life, non-toxicity (Seddiqi et al. 2021), hydrophilicity, crystallinity, availability in wide range of molecular weights, biocompatibility and biodegradability, cellulose is widely used in the pharmaceutical industries to design various types drug delivery systems, grafts, composites, membranes, etc. (Vatanpour et al. 2021; Arca 2016). Figure 4.1 provides an illustration of various cellulose and cellulose-derived product attributes. Also noteworthy is the fact that metal and ceramics are being replaced in industrial applications by polymers strengthened by natural cellulose ﬁbers (Venkatarajan et al. 2021). However, monitoring cellulose’s thermal stability is essential since cellulose rapidly degrades at temperatures around 200-300 °C (Jonoobi et al. 2015).
Fig. 4.1 An illustration of numerous properties that can be attributed to cellulose and its derivatives (created with BioRender.com)
Cellulose-Based Drug Delivery Systems in Lung Disorders
Global Production of Cellulose
French chemist, Anselme Payen was the ﬁrst to conduct study on cellulose in the year 1838 and since then numerous modiﬁcations have been made on its isolation techniques, production, and structural features in an effort to extend the applications of cellulose and its derivatives (Mokhena and John 2020). Textile, paper, food, beverage, pharmaceutical, and cosmetic industries are some of the primary growth drivers for the cellulose industry, according to Global Market Insights Inc. (Global Market Insights 2020). Fortune Business Insights projects that the global cellulose market would increase at a CAGR of 4.2 percent and reach USD 305.08 billion by 2026 (Fortune Business Insights 2018). The size of the cellulose market is being driven by the desire to use natural, biodegradable, and environment-friendly polymers (Expert Market Research 2020). North America, Latin America, Europe, Middle East, Africa, and Asia Paciﬁc region account for majority of the cellulosebased industries, with Asia Paciﬁc having the largest market share (Expert Market Research 2020). The global distribution of cellulose market is credited to the following continents based on their applications, as mentioned below (Fortune Business Insights 2018). • North America has seen a moderate growth for cellulose due to its increasing demand for paper-based products and expanding construction industries. • The market share of cellulose has steadily increased as a result of the expansion of the food and pharmaceutical industries in Europe. Additionally, increase in research on cellulose and its derivatives has added to the cellulose market value. • Asia Paciﬁc region has seen an enormous growth in food, construction, and chemical industries due to which the demand for cellulose has also increased. The expansion of production and supply coming from China and India helps to sustain the growing market for cellulose in the Asia Paciﬁc area. Increase in paper sector and pulp-based industry has increased the market share for cellulose in South America, the Middle East, and Africa. Here, Brazil, Turkey, and South Africa are the countries that supply the cellulose. Figure 4.2 depicts the regions that are expected to dominate the regenerated cellulose market in the near future (Market Watch 2022).
Application of Cellulose and its Derivatives in Lung Diseases
Although cellulose and its derivatives have been explored in innumerable segments, cellulose as an excipient, a polymer and in nanocarrier systems, with variable mechanical characteristics and compositions, are also researched for the management and treatment of lung disorders. The following section provides a brief overview of the approaches undertaken to deliver actives using cellulose or its
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North America (United States, Canada and Mexico)
Europe (Germany, UK, France, Italy, Russia and Turkey)
Asia-Pacific (China, Japan, Korea, India, Australia, Indonesia, Thailand, Philippines, Malaysia and Vietnam)
Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria and South Africa) South America (Brazil, Argentina, Columbia)
Fig. 4.2 Areas predicted to control the regenerated cellulose market in the foreseeable future (created with BioRender.com)
derivatives for respiratory diseases and the list of the approaches are depicted in Table 4.2.
Cellulose and Lung Cancer
Lung cancer is one of the primary causes for cancer-related fatalities. The ﬁrst-line treatment typically advised for lung cancer is an intravenous (IV) infusion of a mixture of chemotherapy drugs (Babu et al. 2013). Chemotherapeutic agents, which induce necrosis and/ or apoptosis and that act on several molecular locations to trigger death of tumor cells, are widely used to treat cancer (Negm et al. 2022). Combination of chemotherapeutic agents allow the drug to distribute throughout the body and boost the effectiveness at lower doses of individual drugs. However, the hydrophobic properties of chemotherapeutic agents and the patients’ resistance to combination therapy limit their administration at high doses. This highlights the need for new strategies to the effectiveness of chemotherapeutic agents (Babu et al. 2013). For effective therapy of cancer, the chemotherapeutic agents should be delivered to the targeted site. Emerging technologies for cancer treatment include development of nanosponges using cellulose, which are small porous spherical particles that have a tendency to encapsulate both hydrophilic and lipophilic drugs in their cavity (Ahmed et al. 2020). EC is a cellulose-derived polymer, wherein the hydroxyl groups are converted to ethyl ether groups by mixing alkali cellulose with ethyl chloride. The level of etheriﬁcation, materials molecular weight, and molecular homogeneity inﬂuence the physical properties and performance of EC-based products. A degree of substitution between 2 to 2.6 is required to develop products that are commercially viable
Cellulose-Based Drug Delivery Systems in Lung Disorders
Table 4.2 List of formulations based on cellulose and its derivatives for lung disorders Type of product Solid dispersions
Active ingredient Rifampin
Pellets (ﬁlmcoated) Dry powder inhalers Microparticles
Cellulose and its derivative Cellulose ω-carboxy alkanoates EC and HPMC
Beclomethasone dipropionate Theophylline
CAB and EC
Clariﬁed, inactivated, concentrated, and diaﬁltered virus particles Curcumin
Magnetic sulfated cellulose
Zincbenzenetricarboxylic acid framework Pranlukast hydrate
Diethylaminopropyl amine-poly(vinyl alcohol)-grafted-poly (lactide-co-glycolide) Lutetium-177 and vemurafenib Brigatinib
Lung tissue engineering
Silk ﬁbroin hydrogel and TEMPOoxidized BC nanoﬁbril pastes Cellulose
Sulfated cellulose membrane
References Arca et al. (2018)
Hadi et al. (2012) Xu et al. (2014) Mishra and Mishra (2012) Feng et al. (2013) Sakagami et al. (2002) Jelvehgari and Montazam (2012) Kalita et al. (2013) Pieler et al. (2016)
Gunathilake et al. (2022) Negm et al. (2022) Kawashima et al. (1998) Dailey et al. (2003)
Imlimthan et al. (2021) Ahmed et al. (2020) Huang et al. (2021)
Liu et al. (2007) Carvalho et al. (2018)
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(Seddiqi et al. 2021). The strength of EC gradually decreases as the temperature rises (Seddiqi et al. 2021). EC is a water-insoluble, non-toxic, non-irritating, colorless, odorless, biocompatible, and well-tolerated polymer used in nano-matrix formulations. Brigatinib is a tyrosine kinase inhibitor that is used to target growth receptors in lung cancer. Ahmed and colleagues fabricated brigatinib-loaded nanosponges made up of EC. During the in vitro release studies, the nanosponges showed two-phase release of brigatinib, wherein an early burst release was desired for immediate action followed by a gradual release from the nanosponges for sustained activity. The quick and gradual release of brigatinib from the nanosponges was facilitated due to the dispersion of aqueous media in the EC-based hydrophobic core. Furthermore, studies carried out in human lung cancer cell line A549 showed prolonged anticancer activity of the developed nanosponges (Ahmed et al. 2020). CMC, another cellulose-derived polymer, is hydrophilic and biodegradable in nature. It has unique properties due to its different degree of substitution and is of great demand in drug delivery systems. Because of its high-water interaction and water-holding capacity, CMC can be employed as an excellent absorbent even at low temperatures (Negm et al. 2022). The molecular weight, degree of substitution, and location of carboxymethyl substituents inﬂuence CMC’s characteristics (Seddiqi et al. 2021). A solvothermal method was used to generate mesoporous nanoparticles of zinc at 1,3,5-benzenetricarboxylic acid framework and then embedded into CMC. The nanocomposite showed a particle size of 22-30 nm, while the combination retained the crystal structure of zinc-benzenetricarboxylic acid framework showing no damage to the morphology. The nanocomposite treatment inhibited cell growth while increasing DNA damage in cancerous cells. It also triggered apoptosis and reduced metastatic effectiveness in colon (DLD1) and lung (A549) cancer cell lines. Hence, cellulose-based zinc nanoparticles were able to demonstrate anti-proliferative effect on lung cancer cells and were capable of slowly inhibiting the growth and progression of cancer (Negm et al. 2022). Dailey and co-workers formulated nanosuspensions of diethylaminopropyl amine-poly(vinyl alcohol)-grafted-poly (lactide-co-glycolide) (DEAPA-PVAL-g-PLGA) alone and with increasing concentrations of CMC. Formulations with distinct positive or negative charges produced stable nanosuspensions, whereas formulations with zeta potentials near to neutrality led to polymer aggregation. Physicochemical studies showed that DEAPA-PVAL-g-PLGA alone formed a colloidal, highly cationic polymer suspension in the aqueous medium. Small amounts of CMC (5 μg CMC/ mg polymer) adsorbed onto the surface of particles caused an electrostatic repulsion, while a larger amount of CMC (10-50 μg CMC/ mg polymer) might have partially coated the nanoparticles with free cationic polymer, leading to aggregation. The free CMC molecules were able to completely coat all precipitated nanoparticles and prevent agglomeration after a threshold CMC concentration had been reached (>50 μg CMC/ mg polymer). With respect to their interactions with A549 cells, cationic formulations showed a very high afﬁnity for the cell membrane, but limited internalization, whereas anionic formulations showed a higher level of internalization despite showing no afﬁnity for the cell membrane. Accordingly, the investigations demonstrated that CMC-based anionic nanosuspensions displayed improved
Cellulose-Based Drug Delivery Systems in Lung Disorders
stability during nebulization, retarded the degradation rate of the product, and were easily nebulized (Dailey et al. 2003). According to published research, cellulose nanocrystals are capable of delivering higher payloads to lung capillaries in vivo. Taking this into account, Imlimthan and co-researchers developed a theranostic-nanocrystal comprising of lutetium-177 (a diagnostic tool) and vemurafenib (a chemotherapeutic drug) to improve the prognosis of lung metastatic melanoma. The therapeutic efﬁcacy of the developed cellulose nanocrystal was tested on BRAF V600E mutation-harboring YUMM1.G1 mouse model. The cellulose nanocrystals demonstrated acceptable radiolabel stability, drug release proﬁle, cellular uptake, and cell growth inhibition in vitro. In vivo biodistribution revealed signiﬁcant retention of cellulose nanocrystals in the lung, liver, and spleen. The median survival time of animals treated with cellulose nanocrystal showed a doubly increase when compared to control groups. Thus, systemic delivery of cellulose nanocrystal can be used as a naturally sourced and renewable nanoscale platform in a clinical setup, for the treatment of BRAF V600Epositive lung metastatic melanoma accompanied with radiotherapy (Imlimthan et al. 2021).
Cellulose and Lung Infections
A virus, bacteria, and sometimes even a fungus can cause lung or respiratory tract infection. Some respiratory tract infections include community-acquired pneumonia (CAP), tuberculosis (TB), avian inﬂuenza A (H7N9), Middle East respiratory syndrome coronavirus (MERS-CoV), and coronavirus disease 2019 (COVID-19) (Hui and Leung 2019). There are few effective strategies using cellulose and its derivatives in the treatment of few lung infections. Mishra and colleagues investigated the potential of doxycycline hyclate-loaded mucoadhesive microparticles for inhalation delivery, which may be beneﬁcial for the clinical treatment of respiratory infections with negligible adverse effects. In the system, sodium CMC functioned as a mucoadhesive agent. Mucoadhesive polymeric matrices provided the advantage of altering the drug’s pharmacokinetics by lengthening its residence time in the lung and decreasing the apparent volume of distribution. The researchers’ successfully prepared dimpled but spherical microparticles having a diameter of approximately 1-5 μm, using the spray-drying technique. The process produced an average yield of 56.27% with encapsulation efﬁciency of 83.74 ± 2.31% and water content of about 4.16 ± 0.52%. In vitro dissolution studies in phosphate buffer displayed biphasic Fickian type of diffusion. Cytotoxicity studies of the microparticles on H1299 human alveolar cell line exhibited acceptable cell viability (Mishra and Mishra 2012). Gunathilake and co-workers explored the beneﬁts of nanocellulose for controlled delivery of curcumin for the treatment of COVID-19. The sulfuric acid hydrolyzed nanocellulose offered the following advantages, such as ease of formulating nanoparticles of desired particle size, shape, and surface features and inclusion of anionic surface charge. These beneﬁts resulted in increased drug loading capacity,
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permeability, improved cellular uptake, higher lung retention, and a better chance of penetrating mucus in the airway. Due to curcumin’s low water solubility, micellar systems made of pH-independent water-soluble biodegradable polymers, such as polyvinyl alcohol, were utilized to boost its solubility. The researchers formulated nanocellulose-polyvinyl alcohol-loaded curcumin nanoparticles. In vitro drug release studies revealed an initial burst followed by a controlled release for roughly 6.5 h. As per the studies, higher curcumin loading in nanocellulose will offer a viable nano-based treatment for COVID-19 (Gunathilake et al. 2022).
Cellulose and Influenza
Inﬂuenza is an acute respiratory illness responsible for a huge mortality rate (Amano and Cheng 2005). Inﬂuenza virus is caused by a negative-stranded RNA virus with a segmented genome enclosed within an envelope (Chen et al. 2021). Inﬂuenza A, B, C, and thogotovirus belong to the same family of virus. The surface glycoproteins, hemagglutinin and neuraminidase, are the causative factors for the infection of host cells (Amano and Cheng 2005). Magnetic sulfated cellulose particles (MSCP) of diameter 100–250 μm were attached to clariﬁed, inactivated, concentrated, and diaﬁltered virus particles to act as a vaccine against inﬂuenza A virus. In the system, the sulfated cellulose backbone worked as a pseudo afﬁnity ligand for the virus particles, with minimum non-speciﬁc binding. The presence of Fe3O4 particles, which are biocompatible and non-toxic, provided the desired magnetic properties. When Pieler et al. vaccinated the mice with antigen-loaded MSCPs, it resulted in signiﬁcant anti-inﬂuenza A antibody response and demonstrated complete protection against the competent inﬂuenza A virus. When compared to the negative control group, the number of ﬂu virus nucleoprotein gene copies in the lungs of the vaccinated mice was found to be reduced by 400-folds. There was no sign of any type of negative effects in mice treated with MSCP formulation. Hence, MSCP can be an interesting and effective tool of protection against viral pathogens (Pieler et al. 2016). Virus-like particles (VLP) are also potential candidates for inﬂuenza virus vaccines. In contrast to inactivated viral vaccines, VLPs exhibit excellent safety proﬁles and superior immunogenicity. Previously, ion exchange membranes were used to purify VLPs; however, this technique was time-consuming and challenging for scale-up. Hence, Carvalho and associates used sulfated cellulose membrane adsorbers (SCMA), as a platform for the puriﬁcation of VLP-based inﬂuenza vaccines. The large pore size of cellulose membrane facilitated the processing of macromolecules. The presence of ligands on the membrane surface permitted mass transfer and reduced the processing time and cost. In addition to this, cellulose membranes can be safely disposed, which avoids the need of column cleaning and regeneration. As SCMA offers substantial modiﬁcations, is readily scalable, requires few steps, and so on, it can be developed further for efﬁcient puriﬁcation of vaccines for inﬂuenza virus (Carvalho et al. 2018).
Cellulose-Based Drug Delivery Systems in Lung Disorders
Cellulose and Tuberculosis
Tuberculosis (TB) is a contagious disease that is signiﬁcantly spread across the world with several reports of relapses and adverse effects. Longer treatment regimens result in poor patient compliance, which contributes to the spread of drug-resistant tuberculosis. One of the primary targets for an impactful treatment is to increase the pulmonary delivery of anti-TB actives. However, intratracheal therapy for TB raises a great concern, as the lungs are incapable of retaining sufﬁcient levels of drug concentration to exhibit the desired therapeutic effect (Feng et al. 2013). Feng and co-workers studied the potential of EC for developing mucoadhesive complex microspheres for pulmonary delivery of an anti-TB molecule, rifabutin. The drug-loaded microspheres were successfully prepared using spray-drying technique. The developed drug-loaded microspheres exhibited biphasic release and long-term lung retention characteristics. EC acted as a core that controlled the release of rifabutin. The diffusion of drug across the EC layer, due to concentration gradient, enabled the drug to retain in the lungs for a prolonged period. Hence, EC can be administered via the pulmonary route and owing to its mucoadhesive property; it can be explored for better management of TB (Feng et al. 2013). First-line drugs are typically taken daily for 6–8 months as a part of the TB treatment regimen. However, the success of the treatment is hampered due to poor patient compliance and decreased adherence to the therapy. Novel drug delivery systems that address this problem need to be developed to increase the effectiveness of the therapy for TB. In a study by Kalita and co-researchers, MCC was successfully synthesized from Setaria glauca (L) P. Beauv, common wild grass, and was investigated for its potential in drug delivery application. Sodium alginate microbeads with MCC and isoniazid were designed and evaluated for in vitro drug release in simulated intestinal ﬂuid. The study results demonstrated sustained release of the drug up to 24 h, which will be beneﬁcial for management of TB. The synthesized MCC showed minimum chemical reactivity, better compatibility, no cytotoxicity, antioxidant capability with thermal stability at 286 °C. These ﬁndings pave way for exploring MCC as a drug delivery vehicle (Kalita et al. 2013). Although rifampin is an important ﬁrst-line drug prescribed for TB, its use for the therapy is constrained by factors like irregular bioavailability, high dosage, unstable in stomach pH, and poor solubility. Arca et al. developed amorphous solid dispersions of rifampin using cellulose ω-carboxyalkanoates. The incorporation of rifampin into cellulose-derived matrices inhibited the acid-catalyzed degradation of rifampin, enhanced its release in the small intestine, and improved its bioavailability. The interaction between the drug and the polymer resulted in an increase in the residence time of the drug between the stomach and the small intestine. This demonstrates the potential of cellulose for the effective treatment of TB (Arca et al. 2018).
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Cellulose and Lung Tissue Engineering
Due to a paucity of available donors or a patient’s prolonged requirement for immunosuppressive medications, lung transplantation might be challenging. Hence, lung tissue engineering can be a smart solution for alleviating shortage of lung transplants (Huang et al. 2021). Tissue engineering is a technique that uses living cells to repair or replace the damaged tissues. One approach is to insert a scaffold device at the location of the damaged tissue and eventually healthy cells will migrate at the location and start repairing the damaged tissue. Another approach is to grow an autologous cell in a culture media over a bioactive scaffold that will guide the proliferation and differentiation for forming 3D tissues (Dugan et al. 2013). 3D printing combined with regenerative cell population is a useful approach to create biological scaffolds for lung tissue engineering. In recent years, 3D printing using biomaterials as inks has also been an interesting method for tissue engineering, wherein biomaterials composed of natural polymers such as chitosan, cellulose, and starch. Have been employed for the preparation of the bioink (Aljohani et al. 2018). Natural polymers are generally used because they are biocompatible, biodegradable, and possess low immunogenic properties (McCarthy et al. 2019; Moohan et al. 2019). 3D printed cellulose nanoﬁbers are used as hydrogels, which show excellent mechanical properties, good shape, high zero shear viscosity, structural stability, and biocompatibility (Liu et al. 2019). A ﬁlamentous architecture is observed when cellulose nanoﬁbers are added to the 3D printing ink; this architecture promotes cell proliferation and has structural resemblance to extracellular matrix (Huang et al. 2019). Huang et al. designed composite biomaterial inks from silk ﬁbroin hydrogel and TEMPO-oxidized bacterial cellulose nanoﬁbril pastes for scaffolding lung tissue by using 3D printing technology. The composite biomaterial inks displayed signiﬁcant pseudoplastic behavior with reversible stress softening property, which is advantageous for 3D printing technology. Presence of oxidized bacterial cellulose supported the mechanical properties of the hydrogel due to its structural connection; nevertheless, it also improved the printability, shape conformity, and ﬁber alignment in the printed scaffolds (Huang et al. 2021).
Cellulose and Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is a condition, which occurs due to inhalation of unpleasant or noxious gas particles. People suffering from COPD experience dyspnea while eating, because greater efforts need to be taken to breathe while eating. In many cases, the nutritional needs of COPD patients are compromised making it difﬁcult to maintain the adequate dietary intake (Collins et al. 2019). L-arginine is used as a nutritional support in COPD because it addresses energy expenditure issues and improves the nutritional parameters. It is generally incorporated into amino acid infusions as an essential component for effective medication. However, the recovery of L-arginine from the aqueous solution requires
Cellulose-Based Drug Delivery Systems in Lung Disorders
the use of an adsorbent. Cellulose, as a ﬁne powder or as a ﬁbriform, was effectively used as an adsorbent for the recovery of L-arginine. A novel water-soluble spherical cellulose adsorbent containing anionic sulfonic group was used by Liu et al. to increase the adsorption of L-arginine from aqueous solutions (Liu et al. 2007). Theophylline is used for the management of COPD. Jelvehgari and Montazam developed microcapsules of theophylline using CAB and EC using the microencapsulation technique. CAB is a cellulose ester, which has low viscosity, good solubility in variety of solvents, and biocompatible with many resins. EC, a cellulose ether, is non-ionic, pH-sensitive, and used as a non-swellable, water-insoluble component in the coating system. The microcapsules were able to control the release of drug from the membranes and reduce the ﬂuctuations of drug concentration in the plasma, which is necessary to manage the adverse effects of the drug (Jelvehgari and Montazam 2012).
Cellulose and Asthma
Asthma is a chronic inﬂammatory disease of the airways that is characterized by recurring attacks of wheezing, shortness of breath, tightness in the chest, and/ or coughing, all of which can change in frequency and severity over time. Common triggers include viruses, pollens, allergens, and exercise. Asthma medications usually fall into two categories, for example, (a) controllers—long-term, maintenance medications that work to reduce inﬂammation and, in turn, improve lung function, and (b) relievers—quick-acting, as-needed medications that alleviate bronchospasm and other symptoms as they occur (Quirt et al. 2018). Kawashima and colleagues developed nanospheres by modifying the surface of pranlukast hydrate, a hydrophobic API, with ultraﬁne hydrophilic particles of HPMCP. After loading these nanospheres onto lactose carriers, they were aerosolized using a Spinhaler. The mode of deposition in the lung was determined in vitro using a twin impinger, wherein the study results revealed an improved inhalation efﬁciency, two-fold increase in emission from device, and a three-fold increase in deep lung deposition of the surface-modiﬁed nanospheres relative to unmodiﬁed powder. These observations may be attributable to the improved surface roughness and hydrophilicity of the hydrophobic drug surface when treated with HPMCP (Kawashima et al. 1998). For the pulmonary delivery of beclomethasone dipropionate, Sakagami and co-workers formulated a microsphere-based aerosol product using HPC as a mucoadhesive polymer. The microspheres developed were either amorphous or crystalline, depending on the type of solvent used for spray-drying. The produced microspheres were found to have a particle size of 2.5-2.9 μm on average. Among the two, amorphous microspheres showed immediate absorption of drug from the lungs (i.e., ≥95% in 180 min) and higher level of metabolite formation, compared to crystalline microspheres (i.e.,