Nanopharmaceuticals: Expectations and Realities of Multifunctional Drug Delivery Systems: Volume 1: Expectations and Realities of Multifunctional Drug Delivery Systems [1 ed.] 0128177780, 9780128177785

Table of contents :
Cover
Nanopharmaceuticals: Expectations and Realities of Multifunctional Drug Delivery Systems Volume 1
Copyright
Contributors
Preface
1 - Solid lipid nanoparticles (SLN): prediction of toxicity, metabolism, fate and physicochemical properties
1. Introduction
2. Toxicity profiling
3. Physicochemical properties
3.1 Encapsulation parameters
3.2 Particle size
3.3 Zeta potential
3.4 Particle morphology
3.5 Differential scanning calorimetry
3.6 Stability of formulations and release profile
4. Administration routes and drug bioavailability
4.1 Topical and dermal routes
4.2 Ocular delivery
4.3 Oral administration
4.4 Parenteral administration
4.5 Nasal and pulmonary delivery
5. Conclusions
Abbreviations
Acknowledgments
References
2 - Role of nanocarriers and their surface modification in targeting delivery of bioactive compounds
1. Bioactive compounds as promising therapeutic agents
1.1 Curcuma sp
1.2 Zingiber officinale
1.3 Silybum marianum L
1.4 Gnetum gnemon
1.5 Physalis angulata
2. Complexity of bioactive compounds
3. Biological barriers
3.1 Physical barriers
3.2 Biochemical barriers
4. Nanocarrier: a strategy to overcome biological barriers
4.1 Lipid-based nanocarrier systems
4.1.1 Liposomes
4.1.2 Nanoemulsions
4.1.3 Solid lipid nanoparticles
5. Safe-by-design bioactive-loaded nanocarrier system development
6. Cellular uptake capability of bioactive-loaded nanocarrier system
7. Surface modification of nanocarriers
8. Biokinetic profile of bioactive-loaded nanocarriers
9. Challenges of bioactive-loaded nanocarrier to clinical translation
9.1 Patents on herbal nanoparticles for breast cancer
10. Conclusion
References
3 - Polymeric nanomicelles as versatile tool for multidrug delivery in chemotherapy
1. Introduction
2. Micelles, principles and characterization
2.1 Preparation methods
2.2 Characterization techniques
2.3 Drug-loading methods
3. Polymeric micelles for codelivery of chemotherapeutics
3.1 Codelivery of chemotherapeutics to overcome multidrug resistance
3.1.1 Codelivery of chemotherapeutics and chemosensitizers
3.1.2 Codelivery of chemotherapeutics and downregulating gene agents
3.2 Codelivery of chemotherapeutics to achieve synergistic effects by methods other than effects on MDR
3.3 Codelivery of chemotherapeutics to mitigate side effects
4. Stimuli-responsive codelivery of polymeric micelles
4.1 pH-sensitive codelivery systems
4.2 Redox-sensitive codelivery systems
5. Targeted codelivery of polymeric micelles
6. Application of polymeric micelles in codelivery for multiple therapies
6.1 Chemo-immunotherapy
6.2 Chemo-angiogenic therapy
6.3 Chemo-photothermal therapy
6.4 Chemo-radiotherapy
6.5 Chemo-enzyme prodrug therapy
7. Conclusions
Acknowledgments
References
4 - Nanoparticulate systems for wound healing
1. Introduction
2. Lipid-based nanoparticles
2.1 Liposomes
2.2 Penetration enhancer vesicles
2.3 Ethosomes
2.4 Transfersomes
2.5 Nanoemulsions
2.6 Solid lipid nanoparticles/Nanostructured lipid carriers
3. Inorganic nanoparticles
3.1 Silver (Ag) nanoparticles
3.2 Gold (Au) nanoparticles
3.3 Metal oxide nanoparticles
3.3.1 Zinc oxide nanoparticles
3.3.2 Iron oxide nanoparticles
3.3.3 Cerium oxide nanoparticles
3.3.4 Titanium dioxide nanoparticles
3.4 Copper (Cu) nanoparticles
3.5 Silicon nanoparticles
3.6 Selenium nanoparticles
4. Conclusions
References
5. Solid dispersions: technologies used and future outlook
1. Introduction
2. Classification of solid dispersions
2.1 First generation
2.2 Second generation
2.3 Third generation
2.4 Fourth generation
2.5 Fifth generation
3. Structure-based classification of solid dispersion
3.1 Solid solutions
3.2 Glass solution
3.3 Eutectic mixtures
4. Drug release mechanism from SDs
5. Applications of SDs
6. Challenges in SD development
7. Techniques for solid dispersions generation
7.1 Solvent evaporation method
7.1.1 Spray drying
7.1.2 Vacuum drying and rotatory evaporation
7.1.3 Freeze drying (lyophilization)
7.1.4 Cryogenic processing
7.1.5 Supercritical fluid technology
7.1.6 Coprecipitation method
7.1.7 Electrostatic spinning
7.1.8 Fluid-bed coating
7.2 Melting method
7.2.1 Hot melt extrusion
7.2.2 Melt agglomeration
7.2.3 KinetiSol technique
7.3 Melting-solvent method
8. Future outlook
9. Conclusion
Abbreviations
References
6 - Nanotoxicity: the impact of increasing drug bioavailability
1. Introduction
2. Nanomedicines, absorption and theranostics
3. Risk assessment process
4. In vitro toxicity
5. In vitro assay interferences
6. Genotoxicity
7. Immunotoxicity
8. Dermal toxicity
9. Nephrotoxicity
10. Liver toxicity
11. Brain toxicity
12. Prediction in vivo of human response to nanomaterials
13. ADME model
14. Organ-on-chip systems
15. Whole-animal models
16. Regulation of nanotechnology products
17. Conclusions and perspectives
References
7. Nanoparticle-based vaccines: opportunities and limitations
1. Chapter outline
1.1 Introduction
1.2 Immune responses after vaccination
1.3 Types of NPs used to deliver vaccines
1.4 Liposomes
1.5 Virus-like particles
1.6 Metal and nonmetal inorganic NPs
1.7 Polymeric NPs
1.8 NP-investing companies and clinical trials
1.9 Nanocytotoxicity
2. Conclusion
References
8. Lipid nanocarriers for delivery of poorly soluble and poorly permeable drugs
1. Introduction
2. Biopharmaceutics Classification System—implications for drug delivery
3. Classification and composition of lipid nanocarriers for oral drug delivery
4. Types of lipid nanocarriers for oral drug delivery
4.1 Vesicular lipid nanocarriers
4.2 Nonvesicular lipid nanocarriers
5. Solubility and permeability enhancement strategies by lipid nanocarriers
6. Mechanisms of interaction of lipid nanocarriers with cell membranes
7. Conclusion and future perspectives
References
9. Nose-to-brain drug delivery: an alternative approach for effective brain drug targeting
1. Introduction
2. Common brain disorders
2.1 Alzheimer disease
2.2 Parkinson disease
2.3 Migraine
2.4 Schizophrenia
2.5 Autism
2.6 Cerebral palsy
2.7 Meningitis
2.8 Myasthenia gravis
2.9 Stroke
3. Anatomy of the nasal cavity
4. Nose-to-brain drug transport pathways
4.1 Neuronal pathway
4.1.1 Olfactory nerve pathway
4.1.2 Trigeminal sensory nerve pathway
4.2 Vascular pathway
5. Strategies to enhance nasal absorption
5.1 Permeation enhancers
5.2 Enzyme inhibitor
6. Novel drug delivery approaches
6.1 Polymeric nanoparticles
6.2 Lipidic nanoparticles
6.3 Inorganic nanoparticles
6.4 Liposomes
6.5 Nanoemulsions
6.6 Dendrimers
7. Recent advancements in the clinical trials of nanoparticles via the nose-to-brain delivery
8. Summary
Acknowledgments
References
10. Trends in the intellectual property (IP) landscape of drug delivery systems: 30 years of growth and evolution
1. Introduction
2. Overview of the IP landscape for drug delivery systems
2.1 Industry trends
2.2 Technology trends
3. Trends in oral drug delivery IP
3.1 Overall trends in oral drug delivery IP
3.2 Trends in oral drug delivery technologies
3.3 Trends in disease areas and pharmaceutical substances
4. Trends in topical drug delivery IP
4.1 Overall trends in topical drug delivery IP
4.2 Trends in topical drug delivery technologies
4.3 Trends in disease areas and pharmaceutical substances
5. Trends in parenteral drug delivery IP
5.1 Overall trends in parenteral drug delivery IP
5.2 Trends in parenteral drug delivery technologies
5.3 Trends in disease areas and pharmaceutical substances
6. Emerging trends in drug delivery IP
7. IP monitoring strategies
8. Conclusion
8.1 About CAS
References
Index
A
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Back Cover

Citation preview

NANOPHARMACEUTICALS EXPECTATIONS AND REALITIES OF MULTIFUNCTIONAL DRUG DELIVERY SYSTEMS VOLUME 1 Edited by

RANJITA SHEGOKAR, PhD Capnomed GmbH, Zimmern, Germany

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-817778-5 For information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre Gerhard Wolff Acquisition Editor: Erin Hill-Parks Editorial Project Manager: Pat Gonzalez Production Project Manager: Punithavathy Govindaradjane Cover Designer: Mark Rogers Typeset by TNQ Technologies

Contributors and Health Sciences, Universidad del Rosario, Bogot
a, DC, Colombia

Hend Abd-Allah Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Egypt

Riham I. El-Gogary Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Egypt

Mona Abdel-Mottaleb Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Egypt; PEPITE EA4267, Univ. Bourgogne Franche-Comté, Besançon, France

N.B. Jadav Centre for Pharmaceutical Engineering Sciences, Faculty of Life Sciences, University of Bradford, Bradford, United Kingdom

Annis Catur Adi Faculty of Health, University of Airlangga, Surabaya, Indonesia

AnCelka B. Kovacevi
c Department of Pharmaceutical Technology, Institute of Pharmacy, Faculty of Biological Sciences, Friedrich-Schiller University Jena, Jena, Germany

Mukta Agrawal Rungta College of Pharmaceutical Sciences and Research, Bhilai, Chhattisgarh, India Amit Alexander Rungta College of Pharmaceutical Sciences and Research, Bhilai, Chhattisgarh, India

Atsarina Larasati Research Center for Nanosciences and Nanotechnology, Bandung Institute of Technology, Bandung, Indonesia

Mahavir Bhupal Chougule Translational Biopharma Engineering Nanodelivery Research Laboratory, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, MS, United States; Pii Center for Pharmaceutical Technology, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, United States; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, United States

Peter Mattei CAS, a Division of the American Chemical Society, Columbus, OH, United States Maha Nasr Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Egypt A. Paradkar Centre for Pharmaceutical Engineering Sciences, Faculty of Life Sciences, University of Bradford, Bradford, United Kingdom Heni Rachmawati School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia; Research Center for Nanosciences and Nanotechnology, Bandung Institute of Technology, Bandung, Indonesia

Juan Bueno Research Center of Bioprospecting and Biotechnology for Biodiversity Foundation (BIOLABB), Armenia, Quindío, Colombia J.R. Campos Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P
olo das Ciências da Sa
ude, Coimbra, Portugal

Kobra Rostamizadeh Zanjan Pharmaceutical Nanotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran; Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States

Anne Marie Clark CAS, a Division of the American Chemical Society, Columbus, OH, United States Diana Diaz-Arévalo Molecular Biology and Immunology Department, Fundaci
on Instituto de Inmunología de Colombia-FIDIC, School of Medicine

A. Santini Department of Pharmacy, University of Napoli “Federico II”, Napoli, Italy

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Contributors

Shailendra Saraf University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India Swarnlata Saraf University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India P. Severino Universidade Tiradentes (Unit), Aracaju, Sergipe, Brazil; Instituto de Tecnologia e Pesquisa, Laborat
orio de Nanotecnologia e Nanomedicina (LNMed), Aracaju, Sergipe, Brazil; Tiradentes Institute, Dorchester, United States Ranjita Shegokar Germany

Capnomed GmbH, Zimmern,

A.M. Silva School of Biology and Environment, University of Tr
as-os-Montes e Alto Douro (UTAD), Vila Real, Portugal; Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Tr
as-os-Montes e Alto Douro (UTAD), Vila Real, Portugal S.B. Souto Department of Endocrinology, S. Jo~ ao Hospital, Alameda Prof. Hern^ani Monteiro, Porto, Portugal

E.B. Souto Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P
olo das Ciências da Sa
ude, Coimbra, Portugal; CEB - Centre of Biological Engineering, University of Minho, Braga, Portugal Asur Srinivasan CAS, a Division of the American Chemical Society, Columbus, OH, United States Amanda Starling-Windhof CAS, a Division of the American Chemical Society, Columbus, OH, United States Tina Tomeo CAS, a Division of the American Chemical Society, Columbus, OH, United States Vladimir P. Torchilin Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States Mingtao Zeng Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States

Preface

(4) establish collaborations between academic scientists, and industrial and clinical researchers.

The book series titled Expectations and Realities of Multifunctional Drug Delivery Systems covers several important topics on drug-delivery systems, regulatory requirements, clinical studies, intellectual properties trends, new advances, manufacturing challenges, etc. written by leading industry and academic experts. Overall, the chapters published in this series reflect the broadness of nanopharmaceuticals, microparticles, other drug carriers and the importance of the respective quality, regulatory, clinical, GMP scale up, and regulatory registration aspects. This series is destined to fill the knowledge gap through information sharing and with organized research compilation between diverse areas of pharma, medicine, clinical, regulatory practices, and academics. Expectations and Realities of Multifunctional Drug Delivery Systems is divided into four volumes: Volume 1: Nanopharmaceuticals Volume 2: Delivery of Drugs Volume 3: Drug Delivery Trends Volume 4: Drug Delivery Aspects

Innovative cutting-edge developments in micro-nanotechnology offer new ways of preventing and treating diseases like cancer, malaria, HIV/AIDS, tuberculosis, and many more. The application of micro-nanoparticles in drug delivery, diagnostics, and imaging is vast. Hence, Volume 1: Nanopharmaceuticals, in the book series mainly reviews advances in drug delivery area via targeted therapy with improved drug efficiency at a lower dose, transportation of the drug across physiological barriers as well as reduced drug-related toxicity. One of the contributions by Campos et al. (Chapter 1) discusses the influence of physicochemical factors affecting long-term stability, release and toxicological profiles of solid lipid nanoparticles. This chapter also reviews the importance of composition and administration routes studied for lipid nanocarrier systems. In another manuscript by Rachmawati et al. (Chapter 2), the authors highlight the current status of drug delivery development for herbal bioactives. Along with various mucosal biocarriers, the authors describe biokinetic and clinical translation challenges with herbal delivery and limitations with regulatory procedures. In this chapter herbal nanocarriers like lipid nanoparticles, nanosuspensions etc. are discussed in detail.

The specific objectives of this book series are to: (1) provide a platform to discuss opportunities and challenges in development of nanomedicine and other drug-delivery systems; (2) discuss current and future market trends; (3) facilitate insight sharing within various areas of expertise; and

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Preface

Chapter 3 by Rostamizadeh et al. describes the development of polymeric micelles for multiple drug delivery in oncology. The co-loading of two or more drugs is possible using polymeric micelles. The authors describe the types of polymers employed, preparation methods, and characterization techniques for such carrier systems. Furthermore, wider applications like chemotherapeutic delivery, stimuli-responsive drug delivery, and targeted-drug delivery via such carriers is discussed in detail. On the other hand, hyaluronic acid nanoparticles are being widely explored in nanomedicines. The promising nanocarriers to deliver drugs in conjugated, selfassembled, or in nanocomplex form are discussed in the book chapter by Nasr et al. in Chapter 4. The authors confirm that the current research shows impressive research findings in areas like osteoarthritis, tissue engineering, cancer targeting, theranostic applications, and so on, which are under further exploration by industry. The work by Jadav and Paradkar (Chapter 5) is aimed at discussing widely studied drug delivery systems in academics and in industry, i.e. solid dispersions. Various aspects like classification of solid dispersions, their formulation optimization, processing and physicochemical characterization are reviewed in this chapter. Chapter 6 by Bueno highlights the importance of understanding nanotoxicity at early stages of development. Although nanocarriers have shown promising results in delivering drugs at target sites or locations, the accumulation of nanoparticles at cellular and tissue levels in excess causes toxicity. Current literature contains very limited information on this topic. This chapter reviews various aspects of nanotoxicity and provides information on key concepts for evaluation of the toxicity. The topic presented by Diaz-Arévalo et al. (Chapter 7) describes the systemic review of nanoparticles-based vaccine development. Initial results of nanocarriers like liposomes, virus like particles, metallic and nonmetallic particles, and polymeric nanoparticles in vaccine therapy are

promising although some limitations like stability and cytotoxicity needs to be overcome. Chapter 8 by Kovacevic discusses delivery of poorly soluble and low-permeable drugs via lipid nanocarriers. An overview of available mechanistic studies in model and in real cell membranes for better understanding of cell internalization processes is provided. The chapter by Alexander et al. (Chapter 9) reviews approaches for effective brain drug delivery using nasal mucosa. This route can deliver drugs effectively at target sites with improved therapeutic performance of drugs. In addition, the authors explain limitations of this drug delivery route and regulatory market approval challenges. Starling-Windhof et al. (Chapter 10) address industry and technology trends in the intellectual property (IP) landscape of pharmaceutical drug delivery over 3 decades. It is fascinating to see the global picture; it makes scientists aware of the trends and special interests of specific geographical regions or markets. This chapter provides information on IP trends in oral, topical, and parenteral drug delivery area. Guidance on emerging trends and IP-monitoring strategies are also presented. In summary, I am sure this book volume and the complete book series will provide you great insights in areas of micro-nanomedicines, drug delivery sciences, new trends, and regulatory aspects. O. Farokhzad, R. Langer, and the National Cancer Institute are gratefully acknowledged for the book cover image, which represents the potential of nanopharmaceuticals in targeting drug molecules. This photograph presented on cover page captures interactions of surface-modified polymeric nanoparticles with prostate cancer cellsdit is an ideal example for drug targeting. All the efforts of experts, scientists, and authors are highly acknowledged for sharing their knowledge, ideas, and insights about the topic. Ranjita Shegokar, PhD Editor

C H A P T E R

1

Solid lipid nanoparticles (SLN): prediction of toxicity, metabolism, fate and physicochemical properties 1

J.R. Campos1, P. Severino2,3,4, A. Santini5, A.M. Silva6,7, Ranjita Shegokar8, S.B. Souto9, E.B. Souto1,10

Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P
olo das Ci^encias da Sa
ude, Coimbra, Portugal; 2Universidade Tiradentes (Unit), Aracaju, Sergipe, Brazil; 3 Instituto de Tecnologia e Pesquisa, Laborat
orio de Nanotecnologia e Nanomedicina (LNMed), Aracaju, Sergipe, Brazil; 4Tiradentes Institute, Dorchester, United States; 5Department of Pharmacy, University of Napoli “Federico II”, Napoli, Italy; 6School of Biology and Environment, University of Tr
as-os-Montes e Alto Douro (UTAD), Vila Real, Portugal; 7Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Tr
as-os-Montes e Alto Douro (UTAD), Vila Real, Portugal; 8Capnomed GmbH, Zimmern, Germany; 9Department of Endocrinology, S. Jo~ao Hospital, Alameda Prof. Hern^ani Monteiro, Porto, Portugal; 10CEB - Centre of Biological Engineering, University of Minho, Braga, Portugal

1. Introduction

formulations [2]. Various controlled drug delivery systems like polymer-based controlledrelease systems, hydrogels, as well as nanoand microparticles have been introduced in recent years in order to improve solubility, stability and bioavailability of poorly water-soluble drugs. In this context, lipid nanoparticles offer attractive and ideal properties for drug or gene delivery. These particles (either composed of solid lipids only in SLNs, or of a blend of solid and liquid lipids in NLCs) stabilized with surfactants have the advantages of other colloidal

Solid lipid nanoparticles (SLNs) gained greater attention as a drug delivery system when in 1991 M€ uller developed them [1]. This promising drug carrier system is at the interface in the preexisting lipid systems (emulsions and liposomes) and polymeric nanoparticle systems. Lipid nanoparticles, known as SLNs or nanostructured lipid carriers (NLCs), have specific features of structure and composition, showing benefits in comparison to conventional

Nanopharmaceuticals https://doi.org/10.1016/B978-0-12-817778-5.00001-4

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© 2020 Elsevier Inc. All rights reserved.

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1. Solid lipid nanoparticles (SLN)

particles (polymeric nanoparticles, fat emulsions, and liposomes) by overcoming their limitations [3,4]. Taking account their polymeric and lipid raw materials, several modifications of drug delivery systems have been proposed to increase the bioavailability of loaded drugs. SLNs are made of a solid lipid matrix and a surfactant layer and they can load poorly watersoluble drugs, delivering them at defined rates and with improved bioavailability [5]. These colloidal drug delivery systems protect the drug against chemical degradation and modify its release profile since the drug is entrapped in the solid lipid matrix [6,7]. These nanoparticles of spherical shape have a mean size of 40e1000 nm [8,9]. The lipid matrix is composed of a solid lipid (or a mixture of solid and liquid lipids) in a 0.1%e30% (w/w) concentration dispersed in aqueous medium, and their stability is ensured by the presence of a surfactant in a 0.5%e5% (w/w) concentration [8] and can be used for lipophilic or hydrophilic drugs [9]. Triglycerides (tristearin), sterols (cholesterol), partial glycids (glyceryl monostearate), fatty acids (stearic acid), as well as waxes (cetylpalmitate) are especially used as lipids in the SLNs. In these systems emulsifiers and polymers are used as stabilizers in order to avoid aggregation of the particles. Examples of stabilizers are bile salts (e.g., taurodeoxycholate), lecithins, and copolymers of polyoxyethylene and polyoxypropylene (Poloxamer) [10]. It is clear that lipid nanocarriers are ideal for sensitive bioactive compounds. SLNs exhibit biocompatibility, matrix with lipophilic nature protecting active compounds of chemical degradation, drug targeting, controlled release profile, and high drug payload [9,12]. Moreover, they are suitable for industrial production mainly because they are easy to scale up, are stable under sterilization conditions, and they have the advantage of being non-toxic or of very low toxicity, because of their composition in Generally

Recognized as Safe (GRAS) excipients [4,6]. SLNs are biodegradable (fulfilling the requirements of preclinical safety) and are also stable in blood, with prolonged lifetime in the bloodstream [13e15]. In addition, compared to liposomes, SLNs exhibit high encapsulation efficiency, stability against light and oxygen, do not need organic solvents for their preparation, and have high drug-loading capacity (mainly for lipophilic compounds) [12,15,16]. On the other hand, SLNs have also limitations, mainly attributed to the risk of polymorphic transitions (from a to b0 , and from b0 to b) which causes stability challenges during administration or storage, resulting in drug expulsion from the particles and eventual particle size increase [6,10,17]. These disadvantages are related to the crystallization behavior and lipid matrix’s polymorphic transitions, which depend on the type of lipids used for the production of SLNs [6]. There are various methods described in the literature to produce SLNs based on solidified emulsion technologies: high shear homogenization and ultrasound, high pressure (hot and cold) homogenization, oil/water (O/ W) and water/oil/water (W/O/W) microemulsions, as well as solvent evaporation [10]. These techniques interfere with various characteristics of the particles, mainly in morphology. According to the literature, the most commonly applied methods are those that use high pressure homogenizers (HPH). M€ uller and Luck developed the HPH technique (European Patent No. 0605497) for obtaining nanoemulsions for largescale parenteral nutrition [10]. There are diverse kinds of equipment with various sizes, prices as well as different capacities. The different equipments work by pulling the liquid in high pressure (100e2000 bar) through a narrow piston (nanometer scale), which is accelerated over a small distance at a high speed (over 1000 km/h). This fluid is subjected to high stress, disrupting the macroscopic oil droplets by cavitation forces and thus generating the nanodroplets [10]. In

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2. Toxicity profiling

the hot process, the hot preemulsion is passed through the hot homogenizer to obtain nanoemulsions, which are then cooled down in order to solidify and crystallize the hot inner liquid phase to obtain SLNs. In the cold process, the drug is firstly ground milled in a mortar mill with the solid lipid at room temperature, and then the obtained powder is dispersed in an aqueous surfactant solution, which is then subjected to HPH. The influence of the type of homogenizer, pressure, and number of cycles employed, and the temperature used to obtain the ideal particle size, have been intensively studied. Depending on the type of lipid, it is possible to use lipid concentrations above 40% and obtain the particle size distribution in a low range (polydispersity index