Chitosan-Based Systems for Biopharmaceuticals: Delivery, Targeting and Polymer Therapeutics

Chitosan is a linear polysaccharide commercially produced by the deacetylation of chitin. It is non-toxic, biodegradable, biocompatible, and acts as a bioadhesive with otherwise unstable biomolecules - making it a valuable component in the formulation of biopharmaceutical drugs. Chitosan-Based Systems for Biopharmaceuticals provides an extensive overview of the application of chitosan and its derivatives in the development and optimisation of biopharmaceuticals. The book is divided in four different parts. Part I discusses general aspects of chitosan and its derivatives, with particular emphasis on issues related to the development of biopharmaceutical chitosan-based systems. Part II deals with the use of chitosan and derivatives in the formulation and delivery of biopharmaceuticals, and focuses on the synergistic effects between chitosan and this particular subset of pharmaceuticals. Part III discusses specific applications of chitosan and its derivatives for biopharmaceutical use. Finally, Part IV presents diverse viewpoints on different issues such as regulatory, manufacturing and toxicological requirements of chitosan and its derivatives related to the development of biopharmaceutical products, as well as their patent status, and clinical application and potential. Topics covered include: chemical and technological advances in chitins and chitosans useful for the formulation of biopharmaceuticals physical properties of chitosan and derivatives in sol and gel states absorption promotion properties of chitosan and derivatives biocompatibility and biodegradation of chitosan and derivatives biological and pharmacological activity of chitosan and derivatives biological, chemical and physical compatibility of chitosan and biopharmaceuticals approaches for functional modification or crosslinking of chitosan use of chitosan and derivatives in conventional biopharmaceutical dosage forms manufacture techniques of chitosan-based microparticles and nanoparticles for biopharmaceuticals chitosan and derivatives for biopharmaceutical use: mucoadhesive properties chitosan-based systems for mucosal delivery of biopharmaceuticals chitosan-based delivery systems for mucosal vaccination chitosan-based nanoparticulates for oral delivery of biopharmaceuticals chitosan-based systems for ocular delivery of biopharmaceuticals chemical modification of chitosan for delivery of DNA and siRNA target-specific chitosan-based nanoparticle systems for nucleic acid delivery functional PEGylated chitosan systems for biopharmaceuticals stimuli-sensitive chitosan-based systems for biopharmaceuticals chitosan copolymers for biopharmaceuticals application of chitosan for anti-cancer biopharmaceutical delivery chitosan-based biopharmaceuticals scaffolds in tissue engineering and regenerative medicine wound healing properties of chitosan and its use in wound dressing biopharmaceuticals toxicological properties of chitosan and derivatives for biopharmaceutical applications regulatory status of chitosan and derivatives patentability and intellectual property issues quality control and good manufacturing practice preclinical and clinical use of chitosan and derivatives for biopharmaceuticals Chitosan-Based Systems for Biopharmaceuticals is an important compendium of fundamental concepts, practical tools and applications of chitosan-based biopharmaceuticals for researchers in academia and industry working in drug formulation and delivery, biopharmaceuticals, medicinal chemistry, pharmacy, bioengineering and new materials development.

Table of Contents:
List of Contributors xvii Foreword xxiii Marıa Jose Alonso Preface xxv Acknowledgments xxvii Part One General Aspects of Chitosan 1 1 Chemical and Technological Advances in Chitins and Chitosans Useful for the Formulation of Biopharmaceuticals 3 Riccardo A. A. Muzzarelli 1.1 Introduction 3 1.2 Safety of Chitins and Chitosans 4 1.3 Ionic Liquids: New Solvents and Reaction Media 5 1.4 Chitin and Chitosan Nanofibrils 8 1.5 Electrospun Nanofibers 10 1.6 Polyelectrolyte Complexes and Mucoadhesion 12 1.7 Conclusions and Future Perspectives 16 2 Physical Properties of Chitosan and Derivatives in Sol and Gel States 23 Marguerite Rinaudo 2.1 Introduction 23 2.2 Chitin 24 2.3 Chitosan 28 2.4 Conclusions and Future Perspectives 36 3 Absorption Promotion Properties of Chitosan and Derivatives 45 Akira Yamamoto 3.1 Introduction 45 3.2 Effect of Chitosan on the Intestinal Absorption of Poorly Absorbable Drugs 47 3.3 Effect of Chitosan Derivatives on the Intestinal Absorption of Poorly Absorbable Drugs 47 3.4 Effect of Chitosan Oligomers on the Intestinal Absorption of Poorly Absorbable Drugs 48 3.5 Colon-Specific Delivery of Insulin Using Chitosan Capsules 51 3.6 Conclusions and Future Perspectives 54 4 Biocompatibility and Biodegradation of Chitosan and Derivatives 57 Ahmad Sukari Halim, Lim Chin Keong, Ismail Zainol, and Ahmad Hazri Abdul Rashid 4.1 Introduction 57 4.2 Biocompatibility Evaluation of Chitosan and Derivatives 58 4.3 Biodegradation of Chitosan and Derivatives 65 4.4 Conclusions and Future Perspectives 69 5 Biological and Pharmacological Activity of Chitosan and Derivatives 75 Teresa Cunha, Branca Teixeira, Barbara Santos, Marlene Almeida, Gustavo Dias, and Jose das Neves 5.1 Introduction 75 5.2 Biological Activity 76 5.3 Chitosan's Usefulness in Therapy and Alternative Medicine 82 5.4 Conclusions and Future Perspectives 84 6 Biological, Chemical, and Physical Compatibility of Chitosan and Biopharmaceuticals 93 Masayuki Ishihara, Masanori Fujita, Satoko Kishimoto, Hidemi Hattori, and Yasuhiro Kanatani 6.1 Introduction 93 6.2 Structural Features of Chitosan and Its Derivatives 94 6.3 Biocompatibility for Chitosan and Its Derivatives 95 6.4 Biocompatibility of Photo-Cross-Linkable Chitosan Hydrogel 98 6.5 Physical and Chemical Compatibility of Chitosan and Its Derivatives 100 6.6 Conclusions and Future Perspectives 102 7 Approaches for Functional Modification or Cross-Linking of Chitosan 107 A. Anitha, N. Sanoj Rejinold, Joel D. Bumgardner, Shanti V. Nair, and Rangasamy Jayakumar 7.1 Introduction 107 7.2 General Awareness of Chitosan Cross-Linking Methods 108 7.3 Modified Chitosan: Synthesis and Characterization 112 7.4 Applications of Modified Chitosan and Its Derivatives in Drug Delivery 118 7.5 Conclusions and Future Perspectives 118 Part Two Biopharmaceuticals Formulation and Delivery Aspects Using Chitosan and Derivatives 125 8 Use of Chitosan and Derivatives in Conventional Biopharmaceutical Dosage Forms Formulation 127 Teofilo Vasconcelos, Pedro Barrocas, and Rui Cerdeira 8.1 Introduction 127 8.2 Advantageous Properties of Chitosan and Its Derivatives 128 8.3 Oral Administration 129 8.4 Buccal Administration 131 8.5 Nasal Administration 132 8.6 Pulmonary Administration 132 8.7 Transdermal Administration 133 8.8 Conclusions and Future Perspectives 133 9 Manufacture Techniques of Chitosan-Based Microparticles and Nanoparticles for Biopharmaceuticals 137 Franca Ferrari, M. Cristina Bonferoni, Silvia Rossi, Giuseppina Sandri, and Carla M. Caramella 9.1 Introduction 137 9.2 Water-in-Oil Emulsion and Chemical Cross-linking 138 9.3 Drying Techniques 141 9.4 Ionic Cross-linking Methods 144 9.5 Coacervation and Precipitation Method 151 9.6 Direct Interaction between Chitosan and Biopharmaceuticals 152 9.7 Conclusions and Future Perspectives 153 10 Chitosan and Derivatives for Biopharmaceutical Use: Mucoadhesive Properties 159 Katharina Leithner and Andreas Bernkop-Schnurch 10.1 Introduction 159 10.2 Mucoadhesion 160 10.3 Chitosan and Its Derivatives 161 10.4 Biopharmaceutical Use of Chitosan and Its Derivatives 171 10.5 Conclusions and Future Perspectives 175 11 Chitosan-Based Systems for Mucosal Delivery of Biopharmaceuticals 181 Sonia Al-Qadi, Ana Grenha, and Carmen Remunan-Lopez 11.1 Introduction 181 11.2 Important Challenges for the Delivery of Biopharmaceuticals by Mucosal Routes 182 11.3 Interest in Chitosan for Mucosal Delivery of Biopharmaceuticals 184 11.4 Chitosan-Based Delivery Nanosystems for Mucosal Delivery of Biopharmaceuticals 188 11.5 Conclusions and Future Perspectives 200 12 Chitosan-Based Delivery Systems for Mucosal Vaccination 211 Gerrit Borchard, Farnaz Esmaeili, and Simon Heuking 12.1 Introduction 211 12.2 Adjuvant Properties of Chitosan 212 12.3 Chitosan in the Delivery of Protein and Subunit Vaccines 213 12.4 Chitosan-Based Formulations of DNAVaccines 215 12.5 Vaccine Formulations Using Chitosan in Combination with Other Polymers 216 12.6 Chitosan Derivatives in Vaccine Carrier Design 217 12.7 Conclusions and Future Perspectives 220 13 Chitosan-Based Nanoparticulates for Oral Delivery of Biopharmaceuticals 225 Filipa Antunes, Fernanda Andrade, and Bruno Sarmento 13.1 Introduction 225 13.2 Challenges on the Oral Delivery of Therapeutic Proteins 226 13.3 Challenges on the Oral Delivery of Genetic Material 227 13.4 Role of Chitosan in the Protection of Biopharmaceuticals in the Gastrointestinal Tract 229 13.5 Chitosan-Based Nanoparticles for Oral Delivery of Therapeutic Proteins 232 13.6 Chitosan-Based Nanoparticles for Oral Delivery of Genetic Material 234 13.7 Conclusions and Future Perspectives 236 14 Chitosan-Based Systems for Ocular Delivery of Biopharmaceuticals 243 Suresh P. Vyas, Rishi Paliwal, and Shivani Rai Paliwal 14.1 Introduction 243 14.2 Ocular Delivery of Biopharmaceuticals 244 14.3 Chitosan: A Suitable Biomaterial for Ocular Therapeutics 244 14.4 Chitosan-Based Systems for Ocular Delivery of Biomacromolecules 245 14.5 Toxicological and Compatibility Aspects of Chitosan-Based Ocular Systems 249 14.6 Conclusions and Future Perspectives 250 15 Chemical Modification of Chitosan for Delivery of DNA and siRNA 255 You-Kyoung Kim, Hu-Lin Jiang, Ding-Ding Guo, Yun-Jaie Choi, Myung-Haing Cho, Toshihiro Akaike, and Chong-Su Cho 15.1 Introduction 255 15.2 Hydrophilic Modification 256 15.3 Hydrophobic Modification 257 15.4 Specific Ligand Modification 259 15.5 pH-Sensitive Modification 264 15.6 Conclusions and Future Perspectives 269 Part Three Advanced Application of Chitosan and Derivatives for Biopharmaceuticals 275 16 Target-Specific Chitosan-Based Nanoparticle Systems for Nucleic Acid Delivery 277 Shardool Jain and Mansoor Amiji 16.1 Introduction 277 16.2 Chitosan-Based Nanoparticle Delivery Systems 283 16.3 Illustrative Examples of DNAVaccine Delivery 286 16.4 Illustrative Examples of Nucleic Acid Delivery Systems for Cancer Therapy 288 16.5 Illustrative Examples of Nucleic Acid Delivery Systems for Anti-Inflammatory Therapy 291 16.6 Conclusions and Future Perspectives 294 17 Functional PEGylated Chitosan Systems for Biopharmaceuticals 301 Hee-Jeong Cho, Goen Kim, Hyeok-Seung Kwon, and Yu-Kyoung Oh 17.1 Introduction 301 17.2 PEGylated Chitosan for the Delivery of Proteins and Peptides 304 17.3 PEGylated Chitosan for Delivery of Nucleic Acids 308 17.4 PEGylated Chitosan for Delivery of Other Macromolecular Biopharmaceuticals 311 17.5 PEGylated Chitosan Used for Cellular Scaffolds 313 17.6 Conclusions and Future Perspectives 313 18 Stimuli-Sensitive Chitosan-Based Systems for Biopharmaceuticals 319 Cuiping Zhai, Jinfang Yuan, and Qingyu Gao 18.1 Introduction 319 18.2 pH-Sensitive Chitosan-Based Systems 319 18.3 Thermosensitive Chitosan-Based Systems 321 18.4 pH-Sensitive and Thermosensitive Chitosan-Based Systems 323 18.5 pH- and Ionic-Sensitive Chitosan-Based Systems 325 18.6 Photo-Sensitive Chitosan-Based Systems 325 18.7 Electrical-Sensitive Chitosan-Based Systems 326 18.8 Magnetic-Sensitive Chitosan-Based Systems 326 18.9 Chemical Substance-Sensitive Chitosan-Based Systems 327 18.10 Conclusions and Future Perspectives 327 19 Chitosan Copolymers for Biopharmaceuticals 333 Ramon Novoa-Carballal, Ricardo Riguera, and Eduardo Fernandez-Megia 19.1 Introduction 333 19.2 Chitosan-g-Poly(Ethylene Glycol) 337 19.3 Chitosan-g-Polyethylenimine 347 19.4 Other Copolymers of Chitosan 357 19.5 Copolymers of Chitosan with Promising Applications 363 19.6 Conclusions and Future Perspectives 368 20 Application of Chitosan for Anticancer Biopharmaceutical Delivery 381 Claudia Philippi, Brigitta Loretz, Ulrich F. Schaefer, and Claus-Michael Lehr 20.1 Introduction 381 20.2 Chitosan and Cancer: Intrinsic Antitumor Activity of the Polymer Itself 382 20.3 Chitosan Formulations Developed for Classic Anticancer Drugs 383 20.4 Biopharmaceuticals Delivered by Chitosan Preparations 384 20.5 Active Targeting Strategies and Multifunctional Chitosan Formulations 388 20.6 Conclusions and Future Perspectives 389 21 Chitosan-Based Biopharmaceutical Scaffolds in Tissue Engineering and Regenerative Medicine 393 Tao Jiang, Meng Deng, Wafa I. Abdel- Fattah, and Cato T. Laurencin 21.1 Introduction 393 21.2 Fabrication of Chitosan-Based Biopharmaceuticals Scaffolds 395 21.3 Applications of Chitosan-Based Biopharmaceutical Scaffolds in Tissue Engineering and Regenerative Medicine 403 21.4 Future Trends: Regenerative Engineering 416 21.5 Conclusions and Future Perspectives 417 22 Wound-Healing Properties of Chitosan and Its Use in Wound Dressing Biopharmaceuticals 429 Tyler G. St. Denis, Tianhong Dai, Ying-Ying Huang, and Michael R. Hamblin 22.1 Introduction 429 22.2 Brief Review of Wound Repair 430 22.3 Wound-Healing Effects of Chitosan 433 22.4 Chitosan for Wound Therapeutics Delivery 440 22.5 Conclusions and Future Perspectives 444 Part Four Regulatory Status, Toxicological Issues, and Clinical Perspectives 451 23 Toxicological Properties of Chitosan and Derivatives for Biopharmaceutical Applications 453 Thomas J. Kean and Maya Thanou 23.1 Introduction 453 23.2 In Vitro Toxicity of Chitosan and Derivatives 454 23.3 In Vivo Toxicity of Chitosan and Derivatives 457 23.4 Conclusions and Future Perspectives 459 24 Regulatory Status of Chitosan and Derivatives 463 Michael Dornish, David S. Kaplan, and Sambasiva R. Arepalli 24.1 Introduction 463 24.2 Source 464 24.3 Characterization 464 24.4 Purity 465 24.5 Applications of Advanced Uses of Chitosan 466 24.6 Regulatory Considerations for Chitosan and Chitosan Derivatives in the European Union, and Medical Devices or Combination Products with Medical Device (CDRH) Lead 468 24.7 Regulatory Pathways 469 24.8 Chitosan Medical Products: US Regulatory Review Processes for Medical Devices or Combination Products with CDRH Lead 469 24.9 Chitosan Wound Dressings 470 24.10 The European Regulatory System: The European Medicines Agency (EMA) and European Directorate for the Quality of Medicines (EDQM) 474 24.11 Further Regulatory Considerations 475 24.12 Conclusions and Future Perspectives 477 24.13 Disclaimer 478 25 Patentability and Intellectual Property Issues Related to Chitosan-Based Biopharmaceutical Products 483 Mafalda Videira and Rogerio Gaspar 25.1 Introduction 483 25.2 Setting the Scene: The Role of Chitosan as a Pharmaceutical Excipient 484 25.3 Addressing the Drivers for Scientific Progress on Chitosan: Innovation and Inventability 495 25.4 Conclusions and Future Perspectives 496 26 Quality Control and Good Manufacturing Practice (GMP) for Chitosan-Based Biopharmaceutical Products 503 Torsten Richter, Maika Gulich, and Katja Richter 26.1 Introduction 504 26.2 Regulatory Requirements for Production 505 26.3 Manufacturing GMP: Fundamental Considerations 508 26.4 Requirements for Rooms, Personnel, and Equipment 511 26.5 Qualification and Validation 511 26.6 Quality Control 513 26.7 Monitoring and Maintenance of a GMP System 519 26.8 Conclusions and Future Perspectives 522 27 Preclinical and Clinical Use of Chitosan and Derivatives for Biopharmaceuticals: From Preclinical Research to the Bedside 525 David A. Zaharoff, Michael Heffernan, Jonathan Fallon, and John W. Greiner 27.1 Introduction 525 27.2 Chitosan as a Parenteral (Subcutaneous) Vaccine Platform 526 27.3 Chitosan as an Immunotherapeutic Platform 530 27.4 Conclusions and Future Perspectives 537 References 539 Index 543

About the Author :
Bruno Sarmento, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal & CICS, Department of Pharmaceutical Sciences, Instituto Superior de Ciências da Saúde–Norte, Gandra, Portugal José das Neves, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal