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

Bruno Sarmento (Editor), Jose das Neves (Editor)
ISBN: 978-0-470-97832-0
584 pages
March 2012
Chitosan-Based Systems for Biopharmaceuticals: Delivery, Targeting and Polymer Therapeutics (0470978325) cover image
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.

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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

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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

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