This important and unique book comprises 12 chapters divided into three parts examining the fundamental aspects, bioadhesive formulations, and drug delivery applications.

Understanding the phenomenon of bioadhesion i.e. its theories or mechanism(s) are of critical importance in developing optimum bioadhesive polymers (used in bioadhesives). Such bioadhesive polymers are the key for exhibiting the process of bioadhesion, controlled/sustained release of drugs, and drug targeting. The use of bioadhesives restricts the delivery system to the site of interest and thus offers a useful and efficient technique for targeting a drug to the desired location for a prolonged duration. This book addresses the various relevant aspects of bioadhesives in drug delivery in an easily accessible and unified manner.

The book containing 12 chapters written by eminent researchers from many parts of the globe is divided into three parts: Part 1: Fundamental Aspects; Part 2: Bioadhesive Formulations; Part 3: Drug Delivery Applications.

The topics covered include: Theories and mechanisms of bioadhesion; bioadhesive polymers for drug delivery applications; methods for characterization of bioadhesiveness of drug delivery systems; bioadhesive films and drug delivery applications; bioadhesive nanoparticles; bioadhesive hydrogels and applications; ocular biodhesive drug delivery systems; buccal bioadhesive drug delivery systems; gastrointestinal bioadhesive drug delivery systems; nasal bioadhesive drug delivery systems; vaginal drug delivery systems; pulmonary bioadhesive drug delivery systems.

Kashmiri Lal Mittal was employed by the IBM Corporation from 1972 through 1993. Currently, he is teaching and consulting worldwide in the broad areas of adhesion as well as surface cleaning. He has received numerous awards and honors including the title of doctorhonoris causa from Maria Curie-Skodowska University, Lublin, Poland. He is the editor of more than 130 books dealing with adhesion measurement, adhesion of polymeric coatings, polymer surfaces, adhesive joints, adhesion promoters, thin films, polyimides, surface modification, surface cleaning, and surfactants. Dr. Mittal is also the Founding Editor of the journalReviews of Adhesion and Adhesives.

Inderbir Singh Bakshi obtained his PhD from Punjabi University, Patiala, India and is now working as Professor of Pharmaceutics at the College of Pharmacy, Chitkara University, Patiala, India. He has 17 years' experience in both industry and academia and has published 75 research/review articles in national& international journals, 3 books, 10 book chapters and seven patents (applied).

Jasjeet Kaur Narang is an Associate Professor in the Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, India. She obtained her M. Pharm and PhD from Jamia Hamdard University, New Delhi in 2001 and 2007 respectively. She did her post-doctorate work at the University of Montreal, Canada. She has published about 90 research articles in both international and national journals, authored three books and contributed many book chapters.

Preface xvii

Part 1: Fundamental Aspects 1

1 Introduction, Theories and Mechanisms of Bioadhesion 3
Kamla Pathak and Rishabha Malviya

1.1 Introduction 4

1.1.1 Historical Perspective 4

1.1.2 Bioadhesion in Biological Systems 5

1.1.3 Bioadhesive/Mucoadhesive 6

1.1.4 Factors Affecting Mucoadhesion 6

1.1.4.1 Molecular Weight of Polymer 6

1.1.4.2 Concentration of Polymer Used 7

1.1.4.3 Flexibility of Polymer Chains 7

1.1.4.4 Swelling 7

1.1.4.5 pH at Polymer-Mucus Interface 7

1.1.4.6 Mucin Turnover Rate 7

1.1.4.7 Stereochemistry 7

1.2 Bioadhesive Interactions 8

1.3 The Mechanistic Approach to Bioadhesion 9

1.4 Factors Controlling Bioadhesion 10

1.4.1 Chemical Interactions 10

1.4.1.1 Mussel Adhesion 10

1.4.1.2 Cell Adhesion to Biomaterials 11

1.4.2 Surface Morphology Effects 11

1.4.3 Physiological Factors 12

1.4.4 Physical and Mechanical Factors 12

1.4.4.1 Wetting Phenomenon 12

1.4.4.2 Interpenetration 12

1.5 Theories of Bioadhesion 13

1.5.1 Wetting Theory 13

1.5.2 Diffusion Theory 15

1.5.3 Electronic Theory 16

1.5.4 Adsorption Theory 16

1.5.5 Fracture Theory 16

1.6 Stages of Mucoadhesion 17

1.7 Modulation of Mucoadhesion 18

1.8 Adhesion Promoters 19

1.9 Surface Free Energy Analysis of Bioadhesion 19

1.10 Molecular Biology in Bioadhesion 20

1.11 Bioadhesives from Marine Sources 21

1.12 Mucoadhesive Drug Delivery Systems 22

1.13 Summary 23

References 23

2 Bioadhesive Polymers for Drug Delivery Applications 29
Kenneth Chinedu Ugoeze

2.1 Introduction 30

2.1.1 Drug Delivery 30

2.2 Bioadhesive/Mucoadhesive Drug Delivery Systems 31

2.2.1 Some Advantages of Bioadhesive/Mucoadhesive Drug Delivery Systems 32

2.2.2 The General Need for Bioadhesive/Mucoadhesive Drug Delivery Systems 33

2.3 Mechanism of Bioadhesion 33

2.4 Requirements for an Ideal Bioadhesive/Mucoadhesive Polymer 34

2.5 Factors Affecting Bioadhesion/Mucoadhesion 35

2.5.1 Polymer Related Factors 35

2.5.1.1 Molecular Weight 36

2.5.1.2 Chain Length 36

2.5.1.3 Flexibility 36

2.5.1.4 Cross-Linking 36

2.5.1.5 Presence of Functional Groups 37

2.5.1.6 Concentration of Active Polymer 37

2.5.2 Environmental Factors 37

2.5.2.1 pH and Charge on the Polymer 38

2.5.2.2 Degree of Hydration 38

2.5.2.3 Initial Contact Time 38

2.5.2.4 Applied Pressure 38

2.5.2.5 Swelling 39

2.5.2.6 Ionic Strength 39

2.5.2.7 Mucus Gel Viscosity 39

2.5.3 Physiological Factors 39

2.5.3.1 Mucin Turnover 39

2.5.3.2 Disease States 39

2.6 Bioadhesive Polymers for Drug Delivery Applications 40

2.6.1 Polymers 40

2.6.1.1 Natural Polymers 40

2.6.1.2 Synthetic Polymers 40

2.6.2 Bioadhesive/Mucoadhesive Polymers 40

2.6.3 Classification of Mucoadhesive Polymers 41

2.6.3.1 Classification Based on the Origin of the Polymer 41

2.6.3.2 Classification Based on Aqueous Solubility of the Polymer 41

2.6.3.3 Classification Based on the Type of Charge on the Polymer 42

2.6.4 Natural Polymers 42

2.6.4.1 Chitosan 42

2.6.4.2 Starch 43

2.6.4.3 Gelatin 44

2.6.4.4 Alginates 44

2.6.4.5 Hyaluronic Acid 45

2.6.5 Synthetic Polymers 45

2.6.5.1 Cellulose Derivatives 45

2.6.5.2 Polyacrylates 46

2.6.5.3 Poly (ethylene glycol) (PEG) 46

2.6.6 Classification Based on Aqueous Solubility of the Polymer 46

2.6.6.1 Water-Soluble Polymers 46

2.6.6.2 Water-Insoluble Polymers 46

2.6.7 Classification Based on the Type of Charge on the Polymer 47

2.6.7.1 Cationic Polymers 47

2.6.7.2 Anionic Polymers 47

2.6.7.3 Non-Ionic Polymers 47

2.7 Prospects of Bioadhesive/Mucoadhesive Polymers in Bioadhesive Drug Delivery 47

2.8 Summary 48

Acknowledgements 49

References 49

3In Vitro,Ex VivoandIn VivoMethods for Characterization of Bioadhesiveness of Drug Delivery Systems 57
Ljiljana Djekic and Martina Martinovic

3.1 Introduction 58

3.2 Mechanisms of Bioadhesion 59

3.3 Bioadhesive Drug Delivery Systems (BDDS) 62

3.3.1 BDDS for Cutaneous Application 62

3.3.2 BDDS for Buccal Application 63

3.3.3 BDDS for Peroral Application 64

3.3.4 BDDS for Vaginal Application 65

3.3.5 BDDS for Nasal Application 66

3.3.6 BDDS for Ocular Application 67

3.4 Methods for Testing Bioadhesive Property of BDDS 68

3.4.1In Vitro/Ex VivoTests 68

3.4.1.1 Bioadhesion Strength Tests 68

3.4.1.2In VitroMethods for Characterization of Bioadhesion at the Molecular Level 81

3.4.2In VivoMethods 85

3.4.2.1 Radiolabelled BDDS Transit Studies 86

3.4.2.2 Gamma Scintigraphy 87

3.4.2.3In VivoDetachment Tests 87

3.5 Summary 89

References 90

Part 2: Bioadhesive Formulations 99

4 Bioadhesive Films for Drug Delivery Systems 101
Kampanart Huanbutta and Tanikan Sangnim

4.1 Introduction 101

4.2 Theories of Bioadhesion 102

4.3 Bioadhesive Film-Forming Agents 103

4.4 Drug Delivery Applications of Bioadhesive Films 105

4.4.1 Topical and Transdermal Drug Delivery 105

4.4.1.1 Patches 105

4.4.1.2 Film-Forming Systems 106

4.4.2 Mucosal Drug Delivery 106

4.4.2.1 Buccal Drug Delivery 106

4.4.2.2 Vaginal Drug Delivery 107

4.4.2.3 Rectal Drug Delivery 107

4.4.2.4 Ocular Drug Delivery 108

4.4.2.5 Nasal Drug Delivery 109

4.4.3 Oral Drug Delivery 109

4.4.3.1 Orodispersible Films (ODFs) 109

4.4.3.2 Sublingual Films 110

4.4.3.3 Oral Colon-Specific Drug Delivery 110

4.5 Current and Novel Bioadhesive Film Fabrication Techniques 111

4.5.1 Solvent Casting 111

4.5.2 Extrusion 111

4.5.3 Rolling 111

4.5.4 2D Printing 112

4.6 Evaluation of Bioadhesive Films 113

4.6.1 Bioadhesive Strength 113

4.6.2 Tensile Strength Measurement 114

4.6.3 Morphology and Thickness 114

4.6.4 Moisture Content 114

4.6.5 Permeation 115

4.6.6 Swelling 116

4.6.7 Irritation 116

4.6.8 Stability 116

4.6.9 Drug Loading and Drug Entrapment Efficiency 117

4.7 Summary 117

4.8 Acknowledgements 118

References 118

5 Redox-Responsive Disulphide Bioadhesive Polymeric Nanoparticles for Colon-Targeted Drug Delivery 123
Erazuliana Abd Kadir and Vuanghao Lim

5.1 Introduction 123

5.2 Mechanism of Disulphide Bond Formation 124

5.3 Disulphide Polymers for Colon Drug Delivery 125

5.4 Colon-Targeted Drug Delivery (CTDD) 126

5.4.1 Condition of the Colon for Drug Delivery 127

5.4.2 Approaches for Colon Drug Delivery 128

5.4.3 Limitations of CTDD 129

5.5 Nanoformulations of Disulphide Polymers 130

5.5.1 Thiolated Pectin Polymers 130

5.5.2 Thiolated Sodium Alginate (TSA) Polymers 131

5.5.3 Thiolated Chitosan (TCS) Polymers 134

5.5.4 Thiolated Hyaluronic Acid Polymers 136

5.5.5 Thiolated Dextran Polymers 137

5.5.6 Other Thiolated Polymers 138

5.6 Summary 140

Acknowledgements 140

References 140

6 Bioadhesive Hydrogels and Their Applications 147
Hitesh Chopra, Sandeep Kumar and Inderbir Singh

6.1 Introduction 147

6.1.1 Bioadhesive Polymer 148

6.1.2 Hydrogels 150

6.1.3 Bioadhesive Hydrogels 155

6.2 Bioadhesive Hydrogel Films 155

6.3 Bioadhesive Hydrogels for Gastrointestinal Delivery 156

6.4 Bioadhesive Hydrogels Administered through Injection 156

6.5 Bioadhesive Hydrogels for Vaginal Delivery 159

6.6 Bioadhesive Hydrogels for Rectal Delivery 160

6.7 Mucoadhesive Hydrogels Based Nanoparticles 161

6.8 Patents and Future Perspectives 161

6.9 Summary 164

References 164

Part 3: Drug Delivery Applications 171

7 Ocular Bioadhesive Drug Delivery Systems and Their Applications 173
Anju Sharma, Mukesh S. Patil, Pravin Pawar, A.A. Shirkhedkar and Inderbir Singh

7.1 Introduction 174

7.2 Anatomy and Physiology of the Eye 175

7.2.1 Anatomy and Function of the Eye 175

7.2.2 Structure of Cornea 176

7.3 Various Bioadhesive/Mucoadhesive Polymers for Ocular Delivery 176

7.3.1 Chitosan as Ocular Bioadhesive 177

7.3.2 Starch (Drum-Dried Waxy Maize Starch, Pregelatinized Starch) 180

7.3.3 Sodium Hyaluronate (SH) as Ocular Bioadhesive 181

7.3.3.1 Functions of Sodium Hyaluronate 181

7.3.3.2 Viscoelasticity 182

7.3.3.3 Contact Angle 182

7.3.3.4 Adherence to the Mucin Layer (Mucoadhesivity) 183

7.3.3.5 Water Retention 184

7.3.3.6 Healing of Superficial Keratitis 184

7.3.3.7 Free Radical Scavenging 184

7.3.4 Alginate Based Ocular Bioadhesive 184

7.3.4.1 General Properties of ALGs 185

7.3.5 Gellan Gum as Ocular Bioadhesive 188

7.3.6 Albumin 189

7.3.7 Collagen Based Ocular Bioadhesive 190

7.3.8 Xanthan Gum 192

7.3.9 Guar Gum 193

7.3.10 Gelatin 193

7.3.11 Tamarind Seed Polysaccharide (Xyloglucan) 195

7.3.12 Arabinogalactan 196

7.3.13 Gum Cordia 197

7.3.14 Bletilla Striata Polysaccharide (BSP) 197

7.3.15 Locust Bean Gum (Carob Bean Gum) 198

7.3.16 Carrageenan 198

7.4 Summary 199

References 200

8 Buccal Bioadhesive Drug Delivery Systems and Their Applications 213
Veera Garg and Shammy Jindal

8.1 Introduction 213

8.1.1 Advantages of a Buccal Bioadhesive System 218

8.1.2 Disadvantages of a Buccal Bioadhesive System 218

8.1.3 Ideal Characteristics of a Bioadhesive Dosage Form 219

8.1.4 Structure of Buccal Mucosa 219

8.2 Theories of Bioadhesion 220

8.2.1 Diffusion Theory 221

8.2.2 Adsorption Theory 222

8.2.3 Wetting Theory 222

8.2.4 Electronic Theory 222

8.2.5 Fracture Theory 223

8.3 Factors Affecting Bioadhesion 223

8.3.1 Bioadhesive Polymer Related Factors 224

8.3.1.1 Molecular Weight of Mucoadhesive Polymer 224

8.3.1.2 Cross-Linking of Mucoadhesive Polymer 224

8.3.1.3 Concentration of Mucoadhesive Polymer 224

8.3.1.4 Mucoadhesive Polymer Chain Length 224

8.3.1.5 Flexibility of Mucoadhesive Polymer Chain 225

8.3.1.6 Charge on Mucoadhesive Polymer 225

8.3.1.7 H-Bonding of Mucoadhesive Polymer 225

8.3.1.8 Spatial Configuration of Mucoadhesive Polymer 225

8.3.1.9 Swelling of Mucoadhesive Polymer 225

8.3.2 Environment Related Factors 226

8.3.2.1 pH 226

8.3.2.2 Saliva 226

8.3.2.3 Salivary Gland 226

8.3.2.4 Hydration 226

8.3.2.5 Mucin Turnover 227

8.3.2.6 Rate of Renewal of Mucoadhesive Cells 227

8.3.2.7 Disease State 227

8.3.2.8 Buccal Membrane Properties 227

8.4 Mechanism of Buccal Absorption 227

8.5 Buccal Bioadhesive Drug Delivery Systems 229

8.5.1 Solid Buccal Bioadhesive Dosage Forms 229

8.5.1.1 Buccal Tablets 229

8.5.1.2 Microspheres 230

8.5.1.3 Lozenges 230

8.5.1.4 Wafers 230

8.5.1.5 Gels 230

8.5.1.6 Patches 230

8.5.2 Liquid Dosage Forms 231

8.6 Quality Control Tests of Buccal Bioadhesive Dosage Forms 231

8.6.1 Moisture Absorption Test 231

8.6.2 Swelling and Erosion Tests 232

8.6.3 Tensile Strength and Elongation at Break 232

8.6.4 Surface pH 233

8.6.5In-VitroBioadhesive Strength Measurement Test 233

8.6.6 Residence Time 234

8.6.6.1Ex-VivoResidence Time 234

8.6.6.2In-VivoResidence Time 234

8.6.6.3 Permeation Test 234

8.6.6.4 Absorption Test 236

8.7 Marketed Formulations 236

8.8 Summary 236

References 237

9 Gastrointestinal Bioadhesive Drug Delivery Systems nd Their Applications 245
Olufunke D. Akin-Ajani and Oluwatoyin A. Odeku

Abbreviations 245

9.1 Introduction 246

9.2 The Mucus Layer 247

9.3 Gastrointestinal Bioadhesive Drug Delivery Systems 247

9.3.1 Solid Bioadhesive Formulations 248

9.3.1.1 Tablets 248

9.3.1.2 Bioadhesive Microparticles/Nanoparticles 249

9.3.1.3 Bioadhesive Patches 251

9.3.2 Semisolid Bioadhesive Formulations 254

9.3.3 Liquid Bioadhesive Formulations 254

9.3.3.1 Suspensions 254

9.3.3.2 Bioadhesive Liquids 255

9.4 Summary 255

References 255

10 Nasal Bioadhesive Drug Delivery Systems and Their Applications 259
Ravindra V. Badhe and Sonali S. Nipate

10.1 Introduction 260

10.1.1 Nasal Route of Administration 260

10.1.2 Nasal Cavity 261

10.1.3 Nasal Route for Brain Drug Delivery 263

10.1.4 Nasal Route for Local and Systemic Drug Delivery 263

10.2 Challenges in Nasal Drug Delivery Formulations 267

10.2.1 Ideal Properties of a Nasal Drug Delivery Formulation 267

10.2.2 Strategies Developed for Improving Nasal Drug Delivery 268

10.3 Mucoadhesion 270

10.3.1 Physiology of Nasal Mucus Layer and Barriers Posed by It 270

10.3.2 Factors Affecting Mucoadhesion 271

10.3.3 Mucoadhesive Polymers Used in Nasal Delivery Formulations 275

10.3.3.1 Chitosan and Its Composites 275

10.3.3.2 Cellulose Derivatives 277

10.3.3.3 Poloxamer or Pluronic 284

10.3.3.4 Polyacrylates 285

10.3.3.5 Lectin - Poly(ethylene glycol)(PEG) - Poly(lactic acid)(PLA)/Poly(lacticco-glycolic acid)(PLGA) 286

10.3.3.6 Miscellaneous Mucoadhesive Agents 287

10.4 Summary 289

References 290

11 Vaginal Bioadhesive Drug Delivery Systems and Their Applications 307
Sanjeevani S. Deshkar, Satish V. Shirolkar and Arun T. Patil

11.1 Introduction 308

11.1.1 Advantages of Vaginal Drug Delivery 308

11.1.2 Limitations 309

11.2 Vaginal Anatomy and Physiology 309

11.2.1 Vaginal Anatomy 309

11.2.2 Physiology of Vagina 310

11.2.2.1 Epithelium 310

11.2.2.2 Vaginal Fluid 311

11.2.2.3 pH 311

11.2.2.4 Microflora 312

11.2.2.5 Cyclic Changes 312

11.2.2.6 Enzymes 312

11.3 Vaginal Absorption of Drug 313

11.3.1 Drugs Administered by Vaginal Route 313

11.4 Conventional Drug Delivery Systems for Vaginal Application 314

11.4.1 Vaginal Rings 314

11.4.2 Vaginal Tablets 315

11.4.3 Suppositories and Pessaries 315

11.4.4 Semisolid Formulations 316

11.4.5 Limitations of Conventional Vaginal Formulations 316

11.5 Mucoadhesive Drug Delivery Systems 317

11.5.1 Mucoadhesive Polymeric Platforms for Vaginal Drug Delivery 318

11.5.1.1 Poly (acrylic acid) (PAA) Derivatives 318

11.5.1.2 Cellulose Derivatives 319

11.5.1.3 Natural Polymers 321

11.5.1.4 New Generation Mucoadhesive Polymers 324

11.5.2 Mucaodhesive Polymers as Enzyme Inhibitors and Permeation Enhancers 325

11.5.3 Novel Mucoadhesive Formulations for Drug Delivery to Vagina 326

11.5.3.1 Mucoadhesive Gels 326

11.5.3.2In SituGelling Systems 327

11.5.3.3 Emulgels 337

11.5.3.4 Vaginal Films 337

11.5.3.5 Microparticulate Drug Delivery Systems 338

11.5.3.6 Nanoparticle Based Drug Delivery Systems 338

11.6 Recent Advancements in Vaginal Drug Delivery Applications 350

11.6.1 Vaginal Immunization 350

11.6.2 Gene Therapy 350

11.6.3 Mucus Penetrating Nanoparticles 351

11.6.4 Personalized Medicine Using Additive Manufacturing Technology 351

11.7 Summary 352

References 352

12 Pulmonary Bioadhesive Drug Delivery Systems and Their Applications 371
Ridhima Wadhwa, Subhashini Bharathala, Taru Aggarwal, Nikita Sehgal, Nitesh Kumar, Gaurav Gupta, Dinesh Kumar Chellappan, Pawan Kumar Maurya, Terezinha De Jesus Andreoli Pinto, Trudi Collet, Harish Dureja, Philip M. Hansbro and Kamal Dua

12.1 Introduction to Pulmonary Drug Delivery Systems 372

12.1.1 Deposition of Inhaled Particles 373

12.1.2 Absorption of Inhaled Particles 374

12.1.3 Challenges of Pulmonary Drug Delivery 375

12.2 Bioadhesives in Pulmonary Drug Delivery Systems 376

12.3 Development of Pulmonary Bioadhesive Drug Delivery Systems 378

12.3.1 Nanoparticles 378

12.3.2 Microparticles 381

12.3.3 Liposomes 383

12.4 Progress and Clinical Challenges for Bioadhesive Drug Delivery with Future Prospects 384

12.4.1 Technological Advancements 384

12.5 Future Prospects and Summary 385

References 386

Index 391