Applications of Polymers in Drug Delivery

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1 Contents 1 Polymers in Drug Delivery Systems Introduction Fundamentals of a Polymeric Drug Delivery System Factors That Affect Drug Release from Polymers Mechanism of Controlled Release Temporal Controlled Systems Delayed Dissolution Diffusion Controlled Release from Monolithic/ Matrix Systems Reservoir Type Systems Osmotic/Solvent Controlled Systems Swelling Controlled Environmental/Stimuli Responsive Systems Thermo-responsive Polymers ph-responsive Polymers Dual Stimuli Responsive Polymers Distribution Controlled Systems Biodegradable/Degradation and Erosion Controlled Systems Polymer Delivery Systems ix

2 Applications of Polymers in Drug Delivery Oral Drug Delivery System Gastro Retentive Drug Delivery System Floating System Hydrodynamically Balanced Systems Bio/Mucoadhesive Systems Hydration-mediated Adhesion Swelling Systems Colon Specific Drug Delivery System ph Sensitive Systems Coating with ph Dependent Polymers Coating with ph Independent Biodegradable Polymers Time Controlled/Dependent System Pressure Controlled System Osmotically Controlled System Pulsatile Drug Delivery System Ion-exchange Based Drug Delivery System Transdermal Drug Delivery System Classification of Transdermal Drug Delivery Reservoir Systems Drug-in-adhesive Systems Matrix-dispersion Systems Micro-reservoir Systems Polymers for Transdermal Drug Delivery System Natural Polymers Synthetic Polymers x

3 Contents Pressure Sensitive Adhesives Backing Membrane Release Liner Mucoadhesive Drug Delivery System Hydrophilic Polymers Hydrogels Thiolated Polymers Lectin-based Polymers Ocular Drug Delivery System Polymers used in Conventional Ocular Delivery Liquid Dosage Forms Semi-solid Dosage Forms Polymers used in Ophthalmic Inserts/Films Implant and Parenteral Drug Delivery System Surgical Implants Microspheres Bioadhesive Microspheres Floating Microspheres Polymeric Microspheres Biodegradable Polymeric Microspheres Synthetic Polymeric Microspheres Injectable In Situ Gel Thermoplastic Paste In Situ Crosslinking System In Situ Polymer Precipitation Thermally-induced Gelling System xi

4 Applications of Polymers in Drug Delivery 1.4 Recent Advancements in Polymer Architecture and Drug Delivery Block Copolymers Polymersomes Hyperbranched Polymers Graft Polymers Star Polymers Dendrimers Recent Patent Trends in Polymeric Drug Delivery Future Developments Applications of Polymers in Buccal Drug Delivery Introduction Advantages of Buccal Drug Delivery Disadvantages of Buccal Drug Delivery Factors Affecting Bioadhesion in the Oral Cavity Functional Groups Molecular Weight Flexibility Crosslinking Density Charge Concentration Hydration (Swelling) Environmental Factors Buccal Polymeric Dosage Forms Semi-solids Solids Powder Dosage Forms Tablets Polymeric Films and Patches Novel Carriers xii

5 Contents 2.5 Conclusions Applications of Polymers in Gastric Drug Delivery Introduction Need for Gastric Retention Benefits and Pitfalls Gastrointestinal Tract Anatomy of the Gastrointestinal Tract Mucus Layer Basic Gastrointestinal Tract Physiology Factors Affecting Gastric Retention Polymers in Gastro Retentive Drug Delivery Systems Cellulosic Hydrocolloids Carbomers or Carbopol Xanthan Gum Guar Gum Chitosan Eudragit Polymers Alginate Polymers Lectin-based Polymers Thiolated Polymers Miscellaneous Polymers Evaluation of Gastro Retentive Drug Delivery Systems In Vitro Evaluation Floating Systems Swelling Systems In Vitro Release In Vivo Evaluation Application of Polymers in Gastric Delivery Systems Floating Drug Delivery System xiii

6 Applications of Polymers in Drug Delivery Effervescent Floating Dosage Forms Non-effervescent Floating Dosage Forms Bioadhesive Drug Delivery System Swelling and Expanding Delivery System Combinational/Amalgamative Delivery System Bioadhesive and Floating Approach Swellable and Floating Approach Bioadhesion and Swelling Approach Bioadhesion and High-density Approach Microparticulate Delivery System Microballoons/Hollow Microspheres Alginate Beads Floating Granules Super Porous Hydrogel Systems Raft Forming Systems Conclusion Applications of Polymers in Small Intestinal Drug Delivery Introduction Advantages of Polymer Coating Benefit from Polymer Coatings with Sustained Release Physiology of the Small Intestine Mucosa of Small Intestine Secretion into the Small Intestine Glands Pancreatic Secretion Biliary Secretions Digestion of the Food Nutrients ph of the Small Intestine Gastrointestinal Motility xiv

7 Contents Transit of the Dosage Form through the Small Intestine Drug Absorption through Small Intestine Peyer s Patch Scope of Small Intestinal Drug Delivery Polymers used in Small Intestinal Drug Delivery Natural Polymers Chitosan Shellac Sodium Alginate Synthetic Polymers Polyacrylic acid Derivatives (Carbomer) Cellulose Derivatives Cellulose Acetate Phthalate Hydroxypropyl Methyl Cellulose Phthalate Polyvinyl Acetate Phthalate Hydroxypropyl Methyl Cellulose Acetate Succinate Cellulose Acetate Trimelliate Polymethacrylates Polymethacrylic Acid-co-ethyl Acrylate as Aqueous Dispersion Polymethacrylic Acid-co-ethyl Acrylate as Powder Polyethyl Acrylate-co-methyl Methacrylate-co-trimethylammonioethyl Methacrylate Chloride Polymethacrylic Acid-co-methyl Methacrylate Polymethacrylic Acid-co- xv

8 Applications of Polymers in Drug Delivery methylmethacrylate Methacrylic Acid - Methyl Methacrylate Copolymer (1:2) Polymethacylic Acid-co-methyl Methacrylate (1:2) Benefits of Polymers in Small Intestinal Drug Delivery Hydroxypropyl Methyl Cellulose Phthalate Hydroxypropyl Methyl Cellulose Acetate Succinate Hydroxypropyl Methyl Cellulose Acetate Maleate Methacrylic Acid Polymers and Copolymers Chitosan Chitosan and Methacrylic Acid Polymer and Copolymers Sodium Alginate Thiolated Tamarind Seed Polysaccharide Conclusion Application of Polymers in Transdermal Drug Delivery Introduction Advantages of Drug Delivery via the Transdermal Route Mechanism of Drug Absorption in Transdermal Drug Delivery Systems Factors Affecting Transdermal Permeation Physicochemical Properties of Penetrant Molecules Physicochemical Properties of the Drug Delivery System Release Characteristics Composition of the Drug Delivery Systems Drug Permeation Enhancer Physiological and Pathological Conditions of the Skin xvi

9 Contents 5.5 Types of Transdermal Drug Delivery Systems Formulation Aspects Matrix Systems Reservoir Systems Micro-reservoir Systems Based on Release Mechanism Passive Transdermal Drug Delivery Systems Active Transdermal Drug Delivery Systems Role of Polymers in Transdermal Drug Delivery Systems Matrix Formers Crosslinked Polyethylene Glycol Acrylic-acid Matrices Ethyl Cellulose and Polyvinyl Pyrrolidone Hydroxypropyl Methylcellulose Chitosan Ethyl Vinyl Acetate Copolymer Gum Copal Damar Batu Organogels Rate-controlling Membrane Ethylene Vinyl Acetate Copolymer Polyethylene Polyurethane Crosslinked Sodium Alginate Copolymer of 2-Hydroxy-3- Phenoxypropylacrylate, 4-Hydroxybutyl Acrylate and Sec-Butyl Tiglate Polysulfone, Polyvinylidene Fluoride (Hydrophilic Membrane) Polytetrafluoroethylene (Hydrophobic Membrane) xvii

10 Applications of Polymers in Drug Delivery Crosslinked Polyvinyl Alcohol Cellulose Acetate Eudragit Chitosan Pressure Sensitive Adhesives Polyisobutylenes Silicones Acrylics Hot-melt Pressure Sensitive Adhesives Hydrogel Pressure Sensitive Adhesives Hydrophilic Pressure Sensitive Adhesives Polyurethanes Backing Layer/Membranes Release Liner Polymers to Enhance Skin Permeation Penetration Enhancers Pulsed Delivery Future Perspectives Conclusion Application of Polymers in Peyer s Patch Targeting Introduction Peyer s Patch Physiology, Structure and Function General Properties and Peyer s Patch Distribution in Different Species M Cell Structure and Function Strategies for Achieving Effective Delivery to the Peyer s Patch General Principles of Peyer s Patch Delivery Effect of Particle Size on Peyer s Patch Peyer s Patch Drug Delivery using Polymeric Carriers xviii

11 Contents Polylactide-co-glycolic Acid Polylactic Acid Poly-D,L-lactide-co-glycolide Polystyrene Chitosan Other Polymer Carrier Uptake of Particles by Peyer s Patches Targets for Peyer s Patch Delivery Lectin-mediated Targeting Microbial Protein-mediated Targeting Yersinia Salmonella Cholera Toxin Virus Protein Vitamin B12 Mediated Targeting Non-Peptide Ligand Mediated Targeting Peptide Ligand Mediated Targeting Claudin-4 Mediated Targeting Monoclonal Antibody Mediated Targeting M Cell Homing Peptide Targeting Immunoglobulin A Conjugates Targeting Summary and Conclusions Applications of Polymers in Colon Drug Delivery Introduction Anatomy of the Colon Correlation between Physiological Factors and use of Polymers in Colon Drug Delivery Systems The ph of the Gastrointestinal Tract Gastrointestinal Transit Time xix

12 Applications of Polymers in Drug Delivery Colonic Motility Colonic Microflora Colonic Absorption Advantages of Colon Drug Delivery Systems Disadvantages of Colon Drug Delivery Systems Polymers for Colon Drug Delivery Systems Pectin Guar Gum Chitosan Amylose Inulin Locust Bean Gum Chondroitin Sulfate Dextran Alginates Cyclodextrin Eudragit Cellulose Ethers Ethyl Cellulose Polymers for Enteric Coating Polyvinyl Alcohol Application of Polymers in Colon Drug Delivery Systems System Dependent on ph System Dependent on Time Reservoir Systems with Rupturable Polymeric Coats Reservoir Systems with Erodible Polymeric Coats Reservoir Systems with Diffusive Polymeric Coats. 267 xx

13 Contents Capsular Systems with Release-controlling Polymeric Plugs Osmotic System Bacterially Triggered System Prodrug Polysaccharide-based Matrix, Reservoirs and Hydrogels Time- and ph-dependent Systems Pressure Controlled Delivery Systems Conclusion Applications of Polymers in Parenteral Drug Delivery Introduction Parenteral Route for Drug Delivery Advantages of Parenteral Administration Disadvantages of Parenteral Administration In Vivo Distribution of Polymer Biodegradation Erosion Degradation Processes Chemical and Enzymic Oxidation Chemical and Enzymic Hydrolysis Polymers for Parenteral Delivery Non-degradable Polymers Biodegradable Polymers Synthetic Polymers Polyesters Polylactones Polyamino acids Polyphosphazenes Polyorthoesters xxi

14 Applications of Polymers in Drug Delivery Polyanhydrides Natural Polymers Collagen Gelatin Albumin Polysaccharides Polymeric Drug Delivery Carriers Polymeric Implants Microparticles Nanoparticles Polymeric Micelles Hydrogels Polymer-drug Conjugates Factors Influencing Polymeric Parenteral Delivery Particle Size Drug Loading Porosity Molecular Weight of the Polymer Crystallinity Hydrophobicity Drug-polymer Interactions Surface Properties: Charge and Modifications Summary Applications of Polymers in Rectal Drug Delivery Introduction Rectal Drug Delivery Anatomy and Physiology of the Rectum Absorption through the Rectum Mechanism of Absorption xxii

15 Contents Factors Affecting Absorption Polymers used in Rectal Dosage Forms Solutions Semi-solids/Hydrogels Suppositories In Situ Gels Conclusion Applications of Polymers in Vaginal Drug Delivery Anatomy and Physiology of the Vagina Vaginal ph Vaginal Microflora Cyclic Changes Vaginal Blood Supply The Vagina as a Site for Drug Delivery Vaginal Dosage Forms Polymers for Vaginal Drug Delivery Polyacrylates Chitosan Cellulose Derivatives Hyaluronic Acid Derivatives Carageenan Polyethylene Glycols Gelatin Thiomers Poloxamers Pectin and Tragacanth Sodium Alginate Silicone Elastomers for Vaginal Rings Thermoplastic Polymers for Vaginal Rings xxiii

16 Applications of Polymers in Drug Delivery Miscellaneous Toxicological Evaluation Conclusion Application of Polymers in Nasal Drug Delivery 11.1 Introduction Nasal Anatomy and Physiology Nasal Vestibule Atrium Olfactory Region Respiratory Region Nasopharynx Biological Barriers in Nasal Absorption Mucus Nasal Mucociliary Clearance Enzymic Barrier P-Glycoprotein Efflux Transporters Physicochemical Characteristics of the Drug Toxicity General Considerations about Polymers used in Nasal Drug Delivery Thermoresponsive Polymers Polymers Sensitive to ph Mucoadhesive Polymer Polymers used in Nasal Drug Delivery Cellulose Derivatives Polyacrylates Starch Chitosan Gelatin xxiv

17 Contents Phospholipids Poly(N-alkyl acrylamide)/poly(n-isopropylacrylamide) Poloxamer Methylcellulose Cyclodextrin Applications of Polymers in Nasal Delivery Local Therapeutic Agents Genomics Proteins and Peptides Vaccines Features of the Nasal Mucosa for Immunisation Conclusion Application of Polymers in Lung Drug Delivery Introduction Anatomy and Physiology of Human Respiratory Tract Barriers in Pulmonary Delivery Polymers for Pulmonary Drug Delivery Natural Polymers Chitosan Gelatin Hyaluronic Acid Dextran Albumin Synthetic Polymers Poly(D,L-lactide-co-glycolide) Polylactic Acid Poly(ɛ-caprolactone) Acrylic Acid Derivatives xxv

18 Applications of Polymers in Drug Delivery Diketopiperazine Derivatives Polyethylene Glycol Conjugates Miscellaneous Polymers Conclusion Future Directions Applications of Polymers in Ocular Drug Delivery Introduction Barriers to Restrict Intraocular Drug Transport Drug Delivery Systems to the Anterior Segment of the Eye Viscous Systems In Situ Gelling Systems Temperature Induced In Situ Gelling Systems Poloxamers Xyloglucan Methyl Cellulose Ionic Strength Induced In Situ Gelling Systems Gellan Gum Alginates Carrageenan ph Induced In Situ Gelling Systems Carbomers (Polyacrylic Acid) Pseudolatexes Mucoadhesive Gels Polymeric Inserts/Discs Contact Lenses Conventional Contact Lens Absorbed with Drugs Molecularly Imprinted Polymeric Hydrogels xxvi

19 Contents Drug-polymer Films Integrated with Contact Lenses Drugs in Colloidal Structure Dispersed in the Lens Scleral Lens Delivery Systems Punctal Plug Delivery Systems Polymeric Drug Delivery Systems for the Posterior Segment of the Eye Intravitreal Implants Particulate Systems (Nanocarriers) Conclusion Abbreviations Appendix Appendix Index xxvii

20 Applications of Polymers in Drug Delivery xxviii