Dionysios Douroumis, Alfred Fahr

Drug Delivery Strategies for Poorly Water-Soluble Drugs (eBook, PDF)

• Format: PDF

Produktbeschreibung

Many newly proposed drugs suffer from poor water solubility, thus presenting major hurdles in the design of suitable formulations for administration to patients. Consequently, the development of techniques and materials to overcome these hurdles is a major area of research in pharmaceutical companies. Drug Delivery Strategies for Poorly Water-Soluble Drugs provides a comprehensive overview of currently used formulation strategies for hydrophobic drugs, including liposome formulation, cyclodextrin drug carriers, solid lipid nanoparticles, polymeric drug encapsulation delivery systems, self-microemulsifying drug delivery systems, nanocrystals, hydrosol colloidal dispersions, microemulsions, solid dispersions, cosolvent use, dendrimers, polymer- drug conjugates, polymeric micelles, and mesoporous silica nanoparticles. For each approach the book discusses the main instrumentation, operation principles and theoretical background, with a focus on critical formulation features and clinical studies. Finally, the book includes some recent and novel applications, scale-up considerations and regulatory issues. Drug Delivery Strategies for Poorly Water-Soluble Drugs is an essential multidisciplinary guide to this important area of drug formulation for researchers in industry and academia working in drug delivery, polymers and biomaterials.

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Produktdetails

• Verlag: John Wiley & Sons
• Seitenzahl: 632
• Erscheinungstermin: 19. Dezember 2012
• Englisch
• ISBN-13: 9781118444771
• Artikelnr.: 37345679

Autorenporträt

Dennis Douroumis University of Greenwich, UK Alfred Fahr Friedrich-Schiller University of Jena, Germany

Inhaltsangabe

List of Contributors xvii Series Preface xxi Preface xxiii 1 Self-Assembled Delivery Vehicles for Poorly Water-Soluble Drugs: Basic Theoretical Considerations and Modeling Concepts 1 Sylvio May and Alfred Fahr 1.1 Introduction 1 1.2 Brief Reminder of Equilibrium Thermodynamics 3 1.3 Principles of Self-Assembly in Dilute Solutions 7 1.3.1 Linear Growth 9 1.3.2 Cooperative Assembly 10 1.4 Solubility and Partitioning of Drugs 11 1.4.1 Simple Partitioning Equilibria 11 1.4.2 Partitioning and Micellization 13 1.4.3 Hydrophobicity and Ordering of Water 15 1.5 Ways to Model Interactions in Colloidal Systems 16 1.5.1 Electrostatic Interactions: The Poisson-Boltzmann Model 17 1.5.2 Chain Packing Model 21 1.6 Kinetics of Drug Transfer from Mobile Nanocarriers 23 1.6.1 Collision Mechanism 25 1.6.2 Diffusion Mechanism 26 1.6.3 Internal Kinetics 26 1.7 Conclusion 29 Acknowledgments 31 References 31 2 Liposomes as Intravenous Solubilizers for Poorly Water-Soluble Drugs 37 Peter van Hoogevest, Mathew Leigh and Alfred Fahr 2.1 Introduction 37 2.2 Intravenous Administration of Poorly Water-Soluble Compounds (PWSC) 40 2.2.1 Solubilizing Vehicles with Precipitation Risk upon Dilution 41 2.2.2 Solubilizing Vehicles Maintaining Solubilization Capacity upon Dilution 43 2.2.3 Mechanistic Release Aspects/Transfer Liposomal PWSC 45 2.2.4 In Vivo Consequences 52 2.2.5 Preclinical Parenteral Assessment Liposomal PWSC 56 2.3 Conclusion 59 References 60 3 Drug Solubilization and Stabilization by Cyclodextrin Drug Carriers 67 Thorsteinn Loftsson and Marcus E. Brewster 3.1 Introduction 67 3.2 Structure and Physiochemical Properties 68 3.3 Cyclodextrin Complexes and Phase Solubility Diagrams 72 3.4 Cyclodextrin Complexes 76 3.4.1 Self-Assembly of Cyclodextrins and their Complexes 76 3.4.2 Thermodynamic and Driving Forces for Complexation 76 3.5 Effects on Drug Stability 77 3.6 Cyclodextrins and Drug Permeation through Biological Membranes 80 3.7 Drug Solubilization in Pharmaceutical Formulations 82 3.7.1 Oral Drug Delivery 84 3.7.2 Sublingual, Buccal, Nasal, Pulmonary, Rectal and Vaginal Drug Delivery 86 3.7.3 Ophthalmic Drug Delivery 87 3.7.4 Dermal and Transdermal Drug Delivery 87 3.7.5 Injectable Formulations 87 3.8 Toxicology and Pharmacokinetics 89 3.9 Regulatory Issues 90 3.10 Conclusion 91 References 91 4 Solid Lipid Nanoparticles for Drug Delivery 103 Sonja Joseph and Heike Bunjes 4.1 Introduction 103 4.2 Preparation Procedures for Solid Lipid Nanoparticles 104 4.2.1 Melt Dispersion Processes 104 4.2.2 Other Top-Down Processes 109 4.2.3 Precipitation from Homogeneous Systems 111 4.2.4 Comparison of the Formulation Procedures and Scale-Up Feasibility 113 4.2.5 Further Processing of Solid Lipid Nanoparticle Suspensions 115 4.3 Structural Parameters and Their Influence on Product Quality and Pharmaceutical Performance 116 4.3.1 Particle Size and Size Distribution 116 4.3.2 Surface Properties 117 4.3.3 Solid State Properties of Solid Lipid Nanoparticles 117 4.3.4 Particle Morphology and Overall Structure of the Dispersions 121 4.4 Incorporation of Poorly Soluble Drugs and In Vitro Release 123 4.4.1 Drug Incorporation 123 4.4.2 In Vitro Drug Release 126 4.5 Safety Aspects, Toxicity and Pharmacokinetic Profiles 129 4.5.1 In Vitro Behavior and Toxicity Studies 129 4.5.2 Bioavailability and Pharmacokinetics 131 4.6 Conclusion 133 References 133 5 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs 151 Naveed Ahmed, C.E. Mora-Huertas, Chiraz Jaafar-Maalej, Hatem Fessi and Abdelhamid Elaissari 5.1 Introduction 151 5.2 Safety and Biocompatibility of Polymers 152 5.3 Encapsulation Techniques of Hydrophobic Drugs 156 5.3.1 The Nanoprecipitation Method 156 5.3.2 The Emulsification Methods 158 5.3.3 Polymersome Preparation 164 5.3.4 Supercritical Fluid Technology 166 5.3.5 The Polymer-Coating Method 167 5.3.6 The Layer-by-Layer Method 171 5.4 Behavior of Nanoparticles as Drug Delivery Systems 173 5.4.1 Mean Size 173 5.4.2 Zeta Potential 173 5.4.3 Encapsulation Efficiency 174 5.4.4 Drug Release Properties 176 5.4.5 General Performance of the Nanoparticles 176 5.5 Conclusion 177 References 180 6 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs 199 Dagmar Fischer 6.1 Introduction 199 6.2 Drug Encapsulation by Monomer Polymerization 200 6.2.1 Emulsion Polymerization 201 6.2.2 Interfacial Polymerization 206 6.2.3 Interfacial Polycondensation 207 6.3 Polymeric Nanospheres and Nanocapsules Produced by Polymerization 209 6.4 Formulation Components 210 6.5 Control of Particle Morphology 212 6.6 Toxicity and In Vivo Performance 213 6.7 Scale-Up Considerations 214 6.8 Conclusion 217 Acknowledgements 217 References 217 7 Development of Self-Emulsifying Drug Delivery Systems (SEDDS) for Oral Bioavailability Enhancement of Poorly Soluble Drugs 225 Dimitrios G. Fatouros and Anette M
ullertz 7.1 Introduction 225 7.2 Lipid Processing and Drug Solubilization 226 7.3 Self-Emulsifying Drug Delivery Systems 227 7.3.1 Excipients Used in SEDDS 227 7.3.2 Self-Emulsification Mechanism 228 7.3.3 Physicochemical Characterization of SEDDS 229 7.3.4 Drug Incorporation in SEDDS 231 7.4 In Vitro Digestion Model 232 7.5 Enhancement of Oral Absorption by SEDDS 235 7.6 Conclusion 238 References 239 8 Novel Top-Down Technologies: Effective Production of Ultra-Fine Drug Nanocrystals 247 C.M. Keck, S. Kobierski, R. Mauludin and R.H. M
uller 8.1 Introduction: General Benefits of Drug Nanocrystals (First Generation) 247 8.2 Ultra-Fine Drug Nanocrystals (_100 Nm) and Their Special Properties 248 8.3 Production of First Generation Nanocrystals: A Brief Overview 250 8.3.1 Hydrosols 250 8.3.2 Nanomorphs 251 8.3.3 NanocrystalsTM by Bead Milling 251 8.3.4 DissoCubes R _ by High Pressure Homogenization 251 8.3.5 NANOEDGE by Baxter 252 8.3.6 Summary of First Generation Production Technologies 252 8.4 Production of Ultra-Fine Drug Nanocrystals: Smartcrystals 252 8.4.1 Fine-Tuned Precipitation 252 8.4.2 The SmartCrystal Concept 253 8.5 Conclusion 259 References 259 9 Nanosuspensions with Enhanced Drug Dissolution Rates of Poorly Water-Soluble Drugs 265 Dennis Douroumis 9.1 Introduction 265 9.2 Crystal Growth and Nucleation Theory 266 9.3 Creating Supersaturation and Stable Nanosuspensions 269 9.4 Antisolvent Precipitation Via Mixer Processing 272 9.5 Antisolvent Precipitation by Using Ultrasonication 277 9.6 Nanoprecipitation Using Microfluidic Reactors 278 9.7 Particle Engineering by Spray: Freezing into Liquid 279 9.8 Precipitation by Rapid Expansion from Supercritical to Aqueous Solution 280 9.9 Conclusion 282 References 283 10 Microemulsions for Drug Solubilization and Delivery 287 X.Q. Wang and Q. Zhang 10.1 Introduction 287 10.2 Microemulsion Formation and Phase Behavior 289 10.2.1 Theories of Microemulsion Formation 289 10.2.2 Structure of Microemulsions 289 10.2.3 Phase Behavior 292 10.3 HLB, PIT and Microemulsion Stability 293 10.4 Microemulsion Physico-Chemical Characterization 293 10.5 Components of Microemulsion Formulations 295 10.5.1 Oils 296 10.5.2 Surfactants 298 10.5.3 Cosurfactants 300 10.5.4 Drugs 302 10.6 Preparation Methods 303 10.7 In Vitro and In Vivo Biological Studies 303 10.7.1 Microemulsions Used as an Oral Delivery System for Poorly Water-Soluble Compounds 303 10.7.2 Microemulsions Used as a Parenteral Delivery System for Poorly Water-Soluble Compounds 311 10.8 Recent Developments and Future Directions 314 10.8.1 Develop Cremophor-Free Microemulsions 314 10.8.2 Dried O/W Emulsions for Oral Delivery of Poorly Soluble Drugs 315 10.8.3 Self-Microemulsifying Drug Delivery System (SMEDDS) 318 References 319 11 Hot Melt Extrusion: A Process Overview and Use in Manufacturing Solid Dispersions of Poorly Water-Soluble Drugs 325 Shu Li, David S. Jones and Gavin P. Andrews 11.1 Introduction: Present Challenges to Oral Drug Delivery 325 11.2 Solid Drug Dispersions for Enhanced Drug Solubility 327 11.3 Hot Melt Extrusion (HME) as a Drug Delivery Technology 329 11.3.1 Historical Review of HME 329 11.3.2 Equipment 329 11.3.3 Screw Geometry 331 11.3.4 HME Processing 332 11.3.5 Product Characteristics 335 11.3.6 Materials Commonly Used in HME for Solubility Enhancement 337 11.4 Solubility Enhancement Using HME 340 11.4.1 Product Structure 340 11.4.2 HME Matrix Carriers 341 11.4.3 HME for the Manufacture of Pharmaceutical Co-Crystals 343 11.5 Representative Case Studies with Enhanced Solubility 344 11.5.1 Increased Dissolution Rate Due to Size Reduction or De-Aggregation 344 11.5.2 Increased Dissolution Rate Due to Drug Morphology Change 345 11.5.3 Controlled or Prolonged Release with Enhanced Release Extent 346 11.5.4 Complexation to Enhance Dissolution Performance 346 11.5.5 Co-Crystal Formation 347 11.6 Conclusion 347 References 348 12 Penetration Enhancers, Solvents and the Skin 359 Jonathan Hadgraft and Majella E. Lane 12.1 Introduction 359 12.2 Interactions of Solvents and Enhancers with the Skin 360 12.2.1 Small Solvents 361 12.2.2 Solvents with Longer Carbon Chains 361 12.3 Skin Permeation Enhancement of Ibuprofen 363 12.3.1 Infinite Dose Conditions 364 12.3.2 Finite Dose Conditions 368 12.4 Conclusion 369 References 369 13 Dendrimers for Enhanced Drug Solubilization 373 Narendra K. Jain and Rakesh K. Tekade 13.1 Introduction 373 13.2 Current Solubilization Strategies 374 13.3 Origin of Dendrimers 374 13.4 What Are Dendrimers? 375 13.5 Synthesis of Dendritic Architecture 375 13.6 Structure and Intrinsic Properties of Dendrimeric Compartments 377 13.7 Dendrimers in Solubilization 378 13.8 Factors Affecting Dendrimer-Mediated Solubilization and Drug Delivery 381 13.8.1 Nature of the Dendritic Core 381 13.8.2 Dendrimer Generation 382 13.8.3 Nature of the Dendrimer Surface 382 13.8.4 Dendrimer Concentration 382 13.8.5 pH of Solution 383 13.8.6 Temperature 384 13.8.7 Solvents 384 13.9 Drug-Dendrimer Conjugation Approaches 386 13.9.1 Physical Loading: Complexation of Water-Insoluble Drugs 386 13.9.2 Covalent Loading: Synthesis of Drug-Dendrimer Conjugate 389 13.10 Dendrimers' Biocompatibility and Toxicity 393 13.10.1 PEGylation Technology: A Way to Enhance Dendrimer Solubility and Biocompatibility 393 13.11 Classification of PEGylated Dendrimers 394 13.11.1 PEGylated Dendrimer 394 13.11.2 Drug-Conjugated PEGylated Dendrimer 397 13.11.3 PEG Cored Dendrimer 397 13.11.4 PEG Branched Dendrimer 398 13.11.5 PEG-Conjugated Targeted Dendrimer 398 13.12 Conclusion 399 References 400 14 Polymeric Micelles for the Delivery of Poorly Soluble Drugs 411 Swati Biswas, Onkar S. Vaze, Sara Movassaghian and Vladimir P. Torchilin 14.1 Micelles and Micellization 411 14.1.1 Factors Affecting Micellization 413 14.1.2 Thermodynamics of Micellization 414 14.2 Chemical Nature and Formation Mechanism of Polymeric Micelles 416 14.2.1 Core and Corona of the Polymeric Micelles 417 14.2.2 Block Co-Polymers as Building Block of Polymeric Micelles 418 14.3 Polymeric Micelles: Unique Nanomedicine Platforms 419 14.3.1 Polymeric Micelles for the Delivery of Poorly Soluble Drugs 421 14.4 Determination of Physico-Chemical Characteristics of Polymeric Micelles 430 14.4.1 Critical Micelle Concentrations (CMC) 430 14.4.2 Particle Size and Stability 432 14.5 Drug Loading 435 14.5.1 Drug-Loading Procedures 437 14.6 Biodistribution and Toxicity 439 14.7 Targeting Micellar Nanocarriers: Example: Drug Delivery to Tumors 443 14.7.1 Passive Targeting 443 14.7.2 Active Targeting: Functionalized Polymeric Micelles 445 14.8 Site-Specific Micellar-Drug Release Strategies 449 14.9 Intracellular Delivery of Micelles 452 14.10 Multifunctional Micellar Nanocarriers 453 14.11 Conclusion 455 References 455 15 Nanostructured Silicon-Based Materials as a Drug Delivery System for Water-Insoluble Drugs 477 Vesa-Pekka Lehto, Jarno Salonen, H
elder A. Santos and Joakim Riikonen 15.1 Introduction 477 15.2 Control of Particle Size and Pore Morphology 478 15.3 Surface Functionalization 482 15.3.1 Stabilization 482 15.3.2 Biofunctionalization 483 15.4 Biocompatibility and Cytotoxicity 485 15.4.1 In Vitro Studies 486 15.4.2 In Vivo and Ex Vivo Studies 490 15.5 Nanostructured Silicon Materials as DDS 492 15.5.1 Drug-Loading Procedures 492 15.5.2 Enhanced Drug Release 495 15.5.3 Intracellular Uptake 500 15.6 Conclusion 502 References 502 16 Micro- and Nanosizing of Poorly Soluble Drugs by Grinding Techniques 509 Stefan Scheler 16.1 Introduction 509 16.2 Kinetics of Drug Dissolution 510 16.3 Micronization and Nanosizing of Drugs 510 16.3.1 Dissolution Enhancement by Micronization and Nanonization 510 16.3.2 Dry and Wet Milling Technologies 511 16.3.3 NanoCrystal R _ Technology 512 16.4 Theory of Grinding Operations 512 16.4.1 Fraction under Compressive Stress 512 16.4.2 Brittle-Ductile Transition and Grinding Limit 514 16.4.3 Milling Beyond the Brittle-Ductile Transition Limit 516 16.4.4 Fatigue Fracture 517 16.4.5 Agglomeration 517 16.4.6 Amorphization 519 16.5 Influence of the Stabilizer 520 16.5.1 Effects of Stabilization 520 16.5.2 Steric and Electrostatic Stabilization 521 16.5.3 Surfactants 523 16.5.4 Polymers 527 16.6 Milling Equipment and Technology 527 16.6.1 Grinding Beads 527 16.6.2 Types of Media Mills 528 16.6.3 Process Parameters 532 16.7 Process Development from Laboratory to Commercial Scale 535 16.7.1 Early Development 535 16.7.2 Toxicological Studies 535 16.7.3 Clinical Studies 536 16.7.4 Drying 536 16.7.5 Further Processing of Drug Nanoparticles 536 16.8 Application and Biopharmaceutical Properties 537 16.8.1 Oral Drug Delivery 538 16.8.2 Parenteral Drug Delivery 540 16.8.3 Extracorporal Therapy 542 16.9 Conclusion 543 References 543 17 Enhanced Solubility of Poorly Soluble Drugs Via Spray Drying 551 Cordin Arpagaus, David R
utti and Marco Meuri 17.1 Introduction 551 17.2 Advantages of Spray Drying 553 17.3 Principles and Instrumentation of Spray Drying Processes 553 17.3.1 Principal Function of a Spray Dryer 553 17.3.2 Traditional Spray Dryers 558 17.3.3 Recent Developments in Spray Drying 561 17.4 Optimizing Spray Drying Process Parameters 563 17.4.1 Drying Gas Flow Rate (Aspirator Rate) 563 17.4.2 Drying Gas Humidity 563 17.4.3 Inlet Temperature 564 17.4.4 Spray Gas Flow 565 17.4.5 Feed Concentration 565 17.4.6 Feed Rate 565 17.4.7 Organic Solvent Instead of Water 566 17.5 Spray Drying of Water-Insoluble Drugs: Case Studies 566 17.5.1 Nanosuspensions 566 17.5.2 Solid Lipid Nanoparticles 568 17.5.3 Silica-Lipid Hybrid Microcapsules 568 17.5.4 Milled Nanoparticles 570 17.5.5 Inhalation Dosage Forms 571 17.5.6 Porous Products 572 17.5.7 Microemulsions 572 17.5.8 Application Examples: Summary 575 17.6 Conclusion 582 References 583 Index 587