Edited by DENNIS DOUROUMIS. School of Science, JJniversity of Greenwich, UK. and ALFRED FAHR. Friedrich-Schiller University ofjena, Germany

Transcription

1 Drug Delivery Strategies for Poorly Water-Soluble Drugs Edited by DENNIS DOUROUMIS School of Science, JJniversity of Greenwich, UK and ALFRED FAHR Friedrich-Schiller University ofjena, Germany WILEY A John Wiley & Sons, Ltd., Publication

2 Contents List of Contributors Series Preface Preface xvii xxi xxiii 1 Self-Assembled Delivery Vehicles for Poorly Water-Soluble Drugs: Basic Theoretical Considerations and Modeling Concepts 1 Sylvia May and Alfred Fahr 1.1 Introduction Brief Reminder of Equilibrium Thermodynamics Principles of Seif-Assembly in Dilute Solutions Linear Growth Cooperative Assembly Solubility and Partitioning of Drugs Simple Partitioning Equilibria Partitioning and Micellization Hydrophobicity and Ordering of Water Ways to Model Interactions in Colloidal Systems Electrostatic Interactions: The Poisson-Boltzmann Model Chain Packing Model Kinetics of Drug Transfer from Mobile Nanocarriers Collision Mechanism Diffusion Mechanism Internal Kinetics 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 Intravenous Administration of Poorly Water-Soluble Compounds (PWSC) Solubilizing Vehicles with Precipitation Risk upon Dilution Solubilizing Vehicles Maintaining Solubilization Capacity upon Dilution 43

3 viii Contents Mechanistic Release Aspects/Transfer Liposomal PWSC In Vivo Consequences Preclinical Parenteral Assessment Liposomal PWSC Conclusion 59 References 60 3 Drug Solubilization and Stabilization by Cyclodextrin Drug Carriers 67 Thorsteinn Loftsson and Marcus E. Brewster 3.1 Introduction Structure and Physiochemical Properties Cyclodextrin Complexes and Phase Solubility Diagrams Cyclodextrin Complexes Self-Assembly of Cyclodextrins and their Complexes Thermodynamic and Driving Forces for Complexation Effects on Drug Stability Cyclodextrins and Drug Permeation through Biological Membranes Drug Solubilization in Pharmaceutical Formulations Oral Drug Delivery Sublingual, Buccal, Nasal, Pulmonary, Rectal and Vaginal Drug Delivery Ophthalmie Drug Delivery Dermal and Transdermal Drug Delivery Injectable Formulations Toxicology and Pharmacokinetics Regulatory Issues Conclusion 91 References 91 4 Solid Lipid Nanoparticles for Drug Delivery 103 Sonja Joseph and Heike Bunjes 4.1 Introduction Preparation Procedures for Solid Lipid Nanoparticles Melt Dispersion Processes Other Top-Down Processes Precipitation from Homogeneous Systems Comparison of the Formulation Procedures and Scale-Up Feasibility Further Processing of Solid Lipid Nanoparticle Suspensions Structural Parameters and Their Influence on Product Quality and Pharmaceutical Performance Particle Size and Size Distribution Surface Properties Solid State Properties of Solid Lipid Nanoparticles Particle Morphology and Overall Structure of the Dispersions 121

4 Contents ix 4.4 Incorporation of Poorly Soluble Drugs and In Vitro Release Drug Incorporation In Vitro Drug Release Safety Aspects, Toxicity and Pharmacokinetic Profiles In Vitro Behavior and Toxicity Studies Bioavailability and Pharmacokinetics Conclusion 133 References Polymerie Drug Delivery Systems for Encapsuiating Hydrophobie Drugs 151 Naveed Ahmed, C.E. Mora-Huertas, Chiraz, Jaafar-Maalej, Hatem Fessi and Abdelhamid Elaissari 5.1 Introduction Safety and Biocompatibility of Polymers Encapsulation Techniques of Hydrophobie Drugs The Nanoprecipitation Method The Emulsification Methods Polymersome Preparation Supercritical Fluid Technology The Polymer-Coating Method The Layer-by-Layer Method Behavior of Nanoparticles as Drug Delivery Systems Mean Size Zeta Potential Encapsulation Efficiency Drug Release Properties General Performance of the Nanoparticles Conclusion 177 References Polymerie Drug Delivery Systems for Encapsuiating Hydrophobie Drugs 199 Dagmar Fischer 6.1 Introduction Drug Encapsulation by Monomer Polymerization Emulsion Polymerization Interfacial Polymerization Interfacial Polycondensation Polymerie Nanospheres and Nanocapsules Produced by Polymerization Formulation Components Control of Particle Morphology Toxicity and In Vivo Performance 213

5 x Contents 6.7 Scale-Up Considerations Conclusion 217 Acknowledgements 217 References Development of Self-Emulsifying Drug Delivery Systems (SEDDS) for Oral Bioavailability Enhancement of Poorly Soluble Drugs 225 Dimitrios G. Fatouros and Anette Müllertz 7.1 Introduction Lipid Processing and Drug Solubilization Self-Emulsifying Drug Delivery Systems Excipients Used in SEDDS Self-Emulsification Mechanism Physicochemical Characterization of SEDDS Drug Incorporation in SEDDS In Vitro Digestion Model Enhancement of Oral Absorption by SEDDS Conclusion 238 References Novel Top-Down Technologies: Effective Production of Ultra-Fine Drug Nanocrystals 247 C.M. Keck, S. Kobierski, R. Mauludin and R.H. Müller 8.1 Introduction: General Benefits of Drug Nanocrystals (First Generation) Ultra-Fine Drug Nanocrystals (<^100 Nm) and Their Special Properties Production of First Generation Nanocrystals: A Brief Overview Hydrosols Nanomorphs Nanocrystals by Bead Milling DissoCubes by High Pressure Homogenization NANOEDGE by Baxter Summary of First Generation Production Technologies Production of Ultra-Fine Drug Nanocrystals: Smartcrystals Fine-Tuned Precipitation The SmartCrystal Concept Conclusion 259 References Nanosuspensions with Enhanced Drug Dissolution Rates of Poorly Water-Soluble Drugs 265 Dennis Douroumis 9.1 Introduction Crystal Growth and Nucleation Theory 266

6 Contents xi 9.3 Creating Supersaturation and Stable Nanosuspensions Antisolvent Precipitation Via Mixer Processing Antisolvent Precipitation by Using Ultrasonication Nanoprecipitation Using Microfluidic Reactors Particle Engineering by Spray: Freezing into Liquid Precipitation by Rapid Expansion from Supercritical to Aqueous Solution Conclusion 282 References Microemulsions for Drug Solubilization and Delivery 287 X.Q. Wang and Q. Zhang 10.1 Introduction Microemulsion Formation and Phase Behavior Theories of Microemulsion Formation Structure of Microemulsions Phase Behavior HLB, PIT and Microemulsion Stability Microemulsion Physico-Chemical Characterization Components of Microemulsion Formulations Oils Surfactants Cosurfactants Drugs Preparation Methods In Vitro and In Vivo Biological Studies Microemulsions Used as an Oral Delivery System for Poorly Water-Soluble Compounds Microemulsions Used as a Parenteral Delivery System for Poorly Water-Soluble Compounds Recent Developments and Future Directions Develop Cremophor-Free Microemulsions Dried O/W Emulsions for Oral Delivery of Poorly Soluble Drugs Self-Microemulsifying Drug Delivery System (SMEDDS) 318 References 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 Solid Drug Dispersions for Enhanced Drug Solubility Hot Melt Extrusion (HME) as a Drug Delivery Technology Historical Review of HME Equipment 329

7 xii Contents Screw Geometry HME Processing Product Characteristics Materials Commonly Used in HME for Solubility Enhancement Solubility Enhancement Using HME Product Structure HME Matrix Carriers HME for the Manufacture of Pharmaceutical Co-Crystals Representative Case Studies with Enhanced Solubility Increased Dissolution Rate Due to Size Reduction or De-Aggregation Increased Dissolution Rate Due to Drug Morphology Change Controlled or Prolonged Release with Enhanced Release Extent Complexation to Enhance Dissolution Performance Co-Crystal Formation Conclusion 347 References Penetration Enhancers, Solvents and the Skin 359 Jonathan Hadgraft and Majella E. Lane 12.1 Introduction Interactions of Solvents and Enhancers with the Skin Small Solvents Solvents with Longer Carbon Chains Skin Permeation Enhancement of Ibuprofen Infinite Dose Conditions Finite Dose Conditions Conclusion 369 References Dendrimers for Enhanced Drug Solubilization 373 Narendra K. Jain and Rakesh K. Tekade 13.1 Introduction Current Solubilization Strategies Origin of Dendrimers What Are Dendrimers? Synthesis of Dendritic Architecture Structure and Intrinsic Properties of Dendrimeric Compartments Dendrimers in Solubilization Factors Affecting Dendrimer-Mediated Solubilization and Drug Delivery 381

8 Contents xiii Nature of the Dendritic Core Dendrimer Generation Nature of the Dendrimer Surface Dendrimer Concentration ph of Solution Temperature Solvents Drug-Dendrimer Conjugation Approaches Physical Loading: Complexation of Water-Insoluble Drugs Covalent Loading: Synthesis of Drug-Dendrimer Conjugate Dendrimers'Biocompatibility and Toxicity PEGylation Technology: A Way to Enhance Dendrimer Solubility and Biocompatibility Classification of PEGylated Dendrimers PEGylated Dendrimer Drug-Conjugated PEGylated Dendrimer PEG Cored Dendrimer PEG Branched Dendrimer PEG-Conjugated Targeted Dendrimer Conclusion 399 References 400 Polymerie 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 Factors Affecting Micellization Thermodynamics of Micellization Chemical Nature and Formation Mechanism of Polymerie Micelles Core and Corona of the Polymerie Micelles Block Co-Polymers as Building Block of Polymerie Micelles Polymerie Micelles: Unique Nanomedicine Platforms Polymerie Micelles for the Delivery of Poorly Soluble Drugs Determination of Physico-Chemical Characteristics of Polymerie Micelles Critical Micelle Concentrations (CMC) Particle Size and Stability Drug Loading Drug-Loading Procedures Biodistribution and Toxicity Targeting Micellar Nanocarriers: Example: Drug Delivery to Tumors Passive Targeting Active Targeting: Functionalized Polymerie Micelles 445

9 xiv Contents 14.8 Site-Specific Micellar-Drug Release Strategies Intracellular Delivery of Micelles Multifunctional Micellar Nanocarriers Conclusion 455 References Nanostructured Silicon-Based Materials as a Drug Delivery System for Water-Insoluble Drugs 477 Vesa-Pekka Lehto, Jarno Salonen, Helder A. Santos and Joakim Riikonen 15.1 Introduction Control of Particle Size and Pore Morphology Surface Functionalization Stabilization Biofunctionalization Biocompatibility and Cytotoxicity In Vitro Studies In Vivo and Ex Vivo Studies Nanostructured Silicon Materials as DDS Drug-Loading Procedures Enhanced Drug Release Intracellular Uptake Conclusion 502 References Micro- and Nanosizing of Poorly Soluble Drugs by Grinding Techniques 509 Stefan Scheler 16.1 Introduction Kinetics of Drug Dissolution Micronization and Nanosizing of Drugs Dissolution Enhancement by Micronization and Nanonization Dry and Wet Milling Technologies NanoCrystal Technology Theory of Grinding Operations Fraction under Compressive Stress Brittle-Ductile Transition and Grinding Limit Milling Beyond the Brittle-Ductile Transition Limit Fatigue Fracture Agglomeration Amorphization Influence of the Stabilizer Effects of Stabilization Steric and Electrostatic Stabilization Surfactants Polymers 527

10 Contents xv 16.6 Milling Equipment and Technology Grinding Beads Types of Media Mills Process Parameters Process Development from Laboratory to Commercial Scale Early Development Toxicological Studies Clinical Studies Drying Further Processing of Drug Nanoparticles Application and Biopharmaceutical Properties Oral Drug Delivery Parenteral Drug Delivery Extracorporal Therapy Conclusion 543 References Enhanced Solubility of Poorly Soluble Drugs Via Spray Drying 551 Cordin Arpagaus, David Rütti and Marco Meuri 17.1 Introduction Advantages of Spray Drying Principles and Instrumentation of Spray Drying Processes Principal Function of a Spray Dryer Traditional Spray Dryers Recent Developments in Spray Drying Optimizing Spray Drying Process Parameters Drying Gas Flow Rate (Aspirator Rate) Drying Gas Humidity Inlet Temperature Spray Gas Flow Feed Concentration Feed Rate Organic Solvent Instead of Water Spray Drying of Water-Insolüble Drugs: Case Studies Nanosuspensions Solid Lipid Nanoparticles Silica-Lipid Hybrid Microcapsules Milled Nanoparticles Inhalation Dosage Forms Porous Products Microemulsions Application Examples: Summary Conclusion 582 References 583 Index 587