Drug Delivery Strategies for Poorly Water-Soluble Drugs

Dennis DouroumisUniversity of Greenwich, UKAlfred FahrFriedrich-Schiller University of Jena, Germany

• List of Contributors xviiSeries Preface xxiPreface xxiii1 Self-Assembled Delivery Vehicles for Poorly Water-Soluble Drugs: Basic Theoretical Considerations and Modeling Concepts 1Sylvio May and Alfred Fahr1.1 Introduction 11.2 Brief Reminder of Equilibrium Thermodynamics 31.3 Principles of Self-Assembly in Dilute Solutions 71.3.1 Linear Growth 91.3.2 Cooperative Assembly 101.4 Solubility and Partitioning of Drugs 111.4.1 Simple Partitioning Equilibria 111.4.2 Partitioning and Micellization 131.4.3 Hydrophobicity and Ordering of Water 151.5 Ways to Model Interactions in Colloidal Systems 161.5.1 Electrostatic Interactions: The Poisson–Boltzmann Model 171.5.2 Chain Packing Model 211.6 Kinetics of Drug Transfer from Mobile Nanocarriers 231.6.1 Collision Mechanism 251.6.2 Diffusion Mechanism 261.6.3 Internal Kinetics 261.7 Conclusion 29Acknowledgments 31References 312 Liposomes as Intravenous Solubilizers for Poorly Water-Soluble Drugs 37Peter van Hoogevest, Mathew Leigh and Alfred Fahr2.1 Introduction 372.2 Intravenous Administration of Poorly Water-Soluble Compounds (PWSC) 402.2.1 Solubilizing Vehicles with Precipitation Risk upon Dilution 412.2.2 Solubilizing Vehicles Maintaining Solubilization Capacity upon Dilution 432.2.3 Mechanistic Release Aspects/Transfer Liposomal PWSC 452.2.4 In Vivo Consequences 522.2.5 Preclinical Parenteral Assessment Liposomal PWSC 562.3 Conclusion 59References 603 Drug Solubilization and Stabilization by Cyclodextrin Drug Carriers 67Thorsteinn Loftsson and Marcus E. Brewster3.1 Introduction 673.2 Structure and Physiochemical Properties 683.3 Cyclodextrin Complexes and Phase Solubility Diagrams 723.4 Cyclodextrin Complexes 763.4.1 Self-Assembly of Cyclodextrins and their Complexes 763.4.2 Thermodynamic and Driving Forces for Complexation 763.5 Effects on Drug Stability 773.6 Cyclodextrins and Drug Permeation through Biological Membranes 803.7 Drug Solubilization in Pharmaceutical Formulations 823.7.1 Oral Drug Delivery 843.7.2 Sublingual, Buccal, Nasal, Pulmonary, Rectal and Vaginal Drug Delivery 863.7.3 Ophthalmic Drug Delivery 873.7.4 Dermal and Transdermal Drug Delivery 873.7.5 Injectable Formulations 873.8 Toxicology and Pharmacokinetics 893.9 Regulatory Issues 903.10 Conclusion 91References 914 Solid Lipid Nanoparticles for Drug Delivery 103Sonja Joseph and Heike Bunjes4.1 Introduction 1034.2 Preparation Procedures for Solid Lipid Nanoparticles 1044.2.1 Melt Dispersion Processes 1044.2.2 Other Top-Down Processes 1094.2.3 Precipitation from Homogeneous Systems 1114.2.4 Comparison of the Formulation Procedures and Scale-Up Feasibility 1134.2.5 Further Processing of Solid Lipid Nanoparticle Suspensions 1154.3 Structural Parameters and Their Influence on Product Quality and Pharmaceutical Performance 1164.3.1 Particle Size and Size Distribution 1164.3.2 Surface Properties 1174.3.3 Solid State Properties of Solid Lipid Nanoparticles 1174.3.4 Particle Morphology and Overall Structure of the Dispersions 1214.4 Incorporation of Poorly Soluble Drugs and In Vitro Release 1234.4.1 Drug Incorporation 1234.4.2 In Vitro Drug Release 1264.5 Safety Aspects, Toxicity and Pharmacokinetic Profiles 1294.5.1 In Vitro Behavior and Toxicity Studies 1294.5.2 Bioavailability and Pharmacokinetics 1314.6 Conclusion 133References 1335 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs 151Naveed Ahmed, C.E. Mora-Huertas, Chiraz Jaafar-Maalej, Hatem Fessi and Abdelhamid Elaissari5.1 Introduction 1515.2 Safety and Biocompatibility of Polymers 1525.3 Encapsulation Techniques of Hydrophobic Drugs 1565.3.1 The Nanoprecipitation Method 1565.3.2 The Emulsification Methods 1585.3.3 Polymersome Preparation 1645.3.4 Supercritical Fluid Technology 1665.3.5 The Polymer-Coating Method 1675.3.6 The Layer-by-Layer Method 1715.4 Behavior of Nanoparticles as Drug Delivery Systems 1735.4.1 Mean Size 1735.4.2 Zeta Potential 1735.4.3 Encapsulation Efficiency 1745.4.4 Drug Release Properties 1765.4.5 General Performance of the Nanoparticles 1765.5 Conclusion 177References 1806 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs 199Dagmar Fischer6.1 Introduction 1996.2 Drug Encapsulation by Monomer Polymerization 2006.2.1 Emulsion Polymerization 2016.2.2 Interfacial Polymerization 2066.2.3 Interfacial Polycondensation 2076.3 Polymeric Nanospheres and Nanocapsules Produced by Polymerization 2096.4 Formulation Components 2106.5 Control of Particle Morphology 2126.6 Toxicity and In Vivo Performance 2136.7 Scale-Up Considerations 2146.8 Conclusion 217Acknowledgements 217References 2177 Development of Self-Emulsifying Drug Delivery Systems (SEDDS) for Oral Bioavailability Enhancement of Poorly Soluble Drugs 225Dimitrios G. Fatouros and Anette M¨ullertz7.1 Introduction 2257.2 Lipid Processing and Drug Solubilization 2267.3 Self-Emulsifying Drug Delivery Systems 2277.3.1 Excipients Used in SEDDS 2277.3.2 Self-Emulsification Mechanism 2287.3.3 Physicochemical Characterization of SEDDS 2297.3.4 Drug Incorporation in SEDDS 2317.4 In Vitro Digestion Model 2327.5 Enhancement of Oral Absorption by SEDDS 2357.6 Conclusion 238References 2398 Novel Top-Down Technologies: Effective Production of Ultra-Fine Drug Nanocrystals 247C.M. Keck, S. Kobierski, R. Mauludin and R.H. M¨uller8.1 Introduction: General Benefits of Drug Nanocrystals (First Generation) 2478.2 Ultra-Fine Drug Nanocrystals (_100 Nm) and Their Special Properties 2488.3 Production of First Generation Nanocrystals: A Brief Overview 2508.3.1 Hydrosols 2508.3.2 Nanomorphs 2518.3.3 NanocrystalsTM by Bead Milling 2518.3.4 DissoCubes R _ by High Pressure Homogenization 2518.3.5 NANOEDGE by Baxter 2528.3.6 Summary of First Generation Production Technologies 2528.4 Production of Ultra-Fine Drug Nanocrystals: Smartcrystals 2528.4.1 Fine-Tuned Precipitation 2528.4.2 The SmartCrystal Concept 2538.5 Conclusion 259References 2599 Nanosuspensions with Enhanced Drug Dissolution Rates of Poorly Water-Soluble Drugs 265Dennis Douroumis9.1 Introduction 2659.2 Crystal Growth and Nucleation Theory 2669.3 Creating Supersaturation and Stable Nanosuspensions 2699.4 Antisolvent Precipitation Via Mixer Processing 2729.5 Antisolvent Precipitation by Using Ultrasonication 2779.6 Nanoprecipitation Using Microfluidic Reactors 2789.7 Particle Engineering by Spray: Freezing into Liquid 2799.8 Precipitation by Rapid Expansion from Supercritical to Aqueous Solution 2809.9 Conclusion 282References 28310 Microemulsions for Drug Solubilization and Delivery 287X.Q. Wang and Q. Zhang10.1 Introduction 28710.2 Microemulsion Formation and Phase Behavior 28910.2.1 Theories of Microemulsion Formation 28910.2.2 Structure of Microemulsions 28910.2.3 Phase Behavior 29210.3 HLB, PIT and Microemulsion Stability 29310.4 Microemulsion Physico-Chemical Characterization 29310.5 Components of Microemulsion Formulations 29510.5.1 Oils 29610.5.2 Surfactants 29810.5.3 Cosurfactants 30010.5.4 Drugs 30210.6 Preparation Methods 30310.7 In Vitro and In Vivo Biological Studies 30310.7.1 Microemulsions Used as an Oral Delivery System for Poorly Water-Soluble Compounds 30310.7.2 Microemulsions Used as a Parenteral Delivery System for Poorly Water-Soluble Compounds 31110.8 Recent Developments and Future Directions 31410.8.1 Develop Cremophor-Free Microemulsions 31410.8.2 Dried O/W Emulsions for Oral Delivery of Poorly Soluble Drugs 31510.8.3 Self-Microemulsifying Drug Delivery System (SMEDDS) 318References 31911 Hot Melt Extrusion: A Process Overview and Use in Manufacturing Solid Dispersions of Poorly Water-Soluble Drugs 325Shu Li, David S. Jones and Gavin P. Andrews11.1 Introduction: Present Challenges to Oral Drug Delivery 32511.2 Solid Drug Dispersions for Enhanced Drug Solubility 32711.3 Hot Melt Extrusion (HME) as a Drug Delivery Technology 32911.3.1 Historical Review of HME 32911.3.2 Equipment 32911.3.3 Screw Geometry 33111.3.4 HME Processing 33211.3.5 Product Characteristics 33511.3.6 Materials Commonly Used in HME for Solubility Enhancement 33711.4 Solubility Enhancement Using HME 34011.4.1 Product Structure 34011.4.2 HME Matrix Carriers 34111.4.3 HME for the Manufacture of Pharmaceutical Co-Crystals 34311.5 Representative Case Studies with Enhanced Solubility 34411.5.1 Increased Dissolution Rate Due to Size Reduction or De-Aggregation 34411.5.2 Increased Dissolution Rate Due to Drug Morphology Change 34511.5.3 Controlled or Prolonged Release with Enhanced Release Extent 34611.5.4 Complexation to Enhance Dissolution Performance 34611.5.5 Co-Crystal Formation 34711.6 Conclusion 347References 34812 Penetration Enhancers, Solvents and the Skin 359Jonathan Hadgraft and Majella E. Lane12.1 Introduction 35912.2 Interactions of Solvents and Enhancers with the Skin 36012.2.1 Small Solvents 36112.2.2 Solvents with Longer Carbon Chains 36112.3 Skin Permeation Enhancement of Ibuprofen 36312.3.1 Infinite Dose Conditions 36412.3.2 Finite Dose Conditions 36812.4 Conclusion 369References 36913 Dendrimers for Enhanced Drug Solubilization 373Narendra K. Jain and Rakesh K. Tekade13.1 Introduction 37313.2 Current Solubilization Strategies 37413.3 Origin of Dendrimers 37413.4 What Are Dendrimers? 37513.5 Synthesis of Dendritic Architecture 37513.6 Structure and Intrinsic Properties of Dendrimeric Compartments 37713.7 Dendrimers in Solubilization 37813.8 Factors Affecting Dendrimer-Mediated Solubilization and Drug Delivery 38113.8.1 Nature of the Dendritic Core 38113.8.2 Dendrimer Generation 38213.8.3 Nature of the Dendrimer Surface 38213.8.4 Dendrimer Concentration 38213.8.5 pH of Solution 38313.8.6 Temperature 38413.8.7 Solvents 38413.9 Drug–Dendrimer Conjugation Approaches 38613.9.1 Physical Loading: Complexation of Water-Insoluble Drugs 38613.9.2 Covalent Loading: Synthesis of Drug–Dendrimer Conjugate 38913.10 Dendrimers’ Biocompatibility and Toxicity 39313.10.1 PEGylation Technology: A Way to Enhance Dendrimer Solubility and Biocompatibility 39313.11 Classification of PEGylated Dendrimers 39413.11.1 PEGylated Dendrimer 39413.11.2 Drug-Conjugated PEGylated Dendrimer 39713.11.3 PEG Cored Dendrimer 39713.11.4 PEG Branched Dendrimer 39813.11.5 PEG-Conjugated Targeted Dendrimer 39813.12 Conclusion 399References 40014 Polymeric Micelles for the Delivery of Poorly Soluble Drugs 411Swati Biswas, Onkar S. Vaze, Sara Movassaghian and Vladimir P. Torchilin14.1 Micelles and Micellization 41114.1.1 Factors Affecting Micellization 41314.1.2 Thermodynamics of Micellization 41414.2 Chemical Nature and Formation Mechanism of Polymeric Micelles 41614.2.1 Core and Corona of the Polymeric Micelles 41714.2.2 Block Co-Polymers as Building Block of Polymeric Micelles 41814.3 Polymeric Micelles: Unique Nanomedicine Platforms 41914.3.1 Polymeric Micelles for the Delivery of Poorly Soluble Drugs 42114.4 Determination of Physico-Chemical Characteristics of Polymeric Micelles 43014.4.1 Critical Micelle Concentrations (CMC) 43014.4.2 Particle Size and Stability 43214.5 Drug Loading 43514.5.1 Drug-Loading Procedures 43714.6 Biodistribution and Toxicity 43914.7 Targeting Micellar Nanocarriers: Example: Drug Delivery to Tumors 44314.7.1 Passive Targeting 44314.7.2 Active Targeting: Functionalized Polymeric Micelles 44514.8 Site-Specific Micellar-Drug Release Strategies 44914.9 Intracellular Delivery of Micelles 45214.10 Multifunctional Micellar Nanocarriers 45314.11 Conclusion 455References 45515 Nanostructured Silicon-Based Materials as a Drug Delivery System for Water-Insoluble Drugs 477Vesa-Pekka Lehto, Jarno Salonen, H´elder A. Santos and Joakim Riikonen15.1 Introduction 47715.2 Control of Particle Size and Pore Morphology 47815.3 Surface Functionalization 48215.3.1 Stabilization 48215.3.2 Biofunctionalization 48315.4 Biocompatibility and Cytotoxicity 48515.4.1 In Vitro Studies 48615.4.2 In Vivo and Ex Vivo Studies 49015.5 Nanostructured Silicon Materials as DDS 49215.5.1 Drug-Loading Procedures 49215.5.2 Enhanced Drug Release 49515.5.3 Intracellular Uptake 50015.6 Conclusion 502References 50216 Micro- and Nanosizing of Poorly Soluble Drugs by Grinding Techniques 509Stefan Scheler16.1 Introduction 50916.2 Kinetics of Drug Dissolution 51016.3 Micronization and Nanosizing of Drugs 51016.3.1 Dissolution Enhancement by Micronization and Nanonization 51016.3.2 Dry and Wet Milling Technologies 51116.3.3 NanoCrystal R _ Technology 51216.4 Theory of Grinding Operations 51216.4.1 Fraction under Compressive Stress 51216.4.2 Brittle-Ductile Transition and Grinding Limit 51416.4.3 Milling Beyond the Brittle-Ductile Transition Limit 51616.4.4 Fatigue Fracture 51716.4.5 Agglomeration 51716.4.6 Amorphization 51916.5 Influence of the Stabilizer 52016.5.1 Effects of Stabilization 52016.5.2 Steric and Electrostatic Stabilization 52116.5.3 Surfactants 52316.5.4 Polymers 52716.6 Milling Equipment and Technology 52716.6.1 Grinding Beads 52716.6.2 Types of Media Mills 52816.6.3 Process Parameters 53216.7 Process Development from Laboratory to Commercial Scale 53516.7.1 Early Development 53516.7.2 Toxicological Studies 53516.7.3 Clinical Studies 53616.7.4 Drying 53616.7.5 Further Processing of Drug Nanoparticles 53616.8 Application and Biopharmaceutical Properties 53716.8.1 Oral Drug Delivery 53816.8.2 Parenteral Drug Delivery 54016.8.3 Extracorporal Therapy 54216.9 Conclusion 543References 54317 Enhanced Solubility of Poorly Soluble Drugs Via Spray Drying 551Cordin Arpagaus, David R¨utti and Marco Meuri17.1 Introduction 55117.2 Advantages of Spray Drying 55317.3 Principles and Instrumentation of Spray Drying Processes 55317.3.1 Principal Function of a Spray Dryer 55317.3.2 Traditional Spray Dryers 55817.3.3 Recent Developments in Spray Drying 56117.4 Optimizing Spray Drying Process Parameters 56317.4.1 Drying Gas Flow Rate (Aspirator Rate) 56317.4.2 Drying Gas Humidity 56317.4.3 Inlet Temperature 56417.4.4 Spray Gas Flow 56517.4.5 Feed Concentration 56517.4.6 Feed Rate 56517.4.7 Organic Solvent Instead of Water 56617.5 Spray Drying of Water-Insoluble Drugs: Case Studies 56617.5.1 Nanosuspensions 56617.5.2 Solid Lipid Nanoparticles 56817.5.3 Silica-Lipid Hybrid Microcapsules 56817.5.4 Milled Nanoparticles 57017.5.5 Inhalation Dosage Forms 57117.5.6 Porous Products 57217.5.7 Microemulsions 57217.5.8 Application Examples: Summary 57517.6 Conclusion 582References 583Index 587