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 Pol
