Drug Delivery Strategies for Poorly Water-Soluble Drugs
Advances in Pharmaceutical Technology
1. Edition January 2013
626 Pages, Hardcover
Wiley & Sons Ltd
ISBN:
978-0-470-71197-2
John Wiley & Sons
Short Description
Many newly proposed drugs suffer from poor water solubility, thus presenting major hurdles in the design of suitable formulations for administration to patients. This work addresses the latest techniques and materials to overcome these hurdles, providing a thorough review of current formulation strategies for a wide range of hydrophobic drugs. With a focus on critical formulation features and clinical studies, the book covers instrumentation, operation principles, applications, scale-up considerations, regulatory issues, and more. An essential guide for researchers in drug delivery, polymers, and biomaterials.
Further versions
Many newly proposed drugs suffer from poor water solubility, thus presenting major hurdles in the design of suitable formulations for administration to patients. This work addresses the latest techniques and materials to overcome these hurdles, providing a thorough review of current formulation strategies for a wide range of hydrophobic drugs. With a focus on critical formulation features and clinical studies, the book covers instrumentation, operation principles, applications, scale-up considerations, regulatory issues, and more. An essential guide for researchers in drug delivery, polymers, and biomaterials.
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
1.4 Solubility and Partitioning of Drugs 11
1.5 Ways to Model Interactions in Colloidal Systems 16
1.6 Kinetics of Drug Transfer from Mobile Nanocarriers 23
1.7 Conclusion 29
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
2.3 Conclusion 59
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
3.5 Effects on Drug Stability 77
3.6 Cyclodextrins and Drug Permeation through Biological Membranes 80
3.7 Drug Solubilization in Pharmaceutical Formulations 82
3.8 Toxicology and Pharmacokinetics 89
3.9 Regulatory Issues 90
3.10 Conclusion 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
4.3 Structural Parameters and Their Influence on Product Quality and Pharmaceutical Performance 116
4.4 Incorporation of Poorly Soluble Drugs and In Vitro Release 123
4.5 Safety Aspects, Toxicity and Pharmacokinetic Profiles 129
4.6 Conclusion 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
5.4 Behavior of Nanoparticles as Drug Delivery Systems 173
5.5 Conclusion 177
6 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs 199
Dagmar Fischer
6.1 Introduction 199
6.2 Drug Encapsulation by Monomer Polymerization 200
6.3 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
7 Development of Self-Emulsifying Drug Delivery Systems (SEDDS) for Oral Bioavailability Enhancement of Poorly Soluble Drugs 225
Dimitrios G. Fatouros and Anette Mullertz
7.1 Introduction 225
7.2 Lipid Processing and Drug Solubilization 226
7.3 Self-Emulsifying Drug Delivery Systems 227
7.4 In Vitro Digestion Model 232
7.5 Enhancement of Oral Absorption by SEDDS 235
7.6 Conclusion 238
8 Novel Top-Down Technologies: Effective Production of Ultra-Fine Drug Nanocrystals 247
C.M. Keck, S. Kobierski, R. Mauludin and R.H. Muller
8.1 Introduction: General Benefits of Drug Nanocrystals (First Generation) 247
8.2 Ultra-Fine Drug Nanocrystals (
8.3 Production of First Generation Nanocrystals: A Brief Overview 250
8.4 Production of Ultra-Fine Drug Nanocrystals: Smartcrystals 252
8.5 Conclusion 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
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
10.3 HLB, PIT and Microemulsion Stability 293
10.4 Microemulsion Physico-Chemical Characterization 293
10.5 Components of Microemulsion Formulations 295
10.6 Preparation Methods 303
10.7 In Vitro and In Vivo Biological Studies 303
10.8 Recent Developments and Future Directions 314
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
11.4 Solubility Enhancement Using HME 340
11.5 Representative Case Studies with Enhanced Solubility 344
11.6 Conclusion 347
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
12.3 Skin Permeation Enhancement of Ibuprofen 363
12.4 Conclusion 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
13.9 Drug-Dendrimer Conjugation Approaches 386
13.10 Dendrimers' Biocompatibility and Toxicity 393
13.11 Classification of PEGylated Dendrimers 394
13.12 Conclusion 399
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
14.2 Chemical Nature and Formation Mechanism of Polymeric Micelles 416
14.3 Polymeric Micelles: Unique Nanomedicine Platforms 419
14.4 Determination of Physico-Chemical Characteristics of Polymeric Micelles 430
14.5 Drug Loading 435
14.6 Biodistribution and Toxicity 439
14.7 Targeting Micellar Nanocarriers: Example: Drug Delivery to Tumors 443
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
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
15.4 Biocompatibility and Cytotoxicity 485
15.5 Nanostructured Silicon Materials as DDS 492
15.6 Conclusion 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
16.4 Theory of Grinding Operations 512
16.5 Influence of the Stabilizer 520
16.6 Milling Equipment and Technology 527
16.7 Process Development from Laboratory to Commercial Scale 535
16.8 Application and Biopharmaceutical Properties 537
16.9 Conclusion 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
17.4 Optimizing Spray Drying Process Parameters 563
17.5 Spray Drying of Water-Insoluble Drugs: Case Studies 566
17.6 Conclusion 582
References 583
Index 587
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
1.4 Solubility and Partitioning of Drugs 11
1.5 Ways to Model Interactions in Colloidal Systems 16
1.6 Kinetics of Drug Transfer from Mobile Nanocarriers 23
1.7 Conclusion 29
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
2.3 Conclusion 59
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
3.5 Effects on Drug Stability 77
3.6 Cyclodextrins and Drug Permeation through Biological Membranes 80
3.7 Drug Solubilization in Pharmaceutical Formulations 82
3.8 Toxicology and Pharmacokinetics 89
3.9 Regulatory Issues 90
3.10 Conclusion 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
4.3 Structural Parameters and Their Influence on Product Quality and Pharmaceutical Performance 116
4.4 Incorporation of Poorly Soluble Drugs and In Vitro Release 123
4.5 Safety Aspects, Toxicity and Pharmacokinetic Profiles 129
4.6 Conclusion 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
5.4 Behavior of Nanoparticles as Drug Delivery Systems 173
5.5 Conclusion 177
6 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs 199
Dagmar Fischer
6.1 Introduction 199
6.2 Drug Encapsulation by Monomer Polymerization 200
6.3 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
7 Development of Self-Emulsifying Drug Delivery Systems (SEDDS) for Oral Bioavailability Enhancement of Poorly Soluble Drugs 225
Dimitrios G. Fatouros and Anette Mullertz
7.1 Introduction 225
7.2 Lipid Processing and Drug Solubilization 226
7.3 Self-Emulsifying Drug Delivery Systems 227
7.4 In Vitro Digestion Model 232
7.5 Enhancement of Oral Absorption by SEDDS 235
7.6 Conclusion 238
8 Novel Top-Down Technologies: Effective Production of Ultra-Fine Drug Nanocrystals 247
C.M. Keck, S. Kobierski, R. Mauludin and R.H. Muller
8.1 Introduction: General Benefits of Drug Nanocrystals (First Generation) 247
8.2 Ultra-Fine Drug Nanocrystals (
8.3 Production of First Generation Nanocrystals: A Brief Overview 250
8.4 Production of Ultra-Fine Drug Nanocrystals: Smartcrystals 252
8.5 Conclusion 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
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
10.3 HLB, PIT and Microemulsion Stability 293
10.4 Microemulsion Physico-Chemical Characterization 293
10.5 Components of Microemulsion Formulations 295
10.6 Preparation Methods 303
10.7 In Vitro and In Vivo Biological Studies 303
10.8 Recent Developments and Future Directions 314
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
11.4 Solubility Enhancement Using HME 340
11.5 Representative Case Studies with Enhanced Solubility 344
11.6 Conclusion 347
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
12.3 Skin Permeation Enhancement of Ibuprofen 363
12.4 Conclusion 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
13.9 Drug-Dendrimer Conjugation Approaches 386
13.10 Dendrimers' Biocompatibility and Toxicity 393
13.11 Classification of PEGylated Dendrimers 394
13.12 Conclusion 399
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
14.2 Chemical Nature and Formation Mechanism of Polymeric Micelles 416
14.3 Polymeric Micelles: Unique Nanomedicine Platforms 419
14.4 Determination of Physico-Chemical Characteristics of Polymeric Micelles 430
14.5 Drug Loading 435
14.6 Biodistribution and Toxicity 439
14.7 Targeting Micellar Nanocarriers: Example: Drug Delivery to Tumors 443
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
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
15.4 Biocompatibility and Cytotoxicity 485
15.5 Nanostructured Silicon Materials as DDS 492
15.6 Conclusion 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
16.4 Theory of Grinding Operations 512
16.5 Influence of the Stabilizer 520
16.6 Milling Equipment and Technology 527
16.7 Process Development from Laboratory to Commercial Scale 535
16.8 Application and Biopharmaceutical Properties 537
16.9 Conclusion 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
17.4 Optimizing Spray Drying Process Parameters 563
17.5 Spray Drying of Water-Insoluble Drugs: Case Studies 566
17.6 Conclusion 582
References 583
Index 587
