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.
Table of Contents
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
