Title Details

Dennis Douroumis
University of Greenwich, UK

Alfred Fahr
Friedrich-Schiller University of Jena, Germany

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