Drug delivery strategies for poorly water-soluble drugs

Title:

Publication Information:

Chichester, West Sussex : Wiley, 2013

Physical Description:

xxv, 600 p. : ill. ; 25 cm.

ISBN:

9780470711972

9781118444771

Subject Term:

Drug delivery systems

Drugs -- Solubility

Added Author:

Douroumis, Dennis

Fahr, Alfred

Available:*

Library	Item Barcode	Call Number	Material Type	Item Category 1	Status
Searching... PSZ JB	30000010307138	RS199.5 D784 2013	Open Access Book	Book	Searching... Unknown

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.

Author Notes

Dennis Douroumis
University of Greenwich, UK

Alfred Fahr
Friedrich-Schiller University of Jena, Germany

Sylvio May and Alfred FahrPeter van Hoogevest and Mathew Leigh and Alfred FahrThorsteinn Loftsson and Marcus E. BrewsterSonja Joseph and Heike BunjesNaveed Ahmed and C.E. Mora-Heurtas and Chiraz Jaafar-Maalej and Hatem Fessi and Abdelhamid ElaissariDagmar FischerDimitrios G. Fatouros and Anette M¿ullertzC.M. Keck and S. Kobierski and R. Mauludin and R.H. M¿ullerDennis DouroumisX.Q. Wang and Q. ZhangShu Li and David S. Jones and Gavin P. AndrewsJonathan Hadgraft and Majella E. LaneNarendra K. Jain and Rakesh K. TekadeSwati Biswas and Onkar S. Vaze and Sara Movassaghian and Vladimir P. TorchilinVesa-Pekka Lehto and Jarno Salonen and Helder Santos and Joakim RiikonenStefan SchelerCordin Arpargaus and David R¿utti and Marco Meuri

List of Contributors	p. xv
Series Preface	p. xvii
Preface	p. xix
1 Self-Assembled Delivery Vehicles for Poorly Water-Soluble Drugs: Basic Theoretical Considerations and Modeling Concepts	p. 1
1.1 Introduction	p. 1
1.2 Brief Reminder of Equilibrium Thermodynamics	p. 3
1.3 Principles of Self-Assembly in Dilute Solutions	p. 7
1.3.1 Linear Growth	p. 9
1.3.2 Cooperative Assembly	p. 10
1.4 Solubility and Partitioning of Drugs	p. 11
1.4.1 Simple Partitioning Equilibria	p. 11
1.4.2 Partitioning and Micellization	p. 13
1.4.3 Hydrophobicity and Ordering of Water	p. 15
1.5 Ways to Model Interactions in Colloidal Systems	p. 16
1.5.1 Electrostatic Interactions: The Poisson-Boltzmann Model	p. 17
1.5.2 Chain Packing Model	p. 21
1.6 Kinetics of Drug Transfer from Mobile Nanocarriers	p. 23
1.6.1 Collision Mechanism	p. 25
1.6.2 Diffusion Mechanism	p. 26
1.6.3 Internal Kinetics	p. 26
1.7 Conclusion	p. 29
Acknowledgments	p. 31
References	p. 31
2 Liposomes as Intravenous Solubilizers for Poorly Water-Soluble Drugs	p. 37
2.1 Introduction	p. 37
2.2 Intravenous Administration of Poorly Water-Soluble Compounds (PWSC)	p. 40
2.2.1 Solubilizing Vehicles with Precipitation Risk upon Dilution	p. 41
2.2.2 Solubilizing Vehicles Maintaining Solubilization Capacity upon Dilution	p. 43
2.2.3 Mechanistic Release Aspects/Transfer Liposomal PWSC	p. 45
2.2.4 In Vivo Consequences	p. 52
2.2.5 Preclinical Parenteral Assessment Liposomal PWSC	p. 56
2.3 Conclusion	p. 59
References	p. 60
3 Drug Solubilization and Stabilization of Cyclodextrin Drug Carriers	p. 67
3.1 Introduction	p. 67
3.2 Structure and Physiochemical Properties	p. 68
3.3 Cyclodextrin Complexes and Phase Solubility Diagrams	p. 72
3.4 Cyclodextrin Complexes	p. 76
3.4.1 Self-Assembly of Cyclodextrins and their Complexes	p. 76
3.4.2 Thermodynamic and Driving Forces for Complexation	p. 76
3.5 Effects on Drug Stability	p. 77
3.6 Cyclodextrins and Drug Permeation through Biological Membranes	p. 80
3.7 Drug Solubilization in Pharmaceutical Formulations	p. 82
3.7.1 Oral Drug Delivery	p. 84
3.7.2 Sublingual, Buccal, Nasal, Pulmonary, Rectal and Vaginal Drug Delivery	p. 86
3.7.3 Ophthalmic Drug Delivery	p. 87
3.7.4 Dermal and Transdermal Drug Delivery	p. 87
3.7.5 Injectable Formulations	p. 87
3.7.6 Toxicology and Pharmacokinetics	p. 89
3.8 Regulatory Issues	p. 90
3.9 Conclusion	p. 91
References	p. 91
4 Solid Lipid Nanoparticles for Drug Delivery	p. 103
4.1 Introduction	p. 103
4.2 Preparation Procedures for Solid Lipid Nanoparticles	p. 104
4.2.1 Melt Dispersion Processes	p. 104
4.2.2 Other Top-Down Processes	p. 109
4.2.3 Precipitation from Homogeneous Systems	p. 111
4.2.4 Comparison of the Formulation Procedures and Scale-Up Feasibility	p. 113
4.2.5 Further Processing of Solid Lipid Nanoparticle Suspensions	p. 115
4.3 Structural Parameters and their Influence on Product Quality and Pharmaceutical Performance	p. 116
4.3.1 Particle Size and Size Distribution	p. 116
4.3.2 Surface Properties	p. 117
4.3.3 Solid State Properties of Solid Lipid Nanoparticles	p. 117
4.3.4 Particle Morphology and Overall Structure of the Dispersions	p. 121
4.4 Incorporation of Poorly Soluble Drugs and In Vitro Release	p. 123
4.4.1 Drug Incorporation	p. 123
4.4.2 In Vitro Drug Release	p. 126
4.5 Safety Aspects, Toxicity and Pharmacokinetic Profiles	p. 129
4.5.1 In Vitro Behavior and Toxicity Studies	p. 129
4.5.2 Bioavailability and Pharmacokinetics	p. 131
4.6 Conclusion	p. 133
References	p. 133
5 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs	p. 151
5.1 Introduction	p. 151
5.2 Safety and Biocompatibility of Polymers	p. 152
5.3 Encapsulation Techniques of Hydrophobic Drugs	p. 156
5.3.1 The Nanoprecipitation Method	p. 156
5.3.2 The Emulsification Methods	p. 158
5.3.3 Polymersome Preparation	p. 164
5.3.4 Supercritical Fluid Technology	p. 166
5.3.5 The Polymer-Coating Method	p. 167
5.3.6 The Layer-by-Layer Method	p. 171
5.4 Behavior of Nanocapsules as Drug Delivery Systems	p. 173
5.4.1 Mean Size of Nanocapsules	p. 173
5.4.2 Zeta Potential	p. 173
5.4.3 Encapsulation Efficiency	p. 174
5.4.4 Drug Release Properties	p. 176
5.4.5 General Performance of the Nanoparticles	p. 176
5.5 Conclusion	p. 177
References	p. 180
6 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs	p. 199
6.1 Introduction	p. 199
6.2 Drug Encapsulation by Monomer Polymerization	p. 200
6.2.1 Emulsion Polymerization	p. 201
6.2.2 Interfacial Polymerization	p. 206
6.2.3 Interfacial Polycondensation	p. 207
6.3 Polymeric Nanospheres and Nanocapsules Produced by Polymerization	p. 209
6.4 Formulation Components	p. 210
6.5 Control of Particle Morphology	p. 212
6.6 Toxicity and In Vivo Performance	p. 213
6.7 Scale-Up Considerations	p. 214
6.8 Conclusion	p. 217
Acknowledgements	p. 217
References	p. 217
7 Development of Self-Emulsifying Drug Delivery Systems (SEDDS) for Oral Bioavailability Enhancement of Poorly Soluble Drugs	p. 225
7.1 Introduction	p. 225
7.2 Lipid Processing and Drug Solubilization	p. 226
7.3 Self-Emulsifying Drug Delivery Systems	p. 227
7.3.1 Excipients Used in SEDDS	p. 227
7.3.2 Self-Emulsification Mechanism	p. 228
7.3.3 Physicochemical Characterization of SEDDS	p. 229
7.3.4 Drug Incorporation in SEDDS	p. 231
7.4 In Vitro Digestion Model	p. 232
7.5 Enhancement of Oral Absorption by SEDDS	p. 235
7.6 Conclusion	p. 238
References	p. 239
8 Novel Top Down Technologies: Effective Production of Ultra-Fine Drug Nanocrystals	p. 247
8.1 Introduction: General Benefits of Drug Nanocrystals (First Generation)	p. 247
8.2 Ultra-Fine Drug Nanocrystals (100 Nm) and Their Special Properties	p. 248
8.3 Production of First Generation Nanocrystals: A Brief Overview	p. 250
8.3.1 Hydrosols	p. 250
8.3.2 Nanomorph	p. 251
8.3.3 NanocrystalsTM by Bead Milling	p. 251
8.3.4 DissoCubes R by High Pressure Homogenization	p. 251
8.3.5 NANOEDGE by Baxter	p. 252
8.3.6 Summary of First Generation Production Technologies	p. 252
8.4 Production of Ultra-Fine Drug Nanocrystals: Smartcrystals	p. 252
8.4.1 Fine-Tuned Precipitation	p. 252
8.4.2 The SmartCrystal Concept	p. 253
8.5 Conclusion	p. 259
References	p. 259
9 Nanosuspensions with Enhanced Drug Dissolution Rates of Poorly Water-Soluble Drugs	p. 265
9.1 Introduction	p. 265
9.2 Crystal Growth and Nucleation Theory	p. 266
9.3 Creating Supersaturation and Stable Nanosuspensions	p. 269
9.4 Antisolvent Precipitation Via Mixer Processing	p. 272
9.5 Antisolvent Precipitation by Using Ultrasonication	p. 277
9.6 Nanoprecipitation Using Microfluidic Reactors	p. 278
9.7 Particle Engineering by Spray: Freezing into Liquid	p. 279
9.8 Precipitation by Rapid Expansion from Supercritical to Aqueous Solution	p. 280
9.9 Conclusion	p. 282
References	p. 282
10 Microemulsions for Drug Solubilization and Delivery	p. 287
10.1 Introduction	p. 287
10.2 Microemulsion Formation and Phase Behavior	p. 289
10.2.1 Theories of Microemulsion Formation	p. 289
10.2.2 Structure of Microemulsions	p. 289
10.2.3 Phase Behavior	p. 292
10.3 HLB, PIT and Microemulsion Stability	p. 293
10.4 Microemulsion Physico-Chemical Characterization	p. 293
10.5 Components of Microemulsion Formulations	p. 295
10.5.1 Oils	p. 296
10.5.2 Surfactants	p. 298
10.5.3 Cosurfactants	p. 300
10.5.4 Drugs	p. 302
10.6 Preparation Methods	p. 303
10.7 In Vitro and In Vivo Biological Studies	p. 303
10.7.1 Microemulsions Used as an Oral Delivery System for Poorly Water-Soluble Compounds	p. 303
10.7.2 Microemulsions Used as a Parenteral Delivery System for Poorly Water-Soluble Compounds	p. 311
10.8 Recent Developments and Future Directions	p. 314
10.8.1 Develop Cremophor-Free Microemulsions	p. 314
10.8.2 Dried O/W Emulsions for Oral Delivery of Poorly Soluble Drugs	p. 315
10.8.3 Self-Microemulsifying Drug Delivery System (SMEDDS)	p. 318
References	p. 319
11 Enhancing Drug Solubility and Bioavailability Using Hot Melt Extruded Solid Dispersions	p. 325
11.1 Introduction: Present Challenges to Oral Drug Delivery	p. 325
11.2 Solid Dispersions/Solutions for Enhanced Drug Solubility	p. 327
11.3 Hot Melt Extrusion (HME) as a Drug Delivery Technology	p. 329
11.3.1 Historical Review of HME	p. 329
11.3.2 Equipment	p. 329
11.3.3 Screws' Geometry	p. 331
11.3.4 HME Processing	p. 332
11.3.5 Product Characteristics	p. 335
11.3.6 Materials Commonly Used in HME for Solubility Enhancement	p. 337
11.4 Solubility Enhancement Using HME	p. 340
11.4.1 Product Structure	p. 340
11.4.2 HME Matrix Carriers	p. 341
11.4.3 HME for the Manufacture of Pharmaceutical Co-Crystals	p. 343
11.5 Representative Case Studies with Enhanced Solubility	p. 344
11.5.1 Increased Dissolution Rate Due to Size Reduction or De-Aggregation	p. 344
11.5.2 Increased Dissolution Rate Due to Drug Morphology Change	p. 345
11.5.3 Controlled or Prolonged Release with Enhanced Release Extent	p. 346
11.5.4 Complexation to Enhance Dissolution Performance	p. 346
11.5.5 Co-Crystal Formation	p. 347
11.6 Conclusion	p. 347
References	p. 348
12 Penetration Enhancers, Solvents and the Skin	p. 359
12.1 Introduction	p. 359
12.2 Interactions of Solvents and Enhancers with the Skin	p. 360
12.2.1 Small Solvents	p. 361
12.2.2 Solvents with Longer Carbon Chains	p. 361
12.3 Skin Permeation Enhancement of Ibuprofen	p. 363
12.3.1 Infinite Dose Conditions	p. 364
12.3.2 Finite Dose Conditions	p. 368
12.4 Conclusion	p. 369
References	p. 369
13 Dendrimers for Enhanced Drug Solubilization	p. 373
13.1 Introduction	p. 373
13.2 Current Solubilization Strategies	p. 374
13.3 Origin of Dendrimers	p. 374
13.4 What Are Dendrimers?	p. 375
13.5 Synthesis of Dendritic Architecture	p. 375
13.6 Structure and Intrinsic Properties of Dendrimeric Compartments	p. 377
13.7 Dendrimers in Solubilization	p. 378
13.8 Factors Affecting Dendrimer-Mediated Solubilization and Drug Delivery	p. 381
13.8.1 Nature of the Dendritic Core	p. 381
13.8.2 Dendrimer Generation	p. 382
13.8.3 Nature of the Dendrimer Surface	p. 382
13.8.4 Dendrimer Concentration	p. 382
13.8.5 pH of Solution	p. 383
13.8.6 Temperature	p. 384
13.8.7 Solvents	p. 384
13.9 Drug-Dendrimer Conjugation Approaches	p. 386
13.9.1 Physical Loading: Complexation of Water-Insoluble Drugs	p. 386
13.9.2 Covalent Loading: Synthesis of Drug-Dendrimer Conjugate	p. 389
13.10 Dendrimers' Biocompatibility and Toxicity	p. 393
13.10.1 PEGylation Technology: A Way to Enhance Dendrimer Solubility and Biocompatibility	p. 393
13.11 Classification of PEGylated Dendrimers	p. 394
13.11.1 PEGylated Dendrimer	p. 394
13.11.2 Drug-Conjugated PEGylated Dendrimer	p. 397
13.11.3 PEG Cored Dendrimer	p. 397
13.11.4 PEG Branched Dendrimer	p. 398
13.11.5 PEG-Conjugated Targeted Dendrimer	p. 398
13.12 Conclusion	p. 399
References	p. 400
14 Polymeric Micelles for the Delivery of Poorly Soluble Drugs	p. 411
14.1 Micelles and Micellization	p. 411
14.1.1 Factors Affecting Micellization	p. 413
14.1.2 Thermodynamics of Micellization	p. 414
14.2 Chemical Nature and Formation Mechanism of Polymeric Micelles	p. 416
14.2.1 Core and Corona of the Polymeric Micelles	p. 417
14.2.2 Block Co-Polymers as Building Block of Polymeric Micelles	p. 418
14.3 Polymeric Micelles: Unique Nanomedicine Platforms	p. 419
14.3.1 Polymeric Micelles for the Delivery of Poorly Soluble Drugs	p. 421
14.4 Determination of Physico-Chemical Characteristics of Polymeric Micelles	p. 430
14.4.1 Critical Micelle Concentrations (CMC)	p. 430
14.4.2 Particle Size and Stability	p. 432
14.5 Drug Loading	p. 435
14.5.1 Drug-Loading Procedures	p. 437
14.6 Biodistribution and Toxicity	p. 439
14.7 Targeting Micellar Nanocarriers: Example: Drug Delivery to Tumors	p. 443
14.7.1 Passive Targeting	p. 443
14.7.2 Active Targeting: Functionalized Polymeric Micelles	p. 445
14.8 Site-Specific Micellar-Drug Release Strategies	p. 449
14.9 Intracellular Delivery of Micelles	p. 452
14.10 Multifunctional Micellar Nanocarriers	p. 453
14.11 Conclusion	p. 455
References	p. 455
15 Nanostructured Silicon-Based Materials as a Drug Delivery System for Water-Insoluble Drugs	p. 477
15.1 Introduction	p. 477
15.2 Control of Particle Size and Pore Morphology	p. 478
15.3 Surface Functionalization	p. 482
15.3.1 Stabilization	p. 482
15.3.2 Biofunctionalization	p. 483
15.4 Biocompatibility and Cytotoxicity	p. 485
15.4.1 In Vitro Studies	p. 486
15.4.2 In Vivo and Ex Vivo Studies	p. 490
15.5 Nanostructured Silicon Materials as DDS	p. 492
15.5.1 Drug-Loading Procedures	p. 492
15.5.2 Enhanced Drug Release	p. 495
15.5.3 Intracellular Uptake	p. 500
15.6 Conclusion	p. 502
References	p. 502
16 Micro- and Nanosizing of Poorly Soluble Drugs by Grinding Techniques	p. 509
16.1 Introduction	p. 509
16.2 Kinetics of Drug Dissolution	p. 510
16.3 Micronization and Nanosizing of Drugs	p. 510
16.3.1 Dissolution Enhancement by Micronization and Nanonization	p. 510
16.3.2 Dry and Wet Milling Technologies	p. 511
16.3.3 NanoCrystal R Technology	p. 512
16.4 Theory of Grinding Operations	p. 512
16.4.1 Fraction under Compressive Stress	p. 512
16.4.2 Brittle-Ductile Transition and Grinding Limit	p. 514
16.4.3 Milling Beyond the Brittle-Ductile Transition Limit	p. 516
16.4.4 Fatigue Fracture	p. 517
16.4.5 Agglomeration	p. 517
16.4.6 Amorphization	p. 519
16.5 Influence of the Stabilizer	p. 520
16.5.1 Effects of Stabilization	p. 520
16.5.2 Steric and Electrostatic Stabilization	p. 521
16.5.3 Surfactants	p. 523
16.5.4 Polymers	p. 527
16.6 Milling Equipment and Technology	p. 527
16.6.1 Grinding Beads	p. 527
16.6.2 Types of Media Mills	p. 528
16.6.3 Process Parameters	p. 532
16.7 Process Development from Laboratory to Commercial Scale	p. 535
16.7.1 Early Development	p. 535
16.7.2 Toxicological Studies	p. 535
16.7.3 Clinical Studies	p. 536
16.7.4 Drying	p. 536
16.7.5 Further Processing of Drug Nanoparticles	p. 536
16.8 Application and Biopharmaceutical Properties	p. 537
16.8.1 Oral Drug Delivery	p. 538
16.8.2 Parenteral Drug Delivery	p. 540
16.8.3 Extracorporal Therapy	p. 542
16.9 Conclusion	p. 543
References	p. 543
17 Enhanced Solubility of Poorly Soluble Drugs Via Spray Drying	p. 551
17.1 Introduction	p. 551
17.2 Advantages of Spray Drying	p. 553
17.3 Principles and Instrumentation of Spray Drying Processes	p. 553
17.3.1 Principal Function of a Spray Dryer	p. 553
17.3.2 Traditional Spray Dryers	p. 558
17.3.3 Recent Developments in Spray Drying	p. 561
17.4 Optimizing Spray Drying Process Parameters	p. 563
17.4.1 Drying Gas Flow Rate (Aspirator Rate)	p. 563
17.4.2 Drying Gas Humidity	p. 563
17.4.3 Inlet Temperature	p. 564
17.4.4 Spray Gas Flow	p. 565
17.4.5 Feed Concentration	p. 565
17.4.6 Feed Rate	p. 565
17.4.7 Organic Solvent Instead of Water	p. 566
17.5 Spray Drying of Water-Insoluble Drugs: Case Studies	p. 566
17.5.1 Nanosuspensions	p. 566
17.5.2 Solid Lipid Nanoparticles	p. 567
17.5.3 Silica-Lipid Hybrid Microcapsules	p. 568
17.5.4 Milled Nanoparticles	p. 570
17.5.5 Inhalation Dosage Forms	p. 571
17.5.6 Porous Products	p. 572
17.5.7 Microemulsions	p. 572
17.5.8 Application Examples: Summary	p. 575
17.6 Conclusion	p. 582
References	p. 583
Index	p. 000

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