Molecular biopharmaceutics : aspects of drug characterisation, drug delivery, and dosage form evaluation / edited by Bente Steffansen, Birger Brodin, Carsten Uhd Nielsen.

Format:

Book

Contributor:

Steffansen, Bente.

Brodin, Birger.

Nielsen, Carsten Uhd.

Series:

ULLA postgraduate pharmacy series

ULLA pharmacy series

Language:

English

Subjects (All):

Biopharmaceutics.

Chemistry, Pharmaceutical.

Drug Discovery.

Pharmaceutical chemistry.

Drug development.

Medical Subjects:

Biopharmaceutics.

Chemistry, Pharmaceutical.

Drug Discovery.

Physical Description:

xviii, 371 pages : illustrations ; 24 cm.

Place of Publication:

Chicago ; London : Pharmaceutical Press, [2010]

Summary:

Molecular Biopharmaceutics covers a complex and developing scientific area, comprehensively encapsulating the essentials of the interplay between the chemistry of drug molecules and membrane transporters. It also aims to guide researchers in setting up experiments that may help in understanding the mechanisms and kinetics involved in transport-drug absorption and delivery. Molecular Biopharmaceutics considers the following aspects of understanding bioavailability by:

physicochemical characterisation

membrane transport

biosimulation methods.

These issues are of increasing importance in drug development. Molecular Biopharmaceutics will be an invaluable resource for postgraduate pharmaceutical science students, biopharmaceutical scholars, scientists within academia and industrial pharmaceutical development.

Contents:

Part 1 Introduction / Benle Steffansen, Carsten Uhd Nielsen, Birger Brodin 1

1.1 Molecular biopharmaceutics 1

1.2 Important definitions and terms 1

1.3 Experimental methods within molecular biopharmaceutics 2

1.4 Classification of drug substances 2

1.5 The book chapters 3

References 4

Part 2 Physicochemical characterisation of drug candidates 5

2.1 Acid/base properties, solubility and distribution of drug candidates / Bente Steffansen, Carsten Uhd Nielsen, Birger Brodin 7

2.1.1 Acid/base properties of drug candidates 7

2.1.2 Solubility in aqueous solution 18

2.1.3 Partition properties of drug candidates 23

2.1.4 Solvation and solid-state limited solubility 28

2.1.5 Solid-state characterisation 29

2.1.6 Conclusions 31

References 31

2.2 Mechanisms of decomposition of drug candidates / Bente Steffansen, Carsten Uhd Nielsen, Birger Brodin 35

2.2.1 Hydrolysis 3

2.2.2 Oxidation 43

2.2.3 Non-oxidative photolytic degradation 46

2.2.4 Degradation by racemisation 47

2.2.5 Polymerisation 47

2.2.6 Conclusions 48

References 48

2.3 Kinetics of decomposition in aqueous solution / Bente Steffansen, Carsten Uhd Nielsen, Birger Brodin 51

2.3.1 First-order and pseudo zero-order kinetics of irreversible reactions 52

2.3.2 Second-order and pseudo first-order kinetics of irreversible reactions 54

2.3.3 Pseudo first-order kinetics of reversible reactions 57

2.3.4 Pseudo first-order reactions of irreversible consecutive reactions 59

2.3.5 Influence of pH on decomposition rate 60

2.3.6 Influence of temperature on decomposition rale 62

2.3.7 Influence of ionic strength on decomposition rate 64

2.3.8 Influence of buffers on decomposition rate 66

2.3.9 Influence of enzymes on decomposition rote 67

2.3.10 Conclusions 68

References 69

2.4 Chemical approaches to improving bioavailability properties of oral drug candidates / Kristina Luthman, Bente Steffansen 71

2.4.1 Lipinski's rule of five 71

2.4.2 Salt formation 72

2.4.3 Bioisosteric replacement 76

2.4.4 Prodrug formation 84

2.4.5 Conclusions 97

References 98

2.5 Preformulation in the industry step by step / Heidi Lopez de Diego 101

2.5.1 Early discovery 102

2.5.2 Lead optimisation 104

2.5.3 Late discovery 105

2.5.4 Early development 106

2.5.5 Full development 111

Part 3 Membrane transport of drug candidates 113

3.1 Structure and function of absorption barriers / Birger Brodin, Bente Steffonsen, Carsten Uhd Nielsen 115

3.1.1 Epithelial morphology 115

3.1.2 The epithelial cell and tight junctions 117

3.1.3 The gastrointestinal tissue barriers 118

3.1.4 The respiratory tract 123

3.1.5 The skin 125

3.1.6 Barrier tissues in the brain 126

3.1.7 The eye 129

3.1.8 Conclusions 131

References 131

3.2 Passive diffusion of drug substances: the concepts of flux and permeability / Birger Brodin, Bente Steffansen, Carsten Uhd Nielsen 135

3.2.1 How do molecules move in solution? The concepts of flux, migration and diffusion 135

3.2.2 Fluxes across barriers and the permeability coefficient 137

3.2.3 Unstirred water layers 141

3.2.4 Fluxes across a barrier under non-steady-state conditions 142

3.2.5 Fluxes of a charged solute in the presence of an electrical potential gradient 144

3.2.6 Use of flux ratios to analyse transport mechanisms 145

3.2.7 Conclusions 146

3.2.8 Examples 147

References 151

3.3 Carrier-mediated transport kinetics / Carsten Uhd Nielsen, Bente Steffansen, Birger Brodin 153

3.3.1 Carrier function and mechanisms 154

3.3.2 Description of carrier-mediated transport kinetics 160

3.3.3 Methods for studying transport via carriers 171

3.3.4 Conclusions 173

References 173

3.4 Classification of human transporters / Pascale Anderľ 175

3.4.1 Classification according to transport mechanisms 177

3.4.2 Transporter classification system 180

3.4.3 Gene ontology 183

3.4.4 Human Genome Organization (HUGO) symbols 185

3.4.5 Pfam 186

3.4.6 Practical approach: SLC15A1 and ABCB1 186

3.4.7 Conclusions 191

References 191

3.5 Absorptive transporters / Carsten Uhd Nielsen, Bente Steffansen, Birger Brodin 193

3.5.1 Searching for absorptive transporters 194

3.5.2 Conclusions 210

References 211

3.6 Efflux transporters / Carsten Uhd Nielsen, Birger Brodin, Bente Steffansen 213

3.6.1 ATP-binding cassette (ABC) transport proteins in the intestine 214

3.6.2 Efflux transporters in the liver 218

3.6.3 Efflux transporters in the kidney 219

3.6.4 Efflux transporters in the brain 221

3.6.5 Conclusions 222

References 222

3.7 Preclinical evaluation of drug transport / Anna-Lena Ungell 225

3.7.1 Mechanisms of drug transport across membranes 226

3.7.2 Tools to assess drug transport during phases of drug discovery 228

3.7.3 Cell cultures 232

3.7.4 Optimising experimental conditions 238

3.7.5 Screening for transporter interaction 239

3.7.6 Influence of metabolism during transport 242

3.7.7 Use of preclinical models for prediction of drug transport in humans 243

3.7.8 The Biopharmaceutics Classification System 245

References 247

Part 4 Describing and predicting bioavailability 255

4.1 In vitro dissolution / Betty Lomstein Pedersen, Anette Müllertz 257

4.1.1 Dissolution mechanism theories 258

4.1.2 Factors influencing dissolution in vitro 260

4.1.3 Factors influencing dissolution in vivo 261

4.1.4 Dissolution equipment described in the pharmacopoeias 265

4.1.5 Selection of dissolution media for in vitro dissolution studies 269

4.1.6 Conclusions 272

References 273

4.2 The Biopharmaceutics Classification System in drug discovery and development / Chi-Yuan Wu 277

4.2.1 Prediction of oral drug absorption 279

4.2.2 Application of the Biopharmaceutics Classification System 285

4.2.3 The Biopharmaceutics Drug Disposition Classification System 291

References 295

4.3 Biosimularion studies / Isabel Gonzalez-Alvarez, Marival Bermejo 297

4.3.1 What is modelling and simulation? 297

4.3.2 How to construct and verify a model 300

4.3.3 How can a biosimulation model be applied for preclinical investigations and dosage form development? 301

4.3.4 Conclusions 329

References 340.

Notes:

Includes bibliographical references and index.

ISBN:

9780853697220

0853697221

OCLC:

488979418