Molecular biopharmaceutics : aspects of drug characterisation, drug delivery, and dosage form evaluation

This is an introductory textbook on molecular biopharmaceutics. "Molecular Biopharmaceutics" involves the study of drug absorption, transport and delivery at the molecular level. In particular, increasing knowledge of the molecular structure and function of membrane transporter proteins and the understanding that they play a significant role in drug transport across biological membranes has lead to growing interest in this area from the pharmaceutical industry. This emerging knowledge of membrane transporter proteins has implications for understanding drug disposition and in turn for the development of more effective drug delivery strategies. The text provides an overview of the field of molecular biopharmaceutics, and explains its importance in drug development. It focuses on describing the interplay between the chemistry of drug molecules and membrane transporters, and will guide researchers in setting up experiments that may help in understanding the mechanisms and kinetics involved in drug absorption, transport and delivery.

Author Notes

Bente Steffansen, Birger Brodin and Carsten Uhd Nielsen are Associate Professors at the Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark.

Benle Steffansen and Carsten Uhd Nielsen and Birger BrodinBente Steffansen and Carsten Uhd Nielsen and Birger BrodinBente Steffansen and Carsten Uhd Nielsen and Birger BrodinBente Steffansen and Carsten Uhd Nielsen and Birger BrodinKristina Luthman and Bente SteffansenHeidi Lopez de DiegoBirger Brodin and Bente Steffonsen and Carsten Uhd NielsenBirger Brodin and Bente Steffansen and Carsten Uhd NielsenCarsten Uhd Nielsen and Bente Steffansen and Birger BrodinPascale AnderléCarsten Uhd Nielsen and Bente Steffansen and Birger BrodinCarsten Uhd Nielsen and Birger Brodin and Bente SteffansenAnna-Lena UngellBetty Lomstein Pedersen and Anette MüllertzChi-Yuan WuIsabel Gonzalez-Alvarez and Marival Bermejo

ULLA pharmacy series	p. x
Preface	p. xi
About the editors	p. xii
Contributors	p. xiv
Abbreviations	p. xv
Part 1 Introduction	p. 1
1.1 Molecular biopharmaceutics	p. 1
1.2 Important definitions and terms	p. 1
1.3 Experimental methods within molecular biopharmaceutics	p. 2
1.4 Classification of drug substances	p. 2
1.5 The book chapters	p. 3
References	p. 4
Part 2 Physicochemical characterisation of drug candidates	p. 5
2.1 Acid/base properties, solubility and distribution of drug candidates	p. 7
2.1.1 Acid/base properties of drug candidates	p. 7
2.1.2 Solubility in aqueous solution	p. 18
2.1.3 Partition properties of drug candidates	p. 23
2.1.4 Solvation and solid-state limited solubility	p. 28
2.1.5 Solid-state characterisation	p. 29
2.1.6 Conclusions	p. 31
References	p. 31
2.2 Mechanisms of decomposition of drug candidates	p. 35
2.2.1 Hydrolysis	p. 3
2.2.2 Oxidation	p. 43
2.2.3 Non-oxidative photolytic degradation	p. 46
2.2.4 Degradation by racemisation	p. 47
2.2.5 Polymerisation	p. 47
2.2.6 Conclusions	p. 48
References	p. 48
2.3 Kinetics of decomposition in aqueous solution	p. 51
2.3.1 First-order and pseudo zero-order kinetics of irreversible reactions	p. 52
2.3.2 Second-order and pseudo first-order kinetics of irreversible reactions	p. 54
2.3.3 Pseudo first-order kinetics of reversible reactions	p. 57
2.3.4 Pseudo first-order reactions of irreversible consecutive reactions	p. 59
2.3.5 Influence of pH on decomposition rate	p. 60
2.3.6 Influence of temperature on decomposition rale	p. 62
2.3.7 Influence of ionic strength on decomposition rate	p. 64
2.3.8 Influence of buffers on decomposition rate	p. 66
2.3.9 Influence of enzymes on decomposition rote	p. 67
2.3.10 Conclusions	p. 68
References	p. 69
2.4 Chemical approaches to improving bioavailability properties of oral drug candidates	p. 71
2.4.1 Lipinski's rule of five	p. 71
2.4.2 Salt formation	p. 72
2.4.3 Bioisosteric replacement	p. 76
2.4.4 Prodrug formation	p. 84
2.4.5 Conclusions	p. 97
References	p. 98
2.5 Preformulation in the industry step by step	p. 101
2.5.1 Early discovery	p. 102
2.5.2 Lead optimisation	p. 104
2.5.3 Late discovery	p. 105
2.5.4 Early development	p. 106
2.5.5 Full development	p. 111
Part 3 Membrane transport of drug candidates	p. 113
3.1 Structure and function of absorption barriers	p. 115
3.1.1 Epithelial morphology	p. 115
3.1.2 The epithelial cell and tight junctions	p. 117
3.1.3 The gastrointestinal tissue barriers	p. 118
3.1.4 The respiratory tract	p. 123
3.1.5 The skin	p. 125
3.1.6 Barrier tissues in the brain	p. 126
3.1.7 The eye	p. 129
3.1.8 Conclusions	p. 131
References	p. 131
3.2 Passive diffusion of drug substances: the concepts of flux and permeability	p. 135
3.2.1 How do molecules move in solution? The concepts of flux, migration and diffusion	p. 135
3.2.2 Fluxes across barriers and the permeability coefficient	p. 137
3.2.3 Unstirred water layers	p. 141
3.2.4 Fluxes across a barrier under non-steady-state conditions	p. 142
3.2.5 Fluxes of a charged solute in the presence of an electrical potential gradient	p. 144
3.2.6 Use of flux ratios to analyse transport mechanisms	p. 145
3.2.7 Conclusions	p. 146
3.2.8 Examples	p. 147
References	p. 151
3.3 Carrier-mediated transport kinetics	p. 153
3.3.1 Carrier function and mechanisms	p. 154
3.3.2 Description of carrier-mediated transport kinetics	p. 160
3.3.3 Methods for studying transport via carriers	p. 171
3.3.4 Conclusions	p. 173
References	p. 173
3.4 Classification of human transporters	p. 175
3.4.1 Classification according to transport mechanisms	p. 177
3.4.2 Transporter classification system	p. 180
3.4.3 Gene ontology	p. 183
3.4.4 Human Genome Organization (HUGO) symbols	p. 185
3.4.5 Pfam	p. 186
3.4.6 Practical approach: SLC15A1 and ABCB1	p. 186
3.4.7 Conclusions	p. 191
References	p. 191
3.5 Absorptive transporters	p. 193
3.5.1 Searching for absorptive transporters	p. 194
3.5.2 Conclusions	p. 210
References	p. 211
3.6 Efflux transporters	p. 213
3.6.1 ATP-binding cassette (ABC) transport proteins in the intestine	p. 214
3.6.2 Efflux transporters in the liver	p. 218
3.6.3 Efflux transporters in the kidney	p. 219
3.6.4 Efflux transporters in the brain	p. 221
3.6.5 Conclusions	p. 222
References	p. 222
3.7 Preclinical evaluation of drug transport	p. 225
3.7.1 Mechanisms of drug transport across membranes	p. 226
3.7.2 Tools to assess drug transport during phases of drug discovery	p. 228
3.7.3 Cell cultures	p. 232
3.7.4 Optimising experimental conditions	p. 238
3.7.5 Screening for transporter interaction	p. 239
3.7.6 Influence of metabolism during transport	p. 242
3.7.7 Use of preclinical models for prediction of drug transport in humans	p. 243
3.7.8 The Biopharmaceutics Classification System	p. 245
References	p. 247
Part 4 Describing and predicting bioavailability	p. 255
4.1 In vitro dissolution	p. 257
4.1.1 Dissolution mechanism theories	p. 258
4.1.2 Factors influencing dissolution in vitro	p. 260
4.1.3 Factors influencing dissolution in vivo	p. 261
4.1.4 Dissolution equipment described in the pharmacopoeias	p. 265
4.1.5 Selection of dissolution media for in vitro dissolution studies	p. 269
4.1.6 Conclusions	p. 272
References	p. 273
4.2 The Biopharmaceutics Classification System in drug discovery and development	p. 277
4.2.1 Prediction of oral drug absorption	p. 279
4.2.2 Application of the Biopharmaceutics Classification System	p. 285
4.2.3 The Biopharmaceutics Drug Disposition Classification System	p. 291
References	p. 295
4.3 Biosimularion studies	p. 297
4.3.1 What is modelling and simulation?	p. 297
4.3.2 How to construct and verify a model	p. 300
4.3.3 How can a biosimulation model be applied for preclinical investigations and dosage form development?	p. 301
4.3.4 Conclusions	p. 329
Appendix 4.3.1 Objective functions	p. 330
Appendix 4.3.2 How does non-linear regression work?	p. 332
Appendix 4.3.3 Software tools, companies and institutions developing biosimulation packages	p. 339
References	p. 340
Index	p. 347

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