Pharmaceutics
`Pharmaceutics
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`The Science of Dosage Form Design
`The Science of Dosage Form Design
`
`Edited by
`Edited by
`Michael E. Aulton BPharm PhD FAAPS MRPharmS
`Michael E. Aulton BPharm PhD FAAPS MRPharmS
`Professor of Pharmaceutical Technology,
`Professor of Pharmaceutical Technology,
`School of Pharmacy,
`School of Pharmacy,
`De Montfort University,
`De Montfort University,
`Leicester, UK
`Leicester, UK
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`SECOND EDITION
`SECOND EDITION
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`ACHURCHILL
`14 CHURCHILL
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`maw+ (cid:9)
`wailiff~" (cid:9)
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`LIVINGSTONE
`LI V I N GSTO N E
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`EDINBURGH LONDON NEW YORK PHILADELPHIA ST LOUIS SYDNEY TORONTO 2002
`EDINBURGH LONDON NEW YORK PHILADELPHIA ST LOUIS SYDNEY TORONTO 2002
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`Ex. 1097 - Page 1
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`CHURCHILL LIVINGSTONE CHURCHILL LIVINGSTONE
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`An imprint of Harcourt Publishers Limited An imprint of Harcourt Publishers Limited
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`
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`© Harcourt Publishers Limited 2002 © Harcourt Publishers Limited 2002
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`,d) is a registered trademark of Harcourt Publishers Limited ,d) is a registered trademark of Harcourt Publishers Limited
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`All rights reserved. No part of this publication may be All rights reserved. No part of this publication may be
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`reproduced, stored in a retrieval system, or transmitted in any reproduced, stored in a retrieval system, or transmitted in any
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`form or by any means, electronic, mechanical, photocopying, form or by any means, electronic, mechanical, photocopying,
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`recording or otherwise, without either the prior permission of recording or otherwise, without either the prior permission of
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`the publishers (Harcourt Publishers Limited, Harcourt Place, the publishers (Harcourt Publishers Limited, Harcourt Place,
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`32 Jamestown Road, London NW1 7BY), or a licence 32 Jamestown Road, London NW1 7BY), or a licence
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`permitting restricted copying in the United Kingdom issued permitting restricted copying in the United Kingdom issued
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`by the Copyright Licensing Agency, 90 Tottenham Court by the Copyright Licensing Agency, 90 Tottenham Court
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`Road, London W1P OLP. Road, London W1P OLP.
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`First published 1988 First published 1988
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`Second Edition 2002 Second Edition 2002
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`
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`Standard edition ISBN 0 443 05517 3 Standard edition ISBN 0 443 05517 3
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`
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`International Student Edition ISBN 0 443 05550 5 International Student Edition ISBN 0 443 05550 5
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`British Library Cataloguing in Publication Data British Library Cataloguing in Publication Data
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`A catalogue record for this book is available from the British A catalogue record for this book is available from the British
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`Library Library
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`Library of Congress Cataloging in Publication Data Library of Congress Cataloging in Publication Data
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`A catalog record for this book is available from the Library of A catalog record for this book is available from the Library of
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`Congress Congress
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`Note Note
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`Medical knowledge is constantly changing. As new Medical knowledge is constantly changing. As new
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`information becomes available, changes in treatment, information becomes available, changes in treatment,
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`procedures, equipment and the use of drugs become procedures, equipment and the use of drugs become
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`necessary. The editor, contributors and the publishers have necessary. The editor, contributors and the publishers have
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`taken care to ensure that the information given in this text is taken care to ensure that the information given in this text is
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`accurate and up to date. However, readers are strongly accurate and up to date. However, readers are strongly
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`advised to confirm that the information, especially with advised to confirm that the information, especially with
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`regard to drug usage, complies with the latest legislation and regard to drug usage, complies with the latest legislation and
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`standards of practice. standards of practice.
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`The The
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`publisher's publisher's
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`policy is to use policy is to use
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`paper manufactured paper manufactured
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`from sustainable forests from sustainable forests
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`Printed in Spain Printed in Spain
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`Ex. 1097 - Page 2
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`Contents Contents
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`What is 'Pharmaceutics'? xiii What is 'Pharmaceutics'? xiii
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`1. The design of dosage forms 1 1. The design of dosage forms 1
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`Peter York Peter York
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`PART ONE PART ONE
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`Scientific principles of dosage form Scientific principles of dosage form
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`design 13 design 13
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`2. Dissolution and solubility 15 2. Dissolution and solubility 15
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`Michael Aulton Michael Aulton
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`3. Properties of solutions 33 3. Properties of solutions 33
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`Michael Aulton Michael Aulton
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`4. Rheology 41 4. Rheology 41
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`Chris Marriott Chris Marriott
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`5. Surface and interfacial phenomena 59 5. Surface and interfacial phenomena 59
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`John Fell John Fell
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`6. Disperse systems 70 6. Disperse systems 70
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`David Attwood David Attwood
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`7. Kinetics and product stability 101 7. Kinetics and product stability 101
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`John Pugh John Pugh
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`8. Pharmaceutical preformulation 113 8. Pharmaceutical preformulation 113
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`James Wells James Wells
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`PART TWO PART TWO
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`Particle science and powder Particle science and powder
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`technology 139 technology 139
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`9. Solid-state properties 141 9. Solid-state properties 141
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`Graham Buckton Graham Buckton
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`10. Particle-size analysis 152 10. Particle-size analysis 152
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`John Staniforth John Staniforth
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`11. Particle-size reduction 166 11. Particle-size reduction 166
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`John Staniforth John Staniforth
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`12. Particle-size separation 174 12. Particle-size separation 174
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`John Staniforth John Staniforth
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`13. Mixing 181 13. Mixing 181
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`Andrew Twitchell Andrew Twitchell
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`14. Powder flow 197 14. Powder flow 197
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`John Stanzforth John Stanzforth
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`PART THREE PART THREE
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`Biopharmaceutical principles of drug Biopharmaceutical principles of drug
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`delivery 211 delivery 211
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`15. Introduction to biopharmaceutics 213 15. Introduction to biopharmaceutics 213
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`Marianne Ashford Marianne Ashford
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`16. The gastrointestinal tract — physiology and 16. The gastrointestinal tract — physiology and
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`drug absorption 217 drug absorption 217
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`Marianne Ashford Marianne Ashford
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`17. Bioavailability — physicochemical and 17. Bioavailability — physicochemical and
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`dosage form factors 234 dosage form factors 234
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`Marianne Ashford Marianne Ashford
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`18. Assessment of biopharmaceutical 18. Assessment of biopharmaceutical
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`properties 253 properties 253
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`Marianne Ashford Marianne Ashford
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`19. Dosage regimens 275 19. Dosage regimens 275
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`Stuart Proudfoot, (updated by John Collett) Stuart Proudfoot, (updated by John Collett)
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`20. Modified-release peroral dosage form 289 20. Modified-release peroral dosage form 289
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`John Collett, Chris Moreton John Collett, Chris Moreton
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`PART FOUR PART FOUR
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`Dosage form design and Dosage form design and
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`manufacture 307 manufacture 307
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`21. Solutions 309 21. Solutions 309
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`Michael Billany Michael Billany
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`22. Clarification 323 22. Clarification 323
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`Andrew Twitchell Andrew Twitchell
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`23. Suspensions and emulsions 334 23. Suspensions and emulsions 334
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`Michael Billany Michael Billany
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`Ex. 1097 - Page 3
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`CONTENTS CONTENTS
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`24. Powders and granules 360 24. Powders and granules 360
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`Malcolm Summers Malcolm Summers
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`25. Granulation 364 25. Granulation 364
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`Malcolm Summers, Michael Aulton Malcolm Summers, Michael Aulton
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`26. Drying 379 26. Drying 379
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`Michael Aulton Michael Aulton
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`27. Tablets and compaction 397 27. Tablets and compaction 397
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`Goran Alderborn Goran Alderborn
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`28. Coating of tablets and 28. Coating of tablets and
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`multiparticulates 441 multiparticulates 441
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`John Hogan John Hogan
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`29. Hard gelatin capsules 449 29. Hard gelatin capsules 449
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`Brian Jones Brian Jones
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`30. Soft gelatin capsules 461 30. Soft gelatin capsules 461
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`Keith Hutchison, Josephine Ferdinando Keith Hutchison, Josephine Ferdinando
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`31. Pulmonary drug delivery 473 31. Pulmonary drug delivery 473
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`Kevin Taylor Kevin Taylor
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`32. Nasal drug delivery 489 32. Nasal drug delivery 489
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`Peter Taylor Peter Taylor
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`33. Transdermal drug delivery 499 33. Transdermal drug delivery 499
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`Brian Barry Brian Barry
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`34. Rectal and vaginal drug delivery 534 34. Rectal and vaginal drug delivery 534
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`Josef Tukker Josef Tukker
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`35. Delivery of pharmaceutical proteins 544 35. Delivery of pharmaceutical proteins 544
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`Daan Crommelin, Ewoud van Winden Daan Crommelin, Ewoud van Winden
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`Albert Mekking Albert Mekking
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`36. Packs and packaging 554 36. Packs and packaging 554
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`Dixie Dean Dixie Dean
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`37. Pharmaceutical plant design 571 37. Pharmaceutical plant design 571
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`Michael Aulton, Andrew Twitchell Michael Aulton, Andrew Twitchell
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`38. Heat transfer and the properties and use 38. Heat transfer and the properties and use
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`of steam 586 of steam 586
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`Andrew Twitchell Andrew Twitchell
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`PART FIVE PART FIVE
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`Pharmaceutical microbiology 597 Pharmaceutical microbiology 597
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`39. Fundamentals of microbiology 599 39. Fundamentals of microbiology 599
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`Geoff Hanlon Geoff Hanlon
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`40. Pharmaceutical applications of 40. Pharmaceutical applications of
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`microbiological techniques 623 microbiological techniques 623
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`Norman Hodges Norman Hodges
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`41. The action of physical and chemical agents 41. The action of physical and chemical agents
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`on microorganisms 643 on microorganisms 643
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`Geoff Hanlon, Norman Hodges Geoff Hanlon, Norman Hodges
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`42. Microbiological contamination and 42. Microbiological contamination and
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`preservation of pharmaceutical preservation of pharmaceutical
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`products 658 products 658
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`Malcolm Parker, Norman Hodges Malcolm Parker, Norman Hodges
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`Index 669 Index 669
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`Ex. 1097 - Page 4
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`19 19
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`Dosage regimens Dosage regimens
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`Stuart Proudfoot (updated by John Collett) Stuart Proudfoot (updated by John Collett)
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`CHAPTER. CONTENTS CHAPTER. CONTENTS
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`Dosage regimens: their influence on the Dosage regimens: their influence on the
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`concentration—time profile of a drug in the concentration—time profile of a drug in the
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`body 275 body 275
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`One-compartment open model of drug disposition One-compartment open model of drug disposition
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`in the body 276 in the body 276
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`Rate of drug input versus rate of drug output 276 Rate of drug input versus rate of drug output 276
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`Elimination rate constant and biological half-life of a Elimination rate constant and biological half-life of a
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`drug 277 drug 277
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`Concentration—time curve of a drug in the body Concentration—time curve of a drug in the body
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`following the: peroral administration of equal following the: peroral administration of equal
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`doses of a drug at fixed intervals of time 278 doses of a drug at fixed intervals of time 278
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`important faCtors influencing iteady-state Plaarria important faCtors influencing iteady-state Plaarria
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`drug concentrations 261 drug concentrations 261
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`,Dose size and frequency of adMinistration p281 ,Dose size and frequency of adMinistration p281
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`Size of dose 281 Size of dose 281
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`interval between successive equal doses 281 interval between successive equal doses 281
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`Summary of the effects of dose size and Summary of the effects of dose size and
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`frequency of administration 282 frequency of administration 282
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`The concept of `loading doses' 284 The concept of `loading doses' 284
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`Influence of changes in the apparent elimination Influence of changes in the apparent elimination
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`rate constant of a. drUg: the problem of patients rate constant of a. drUg: the problem of patients
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`with renal impairment 285 with renal impairment 285
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`Influence of the `overnight no-dose period' 286 Influence of the `overnight no-dose period' 286
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`Concluding comments 287 Concluding comments 287
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`Bibliography 288 Bibliography 288
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`3 3
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`2 2
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`DOSAGE REGIMENS: THEIR INFLUENCE DOSAGE REGIMENS: THEIR INFLUENCE
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`ON THE CONCENTRATION-TIME ON THE CONCENTRATION-TIME
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`PROFILE OF A DRUG IN THE BODY PROFILE OF A DRUG IN THE BODY
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`The subject of dosage regimens is concerned with The subject of dosage regimens is concerned with
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`the dose, time of administration and drug plasma the dose, time of administration and drug plasma
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`levels factors associated with multiple dosing of a levels factors associated with multiple dosing of a
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`drug. The influence that physiological factors, the drug. The influence that physiological factors, the
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`physicochemical properties of a drug and dosage physicochemical properties of a drug and dosage
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`form factors can have in determining whether a form factors can have in determining whether a
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`therapeutically effective concentration of a drug is therapeutically effective concentration of a drug is
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`achieved in the plasma following peroral adminis-achieved in the plasma following peroral adminis-
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`tration of a single dose of drug has been discussed tration of a single dose of drug has been discussed
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`previously in Chapters 16, 17 and 18. previously in Chapters 16, 17 and 18.
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`Some drugs, such as hypnotics, analgesics and Some drugs, such as hypnotics, analgesics and
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`antiemetics, may provide effective treatment follow-antiemetics, may provide effective treatment follow-
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`ing the administration of a single dose. However, ing the administration of a single dose. However,
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`the duration of most illnesses is longer than the the duration of most illnesses is longer than the
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`therapeutic effect produced by the administration therapeutic effect produced by the administration
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`of a single dose of a drug in a conventional dosage of a single dose of a drug in a conventional dosage
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`form, i.e. a dosage form which is formulated to give form, i.e. a dosage form which is formulated to give
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`rapid and complete drug release. In such cases rapid and complete drug release. In such cases
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`doses are usually administered on a repetitive basis doses are usually administered on a repetitive basis
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`over a period of time determined by the nature of over a period of time determined by the nature of
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`the illness. For instance, one 250 mg ampicillin the illness. For instance, one 250 mg ampicillin
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`capsule may be administered every 6 hours for a capsule may be administered every 6 hours for a
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`period of 5 days to treat a bacterial infection. Such period of 5 days to treat a bacterial infection. Such
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`a regimen, in which the total dose of drug (i.e. in a regimen, in which the total dose of drug (i.e. in
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`this example 5 g) administered over 5 days is given this example 5 g) administered over 5 days is given
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`in the form of multiple doses (i.e. each of 250 mg) in the form of multiple doses (i.e. each of 250 mg)
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`at given intervals of time (i.e. every 6 hours) is at given intervals of time (i.e. every 6 hours) is
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`known as a multiple-dosage regimen. known as a multiple-dosage regimen.
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`The proper selection of both the dose size and the The proper selection of both the dose size and the
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`frequency of administration is an important factor frequency of administration is an important factor
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`that influences whether a satisfactory therapeutic that influences whether a satisfactory therapeutic
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`plasma concentration is achieved and maintained plasma concentration is achieved and maintained
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`over the prescribed course of treatment. Thus the over the prescribed course of treatment. Thus the
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`design of a multiple-dosage regimen is crucial to design of a multiple-dosage regimen is crucial to
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`successful drug therapy. successful drug therapy.
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`275 275
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`Ex. 1097 - Page 5
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`BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY
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`ONE-COMPARTMENT OPEN MODEL OF ONE-COMPARTMENT OPEN MODEL OF
`DRUG DISPOSITION IN THE BODY
`DRUG DISPOSITION IN THE BODY
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`In order to understand how the design of a dosage In order to understand how the design of a dosage
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`regimen can influence the time course of a drug in regimen can influence the time course of a drug in
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`the body, as measured by its plasma concentration—the body, as measured by its plasma concentration—
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`time curve, consider that the complex kinetic time curve, consider that the complex kinetic
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`processes of drug input, output and distribution in processes of drug input, output and distribution in
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`the body may be represented by the pharmacokinetic the body may be represented by the pharmacokinetic
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`model of drug disposition, the one-compartment model of drug disposition, the one-compartment
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`open model, shown in Figure 19.1. In this case the open model, shown in Figure 19.1. In this case the
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`drug is considered to be distributed instantly drug is considered to be distributed instantly
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`throughout the whole body following its release throughout the whole body following its release
`and absorption from the dosage form. Thus the
`and absorption from the dosage form. Thus the
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`body behaves as a single compartment in body behaves as a single compartment in
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`which absorbed drug is distributed so rapidly that which absorbed drug is distributed so rapidly that
`a concentration equilibrium exists at any given
`a concentration equilibrium exists at any given
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`time between the plasma, other body fluids, time between the plasma, other body fluids,
`and the tissues into which the drug has become
`and the tissues into which the drug has become
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`distributed. distributed.
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`To assume that the body behaves as one-To assume that the body behaves as one-
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`compartment open model does not necessarily compartment open model does not necessarily
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`mean that the drug concentrations in all mean that the drug concentrations in all
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`body tissues at any given time are equal. The model body tissues at any given time are equal. The model
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`does assume, however, that any changes that does assume, however, that any changes that
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`occur in the plasma reflect quantitatively changes occur in the plasma reflect quantitatively changes
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`occurring in the concentration of drug at the site(s) occurring in the concentration of drug at the site(s)
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`of action. of action.
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`Rate of drug input versus rate of drug Rate of drug input versus rate of drug
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`output output
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`In a one-compartment open model, the overall In a one-compartment open model, the overall
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`kinetic processes of drug input and drug output are kinetic processes of drug input and drug output are
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`described by first-order kinetics. In the case of a described by first-order kinetics. In the case of a
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`perorally administered dosage form, the process of perorally administered dosage form, the process of
`drug input into the body compartment involves drug
`drug input into the body compartment involves drug
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`release from the dosage form and passage of the release from the dosage form and passage of the
`drug across the cellular membranes constituting the
`drug across the cellular membranes constituting the
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`gastrointestinal barrier. The rate of input or absorp-gastrointestinal barrier. The rate of input or absorp-
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`tion represents' the net result of all these processes. tion represents' the net result of all these processes.
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`The rate of ini)ut (absorption) at any given time is The rate of ini)ut (absorption) at any given time is
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`proportional to the concentration of drug, which proportional to the concentration of drug, which
`is assumed to be in an absorbable form, in solution
`is assumed to be in an absorbable form, in solution
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`in the gastrointestinal fluids at the site(s) of absorp-in the gastrointestinal fluids at the site(s) of absorp-
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`tion, i.e. the effective concentration, C„ of drug at tion, i.e. the effective concentration, C„ of drug at
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`time t. Hence: time t. Hence:
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`rate of drug input at time t « Ce (cid:9)rate of drug input at time t « Ce (cid:9)
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`(19.1)
`(19.1)
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`
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`and and
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`rate of drug input at time t = —ka Ce (19.2) rate of drug input at time t = —ka Ce (19.2)
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`where ka is the apparent absorption rate constant. where ka is the apparent absorption rate constant.
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`The negative sign in Eqn 19.2 indicates that the The negative sign in Eqn 19.2 indicates that the
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`effective concentration of drug at the absorption effective concentration of drug at the absorption
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`site(s) decreases with time. The apparent absorption site(s) decreases with time. The apparent absorption
`rate constant gives the proportion (or fraction) of
`rate constant gives the proportion (or fraction) of
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`drug that enters the body compartment per unit drug that enters the body compartment per unit
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`time. Its units are time-1, e.g. h-'. time. Its units are time-1, e.g. h-'.
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`Unlike the rate of drug input into the body com-Unlike the rate of drug input into the body com-
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`partment, the apparent absorption rate constant, ka, partment, the apparent absorption rate constant, k a,
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`is independent of the effective concentration of drug is independent of the effective concentration of drug
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`at the absorption site(s). Because the rate of drug at the absorption site(s). Because the rate of drug
`input is proportional to the effective drug concentra-
`input is proportional to the effective drug concentra-
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`tion, it will be maximal following the administration tion, it will be maximal following the administration
`of a dose contained in a peroral dosage form which
`of a dose contained in a peroral dosage form which
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`gives rapid and complete drug release. The rate of gives rapid and complete drug release. The rate of
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`drug input will decrease gradually with time as a drug input will decrease gradually with time as a
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`consequence of the effective drug concentration at consequence of the effective drug concentration at
`the absorption site(s) decreasing progressively with
`the absorption site(s) decreasing progressively with
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`time, chiefly as a result of absorption into the body time, chiefly as a result of absorption into the body
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`compartment. Other processes, such as chemical compartment. Other processes, such as chemical
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`degradation and movement of drug away from the degradation and movement of drug away from the
`absorption site(s), will also contribute to the gradual
`absorption site(s), will also contribute to the gradual
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`decrease in the effective drug concentration with decrease in the effective drug concentration with
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`time. time.
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`In the case of a one-compartment open model, the In the case of a one-compartment open model, the
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`rate of drug output or elimination is a first-order rate of drug output or elimination is a first-order
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`process. Consequently, the magnitude of this para-process. Consequently, the magnitude of this para-
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`meter at any given time is dependent on the concen-meter at any given time is dependent on the concen-
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`tration of drug in the body compartment at that tration of drug in the body compartment at that
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`time. Immediately following administration of the time. Immediately following administration of the
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`first dose of a peroral dosage form, the rate of drug first dose of a peroral dosage form, the rate of drug
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`output from the body will be low as little of the drug output from the body will be low as little of the drug
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`will have been absorbed into the body compartment. will have been absorbed into the body compartment.
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`However, as absorption proceeds — initially at a However, as absorption proceeds — initially at a
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`higher rate than the rate of drug output — the net higher rate than the rate of drug output — the net
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`concentration of drug in the body will increase with concentration of drug in the body will increase with
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`time. Likewise, the rate of drug output from the time. Likewise, the rate of drug output from the
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`Drug in Drug in
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`Drug (cid:9)Drug (cid:9)
`in -op, solution in
`in —op— solution in
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`gastrointestinal gastrointestinal
`dosage (cid:9)
`dosage (cid:9)
`fluids
`fluids
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`form (cid:9)form (cid:9)
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`
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`INPUT INPUT
`
`
`Drug in Drug in
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`body body
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`compartment compartment
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`
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`OUTPUT (cid:9)OUTPUT
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`Drug Drug
`ow in
`in
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`urine urine
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`
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`Fig. 19.1 One-compartment open model of drug disposition for a perorally administered drug. Fig. 19.1 One-compartment open model of drug disposition for a perorally administered drug.
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`276
`276
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`Ex. 1097 - Page 6
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`DOSAGE REGIMENS DOSAGE REGIMENS
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`body compartment will also increase with time. As body compartment will also increase with time. As
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`the rate of drug output is increasing with time while the rate of drug output is increasing with time while
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`the rate of input into the body compartment is the rate of input into the body compartment is
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`decreasing with time, the situation is eventually decreasing with time, the situation is eventually
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`reached when the rate of drug output just exceeds reached when the rate of drug output just exceeds
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`that of drug input. Consequently, the net concentra-that of drug input. Consequently, the net concentra-
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`tion of drug in the body compartment will reach a tion of drug in the body compartment will reach a
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`peak value and then begin to fall with time. The peak value and then begin to fall with time. The
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`ensuing decreases in the net concentration of drug in ensuing decreases in the net concentration of drug in
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`the body will also cause the rate of drug output to the body will also cause the rate of drug output to
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`decrease with time. decrease with time.
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`These changes in the rates of drug input and These changes in the rates of drug input and
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`output relative to each other with time are responsi-output relative to each other with time are responsi-
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`ble for the characteristic shape of the concentra-ble for the characteristic shape of the concentra-
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`tion—time course of a drug in the body shown in tion—time course of a drug in the body shown in
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`Figure 19.2 following peroral administration of a Figure 19.2 following peroral administration of a
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`single dose of drug. single dose of drug.
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`It is evident from the above discussion and It is evident from the above discussion and
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`Figure 19.2, that the greater the rate of drug input Figure 19.2, that the greater the rate of drug input
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`relative to that of drug output from the body com-relative to that of drug output from the body com-
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`partment over the net absorption phase, the higher partment over the net absorption phase, the higher
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`will be the peak concentration achieved in the will be the peak concentration achieved in the
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`body or plasma following peroral administration of body or plasma following peroral administration of
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`a single dose of drug. This interplay explains why a single dose of drug. This interplay explains why
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`increases in dose size and formulation changes in increases in dose size and formulation changes in
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`dosage forms which produce increases in the effec-dosage forms which produce increases in the effec-
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`tive concentration of drug at the absorption site(s), tive concentration of drug at the absorption site(s),
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`result in higher peak plasma and body concentra-result in higher peak plasma and body concentra-
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`tions being obtained for a given drug. It should tions being obtained for a given drug. It should
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`also be noted that any unexpected decrease in the also be noted that any unexpected decrease in the
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`rate of drug output relative to that of drug input, rate of drug output relative to that of drug input,
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`which may occur as the result of renal impairment, which may occur as the result of renal impairment,
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`is also likely to result in higher plasma and body is also likely to result in higher plasma and body
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`concentrations of drug than expected, and the pos-concentrations of drug than expected, and the pos-
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`sibility of the patient exhibiting undesirable side-sibility of the patient exhibiting undesirable side-
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`effects. The adjustment of dosage regimens in effects. The adjustment of dosage regimens in
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`cases of patients having severe renal impairment is cases of patients having severe renal impairment is
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`considered later in this chapter. considered later in this chapter.
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`Elimination rate constant and biological Elimination rate constant and biological
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`half-life of a drug half-life of a drug
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`In the case of a one-compartment open model the In the case of a one-compartment open model the
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`rate of elimination or output of a drug from the body rate of elimination or output of a drug from the body
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`compartment follows first-order kinetics (Chapter 7) compartment follows first-order kinetics (Chapter 7)
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`and is related to the concentration of drug, C, and is related to the concentration of drug, C,
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`
`Absorption Absorption
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`phase phase
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`
`Elimination Elimination
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`phase phase
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`
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`1 1
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`
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`Rate of drug input = rate of drug output Rate of drug input = rate of drug output
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`Time following administration Time following administration
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`of a single dose of a single dose
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`a — b rate of drug absorption > rate of drug elimination a — b rate of drug absorption > rate of drug elimination
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`c—d rate of drug elimination > rate of drug absorption c—d rate of drug elimination > rate of drug absorption
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`Fig.192 Concentration—time course of a drug in the body following peroral administration of a single dose of drug which confers Fig.192 Concentration—time course of a drug in the body following peroral administration of a single dose of drug which confers
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`one-compartment open model characteristics on the body. one-compartment open model characteristics on the body.
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`
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`277 277
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`Ex. 1097 - Page 7
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`

`

`BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY
`BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY
`
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`remaining in the body compartment at time t, by the remaining in the body compartment at time t, by the
`following equation:
`following equation:
`
`
`rate of elimination at time t = -ke C, (cid:9)rate of elimination at time t = -ke C't (cid:9)
`(193) (19.3)
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`where ke is the apparent elimination rate constant. where ke is the apparent elimination rate constant.
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`The negative sign in Eqn 19.3 indicates that elimi-The negative sign in Eqn 19.3 indicates that elimi-
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`nation is removing drug from the body compart-nation is removing drug from the body compart-
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`ment. ment.
`The apparent elimination rate constant of a drug
`The apparent elimination rate constant of a drug
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`gives the proportion or fraction of that drug which is gives the proportion or fraction of that drug which is
`eliminated from the body per unit time. Its units are
`eliminated from the body per unit time. Its units are
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`in terms of time-1. The apparent elimination con-in terms of time-1. The apparent elimination con-
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`stant of a given drug therefore provides a quantita-stant of a given drug therefore provides a quantita-
`tive index of the persistence of that drug in the body.
`tive index of the persistence of that drug in the body.
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`An alternative parameter used is the biological or An alternative parameter used is the biological or
`elimination half-life of the drug, 1112. This is the time
`elimination half-life of the drug, 412. This is the time
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`required for the body to eliminate 50% of the drug required for the body to eliminate 50% of the drug
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`that it contained. Thus, the larger the biological half-that it contained.Thus, the larger the biological half-
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`life exhibited by a drug, the slower will be its elimi-life exhibited by a drug, the slower will be its elimi-
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`nation from the body or plasma. nation from the body or plasma.
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`For a drug whose elimination follows first-order For a drug whose elimination follows first-order
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`kinetics, the value of its biological half-life is inde-kinetics, the value of its biological half-life is inde-
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`pendent of the concentration of drug remaining in pendent of the concentration of drug remaining in
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`the body or plasma. Hence, if a single dose of a drug the body or plasma. Hence, if a single dose of a drug
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`having a biological half-life of 4 hours was adminis-having a biological half-life of 4 hours was adminis-
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`tered perorally, then after the peak plasma concen-tered perorally, then after the peak plasma concen-
`tration had been reached the plasma concentration
`tration had been reached the plasma concentration
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`of drug would fall by 50% every 4 hours until all the of drug would fall by 50% every 4 hours until all the
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`drug had been eliminated or a further dose was drug had been eliminated or a further dose was
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`administered. The relationship between the numbers administered. The relationship between the numbers
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`of half-lives elapsed and the percentage of drug elim-of half-lives elapsed and the percentage of drug elim-
`inated from the body following administration of a
`inated from the body following administration of a
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`single dose is given in Table 19.1. single dose is given in Table 19.1.
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`An appreciation of the relationship between the An appreciation of the relationship between the
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`percentage of drug eliminated from the body and the percentage of drug eliminated from the body and the
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`number of biological half-lives elapsed is useful number of biological half-lives elap