`Science and
`Practce
`of Pharmacy
`
`MYLAN - EXHIBIT 1016
`
`MYLAN - EXHIBIT 1016
`
`
`
`Editor: Daniel Limmer
`Managing Editor: Matthew J. I-Iauber
`Marketing Manager: Anne Smith
`
`Lippincott Williams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may
`be reproduced in any form or by any means, including photocopying, or utilized
`by any information storage and retrieval system without written permission
`from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence or
`otherwise) for any injury resulting from any material contained herein. This
`publication contains information relating to general principles of medical care
`which should not be construed as specific instructions for individual patients.
`Manufacturers’ product information and package inserts should be reviewed for
`current information, including contraindications, dosages and precautions.
`
`Printed in the United States ofAmerica
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila-
`delphia College of Pharmacy and Science
`
`Copyright 2000, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-683306472
`
`The publishers have made every effort to trace the copyright holders for borrowed
`material. Ifthey have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportun.it_v.
`
`The use of structural formulas fiom USAN an.d the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon-
`sible for any inaccurac-_v contained herein.
`Notiee~—Th is text‘ is not intended to represent, nor shall it be interpreted to be, the
`equivalent of or a substitute for the offieial United States Pharmacopeia (USP)
`and/or the National Formulary (NF). In the event of any difference or discrep-
`ancy between the current offlcial USP or NF standards of strength, quality,
`purity, pacleaging and labeling for drugs and representations ofthem herein, the
`colztext and effect of the official compcndia shall prevail.
`
`To purchase additional copies of this book call our customer service department
`at (800) 638-3030 or fax orders to (301) 824-7390. International customers
`should call (301) 714-2324.
`
`02 03 04
`.2 3 4 5 6 7 8 9 10
`
`
`
`Table of Contents
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Biotechnology and Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Aerosols .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`t
`Quality Assurance and Control
`.
`.
`.
`.
`.
`Stability of Pharmaceutical Products .
`Bioavailability and Bioequivalency Testing .
`Plastic Packaging Materials .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Pharmaceutical Necessities .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`Part 6 Pharmacodynamics
`
`Diseases: Manifestations and Pathophysiology .
`Drug Absorption, Action, and Disposition .
`.
`.
`.
`.
`Basic Pharmacokinetics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Clinical Pharmacokinetics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Principles of immunology .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Adverse Drug Reactions .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Pharmacogenetics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Pharmacological Aspects of Substance Abuse .
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`Part 7 Pharmaceutical and Medicinal Agents
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`19
`28
`33
`38
`47
`
`60
`70
`81
`
`91
`124
`159
`183
`198
`208
`227
`246
`263
`275
`288
`316
`335
`
`359
`385
`409
`
`441
`458
`469
`
`49
`50
`51
`52
`53
`54
`55
`
`56
`57
`58
`59
`60
`61
`62
`63
`
`64
`65
`66
`67
`68
`69
`70
`71
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`
`944
`963
`980
`986
`995
`1005
`1015
`
`1053
`1098
`1127
`1145
`1156
`1165
`1169
`1175
`
`1185
`1200
`1219
`1243
`1274
`1297
`1305
`1314
`1322
`1328
`1333
`1344
`1354
`1358
`1395
`1400
`1407
`1421
`1429
`
`’ Pa}? 1__Orientatian
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Scope of Pharmacy .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Evolution of Pharmacy .
`.
`.
`.
`.
`.
`_.
`.
`.
`.
`.
`.
`.
`Ethics and Professionalism .
`.
`.
`.
`The Practice of Community Pharmacy .
`.
`.
`.
`Pharmacists in industry .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Pharmacists in Government
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Pharmacists and Public Health .
`.
`.
`.
`.
`.
`.
`information Resources in Pharmacy and the
`Pharmaceutical Sciences .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Clinical Drug Literature .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Research .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`,
`_
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`Part 2 Pharmaceutics
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Pharmaceutical Calculations .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Statistics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Molecular Structure, Properties, and States of Matter. .
`Complex Formation .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Thermodynamics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Solutions and Phase Equilibria .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Ionic Solutions and Electrolytic Equilibria .
`.
`.
`.
`.
`.
`.
`.
`.
`Tonicity, Osmoticity, Osmolality, and Osmolarity. .
`.
`Chemical Kinetics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`lnterfacial Phenomena .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Colloidal Dispersions .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Coarse Dispersions .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Rheology .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`Part 3 Pharmaceutical Chemistry
`
`.
`.
`.
`.
`.
`Inorganic Pharmaceutical Chemistry .
`.
`.
`.
`.
`.
`Organic Pharmaceutical Chemistry .
`.
`.
`.
`.
`.
`.
`Natural Products .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Drug Nomenclature-—United States Adopted
`.
`.
`.
`Names .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Structure—Activity Relationship and Drug Design. .
`Fundamentals of Radionuclides .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`1 00
`
`3\lO~U\l>~(.Jl\)
`
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`
`24
`25
`26
`27
`
`28
`29
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Diagnostic Drugs and Reagents .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Topical Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Gastrointestinal and Liver Drugs .
`.
`.
`.
`Blood, Fluids, Electrolytes, and Hematological Drugs.
`.
`.
`.
`Cardiovascular Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Respiratory Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Sympathomimetic Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Cholinomimetic Drugs ._
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Adrenergic and Adrenergic Neuron Blocking Drugs. .
`Antimuscarinic and Antlspasmodic Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`Skeletal Muscle Relaxants .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Diuretic Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Uterine and Antimigraine Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Hormones and Hormone Antagonists .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`General Anesthetics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Local Anesthetics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Sedative and Hypnotic Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`A
`Antiepileptic Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Psychopharmacologic Agents .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Analgesic, Antipyretic, and Anti—|nflammatory
`Drugs .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Histamine and Antihistaminic Drugs .
`.
`.
`.
`.
`.
`.
`.
`Central Nervous System Stimulants .
`.
`.
`.
`.
`.
`.
`.
`.
`Antineoplastic and lmmunoactive Drugs .
`.
`.
`.
`Anti-lnfectives .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Parasiticides .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`immunizing Agents and Allergenic Extracts .
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`Part 8 Pharmacy Practice
`
`84
`85
`86
`87
`88
`89
`
`Part 8A Pharmacy Administration
`90
`91
`92
`93
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Laws Governing Pharmacy .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Pharmacoeconomics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Marketing Pharmaceutical Care Services .
`Documenting and Billing for Pharmaceutical Care
`Services .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`t
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Community Pharmacy Economics and
`Management .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Product Recalls and Withdrawals
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`94
`
`95
`
`.
`.
`,
`
`.
`
`.
`
`.
`.
`A
`
`.
`
`.
`
`.
`.
`.
`
`.
`
`.
`
`Part 8D Fundamentals of Pharmacy Practice
`96 Drug Education .
`
`xiv
`
`1444
`1464
`1471
`1477
`1507
`1562
`1567
`
`1595
`1625
`1634
`
`1640
`
`1650
`1666
`
`1677
`
`Part 4 Pharmaceutical Testing, Analysis and Control
`
`30
`31
`32
`33
`34
`35
`
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`47
`48
`
`.
`.
`.
`.
`.
`.
`.
`.
`Analysis of Medicinals .
`.
`.
`.
`.
`.
`.
`.
`.
`Biological Testing .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`t
`Clinical Analysis .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Chromatography .
`.
`.
`.
`instrumental Methods of Analysis .
`Dissolution .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`l
`.
`.
`.
`.
`.
`
`Part 5 Pharmaceutical Manufacturing
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Separation .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`t
`.
`.
`.
`.
`.
`.
`.
`.
`Powders .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`_
`.
`.
`.
`.
`.
`.
`.
`Preformulation .
`Solutions, Emulsions, Suspensions, and Extracts .
`Sterilization .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Parenteral Preparations t
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Intravenous Admixtures .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Ophthalmic Preparations .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Medicated Topicals .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Oral Solid Dosage Forms .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Coating of Pharmaceutical Dosage Forms .
`.
`.
`.
`Control|ed—Re|ease Drug—De|ivery Systems .
`.
`.
`.
`The Introduction of New Drugs .
`.
`.
`t
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`t
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`485
`540
`552
`587
`614
`654
`
`669
`681
`700
`721
`753
`780
`807
`821
`836
`858
`894
`903
`930
`
`
`
`I
`
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`1687
`1706
`1716
`1725
`1738
`1746
`
`113
`114
`115
`116
`117
`118
`119
`
`The Patient; Behavioral Determinants .
`Patient Communication .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Patient Compliance
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Pharmacoepidemiology .
`Integrated Health-Care Delivery Systems .
`Home Health Patient Care
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`Aseptic Technology for Home-Care
`Pharmaceuticals .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`.
`
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`
`.
`.
`
`.
`
`_
`
`1948
`1957
`1966
`1980
`1990
`2012
`
`2020
`
`Appendixes
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`97 The Prescription .
`.
`.
`98 Extemporaneous Prescription Compounding .
`.
`.
`99 Poison‘gControl
`.
`.
`.
`.
`.
`.
`.
`T
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`100 Nutrition in Pharmacy Practice
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`101 Self—Care/Diagnostic Products .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`102 Drug Interactions .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`103 Complementary and Alternative Medical Health
`Care .
`.
`.
`.
`.
`.
`‘
`.
`.
`.
`=
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Nuclear Pharmacy Practice
`.
`.
`.
`Enzymes
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Vitamins and Other Nutrients .
`Pesticides .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`104
`105
`106
`107
`108
`109
`
`1762
`1781
`1792
`1796
`1525
`1646
`1857
`
`Dose Equivalents .
`Periodic Chart .
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`2033
`2034
`2036
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`Surgical Supplies .
`Health Accessories .
`
`Part BC Patient Care
`
`110 Ambulatory Patient Care .
`1 11 Institutional Patient Care
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`Logarithms .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`_
`
`.
`
`.
`
`.
`
`,
`
`.
`
`.
`
`.
`
`.
`
`Glossary and Index
`
`.
`.
`
`2037
`2039
`
`1 12 Long—Term Care Facilities .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`_
`
`1893
`1911
`1932
`
`Glossary .
`Index .
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`_
`.
`
`_
`_
`
`_
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`_
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`_
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`XV
`
`
`
`Ophthalmic Preparations
`
`CHAPTER 43
`
`Gerald Hecht, PhD
`Senior Director, Pharmaceutical Sciences
`Aicon Laboratories
`Fort Worth, TX 76101
`
`
`
`Ophthalmic preparations are sterile products essentially free
`from foreign particles, suitably compounded and packaged for
`instillation into the eye. Ophthalmic preparations include so-
`lutions, suspensions, ointments, and solid dosage forms. The
`solutions and suspensions are, for the most part, aqueous.
`Ophthalmic oint1nents usually contain a white petrolatum-
`mineral oil base.
`Ophthalmic preparations can be grouped broadly into two
`divisions of major significance to the pharmacist. These include
`single or multidose prescription products and the category de-
`scribed as OTC or over-the-counter ophthalmic products. The
`latter group has been subjected to a searching review and
`analysis by a body of experts as a part of the Food and Drug
`Administration’s (FDA) OTC Drug Review process.
`The single dominant factor characteristic of all ophthalmic
`products is the specification of sterility. Any product intended
`for use in the eye regardless of form, substance, or intent must
`be sterile. This requirement increases the similarity between
`ophthalmic and parenteral products; however the physiology
`of the human eye in many respects imposes more rigid
`formulation requirements. This is considered in the following
`discussion.
`
`Preparations intended for the treatment of eye disorders
`can be traced to antiquity. Egyptian papyri writings describe
`eye medications. The Greeks and Romans expanded such uses
`and gave us the term Collyria. Collyria refers collectively to
`materials that were dissolved in water, milk, or egg white for
`use as eyedrops. In the Middle Ages Collyria included mydriatic
`substances to dilate the pupils of milady’s eyes for cosmetic
`purposes, thus the term belladonna, or beautiful lady.
`From the time of belladonna collyria, ophthalmic technology
`progressed at a pharn1aceutical'snail’s pace well into modern
`times. It was not until after World War II that the concept of
`sterility became mandatory for ophthalmic solutions. Prior to
`World War II and continuing into the 1940s very few ophthal-
`mic preparations were available commercially or were de-
`scribed officially. The USP XIV, official in 1950, included only
`three ophthalmic preparations, and all three were ointments.
`Preparations to be used in the eye, either solutions or oint-
`ments, invariably were compounded in the community or hos-
`pital pharmacy and were intended for immediate (prescription)
`use. Such preparation and prompt use is reflected in the phar-
`maceutical literature of the times. The stability of ophthalmic
`preparations is discussed in terms of days or a few months.
`One of the most important attributes of ophthalmic products
`is the requirement of sterility. Even that, however, is a sur-
`prisingly recent event. The USP XV in 1955 was the first
`official compendium to include a sterility requirement for oph-
`thalmic solutions. The FDA in 1953 adopted the position that a
`nonsterile ophthalmic solution was adulterated. Sterile oph-
`thalmic products were, of course, available prior to the mid--
`1950s; however the legal requirement of sterility dates only
`from 1955.
`
`The sterility requirements for ophthalmic ointments ap-
`peared first in the USP XVIII, Third Supplement (1972). Prior
`to that date there was no legal requirement for a sterile oph-
`thalmic ointment. This probably was due to the difficulty (at
`that time) of testing for sterility in such nonaqueous systems
`and also the anticipated difficulties in sterilizing and maintain-
`ing sterile conditions during the manufacture and filling of
`ointments on a large scale.
`
`ANATOMY AND PHYSIOLOGY OF THE EYE
`
`The human eye is a challenging subject for topical administra-
`tion of drugs. The basis of this can be found in the anatomical
`arrangement of the surface tissues and in the permeability of
`the cornea. The protective operation of the eyelids and lacrimal
`system is such that there is rapid removal of material instilled
`into the eye, unless the material is suitably small in volume
`and chemically and physiologically compatible with surface
`tissues. Figures 43-11 and 43-21 include pertinent anatomy of
`the human eye.
`EYELIDS—-The eyelids serve two purposes: mechanical
`protection of the globe and creation of an optimum milieu for
`the cornea. The eyelids are lubricated and kept fluid—filled by
`secretions of the lacrimal glands and specialized cells residing
`in the bulbar conjunctiva. The antecharnber has the shape of a
`narrow cleft directly over the front of the eyeball, with pocket-
`like extensions upward and downward. The pockets are called
`the superior and inferior fornices (vaults), and the entire space,
`the cul-de-sac. The elliptical opening between the eyelids is
`called the palpebral fissure.
`EYEBALL—The wall of the human eyeball (bulbus, globe)
`is composed of three concentric layers.
`1. The outer fibrous layer.
`2. A middle vascular layer—the uvea or uveal tract, consisting of the
`choroid, the ciliary body, and the iris.
`3. A nervous layer—the retina.
`
`The outer layer is tough, pliable, but only slightly stretchable.
`In its front portion—the portion facing the outside world—the
`fine structure of the outer layer is so regular and the water
`content so carefully adjusted that it acts as a clear, transparent
`window (the cornea). It is devoid of blood Vessels. Over the
`remaining two-thirds the fibrous coat is opaque (the white of
`the eye) and is called the sclera. It contains the microcircula—
`tion, which nourishes the tissues of this anterior segment, and
`is usually white except when irritated and vessel dilatation
`occurs.
`
`The eyeball houses an optical apparatus that causes in-
`verted reduced images of the outside world to form on the
`retina, which is a thin translucent membrane. The optical
`apparatus consists, in sequence, of the precorneal film, the
`cornea, the aqueous humor, the pupil, the crystalline lens, the
`
`821
`
`
`
`compounds, approximately 0.7% protein, and the enzyme ly-
`sozyine. Small accessory lacrimal glands are situated in the
`conjunctival fornices. Their secretion suffices for lubrication
`and cleansing under ordinary conditions and for maintaining a
`thin fluid film covering the cornea and conjunctiva (the precor—
`neal film). The mucin-protein layer of the film is especially
`important in maintaining the stability of the film. The main
`lacrimal gland is called into play only on special occasions. The
`sebaceous glands of the eyelids secrete an oily fluid that helps
`to prevent overflowing of tears at the lid margin and reduces
`evaporation from the exposed surfaces of the eye by spreading
`over the tear film.
`
`Spontaneous blinking replenishes the fluid film by pushing
`a thin layer of fluid ahead of the lid margins as they come
`together. The excess fluid is directed into the lacrimal lake——a
`small, triangular area lying in the angle bound by the inner-
`most portions of the lids. The skin of the eyelids is the thinnest
`in the body and folds easily, thus permitting rapid opening and
`closing of the palpebral fissures. The movement of the eyelids
`includes a narrowing of the palpebral fissures in a zipper-like
`action from the lateral canthus toward the medial canthus
`(canthi: the corners where the eyelids meet). This aids the
`transport or movement of fluid toward the lacrimal lake.
`Tears are drained from the lacrimal lake by two small
`tubes—the lacrimal canaliculi-—which lead into the upper part
`of the nasolacrimal duct, the roomy beginning of which is called
`the lacrimal sac. The drainage of tears into the nose does not
`depend merely on gravity. Fluid enters and passes along the
`lacrimal canaliculi by capillary attraction aided by aspiration
`caused by contraction of muscle embedded in the eyelids. When
`the lids close, as in blinking, contraction of the muscle causes
`dilatation of the upper part of the lacrimal sac and compression
`of its lower portion.. Tears are thus aspirated into the sac, and
`any that have collected in its lower part are forced down the
`nasolacrimal duct toward its opening into the nose. As the lids
`open,
`the muscle relaxes. The upper part of the sac then
`collapses and forces fluid into the lower part, which at the same
`time is released from compression. Thus, the act of blinking
`exerts a suction force-pump action in removing tears from
`the lacrimal lake and emptying them into the nasal cavity.
`
`
`
`EXCRETOR‘! DUCTS
`
`LACRIM./-\L GLAND
`
`NASAL
`SEPT‘u':‘-/1
`
`LACRIMAL SAC
`
`
`
`"VALVE" OF HASNER
`(LACRIMAL PLKCA)
`
`Figure 43-2. Nasolacrimal duct.‘
`
`EXCRETORY DUCT
`
`
`
`‘LACRIMAL _
`
`822
`
`CHAPTER 43
`
`
`
`CONJUNCTIVA T _r_
`' CONJUNCTIVALsAc——j
`
`_
`
`.
`
`
`cmmosfi
`:3/m\1f\1ZDS OF
`carers or
`/
`HENLETI
`4
`5
`MEIBOMIAN
`
`GLANDS7
`TARSAL PLATE
` GLANDS OF
`
`
`
`VITREOUS
`
`ZEIS
`(SEBACEOUS)
`
`GLANDS OF MoLL/
`(swam
`
`
`
`Figure 43-1. The eye: vertical section._‘
`
`vitreous humor, and the retina. The aqueous and vitreous
`humors are layers of clear fluid or gel-like material interposed
`between the solid structures. The pupil, a round centric hole in
`a contractile membranous partition (called the iris), acts as the
`variable aperture of the system. The crystalline lens is a re-
`fractive element with variable power controlled and supported
`by a muscle incorporated in the ciliary body. The choroid is the
`metabolic support for the retina.
`The optical function of the eye calls for stability of its di-
`mensions, which is provided partly by the fibrous outer coat;
`more effective as a stabilizing factor is the intraocular pres-
`sure, which exceeds the pressure prevailing in the surrounding
`tissues. This intraocular pressure is the result of a steady
`production of specific fluid, the aqueous humor, which origi-
`nates from the ciliary processes and leaves the eye by an
`intricate system of outflow channels. The resistance encoun-
`tered during this passage and the rate of aqueous production
`are the principal factors determining the level of the intraocu-
`lar pressure. In addition to this hydromechanical function, the
`aqueous humor acts as a carrier of nutrients, substrates, and
`metabolites for the avascular tissues of the eye.
`The bones of the skull join to form an approximately
`pyramid—shaped housing for the eyeball, called the orbit.
`CONJ'UNCTIVA—-The conjunctival membrane covers the
`outer surface of the white portion of the eye and the inner
`aspect of the eyelids. In most places it is attached loosely and
`thus permits free movement of the eyeball. This makes possible
`subconjunctival injections. Except for the cornea the conjunc-
`tiva is the most exposed portion of the eye.
`LACRIMAL SYSTEM—The conjunctival and corneal sur-
`faces are covered and lubricated by a film of fluid secreted by
`the conjunctival and lacrimal glands. The secretion of the lac-
`rimal gland, the tears, is delivered through a number of fine
`ducts into the conjunctival fornix. The secretion is a clear,
`watery fluid containing numerous salts, glucose, other organic
`
` .../‘-"
`
`WOLFRlNG'S
`
`
`
`Lacrimation is induced reflexly by stimulation of nerve endings
`of the cornea or conjunctiva. The reflex is abolished by anes-
`thetization of the surface of the eye and by disorders affecting
`its nerve components.
`"
`'
`’
`’
`'
`The normal cul-de—sac usually is free of pathogenic organ-
`isms and often found sterile. The sterility may be due partly to
`the action of lysozyme in the tears, which normally destroys
`saprophytic organisms but has little action against pathogens.
`More effective in producing sterility may be the fact that the
`secretions, which are normally sterile as they leave the glands,
`constantly wash the bacteria, dust, etc, down in the nose. In
`certain diseases the lacrimal gland, like other glandular struc-
`tures in the body, undergoes involution, with the result that
`the lacrimal fluid becomes scanty. Furthermore, changes in the
`conjunctival glands may lead to alteration in the character of
`the secretion so that quality as well as quantity of tears may be
`abnormal. This may lead to symptoms of dryness, burning, and
`general discomfort and may interfere with visual acuity.
`PRECORNEAL FILM——The cornea must be wet to be an
`optically adequate surface; when dry, it loses both its regular
`gloss and its transparency. The precorneal film, part of the tear
`fluid, provides this important moist surface. Its character de-
`pends on the condition of the corneal epithelium. The film,
`compatible with both aqueous and lipid ophthalmic prepara-
`tions, is composed of a thin outer lipid layer, a thicker middle
`aqueous layer, and a thin inner mucoid layer. It is renewed
`during each blink, and when blinking is suppressed, either by
`drugs or by mechanical means, it dries in patches. It seems to
`be unaffected by the addition of concentrations of up to 2%
`sodium chloride to conjunctival fluid. A pH below 4 or above 9
`causes derangement of the film. The film affects the movement
`of contact lenses and forms more easily on glass than on plastic
`prostheses.
`CORNEA——The cornea, from 0.5 to 1 mm thick, consists
`mainly of the following structures (from the front backward):
`1. Corneal epithelium.
`2. Substantia propria (stroma).
`3. Corneal endothelium.
`
`The cornea is transparent to ordinary diffuse light, largely
`because of a special laminar arrangement of the cells and fibers
`* and because of the absence of blood vessels. Cloudiness of the
`cornea may be due to any one of several factors including excess
`pressure in the eyeball as in glaucoma, and scar tissue due to
`injury, infection, or deficiency of oxygen or excess hydration
`such as may occur during the wearing of improperly fitted
`contact lenses. A wound of the cornea usually heals as an
`opaque patch that can be a permanent impairment of vision
`unless it is located in the periphery of the cornea.
`The chief refraction of light for the eye occurs at the outer
`surface of the cornea where the index of refraction changes
`from that of air (1.00) to that of precorneal substance (1.38).
`Any alteration in its shape or transparency interferes with the
`formation of a clear image; therefore, any pathological process,
`however slight, may interfere seriously with the resolving
`power or visual acuity of the eye.
`The normal cornea possesses no blood vessels except at the
`corneoscleral junction. The cornea, therefore, must derive its
`nutrition by diffusion and must have certain permeability char-
`acteristics; it also receives nourishment from the fluid circulat-
`ing through the chambers of the eye and from the air. The fact
`that the normal cornea is devoid of blood vessels is an impor-
`tant feature in surgical grafting. The corneal nerves do not
`supply all forms of sensation to the cornea. Pain and cold are
`well supplied. The pain fibers have a very low threshold, which
`makes the cornea one of the most sensitive areas on the surface
`of the body. It now is agreed generally that the cornea pos-
`sesses a true sense of touch; nerve endings supplying the sen-
`sation of heat are lack_ing.
`The corneal epithelium provides an efficient barrier against
`bacterial invasion. Unless its continuity has been broken by an
`abrasion (a traumatic opening or defect in the epithelium),
`
`OPHTHALMlC PREPARATIONS
`
`823
`
`pathogenic bacteria, as a rule, cannot gain a foothold. Trauma,
`therefore, plays an important part in most of the infectious
`diseases of the cornea that occur exogenously. Any foreign body
`that either scratches the cornea or lodges and becomes embed-
`ded in the cornea is of serious moment because of the role it
`may play in permitting pathogenic bacteria to gain a foothold.
`A means of detecting abrasions on the corneal surface is
`afforded by staining the cornea with sodium fluorescein. If
`there is an abrasion on the epithelium, the underlying layer
`stains a brilliant green, so that even pinpoint abrasions show
`up quite clearly. Abrasion may occur during tonometry; ie,
`during the measurement of ocular tension (pressure) with a
`tonometer. Care must be used in applying the device to the
`cornea to avoid abrasion of the cornea. Corneal abrasions some-
`times result from wearing contact lenses. Every corneal abra-
`sion is subject to infection.
`
`BIOAVAILABILITY
`
`PHYSICAL CONSIDERATION—Under normal condi-
`tions the human tear volume averages about 7 uL.2 The esti-
`mated maximum volume of the cul-de—sac is about 30 ;.:.L, with
`drainage capacity far exceeding lacrimation rate. The outflow
`capacity accommodates the sudden large volume resulting from
`the instillation of an eyedrop. Most commercial eyedrops range
`from 50 to 75 ML in volume; however, much in excess of 50 ML
`probably is unable to enter the cul-de—sac.
`Within the rabbit cul-de—sac, the drainage rate has been
`shown to be proportional to the instilled drop volume. Multiple
`drops administered at intervals produced higher drug concen-
`trations. Ideally, a high concentration of drug in a minimum
`drop volume is desirable. Patton3 has shown that approxi-
`mately equal tear-film concentrations result from the instilla-
`tion of 5 pL of 1.61 X 10-2 M pilocarpine nitrate or from 25 pL
`of 1.0 X 10-2 M solution. The 5 ML contains only 38% as much
`pilocarpine, yet its bioavailability is greater because of de-
`creased drainage loss.
`There is a practical limit or limits to the concept of mini-
`mum dosage volume. There is a difficulty in designing and
`producing a dropper configuration that will deliver small vol-
`umes reproducibly. Also, the patient often cannot detect the
`administration of such a small volume. This sensation or lack
`of sensation is particularly apparent at the 5.0 to 7.5-p.L dose-
`volume range.
`The concept of dosage—volume drainage and cul-de—sac ca-
`pacity directly affects the prescribing and administering of
`separate ophthalmic preparations. The first drug administered
`may be diluted significantly by the administration of the sec-
`ond. On this basis combination drug products for use in oph-
`thalmology have considerable merit.
`CORNEAL ABSORPTION—Drugs administered by in-
`stillation must penetrate the eye and do so primarily through
`the cornea. Corneal absorption is much more effective than
`scleral or conjunctival absorption, in which re1nov.al by blood
`vessels into the general circulation occurs.
`Many ophthalmic drugs are weak bases and are applied to
`the eye as aqueous solutions of their salts. The free base and
`the salt will be in an equilibrium that will depend on the pH
`and the individual characteristics of the drug molecule. To aid
`in maintaining storage stability and solubility, the medication
`may be acidic at the moment of instillation but, usually, the
`neutralizing action of the lacrimal fluid will convert it rapidly
`to the physiological pH range (~ pH 7.4), at which there will be
`enough free base present to begin penetration of the corneal
`epithelium. Once inside the epithelium the undissociated free
`base dissociates immediately to a degree. The dissociated inci-
`ety then will tend to penetrate the stroma because it is water-
`soluble. At the junction of the stroma and endothelium the
`same process that took place at the outer surface of the epithe-
`lium must occur again. Finally, the dissociated drug leaves the
`
`
`
`—
`
`824
`
`CHAPTER 43
`
`endothelium for the aqueous humor. Here it can readily diffuse
`to the iris and the ciliary body, the site of its pharmacological
`action.
`_
`t
`W
`_
`t
`I
`The cornea can be penetrated by ions to a small, but mea-
`surable, degree. Under comparable conditions, the per1neabili-
`ties are similar for all ions of small molecular weight, which
`suggests that the passage is through extracellular spaces. The
`diameter of the largest particles that can pass across the cel-
`lular layers seems to be in the range of 10 to 25 A. An instilled
`drug is subject to protein binding in the tear fluid and meta-
`bolic degradation by enzymes such as lysozyme, in addition to
`the losses by simple overflow and lacrimal drainage.
`Since the cornea is a membrane including both hydrophilic
`and. lipophilic layers, most effective penetration is obtained
`with drugs having both lipid and hydrophilic properties. Highly
`water soluble drugs penetrate less readily. As an exampl