Parenteral Medications
`"OIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. liebermnn, and lean lnchmun
`
`
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`AstraZeneca Exhibit 21 13 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017—00900
`
`

`

`Parenteral Medications
`ttolumet
`Serond Edition, Revised and Expanded
`
`Edited by
`
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. liebermnn
`
`H.H. Lieberman Associates, inc.
`Consultant Services
`
`Livingston, New Jersey
`
`leon larhmun
`
`Lachman Consultant Services
`
`Wesrbunt, New York
`
`Marcel Dekker, Inc.
`
`New York I Basel - Hong Kong
`
`AstraZeneca Exhibit 21 13 p. 2
`
`

`

`Library of Congress Cataioging - “1— Publication Data
`
`Pharmaceutical dosage forms, parenteral medications I edited by
`Kenneth E. Avis, Herbert A. Lieberman, and Leon Laohman. -- 2nd ed. .
`rev. and expanded.
`p.
`cm.
`
`Includes bibliographical references and index.
`ISBN 0-3243—8576-2 (v. 1 : elk. paper)
`1. Parenteral solutions.
`2. Pharmaceutical technology.
`Kenneth E.
`II. Lieberman, Herbert A.
`III. Laohman. Leon.
`[DNLM: 1. Infusions. Parenteral.
`WB 354 P536]
`RSZDI.P3TP48 1992
`615'. 19--dc20
`DNLMIDLC
`
`2. Technology, Pharmaceutical.
`
`I. Avis,
`
`for Library of Congress
`
`91 -38063
`CIP
`
`This book is printed on acid—free paper.
`
`Copyright © 1992 by MARCEL DEKKER, INC. All Rights Reamer!
`
`Neither this book nor any part may be reproduced. or transmitted in any form
`or by any means; electronic or mechanical, including photocopying. micro-
`filming, and recording, Or by any information storage and retrieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKJCER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last_ digit):
`10 9 S 7 6 5 4 3 2 ]
`
`PRINTED IN TEE UNITED STATES OF AMERICA
`
`AstraZeneca Exhibit 2113 p. 3
`
`

`

`Contents
`
`Preface
`Contributors
`
`Contents of Pharmaceutical Dosage Forms: Parenteral Medications,
`Second Edition, Revised and Expanded, Volumes 2 and 3
`Contents of Pharmaceutical Dosage Forms: Tablets, Second Edition.
`Revised and Expanded, Volumes 1-3
`Contents of Pharmaceutical Dosage Forms: Dispense Systems,
`Volumes 1 and 2
`
`E.E:-
`
`xiii
`
`xv
`
`xvii
`
`Chapter 1 The Parenteral Dosage Form and Its Historical Development
`
`1
`
`Kenneth E. Arts
`
`1. The Dosage Farm
`11.. History of Parenteral Medications
`Appendix A: Glossary of Terms
`Appendix 3': Highlights in the History of
`Parenteral Medications
`References
`
`Chapter 2
`
`Parenteral Drug Administration: Routes. Precautions,
`Problems, Complications, and Drug Bel-Wary Systems
`
`Richard J. Dame. Michael J. Alters. and
`Salvatore J. Tums
`
`Introduction
`I. General Indications for Parenteral
`
`Administration of Drugs
`ll. Pharmaceutical Factors Affecting Parenteral
`Administration
`
`Specific Routes of Administration
`III.
`IV . Distribution of Parenterally Administered Agents
`
`1
`4
`12
`
`19
`15
`
`1'?
`
`1’?
`
`18
`
`19
`
`21
`39
`
`vii
`
`AstraZeneca Exhibit 2113 p. 4
`
`

`

`viii
`
`Contents
`
`V'. Precautions. Problems. Hazards, and
`Complication Associated with Parenteral Drug
`Administration
`
`VI. Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`References
`
`_
`
`Chapter 3 Biopharmaceutics of Injectable Medications
`
`So! Motola
`
`I.
`
`Introduction
`
`II. Physioochemical and Physiological Factors
`Affecting Drug Absorption by Injection: An
`Overview
`
`111. Application of Pharmacokinetics to Biopharmr
`centic Investigations: Pharmacokinetic Models
`"IV. Examples of BiopharmaeeuticlPharmaeokmetio
`Principles
`V. Regulatory Considerations for Bioequivalence
`Studies
`
`VI. Bioequivolence Study of Two Injeotable Forms
`of the Same Drug
`Summary
`References.
`
`VII.
`
`Chapter 4
`
`Preformulation Research of Parenteral Medications
`
`So! Morale and Shreamm N. Aghorkor
`
`I .
`
`Introduction
`
`II. Drug Substance Physieochemical Properties
`III. Accelerated Stability Evaluation
`IV. General Modes of Drug Degradation
`V. Preformulatlon Studies for Proteins and Peptides
`VI.
`Preformulation Screening of Parenteral
`Packaging Components
`Summary
`VII.
`VIII. Preformulation Worksheet
`
`References
`
`Chapter 5
`
`Formulation of Small Volume Parenterals
`
`Patrick P. DeLuca and James C. Boylon
`
`I .
`
`Introduction
`
`Formulation Principles
`II.
`III. Container Effect-e. on Formulation
`1V. Stability Evaluation
`V.
`Process Effects
`References
`
`41
`
`49
`56
`5'?
`
`59
`
`59
`
`60
`
`7'?
`
`9%
`
`108
`
`109
`111
`112
`
`115
`
`115
`
`115
`140
`150
`154
`
`158
`183
`163
`
`169
`
`1'?3
`
`17 3
`
`174
`22?"
`234
`244
`245
`
`AstraZencca Exhibit 2113 p. 5
`
`

`

`Contents
`
`ix
`
`Chapter 6
`
`Formulation of Large Volume Parenterals
`
`Levit J. Demorest and Jeffrey G. Hamilton
`
`I.
`II.
`III.
`IV.
`V.
`
`Introduction ‘
`
`Concepts of Formulation
`Formulation Development
`Sqution Quality
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and Proteins
`
`YuHChong John Wang
`
`I.
`II.
`III.
`IV.
`
`V.
`
`Introduction
`
`
`Characteristics of Proteins and Peptides
`Formulation Principles
`Compatibility with Packaging Components and
`Infusion Sets
`Formulation of Market Products
`References
`
`Chapter 8
`
`Sterile
`
`Diagnostics
`
`Leif E.
`
`Olsen
`
`Introduction
`
`II.
`III.
`IV.
`
`VI.
`VII.
`
`Diagnostic Products Defined
`Sterile Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterals
`
`R. Poul Abendroth and Robert N. Clark
`
`I.
`II.
`III.
`
`IV .
`V .
`VI .
`VII.
`VIII.
`
`Introduction
`The Nature of Glass
`
`United States Pharmacopeia Glassware
`Classifications
`The Manufacture of Glass Containers
`Chemical Performance
`Mechanical Performance
`
`The Container and Closure as a System
`Quality Assurance
`References
`
`249
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321
`
`323.
`321
`322
`325
`330
`351
`359
`359
`
`351
`
`381
`381
`
`362
`369
`375
`380
`380
`382
`384
`
`AstraZeneca Exhibit 2113 p. 6
`
`

`

`a:
`
`Contents
`
`Chapter 10 Use of Plastics for Parenteral Packaging
`
`John M. Anes. Robert S. Nose, and
`Charles H. White
`
`I.
`II.
`III.
`IV.
`V.
`VI.
`
`Introduction
`Fundamentals
`Fabrication Processes
`
`Important Criteria for Selection of Plastics
`Plastics Used in Parenteral Packaging
`Quality Assurance of Parenteral Containers
`References
`
`Chapter 11 Elastomeric Closures for Parenterals
`
`Edward J. Smith and Robert J. Nash
`
`II
`
`II.
`III.
`IV.
`V.
`VI .
`VII.
`VIII.
`IX .
`
`XI.
`
`Elaetomeric Parenteral Packaging Components:
`A Physical Description
`Physical Description of Rubber
`Types of Rubber Used in Parenteral Packaging
`Closure Design
`Rubber Compdunding
`Vulcanization Process
`Closure Manufacture and Control
`
`Closure Design Qualification
`Regulatory Considerations
`Interaction of Drug Formnlations with
`Rubber Closures
`
`Contemporary Closure-Related Issues
`References
`
`Chapter 12 Parenteral Products in Hospital and Home Care
`Pharmacy Practice
`
`John W. Levchuk
`
`1.
`II.
`
`III.
`IV.
`
`V.
`VI.
`VII.
`
`Introduction
`
`The Preparation of Sterile Dosage Forms in the
`Hospital and in Home Care
`Dispensing and Compounding Processes
`Technology of Sterile Compounding in the
`Hospital Pharmacy
`Clinical Supply and Use of Sterile Products
`Quality Assurance
`Conclusion
`
`Appendix: Abbreviated Sequence for Preparing a
`Series of Extemporaneously Compounded LV.
`Admixtures
`References
`
`Index
`
`387
`
`387
`. 389
`398
`407
`422
`439
`443
`
`445
`
`445
`450
`451
`462
`463
`470
`477
`494
`503
`
`505
`50'?
`503
`
`513
`
`513
`
`513
`524
`
`532
`547
`552
`562
`
`56 3
`566
`
`569
`
`AstraZencca Exhibit 2113 p. 7
`
`

`

`3 B
`
`iopharmaceutics of
`lnjectable- Medications
`
`Sol Motola*
`
`Whitehall Laboratories, Hommonton, New Jersey
`
`I.
`
`INTRODUCTION
`
`Biopharmaceutics is the subject in pharmaceutical sciences that examines the in-
`fluence of physicochemical changes in drug and [or formulation design on the ab-
`sorption of drugs. Over the last three decades, this area of research has a—
`merged as one of the most influential factors in guiding the development of phar—
`maceutical dosage farms. As. a result, there has been a rapid. increase in the
`number of scientific publications and textbooks on this subject. Pharmacy
`schools throughout the world now include biopharmaceutics in both undergrad—
`uate and graduate programs. Moreover, practically every new drug product in-
`troduced during this period has been designed based on 'biopharmaceutical data.
`To date, most biopharmaoeutical investigations have been in support of or—
`ally adnnnistered dosage forms since they are the predominant ones used in cur-
`rent therapy. Although there have been a significant number of studies reported
`on the rates of absorption. distribution, metabolism. and excretion of parenteral-
`ly administered drugs, only a few have been designed to elucidate which prop-
`erties of the injection formulation or injection site influence these rates. The
`Danish pharmacologist Sohou was one of the first to study extensiver the
`physiological factors that influence the absorption of drugs from subcutaneous
`connective tissue.
`In a 1961 review article [1], he described. from a pharma—
`cological viewpoint, how the rate of absorption of subcutaneously administered
`hormones and drugs could be altered depending on the effect the injection had
`on the physiological condition of the connective tissues , the capillary membrane.
`and the capillary blood flow at the subcutaneous its.
`During the same year, Wagner [2] reviewed the literature comprising the
`discipline that had just been coined biophormaoeutics by Gerhard Levy. He re-
`viewed important physiocochemicel factors influencing drug absorption from
`various modes of administration. Besides correctly predicting the important
`
`$
`
`Current affiliation: Wyeth-Ayerst Laboratories, Radnor, Pennsylvania.
`
`59
`
`AstraZencca Exhibit 2113 p. 8
`
`

`

`60
`
`Match:
`
`role this discipline would serve in the future of pharmacy, he suggested many
`of the areas for study that have influenced biopharmaceutical investigations of
`injectable dosage forms.
`Ballard applied this information to research on intramuscular injections
`and, from a pharmaceutical viewpoint. published an influential review article
`dealing with biopharmaceutical factors influencing intramuscular and subcuv
`taneous injections [3] . Although interest continues in this area of research,
`as noted by periodic reviewa [4- 7] , relatively little new basic information has
`been uncovered. leaving more for more in—depth studies.
`Not long ago, drugs administered by injection were assumed to provide
`rapid and complete absorption, particularly when compared to oral administra—
`tion. During the last '30 years, this assumption has been shown not always to
`be true. These findings [8—13], coupled with more numerous examples of in—
`complete absorption from oral dosage forms, have stimulated research on:
`(1) drug- absorption and how it is affected by the design of the dosage form
`(biopharmaceutlcs);
`(2) the extent to which drugs are biologically available
`to the blood stream relative to the amount administered (unavailability); and
`
`(3) the rates and extents to which drugs are absorbed, distributed, metabo-
`lized, and excreted by the body (pharmacolclnetics).
`The aim of this chapter is to provide the formulator of injeetable medica-
`tion with a basic understanding of the major physicochemical and physiological
`factors currently considered to play an important role in influencing absorp-
`tion of drugs administered by injection. Selected topics in pharmacokinetics
`will be covered primarily to demonstrate their utility in the analysis of bio-
`pharmaceutical experiments. The overall goal is for the formulator to be able
`to apply this knowledge in designing injectsble dosage formulations that will
`provide predictable drug delivery to the patient.
`
`ll. PHYSICOCHEMICAL AND PHYSIOLOGICAL FACTORS AFFECTING
`DRUG ABSORPTION BY INJECTION: AN OVERVIEW
`
`An intravascular (intraveneous) injection places a drug directly into the bleed-
`stream. bypassing conventional physicochemical and physiological influences.
`Injection of a drug into an extravascular site [all others) leads to the initiation
`of events that collectively make up the absorption process. Depending on the
`type of formulation- administered. varying degrees of a depot are established.
`Eventual drug- adsorption into the bloodstream is influenced by several physico-
`chemical and physiological factors. the two considered most important being
`passive diffusion and bleed flow [14-161 . The relative importance of these
`factors depends on the capillary bed density at the injection site, the physical
`form of the drug, and the drug's molecular size. Hence an examination of
`these and other influential physicochemical and physiological factors is impor—
`tant in providing the pharmaceutical formuletor with information that can be
`used to design formulations yielding acceptable absorption characteristics.
`
`A. Physicochemicai Factors Affecting Drug
`Absorption by Injection
`
`As stated, no absorption step is necessary when a drug is administered direct—
`ly into the bloodstream; therefore. there are no physicochemical factors to
`
`AstraZeneca Exhibit 2113 p. 9
`
`

`

`Biophcrmoceutics of miserable Medication
`
`6.1
`
`affect absorption. Drugs given by extravascular injection require an absorp-
`tion step before they can enter the bloodstream. Even drugs that are admin-
`istered by the intraspinal {intrathecal} and intracardiac routes and are in very
`close proximity to the bloodstream must first undergo local penetration and
`permeation and then penetrate lecal capillaries in order to reach the blood-
`stream. At other extraVascular sites, such as intramuscular. subcutaneous.
`and intradermal, the drug is exposed to a relatively small localized region.
`From such regions, the drug travels to the blood or lymphatic circulation
`{only for high—molecular-Weight molecules) by means of physical penetration
`and permeation processes which are associated with passive diffusion and pars
`titioning through the capillary membrane and into the bloodstream
`
`Drug Solubility
`
`A major physicochemical criterion for absorption by passive diffusion and par—
`titioning is drug solubility. Regardless of the dosage form administered. a
`drug must be in solution in an aqueous system for it to be exposed to proces-
`ses that will eventually result in its absorption into the bloodstream. Only
`the fraction of drug in solution is available for absorption. Drugs that remain
`in solution at the injection site are generally absorbed quickly and easily, all
`other influencing factors being constant.
`A critical difference between the pH of the administered drug solution and
`the physiological pH at the injection site (andior solubility of the drug in a
`cosolvent vehicle and in physiological tissue fluid) can cause an unpredicted
`decrease in absorption due to precipitation of the drug at the injection site.
`Phenytoin, a commercial brand of diphenylhydsntoin., is a very insoluble free
`acid and is formulated as the sodium salt in a solution of 40% propylene glycol,
`10% alcohol, and water for injection. The pH must be adjusted to pH 12 with
`sodium hydroxide to solubilise the drug. The propylene EIYCOI helps to solu-
`bilize the free acid fraction available at this pH. When injected into muscle
`tissue the large difference in pH causes conversion of the sodium salt to the
`less soluble free acid which precipitates .in tissue fluids at the injection site.
`Simultaneous dilution of the propylene glycol with tissue fluid contributes to
`free acid precipitation. Most of the drug is therefore available only slowly.
`depending predominantly 0n the dissolution rate of diphenylhydantoin crystals.
`Thus camplete absorption takes 4 to 5 days [10] . Similar reductions in bio~
`availability due to drug precipitation caused by pH and solubility changes
`have been reported for Diasepam Injection [11] , Ghlordiasepoxlde Injection
`[l2] , and Digoxin Injection [13] .
`
`Passive Diffusion
`
`Passive diffusion involves the spontaneous movement of solute molecules in
`solution from an area of higher concentration on one side of a semipermeable
`membrane to an area of lower concentration on the other side of the membrane.
`
`In the biological system, a drug in solution passes from the extracellular to
`the intracellular tissue fluids by passive diffusion.
`The rate of passage of a drug through a biological membrane by passive
`diffusion is affected by several physicochemical factors. such as concentration
`gradient. partition coefficient, ionization. macromolecular binding, and os-
`molallty. in addition to differences in physical form of the medication.
`
`AstraZer-leca Exhibit 2113 p. 10
`
`

`

`62
`
`Mototo
`
`Concentration Gradient. The rate at which a drug molecule crosses a semi~
`permeable membrane by passive diffusion is described by Fick's law, cxpresssd
`by the following equation for the unidirectional case:
`
`g3 u DA‘IC1 w CZ)
`
`dt
`
`R
`
`(1)
`
`where
`
`33% = Flux or amount of transfer of substance per unit of time
`D
`'- diffusion constant
`A
`-
`surface area available for diffusion
`
`Cl = concentration of diffusing" substance in extracellular fluid
`02 2
`concentration of diffusete in the intracellular fluid
`9.
`=
`thickness of the membrane
`
`For any particular membrane where A, and E are constant, the diffusion rate
`is controlled by D(Cl ~ C12). The magnitude of the diffusion constant B is in~
`fluenced by the physicochemical properties of the drug molecule and the char”
`acteristics of the membrane.
`
`For any given drug in 9. contained in vitro system, the rate of oessive
`diffusion is controlled by the cencentretion gradient (C 1 ~ Cg) that exists be"
`tween both sides of the memhrene. The rate at which drug molecules move
`from side 1 to side 2 will decrease as the magnitude of C2 decreases and apprw
`aches C 1~ When 01 equals 02 the system is at equilibrium This is described
`mathematically as follows:
`
`INC ‘* C)
`in: W12
`
`Slow
`{it “D
`
`(2)
`
`(3)
`
`However, the concentration gradient (C1 - C3) does not become a rate-limiting
`factor in vivo because of unidirectional movement of the drug through the
`membrane.
`In this case, as the drug reaches the other side of the membrane
`it is removed by the blood, leading to distribution, metabolism, andlor excre-
`tiOn. Therefore, Cl remains considerany greater than C2 at all times until
`the transfer is complete. This is referred to as a “sink” condition and Eque~
`tion (2) reduces to
`
`m__ M
`
`(4)
`
`Partition Coefficient. The distribution of a solute between an aqueous
`
`environment and a lipid membrane is analogous to the distribution of a solute
`between two immiscible solvents such as water and oil. This type of distrihw
`
`AstraZeneca Exhibit 2113 p. 11
`
`

`

`Biophcr'moceutics of miserable Medication
`
`63
`
`tion, called partitioning, plays an important role: in passive diffusion. The
`equation that describes partitioning is:
`
`c
`Partition coefficient (PC) = K = c—8
`b
`
`(5)
`
`where, by convention,
`c
`concentration of solute in the on or lipid phase
`c: = concentration of nonionized solute in the aqueous phase at a de-
`fined 191-!
`= partltibn coefficient
`
`K
`
`The influence of the partition coefficient on passive diffusion of a drug through
`a biological membrane can be illustrated by considering the relative transfer of
`drugs with high and low partition coefficients. A drug: with. a. high partition
`coefficient (lipid soluble) will pass readily from. the aqueous phase into the
`membrane, whereas one with a low partition. coefficient (water soluble) will
`remain in the aqueous phase and not pass appreciably into the membrane. As
`stated earlier. in a biological system. diffusion takes place as a unidirectional
`process; this is equally true for the process of partitioning. The drug with
`a higher partition coefficient will exhibit a higher rate of diffusion .. do ldt.
`Thus lipid—soluble drugs are absorbed and distributed more rapidly than are
`water- soluble drug‘s.
`
`Ionization. Whereas partitioning of neutral moleoules takes place in rela~
`tion to their oil-water solubility, this is not true for ionized drug's.
`Ionization
`has a profound effect on drug absorption ,. distribution, and excretion. The
`degree of ionization of an acid or base is determined by the ionization constant
`of the compound,- pKa, in addition to the pH , temperature, and ionic strength
`of the solution. Since in a biological system temperature and ionic strength
`are essentially constant, their influence can be neglected.
`The relationship between pH and pKa can be readily seen by the fullowing
`derivation.
`In water, a weak acid, HA. ionizes (or dissociates) according to
`the following equation:
`
`HA + H20 vi 1130+ + A"
`
`The equilibrium constant for the reaction is written conventionale as
`
`[1130*] HQ
`[HA1 [H20]
`
`Keq *
`
`(a)
`
`(7)
`
`Since the molar concentration of water (55.3 mol liter’l at 25°C) is much larger
`than any of the other values and remains essentially constant during the reac-
`tion. one can write
`
`[H305 [A‘J
`Keq [H20] =Kion = WT—
`
`(8)
`
`AsUacheca Exhibit 2113 p. 12
`
`

`

`64
`
`Morale
`
`Taking- the logarithm of both sides of Equation (8) and transposing- log Kim
`and log- [H30+] to opposite sides yields
`
`-
`
`.Léi
`+ _ _
`log [H30 ] — log Kion +103; [HA]
`
`(9)
`
`By employing conventional definitions for pH and min, Equation (9) becomes
`
`__
`
`pH _ pKB + log #15
`
`A~l
`
`(10)
`
`Equation (10) , known as the Henderson-Hasselbach equation, is very useml
`in predicting the ionization properties of weak acids and bases, particularly
`with respect to their ability to partition into lipid-s.
`A similar equation describes the ionization of a. Weak base, but by conven-
`tion, the reaction is written as the ionization of the protonated weak base, BH":
`
`BH+ + on}; B + P120
`
`yielding
`
`l
`pH = pKa + log
`
`
`[B1
`[BE ]
`l
`
`(11)
`
`{12)
`
`where the symbol 'pK designates the ionization of the protonated base.
`Several obviou gut important relationships between pH and pita can be
`seen through inspection of Equation (10-) , particularly as they affect partition-
`ing:
`
`1. When the concentration of acid. [HA] equals the concentration of the
`anion [A'] in a solution of a weak acid, the ratio [A‘] [[HA] 2 1. Since
`log 1 = 0, pH = pKa.
`2. The degree of ionization of" weal: acids and bases changes rapidly as
`the difference between pH and pKa becomes greater until the pH value
`of the solution is 2 units away from pKa, at which time further changes
`in pH have little effect on the degree of ionization of the acid. or base.
`This concept can be easily demontrated by rearranging Equation (10)
`to the form
`
`pH - pKa -= log
`
`
`[11‘]
`[HA]
`
`“3’
`
`and examining the difference in the ratio log [A‘] {[HA] as the differ—
`ence, pH — pita.- goes through changes from 2 to. 0.01 as 3110er below:
`
`.
`_
`pH pita
`
`
`= um =
`logmA]
`
`2
`
`1
`
`Ionized form [A'I
`
`= 100
`
`10
`
`Nonionized form [HA] =
`
`l
`
`1
`
`G
`
`1
`
`1
`
`0.1
`
`0.01
`
`1
`
`10
`
`1
`
`100
`
`Therefore, if there were a 3 unit difference betWeen pH and pKa,
`one would only see less than a 1% further change in ionization.
`
`Astra-Zeneca Exhibit 2113 p. 13'
`
`

`

`Biophormaceutics or Injectebls Medication
`
`E5
`
`3. When dealing with ionized and nonionized forms of a drug, the rela-
`tionship to lipid solubility and partition coefficient becomes apparent.
`The neutral (nonionized) fraction of the drug is more readily parti-
`tioned into the nonpolar lipid membrane. During partitioning of the
`nonionised molecule the fraction of remaining ionized drug rapidl}r
`equilibrates so that nonionized drug is again formed and available for
`partitioning. This dynamic process takes place until the entire drug
`partitions through the membrane.
`
`When the pH of a medium causes most of the drug to be in the ionized form
`(e.g. , medium 131-! = 7 for an acidic drug with pita == 5), slow absorption can
`be expected since the partitionable nonionized form constitutes only a small
`fraction of the total drug. less than 1% in the case above.
`A rank order demonstration of the effect of medium pH and drug: pita on
`partitioning is shown by the following hypothetical example. A beaker eon-
`talning a buffer solution is separated equally into two compartments by a semi-
`permeable lipid membrane [see Fig. 1) that allows only the nonionized weal:
`acid (pita = 5) to pass through. A quantity of the weak acid drug is dissolved
`in a negligible volume of" buffer solution; the solution is then quickly injected
`into the left compartment, resulting in a homogeneous solution in that compart-
`ment.
`
`After each equilibrium partitioning- step takes place (Le. , HA partitions
`through the membrane, leaving a- and n+ behind). the buffer 301mm on the
`right side of the membrane (side becoming enriched with EA) is replaced with
`fresh buffer. The species A' on the left side reequilabrates with H+ to form
`more HA and the process is repeated until eventually all the drug is partitioned
`as HA.
`
`Referring- to the Henderson-Hassolbach equation [Eq. (1011. consider the
`following two cases. which will demonstrate the effect of pH and pita on parti-
`tioning.
`
`
`
`Figure 1 Beaker containing buffer solution in which a semipermeable. lipid
`membrane separates the solution into two compartments. Weak acid HA placed
`in the left side equilibrates according to Equation (6) , allowing only HA. to
`partition through the membrane.
`
`AstraZeneca Exhibit 2113 p. 14
`
`

`

`
`
`66
`
`Motels
`
`In this
`Case 1: Buffer solution on both sides of the membrane at pH 5.
`case Equation (10) indicate that log [A'JIIHA] = 1; thus [A']
`= [HA].
`
`Thus 50% of the total weak acid is in the neutral form HA. able to partition
`through the membrane. The remaining ionized portiOn, A" , is unable to par-
`tition into lipid.
`The hypothetical profile for the system, based on the percent of HA re~
`maining in the left compartment versus the number of equilibrations and buf-
`fer solution replacements of the right compartment, is shown. in Figure 2. At
`pH 5 following four equilibrations . only 6% A" remains in the left compartment
`(approximately 94% of HA has partitioned).
`
`Case 2: Buffer solution in both campertmsnts at pH 7. Equation (10)
`now indicates that log [A'] ([HA] = 100. Substituting these
`values into Equation (10) yields
`
`100
`7=5+logT
`
`Therefore only 0.99 of the total drug, HA + A‘ . is in the term
`HA, able to be partitioned.
`
`The hypothetical profile for this. system under the conditions stated is shown
`in Figure 2.
`In this case at pH 7. after faur eqtfilihrations 96% HA remains in
`the left compartment and only 45511.38 been able to partition through the mem—
`brane. Since 0.99% of the amount of HA present can partition during each
`equilibration, one can calculate that it "would take 95 equilibrations (Le. ,
`94/0. 99) to partition the same amount of HA as was partitioned by four equili-
`brations at pH E in case 1.
`
`as.HAREMAINING
`
`
`
` s 1 a
`EQUILI'BRATIDNS
`
`
`
`Figure 2 Hypothetical case of oomparstive partitioning versus number of equili—
`brations for weak acid HA (pKa 5) , partitioning through a lipid membrane
`from buffer solutions at pH 5 (A) and pH 7 (0).
`
`Astra-Zoneca Exhibit 2113 p. 15
`
`

`

`Btophcrmoceutics of Injectchle Medication
`
`67
`
`These examples are meant to show the relationship between formulation
`pl—I, drug pKL, and the amounts of partitionable nonionized weak acid or week
`base species available for absorption from an. injectable solution dosage form.
`
`Binding to Macromolecules. Biological fluids contain macromolecules such
`as proteins which may have affinity for certain drugs. These macromolecules
`are generally too large to pass through biological membranes by filtration,
`nor do they haVe the lipid solubility required for passive diffusion. There—
`fore, they are confined within their immediate boundaries. When a. one be—
`comes adsorbed or oomplexed on such macromolecules. its effective "free." con-
`centration of diffusable form becomes lowered. The equation describing this
`reaciton is
`
`1.
`Drug + macromolecule f- drug — macromolectfle complex
`2
`
`k
`
`where
`
`k1 = adsorption rate constant
`k2 = desorption rate constant
`
`The equilibrium constant is then expressed as
`
`K = [drug - macroniolecule]
`[drug] [macromolecule]
`
`(14)
`
`[15)
`
`where K, the association constant, provides a quantitative measure of the
`affinity of the drug for the particular macromolecule. Significant binding to
`macromolecules such as serum protein reduces the concentration of free drug
`in the tissue fluids and hence reduces the rate of passive diffusion by lower-
`ing the concentration gradient in accordance with Ficlc‘s law [Eq. (1)]. Since
`binding is an equilibrium process and thus readily reversible, the drug can
`eVentually be desorbed.
`It is important to note that protein binding reduces
`the rate of passive diffusion but does not prevent it. Protein binding has a
`significant effect on passive diffusion when the drug is bound by more than
`90% because the desorption rate from the drug-protein complex is usually slow-
`er than the diffusion rate of the drug through membranes.
`
`Osmolality. A solution is osoosmotic with tissue fluid when the total cum-
`ber of dissolved particles in the two systems are equal.
`In general, injectable
`products are formulated to be isoosmotic to reduce the possibility of irritation
`that can result if osmotic differences. between tissue fluid or red blood cell
`
`contents and the injection product are great. The effect of'large differences
`in solution osmolality on passive diffusion can be described by considering the
`following conditions:
`(1) hypoosmotic, (2) isoosmotic, and (3) hyperosmotio.
`When an injection solution is hypoosmotic. it contains fewer solute particles
`than does the tissue fluid. Based on the law of" osmosis. solvent passes from
`a region of lower concentration of solute to one of lugher concentration to re-
`duce the pressure differential caused by the dissolved solute particle imbalance.
`Therefore, the extratrascular injection of a grossly hypocsmotic solution
`would cause the movement of fluid away from the repository injection site.
`In
`
`AsUacheca Exhibit 2113 p. 16
`
`

`

`68
`
`Motel-a
`
`this case, the apparent concentration of drug would increase, resulting in an
`incroaSe in rate of passive diffusion. Conversely, the extravascular injection
`of a grossly hyperosmotic solution causes an influx of fluid to the repository
`injection site, resulting in dilution of drug concentration and an apparent de-
`crease in rate of diffusion.
`Increasing the osmolality of atropine solutions by
`the addition of either prolidoxine chloride or sodium chloride led to an appar-
`ent reduction in intramuscular absorption,I determined by its effect on reduc-
`tion of heart rate [1?] . When an isooamotic solution is injected, there is no
`
`fluid flux either to or away from the injection site, hence no demonstrable
`effect on passive diffusion.
`It is important to differentiate between the terms isotonic and isoosmotic.
`They are synonymous only when the dissolved solute cannot pass through
`membranes of red blood cells. However, when such passage does occur, as
`with aqueous solutions of urea, alcohol, or boric acid, the solution acts as if
`it were pure water and both solute and solvent pass through the membrane
`into the red blood cells, causing them to swell and burst (hemoly-sis). The
`solution was considered isotonic based on sodium chloride equivalent calcula-
`tions or as determined by its freezing-point depression; however. it was ac-
`tually hypotonic or hypoosmotic with respect to red blood cells. The term
`isotonic should be used Only to describe solutions having equal osmotic pres-
`sures with respect to a particular membrane. Therefore, it is important to
`examine the osmotic behavior of new drug substances toward red blood cells
`befiore deciding whether an adjustment is to be made.
`In order to make an
`isooamotic aqueous solution of a nonoamotic contributing substance such as
`urea, an external agent such as sodium chloride, sorbitol, or other osmotic—
`producing substance must be added at its isotonic level. such as 0. 9% sodium
`chloride.
`
`Volume of Injection- From Fields law, far the sink condition ((32 = D} it
`was shown by Equation (4) that do ldt = K01. When the volume V1 of drug
`solution at the shoorption site remains neaflyr constant, the rate of passive
`diffusion will be equal to
`
`.
`9.9. =
`dt
`
`A
`.1
`K v1
`
`(13)
`
`where A1 is the amount of drug at the site at any,' time. Thus the diffusion
`rate is inversely proportional to volume V1, and absorption rates should in-
`crease when volumes decrease [3] . Smaller injected. volumes have been re-
`ported to enhance drug absorption [18] . Another way of expressing this is
`to consider the ratio of tissue surface area to volume of injection. An. increase
`in injection volume with a relatively confined area results in a lowering of the
`tissue surface area—to-volume ratio. Since passive diffusion is directly propor—
`tional to surface area, an increase in injection volume should cause a lowering
`in the rate of passive diffusion. A physiological reason to keep injection vol-
`umes small is to help minimize or reduce pain caused by hydrostati