Pharmaceutical
`Dosage Forms:
`Parenteral Medications
`Volume1
`
`Second Edition, Revised and Expanded
`Edited by
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A·. Lieberman
`
`H.H. Lieberman Associates, Inc.
`Consultant Services
`Livingston, New Jersey
`
`Leon Lachman
`
`Lachman Consultant Services
`Westbury, New York
`
`Marcel Dekker, Inc.
`
`New York • Basel • Hong Kong
`
`MYLAN PHARMS. INC. EXHIBIT 1024 PAGE 1
`
`

`
`Li brary of Cong r ess Cataloging - in - Pub lication Data
`
`2nd ed. ,
`
`Pharmaceutical dosage forms, parenteral medications I edited by
`Kenneth E. A vis, Herbert A. Lieberman, and Leon Lachman .
`rev. and expanded.
`cm.
`p.
`Includes bibliographical references and index.
`ISBN 0-8247-8576-2 (v. 1 : alk. paper)
`1. Parenteral solutions . 2. Pharmaceutical technology. I. Avis,
`Kenneth E. II. Lieberman, Herbert A.
`III . Lachman, Leon.
`[DNLM: 1. Infusions, Parenteral. 2. Technology, Pharmaceutical.
`WB 354 P536]
`RS201.P37P48 1992
`615'. 19-- dc20
`DNLM/DLC
`for Library of ConITT'ess
`
`91 -38063
`CIP
`
`This book is printed on acid-free paper.
`
`Copyright @ 1992 by MARCEL DEKKER, INC. All Rights Reser ved
`
`Neither this book nor any part may be reproduced or transmitted in any form
`or by any means, electronic or mechanical, including photocopying, micro(cid:173)
`filming, and recording, or by any information storage and retr ieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing Oast digit):
`1098765432 1
`
`PRINTED JN T HE UNITED STAT ES OF AMERICA
`
`MYLAN PHARMS. INC. EXHIBIT 1024 PAGE 2
`
`

`
`5
`.formulation of Small Volume
`Parenterals
`
`Patrick P. De l uca
`
`University of Kentucky College of Pharmacy, Lexington, J(entucky
`
`J ames C. Boy lan
`
`Abbott Laboratories, Abbott Park, Illinois
`
`I.
`
`I NT RO DU CTI ON
`
`Whereas a parenteral can be defined as a sterile drug, solution, or suspension
`that is packaged in a manner suitabl~ for administration by hypodermic injec(cid:173)
`tion, either in the form prepared or following the addition of a s uitable solv(cid:173)
`ent or suspending agent [ 1] , the term small volume parenteral (SVP) has been
`officially defined by the United States Pharmacopeia (USP) [2] as" .
`.
`. an
`injection that is packaged in containers labeled as containing· 100 ml or less . "
`The USP categorizes sterile preparations for parenteral use according to the
`physical state of the product as follows:
`
`1. Solutions or emulsions of medicameµts suitable for injection
`2. Dry solids or liquid concentrates containing no additives which, upon
`the addition ·of suitable solvents, yield solutions conforming in all
`respects to requirements for injections
`3. Preparations the same as describe d in class 2 but containing one or
`more additional substances
`4. Suspensions of solids in a suitable medium which are not to be injected
`intravenously or into the spinal column
`5. Dry solids which, upon the addition of suitable vehicles, become
`sterile· suspensions
`
`"
`Althou gh the t erm sterile pharmaceuticals is applicable to all i njections (r adio-
`pharmaceuticals included), ophthalmic preparations, and irrigating solutions,
`this chapter emphasizes the formulation ,of injectable dosage forms.
`The successful formulation of an injectable preparation requires a broad
`knowledge of physical, chemical, and biological principles as well as expertise
`in the application of these principles . Such knowledge and expertise are re(cid:173)
`quired to effect rational decisions regarding the selection of:
`( 1) a suitable
`
`173
`
`MYLAN PHARMS. INC. EXHIBIT 1024 PAGE 3
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`

`
`174
`
`. DeLuca and Boylan
`
`vehicle (aqueous, nonaqueous, or cosolvent); (2) added substances (anti(cid:173)
`microbial ag·ents, antioxidants, buffers, chelating agents, and tonicity con(cid:173)
`tributors); and (3) the .appropriate container and container components. In(cid:173)
`herent in the above decisions is the obligatory concern for product safety,
`eff'eC'.tiveness, stability, and reliability. This chapter focuses on the physical(cid:173)
`chemical aspects of preparing a stable product in a suitable container recog(cid:173)
`nizing that safety must be established through evaluation of toxicity, tissue
`tolerance, pyrog·enicity, sterility, and tonicity, and efficacy must be demon(cid:173)
`strated through controlled clinical investigations.
`The majority of parenteral products a1•e aqueous solutions, preferred be(cid:173)
`cause of their physiologic compatibility and versatility with reg·ard to route
`of administration. However, cosolvents or nonaqueous substances are often
`required to effect solution or stability. Furthermore, the desired properties
`are sometimes attained throug·h the use of a suspension or an emulsion. Al(cid:173)
`though each of these dosage forms have distinctive characteristics and formu(cid:173)
`lation requirements, certain physical-chemical principles are common. Those
`common principles will be discussed in a g·eneral manner and the differences
`distinctive of each system will be emphasized. It is important to recognize
`that the pharmaceutical products derived from biotechnology are on the in(cid:173)
`c rease and the formulation of these products requires some unique skills and
`novel approaches. An attempt will be made to cover some of the formulation
`approaches for proteins and peptides .
`
`II. FORMULATION PRINCIPLES
`
`A.
`
`Influence of the Route of Administration
`
`Since parenteral preparations are introduced directly into the intra- or extra(cid:173)
`cellular fluid compartments , the lymphatic system, or the blood, the nature
`of the product and the desired pharmacological action are factors determining
`the particular route of administration tq be employed. The desired route of
`administration,_ in turn, places certain requirements and limitations on the
`formulations as well as the devices used for administering the dosage forms.
`Consequently, a variety of routes of administration (see Chap. 2) are cur(cid:173)
`rently used for parenteral products.
`One of the most important considerations in formulating a parenteral prod(cid:173)
`uct is the· appropriate volume into which the drug should be incorporated.
`The intravenous route is the only route by which large volumes (i.e., greater
`than 10 ml) can be administered, although the rate of administration must be
`carefully controlled. Volumes up to 10 ml can be administered intraspinally,
`while the intramuscular route is normally limfted to 3 ml, subcutaneous to 2
`ml and intradermal to 0. 2 ml.
`The choice of the solvent system or vehicle is directly related to the in(cid:173)
`tended route of administration of the product. Intravenous and intraspinal
`injections are generally res~ricted to dilute aqueous solutions, whereas oily
`solutions, cosolvent solutions, suspensions, and emulsions can be injected
`intramuscularly and subcutaneously.
`Isotonicity is another fac:tor that must be taken into consideration. Al(cid:173)
`though isotonic solutions are' less irritating, cause less toxicity and eiiminate
`the possibility of hemolysis, it is not essential that all injections be isotonic .
`In fact, for subcutaneous and intramus.cular injections hypertonic solutions
`
`MYLAN PHARMS. INC. EXHIBIT 1024 PAGE 4
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`

`
`192
`
`DeLuca and Boylnn
`
`Sterile WFI and Bacteriostatic WFI are permitted to contain higher levels
`of solids than WFI because of the possible leaching· of glass container con(cid:173)
`stituents into the water during sterilization and storag·e. Bacteriostatic WFl
`should not be sold in container~ larger: than 30 ml to prevent injection of un(cid:173)
`acceptably large amounts of bacteriostatic ag·ents (such as phenol and thi (cid:173)
`merosal).
`
`Water Miscible. These cosolvents have already been discussed. Although
`water- miscible solvents are used in parenterals, principally to enhance drug
`solubility, it is important to mention that they also serve as stabilizers for
`those drugs that degrade by hydrolysis. Mixed-solvent systems may be irri(cid:173)
`tating or increase toxicity, especially when present in large amounts or higher
`concentrations. A solution containing a high percentage of ethanol will pro (cid:173)
`duce pain on injection. It is also important to be aware that when such prep(cid:173)
`arations are administered intravenously, too rapid an injection could result
`in the precipitation of the drug in the blood stream [ 25]. Excellent reviews
`of water-miscible solvents used in parenteral products have been published
`[16,17].
`Nonaq ueous . Drugs that are insoluble in aqueous systems are often incor(cid:173)
`porated in metabolizable oils. Steroids, hormones, and vitamins are incor(cid:173)
`porated in veg·etable oils such as peanut, sesame, corn, olive, and cottonseed.
`Oil injections are only administered intramuscularly. There are strict speci(cid:173)
`fications for the vegetable oils used in manufacturing intramuscular injections.
`Storage of these preparations is important if stability is to be maintained.
`For example, they should not be subjected to conditions above room tempera(cid:173)
`ture for extended periods of time. Although the oils used for injections are
`of vegetable origin, federal r~gulations require that the specific oil be listed
`on the label of a product, because some patients have exhibited allergic r e (cid:173)
`sponses to certain vegetable oils.
`Sesame oil is the preferred oil for most of the compendia! injections formu (cid:173)
`lated with oil.
`lt is the most stable of the vegetable oils (except to lig·ht),
`because it contains natural antioxidants. Sesame oil has also been used to
`obtain slow release of fluphenazine esters given intramuscularly [ 41]. Ex(cid:173)
`cessive unsaturation of an oil can produce tissue irritation. The use of in(cid:173)
`jections in oil has diminished somewhat in preference to aqueous suspensions,
`which generally have less irritating and sensitizing properties. Benzyl ben(cid:173)
`zoate may be used to enhance steroid solubility in oils if desired. Table 4
`summarizes the oil injections official in USP XXII .
`
`C. Added Substances
`
`Added substances such as antioxidants, buffers, bulking· agents, chelating
`agents. antimicrobial agents, solubilizing agents, surfactants, and tonicity(cid:173)
`adjusting agents must frequently be incorporated into parenteral formulas in
`order to provide safe, efficaciou_s, and elegant parenteral dosage forms . Any
`additive to a formulation must be justified by a clear purpose and function.
`Hospital pharmacists who are involved in intravenous additive programs should
`be aware of the types of additives present in products that are being com ~
`bined .
`Pharmacopeias often specify the type and amount of additive substances
`that qiay be included in injectable products. These requirements often vary
`
`MYLAN PHARMS. INC. EXHIBIT 1024 PAGE 5