Pharmaceutical
`Dosage Forms
`·and Drug
`Delivery Systems
`
`Howard C. Ansel, Ph.D.
`Panoz Professor of Pharmacy, Department of
`Pharmaceutics, College of Pharmacy
`The University of Georgia
`
`Nicholas G. Popovich, Ph.D.
`Professor and Head, Department of Pharmacy
`Practice, School of Pharmacy and Pharmacal
`Sciences
`Purdue University
`
`Loyd V. Allen, Jr., Ph.D.
`. .
`Professor and Chair, Department of Medicinal
`Chemistry and Pharmaceutics, College of
`Pharmacy
`The University of Oklahoma
`
`SIXTH EDITION
`
`A Lea & Febiger Book
`
`Williams & Wilkins
`
`BALTIMORE • PHILADELPHIA • HONG KONG
`LONDON• MUNICH• SYDNE.Y • TOKYO
`
`A WAVERLY COMPANY
`
`1995
`
`Novartis Exhibit 2185.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Copyright © 1995
`Williams & Wilkins ·
`200 Chester Field Parkway
`Malvern, PA 19355 USA
`
`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.
`·
`·
`Accurate indications, a.dverse reactions, and dosage schedules for drugs are provided in this book, but it is pos(cid:173)
`sible they may charige·. The reader is urged to review the package information data of the manufacturers of the
`medications mentioned.
`Printed in the United States of America
`
`Library of Congress Cataioging in Publication Data
`
`94 95 96 97 98
`1 2 3 4 5 6 7 8 9 10
`
`Ansel, Howard C., 1933-
`··.
`Pharmaceuticai dosage forms and drug delivery systems / Howard C.
`· Ansel, Nicholas G. Popovich, Lloyd V. Allen, Jr.-6th ed.
`p. cm. -
`Includes bibliographical references and index.
`ISBN 0-683-00193-0
`1. Drugs-Dosage forms. 2. Drug delivery systems.
`II. Allen, Loyd V. m. Title.
`:i. Popovich, Nicholas G.
`[DNLM: 1. Dosage Forms. 2. Drug Delivery Systems. QV 785 A618i
`1995]
`RS200.A57 1995
`615'.l-dc20
`DNLM/DLC
`for Library of Congress
`
`94-22471
`CIP
`.
`
`·
`
`The use of portions of the text of USP23/NF18~ copyright 1994, is by permiss~on Jf the USP Convention, Inc.
`
`The Convention is not responsible for any inaccuracy of quotation or for any false or misleading implication
`that may arise from separation of excerpts from the original context or by obsolescence resulting from publica-
`tion of a supplement.
`·
`
`PRINTED IN THE UNITED STATES OF AMERICA
`Print No. 4 3 2 1
`
`Ii,.
`
`Novartis Exhibit 2185.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`-
`
`Contents
`
`CHAPTER 1
`
`Introduction to Drugs and Pharmacy
`CHAPTER2
`New Drug Development and Approval Process
`
`CHAPTER3
`Dosage Form Design: Biopharmaceutic
`Considerations
`·
`
`CHAPTER4
`Dosage Form Design: General Considerations,
`· Pharmaceutic Ingredients, and Current Good
`Manufacturing Practice
`
`CHAPTERS
`Peroral Solids, Capsules, Tablets, and Controlled(cid:173)
`Release Dosage Forms
`
`CHAPTER6
`Oral Solutions, Syrups, and Elixirs
`CHAPTER 7
`Oral Suspensions, Emulsions, Magmas, and Gels
`CHAPTERS
`Parenteral Medications and Sterile Fluids
`CHAPTER9
`Biotechnology and Drugs
`CHAPTER 10
`· Transdermal Drug Delivery Systems, Ointments,
`Creams, Lotions, and Other Preparations
`
`CHAPTER 11
`Ophthalmic, Nasal, Otic, and Oral Preparations
`Applied Topically
`
`CHAPTER 12
`Suppositories and Other Rectal, Vaginal, and
`Urethral Preparations
`
`CHAPTER 13
`Aerosols, Inhalations, and Sprays
`CHAPTER 14
`Radiopharmaceuticals and Miscellaneous
`Preparations
`
`1
`
`21
`
`55
`
`99
`
`155
`
`226
`
`253
`
`286
`
`337
`
`357
`
`396
`
`424
`
`443
`
`460
`
`xi
`
`Novartis Exhibit 2185.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Parenteral Medications and Sterile Fluids
`
`CONSIDERED IN this chapter are important phar(cid:173)
`maceutical dosage forms that have the common
`characteristic pf being prepared to be. sterile; that
`is, free from contaminating microorganisms.
`Among these sterile dosage forms are the var(cid:173)
`ious small- and large-volume injectable prepara(cid:173)
`tions, irrigation fluids intended to bathe body
`wounds or surgical openings, dialysis solutions,
`biological preparations as vaccines, toxoids, anti(cid:173)
`toxins, and blood replenishment products. Steril(cid:173)
`ity in these preparations is of utmost importance
`because they are placed in direct contact with
`the internal body fluids or tissues where infec(cid:173)
`tion can easily arise. Ophthalmic preparations
`which are also prepared to be sterile will be dis(cid:173)
`cussed separately in Chapter 11.
`
`Injections
`Injections are sterile, pyrogen-free prepara(cid:173)
`tions intended to be administered parenterally.
`The term parenteral refers to the injectable routes
`of administration. The term has its derivation
`from the Greek words para and enteron, meaning
`outside of the intestine, and denotes routes of
`administration other than the oral route. Pyro(cid:173)
`gens are fever-producing organic substances aris(cid:173)
`ing from microbial contamination and are re(cid:173)
`sponsible for many of the febrile reactions which
`occur in patients following intravenous injection.
`Pyrogens and the determination of their pres(cid:173)
`ence in parenteral preparations will be discussed
`later in this chapter. In general, the parenteral ·
`routes of administration are undertaken when
`rapid drug action is desired, as in emergency
`situations; when the patient is uncooperative,
`unconscious, or unable to accept or tolerate med(cid:173)
`ication by the oral route, or when the drug itself
`is ineffective by other routes. With the exception
`of insulin injections, which are con;unonly self(cid:173)
`administered by diabetic patients, 'most injec(cid:173)
`tions are administered by the physician, his as-
`
`286
`
`sistant, or nurse in the course of medical treat(cid:173)
`ment. Thus injections are employed mostly in
`the hospital, extended . care facility, and clinic
`and less frequently in the home. An exception
`would be in home health care programs in which
`health professionals pay scheduled visits to pa(cid:173)
`tients in their homes, providing needed treat(cid:173)
`ment, including intravenous medications. These
`programs enable patients who do not require or
`are unable to pay for more expensive hospitaliza(cid:173)
`tion to remain in the familiar surroundings of
`their homes while receiving appropriate medical
`care. The pharmacist supplies injectable prepara(cid:173)
`tions to the phy~ician and nurse~ as required for
`their use in the institutional setting, clinic, office,
`or home health care program.
`Perhaps the earliest injectable drug to receive
`official recognition was the hypodermic mor(cid:173)
`phine solution which appeared first in the 1874
`addendum to the 1867 British Pharmacopeia,
`and later, in 1888 in the first edition of the Na(cid:173)
`tional Formulary of the United States. Today,
`there are literally hundreds of drugs and drug
`products available for parenteral administration.
`Interesting historical accounts of the origin
`and development of injection therapy may be
`found in the references cited.
`
`Parenteral Routes of Administration
`Drugs may be injected into almost any organ
`or area of the body, including the joints (intra(cid:173)
`articular ), a joint-fluid area (intrasynovial), the
`spinal column (intraspinal), into spinal fluid (in(cid:173)
`trathecal), arteries (intra-arterial), and in an emer(cid:173)
`gency, even into the heart (intracardiac). Hoo/(cid:173)
`ever, most commonly injections are performed
`into a vein (intravenous, I. V.), into a muscle (intra(cid:173)
`muscular, IM.), into the skin (Intradermal, J.D.,
`intracutaneous), or under the skin (subcutaneous,
`S.C., Sub-Q, 5_.Q., hypodermic, "Hypo.") (Fig. 8-1).
`
`Novartis Exhibit 2185.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Parenteral Medications and Sterile Fluids
`
`287
`
`Dermis
`
`Subcutaneous
`Tissue
`
`S1,1llCL1taneous
`Adipose
`Tissue
`
`Muscle and Vein
`
`Fig. 8-1. Routes of parenteral administration. Numbers on needles indicate size or gauge of needle based on outside diameter
`of needle shaft. (Turco, S. and King, R.E., Sterile Dosage Forms: Their Preparation and Clinical Applications. 3rd Ed.,
`Courtesy of Lea & Febiger, 1987.)
`
`Intravenous Route
`The intravenous injection of drugs had its sci(cid:173)
`entific origin in 1656 in the experiments of Sir
`Christopher Wren, architect of St. Paul's Cathe(cid:173)
`dral and amateur physiologist. Using a bladder
`and quill for a syringe and needle, he injected
`wine, ale, opium, and other substances into the
`veins of dogs and studied their effects. Intrave(cid:173)
`nous medication was first given to man by Jo(cid:173)
`hann Daniel Major of Kiel in 1662, but was aban(cid:173)
`doned for a period because of the occurrence of
`thrombosis and embolism in the patients so
`treated. The invention of the hypodermic syringe
`toward the middle of the 19th century created a
`new interest in intravenous techniques· and to(cid:173)
`ward the turn of the century, intravenous admin(cid:173)
`istration of solutions of sodium chloride and glu(cid:173)
`cose became popular. Today, the intravenous
`administration of drugs is a routine occurrence
`in the hospital, although there are still recog(cid:173)
`nized dangers associated with the practice.
`Thrombus and embolus formation may be in(cid:173)
`duced by intravenous needles and catheters, and
`the possibility of particulate matter in parenteral
`solutions poses concern for those involved in the
`
`development, administration, and use of intrave(cid:173)
`nous solutions.
`Intravenously administered drugs provide
`rapid action compared to other routes of admin(cid:173)
`istration and because drug absorption is not a
`factor, optimum blood· levels may be achieved
`with the accuracy and immediacy not possible
`by other routes. In emergency situations, the in(cid:173)
`travenous administration of a drug may be a life(cid:173)
`saving procedure because of the placement of. the
`drug directly into the circulation and the prompt
`action which ensues. On the negative side, once
`a drug is administered intravenously, it cannot
`be retrieved. In the case of an adverse reaction to
`the drug, for instance, the drug cannot be easily
`removed from the circulation as it could, for ex(cid:173)
`ample, by the induction of vomiting following
`the oral administration of the same drug.
`Although most superficial veins are suitable
`for venipuncture, the veins of the antecubital
`area (situated in front of the elbow) are usually
`selected for direct intravenous injection. The
`veins in this location are large, superficial and
`easy to see and enter. Most clinicians insert the.
`needle with the bevel facing upward, at the most
`
`Novartis Exhibit 2185.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`288
`
`Parenteral Medications and Sterile Fluids
`
`acute angle possible with the vein, to ensure that
`the direction of flow of the injectable is that of
`the flow of the blood. Strict aseptic precautions
`must be taken at all times to avoid risk of infec(cid:173)
`tion. Not only are the injectable solutions sterile,
`the syringes and needles employed must also be
`sterilized and the point of entrance must be dis(cid:173)
`infected to reduce the chance of carrying bacteria
`from the skin into the blood via the needle. Prior
`to injection, administration personnel must with(cid:173)
`draw the plunger of the syringe or squeeze a
`special bulb found on most I.V. sets to ensure
`that the needle has been properly located. In both
`instances, a "flashback" of blood into the admin(cid:173)
`istration set or the syringe indicates proper
`placement of the needle within the vein.
`Both small and large volumes of drug solu(cid:173)
`tions may be administered intravenously. The
`use of 1000-mL containers of solutions for intra(cid:173)
`venous infusion is corrurion:place in the hospital.
`These solutions containing such agents as nu(cid:173)
`trients, blood extenders, electrolytes, amino
`acids, and other therapeutic agents are generally
`administered through an indwelling needle or
`catheter by continuous drip. The drip or flow
`rates may be adjusted by the clinician according
`to the needs of the patient. Generally, flow rates
`of 2 to 3 mL per minute are employed. For intra(cid:173)
`venous infusion, the needle or catheter is gener(cid:173)
`ally placed in the prominent veins of the forearm
`or leg and taped firmly to the patient so that it
`will not slip from place during infusion. The
`main hazard of intravenous infusion is the possi(cid:173)
`bility of thrombus formation induced by the
`touching of the. wall of the vein by the catheter
`or needle. Thrombi are more likely to occur when
`the infusion solution is of an irritating nature to
`the biologic tissues. A thrombus is a blood clot
`formed within the blood vessel (or heart) due
`usually to a slowing of the circulation or to an
`alteration of the blood or vessel wall. Once such
`a clot cixculates, it becomes an embolus, carried
`by the blood stream until it lodges in a blood
`vessel, obstructing it, and resulting in a blockage
`or occlusion: referred to as an embolism. Such an
`obstruction may be a critical hazard to the pa(cid:173)
`tient, depending upon the site and severity of
`the obstruction.
`Intravenously administered drugs ordinarily
`must be in aqueous solution; they must mix with
`the circulating blood and not precipitate from
`solution. Such· an event could lead to pulmonary
`rnicrocapillary occlusion and the subsequent
`blockage of blood passage. An intravenously de-
`
`livered fat emulsion (Intralipid, 10%, Clintec) has
`gained acceptance for use as a source of calories
`and essential fatty acids for patients requiring
`parenteral nutrition for extended periods of time
`(usually for more thanS days). The product con(cid:173)
`tains up to 20% soybean oil emulsified with egg
`yolk phospholipids, in.a vehicle of glycerin in
`water for injection. The emulsion is administered
`via a peripheral vein or by central venous infu(cid:173)
`sion.
`Naturally, the intravenous route is utilized in
`the administration of blood transfusions and it
`also serves as the point of exit in the. removal of
`blood from patients for diagnostic work and for
`obtc:tining blood from donors.
`In the late 1980s, automated intravenous deliv(cid:173)
`ery systems became commercially available for
`intermittent, self-administration of analgesics.
`Patient-controlled analgesia (PCA) has been
`used to control the pain associated with postop(cid:173)
`erative pain from a variety of surgical proce(cid:173)
`dures, labor, sickle cell crisis, and chronic pain
`associated with cancer. For patients with chronic
`malignant pain, PCA allows a greatex degree of
`ambulation and ihdependence.1
`The typical PCA device includes a syringe or
`chc:tmber that contains the analgesic drug and a
`programmable electomechanical unit. The unit,
`which might be compact enough to be worn on
`a belt or carried in a pocket (e.g., WalkMed®
`PCA-Medex, Inc.), controls the delivery of drug
`by advancing a piston when the patient presses
`a button. The drug can be loaded into the device
`by a health care professional or dispensed from
`preloaded cartridges available through the man(cid:173)
`ufacturer. The devices take advantage of intrave(cid:173)
`nous bolus injections to produce rapid analgesia,
`along with slower infusion to produce steady(cid:173)
`state opiate concentrations for sustained pain
`control.
`The advantage of the PCA is its ability to pro(cid:173)
`vide constant and uniform analgesia. The typical
`intramuscular injection of an opiod into a depot
`muscular site may result in variable absorption,
`leading to unpredictable blood concentrations.
`Further, these injections are usually given when
`needed and axe often inadequate to treat the
`pain. The PCA can prevent pharmacokinetic and
`pharmacodynarnic differences between patients
`from interfering with the effectiveness of analge(cid:173)
`sia. Because opiod kinetics differ greatly between
`patients, the rates of infusion must be tailored.2
`PCA devices can be 11sed for intravenous, sub(cid:173)
`cutaneous, or epidural. administration. Gener·
`
`Novartis Exhibit 2185.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Parenteral Medications and Sterile Fluids
`
`289
`
`sion and that drugs in aqueous preparations
`' would be more rapidly absorbed than when in
`oleaginous preparations. The physical type of
`preparation employed is based on the properties
`. of the drug itself and on the therapeutic goals
`desired.
`Intramuscular injections are performed deep
`into the skeletal muscles. The point of injection
`should be as far as possible from major nerves
`and blood vessels. Injuries to patients from intra(cid:173)
`muscular injection usually are related to the
`point at which the needle entered and where the
`medication was deposited. Such injuries include
`paralysis resulting from neural damage, ab(cid:173)
`scesses, cysts, embolism, hematoma, sloughing
`of the skin, and scar formation .
`In adults, the upper outer quadrant of the glu(cid:173)
`teus maximus is the most frequently used site
`for intramuscular injection. In infants, the gluteal
`area is small ai:td composed primarily of fat, not
`muscle. What muscle there is is poorly devel(cid:173)
`oped. An injection in this area might be pre,;.
`sented dangerously close to the sciatic nerve, es(cid:173)
`pecially if the child is resisting the injection and
`squirming or fighting. Thus, in infants and
`young children, the deltoid muscles of the upper .
`arm or the midlateral-muscles of the thigh are
`preferred. An injection given in the upper or
`lower portion of the deltoid would'.be well away
`from the radial nerve. The deltoid may also be
`used in adults, but the pain is more noticeable
`here than in the gluteal area. If a series of injec(cid:173)
`tions are to be given, the injection site is usually
`varied. To be certain that a blood vessel has not
`been entered, the clinician may aspirate slightly
`on the syringe following insertion of the needle
`to observe if blood enters ·the syringe. Usually,
`the volume of medication which may be conven(cid:173)
`iently administered by the intramuscular route
`is limited; generally a maximum of 5 mL is ad(cid:173)
`ministered intramuscularly in the gluteal region
`and 2 mL in the deltoid of the arm.
`The Z-Track Injection technique is useful for
`intramuscular injections of medications that
`stain upper tissue, e.g., iron dextran injection, or
`those that irritate tissue, e.g., Valium, by sealing
`these medications in the lower muscle. Because
`of its staining qualities, iron dextran injection,
`for example, must be injected only into the mus(cid:173)
`cle mass of the upper outer quadrant of the but(cid:173)
`tock. The skin is displaced laterally prior to injec(cid:173)
`tion, then the needle is inserted and syringe
`aspirated, and the injection performed slowly
`and smoothly. The needle is then withdrawn and
`
`. ;
`
`',:-:,.,, -~~::::· .
`'~$:~'.:'.
`
`. ">~~ ,1:: .. ri'.jl
`
`Fig. 8-2. PCA Plus II (LifeCare 4100)-Patient-controlled
`analgesic infuser. (Courtesy of Abbott Hospital Products
`Division.)
`
`ally, these devices are either demand dosing (i.e.,
`a fixed dose of drug is injected intermittently) or
`constant-rate infusion plus demand dosing.2 Regard(cid:173)
`less of type utilized, the physician or nurse estab(cid:173)
`lishes the loading dose, the. rate of background
`infusion, dose per demand, lockout interval (i.e.,
`minimum time between demand doses), and
`maximum dosage over a specified time interval.
`Fig. 8-2 demonstrates the PCA Plus II (Lifecare
`4100) infuser. With this '!,evice the patient pushes
`a button on a pendant to deliver a prescribed
`quantity of the analgesic.
`
`Intramuscular Route
`·
`Intramuscular injections of drugs provide
`drug effects that are less rapid, but generally of
`greater duration than those obtained from intra(cid:173)
`venous admil:ristration.3 Aqueous or oleaginous
`solutions or suspensions of drug substances may
`be administered intramuscularly. Depending
`upon the type of preparation employed; the ab(cid:173)
`sorption rates may vary widely. Generally it
`would be expected that drugs in solution would
`be more rapidly absorbed than those in suspen-
`
`Novartis Exhibit 2185.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`290
`
`Parenteral Medications and Sterile Fluids
`
`the skin released. This creates a "Z" pattern that
`blocks infiltration of medication into the subcu(cid:173)
`taneous tissue. The injection is 2 to 3 inches deep,
`and a 19- to 20-gauge needle is utilized. To fur(cid:173)
`ther prevent any staining of upper tissue, usually
`one needle is used to withdraw the iron dextran
`from J.ts ampul, and then replaced with another
`for the purposes of the injection.
`
`Subcutaneous Route
`
`The subcutaneous route may be utilized for
`the injection of small amounts of medication. The
`injection of a drug beneath the surface of the skin
`is usually made in the loose inters.titial tissues of
`the outer surface of the upper arm, the anterior
`surface of the thigh, and the lower portion of the
`abdomen. The site of injection is usually rotated
`when injections are frequently given, e.g., daily
`insulin injections. Prior to injection, the skin at
`the injection site should be thoroughly cleansed.
`The maximum amount of medication that can be
`comfortably injected subcutaneously is about 1.3
`mL and amounts greater than 2 mL will most
`likely cause painful pressure. Syringes with .up
`to 3 mL capacities and utilizing needles with 24
`to 26 gauges are · used for subcutaneous injec(cid:173)
`tions, These needles will have cannula lengths
`that vary between ¾ inch to 1 inch. Most typi(cid:173)
`cally, subcutaneous insulin needles are between
`25 to 28 gauge with needle length between ¾ to
`3/s inch. Upon insertion, if blood appears in the
`syringe a new site should be selected.
`Drugs which are irritating or those which are
`present in thick suspension form may produce
`induration, sloughing, or abscess formation and
`may be painful to the patient Such preparations
`should be considered not suitable for subcutane(cid:173)
`ous injection.
`
`Intradermal Route
`
`A number of substances may be effectively in(cid:173)
`jected into the corium, the more vascular layer
`of the skin just beneath the epidermis. These sub(cid:173)
`stances include various agents for diagnostic de(cid:173)
`terminations, desensitization, or immunization.
`The usual site for intradermal injection is the an(cid:173)
`terior surface of the forearm. A short (¾ in.) and
`narrow gauge (23- to 26-gauge) needle is usually
`employed. The needle is inserted horizontally
`into the skin with the bevel facing upward. The
`injection is made when the bevel just disappears
`into the corium. Usually only about 0.1 mL vol(cid:173)
`umes may be administered in this manner.
`
`Official Types of Injections
`According to the USP, injections are separated
`into five distinct types, generally defined as fol-
`lows:
`·
`
`1. Medicaments or solutions, or emulsions suit(cid:173)
`able for injection, bearing titles of the form,
`" _ _ _ Injection." (Ex: Insulin Injection,
`USP)
`2. Dry solids or liquid concel).trates containing
`no buffers, diluents, or other added sub(cid:173)
`stances, and which, upon the addition of
`suitable solvents, yield solutions conforming
`in all aspects to the requirements for injec(cid:173)
`tions, and which are distinguished by titles
`of the form, "Sterile _ _ _ '.' (Ex: Sterile
`Ampicillin Sodium, USP)
`3. Preparations the same as those described in
`(2) except that they contain one or more buff(cid:173)
`ers, diluents, or other added substances, and
`which are distinguished by titles of the form,
`11 ---for Injection" (Ex: Methicillin So(cid:173)
`dium for Injection, USP)
`4. Solids which are suspended in a suitable
`fluid medium and which are not to be in(cid:173)
`jected intravenously or into the spinal canal,
`distinguished by titles of the form, "Ster-
`ile _ _ _ Suspension." (Ex: Sterile Dexa-
`methasone Acetate Suspension, USP)
`5. Dry solids, which, upon the addition of suit(cid:173)
`able vehicles, yield preparations conforming
`in all respects to the requirements for Sterile
`Suspensions, and which are distinguished
`by titles of the form, "Sterile _ _ _ for Sus-
`pension." (Ex: Sterile Ampicillin for Suspen(cid:173)
`sion, USP)
`
`The form in which a given drug is prepared
`for parenteral use by the manufacturer depends
`upon the n,ature of the drug itself, with respect
`to its physical and chemical characteristics, and
`also upon certain therapeutic considerations.
`Generally, if a drug is unstable in solution, it
`may be prepared as a dry powder intended for
`reconstitution with the proper solvent at the time
`of its administration, or it may be prepared as a
`suspension of the drug particles in a vehicle in
`which the drug is insoluble. If the drug is un(cid:173)
`stable in the presence of water, that solvent may
`be replaced in part or totally by a solvent in
`which the drug is insoluble. If the drug is insolu(cid:173)
`ble in water, an injection may be prepared as all
`aqueous suspension or as a solution of the drug
`in a suitable nonaqueous solvent, such as a vege-
`
`I
`l
`j
`
`Novartis Exhibit 2185.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`table oil. If an aqueous solution is desired, a
`water-soluble salt form of the insoluble drug is
`frequently prepared to satisfy the required solu(cid:173)
`bility characteristics. Aqueous or blood-miscible
`solutions may be injected directly into the blood
`stream. Blood-immiscible liquids, e.g., oleagi(cid:173)
`nous injections and suspensions, can interrupt
`the normal flow of blood within the circulatory
`system, and their use is generally restricted to
`other than intravenous administration. The onset
`and d,uration of action ·of a drug may be some(cid:173)
`what controlled by the chemical form of the drug
`used, the physical state of the injeqion (solution
`or suspension), and the vehicle employed. Drugs
`that are very soluble in body fluids generally
`have the most rapid absorption and onset of ac(cid:173)
`tion. Thus, drugs in aqueous solution have a
`more rapid onset of action than do drugs in ole(cid:173)
`aginous solution. Drugs in aqueous suspension
`are also more rapid acting than drugs in oleagi(cid:173)
`nous suspension due to the greater miscibility
`of the aqueous preparation with the body fluids ·
`after injection and the subsequent more rapid
`contact of the drug particles with the body fluids.
`Oftentimes more prolonged drug action is de(cid:173)
`sired to reduce the necessity of frequently re(cid:173)
`peated injections. These long-acting types of in(cid:173)
`jections are commonly referred to a$ repository
`or "depot" types of preparations.
`The solutions and suspensions of drugs in(cid:173)
`tended for injection are prepared in the same
`general manner as was discussed previously in
`this text for oral solutions (Chapter 6) and oral
`suspensions (Chapter 7), with the following dif(cid:173)
`ferences:
`
`1. Solvents or vehicles used must meet special
`purity and other standards assuring their
`$afety by injection.
`2. The use of added, substances, as buffers, sta(cid:173)
`bilizers, and antimicrobial preservatives, fall
`under specific guidelines of use and are re(cid:173)
`stricted in certain parenteral products. The
`use of coloring agents is strictly prohibited.
`3. Parenteral products are always sterilized
`and meet sterility standards and must be py(cid:173)
`rogen-free.
`4. Parenteral solutions must meet compendia!
`standards for particulate matter.
`5: Parenteral products must be prepared in en(cid:173)
`vironmentally controlled areas, under strict
`sanitation standards, and by personnel spe(cid:173)
`cially trained and clothed to maintain the
`sanitation standards.
`
`Parenteral Medications and Sterile Fluids
`
`291
`
`6. Parenteral products are packaged in special
`hermetic containers of specific and high
`quality. Special quality control procedures
`are utilized to ensure their hermetic seal and
`sterile condition.
`7. Each container of an injection is filled to a
`volume in slight excess of the labeled "size''
`or volume to be withdrawn. This overfill per(cid:173)
`mits the ease of withdrawal and administra(cid:173)
`tion of the labeled volumes.
`8. There are restrictions over i:he volume of in(cid:173)
`jection permitted in multiple-dose contain(cid:173)
`ers and also a limitation over the types of
`containers (single-dose or multiple-dose)
`which may be used for certain injections.
`9. Specific labeling regulations apply to injec(cid:173)
`tions.
`10. Sterile powders intended for solution or sus(cid:173)
`pension immediately prior to injection are
`frequently packaged as lyophilized or freeze(cid:173)
`dried powders to permit ease of solution or
`suspension upon the addition of the solvent
`or vehicle.
`
`Solvents and Vehicles for Injections
`The most frequently used solvent in the large(cid:173)
`scale manufacturer of injections is Water for Injec(cid:173)
`tion, USP. This water is purified by distillation
`or by reverse osmosis and meets the same stan(cid:173)
`dards for the presence of total solids as does Puri(cid:173)
`fied Water, USP, not more than 1 mg per 100 mL
`Water for Injection, USP and may not contain
`added substances. Although water for injection
`is not required to be sterile, it must be pyrog~(cid:173)
`free. The water is intended to be used in the man(cid:173)
`uf~cture of injectable products which are to be
`sterilized after their preparation. Water for injec(cid:173)
`tion should be stored in tight containers at tem(cid:173)
`peratures below or above the range in which mi(cid:173)
`crobial growth occurs. Water for injection is
`intended to be used within 24 hours following
`its collection. Naturally, the water should be col(cid:173)
`lected in sterile and pyrogen-free containers. The
`containers are usually glass or glass-lined.
`Sterile Water for Injection, USP is water for injec(cid:173)
`tion which has been sterilized and packaged in
`single-dose containers of not greater than I-liter
`size. As water for injection, it must be pyrogen(cid:173)
`free and may not contain an antimicrobial agent
`or other added substance. This water may con(cid:173)
`tain a slightly greater amount of total solids than
`water for injection due to the leaching of solids··
`from the glass-lined tanks during the steriliza-
`
`Novartis Exhibit 2185.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`292
`
`Parenteral Medications and Sterile Fluids
`
`tion process. This water is intended to be used as
`a solvent,. vehicle or diluent for already-sterilized
`and. packaged injectable medications. The one(cid:173)
`liter bottles, cannot be ad.ministered. intrave(cid:173)
`nously because they have no tonicity .. Thus, they
`are used for reconstitution of multiple antibiot~
`ics. In use, the water is aseptically added. to the
`vial of medication to prepare the desired injec~
`tion. For fustam:e, a suitable injection may be· pre,-.
`pared from the dry powder, Sterile Ampicillin
`Sodium,. USP,. by the aseptic addition of sterile
`water for injection ..
`Bacteriostatic Water for Injection, USP is sterile
`water for injection containing one or more suita~
`ble antimicrobial: agents. If is packaged fu. pre(cid:173)
`filled syringes or in vial:s containing not more
`than30mLof the water. The container label must
`state the name and proportion of the antimicro,..
`bial agent(s) present. The water is employed as
`a sterile vehicle in the preparation of small vol(cid:173)
`umes of injectable preparations. The presence of
`the bacteriostatic agent gives the flexibility for
`multiple-dose vials. If the first person to with(cid:173)
`drawmedication inadvertently contaminates the
`vial contents, the preservative will destroy the
`microorganism. Because of the presence of anti(cid:173)
`mic!obial agents the water must only be used in
`parenterals that are administered in small vol(cid:173)
`umes. Its use in parenterals administered in large
`volume is restricted due to the excessive and per~
`haps toxic amounts of the antimicrobial agents
`which would be injected along with the medica(cid:173)
`tion. Generally, if volumes of greater than 5 mL
`of solvent are required, sterile water for injection
`rather than bacteriostatic water for injection is
`preferred. In using bacteriostatic water for injec(cid:173)
`tion, due regard must also be given to the chemi(cid:173)
`cal compatibility of the bacteriostatic. agent(s)
`present with the particular medicinal agent
`being dissolved or suspended.
`Sodium Chloride Injection, USP is a sterile iso(cid:173)
`tonic solution of sodium chloride in Water for
`Injection. It contains no antimicrobial agents. The
`sodi