`

`Editor: Donna Balado
`Managing Editor: jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott Wllliams & Wilkins
`
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`
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`
`All rights reserved. This book is protected by copyright. No part of this book may be re-
`produced in any form or by any means, including photocopying, or utilized by any infor—
`mation 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 in—
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturers’product information and pack—
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
`Library of Congress Cataloging-in-Publication Data
`
`Ansel, Howard C., 1933—
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, Lode. Allen, Jr, Nicholas G. Popovich. —— 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0—683—30572—7
`2. Drug delivery systems.
`1. Drugs—Dosage forms.
`11. Popovich, Nicholas G.
`III. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems, QV 785 A618i 1999]
`RS200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, Lode.
`
`99—17498
`CIP
`
`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 opportunity.
`-
`
`The use of portions of the text of USP23/NF18, copyright 1994, is by permission of 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 publication of a supplement.
`
`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.
`
`99 00 01 02
`1 2 3 4 5 6 7 8 9 10
`
`AstraZeneca Exhibit 2106 p. 2
`
`

`

`
`
`Contents
`
`Preface
`
`Acknowledgments
`
`Section I. PRINCIPLES OF DOSAGE FORM DESIGN AND DEVELOPMENT
`
`I
`
`2
`
`3
`
`4
`
`5
`
`Introduction to Drugs and Pharmacy
`
`New Drug Development and Approval Process
`
`Dosage Form Design: Pharmaceutic and
`Formulation Considerations
`'
`
`Dosage Form Design: Biopharmaceutic and
`Pharmacokinetic Considerations
`
`Current Good Manufacturing Practices and Good
`Compounding Practices
`
`Section II. SOLID DOSAGE FORMS AND MODIFIED-RELEASE DRUG DELIVERY SYSTEMS
`
`6
`
`7
`
`8
`
`Powders and Granules
`
`Capsules and Tablets
`
`‘
`
`Modified~Release Dosage Forms and Drug Delivery Systems
`
`Section III. SEMI-SOLID AND TRANSDERMAL SYSTEMS
`
`9
`
`IO
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`'244
`
`263
`
`ix'
`
`AstraZeneca Exhibit 2106 p. 3
`
`

`

`x
`
`Contents
`
`Section IV. PHARMAEEUTICAL INSERTS
`
`II
`
`Suppositories and Inserts
`
`Section V. LIQUID DOSAGE FORMS
`
`I 2
`
`I3
`
`S olutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`I 4
`
`I 5
`
`I6
`
`Parenterals
`
`Biologicals
`
`Ophthalmic Solutions and Suspensions
`
`Section VII. NOVEL AND ADVANEED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVIEES
`
`Radiopharmaceuticals
`
`Products of Biotechnology
`
`Novel Dosage Forms and Drug Delivery Technologies
`
`Systems and Techniques of Pharmaceutical Measurement
`
`I 7
`
`I8
`
`I9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
`AstraZeneca Exhibit 2106 p. 4
`
`

`

`Section VI. Sterile Dosage Forms and Delivery Systems
`
`PARENTERALS
`
`
`
`Chapter at a Glance
`
`Injections
`Parenteral Routes ofAdministration
`hit-ravenous Route
`httrsmuscula: Route
`Subcutaneous Route
`Intradermal Rouse
`
`Specialized Access
`Qfl‘imhl Types of Injections
`Solvents and Vehicles for Injections
`Nonaqueous Vehicles
`Added Substances-
`Methods ofSterilization
`Steam Sterilization
`
`Dry-Heat Sterilization
`Sterilization by Filtiation
`Gas Sterilization
`
`Sterilization by Ionizing Radiation
`Validation of Sterility
`Pyrosens and Prose“ Tesh'ns
`The Industrial Properation ofParenteral
`Products
`Packaging, Labeling, and Storage of Injec-
`lions
`Quality Assurancefor Pharmacy-Prepared
`Sterile Products
`
`Available Injections
`Small Volume Parenterals-
`Insulin Injection (Regular)
`Human Insulin
`
`Lispro Insulin Solution
`IsoPhane Insulin Suspension
`(NPH Insulin)
`lsoplmne Insulin Suspension and
`Insulin Injection
`Insulin Zinc SuSpension
`Extended Insulin Zinc Suspension
`Prompt Insulin Zinc Suspension
`Insulin Infilsion Pumps
`Large Volume Pare-metals (LVPs)
`Maintenance Therapy
`Replacement Therapy
`Water Requirement
`Electrolyte Requirement
`Caloric Requirements
`Parenteral Hyperelimeniaiion
`Enterel Nutrition
`
`In-tmoenous Infilsion Devices
`Special considerations associated with
`parenteral therapy
`Adsorption of Drugs
`Handling/Disposal of Chemotherapeutic
`Agentsfor Cancer
`Other Eject-able Products—Pellets or
`Implants
`Leoonorgestrel Implants
`Inigalion and Dialysis Solutions
`Irrigation Solutions
`Dialysis Solutious
`
`CONSIDERED 1N this chapter are important pharma-
`ceutical dosage forms that have the common char-
`acteristic of being prepared to be sterile; that is, free
`from contaminating microorganismsAmongthese
`sterile dosage forms axe the various small— and
`large-volume injectable preparations, ioigafion flu-
`
`ids intended to bathe body Wounds or surgical
`openings, and dialysis solutions. Biological prepa-
`rations as vaccines, toxoids, and antltoadns are also
`among this group and discussad in Chapter 15.
`Sterility in these preparations is of utmost impor-
`tanCe because they are placed in direct contact with
`
`397
`
`AstraZeneca Exhibit 2106 p. 5
`
`

`

`398
`
`Parental-ole
`
`the mtemal body fluids or tissues where infection
`an easily arise. Ophthalmic preparations, which
`are also prepared to be sterile, vn'll be discussed
`separately in Chapter 16.
`
`Inj actions
`
`Injections are sterile, pyrogen-free preparations
`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 micron, meaning
`outside of the intestine, and denotes routes of ad-
`ministration other than the oral route. Pyrogens
`are toilet-producing organic substances arising
`from microbial contarrfination and are respons-
`ible fior many of the febrile reactions which occur
`in patients following intravenous injection. Pyro-
`gans and the determination of their presence 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 medication by
`the oral route, or when the drug itselfis ineffective
`by other routes. With the exception of insulin in~
`jections, which are commonly self-administered
`by diabetic patients, most injections are adminis-
`tered by the physician, hisfher assistant, or nurse
`in the course of medical treatment. Thus injec-
`tions are employed mostly in the hospital, ex-
`tended 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 patients in their homes,
`providing needed treatment.
`including intra-
`venous medications. These programs enable pa-
`tients who do not require or are unable to pay for
`more expensive hospitalization to remain in the
`familiar surroundings of their homes while-recaiv-
`ing appropriate medical care. The pharmacist
`supplies injectable preparations. to the physician
`and nurse, as required for their use in the instith
`tional setting, clinic, office, or home health Care
`program.
`Perhaps the earliest injectable drug to receive of-
`ficial recognition was the hypodermic morphine
`solution, which appeared first in the 1874 adden-
`dum to the 1867' British Pharmacopeia, and later, in
`1888 in the first edition of the National Formulary
`of the United States.‘l'oday, there are literally hun-
`dreds of drugs and drug products available for par
`enteral administration.
`
`Parenteral Routes ofAdministratiou
`
`Drugs may be injected into almost any Organ or
`area. of the body. including the joints (intro-articu-
`lar), a jointafluid area (intrasyncuisl), the spinal col-
`umn (intruspincl), into Spinal fluid (inflatheccl), ar-
`teries (titre-arterial), and in an emergency, even
`into the heart (intracerdiad. However, most com-
`monly injections are performed into a vein (inim-
`oenous, IV}, into a muscle (intramuscular IM), into
`the skin Clntradennal, ID, innumtamus), or under
`the skin (subartaneous, SC, Sub-Q, SQ, hypodermic,
`Hypo) (Hg.14.1}.
`
`Intravenous Route
`
`The intravenous injection of drugs had its scien-
`tific origin in 1656 inthe experiments ofSir Christo-
`pher Wren, architect of St. Paul’s Cathedral 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. Intravenous medication was
`
`first given to humans bonhann Daniel Major ofKiel
`in 1662, but was abandoned tor a period because of
`the occurrence of thrombosis and embolism in the
`
`patients so treatedThe Motion ofthe hypodermic
`syringe toward the middle of the 19th century cre-
`ated a new interest in intravenous techniques and
`toward the turn of the century, miravenous admin-
`istration of solutions of sodium chloride and glucose
`became popular.Today, the intravenous administra-
`tion of drugs is a routine occurrence in the hospital,
`although there are still recognized dangers associ-
`ated with the practice. 'Ihrombus and embolus for-
`mation may be induced by hitravenous needles and
`catheters, and the possibility of particulate matterin
`parenteral solutions poses concern for those in-
`volved in the development, administration, and use
`of intravenous solutions.
`
`hitravenously administered drugs provide rapid
`action compared with other routes of administra-
`tion and because dnig absorption is not a factor,
`opfimmn blood levels maybe achieved with the ac-
`curacy and immediacy not possible by other routes.
`In emergency situations, the intravenous adminis-
`tration ofadrug may be elite-saving procedure be—
`cause of the placement of the drug directly into the
`circulation and the prompt action which encues.
`On the negative side, once a drug is administered
`mtravenously, it cannot be retrieved. In the case of
`an adverse reaction to the drug, for We, the
`drug cannot be easily rammed from the circulation
`as it could, for example, by the induction of VOTniF
`ing after the oral administration of the same drug.
`
`AstraZeneca Exhibit 2106 p. 6
`
`

`

`,l
`
`. Intravenous
`
`.
`
`Subcutaneous
`
`Parenteral:
`
`399
`
`
`
`Subcutaneous
`Tissue
`
`Suhcu l anon us
`Nlimst
`Tissue
`
`Muscle and Vein
`
`Fig. 14.1 Routes-ofpcrenteml'adminimfion. Numbers on needles indicate size arguuge ofnmll‘e based on outside dimer of
`needle shaft. (Reprinted with musics from limo S, King RE. Sterile Dosage Poms: Their Preparation and Clinical Applica-
`tions. an: Ed. Let: s Febigea; 1937,)
`
`Although most superficial veins are suitable for
`venipuncmre, the veins of. the antecubital area (sit—
`uated in front of the elbow) are usually Selected for
`direct intravenous injection. The veins in this loca-
`tion are large, superficial, and easy to see and enter.
`Moat clinicians insert the needle with the bevel fac-
`
`ing upward, at the most acute angle possible with
`the vein, to ensure that the direction of flow of the
`mjectable is that of the flow of the blood. Strict
`aseptic precautions must be taken at all times to
`avoid risk of. infection. Not only are the iniectabie
`solutions sterile, the syringes and needles. used
`must also be sterilized and the point of entrance
`must be disinfected to reduce the chance of carry-
`ing bacteria from the skin into the blood via the
`needle. Before injection, administration personnel
`mustwithdraw the plunger of the syringe or squeeze
`a special bulb found on most IVsets to ensure that
`the needle has been properly located. In both in-
`stances, a”flashbacl<”of blood into the admirfistra-
`lion set or the syringe indicates proper placement
`of the needle within the Vein.
`
`Both small and large volumes of drug solutions:
`may be administered intravenously. The use of
`1000~mL containers of solutions for intravenous
`
`infusion is commonplace in the hospitaLThese so-
`lutions containing such agents as nutrients, blood
`extenders, electrolytes, amino acids, and other ther-
`apeutic agents are .admirustered through an in-
`dWEIling needle or catheterby continuous infizsion.
`The infusion or flow rates may be adjusted by the
`clinician according to. the noeds of the patient.
`Generally, flow rates for intravenous fluids are ex—
`pressed in mUhour, and range from 42 to 150
`mthour. Lower rates are used for “keep open”
`lines.For bit-ravenous infusion, the needle or catheter
`is placed in the prominent veins of the forearm or
`leg and taped firmlyto the patient so that it will not
`slip from place during infusion.The main hazard of
`'inuavemns infilsion is the possibility 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 usuallyr to a slowing of the cir-
`culation or to an alteration of the blood or VESSEl
`wall. Once such a clot circulates, it becomes an em-
`bolus,-carried by the blood stream until it lodgEs in
`a blood vessel, obstructing it, and rosulting. in a
`
`AstraZencca Exhibit 2106 p. 7
`
`

`

`400
`
`Parenteral;
`
`blookag'e or occlusion referred to as an embolism.
`Such an obstruction may be a critical hazard to the
`patient, dependingupon the site and severity ofthe
`obstruction.
`
`Intravenoust administered drugs ordinarilymust
`be in aqueous solution; they must mix with the cir-
`wlating blood and not precipitate from solution.
`Such an event could lead to pulmonary microcap-
`illary occlusion and the subsequent blockage of
`blood passage. Intravenously delimited fat enmi-
`sions (e.g., Intralipid, 10%;20% [Clintec], Liposyn
`II, 10%;20% [Abbott], Liposyn III, 1096:2096 [Ab-
`bottD have gained acceptance foruse as a source of
`calories and essential tarot acids for patients re—
`quiring parenteral nutrition for extended periods of
`time (usually for more than 5 days). The product
`contains up to 20% soybean oil emulsified with egg
`yolk phospholipids, in a Vehicle of glycerin in wa-
`ter for injection. The emulsion is administered via a
`peripheral vein or by central venous infusion.
`Naturally, the intravenous route is used 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 obtaining
`blood from donors.
`
`In the late 1980s, automated intravenous delivery
`systems became commercially available for inter-
`mittent, self-administration of analgesics. Patient-
`oonirolled analgesia (PCA) has been used to control
`the pain associated with postoperative pain from a
`variety of surgical procedures, labor, sickle cell Crisis,
`and chronic pain asaociated with canoes: For patients
`with chronic malignant pain, PCA allows a greater
`degree of ambulation and independence (1).
`The typical PCA device includes a syringe or
`chamber that contains the analgch drug and
`a programmable electomech apical unit. The unit,
`which might be compact enough to be worn on a
`belt or carried in a pocket (e.g., ‘l’i’alklvledTM PCA—
`Medex, Inc), controls the delivery of drug by ad-
`vancing 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 car-
`tridges available through the manufacturer.The de-
`vices take advantage of intravenous bolus injec—
`tions to produce rapid analgesia, along with slower
`infusion to produce steady-state opiate cancentra—
`tions for sustained pain control.
`The advantage of the PCA is its ability to provide
`constant and uniform analgesia. The typical intra-
`muscular injection of an opioid into a depot
`muscular site may remit in variable absorption,
`leading to unpredictable blood concentrations. Fur—
`ther, these injections are usually given when needed
`
`and are often inadequate to treat the pain. The
`PCA can prevent pharmacoldnefic and pharmaco-
`dynamic differences between patients from inter-
`fering with the effectiveness of analgesia. Because
`opioid kinetics differ greatly among patients, the
`rates of infusion must be tailored (2).
`The PCA also permits patients to medicate them-
`selves when there is breakthrough pain. It elimi-
`nates the delay between the time of the patiean
`perception of pain and receiving the analgesic med-
`ication. Rather, it saves nursing time. Otherwise,
`the nurse must check analgesic orders given by the
`physician, sign out the pain reliever from a con-
`trolled, locked location, and then administer the
`medication to the patient.
`The PCA also provides better pain control with
`less side effects by rrdnimizing the variations be-
`tween suboptimal pain relief and overuse of mar“
`cotics.When the side effect profile of PCA patients
`is compared to patients maintained on IM nar-
`cotics, nausea, sedation, and respiratory depression
`occur less often in the PCA group. Lastly, patients
`accept the PCA as a favorable mode of relief, per-
`haps due to the sense of beingin control and talc—
`ing an active part in their pain relief.
`
`t
`
`i:
`‘*'l
`l;
`
`s
`
`Fig. 14.2 PCA Phts H (LifeCare flow-Patient-cantrollad
`analgesic infirm (Courtesy of Abbott Hospital Products
`Division.)
`
`AstraZeneca Exhibit 2106 p. 8
`
`

`

`PCA devices can be used for intravenous, subcu-
`taneous, or epidural adrrdnistration. Usually, these
`devices are either demand dosing (i.e., a fixed dose
`of drug is injected intermittently) or constant-rate
`infioian plus dammit dasng (2). Regardless of type
`utilized, the physician or nurse establishes the load-
`ing dose, the rate of background infusion, dose per
`demand, lockout interval (to, mirfimum time be-
`tween demand doses), and maidmurn dosage over
`a specifiedtirne interval Figure 1.4.2 demonstrates
`the PCA Plus [I (Lifecare 4100) infuser. With this
`device, the patient pushes a button on a pendant to
`deliver a prescribed quantity of the analgesic.
`
`Intramuscular Route
`
`Intramuscular injections of drugs provide drug
`reflects that are less rapid, but generally of greater
`duration than those obtained from intraVenousad—
`
`ministration (3)..Aqueous or oleaginous- solutions
`or suspensions of
`substances may be admin—
`istered intramuscularljz Depending on the type of
`preparation empluyed, the absorption rates may
`vary widely. it would be expected that drugs in so-
`lution would be more rapidly absorbed than those
`in suspension and that dmgs in aqueous prepara-
`tions 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.‘lhe point of injection-should be
`as far as possible from major haves and blood Ves-
`sels. Injuries to patients from intramuswlar injection
`Usually are related to the point at which the needle
`entered and where the medication was depoaited
`Such injuries include paralysis resulting from neural
`damage, abscesses, cysts, embolism, hematoma,
`sloughing' of the skin, and scar formation.
`in adults, the upper outer quadrant of the gluteus
`maximus is the most frequently used site for intra-
`muscular injection. In infants, the gluteal area is
`small and composed primarily of fat, not muscle.
`What muacle there is is. poorly developed. An in-
`jection in this area might be presented dangerously
`close to the sciatic nerve, especially'if the child is re—
`sisting the injection and squirming or fighting.
`Thus, in infants and young children, the deltoid
`muscles of the upper arm or the rnidlateral muscles
`of the thigh are preferred. An injection given in the
`upper or lower portion of the deltoid would be Well
`sulfa}r 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 injections are
`to be given, the injection site-is usually varied’To be
`
`Parenmls
`
`4111
`
`certain that a blood vessel has not been entered,
`the clinician may aspirate slightly on the syringe
`following insertion of the needle to observe itblood
`enters the syringe- Usually, the volume of medica—
`tion which may be conveniently administered by
`the intramuscular route islimited; generallya max~
`imurn of .5 mL is administered intranmscula‘rly in
`the gluteal region and 2 mL in the deltoid of the
`arm.
`
`The Z—‘I'rack Injection technique is useful ior in-
`tramuscular 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 amm-
`ple, must be injected o'nlj,r into the muscle mass of
`the upper outer quadrant. of the buttockflhe skin is
`displaced laterally prior to injection, then the nee-
`dle is inserted and syringe aspirated, and the injec-
`tion performed slondy and smoothly. The needle is
`then withde and the skin released.This creates
`
`a"Z”pattem that blocks infiltration of medication
`into the subcutaneous tissue'l‘he injection is 2 to 3
`inches deep, and a 20 to 22 gauge needleis utilized.
`To further prevent any staining of upper tissue,
`usually One noodle is used to withdraw the iron
`demon from its ampuL. and then replacedwith an-
`other for the purposes of the injection.
`
`Subcutaneous Route
`
`The subcutaneous route may be utilized 501' the
`injection of small amounts of medication. The in-
`jection of a drug beneath the surface of the skin is
`usually made in the loose interstitial 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 injec-
`tions are frequently given, e.g.,
`insulin injec-
`tions. Prior to injection, the skin at the injection
`site should be thoroughly cleansed. The masdmum
`amount of medication that can be comfortably in-
`jectedsubcutaneously is about 1.3 mL and amounts
`greater than 2 mL will most likely cause painful
`presents. Syringes with up to 3 mL capacities and
`utilizing needles with 24 to 26 gauges are used for
`subcutaneous injections. These neadles will haVe
`cannula lengths that vary between 3f8 inch to 1
`inch. Most typically, subcutaneous insulin needles
`are between 25 to .30 gauge with needle length be-
`tween 5!16 to SIB inch. Upon insertion, if blood ap-
`pears in the syringe, a new site shOuld be selected.
`Drugs that are irritating or those that are present
`in thick suspension form may produce induration,
`sloughing, or abscess formation and may be painful
`
`AstraZeneca Exhibit 2106 p. 9
`
`

`

`402.
`
`Fareamls
`
`to the patient. Such preparations should be consid-
`ered not suitable for subcutaneous injection.
`
`Intradermal Route
`
`A number of substances may be effectively in-
`jected into the cerium, the more vascular layer
`of the skin just beneath the epidermis. These
`substancas include various agents for diagnostic
`deteminations, desensitization, orinununization.
`The usual site for intradennal injection is the ante-
`rior surface of the forearm A short (SIS in.) and
`narrow gauge (23— to 26-gauge) needle is usually
`employed. The needle is inserted horizontally into
`the skinwith the bevel facingupward.The injection
`is made when the bevel just disappears into the
`corium. Usually only about 0.1 mL Volumes-maybe
`administered in this manner.
`
`Specialized Access
`
`In those instances where it is necessary to ad—
`minister repeated injections over a period of time,
`it might be more prudent to employ devices that
`provide continued access and help eliminate pa-
`tient pain associated with administration'lhus, it is
`important to list a few at
`Several types of central venous catheters are
`used in institutions and on an outpatient basis'l'hese
`are used for a variety ofparenteral medications [e.g.,
`cancer chemotherapy, long—rem antibiotic therapy,
`total parenteral nutrition solutions), and their placer
`mentcsnremainforafewdaystoseveralmonths.
`When not in use, these require heparinizatlon to
`maintain potency of the catheter lumon.
`The use of plastic,
`indwelling catheters helps
`eliminate the need for multiple punctures drung IV
`therapy. Composed ofpolyvinyl ctrloride,Teflon, and
`polyethylend these should be radiopaque to ensure
`that they demonstrate visibility on x—ray
`Usu—
`ally, these must be removed within48 hours after in-
`sertion.'Ihe choice of catheter depends upon-several
`factors (e._g,, length of time of the infusion, purpose
`of the infusion, the conditionlavailability' of the
`veins).Three types of catheters are available: plain
`plastic, catheter-over—needle or catheter—outside-
`needle, and catheter-inside-needle.
`Implantable devices provide long—term venous
`access in various diseaSES. Browse and Hickman
`
`catheters are notable examplesflhese do carrya risk
`of morbidity, including fracture of the catheters, en-
`trance site infection, and catheter sepsis'I‘hese have
`been developed to overcome catheter complica-
`tions and are designed to provide repeated access to
`the infusion site'l'he delivery catheter can be placed
`in a vein, cayity, artery; or CNS system. A Huber
`
`point needle allows system access through the skin
`into a self—sealing silicone plug positioned in the
`center of the portal.
`
`Ofiior'al Types of Injections
`
`According to the USP, injections are Separated
`into five general types, all of which are suitable for,
`and intended for, parenteral administration. These
`may contain buffers, preservatives, and other added
`substances.
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`[Drug] mimics—liquid preparations that are
`drug substances or solutions thereof.
`(Ex: In-
`sulin Injection, USP)
`[Drug]firl’ry'eciion—Dn; solids that, upon the ad-
`dition of suitable vehicles, yield solutions con-
`formingmall respects to the requirements forlo-
`jections. (Bx: Cefainandole Sodium for Injection)
`[Drug] Injectable Emulsion-liquid preparations
`of drug substances dissolved or dispersed in a
`suitable emulsion medium. (Ex: Prop ofol)
`[Drug]
`Iiy’ectoble Suspension—qu pre-
`parations of solids suspended in a suitable liq-
`uid medium. (Ex: Methylprednisolone Acetate
`Suspension)
`[Drug] forInjectable Suspension—Drysolids that,
`upon the
`addition
`of
`suitable vehicles,
`yield preparations conforming in all respects to
`the requirements for Injectabls Suspensions. (Ex:
`Imipenern)
`
`Tine form in which a given drug is prepared for
`parenteral use by the manufacturer depends upon
`the nature 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 maybe prepared as a suspension of the drugpar-
`tides in a vehicle in width the drug is insoluble. If
`the drug is unstable in the presence of water. that
`solvent may be replaced in part or totally by a sol-
`ventinwhich the drugis'insolublelt’the dru is in-
`soluble in watt-man injection may be prepare as an
`aqueous suspension or as a solution of the drug in
`a suitable nonaqueous solvent, such as a Vegetable
`oil. If an aqueous solution is desired, a water-solu-
`ble salt form ofthe insoluble drug is frequently pre-
`pared to satisfy the required solubility Characteris—
`tics. Aqueous or blood-trusdee solutions may be
`injected directly into the blood stream. Blood—im-
`miscible liquids, e.g., oleaginous injections and sus-
`
`Astra-Zoneca Exhibit 2106 p. 10
`
`

`

`pensions, can interrupt the normal flow of blood
`within the circrflatory system and their use is gen-
`erally restricted to other than intravenous adminis-
`tration.The onset and duration of action of-a drug
`may be somewhat controlled by the chemical form
`of the: drug used, the physical state of the injection
`(solution or suspension), and the vehicle employed.
`Drugs that are very soluble in body fluids generally
`have the most rapid absorption and onset ofaction.
`Thus, drugs in aqueous solution have a more rapid
`Onset of action than do drugs in oleaginous solu-
`tion. Drugs in aqueous suspension are also more
`rapid acting than drugs in oleaginous suspension
`due to the greater miscibility of the aqueous prepa-
`ration 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 desired to reduce the necessity of fre-
`quently repeated injections.’Ihese long—ac’dng types
`of injections are commonly referred to as repository
`or”depot”types of preparations.
`The solutions and suspensions of drugs intended
`for injection are prepared in the same general man-
`ner as was discussed previously in this text for so-
`lutions (Chapter 12) and disperse systems (Chap—
`ter 13), with the following differences:
`
`1. Solvents or vehicles used must meet special pu-
`rity and other standards assuring their safetyby
`injection.
`2. The use of added substances, as buffers, stabi—
`
`lizers, and antimicrobial preservatives, fall un-
`der specific guidelines of use and are restricted
`in certain parenteral products. The use of color-
`ing agents is strictly prohibited.
`3. Parenteral products are always sterilized and
`meet sterility standards and must be pyrogen-
`free.
`
`4. Parmteral solutions must meet compendial stan-
`dards for particulate matter.
`5. Parenteral products must be prepared in envi-
`ronmentally controlled areas, under strict sani-
`tation standards, and by personnel specially
`trained and clothed to
`the sanitation
`standards.
`
`6. Parenteral products are packaged in Special her—
`metic 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 ml-
`ume in slight excess of the labeled"'size”’or vol-
`nine to be withdrawn. This oVerfill permits the
`ease oiwithdrawal and administration of the la-
`beled volumes.
`
`Parentemls
`
`403
`
`8. There are restrictibns over the volume of injec-
`tion permitted in multiple-dose containers and
`also a limitation over the types of containers
`(singled'ose or multiple-dose) which may be
`used for certain injections.
`9. Specific labeling regulations apply to injections.
`10. Sterile powders intended for solution or sus-
`pension immediately prior to injection are fre-
`quently packaged as lyophilized or Freeze-dried
`powders to permit ease of solution or suspen-
`sion upon the addition of the solvent or vehicle.
`
`Schants and Vehicles for Infectious
`
`The most frequently used solvent in the large-
`scale manufacturer ofinjections is Waterfor Injection,
`USP. This water is purified by distillation or by re-
`verse osmosis and meets the same standards for the
`
`presence of total solids as does Purified Water, USE
`not more than 1 mg per 100 mL Water for Injection
`USP and. may not contain added substances. Al-
`though water for injection is. not required to be ster-
`ile, it must be pyrogen-fiee. The water is intended to
`be used in the manufacture of injectable products
`which are to be sterilized after their preparationl’th-
`ter for injection should be stored in tight containers
`at temperatures below or abow the range in which
`microbial growth occurs. Water for injection is in-
`tended to be used within 24 hours following its col-
`lection. Naturally, the water should be collected in
`sterile and pyrogen-fi-ee containers. The containers
`are usually glass or glass—lined.
`Sterile Waterfor Injection, USP is water for injec-
`11011 which has been sterilized and packaged insin-
`gle-dose containers of not greater than l-liter size.
`As water for injection, it must be pyrogen—free and
`may not contain an antimicrobial agent or other
`added substance.This water may contain a slightly
`greater amount of total solids than water for injec-
`tion due to the leaching of solids from the glass-
`lined tanks during the sterilization process. This
`water is intended to be used as a solvent, vehicle
`
`or diluent for already-sterilized and packaged in-
`jectable medications. The one