Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 LippincottW1lliams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may be 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 Cata1oging-in-Publication Data
`
`Ansel, Howard C., 1933-
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, LoydV. Allen, ]r., 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.
`II. Popovich, Nicholas G.
`III. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A6181 1999]
`RS200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, LoydV.
`
`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
`
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`

`
`
`
`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: Biopharrnaceutic 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-SOI.ID AND TRANSDERMAI. SYSTEMS
`
`9
`
`I0
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`'244
`
`263
`
`ix"
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`

`
`x
`
`Contents
`
`Section IV. PHARMACEUTICAL INSERTS
`
`I I
`
`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 ADVANCED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVICES
`
`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
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`

`
`Section VI. Sterile Dosage Forrns and Delivery Systems
`
`PARENTERALS
`
`
`
`Chapter at a Glance
`
`Injections
`Parenteral Routes ofAdministration
`Intravenous Route
`Intramuscular Route
`Subcutaneous Route
`Intradermal Route
`
`_
`Specialized Access
`Ofiicial Types of Injections
`Solvents and Vehicles for Injections
`Nonaqueous Vehicles
`Added Substances
`Methods ofsterilization
`Steam Sterilization
`
`Dry-Heat
`Sterilization by Filtiatiotn
`Gas Sterilization
`
`Stefllizafion by Ionizing Radiation
`Validation of Sterility
`Pyrosens and Pymser} Testing
`The Industrial Preparation. ofParenteral
`Products
`Packaging, Labeling, and Storage of Injec-
`lions
`Quality Assurancefor Pharmacy-Prepared
`Sterile Products
`
`Available Injections
`Small Volume Parenterals
`Insulin Injecti'on (Regular)
`Human Insulin
`
`Lispro Insulin Solution
`Isophane Insulin Suspension
`(NPH Insulin)
`Isoplmne Insulin Suspension and
`Insulin Injection
`Insulin Zinc Suspension
`Extended Insulin Zinc Suspension
`Prompt Insulin Zinc Suspension
`Insulin Infusion Pumps
`Large Volume Parenterals (LVPs)
`Maintenance Therapy
`Replacernent Therapy
`Water Requirement
`Electrolyte Requirement
`Caloric Requirements
`Parenteral Hyperalimentation
`Enteral Nutrition
`
`Intravenous Infusion Devices
`Special considerations associated with
`parents-1_'a1 therapy
`Adsorption of Drugs
`Handling/Disposal of Chernotlierapeutic
`Agentsfor Cancer
`Other Injectable Products—I-‘ellets or
`Implants
`Leoonorgestrel Implants
`Irrigation and Dialysis Solutions
`Irrigation Solutions
`Dialysis Solutions
`
`CONSIDERED IN this chapter are important pharma-
`ceutical dosage forms that have the common char-
`acteristic of being prepared to be sterile; that is, free
`f1'om-contaminating microorganisms. Among these
`sterile" dosage forms are the various small- and
`large-volume injectable preparations, irzigation flu-
`
`ids intended to bath: body wounds or surgical
`openings, and dialysis solutions. Biological prepa-
`rations as vaccines, tonoids, and a11titoxi11s- are also
`
`among this group and discussed in Chapter 15.
`Stefility in these preparations is of utmost impor-
`tance because they are placed in direct contact with
`
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`398
`
`.Parenterais
`
`the internal body fluids or tissues where infection
`can easily arise. Ophthalmic preparations, which
`are also prepared to be sterile, will be discussed
`separately in Chapter 16..
`
`Injections
`
`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 enter-on, meaning.
`outside of the intestine, and denotes routes of ad-
`ministration other than the oral route. Pyrogens
`are fever-producing organic substances arising
`from microbial contamination and are respons-
`ible for many of the febrile reactions which occur
`in patients following intravenous injection. Pyro-
`gens 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 cli11ic 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 receiv-
`ing appropriate medical care. The pharmacist
`-supplies injectable preparations to the physician
`and nurse, as required for their use in the institu-
`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 Pharmacopeie, and later, in
`1888 in the first edition of the National Formulary
`of the United States. Today, there are literally hun-
`dreds of drugs and drug products available for par-
`enteral administration.
`
`Parenteral Routes ofAdministration
`
`Drugs may be injected into almost any organ or
`area of the body, including the joints (iubu-urt:'cu-
`tar), ajoint-fluid area (intrasynooial), the spinal col-
`umn (irttraspiuui), into spinal fluid (intrathecal), ar-
`teries (intro-arterial). and in an emergency, even
`into the heart fiutracardiacl. However, most com-
`monly injections are performed into a vein (intro-
`oenous, IV), into a muscle (intramuscular; IM). into
`the skin (Intmdermal, ID, intrccutaneous), or under
`the skin (subcutaneous, SC, Sub-Q, SQ, hypodennic,
`Hypo) (Fig. 14.1).
`
`Intravenous Route
`
`The intravenous injection of drugs had its scien-
`tific origin in 1656 in the experiments of Sir 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 bylohann Daniel Major ofI(iel
`in 1662, but was abandoned for a period because of
`the occurrence of thrombosis and embolism in the
`
`patients so treated.The invention 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, intravenous 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. Thrombus and embolus for-
`mation may be induced by intravenous needles and
`catheters, and the possibility ofparticulate matterin
`parenteral solutions poses concern for those in-
`volvedin the development, adrninistration, and use
`of intravenous solutions.
`
`Intratvenously administered drugs provide rapid
`action compared with other routes of administra-
`tion and because drug absorption is not a factor
`optimum blood levels may be achieved with the ac-
`curacy and immediacy not possible by other routes.
`In emergency situations, the intravenous adminis-
`tration ofadrug may be alife-savingprocedure be-
`cause 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 example, by the induction of vomit-
`ing after the oral administration of the same drug.
`
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`
`Parenteral:
`
`399
`
`
`
`Subcutaneous .
`Tissue
`
`Su'l1cuI emcous
`mlipnse
`Tissue
`
`Muscle and Vein
`
`Fig, 14.1 Routes ofpsreruerai admznisn-cflon.Numbers on needles indicate -size orgsuge ofnosdie based on outside diameter of
`needle shaft. (Reprinted with pemisstonfiom Time 3, King RE. Sterile Dosage Forms: Their Preparation and Clinical Applica-
`tians,.3'rd Ed. tea &'Febige7; 1937.)
`
`Although most superficial veins are suitable for
`venipuncture, 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.
`Most clinidans 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
`injectable is that of the flow of the blood. Strict
`aseptic precautions must be taken at all times to
`avoid risk ot infection. Not only are the injectable
`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
`must withdraw the plunger of the syringe or squeeze
`a special bulb found on most IV sets to. ensure that
`the needle has been properly located. In both in-
`stances, a"'t1ashback”of blood into the adrninistra-
`tion 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-rnL containers of solutions for intravenous
`
`infusion is commonplace in the hospital.These so-
`lutions containing such agents as nutrients, blood
`extenders, electrolytes, amino acids, and other ther-
`apeutic agents are administered through an in-
`dwelling needle or catheter by continuous infusion.
`The infusion or flow rates may be adjusted by the
`clinician according to the needs of the patient.
`Generally, flow rates for intravenous fluids are ex-
`pressed in n'LL!hour, and range Erom 42 to 1-50
`rnllhour. Lower rates are used for "keep open”
`lines. For intravenous infusion, the needle or catheter
`is 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 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 biologc tissues. A
`thrombus is a blood clot formed within the blood
`
`vessel [or heart) due usually 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 resulting in at
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`

`
`400
`
`Perenternls
`
`blockage or occlusion referred to as an embolism.
`Such an obstruction may be a critical hazard to the
`patient, depending upon the site and severity of the
`obstruction.
`
`intravenously administered drugs ordinarily must
`be in aqueous solution; they must mix with the cir-
`culating blood and not precipitate from solution.
`Such an event could lead to pulmonary microcap-
`illary occlusion and the subsequent blockage of
`blood passage. Intravenously delivered fat emul-
`sions (e.g., lntralipid, 10%;20% [Clintec], Liposyn
`ll, 10%;20% [Abbott], Liposyn ID, 10%;20% [Ab-
`bott]) have gained acceptance for use as a source of
`calories and essential fatty 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, sel.f-adrrunistration of analgesics. Patient-
`controlled 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 associated with cancer. For patients
`with chronic malignant pain, PCA allows a greater
`degree of arnbulation and independence (1).
`The typical PCA device includes a syringe or
`chamber that contains the analgesic drug and
`a programmable electornechanical unit. The unit,
`which might be compact enough to be worn on a
`belt or carried in a pocket (e.g., Wall<MedTM 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 concentra-
`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 result 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 pharmacolcinetic and pharmaco-
`dynarnic diflferences 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 patients
`perception of pain and receiving the analgesic med-
`ication. Further, 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 I-‘CA also provides better pain control with
`less side effects by minimizing the variations be-
`tween suboptimal pain relief and overuse of nar-
`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 P0X group. Lastly, patients
`accept the PQA as a favorable mode of relief, per-
`haps due to the sense of being in control and tak-
`ing an active part in their pain relief.
`
`Fig. 14.2 PO41 Plus if (LifeCan2 4100)-Patient-corztrolled
`analgesic infirser. (Courtesy of Abbott Hospital Products
`Division.)
`
`Astrazeneca Ex. 2106 p. 8
`
`

`
`PCA devices can be used for intravenous, subcu-
`taneous, or epidural administration. Usually, these
`devices are either demand dosing (i.e., a fixed dose
`of drug is injected intermittently) or constant-rate
`infilsiou plus demami closing (2). Regardless of type
`utilized, the physician or nurse establishes the load-
`ing dose, the rate of background in.t'usion, dose per
`demand, lockout interval (i.e.,
`time be-
`tween demand doses), and maximurn dosage over
`s. specified time interval. Figure 14.2 demonstrates
`the PCA Plus ll (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
`eflects that are less rapid, but generally of greater
`duration than those obtained from intravenous ad-
`
`ministration (3). Aqueous or oleaginous solutions
`or suspensions of
`substances may be "admin-
`istered intramuscularly. Depending on the type of
`preparation employed, 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 drugs 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.
`IntraJ:nu.scular injections are performed deep into
`the skeletal muscles.The point ofinjection should be
`-as far as possible from major nerves and blood ves-
`sels. Injuries to patients from intramuscular injection
`usually are related to the point at which the needle
`entered and where the medication was deposited.
`Such include paralysis resulting from neural
`damage, abscesses, cysts, embolism, hernatoma,
`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 muscle 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 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 injections are
`to be given, the injection site is usually varied.Ib be
`
`Pmmterals
`
`401
`
`certain that a. blood vessel has not been entered,
`the clinician may aspirate slightly on the syringe
`following insertion ofthe needle to observe ifblood
`enters the -syringe. Usually, the volume of medica-
`tion which may be conveniently administered by
`the intramuscular route is limited; generally a max-
`imum of 5 mL is administered intramuscularly in
`the gluteal region and 2 mL in the deltoid of the
`arm.
`
`The Z-'I'raclt Injection technique is useful for 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 exam-
`ple, must be injected only into the muscle mass of
`the upper outer quadrant of the buttocl<.'I'he skin is
`displaced laterally prior to injection, then the neo-
`die is inserted and syringe aspirated, and the injec-
`tion performed slowly and smoothly. The needle is
`then withdrawn and the skin released. This creates
`
`a"Z" pattern that blocks infiltration of medication
`into the subcutaneous tissue.‘I'he injection is 2 to 3
`inches deep, and a 20 to 22 gauge needle is utilized.
`To further prevent any staining of upper tissue,
`usually one needle is used to withdraw the iron
`dextran from its ampul. and then replaced with an-
`other for the purposes of the injection.
`
`Subcutaneous Route
`
`The subcutaneous route maybe utilized for 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 maximum
`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
`pressure. Syringes with up to 3 mL capacities and
`utilizing needles with 24 to 26 gauges are used for
`subcutaneous injections. These needles will have
`cannula lengths that vary between 338 inch to 1
`inch. Most typically, subcutaneous insulin needles
`are between 25 to 30 gauge with needle length be-
`tween 51116 to 5J8 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 maybe painful
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`

`
`402.
`
`Parenterols
`
`to the patient. Such preparations should be consid-
`ered not -suitable for subcutaneous injection.
`
`Intraderroal Route
`
`A number of substances may be effectively in-
`jected into the ooriurn, the more vascular layer
`of the skin just "beneath the epidermis. These
`substances include Various agents for diagnostic
`determinations. desensitization, or immunization.
`The usual site for intradermal injection is the ante-
`rior surface of the forearm. A short (SIB in.) and
`narrow gauge (23— to 26-gauge) needle is usually
`employed. The needle is inserted horizontally into
`the sldnwith the bevel facing upWard..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 aduu‘.nistration.'Il1us. it is
`important to list a few at this juncture.
`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—term antibiotic" therapy.
`total parenteral nutrition solutions). and their place-
`ment can remain for a few days to several months.
`When not in use, these require heparinization to
`maintain patency of the catheter lumen.
`The use of plastic,
`catheters helps
`eliminate the need for multiple punctures dining IV
`therapy. Composed ofpolyvinyl |:hloride,Teflon, and
`polyethylene, these should be radiopaque to ensure
`that they demonstrate visibility on x-ray
`Usu-
`ally, these must be removed within 48 hours after in-
`sertion. The 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. Broviac and I-Iickman
`
`catheters are notable e:<amp1es.'I'.hese do carry arisk
`of morbidity, including fracture of the catheters. en-
`trance site iztfection, and catheter sepsis.These have
`been developed to overcome catheter complica-
`tions and are designed toprovide repeated access to
`thejnfusion site.The delivery catheter can be
`in a vein. cavity. 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.
`
`Ojfflcfal Types of Infectious
`
`According to the USP. injections are separated
`into five general types. all ofwhich are suitable for,
`and intended for, parenteral administration. These
`may contain buffers, preservatives, and other added
`substances.
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`[Drug] In}'ection—l..iquid preparations that are
`drug substances or solutions thereof. (Ex: In-
`sulin Injection. USP)
`[Dn1g])‘brIrjeciio?r—Drysolids that, upon the ad-
`dition of suitable vel-ticles. yield solutions con-
`forminginall respects to the requirements ‘forlo-
`jections. (Ex: Cefamandole Sodium for Injection)
`[Drug] Injectable Emulsirm—Liquid preparations
`of drug substances dissolved or dispersed in a
`-suitable emulsion medium. (Ex: Propofol)
`pre-
`[Drug]
`Injectcble
`Su5pensicn—-Liquid
`parations of -solids -suspended in a suitable liq-
`uid medium. (Ex: Methylprednisolone Acetate
`Suspension)
`[Drug] forlnjectable Su5pensian—Drysol.ids that,
`upon the
`addition
`of
`suitable Vehicles,
`yield preparations conforming in all respects to
`the requirements for Injectable Suspensions. (EX:
`Imipenem)
`
`The 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 adrninistra.tion, or
`it may be prepared as a suspension of the drug par-
`ticles in a vehicle inwhich 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-
`ventin which the drugis insoluble. Ifthe dru is in-
`soluble in water; an 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 requisred solubility characteris-
`tics. Aqueous or blood-miscible solutions ‘may be
`injected directly into the blood stream. Blood—im-
`miscible liquids, e.g., oleaginous injections and sus-
`
`Astrazeneca Ex. 2106 p. 10
`
`

`
`pensions, can interrupt the normal flow of blood
`within the circulatory system, and their use is gen-
`erallyrestricted 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 of action.
`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 ofthe drug particles
`with the body fluids. Oftentimes more prolonged
`drug action is desired to reduce the necessity of fre-
`quently repeated injecfions.‘I'hese long—acting types
`of injections are commonly referred to as repository
`or“'depot” types of preparations.
`The solutions and suspensions ofdrugs 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 safety by
`injection.
`2. The use of added substances, as buffers. stabi-
`
`lizers, and antirnicrobial 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.
`
`ii. Parenteral solutions mustmeet compend.ia1.stan-
`dards for particulate matter.
`5. Parenteral products must be prepared in envi-
`ronmentally controlied areas, under strict sani-
`tation standards, and by personnel -specially
`trained and clothed to maintain the -sanitation
`standards.
`
`6. Parenteral products are packaged in special her-
`metic containets 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 vol-
`ume in slight excess of the labeled"s1'ze”'or vol-
`ume to be withdrawn. This overtill permits the
`ease ofwithdrawal and administration of the la-
`beled volumes.
`
`Parenterals
`
`403
`
`'8. There are restrictions over the volume of injec-
`tion permitted in multiple-dose containers 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 injections.
`10. Sterile powders intended for solution or sus-
`pension immediately prior to injection are fre-
`quently packaged as lyoplrilized or freeze-dried
`powders to permit ease of solution or suspen-
`sion upon the addition of the solvent or vehicle.
`
`Solvents and Vehicles for Infectious
`
`The most frequently used solvent in the large-
`scale manufacturer ofinjections is Waterforlnjecfion.
`USP. This water is purified by distillation or by re-
`verse osrnosis 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-free. The water is intended to
`be used in the manufacture of injectable products
`which are to be sterilized after their preparation.Wa-
`ter for injection should be stored in tight containers
`at temperatures below or above 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-free containers. The containers
`-are usually glass or glass-lined.
`Sterile Water Irrjectiorz, LISP is water for injec-
`tion which has been sterilized and packaged in sin-
`gle-close containers of not greater than 1-liter size.
`As water for injection, it must be pyrogen-free and
`may not contain an antimicrobial agent or other
`added substance.'I'l'Lis 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