Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 LippincottW1lliams & Wflkins
`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 Cataloging-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.
`Il. Popovich, Nicholas G.
`Ill 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, LoydV.
`
`99-17498
`CIP
`The publishers have made every efiort 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 excerpm 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 O2
`1 2 3 4 5 6 7 8 9 10
`
`Astrazeneca Ex. 2106 p. 2
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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-SOLID AND TRANSDERMAL SYSTEMS
`
`_
`
`9
`
`TO
`
`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
`
`II
`
`Suppositories and Inserts
`
`Section V.
`
`LIOUID DOSAGE FORMS
`
`I 2
`
`I3
`
`Solutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`T4
`
`T5
`
`T6
`
`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
`
`T7
`
`T8
`
`T9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
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`

`
`Section VI‘. Sterile Dosage Forms and Delivery Systems
`
`PARENTERALS
`
`
`
`Chapter at a Glance
`
`"
`
`.
`.
`.
`I
`1“9°°”°“5
`Parenteral Routes oféldmmastnitton
`Intravenous Route
`Intramuscular Route
`Subcutaneous Route
`Ird:rade1'n'I£1 Route
`
`0 Specialized ?}cess
`fiuzul‘' Types o
`‘actions
`Solvents and Vehzgfles Injections
`Nonoqueous Vehicles
`Added Substances
`Methods ofSrerilizstion
`
`
`Steam Sterihza‘' tion
`
`Dry-Heat Sterilization
`Sterilizafion by Filiiratian
`Gas Sterilization
`
`Sim-ilizalion by Ionizing Radiation
`Validation ofSterility
`Pywsem and Prrosen Twins
`The Industrial Preparation‘ of Parenteral
`Products
`
`Packaging, Labeling, and Storage qfInjeo—
`lions
`
`Quality Assurancefor Phermacy«Prepored
`Sterile Products
`Available Injections
`Small Volume Parenterals
`
`Insulin Injection (Regular)
`Human Insulin
`
`Lispro Insulin Solution
`Isopluzne Insulin Suspension
`(NPI-I Insulin)
`Isaphsne 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
`
`Water Requirement
`Electrolyte Requirement
`Caloric Requirements
`Parenteral Hyperalimentotion
`Enters! Nutrition
`
`Chernothempeutic
`
`Intravenous Infusion Devices
`Special considerations associated with
`parentegal therapy
`Adsorption ofDrufs
`.l-fondling/Disposa
`Agentsfor Cancer
`Other Injectable I’roducts—Pel1ets or
`Implants
`Leoonorgestrel Implants
`Irrigation and Dialysis Solutions
`Irrigation Solutions
`Dialysis Solutions
`
`CONSIDERED IN this chapter are importsntpha:ma-
`oeutlcal dosage forms that have the cormtoon char-
`actefisfic ofbeingprepaxed to be stelfle; that is, free
`from oonl:am1'natiJ1.g rnicrooIganisms.Among these
`sterile dosage forms are the various small- and
`_1arge-Wmlume injactahle preparations, irrigation flu-
`
`ids intended to bathe body wounds or suxgizal
`openings, -and dialysis solutions. Biological prepa-
`rations ss vaccines, toxoids, and antitoxins are also
`among this group and discussed in Chapter 15.
`Sterility in these preparations is of utmost impor-
`tancebecausethey are placedindirectcontactwith
`39'7"
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`

`
`.398
`
`Parenteral:
`
`the internal body fluids or tissues where
`can easily arise. Ophthalmic preparations, which
`are also prepared to be sterile, will be discussed
`separately in Chapter 16.
`
`Injections
`
`Injections are sterile, pyrogen-tree 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 porn and cataract. 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
`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 itself is ineffective
`by other routes. With the exception of insulin in-
`jections, which are cornrnonly seLf—ad.u15rti.stered
`by diabetic patients, most injections are adminis-
`tered by the physician. hisfl-tar 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 horne.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 payfor
`more expensive hospitalization to remain in the
`familiar surroundings of their homeswhile receiv-
`ing appropriate medical care. The pharmacist
`supplies. injectable preparations to the ‘physician
`and nurse, as required for their use in the institu-
`tional sel.-ti.ng,. clinic, office. or home health care
`P103173“-
`Perhaps the earliest injectable drug to receive of-
`tidal recognition was the hypodermic morphine
`solution, which appeared first in the 1871; adden-
`dum to the 1867 British Pharrnacopeia, and later, in
`1888 in the first edition of the National Fonruilary
`of the United States.Today, there are literally hun-
`dreds-of drugs and drugproducts available for par-
`enteral administration.
`
`Parenteral Routes ofAdministration
`
`Drugs may be injected into almost any organ or
`area of the body, including the joints (:'rrmI-crtioo
`tor), a joint-fluid area (fnousynooial), the spinal col-
`umn finosspinali. into spinal fluid (int:-athecafl. ar-
`teries (intro-arterial), and in an emergerlcy, even
`into the heart (inoacurdisc). However, most com-
`monly injections are performed into a vein (intra-
`venous, IV), into a muscle fintnznrusculei: I-M). into
`the skin (Intmdermol, JD, intrucaianeousj, or undtn‘
`the skin fsubcutarteous, SC, Sub-Q, "SQ, hypodermic,
`Hypo} {Fig.14.1l.
`
`Intravenous Route
`
`The intravenous injection of drugs had its scien-
`tificotzigininlfififiin theexpefirrLentsofSirCh.risto-
`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
`
`firstgiventohumansby]ohannDanie1MajorofKiel
`in 1662, but was abandoned for a period because of
`the occurrence of thrombosis and embolism in the
`patients so treated.'I'he invention of the hypodermic
`syringe toward the middle ofthe 19th century cre-
`ated a new interest in intravenous techrtiques and
`toward the rum of the century", intravenous admin-
`istration of solutions of sodium chloride and glucose
`became popular. Today, the intravenous administra-
`.tion of drugs isa routine occurrence in the hospital,
`although there are still recognized dangers associ-
`ated with the practice. 'I'hrombu.s and ernbolus for-
`mation may be induced by intravenous needles and
`catheters. and the possibility of particulate rnatterin
`parenteral solutions poses concern for those in-
`volved in the development.
`and use
`of intravenous solutions.
`
`Intravenously administered drugs provide rapid
`action compared with other routes of administra-
`tion and because drug absorption is not a factor;
`optimum blood levels maybe achieved with the ac-
`curacy and immediacy not possible byother routes.
`In emergency situations, the intravenous adminis-
`tration of adrugmaybe alife-saving procedure 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
`intravenousigr, it cannot be retrieved. In the case of
`an adverse reaction to the drug, for instance, the
`drug cannot be easily removed from the
`as it could, for example, by the induction of vomit-
`ing after the oral administration of the same dnig.
`
`Astraleneca Ex. 2106 p. 6
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`

`
`Parmterlzls
`
`399
`
`Subcutaneous
`Tissue
`
`Sui Ioulalllaous
`ndlpuse
`
`Tissue
`
`Muscle and Vein
`
`
`,._.,_.
`'--—-
`- "
`'
`-
`§E':::_ ‘in I
`I
`_
`Ir! .
`
`J?‘
`
`
`
`
`
`ni
`
`Fig. 1;-1.1 Routes Qfpnrenieral odiriinistrsttian. Numbers on needles indlhztesfxa orgeuge tfnesdle buses! on outside-diarneter of
`needle shajl: (Reprinted with permission from 'limo'S,1Cing RE. Sterile Dosage Farms: Their Preparation and Clinical Applica-
`tto1Is.3rd Ed. Leaérfebigea: 1937.)
`
`Although most supedicial veins axe suitable for
`venipuncture, the veins of the antecubital area (sit-
`uated lnfront ofthe elbow) are usuallyselected for
`direct intravenous i.niec_i:ion;T'he veins in this loca-
`tion are large, superficial and easy to -see and enter.
`Most 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
`
`injectable 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 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
`needleflefore injection, administration personnel
`mustwlthdrawthe plunger of the syringe orsqueeze
`a special bulb found on mostwsets-to ensure that
`the needle has been properly located. In both in-
`stances, a”flashback"of blood into the admi'nistra.-
`tion set or the syringe indicates proper placement
`of the needle within the
`
`Both small and large volumes of drug solutions
`may be administered intravenously The use of
`1000-mL. containers of solutions for intravenous
`
`i.n.Eusion is commonplace in the hospital.These so-
`lutions containing such agents as nutrients, blood
`extenders, electrolytes, amino acids, and other that-
`apeutic agents are aclministered through an in-
`dwelling needle-or catheter by continuaus'irLf'usior1.
`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 muhout. -and range from 42 to 150
`mL/hour. Lower rates are used for "keep open”
`1ines.Forint:svenous infusion, the needle orcatheter
`is placed in the prominent veins of the forearm or
`leg and taped Elrrnly to the patient so that it w'Il1.not
`slip from place during lI1fL‘lSlO1‘bThI.’. 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 biologic tissues. A
`thrombus is a. blood clot formed within the blood
`
`vessel {or heart) clue usually to a slowing of the air-
`culation or to an alteration. -of the blood or vessel
`wall. Once such a clot circulates. it becomes an em.-
`
`liolus, carried by the blood stream until it lodges in
`a blood vessel. obstructing it, and resulting in as
`
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`
`

`
`400
`
`Parenterals
`
`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.
`
`lntravenously 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 rnicrocap-
`illary occlusion and the subsequent blockage of
`blood passage. Intravenously delivered fat emul-
`sions (e.g., Intralipid, 10%;2D% [Clintec], Liposyn
`II, 10%;2o% [Abbott], Liposyn III, 10%;2D% [Ab-
`bott]J 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 injeclionffhe 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-
`controiled analgesia (PICA) has been used to conu'ol
`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 ambulation 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., Wallctvledm PCA-
`Medex, Inc), controls the delivery of drug by ad-
`vancinga 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 rnanufacturer.'I'he 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 pharrnacoldnetic and pham1aco~
`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 pemiits patients to meditate them-
`selves when there is breakthrough pain. It elirni—
`nates the delay between the time of the patient’s
`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 PCA 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 PCA group. Lastly, patients
`accept the PCA 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 PCA Plus if l'LifeCcre 4100)-Patient-controlled
`analgesic fnfitsen (Courtesy of Abbott Hospital Products
`Division.)
`
`Astrazeneca Ex. 2106 p. 8
`
`

`
`PCA devices can he used for intravenous, subcu-
`
`taneous, or epidural administration. Usually, these
`devices are either demand dosing (Le, a fixed dose
`of drug is injected intermittently) or coaster-it-rate
`fisfitsion plus demand dosing (2). Regardless of type
`utilized, the physician ornurse establishes the load-
`ing dose, the rate-of background infusion, dose per
`dernantl, lockout interval (i.e., minimum time be-
`tween demand doses), and maximum dosage over
`at specified time interval. Figure 14.2 demonstrates
`the PCA Plus II (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 dnags provide drug
`Effects that are less rapid, but generally of greater
`duration than those obtained fromintrsvenous ad-
`
`(3). Aqueous or oleaginous solutiors
`or suspensions of drug substances may be admin-
`istered intrarnusculsrly. Depending on the type of
`preparation employed, the absorption rates may
`vary widely. It would be expected that drugs inso-
`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. 'I‘he physical type of
`preparation employed is based on the properties of
`the drug ilself and on the therapeutic goals desired.
`Intramuscular injections are performed deep into
`the skeletal Iinuscle-s.'I'he point of injection shoulclbe
`as fares possible from major nerves and blood ves-
`sels. Injuries to patients from inrrarnuscularinjection
`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, abscesses, cysts, ernbolisrn, hernaboma,
`sloughing of the skin, and scar formation.
`In "adults, the upper outer quadrant of the giuteus
`maarimus 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-
`jectionin this area might be presented dangerously
`closets the sciatic nerve, especially if the child ‘rare-
`
`sisting the injection and squ1rnung''
`or fighting.
`Thus, in infants and young children, the deltoid
`muscles of the upper arm or the rnidlateral muscles
`of the thigh are preferrecl.An injection given in the
`upper or lower portion of the deltoid would be well
`away from the radial nerve.The.de1boid 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 vaIied.'I‘o be
`
`Parentemls
`
`-EDI
`
`certain that a blood vessel has not been entered,
`the
`may aspirate slightly on the syringe
`follcrwinginsertion of the needle to observe ifblood
`enters the syringe. Usually, the volume ofn1edica—
`tion which may be conveniently administered by
`the intrarnuscular route is limited; generailya max‘-
`imum of 5 ml. is administered intramuscularly in
`the gluten] region and 2 mL in the deltoid of the
`arm.
`
`The zfifiack Injection technique is useful for in-
`tramuscular
`of medications that stain
`upper tissue, e.g., iron clextran injection, or those
`that irritate tissue, e.g., Vbliurn, 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 buttock.Tt1e skin is
`displaced laterally prior to injection. then the nee-
`dle-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 blodrs infiltration of rned.ica.ti_o_n
`into the subcutaneous tissue.The injection is 2 to 3
`inches deep, and a 20 to 22 gauge needle is utilized.
`'Ib further" prevent any
`of upper tissue,
`usually one needle is used to withdraw the iron
`dextran from its arnpul, and then replaced with an-
`other for the purposes. of the injection.
`
`Subcutaneous Route
`
`The subcutaneous route may be 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 theloose interstitial tissues of the
`outer surface of the upper arm. the anterior surface
`of the thigh, and thelower portion of the abdomen.
`The site of injection is usually rotated when injec-
`tions are frequently given, e.g., -daily insulin injec-
`tions. Prior to injection. the skin at the injection
`site should be thoroughly cleansed. The rnasdrnum
`amount of medication that can be comfortably in-
`jccted subcutaneouslyis about 1.3 l1'I.l.-. 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 3i8 inch to 1
`inch. Most typically, subcutaneous insulin needles
`are between 25 to 30 gauge with needle long-th be»
`tween 5:16 to 513 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
`suspension form may produce induration.
`in
`slouglung, or abscess formation and may be
`
`Astraleneca Ex. 2106 p. 9
`
`

`
`402
`
`Purcntemls
`
`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 corium, the more vascular layer
`of the skin just beneath the epiderniis. Tliese
`substances include
`agents for diagnostic
`determinations, desensitization. or immunization.
`The usual site forintradenna1.injection is the ante-
`rior" surface of the fiorearrn. A short (SIS in.) and
`narrow gauge (23- to '26-gauge) needle is usually
`emp1oyed.'I'he needle is inserlied hocizontallyinto
`thesldnwith tlIebevelfacingu,pward.'IheirL3'ecIion
`is made when the bevel just disappears into the
`coriurn. Usually only about 0.1 mL volumes may be
`admhdstered in this manner.
`
`Specialized Access
`
`In those instances when: it is necesmry 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-
`tientpainassociated with ad.mi.nisl:ration.'I'l'1_us, itis
`important to lists few at this juncture.
`Several types of central venous catheters are
`used ininstitutiorns and on an outpatient basis.T'hese-
`are used for avaiiety of parenteral medications (rag...
`cancer chemotherapy, long—term antibiotic therapy,
`total parenteral nutrition solutions), and their place-
`rnentcanrernainforafewdmtoseveralmonths.
`Whennotinusetheserequireheparlrlizatlonto
`maintain potency of the catheter lumen.
`The use of plastic. indwelling catheters helps
`eliminate the need for multiple punctures. during IV
`therapy. Composed ofpolyvinyl chlorideflhflon, and
`polyethylene, these should be radiopaque to ensure
`that they demonstrate
`on x-ray films. Usu-
`ally,.thesemust be removedwithin 48 hours after in-
`sertion.The choice of catheter depends upon several
`factors (e.g., length of lime of the
`purpose
`of the infusion, the
`of the
`veins}.'I‘hree types of catheters are avaflable: plain
`plastic. ca.thetcr~over-needle or catheter-outside
`needle, and catheter-inside-needle.
`
`Implantable devices provide long-term venous
`access in various diseases. Broviac and Hickman
`
`cathetersarenotable examples.These do carryarisk
`of morbidity, including fracture of the catheters, en-
`trance site infection, and catheter sepsis.'I‘hese have
`been developed to- overcome catheter complica-
`tions andare designed to provide repeated access to
`the infusion site.The delivery catheter can be placed
`inavein, cavity, artery, orCNS system.AHuher
`
`point needle allows system access through the skin
`into a self-sealing silicone plug positioned in the
`center of the portal.
`
`Ofiicial Types of Injections-
`
`According to the USP, injections are separated
`into five general types, all of which -are suitable for,
`and intended for. parenteral adniinistration These
`may contain butters, preservatives, and other added
`substances.
`
`1.
`
`3.
`
`[Drug] Injection—Liquid preparations that are
`drug substances or solutions thereof. (Ex: In-
`sulin Injection, USP)
`2. [DrugIjor;tr:jsctiort—Dr_ysolidsthat,upontt1ead-
`dition of suitable vehicles,
`solutions con-
`forming in all respects to the 1'equj1emenl’s forIn-
`jeclions. (Ex: Cefamandole Sodiumforlnjection)
`[Drug] Infeciabie Emulsion-[.iquidpreparations
`of drug substances dissolved or dispersed in a
`suitable emulsion medium. (Ex: Propofolj
`4. [Drug]
`Injsctcbie Suspensicn—Liquid pre-
`of solids suspended in a suitable liq-
`uid medium. (ER: Mettqtlpredhisolone Acetate
`Suspension)
`[Drug] forinjedable Suspension-—-Drysolids that,
`upon the
`addition of
`suitable vehicles,
`yield preparations conforming in all respects to
`the requirements for Injectable Suspensions.
`Imipenern)
`
`5.
`
`The form in which a given drug is- prepared for
`parenteral useby 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, it a
`drug is unstable in. solution, it may be prepared .3-
`a dry powder intended for reconstitution with the
`proper solvent at the time of its aclminisirat-ion, or
`it may he prepared as a_ suspension of the dru_gpar-
`titles in a vehicle in which the drug is insoluble. If
`the drug is unstable in the presence of water, that
`solvent may be replaced in part or totellyby a sol-
`vent in which the drug_is.insoluhle. If the tin:
`is in-
`soluble in water. an injection. rnaybeprepa
`as-an
`aqueous suspension or also solution of the drug in
`a suitable nonaqueous solvent. such as a vegetable
`oil. If an aqueous solution is desired, a water-solo:
`ble salt form of the insoluble drug is Eequently pre-
`pared to satisfir the required solubility characteris-
`tics. Aqueous or blood-miscible solutions may be
`injected directly into the blood stream. Blood_—«irn.-
`rniscible iiquids, e.g.,.o1eaginous injections and sus-
`
`Astcraleneca 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 ofa drug
`may be somewhat controlled by the chemical form
`of the drug used, the physical state of the injection
`(solution or suspension), and the
`employed.
`Drugs that are very soluble in body fluids generally
`have the most rapid absorption andonsetof
`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
`of the aqueous prepa-
`ration with the body fluids after injection and the
`subsequentmore rapid contact of the drugparticles
`with the body fluids. Oftentimes more prolonged
`dmgaction is desired to reduce the necessity of fre-
`quently repeated injections.'I‘hese long-acdrig types
`ofinjections are comrnonlytefen-ed to as repository
`or"depot”types of preparations.
`The solutions and suspensions oidrugs intended
`for injeclionareprepared in the same general man-
`ner as was discussed previously in dais text for so-
`lutions (Chapter 12} .a.nd disperse systems (Chap-
`ter 13), with the following differences:
`
`1. Solvents orvehicles 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 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 p3mogen—
`free.
`
`4. FarerIteralsolutionsmostmeetcoInpendialstan-
`dards for particulate matter.
`5. Parenteral products must be prepared in envi-
`ronrnentally controlled 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 containers of specific and high quality.
`Special quality control procedures are utilized to
`ensure their herrneticseal and sterile condition.
`
`7.. Each container of an injection is filled to a vol-
`ume in slight excess of the labe1ed”size"'or vol-
`ume to be witl1drawn.This overfill permits the
`case-ofwithdrawal and administration of the la.-
`beled volumes.
`
`Parmternls
`
`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 labelingregulations apply to injections.
`10. Sterile powders intended for solution or sus-
`pension irnrnediately prior to injection are fre-
`quently packaged
`lyophilized or Breeze-dried
`powders to peonit ease of solution or suspen-
`sion upon the addition of the solvent orvehicle.
`
`Solvents and Vehicles. for Injections
`
`The most frequently used solvent in the large-
`scalc manufacturerof is WaferfiJrI7y'ect:'om
`UEP.'I'hiswaterisp1ni.fied bydislillafion or byte-
`verse osmosis and meets the same standards for the
`
`presence of total solids as does Purified Water; USE
`not more than 1 rngper 100 ml. Waterforlnjeclion,
`USP and may not contain added substances. Al-
`though waterfor injection is not required to be ster-
`i1e,.‘1‘t must be pyrogen-free.’I'l1e water is intended to
`be used" in the manufacture of injectable products
`which are to be sterilized after theilrpreparation. Wil-
`ter for injection should be stored in light 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 followingits col-
`lection. Naturally, the water should be collected in
`sterile and pyroge-:I.—free containers. The
`are usually glass -or glass-lined.
`Sterile Water for Injection, LISP is water for injec-
`tion which has been sterilized and packaged in sin-
`gle-rlose containers of not greater than 1-liter size.
`As water for injection, it must be pyrogen-tree and
`may not contain an antirnicrobial agent or other
`added substance. This water maycontain 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-
`jectsble medications. The one-liter bottles cannot
`be administered intravenously because th