Modern
`
`Pharmaceutics
`
`
`
`Second Edition, Revised and Expanded
`
`edited by
`
`GILBERT S. BANKER
`University of Minnesota
`Minneapolis. Minnesota
`
`CHRISTOPHER T. RHODES
`
`University of Rhode Island
`Kingston, Rhode Island
`
`
`
`MARCEL DEKKER, INC.
`
`New York and Base]
`
`ALKERMES EXH. 2007
`ALKERMES EXH. 2007
`|PR2016—1095 & |PR2016—1096
`Luye v. Alkermes
`Luye v. Alkermes
`IPR2016-1095 & IPR2016-1096
`
`
`

`
`
`
`
`Library of Congress Cataloging-in—Publication Data
`
`Fri]
`
`Modern pharmaceutics .
`
`(Drugs and the pharmaceutical sciences ; V. 40)
`Includes bibliographical references.
`1. Drugs—-Dosage forms.
`2. Biopharmaceutics.
`3. Pharmacokinetics.
`4. Pharmaceutical industry--Quality
`control.
`I. Banker, Gilbert S.
`11. Rhodes,
`Christopher T.
`III. Series.
`RS200.M63
`1989
`615'.1
`ISBN 0—8247—7499—X
`
`89—23365
`
`COPYRIGHT 6 199057 MARCEL DEKKER,
`\
`1.
`
`INC. ALL RIGHTS RESERVED
`
`Neither this bookrfior any part may be reproduced or transmitted in any
`form or by any means, electronic or mechanical,
`including photocopying,
`microfilming, and recording, or by any information storage and retrieval
`system, without permission in writing from the publisher.
`
`INC.
`MARCEL DEKKER,
`270 Madison Avenue, New York, New York 10016
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
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`mi,
`
`13
`
`Parenteral Products
`
`JAMES C. BOYLAN
`
`Abbott Laboratories, Abbott Park, Illinois
`
`ALAN L. FITES
`
`Eli Lilly and Company, Indianapolis, Indiana
`
`I.
`
`INTRODUCTION
`
`The earliestfoundation for injectable products can be traced to Hippocrates,
`who recommended strict exclusion of certain unsanitary agents during the
`treatment of wounds [1].
`It was not until the seventeenth century, however,
`that the circulatory system was described and the first intravenous injections
`were made.
`In 1628, William Harvey presented his historic thesis on the
`circulation of blood.» In 1657, Sir Christopher Wren successfully injected
`opium intravenously into dogs using a bladder connected to a small tube.
`This was followed in 1665 by the first successful intravenous injection of a
`drug into a human being by Major, Elsholtz, and Fabricius [2,3].
`Sterilization is an essential prerequisite of safe parenteral administration.
`In 1782, Scheele preserved vinegar by boiling it in closed vessels,
`leading
`the way to heat sterilization of products [2]. Robert Koch,
`in collaboration
`with Gaffky and Loffler, experimented with steam as a disinfectant in 1881
`[41-
`
`Alexander Wood of Edinburgh, Scotland, gave the first successful sub-
`cutaneous injection using a hypodermic syringe in 1853.
`In 1894, a German
`living in Paris invented the modern hypodermic syringe [2]. The basis for
`the development of modern intravenous therapy was laid in the early nine-
`teenth century by Scheele and Dieffenbach and two veterinarians, Viborg
`and Hertwig. The latter carried out carefully designed experiments on
`horses [5].
`The first official injection (morphine) appeared in the British Pharma-
`copoeia (BP) of 1867.
`It was not until 1898 when cocaine was added to the
`BP that sterilization was attempted.
`In this country the first official injec-
`tions may be found in the National Formulary (NF), published in 1926.
`Monographs were included for seven sterile glass-sealed ampoules. The
`United States Pharmacopeia (USP) published in the same year contained a
`chapter on sterilization but no monographs for ampoules. The current USP
`contains monographs for 470 injectable products.
`
`1591
`
`tan ,
`-20.
`
`
`
`

`
`
`
`H92
`
`Boylan and Fites
`
`intramuscular
`Parenteral administration of drugs by intravenous (IV),
`(IM), or subcutaneous (SC) routes is now an established and essential part
`of medical practice, although the parenteral route is relatively new when
`one considers the long history of drugs. Advantages for parenterally
`administered drugs include primarily the following: rapid onset, predictable
`effect, predictable and nearly complete bioavailability, and avoidance of the
`gastrointestinal tract (GIT), hence the problems of variable absorption,
`drug inactivation, and GI distress.
`In addition,
`the parenteral route pro-
`vides reliable drug administration in very ill or comatose patients.
`The pharmaceutical industry directs considerable effort toward maximiz-
`ing the usefulness and reliability of oral dosage forms in an effort to mini-
`mize the need for parenteral administration. Factors that contribute to this
`include certain disadvantages of the parenteral route,
`including the frequent
`pain and discomfort of injections with all the psychological fears associated
`with "the needle," plus the realization that an incorrect drug or dose is
`often harder or impossible to counteract when it has been given parenterally
`(particularly intravenously) rather than orally.
`In recent years, parenteral dosage forms, especially IV forms, have
`gained immensely in use. The reasons for this growth are many and varied,
`but they can be summed up as ( 1) new and better parenteral administration
`techniques;
`(2) new forms of nutritional therapy such as intravenous lipids,
`amino acids, and trace metals;
`(3) the need for simultaneous administration
`of multiple drugs in hospitalized patients on IV therapy, and (4) the exten-
`sion of parenteral therapy into the home. Parenteral systems have been
`developed in the last decade or two that will maintain an unconscious or
`critically ill patient for many months, even years, at a proper hydration
`level and balanced electrolyte state, while providing balanced nutrition
`sufficient to maintain tissue synthesis and support.
`Many important drugs are available only as parenteral dosage forms.
`Notable among these are insulin, several cephalosporin antibiotic products,
`and drugs such as heparin, protamine, and glucagon.
`In addition, other
`drugs such as lidocaine hydrochloride and many anticancer products are
`used principally as parenterals. Reasons that certain drugs are relegated
`largely or exclusively to the parenteral route are very inefficient or unreli-
`able absorption from the GIT, destruction or inactivation in the GIT, exten-
`sive mucosal or first-pass metabolism following oral administration -or clinical
`need in particular medical situations for rapid, assured high blood and
`tissue levels.
`
`Along with this astounding growth in the use of parenteral medications,
`the hospital pharmacist has developed from a health professional who had
`little real contact and only a passing acquaintance with parenteral products
`to a very knowledgeable, key individual in most hospitals, having respons-
`ibility for hospital-wide IV admixture programs, parenteral unit-dose pack-
`aging, and often central surgical supply. By choice, by expertise, and by
`responsibility the pharmacist as accumulated the greatest fund of information
`regarding parenteral drugs—not only their clinical use, but also their
`_
`stability,
`incompatibilities, methods of handling and admixture, and proper
`packaging. More and more, nurses and physicians are looking to the phar-
`macist for guidance on parenteral products.
`To support the institutional pharmacist in preparing IV admixtures
`(which typically involves adding one or more drugs to large-volume parenteral
`fluids), equipment manufacturers have designed laminar flow units, transfer
`devices, and filters specifically adaptable to a variety of hospital programs.
`
`

`
`Parenteral Products
`
`.
`
`I493
`
`The nurse and physician have certainly not been forgotten either. A wide
`spectrum of IV and IM administation devices and aids have been made avail-
`able in recent years for bedside use. Many innovative practitioners have
`made suggestions to industry that have resulted in product or technique
`improvements, particularly in IV therapy.
`
`II. ROUTES OF PARENTERAL ADMINISTRATION
`
`The principal routes of parenteral administration of drugs to achieve sys-
`temic effects are (1) subcutaneous,
`(2) intramuscular, and (3) intravenous;
`other more specialized routes are (4) intrathecal,
`(5) intracisternal,
`(6)
`intra-arterial,
`(7) intraspinal, and (8) intradermal. The intradermal route
`is not typically used to achieve systemic drug effects. The similarities and
`differences of the routes or their definitions are highlighted in Table 1.
`The major routes will be discussed separately.
`
`A. The Subcutaneous Route
`
`the superficial fascia
`Lying immediately under the skin is a layer of fat,
`(see Fig. 1 in Chapter 8), that lends itself to safe administration of a great
`variety of drugs,
`including vaccines, insulin, scopolamine, and epinephrine.
`Subcutaneous (SC; also SQ or sub-Q) injections are usually administered in
`volumes up to 2 ml using a §- to 1-in. 22-gauge (or smaller) needle. Care
`must be taken to ensure that the needle is not in a vein. This is done by
`lightly pulling back on the syringe plunger (aspiration) before making the
`injection.
`If the needle is inadvertently located in a vein, blood will appear
`in the syringe and the injection should not be made. The injection site may
`be massaged after injection to facilitate drug absorption. Drugs given by
`this route will have a slower onset of action than by the IM or IV routes,
`and total absorption may also be less.
`Sometimes dextrose or electrolyte solutions are given subcutaneously in
`amounts from 250 to 1000 ml. This technique, called hypodermoclysis,
`is
`used when veins are unavailable or difficult to use for further medication.
`
`Irritation of the tissue is a danger with this technique. Administration of
`the enzyme hyaluronidase can help by increasing absorption and decreasing
`tissue distention.
`Irritating drugs and vasocontrictors can lead to abscesses,
`necrosis, or inflammation when given subcutaneously. Body sites suitable
`for SC administration include most portions of the arms and legs plus the
`abdomen. When daily or frequent administration is required,
`the injection
`site can and should be continuously changed or rotated, especially by
`diabetic patients self-administering insulin.
`
`B. The Intramuscular Route
`
`The IM route of administration is second only to the IV route in rapidity of
`onset of systemic action.
`Injections are made into the striated muscle fibers
`that lie beneath the subcutaneous layer. The principal sites of injection are
`the gluteal (buttocks), deltoid (upper arm), and vastus lateralis (lateral
`thigh) muscles. The usual volumes injected range from 1.0 to 3.0 ml, with
`volumes up to 10.0 ml sometimes being given (in divided doses) in the
`gluteal or thigh areas (Table 1).
`It is again important to aspirate before
`injecting to ensure that the drug will not be administered intravenously.
`Needles used in administering IM injections range from 1 to 1% in. and 19 to
`22 gauge,
`the most common being 1% in. and 22 gauge.
`
`
`
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`use
`
`Boylan and Fites
`
`The major clinical problem arising from 1M injections is muscle or neural
`damage.
`Since damage occurs with nearly all classes of drugs,
`the injury
`normally results from faulty technique rather than the medication. Pain and
`injury following IM injection will be less if the patient can relax the muscle
`being injected before and during administration.
`Most injectable products can be given intramuscularly. As a result,
`there are numerous dosage forms available for this route of administration:
`solutions, oil-in-water (o/W) or water-in-oil (W/0) emulsions, suspensions
`(aqueous or oily base), colloidal suspensions, andvreconstitutable powders.
`Those product forms in which the drug is not fully dissolved generally
`result in slower, more gradual drug absorption, a slower onset of action,
`and sometimes longer-lasting drug effects.
`lntramuscularly administered products typically form a "depot" in the
`muscle mass from which the drug is slowly absorbed. The peak drug con-
`centration is usually seen within 1 to 2 hr. Factors affecting the drug-
`release rate from an IM depot include the compactness of the depot (the less
`compact and more diffuse,
`the faster the release),
`the rheology of the
`product (affects compactness), concentration and particle size of drug in
`the vehicle, nature of the solvent or vehicle, volume of the injection,
`tonicity
`of the product, and physical form of the product. Particle size and specific
`surface of procaine penicillin are the two most important factors in preparing
`aqueous suspensions for depot repository effect.
`It is reported that the
`specific surface should exceed 10,000 cm2/ g and the particle size should
`cover a relatively broad distribution [6]. Thioxtropic aqueous suspensions"
`containing between 40 and 70% of such solids are both more injectable and
`form more compact spherical deposits which provide the best prolonged
`therapeutic response.
`
`C. The Intravenous Route
`
`Intravenous medication is injected directly into a vein either to obtain an
`extremely rapid and predictable response or to avoid irritation of other
`tissues. This route of administration also provides for maximum availability
`and assurance in delivering the drug to the site of action. However, a
`major danger of this route of administration is that the rapidity of absorp-
`tion makes antidoting very difficult,
`if not impossible,
`in most instances.
`Care must also be used to avoid too rapid a drug administration by the IV
`route because irritation or an excessive drug concentration at the target
`organ (drug shock) can occur. The duration of drug activity is dependent
`on the initial dose and the distribution, metabolism, and excretion properties
`(pharmacokinetics) of the drug. For most drugs the biological half-life is
`independent of the initial dose because the elimination process is first order.
`Thus an intravenous drug with a short half-life would not provide a sus-
`tained blood level. The usual method of administration for drugs with short
`half-lives is to use continuous IV drip.
`Intravenous injections (vein punc-
`ture) normally range from 1 to 100 ml and are given with either a 20- or
`22-gauge 1%-in. needle, with an injection rate of 1 ml per 10 sec for volumes
`up to 5 ml and 1 ml per 20 sec for volumes over 5 ml. Only drugs in
`aqueous or hydroalcoholic solutions are to be given by the IV route.
`Large proximal veins, such as those located inside the forearm, are most
`commonly used for‘IV administration. Due to the rapid dilution in the cir-
`culating blood and the general insensitivity of the venous wall to pain,
`the
`IV route may be used to administer drugs that would be too irritating or
`caustic to give by other routes (e.g. , nitrogen mustards), provided that
`
`
`
`
`
`

`
`Parenteral Products
`
`497
`
`proper dosing procedures are employed. The risk of thrombosis is increased
`when extremity sites such as the wrist or ankle are used for injec ion sites,
`or when potentially irritating IV products are used, with the ris
`further
`increasing in patients with impaired circulation. A certain level of knowledge
`and skill are required to safely employ parenteral administration, especially
`by the IV route. While not within the scope of this chapter,
`the interested
`reader can learn more about parenteral administration procedures by review-
`ing some other works on this subject [7-10].
`The IV infusion of large volumes of fluids (100 to 1000 ml) has become
`increasingly popular (Figs.
`1 and 2). This technique, called venoclysis,
`utilizes products known as large-volume parenterals (LVPs).
`It is used to
`supply electrolytes and nutrients,
`to restore blood volume,
`to prevent tissue
`dehydration, and to dilute toxic materials already present in body fluids.
`Various parenteral drug solutions may often be conveniently added to the
`LVP products as they are being administered (Figs. 3 to 5), or prior to
`administration,
`to provide continuous and prolonged drug therapy.
`Such
`drug additions to LVP has become very common in hospitals. Combining
`parenteral dosage forms for administration as a unit product is known as
`IV admixtures. Pharmacists practicing such IV additive product preparation
`must be very knowledgeable to avoid physical and chemical incompatibilities
`in the modified LVP, creation of any therapeutic incompatibilities with other
`drugs being given parenterally or by any other route, or loss of sterility
`
`Figure 1 Administration of an intravenous fluid by continuous flow.
`
`

`
`1:93
`
`Boylan and Fites
`
`
`
`Figure 2 Direct intravenous administration using gum rubber injection site.
`
`or addition of extraneous matter during IV addition, since any of these
`situations could produce a life-threatening circumstance [10].
`Large volume parenterals are most commonly used to provide water,
`electrolytes, and/or nutrients (e.g. ,
`lipids and/or amino acids) to seriously
`ill patients, and include such products as Sodium Chloride Injection [USP]
`(0.9% saline), which replenish fluids and electrolytes, and 5% Dextrose
`Injection [USP], which provides fluid plus nutrition (calories) or various
`combinations of dextrose and saline.
`In addition, numerous other nutrient
`and ionic solutions are available for clinical use,
`the most popular of which
`are solutions of essential amino acids or lipid emulsions. These solutions
`are modified to be hypertonic,
`isotonic, or hypotonic to aid in maintaining
`both fluid, nutritional, and electrolyte balance in a particular patient accord-
`ing to need.
`Indwelling needles or catheters are required in LVP adminis-
`tration. Care must be taken to avoid local or systemic infections and/or
`thrombophlebitis due to faulty injection or administration technique.
`
`D. Other Parenteral Routes
`
`Other more specialized parenteral routes are listed and described briefly in
`Table 1. The intra-arterial route involves injecting a drug directly into an
`artery. This technique is not simple and may require a surgical procedure
`to reach the artery.
`It is important that the artery not be missed since
`serious nerve damage can occur to the nerves lying close to arteries. Doses
`given by this route should be minimal and given gradually since, once
`
`

`
`Parenteral Products
`
`1499
`
`the
`
`the drug effect cannot be neutralized. As shown in Table 1,
`injected,
`intra-arterial route is used to administer radiopaque contract media for
`viewing of an organ such as the heart or kidney or to perfuse an antineo-
`plastic agent at the highest possible concentration to the target organ.
`The intrathecal route is employed to administer a drug directly into the
`cerebrospinal fluid at any level of the cerebrospinal axis. This route is
`used when it is not possible to achieve sufficiently high plasma levels to
`achieve adequate diffusion and penetration into the cerebrospinal fluid.
`This is not the same route as used to achieve spinal anesthesia, where the
`drug is injected within the dural membrane surrounding the spinal cord, or
`in extradural or epidural anesthesia (caudal or sacral anesthesia), where
`the drug is deposited outside the dural membrane and within the bony spinal
`caudal canals. Parenteral products administered by the intrathecal, intra-
`spinal, and intracisternal routes must be of the highest purity, due to the
`sensitivity of nerve tissue.
`
`E.
`
`Intradermal Administration
`
`Intradermal (ID) administration involves injection into the skin layer (see
`Fig. 3 in Chapter 8). Examples of drugs administered by this route are
`allergy test materials.
`Since intradermal drugs are normally given for diag-
`nostic purposes,
`it is important that the product per se be nonirritating.
`
`
`
`
`
`Figure 3 Addition of intravenous medication directly to primary intravenous
`solution container.
`
`

`
`500
`
`Boylan and Fites
`
`"Piggybacking" of a small-volume intravenous fluid into the pri-
`Figure 4
`mary large-volume intravenous solution.
`
`Therefore, volumes are normally given at 0.05 ml per dose and the solutions
`are isotonic.
`Intradermal medication is usually administered with a §- or
`5/ 8-in. 25- or 26-gauge needle,
`inserted at an angle nearly parallel to the
`skin surface. Absorption is slow and limited from this site since the blood
`vessels are extremely small, although the area is highly vascular. The site
`should not be massaged after the injection of allergy test materials.
`Skin
`testing includes not only allergens such as pollens or dust, but also micro-
`organisms as in the tuberculin or histoplasmin skin tests.
`
`III.
`
`SPECIALIZED LARGE-VOLUME PARENTERAL
`AND STERILE SOLUTIONS
`
`Large-volume parenterals designed to provide fluid (water), calories (glucose
`solutions), electrolytes (saline solutions), or combinations of these materials
`have been described. Several other specialized LVP and sterile solutions
`are also used in medicine and will be described here, even though two
`product classes (peritoneal dialysis and irrigating solutions) are not parenteral
`products.
`
`A . Hyperalimentation Solutions
`
`Parenteral hyperlimentation involves administration of large amounts of
`nutrients (e.g. , carbohydrates, amino acids, and vitamins) so as to maintain
`
`

`
`Parenteral Products
`
`501
`
`ROW 57! TUS
`
`
`
`Figure 5 Electronic flow control device for the administration of accurate
`quantities of intravenous fluids.
`
`a patient who is unable to take food orally, for periods up to several hun-
`dred days, at caloric intake levels of 4000 cal/day or more. Earlier methods
`of parenteral alimentation, which involved IV administration, were not
`typically able to maintain patients without a weight loss and gradual deterio— ’
`ration in physical condition. Parenteral‘ hyperalimentation involves continuous
`administration of the nutrient solution into the superior vena cava by means
`of an indwelling catheter. Available hyperalimentation solutions vary in
`various amino acids, vitamins, minerals, and electrolytes. The method per-
`mits administration of life-saving or life-sustaining nutrients to comatose
`patients or patients undergoing treatment for esophageal obstruction, GI
`diseases (including cancer), ulcerative colitis, and other disease states.
`
`B.
`
`Peritoneal Dialysis Solutions
`
`These sterile solutions are injected continuously into the abdominal cavity,
`bathing the peritoneum (the semipermeable membrane covering the viscera
`of the abdominal cavity), and are then continuously Withdrawn. The purpose
`of peritoneal dialysis is to remove toxic substances from the body or to aid
`and accelerate the excretion function normal to the kidneys. The process
`is employed to counteract some forms of drug or chemical toxicity as well as
`
`

`
`.~vAVN“‘
`
`502
`
`Boylan and Fites
`
`to treat acute renal insufficiency. Peritoneal dialysis solutions contain glu-
`cose and have an inoic content similar to normal extracellular fluid. Toxins
`
`or metabolites diffuse into the circulating dialysis fluid through the perito-
`neum and are removed. At the same time, excess fluid is removed from the
`patient if the glucose content renders the dialysis solution hyperosmotic.
`An antibiotic is often added to these solutions as a prophylactic measure.
`
`C.
`
`lrrigating Solutions
`
`These solutions are intended to irrigate, flush, and aid in cleansing body
`cavities and wounds. Although certain IV solutions such as normal saline
`may be used as irrigating solutions, solutions designed as irrigating solutions
`should not be used parenterally.
`Since irrigating solutions used in treat-
`ment of serious wounds infuse into the bloodstream to some degree,
`they
`must be sterile, pyrogen-free and made and handled with the same care as
`parenteral solutions .
`
`IV. DESIGN OF PARENTERAL PRODUCTS AND
`METHODS OF PREPARATION
`
`Beside the type of dosage form, other factors that influence parenteral drug
`availability include the physicochemical properties of the drug and the biolog-
`ical characteristics and disease state of the patient. Major factors that affect
`the onset and duration of drug activity may be summarized as follows:
`(1)
`route of parenteral administration;
`(2) choice of dosage regimen (continuous
`infusion, or repeated dosing and dose scheduling); and (3) selection, prepara-
`tion, and form of the formulation,
`including active drug and nonactive
`ingredients [11].
`Intramuscular and subcutaneous routes of parenteral administration
`require drug absorption before blood or cerebrospinal fluid levels can be
`achieved. The rate at which the drug is absorbed has a significant influence
`on the concentration of the drug in the blood. With an IM suspension, drug
`dissolution is usually the rate-limiting step in the absorption of the drug at
`the injection site [12]. The absorption of the drug following IM administra-
`tion is greatly influenced by the physicochemical properties of the drug.
`Properties of the drug that influence absorption include [12]:
`
`QO3U1>J>OOl\’)l-‘
`
`Solubility of the drug in biological fluids at the injection site
`Lipid solubility or oil/water partition coefficient of the drug
`pKa of the drug
`Dissolution rate of solid drug from the dosage form
`pH of the vehicle
`
`Particle size of the drug in a suspension
`Presence of other ingredients in the dosage form which may interact
`with the drug
`
`The route of administration not only affects the type of injectable prod-
`uct given, but to a more limited extent the total volume to be given per
`dose. Most parenteral solutions may be given directly or by dilution with
`IV fluids. Many products are too potent to be given undiluted but have
`been formulated as a concentrated drug product because of stability, pack-
`aging, or economy reasons.
`Solutions, suspensions, or emulsions for IM
`use should be formulated so that a unit dose is contained in a volume of
`2.0 to 2.5 ml or less,
`if possible.
`
`

`
`Parenteral Products
`
`V
`
`503
`
`Formulating a drug for IM use with a longer duration of activity may be
`achieved by physical, chemical, or physiological methods. Because of their
`physical properties and the ability to retard drug dissolution release, sus-
`pensions, emulsions, oils, and implants provide basic methods for extending
`drug action.
`Increasing particle size and viscosity will lower drug dissolu-
`tion in the tissue fluid and result in lower absorption rates and usually
`extended drug activity.
`Similarly,
`the preparation of less soluble salts or
`esters, or the use of crystalline rather than amorphous forms or polymorphs,
`can reduce onset and prolong duration.
`Lee and Robinson [13] list the following physical methods to achieve
`controlled drug delivery in parenteral preparations:
`
`1. Use of polymers to complex (or absorb) drug molecules in solution
`and/or to increase the viscosity of the medium
`2. Suspension of the drug
`a. Aqueous
`b. Suspension of polymer particles into which drug is dispersed
`c. Suspension of microcapsules of drug
`Oil solutions
`
`C301)-500
`
`Oil suspensions
`Emulsions
`
`Implants and pellets
`
`These methods are discussed in detail. A combination of the methods are
`
`generally utilized to obtain the desired effect.
`The various insulin products provide excellent examples of how drug
`form and physical properties may be altered and controlled to tailor the on-
`set and duration of the product(s). Zinc may be combined with insulin to
`form an insoluble complex, which may be obtained either as an amorphous
`precipitate or as crystals, depending on pH. The amorphous precipitate
`(known as semilente insulin) is rapidly absorbed following SC injection and
`has a short duration of action. The chemically identical but crystalline solid
`(known as ultralente insulin) has a longer duration of action,
`is much more
`slowly absorbed, and has a long onset. A physical mixture of 70% of the
`crystalline ultralente and a 30% of the amorphous semilente forms produces
`a product known as lente insulin, which combines rapid onset and long
`action.
`
`A long-acting injectable dosage form was developed for a somatostatin
`analog by absorbing the peptide on zinc phosphate. The resulting floccu-
`lated suspension of the somatostatin peptide significantly increased the dura-
`tion of growth hormone suppression as compared to a suspension of somato-
`statin [14].
`the crystal or amorphous forms of a drug are of concern
`In other cases,
`in parenteral product design based on ease of product design or ability to
`sterilize the product. Penicillin G may be cited as one such example, where
`both the sodium and potassium salts may be obtained as either an amorphous
`or crystalline form. The amorphous form, although more rapidly soluble,
`is
`decomposed by heat sterilization, whereas the crystalline form can withstand
`dry heat for several hours without significant decomposition [15]. Crystal-
`line tobramycin can be exposed to dry heat temperatures exceeding 100°C
`with no adverse effects. Whereas,
`the amorphous form degrades rapidly
`under similar conditions.
`
`Concepts in drug delivery which have received increasing attention include
`drug carrier systems,
`implants,
`intravenous infusers, and implantable infusion
`
`

`
`5011
`
`Boylan and Fites
`
`liposomes, and emul-
`pumps [16—18]. Carrier systems include microspheres,
`sions. Drugs are incorporated into these systems to increase the duration
`of drug action and to provide selective delivery of the drug to a specific
`target site or organ.
`Implants are utilized for the same reason. Unwanted
`side effects and adverse reactions are usually reduced because of selective
`delivery, which also results in a lower concentration of drug required to
`achieve the desired therapeutic effect.
`Infusion pumps provide a delivery
`system with uniform, continuous flow. A specific close of drugs such as
`insulin may be administered to a patient on a continual or intermittent basis.
`
`A. Solutions
`
`Solutions of drugs
`The most common of all injectable products are solutions.
`suitable for parenteral administration are referred to as injections. Although
`usually aqueous,
`they may be mixtures of water with glycols, alcohol, or
`other nonaqueous solvents. Many injectable solutions are manufactured by
`dissolving the drug and a preservative, adjusting the pH, and sterile filter-
`ing the resultant solution through a 0.22-um membrane filter. Most solutions
`have a viscosity and surface tension very similar to water, although strepto-
`mycin sulfate injection and ascorbic acid injection, for example, are quite
`viscous.
`
`Sterile filtration with subsequent aseptic filling is common because of
`_ the heat sensitivity of most drugs. With those drug solutions that can with-
`stand heat,
`it is preferable to terminally autoclave-sterilize after filling,
`since this better assures product and package sterility.
`Large-volume parenterals (LVPS) and small-volume parenterals (SVPS)
`containing no antimicrobial agent should be terminally sterilized.
`It is
`standard practice to include an antimicrobial agent in SVPs which cannot
`be terminally sterilized or are intended for multiple-dose use. The general
`exceptions are products that pass the USP Antimicrobial Preservative Effec-
`tiveness Test
`[19] because of the preservative effect of the active ingredient,
`vehicle, pH, or a combination of these. For example, some barbiturate prod-
`ucts have a pH of 9 to 10 and a vehicle that includes glycol and alcohol.
`Injections and infusion fluids must be manufactured in a manner that
`will minimize or eliminate haze and color. Parenteral solutions are generally
`filtered through 0.22-um membrane filters to achieve sterility and remove
`particulate matter. Prefiltration through a coarser filter is often necessary
`to ma