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`PP.
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`Ilealications
`
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`. "„,I
`Parenteral
`»fo "lame 11
`Second Edition, Revised and Expanded
`Mted by
`Kenneth K. Avis
`The University of Tennessee
`Memphis, Tennessee
`Herbert A. Lieberrnan
`H.H. Lieberman Associates,
`inc.
`Consultant Services
`Livingston, New Jersey
`
`Lachman Consultant Services
`Westbury, New York
`
`MARCEL
`
`1M
`
`DEKKER
`
`MARCEL DEKKER,INC.
`
`NEW YORK BASEL
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`First Indian Reprint 2005
`Library of Congress Cataloging-in-Publication
`
`Data
`
`/ edited by
`dosage forms, parenteral medications
`Pharmaceutical
`and Leon Lachman, —2nd ed.
`Kenneth E. Avis, Herbert A, Lieberman,
`rev. and expanded.
`cm.
`p.
`and index.
`references
`Includes bibliographical
`ISBN 0-8247-8576-2
`1. Parenteral
`2. Pharmaceutical
`solutions.
`Kenneth E, II. Lieberman, Herbert A,
`III. La chm an, Leon.
`[DNLM; .1.Infusions, Parenteral.
`2. Technology, Pharmaceutical.
`WB 354 P536]
`R8201 .P37P48 1992
`615'. 19—dc20
`DNLM/DLC
`for Library of Congress
`
`technology.
`
`I, Avis,
`
`91 - 38063
`CIP
`
`Copyright
`
`1992by MARCEL DEKKER, INC. All Rights Reserved
`this book nor any part may be reproduced or transmitted in any form
`Neither
`including photocopying, micro-
`or by any means, electronic or mechanical,
`filming, and recording, or by any information storage and retrieval
`system,
`without permission in writing from the publisher.
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Printed and bound by Replika Press Pvt. Ltd., India,
`
`FOR SALE IN INDIAN SUBCONTINENT ONLY.
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`University,
`
`Richmond,
`
`Indianapolis,
`
`Indiana
`
`Parenteral
`l3rug Administration: Routes,
`Precautions, Problems, Complications,
`and l3rug Delivery Systems
`Richard J. Ouma
`Medical College of Virginia, Virginia Commonwealth
`Vtr ginia
`Michael J. Akers
`Eli Lilly and Company,
`Salvatore J. Turco
`Temple University,
`
`Philadelphia,
`
`Pennsylvania
`
`from para enteron (Greek), meaning "to avoid the intestines,"
`Parenteral,
`in its broadest
`any drug (or fluid) whose delivery
`sense,
`does not
`includes
`for entry into body tissues. Although
`ap-
`utilize the alimentary
`canal
`drugs
`plied topically to the eye, ear, and skin, or even inhaled, may be broadly
`health care deliveries
`interpreted
`as parenterals, medical
`and pharmaceutical
`injected or infused directly into
`to those drugs
`the definition
`generally
`limit
`tissues,
`tissue spaces, vessels, or body compartments.
`of techniques
`parenterals,
`for administering
`The development
`coupled
`designs of new devices to achieve and monitor
`their delivery,
`with innovative
`occur almost daily and are enabling therapeutics
`to approach
`an exact science.
`therapy is not restricted to hospitals or clinics but
`parenteral
`In addition,
`is
`(e.g.
`forms of delivery
`even in its most
`being increasingly
`invasive
`employed,
`intravenous),
`at home and in the work place. Most pa-
`to manage patients
`ther-
`to almost every form of parenteral
`tients readily accept or easily adapt
`even when the route of de-
`self-administer
`their own drugs,
`apy, and many
`(e,g., home infusion programs).
`livery is intravenous
`offers many advantages
`Parenteral
`over therapy
`administration
`given by
`routes. Most notably,
`therapeutists
`can reliably predict with
`nonparenteral
`of the agents
`accuracy the pharmacokinetics
`considerable
`and pharmacology
`they prescribe;
`lethal pro-
`a rapidly progressive
`they can quickly interdict
`cess or disease; and, even though the physiology
`and pathology of patients
`they can "fine tune," stratify and quantitate
`results.
`may be complicated,
`is not without
`despite these advantages,
`parenteral
`administration
`However,
`
`17
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`Duma et al.
`
`the professional must
`that
`risks and limitations
`certain, measurable
`and costs.
`ly weigh in terms of risks, benefits,
`the usage of parenteral
`to review and update
`This chapter will attempt
`is
`since the subject
`in today's practice of medicine.
`However,
`administration
`that
`the reader must appreciate
`some
`is growing,
`and the technology
`dynamic
`contained herein may become quickly outdated.
`of the material
`
`intelligent-
`
`I. GENERAL INDICATIONS FOR PARENTERAL
`ADMINISTRATION OF DRUGS
`
`The parenteral
`of the following
`
`routes of drug administration
`reasons:
`
`are indicated for one or more
`
`of the drug in ques-
`concentrations
`To ensure delivery of adequate
`tion to diseased tissues or target areas of the body, especially when
`transport of that drug into the tissues or tar-
`or marginal
`inadequate
`intraventricular
`injection
`Example: Direct
`get areas is anticipated.
`of drugs (e.g., antibiotics
`which cross
`such as the aminoglycosides)
`barrier" poorly may be used in certain
`the "blood-brain-meninges
`and/or ventriculitis.
`patients with bacterial or fungal meningitis
`the user to exert direct control over certain pharmacologic
`To permit
`such as the time of drug onset,
`serum peak and trough
`parameters,
`and rate of elimination of the drug from
`tissue concentrations,
`levels,
`or direct cardiointraventricular
`Intravenous
`the body.
`Example;
`effects in emergencies
`to achieve immediate
`routes may be desirable
`such as might occur in the control of life-threatening
`hypotension,
`routes may be desir-
`or intramuscular
`or arrhythmias;
`hypertension,
`effects, such as the use of
`able to obtain protracted or sustained
`of infections.
`penicillin G in the treatment
`benzathine
`is desirable,
`to
`To allow the therapist, when outpatient management
`especially when the patient
`dosage and drug compliance,
`guarantee
`The use of long-
`cannot be relied upon to self-medicate.
`Example:
`penicillins may be used to manage
`intramuscular
`acting (monthly)
`to pre-
`for rheumatic heart disease in order
`children prophylactically
`vent Group A streptococcal pharyngitis.
`that cannot be achieved through oral ad-
`a biologic effect
`To deliver
`perhaps because of nonabsorbance
`from the alimentary
`ministration,
`pep-
`Therapeutic
`by gastric acidity.
`canal or degradation
`Example:
`other
`growth hormone,
`tides and proteins
`such as insulin,
`human
`antibiotics
`from recombinant DNA technology,
`and polyene
`products
`agent amphotericin 8).
`(such as the antifungal
`a drug when the desired route (e.g., oral) may not be
`To administer
`In patients who are aspirating or who have had
`available.
`Example:
`(e.g,,
`stream diverted or removed
`tract
`the upper gastrointestinal
`route may be necessary.
`because of a carcinoma)
`a parenteral
`to minimize or avoid sys-
`To provide a local effect when it is desirable
`temic toxic effects or reactions.
`Examp/e; Methotrexate may be given
`of
`involvement
`to patients with leukemia
`and leukemic
`intrathecally
`toxic effects that would occur if
`to avoid the systemic,
`the meninges
`route was employed.
`an intravenous
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`Parentera/ Drug Administration
`
`or uncon-
`uncooperative,
`to the unconscious,
`7. To administer
`drugs
`Patients with uncontrollable
`grand mal
`trollable patient.
`Example:
`of drugs
`seizures often will not cooperate in the oral administration
`or will be at risk to aspirate if compelled
`to take medicines by mouth.
`from narcotic abuse, ariesthetic usage,
`patients unconscious
`Similarly,
`such as those suffering delerium
`or trauma, or uncooperative
`patients
`by using paren-
`tremens or a psychosis, may be satisfactorily managed
`routes.
`teral
`and to
`rapid correction of fluid and electrolyte
`imbalances
`8. To permit
`or
`short- or long-term nutritional
`needs
`(hyperalimentation
`supply
`suffering severe dehydration
`Patients
`feeding).
`parenteral
`Example:
`(e.g,, heat stroke)
`for a variety of reasons
`or electrolyte
`depletion
`solutions;
`electrolyte
`can be rapidly corrected with intravenous
`and
`tracts have been resected for one reason
`patients whose intestinal
`"fed" a complete diet of all
`the neces-
`or another may be intravenously
`for prolonged
`and
`and vitamins
`sary amino acids, glucose, minerals,
`periods of time.
`indefinite
`for
`9. To achieve a desired local effect. Example:
`Local anesthetics
`for inflamed
`joints
`agents
`tooth extractions or local anti-inflammatory
`may be injected directly into the site in question to avoid systemic
`effects or "systemic" dosages.
`
`II. PHARMACEUTICAL
`FACTORS AFFECTINC
`PARENTERAL ADMINISTRATION
`
`dictate the method or route of paren-
`characteristics
`Certain pharmaceutical
`and once the dosage form is injected or infused;
`influ-
`teral administration,
`These characteristics will be
`ence the rate and extent of drug availability.
`is also referred to Chapter
`the reader
`reviewed briefly in this section, but
`3
`factors affecting paren-
`for a more detailed treatment of the biopharmaceutical
`teral drug availability.
`
`A. Solubility of the Drug and Volume of the injection
`in water, before it can be
`preferably
`solubilized,
`A drug must be completely
`injection. Both the extent of drug solubility
`in
`by intravenous
`administered
`effect
`for the desired therapeutic
`vehicle and the dose required
`its intended
`routes other
`Parenteral
`than the
`the volume of the injection,
`will determine
`the maximum volume of medication
`regarding
`intravenous
`one have limitations
`(e.g,, intradermal,
`intraventricular,
`intraocular,
`intramuscular,
`administered
`to name a few).
`and intrathecal,
`
`B. Vehicle Characteristics
`route,
`by any parenteral
`Drugs in aqueous vehicles may be administered
`vehicles, which may or may not be water mis-
`whereas drugs
`in nonaqueous
`route. The in-
`by the intramuscular
`cible, are administered most
`frequently
`(e.g.,
`in mixed solvent
`systems
`route may be used for a few drugs
`travenous
`but precautions must be applied in adjust-
`and phenytoin),
`digoxin,
`diazepam,
`at the site of infusion.
`ing the rate of drug infusion to avoid drug precipitation
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`20
`
`Duma et al
`
`are also available
`Large volume parenteral
`fat emulsions
`by the intravenous
`route. Nonaqueous
`that are more viscous
`vehicles
`than water vehicles will
`the rate of injection through
`needle and the rate of ab-
`affect
`a small-gauge
`sorption from the injection site.
`
`C.
`pH and Osmolality of injectable Solutions
`should be formulated
`injections
`administered
`Ideally,
`at a pH and osmolality
`to that of biological
`fluids. Unfortunately,
`this is not possible for
`similar
`dosage forms, as many parenteral
`many parenteral
`are unstable
`at neu-
`drugs
`tral pH. Therefore,
`such drugs are formulated
`at the pH at which they are
`most stable.
`(a nondiuretic
`For example,
`deriva-
`diazoxide
`benzothiadiazine
`at a pH of 11.6, the pH at which it is most stable. Many
`tive) is formulated
`forms of weak bases. Thus the pH of a dosage form
`parenteral
`drugs are salt
`the salt of a weak base may be as low as 2.0 (e,g., tetracycline
`containing
`the salt of a weak acid
`or the pH of a dosage form containing
`hydrochloride),
`may be as high as 12.0 (e.g., Dilantin)
`in order to maintain
`the active in-
`in solution.
`gredient
`dosage forms with extreme pH values may be
`Although
`the rate and volume of injection must
`route,
`by any pare'nteral
`administered
`be controlled to minimize
`pain and irritation
`to the patient
`to the
`and damage
`tissues.
`surrounding
`are hyperosmotic with biological
`Certain parenteral
`formulations
`fluids
`high dose of active ingredient(s)
`in order to achieve
`and contain a relatively
`a desired level of biological activity.
`For example, water-soluble
`contrast
`spinal anesthetics,
`media,
`sodium sulfacetamide,
`diazoxide,
`ophthalmic
`and
`osmotic diuretics
`are a few hypertonic
`parenteral
`formulations
`containing
`high
`biological action(s).
`drug concentrations
`to achieve an appropriate
`Products
`of parenteral
`or admixed with high concentrations
`are formulated
`nutrition
`of amino acids, dextrose,
`and other essential
`ingredients,
`resulting in very
`These solutions,
`solutions,
`hypertonic
`called hyperalimentation
`solutions,
`are so hypertonic
`that
`they must be administered
`via a large vein such as the
`subclavian.
`The blood in this vein enters directly into the heart, which allows
`the hypertonic
`larger volume of blood.
`solution to be rapidly
`diluted by a still
`parenteral
`Generally,
`hypertonic
`dosage forms are contraindicated
`for
`or intramuscular
`subcutaneous
`injections. Whereas
`the vitreous humor,
`can
`tolerate only very narrow ranges of osmotic values
`from an injected medication.
`Therefore,
`stability and solubility
`although
`problems may prevent dosage forms
`at physiological
`from being formulated
`they should be formulated with
`pH,
`solute contents
`to those of biological
`fluids.
`approximately
`equal
`
`D. Type of Dosage Form
`Parenteral
`include solutions,
`dosage forms
`and sterile solids
`suspensions,
`If the dosage form is a suspension,
`for reconstitution.
`it may be administered
`or subcutaneous
`only by the intramuscular
`route.
`Particles
`should not be
`or by other parenteral
`present
`in dosage forms administered
`intravenously
`routes in which the medication
`enters directly into a biological
`fluid or sensi-
`tive tissue (e.g., brain or eye). Reconstituted
`solids should be completely
`dissolved in the reconstituting
`diluent before they are administered
`intraven-
`ously.
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`21
`
`Parentera! Drug Administration
`E. Formulation
`ingredients
`active
`As discussed in Chapter 5, parenteral
`formulations may contain various
`for a variety
`and inactive excipients other
`than the main therapeutic
`agent,
`of reasons.
`agents are added to the
`For multidose parenterals,
`antimicrobial
`of sterility.
`for the preservation
`these agents may be
`However,
`formulation
`to be administered
`into the cerebrospinal
`fluid
`contraindicated
`in medications
`Several paren-
`fluid because of the toxicity they may produce.
`or intraocular
`contain surface-active
`(such as polysorbate
`80) to
`agents
`teral
`formulations
`Surface-active
`agents are
`in the solution vehicle.
`drug solubility
`maintain
`so their presence must be recognized
`permeability,
`known to alter membrane
`or intramuscular
`such dosage forms by the subcutaneous
`when administering
`routes.
`release of drug delivery
`field of sustained
`The expanding
`and prolonged
`and additives
`that at
`times aid in achieving the
`employs various
`formulations
`of drug action. These additives
`are primarily
`desired duration
`high-molecular-
`weight polymers or oily solvents.
`these macromole-
`containing
`Formulations
`or intramuscular
`routes to permit
`cules are administered
`by the subcutaneous
`tissues of the body.
`the delayed release of the active ingredient within deeper
`
`III. SPECIFIC ROUTES OF ADMINISTRATION
`routes of parenteral
`Three primary
`are commonly
`administration
`employed:
`and subcutaneous.
`These three routes
`intravenous,
`intramuscular,
`satisfy
`to a large extent
`parenterals;
`reasons
`for administering
`the four principal
`(I) for therapy
`(definitive or palliative),
`(2) for prevention,
`(3) for diagnosis,
`in order
`and (4) for temporarily
`altering tissue function(s)
`to facilitate other
`routes,
`Besides these three primary
`forms of therapy.
`ones are
`additional
`intra-
`special circumstances:
`for example,
`utilized under
`'subconjunctival,
`intra-articular,
`intrathecal,
`In the sections to follow,
`and so on.
`ocular,
`routes of parenteral
`are reviewed in
`the primary
`and special
`administration
`order. Each review will
`description,
`include four subheadings:
`alphabetical
`and method of drug or fluid delivery.
`precautions,
`indications,
`
`A. Primary Routes
`Intramuscular
`Injection directly into the body of a relaxed muscle.
`Description.
`(i.m.) route is one of the most popular
`Indications.
`The intramuscular
`and for the patient
`routes available,
`both for the administrator
`and convenient
`[I], especially for a child [2]. Therefore, whenever
`it is possible and prac-
`route is used. The intramuscular
`ticable,
`the intramuscular
`route provides
`release of drugs
`as aqueous or oily solutions
`for prolonged
`a means
`formulated
`or suspensions.
`route is preferred over the subcutaneous
`The intramuscular
`route when a rapid rate of absorption
`is desired and over the intravenous
`route when for one reason or another
`direct-
`the drug cannot be administered
`ly into the vascular
`compartment,
`the rate of drug absorption
`Many factors affect
`from an intramuscular
`injection [2]; they will be discussed later
`in this chapter. Drugs commonly
`
`) ttta et al
`galen "
`ss wtil
`-"@of ab
`
`olality
`r-'or
`j'at neu-
`sy are
`'riva
`";.Many
`age form
`'[inc
`ak acid
`=;:in-
`ybe
`,':mast
`'Q the
`
`'jds
`(I|i[eve
`st
`nd
`"g,high
`ducts
`
`s s
`
`the
`'ai]ows
`food.
`
`'an
`'lion,
`'forms
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`Duma et at.
`
`injected by intramuscular
`include lidocaine,
`administration
`cephalosporins,
`salts of penicillin G (procane penicillin
`aminoglycosides,
`insoluble
`diazepam,
`G), corticosteroids,
`narcotics, narcotic antagonists,
`steroids,
`and contraceptive
`to name a few.
`Precautions.
`injections are much easier
`intramuscular
`to ad-
`Although
`injections,
`than other
`is to avoid entering a blood
`the main precaution
`minister
`(especially an artery), which might
`vessel
`lead to infusion of a toxic agent
`or a toxic vehicle directly to an organ or tissue. This can be prevented
`usu-
`ally by pulling back on the plunger of the syringe;
`if blood does not appear,
`in a vessel. Also,
`the needle is probably
`striking of or
`the accidental
`not
`injection into a peripheral
`nerve may result
`nerve palsy with
`in a peripheral
`or without
`sensory damage. Occasionally, when a large bolus of drug is in-
`jected into the muscle,
`local damage or muscle infarction may result,
`leading
`to a sterile abscess or to elevation of serum levels of muscle enzymes.
`The
`latter complication may present
`confusing
`diagnostic problems,
`especially in
`suspicion of having a myocardial
`patients under
`infarction or hepatitis.
`If materials
`a septic abscess
`contaminated with microorganisms
`are injected,
`may result.
`precautions must be taken to ensure ster-
`Therefore,
`appropriate
`to injection.
`ility prior
`In patients with poor hygiene or skin care, microorga-
`from the skin flora may be punched
`nisms
`the time of in-
`in by the needle at
`jection,
`resulting in staphylococcal
`or streptococcal
`abscesses;
`and rarely in
`[3] (especially if epinephrine
`such situations
`as gas gangrene
`is injected)
`[4] .
`or tetanus
`note of caution:
`An important
`the intramuscular
`route should never be
`in patients with significant
`failure or shock, when uptake into
`heart
`employed
`the vascular
`compartment may be expectantly
`poor. This caution should be
`followed especially if immediately
`high serum or plasma concentrations
`of the
`drug are desired or if rapid distribution
`to a distal organ is mandatory.
`(Fig. I), includ-
`Method. Various muscle sites are available
`for delivery
`ing the gluteal, deltoid,
`triceps, pectoral,
`and vastus
`lateralis muscles.
`In
`the site of choice often is the gluteal muscle, because large volumes
`adults
`of drug may be injected and tolerated.
`lateralis of the
`the vastus
`However,
`thigh may also be used because it not only tolerates
`large volumes of medica-
`tion, but
`it is also away from any major vessels or nerves.
`For rapid absorp-
`tion and small volumes
`the deltoid muscle is preferred,
`as some stud-
`(&2 ml),
`ies suggest
`that blood flow in the deltoid muscle is 7% greater
`than that of
`[5].
`the vastus
`lateralis
`than that of the gluteus maximus
`and 17% greater
`For this reason,
`in adults
`the deltoid is the preferred site for vaccine admin-
`istration,
`In infants
`and small children,
`the vastus
`lateralis of the thigh is
`often preferred because it is better developed
`than other muscle groups, de-
`on the site selected,
`pending
`The skin is first cleaned with alcohol or a suit-
`able disinfectant,
`and the plunger
`on the syringe is always
`retracted prior
`to injeciton to be sure that
`the needle is not
`in a vessel.
`For deep intramus-
`cular
`injections,
`as might be used for irritating medications
`such as iron prep-
`a "z-track" injection method is employed.
`arations,
`Intravenous
`Description.
`
`Injections or infusions directly into a vein.
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`Parenteral Drug Administration
`
`23
`
`for intramuscular
`injections,
`Figure 1 Some common sites employed
`Upper
`2 in. below
`left;
`located in the outer upper quadrant
`posterior gluteal,
`about
`the iliac crest. Upper
`2 in. below the acromion
`right:
`deltoid located about
`left:
`process.
`located in the triangle
`ventrogluteal,
`formed by one
`Lower
`iliac spine and the other on the iliac crest.
`finger on the anterior
`superior
`third and lateral as-
`Lower right:
`lateralis,
`vastus
`located along the middle
`The "bull'-eye" indicates
`pect of the thigh.
`site of injection.
`the approximate
`
`(i.v.) administration
`of drugs,
`Indications.
`fluids,
`Intravenous
`and/or
`is one of the most common parenteral
`routes employed
`electrolytes
`in hospitals
`It is especially convenient
`for rapidly infusing large volumes of fluid.
`today.
`(I) to guarantee
`for use of this route are:
`de-
`The most common indication
`or shock exists;
`(2) to restore rapid-
`livery and distribution
`when hypotension
`(3) to achieve an immediate
`ly electrolyte
`and fluid balance;
`pharmacologic
`effect, especially in emergencies,
`such as the treatment of certain arrythmias
`or of seizures;
`(4) to treat serious,
`infections or conditions;
`life-threatening
`(5) to provide continuous
`are
`when patients
`nutrition
`(hyperalimentation)
`and (6) to avoid complications which might
`result
`to be fed by mouth;
`unable
`(e.g., hematomas
`if other administration
`the site of
`routes were employed
`at
`in a patient with a bleeding diathesis).
`In addition,
`injections
`intramuscular
`route may be used for a variety of other purposes,
`the intravenous
`such as
`blood transfusion,
`to name a few.
`plasmapheresis,
`and hemodynamic monitoring,
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`24
`
`Duma et al.
`and variety of complications may occur us-
`A large number
`Precautions.
`(1) thrombosis with or with-
`A few of these are;
`route.
`ing the intravenous
`(2) injection of
`the site of injection or infusion;
`infection at
`out complicating
`toxins, particulate matter, or air; (3) the occurrence of phys-
`microorganisms,
`to or at the time of in-
`between agents prior
`incompatibilities
`ical or chemical
`of drugs or fluids;
`and
`or excessive administration
`(4) uncontrolled
`jection;
`the site of administration.
`of injections or infusions
`at
`When
`(5) extravasation
`tip may break off and
`rarely the catheter
`catheters
`are utilized,
`indwelling
`in the heart, or in the lung.
`lodge in a major vessel,
`possible for the
`are chosen whenever
`The upper extremities
`Method.
`sites as possible should be pre-
`site of injection or infusion.
`As many venous
`veins (e.g., those over the
`the most peripheral
`served for future use;
`thus
`are selected for initial use. When arm sites are no longer available,
`hand)
`foot veins may be utilized;
`or dorsal
`(femoral and saphenous)
`the leg veins
`and in small children the scalp veins.
`Selection of a vein depends on the size of the needle or catheter
`intended
`to be re-
`flow rate anticipated,
`to be infused,
`volume
`type of fluids
`for use,
`to be given, degree of patient mobility de-
`ceived, concomitant medications
`or
`the venipuncture
`sired, and of course the skill of the person performing
`fossa are among the most com-
`The veins in the ante-cubital
`catheterization,
`Other veins
`monly chosen, because they are large and readily punctured.
`and the metacarpal
`radial at the wrist,
`are basilic, cephalic,
`utilized commonly
`and dorsal venons plexuses.
`to be less with needles
`the risk of infection appears
`than with
`Although
`(6], an 8-in.
`plastic cathe-
`long intravenous,
`catheters
`intravenous
`indwelling
`Such cathe-
`veins.
`ter is commonly used for delivery of fluids via peripheral
`thus providing more comfort
`considerably,
`ters reduce the risk of infiltration
`the in-
`reducing time and labor costs of nursing in managing
`to the patient,
`predictions more reliable,
`and avoiding
`pharmacokinetic
`rendering
`fusion,
`If
`adverse side effects, such as cellulitis
`and occasionally tissue sloughing.
`cut-downs of deep veins
`sites become exhausted,
`surgical
`insertion
`peripheral
`catheters may be performed. When long-term,
`of indwelling
`with implantation
`or internal
`jugu-
`the subclavian
`usage is anticipated,
`repeated, or prolonged
`These veins are es-
`in the upper chest may be utilized.
`lar (central) veins
`fluids are to be infused,
`as physicochemical
`if hyperosmolar
`pecially useful
`or chemical
`formu-
`and venospasm produced by the hyperosmolarity
`irritation
`silastic
`In such instances,
`lation of the fluids may be reduced or negated.
`(e.g., Broviac, Hick-
`central venous access catheters
`tunnelled,
`implanted,
`the tip of the
`man, Groshong, Port-A-Cath)
`tailored to each patient
`so that
`These devices
`rests just above the right atrium,
`are often utilized.
`catheter
`indefinitely
`they can remain in place and be maintained
`so that
`are designed
`for the life of the patient.
`a 1- to 2-in.
`If needles are to be used for intrave'nous
`infusion,
`long,
`18 to 22 gauge (Table I), stainless
`steel needle is commonly used.
`beveled,
`the device is inserted percutaneously
`Whether using a catheter or needle,
`site and pre-
`cleaning the skin-insertion
`into the vein only after thoroughly
`associated
`to be more commonly
`Since infections
`appear
`paring it aseptically.
`than with needles, more time and care
`catheters
`intravenous
`with indwelling
`to be given to skin preparation with catheter use than with needle in-
`needs
`Such aseptic practices are especially important when "long-term"
`sertion.
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`Parenteral Drug Administration
`
`25
`
`Table I Needle Selection
`Length range (in, )
`4-6
`
`Injection site
`
`Intra-abdominal
`Intra- articular
`Intracardiac
`Intradermal
`Intraocular
`Anterior
`chamber
`Intravitreal
`Retrobulbar
`Subconjunctial
`Intrapleural
`Intrathecal
`Adult
`Pediatric
`Neonatal
`Intravenous
`Metal needle
`Winged needle
`Plastic needle
`Intracatheter
`In-lying catheter
`Silastic catheter
`Hypodermoclysis
`Adult
`Pediatric
`Subcutaneous
`
`Gauge range
`
`14-18
`19- 22
`18- 21
`24- 26
`
`25
`25
`25
`25
`13-18
`
`20- 22
`25
`27
`
`15- 25
`16- 23
`15- 21
`15- 21
`14, 15
`12- 19
`
`19
`20- 22
`24- 25
`
`4-6
`1/4-5/8
`
`1-3
`1-3
`Ig
`1$
`5-6
`
`3-5
`1- 1$
`1/2-1
`
`1-2
`3/4-1$
`3-5
`8- 11$
`12, 26
`13- 23
`
`2
`I-1$
`1/4- 5/8
`
`vein or vena cava are utilized
`inserted into the subclavian
`silastic catheters
`being
`a tourniquet
`(vide supra).
`The mechanics of insertion usually
`involve
`the vein (thus,
`to the site of insertion in order
`to congest
`applied proximal
`the device may be easily inserted.
`If a catheter
`the vein),
`so that
`expanding
`Afterwards,
`it is inserted over a needle used for the initial puncture,
`is used,
`cathe-
`in place. The indwelling
`is left
`and the catheter
`the needle is removed,
`is anchored to the extremity or body
`ter or needle, whichever
`is utilized,
`often
`dressings,
`sterile occlusive or nonocclusive
`by means of appropria'te,
`in-
`to reduce the risk of a complicating
`impregnated with antibiotic ointments
`catheters often contain heparin locks to ensure against
`fection.
`Indwelling
`thrombosis.
`clotting and loss of patency from venous
`
`Subcutaneous
`Injection into the loose connective
`Description.
`the skin (dermis) .
`
`and adipose tissue beneath
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`Pled)l'mlllBtloA ReseBI'ch Of
`Pat"entem"al Meditations
`
`Sol Motola*
`Whitehall Laboratories, Hammonton,
`
`New Zersey
`
`Shreeram N. Agharkar
`Bristol-Myers Squibb Company, Syracuse, New York
`
`I.
`
`INTRODUCTION
`
`investigations
`to pharmaceutical
`research relates
`and analytical
`Preformulation
`efforts for all dosage
`that both preceed and support
`development
`formulation
`specific,
`are designed to generate data characterizing
`forms. Experiments
`properties of the drug substance
`important,
`physicochemical
`pharmaceutically
`excipients,
`and its combination with selected solvents,
`com-
`and packaging
`stressed conditions of tempera-
`These studies are carried out under
`ponents.
`and oxygen in order
`to accelerate and detect potential
`ture,
`light, humidity,
`and biopharmaceutical
`reactions.
`Taking into account early pharmacological
`necessary to guide the form-
`studies yield key information
`data, preformulation
`of an elegant,
`stable dosage form
`toward the development
`ulator
`and analyst
`of the clinical
`and marketed
`Prior to development
`with good bioavailability.
`necessary to de-
`studies yield basic knowledge
`dosage form, preformulation
`for toxicological use.
`velop suitable
`formulations
`rapid pro-
`field,
`research leads in a highly competitive
`Due to important
`as soon as possible.
`should be initiated
`and clinical studies
`gress is essential,
`program (i.e,, one typically
`taking 6 to
`preformulation
`Thus an expeditious
`If clinical program acceleration
`required.
`is generally
`10 weeks to complete)
`and develop crucial de-
`studies
`it may be necessary to streamline
`is desired,
`Should interim results
`indicate
`time periods.
`data in shorter
`cision-making
`expansion of the
`a more stable or more soluble drug form is needed,
`that
`interest
`areas of particular
`original program will be necessary.
`Additionally,
`such as the elucidation of a reaction mechanism or the investigation
`may arise,
`Such studies may be of prime importance
`phenomena.
`of unusual
`solubility
`initially or as second-phase
`preformulation
`and are often addressed either
`impact on the overall program,
`on their potential
`studies, depending
`
`*Current
`
`affiliation: Wyeth-Ayerst
`
`Laboratories, Radnor, Pennsylvania
`
`115
`
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`g)~ii:== =
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`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`p
`
`re
`
`a)sl
`
`Cli
`
`C&
`
`r(
`fq
`o)
`ti!
`
`~
`
`Ti
`
`Mo to la o nd A gharkar
`
`research has been described in de-
`subject of preformulation
`The general
`[1-5] and is in wide use throughout
`the pharma-
`investigators
`tail by several
`have dealt mainly with studies designed
`These presentations
`industry.
`ceutical
`have been made to certain
`Some specific applications
`for solid dosage forms.
`[6,7], The objective of this chapter
`is to outline
`interest
`areas of parenteral
`data necessary to characterize
`preformulation
`methods used in developing
`to a paren-
`properties of new drugs
`important
`physicochemical
`significant
`program,
`teral
`development
`formulation
`
`'16
`
`tt
`
`,t
`
`it
`
`;:5
`;lt
`'t
`tg
`
`,'ji
`
`II. DRUC SUBSTANCE PHYSICOCHEMICAL PROPERTIES
`that either characterize
`properties of drug substances
`Typical physicochemical
`of a parenteral
`formula-
`on the development
`or may exert significant
`influence
`tion are listed in Table 1.
`
`A. Molecular Structure
`and Weight
`and are among
`of a drug substance
`These are the most basic characteristics
`the investigator
`structure
`From the molecular
`the first
`items to be known.
`and functional
`potential properties
`group
`regarding
`can make initial
`judgments
`as described in Section IV.
`reactivities,
`
`B. Color
`structure
`relating to
`a function of a drug's
`inherent
`chemical
`Color is generally
`to the extent of conju-
`relates
`Color intensity
`a certain level of unsaturation.
`as well as the presence of chromophores
`-NO2,
`such as -NH~,
`gated unsaturation
`to have
`Some compounds may appear
`and -CO- (ketone), which intensify color,
`can often be due to
`saturated.
`Such a phenomenon
`structurally
`color although
`colored impurities
`intensely
`traces of highly unsaturated,
`the presence of minute
`These substances may be prone to increased
`products.
`degradation
`and/or
`A signifi-
`and light.
`stress conditions of heat, oxygen,
`color formation under
`factor to the shelf life of a parenteral
`cant color change can become a limiting
`stability is noted,
`even before a significant
`change in chemical
`product
`
`t
`
`!CD
`
`Table I Physicochemical
`
`Properties of Drug Substances
`
`and weight
`
`structure
`
`Molecular
`Color
`Odor
`Melting point
`profile
`analytical
`Thermal
`Particle size and shape
`potential
`Hygroscopicity
`constant
`Ionization
`Optical activity
`
`Solubility
`profile
`pH solubility
`Polymorphism potential
`Solvate formation
`spectra
`Absorbance
`Light stability
`stability
`Thermal
`pH stability profile
`
`LUYE1020
`IPR of Patent No. 6,667,061
`
`

`
`140
`
`Motola and Agharkar
`
`atoms or groups
`carbon atom is one that has four different
`An asymmetric
`bonded to it. An example
`is shown below for epinephrine.
`During chemical
`a 50: 50 mixture of both the d and I forms is obtained and since they
`synthesis
`rotation ter], the resulting molecule may show a
`have the same specific optical
`active is selected
`is more biologically
`The form that
`zero specific rotation.
`only the I form is an active vaso-
`In the case of epinephrine,
`for development.
`Because of this an equal mixture of d and I would be 50's po-
`constrictor.
`is totally inactive.
`tent and the d form, which in this example
`
`OH
`I»
`HO W C- CHe NHCHe
`
`I
`
`HO
`
`Epinephrine
`the above, when working with an optically active compound dur-
`Considering
`rotation since
`it is essential
`to monitor optical
`studies,
`ing preformulation
`chemical assay alone will not always coincide with biological activity,
`Examples
`are listed in
`used in parenterals
`compounds
`of optically active pharmaceutical
`Table 11.
`
`I I I. ACCELERATED STABI LI TY EVALUATION
`A. Drug Substance
`stress tests are performed
`Various
`the effect of heat,
`light, oxygen,
`
`to establish
`on solid and solution sam