`
`MEDICATION
`
`Formerly Husa's Pharmaceutical Dispensing
`
`A Manual on the Formulation of Pharmaceutical Products,
`the Dispensing of Prescriptions, and
`The Professional Practice of Pharmacy
`
`
`
`
`EDITOR
`
`ERIC W. MARTIN PhC,BSc,MS,PhD,
`
`I.
`if
`
`if.
`
`i}
`I:
`
`if
`I}
`
`1.3"
`
`I;
`
`i3;
`
`"
`
`fidjuncl: Professor of Biomedical Communication. Columbin Univmity
`College of Pharmaceutical Sciences: Director of Medical Communication,
`Lndcrla Laboratories, Division of Anwrican Cynnamid Company. Formerly
`EdjLor. Jodi-no! of
`the Amrican Pharmaceutical Association, Executive
`Editor. Pfizer‘s Spectrum, Editor-in-Chief, Remingmn’s Pharmaceutical
`Sciences: Author of Techniques of Medimtt'on, Hazards of Medication, and
`;'_mn1e 80 other biomedical publications; licensed phamaciat in Canada and
`'5.
`the United States; Fbunder and first Pmaident, Drug Infomution Asuncion
`.'
`tim; President. American Medical Writers Amciution, 1970-19“: Fellow
`MAS, American Medical Writexa Association. and Inbomational Academy
`of Law and Science. etc.
`
`5
`
`‘.-
`
`SEVENTH EDITION
`
`MACK PUBLISHING COMPANY
`
`1971
`
`SHIRE EX. 2016
`
`
`
`I.
`
`KVK v. SHIRE
`IPR2018-00290
`b—“_-‘_
`
`r/!2
`
`SHIRE EX. 2016
`KVK v. SHIRE
`IPR2018-00290
`
`
`
`
`
`:_
`
`--——-,-_1.-..
`
`_
`
`'
`
`© Copyright 1971 by
`MACK PUBLISHING COMPANY
`Easton, Pennsylvania
`
`All Rights Reserved
`This book or any part thereof must
`not be reproduced in any form without the
`written permission of the publisher.
`
`Library of Congress Catalog Card Number: 70-165831
`Printed in the United States of America
`
`
`
`i
`
`| |1
`
`1
`
`'
`
`I
`
`i
`
`:
`
`I
`{'-
`
`
`
`
`
`CHAPTER 27
`
`Prolonged-Action Medications
`
`
`
`Chapter preparation by
`Edwud Stamps], Edl}
`Professor and Chairman
`Department of Pharmacy
`Brooklyn College of Pharmacy
`Long Island University
`Brooklyn. NEW York 11216
`
`Significant advances have been made
`over the years in learning how to develop
`forms of medication which will efl‘ec-
`
`tively provide the patient with a pre-
`scribed dose for a specific period of time}l
`When drugs were administered almost
`exclusively by the oral route, it was rec-
`ognized that certain drugs varied consid-
`erably as to the duration of their efi'ects.
`Parenteral administration emphasized
`this characteristic by eliminating the
`variable due to gastrointestinal absorp-
`tion, and such administration served to
`focus attention upon the fate of the drug
`Within the body. In addition, parenteral
`administration provided insight into the
`physical and chemical factors determin-
`ing the duration of the drug’s sojourn
`and the concurrent duration of action.2
`
`Although the interval of drug levels
`and subsequent decline in these levels do
`vary, drugs may be classified broadly ac—
`cording to rapidity of action as: (1) in-
`stantaneous, (2) immediate, (3) delayed,
`(4) prolonged (5)
`immediate and pro:
`longed, and (6)
`immediate combined
`with delayed and prolonged-action. “In-
`stantaneous" connotes release within a
`
`1002
`
`moment, “immediate” connotes release
`Within an hour, “delayed” indicates a de-
`lay of release of drug for several hours
`after administration, and “prolonged”
`indicates a slowr and steady release of
`drug during an extended period of several
`hours, days, or months.
`Products that
`release a therapeuti~
`(sally-active constituent over a period of
`time have become popular and are
`known as prolonged-action products.
`Most commercially available prepares
`tions having prolonged action provide a
`combination of immediate and prolonged
`action and are usually designated as pro-
`longed-action, sustained-release, sustained-
`uctz'on, continuous-action,
`timedudisinte-
`gration, or timed-release medication; how-
`ever, these designations are also appli-
`cable but not usually used commercially
`to describe prolonged—acting products
`having a combination of delayed and
`prolonged action.
`Although “prolonged—action medica—
`tion” is synonymously used with “sue-
`tained~action medication" in discussions
`
`and in this chapter to connote a combi-
`nation of
`immediate
`and prolonged
`
`
`....-._,J........:"j,.
`
`“Amen-Wumorv-é:'49"
`
`
`.-...__._,,:.;,.,,g..._u..-
`-wwivnhfill""fl}i‘}t¥‘=".w.
`
`..u.i'._i.|a.\._:.vw--MN.
`
`
`'“has.
`
`
`
`BloodLeve1
`
`are inevitat
`
`action, N-
`vided a n:
`
`I
`
`'
`
`5
`types of 1
`a sustain '
`
`_
`
`product
`amount 0
`desired th
`tional am
`response
`number (2
`
`suiting {in
`trial desire
`teined be
`desired
`
`equal to
`eliminate
`
`that a pr:
`vides an
`to cause
`but the
`
`placemei
`rate tha1
`inactiva‘l
`rate Whit
`apeutic :
`tional s
`and Pat
`
`most pr:
`peutic I'l
`riod are
`cause of
`age forn
`to drug :
`
`Advert
`There
`
`temptin
`the mos
`tain tht
`' period 1:
`
`
`
`r/!4
`
`
`
`
`
`hours
`
`q
`
`BloodLevel
`
`B
`
`12
`
`Fig 2?-1—Tha “peak” and “valley" effects which
`are Inevitable with divided doses.
`
`action, Nelson“ and Parrott“ have pro—
`vided a more finite explanation of these
`types of medication. They indicate that
`a sustained-release or sustained-action-
`
`sufficient
`product provides an initial
`amount of drug to cause a rapid onset. of
`desired therapeutic response, and an addi-
`tional amount of drug that maintains the
`response at the initial level for a desired
`number of hours beyond the activity re—
`sulting from a conventional dose; the ini-
`tial desired therapeutic response is main—
`tained because the rate of release of the
`
`concentration is
`therapeutic
`desired
`equal to the rate at which the drug is
`eliminated or inactivated. They indicate
`that a prolonged-action product also pro-
`vides an initial sufficient amount of drug
`to cause a quick therapeutic response,
`but the product then provides for re-
`placement of the disappearing drug at a
`rate that is not equal to elimination or
`inactivation;
`the drug is replaced at a
`rate which increases the duration of ther-
`
`apeutic activity compared with conven—
`tional single-dose medication. Nelson‘1
`and Parrott“ furthermore state that
`
`most preparations that provide a thera—
`Deutic response during an extended pew
`riod are prolonged-action products be—
`cause of the difficulty of formulating dos-
`age forms wherein drug release is equal
`1;0 drug elimination or inactivation.
`
`Advantages
`There are several reasons“? for at-
`ttempting to prolong the action of a drug,
`the most important of which is to main- -
`tain the therapeutic efi‘ect for a longer
`Period than can be obtained after the ad-
`
`.
`
`
`
`LEVEI
`BIGGG
`
`hours
`
`4
`
`--
`
`B
`
`12
`
`21-2—The effect of orallyadministered
`I Fig
`prolonged-action medication.
`
`ministration of conventional single—dose
`medication. Other reasons are: (1) to re
`duce the number and frequency of doses
`administered, {2)
`to eliminate dips in
`drug concentration which are inevitable
`with divided doses [Fig 27-1) and thus
`maintain an even level of drug concentra-
`tion in the body (Fig 2'7—2), (3) to reduce
`the total amount of drug needed to ob-
`tain the desired therapeutic response,
`(4)
`to eliminate the inconvenience of
`night-time administration of drugs.
`(5)
`to lessen the possibility of the patient's
`defaulting from treatment by forgetting
`to take his medication, (5) to reduce the
`incidence and intensity of undesirable
`side eifects caused by excessively high
`peak blood levels of drug that may result
`from the administration of conventional
`
`dosage forms, and (7) to reduce or pre-
`vent the irritation of the gastrointestinal
`tract caused by some orally-administered
`drugs released in high concentration.
`
`Contraindications or
`
`Disadvantages
`
`Dragstedt" has pointed out that cer-
`tain drugs should not be administered in
`a prolonged-acting dosage form:
`{1)
`drugs whose precision of dosage is impor-
`tant (like the anticoagulants and digitalis
`glycosides), {2) drugs whose absorption
`from the gastrointestinal
`tract
`is im-
`paired or erratic, and (3) drugs with a
`total dose more than two or three times
`
`the usual therapeutic dose unless such
`drugs are known to have substantially
`Wide margins of safety between their
`therapeutic and toxic ranges .
`Campbell and MorrisonB have pointed
`
`
`
`
`
`r/!5
`
`
`
`
`
`1004
`
`Prolonged-Action Medications
`
`out that prolongedeaction preparations
`are contraindicated for drugs having an
`inherently long biologic half-life (such as
`long-acting sulfonamides). Furthermore,
`they point out that it is inadvisable for
`the physician to prescribe prolonged-ac—
`tion preparations unless they possess
`clear advantages over conventional prod-
`ucts;
`cg,
`sustained—release
`riboflavin
`preparations appear unwarranted and
`unnecessary.
`
`the prolonged effects of
`Sometimes,
`sustained-action nitrites may obscure
`the warning signs of pain, as in angina
`pectoris, and overexertion with fatal re»
`sults may ensue.u
`Lev 5” has indicated the following dis-
`advantages of prolonged—release medica-
`tion: (1) it is comparatively more costly
`than medication in a conventional dos
`
`age form, {2) it does not permit prompt
`termination of chemotherapy when this
`is desired or required,
`(3) it is limited
`usually to a single available unit dose or
`multiples thereof and more accurate ad-
`justment is rarely feasible because pro-
`longed-release dosage forms should not
`be broken or reduced to small particles
`by grinding, and (4) it is designed on the
`basis of an average elimination rate to
`provide the ideal of maintaining a- de-
`sired therapeutic effect, and is therefore
`dependent on continuous replacement of
`drug eliminated; however, the ratm of
`drug elimination are unequal and vary
`widely and thus there is the possibility of
`drug accumulation on the one hand be-
`cause of too slow an elimination and
`underdosage on the other hand because
`of too rapid an elimination.
`
`Drug Availability
`
`In order to have clinical effectiveness,
`the administered drug must be capable
`of being available in the body for absorp-
`tion by the patient, is, the drug must be
`capable of solution before it can be ab—
`sorbed.
`However, the Word “av ailable” is now
`used by many to indicate physiologic or
`biologic availability: the degree to which
`the drug is absorbed by either passive
`absorption, active transport, or special-
`ized transport. Passive absorption in-
`volves simple diifusion across body mem-
`branes; with active transport, certain
`membranes possess components, known
`as “carriers," which facilitate transport
`across
`the membranes.“ Specialized
`transport involves pinocyto-s or phago-
`cytosis, and, at present, only some fats
`are known to be absorbed by this pro-
`cess.“
`In passive absorption, Nelson states
`that the rate at which the drug leaves the
`absorption site and enters the circulation
`is directly dependent on the concentra-
`tion of the drug at the absorption site.
`As absorption proceeds, the rate becomes
`progressively slower. When absorption
`
`studies indicate that absorption rate is
`independent of concentration at the ab-
`sorption site, this observation is taken to
`be indicative of a transport process in
`absorption. ‘"
`For a more detailed discussion of drug
`availability, see Chapter 3 on Bioeooii-
`cbiiity, page 63.
`
`Drug Distribution
`
`A simplified scheme for drug distribu-
`tion was provided by Teorelln and sim-
`plified by Wagner.” See Fig 27~3 for
`Wagner’s scheme. According to Wag-
`ner, 1' the drug in the depot may enter the
`blood and return to the depot. [The de-
`pot may be the gastrointestinal tract-i
`Any drug in the blood is in equilibrium
`with drug in tissues, organs, and other
`fluids of distribution and the drug is con
`stantly being excreted in the urine un—
`changed or as metabolites.
`
`Drug Blood Level
`
`Many administered drugs are not uni-
`formly distributed throughout the body
`and sometimes do not even appear in the
`blood stream. Even if the drug appears
`
`Drug in'I
`
`
`
`Drug
`in Dc:J
`
`:1
`1i
`i
`i
`
`j
`
`- r,
`'.
`._1-‘-
`-. j; -_
`
`
`
`Fig 21-3-—
`lion."
`
`in the
`blood I:
`action;
`may clc
`consent
`action.‘
`in the i
`the blor
`neverth
`
`tration
`measur.
`Therefr
`is to no
`trati on
`This on
`level or
`
`Hall:
`the re]:
`decrees
`orized
`rapidl)
`"sustaj
`inatior
`less it
`(lacs 5
`
`
`
`r/!6
`
`
`
`
`
`Drug in Tissues and Other Fluids of Distribu-
`tion
`
`H
`
`-——9 Drug
`Drug
`in Depot 9—” in Blood
`
`—~ Urinary
`Excretion of
`Unchanged
`Drug
`
`l
`
`Drug Metabolite(s} —~ Urinary
`Excretion of
`Metabolite(s)
`
`Fig 27-3—-Simplified scheme for drug distribu-
`lion.“
`
`its concentration in the
`in the blood,
`blood may not parallel the physiological
`action;
`the concentration in the blood
`may closely or only remotely reflect the
`concentration in the tissues at its site of
`
`action. 1‘ Generally, drug concentration
`in the target body tissue rather than in
`the blood stream should be emphasized;
`nevertheless, an insight into drug concenw
`tration in the body is usually reflected by
`measuring its concentration in the blood.
`Therefore, the usual aim in therapeutics
`is to maintain a certain constant concen-
`
`tration of the drug in the blood stream.
`This concentration is referred to as blood
`level or drug blood level.
`
`Urinary Excretion Role
`Campbell, Nelson,
`and Chapman15
`have pointed out that the evaluation of
`
`Prolonged-Action Medications
`
`1005
`
`the release of drugs requires recognition
`of the fundamental
`relationship that
`exists between (1) concentration of drug
`in the blood or other fluids of distribu-
`tion, and (2) excretion rate of the drug.
`It has been established both by experi-
`mental and theoretical considerations
`that, for several drugs and certain other
`exogenous substances, urinary excretion
`rate is directly proportional to concentra-
`tion in the blood. Therefore, instead of
`drug absorption studies to measure drug
`blood level at various times after drug
`administration, Nelson and Schalde-
`muse" state that urinary excretion data
`are frequently capable of supplying
`quantitative information on the absorp-
`tion of drugs, without the inconvenience
`of blood sampling, even though such uri-
`nary excretion data are less direct.
`
`Other Indices of Absorption
`
`Whatever measurements are chosen as
`
`the index of pharmacological action or
`absorption, no valid comparison and
`evaluation of drugs can be made without
`them. 1' Besides either drug blood level
`or urinary excretion data, the index may
`result from a measurement of: the rela~
`tive concentration of the drug in cerebro»
`spinal fluid;
`the blood-sugar level;
`the
`electrolytes excreted in the urine: or, as
`with antibiotics, the antibacterial activ-
`ity of the serum or urine. ” Also, see pages
`1032 1038 for clinical, nutritional, toxic-
`ity,
`radioactive, and roentgenographic
`studies.
`
`slowing excretion or elimination, slowing
`
`Methods of Prolonging Absorption
`
`Hollister and Levyl" indicated that
`the relative elimination rate of salicylate
`decreases with increasing dose, and the-
`orized that high doses administered in
`1'apidly—ahsorbed form have their own
`"Sustaining” efl'ect relative to the elim-
`ination rate of lower dosesm Neverthe-
`less. it is not usually desirable to pro-
`duce a prolonged blood level by giving
`
`massive doses. Not only is there a limit
`to the quantity of a drug that can
`be safely introduced into the body in
`massive dosage at one time, but it is gen-
`erally an ineffective as well as dangerous
`method for the production of prolonged
`actionr“ Some methods for prolonging
`drug action are: slowing inactivation,
`
`r/!7
`
`
`
`
`
`1006
`
`Prolonged—Action Medications
`
`absorption, or utilizing frequent dosage.
`The last method is not very desirable.
`
`Slowing Inactivation and
`Slowing Excretion
`
`Although inactivation and excretion
`can be mistakenly considered synony—
`mous because excreted drugs are inacti—
`vated or out of the sphere of action, slow
`inactivation is specifically considered to
`be the action of specific nonexcretory
`mechanisms.
`Inactivation of a drug may be slowed
`by inhibiting the enzymes that inactivate
`the drug. 1' For example, the activity of
`acetylcholine is inhibited by cholinester-
`ase; therefore, by using an anticholinee
`terase like neostigmine that combines
`with cholinesterase,
`the hydrolysis of
`acetylcholine is slowed and its activity
`is prolonged.
`Drug excretion or elimination fiom the
`body by Way of the urine may be rapid or
`slow, and such elimination depends on
`glomerular filtration, secretion by the
`tubules, and tubular reebsorption. Drugs
`which are to a Considerable extent reab-
`sorbed by tubular cells have a prolonged
`stay in the body, 9g, sulfamerazine. 1‘"
`While it is often possible to govern the
`rate and amount of drug absorption, it is
`only rarely possible to govern the rate of
`drug excretion. The method used to slow
`drug excretion consists of the reversible
`inhibition of renal excretinn.21 Carin-
`amide (caronamide or 4’-carboxypheny1—
`methanesulfonanilide) given with peni-
`cillin to dogs caused an increase in peni-
`cillin plasma concentration and a slowing
`of penicillin excretion by the kidneys" by
`blocking a particular excretory mecha-
`nism in each kidney. More recently, pro-
`benecid (Benemid) has been used to pro-
`long and maintain the therapeutic effect
`of penicillin by slowing renal tubular ex-
`cretion of penicillin with no apparent evi-
`dence of kidney damage. Probenecid
`interferes with the renal tubular excre-
`tion of p-arninosalicylic acid as well as
`p-aminobenzoic acid by inhibiting their
`conjugation with glycine. Recently, liter-
`
`ature indicates that probenecid also de-
`creases the urinary excretion of p-amino-
`hippuric
`acid,
`phenolsulfonphthalein,
`pantothenic acid, 17-ketosteroids, and
`sodium iodomethamate.” Therefore,
`probenecid is useful as an adj uvant to in-
`tensive therapy with some compounds by
`increasing and prolonging the drug
`plasma
`concentration. However,
`the
`practical problem of conveniently main-
`taining an effective concentration of the
`interfering drug itself has severely re-
`stricted the method of slowing eXcretion
`of another drug by the reversible inhibi-
`tion of renal excretion."
`
`Slowing Absorption
`
`The rate and the extent of absorption
`(per cent of the dose absorbed) are very
`important factors in influencing blood
`and tissue levels with respect to time
`after administration and,
`therefore,
`in
`influencing the intensity of biological
`action.“
`
`Nelson“ and Dominguez"I have au—
`thored excellent reviews on the kinetics
`
`of absorption, distribution, and excre-
`tion. Wagner has pointed out that the
`rate of intravenous injection may be con-
`trolled; by all other routes of. administra-
`tion, a drug enters the blood stream at an
`unknown rate. Under certain circum-
`stances, however, this rate can be deter-
`mined. Dominguez, Nelson, Swintosky
`et at, and others have separately shown
`that many orally-administered drugs ex—
`hibit a steady state of diffusion during
`absorption, first-order“ metabolic con-
`version, or first-order urinary excretion
`of unchanged drug and metabolite(s).“
`If these fundamental premises are ful-
`filled by a specific drug, then a calcula-
`tion can be made of the instantaneous
`rate of absorption at different times after
`oral administration by at least
`three
`
`
`" If the rate of a chemical reaction is independent of
`the concentration of the reactants, the reaction is refErrEd
`to an a urn-order Function. Other reactions mayW at
`:1 rate dependant on the concentration of one of the reall-
`tants remaining at one time; the rate varies, in these cases.
`on the first power or exponent of reactant concentration.
`and these reactions are referred to as first-order reactions.
`
`known rm
`excellent
`
`It is re
`ads of 310
`to fairly-
`as insulir.
`cillin; etc
`mire is sea
`such slo*
`roxin. di
`amin, etc
`The pl
`providing
`absorptic
`tion of tl‘.
`lating be
`tors invo
`
`ahsorptit
`vasocons
`tion rat
`creased
`size and
`surface 1
`um, visc
`eeterifice
`
`disintegr
`ing actio
`complex
`
`Route c
`
`Wilson
`ation of
`concenta
`
`acts, ant
`absorpti
`Neverth
`adrninis
`rate of a
`Pore:
`ables, tl
`when r.
`
`emerge:
`tion of ‘
`rapid a:
`after
`3
`slower
`Ballard
`that (1)
`in the
`labeled
`muscul:
`T10 marl
`
`i.
`”3'£1"
`fit
`
`
`
`r/!8
`
`
`
`known methods as described in Wagner’s
`axcellent reviews of BiOpharmaceutics.“
`It is relevant to point out that meth-
`ods of slowing absorption are applicable
`to fairly-rapidly-eli'minated drugs such
`as msufinmgt'
`ropin, heparin, peni-
`cillin, etc. Furthermore, no useful mea-
`sure is served in slowing the absorption of
`such slowly-eliminated drugs as
`thy—
`roxin, digitalis glycosides, cyanacobalt
`amin, etc.”
`The principle common to the factors
`providing prolonged action by slowing
`absorption is to decrease the rate of solu-
`tion of the active ingredient in the circu-
`lating body fluids. Among the many fac-
`tors involved in a slowing of the rate of
`absorption are: route of administration,
`vasoconstriction,
`immiscibility, dissolu—
`tion rate,
`relative insolubility or de
`creased Solubility,
`ionization, particle
`size and surface area, polymorphism,
`surface tension of the dissolution medi-
`um, viscosity and nature of the vehicle,
`esterification, polymerization,
`slowing
`disintegration and dissolution rate, leach-
`ing action, adsorption, ion exchange, and
`complexation.
`
`Route of Administration
`
`Wilson” states that intensity and dur-
`ation of action of a drug depend on its
`concentration on the cells on which it
`
`acts, and this is determined by its rate of
`absorption, distribution, and excretion.
`Nevertheless, the choice of the route of
`administration usually influences
`the
`rate of absorption.
`Parenteral Route—In using inject-
`ables, the intravenous route is employed
`When rapid action is essential during
`Emergencies. Intramuscular administra-
`tion of water-soluble drugs provides less
`rapid action, while the rate of absorption
`after
`subcutaneous administration is
`Blower and more even. Neverthelem,
`Ballard, 2“ citing other soarces, indicate;
`Phat (1) there is not significant difference
`In the absorption rate of radioactive-
`lfibeled lente insulin from either intra-
`muscular or subcutaneous sites, and (2)
`“0 markedly different results were found
`
`Prolonged-Action Medicatihns
`
`1007
`
`after either intramuscular or subcutane-
`ous administration of the antimalarial
`
`cycloquanil pamoate.
`Drugs in a solid pellet form may be im-
`planted under the skin and slowly ab-
`sorbed
`over a period
`of weeks
`or
`months."I Miller“ has described pellets
`as small, rod- or ovoid-shaped, sterile
`bodies (3.2 X 8 mm) in a compressed
`form. These are intended for subcutane~
`ous implantation in body tissue (cg, the
`thigh) to serve as a depot for providing
`slow release of drug over an extended
`period of time. The sterile pellets are
`either inserted under the skin of the thigh
`with a special
`injector (Kearns Pellet
`Incisor) or by means of an incision.
`The NND“ stated that a pellet con-
`taining 120 mg of desoxycorticosterone
`acetate is slowly absorbed and provides
`an effect approximately equivalent to
`that of daily injections of 0.5 mg. Such
`120 mg pellets are effective for 9 to 15
`months. Goodman and Gilman," quot-
`ing other sources, stated in 1941 that the
`subcutaneous implantation of crystal-
`line pellets of desoxycorticosterone has
`proved to be an efi'ective and convenient
`method for controlling Addison’s disease
`in patients. In 1953, these same authors"
`pointed out that the desoxycorticoste-
`rone compound can maintain the life of
`the Addisonian patient, but the patient
`is very susceptible to stress. Therefore,
`cortisone of hydrocortisone should be
`added to the therapeutic regimen.
`In order to maintain a constant level
`of riboflavin in the tissues, Bromberg
`et cl“ implanted riboflavin pellets in pa-
`tients. The method was particularly ad-
`vantageous in patients who could not be
`trusted to take medication regularly. Pel-
`lets containing 50 mg of riboflavin fueled
`with 50 mg of cholesterol maintained a
`high riboflavin level in man and animals
`for 45 days.
`Parenteral absorption has been re—
`viewed by Wagner.“ The absorption of
`implanted solid drug has been reviewed
`by Ballard and Nelson. " The latter in-
`vestigatorsu indicated that absorption of
`implanted medication is affected by such
`
`
`
`
`
`
`
`r/!9
`
`
`
`
`
`1008
`
`Prolonged-Action Medications
`
`factors as the site of implantation, body
`movaments, and diluents; furthermore,
`little quantitative information is avail-
`able concerning the magnitude of the
`effect. Subsequently, Ballard” showed
`the quantitative relationship that may
`exist between drug-pellet-absorption rate
`and the degree of animal physical activ—
`ity. There was significantly greater ab-
`sorption of procaine penicillin G pellets
`in more active animals (rodents).
`Crumbling of the pellets may result in
`increased absorption and over-dosage,“
`with possible hazard to the patient. Fur-
`thermore, the administration of pellets
`ofl'ers diiliculties in administration and
`sometimes causes local disorders even
`
`when properly administered;
`they are rarely used.“
`Oral Route—~The oral route of ad-
`ministration is the most convenient as
`well as the most common method of ad:
`
`therefore,
`
`ministering drugs. With the exception of
`the sublingual route of administration
`(eg,
`nitroglycerin,
`isoprenaline,
`etc),
`drugs are usually absorbed slowly when
`administered by the oral route. If a drug
`is permitted to remain in the mouth, con»
`siderable absorption may occur through
`the mucous membrane. However,
`if a
`drug is swallowed rapidly, absorption
`may commence as soon as it reaches the
`stomach-“
`
`from the
`absorbability
`Although
`mouth and stomach is primarily a prop-
`erty of the specific drug, the dosage form
`also influences absorption. For example,
`solutions are usually absorbed faster than
`either powdered medication or com-
`pressed tablets because solid medica-
`tions can only be absorbed after they
`have undergone deaggregation and disso-
`lotion.
`
`Absorption from the stomach varies
`with the amount of food in the stomach,
`the solvent vehicle (if any), the form of
`the drug, *9 and the volume and constitu-
`, ents of gastric juice.
`It has been well established that the
`volume and constituents of gastric juice
`contained within the stomach at any
`time are not constant. These variations
`
`do influence the disintegration time of
`tablets. Usually, a tablet which disinte.
`grates at a slower rate cannot be er:-
`pected to make its medication as readily
`available for absorption.
`Abbott at cl,“ have stated that In“.
`coicl material present
`in gastric juice
`may, under certain conditions (ie, swal~
`lowing a tablet dry without water), coat
`a tablet to render it more resistant to dis-
`integration and prolong its disintegra—
`tion time. These investigators“ also
`pointed out'that a similar phenomenon
`may occur if a tablet is ingested in the
`early morning on an empty stomach
`which contains a large proportion of mu-
`cous. A high mucoid content of gastric
`juice may increase disintegration time to
`16 or more times the usual tablet-disinte-
`
`gration time."
`For a more detailed discussion of the
`factors and mechanisms affecting gastro-
`intestinal absorption,
`the reviews by
`Wagner “ should be read.
`Rectal Route—Enesco et at,“ in
`studying the comparative absorption of
`six drugs in 63 normal individuals, found
`that each of the following five drugs, in
`separate aqueous solutions,
`is absorbed
`more quickly rectally than orally:
`so—
`dium salicylate, chloral hydrate, methy~
`lene blue, atropine Sulfate, and morphine
`sulfate.
`_
`CaCchillo and Hassler,“ in studying
`the absorption of acetylsalicylic acid
`from the oral route as well as from vari-
`ous Suppository bases administered rec-
`tally, measured drug concentration in
`the blood two hours after administration
`of the dosage form. These investigators“
`found that there was no significant differ—
`ence between the absorption of acety1~
`salicylic acid from tablets given orally
`and the absorption from a Carbowax
`base given rectally; howeVer, there was
`significantly greater absorption from the
`oral tablets and the Carbowax-type reo—
`tal Suppositories than from either thetr
`broma oil or glycerinated gelatin rectal
`suppositories. 0n the other hand, Peter-
`son et al,“ using sodium iodide labeled
`with radio-iodine to compare the rate of
`
`
`
`“Tag-pm‘_
`
`
`
`a..-H—-.-u.*w..~.
`
`
`
`
`
`absorption fro:
`ministered to 1
`tion from a El)
`ter than from :
`sorption from '
`from a theob:
`Peterson ct ol,’
`I-lassler" have
`get rule exist!
`ease of sheer;
`turn, and (2) i
`undertaken to
`the base that
`tic-n. See page
`Most medic.‘
`
`-
`
`suppository fo
`theobroma oil
`are usually co:
`absorbed and
`action over a
`states that the
`absorption of
`inals which an -
`released becaI
`
`greater aflinii
`phase than t
`the body ca
`drugs in a the
`leased readily
`tion of theobr
`Gradnick“a
`
`the importani
`preparation
`media give
`water-soluble
`cation more E
`
`Contrary 1
`Peterson er a
`it has been
`
`Sperandio” 1
`action of pen
`bital sodium,
`albino rats n
`shorter in tt
`ethylene gly
`Wagner“ eta
`strom obsen
`lieu of hexoh
`was better fr
`it Carbowax
`
`Riegelman
`in 1958 that
`
`'ln_.’,4.“Wm“....i..__,_,.-l..-....
`
`r/!;
`co
`
`
`
`
`
`"''"."'-‘.'."-!":
`
`absorption From rectal suppositories ad-
`ministered to rats, showed that absorp-
`tion from a glycerogalatin base was bet—
`ter than from a Carbowax base, and ab-
`sorption from the latter was better than
`from a theobroma oil base. However,
`Peterson 9: at," as well as Cacchillo and
`Hassler“ have emphasized that (1) no
`set rule exists concerning the relative
`ease of absorption of drugs by the rec-
`tum, and (2) individual studies must be
`undertaken to determine for each drug
`the base that is best suited for absorp»
`tion. See pages 840—844.
`Most medicinal agents administered in
`suppository form by the rectal route in a
`theobroma oil base for systemic action
`are usually considered to be most slowly
`absorbed and to provide a therapeutic
`action over a long period of time. Tics“
`states that theobrm'na oil may retard the
`absorption of certain medicinals. Medic-
`inals which are oil-soluble are not readily
`released because the medicament has a
`
`greater affinity for the suppository oil
`phase than the aqueous fluids bathing
`the body cavity. Even water-soluble
`drugs in a theobroma oil base are not re-
`leased readily because of the barrier ac-
`tion of theobroma oil.
`
`Gradnick" has likewise pointed out
`the importance of the media used in the
`preparation
`of
`suppositories. Fatty
`media give slow absorption, whereas
`Water~soluble media liberate their medi-
`
`cation more easily.
`Contrary to Cacchillo and Hassler,“
`Peterson 2: oil,“ Tics,"I and Gradnick,”
`it has been indicated by Hassler and
`Snerandio” that the onset of hypnotic
`action of pentobarbital sodium. secobar-
`liital sodium, and amobarbital sodium in
`albino rats was faster and the duration
`Shorter in theohroma oil than in poly-
`ethylene glycol polymer suppositories.
`Wagner“ stated that Samelius and An-
`3tl'om observed that the rectal absorp-
`ti0n of hexobarhital sodium in the rabbit
`Was better from theobroma oil than from
`a Carbowax base.
`. Riegelman and Crowell“ pointed out
`In 1958 that a number of different in. viva
`
`Prolonged-Action Medications
`
`1009
`
`rectal absorption studies have been con-
`ducted to evaluate separately or con-
`corrutantly, at difl’erent time intervals,
`the level of drug in the blood, urine, and
`the tissues, as well as the specific physi-
`ological response. Howaver, unlike the
`direct radiological approach, such studies
`have provided much meaningful data by
`an indirect approach to the absorption
`problem. Such indirect in vivo studies are
`based on the assumption that the rate of
`rectal absorption bears a constant and
`direct relationship to the amount of drug
`in a certain body fluid {or organ) or to
`the blood level required to elicit a phar-
`macological response. Furthermore, un-
`less there is a direct proved relationship
`between the rate of absorption at the rec-
`tal site and the drug concentration in the
`organ or the blood, it is difficult to draw
`general conclusions.“
`Riegelman and Crowell“ used a direct
`radiological method for detecting the
`events taking place at the site of absorp-
`tion, and indicated that the diffusion of
`the drug within the vehicle affected or
`limited the rate of the absorption pro-
`cess. These investigators“ also indicated
`the possibility that the rate of solution
`and the rate of diffusion from the solid-
`
`liquid interface is the controlling factor
`for absorption. Using radio-tagged iodo-
`form and
`radio-tagged
`2.4,6-triiodo-
`phenol, at more than one pH at which
`each drug is undissociated, these investi~
`gators showed that a solution of either
`drug in a solid oleaginous vehicle resulted
`in a very prolonged absorption time“
`compared with a solution of either drug
`in a solid or liquid polyethylene glycol
`vehicle.”
`
`Wagner’s” article on bioph armaceutics
`provides a more expanded review of rec-
`tal absorption.
`
`combination of epinephrine with local
`
`Vasoconstricfion
`
`The incorporation of a vasoconstrictor
`in a solution of a drug that is to be in»
`jected subcutaneously tends to slow ab-
`sorption or release over a prolonged pe-
`riod of time. This technique is used in the
`
`r/!21
`
`
`
`
`
`1010
`
`Prolonged-Action Medications
`
`
`
`anesthetics. ’5 Specifically, since the anes-
`thetic effect of procaine hydrochloride is
`not maintained,
`it is usually adminis
`tered as a vasoconstrictor, to slow the
`rate of absorption of procaine.” The
`preparation usually used is the official
`procaine