..—‘r‘r‘-‘<??"§?‘“-'3
`
`DISPENSING OF
`MEDICATION
`
`Formerly Huscfs 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,
`
`-Adjunct. Professor of Biomedical Communication, Culumbia University
`College of Pharmaceuficsl Scxiernces; Director of Medical Communication,
`Imflerle Labomtoitims, Division of An1e1'iI_-an Cyanamid Company. Formerly
`Editor, Jofirrmi of the Anwrican Phdrnmcautiml Associaifon, Executive
`Editor,
`Pfizem-’a Spectrum, Editor-in-Chief. Reming-£on’s P.’zar:-naceutiml
`Sciences; ifiuthnr of Techniques of Medimtion, Hazards of Jlefsdicatian, and
`some 30 other biomedical publications; licensafl phannacifit in Canada and
`the United States; Founder and first Pxeaident, Drug Information A880[:ia—
`tinn; President, American Medical Writers Association. 19'iI'D—].9"i’1; Fellow
`AAAS, American Nledical Wxitem Association, and Inbenlatinnal Academy
`of Law and Science, etc.
`
`SEVENTH EDITION
`
`MACK PUBLISHING COMPANY
`
`1971
`
`Amerigen Ex. 1061, p. 1
`Amerigen Ex. 1061, p.
`
`
`

`
`
`
`© 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:
`Printed in the United States of America
`
`70-166831
`
`Amerigen Ex. 1061, p. 2
`
`

`
`
`
`CHAPTER 27
`
`Prolonged-Action Medications
`
`
`
`' Chapter preparation by
`: Edward. Ste-mpel, EdD
`= Profiassor and Chairman
`Department of Plmrmacy
`lrooklyn (loflege of Ptuunnacy
`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 effec-
`
`tively provide the patient with a pre-
`scribed dose for a specific period of time.‘
`W'hen 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 eifects.
`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.’
`
`Although the interval of drug levels
`and subsequent decline in these levels do
`very, 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
`
`
`
`
`
`BloodLevel
`
`hours
`
`Fig27-1~Tl
`are inevital:
`
`:
`.
`
`action, N=
`vided a It
`
`types of I
`a sustain =
`
`product
`amount 0 5
`desired th
`
`tional am :
`response
`number (2
`
`5
`
` tained be
`
`suiting fr:
`tial desirc
`
`desired
`
`equal to
`eliminate
`
`that a pr:
`vides an
`to cause
`but the
`
`
`
`:
`
`.
`
`placemei
`rate tha1
`inactivai
`rate whit
`apeutic :
`tional s
`and Pa)
`
`most pr:
`peutic l‘.‘{
`riod are
`cause of
`age forn
`to drug {
`
`Advu n
`
`There
`
`temptin
`the moss
`tain the
`' period 1.‘
`
`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 slow and steady release of
`drug during an extended period of several
`hours, days, or months.
`Products that
`release a therapeuti-
`cally-active constituent over a period of
`time have becorne popular and are
`known as prolonged-action products.
`Most commercially available prepara-
`tions having prolonged action provide a
`combination of immediate and prolonged
`action and are usually designated as pro-
`longed-action, sustained-release, sustained-
`action, continuous-action,
`timed-ciis£nte-
`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 “sus«
`tained-action rnedication” in discussions
`
`and in this chapter to connote a combi-
`nation of
`immediate
`and prolonged
`
`Amerigen Ex. 1061, p. 3
`
`Amerigen Ex. 1061
`
`5 E-‘-'
`
`

`
`
`
`BloodLevel
`
`hours
`
`:4
`
`3
`
`"I2
`
`Fig 27-1—The "peak"and"val|ey" effects which
`are inevitable with divided doses.
`
`action, Nelson3 and Parratt“ have pro-
`vided a more finite explanation of these
`types of medication-. They indicate that
`a sustained-release or sustained-action‘
`
`product provides an initial sufficient
`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
`
`desired therapeutic concentration is
`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-
`lnlacement 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“
`and Parrott“ furthermore state that
`
`most preparations that provide a thera-
`lleutic response during an extended pe-
`riod are prolonged-action products be-
`cause of the difliculty of formulating dos-
`age forms wherein drug release is equal
`to drug elimination or inactivation.
`
`Advantages-
`There are several reasons‘ “"' for at-
`Tempting to prolong the action of a drug,
`the most important of which is to main- .
`tain the therapeutic effect for a_ longer
`' Period than can be obtained after the ad-
`
`Prolonged-Action Medications
`
`1003
`
`BloodLevel
`
`hours
`
`4
`
`I
`
`3
`
`12
`
`2?-2-—The effect of orally-administered
`I Fig
`proionged-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 27-2), (3) to reduce
`the total amount of drug needed to ob-
`tain the dered 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, (6) to reduce the
`incidence and intensity of undesirable
`side effects 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 or-a.lly—adm.inistered
`drugs released in high concentration.
`
`'
`
`Coniraindicaiions 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 Morrison‘ have pointed
`
`Aerige Ex. 1061',_:
`Amerigen Ex. 1061, p. 4
`
`

`
`
`
`1004
`
`Prolonged-Action Medications
`
`'
`
`out that prolonged-action 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;
`eg,
`sustained-release ' riboflavin
`preparations appear unwarranted and
`unnecessary.
`the prolonged effects of
`Sometimes,
`sustained~ac'tion nitrites may obscure
`the warning signs of pain, as in angina
`pectoris, and overexertion with fatal re-
`sults may ensue.”
`Levy’ 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 ratw 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, ie, the drug must be
`capable of solution before it can be ab-
`sorbed.
`However, the word “available” 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 diffusion across body mem-
`branes; with active transport, certain
`membranes possess components, known
`as “carriers,” which facilitate transport
`across
`the membranes.“ Specialized
`transport involves pinocytosis or phago-
`cytosis, and, at present, only some fats
`are known to be absorbed by this pro-
`‘ cess. 9*’
`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. VVhen 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. 1"
`For a more detailed discussion of drug
`availability, see Chapter 3 on B£0flDGit-
`ability, page 63.
`
`Drug Disiribulion
`
`'
`
`A simplified scheme for drug diQ;ribu-
`tion was provided by Teorell“ and sim-
`plified by Wagner. 13- See Fig 27-3 for
`Wagner’s scheme. According to Wag-
`ner, ‘3 the drug in the depot may enter the
`blood and return to the depot- (The de-
`pot may be the gastrointestinal tract.)
`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 uI1~
`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
`
`Amerigen Ex. 1061, p. 5
`Amerigen Ex. 1061,
`
`- Fig 27-3-
`tion ._“
`
`I
`
`in the
`- blood rr
`action;
`may clc '-
`_ concent
`action. 1
`'_ in :
`the blot
`neverth
`tration
`measuri
`
`.
`
`Therefc
`is to me
`
`tration
`This co
`level or
`
`Urinur
`
`. Cam
`
`have pu
`
`Hollf
`the rel:
`decrea:
`orized .
`rapidly
`"sustai
`inatior
`. less,
`it
`- duce 2
`
`'
`
`

`
`
`
`
`
`Drug in Tissues and Other Fluids of Distribu-
`tion
`
`H
`
`Drug ml Drug
`in Depot ‘
`in Blood
`
`—> Urinary
`Excretion of
`Unchanged
`Drug
`
`' Drug Metabolite(s) —+ Urinary
`Excretion of
`Metabolite (3)
`
`Fig 2?-3-Simplified scheme for drug distribu-
`tion."
`
`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-“ Generally, drug concentration
`in the target body tissue rather than in
`the blood stream should be emphasized;
`nevertheless, an insight into drug concen-
`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 Rafe
`
`Campbell, Nelson, and Chapman”
`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—
`mose“ 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. 17 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. 17 Also, see pages
`1032-1038 for clinical, nutritional, toxic-
`ity,
`radioactive, and roentgenographic
`studies.
`
`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
`rapidly-absorbed form have their own
`“Sustaining” effect relative to the elim-
`ination rate of lower doses. 1”“ Neverthe-
`1935, 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
`action.“ Some methods for prolonging
`drug action are: slowing inactivation,
`slowing excretion or elimination, slowing
`
`mrige Ex. 1061, p. B?
`Amerigen Ex. 1061, p. 6
`
`5
`i
`’
`
`-
`
`
`
`

`
`
`
`known In:
`excellent
`
`It is re?
`ods of slo
`to fairly-
`as insulir
`cillin, etc
`sure is sea
`such slo‘
`roxin, di
`amin, etc
`The pr
`
`providing
`absorptic
`tion of tl‘.
`lafing bo
`tors invo
`absorptit
`vasocons
`tion rat
`' creased
`size and
`surface 1
`
`um, visc
`esterifics
`
`disintegr
`ing actio
`complex.
`
`Route C
`
`Wilsoi
`ation of
`concent)
`
`acts, ant
`absorpti
`Nevertb
`adminis
`rate of 5
`Pare]
`
`ables tl
`when r;
`emerger
`tion of -
`rapid ac
`after
`s
`slower
`Ballard
`
`that (1)
`in the
`labeled
`Inuscu];
`no ‘marl
`
`
`
`-.......,.;.;_......_..,_._._...e..._-3...
`
`i
`.f.'
`3"
`
`-
`
`
`
`1006
`
`Prolonged-Action Medications
`
`absorption, or utilizing frequent dosage.
`The last method is not very desirable.
`
`Slowing lrluciivulion 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
`byinhibiting the enzymes that inactivate
`the drug.” For example, the activity of
`aoetylcholine is inhibited by cholinester-
`ase; therefore, by using an anticholines—
`terase like neostigmine that combines
`with cholinesterase,
`the hydrolysis of
`acetylcholine is slowed and its activity
`is prolonged.
`Drug excretion or elimination from 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 reabsorption. Drugs
`which are to a considerable extent reab-
`sorbed by tubular cells have a prolonged
`stay in the body, eg, sulfamerazine.“
`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 ex_cretion consists of the reversible
`inhibition of renal excretion.“ Carin-
`
`amide (caronamide or 4’-carboxyphenyl-
`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 efl'ect
`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-aminosalicylic 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 iodon‘1ethamate.”“ 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“ have au-
`thored excellent reviews onthe 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 rcfierrcd
`to as a.zsm—o1-der reaction. Other reactions may proceed at
`a rate dependent on the concentration of one of the reac-
`tantr: remaining at one time; the rate varies, in these 0.3563»
`as the first power or exponent of reactant concentration.
`and these reactions are 1~erl:‘eL-red to as first—or¢£er reactions.
`
`Amerigen Ex. 1061, p. 7
`Amerigen Ex. 1061
`
`
`

`
`
`
`known methods as described in Wagner’s
`excellent reviews of Biopharmaceutics.“
`It is relevant to point out that meth-
`ods of slowing absorption are applicable
`to fairly-rapidly-elijmsinated drugs such
`as insulin,\c_c_>;tioo”tropin, hepa_rin, peni-
`cillin, etc. Furthermore, no useful mea-
`sure is served in slowing the absorption of
`such slowly-eliminated drugs as thy-
`roxin, digitalis glycosides, cyanacobal-
`amin, etc.”
`The principle common to the factors
`moviding 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,
`imrniscibility, 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.
`
`Roule 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
`Fate 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
`510Wer and more even. Nevertheless,
`Ballard,“ citing other sources, indicates
`that (1) there is not significant difference
`131 the absorption rate of radioactive-
`labeled lente insulin from either intra-
`muscular or subcutaneous sites, and (2)
`310 markedly different results were found
`
`Prolonged-Action Medications
`
`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-“ Miller“° has described pellets
`as srnall,
`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 (eg, 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 effective and convenient
`method for controlling Addison’s disease
`in patients. In 1958, 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 or hydrocortisone should be
`added to the therapeutic regimen-
`In order to maintain a constant level
`of riboflavin in the tissues, Bromberg
`et al“ 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 fused
`with 50
`of cholesterol maintained a
`high riboflavin level in man and animals
`for 45 days.
`Parenteral absorption has been re-
`viewed by Wagner. 35 The absorption of
`implanted solid drug has been reviewed
`by Ballard and Nelson.“ The latter in-
`vestigators“ indicated that absorption of
`implanted medication is affected by such
`
`
`
`Amerigen Ex. 1061, p. 8
`Amerigen Ex. 1061, p-.
`
`

`
`
`
`1008
`
`Prolonged-Action Medications
`
`factors as the site of implantation, body
`movements, 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 {r odents).
`Crumbling of the pellets may result in
`increased absorption and ovei-dosage,“
`with possible hazard to the patient. Fur
`thermore, the administration of pellets
`offers difliculties in administration and
`sometimes causes local disorders even
`
`when properly administered;
`they are rarely used. 3“
`Oral Rc-ute%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 suhlingual 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-
`lution.
`
`Absorption from the stomach varies
`with the amount of food in the stomach,
`the solvent vehicle (if any), the form of
`the drug, 4” 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
`
`I
`
`do influence the disintegration time of
`tablets. Usually, a tablet which diSinte._'
`grates at a slower rate cannot be ex.
`pected to make its medication as readily
`available for absorption.
`Ahhott et al,“ .have stated that Ii-1114-u
`coid material present
`in gastric juice
`may, under certain conditions (is, swaj.
`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 storrlach
`which contains a large proportion of mu-
`cous. A high Inucoid 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 afi"e(:ting gastro-
`intestinal absorption,
`the reviews by
`Wagner 44 should be read.
`Rectal RoI.1te—Enesco et al,” 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 ‘"5
`found that there was no significant differ—
`enco between the absorption of acetyl~
`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_rec—
`tal suppositories than from either theo-
`broma oil or glycerinated gelatin rectal
`suppositories. On the other hand, Peter-
`son et al,“ using sodium iodide labeled
`with radio-iodine to compare the rate of
`
`
`
`Amerigen Ex. 106:1.‘
`Amerigen Ex. 1061, p. 9
`
`-
`
`_ absorption fro]
`ministered to J
`tion from a 513 .
`ter than from :
`E
`sorption from '
`.
`fwm a the0_b1 Z
`Peterson st cl,’
`;
`EIassle:r*‘ have i
`set rule exist:
`'
`' ease of absorp ;-
`tum, and (2) ii
`undertaken to 5
`the base that
`tion. See page:
`medicf
`suppository IEO
`theobroma oil
`are usually co:
`ahsorbed and
`action over a
`states that thé
`
`5
`
`:
`:
`'-
`
`absorption of
`inals which ar-
`released becai
`greater aflinil
`-phase than t".
`the body ca
`drugs in a the
`leased readily
`tion of theobr
`Gradnick”
`
`the important
`preparation
`media give
`water-soluble
`cation more e
`Contrary 1
`Peterson at o;
`it has been
`Sperandio5° 1
`action of pen
`bital sodium,
`albino rats vi
`Shorter in tl'.
`ethylene gly
`Wagner‘-1 sts
`Sllrom ohserx
`tion of hexob
`was better fr
`61 Carbowax
`Riegelman
`in 1958 that
`
` .
`
`
`
`
`
`,-.;..NL.-..5..,...ic«'-.=.'.-3-}:my.I.-q_v}._ot'e~-iv.'
`
`

`
`
`
`
`
`
`
`
`
`
`
`absorption from rectal suppositories ad-
`ministered to rats, showed that absorp-
`tion from a glycerogelatin base was bet-
`ter than from a Carbowax base, and ab-
`sorption from the latter was better than
`fmms theobroma oil base. However,
`Peterson et al,“ as well as Cacchillo and
`Hassler“ have emphasized that (1) no
`set rule exists concerning the relative
`easeof 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. Tice“
`states that theobroma oil Inay retard the
`absorption of certa_i_n medicinals. lVIedic~
`irlals 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 Hassle1‘,"“
`Peterson et cl,“ Tice,“ and Gradnick,”
`it has been indicated by Hassler and
`Sperandio” that the onset of hypnotic
`action of pentobarbital sodium, secobar-
`bital sodium, and arnobarbital sodium in
`albino rats was faster and the duration
`Shorter in theobroma oil than in poly-
`ethylene glycol polylner suppositories.
`Wagner“ stated that Samelius and An-
`Strom observed that the rectal absorp-
`tion of hexobarbital sodium in the rabbit
`Was better from theobroma oil than from
`51 Carbowax base.
`i
`I Riegelman and Crowell" pointed out
`1n 1958 that a number of different in viva
`
`Prolonged-Action Medications
`
`1009
`
`rectal absorption studies have been cons
`ducted to evaluate separately or con-
`comitantly, at dilferent time intervals,
`the level of drug in the blood, urine, and
`the tissues, as well as the specific physi-
`ological response. However, 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 aifected, 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’s55 article on bi opharmaceutics
`provides a more extended review of rec-
`tal absorption.
`
`Vasoconsfriction
`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
`combination of epinephrine with local
`
`Amerigen Ex. 106