BIOPHARMACE.UTICS
`AND
`RELEVANT
`PHARMA CO KINETICS
`
`Page 1 of 11
`
`KVK-TECH EXHIBIT 1026
`
`

`

`~
`
`BIO PHARMACEUTICS
`AND
`RELEVANT
`PHARMA CO KINETICS
`
`by JOHN G. WAGNER, Phm.B., B.S.P., B.A., Ph.D.
`l
`PROFESSOR OF PHARMACY, COLLEGE OF PHARMACY, AND
`ASSISTANT DIRECTOR FOR RESEARCH AND DEVELOPMENT,
`PHARMACY SERVICE, UNIVERSITY HOSPITAL,
`THE UNIVERSITY OF MICHIGAN, ANN ARBOR, MICHIGAN
`
`WITH A SPECIAL CHAPTER ON 'QUA LITY CONTROL'
`by M. Pernarowski, B.S.P., M.S., Ph.D.
`PROFESSOR OF PHARMACEUTICAL CHEMISTRY,
`FACULTY OF PHARMACY, UNIVERSITY OF BRITISH COLUMBIA,
`VANCOUVER, BRITISH COLUMBIA, CANADA
`
`FIRST EDI TION 1971
`
`DRUG INTELLIGENCE PUBLICATIONS, HAMILTON, IL LINOIS 62341
`
`Page 2 of 11
`
`

`

`COPYRIGHT © BY DRUG INTELLIGENCE PUBLICATIONS 1971
`
`All rights reserved.
`
`No part of this book may be reproduced
`
`in any form without written
`
`permission of the copyright holder
`
`Library of Congress Catalog Number 75-160736
`
`Printed in the United States of America by The Hamilton Press, Hamilton, Illinois 62341
`
`Page 3 of 11
`
`

`

`CHAPTER 23
`
`Enteric Coatings
`
`Definition
`
`AN ENTERIC COATING IS ONE THAT RESISTS THE ACTION OF
`stomach fluids and disintegrates in the intestines.
`
`Reasons for Enteric Coating
`These are: ( 1) to prevent gastric digestion of a sus(cid:173)
`ceptible compound such as protein, or hydrogen ion
`catalyzed decomposition of a susceptible drug such as
`erythromycin;
`(2)
`to prevent nausea and vomiting
`caused by a drug, e.g., emetine, atabrine, iron salts and
`diethylstilbestrol; ( 3) to prevent dilution of a drug before
`reaching its site of action in the intestine, e.g., intestinal
`antiseptics and anthelmintics; ( 4) to prevent hindrance
`of gastric digestion of normal foodstuff by a drug, e.g.,
`alkaline medicaments; (5) to provide delayed action of
`a drug, e.g., barbiturates, amphetamines and aspirin;
`( 6)
`to deliver medication to the intestinal tract for
`optimum absorption in the duodenum and jejunum.
`
`Requirements pf a Good Enteric Coating
`These are: ( 1) the coating must be nontoxic; ( 2) the
`components of the coating and their degradation prod(cid:173)
`ucts, if any, must be physiologically inactive; (3) opti(cid:173)
`mally, the coating should not disintegrate or dissolve in
`158
`
`the stomach during the time that the enteric coated
`dosage form remains in the stomach; ( 4) the enteric
`coated dosage form should disintegrate and release its
`contained medication as rapidly as possible once the
`dosage form empties from the stomach into the intestines.
`
`Composition of Enteric Coatings
`The patent and non-patent literature on enteric coat(cid:173)
`ings is very extensive and much of it has been reviewed
`by Wagner (1956 and 1966); hence the reader is re(cid:173)
`ferred to the two chapters in Rem.ington's Practice of
`Pharmacy for the review of early literature and refer(cid:173)
`ences.
`In general, there are two types of enteric coatings.
`First, those which are intended to be digestible by
`enzymes in the intestinal tract. These include such
`substances as keratin, formalized gelatin, glycerides,
`waxes, etc. This type of coating usually does not meet
`the requirements of a good enteric coating since the
`surface area of the "digestible substance" exposed to the
`enzyme is so small that the digestion is much too slow.
`Second, most current enteric coatings contain an ionizable
`polyacid and, most frequently, a long-chain polymer with
`ionizable carboxyl groups which is also a film-forming
`agent. Usually the polymeric agent is applied to the
`
`Page 4 of 11
`
`

`

`METHODS & THEORY
`
`159
`
`dosage units dissolved in an organic solvent. The coating
`solution may also contain other substances, such as a
`plasticizer to aid in film formation, and a surface active
`agent. A dusting powder, such as talcum, is added
`during the coating of the dosage units to prevent the
`dosage units from sticking together; sometimes powder
`such as talcum is also suspended in the solution of the
`polymeric agent in the organic solvent.
`
`Methods of Application of Enteric Coatings
`There are four principal methods of applying enteric
`coatings to tablets. These are: ( 1) manual pan coating;
`(2) programmed pan coating; (3) fluidized-bed coating;
`and ( 4) compression coating. The oldest method, and
`probably the one still most widely used, is manual pan
`coating. Figure 23.1 shows various sizes of coating pans
`in a pharmaceutical development laboratory. Figure 23.2
`shows a row of production-size coating pans which have
`a diameter of 36 inches. Larger pans are also used in(cid:173)
`cluding some giant doughnut-shaped coating pans which
`handle the volume of a dozen regular commercial-size
`pans. In programmed pan coating most of the operations
`normally performed manually are done by machines but
`
`Figure 23.1. Coating pans in a Coating Development
`Laboratory (courtesy of The Upjohn Company)
`
`the revolving coating pan is similar to that used in
`manual pan coating. In fluidized-bed coating the tab(cid:173)
`lets are suspended in a column by rapidly moving air
`introduced at the bottom of the column and the coating
`solution
`is sprayed onto the tablets while they are
`suspended in the air. In compression coating the com(cid:173)
`ponents of the enteric coating are mixed in the dry
`state and applied by compression around the core
`tablet thus producing essentially a tablet-within-a tab(cid:173)
`let.
`
`Theory of Enteric Coatings and Their Properties
`In man the stomach contents are usually in the pH
`range 1 to 3.5 and pH 1 .to 2.5 is the most common
`range. During the night the human stomach usually has
`the lowest acidity. During the day the taking of meals
`is the most frequent cause of changes in acidity of the
`stomach contents. The high acidities, near pH 1, are
`usually recovered within a short time after the meals
`are eaten. In man the duodenal contents are usually
`
`Page 5 of 11
`
`

`

`160
`
`Figure 23.2. Row of gal(cid:173)
`vanized Iron, production·
`size coating pans
`( courtesy of The
`Upjohn Company)
`
`in the range pH 5 to 7. There is a gradual decrease in
`acidity in moving from the duodenum to the ileo-cecal
`valve, ranging from approximately pH 5 to 6, on the
`average, in the duodenum to about pH 8 in the lower
`ileum. Hence, when an enteric coated dosage unit moves
`from
`the stomach through the pylorus to
`the duo(cid:173)
`denum there is a very abrupt and marked change in
`acidity to which it is exposed in practically all human
`subjects and patients. The transfer of a given coated
`particle, granule, tablet or capsule takes only a frac(cid:173)
`tion of a second. However, as indicated below, the
`individual coated particles may empty from the stom(cid:173)
`ach over prolonged periods of time and a single enteric
`coated tablet or capsule may empty from the stomach
`in anywhere &om about one-half hour to 12 hours. The
`upper part of the small intestine is the best absorbing
`
`surface for drugs hence a good enteric coating must
`be capable of breaking up or dissolving and allowing
`release of the drug contained in the coated dosage
`unit in a Buid with a pH between about 5 and 7 or
`even somewhat lower.
`As indicated above most modern enteric coatings
`contain a polymeric acid which has ionizable carboxyl
`groups. The degree of ionization of such a weak acid
`depends upon both the pH of the solution and the
`relative strength of the acid groups as indicated by
`their pK. value. The ionization may be represented as:
`R-COOH + OH- ~ R-COO· + H,O
`Below some pH, which is 2 to 4 pH units below the
`pK. of the acid group, practically all the polymeric acid
`will be undissociated (i.e., in its R-COOH form) and,
`
`Eq. 23.1
`
`Page 6 of 11
`
`

`

`DISINTEGRATION TIME
`
`161
`
`pM
`
`•
`
`90
`
`••
`
`70
`
`60
`
`so
`
`••
`
`30
`
`lO
`
`10
`
`0
`
`Figure 23.3. Wustratlng the type of plot which would show
`a spectrum of enteric coatings. Curve A corresponds to
`styrene-maleic acid, copolymer with pK •, = 4.25; curve B
`corresponds to Resin SC·2 with pK • = 4.83; and curve C
`corresponds approximately to shellac with pKo between
`6.9 and 7 .5 but taken as 6.3
`
`for the type of polymeric acids used in enteric coatings,
`it will be insoluble. As the pH is progressively raised
`the equilibrium shown in Equation 23.1 shifts more
`and more to the right, causing the formation of more
`and more R-COO· groups. The polymeric acid becomes
`more and more soluble also as the pH is raised. As
`the polymeric acid in the coating dissolves, water pene(cid:173)
`trates to the core tablet and eventually disintegration
`occurs. There is a spectrum of enteric coatings as
`illustrated in Figure 23.3. The position of the ionization
`curve relative to the pH scale for each of the polymeric
`acids used in enteric coatings depends upon the pK.
`of the dissociating acidic group in the polymeric acid.
`While developing a new enteric coating when he worked
`for The Upjohn Company the author studied several
`polymeric acids. Styrene-maleic acid copolymer has a
`pK. of 4.25; Resin SC-2 ·has a pK. of 4.83; shellac has
`an apparent pK, between 6.9 and 7.5; cellulose acetate
`phthalate and starch acetate phthalate have pK,
`values somewhere between those of Resin SC-2 and
`shellac. Hence each of these polymeric substances has
`its ionization curve at a different position in a plot such
`as shown in Figure 23.3. If appreciable ionization of
`the polymer occurs at too low a pH then the enteric
`coating will not perform its intended ftµ1ction
`in the
`stomach. Hence the ionization curve cannot be too far
`to the left in Figure 23.3. If the curve is too far to the
`right then the enteric coating will not dissolve allowing
`release of the drug from the dosage form at a pH which
`corresponds to· that found in the upper small intestine
`of roan. In actual practice, the pH ra,nge in which the
`disintegration time of enteric coated tablets decreases
`rapidly with increase in pH of the fluid to which they
`are exposed corresponds to the pH range where the
`percent ionization of the polymeric acid is changing
`most rapidly, i.e., in a narrow pH range in either side
`of the pK. of the polymeric acid function. This can
`be seen from the data in Table 23.1 which gives the
`average disintegration time of a lot of tablets (which
`was enteric coated with styrene-maleic acid copolymer,
`dibutyl phthalate and talc) as a function of the pH
`It should be noted that the disin(cid:173)
`of the test fluid.
`tegration time changes most rapidly in the pH range
`near the pK. of 4.25 for this polymeric acid.
`
`Table 23.1 Disintegration Times of Tablets Coated with
`Styrene-Maleic Acid Copolymer, Dibutyl Phthalate and
`Talc1
`
`PH OF TEST FLUID
`
`AVERAGE DISINTEGRATION
`TIME (MINS)
`
`3.7
`4.0
`4.8
`6.9
`
`49.5
`41.6
`24.3
`23.8
`
`1Tablet lot CII·S from Wagner et at., Enterlc Coating V, 1960
`
`Factors Affecting Disintegmtion Time of
`Enteric Coated Tablets
`Many factors
`influence the disintegration time of
`enteric coated tablets. For those coatings containing
`
`Page 7 of 11
`
`

`

`162
`
`52
`
`48
`"'
`w ....
`~ 44
`j
`g
`@40
`C>
`z
`
`~36
`u
`I,!
`0:
`~ 32
`z
`w ...
`o 28
`w
`::E
`;::
`z 24
`0
`
`ii 0: /3 20
`
`....
`z
`iii
`: 16
`<l w
`::E
`-' 12
`<l
`E g
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`1
`
`I
`-~
`' I
`'
`~/
`/
`.,
`'I
`'
`
`I
`
`f
`
`I '
`
`8
`
`4
`
`160
`140
`120
`100
`80
`60
`4
`20
`0
`MEAN WEIGHT Of TALC APPLIED PER TABLET (Wpl IN MILLIGRAMS
`
`_ ___ TABLETS COATED WITH CELLULOSE ACETATE PHTHALATE .
`._._. TABLETS COATED WITH STARCH ACETATE PHTHALATE
`o---<> TABLETS COATED WITH STYRENE-MALEIC ACID COPOLYMER
`
`Figure 23.4. Correlation of Initial dlslntegratlon time 0£
`enteric coating with the mean weight 0£ talc applied as
`dusting powder per tablet
`
`an ionizable polymeric acid the pK. of the ionizable
`acidic groups is very important and this has been dis.
`cussed above. The method of applying the coating is
`also very important. If the same amounts of coating
`ingredients were applied to. part of a lot of tablets
`by the manual pan coating method and to another part
`of the same lot of tablets by fluidized-bed coating the
`disintegration time of the two lots of enteric coated
`tablets would probably be different.
`In general, in
`such a case, the disintegration time of the tablets coated
`in the fluidized-bed would be less than the disintegra.
`tion time of the tablets coated manually in a pan.
`Although enteric coatings had been prepared for
`some 70 years previously it was not until the period
`1953-1960 that a scientific approach was applied by
`the author (Wagner et al. 1958 to 1960) to disclose
`what factors really affected the disintegration time of
`enteric coated tablets. Until then enteric coating was
`considered just an "art" and no one knew for sure why
`one batch of tablets differed from another. _ The first
`approach of the author was to watch the manual pan
`coating process carefully, keeping track of exactly how
`much of each ingredient was utilized during the coating
`of each batch of tablets and the time intervals between
`applications. The next approach was to coat the same
`lot of tablets with different amounts of ingredients by
`taking samples successively as the coating process con(cid:173)
`tinued. Later experiments were performed in which
`one ingredient was held constant in amount while an(cid:173)
`other ingredient was varied in amount. All tablets
`coated in such studies were carefully tested for disin(cid:173)
`tegration time in artificial gastric Huid, pH 1.2, and in
`artificial intestinal fluids of several pH values. Enough
`tablets were tested to be representative of each batch.
`The standard deviation of disintegration time was used
`as a measure of variability of disintegration time from
`tablet to tablet. These studies disclosed that almost
`every ingredient, as well as the core tablet, affected
`the disintegration time of the final enteric coated tab(cid:173)
`lets. For the first time it was shown that the amount
`of dusting powders such as talc, used during the enteric
`coating process, was extremely important. This is il(cid:173)
`lustrated in Figure 23.4 where the initial mean dis(cid:173)
`integration time of the enteric coating is plotted against
`the mean weight of talc applied per tablet for three
`different enteric polymers. "Initial" here means the
`disintegration time of freshly coated tablets. The "dis(cid:173)
`integration time of the enteric coating" was obtained by
`subtracting the disintegration time of the subcoated tab(cid:173)
`the disintegration time of the final enteric
`let from
`coated tablet. One can see from Figure 23.4 that there
`is a sharp rise in disintegration time with small increase
`in the amount of talc applied per tablet for each type
`of coating. Most of the difference in location of the
`lines is due to the relative "tackiness" of the enteric
`coating solution during application and drying off of
`the solvent i.e., more dusting powder need be used
`with one enteric coating solution than with another.
`This is emphasized in Figure 23.5 where the initial
`disintegration time of the enteric coating is plotted
`
`Page 8 of 11
`
`

`

`163
`
`STOMACH EMPTYING
`,.
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`.,
`
`I
`I
`I
`I
`I
`I
`
`I.
`I
`\·
`I
`I • i /
`V
`l
`' I
`
`50
`
`~ w
`
`i 42
`
`!
`~ 38
`
`! ~ 34
`" II « E 30
`
`~
`w 26
`!
`
`~ 22 i ~ 18
`
`ll
`~
`~ 14
`~
`
`1·~
`
`against the ratio of the grams of talc applied per milli(cid:173)
`liter of coating solution per tablet. Since the amount
`of dusting powder and coating solution used on a given
`batch of tablets varied not only for one tablet coater
`from day to day but also from tablet coater to tablet
`coater, one can readily see why the disintegration time
`may vary all over the map when enteric coating is
`treated as an "art." In fluidized-bed coating less or no
`dusting powder need be used than in manual pan
`coating, offering a distinct advantage. The overall mean
`weight of enteric coating applied per tablet is important
`as illustrated by Figure 23.6. This t1gure indicates that
`for these two types of enteric coatings the disintegra(cid:173)
`tion time of the enteric coating is directly proportional
`to the mean weight of enteric coating applied per tablet
`but that the slope of the line is very dependent upon
`the type of coating. ·
`
`Stomach Emptying
`Stomach emptying of enteric coated dosage forms has
`been formerly discussed in Chapter 1, 11 and 12 but
`is emphasized again here since the concept is extremely
`important in biopharmaceutics. Small amounts of liquids
`appear to empty from the human stomach at essentially
`constant (zero order) rates. Large volume liquid test
`meals appear to empty largely at first order rates i.e.,
`the rate of emptying is directly proportional to the
`volume of the liquid test meal remaining in the stomach.
`The emptying .rate of solid enteric coated units appears
`to depend upon the size of the particles and appears
`to obey the laws of probability.
`If you administer a single enteric coated tablet to
`one patient the tablet may empty from the stomach in
`one-half hour or less or it may remain in the stomach
`for ten hours or more before emptying. If the tablet ·
`stays in the stomach the patient receives no medication
`if the coating remains intact. If the tablet administered
`is laminated with an outer, quickly available dose and
`an inner enteric coated core then shortly after admin(cid:173)
`istration the dose of drug in the outer portion of
`the tablet will be available for absorption but the
`availability of the dose in the enteric coated core tablet
`depends upon when the tablet empties from the stomach
`into the intestine. If the core tablet empties rapidly the
`patient, in essence, receives a double dose of the medica(cid:173)
`ment.
`The emptying time of enteric coated tablets in the
`starved dog also obeys the laws of probability but em(cid:173)
`ptying in the dog is spread over lower time values than
`the distribution of emptying times in man. Wagner
`et al,. ( 1958) studied the emptying of enteric coated
`tablets from the stomachs of dogs. Compressed tablets
`containing barium sulfate were made with a %-inch oval
`punch; the tablets were subcoated then enteric coated
`such that their final volume was estimated to be about
`300-319 cubic millimeters. Dogs traiued to lie quietly
`on the x-ray table were used. The dogs were fasted
`overnight and, in all except two cases, 50 ml. of 0.lN
`hydrochoric acid were administered
`just before the
`tablets. X-ray photographs were taken 45 minutes fol-
`
`I
`I
`I
`
`--=-o;"'100~ - -~o.9~00
`o'--,o=-=,oo""""--..,0""300""'""---=o~c500==--
`GRAMS Of TALC /M'LUUTER OF SOUJTIOPf PER TA8ltT
`---"4 TABLETS COATED WITH CEU.UI.OSE 4C£TATE PHTH.AI.ATE
`
`~. _., TA81..tT$ COATED WrTH STAACH ACETATE PHTHALATE.
`c,.-o TA8L£T$ COATEO WITH STYAEN£• MAl£1C ACID COPOI.YM(R,
`
`Figure 23.5. Correlation of Initial disintegration time of
`enterlc coating with the ratio: grams of talc/
`milliliter of solution per tablet
`
`Figure 23.6. A plot of the average disintegration time of the
`enteric coating (T., in minutes when the tablets were placed
`directly In artificial Intestinal fluid, pH 6.9, against the
`average weight of enteric coating per tablet, (W., In
`milligrams). Coatings: 0-- -0; starch acetate phthalate,
`dlbutyl phthalate and talc: o ..... o and 0 -0 two
`dl.fferent groups of tablets coated with styrene maleic acid
`copolymers, dibutyl phthalate and talc. Reproduction from
`Wagner et aL., 1960 with permission of the copyright owner
`
`80
`
`70
`
`60
`
`50
`
`V>
`~ 40
`~
`~
`::;;
`~ 30
`I~
`
`20
`
`10
`
`0
`
`0
`
`rt
`l
`I
`I
`
`j
`
`20
`
`100
`80
`60
`40
`We (IN MILLIGRAMS)
`
`120
`
`140
`
`160
`
`Page 9 of 11
`
`

`

`164
`
`lowing administration of the tablets and at intervals of
`15 minutes or less thereafter. A total of 112 tablets in
`groups of four or 28 tests were made. Each figure
`entered in Table 23.2 represents as accurate an estimate
`as possible of the average retention time in the stomach
`of the four enteric coated tablets of each test.
`
`Table 23.2 Period of Retention of Enteric Coated
`Tablets (in Minutes) in the stomach of the Starved Dog.
`
`TABLE LOT
`
`000 NUMBER
`2
`
`I
`
`II
`
`III
`
`IV
`
`V
`
`67
`99
`45
`65
`100
`80
`135&
`70
`71
`45
`
`146
`87
`90
`90
`100
`205
`101&
`101
`
`210
`
`150
`
`3
`
`102
`86
`70
`75
`80
`55
`
`70
`60
`
`aNo acid was administered. In all other tests 50 ml of O.lN
`hydrochloric acid was administered with four enterlc coated
`tablets after an overnlght fast.
`
`The data in Table 23.2 were evaluated by a statistical
`test known as the W-test to determine whether the
`retention or emptying times were normally or log(cid:173)
`normally distributed. The hypothesis of normality was
`rejected (p<0.01). The hypothesis of log-normality
`was not rejected (0.lO<p<0.05). The average of the
`natural (base e ) logarithms ( ln M) of the number in
`Table 23.2 was 4.480 with a standard deviation (o-. ) of
`
`Figure 23.7. Theoretical curve for emptying rate of enteric
`coated tablets from stomachs of starved dogs based on
`the data In Table 23.2 and Equations 23.2 and 23.8
`
`!.~-
`
`- - -- - - - - - - - - - - - - - -~
`
`1. 2
`
`.. 1. 0
`i
`' f
`.. ..
`;:: 0,8
`.. t:
`
`; 0.6
`
`~
`0,4
`
`0.2
`
`0
`
`100
`
`200
`
`300
`
`TIME
`
`IM MINUTES
`
`0.386. The theoretical logarithmic normal density func(cid:173)
`tion curve based on these values is shown in Figure
`23.7. The curve was generated by means of Equations
`23.2 and 23.3.
`
`Emptying ra te (%/ min) =
`
`100
`- - - - --
`yz; . .,. ·t
`
`• Eq 23.2
`e-Z· /,
`
`z =
`
`In t -
`
`ln M
`
`u .
`
`Eq 23.3
`
`using the value of 4.480 for lnM and the value of
`0.386 for u •.
`When dogs were fed 30 minutes prior to adminis(cid:173)
`tration of groups of four enteric coated tablets in this
`series of studies the tablets were retained in the stomach
`for a period exceeding seven and one-half hours. This
`to determine the resistance
`phenomenon allows one
`of the enteric coated tablet to strongly acidic conditions
`in vivo.
`Nelson ( 1963) evaluated data on the emptying of
`enteric coated tablets from the stomach of man, which
`he obtained from one report, and concluded the data
`fit a normal distribution curve rather than a log-normal
`curve. As mentioned in Chapter 12 Wagner et al.
`(1960) calculated that 174 tablets, freshly enteric coated
`with ammoniated shellac, were emptied
`.from
`the
`stomach of human subjects after an average time of
`3.61 hours with a standard deviation of 1.47 hours. At
`the time these data were evaluated no test was made
`to determine if they were normally or log-normally
`distributed. Assuming the emptying times were nor(cid:173)
`mally distributed tl1en the theoretical curve based on
`the mean of 3.61 hours and standard deviation of 1.47
`hours is shown in Figure 23.8.
`Prior to a definitive statistical test such as the W-test
`or Chi-square test for the type of distribution, one can
`get an idea of the type of distribution by plotting the
`cumulative percent of tablets or other dosage units
`emptied from
`the stomach against time on normal
`probability graph paper, logarithmic normal probability
`graph paper and logistic ruling paper. If a reasonably
`straight line can be drawn through the data points
`plotted on one of these types of graph paper then the
`equation to satisfy the data is obvious and plots such
`as Figure 23.7 and 23.8 may then be readily drawn .
`If only one line represents the data on logistic ruling
`graph paper then the cfata are described hy Equa(cid:173)
`tion 23.4
`
`E
`
`100 t6
`
`1 ·
`- + t2
`a
`
`Eq 23.4
`
`where E is the
`a is the value
`
`cumulative percent emptied to
`of ln (~ ) when t = 1,
`100-E
`is the slope factor and representative of the spread
`of the data.
`
`time t,
`and S
`
`Page 10 of 11
`
`

`

`The most important point to remember is that when
`the dose of drug is contained in only one coated tablet
`and administered to one patient then the tablet empties
`from the stomach at only one time (i.e., one point) on
`a distribution curve such as shown in Figures 23.7 and
`23.8. When the dose is contained in a large number
`of small coated units, then each dose of the drug will
`in essence result in a stomach emptying pattern that
`is an entire distribution curve itself. This is supported
`by the work of Wagner et al. (1960) and by the human
`studies done with coated granules of prednisolone dis(cid:173)
`cussed in Chapter 22. Hence optimum enteric coated
`dosage forms would be th.ose where a large number
`of coated granules or pilules were contained in a capsule
`rather than a large tablet with a single enteric coating
`around th.e tablet.
`
`Miscellaneous
`Methods of determining disintegration time of enteric
`coated tablets and granules in the intestinal tract of
`man were discussed in Chapter 11.
`Correlation of disintegration times of enteric coated
`tablets determined in vivo and in vitro was discussed
`in Chapter 12.
`
`References
`
`1. Wagner, J. G.: The Coating of Tablets, Pills and
`Capsules, Chapter 33 in Remington's Practice of Pharmacy,
`R.R.P. XI, Editors: E. W. Martin and E. F. Cook, The
`Mack Publishing Company, Easton, Penn., 1956, pp. 400-419.
`2. Wagner, J. G., Veldkamp, W. and Long, S.: Cor(cid:173)
`relation of in Vivo with in Vitro Disintegration Times of
`Enteric Coated Tablets, J. Am. Pharm. Assoc. Sci. Ed. 47:
`681-685, 1958.
`3. Wagner, J. G., Brignall, T. W. and Long, S. : Enteric
`Coatings II. Starch (and Amylose) Acetate Phthalates, J. Am.
`Pharm. Assoc. Sci. Ed. 48:244-249, 1959.
`4. Wagner, J. G.: A Note on the Correlation of in Vivo
`with in Vitro Disintegration Times of Enteric Coated Tab(cid:173)
`lets, ]. Am. Pharm. Assoc. Sci. Ed. 49: 179 only, 1960.
`5. Wagner, J. G. and Long, S.: Enteric Coating III.
`An Improved Enteric Coating and its in Vitro Evaluation,
`]. Am. Pharm. Assoc. Sci. Ed. 49:121-127, 1960.
`6. Wagner, J. G., Veldkamp, W. and Long, S.: Enteric
`Coating IV. in Vivo Testing of Granules and Tablets Coated
`with Styrene-Maleic Acid Copolymer, ]. Am. Pharm. Assoc.
`Sci. 49: 128-132, 1960.
`7. Wagner, J. G., Ryan, G. W., Kubiak, E. and Long,
`S.: Enteric Coatings V. pH Dependence and Stability, J.
`Am. Pharm. Assoc. Sci. Ed. 49: 133-139, 1960.
`8. Wagner, J. G.: The Coating of Tablets, Capsules and
`Pills. Chapter 37
`in Remington's Practice of Pharmacy,
`R.R.P. XII, Edition: E. W. Martin and E. F. Cook, The
`Mack Publishing Company, Easton, Penn., 1966, pp. 476-494.
`9. Wagner, J. G.: Biopharmaceutics: Absorption Aspects,
`]. Pharm. Sci. 50:359-387, 1961.
`10. Nelson, E.: Pharmaceuticals for Prolonged Action,
`Clin. Pharmacol. Therap. 4:283-292, 1963.
`1 l. Gronroos, J. A. and Toivanen, A. : Blood Ethionamide
`Levels After Administration of Enteric-Coated and Uncoated
`Tablets, Current Therap. Res. 6: 105-114, 1964.
`12. Corbus, H. F.: Enteric Coated Thyroid as a Cause
`of Relapse in Myxedema, Calif. Med. 100: 364-365, 1964.
`13. Goldberg, W. M. and Chakrabarti, S. G.: The Rela(cid:173)
`tionship of Dosage Schedule to the Blood Level of Qufoi(cid:173)
`dine, Using All Available Quinidine Preparations, Can. Med.
`Assoc. ]. 91: 991-996, 1964.
`
`LITERATURE
`
`165
`
`TIME
`
`IN HOURS
`
`Figure 23.8. Theoretical curve for emptying rate of enterlc
`coated tablets from stomach of fasted human subject
`based on a mean of 3.61 hours and a standard
`deviation of 1.47 hours
`
`13. Levy, G. and Hollister, L. E.: Failure of U.S.P. Dis(cid:173)
`integration Test to Assess Physiologic Availability of Enteric
`Coated Tablets, N.Y. State ]. Med. December 15, 1964,
`pp. 3002-3005.
`14. Editorial and Annotation Section: Small Bowel Ul(cid:173)
`ceration and Enteric Coated Potassium Chloride-Thiazide
`Medication, Can. Med. Assoc. ]. 92: 188-190, 1965.
`15. Leonards, J. R. and Levy, G.: Absorption and Me(cid:173)
`tabolism of Aspirin Administered in Enteric-Coated Tablets,
`]. Am. Med. Assoc. 193:99-104, 1965.
`16. Clark, R. L. and Lasagna, L.: How Reliable Are
`Enteric-Coated Aspirin Preparations?, C!in. Pharmacol.
`Therap. 6:568-574, 1965.
`17. Ditlefson, E. M. L. and Loken, H. F.: Quinidine
`Concentrations in Serum Following Two Different Types of
`Delayed-Absorption Tablets, Acta Med. Scand. 179: 333-336,
`1966.
`Intestinal Absorption of Quinine
`18. Rasmussen, S.:
`from Enteric Coated Tablets, Acta Pharmacol. Toxicol 24:
`331-345, 1966.
`19. Levy, G. and Jusko, W. J.: Case History of a Phar(cid:173)
`maceutical Formulation Failure, C!in. Pharmacol. Therap. 8:
`887-889, 1967.
`20. Tikkanen, R. : Absorption of Drug Contents of En(cid:173)
`teric-Coated Tablets, Nord. Med. 78: 1564-1567, 1967.
`21. Rasmussen, S.: Correlation Between in Vitro and in
`Viuo Disintegration Times o( Enleric-Coated Tablets, J.
`Pharm. Sci. 57 : 1360-1363, 1968.
`22. Fosdick, W. M. and Shepherd, W. L.: Enteric Coated
`Microspherules. A Clinical Appraisal of Two Forms of Aspirin,
`]. Clin. Pharmacol. ]. New Drugs 9:126-129, 1969.
`23. Baum. J.: Blood Salicylate Levels and Clinical Trials
`with a New Form of Enteric-Coated Aspirin: Studies in
`Rheumatoid Arthritis and Degenerative Joint Disease, ]. Clin.
`Pharmacol. ]. New Drugs 10: 132-137, 1970.
`
`Page 11 of 11
`
`