DRUG DELIVERY
`TO THE
`GASTROINTESTINAL
`TRACT
`
`_ Editors
`J.G. HARDY
`Principal Physicist
`Department of Medical Physics
`University Hospital, Queen’s Medical Centre, Nottingham
`S.S. DAVIS
`Lord Trent Professor of Pharmacy
`Department of Pharmaceutical Sciences, University of Nottingham
`CLIVE G. WILSON
`Senior Lecturer in Pharmacology
`The Medical School, University of Nottingham
`
`
`
`ELLIS HORWOODLIMITED
`Publishers - Chichester
`
`Halsted Press: a division of
`JOHN WILEY & SONS
`New York - Chichester - Brisbane - Toronto
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`

`
`
`First published in 1989 by
`ELLIS HORWOOD LIMITED
`Market Cross House, Cooper Street,
`Chichester, West Sussex, PO19 1EB, England
`oe ublisher’s colophon is reproduced from James Gillison’s drawing of the ancient Market Cross,
`
`Chichester.
`
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`‘
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`© 1989 J. G. Hardy, S. S. Davis and C. G. Wilson/Ellis Horwood Limited
`
`British Library Cataloguing in Publication Data
`Hardy, J. G.
`Drugdelivery and the gastrointestinal tract.
`1. Man. Gastrointestinal tract. Drugs
`Absorption.
`I. Title.
`II. Davis, Stanley S., III. Wilson, Clive George
`615'.73
`
`Library of Congress data available
`ISBN 0-7458-0656-2 (Ellis Horwood Limited)
`ISBN 0-470-21546-1 (Halsted Press)
`Printed in Great Britain by The Camelot Press, Southampton
`
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`without the permission of Ellis Horwood Limited, Market Cross House, Cooper Street, Chichester, West
`Sussex, England.
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`84
`
`Enteric Coatings and Delayed Release
`
`(Ch. 7
`
`GASTROINTESTINAL pH
`
`\
`
`Viewsas to the precise pH at which enteric coating polymers should
`dissolve have had to change in recent years as more accurate assessments
`of the gastrointestinal tract have been made using miniature pH electrodes
`and radiotelemetry.
`The pH ofthe gastric fluid in the fasting stomach lies predominantly
`within the range 0.8 to 2.0, although a small percentage of healthy
`individuals are sufficiently achlorhydric to show occasional high fasting
`pH values up to about 5. The buffering and dilution of acid that is caused
`by ingestion of food results in a transientrise to pH 4 - 5 or higher, butthis
`provokesfurther gastric secretion and restores a strongly acid pH within 30
`to 45 minutes (Fimmelet al., 1985). Gastric acid is subsequently neutral-
`ised by bicarbonate in the duodenum, where the pH rises rapidly to about
`5.5 at the jejunal junction, in both the fasted and post-prandial states.
`Whereas gastric pH has been relatively well defined, fewer studies have
`been carried out into intestinal conditions and data are consequently more
`limited. The proximal jejunum usually lies within the pH range 5.0 to 6.5
`(Ovesenet al., 1986). The pH rises slowly along the length of the small
`intestine to reach only pH 6 to 7 in most subjects, although high values in
`the range 7 to 9 have occasionally been found (Hardy et al., 1987a). The
`caecum and ascending colon are usually more acid than the small intestine,
`by ahalfto one pH unit, but ahigher pH of6.0 - 7.0 or aboveis restored more
`distally. The contents of the gut are not homogeneousand the pH recorded
`by a radiotelemetry capsule is ofthe local pH in the immediate environment
`of the device, rather than reflecting either the average pH of the lumenor
`the pH at the gut wall. Nevertheless, such results accurately reflect the range
`of conditions to which an enteric coated dosage form might be exposed in
`its transit through the intestines.
`A summary ofthe pH rangefor healthy subjects is given in Table 1, but
`intra- and inter-subject variability as well as the effects ofdisease states will
`result in a small but significant proportion of readings lying outside these
`values. pH is of course also affected by the administration of some drugs
`particularly antacids and H.,- antagonists.
`Various polymers are available for use in enteric coatings. All are
`insoluble and impermeablein acid but begin to dissolve at pH valuesin the
`range 4.5 to 7.0. Products coated using polymers that dissolve at the lower
`end of the pH range may be proneto release in the stomachin a proportion
`of instances, whether owingto a high fasting pH orto the buffering effects
`of ingested food. To ensure full gastric resistance, a coating impermeable
`to at least pH 5.0 is therefore essential. With polymers that dissolve at
`relatively high pH values, concern arises as to whether the coating will
`
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`

`Ch, 7]
`
`Enteric Coatings and Delayed Release
`
`85
`
`Table 1 - Ranges of Gastrointestinal pH typically Found in Healthy
`Subjects.
`
`Location
`
`Stomach
`Jejunum
`Tleum
`Colon
`
`pH
`
`0.8-5.0
`5.0-6.5
`6.0-7.5
`6.0-8.0
`
`dissolve sufficiently promptly in the small intestine to provide adequate
`opportunity for drug absorptionin all instances.
`
`ENTERIC POLYMERS
`
`Polymers that are used in enteric coating depend on the presence of
`ionisable carboxyl groups in their molecularstructure for their pH sensitiv-
`ity. A sufficient proportion of these acid groups, about 10%, must be
`ionised for water solubility to be achieved. This degree of ionisation is
`reached, as defined by the Henderson-Hasselbach equation, when pH rises
`to within one pH unit of the pK, value:
`
`pH-pK = log concentration ionised
`
`concentration unionised
`
`.
`
`Thereis not in fact a precise pH threshold above which a material is soluble,
`rather a range of about one pH unit over which a polymer coating varies
`from being virtually impermeable to being quite readily soluble andfast to
`rupture. An awareness that the intestinal tract is not as alkaline as once
`believed, and consideration ofthe in vive performancesofenteric coatings,
`haveled to the introduction ofpolymersthatrelease at increasingly acid pH
`values. A list of commonly used enteric coating materials is given in Table
`2, together with the pH valuesat and above which the polymers will dissolve
`moderately readily in buffer solutions in vitro, Although Shellac is now
`considered to be soluble at too high a pH and has become largely super-
`seded,it is included in Table 2 for comparison.
`The threshold values range from below pH 5, particularly for some
`newer materials, to about pH 6 for cellulose acetate phthalate and Eudragit
`L, and to pH 6.6 - 6.8 for Eudragit S. Mixed films may be formulated from
`compatible polymers to achieve intermediate effects, for example between
`CAP and CAT and between Eudragit L and S. The threshold values are
`
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`

`86
`
`Enteric Coatings and Delayed Release
`
`[Ch. 7
`
`Table 2 - Commonly used Enteric Coating Materials.
`So
`
`Enteric polymer
`
`Threshold pH
`
`cellulose acetate trimellitate (CAT)
`HPMCP
`polyvinyl acetate phthalate (PVAP)
`HPMCP50
`HPMCP55
`Eudragit L30D
`Aquateric
`cellulose acetate phthalate (CAP)
`Eudragit L
`EudragitS
`Shellac
`
`4.8*
`454.8
`5.0
`5:2
`5.4
`5.6
`5.8
`6.0
`6.0
`6.8
`7.2F
`
`HPMCP=hydroxypropylmethylcellulose phthalate
`* Manufacturer's data
`T Increases on storage
`
`affected in practice by the choice of plasticiser and pigments incorporated
`with the polymers, by the thickness of the coating and by the formulation
`of the table core and the disintegration forces exerted. The values shown
`in Table 2 were obtained using McIlvainecitrate-phosphate buffer solution
`while the pH at which disintegration occurs in man will be influenced by the
`constituents of physiologicalfluids, for eA bile salts increasing the
`dissolution rate of CAP.
`Enteric coatings have been applied to tablets, usually from a solution of
`the polymerin alcohol, acetone or another organic solvent. This provides
`a fast and reliable technique. An amount of coating corresponding to
`typically 6-8% of the tablet weight, or about 12 mgcm7, is necessary to
`achieve acid resistance and impermeability. More recently, aqueous based
`latex suspensions have been developed to overcomethe flammability and
`environmental concerns that exist over the use of organic solvents. A
`further practical: benefit of latex dispersions is that their viscosity is
`independent ofmolecular weight and polymerchain length so that they can
`be used at high solids concentrations. The coating process consequentlyis
`about as fast as for solvent based methods. Their use has not proved
`Straightforward, however, and a much more precise coating method is
`required in order to achieve complete polymer coalescence and to avoid a
`slightly porous, non-resistant matrix structure. A higher quantity of
`polymeris also necessary, typically 10-12% of the tablet weight.
`
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`

`Ch. 7]
`
`Enteric Coatings and Delayed Release
`
`87
`
`EVALUATION IN VITRO
`
`In vitro methods for the critical assessment of enteric coated dosage
`forms are as yet incompletely developed and the compendial tests mayfail
`to discriminate between satisfactory and unsatisfactory formulations. Such
`tests examine resistance for 1-2 hours in 0.1 M acid and disintegration
`within 1-2 hours in buffer at pH 6.8 or sometimeshigher, the 1985 United
`States Pharmacopoeia having specified pH 7.5. The pH at the buffer stage
`may be too high in the light of current knowledge. Whereasthetests will
`provide a check for faults arising during manufacture, such as damaged or
`incomplete and porous coatings, there have been a numberofinstances of
`products meetingthe test criteria but resulting in low bioavailability. The
`compendial standards can be satisfied by all the current enteric polymers
`listed in Table 2 provided that a sufficient, continuous coating is achieved,
`yet it has been demonstratedthat different applications require polymers of
`different threshold pH values. Assessmentof release in pH 6 buffer might
`well be a more suitable standard for some applications, althoughastill
`lower pH buffer and shorter time limit would seem necessary for poorly
`absorbed drug substances that must be rapidly released in the small
`intestine, as has been proposedfor erythromycin for example (Watanabe et
`al., 1977).
`Since 1986 the United States Pharmacopoeia has adopted dissolution
`rather than disintegration criteria for enteric coated products, applying
`assays and release limits at both the acid and buffer stages, with 0.1 M acid
`and pH 6.8 buffer being specified as the media. Additional evaluation at an
`intermediate pH value,for example at pH 4, maybe particularly appropriate
`during developmentof a new product. This could be usedto establish that
`the coating would withstand a transient rise in gastric pH, as commonly
`occurs, as well as to help in establishing the stability of the proposed
`coating. Phthalate ester groups, particularly in CAP, are known to be
`susceptible to hydrolysis during storage, with the gradual formation of
`phthalic acid and a reduction in acid resistanae ofthe polymerm films. Such
`changesin the resistance of the coating may be detected at an earlier stage
`if samples are examined at an intermediate pH rather than in 0.1 M acid
`alone.
`
`EXPERIENCE OF ENTERIC COATINGS IN MAN
`
`Reduced Bioavailability
`Several early reports exist together with a few more recent instances of
`enteric coated tablets that have met compendial standards, particularly in
`
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`

`88
`
`Enteric Coatings and Delayed Release
`
`[Ch. 7
`
`vitro disintegrationtests, but have failed to provide drug absorption in man.
`A numberof these examples were linked to the previously widespread use
`of Shellac as the coating polymer; now largely discarded owingtoits being
`soluble only in alkaline conditions above pH 7. Levy and Jusko (1967) for
`example, compared aspirin in solution against a leading United States brand
`of enteric coated aspirin tablet which was coated with Shellac. The tablets
`failed to provide therapeutic plasma levels. Wagneretal. (1973) reported
`zero plasmalevels in all eight subjects administered p-aminosalicylic acid
`in enteric coated form. Intact tablets and large fragments were recovered
`from the faeces. The coating had split though not dissolved, showing that
`poor formulation of the tablet core wasat fault as well as the coating.
`Erythromycin is rapidly degraded by gastric acid and is therefore
`administered as a stable esteror, preferably, as the active base contained in
`an enteric coating. Of 16 Japanese brandsof enteric coated erythromycin
`tablets examined in vitro by Watanabe et al. (1977), four showed slow
`dissolution in the pH 7 buffer used and were subsequently evaluated for
`bioavailability in man. Three of the brands exhibited similar absorption
`profiles and were bioequivalent, but the fourth showed negligible absorp-
`tion in all subjects. This tablet was found not to dissolve at pH 6.5 or below,
`whereas the bioequivalent formulations all released the drug at pH 5.5. It
`was concludedthat the high pH of 6.5 to 7.0 required for dissolution of the
`coating delayed release oferythromycin beyondits principle site of absorp-
`tion in the proximal small intestine, and the choice of coating polymer was
`therefore critical to produce efficacy.
`These and certain other instances of reduced bioavailability have
`illustrated the resistance of some coating materials to release sufficiently
`early in the intestinal tract, while some further, mainly older, coating
`polymers may failed to release at all. For drugs where absorption from
`distal regions ofthe intestinal tract is poor, the coating must dissolve rapidly
`in the small intestine. This requirement may conflict with the need for
`gastric resistance but, in the case of erythromycin for example, coatings
`soluble at pH 5.0 to 5.5 have consistently been reported to give satisfactory
`bioavailability without apparent evidence of premature release or signifi-
`cant acid degradation.
`
`Delayed Absorption
`Enteric coated dosage forms will show some delay in absorption in
`comparison with immediate release preparations. If the enteric coating is
`effective, disintegration and drug release will not occur until the dosage
`form has passed through the stomach andthe coating has dissolved in the
`intestine. A potential variable in this sequenceis the gastric emptying time,
`particularly followingthe intake of food. Large particles tendto be retained
`while the stomachis in the digestive phase.
`
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`

`Ch. 7]
`
`Enteric Coatings and Delayed Release
`
`89
`
`Leonards and Levy (1965) compared the absorption of aspirin solu-
`tions with that ofenteric coatedtablets in fasted volunteers. They foundthat
`peak plasma concentrationsfor the solutions occurred consistently at about
`1 hourafter dosing but at about 4 to 6 hours for the tablets, although the two
`forms were bioequivalent. A comparison of uncoated and enteric coated
`aspirin tablets, again in fasted subjects, showed timesto reach peak plasma
`concentrations of 1.5 hours and 2.7 hours respectively, although the
`maximum concentrations and extent of absorption were similar in magni-
`tude (Latini et al., 1986). Gastric emptying in the fasted state is usually
`rapid, occurring within an hour. The delays in absorption of the enteric
`coated forms of about 4 hours and 1.2 hours in these studies is probably
`attributable to the time taken for dissolution of the enteric polymers; the
`dissolution being much slowerin the first study than in the second.
`Following the ingestion of a meal, large indigestible particles, including
`enteric coated tablets, tend to be retained in the stomach fora period of 2 to
`4 hours according to the amountand nature ofthe food. Small particles tend
`to empty along with the meal. Where tablets are retained following a meal
`they will eventually be cleared from the stomach once the interdigestive
`state is reached, by the peristaltic waves of the migrating motor complex.
`Delayed gastric emptying, with a consequent delay in absorption, has
`therefore been found when enteric coated tablets have been administered
`with or soon after a meal, although bioavailability and even peak plasma
`concentrations are not usually affected. Fischer et al. (1985) for example,
`found that the time to reach peak plasmalevels after dosing with enteric
`coated valproic acid tablets was extended from 3.6 hours to 8.1 hours when
`they were administered after breakfast rather than fasted, although peak
`concentrations and area underthe curve values were similar, Many reports
`critical of the variability of enteric coated products when given with food,
`havefailed to recognise the marked effects that food also has on absorption
`from uncoated products. Fischer et al., however,
`included uncoated
`material as a comparisonin their study and found that peak concentrations
`werethen reached at 5.2 hours when fed comparedto 2.3 hours fasted (Table
`3). Thus food was shown to be as importanta factor as the enteric coating
`in determining the onset of drug absorption. Subsequent monitoring of
`seizure frequency in epileptic patients detected differences in the onset of
`clinical response according to the type of formulation and the timingofits
`administration relative to food intake.
`In some instances, where an earlier onset of activity or a greater
`reproducibility is important, there may be benefit in the use of small tablets
`of diameterless than about 5 mm. The argumentfor limiting the tablet size
`follows the work of Meyeret al. (1985). In studiesinitially using dogs,it
`was shown that gastric emptying of spheres up to 5 mm diameter occurred
`evenin the fed state, albeit somewhat more slowly as sphere size increased
`
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`

`90
`
`Enteric Coatings and Delayed Release
`
`[Ch. 7
`
`over the 1-5 mm range. The data have been shown to extrapolate to man,
`and support the use of such mini-tablets in enteric coating applications.
`Only abovethis range is emptying delayed until the fasted state is reached.
`Atablet with a core mass of about 70 mg can be achieved within the 5 mm
`limit, which is a sufficient dose for more potent drug compounds, while
`several such coated tablets can be filled into size 1 or size 2 gelatine capsules
`should a higher dosage be required.
`
`Table 3 - Effect of Meals on the Time to Reach Peak Plasma Concen-
`trations(+ Standard Deviation) from Enteric Coated and Uncoated
`Valproic Acid Tablets (Fischer et ai.,1985)
`
`Tablet
`
`enteric coated
`
`uncoated
`
`Timeafter administration (h)
`Fasted
`Fed
`
`3.6
`(1.3)
`2a
`(0.8)
`
`8.1
`(3.6)
`§.2
`(1.7)
`
`Multiparticulate Systems
`Subdivision of enteric coated dosage formsinto fine multiparticulate
`systems has been extensively investigated as a means of reducing variabil-
`ity in gastric retention betweenthe fasted and fed states. Multiparticulates
`in the form ofgranulesor pellets of particle size about 1 mm orlessare able
`to pass, together with digested food, throughthe pylorus during the
`digestive phase.
`The emptying of such particlesis still slowed by the presence of food,
`although the prolonged retention that can arise withlarge tablets is avoided.
`Davis et al. (1986) showed from a series of studies that the half-times for
`such pellets to empty from the stomach increased from about 1 hourin the
`fasted state to 2 hours after a light breakfast (1500 kJ) and 3-4 hours after
`a heavy breakfast (3600 kJ). Pellets administered with a meal become
`intimately mixedwith the solid content so that they empty from the stomach
`over aperiod of some hours. O’Reilly et al. (1987) investigated whetherthe
`timing of pellet administration relative to food intake would affect transit
`times through the stomach. Thepellets exhibited closely similar gastric
`emptying whether given midway through the meal or ten minutesafter, a
`linear emptying pattern being found with a half-time of 3.5 to 4.0 hours.
`When given 10 minutes before eating, the rate of emptying was faster
`initially but then slowed to give a similar half-time of 3.3 hours. No
`differences in emptying characteristics were found between adminstering
`
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`

`Ch. 7]
`
`Enteric Coatings and Delayed Release
`
`91
`
`the pellets in a gelatin capsule or pre-dispersed in the meal.
`An absorption study comparing erythromycin pellets administered
`either with a light breakfast or an hour before showed in both instancesalag
`time of 1 hour before blood concentrationsof the drug were first detected,
`as against a rapid onset of absorption from an uncoated control (Conduit et
`al., 1987). Where the coated pellets had been dosed before breakfast, arapid
`increase in plasma concentrations occurred, reaching a maximum after a
`further hour. The onset of absorption was thus in accordance with gastric
`emptying of about 1 hourfor pellets dosed fasted, and the subsequentrapid
`rise in plasma concentrations correlates with a bolus release of drug in the
`intestine. In contrast, for the dose administered with food, where a phased
`pattem of emptying would be predicted, absorption was more gradual,
`occurring over a period of 4 to 6 hours from dosing and resulting in much
`lower plasma peak concentrations.
`In a comparison between coated pellet and tablet formulations of
`erythromycin each administered 1 hour before meals, absorption was
`predictably found to be similar, because both forms would have emptied
`rapidly from the fasted stomach (Joseffson et al., 1986). Peak plasma
`concentrations were reached at about 3 hours in both instances. For
`comparison, the drug was also administered in uncoated form,resulting in
`rapid absorption but reduced bioavailability because of the drug being acid
`labile.
`A comparison in fed subjects of aspirin absorption from different
`marketed brands showed on averagean earlier and higher plasma peak from
`enteric coated tablets compared to pellets, attributable to bolus release from
`the tablets once the coating had been dissolvedin the intestine (Edgar etal.,
`1984). The pellets resulted in absorption over a period of several hours to
`resultin alower plasma peak but more uniform concentrationsoverthe day,
`as well as less inter-subject variability. While the different formulations
`were bioequivalent,the flatter and more sustained plasmaprofiles resulting
`from the enteric coated pellets were considered preferable to the tablet
`profiles in the treatment of rheumatic and degenerative joint disease.
`A numberof conclusions is evident from these and similar studies.
`Enteric coated dosage forms show mostrapid absorption and most repro-
`ducible profiles when administered in the fasted state. Both tablet and
`multiparticulate presentations show a delay in absorption if administered
`with or soon after food. Miultiparticulates tend to empty from the fed
`stomachin a linear manner, over a period of about 4 hours depending on
`the size of the meal, whereas gastric emptying of large tablets taken after
`food is more variable. If frequent meals are ingested, gastric emptying of
`a tablet may occasionally be prolonged for more than 10 hours, although the
`median emptying time in a numberofstudies has been about 3 hours. In
`order to minimise variations in plasma concentrations, it may be appropri-
`
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`

`92
`
`Enteric Coatings and Delayed Release
`
`[Ch. 7
`
`ate to adminster enteric coated products an hour before food, particularly in
`the case oftablet formulations,to reduce the possibility ofprolonged gastric
`retention.
`
`RECENT DEVELOPMENTS
`
`Enteric coatings were once reserved primarily for compressed tablets
`but have becomeusedin pellet and granule presentations as well as for hard
`and soft gelatin capsules. The principles of enteric coating may be further
`extended to delay the release of drug compounds until the distal ileum or
`colon is reached, either to achieve a bolus release in the more distal
`segments and a high local concentration, or to avoid the loss of some drugs
`through absorption and degradation if released earlier. Many drug mole-
`cules are absorbed from the colon whilst others may exert a topical action,
`for example in the treatment of inflammatory boweldisease.
`Theeffects of Eudragit L and Eudragit S coatings on the site of drug
`release from gelatin capsules were compared by Myers et al. (1987),
`uncoated capsules being used as a control. The capsules also contained
`barium sulphate to render them radiopaque. Thesite of disintegration and
`extent of drug absorption were then determined by a combination of
`radiography and analysis of blood samples. For these formulations, which
`wererelatively thinly coated, Eudragit L resulted on averagein release in
`the mid-small intestine whereas Eudragit S showed release in the ileo-
`caecal region.
`Gammascintigraphy permits more frequent imaging than is possible
`with x-rays, and has been usedto evaluate the point of disintegration of an
`enteric coated delayed-release tablet preparation in man (Hardy et al.,
`1987b). The tablets contained 5-aminosalicylic acid for the treatment of
`inflammatory bowel disease, and the study was carried out in 13 patients
`with Crohn’s disease or ulcerative colitis.
`Indium-111 was used as the
`radiolabel, being incorporated into the tablet core before the coating was
`applied. The polymerusedin the coating was Eudragit L,so that the tablets
`would only begin to dissolve once they had passed through the stomach. A
`relatively thick polymer coating was applied, designed to delay any drug
`release until the preparation had reached its proposed site of action in the
`terminal ileum and proximal colon. From considerations of the rate of
`intestinal transit, the coating was required to be resistant to the gastric
`environmentbutto release the contents 3 to 4 hours after entering the small
`intestine.
`The tablets were taken after a light breakfast and wereall in the stomach
`at the time of recording the first images immediately after dosing. The
`median timefor gastric emptying was 2.9 hours,and the enteric coating was
`
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`

`Ch. 7]
`
`Enteric Coatings and Delayed Release
`
`93
`
`7.0 hours
`
`11 hours
`
`‘
`
`24 hours
`
`10 24h
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10 4h
`
`6
`
`2
`
`4
`
`6
`
`8
`
`Figure 1 - Gastrointestinal transit of the tablet in a patient with ulcerative colitis showing
`tablet dispersion in the terminal ileum.
`‘Inset graphs show plasma concentrations (1g ml") at the corresponding stages for (0) 5-
`aminosalicylic acid and (0) acetyl-5- aminosalicyle acid.
`
`effective in preventing tablet disintegration and drug release in the stomach.
`Disintegration took place on average 3.2 hours after gastric emptying, and
`occurred in the terminal ileum in mostofthe patients,as illustrated in Figure
`1, Dispersed preparation was observed within the proximal colon in all
`instances except for one patient who had undergonea total colectomy,
`although even in this case disintegration had occurred before the prepara-
`tion was excreted. Transit rates through the colon are much slower than
`through the small intestine, and slowerfor fine dispersed particles than for
`larger, non-disintegrating units. The dispersed preparation was therefore
`observed to be retained in mostpatients throughoutthe full 24 hour course
`of the study, in someinstances even following defaecation at over 20 hours.
`Analysis of blood samples showed a close correlation between tablet
`disintegration as observed by gammascintigraphyandthefirst detection of
`drug in the blood (Figure 2). The study therefore demonstrated the
`reliability of such an enteric coating technique for delivery to the ileum and
`proximal colon.
`i
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1032-0013
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1032-0013
`
`

`

`94
`
`Enteric Coatings and Delayed Release
`
`[Ch. 7
`
`(hours)
`TimeofDrugDetectioninPlasma
`
`
`0
`
`2
`
`gh
`
`6
`
`8
`
`10
`
`Tablet Dispersion Time (hours)
`
`Figure 2 - Relationship between tablet dispersion and 5-aminosalicylic acid absorption
`(r =0.988, P <0.001).
`
`CONCLUSION
`
`The aspects addressed in this chapter indicate that enteric coating has
`become a more reliable and predictable technique than previously, provid-
`ing that due consideration is given to selection ofthe coating polymer. This
`choice has been helped by more accurate assessmentsofgastrointestinal pH
`and by the general move towardscoatingsthat dissolve underslightly more
`acid conditions. Coatings soluble as low as pH 5 to 5.5 have shown no
`apparent evidence of premature release in the stomach in a number of
`studies. The current, widely accepted compendial test criteria are poorly
`predictive of.release in man, however,and greater thought should be given
`to the site of drug absorption and the selection of more relevant test media
`below pH 6.8. Drug release and absorption from enteric coated dosage
`formsis affected by food, as also is absorption from uncoated presentations,
`but it may be appropriate to adminster the coated products an hourbefore
`meals to achieve more consistent gastric emptying. The subdivision of
`dosage forms into multiparticulates and small tablets also avoids the pos-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1032-0014
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1032-0014
`
`

`

`Ch. 7]
`
`Enteric Coatings and Delayed Release
`
`95
`
`sibility of prolonged gastric retention, although an extended pattern of
`gastric emptying and dissolution may not achieve the required therapeutic
`concentrations in some instances.
`
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`
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`erythromycin, Acta Therapeutica, 13, 5-16.
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