lllllllllllllllllllllllllllllllllllllllllllllll||||lIllllllllllllllllllllll
`US005601843A
`
`United States Patent
`
`5,601,843
`[11] Patent Number:
`Gimet et al.
`
`
`[45] Date of Patent: Feb. 11, 1997
`
`[191
`
`[54]
`
`[75]
`
`[731
`
`[21]
`
`[22]
`
`[631
`
`[511
`[52]
`
`[58]
`
`[56]
`
`PHARMACEUTICAL TABLET
`COMPOSITION
`
`Inventors: Rene A. Gimet, Valbonne; Jean C.
`Jinot, Cagnes‘sur-Mer; Christian
`Magnet, Chanceaux sur Choisille;
`Isabelle Maroteaux, Antibes, all of
`France; Francoise M. Nevoux,
`Evanston, 111.; Roger E. Scoyer,
`Jemeppe-sur-Sambre, Belgium;
`Barbara J. Struthers, Deerfield, Ill.
`
`Assignee: G. D. Searle & Co., Chicago, Ill.
`
`Appl. No: 276,299
`
`Filed:
`
`Jul. 18, 1994
`
`Related U.S. Application Data
`
`Continuation of Ser. No. 973,451, Nov. 9, 1992, abandoned,
`which is a continuation of Ser. No. 518,353, May 3, 1990,
`abandoned.
`
`Int. Cl.6 ................................ A61K 9/30; A61K 9/28
`U.S. Cl.
`.......................... 424/475; 424/464; 424/472;
`424/474; 424/476; 514/573
`Field of Search ..........................L .......... 424/464, 472,
`424/474, 475, 476, 490, 498; 514/573
`
`References Cited
`
`OTHER PUBLICATIONS
`
`IMS Market letter May 1987 vol. 14.
`James et al. Arzneimittelforschung Hyperalgesia after treat—
`ment of mice with etc. 28 804—7 Jan. 1978.
`
`Mikami et al. J. Pharm. Pharmacol. The Potentiating effects
`of prostaglandins on etc. 31 856-7 Jan. 1979.
`Walter et a1. Agents and Actions Efl’ects of analgesics on
`bradykin—induced etc. 27 375—7 Jan. 1979.
`Taiwo et al. J. Neurosci. Prostaglandins Inhibit Endogenous
`Pain Control etc. 8 1346—9 Jan. 1988.
`
`Prostaglandin
`et. Brain Research
`Pateromichelakis
`El—induced sensitization of Aa etc. 232 89—96 Jan. 1982.
`
`Sanyal et al. Clin. Exp. Pharmacol. Physiol. Prostaglandins:
`antinociceptive effect of etc. 4 247—55 Jan. 1977.
`Bhattacharya et a1. Clin. Exp. Pharmacol. Physiol. Poten—
`tiation of antinociceptive action of etc. 2 353—357 Jan. 1975.
`Ferri et a1. Psychopharmacologia Decreased antinociceptive
`effect of morphine etc. 39 231—5 Jan. 1974.
`Sanyal et
`a1. Psychopharmacology The antinociceptive
`eifect of etc. 60 159—63 Jan. 1979.
`
`G. D. Searle & Co. Physician’s Desk Reference Cytotec
`(misoprostol) Drug Information 44 2056—7 Jan. 1990.
`IMS IMS Marketletter IMS Marketletter Apr. 1988.
`
`Primary Examiner—Gollamudi S. Kishore
`Attorney, Agent, or Firm—Roger A. Williams
`
`U.S. PATENT DOCUMENTS
`
`[57]
`
`ABSTRACT
`
`4,707,495
`4,816,472
`4,865,847
`
`4,975,283
`
`.. 514/352 4,954,512
`
`11/1987 Rosenthale et al.
`3/1989 Valcavi ............
`9/1989 Gosswein
`..
`9/1990 Oguro et a1.
`12/1990 Patell
`...................................... 424/470
`
`.................... 514/530
`514/428
`424/439
`
`A pharmaceutical composition including a core of an
`NSAID selected from diclofenac and piroxicam which core
`is surrounded by a mantle coating of a prostaglandin,
`wherein an intermediate coating can be present between the
`NSAID core and prostaglandin mantle coating.
`
`FOREIGN PATENT DOCUMENTS
`
`2135881
`
`9/1984 United Kingdom ......... A61K 31/557
`
`10 Claims, 1 Drawing Sheet
`
`26
`
`
`
`24
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 1
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 1
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 1
`
`

`

`US. Patent
`
`Feb. 11, 1997
`
`5,601,843
`
`10
`
`12
`
`16
`
`I4
`
`22
`
`FIG 1
`
`18
`
`20
`
`26
`
`FIGZ
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 2
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 2
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 2
`
`

`

`1
`PHARMACEUTICAL TABLET
`COMPOSITION
`
`5,601,843
`
`2
`
`This application is a continuation of application Ser. No.
`07/973,451 filed Nov. 9, 1992 (now abandoned) which was
`a continuation of application Ser. No. 07/518,353 filed May
`3, 1990 (now abandoned).
`BACKGROUND OF THE INVENTION
`
`The invention herein is directed to a pharmaceutical
`composition which consists of a core/mantle tablet having
`an inner core and an outer mantle coating surrounding the
`inner core. The inner core consists of an NSAID selected
`from diclofenac and piroxicam. The mantle coating consists
`of a prostaglandin such as will be described hereinafter in
`more detail.
`
`Nonsteroidal anti-inflammatory drugs (NSAIDs) com-
`prise a class of drugs which have long been recognized as
`having high therapeutic value especially for the treatment of
`inflammatory conditions such as exhibited in inflammatory
`diseases like osteoarthritis (OA) and rheumatoid arthritis
`(RA). While the NSAIDs present a beneficial therapeutic
`value they also exhibit undesirable side effects. An espe—
`cially undesirable side effect of the administration of
`NSAIDs is the ulcerogenic effects generally associated with
`chronic use. The chronic use of NSAIDs, the use of high
`dosages of NSAIDs and the use of NSAIDs by the elderly
`can lead to NSAID induced ulcers. NSAID induced ulcers in
`
`the stomach can be dangerous. Such ulcers generally exhibit
`few or no symptoms and may cause dangerous bleeding
`when undetected. In some instances, bleeding ulcers can
`prove fatal. The United States Food and Drug Administra-
`tion requires a class warning for all NSAIDs, which states:
`Serious gastrointestinal toxicity such as bleeding, ulceration,
`and perforation can occur at any time, with or without
`warning symptoms,
`in patients treated chronically with
`NSAID therapy.
`Certain prostaglandins have been shown to prevent
`NSAID induced ulcers. Acceptable prostaglandin com-
`pounds for the invention herein and their preparation are
`described in U.S. Pat. Nos. 3,965,143, 4,060,691, 4,271,314
`and 4,683,328. The prostaglandin compound commercially
`available under the USAN (United States Adopted Name)
`name misoprostol is a pharmaceutically acceptable prostag-
`landin which has been accepted for use in the treatment of
`NSAID induced ulcers in many countries,
`including the
`United States. Misoprostol
`is commercially available by
`prescription in such countries.
`While prostaglandins are beneficial compounds and have
`found therapeutic usage, prostaglandins are generally con—
`sidered highly unstable. Therefore, it is desirable to find
`prostaglandins with the desired anti-ulcerogenic properties
`and which can be stabilized or provided in stabilized for-
`mulations especially with respect to contemplated oral meth-
`ods of delivery.
`It would be desirable to provide a pharmaceutical com-
`position which would exhibit the beneficial properties of an
`NSAID and which composition would exhibit the beneficial
`properties of a prostaglandin for countering (by inhibiting,
`reducing or preventing) the ulcerogenic side effects atten-
`dant to NSAID administration.
`
`SUMMARY OF THE INVENTION
`
`The invention herein is directed to a pharmaceutical
`composition comprising a core consisting of an NSAID
`selected from diclofenac and piroxicam and a mantle coating
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`consisting of a prostaglandin surrounding the core. The
`prostaglandin preferably is an orally available prostaglandin.
`Acceptable prostaglandins for use herein include prostag—
`landins having the following structure
`
`
`
`wherein R represents hydrogen or lower alkyl having 1 to 6
`carbon atoms; R1 represents hydrogen, vinyl or lower alkyl
`having 1 to 4 carbon atoms and the wavy line represents R
`or S stereochemistry; R2, R3, and R4 are hydrogen or lower
`alkyl having 1 to 4 carbon atoms or R2 and R3 together with
`carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or
`R3 and R4 together with carbons X and Y form a cycloalk-
`enyl having 4 to 6 carbons and wherein the X-Y bond can
`be saturated or unsaturated.
`
`Another embodiment of the invention herein is a phar-
`maceutical composition wherein a coating is provided which
`is an intermediate coating that surrounds the core but lies
`underneath the mantle coating. Such an intermediate coating
`can be an additional coating for preventing contact between
`the NSAID and the prostaglandin to thereby inhibit any
`deleterious or otherwise non-beneficial interaction of the
`
`NSAID and prostaglandin such as degradation of the pros—
`taglandin. Such an intermediate coating can be an enterie
`coating which aids in reducing the likelihood of the NSAID
`dissolving in the stomach and thereby directly exposing the
`stomach to the NSAID.
`
`A preferred pharmaceutical composition herein has a
`structure wherein the core comprises the NSAID, diclofenac
`in a therapeutic amount such as from 25 to 75 milligrams
`(mg) and a mantle coating surrounding the core comprising
`the prostaglandin misoprostol in a therapeutic amount of
`about 100 to 200 micrograms (meg).
`Another embodiment of the invention herein is a phar-
`maceutical composition including an NSAID core, an under—
`coating on the core surface of hydroxypropyl methylcellu-
`lose (HPMC), an enteric coating, an overcoat on the enteric
`coating of HPMC, and a mantle coating of the prostaglandin.
`The invention herein will be more fully understood with
`regard to the following brief description of the accompany-
`ing drawings and the following detailed description.
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 3
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`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 3
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`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 3
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`

`

`5,601,843
`
`4
`straight side wall (cylindrical) portion although such a tablet
`is not shown in the drawings herein. For ease of discussion
`herein a vertical cross sectional view providing an oval cross
`section will be used to describe the invention herein
`
`although it is understood that other shapes can be used
`without departing from the intended scope of the invention.
`A generally oval cross-section is shown in FIG. 1. The tablet
`10 includes an inner core 12 which is comprised of an
`NSAID that is compatible with the prostaglandin as will be
`described in further detail hereinafter. The inner core 12 can
`
`consist of the NSAID, diclofenac or piroxieam or the
`pharrnaceutically acceptable salts of such NSAIDs. The
`inner core 12 can be formulated by compressing the
`diclofenac or piroxicam in any suitable tableting equipment
`using compression tableting techniques well known in the
`art.
`
`For a tablet wherein the inner core comprises diclofenac
`it has been found that the diclofenac can be present as
`diclofenac sodium. The diclofenac can be present in any
`therapeutically acceptable amount. For normal pharmaceu-
`tically acceptable dosing of diclofenac, diclofenac is admin—
`istered in a therapeutic dosing range using tablets containing
`from 25 mg to 75 mg per tablet. The Physicians’ Desk
`Reference (PDR), 44th Edition, states that the recommended
`dosage for treating osteoarthritis is 100 to 150 mg per day in
`divided doses. For treating rheumatoid arthritis the recom-
`mended dosage is 150 to 200 mg per day in divided doses.
`For ankylosing spondylitis the recommended dosage is 100
`to 125 mg per day in divided doses. The inner core for the
`pharmaceutical composition herein can contain an amount
`from 25 to 75 mg of diclofenac and preferably a dosage of
`50 mg. Various excipients such as binders, bulking agents,
`lubricants, fillers and the like, can be combined with the
`diclofenac in the core as is well known in the pharmaceutical
`art. Excipients used are selected from those which do not
`exhibit a destabilizing effect on either the diclofenac or
`prostaglandin.
`the piroxicam can be
`If the inner core is piroxicam,
`present in a therapeutically acceptable amount. Currently,
`commercially available piroxicam tablets contain either 10
`mg or 20 mg of piroxicam. The PDR, 44th Edition, recom—
`mends that piroxicam be administered in a single daily dose
`of 20 mg for rheumatoid arthritis and osteoarthritis. For the
`pharmaceutical composition herein the inner core can con—
`tain from 10 to 20 mg of piroxicam. Various excipients can
`be used in constructing a piroxicam core which excipients
`do not exhibit a destabilizing effect on either the piroxicam
`or the prostaglandin.
`A mantle coating 14 surrounds the inner NSAID core and
`encapsulates the NSAID. The mantle coating includes a
`prostaglandin and more preferably an orally available pros-
`taglandin.
`The terms “prostaglandin” and/or its accepted acronym
`“PG” or, as more appropriately for the E-series prostaglan-
`dins, “PGE,” are used herein to refer to naturally occurring
`or man—made E—series prostaglandins and their analogs and
`derivatives.
`
`It has been found herein that acceptable prostaglandins
`include E1 prostaglandins represented by the following
`Formula I:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`6O
`
`65
`
`3
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a schematic representation of a tableted phar—
`maceutical composition herein illustrating the core/mantle
`structure;
`
`FIG. 2 is a schematic representation of another embodi-
`ment of a tableted pharmaceutical composition herein; and
`FIG. 3 is a schematic representation of still another
`embodiment of a tableted pharmaceutical composition
`herein.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The invention herein is directed to a pharmaceutical
`composition which is a core/mantle tablet consisting of a
`core of a nonsteroidal anti—inflammatory drug (NSAID)
`selected from diclofenac and piroxicam. Surrounding the
`core is a mantle coating which consists of a prostaglandin of
`the structure
`
`“‘\‘\/\/\/COOR
`R1
`R2
`
`/
`
`OH
`
`x Y
`
`R4
`
`R
`
`3
`
`‘\
`
`__WCOOR
`R1
`R2
`
`/
`
`0H
`
`x Y
`
`R4
`
`R
`
`3
`
`‘\
`
`.—WCOOR
`R1
`R2
`
`/
`
`OH /
`
`x Y
`
`R4
`
`R
`
`3
`
`0 I
`
`0 I
`
`0 I
`
`5
`no
`
`5
`HO
`
`5
`HO
`
`wherein R represents hydrogen or lower alkyl having 1 to 6
`carbon atoms; R1 represents hydrogen, vinyl or lower alkyl
`having 1 to 4 carbon atoms and the wavy line represents R
`or S stereochemistry; R2, R3, and R4 are hydrogen or lower
`alkyl having 1 to 4 carbon atoms or R2 and R3 together with
`carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or
`R3 and R4 together with carbons X and Y form a cycloalk-
`enyl having 4 to 6 carbons and wherein the X—Y bond can
`be saturated or unsaturated.
`
`The pharmaceutical composition herein can be described
`with regard to the accompanying drawings wherein FIGS. 1,
`2 and 3 represent separate embodiments of the tableted
`composition herein.
`The pharmaceutical composition will first be described
`with regard to the embodiment shown in FIG. 1. FIG. 1
`represents a schematic illustration of a pharmaceutical com-
`position herein. The pharmaceutical composition consists of
`a core/mantle tablet 10 which can have any geometric shape.
`For example, a bi—convex tablet (general pill shape) can be
`used which has a generally oval cross section taken along a
`vertical cross section and a circular cross section taken along
`a horizontal cross section. A bi—convex tablet can include a
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 4
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`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 4
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`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 4
`
`

`

`
`
`5,601,843
`
`6
`
`oxo-lR,1ot-cyclopentyl]-4Z—heptenoate represented by the
`following Formula:
`
`“0‘
`
`0\
`
`:
`OH
`
`0\
`
`CH3
`
`0
`
`CH3
`
`OH /
`
`E2 prostaglandins represented by the following Formula II:
`0
`
`10
`
`NW COOR
`Rx
`R2
`
`15
`
`5
`HO
`
`/
`
`OH
`
`x Y
`
`R4
`
`R
`
`3
`
`and E3 prostaglandins represented by the following Formula 20
`III:
`
`25
`
`30
`
`wherein R represents hydrogen or lower alkyl having 1 to 6
`carbon atoms, R1 represents hydrogen, vinyl or lower alkyl
`having 1 to 4 carbon atoms and the wavy line represents R
`or S stereochemistry; R2, R3, and R4 are hydrogen or lower
`alkyl having 1 to 4 carbon atoms or R2 and R3 together with 35
`carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or
`R3 or R4 together with carbons X and Y form a cycloalkenyl
`having 4 to 6 carbon and wherein the X-Y bond can be
`saturated or unsaturated.
`
`By lower alkyl is meant straight or branched chain alkyl 40
`such as methyl, ethyl, propyl, isopropyl, butyl, secondary
`butyl or tertiary butyl, pentyl, or hexyl with the indicated
`limitation of the number of carbon atoms. The bond between
`carbon X and carbon Y can be saturated or unsaturated.
`It has been found herein that acceptable prostaglandins
`include misoprostol represented by the following Formula: 45
`O
`O
`\ W CH3
`
`“0
`0/
`
`CH3
`
` OH
`01-1
`
`cn3
`
`50
`
`the prostaglandin enisoprost, (i)methyl 110t,l6—dihydroxy- 55
`16-mcthyl-9-0xoprosto-4Z,13E-diene-1-oate,
`represented
`by the following Formula:
`
`60
`
`65
`
`and the prostaglandin methyl 7-[ZB~[6-(1-cyclopenten-1-
`yl)-4-hydroxy-4—methyl-1E,5E-hexadienyl]-30t-hydroxy—5-
`
`With regard to the illustrated structures, the dashed line
`indicates the grouping being behind the plane of the paper
`and the solid, blackened triangular shape indicates that the
`group is in front of the plane of the paper.
`The prostaglandins useful
`in the composition of the
`invention herein can be prepared by known reaction
`schemes such as by the methods taught in U.S. Pat. Nos.
`3,965,143; 4,271,314; and 4,683,328. The individual iso—
`mers can be obtained by chromatographic separation.
`When the prostaglandin is misoprostol, (i)methyl Her,
`1 6-dihydroxy—l6-methyl-9-oxoprost—13E~en~1-oate,
`the
`misoprostol is present in an amount from about 50 to about
`500 mcg and preferably from about 100 to about 200 mcg.
`A second embodiment of the composition is shown in
`FIG. 2. In FIG. 2 a tablet 16 is schematically illustrated in
`cross section. The tablet 16 includes an inner core 18 of an
`NSAID diclofenac, piroxicam or their salts such as disclosed
`with regard to the core 12 of FIG. 1. Surrounding the core
`18 is an enteric coating 20. The enteric coating 20 can be
`formulated from any suitable enteric coating material, many
`of which are known to those skilled in the art and many of
`which are employed for coating commercially available
`NSAID’s. The coating 20 aids in segregating the NSAID
`from the prostaglandin and in directing the dissolution of the
`NSAID core in the lower GI.
`tract as opposed to the
`stomach. The coating 20 can aid in the prevention of
`degradation of the prostaglandin by the presence of the
`NSAID. The enteric coating can be coated onto the inner
`core using standard coating techniques. For example, aque—
`ous or solvent coating techniques can be used to apply the
`enteric coating to the inner core. Surrounding the coated
`inner core is a mantle 22 consisting of a prostaglandin as
`described with regard to mantle 14 in the composition
`embodiment represented in FIG. 1.
`A third embodiment of the composition is shown in FIG.
`3. In FIG. 3 a tablet 24 is illustrated in cross section. The
`tablet 24 consists of an inner core 26 comprising an NSAID
`or its salt as disclosed with regard to the core 12 of FIG. 1.
`Surrounding the core 26 is an undercoat 28 which can
`provide a surface for the enteric coat which undercoat can
`have a greater affinity for the enteric coat than the core alone.
`The coating 28 can be any suitable coating material and
`preferably is HPMC in an amount about two percent (2%) by
`weight of the core.
`An aqueous enteric coating 30 can be used to segregate
`the NSAID from the prostaglandin and to aid in controlling
`release of the NSAID. The undercoat 28 prevents water
`which can be present in the aqueous enteric coat 30 from
`penetrating into the NSAID core to cause any undesirable
`effects on the NSAID which might be caused by water. The
`enteric coating 30 can aid in the prevention of degradation
`of the prostaglandin by the presence of the NSAID as well
`as direct delivery of the NSAID in the lower GI. tract rather
`than the stomach. Any aqueous enteric coating can be used
`and the enteric coating can be coated onto the inner core
`using standard coating techniques as described with regard
`to the embodiment shown in FIG. 2.
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 5
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`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 5
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`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 5
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`

`

`7
`An overcoat 32 is coated over the enteric coat 30. The
`
`5,601,843
`
`overcoat 32 can provide an intermediate coating providing
`aflinity between the enteric coat and mantle. The overcoat
`can be any suitable material, preferably the overcoat is
`HPMC in an amount about three percent (3%) by weight of
`the core. The overcoat 32 prevents water which can be
`present in the aqueous enteric coating from passing into the
`prostaglandin mantle. Further, the overcoat can aid in main-
`taining the integrity of the enteric coating during the com-
`pression coating step as the mantle is formed on the tablet.
`A mantle 34 consisting of a prostaglandin as described
`with regard to mantle 14 in the composition embodiment
`shown in FIG. 1 is coated, such as by compression coating,
`over the overcoat 32.
`It has been found herein that an especially preferred 15
`composition is the use of misoprostol as the prostaglandin in
`the mantle and the use of diclofenac in the inner core.
`The invention will be further described with regard to the
`following examples.
`
`5
`
`10
`
`20
`
`EXAMPLE 1
`
`A pharmaceutical tablet composition was prepared con-
`sisting of a diclofenac sodium central core and a misoprostol
`mantle. The tablet had the following composition.
`
`Unit Formula (mg)
`
` Core
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystallinc cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`purified water
`Mantle
`
`nfisoprostol:l—IPMC dispersion (1:100)
`misoprostol
`hydroxypropyl methylcellulose (HPMC)
`crospovidone
`colloidal silicon dioxide
`hydrogenated castor oil
`micrycrystalline cellulose
`
`50.0
`13.0
`12,9
`8.4
`4.8
`0.9
`
`0.2
`20.0
`10.0
`05
`1.0
`233.3
`
`EXAMPLE 2
`
`A pharmaceutical tablet composition was prepared con-
`sisting of a diclofenac sodium central core, an enteric
`coating and a misoprostol mantle. The tablet had the fol-
`lowing composition.
`
`Unit Formula (mg)
`
` Core
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K~30
`magnesium stearate
`purified water
`Core coating
`
`cellulose acetate phthalate
`diethyl phthalate
`Mantle
`misoprostol:HPMC dispersion (1:100)
`
`50.0
`13.0
`1219
`8.4
`4.8
`0.9
`
`5.4
`1.5
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`-continued
`
`Unit Formula (mg)
`
`misoprostol
`hydroxypropyl methylccllulose
`crospovidone
`collodial silicon dioxide
`hydrogenated castor oil
`microcrystalline cellulose
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`EXAMPLE 3
`
`A pharmaceutical tablet composition was prepared con-
`sisting of a diclofenac sodium central core, an aqueous
`enteric coating, an overcoat and a misoprostol mantle. The
`tablet had the following composition.
`
`Unit Formula (mg)
`
` Core
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K—30
`magnesium stearate
`Enteric coating (aqueous)
`
`methacrylic acid
`copolymer type C
`sodium hydroxide
`talcum
`triethyl citrate
`Overcoating
`
`HPMC
`polyethylene glycol (PEG 400)
`Mantle
`
`rnisoprostolzflPMC dispersion (1:100)
`misoprostol
`hydroxypropyl methylcellulose
`crospovidone
`colloidal silicon dioxide
`hydrogentated Castor oil
`micrycrystalline cellulose
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`3.68
`0.049
`1.84
`0.37
`
`2.72
`0.054
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`EXAMPLE 4
`
`A pharmaceutical tablet composition was prepared con-
`sisting of a diclofenac sodium central core, an undercoat, an
`enteric coating, and a misoprostol mantle. The tablet had the
`following composition.
`
`Unit Formula (mg)
`
`Core
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Undercoat
`
`HPMC
`PEG 400
`Enteric coating (aqueous)
`
`methacrylic acid
`copolymer type C
`sodium hydroxide
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`1.84
`0.037
`
`3.68
`0.049
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 6
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 6
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 6
`
`

`

`9
`-continued
`
`10
`-continued
`
`5,601,843
`
`Unit Formula (mg)
`talcum
`1.84
`tn'ethyl citrate
`0.37
`Mantle
`
`misoprostolzl-IPMC dispersion (1:100)
`0.2
`misoprostol
`20.0
`hydroxypropyl methylccllulose
`10.0
`crospovidone
`0.5
`colloidal silicon dioxide
`1.0
`hydrogenated castor oil
`
`microcrystalline cellulose 233.3
`
`EXAMPLE 5
`
`A pharmaceutical tablet composition was prepared con—
`sisting of a diclofenac sodium central core, an undercoat, an
`enteric coating, an overcoat and a misoprostol mantle. The
`tablet had the following composition.
`
`
`Unit Formula (mg)
` Core
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Undereoat
`
`HPMC
`PEG 400
`Enterie coating (aqueous)
`
`methacrylic acid
`copolymer type C
`sodium hydroxide
`talcum
`tricthyl citrate
`Overcoating
`
`HPMC
`PEG 400
`Mantle
`
`500
`13.0
`12.9
`8.4
`4.8
`0.9
`
`1.84
`0.037
`
`3.68
`0.049
`1.84
`0.37
`
`2.72
`0.054
`
`misoprostolePMC dispersion (1:100)
`0.2
`misoprostol
`20.0
`hydroxypropyl methylcellulose
`10.0
`crospovidone
`0.5
`colloidal silicon dioxide
`1.0
`hydrogenated castor oil
`
`microcrystalline cellulose 233.3
`
`EXAMPLE 6
`
`A pharmaceutical tablet composition was prepared con-
`sisting of a diclofenac sodium central core, an enteric
`coating, an overcoat and a misoprostol mantle. The tablet
`had the following composition.
`
`
`Unit Formula (mg)
`
`Enteric coating (aqueous)
`
`methacrylic acid
`copolymer type C
`talcum
`triethyl citrate
`Overcoating
`
`HMPC
`PEG 400
`Mantle
`
`3.68
`1.84
`0.37
`
`2.72
`0.054
`
`misoprostolzl-IPMC dispersion (1:100)
`0.2
`misoprostol
`20.0
`hydroxypropyl methylcellulose
`10.0
`crospovidone
`0.5
`colloidal silicon dioxide
`1.0
`hydrogenated castor oil
`
`microcrystalline cellulose 233.3
`
`EXAMPLE 7
`
`A pharmaceutical tablet composition was prepared con-
`sisting of a diclofenac sodium central core, an enteric
`coating, an overcoat and a misoprostol mantle. The tablet
`had the following composition.
`
`
`10
`
`15
`
`20
`
`25
`
`Unit Formula (mg)
` Core
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Enteric coating (aqueous)
`
`Aquateric
`polysorbate 80
`diethy1 phthalatc (DEF)
`Overcoating
`
`HMPC
`PEG 400
`Mantle
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`6.53
`0.13
`1.96
`
`2.72
`0.054
`
`misoprostolzl-IPMC dispersion (1:100)
`0.2
`misoprostol
`20.0
`hydroxypropyl methylcellulose
`10.0
`crospovidone
`0.5
`colloidal silicon dioxide
`1.0
`hydrogenated castor oil
`
`microcrystalline cellulose 233.3
`
`EXAMPLE 8
`
`A pharmaceutical tablet composition was prepared con-
`sisting of a diclofenac sodium central core, an undercoat, an
`enteric coating, and a misoprostol mantle. The tablet had the
`following composition.
`
`
`Unit Formula (mg)
` Core
`
`Unit Formula (mg)
` Core
`
`60
`
`diclofenac sodium
`lactose (monohydratc)
`microcrystallinc cellulose
`cornstarch
`povidone K-30
`magnesium stcarate
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`65
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`
`50.0
`13.0
`12.9
`8.4
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 7
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 7
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`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 7
`
`

`

`11
`—c0ntinued
`
`Unit Formula (mg)
`
`povidone K-30
`magnesium stearate
`Undercoat
`
`HPMC
`PEG 400
`Enteric coating (aqueous)
`
`Aquateric
`polysorbatc 80
`diethyl phthalate (DEP)
`Mantle
`
`misoprostolePMC dispersion (1:100)
`misoprostol
`hydroxypropyl methylcellulose
`crospovidonc
`colloidal silicon dioxide
`hydrogenated castor oil
`microcrystalline cellulose
`
`4.8
`0.9
`
`1.84
`0.037
`
`6.56
`0.13
`1.97
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`EXAMPLE 9
`
`A pharmaceutical tablet composition was prepared con-
`sisting of a diclofenac sodium central core, an undercoat, an
`enteric coating, an overcoat and a misoprostol mantle. The
`tablet had the following composition.
`
`
`Unit Formula (rng)
`
` Core
`
`diclofenac sodium
`lactose (monohydratc)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Undercoat
`
`HPMC
`PEG 400
`Enteric coating (aqueous)
`
`Aquateric
`polysorbale 80
`diethyl phthalate (DEP)
`Ovcreoating
`
`HMPC
`PEG 400
`Mantle
`
`misoprostolzl—IPMC dispersion (1:100)
`misoprostol
`hydroxypropyl methylccllulose
`crospovidone
`colloidal silicon dioxide
`hydrogenated castor oil
`microcrystalline cellulose
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`1.84
`0.037
`
`6.56
`0.13
`1.97
`
`2.70
`0.054
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`The composition that is the invention herein provides an
`ease of delivery of an NSAID for its therapeutic value such
`as the alleviation of inflammation in a system which limits
`the undesirable side alIects of ulcerogenesis associated with
`such NSAID therapy. That is, the composition herein con—
`sisting of essentially a core/mantle tablet provides a pros-
`taglandin along with the NSAID whereby the prostaglandin
`
`5,601,843
`
`12
`
`can be administered for its beneficial therapeutic value in
`preventing and or
`inhibiting the incidence of NSAID
`induced ulcers.
`
`A particularly beneficial aspect of the invention herein is
`that the combination of the two components in a core/mantle
`tablet assures compliance with the therapeutic regimen of
`the two active components. That is, a co—administration of
`the active components (NSAID and prostaglandin) sepa—
`rately can be diflicult to achieve and can be difficult for a
`patient
`to faithfully follow. By placing the two active
`components in the same tablet or composition, adherence to
`the therapeutic regimen is controlled as the administration of
`the tablet containing the NSAID assures compliance of the
`administration of the prostaglandin also present in the tablet.
`The composition herein is especially utile as the compo-
`sition herein exhibits a stability for the prostaglandin and the
`NSAID.
`We claim:
`
`1. A pharmaceutical tablet composition comprising:
`a. a core consisting of a therapeutically-effective amount
`of a nonsteroidal anti-inflammatory agent selected from
`diclofenac and piroxicam; and
`b. a mantle coating surrounding the core comprising a
`therapeutically—eflective amount of misoprostol.
`2. A pharmaceutical composition as recited in claim 1
`wherein the NSAID comprises diclofenac.
`3. A pharmaceutical composition as recited in claim 1
`wherein the NSAID comprises piroxicam.
`4. A pharmaceutical composition as recited in claim 1
`further comprising an intermediate enteric coating surround-
`ing the core.
`5. A pharmaceutical composition as recited in claim 1
`wherein the NSAID comprises diclofenac from about 25 to
`75 mg and the mantle coating comprises a prostaglandin
`formulation containing an amount of about 200 mcg of
`misoprostol.
`6. A method of treating inflammation comprising orally
`administering to a patient in need of such treatment, a
`therapeutically eflective amount to treat inflammation of a
`composition comprising
`a. a core consisting of a therapeutically-eflecfive amount
`of a nonsteroidal anti-inflammatory agent selected from
`diclofenac and piroxicam; and
`b. a mantle coating surrounding the core comprising a
`therapeutically-effective amount of misoprostol.
`7. A method as recited in claim 6 wherein the nonsteroidal
`anti-inflammatory agent comprises diclofenac.
`8. A method as recited in claim 6 wherein the nonsteroidal
`anti-inflammatory agent comprises piroxicam.
`9. A method as recited in claim 6 wherein the NSAID
`comprises diclofenac from about 25 to 75 mg and the mantle
`coating comprises a prostaglandin formulation containing an
`amount of about 200 mcg of misoprostol.
`10. A pharmaceutical tablet composition comprising:
`a. a core comprising from about 25 to 75 mg of diclofenac
`sodium;
`b. an enteric coating surrounding the core; and
`c. a mantle coating surrounding the enteric coating, the
`mantle coating comprising from about 100 to about 200
`pg misoprostol.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 8
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 8
`
`MYLAN PHARMS. INC. EXHIBIT 1071 PAGE 8
`
`