United States Patent [19]
`Gimet et al.
`
`11111111111111 m 1111111111111111111111111111111111111�11111111111111
`
`
`
`
`
`
`
`US005698225A
`5,698,225
`
`[11] Patent Number:
`
`[45] Date of Patent:
`*Dec. 16, 1997
`
`[54] PHARMACEUTICAL COMPOSITION
`
`
`
`References Cited
`
`[51] Int. Cl.6 ................................ MilK 9/30; A61K 9/28
`[52] U.S. Cl ...........................
`424/475; 424/464; 424/472;
`[75] Inventors: Rene Antoine Gimet, Valbonne; Jean
`
`424/474; 424/476; 514/573
`Charles Jinot, Cagnes-sur Mer;
`[58] Field of Search ..................................... 424/475, 464,
`Christian Magnet, Chanceaux sur
`424/472, 474, 676; 514/573
`
`Choislle; Isabelle Maroteaux, Antibes,
`
`all of France; Francoise M. Nevoux,
`[56]
`lll.; Roger E. Scoyer,
`Evanston,
`
`Jemeppe-sur Sambre, Belgium;
`Deerfield, lli.
`Barbara J, Struthers,
`[73] Assignee: G. D. Searle & Co., Chicago, ill.
`
`[ * ] Notice: The term of this patent shall not extend
`
`beyond the expiration date of Pat. No.
`5,601,843.
`
`U.S. PATENI' DOCUMENTS
`
`
`4,707,495 11/1987 Rosenthale et al ..................... 514/530
`
`
`4,816,472 3/1989 Valcavi .................................... 514/428
`
`4,865,847 9/1989 Gosswein ................................ 424/439
`4,954,512
`9/1990 Oguro et al ............................. 514/352
`
`4,975,283 12/1990 Patell ...................................... 424/470
`
`5,601,843 2/1997
`Gimet.
`Primary Exami ner-G ollamudi S. Kishore
`Attorney, Agent, or Firm- Roger A. Williams
`ABSTRACT
`[57]
`
`[21] Appl. No.: 794,027
`
`[22] Filed: Feb. 3, 1997
`
`
`
`
`
`Related U.S. Application Data
`
`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
`
`of Ser. No. 276,299, Jul. 18, 1994,
`[63] Continuation
`Pat. No.
`5,601,843,
`ofSer. No. 973,451,
`
`NSAID core and prostaglandin mantle coating.
`which is a continuation
`Nov.
`9, 1992, abandoned, which is a continuation of Ser. No.
`
`518,353, May 3, 1990, abandoned.
`
`4 Claims, 1 Drawing Sheet
`
`34
`
`32
`
`24
`
`

`
`U.S. Patent
`
`Dec. 16, 1997
`
`5,698,225
`
`FIGl
`
`16
`
`32
`
`24
`
`

`
`5,698,225
`
`1
`PHARMACEUTICAL COMPOSITION
`
`2
`selected from diclofenac and piroxicam and a mantle coating
`
`
`
`
`consisting of a prostaglandin surrounding the core. The
`
`prostaglandin preferably is an orally available prostaglandin.
`This is a continuation application of application Ser. No.
`
`
`Acceptable prostaglandins for use herein include prostag-
`0 8/276,299, filed on Jul. 1 8, 1994, now U.S. Pat No.
`5 landins having the following structure
`5,601,843 which was a continuation of Ser. No. 07/973,451
`
`filed Nov. 9, 1992 (now abandoned) which was a continu­
`0
`COOR
`ation of Ser. No. 07/518,353 filed on May 3, 1990 (now
`,,,••�
`abandoned).
`
`BACKGROUND OF THE INVENITON
`
`10
`The invention herein is directed to a pharmaceutical
`
`of a core/mantle tablet having
`composition which consists
`an inner core and an outer mantle coating surrounding the
`
`
`inner core. The inner core consists of an NSAID selected
`The mantle coating consists 15
`
`from diclofenac and piroxicam.
`
`
`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
`for the treatment of 20 having high therapeutic value especially
`
`
`inflamma tory 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
`of 25 cially undesirable side effect of the administration
`
`
`
`
`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 30
`wherein R represents hydrogen or lower alkyl having 1 to 6
`
`few or no symptoms and may cause dangerous bleeding
`
`carbon atoms; R1 represents hydrogen, vinyl or lower alkyl
`In some instances, bleeding ulcers can
`when undetected.
`having 1 to 4 carbon atoms and. the wavy line represents R
`
`prove fatal. The United States Food and Drug Administra­
`
`
`or S stereochemistry; R2, R3, and R4 are hydrogen or lower
`alkyl having 1 to 4 carbon atoms or R2 and R3 together with
`
`tion requires a class warning for all NSAIDs, which states:
`35
`carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or
`
`
`
`Serious gastrointestinal toxicity such as bleeding, ulceration,
`
`R3 and R4 together with carbons X and Y form a cycloalk­
`and perforation can occur at any time, with or without
`enyl having 4 to 6 carbons and wherein the X-Y bond can
`
`warning symptoms, in patients treated chronically with
`be saturated or unsaturated.
`NSAID therapy.
`
`Another embodiment of the invention herein is a phar-
`40 maceutical composition wherein a coating is provided which
`Certain prostaglandins have been shown to prevent
`
`
`
`NSAID induced ulcers. Acceptable prostaglandin com­
`
`
`is an intermediate coating that surrounds the core but lies
`underneath the mantle coating. Such an intermediate coating
`pounds for the invention herein and their preparation are
`
`can be an additional coating for preventing contact between
`described in U.S. Pat Nos. 3,965,143, 4,060,691, 4,271,314
`
`the NSAID and the prostaglandin to thereby inhibit any
`
`and 4,683,328. The prostaglandin compound commercially
`
`
`deleterious or otherwise non-beneficial interaction of the
`available under the USAN (United States Adopted Name)
`45 NSAID and prostaglandin
`such as degradation of the pros­
`
`
`
`name misoprostol is a pharmaceutically acceptable prostag­
`
`
`taglandin. Such an intermediate coating can be an enteric
`landin which has been accepted for use in the treatment of
`coating which aids in reducing the likelihood of the NSAID
`
`NSAID induced ulcers in many countries, including the
`
`
`dissolving in the stomach and thereby directly exposing the
`
`
`United States. Misoprostol is commercially available by
`stomach to the NSAID.
`prescription in such countries.
`50
`A preferred pharmaceutical composition herein has a
`
`While prostaglandins are beneficial compounds and have
`structure wherein the core comprises the NSAID, diclofenac
`
`
`found therapeutic usage, prostaglandins are generally con­
`amount such as from 25 to 75 milligrams
`in a therapeutic
`(mg) and a mantle coating surrounding the core comprising
`
`
`
`sidered highly unstable. Therefore, it is desirable to find
`
`
`prostaglandins with the desired anti-ulcerogenic properties
`
`the prostaglandin misoprostol in a therapeutic amount of
`
`and which can be stabilized or provided in stabilized for­
`55 about 100 to 200 micrograms (meg).
`
`
`mulations especially with respect to contemplated oral meth­
`Another embodiment of the invention herein is a phar­
`ods of delivery.
`
`maceutical composition including an NSAID core, an under­
`It would be desirable
`coating on the core surface of hydroxypropyl methylcellu­
`to provide a pharmaceutical com­
`lose (HPMC), an enteric coating, an overcoat on the enteric
`
`position which would exhibit the beneficial properties of an
`60 coating of HPMC, and a mantle coating of the prostaglandin.
`NSAID and which composition would exhibit the beneficial
`The invention herein will be more fully understood
`with
`properties of a prostaglandin for countering (by inhibiting,
`
`regard to the following brief description of the accompany­
`
`reducing or preventing) the ulcerogenic side effects atten­
`
`ing drawings and the following detailed description.
`dant to NSAID administration.
`BRIEF DESCRIPTION OF THE DRAWINGS
`65
`
`FIG. 1 is a schematic representation of a tableted phar­
`The invention herein is directed to a pharmaceutical
`
`maceutical composition herein illustrating the core/mantle
`composition comprising a core consisting of an NSAID
`structure;
`
`0
`
`••'''�c
`
`OOR
`
`0
`
`,,-.""�C
`
`OOR
`
`SUMMARY OF THE INVENITON
`
`

`
`5,698,225
`
`OF THE
`
`••'''�COOR
`
`4
`3
`
`A generally oval cross-section is shown in FIG. 1. The tablet
`FIG. 2 is a schematic representation of another embodi­
`
`
`
`ment of a tableted pharmaceutical composition herein; and
`10 includes an inner core U which is comprised of an
`
`FIG. 3 is a schematic representation of still another
`
`NSAID that is compatible with the prostaglandin as will be
`embodiment of a tableted pharmaceutical composition
`
`described in further detail hereinafter. The inner core 12 can
`herein.
`
`5 consist of the NSAID, diclofenac or piroxicam or the
`
`pharmaceutically acceptable salts of such NSAIDs. The
`DETAilED
`DESCRIPTION
`
`
`inner core 12 can be formulated by compressing the
`lNVENTION
`
`diclofenac or piroxicam in any suitable tableting equipment
`
`The invention herein is directed to a pharmaceutical
`using compression tableting techniques well known in the
`
`composition which is a core/mantle tablet consisting of a
`10 art.
`
`
`core of a nonsteroidal anti-inflammatory drug (NSAID)
`For a tablet wherein the inner core comprises diclofenac
`
`
`selected from diclofenac and piroxicam. Surrounding the
`
`it has been found that the diclofenac can be present as
`
`
`core is a mantle coating which consists of a prostaglandin of
`the structure
`
`diclofenac sodium. The diclofenac can be present in any
`
`15 therapeutically acceptable amount. For normal pharmaceu­
`
`
`
`
`tically acceptable dosing of diclofenac, diclofenac is admin­
`
`
`istered in a therapeutic dosing range using tablets containing
`
`
`Desk from 25 rng to 75 mg per tablet. The Physicians'
`Reference (PDR), 44th Edition, states that the recommended
`20 dosage for treating osteoarthritis is 100 to 150 mg per day in
`
`the recom­divided doses. For treating rheumatoid arthritis
`
`
`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
`25 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
`30
`
`art. Excipients used are selected from those which do not
`
`
`exhibit a-destabilizing effect on either the diclofenac or
`prostaglandin.
`If the inner core is piroxicam, the piroxicam can be
`
`
`35 present in a therapeutically acceptable amount. Currently,
`
`commercially available piroxicam tablets contain either 10
`mg or 20 rng of piroxicam. The PDR, 44th Edition, recom­
`
`
`mends that piroxicam be administered in a single daily dose
`of 20 rng for rheumatoid arthritis and osteoarthritis. For the
`
`wherein R represents hydrogen or lower alkyl having 1 to 6
`
`
`40 pharmaceutical composition herein the inner core can con­
`
`carbon atoms; R1 represents hydrogen, vinyl or lower alkyl
`
`tain from 10 to 20 rng of piroxicam. Various excipients can
`having 1 to 4 carbon atoms and the wavy line represents R
`be used in constructing a piroxicam core which excipients
`
`or S stereochemistry; R2, �. and� are hydrogen or lower
`
`do not exhibit a destabilizing effect on either the piroxicam
`
`
`with alkyl having 1 to 4 carbon atoms or R2 and R3 together
`or the prostaglandin.
`carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or
`45
`A mantle coating 14 surrounds the inner NSAID core and
`
`R3 and R4 together with carbons X and Y form a cycloalk­
`
`encapsulates the NSAID. The mantle coating includes a
`enyl having 4 to 6 carbons and wherein the X-Y bond can
`
`
`prostaglandin and more preferably an orally available pros­
`be saturated or unsaturated.
`taglandin.
`
`The pharmaceutical composition herein can be described
`The terms "prostaglandin" and/or its accepted acronym
`
`
`with regard to the accompanying drawings wherein FIGS. 1, 50
`"PG" or, as more appropriately for the E-series
`
`2 and 3 represent separate embodiments of the tableted
`
`prostaglandins, "PGE," are used herein to refer to naturally
`composition herein.
`
`occurring or man-made E-series prostaglandins and their
`The pharmaceutical composition will first be described
`analogs and derivatives.
`with regard to the embodiment shown in FIG. 1. FIG. 1
`
`represents a schematic illustration of a pharmaceutical com-55
`
`It has been found herein that acceptable prostaglandins
`
`
`
`include E1 prostaglandins represented by the following
`
`
`position herein. The pharmaceutical composition consists of
`
`a core/mantle tablet 10 which can have any geometric shape.
`Formula I:
`
`
`For example, a bi-convex tablet (general pill shape) can be
`0
`used which has a generally oval cross section taken along a
`vertical cross section and a circular cross section taken along 60
`
`a horizontal cross section. A hi-convex tablet can include a
`
`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 65
`although it is understood that other shapes can be used
`without departing from the intended scope of the invention.
`
`0
`
`,,,••�
`
`COOR
`
`0
`
`0
`
`, •• ··�
`
`cooR
`
`,,,••�
`
`COOR
`
`

`
`5
`
`
`� prostaglandins represented by the following
`Formula II:
`
`6
`
`5,698,225
`
`0
`
`,,,•'�cOOR
`
`5
`
`10
`
`and E3 prostaglandins
`
`ill:
`
`
`
`0
`
`,,,•'�cOOR
`
`With regard to the illustrated structures, the dashed line
`
`represented by the following Formula
`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.
`
`15 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.
`
`
`20 When the prostaglandin is misoprostol, (±)methyl lla,
`
`16-dihydroxy-16-methyl-9-oxoprost-BE-en-1-oate, the
`
`misoprostol is present in an amount from about 50 to about
`500 meg and preferably from about 100 to about 200 meg.
`wherein R represents hydrogen or lower alkyl having 1 to 6
`
`A second embodiment of the composition is shown in
`25 FIG. 2. In FIG. 2 a tablet 16 is schematically illustrated
`carbon atoms, R1 represents hydrogen, vinyl or lower alkyl
`in
`
`cross section. The tablet 16 includes an inner core 18 of an
`having 1 to 4 carbon atoms and the wavy line represents R
`
`
`NSAID diclofenac, piroxicam or their salts such as disclosed
`or S stereochemistry; R2, R3, and R4 are hydrogen or lower
`with regard to the core 12 of FIG. 1. Surrounding the core
`alkyl having 1 to 4 carbon atoms or R2 and R3 together with
`18 is an enteric coating 20. The enteric coating 20 can be
`
`carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or
`
`30 formulated from any suitable enteric coating material, many
`R3 or R4 together with carbons X andY form a cycloalkenyl
`of which are known to those skilled in the art and many of
`having 4 to 6 carbon and wherein the X-Y bond can be
`which are employed for coating commercially available
`
`saturated or unsaturated.
`NSAID's. The coating 20 aids in segregating the NSAID
`By lower alkyl is meant straight or branched chain alkyl
`
`
`from the prostaglandin and in directing the dissolution of the
`35 NSAID core in the lower G.l tract as opposed to the
`such as methyl, ethyl, propyl, isopropyl, butyl, secondary
`stomach. The coating 20 can aid in the prevention of
`butyl or tertiary butyl, pentyl, or hexyl with the indicated
`
`
`degradation of the prostaglandin by the presence of the
`
`limitation of the number of carbon atoms. The bond between
`NSAID. The enteric coating can be coated onto the inner
`carbon X and carbon Y can be saturated or unsaturated.
`
`core using standard coating techniques. For example, aque-
`n has been found herein that acceptable
`40 ous or solvent coatin g techniques
`prostaglandins
`can be used to apply the
`
`
`
`include misoprostol represented by the following Formula: 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
`in FIG. 1.
`embodiment represented
`45 A third embodiment of the composition is shown in FIG.
`3. In FIG. 3 a tablet 24 is illustrated in cross section.
`The
`of an inner core 26 comprising an NSAID
`tablet 24 consists
`with regard to the core 12 of FIG. 1.
`or its salt as disclosed
`Surrounding the core 26 is an undercoat 28 which can
`so provide a surface for the enteric coat which undercoat can
`
`have a greater affinity for the enteric coat than the core alone.
`the prostaglandin enisoprost. (±)methyl lla,16-dihydroxy-
`
`The coating 28 can be any suitable
`coating material and
`
`16-methyl-9-oxoprosto-4Z,l3E-diene- 1-oate, represented
`
`preferably is HPMC in an amount about two percent (2%) by
`
`by the following Formula:
`weight of the core.
`55 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
`60 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 G.l tract rather
`and the prostaglandin methyl 7-[2B-[6-(1-cyclopenten-1-yl)
`
`than the stomach. Any aqueous enteric coating can be used
`
`-4-hydroxy-4-methyl-1E,5E-hexadienyl]-3a-hydroxy-5-
`65 and the enteric coating can be coated onto the inner core
`
`oxo-1R,1a-cyclopentyl]-4Z-heptenoate represented by the
`
`using standard coating techniques as described with regard
`to the embodiment shown in FIG. 2.
`
`following Formula:
`
`

`
`5,698,225
`
`8
`-continued
`
`Unit Formula (mg)
`
`misoprostol:HPMC dispersion (1:100)
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`EXAMPLE3
`
`7
`An overcoat
`32 is coated over the enteric coat 30. The
`
`overcoat 32 can provide an intermediate coating providing
`affinity 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 5
`misoprostol
`
`the core. The overcoat 32 prevents water which can be
`hydroxypropyl metbylcellulose
`present in the aqueous enteric coating from passing into the
`crospovidone
`
`
`prostaglandin mantle. Further, the overcoat can aid in main­
`
`
`colloidal silicon dioxide
`
`
`taining the integrity of the enteric coating during the com­
`
`hydrogenated castor oil
`microcrystalline cellulose
`pression coating step as the mantle is formed on the tablet.
`10
`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,
`32.
`over the overcoat
`It has been found herein that an especially
`preferred 15
`A pharmaceutical tablet composition
`was prepared con­
`
`
`
`composition is the use of misoprostol as the prostaglandin in
`
`
`sisting of a diclofenac sodium central core, an aqueous
`
`
`the mantle and the use of diclofenac in the inner core.
`
`
`enteric coating, an overcoat and a misoprostol mantle. The
`The invention will be further described with regard to the
`
`tablet had the following composition.
`following examples.
`
`EXAMPLE 1
`
`Unit Formula (mg)
`
`20
`
`Core
`A pharmaceutical tablet composition
`was prepared con­
`
`sisting of a diclofenac sodium central core and a misoprostol
`diclofenac sodium
`
`
`mantle. The tablet had the following composition. 25
`
`lactose (monohydrate)
`
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Enteric coating (aqueous)
`methacrylic acid
`
`Core
`diclofenac sodium
`lactose (monohydrate)
`
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`purified
`water
`Maotle
`misopros
`
`tol:HPMC dispersion (1:100)
`
`hydroxypropyl methylcellulose (HPMC)
`
`misoprostol
`
`crospovidone
`
`colloidal silicon dioxide
`hydrogenated castor oil
`microcry stalline cellulose
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`EXAMPLE2
`
`Unit Formula (mg)
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`3.68
`0.049
`1.84
`0.37
`
`2.72
`0.054
`
`copolymer type C
`sodium hydroxide
`talcum
`triethy I citrate
`Overcoating
`
`HPMC
`polyethylene glycol (PEG 400)
`Mantle
`misoprostol:HPMC dispersion (1:100)
`
`misoprostol
`hydroxypropyl methylcellulose
`crospovidone
`colloidal silicon dioxide
`hydrogenated castor oil
`microcrystalline cellulose
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`30
`
`35
`
`40
`
`45
`
`A pharmaceutical tablet composition
`was prepared con­
`
`sisting of a dictofenac sodium central core, an enteric
`A pharmaceutical tablet composition was prepared con­
`
`coating and a misoprostol mantle. The tablet had the fol-50
`
`sisting of a diclofenac sodium central core, an undercoat, an
`lowing composition.
`
`enteric coating, and a misoprostol mantle. The tablet had the
`following composition.
`
`EXAMPLE4
`
`Core
`diclofcnac sodium
`lactose (monohydrate)
`microcry stalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`purified
`water
`Core coating
`
`
`cellulose acetate phthalate
`dicthy I phthalate
`Mantle
`
`Unit Formula (mg)
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`5.4
`1.5
`
`55
`
`60
`
`Core
`
`diclofenac sodium
`
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Und=oat
`
`65
`
`HPMC
`PEG400
`
`Unit Formula (mg)
`
`50.0
`13.0
`129
`8.4
`4.8
`09
`
`1.84
`0.037
`
`

`
`9
`-continued
`
`5,698,225
`
`10
`
`Unit Formula (mg)
`
`Unit Formula (mg)
`
`Enteric coating (aqueous)
`methacrylic acid
`
`copolymer type C
`sodium hydroxide
`talcum
`triethy I citrate
`Mantle
`misoprostol:HPMC dispersion
`
`(1: 100)
`
`3.68
`0.049
`1.84
`0.37
`
`misoprostol
`hydroxypropyl methylcellulose
`crospovidone
`
`
`colloidal silicon dioxide
`
`
`hydrogenated castor oil
`
`microcrystalline cellulose
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`EXAMPLES
`
`Core
`
`5
`
`diclofenac sodium
`
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Enteric coating (aqueous)
`
`methacrylic acid
`
`10
`
`copolymer type C
`talcum
`I citrate
`triethy
`Overcoating
`
`15
`
`HPMC
`PEG400
`Mantle
`
`
`misoprostol:HPMC dispersion (1: 100)
`
`20
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`3.68
`1.84
`0.37
`
`2.72
`0.054
`
`misoprostol
`hydroxypropyl methylcellulose
`crospovidone
`
`
`colloidal silicon dioxide
`
`hydrogenated castor oil
`microcrystalline cellulose
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`A pharmaceutical tablet composition was prepared con­
`
`
`
`
`sisting of a diclofenac sodium central core, an undercoat, an 25
`
`
`enteric coating, an overcoat and a rnisoprostol mantle. The
`
`tablet had the following composition.
`
`Unit Formula (mg) 30
`
`EXAMPlE?
`
`A pharmaceutical tablet composition was prepared con­
`
`
`sisting of a diclofenac sodium central core, an enteric
`coating, an overcoat and a rnisoprostol mantle. The tablet
`
`had the following composition.
`35
`
`Unit Formula (mg)
`
`50.0
`13.0
`129
`8.4
`4.8
`09
`
`Core
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Undercoat
`
`HPMC
`PEG400
`Enteric coating (aqueous)
`methacrylic acid
`
`copolymer type C
`sodium hydroxide
`talcum
`
`triethyl citrate
`Overcoating
`
`HPMC
`PEG400
`Mantle
`
`misoprostol:HPMC dispersion
`(1:100)
`
`1.84
`0.037
`
`40
`
`3.68
`0.049
`1.84
`0.37
`
`2.72
`0.054
`
`Core
`
`diclofenac sodium
`
`lactose (monohydrate)
`
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Enteric coating (aqueous)
`
`Aquateric
`polysorbate
`80
`diethyl phthalate (DEP)
`Overcoating
`
`HPMC
`PEG400
`Mantle
`misoprostol:HPMC dispersion (1:100)
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`6.53
`0.13
`1.96
`
`2.72
`0.054
`
`misoprostol
`hydroxypropyl methylcellulose
`crospovidone
`
`colloidal silicon dioxide
`
`hydrogenated castor oil
`microcry stalline cellulose
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`EXAMPlE
`
`8
`
`45
`
`50
`
`55
`
`60
`
`misoprostol
`
`hydroxypropyl methylcellulose
`crospovidone
`
`colloidal silicon dioxide
`hydrogenated castor oil
`microcrystalline cellulose
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`EXAMPLE6
`
`A pharmaceutical tablet composition was prepared con­
`
`A pharmaceutical tablet composition was prepared con­
`
`sisting of a diclofenac sodium central core, an enteric 65
`
`
`sisting of a diclofenac sodium central core, an undercoat, an
`coating, an overcoat and a rnisoprostol mantle. The tablet
`
`enteric coating, and a rnisoprostol mantle. The tablet had the
`
`had the following composition.
`
`following composition.
`
`

`
`11
`
`5,698,225
`
`12
`-continued
`
`
`
`Unit Formula (mg)
`
`Unit Formula (mg)
`
`Core
`
`diclofenac sodium
`
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povioone K-30
`magnesium stearate
`Undercoat
`
`HPMC
`PEG400
`
`Enteric coating (aqueous)
`
`Aquateric
`polysorbate 80
`die thy I phthalate
`(DEP)
`Mantle
`misop rostol:HPMC dispersion
`(1:100)
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`1.84
`0.037
`
`6.56
`°·13
`1.97
`
`5
`
`crospovidone
`
`
`colloidal silicon dioxide
`hydrogenated castor oil
`
`microcrystalline cellulose
`
`10.0
`0.5
`1.0
`233.3
`
`The composition that is the invention herein provides an
`
`10
`ease of delivery of an NSAID for its therapeutic value such
`
`as the alleviation of inflammation in a system which limits
`
`
`the undesirable side affects of ulcerogenesis associated with
`
`such NSAID therapy. That is, the composition herein con-
`
`
`tablet provides a pros-15 sisting of essentially a core/mantle
`
`taglandin along with the NSAID whereby the prostaglandin
`
`can be administered for its beneficial therapeutic value in
`
`preventing and or inhibiting the incidence of NSAID
`induced ulcers.
`
`20 A particularly beneficial aspect of the invention herein is
`
`0.2
`misoprostol
`
`
`that the combination of the two components in a core/mantle
`20.0
`
`hydroxypropyl methylcellulose
`10.0
`
`
`tablet assures compliance with the therapeutic regimen of
`crospovidone
`0·5
`
`
`colloidal silicon dioxide
`
`the two active components. That is, a co-administration of
`1.0
`hydrogenated castor oil
`
`the active components (NSAID and prostaglandin) sepa-
`233.3
`microctyst alline cellulose
`25 rately can be difficult 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
`A pharmaceutical tablet composition was prepared con­
`
`
`
`
`30 administration of the prostaglandin also present in the tablet.
`
`
`sisting of a diclofenac sodium central core, an undercoat, an
`
`
`enteric coating, an overcoat and a misoprostol mantle. The
`
`tablet had the following composition.
`
`EXAMPLE9
`
`The composition herein is especially utile as the compo­
`
`
`
`sition herein exhibits a stability for the prostaglandin and the
`NSAID.
`We claim:
`
`
`Unit Formula (mg)
`
`35
`
`1. A pharmaceutical composition comprising:
`
`Core
`
`diclofenac sodium
`
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povioone K-30
`magnesium stearate
`Undercoat
`
`HPMC
`PEG400
`Enteric coating (aqueous)
`
`Aquateric
`polysorbate 80
`
`diethyl phthalate (DEP)
`Overcoating
`
`HPMC
`PEG400
`Mantle
`misoprostol:HPMC dispersion (1:100)
`
`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
`
`misoprostol
`hydroxypropyl methylcellulose
`
`0.2
`20.0
`
`40
`
`a. a core consisting of a therapeutically-effective amount
`
`
`of a nonsteroidal anti-inflammatory agent; and
`b. a mantle coating surrounding the core comprising a
`
`therapeutically-effective amount of misoprostol.
`2. A method of treating inflammation comprising orally
`
`administering to a patient in need of such treatment, a
`
`therapeutically effective amount to treat inflammation of a
`
`composition comprising
`45
`a. a core consisting of a therapeutically-effective amount
`
`
`
`of a nonsteroidal anti-inflamma tory agent; and
`b. a mantle coating surrounding the core comprising a
`
`
`therapeutically-effective amount of misoprostol.
`3. A pharmaceutical composition as recited in claim 1
`so
`further comprising an intermediate coating surrounding the
`
`core wherein the intermediate coating comprises an enteric
`coating.
`4. A pharmaceutical composition as recited in claim 1
`
`55 wherein the prostaglandin mantle coating comprises a sta­
`
`bilized prostaglandin formulation.
`
`* * * * *