United States Patent [19]
`Gimet et al.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`5,698,225
`*Dec. 16, 1997
`
`[54] PHARMACEUTICAL COMPOSITION
`
`[75] Inventors: Rene Antoine Gimet, Valbonnc; Jean
`ChaPIQS 11110‘, CagneS-SHI Men
`(31111591111 Magnet’ Chance“ s"I_
`Cho1slle; Isabelle Maroteaux, Antlbes,
`all of France; Francoise M. Nevoux,
`Evanston, 111.; Roger E. Scoyer,
`Jemeppe-sur Sambre, Belgium;
`Barbara J. Struthers, Deer?e1d,1]l.
`
`[73] Assignce: G. D. Searle 8: Co., Chicago, 111.
`
`[*1 N01166:
`
`The term of this patent shall not extend
`beyond the expiration date of Pat. No.
`5,601,343-
`
`[51] Int. Cl.6 .............................. .. A61K 9/30; A61K 9/28
`[52] US. Cl. ........................ .. 424/475; 424/464; 424/472;
`424/474; 424/476; 514/573
`[58] Field of Search ................................... .. 424/475, 464,
`424/472, 474, 676; 514/573
`
`[56]
`
`References Cited
`
`DOCUM S
`U'S' P
`4,707,495 11/1987 Rosenthale et a1. .................. .. 514/530
`4,316,472
`3/1989 Valcavi .............. ..
`514/428
`4,865,847
`9/1989 Gosswein
`424/439
`4,954,512
`9/1990 Oguro et a1.
`514/352
`4,975,283 12/1990 Pntcll ....... ..
`424/470
`5,601,843
`2/1997 Glmet'
`Primary Examiner—G011a.mudi S. Kishore
`Attorney, Agent, or Firm—Roger A. Williams
`
`[22] F?ed:
`
`Feb’ 3’ 1997
`
`. .
`
`R l
`
`.
`.
`e ated U s Apphcauon Data
`[63] Continuation of Set. N0. 276,299, Jul. 18, 1994, Pat. No.
`5,601,843, which is acon?nuation of Ser. No. 973,451, Nov.
`9, 1992, abandoned, which is a continuation of Ser. No.
`513,353, May 3, 1990, abandoned.
`
`A pharmaceutical composition including a core of an
`NSAID selected from diclofenac and piroxicam which core
`is surrounded by a mantle coating of a prostaglandln,
`.
`.
`.
`wherein an intermediate c°a?flg "a" be PM?“ between the
`NSAID core and Prostaglandm mantle coatmg
`
`4 Claims, 1 Drawing Sheet
`
`26
`
`24
`
`Lupin Exh. 1007
`
`

`
`US. Patent
`
`Dec. 16, 1997
`
`5,698,225
`
`12
`
`14
`
`16
`
`18
`
`FIG 1
`
`FIG2
`
`

`
`1
`PHARMACEUTICAL COMPOSITION
`
`5,698,225
`
`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.
`Acceptable prostaglandins for use herein include prostag
`landins having the following structure
`
`This is a continuation application of application Ser. No.
`08/276,299, ?led on Jul. 18, 1994, now US. Pat No.
`5,601,843 which was a continuation of Ser. No. 07/973,451
`?led Nov. 9, 1992 (now abandoned) which was a continu
`ation of Ser. No. 07/518,353 ?led on 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 piroxicarn. The mantle coating consists
`of a prostaglandin such as will be described hereinafter in
`more detail.
`Nonsteroidal anti-in?ammatory drugs (NSAIDs) com
`prise a class of drugs which have long been recognized as
`having high therapeutic value especially for the treatment of
`in?ammatory conditions such as exhibited in in?ammatory
`diseases like osteoarthritis (OA) and rheumatoid arthritis
`(RA). While the NSAIDs present a bene?cial therapeutic
`value they also exhibit undesirable side e?’ects. An espe
`cially undesirable side e?’ect 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 NSAlDs 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 US. 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 bene?cial compounds and have
`found therapeutic usage, prostaglandins are generally con
`sidered highly unstable. Therefore, it is desirable to ?nd
`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 bene?cial properties of an
`NSAID and which composition would exhibit the bene?cial
`properties of a prostaglandin for countering (by inhibiting,
`reducing or preventing) the ulcerogenic side e?iects atten
`dant to NSAID administration.
`
`25
`
`30
`
`45
`
`50
`
`55
`
`SUMIMARY OF THE INVENTION
`The invention herein is directed to a pharmaceutical
`composition comprising a core consisting of an NSAID
`
`65
`
`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-bene?cial interaction of the
`NSA]]) and prostaglandin such as degradation of the pros
`taglandin. Such an intermediate coating can be an enteric
`coating which aids in reducing the likelihood of the NSAlD
`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 srnrounding the core comprising
`the prostaglandin misoprostol in a therapeutic amount of
`about 100 to 200 micrograms (mcg).
`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.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a schematic representation of a tableted phar
`maceutical composition herein illustrating the core/mantle
`structure;
`
`

`
`5,698,225
`
`3
`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-in?ammatory drug (NSAID)
`selected from diclofenac and piroxicarn. Surrounding the
`core is a mantle coating which consists of aprostaglandin of
`the structure
`
`15
`
`25
`
`35
`
`4
`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 piroxicam or the
`pharmaoeutically acceptable salts of such NSAlDs. 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, ?llers 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 eifect on either the diclofenac or
`prostaglandin.
`'
`If the inner core is piroxicam, the piroxicarn can be
`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 e?ect 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
`prostaglandins, “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:
`
`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 ?rst be described
`with regard to the embodiment shown in FIG. 1. FIG. 1
`represents a schematic illustration of a pharmaceutical com
`position herein. The pharmaoeutical 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 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
`although it is understood that other shapes can be used
`without departing from the intended scope of the invention.
`
`40
`
`50
`
`55
`
`65
`
`

`
`5
`E2 prostaglandins represented by the following Formula II:
`
`5 ,698,225
`
`111:
`
`20
`
`50
`
`wherein R represents hydrogen or lower alkyl having 1 to 6
`carbon atoms, R1 represents hydrogen, vinyl or lower alkyl
`25
`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 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
`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:
`
`35
`
`30
`
`When the prostaglandin is misoprostol, (i)methyl 11oz,
`16-dihydroxy-16-methyl-9-oxoprost-13E-en- l-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 G.I. tract as opposed 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 a?inity for the enteric coat than the core alone.
`the prostaglandin enisoprost; (i)methyl 1lot,16-dihydroxy
`The coating 28 can be any suitable coating material and
`l6-methyl-9-oxoprosto-4Z,l3E-diene-l-oate,*********************8 0 Td(cid:10)(represented )Tj(cid:10)70 Tz 10.2857 0 0 10.2857 56.4 204.054 Tm(cid:10)(by )Tj(cid:10)58.3333 Tz 1.12 0 Td(cid:10)(the )Tj(cid:10)62.2222 Tz 1.33 0 Td(cid:10)(following )Tj(cid:10)65.625 Tz 3.64 0 Td(cid:10)(Formula: )Tj(cid:10)80.5556 Tz 7.2 0 0 7.2 276.48 189.36 Tm(cid:10)(55 )Tj(cid:10)128.9474 Tz 6.5143 0 0 6.5143 74.4 185.28 Tm(cid:10)(o )Tj(cid:10)119.7368 Tz 4.3429 0 0 4.3429 115.68 176.3707 Tm(cid:10)(o )Tj(cid:10)515.7895 Tz 9.174 0 Td(cid:10)(— )Tj(cid:10)193.4211 Tz 16.745 0 Td(cid:10)(O )Tj(cid:10)47.9905 Tz 16.1143 0 0 16.1143 101.52 164.7631 Tm(cid:10)(“‘o )Tj(cid:10)138.6968 Tz 1.087 0 Td(cid:10)(\/—\/\n/ )Tj(cid:10)50.8865 Tz 7.104 0 Td(cid:10)(\CHB )Tj(cid:10)90.4393 Tz 7.3714 0 0 7.3714 168.48 157.413 Tm(cid:10)(CH3 )Tj(cid:10)113.9535 Tz 6.512 0 Td(cid:10)(0 )Tj(cid:10)1362.5 Tz 12.8 0 0 12.8 121.68 140.3587 Tm(cid:10)(W )Tj(cid:10)53.125 Tz 8.288 0 Td(cid:10)(CH’ )Tj(cid:10)46.875 Tz 3.788 0 Td(cid:10)(60 )Tj(cid:10)50.2564 Tz 11.1429 0 0 11.1429 73.68 133.2983 Tm(cid:10)(Oil )Tj(cid:10)73.5897 Tz 8.529 0 Td(cid:10)(OH )Tj(cid:10)64.1975 Tz 10.8 0 0 10.8 56.4 103.7234 Tm(cid:10)(and )Tj(cid:10)55.5556 Tz 1.333 0 Td(cid:10)(the )Tj(cid:10)57.5499 Tz 1.178 0 Td(cid:10)(prostaglandin )Tj(cid:10)66.0494 Tz 4.689 0 Td(cid:10)(methyl )Tj(cid:10)56.2963 Tz 2.578 0 Td(cid:10)(7-[2B-[6-( )Tj(cid:10)57.3099 Tz 3.489 0 Td(cid:10)(l-cyclopenten-l-yl) )Tj(cid:10)66.6346 Tz 10.2857 0 0 10.2857 56.4 93.5546 Tm(cid:10)(-4-hydroxy-4-methyl-1E,5E-hexadienyl]-3oc-hydroxy-S- )Tj(cid:10)56.3889 Tz 21.373 0 Td(cid:10)(65 )Tj(cid:10)57.545 Tz 10.9714 0 0 10.9714 56.4 83.4231 Tm(cid:10)(oxo-1R,lot-cyclopentyl]-4Z-heptenoate )Tj(cid:10)58.3333 Tz 13.103 0 Td(cid:10)(represented )Tj(cid:10)65.625 Tz 4.222 0 Td(cid:10)(by )Tj(cid:10)55.9028 Tz (the )Tj(cid:10)61.7901 Tz 10.2857 0 0 10.2857 55.92 73.44 Tm(cid:10)(following )Tj(cid:10)65.1389 Tz 3.617 0 Td(cid:10)(Formula: )Tj(cid:10)73.8281 Tz 9.7524 0 0 9.7524 298.8 622.8906 Tm(cid:10)(With )Tj(cid:10)64.2578 Tz 2.116 0 Td(cid:10)(regard )Tj(cid:10)59.4727 Tz 2.609 0 Td(cid:10)(to )Tj(cid:10)62.8906 Tz 1.034 0 Td(cid:10)(the )Tj(cid:10)55.9304 Tz 1.452 0 Td(cid:10)[(illustrated )28(structures, )]TJ(cid:10)61.5234 Tz 8.047 0 Td(cid:10)(the )Tj(cid:10)70.4102 Tz (dashed )Tj(cid:10)56.3965 Tz 4.356 0 Td(cid:10)(line )Tj(cid:10)57.9573 Tz 10.0457 0 0 10.0457 289.92 613.6705 Tm(cid:10)(indicates )Tj(cid:10)59.727 Tz 3.44 0 Td(cid:10)(the )Tj(cid:10)66.6951 Tz 1.362 0 Td(cid:10)(grouping )Tj(cid:10)65.3015 Tz 3.488 0 Td(cid:10)(being )Tj(cid:10)67.6906 Tz 2.246 0 Td(cid:10)(behind )Tj(cid:10)59.727 Tz 2.7 0 Td(cid:10)(the )Tj(cid:10)65.3015 Tz 1.314 0 Td(cid:10)(plane )Tj(cid:10)63.7088 Tz 2.294 0 Td(cid:10)(of )Tj(cid:10)61.0542 Tz 1.003 0 Td(cid:10)(the )Tj(cid:10)67.6906 Tz 1.362 0 Td(cid:10)(paper )Tj(cid:10)68.9591 Tz 10.2476 0 0 10.2476 290.16 603.9355 Tm(cid:10)(and )Tj(cid:10)58.5502 Tz 1.522 0 Td(cid:10)(the )Tj(cid:10)50.0929 Tz (solid, )Tj(cid:10)65.4895 Tz 3.49 0 Td(cid:10)(blackened )Tj(cid:10)56.2082 Tz 3.817 0 Td(cid:10)(triangular )Tj(cid:10)65.5762 Tz 3.654 0 Td(cid:10)(shape )Tj(cid:10)56.8154 Tz 2.248 0 Td(cid:10)(indicates )Tj(cid:10)55.6227 Tz 3.372 0 Td(cid:10)(that )Tj(cid:10)58.5502 Tz 1.616 0 Td(cid:10)(the )Tj(cid:10)71.3429 Tz 9.5314 0 0 9.5314 290.16 594.5624 Tm(cid:10)(group )Tj(cid:10)52.458 Tz 2.442 0 Td(cid:10)(is )Tj(cid:10)60.8513 Tz 0.957 0 Td(cid:10)(in )Tj(cid:10)59.5923 Tz 1.032 0 Td(cid:10)(front )Tj(cid:10)69.2446 Tz 2.09 0 Td(cid:10)(of )Tj(cid:10)62.9496 Tz 1.083 0 Td(cid:10)(the )Tj(cid:10)67.9856 Tz 1.435 0 Td(cid:10)(plane )Tj(cid:10)65.048 Tz 2.392 0 Td(cid:10)(of )Tj(cid:10)62.9496 Tz 1.007 0 Td(cid:10)(the )Tj(cid:10)61.5508 Tz 1.435 0 Td(cid:10)(paper. )Tj(cid:10)76.1369 Tz 10.1571 0 0 10.1571 298.56 584.6641 Tm(cid:10)(The )Tj(cid:10)60.4782 Tz 1.867 0 Td(cid:10)(prostaglandins )Tj(cid:10)59.0717 Tz 5.647 0 Td(cid:10)(useful )Tj(cid:10)57.1027 Tz 2.646 0 Td(cid:10)(in )Tj(cid:10)59.0717 Tz 1.181 0 Td(cid:10)(the )Tj(cid:10)65.5159 Tz 1.607 0 Td(cid:10)(composition )Tj(cid:10)64.9789 Tz 4.844 0 Td(cid:10)(of )Tj(cid:10)59.0717 Tz 1.276 0 Td(cid:10)(the )Tj(cid:10)66.3704 Tz 9.6429 0 0 9.6429 289.92 575.1367 Tm(cid:10)(invention )Tj(cid:10)64.2963 Tz 4.181 0 Td(cid:10)(herein )Tj(cid:10)71.9012 Tz 2.937 0 Td(cid:10)(can )Tj(cid:10)72.5926 Tz 1.867 0 Td(cid:10)(be )Tj(cid:10)70 Tz 1.419 0 Td(cid:10)(prepared )Tj(cid:10)76.7407 Tz 3.932 0 Td(cid:10)(by )Tj(cid:10)87.1111 Tz 1.493 0 Td(cid:10)(known )Tj(cid:10)65.3333 Tz (reaction )Tj(cid:10)72.508 Tz 9.6935 0 0 9.6935 290.4 565.2776 Tm(cid:10)(schemes )Tj(cid:10)68.0868 Tz 3.441 0 Td(cid:10)(such )Tj(cid:10)57.7706 Tz 2.005 0 Td(cid:10)(as )Tj(cid:10)76.3398 Tz 1.089 0 Td(cid:10)(by )Tj(cid:10)61.8971 Tz 1.287 0 Td(cid:10)(the )Tj(cid:10)73.687 Tz 1.436 0 Td(cid:10)(methods )Tj(cid:10)63.9603 Tz 3.466 0 Td(cid:10)(taught )Tj(cid:10)61.8971 Tz 2.6 0 Td(cid:10)(in )Tj(cid:10)88.0314 Tz 1.139 0 Td(cid:10)(US. )Tj(cid:10)56.739 Tz 1.981 0 Td(cid:10)(Pat. )Tj(cid:10)69.1184 Tz 1.783 0 Td(cid:10)(Nos. )Tj(cid:10)62.5447 Tz 10.0408 0 0 10.0408 289.92 555.0735 Tm(cid:10)[(3,965,143; )-50(4,271,314; )]TJ(cid:10)71.7073 Tz 8.318 0 Td(cid:10)(and )Tj(cid:10)62.1463 Tz 1.649 0 Td(cid:10)(4,683,328. )Tj(cid:10)79.6748 Tz 4.087 0 Td(cid:10)(The )Tj(cid:10)60.5528 Tz 1.793 0 Td(cid:10)(individual )Tj(cid:10)58.4282 Tz 4.016 0 Td(cid:10)(iso )Tj(cid:10)74.0501 Tz 9.4531 0 0 9.4531 289.92 545.7699 Tm(cid:10)(mers )Tj(cid:10)71.9344 Tz 2.133 0 Td(cid:10)(can )Tj(cid:10)74.0501 Tz 1.599 0 Td(cid:10)(be )Tj(cid:10)67.174 Tz 1.219 0 Td(cid:10)(obtained )Tj(cid:10)78.2815 Tz 3.504 0 Td(cid:10)(by )Tj(cid:10)70.5239 Tz 1.269 0 Td(cid:10)(chromatographic )Tj(cid:10)61.1635*******************aration.
`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
`e?’ects 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.I. 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.
`
`

`
`5,698,225
`
`8
`-continued
`
`7
`An overcoat 32 is coated over the enteric coat 30. The
`overcoat 32 can provide an intermediate coating providing
`
`a?inity 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
`0.2
`misoprostol
`the core. The overcoat 32 prevents water which can be
`20.0
`hydroxypropyl methylcellulose
`present in the aqueous enteric coating from passing into the
`10.0
`crospovic‘one
`prostaglandin mantle. Further, the overcoat can aid in main
`colloidal silicon dioxide
`0.5
`
`taining the integrity of the enteric coating during the com pression coating step as the mantle is formed on the tablet.
`hydrogenated castor oil
`1.0
`microcrystalline cellulose
`233.3
`
`misoprostolzl-IPMC dispersion (1:100)
`
`Unit Formula (mg)
`
`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
`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.
`
`20
`
`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.
`
`EXAMPLEI
`
`Unit Formula (mg)
`
`A pharmaceutical tablet composition was prepared con
`sisting of a diclofenac sodium central core and a misoprostol
`mantle. The tablet had the following composition.
`
`25
`
`Unit Formula (mg)
`
`Core
`
`diclofenac sodium
`lactose (mouohydrate)
`microcrystalline cellulose
`cornstarch
`povickme 31-30
`magnesium stearate
`puri?ed water
`Mantle
`mimtokI-[PMC dispersion (1:100)
`misoprostol
`hydroxypropyl methylcellulose (HPMC)
`crospovidone
`colloidal silicon dioxide
`hydrogenated castor oil
`microcrystalline cellulose
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`30
`
`35
`
`45
`
`Core
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium steamte
`Fmteric coating (aqueous)
`methacrylic acid
`
`copolymer type C
`sodium hydroxide
`talcum
`triethyl citrate
`Overeoating
`
`HPMC
`polyethylene glycol (PEG 400)
`Mantle
`misoprostohHPMC dispersion (1:100)
`
`misoprostol
`hydroxypropyl methylcellulose
`crospovidoue
`colloidal silicon dioxide
`hydrogenated castor oil
`microcrystalline 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 2
`
`A pharmaceutical tablet composition was prepared con
`sisting of a dictofenac sodium central core, an enteric
`coating and a misoprostol mantle. The tablet had the fol
`lowing composition.
`
`EXAMPLE 4
`
`50
`
`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.
`
`2°}:
`
`diclofenac sodium
`lactose (mouohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`' puri?ed water
`Core coating
`_—
`cellulose acetate phthalate
`diethyl phthalate
`Mantle
`‘
`
`Unit Formula (mg)
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`5.4
`1.5
`
`55
`
`60
`
`Gore
`'_
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidoue K-30
`magnesium stearate
`Undercoat
`
`65
`
`HPMC
`PEG 400
`
`Unit Formula (mg)
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`1.84
`0.037
`
`

`
`5,698,225
`
`10
`
`Unit Formula (mg)
`
`Unit Formula (mg)
`
`9
`-continued
`
`Enteric coating (aqueous)
`methacrylic acid
`
`copolymer type C
`sodium hydroxide
`talcum
`tr'iethyl citrate
`Mantle
`misoprostolzI-[PMC dispersion (1:100)
`
`misoprostol
`hydroxypropyl methylcellulose
`crospovidone
`colloidal silicon dioxide
`hydrogenated castor oil
`microcrystalline cellulose
`
`3.68
`0.049
`1.84
`0.37
`
`0.2
`20.0
`10.0
`0.5
`1.0
`233.3
`
`EXAMPLE 5
`
`A pharmaceutical tablet composition was prepared con
`
`enteric coating, an overcoat and a misoprostol mantle. The
`tablet had the following composition.
`
`Core
`5 _
`diclofenac sodium
`lactose (monolrydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Friteric coating (aqueous)
`methacrylic acid
`
`10
`
`15
`
`20
`
`copolymer type C
`talcum
`triethyl citrate
`Overcoating
`
`HIPMC
`PEG 400
`Mantle
`misoprostokHPMC dispersion (1:100)
`
`misoprostol
`hydroxypropyl methylcellulose
`crospovidone
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`3.68
`1.84
`0.37
`
`2.72
`0.054
`
`0.2
`20.0
`10.0
`
`[11(5)
`
`of a diclofenac sodium central core, an undercoat, an 25
`
`25
`diclofenac sodium
`lactose (mollohydl'ate)
`microcrystalline cellulose
`cornstarch
`povitbne K-30
`magnesium stearate
`Undercoat
`——
`
`gélgoo
`E ric coating (aqueous)
`meth
`he acid
`m
`
`coporlynij;
`talcum
`triethyl citrate
`-
`m
`HPMC
`PEG 400
`Mantle
`mrsoprostoLHPMC dispersion (1.100)
`
`.
`
`_
`
`.
`
`.
`
`_
`
`Unit Formula (mg)
`
`30
`
`EXAMPLE 7
`
`50.0
`139
`12.9
`8.4
`4.8
`09
`
`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.
`
`35
`
`Core
`
`'
`Unit Formula (mg)
`
`4O
`
`45
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesimn stearate
`Erteric coating (aqueous)
`.
`Aquaterrc
`polysorbate 80
`diethyl phthalate (DEP)
`2 72
`0.054 w
`5O
`
`L84
`0.37
`
`'
`
`50.0
`13.0
`12.9
`8.4
`4.8
`0.9
`
`6.53
`0.1a
`1.96
`
`2.72
`
`0.054
`
`0 2
`'
`.
`05
`1.0
`233.3
`
`-
`misoprostol
`
`hydmmropyl mcthykeuulose
`crospovidone
`colloidal silicon dioxide
`
`hydrogenated castor oil . .
`
`mrcrocrystallme cellulose
`
`0.2
`
`20.0
`10.0
`0.5
`1.0
`233.3
`
`55
`
`HPMC
`
`PEG 400
`
`Mantle
`.
`
`_
`
`.
`
`.
`
`_
`
`mrsoprostol.HPMC dispersion (1.100)
`.
`msml
`"'15 :F
`
`hydmxxnpg’pyl methylccuulose crospov no
`colloidal silicon dioxide
`hydrogenated castor oil
`microcrystalline cellulose
`
`EXAMPLE6
`
`EXAMPLE 8
`
`A pharmaceutical tablet composition was prepared con
`A pharmaceutical tablet composition was prepared con
`sisting of a diclofenac Sodium Central Core, all cntel‘ic 65 sisting of a diclofenac sodium central core, an undercoat, an
`coating, an overcoat and a misoprostol 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)
`
`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
`ease of dehvery of an NSAID for 1ts therapeutic value such
`as the alleviation of in?ammation in a system which limits
`the undesirable side affects of ulcerogenesis associated with
`HPMC
`such NSAID therapy. That 1s, the COInpOSltlOlhh?I‘ClJl con
`Emma coating (aquwus)
`— 15 slstrng of essentially a core/mantle tablet prov1des a pros
`Aqum?ic
`6-56
`taglandin along with the NSAID whereby the prostaglandin
`gelfls‘fb?hfgm (DEF)
`can be administered for its bene?cial therapeutic value in
`Mange P
`preventing and or inhibiting the incidence of NSAID
`mifprostoltHPMC dispersion (11100)
`induced ulcers.
`misopmml
`20 A particularly bene?cial aspect of the invention herein is
`hydroxypmpyl methylcellulose
`that the comblnatlon of the two components in a core/mantle
`cmsgovidq?f
`_
`_
`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
`25 rately can be di?icult to achieve and can be di?icult 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 composition comprising:
`a. a core consisting of a therapeutically-effective amount
`of a nonsteroidal anti-in?ammatory agent; and
`b. a mantle coating surrounding the core comprising a
`therapeutically-ell’ective amount of misoprostol.
`2. A method of treating in?ammation comprising orally
`administering to a patient in need of such treatment, a
`therapeutically e?ective amount to treat in?ammation of a
`composition comprising
`a. a core consisting of a therapeutically-effective amount
`of a nonsteroidal anti-in?ammatory agent; and
`b. a mantle coating surrounding the core comprising a
`therapeutically-elfective amount of misoprostol.
`3. A pharmaceutical composition as recited in claim 1
`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
`wherein the prostaglandin mantle coating comprises a sta
`bilized prostaglandin formulation.
`
`10
`
`45
`
`50
`
`55
`
`.
`
`. .
`
`.
`
`* * * * *
`
`Cote
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`gargxi’gmlfggmm
`Undcmat
`
`PEG 400
`
`mimmmm cellulose
`
`50.0
`13.0
`12.9
`8.4
`3:3
`
`1'84
`
`0.037
`
`'
`
`0‘2
`20.0
`10-0
`2'3
`2333
`
`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 (mg)
`
`Core
`
`diclofenac sodium
`lactose (monohydrate)
`microcrystalline cellulose
`cornstarch
`povidone K-30
`magnesium stearate
`Undercoat
`
`HPMC
`PEG 400
`Enteric coating (aqueous)
`
`Aquateric
`polysorbate 80
`diethyl phthalate (DEP)
`Overcoating
`
`HPMC
`PEG 400
`Mantle
`misoprostohH'PMC dispersion (1:100)
`
`misoprostol
`hydxoxypropyl methylcellulose
`
`50.0
`13.0
`12.9
`8.4