Exhibit 1011
`
`U.S. Patent No. 6,183,779 (“the ‘779 Patent”)
`
`

`
`(12) United States Patent
`Ouali et al.
`
`US006183779B1
`(10) Patent N0.:
`US 6,183,779 B1
`(45) Date of Patent:
`Feb. 6, 2001
`
`(54) STABILIZED PHARMACEUTICAL
`COMPOSITION OF A NONSTEROIDAL
`ANTI-INFLAMMATORY AGENT AND A
`PROSTAGLANDIN
`(75) Inventors: Aomar Ouali, Boisbriand; Abul Kalam
`Azad, Montreal, both of (CA)
`(73) Assignee: Pharmascience IIlC., Montreal (CA)
`(*) Notice;
`Under 35 U_S_C_ 154(k)), the term of this
`patent Shall be extended for () days_
`(21) AppL NO‘, 09/273,692
`(22) Filed:
`Mar. 22, 1999
`
`_
`_
`7
`(51) Int. Cl. ............................. .. AA6611I§<99/22,~A61K 9/24,
`62’ A61K 9/54
`(52) US. Cl. ........................ .. 424/472; 424/451; 424/457;
`424/458; 424/465; 424/468; 424/470; 424/474;
`424/489; 514/7723; 514/781; 514/970
`,
`(58) Field of Search ................................... .. 424/472, 474,
`424/451’ 464’ 465’ 489’ 470’ 457’ 426588’
`
`(56)
`
`379287588
`3j954j7s7
`4,301,146
`5,015,481
`5,601,843
`
`References Cited
`US. PATENT DOCUMENTS
`_
`""""""""""""""" "
`12/1975 Robert "N11332::1:11:13: 424/234
`5/1976 Monkhouse _____ __
`260/308 D
`11/1981 Sanvordeker . . . . .
`. . . . .. 424/80
`5/1991 Franz et al. ..... ..
`424/494
`2/1997 Gimet et al. ....................... .. 424/475
`
`5,698,225 * 12/1997 Gimet etal. ....................... .. 424/475
`FOREIGN PATENT DOCUMENTS
`91/16895
`11/1991 (W0) .
`99/12524
`3/1999 (W0) .
`99/65496
`12/1999 (W0) -
`00/01368
`1/2000 (W0) -
`00/15200
`
`3/2000 OTHER PUBLICATIONS
`Searle HealthNet Prescribing Information for Arthrotec®
`(downloaded from http://WWW.searlehealthnet.com/pi/ar
`throtec.html on Oct. 27, 1998).
`Information for the Patient: ControtecTM.
`* ‘med by exammer
`Primary Examiner—James M. Spear
`(74) Attorney) Agent) Or Firm_Dianne E‘ Reed; J. Elm
`Hartrum; Reed & Associates
`(57)
`ABSTRACT
`A pharmaceutical composition is provided for the oral
`administration of an NSAID and a prostaglandin‘ The Com_
`position is a solid dosage form Wherein the NSAID is
`enterically coated and the prostaglandin is present along
`With an effective stabilizing amount of a prostaglandin
`stabilizing agent such as hydroXypropyl methylcellulose or
`polyvinylpyrrolidone. Exemplary dosage forms are bilayer
`tablets in Which the prostaglandin is misoprostol and the
`NSAID is diclofenac, piroXicam, or ‘a pharmaceutically
`acceptable Salt thereof" Methods for ‘15mg the Composmon
`to treat NSAID-responsive conditions, disorders and dis
`eases are Provided as Well
`
`35 Claims, 1 Drawing Sheet
`
`10 W
`11
`12
`
`

`
`U.S. Patent
`
`Feb. 6, 2001
`
`US 6,183,779 B1
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`FIG. 1
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`FIG. 2
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`1
`STABILIZED PHARMACEUTICAL
`COMPOSITION OF A NONSTEROIDAL
`ANTI-INFLAMMATORY AGENT AND A
`PROSTAGLANDIN
`TECHNICAL FIELD
`This invention relates generally to pharmaceutical
`compositions, and more particularly relates to a pharmaceu
`tical composition containing a combination of a nonsteroidal
`anti-in?ammatory drug (NSAID) and a prostaglandin.
`BACKGROUND
`Nonsteroidal anti-in?ammatory agents such as
`diclofenac, difenpiramide, fenbufen, ?ufenamic acid,
`ibuprofen, indomethacin, ketoprofen, meclofenamate
`sodium, mefenamic acid, nabumetone, naproxen, piroxicam,
`suprofen and tiaprofenic acid, are Widely used to relieve
`mild to moderate pain, for fever, and to treat in?ammatory
`conditions. Sodium diclofenac, for example, is particularly
`effective for relief of musculoskeletal and joint disorders
`such as rheumatoid arthritis, an autoimmune disease,
`osteoarthritis and ankylosing spondilitis; periacicular disor
`ders such as bursitis and tenditis; soft-tissue disorders such
`as sprains and strains, and other painful conditions such as
`renal colic, acute gout, dysmenorrhoea, and for relieving
`pain folloWing some surgical disorders. The NSAIDs are
`non-habit forming drugs and thus offer a signi?cant advan
`tage over traditional opioid-based drugs; furthermore, as
`NSAIDs are by de?nition “nonsteroidal,” the side effects
`commonly associated With oral administration of steroids
`are avoided as Well. HoWever, it is recogniZed that NSAIDs
`also exhibit some undesirable side effects, particularly at
`high dosages and/or With chronic oral administration.
`Generally, high dosages and chronic use of NSAIDs are
`associated With problems such as gastrointestinal and duode
`nal bleeding, ulceration and perforation.
`In vieW of the advantages of NSAIDs over opioid-based
`drugs and steroidal agents, steps have been undertaken to
`minimiZe the drugs’ adverse effects. In one approach,
`NSAIDs have been administered locally, such as by
`injection, by topical administration of, for example, an
`ointment or cream, by use of a transdermal patch, or by an
`inhalation device. Although local administration is
`desirable, administration of an effective amount of the active
`agent is difficult or inconvenient. In another approach to
`reduce the adverse effects of NSAIDs, the agents are
`ingested after food or milk, or are taken in combination With
`antacids, histamine H2-receptor antagonists, omepraZole, or
`sucralefate.
`In yet another approach to reduce the undesirable gas
`trointestinal effects resulting from the oral administration of
`NSAIDs, the agents have been co-administered With some
`prostaglandins, particularly “E-series” prostaglandins such
`as PGEl, PGE2, misoprostol, and derivatives thereof; see,
`e.g., US. Pat. No. 3,781,429 to Partridge, US. Pat. No.
`3,927,213 to Lippman, US. Pat. No. 3,928,588 to Robert,
`and US. Pat. No. 5 ,015 ,481 to FranZ et al. Administration of
`a prostaglandin With an NSAID has been shoWn to reduce
`the ulcerogenicity of the NSAID. HoWever, prostaglandins
`are unstable compounds and degrade readily in the presence
`of NSAIDs, thus requiring a stabiliZing agent such as
`
`US 6,183,779 B1
`2
`hydroxypropyl methylcellulose (HPMC) or polyvinylpyr
`rolidone (PVP) Which can, in turn, lessen the activity of an
`NSAID. See, for example, US. Pat. No. 4,301,146 to
`Sanvordeker, Which discloses prostaglandin E-type com
`pounds stabiliZed With hydroxypropyl methylcellulose or
`polyvinylpyrrolidone before being pressed into tablets, US.
`Pat. No. 3,954,787 to Monkhouse, Which discloses that
`lyophiliZed compositions of prostaglandin E and sodium
`chloride, cyclodextrin or polyvinylpyrrolidone are stable,
`and US. Pat. No. 5,015,481 to FranZ et al., Which discusses
`the destabiliZation of prostaglandins in the presence of the
`NSAIDs diclofenac and piroxicam.
`There is, accordingly, a need in the art to provide a
`composition for administering an NSAID Wherein the unde
`sirable gastrointestinal side effects of the drug are minimiZed
`but Wherein the drug’s therapeutic effectiveness is main
`tained. The present invention is addressed to the aforemen
`tioned need in the art and provides a stabiliZed pharmaceu
`tical composition of an NSAID and a prostaglandin, i.e., a
`composition in Which the prostaglandin is stabiliZed and the
`ef?cacy of the NSAID is maintained.
`SUMMARY OF THE INVENTION
`Accordingly, it is a primary object of the invention to
`provide a stabiliZed pharmaceutical composition for oral
`administration of an NSAID and a prostaglandin.
`It is another object of the invention to provide such a
`composition Wherein the NSAID is enterically coated.
`It is yet another object of the invention to provide such a
`composition that additionally includes a prostaglandin
`stabiliZing agent.
`It is still another object of the invention to provide such
`a composition in Which the enterically coated NSAID and
`the prostaglandin are present in discrete regions of the
`composition, such as in a bilayer tablet Wherein the enteri
`cally coated NSAID is present in a ?rst layer and the
`prostaglandin and the prostaglandin stabiliZing agent are
`present in a second layer.
`Another object of the invention is to provide a method for
`treating a patient With an NSAID-responsive condition,
`disease or disorder, Wherein the method comprises admin
`istering an NSAID to the patient in a stabiliZed pharmaceu
`tical composition as provided herein.
`Still another object of the invention is to provide a method
`for reducing the undesirable gastrointestinal side effects
`associated With the oral administration of an NSAID,
`Wherein the method comprises co-administering a prostag
`landin With the NSAID in a stabiliZed pharmaceutical com
`position as provided herein.
`Additional objects, advantages and novel features of the
`invention Will be set forth in part in the description Which
`folloWs, and in part Will become apparent to those skilled in
`the art upon examination of the folloWing, or may be learned
`by practice of the invention.
`In one embodiment, the ?rst layer of the bilayer tablet
`comprises an enterically coated nonsteroidal anti
`in?ammatory agent, and the second layer comprises a pros
`taglandin and a stabiliZing agent.
`In another embodiment, a method of treating a patient is
`provided for carrying out the present therapeutic method
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`comprising administering to the patient a pharmaceutical
`composition bilayer tablet as described herein.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIGS. 1 and 2 are schematic representations of dosage
`forms of the invention.
`DETAILED DESCRIPTION OF THE
`INVENTION
`OvervieW and De?nitions
`Before describing the present invention in detail, it is to
`be understood that this invention is not limited to particular
`drugs or drug delivery systems, as such may vary. It is also
`to be understood that the terminology used herein is for the
`purpose of describing particular embodiments only, and is
`not intended to be limiting.
`It must be noted that, as used in this speci?cation and the
`appended claims, the singular forms “a,” “an” and “the”
`include plural referents unless the context clearly dictates
`otherWise. Thus, for example, reference to “a pharmacologi
`cally active agent” includes a combination of tWo or more
`pharmacologically active agents, reference to “a stabiliZer”
`includes combinations of tWo or more stabiliZers, reference
`to “a prostaglandin” includes combinations of tWo or more
`prostaglandins, and the like.
`In describing and claiming the present invention, the
`folloWing terminology Will be used in accordance With the
`de?nitions set out beloW.
`The terms “active agent,” “drug” and “pharmacologically
`active agent” are used interchangeably herein to refer to a
`chemical material or compound Which, When administered
`to an organism (human or animal) induces a desired phar
`macologic effect. Included are derivatives and analogs of
`those compounds or classes of compounds speci?cally men
`tioned Which also induce the desired pharmacologic effect.
`An “enterically coated” drug or tablet refers to a drug or
`tablet that is coated With a substance—i.e., With an “enteric
`coating”—that remains intact in the stomach but dissolves
`and releases the drug once the small intestine is reached.
`By “pharmaceutically acceptable carrier” or “pharmaceu
`tically acceptable vehicle” are meant materials that are
`suitable for oral administration and not biologically or
`otherWise undesirable, i.e., that may be administered to an
`individual along With an active agent Without causing any
`undesirable biological effects or interacting in a deleterious
`manner With any of the other components of the pharma
`ceutical composition in Which it is contained.
`Similarly, a “pharmaceutically acceptable” salt, ester or
`other derivative of an active agent as provided herein is a
`salt, ester or other derivative Which is not biologically or
`otherWise undesirable.
`“Stabilizing agents” as used herein refer to compounds
`that loWer the rate at Which the prostaglandins degrade,
`particularly in an oral pharmaceutical formulation, in the
`presence of an NSAID, and under environmental conditions
`of storage.
`By “incompatible, as in tWo drugs that are “incompat
`ible” With respect to each other is meant that in close
`physical proximity a ?rst drug may have a deleterious effect
`on the physical or chemical stability of a second drug, and/or
`vice versa.
`By the terms “effective amount” or “therapeutically effec
`tive amount” of an agent as provided herein are meant a
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`US 6,183,779 B1
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`nontoxic but sufficient amount of the agent to provide the
`desired therapeutic effect. As Will be pointed out beloW, the
`exact amount required Will vary from subject to subject,
`depending on the age, Weight, and general condition of the
`subject, the severity of the condition being treated, and the
`like. Thus, it is not possible to specify an exact “effective
`amount.” HoWever, an appropriate “effective” amount in
`any individual case may be determined by one of ordinary
`skill in the art using only routine experimentation.
`By a “pharmacologically acceptable” compound is meant
`a material Which is not biologically or otherWise
`undesirable, i.e., the material may be administered to an
`individual along With the selected active agent Without
`causing any undesirable biological effects or interacting in a
`deleterious manner With any of the other components of the
`pharmaceutical composition in Which it is contained.
`Similarly, a “pharmacologically acceptable” salt or a “phar
`macologically acceptable” ester of a compound as provided
`herein is a salt or ester Which is not biologically or otherWise
`undesirable.
`The invention, as noted above, is in one embodiment a
`stabiliZed pharmaceutical composition for administration of
`an NSAID and a prostaglandin, Wherein the NSAID is
`enterically coated. Preferably, the composition is comprised
`of tWo discrete regions, Wherein the enterically coated
`NSAID is present in a ?rst region and the prostaglandin is
`present in a second region, along With a prostaglandin
`stabiliZing agent; an exemplary such composition is a
`bilayer tablet as shoWn in FIG. 1. The tablet 10 can have any
`geometric shape, although a generally oval shape is shoWn.
`The tablet 10 includes a ?rst layer 11 and an adjacent second
`layer 12; alternatively, as shoWn in FIG. 2, the tablet can
`comprise a ?rst region 13 adjacent to a second region 14.
`The invention is not limited With respect to the selected
`NSAID; the stabiliZed compositions of the invention can
`contain any NSAID, NSAID derivative, or combination of
`NSAIDs. Typical NSAIDs include, but are not limited to,
`acetylsalicylic acid, apaZone, diclofenac, difenpiramide,
`di?unisal, etodolac, fenbufen, ?ufenamic acid, ?urbiprofen,
`ibuprofen, indomethacin, ketoprofen, ketorolac,
`meclofenamate, mefenamic acid, nabumetone, naproxen,
`oxaproZin, piroxicam, sulindac, suprofen, tiaprofenic acid
`and tolmetin. Pharmaceutically acceptable analogs of such
`NSAIDs are suitable as Well, particularly pharmaceutically
`acceptable salts. Diclofenac, piroxicam and their salts (e.g.,
`diclofenac sodium) are particularly preferred.
`The NSAID is present in the composition in a therapeu
`tically effective amount; preferably, the composition is in
`unit dosage form. The amount of NSAID administered Will,
`of course, be dependent on the age, Weight, and general
`condition of the subject, the severity of the condition being
`treated, and the judgment of the prescribing physician.
`Suitable therapeutic amounts Will be knoWn to those skilled
`in the art and/or are described in the pertinent reference texts
`and literature. For diclofenac sodium, for example, a thera
`peutic dose is typically in the range of approximately 25 mg
`to about 75 mg per tablet, optimally about 50 mg per tablet.
`The therapeutic dosing range for a tablet containing piroxi
`cam is about 5 mg to about 50 mg per tablet, optimally about
`20 mg per tablet, While the therapeutic dosing range for a
`tablet containing naproxen is about 250 mg to 750 mg per
`tablet.
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`5
`The NSAID is enterically coated Within the stabilized
`composition of the invention. Generally, the enteric coating
`comprises a polymeric material that prevents NSAID release
`in the loW pH environment of the stomach but that ioniZes
`at a slightly higher pH, typically a pH of 4 or 5, and thus
`dissolves sufficiently in the small intestines to gradually
`release the active agent therein. Accordingly, among the
`most effective enteric coating materials are polyacids having
`a pKa in the range of about 3 to 5. Suitable enteric coating
`materials include, but are not limited to, polymeriZed
`gelatin, shellac, methacrylic acid copolymer type C NF,
`cellulose butyrate phthalate, cellulose hydrogen phthalate,
`cellulose proprionate phthalate, polyvinyl acetate phthalate
`(PVAP), cellulose acetate phthalate (CAP), cellulose acetate
`trimellitate (CAT), hydroxypropyl methylcellulose
`phthalate, hydroxypropyl methylcellulose acetate, dioxypro
`pyl methylcellulose succinate, carboxymethyl ethylcellulose
`(CMEC), hydroxypropyl methylcellulose acetate succinate
`(HPMCAS), and acrylic acid polymers and copolymers,
`preferably formed from methyl acrylate, ethyl acrylate,
`methyl methacrylate and/or ethyl methacrylate With copoly
`mers of acrylic and methacrylic acid esters (Eudragit NE,
`Eudragit RL, Eudragit RS) particularly preferred.
`The NSAID-containing region or layer can also contain
`various excipients, as is Well knoWn in the pharmaceutical
`art, provided such excipients do not exhibit a destabiliZing
`effect on any components in the composition. Thus, excipi
`ents such as binders, bulking agents, diluents, disintegrants,
`lubricants, ?llers, carriers, and the like can be combined With
`the NSAID in the core. For solid compositions, diluents are
`typicall necessary to increase the bulk of a tablet so that a
`practical siZe is provided for compression. Suitable diluents
`include dicalcium phosphate, calcium sulfate, lactose,
`cellulose, kaolin, mannitol, sodium chloride, dry starch and
`poWdered sugar. Binders are used to impart cohesive quali
`ties to a tablet formulation, and thus ensure that a tablet
`remains intact after compression. Suitable binder materials
`include, but are not limited to, starch (including corn starch
`and pregelatiniZed starch), gelatin, sugars (including
`sucrose, glucose, dextrose and lactose), polyethylene glycol,
`Waxes, and natural and synthetic gums, e.g., acacia sodium
`alginate, polyvinylpyrrolidone, cellulosic polymers
`(including hydroxypropyl cellulose, hydroxypropyl
`methylcellulose, methyl cellulose, hydroxyethyl cellulose,
`and the like), and Veegum. Lubricants are used to facilitate
`tablet manufacture; examples of suitable lubricants include,
`for example, magnesium stearate, calcium stearate, and
`stearic acid, and are preferably present at no more than
`approximately 1 Wt. % relative to tablet Weight. Disinte
`grants are used to facilitate tablet disintegration or
`“breakup” after administration, and are generally starches,
`clays, celluloses, algins, gums or crosslinked polymers. If
`desired, the pharmaceutical composition to be administered
`may also contain minor amounts of nontoxic auxiliary
`substances such as Wetting or emulsifying agents, pH buff
`ering agents and the like, for example, sodium acetate,
`sorbitan monolaurate, triethanolamine sodium acetate, tri
`ethanolamine oleate, etc. If desired, ?avoring, coloring
`and/or sWeetening agents may be added as Well. Other
`optional components for incorporation into an oral formu
`lation herein include, but are not limited to, preservatives,
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`US 6,183,779 B1
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`suspending agents, thickening agents, and the like. Fillers
`include, for example, insoluble materials such as silicon
`dioxide, titanium oxide, alumina, talc, kaolin, poWdered
`cellulose, microcrystalline cellulose, and the like, as Well as
`soluble materials such as mannitol, urea, sucrose, lactose,
`dextrose, sodium chloride, sorbitol, and the like.
`The second region or layer of the composition contains a
`prostaglandin to reduce or eliminate the undesirable side
`effects of the NSAID folloWing oral administration. Thus,
`preferred prostaglandins are those Which are effective in this
`regard, ie are typically “anti-ulcerogenic.” The prostaglan
`din is selected from the group consisting of naturally occur
`ring prostaglandins, derivatives of naturally occurring pros
`taglandins such as hydrolyZable loWer alkyl esters thereof,
`synthetic prostaglandins and semisynthetic prostaglandins.
`The “naturally occurring” prostaglandins useful in con
`junction With the present invention are PGEO, PGEl, PGAl,
`PGBl, PGFm, 19-hydroxy-PGA1, 19-hydroxy-PGB1,
`PGE2, PGA2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2,
`PGE3, PGFm and PGI2. The term “synthetic prostaglandin
`derivatives” is intended to encompass knoWn or unknoWn
`compounds related to the aforementioned naturally occur
`ring prostaglandins that are chemically synthesiZed using
`starting materials other than one of the naturally occurring
`prostaglandins. The term “semisynthetic prostaglandin
`derivatives” refers to knoWn or unknoWn compounds related
`to the aforementioned naturally occurring prostaglandins
`and that are synthesiZed therefrom. Synthetic and semisyn
`thetic prostaglandins include, but are not limited to, carbo
`prost tromethamine, dinoprost tromethamine, dinoprostone,
`lipoprost, gemeprost, metenoprost, sulprostone and tiaprost.
`The preferred prostaglandin is misoprostol, present in an
`amount of about 50 to 500 pg per tablet, more preferably
`about 100 to 200 pg per tablet. Misoprostol is released
`immediately in the gastrointestinal tract, and produces its
`gastric anti-secretory effect thereby effectively reducing
`and/or eliminating the ulcerogenocity of the NSAID.
`The region or layer of the present pharmaceutical com
`position containing the prostaglandin also contains a pros
`taglandin stabiliZing agent such as hydroxypropyl methyl
`cellulose or polyvinylpyrrolidone, as disclosed in US. Pat.
`No. 4,301,146 to Sanvordeker. Other stabiliZing agents
`include, but are not limited to: cellulosic polymers such as
`hydroxypropyl cellulose, hydroxyethyl cellulose, methyl
`cellulose, ethyl cellulose, cellulose acetate, cellulose acetate
`phthalate, cellulose acetate trimellitate, hydroxypropyl
`methylcellulose phthalate, microcrystalline cellulose and
`carboxymethylcellulose sodium; and vinyl polymers and
`copolymers such as polyvinyl acetate, polyvinylacetate
`phthalate, vinylacetate crotonic acid copolymer, and
`ethylene-vinyl acetate copolymers. The stabiliZing agent is
`present in an amount effective to provide the desired stabi
`liZing effect; generally, this means that the ratio of prostag
`landin to the prostaglandin stabiliZing agent is at least about
`1:500 W/W, more preferably about 1:99 W/W.
`The prostaglandin-containing region or layer can also
`contain various excipients, as discussed With respect to the
`NSAID-containing region or layer, i.e., excipients that do
`not exhibit a destabiliZing effect and include, for example,
`binders, bulking agents, diluents, disintegrants, lubricants,
`?llers, carriers, and the like.
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`US 6,183,779 B1
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`The active agents in the present composition, i.e., both the
`NSAID and the prostaglandin, may be administered in the
`form of a pharmacologically acceptable salt, ester, amide,
`prodrug or analog or as a combination thereof Salts, esters,
`amides, prodrugs and analogs of the active agents may be
`prepared using standard procedures knoWn to those skilled
`in the art of synthetic organic chemistry and described, for
`example, by J. March, “Advanced Organic Chemistry:
`Reactions, Mechanisms and Structure,” 4th Ed. (NeW York:
`Wiley-Interscience, 1992). For example, basic addition salts
`are prepared from the neutral drug using conventional
`means, involving reaction of one or more of the active
`agent’s free hydroxyl groups With a suitable base. Generally,
`the neutral form of the drug is dissolved in a polar organic
`solvent such as methanol or ethanol and the base is added
`thereto. The resulting salt either precipitates or may be
`brought out of solution by addition of a less polar solvent.
`Suitable bases for forming basic addition salts include, but
`are not limited to, inorganic bases such as sodium hydroxide,
`potassium hydroxide, ammonium hydroxide, calcium
`hydroxide, trimethylamine, or the like. Preparation of esters
`involves functionaliZation of hydroxyl groups Which may be
`present Within the molecular structure of the drug. The esters
`are typically acyl-substituted derivatives of free alcohol
`groups, i.e., moieties Which are derived from carboxylic
`acids of the formula RCOOH Where R is alkyl, and prefer
`ably is loWer alkyl. Esters can be reconverted to the free
`acids, if desired, by using conventional hydrogenolysis or
`hydrolysis procedures. Preparation of amides and prodrugs
`can be carried out in an analogous manner. Other derivatives
`and analogs of the active agents may be prepared using
`standard techniques knoWn to those skilled in the art of
`synthetic organic chemistry, or may be deduced by reference
`to the pertinent literature.
`Bilayer tablets as shoWn in FIGS. 1 and 2 provide several
`manufacturing advantages. The bilayer tablet is made in a
`single step compression, thereby eliminating the operations
`of prior methods involving ?rst compressing one of the
`actives as a core tablet and subsequently coating the core,
`and additionally eliminating the concomitant steps of
`in-process and quality controls for manufacturing tWo dif
`ferent tablets. Thus, the bilayer tablet is easier and more
`economical to manufacture than prior compositions that
`separate a ?rst drug and a second drug into physically
`discrete regions of a single dosage form.
`The tablets are manufactured by ?rst enterically coating
`the NSAID and separately stabiliZing the prostaglandin With
`the stabiliZing agent. Apreferred method for forming tablets
`herein is by direct compression of the poWders containing
`the enterically coated NSAID and prostaglandin, optionally
`in combination With diluents, binders, lubricants,
`disintegrants, colorants or the like. As an alternative to direct
`compression, compressed tablets can be prepared using
`Wet-granulation or dry-granulation processes. Tablets may
`also be molded rather than compressed, starting With a moist
`material containing a suitable Water-soluble lubricant. Pre
`ferred tablets herein are manufactured using compression
`rather than molding, hoWever.
`In an alternative embodiment, the enterically coated
`NSAID and the stabiliZed prostaglandin are mixed into a
`single granulation, and the admixture is compressed into a
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`60
`
`65
`
`8
`tablet or ?lled into a capsule. In the admixture, there is a
`random possibility of the NSAID and the prostaglandin
`coming into contact With each other. HoWever, the enteric
`coating on the NSAID granules provides a physical barrier
`betWeen the NSAID and the prostaglandin, thereby mini
`miZing direct physical contact betWeen the tWo active
`agents. Capsule materials may be either hard or soft, and are
`preferably sealed, such as With gelatin bands or the like.
`Tablets and capsules for oral use Will generally include one
`or more commonly used excipients as discussed earlier
`herein.
`For administration of the dosage form, i.e., the tablet or
`capsule containing the enterically coated NSAID and the
`stabiliZed prostaglandin, a total Weight in the range of
`approximately 100 mg to 1000 mg is used. The dosage form
`is orally administered to a patient suffering from a condition
`for Which an NSAID Would typically be indicated,
`including, but not limited to: alleviation of pain, e.g.,
`arthritic pain, lumbosacral pain, musculo-skeletal pain, pain
`associated With a sore throat, and the like; treatment of
`in?ammatory conditions and diseases such as osteoarthritis
`and rheumatoid arthritis; and treatment of psoriasis.
`It is to be understood that While the invention has been
`described in conjunction With the preferred speci?c embodi
`ments thereof, that the foregoing description as Well as the
`examples Which folloW are intended to illustrate and not
`limit the scope of the invention. Other aspects, advantages
`and modi?cations Within the scope of the invention Will be
`apparent to those skilled in the art to Which the invention
`pertains.
`All patents, patent applications, and publications men
`tioned herein are hereby incorporated by reference in their
`entireties.
`
`EXAMPLE 1
`A misoprostol-HPMC complex 1% Was made by mixing
`misoprostol With HPMC in a ratio of 1:99. Misoprostol, an
`oily, viscous liquid Was stabiliZed as a solid dispersion using
`hydroxypropyl methycellulose as substrate and spraying
`misoprostol from an alcoholic solution in a ?uid-bed granu
`lator. The granules so obtained Were mixed With excipients
`as described in Example 2.
`EXAMPLE 2
`The granules of the misoprostol-HPMC complex pre
`pared in Example 1 Were mixed With the folloWing excipi
`ents.
`
`Ingredient
`Misoprostol-HPMC Complex 1%
`Microcrystalline Cellulose PH 102
`Crospovidone XL
`Microcrystalline Cellulose PH 102
`Hydrogenated Castor Oil Powder
`Colloidal Silicon Dioxide
`
`mg per 200 mg
`20.0
`141.8
`8.0
`29.0
`0.8
`0.4
`
`The blend so obtained Was used in the preparation of the
`bilayer tablets as described in Examples 5 and 6 beloW.
`EXAMPLE 3
`A blend of enterically coated granules of diclofenac Was
`prepared as folloWs.
`
`

`
`US 6,183,779 B1
`
`Ingredient
`
`mg per 200 mg
`
`Granulation I
`
`Diclofenac Sodium
`Lactose Hydrous Spray Dried
`Microcrystalline Cellulose PH 102
`Starch (Corn) Tablet White
`Povidone PVK-30
`Granulation II
`Methacrylic Acid Copolymer Type C
`Triacetin
`Antifoam 1520-US
`Microcrystalline Cellulose PH 102
`Hydrogenated Castor Oil PoWder
`
`50.0
`15.0
`16.0
`9.0
`4.0
`
`5.4
`0.54
`0.06
`98
`2
`
`In the ?rst step, granulation I Was prepared by blending
`diclofenac sodium With lactose hydrous spray dried, micro
`crystalline cellulose PH 102, starch (corn) tablet White, and
`an aqueous solution of Povidone PVK-30 in a ?uid-bed
`granulator. The granules so obtained Were enteric coated in
`a ?uid-bed granulator by the application of an enteric
`dispersion system containing methacrylic acid copolymer
`type C, NF, triacetin, and antifoam 1520-US. The enterically
`coated diclofenac granules Were then blended With micro
`crystalline cellulose PH 102 and hydrogenated castor oil
`powder.
`
`EXAMPLE 4
`A second composition of the diclofenac layer for the
`pharmaceutical delivery system of bilayer tablet Was pre
`pared consisting of enterically coated granules of diclofenac.
`The tablet had the folloWing composition, and the excipients
`Were blended according to Example 3.
`
`Ingredients
`
`mg per 200 mg
`
`Granulation I
`
`Diclofenac Sodium
`Lactose Hydrous Spray Dried
`Microcrystalline Cellulose PH 102
`Starch (Corn) Tablet White
`Povidone PVK-30
`Granulation II
`Methacrylic Acid Copolymer Type C
`Triacetin
`Antifoam 1520-US
`Hydrogenated Castor Oil PoWder
`
`50.0
`15.0
`18.0
`9.0
`4.0
`
`2.70
`0.27
`0.03
`1.0
`
`EXAMPLE 5
`A bilayer tablet Was prepared containing a misoprostol
`solid dispersion and enterically coated granules of
`diclofenac. The enterically coated NSAID prepared in
`Example 3 Was ?rst placed in the tablet press, followed by
`the misoprostol blend prepared in Example 2. The tableting
`mechanism Was then actuated to give a bilayer tablet.
`EXAMPLE 6
`The misoprostol blend, prepared in Example 2, is mixed
`With the diclofenac blend prepared in either Example 3 or
`Example 4. The admixture so obtained is compressed into a
`tablet, or is ?lled into a capsule shell.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`10
`What is claimed is:
`1. A solid pharmaceutical composition for oral
`administration, comprising:
`a therapeutically effective amount of enterically coated
`granules of a nonsteroidal anti-in?ammatory drug
`(NSAID);
`an effective anti-ulcerogenic amount of a prostaglandin;
`and
`an effective stabilizing amount of a prostaglandin stabi
`lizing agent.
`2. The composition of claim 1, comprising a dosage form
`having tWo discrete regions, Wherein the enterically coated
`NSAID is present in the ?rst of said tWo regions and the
`prostaglandin and prostaglandin stabilizing agent are present
`in the second of said tWo regions.
`3. The composition of claim 2, comprising a bilayer
`tablet.
`4. The composition of claim 2, comprising a capsule.
`5. The composition of claim 1, comprising an admixture
`of the enterically coated NSAID, prostaglandin and pros
`taglandin stabilizing agent.
`6. The composition of claim 5, in the form of a tablet.
`7. The composition of claim 1, Wherein the