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`US006319519B2
`
`(12) United States Patent
`Woolfe et al.
`
`(10) Patent No.: US 6,319,519 B2
`(45) Date of Patent:
`Nov. 20, 2001
`
`(54) ANTI-INFLAMMATORY PHARMACEUTICAL
`FORMULATIONS
`
`(56)
`
`
`
`References Cited
`
`(75) Inventors: Austen John Woolfe, North Weald;
`
`Gordon Mcintyre, Bishops
`Stortford,
`both of (GB); Nitin Vadilal Sheth,
`
`Goshen, NY (US)
`
`U.S. PATENT DOCUMENTS
`
`5,232,704 8/1993 Franz et a!. .......................... 424/456
`
`FOREIGN PATENT DOCUMENTS
`
`Norton HealthCare Ltd., Essex (GB)
`(73) Assignee:
`
`
`1020182A2 7/2000 (EP) .
`
`1068867A2 1!2001 (EP) .
`
`W091!16886 11/1991 (WO) .
`
`
`( *) Notice: Subject to any disclaimer, the term of this
`
`W091!16895 11/1991 (WO) .
`
`
`
`patent is extended or adjusted under 35
`
`W000/01368 1!2000 (WO) .
`U.S.C. 154(b) by 0 days.
`
`W000/15200 3/2000 (WO) .
`
`W00056339 9/2000 (WO) .
`
`
`
`(21) Appl. No.: 09/789,365
`
`W0/91!16895 11/1991 (WO) .......................... A61K/31!557
`
`Filed: Feb. 20, 2001
`(22)
`
`
`
`Related U.S. Application Data
`
`(63)
`
`
`
`1999, now abandoned
`(60)
`
`
`
`1998.
`
`ABSTRACT
`
`Primary Examiner-Thurman K. Page
`
`Assistant Examiner-Chareese L. Evans
`
`(74) Attorney, Agent, or Firm-B eyer Weaver & Thomas,
`LLP
`Continuation of application No. 09/346,122, filed on Jul. 1,
`(57)
`Provisional application No. 60/091,960, filed on Jul. 7,
`
`
`
`
`A pharmaceutical dosage form comprising a tablet contain­
`Int. Cl? ....................................................... A61K 9/24
`
`
`ing a non-steroidal anti inflammatory drug and misoprostol,
`(51)
`
`
`
`wherein the non-steroidal anti inflammatory drug is in the
`
`U.S. Cl. .......................... 424/472; 424/464;
`(52)
`424/465;
`form of coated pellets.
`
`
`
`424/490; 424/494; 424/497; 424/499
`Field of Search .....................................
`(58)
`
`424/464, 465,
`28 Claims, No Drawings
`
`424/472, 480, 489, 490, 494, 495, 497
`
`

`
`
`
`US 6,319,519 B2
`
`1
`ANTI-INFLAMMATORY PHARMACEUTICAL
`FORMULATIONS
`
`2
`not occur. Techniques which can be used include coating the
`
`
`
`
`
`
`drug on a non-pariel core preferably composed of inert sugar
`
`
`or similar substance and then overcoating with the required
`This application claims the benefit of U.S. Provisional
`
`
`coating before compression.
`
`
`Application No. 60/091,960 filed on Jul. 7, 1998, which is 5
`A preferred method is to form pellets by co-acervation or
`
`
`
`
`incorporated herein by reference.
`
`
`
`
`alternatively by precipitation of the pellets from solution as
`
`
`described by Zaruboru, Fell and Collett, (Int.J.Pharm, 1995,
`
`
`This application is a continuation of Ser. No. 09/346,122
`
`
`125, 151-5).
`Jul. 1, 1999 now abandoned,.
`
`This invention relates to pharmaceutical formulations of
`
`
`
`In another preferred technique the pellets may be formed
`
`
`
`
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`
`
`anti-inflammatory drugs, particularly non-steroid and anti­
`10
`by spheronisation,
`
`
`rotogranulation or a similar technique.
`
`inflammatory drugs (NSAlDs).
`
`
`Preferably the pellets should be soft enough to deform
`These NSAlDs are used for the treatment of inflamma­
`
`
`
`
`slightly under compression to avoid cracking but not too soft
`
`
`
`tory conditions such as osteoarthritis or rheumatoid arthritis.
`
`so as to deform significantly which will also cause cracking
`
`A side effect of the oral administration of NSAlDs particu­
`
`
`
`or rupture of the coat. A suitable mixture of drug with a
`
`larly with long term usage, is a liability to ulcerogenic
`15
`
`
`
`
`suitable amount of an excipient or several excipients can be
`
`
`
`
`effects. NSAlD induced ulcers in the stomach are potentially
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`
`
`
`found by simple, routine experiments. Suitable excipients
`
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`dangerous because few or no symptoms may be detected
`
`
`
`
`include polyvinyl pyrolidone, sugars and cellulose deriva­
`
`
`until significant damage has been caused. Certain
`
`
`
`
`tives particularly microcrystalline cellulose. A coating for
`
`
`
`prostaglandins, for example misoprostol have been shown to
`
`
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`20 the pellets may employ cellulose derivatives eg hydroxypro­
`
`reduce and even prevent such ulcers.
`
`
`pyl methyl cellulose, methacrylic acid and derivatives eg
`
`
`It has been found experimentally that it is necessary for
`
`methyl methacrylates for example, Eudragrit® (Rhom
`
`
`
`
`the prostaglandin to be released before the NSAlD so as to
`
`
`Pharma), especially Eudragrit L or S. Other standard enteric
`
`
`protect the stomach from the effects of the NSAlD. It is
`
`
`
`coating materials for example phthalates, eg cellulose
`
`
`therefore preferable that the NSAlD is coated to delay
`
`
`
`release. The coating may be a standard hydroxypropyl
`
`
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`25 acetate phthalate or preferably hydroxypropylacetate phtha­
`
`
`
`late or polyvinylacetate phthalate. Mixtures of these and
`
`
`methyl cellulose coat of a thickness sufficient to delay
`
`
`
`other materials may be used to produce delay release coated
`
`
`
`
`release in the stomach for a short period, an enteric coat to
`
`
`
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`beads. Normally coating will include plasticisers eg poly-
`
`
`
`delay NSAlD release until it reaches the intestine, or a delay
`
`
`
`
`ethylene glycol, triacilin or phthalate esters.
`
`
`
`release coating to allow drug release over a period of time
`
`
`
`It has been found in practice that smaller pellets are better
`
`to permit less frequent dosing.
`30
`
`
`
`for use in accordance with this invention, preferably
`
`
`
`In addition the coating may act as a barrier between the
`
`
`between 0.25 mm to 1.5 mm in diameter. Most preferably
`
`
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`NSAlD and the prostaglandin to prevent decomposition of
`
`
`
`pellets between 0.8 mm to 1.2 mm diameter are employed.
`
`
`
`the prostaglandin caused by instability in the pressure of the
`
`
`
`Pellets of this diameter show less tendency to crack under
`NSAlD.
`
`35 the compression forces.
`
`
`
`EP-527887B discloses a pharmaceutical composition
`The external compression material will include a
`
`
`
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`
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`comprising a core of an NSAlD surrounded by a coating
`
`
`
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`prostaglandin, preferably misoprostol together with inert
`
`
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`containing the prostaglandin. The core is preferably coated
`
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`excipients. The prostaglandin may be used neat or it may be
`
`
`with a barrier of enteric coat before a mantle coat is added.
`
`
`
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`preferably diluted on an inert material. A preferred material
`
`
`
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`No experimental details are given. It appears that this dosage
`
`
`
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`40 is misoprostol diluted on hydroxypropyl methyl cellulose or
`
`
`
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`form is made by press-coating, ie a tablet core containing the
`
`
`
`polyvinyl pyrolidone. Other diluents may be used. The other
`drug is made, and coated before being put in a second
`
`
`
`materials which may be employed include inert fillers,
`
`
`tableting operation to cover the coated core. Such a proce­
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`
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`binders, lubricants and colorants as used in normal pharma­
`
`
`
`dure requires use of specialised equipment which is not a
`
`
`
`
`
`
`useful material for this ceutical tablet making. An especially
`
`
`normal pharmaceutical production tool and hence would
`need significant investment.
`
`
`
`45 invention is microcrystalline cellulose. The dosage of pros­
`
`
`
`taglandin will be chosen to be suitable to prevent or reduce
`
`
`
`According to the present invention an oral pharmaceu­
`
`
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`stomach ulceration caused by the NSAlD. A suitable dose of
`
`
`
`tical dosage form comprises a tablet containing a non­
`
`
`
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`misoprostol is between 100-200 micrograms per tablet but
`
`
`
`steroidal anti inflammatory drug and misoprostol, wherein
`
`
`this may be increased or decreased depending on the NSAlD
`
`
`the non-steroidal anti inflammatory drug is in the form of
`50 used.
`coated pellets.
`
`
`The NSAlD is preferably but not exclusively one of
`The coated pellets and prostaglandin mixture are then
`
`
`
`
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`reasonably low weight per standard dose. That is an NSAlD
`
`
`
`
`compressed on conventional tableting equipment. Tablets
`
`
`where the usual dose is 200 mg or below. Examples of such
`
`may have a break line or break lines to facilitate smaller
`
`
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`NSAlDs include indomethacin, piroxicam, meloxicam,
`
`
`doses. The tablet may be film or sugar coated if required.
`
`
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`flubiprofen, naproxan, ketoprofen, tenoxicam or similar
`
`
`
`
`Bilayer tablets may be employed. The non-steroidal anti
`55
`
`
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`molecules. Most preferably the drug is diclofenac sodium.
`
`
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`inflammatory drug and excipients may be compressed into
`
`
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`the lower half of the tablet and the misoprostol together with
`
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`Enteric coated or delay release coated pellets have not
`
`
`
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`excipients superimposed and pressed onto it. A barrier layer
`been widely used because many workers have found damage
`
`
`
`may be provided between the two active ingredient­
`
`or cracking to the enteric or delay release coating during the
`
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`
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`containing layers. The misoprostol containing layer may
`tablet compression stage. The present invention will work 60
`
`
`
`
`
`
`
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`incorporate excipients to facilitate rapid dissolution of this
`
`
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`most effectively if the coating remains intact during com­
`
`active ingredient.
`pression.
`It is possible to produce such pellets by conventional The invention is further described by means of example
`
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`means although care is needed to ensure coat cracking does but not in any limitative sense.
`
`

`
`
`
`US 6,319,519 B2
`
`3
`EXPERIMENT 1
`
`
`
`The following ingredients were employed.
`
`Diclofenac Pellets Enteric Coated 40%
`
`
`
`Misoprostol Dispersion on HPMC (1:100)
`
`1) Microcrystaline Cellulose (Avicel102)
`
`2) Sodium Stored Glycollate
`
`3) Hydrogenated Cottonseed Oil
`
`123 mg
`20 mg
`33 mg
`3 mg
`1 mg
`
`5
`
`EXPERIMENT 2
`
`EXPERIMENT 3
`
`
`
`The following ingredients were employed.
`
`Mix 1
`
`Mix 2
`
`Diclofenac Pellets Enteric Coated 40%
`
`123 mg
`
`Microcrystalline Cellulose
`133 mg
`Sodium Starch Glycollate
`3 mg
`
`
`Hydrogenated Cottonseed Oil
`1 mg
`
`Misoprostol dilution (1 :100)
`20 mg
`
`Microcrystalline Cellulose
`196 mg
`3 mg
`Sodium starch Glycollate
`1 mg
`
`
`Hydrogenated Cottonseed Oil
`
`4
`including a layer of non-steroidal anti inflammatory drugs
`
`
`
`
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`sprayed or otherwise coated on a non-pariel core.
`
`5. A dosage form as claimed in claim 1 wherein
`the
`
`
`coating is an enteric coating.
`
`6. A dosage form as claimed in claim 5 wherein the enteric
`
`
`
`
`coating is selected from: a methylmethacrylate copolymer, a
`
`
`
`
`
`polyvinylacetate phthalate, cellulose acetate phthalate, or
`
`
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`hydroxypropylmethyl cellulose phthalate.
`
`7. A dosage form as claimed in claim 6 wherein the
`enteric
`
`10 coat includes a plasticiser.
`
`8. A dosage form as claimed in claim 5 including
`a barrier
`The excipients 1+2 and misoprostol were sieved through
`
`
`
`
`inert coat disposed between the drug core and the enteric
`
`
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`pellets were added and a 250 ,urn screen. The diclofenac
`coating.
`
`
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`blended for 15 min in a cube blender. The lubricant 3) was
`9. A dosage form as claimed in claim 7 wherein
`
`the barrier
`
`
`added and the mixture was reblended for 5 min and com-15
`
`coat is a cellulose derivative.
`
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`pressed at 180 mg/tablet.
`
`10. A dosage form as claimed in claim 1 wherein
`the
`
`
`
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`pellets are coated with a barrier coat adapted to delay release
`
`
`of the non-asteroidal anti inflammatory drug.
`
`11. A dosage form as claimed in claim 1 wherein
`the
`The mixture from Experiment 1 was blended with the
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`20 pellets are coated with a delay release coat adapted to release
`
`
`
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`equivalent of another 100 mg of microcrystalline cellulose
`
`
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`the drug throughout the gastrointestinal tract.
`
`and was then compressed at 280 mg/tablet.
`
`12. A dosage form as claimed in claim 11 wherein
`the
`
`
`
`delay release coat is formed from a methacrylate polymer or
`
`
`
`a mixture of a methacrylate polymer and a cellulose deriva-
`25 tive.
`13. A dosage form as claimed in claim 1 wherein
`
`the
`
`
`pellets have a diameter of 0.25 to 1.5 mm.
`
`14. A dosage form as claimed in claim 13 wherein
`the
`
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`pellets have a diameter of 0.8 to 1.2 mm.
`
`15. A dosage form as claimed in claim 1 including
`one or
`30
`
`
`
`
`more additional excipients selected from binders, lubricants,
`
`
`
`colorants, bulking agents and disintegrants.
`
`16. A dosage form as claimed in claim 1 wherein
`the
`
`
`non-steroidal anti inflammatory drug is diclofenac.
`
`17. A dosage form as claimed in claim 1 wherein
`the
`35
`
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`non-steroidal anti inflammatory drug is ketoprofen.
`
`
`
`Mixture 1 was prepared with sieved excipients and then
`
`18. A dosage form as claimed in claim 1 wherein
`the
`
`
`compressed to form a layer, having a weight of 260 mg.
`
`
`non-steroidal anti inflammatory drug is naproxen.
`
`
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`Mixture 2 was prepared and compressed on top of the
`
`19. A dosage form as claimed in claim 1 wherein
`the
`
`diclofenac layer to atop weight of 120 mg, ie total 360 mg.
`
`
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`40 non-steroidal anti inflammatory drug is selected from piroxi­
`
`
`
`
`The resulting bilayer tablets were overcoated with an
`cam and meloxicam.
`
`
`HPMC taste masking coat. The bead diameter was 1.05 to
`
`20. A dosage form as claimed in claim 1 comprising
`a
`1.16 mm.
`
`
`
`tablet overcoated with a sugar or cellulose film barrier
`Results
`coating.
`
`Experiment 1 using USP baskets
`21. A dosage form as claimed in claim 1 comprising
`
`a
`45
`
`
`Dissolution in acid 0.1 MHCL for 2 hrs
`
`
`
`tablet overcoated with a barrier or taste masking coating.
`
`22. A dosage form in claim 1 comprising
`as claimed
`a
`Less than 4% release.
`
`
`
`
`
`tablet wherein the ratio of diclofenac to excipients either in
`
`Dissolution in ph 6.8 buffer
`
`
`
`the whole tablet or in the diclofenac layer is between 70:30
`
`98-106% release after 1 hr
`
`
`
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`Scanning Electronic Microscopy showed no breakage of 50
`and 30:70 parts by weight.
`23. A method of manufacture
`
`
`
`
`the enteric coating of the pellets after compression.
`of a pharmaceutical dosage
`
`in claim 1 wherein
`form as claimed
`
`the pellets are formed by
`
`What is claimed is:
`1. A pharmaceutical
`
`
`
`
`extrusion and spheronisation of a mixture containing a
`
`dosage form comprising a tablet
`
`
`
`non-steroidal anti inflammatory drug, followed by coating
`comprising a non-steroidal anti inflammatory drug, miso­
`
`
`
`
`prostol and an excipient to facilitate dissolution of the
`
`
`
`
`55 with a barrier coat.
`24. A method of manufacture
`
`
`
`misoprostol before dissolution of the non-steroidal anti
`of a dosage form as claimed
`in claim 1 wherein
`
`
`
`inflammatory drug, wherein the non-steroidal anti inflam­
`
`
`the pellets are made by coasservation or
`
`matory drug is in the form of coated pellets.
`
`precipitation from solution.
`
`
`
`2. A dosage form as claimed in claim 1 containing 25. A method as claimed in claim 24 wherein
`a
`an enteric
`
`
`
`
`
`
`
`uniform mixture of coated non-steroidal anti inflammatory coat is formed by contacting solutions of an alkali salt of a
`60
`
`pellets and misoprostol.
`
`
`
`non-steroidal anti inflammatory drug, and enteric form
`
`3. A dosage form as claimed in claim 1 comprising
`
`
`forming polymer and an acid.
`a
`
`26. A method as claimed in claim 24 wherein
`bilayer tablet containing coated non-steroidal anti inflam­
`
`
`
`
`the miso­
`
`
`
`
`
`
`
`matory pellets in one layer and misoprostol in a second prostol is absorbed onto hydroxypropylmethylcellulose or
`layer.
`
`
`
`65 other cellulose derivative prior to incorporation into a tablet.
`
`4. A dosage form as in claim 1 wherein
`27. A method of manufacture
`claimed
`the pellets
`
`of a pharmaceutical tablet
`
`
`
`
`
`
`
`include an overcoating of a barrier layer upon a pellet comprising the steps of mixing a coated pellet containing a
`
`

`
`
`
`US 6,319,519 B2
`
`5
`6
`non-steroidal anti inflammatory drug together with a powder
`
`
`
`lubricants; compressing the mixture to form the bottom half
`
`
`
`
`
`
`containing misoprostol absorbed on a cellulose, polyvinyl­
`
`
`
`of a tablet and superimposing a mixture of misoprostol
`
`
`
`
`chloride or other excipient optionally together with one or
`
`
`
`absorbed on a cellulose or polyvinylchloride or other mate­
`
`
`
`
`
`more binding agents, bulking agents, disintegrants and lubri­
`
`
`
`
`rial together with or more optional excipients selected from
`
`
`cants and compressing the mixture to form tablets.
`
`
`
`
`5 binders, bulking agents, disintegrants and lubricants; to form
`28. A method of manufacture
`
`of a pharmaceutical bilayer
`
`
`a tablet suitable for human administration.
`
`
`
`
`
`tablet consisting of mixing, coated pellets containing a
`
`
`
`non-steroidal anti inflammatory drug with optional excipi­
`
`
`
`
`
`ents selected from binders, bulking agents, disintegrants and
`
`* * * * *