FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL COMPOSITION'
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

Technical Field
The present invention relates to pharmaceutical composition, containing a combination of a nonsteroidal anti-inflammatory drug (NSAID) and a Prostaglandin.
Background Of Invention
Nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a class of drugs which have therapeutic value especially for the treatment of inflammatory conditions such as exhibited in inflammatory diseases like osteoarthritis and rheumatoid arthritis. While the NSAIDs present a beneficial therapeutic value, they also exhibit an undesirable ulcerogenic effect generally associated with chronic use. NSAID induced ulcers in the stomach can be dangerous. Such ulcers generally exhibit few or no symptoms and may cause bleeding when undetected. In some instances, bleeding ulcers can prove fatal.
Certain prostaglandins have been shown to prevent NSAID induced ulcers. Misoprostol is one such prostaglandin which has been accepted for use in the treatment of NSAID induced ulcers in many countries, including the United States.
It is desirable to provide a pharmaceutical composition which exhibits the beneficial properties of an NSAID and which also exhibits the beneficial properties of misoprostol for countering the ulcerogenic side effects attendant to NSAID administration. This can be achieved by combining an NSAID and misoprostol in a single pharmaceutical tablet. However, this is not easy to do, because misoprostol is highly unstable, and it is thus desirable not to have the misoprostol and NSAID mixed together, so as to prevent any deleterious effect of the NSAID on the stability of the misoprostol.
One solution to this problem, which is disclosed in U.S. Pat. No. 5,601,843 is to produce a composition in the form of a tablet comprising within it a smaller tablet wherein the smaller tablet i.e. the inner tablet may be coated with an inert film coating. The inner tablet comprises the NSAID and the outer tablet comprises the misoprostol.
Another solution to the aforesaid problem is given in US Pat. No.6,740,340 which describes process to prepare pharmaceutical tablet comprising a shell in which is

embedded one smaller tablet comprising an NSAID and the other smaller tablet comprises misoprostol, whereby the two smaller tablets being protected by said shell. The tablet containing diclofenac or salt thereof is coated with an enteric film coating and the misoprostol is used in the form of dispersion in hydroxypropyl methylcellulose.
Another approach to solve the above mentioned problem is given in US Pat. No.6,287,600.It provides a composition in which the enterically coated NSAID and prostaglandin are present in discrete regions of the composition, such as in a bilayer tablet wherein the enterically coated NSAID is present in a first layer and the prostaglandin with a prostaglandin stabilizing agent such as hydroxypropyl methylcellulose or polyvinylpyrrolidone are present in a second layer.
The approach in US Pat. No. 6,656,503 suggests a pharmaceutical composition in the form of a tablet comprising a core and a thin solvent based film coating applied over the core, wherein the core comprises an NSAID and the film coating comprises a polymer and misoprostol. The NSAID core is coated with an enteric coat. An inert overcoating is applied over the enteric coating prior to applying the polymer and misoprostol coating.
Thus there still remains a need to provide stable pharmaceutical composition comprising NSAID and Prostaglandin to solve the problem of ulcerogenic effect of NSAID and the unstability of Prostaglandin when given along with NSAID as a single dose.
Accordingly, the present invention provides a stabilized pharmaceutical composition of an NSAID and a prostaglandin, wherein the prostaglandin is stabilized and the efficacy of the NSAID is maintained with other pharmaceutically acceptable carriers.
Objectives of the invention
The object of the present invention is to provide a pharmaceutical composition comprising an NSAID or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof and a prostaglandin or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof with other pharmaceutically acceptable carriers.

A further object of the present invention is to provide a pharmaceutical composition comprising an NSAID or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof and a prostaglandin or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof with other pharmaceutically acceptable carriers thus providing a stable formulation.
A still further object is to provide a pharmaceutical composition that avoids the ulcerogenic effect of NSAID.
Another object is to provide a pharmaceutical composition that avoids the unstability of prostaglandins.
Yet another object of the present invention is to provide a method for the manufacture of the above mentioned pharmaceutical composition.
Summary of the invention
According to first aspect, there is provided by the present invention a solid oral pharmaceutical composition comprising a nonsteroidal anti-inflammatory drug (NSAID) or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof and prostaglandin or its salts, solvates, tautomers, derivatives, enantiomers, isomers ,hydrates, prodrugs or polymorphs thereof; with other pharmaceutically acceptable carriers.
In another aspect of the present invention there is provided a solid oral pharmaceutical composition comprising a nonsteroidal anti-inflammatory drug (NSAID) or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof and a prostaglandin or its salts, solvates, tautomers, derivatives, enantiomers, isomers .hydrates, prodrugs or polymorphs thereof ; with other pharmaceutically acceptable carriers wherein the NSAID is coated by prostaglandin from three sides except one side that remains open.
According to another aspect of the present invention there is also provided a process for the manufacture a pharmaceutical composition comprising an NSAID or its salts,

solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof and a prostaglandin or its salts, solvates, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof with other pharmaceutically acceptable carriers.
Detailed Description of Invention
As stated above, combining an NSAID and Prostaglandin in a single tablet is not an easy task, because prostaglandins are highly unstable, and it is thus desirable not to have the prostaglandin and NSAID mixed together, so as to prevent any deleterious effect of the NSAID on the stability of prostaglandin.
The present invention provides a pharmaceutical composition comprising an NSAID or its salts, solvates, tautomers ,derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof and a prostaglandin or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof with other pharmaceutically acceptable carriers which resolves the problem in the prior art.
The present invention provides a solid oral pharmaceutical composition preferably in the form of a tablet comprising a core, wherein the core comprises an NSAID which is compressed with Prostaglandin granules on three sides with one side open. The NSAID and Prostaglandin is preferably separated by enteric coating.
The NSAID may be selected from, but is not limited to acetylsalicylic acid, apazone, diclofenac, difenpiramide, diflunisal, etodolac, fenbufen, flufenamic acid, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, suprofen, tiaprofenic acid and tolmetin or their pharmaceutically accepted salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof. Diclofenac, piroxicam and their salts (e.g., diclofenac sodium) are particularly preferred.
The NSAID is present in the composition in a therapeutically effective amount. Where diclofenac or a salt thereof is used, the amount per tablet will preferably be from about 25 to about 75 mg. Where piroxicam or a salt thereof is used, the amount per tablet will preferably be from about 5 mg to about 50 mg per tablet.

The Prostaglandin may be selected from, but is not limited to prostacyclin or thromboxane or derivative thereof, or a prodrug thereof. Examples include, without limitation, alfaprostol, beraprost, carboprost, cloprostenol, enprostil, fenprostalene, fluprostenol, gemeprost, latanoprost, limaprost, luprostiol, misoprostol, ornoprostil, prostacyclin, prostaglandin El, prostaglandin E2, prostaglandin F2[alpha], prostalene, rioprostil, rosaprostol, sulprostone, taprostene, thromboxane A2, thromboxane B2, tiaprost, trimoprostil, unoprostone, or their pharmaceutically accepted salts, solvates ,tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof. Preferred are prostaglandins El and E2 and derivatives thereof, including enprostil, gemeprost, limaprost, misoprostol, ornoprostil, rioprostil and sulprostone. Preferred prostaglandin is misoprostol.
The term 'NSAID or Prostaglandin' used in the entire specification and claims is incorporated in a broad sense to include not only 'NSAID or Prostaglandin' per se but also its pharmaceutically accepted salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
The core tablet containing NSAID or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates .prodrugs or polymorphs thereof may contain, along with the NSAID or salt thereof, usual tablet excipients known in the art such as filler, disintegrant, binders, lubricants and the like.
Suitable filler materials may include, but are not limited to 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. Most preferably lactose monohydrate, microcrystalline cellulose may be added in an amount ranging from 60% to 90% by weight of the formulation.
Suitable disintegrant materials may include, but are not limited to and are generally starches, clays, celluloses, algins, gums or crosslinked polymers ,one or more of low substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl

cellulose, sodium carboxymethyl cellulose, sodium starch glycollate, crospovidone, croscarmellose sodium, starch, crystalline cellulose, hydroxypropyl starch, and partially pregelatinized starch.. Most preferably, maize starch, starch glycolate are used as disintegrant and may be added in an amount ranging from 5 to 20% by weight of the formulation.
Suitable binder materials may include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, 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. Most preferably, a binder used in the invention is polyvinylpyrrolidone .The binders can be added in a quantity ranging from 1 to 15% by weight of the formulation.
Suitable lubricant materials may include, but are not limited to stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated caster oil, sucrose esters of fatty acid, microcrystalline wax, colloidal silicon dioxide and equivalents thereof and may be added in an amount ranging from 0.5 to 5% by weight of the formulation.
Preferably, the tablet containing the NSAID or salt thereof may be coated with an enteric material to prevent the NSAID or salt thereof from dissolving until after it has passed through the stomach and entered the small intestine. The enteric coating solution may be formulated with any suitable enteric coating polymers, which are known to those skilled in the art. 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, dioxypropyl 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 copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS) particularly preferred. The polymer used

in the film coating may be any water-soluble polymer which will form a film coating when sprayed onto a tablet. Preferably water-soluble cellulose derivatives may be used. Most preferably hydroxypropyl methylcellulose and methacrylate copolymer may be used in the formulation.
Examples of suitable anti tacking agent may include one or more of talc, magnesium stearate, glyceryl monostearate, titanium dioxide and the like. Most preferably, purified talc may be used in the formulation.
Examples of suitable plasticizer may include one or more of dioctyl phthalate (DOP), diethyl phthalate, dilauryl phthalate, dioctyl adipate, diisodecyl adipate, tributyl phosphate, trioctyl phosphate, propylene adipate glycol polyester, butylene adipate glycol polyester, epoxidized is soybean oil, chlorinated paraffin. Preferably, diethyl phthalate may be used in the formulation.
Prostaglandin granules may be prepared along with other excipients like filler, disintegrant, lubricant and the like. The amount of prostaglandin per tablet will preferably be in an amount ranging from about 1-6% by weight of the formulation.
The present invention also provides a method to manufacture the tablet according to the present invention.
The method includes coating the core containing NSAID with the prostaglandin on all three sides, leaving one side open. The NSAID core can be prepared by tabletting procedures known in the art for example compressing the granules of NSAID and then coating the same with suitable enteric coating. The compression of granules can be done by procedures well established in the art such as direct compression, wet granulation, and dry granulation. A seal coat may preceed the enteric coat. The prostaglandin granules can similarly be produced by techniques known in the art. Before incorporation into the dosage form, the prostaglandin should be separately stabilized with the stabilizing agent. Suitable examples of stabilizing agent may include one or more of 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. Suitable stabilization procedures are well known to those skilled in the art.
According to a preferred embodiment the method then involves laying a bed of prostaglandin granules in the die cavity and then placing the NSAID over the bed of granules and compressing the same to yield the tablets according to the present invention.
The present invention further provides a method for the treatment in a mammal, such as a human which includes but is not limited to causing alleviation of pain e.g., arthritic pain, lumbosacral pain, musculoskeletal pain, pain associated with a sore throat, and the like; treatment of inflammatory conditions and diseases such as osteoarthritis and rheumatoid arthritis; and treatment of psoriasis.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example 1
Tablets containing diclofenac sodium and misoprostol are made with a composition as follows:

Sr. No Ingredients Qty (mg/tab)
Core tablet
1. Diclofenac sodium 50.00
2. Microcrystalline cellulose PH 101 13.00
3. Lactose Monohydrate 20.00
4. Maize Starch 10.00
5. Polyvinylpyrrolidone K-30 5.50
6. Purified talc 0.50
7. Magnesium stearate 1.00
8. Purified water -
HPMC Coat
9. Methyl cellulose E5LV 2.00
10. Purified water -
11. IsoPropyl Alcohol -
Enteric coat
12 Methacrylic acid and methyl methacrylate copolymer L 100-55 1.77
13. Purified talc 0.588
14. Diethyl Pthalate 0.235
15 Isopropyl alcohol -
Misoprostol blend
16. Misoprostol 1%HPMC dispersion) 20.00
17. Microcrystalline cellulose PH 102 427.50
18. Sodium starch glycolate 50.00
19. Hydrogenated castor oil Type I 2.50
Process:-
The core tablet of diclofenac sodium was prepared. The core tablet was coated with HPMC coat. These were then followed by enteric coating. Misoprostol granules were prepared. The misoprostol granules were placed in the die cavity followed by the tablet enteric coated tablet of diclofenac and compressed.

Example2:-

Sr. No Ingredients Qty (mg/tab)
Core tablet
1. Diclofenac sodium 75.00
2. Microcrystalline cellulose PH 101 19.50
3. Lactose Monohydrate 30.00
4. Maize Starch 15.00
5. Polyvinylpyrrolidone K-30 8.25
6. Purified talc 0.75
7. Magnesium stearate 1.50
8. Purified water
HPMC Coat
9. Methyl cellulose E5LV 2.56
10. Purified water -
11. IsoPropyl Alcohol -
Enteric coat
12 Methacrylic acid and methyl methacrylate copolymer L 100-55 1.508
13. Purified talc 0.754
14. Diethyl Pthalate 0.301
15 Isopropyl alcohol -
Misoprostol blend
16. Misoprostol 1%HPMC dispersion) 20.00
17. Microcrystalline cellulose PH 102 427.50
18. Sodium starch glycolate 50.00
19. Hydrogenated castor oil Type I 2.50
Process:-
The core tablet of diclofenac sodium was prepared. The core tablet was coated with HPMC coat. These were then followed by enteric coating. Misoprostol granules were

prepared. The misoprostol granules were placed in the die cavity followed by the tablet enteric coated tablet of diclofenac and compressed.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.
It must be noted that, as used in this specification 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 diluent" includes a combination of two or more diluents, 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.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.