WO2011036533A1

WO2011036533A1 - Pharmaceutical composition comprising prasugrel and triflusal

Info

Publication number: WO2011036533A1
Application number: PCT/IB2010/002356
Authority: WO
Inventors: Prashant Patole; Neelima Khairatkar-Joshi; Sanket Jadhav; Sunil Chaudhari; Ulhas Dhuppad
Original assignee: Glenmark Pharmaceuticals Limited
Priority date: 2009-09-23
Filing date: 2010-09-21
Publication date: 2011-03-31

Abstract

The present invention relates to pharmaceutical composition for oral administration comprising prasugrel or its salt and triflusal, as well as to a process for preparation of such composition, and use of such composition for treating a platelet aggregation disorder in a subject.

Description

PHARMACEUTICAL COMPOSITION COMPRISING PRASUGREL AND

TRIFLUSAL

PRIORITY DOCUMENT(S)

This patent application claims priority to Indian Provisional Patent

Application numbers 2208/MUM/2009 (filed on September 23, 2009) and 1277/MUM/2010 (filed on April 19, 2010), the contents of each of which are incorporated by reference herein. TECHNICAL FIELD

The present application relates to a pharmaceutical composition comprising prasugrel and triflusal. More particularly, the present application relates to pharmaceutical composition for oral administration comprising prasugrel or its salt and triflusal, as well as a process for preparation of such composition, and use of such composition for treating a platelet aggregation disorder in a subject.

BACKGROUND

Platelets are circulating anuclear cells that are believed to play a major role in haemostasis. Platelet aggregation, among other things, is believed to involve the clumping together of platelets using fibrinogen and von Willebrand factor as connecting agents. Although the platelet aggregation is an essential process for formation of thrombus or embolus during clotting of blood, an increased platelet aggregation is believed to contribute in the obstruction of blood vessels leading to events such as stroke, myocardial infarction, pulmonary embolism.

Prasugrel hydrochloride (Formula I) is chemically 5-[(l RS)-2-cyclopropyl- l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride.

(Formula I) Prasugrel hydrochloride is commercially available as 5 mg and 10 mg tablets (EFFIENT®) in the United States. Prasugrel hydrochloride is indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome.

Prasugrel is disclosed in U.S. Patent numbers 5,288,726 and 6,693, 1 15.

Triflusal (Formula II) is chemically 2-acetyloxy-4-(trifluoromethyl) benzoic acid.

(Formula II)

Triflusal is available as DISGREN® capsules in Mexico, Italy and Spain, each capsule containing 300 mg of triflusal. Triflusal is indicated for secondary prophylaxis after a first ischemic episode coronary or cerebrovascular event of myocardial infarction, stable or unstable angina, non-haemorrhagic stroke temporary or permanent reduction of graft occlusion after performing a coronary bypass.

International Publication number WO 2009/100534 discloses

pharmaceutical composition comprising triflusal.

There is always a need for newer therapies and compositions for treating a platelet aggregation disorder in a subject.

SUMMARY

The inventors of the present invention have invented a pharmaceutical composition for oral administration comprising prasugrel and triflusal.

Thus, in an embodiment, the present invention provides a pharmaceutical composition for oral administration comprising an effective dose of prasugrel or its pharmaceutically acceptable salt, and an effective dose of triflusal or its pharmaceutically acceptable salt.

In an embodiment, the present invention provides a pharmaceutical composition for oral administration comprising an effective dose of prasugrel or its salt and an effective dose of triflusal. Preferably, the prasugrel or its salt and the triflusal are present in the composition in a weight ratio from 1 :5 to 1 :300, or from 1 :20 to 1 :200. In yet another preferred embodiment, the prasugrel or its salt and the triflusal are present in the composition in a weight ratio from 1 :30 to 1 : 180, or from 1 :50 to 1 : 150.

In an embodiment, the pharmaceutical composition for oral administration comprises an effective dose of prasugrel or its salt ranging from about 1 mg to about 30 mg, or preferably from about 3 mg to about 15 mg. More preferably, the effective dose of prasugrel ranges from about 5 mg to about 10 mg.

In an embodiment, the pharmaceutical composition for oral administration comprises an effective dose of triflusal ranging from about 100 mg to about 1000 mg, or preferably from about 200 mg to about 900 mg. More preferably, the effective dose of triflusal ranges from about 300 mg to about 900 mg.

In a preferred embodiment, the pharmaceutical composition for oral administration comprises an effective dose of prasugrel ranging from about 5 mg to about 10 mg, and an effective dose of triflusal ranging from 300 mg to about 900 mg.

In an embodiment, the prasugrel salt is prasugrel hydrochloride.

In an embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

In another embodiment, the present invention provides a method of treating a platelet aggregation disorder in a subject, the method comprising orally administering to the subject a pharmaceutical composition comprising an effective dose of prasugrel or its salt, and an effective dose of triflusal. Preferably, the prasugrel or its salt and the triflusal are present in the composition in a weight ratio from 1 :5 to 1 :300, or from 1 :20 to 1 :200.

In the context of present invention, the platelet aggregation disorder includes but is not limited to acute coronary syndrome, acute coronary syndrome managed by percutaneous cardiovascular intervention, atherosclerosis, deep vein thrombosis, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, coronary artery disease, cerebrovascular disease, stroke, myocardial infarction, arterial embolus, unstable angina pectoris, peripheral arteriopathy, restenosis, ischemia-induced dementia, and thrombotic cardiovascular events arising out of acute coronary syndrome (typically managed by percutaneous coronary intervention).

In an embodiment, the pharmaceutical composition of above-said method comprises prasugrel or its salt in an amount ranging from about 1 mg to about 30 mg, and triflusal in an amount ranging from about 100 mg to about 1000 mg.

In yet another embodiment, the present invention also provides a use of an effective dose of prasugrel or its salt and an effective dose of triflusal in the manufacture of a medicament for oral administration for the treatment of a platelet aggregation disorder in a subject.

In an embodiment, the effective dose of prasugrel or its salt used in the manufacture of the medicament ranges from about 1 mg to about 30 mg, or from about 3 mg to about 15 mg, and the effective dose of triflusal ranges from about 100 mg to about 1000 mg, or from about 200 mg to about 900 mg.

In yet another embodiment, the present invention provides a

pharmaceutical composition for oral administration comprising an effective dose of prasugrel or it^'s salt and an effective dose of triflusal or its salt for use in the treatment of a platelet aggregation disorder.

In an embodiment, the pharmaceutical composition for use in the treatment of a platelet aggregation disorder comprises an effective dose of prasugrel or its salt ranging from about 1 mg to about 30 mg, and an effective dose of triflusal in an amount ranging from about 100 mg to about 1000 mg.

In yet another embodiment, the present invention provides a process for the preparation of a pharmaceutical composition comprising an effective dose of prasugrel or its salt, and an effective dose of triflusal, wherein the process comprises admixing prasugrel or its salt with triflusal. Alternatively, prasugrel and triflusal are formulated in the composition in such a way that they are not in intimate contact with each other. Preferably, the prasugrel or its salt and the triflusal are present in the composition in a weight ratio from 1 :5 to 1 :300, or from 1 :20 to 1 :200. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 represents the mean thrombus weight in the arteriovenous-shunt model in Sprague Dawley rats.

Figure 2 represents the mean bleeding time in the tail-transection bleeding model in Sprague Dawley rats.

DETAILED DESCRIPTION

The present invention relates to pharmaceutical composition comprising prasugrel and triflusal. Without being bound by any particular theory, the inventors of the present invention believe that a pharmaceutical composition for oral administration comprising prasugrel and triflusal would be advantageous in the treatment of a platelet aggregation disorder.

The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth in the earlier filed provisional application/s from which the priority is claimed are in conflict, the definition in the present application shall control the meaning of the terms.

The term "effective dose" (synonymously "therapeutically effective amount") as used herein denotes an amount of an active ingredient that, when administered to a subject for treating a state, disorder or condition, produces an intended therapeutic benefit in a subject.

The term "active ingredient" (used interchangeably with "active" or "active°substance") as used herein includes prasugrel, triflusal and their pharmaceutically acceptable salts.

By "salt" or "pharmaceutically acceptable salt", it is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts and esters include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, propionate, furoate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.

The term "treating" or "treatment" as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression or inhibition of a disorder involving platelet aggregation.

By the term "platelet aggregation disorder", it is meant to any condition or disease having an etiology attributable to platelet aggregation or thrombus or embolus formation and includes but not limited to thrombotic cardiovascular events (including stent thrombosis); acute coronary syndrome; atherosclerosis; deep vein thrombosis; portal vein thrombosis; renal vein thrombosis; jugular vein thrombosis; cerebral venous sinus thrombosis; coronary artery disease;

cerebrovascular disease; stroke; myocardial infarction; arterial embolus; unstable angina pectoris; peripheral arteriopathy; restenosis; ischemia-induced dementia; cardiovascular events arising out of acute coronary syndrome (typically managed by percutaneous coronary intervention); and ischemic episode coronary or cerebrovascular event of myocardial infarction, stable or unstable angina, and non- haemorrhagic stroke.

Thrombosis is the formation of a blood clot inside the blood vessels thus obstructing the blood flow through the circulatory system. If the clot breaks free into an emboli it may lead to thromboembolism.

Angina is severe chest pain caused due to ischemia. It may be classified into stable, unstable and microvascular. Unstable angina (also called as crescendo angina) is defined as angina pectoris that changes or worsens. Its pathophysiology is the reduction of coronary flow due to transient platelet aggregation on apparently normal endothelium, coronary artery spasms or coronary thrombosis.

Coronary artery disease (or coronary heart disease) is atherosclerosis of one or more of the coronary arteries. It is a condition in which plaque builds up inside the coronary arteries which narrows them and thus reduces the blood flow to the heart muscles. Myocardial infarction (MI) is a medical condition that occurs when the blood supply to a part of the heart is interrupted, most commonly due to rupture of a vulnerable plaque in a coronary artery. It may also occur when a coronary artery temporarily contracts or goes into a severe spasm, effectively shutting off the flow of blood to the heart. In either case, the resulting ischemia or oxygen shortage causes damage and potential death of heart tissue.

Stroke are classified as either ischemic or hemorrhagic, the former accounting for approximately 80% of all events. Ischemic stroke, similar to heart attack, is caused by tan interruption of blood flow to the brain. The resulting lack of oxygen supply causes damage to brain tissue. Ischemic stroke is either caused by thrombotic stroke or embolic stroke. Hemorrhagic stroke which accounts for about 20% of strokes is characterized by uncontrolled bleeding in the brain. This flooding of the brain kills brain cells.

Acute coronary syndrome (ACS) is a set of signs and symptoms related to the heart. The subtypes of ACS include unstable angina and MI. It is usually associated with coronary thrombosis.

The term "subject" includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife). Preferably, the subject is a human.

By "pharmaceutically acceptable excipients", it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.

The effective dose of prasugrel or its salt varies depending on the disease severity, the body weight of the subject, the route of administration, the type of composition and such other factors. Preferably, the effective dose of prasugrel or its salt to be orally administered per day varies from about 1 mg to about 30 mg, or more preferably from about 3 mg to about 15 mg.

The effective dose of triflusal or its salt varies depending on the disease severity, the body weight of the subject, the route of administration, the type of composition and such other factors. Preferably, the therapeutically effective amount of triflusal or its salt to be orally administered per day varies from about 100 mg to about 1000 mg, or more preferably from about 200 mg to about 900 mg.

In an embodiment, the prasugrel salt is prasugrel hydrochloride.

Separately contemplated is a pharmaceutical composition in the form of a pharmaceutical package or kit comprising prasugrel or its pharmaceutically acceptable salt, triflusal or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient. Thus, the pharmaceutical composition as described herein ma be in the form of a single dosage form (fixed dose

composition in which the active ingredients are present together) or the actives may be administered separately (simultaneously or sequentially), each in its individual dosage forms but as part of the same therapeutic treatment, program or regimen.

The pharmaceutical composition for oral administration may be in the form^' of, for example, tablet, capsule, granules (synonymously, "beads" or "particles" or "pellets"), suspension, emulsion, powder, dry syrup, and the like. The capsule may contain granule/ pellet/particle/ mini-tablets/mini-capsules containing the active ingredients. The tablet may be in the form of multilayered tablets (e.g. bilayered tablets) or a tablet within a tablet or core and coat based tablets. Alternatively, the pharmaceutical composition may be in the form of a capsule containing minitablets and powder filled together. Preferably, the pharmaceutical composition is a capsule · which contains triflusal as a compacted powder and one or more minitablets comprising prasugrel or its salt.

In an embodiment, the pharmaceutical composition for oral administration contains both the active ingredients either admixed together or formulated

separately (not in intimate contact with each other). Preferably, the present invention contemplates a pharmaceutical composition for oral administration wherein prasugrel or its salt and triflusal are not intimately admixed together, or at least the contact between both of them is minimized.

As set forth above, the pharmaceutical composition includes a

pharmaceutically acceptable excipient, which includes but is not limited to one or more of the following; diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents/viscosifying agents, surfactants, solvents and the like.

Non-limiting examples of diluents include microcrystalline cellulose

("MCC"), silicified MCC (e.g., PROSOLV™), microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like;

cores/beads such as insoluble inert materials like glass particles/beads or silicon dioxide, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate, cellulose derivatives; soluble cores such as sugar spheres of sugars like dextrose, mannitol, sorbitol, or sucrose; insoluble inert plastic materials such as spherical or nearly spherical core beads of polyvinyl chloride, polystyrene or any other pharmaceutically acceptable insoluble synthetic polymeric material, acacia, guar gum, alginic acid, dextrin, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL®), low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (e.g.,

METHOCEL®), carboxymethyl cellulose sodium, povidone (various grades of KOLLIDON®, PLASDONE®), carboxymethyl cellulose calcium, croscarmellose sodium, (e.g., Ac-Di-Sol®, PRIMELLOSE®), crospovidone (e.g., KOLLIDON®, POLYPLASDONE®), povidone K-30, polacrilin potassium, polyethylene glycols, sodium starch glycolate (e.g., PRIMOGEL, EXPLOTAB®), and the like.

Non-limiting examples of glidants and lubricants include stearic acid, magnesium stearate, calcium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate, opacifiers, colorants, and other commonly used carriers.

Non-limiting examples of preservatives include phenoxyethanol, benzalkonium chloride, parabens such as methyl paraben and propyl paraben and their sodium salts, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, and the like and mixtures thereof.

Non-limiting examples of buffering agents include sodium hydroxide, potassium hydroxide, sodium citrate, ammonium hydroxide and the like and mixtures thereof. Non-limiting examples of chelating agents include

ethylenediaminetetraacetic acid ("EDTA"), disodium edetate and EDTA derivatives, and the like and mixtures thereof.

Non-limiting examples of polymers include gum arabic, sodium based lignosulfonate, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, ethylene glycol dimethacrylate, and the like and mixtures thereof. Non-limiting examples of gelling agents/viscosifying agents include, carbomers (carbopol), modified cellulose derivatives, naturally-occurring, synthetic or semi-synthetic gums such as xanthan gum, acacia and

tragacanth, sodium alginate, gelatin, modified starches, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; co-polymers such as those formed between maleic anhydride and methyl vinyl ether, colloidal silica and methacrylate derivatives, polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, polyvinyl alcohol and the like and mixtures thereof.

Non-limiting examples of surfactants include, poloxamer, polyoxyethylene sorbitan esters (known as POLYSORBATE or TWEEN), polyethoxylated castor oil (CREMOPHOR), methyl glucose sesquistearate, PEG-20 methyl glucoside sesquistearate, caprylocaproyl macrogol-8 glycerides, lauroyl macrogol-32- glycerides Steareth-21, polyethylene glycol 20 sorbitan monostearate, polyethylene glycol 60 sorbitan monostearate, polyethylene glycol 80 sorbitan monostearate, Steareth-20, Ceteth-20, PEG- 100 stearate, sodium stearoyl sarcosinate, hydrogenated lecithin, sodium cocoylglyceryl sulfate, sodium stearyl sulfate, sodium stearoyl lactylate, PEG-20 glyceryl monostearate, sucrose monostearate, sucrose polystearates, polyglyceryl 10 stearate, polyglyceryl 10 myristate, steareth 10, DEA oleth 3 phosphate, DEA oleth 10 phosphate, PPG-5 Ceteth 10 phosphate sodium salt, PPG-5 Ceteth 10 phosphate potassium salt, steareth-2, PEG-5 soya sterol oil, PEG- 10 soya sterol oil, diethanolamine cetyl phosphate, sorbitan monostearate, diethylenglycol monostearate, glyceryl monostearate, and the like and mixtures thereof.

Non-limiting examples of solvents include, water; tetrahydrofuran;

propylene glycol; liquid petrolatum; ether; petroleum ether; alcohols, e.g., ethanol, isopropyl alcohol and higher alcohols; aromatics, e.g. toluene; alkanes, e.g., pentane, hexane and heptane; ketones, e.g., acetone and methyl ethyl ketone; chlorinated hydrocarbons, e.g., chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride; acetates, e.g., ethyl acetate; lipids, e.g., isopropyl myristate, diisopropyl adipate and mineral oil and the like and mixtures thereof.

In another embodiment, the present invention provides a method of treating platelet aggregation disorder in a subject, the method comprising orally administering to the subject a pharmaceutical composition comprising an effective dose of prasugrel or its salt, and an effective dose of triflusal. Preferably, the prasugrel or its salt and the triflusal are present in the composition in a weight ratio from 1 :5 to 1 :300 or from 1 :20 to 1 :200.

In an embodiment, the platelet aggregation disorder is a cardiovascular event arising out of ACS. In a preferred embodiment, the ACS is managed or is to be managed by percutaneous coronary intervention.

In an embodiment, the present invention provides a method for treating thrombotic cardiovascular events in a subject with acute coronary syndrome managed or to be managed by percutaneous coronary intervention, wherein the method comprises administering to the subject a pharmaceutical composition comprising an effective dose of prasugrel or its salt, and an effective dose of triflusal or its salt. Preferably, the prasugrel or its salt and the triflusal are present in the composition in a weight ratio from 1 :5 to 1 :300 or from 1 :20 to 1 :200

In an embodiment, the pharmaceutical composition of the of above-said method comprises prasugrel or its salt in an amount ranging from about 1 mg to about 30 mg, and triflusal or its salt in an amount ranging from about 100 mg to about 1000 mg.

In yet another embodiment, the present invention provides a process for the preparation of a pharmaceutical composition comprising an effective dose of prasugrel or its salt, and an effective dose of triflusal, wherein the process comprises admixing prasugrel or its salt with triflusal. Alternatively, prasugrel and triflusal are formulated in the composition in such a way that they are not in intimate contact with each other. Preferably, the prasugrel or its salt and the triflusal are present in the composition in a weight ratio from 1 :5 to 1 :300, or from 1 :20 to 1 :200. The process for the preparation may be dry blending, direct compression, dry granulation (e.g., compaction or slugging), aqueous granulation or nonaqueous granulation.

For example, the process for preparing the pharmaceutical composition may include (1) granulating either or both the active ingredients, combined or separately, along with pharmaceutically acceptable carriers so as to obtain granulate, and (2) converting the granulate into suitable dosage forms for oral administration. The typical processes involved in the preparation of the pharmaceutical compositions include various unit operations such as mixing, sifting, solubilizing, dispersing, granulating, lubricating, compressing, coating, and the like. These processes, as contemplated by a person skilled in the formulation art, have been incorporated herein for preparing the pharmaceutical compositions of the present invention.

Preferably, the prasugrel or its salt and the triflusal or its salt are present in the medicament in a weight ratio from 1 :5 to 1 :300, or from 1 :20 to 1 :200.

In another embodiment, the present invention provides a pharmaceutical composition for oral administration comprising effective dose of prasugrel or its salt and an effective dose of triflusal or its salt, wherein the prasugrel or its salt and triflusal or its salt are present in a weight ratio from 1 :5 to 1 :300, for the treatment of a thrombotic cardiovascular event in a subject with acute coronary syndrome managed or to be managed by percutaneous coronary intervention in the subject.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

EXAMPLES

EXAMPLES 1- 4: Pharmaceutical compositions comprising prasugrel HCL and triflusal.

Ingredient Composition (mg)

Example 1 Example 2 Example 3 Example 4

Prasugrel HCL eq. to

5 10 5 10 Prasugrel

Triflusal 300 300 300 300

Lactose monohydrate 200 — 200 —

Microcrystalline cellulose — 200 — 200

Starch 50 50 50 50

Povidone 15 — — —

Hydroxypropyl cellulose -- 15 15

Hydroxypropyl

methylcellulose - ~ 15 ~

Croscarmellose sodium 35 35 ~ —

Sodium starch glycollate -- — 35 --

Crospovidone — — — 35

Magnesium stearate 5 5 5 5 Water/isopropyl alcohol* q. s. q. s. q. s. q. s.

COATING

Opadry* 10 10 10 10

Water/isopropyl alcohol q. s. q. s. q. s. q. s.

- evaporate during process

*- commercially available from Colorcon.

Manufacturing process:

1. Lactose monohydrate/microcrystalline cellulose, prasugrel hydrochloride, triflusal and starch are sized through ASTM Sieve # 40 and blended together in a granulator.

2. Povidone/hydroxypropyl cellulose/hydroxypropyl methylcellulose is dispersed in the water/isopropyl alcohol and stirred well to obtain a uniform dispersion.

3. The blend of Step 1 is granulated with the dispersion of Step 2 to obtain wet granules. The wet granules are dried in a fluid bed drier and the dried granules are sized through ASTM Sieve # 20.

4. Croscarmellose sodium/sodium starch glycollate/crospovidone is sized through ASTM Sieve # 60 and blended with the granules of Step 3.

5. The granules of Step 4 are lubricated by adding and mixing magnesium stearate that has been previously sized through ASTM Sieve # 60.

6. The lubricated blend of Step 5 is compressed into tablet on a rotary tablet press and the tablet is further coated with Opadry dispersed in

water/isopropyl alcohol.

7. Alternately, the lubricated blend of Step 5 is filled into a hard gelatin capsule.

EXAMPLES 5 - 6: Pharmaceutical compositions comprising Prasugrel HCL and Triflusal.

Ingredient Composition (mg)

Example 5 Example 6

Prasugrel HCL eq. to Prasugrel 5 10

Triflusal 600 600 Mannitol (Perlitol SD 200) 77.01 82.50

Hypromellose (5 cps) 2.00 2.00

Microcrystalline cellulose 10.00 10.00

Croscarmellose sodium 5.00 5.00

Magnesium stearate 0.50 0.50

Opadry White* 3.00 3.00

Isopropyl alcohol* q. s. q. s.

Dichloromethane* q. s. q. s.

- evaporate during process

*- commercially available from Colorcon.

Manufacturing process:

1. Prasugrel hydrochloride and Mannitol (Perlitol SD200) were sized through ASTM Sieve # 60 and mixed in a blender.

2. Hypromellose, microcrystalline cellulose and croscarmellose sodium were sized through ASTM Sieve # 40 and were mixed with the blend of Step 1 in a blender.

3. The blend of Step 2 was lubricated with magnesium stearate previously sized through ASTM Sieve # 60.

4. The lubricated blend of Step 3 was compressed into tablet and coated with Opadry AMB dispersed in a mixture of isopropyl alcohol and

dichloromethane.

5. The tablet of Step 4 was placed in an empty hard gelatin/HPMC capsule;

Triflusal was filled in the capsule and locked.

EXAMPLES 7 - 10: Pharmaceutical compositions comprising Prasugrel HCL and

Triflusal.

Ingredient Composition (mg)

Example Example Example Example

7 8 9 10

Prasugrel HCL 5.49 10.98 5.49 10.98

Triflusal 300 300 300 300

Mannitol (Perlitol SD 200) 77.01 71.52 77.01 71.52 Hypromellose (5 cps) 2.00 2.00 2.00 2.00

Microcrystalline cellulose 10.00 10.00 10.00 10.00

Croscarmellose sodium 5.00 5.00 5.00 5.00

Magnesium stearate 0.50 0.50 0.50 0.50

Opadry AMB* 3.00 3.00 — —

Opaglos* — — 3.00 3.00

Isopropyl alcohol" q. s. q. s. q. s. q. s.

DichIoromethane q. s. q. s. q. s. q. s. evaporate during process

commercially available from Colorcon.

Manufacturing process:

2. Hypromellose, microcrystalline cellulose and croscarmellose sodium were sized through ASTM Sieve # 40 and were mixed with the blend of Step 1.

4. The lubricated blend of Step 3 was compressed into tablet and coated with Opadry AMB/Opaglos dispersed in a mixture of isopropyl alcohol and dichloromethane.

5. The tablet of Step 4 was placed in an empty hard gelatin/ HPMC capsule;

Triflusal was filled in the capsule and locked.

EXAMPLES 1 1 and 12: Pharmaceutical compositions comprising Prasugrel HCL and Triflusal.

Ingredient Composition (mg)

Example 11 Example 12

Prasugrel HCL 5.49 10.98

Triflusal 300 300

Starch 50 44.51

Povidone 30 8.0 8.0

Aerosil (Colloidal silicon dioxide) 3.5 3.5 Hypromellose 5cps 15.0 15.0

Triethyl citrate 3.0 3.0

Isopropyl alcohol* q. s. q. s.

Dichloromethane* q. s. q. s.

Manufacturing process:

1. Triflusal, povidone, Aerosil and Starch is mixed together in a mixer and this blend is passed through ASTM Sieve #30.

2. The blend of Step 1 is compressed into tablets.

3. Prasugrel hydrochloride, Hypromellose and Triethyl citrate is dissolved in a mixture of isopropyl alcohol and dichloromethane with constant stirring.

4. The tablets of step 2 are coated with the coating solution of Step 3 in a suitable coating machine.

EXAMPLES 13 and 14: Pharmaceutical compositions comprising Prasugrel HCL and Triflusal.

Manufacturing process:

1. Triflusal, povidone K30, Aerosil and Starch are mixed together in a

mixer/blender and the blend is passed through ASTM Sieve #30.

2. Prasugrel hydrochloride, Mannitol (Perlitol SD200), are passed through ASTM Sieve #60 and mixed geometrically in a blender. 3. Hypromellose (%cps), Microcrystalline Cellulose, and croscarmellose are passed through ASTM Sieve #40 and mixed with the blend of Step 2.

4. Blend of Step 3 is lubricated with Magnesium strearate previously sized through ASTM Sieve #60.

5. The blends of Step 1 and Step 4 are compressed together into bi layer tablets.

EXAMPLE 15: Animal studies for the combination of prasugrel and triflusal. Female Sprague Dawley rats of about 7-8 weeks of age were distributed into different groups (n = 7-10 per group). The effect of the drugs and combinations were evaluated in the Arteriovenous (AV)-shunt and the tail-transection bleeding model.

AV-SHUNT MODEL: The animals were grouped as per Table 1. Table 1 : Animal groups

After two hours of administration of the drugs, the animals were anesthetized using a mixture of ketamine and xylamine in a ratio of 4: 1. The common carotid artery was cannulated with a 80 mm polyethylene catheter (PE- 60; internal diameter [ID], 0.76 mm) connected with a 60 mm Tygon® tube (ID, 3.2 mm) containing a rough thrombogenic braided silk thread (60 ^χ 0.26 mm) folded into a double string. The left jugular vein was isolated and cannulated with 20 mm polyethylene tube (PE-60; ID, 0.76 mm) connected with a 60 mm polyethylene catheter (PE-160; ID, 1.14 mm). The two tubes were then filled with saline and connected to form an AV shunt. The shunt was opened for 15 minutes. The thread covered with the thrombus was then withdrawn and was weighed immediately. The results are provided in Table 2.

Table 2: Mean wet weight of thrombus for various groups

The results are further depicted in Figure 1. The results indicated that there was a significant reduction in the thrombus weight in the combination group (p<0.0001) when compared to the control group. When compared to Group I, there was a 24.32 percent, 1 1.72 percent and 52.1 percent reduction in the wet thrombus weight in Group II, Group III and Group IV respectively.

TAIL-TRANSECTION BLEEDING MODEL: The animals were grouped according to Table 3.

Table 3: Animal groups

Group Group Treatment (by oral gavage)

description "

Group A Control 0.5% methyl cellulose with

Tween 80 (0.01%) in

distilled water

Group B Prasugrel-treated Prasugrel (0.1 mg/kg)

Group C Triflusal-treated Triflusal (10 mg/kg),

Group D Combination- Triflusal (10 mg/kg) and

treated Prasugrel (0.1 mg/kg) Two hours after administration of the drugs, the animals were subjected to testing. The tail was transected 4 mm from the tip by a dorsoventral cut using a scalpel blade and was immediately immersed into a physiological saline solution. Bleeding time was recorded as the time till the permanent cessation of bleeding (defined as no bleeding at least for 30 sec). Bleeding times exceeding 15 min were recorded as 900 sec. The results are provided in Table 4.

Table 4: Mean bleeding times for various groups

The results are further depicted in Figure 2. The results indicate that there was a significant increase in the bleeding time in the combination group

(p<0.0001) when compared to the control group. When compared to Group A, there was a 65.37 percent, 2.64 percent and 179.02 percent increase in the bleeding time in Group B, Group C and Group D, respectively.

Claims

CLAIMS We claim:

1. A pharmaceutical composition for oral administration comprising: (a) an effective dose of prasugrel or its salt, and (b) an effective dose of triflusal or its salt.

2. The pharmaceutical composition of claim 1, wherein weight ratio of prasugrel or its salt to triflusal ranges from 1 :5 to 1 :300.

3. The pharmaceutical composition of claim 1, wherein weight ratio of prasugrel or its salt to triflusal ranges from 1 :20 to 1 :200.

4. The pharmaceutical composition of claim 1, wherein weight ratio of prasugrel or its salt to triflusal ranges from 1 :30 to 1 : 180.

5. The pharmaceutical composition of claim 1, wherein the effective dose of prasugrel or its salt ranges from about 1 mg to about 30 mg.

6. The pharmaceutical composition of claim 1, wherein the effective dose of prasugrel or its salt ranges from about 3 mg to about 15 mg.

7. The pharmaceutical composition of claim 1 , wherein the effective dose of triflusal ranges from about 100 mg to about 1000 mg.

8. The pharmaceutical composition of claim 1, wherein the effective dose of triflusal ranges from about 200 mg to about 900 mg.

9. A pharmaceutical composition for oral administration comprising: (a) about 5 mg to about 10 mg of prasugrel hydrochloride, (b) about 300 mg to about 900 mg of triflusal, and (c) a pharmaceutically acceptable excipient.

10. A method of treating a platelet aggregation disorder in a subject, the method comprising orally administering to the subject the pharmaceutical composition of any one of claims 1-9.

1 1. The pharmaceutical composition of any one of claims 1-9, for use in the treatment of a platelet aggregation disorder in a subject.

12. Use of an effective dose of prasugrel or its salt and an effective dose of triflusal in the manufacture of a medicament for oral administration for the treatment of a platelet aggregation disorder in a subject.

13. The use according to claim 12, wherein the effective dose of prasugrel or its salt ranges from about 3 mg to about 15 mg, and the effective dose of triflusal ranges from about 200 mg to about 900 mg.