FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title
PHARMACEUTICAL COMPOSITION COMPRISING PRASUGREL AND
ASPIRIN
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

PHARMACEUTICAL COMPOSITION COMPRISING PRASUGREL AND
ASPIRIN
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising prasugrel and aspirin and the process for preparation of said composition.
BACKGROUND OF THE INVENTION
Prasugrel is a new oral antiplatelet from thienopyridine class. It is a prodrug requiring in vivo metabolism to form an active metabolite that inhibits platelet activation and aggregation by binding irreversibly to P2Y12 class of ADP receptors on platelets. It is currently marketed under the brand name of Effient® by Eli Lilly and Daiichi Sankyo. Prasugrel is indicated for the thrombotic cardiovascular (CV) events in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) such as patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI), patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.
Acetyl salicylic acid (Aspirin) is the most widely used antiplatelet agent today, which inhibits platelet cyclooxygenase-1 (COX-1) by irreversible acetylation and ultimately prevents thromboxane A2 generation. Aspirin is available in combination with antiplatelet agent such as Dipyridamole. Aspirin is a moisture sensitive drug and can hydrolyse into acetic and salicylic acids when exposed to high humidity and elevated temperatures and hence difficult to formulate.
Various clinical trials have shown the beneficial effect of aspirin when co-administered with Prasugrel for the prevention of atherothrombotic events in patients with acute coronary syndrome undergoing primary or delayed percutaneous coronary intervention (PCI). This combination acts synergistically through complementary and independent mechanisms.

WO2002051412 discloses pharmaceutical composition of prasugrel and aspirin and method of treating disease caused by thrombus or embolus. However prior art do not disclose combination formulation of Prasugrel and aspirin wherein prasugrel is in immediate release and aspirin is available in delayed release form. Again preparation of fixed dose combination of prasugrel and aspirin poses challenges to the formulators to formulate stable composition due to susceptibility of the prasugrel to hydrolysis and oxidation, certain excipients like povidone and crospovidone (usually containing trace peroxides) and manufacturing processes (e.g. wet granulation) are not recommended. It is also observed that intimate mixing of Prasugrel and aspirin in a combination formulation increases impurity in the formulation. Moreover, fixed dose combination of aspirin and prasugrel is not available in the market. Inventors of the present invention have surprisingly found easy to manufacture and stable fixed dose pharmaceutical compositions comprising prasugrel and aspirin by various techniques disclosed herein, which increases patient compliance.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising prasugrel and aspirin and process for preparing such compositions.
In one aspect, the specification discloses a stable pharmaceutical composition comprising;
(i) immediate release component comprising prasugrel, and
(ii) delayed release component comprising aspirin.
In another aspect, the specification discloses pharmaceutical composition comprising prasugrel and aspirin, wherein the composition is in the forms of monolithic, bilayered, multilayered, inlayered or multiparticulate system.
In another aspect, the specification discloses pharmaceutical composition comprising prasugrel and aspirin, wherein immediate release component comprising prasugrel is

combined with delayed release component comprising aspirin and filled into capsule or compressed into tablet.
In another aspect, the specification discloses a process for preparing prasugrel component, wherein the process comprises:
(a) blending prasugrel with one or more suitable pharmaceutical excipients;
(b) lubricating the blend of step (a);
(c) optionally coating the granules of step (b) and lubricating it.
In another aspect, the specification discloses a process for preparing aspirin component, wherein the process comprises:
(a) granulating mixture of aspirin, and suitable pharmaceutical excipients;
(b) optionally blending the granules with suitable pharmaceutical excipients and lubricating it;
(c) optionally coating the granules of step (a) using enteric polymer and lubricating it.
In another aspect the aspirin component is enteric coated aspirin granules or pellets. Such granules or pellets may be prepared by suitable techniques like spray drying, spheronization or enteric coated aspirin tablet.
In another aspect, the specification discloses a process for preparing a stable pharmaceutical composition comprising:
(i) compressing the mixture of the prasugrel component and the aspirin component into tablet and coating the tablet using suitable film forming polymer, or (ii) filling the mixture of the prasugrel component and the aspirin component into
capsules, or (iii) compressing the blend of the prasugrel component and the aspirin component into a bilayer tablet, or

(iv) compressing the prasugrel component into a tablet and coating the tablet and
filling it with aspirin component into a capsule, or (v) filling aspirin component into a capsule (inner capsule) and putting this
capsule into another capsule (outer capsule) comprising prasugrel component,
or (vi) compressing the prasugrel component into a tablet and coating the tablet;
compressing aspirin component into a tablet and enteric coating the tablet;
filling both the tablet into a capsule, or (vii) compressing aspirin component into a tablet and enteric coating the tablet;
filling the tablet along with prasugrel component into a capsule, or (viii) compressing the prasugrel component into a tablet and coating the tablet
and filling it along with aspirin enteric coated granules or pellets into a
capsule, or (ix) filling prasugrel component and aspirin enteric coated granules or pellets into
a capsule, or (x) compressing the aspirin component into tablet or mini-tablet optionally
coating with enteric polymer and inlayed tablet prepared by compressing the
prasugrel component along with prepared tablet or mini-tablet of aspirin.
DETAILED DESCRIPTION OF THE INVENTION
The term "pharmaceutical composition" as described herein includes oral solid dosage form such as tablet, capsule, mini tablet, etc.
The term "prasugrel" as described herein is defined to include prasugrel free acid or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, enantiomers thereof. Prasugrel may be in a crystalline or amorphous form, or mixtures thereof. Prasugrel as described herein may be of varying particle size, for example it may be in micronized or non-micronized form. Prasugrel may be present in an amount ranging from 2 mg to 100 mg in the composition or in amount ranging from 1 % to 50 % by weight of the composition.

The term "aspirin" as described herein is acetyl salicylic acid. Aspirin may be present in an amount ranging from 25 mg to 500 mg in the composition or in amount ranging from 10 % to 70 % by weight of the composition.
In one embodiment, present invention provides a stable pharmaceutical composition comprising:
(i) immediate release component comprising prasugrel, and
(ii) delayed release component comprising aspirin.
The term "component" as described herein means a portion or a part of the pharmaceutical composition. The "component" is in the form of a powder, granule, bead, pellet, spheroid, mini-tablet, micro-tablet, which may be coated or uncoated.
The pharmaceutical compositions as described herein comprise one component comprising prasugrel, with pharmaceutically acceptable excipients and another component comprising aspirin with pharmaceutically acceptable excipients.
The pharmaceutical compositions as described herein may comprise at least one pharmaceutically acceptable excipient selected from diluent, binder, glidant, lubricant, disintegrant, surfactant, film forming polymer, plasticizer or complexing agent.
A diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate; sugars such as dextrose, lactose or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol or erythritol; or mixtures thereof. The diluent may be present in an amount ranging from 1 % to 90 % by weight of the composition.
A disintegrant may be selected from low-substituted hydroxypropylcellulose, starch, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and mixtures thereof. The

disintegrate may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
A binder may be selected from starches such as maize starch, corn starch, pregelatinized starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone, gelatin, zein, polymethacrylates, sodium alginate, gums, synthetic resins or mixtures thereof. The binder may be present in an amount ranging from 0.1% to 20% by weight of the composition.
A lubricant or glidant may be selected from talc, metallic stearate such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate; or mixtures thereof. The lubricant or glidant may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
A surfactant may be selected from one or more non-ionic or ionic (i. e., cationic, anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions. Suitable surfactants include mono fatty acid esters of polyoxyethylene sorbitan such as those sold under the brand name Tween®; sodium lauryl sulfate, polyoxyethylene castor oil derivatives such as those sold under the brand name Cremophor®, polyethoxylated fatty acids and their derivatives, propylene glycol fatty acid esters, sterol and sterol derivatives; sorbitan fatty acid esters and their derivatives, sugar esters, polyoxyethylene-polyoxypropylene block copolymers such as those sold under the brand name Poloxamer®, soy lecithin, or mixtures thereof. The surfactant may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
A complexing agent may be selected from cyclodextrin class of molecules, such as cyclodextrins containing from six to twelve glucose units, especially, alpha- cyclodextrin,

beta-cyclodextrin, gamma-cyclodextrin, or their derivatives, such as hydroxypropyl beta cyclodextrins, or mixtures thereof,
Film forming polymers may be selected from hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropyl cellulose, povidone, polydextrose, lactose, maltodextrin, acrylic polymer, or mixtures thereof.
The enteric polymer may be selected from cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer or methacrylate-methacrylic acid-octyl acrylate copolymer.
The coating may also comprise of a plasticizer such as glyceryltriacetate, dibutyl sebacate, diethylphthalate, polyethylene glycol, propylene glycol, glycerol, hydrogenated castor oil, copolymers of propylene oxide and ethylene oxide, or mixtures thereof. Such compositions are also available under the brand name of Opadry® or Lustreclear®, sold by Colorcon.
The pharmaceutical compositions may additionally contain excipients such as colorants selected from known F.D. & C. and D. & C. dyes, and the like.
The pharmaceutical composition as described herein may be obtained in the form of a tablet or a capsule. The composition may comprise a first component of immediate release prasugrel and one or more pharmaceutical excipient, a second component of aspirin in delayed release form. Each component may be prepared using suitable technique such as wet granulation, dry granulation or direct compression however prasugrel component is preferably prepared using dry granulation wherein the prasugrel component may be prepared by mixing with at least one pharmaceutically acceptable excipient like mannitol, hydroxypropyl methylcellulose and finally lubricated.

Aspirin component may be prepared using dry granulation or direct compression, preferably aspirin component may be prepared by taking aspirin and coated using suitable polymer such as hydrogenated castor oil with citric acid anhydrous and optionally enteric coating using enteric polymer.
Alternatively, aspirin component may be granules or pellets prepared using aspirin and one or more suitable pharmaceutical excipients by suitable techniques like spray drying, spheronization. Such prepared granules or pellets may also be enteric coated to obtain enteric coated aspirin granules or pellets.
In one of the preferred embodiment, a pharmaceutical composition may be prepared by preparing prasugrel component by blending prasugrel with one or more pharmaceutical excipient like mannitol, lubricating the blend, compressing into tablet and coating with film forming polymer composition; preparing aspirin component by blending the mixture of one or more pharmaceutical excipients, compressing into tablet and coating the tablet with enteric polymer, optionally film coating; followed by filling both the tablets into- a capsule. Inventors have surprisingly found that placing prasugrel component first followed by aspirin component into capsule provides better dissolution profile for the prasugrel.
In another preferred embodiment, a pharmaceutical composition may be prepared by preparing prasugrel component by blending prasugrel with one or more pharmaceutical excipient like mannitol, filling it into capsule and placing enteric coated aspirin tablet as prepared in the above embodiment into the capsule containing prasugrel component.
In another preferred embodiment, a pharmaceutical composition may be prepared by preparing prasugrel component by blending prasugrel with one or more pharmaceutical excipient like mannitol, lubricating the blend, compressing into tablet and coating with film forming polymer composition; filling the prepared tablet into a capsule along with aspirin enteric coated granules or pellets.

In another preferred embodiment, a pharmaceutical composition may be prepared by preparing prasugrel component by blending prasugrel with one or more pharmaceutical excipient like mannitol, filling it into a capsule along with aspirin enteric coated granules or pellets.
In another embodiment, a pharmaceutical composition may be prepared by preparing prasugrel component by blending prasugrel with one or more pharmaceutical excipient like mannitol; aspirin component may be prepared by the process described earlier, lubricating and compressing into tablet or mini-tablet, coating it with enteric polymer and optionally film coating; the blend of prasugrel component compressed along with the tablet or mini-tablet of the aspirin component in such way that it remains inlayed at any position in the blend of prasugrel component.
In another embodiment, a pharmaceutical composition may be prepared by preparing prasugrel component by blending prasugrel with one or more pharmaceutical excipient like mannitol, lubricating the blend; aspirin component containing enteric coated granules of aspirin and lubricating it; followed by compressing both the component into monolithic or bilayer tablet.
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:

EXAMPLE 1:
Prasugrel component:
Sr.
No Ingredient Function Qty./Tablet
(mg)
Intragranular
1 Prasugrel HC1 Active 10.98
2 Microcrystalline cellulose PH 112 Diluent 64.96
3 Pearlitol SD 200 Diluent 95.06
4 Croscarmellose sodium Disintegrant 7.5
5 Talc (Luzenac) Glidant 5.0
6 Hydroxy propyl methyl cellulose (3 cps) (HPMC 3 cps) Stabilizer 12.5

Sr. No Ingredient Function Qty/Tablet
(mg)
Lubrication
7 Magnesium stearate Lubricant 4.00
Total 200.0
Fil m coating composition:
Sr. No Ingredient Function Qty./Tablet
(mg)
1 Hydroxy propyl methyl cellulose (6cps) Film forming polymer 3.47
2 Lactose monohydrate Adhesive 0.86
3 Triacetin Plasticizer 0.50
4 Titanium dioxide Opacifier 1.10
5 Ferric Oxide Red Colorant 0.025
6 Talc (Luzenac) Anti tacking 0.05
7 Isopropyl alcohol Vehicle q.s.
8 Methyl chloride Vehicle q.s.
Total 6.00
Aspirin component:
Sr. No Ingredient Function Qty./Tablet
(mg)
Intragranular
1 Aspirin Active 150.00
2 Microcrystalline cellulose PH 112 (MCCPH112) Diluent 40.00
3 Low-sub. hydroxypropyl cellulose Disintegrant 8.00
4 Stearic acid (fine grade) Lubricant 2.00
Total 200.00

Seal coating:
Sr. No Ingredient Function Qty./Tablet
(mg)
1 Hydroxy propyl methyl cellulose (MethocelE15) Film former 4.20
2 Ethyl cellulose 10 cps Film former 1.20
3 Diethyl phthalate Plasticizer 0.60
4 Methanol Vehicle qs
5 Methylene chloride Vehicle qs
Enteric coating
1 Eudragit® L30 D55* Enteric coating 10.71

Seal coating:
Sr.
No Ingredient Function Qty./Tablet (mg)
polymer
2 Talc (Luzenac) Anti-tacking agent 3.38
3 Triethyl citrate Plasticizer 2.49
4 Ferric oxide yellow Colorant 0.10
5 Purified water Vehicle qs
Total 222.68
*30% aqueous dispersion
Procedure:
Manufacturing Process for the Prasugrel component:
1. Prasugrel hydrochloride was sifted along with talc and Pearlitol SD 200 through appropriate sieve. MCC PH 112, Pearlitol SD 200, HPMC 3 cps, Croscarmellose sodium were also sifted through appropriate sieve.
2. The Material of step-1 was blended in conta blender.
3. Magnesium stearate was sifted through appropriate sieve separately.
4. The blend of step-2 was lubricated with the magnesium stearate obtained from step-3 and compressed into tablet.
5. HPMC 6 cps was dispersed in Isopropyl alcohol and this dispersion was added to methylene chloride with constant stirring.
6. Talc, Ti02, Lactose monohydrate, Ferric oxide red were dispersed into isopropyl alcohol and milled using colloid mill and added to dispersion of step-5 followed by addition of Triacetin with stirring.
7. Compressed tablets were coated using coating solution of Step 6.
Manufacturing Process for the Aspirin component:
1. Microcrystalline cellulose PH 112, Low-sub. hydroxypropyl cellulose were sifted through appropriate sieve.
2. The ingredients of step-1 were sifted with Aspirin in blender followed by lubrication with stearic acid.
3. The blend of step-2 was compressed using suitable punches.

4. Hydroxy propyl methyl cellulose (Methocel E15), Ethyl cellulose (10 cps), Diethyl phthalate were dissolved in mixture of Methanol and methylene chloride, followed by seal coating of the tablet prepared in step-3.
5. The talc (Luzenac), triethyl citrate and ferric oxide yellow were dispersed in purified water and mixed with Eudragit® L30 D55 dispersion and using this final dispersion the seal coated tablets prepared in step-4, were coated till the desired weight gain was achieved.
Capsule filling:
Prepared Prasugrel tablet was placed first followed by placing prepared Aspirin (EC) tablet into Hard Gelatin Capsule (HGC).

EXAMPLE 2:
Prasugrel component
Sr. No Ingredient Function Qty./Tablet (mg)
Intragranular
1 Prasugrel HC1 Active 10.98
2 Microcrystalline cellulose PH 112 Diluent 64.96
3 Pearlitol SD 200 Diluent 95.06
4 Croscarmellose sodium Disintegrant 7.5
5 Talc (Luzenac) Glidant 5.0
6 Hydroxy propyl methyl cellulose (3 cps) Stabilizer 12.5
Lubrication
7 Magnesium stearate Lubricant 4.00
Total 200.0
Aspirin (Enteric coated) com ponent:
Sr.
No Ingredient Function Qty/Tablet
(mg)
Intragranular
1 Aspirin Active 150.00
2 Microcrystalline cellulose PH 112 (MCC PH 112) Diluent 23.00
3 Crospovidone XL 10 Disintegrant 10.00
4 Colloidal silicon dioxide (Aerosil) Glidant 3.00
5 Stearic acid (fine grade) Lubricant 4.00
6 Talc (Luzenac) Glidant 10.00
Total 200.00

Enteric coating composition:
Sr.
No Ingredient Function Qty/Tablet (mg)
1 Hypromellose phthalate Enteric coating polymer 15.30
2 Talc Anti tacking 1.20
3 Titanium dioxide Opacifier 1.80
4 Ferric Oxide yellow Colorant 0.17
5 Diethyl phthalate Plasticizer 1.53
6 Methanol Vehicle q.s.
7 Methyl chloride Vehicle q.s.
Total 20.00
Procedure:
Manufacturing Process for the Prasugrel component:
1. Prasugrel hydrochloride was sifted along with talc and Pearlitol SD 200 through appropriate sieve. MCC PH 112, Pearlitol SD 200, HPMC 3 cps and Croscarmellose sodium were also sifted through appropriate sieve.
2. The Material of step-1 was blended in conta blender.
3. Magnesium stearate was sifted through appropriate sieve separately.
4. The blend of step-2 was lubricated with the magnesium stearate obtained from step-3.
Manufacturing Process for the Aspirin component:
1. Microcrystalline cellulose PH 112, Crospovidone XL 10, Colloidal silicon dioxide, Stearic acid and Talc were sifted through appropriate sieve.
2. The ingredients of step-1 were sifted with Aspirin in blender.
3. The blend of step-2 was compressed using suitable punches.
4. HPMC phthalate was dissolved in part of mixture of Methanol and methylene chloride.
5. Talc, TiO2and Ferric oxide yellow were dispersed in part of mixture of Methanol and methylene chloride and milled it in colloid mill. Followed by addition of this solution to the mixture of step-4 and finally diethyl phthalate was added to this solution with constant stirring.

6. The Aspirin tablets prepared in step-3 were coated using the solution of step-5 till the
desired weight gain was achieved. Capsule filling:
Prasugrel component and Aspirin (EC) tablet prepared were placed into HGC.

Example 3:
Prasugrel component:
Sr. No Ingredient Function Qty./Tablet
(mg)
Core formula composition
1 Prasugrel HC1 Active 10.98
2 Microcrystalline cellulose PH 112 Diluent 64.96
3 Pearlitol SD 200 Diluent 95.06
4 Croscarmellose sodium Disintegrant 7.5
5 Talc (Luzenac) Glidant 5.0
6 Hydroxy propyl methyl cellulose (3 cps) Stabilizer 12.5
Lubrication
7 Magnesium stearate Lubricant 4.00
Total 200.0
Film coating composition:
Sr.
No Ingredient Function Qty./Tablet
(mg)
1 Hydroxy propyl methyl cellulose (6 cps) Film forming polymer 3.47
2 Lactose monohydrate Adhesive 0.86
3 Triacetin Plasticizer 0.50
4 Titanium dioxide Opacifier 1.10
5 Ferric Oxide Red Colorant 0.025
6 Talc (Luzenac) Anti tacking 0.05
7 Isopropyl alcohol Vehicle q.s.
8 Methyl chloride Vehicle q.s.
Total 6.00
Aspirin compone nt:
Sr.
No Ingredient Function Qty./Tablet
(mg)
1 Aspirin (as granules #16 #40) Active 75.00
2 Eudragit® L30 D55* Enteric coating polymer 5.63 !
3 Talc Anti tacking 1.00
4 Triethyl citrate Plasticizer 0.63

Sr. No Ingredient Function Qty./Tablet (nig)
5 Purified water Vehicle q.s
Total 82.25
*30% w/w aqueous dispersion
Procedure:
Manufacturing Process for the Prasugrel component:
1. Prasugrel hydrochloride was sifted along with talc and Pearlitol SD 200 through appropriate sieve. MCC PH 112, Pearlitol SD 200, HPMC 3 cps, Croscarmellose sodium was also sifted through appropriate sieve.
2. The Material of step-1 was blended in conta blender.
3. Magnesium stearate was sifted through appropriate sieve separately.
4. The blend of step-2 was lubricated with the magnesium stearate obtained from step-3 and compressed into tablet.
5. HPMC 6 cps was dispersed in Isopropyl alcohol and this dispersion was added to methylene chloride with constant stirring.
6. Talc, Ti02, Lactose monohydrate, Ferric oxide red were dispersed into isopropyl alcohol and milled using colloid mill and added to dispersion of step-5 followed by addition of Triacetin with stirring.
7. Compressed tablets of step-4 were coated using coating solution of step-6.
Aspirin component (Aspirin enteric coated granules);
1. Talc was suspended in water with high shear, followed by addition of triethyl citrate.
2. The Eudragit® L30 D55 (30% w/w aqueous dispersion) was added to the suspension of step-1 and mixed gently.
3. The aspirin (as granules #16 #40) were enteric coated by spraying the dispersion of step-2 in fluid bed processor.
4. The coated granules of step-3 were dried to remove the water residue.
Capsule filling:
Prasugrel tablet prepared and Aspirin (enteric coated granules) component were placed into HGC.

Example :4:
Prasugrel component:
Sr. No Ingredient Function Qty./Tablet (mg)
Core formula composition
1 Prasugrel HC1 Active 10.98
2 Microcrystalline cellulose PH 112 Diluent 64.96
3 Pearlitol SD 200 Diluent 95.06
4 Croscarmellose sodium Disintegrant 7.5
5 Talc (Luzenac) Glidant 5.0
6 Hydroxy propyl methyl cellulose (3 cps) Stabilizer 12.5
Lubrication
7 Magnesium stearate Lubricant 4.00
Total 200.0
Aspirin component:
Sr. No Ingredient Function Qty./Tablet
(mg)
1 Aspirin (as granules #16 #40) Active 75.00
2 Eudragit® L30 D55* Enteric coating polymer 5.63
3 Talc Anti tacking 1.00
4 Triethyl citrate Plasticizer 0.63
5 Purified water Vehicle q.s
Total 82.25
*30 % w/w aqueous dispersion
Procedure:
Manufacturing Process for the Prasugrel component:
1. Prasugrel hydrochloride was sifted along with talc and Pearlitol SD 200 through appropriate sieve. MCC PH 112, Pearlitol SD 200, HPMC 3 cps and Croscarmellose sodium were also sifted through appropriate sieve.
2. The Material of step-1 was blended in conta blender.
3. Magnesium stearate was sifted through appropriate sieve separately.
4. The blend of step-2 was lubricated with the magnesium stearate obtained from step-3.

Aspirin component;
Aspirin enteric coated granules were prepared as described in example-3. Capsule filling:
Prasugrel component and Aspirin (enteric coated granules) component were placed
into HGC.

Example-5:
Aspirin component:
Sr. No Ingredient Function Qty./Tablet
(mg)
1 Aspirin (granules) Active 150.00
2 Microcrystalline cellulose PH 112 Diluent 23.00
3 Crospovidone XL 10 Disintegrant 10.00
4 Colloidal silicon dioxide (Aerosil) Glidant 3.00
5 Stearic acid (fine grade) Lubricant 4.00
6 Talc fluzenac) Glidant 10.00
Total 200.0
Enteric coating:
Sr. No Ingredients Function Qty./Tablet
mg
1 Hypromellose phthalate Enteric coating polymer 15.30
2 Talc Anti tacking agent 1.20
3 Ti02 Opacifier 1.80
4 Ferric oxide yellow Colorant 0.17
5 Triethyl citrate Plasticizer 1.53
6 Methanol Vehicle q.s.
7 Methylene chloride Vehicle q.s.
Total 20.0
Sea l coating:
Sr.
No Ingredients Function Qty./Tablet mg
2 Hydroxypropyl methyl Cellulose (Metho E 15) Polymer 1.7
2 Talc Glidant 1.6
3 Titanium Dioxide Opacifier 0.4
4 PEG 6000 Plasticizer 0.2

Sr.
No Ingredients Function Qty./Tablet mg
5 Talc Glidant 0.25
6 Colloidal Silicon Dioxide (Aerosil) Glidant 0.25
7 Isopropyl alcohol Vehicle q.s.
8 Methylene chloride Vehicle q.s.
Total 4.4
Prasugrel Component
Sr. No Ingredient Function Qty ./Tablet (mg)
Core formula composition
1 Prasugrel HC1 Active 10.98
2 Microcrystalline cellulose PH 112 Diluent 145.02
3 Pearlitol SD 200 Diluent 800,0
4 Croscarmellose sodium Disintegrant 44.0
5 Talc (Luzenac) Glidant 5.0
6 Hydroxy propyl methyl cellulose (3 cps) Stabilizer 70.0
Lubrication
7 Magnesium stearate Lubricant 25.0
Total 1100.0

Film coating composition
Sr. No Ingredients Function Qty./Tablet mg
1 Hydroxy Propyl Methyl Cellulose (6 Cps) Film forming polymer 23.15
2 Lactose monohydrate Adhesive 5.73
3 Triacetin Plasticizer 3.33
4 Titanium Dioxide Opacifier 7.34
5 Ferric Oxide Red Colorant 0.12
6 Talc (Luzenac) Anti tacking 0.33
7 Isopropyl alcohol Vehicle q.s.
8 Methylene chloride Vehicle q.s.
Total 40.00
Procedure:
Manufacturing Process for the Aspirin component:
1. Microcrystalline cellulose PH 112, Crospovidone XL 10, Colloidal silicon dioxide, Stearic acid and Talc were sifted through appropriate sieve.

2. The sifted ingredients of step 1 were blended with Aspirin in blender followed by compression of the blend into tablet using suitable punches.
3. HPMC phthalate was dissolved in part of a mixture of Methanol and methylene chloride.
4. Talc, TiO2 and Ferric oxide yellow were dispersed in part of the mixture of Methanol and methylene chloride and milled it in colloid mill and resultant solution was added to the mixture obtained in step 3. Diethyl phthalate was added to this solution with constant stirring.
5. The compressed tablets of Aspirin prepared in step 2 were coated using solution of step 4 till the desired weight gain achieved. (Enteric coating)
6. Hydroxypropyl methyl Cellulose (Metho E 15), Talc, Titanium Dioxide, PEG 6000 and Colloidal Silicon Dioxide (Aerosil) were dispersed in isopropyl alcohol and methylene chloride with proper stirring. The enteric coated tablets obtained in step 5 were coated using this solution till the desired weight gain achieved.
Manufacturing Process for the Prasugrel component:
1. Prasugrel HC1, along with talc and partial amount of Pearlitol were sifted through appropriate sieve. MCC PH 112, Pearlitol SD 200, HPMC 3 cps and Croscarmellose sodium were also sifted through appropriate sieve.
2. The sifted ingredients of step-1 were blended in conta blender.
3. Magnesium stearate was sifted through appropriate sieve and used to lubricate the blend of step-2.
4. The lubricated blend was compressed into tablets using suitable punches by placing Aspirin tablets (Enteric and seal coated) in it.
5. HPMC 6 cps was dispersed in Isopropyl alcohol and this dispersion was added to methylene chloride with constant stirring.
6. Talc, Ti02, Lactose monohydrate, Ferric oxide red were dispersed in isopropyl alcohol and milled in colloid mill. The resulting solution was added to the solution of step-5 and finally Triacetin was added to this solution with stirring.
7. The compressed tablets of step-4 were coated using coating solution of Step-6.

Example :6: Aspirin (Enteric coated) tablet
Sr. No Ingredient Function Qty./Tablet
(mg)
1 Aspirin Active 150.00
2 Microcrystalline cellulose PH 112 Diluent 40.00
3 Low substituted hydroxy propyl cellulose Disintegrant 8.00
4 Stearic acid (fine grade) Lubricant 2.00
Total 200.0

Seal Coa ting
Sr. No. Ingredients Function Qty./Tablet (mg)
1 Hydroxy propyl methyl cellulose (MethocelE15) Film former 4.20
2 Ethyl cellulose (10 cps) Film former 1.20
3 Diethyl phthalate Plasticizer 0.60
4 Methanol Vehicle qs
5 Methylene chloride Vehicle qs
Total 206.0

Enteric coating
Sr. No. Ingredients Function Qty./Tablet (mg)
1 Eudragit® L30 D55* Enteric coating polymer 35.70
2 Talc (Luzenac) Anti-tacking agent 3.38
3 Triethyl citrate Plasticizer 2.49
4 Ferric oxide yellow Colorant 0.10
5 Purified water® Vehicle Qs
Total 222.68
*D sol ispersi ids) on co ntaining 30% w/w sol id content. (3 5.70 mg disper sion contains 10.71 mg
Procedure:
Manufacturing Process for the Aspirin component:
1. Microcrystalline cellulose PH 112, Low substituted hydroxy propyl cellulose and Stearic acid were sifted through appropriate sieve.
2. The sifted ingredients were blended with Aspirin in blender.
3. The aspirin blend was compressed using suitable punches.

4. Hydroxy propyl methyl cellulose and Ethyl cellulose were dissolved in part amount of mixture of Methanol and methylene chloride. Then diethyl phthalate was added to this solution with constant stirring.
5. The compressed Aspirin tablets were coated using this coating solution till the desired weight gain is achieved. (Seal coating)
6. Talc and color in purified water were milled and mixed with Eudragit® L 30D55. Then Triethyl citrate was added to it.
7. The seal coated tablets were coated with above coating solution of step 6 till desired weight gain is achieved (Enteric coating).

Prasugrel Tablet (Film coated)
Sr.
No. Ingredient Function Qty ./Tablet
(mg)
Core formula composition
1 Prasugrel hydrochloride Active 10.98
2 Talc (Luzenac) Anti-static 5.00
3 Mannitol (Pearlitol SD 200) Diluent 78.52
4 Microcrystalline cellulose (Avicel PH 112) Diluent 65.00
5 Hydroxypropylmethyl cellulose (3 cps) Binder 7.50
6 Croscarmellose Sodium Disintegrant 19.00
Lubrication
7 Magnesium stearate Lubricant 4.00
Total 190.00

Film coating composition
Sr. No. Ingredients Function mg/tab
1 Hydroxy Propyl Methyl Cellulose (6 Cps) Film forming po lymer 3.34
2 Lactose monohydrate Adhesive 0.82
3 Triacetin Plasticizer 0.47
4 Titanium Dioxide Opacifier 1.00
5 Ferric Oxide Red Colorant 0.02
6 Talc (Luzenac) Anti tacking 0.05
7 Isopropyl alcohol Vehicle qs
8 Methylene chloride Vehicle qs
Total 195.70

Manufacturing Process for the Prasugrel component:
1. Prasugrel HC1, talc and partial amount of Pearlitol were sifted through appropriate sieve. Then MCC PH 112, Pearlitol SD 200, HPMC 3 cps and Croscarmellose sodium were sifted through appropriate sieve. The coated aspirin granules were sifted through appropriate sieve.
2. The sifted ingredients were blended in conta blender.
3. Magnesium stearate was sifted through appropriate sieve.
4. The above blend was lubricated with sifted magnesium stearate.
5. The lubricated blend was compressed into tablets using suitable punches.
6. HPMC 6 cps was dispersed in Isopropyl alcohol and then this dispersion was added to methylene chloride with constant stirring.
7. Talc, TiO2, Lactose monohydrate and Ferric oxide red were dispersed in isopropyl alcohol, milled in the colloid mill and then this solution was added to above solution. Triacetin was added to this solution with stirring.
8. The compressed tablets were coated using coating solution of Step 7.
Capsule filling
One Prasugrel tablet and one Aspirin (enteric coated) tablet were placed in a hard gelatin
capsule.

We claim:
1. A stable pharmaceutical composition comprising:
a) immediate release component comprising prasugrel, and
b) delayed release component comprising aspirin.

2. The stable pharmaceutical composition according to claim 1, wherein the composition is in the form of monolithic, bilayered, multilayered, inlayered or multiparticulate system.
3. The stable pharmaceutical composition according to any of the preceding claims, wherein the immediate release component comprising prasugrel is combined with delayed release component comprising aspirin, and filled into capsule or compressed into tablet.
4. The stable pharmaceutical composition according to any of the preceding claims, wherein the aspirin component can be enteric coated granules or pellets or tablet.
5. A process for preparing prasugrel component, wherein the process comprises:

a) blending prasugrel with one or more suitable pharmaceutical excipients;
b) lubricating the blend of step a);
c) optionally coating the granules of step b) and lubricating it.
6. A process for preparing aspirin component, wherein the process comprises:
a) granulating mixture of aspirin, and suitable pharmaceutical excipients;
b) optionally blending the granules with suitable pharmaceutical excipients and lubricating it;
c) optionally coating the granules of step a) using enteric polymer and lubricating it.
7. A process for preparing a stable pharmaceutical composition comprising:
i) compressing the mixture of the prasugrel component and the aspirin component into tablet and coating the tablet using suitable film forming polymer, or

ii) filling the mixture of the pfasugrel component and the aspirin component into
capsule, or iii) compressing the blend of the prasugrel component and the aspirin component into
a bilayer tablet, or iv) compressing the prasugrel component into a tablet and coating the tablet and
filling it with the aspirin component into a capsule, or v) filling aspirin component into a capsule (inner capsule) and putting this capsule
into another capsule (outer capsule) comprising prasugrel component, or vi) compressing the prasugrel component into a tablet and coating the tablet;
compressing aspirin component into a tablet and enteric coating the tablet; filling
both the tablets into a capsule, or vii) compressing aspirin component into a tablet and enteric coating the tablet; filling
the tablet along with prasugrel component into a capsule, or viii) compressing the prasugrel component into a tablet and coating the tablet and
filling it along with aspirin enteric coated granules or pellets into a capsule, or ix) filling prasugrel component and aspirin enteric coated granules or pellets into a
capsule, or x) compressing the aspirin component into tablet or mini-tablet, optionally coating
with enteric polymer and inlayed tablet prepared by compressing the prasugrel
component along with prepared tablet or mini-tablet of aspirin.