DESC:TITLE OF THE INVENTION:
“PHARMACEUTICAL COMPOSITION OF PRASUGREL AND ASPIRIN”
FIELD OF THE INVENTION:
The present invention relates to an oral pharmaceutical composition comprising solid dosage form of Prasugrel and Aspirin tablets in hard gelatin capsules. The composition is suitable for use in the treatment of percutaneous coronary intervention.
BACKGROUND OF THE INVENTION:
Prasugrel is an oral antiplatelet from thienopyridine class. It is a platelet inhibitor and an irreversible antagonist of P2Y12 ADP receptors. It was developed by Daiichi Sankyo Co. and produced by Ube and currently marketed in the United States in cooperation with Eli Lilly and Company.

Prasugrel was approved for use in Europe in February 2009 and in the US in July 2009, for the reduction of thrombotic cardiovascular events (including stent thrombosis) in people with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI)


PRASUGREL

Aspirin is a medication used to reduce pain, fever, or inflammation. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever. Aspirin given shortly after a heart attack decreases the risk of death. Aspirin is also used long-term to help prevent further heart attacks, ischaemic strokes, and blood clots in people at high risk. It may also decrease the risk of certain types of cancer, particularly colorectal cancer. For pain or fever, effects typically begin within 30 minutes.
Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and works similarly to other NSAIDs but also suppresses the normal functioning of platelets.

Aspirin

Prasugrel and Aspirin combination is approved in India on Jan 15, 2014 and used to cure percutaneous coronary intervention (PCI).
IN146/MUM/2011 claims composition comprising an immediate release component comprising Prasugrel, wherein Prasugrel is present in amount ranging from 1 % to 50 % by weight of the composition, and delayed release component comprising aspirin, wherein aspirin is present in amount ranging from 10 % to 70 % by weight of the composition.
The above attempts only provided compositions of Prasugrel and Aspirin, which shown less Bioavailability. Therefore, it needs to prepare alternate compositions of Prasugrel and Aspirin with enhanced stability, shows more content uniformity, blend uniformity and bioavailability.
In order to solve the above problem, the present inventors have developed a composition, which provides stable product, as well as improved content uniformity, blend uniformity and bioavailability.

SUMMARY OF THE INVENTION:
The present invention relates to an oral pharmaceutical dosage form composition having an
Immediate release tablet and an delayed release tablet filled in capsule comprising:
a) An immediate release tablet comprising Prasugrel 1% to 30% by weight of the composition and
b) A delayed release tablet comprising Aspirin 71% to 85% by weight of the composition.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a stable oral pharmaceutical composition comprising Prasugrel and Aspirin with acceptable excipients.
The present invention relates to an oral pharmaceutical dosage form composition having an immediate release tablet and a delayed release tablet filled in capsule comprising:
a) An immediate release tablet comprising Prasugrel 1% to 30% by weight of the composition, and
b) A delayed release tablet comprising Aspirin 71% to 85% by weight of the composition.
According to an embodiment of the present invention oral pharmaceutical composition comprising Prasugrel tablets and Aspirin tablets.
According to the embodiments of the present invention Prasugrel tablet composition comprising Prasugrel with one or more pharmaceutical acceptable excipients sifted, blended altogether, lubricated and further compressed in to tablets which are coated with coating solution.
According to the embodiments of the present invention Aspirin tablet composition comprising aspirin with one or more pharmaceutical acceptable excipients sifted, blended and compressed. Thus obtained tablets were seal coated and then enteric coated further.
According to an embodiment of the present invention a pharmaceutical composition comprising immediate release component comprising Prasugrel combined with delayed release component Aspirin and filled in to capsules.
The term “composition” or “pharmaceutical composition” or “ solid dosage forms” such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
The term ‘excipient’ means a pharmacologically inactive component such as diluent, disintegrant, carrier, filler, lubricant, binder, and solvent, coating agent or the like. These are generally safe, nontoxic. Reference to an excipient includes both one and more than one such excipient.
The term ‘stable’ refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.
Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", “having”, “containing” "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
According to the embodiments of the present invention diluent includes, but are not limited to, Micro crystalline cellulose, starch, pregelatinized starch, calcium carbonate, dibasic, tribasic calcium phosphate, calcium phosphate, lactose, dextrose, calcium phosphate, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, maltodextrin and mixtures thereof.
According to the embodiments of the present invention disintegrant includes, but are not limited to, starches, croscarmellose sodium, carmellose, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate, low-substituted hydroxypropylcellulose, crospovidone and mixtures thereof.
According to the embodiments of the present invention lubricant includes, but are not limited to, anti-tacking agent, sodium lauryl sulphate, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glycerylpalmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearylfumarate, sodium benzoate, mineral oil, glycerine fumarate and mixtures thereof.
According to the embodiments of the present invention film coating agents includes, but are not limited to talc, polyvinyl alcohol (part hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350), Hypromellose, Lactose, Triacetin, Talc, Titanium oxide and iron oxide.
According to the embodiments of the present invention seal coating agents includes, but are not limited to Hydroxypropyl methyl cellulose, Talc, PEG 6000, isopropyl alcohol
According to the embodiments of the present invention Enteric coating agents includes, but are not limited to Methcrylic acid, ethyl acrylate, Polysorbate, sodium lauryl sulphate, Talc, Triethyl citrate.
According to the embodiments of the present invention solvents includes, but are not limited to acetone, isopropyl alcohol, purified water, ethanol, polyol (for example, propylene glycol , glycerol and liquid polyethylene glycol, and the like).
The pharmaceutical composition comprising a tablet of 10mg Prasugrel and 75mg of Aspirin.
According to embodiment of the present invention composition will provide stable product, as well as improved content uniformity, blend uniformity and bioavailability.
According to the embodiments of the present invention, a pharmaceutical stable dosage form composition comprising immediate release tablet and delayed release tablet filled in capsule.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Examples-1
Prasugrel Hydrochloride Tablets 10 mg
S.No. Ingredients mg/Tablet % w/w
1 Prasugrel Hydrochloride 10.98 5.49
2 Microcrystalline cellulose 112 (Hicel XL90M) 90.00 45.00
3 Mannitol (Pearlitol 50 DC) 34.52 17.26
4 Mannitol (Pearlitol 400 DC) 45.00 22.50
5 Hydroxypropyl methyl cellulose E5 LV 6.00 3.00
6 Croscarmellose sodium (Primellose) 12.00 6.00
7 Magnesium Stearate (Ligamed MF-2-V) 1.50 0.75
Total weight of uncoated tablets 200.00 100.00
Film Coating (3.0% w/w Build up and 15.0% w/w Solids)
6 Opadry II (32k540142) Pink 6.00 NA
7 Purified water NA
Total weight of coated tablets 206.00

Aspirin Enteric coated Tablets 75 mg
S.No. Ingredients mg/Tablet % w/w
1 Acetylsalicylic acid IP 75.00 71.42
2 Microcrystalline cellulose 102 (Hicel 90M) 7.50 7.14
3 Maize starch B 7.50 7.14
Uncoated tablet weight (mg) 90.00 --
Seal coating:
4 Hydroxypropyl Methyl cellulose E5 LV 2.13 2.03
5 Talc (Luzenac) 0.75 0.71
6 PEG 6000 0.13 0.12
7 Isopropyl alcohol q.s --
8 Purified water q.s --
Seal coated tablet weight (mg) 93.01
Enteric coating:
9 Methacrylic Acid, ethyl acrylate copolymer (1:1) dispersion 30 (Ecopol L30D55) 6.4 6.09
10 Polysorbate 80 (Tween 80) 0.86 0.82
11 Sodium lauryl sulphate 0.04 0.04
12 Talc (Luzenac) 4.1 3.90
13 Triethyl citrate 0.6 0.57
14 Purified water q.s qs
Total weight of uncoated tablets 105.01 100.00
$ Opadry II (32k540142) Pink contains Hypromellose, Lactose monohydrate, Triacetin, Talc, Red Iron oxide Non-IRR and Titanium Dioxide.
BRIEF MANUFACTURING PROCESS:
Prasugrel Hydrochloride film coated Tablets 10 mg:
1. Sifting:
I. Co-sift Prasugrel Hydrochloride and Mannitol 50 C through 40 # mesh.
II. Co-sift the step I with microcrystalline cellulose PH 112, Hydroxypropyl methyl cellulose E5 Lv and Croscarmellose sodium through 40# mesh.
III. Co-sift the step II with mannitol 400 DC through 40# mesh.
2. Prelubrication: Co-sift Mannitol 400DC through 40 # mesh and blend the step III through 40 # mesh and blend in a suitable blender upto 15 minutes.
3. Sift Magnesium stearate through 60# mesh.
4. Lubrication: Blend the step 2 materials with step 3 for 5 mins.
5. Compression: Compress the above blend by using suitable punches.
6. Coating: Compressed tablets of step 5 are coated with the coating dispersion of Opadry II Pink in purified water.
Aspirin Enteric coated tablets 75 mg:
1. Sifting:
I. Co-sift Acetyl salicylic acid and Microcrystalllline cellulose PH 102 and Maize starch through 40# mesh.
II. Again sift step I through 40 # mesh.
2. Blending: Blend the step II materials in a suitable blender up to 25 minutes.
3. Compression: Compress the above blend by using suitable punches.
4. Seal coating:
III. Prepare the seal coating dispersion by adding HPMC E5 LV in purifed water and Isopropyl alcohol mixture (1:1) under stirring and continue stirring till clear solution appears.
IV. Add Talc and PEG 6000 to step III under continous stirring and coat the compressed tablets of step 3 with seal coating dispersion.
5. Enteric coating:
V. Prepare the enteic coating dispersion by adding polysorbate 80, triethyl citrate, sodium lauryl sulphate and talc in purifed water under stirring.
VI. Add the step V to Methacrylic Acid, ethyl acrylate copolymer (1:1) dispersion 30 (Ecopol L30D55) under stirring and coat the seal coated tablets with enteric coating dispersion.
6. Capsules Filling:
Fill the empty hard gelatin capsules of size “0“ with Prasugrel Hydrochloride film coated Tablets 10 mg of step 6 and Aspirin Enteric coated tablets 75 mg of step 5, with one tablet of each.

,CLAIMS:We Claim:
1) A pharmaceutical composition comprising a) an immediate release component containing Prasugrel, one or more pharmaceutically acceptable excipients thereof; and b) an delayed release component containing Aspirin, one or more pharmaceutically acceptable excipients thereof.

2) The pharmaceutical composition as claimed in claim 1, wherein an immediate release component comprising about 1% to 30% by weight of Prasugrel based on total amount of drug substance and one or more pharmaceutically acceptable excipients thereof; and An delayed release component comprising about 71% to 85% by weight of Aspirin based on total amount of drug substance and one or more pharmaceutically acceptable excipients thereof.

3) The pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of monolithic, bilayered, multi-layered, in layered or multi particulate system.

4) The 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 soft gelatin capsule.

5) The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutically acceptable excipients is selected from a suitable diluent, a suitable disintegrant, a suitable colorant, a suitable binder, a suitable glidant, a suitable lubricant and the like or mixture thereof and optionally a pharmaceutical acceptable excipient.

6) The stable pharmaceutical composition according to any of the preceding claims, wherein the aspirin component can be enteric coated granules or pellets or tablet.

7) The pharmaceutical composition as claimed in claim 1, wherein the composition is administrated once or twice a day administration.