PLATELET INHIBITING FORMULATIONS

INTRODUCTION

The present invention relates to antiplatelet pharmaceutical formulations comprising aspirin and clopidogrel. More particularly, the invention relates to stable antiplatelet pharmaceutical formulations comprising aspirin and clopidogrel for oral administration. Specific embodiments of the invention relate to stable pharmaceutical formulations comprising a combination of enteric-coated aspirin and clopidogrel, including its pharmaceutically acceptable salts or solvates for oral administration. Also included are processes for preparing formulations and methods of using formulations for treating various types of diseases in mammals.

Coagulation is a process initiated by a wide variety of stimuli. After coronary artery bypass grafting, stenting etc. anticoagulant agents are used to prevent complication following such procedures. Initially a whole variety of anticoagulant and antiplatelet agents were administered to the patients. There has been a lot of interest in the study of the role played by the platelets in the development of diseases associated with atherosclerosis (myocardial infarction, cerebral attack, peripheral arterial diseases and the like).

The well established role of the platelets in arterial thrombosis has allowed the development of various medicaments, which inhibit the functions of the platelets. A variety of antiplatelet agents are available which differ in various parameters, for e.g. modes of action, antiplatelet potency, onset of action, costs and specific circumstances and temporal framework in which they are used.

The discovery of the essential role of ADP in thrombotic process has led to the development of a potent antithrombotic agent such as ticlopidine which is reported in U.S. Patent No. 4,051,141. Ticlopidine selectively inhibits the platelet aggregation induced by ADP as well as other agonists, mediated by ADP.

French Patent 2307538 describes the combination of ticlopidine and aspirin as an antiplatelet aggregation agent. The hemodynamic effect of the combination of ticlopidine and aspirin is superior to ticlopidine alone. But this combination is not sufficient or useful for indication in the secondary prevention of vascular accidents in atherometous disease or alternatively in endarterectomy of fitting of metallic endovascular prosthesis.

Clopidogrel is a thienopyridine derivative and is a more potent platelet inhibitor which acts by inhibiting the adenosine diphosphate (ADP) receptor mediated platelet activation. It is preferred over other antiplatelet agents because of fewer side effects.

European Patent 099802 discloses clopidogrel as a potent antithrombotic, which acts through a mechanism identical to that of ticlopidine.
Depending on the aggregation agents used, clopidogrel is 10 to 50 times more effective than ticlopidine. Unlike the latter, clopidogrel exhibits a practically immediate anti-aggregation activity which appears within 15 minutes after administration, whereas ticlopidine requires, in order to be effective, a prolonged administration of at least 3 days at a much higher dose.

Aspirin is an antiplatelet agent, which acts by blocking the conversion of arachidonic acid in the platelet. It is relatively a weak antiplatelet agent as it inhibits only one pathway by which platelet activation and aggregation occurs. It is administered in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention.

Aspirin is known to be moisture sensitive and thermolabile leading to disintegration into acetic acid and salicylic acid, even though dosage forms containing aspirin are processed, packed and stored carefully.

Pharmaceutical formulations in unit galenical forms suitable for the concomitant administration of aspirin and other anti-aggregating agents are advantageous as it has been clearly demonstrated that doses of each one of the constituents of the combination can be prebound, and do not require adjusting as a function of the patients to be treated.
Combination dosage forms of aspirin with other potent active ingredients typically suffer from instability on long-term storage resulting in shortening of the shelf life of the product.
Several combination studies have been carried out with aspirin and other active principles, but many drawbacks have been demonstrated during the production of the galenic forms, containing aspirin combined with salts of an active principle. Many publications demonstrated the incompatibility between aspirin and other solid active principles.

U.S. Patent No. 5,989,578 discloses a pharmaceutical composition comprising aspirin and clopidogrel in free form or in the form of a pharmaceutically acceptable salt. This patent discloses joint administration of clopidogrel and aspirin resulting in a significant effect in relation to the aggregation of the platelets with collagen, i.e., when the products were administered in combination, the anti-aggregation effect obtained was always greater than the mere sum of the effects of the two test products taken separately.

Indian Patent Application No. 1180/MUM/2004 discloses novel stable antiplatelet formulations comprising a combination of enteric-coated aspirin tablets and granules of clopidogrel, which are filled into a hard gelatin capsule.
Formulating combination dosage forms of aspirin and clopidogrel has not proven to be an easy task. Therefore, there remains a need for preparing combination dosage forms of aspirin and clopidogrel for oral administration. Ideally, such formulations are conveniently prepared, and show a faster anti-platelet effect when administered to a subject in need of therapy through the most acceptable oral route of administration.

SUMMARY

The present invention relates to novel antiplatelet pharmaceutical formulations comprising aspirin and clopidogrel. More particularly the invention relates to stable antiplatelet pharmaceutical formulations comprising aspirin and clopidogrel for oral administration. Specific embodiments of the invention relate to stable pharmaceutical formulations comprising a combination of enteric-coated aspirin and clopidogrel, including its pharmaceutically acceptable salts or solvates for oral administration.

An aspect of the present invention provides pharmaceutical formulations comprising a combination of antiplatelet agents.
Another aspect of the invention provides antiplatelet formulations comprising a combination of antiplatelet agents along with pharmaceutically acceptable excipients for oral administration.

Another aspect of the invention provides antiplatelet formulations comprising a combination of enteric-coated aspirin and clopidogrel, which are filled into a hard gelatin capsule.

Another aspect of the invention provides antiplatelet formulations comprising aspirin in the form of enteric-coated granules or tablets and clopidogrel in the form of tablets, which are filled into a hard gelatin capsule.

Another aspect of the invention provides stable antiplatelet formulations comprising aspirin in the form of enteric-coated tablets and clopidogrel in the form of tablets.

Another aspect of the invention provides stable antiplatelet formulations comprising aspirin in the form of enteric-coated tablets and clopidogrel in the form of tablets, wherein total impurities are less than about 2%, or less than about 1%, by weight of labeled drug contents.

Another aspect of the invention provides a tablet-in-tablet formulation comprising aspirin and clopidogrel, which may optionally be filled into a hard gelatin capsule.

DETAILED DESCRIPTION

The present invention relates to antiplatelet pharmaceutical formulations comprising aspirin and clopidogrel. More particularly the invention relates to stable antiplatelet pharmaceutical formulations comprising aspirin and clopidogrel for oral administration. Specific embodiments of the invention relate to stable pharmaceutical formulations comprising a combination of enteric-coated aspirin and clopidogrel, including its pharmaceutically acceptable salts or solvates for oral administration. Also included are processes for preparing such formulations and methods of using such formulations for treating various types of diseases in mammals.
As used herein, the term "formulation" refers to a fixed dose combination comprising aspirin and clopidogrel, in a form suitable for administration to a human. Often, a formulation comprises one or more pharmaceutically acceptable excipients, in addition to the active ingredients.

The term "pharmaceutically acceptable" means an ingredient that is useful for preparing pharmaceutical formulations that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.

The term "stability" includes both physical and chemical stability, suitable for commercial activities. This implies maintenance of original formulation specifications after manufacture, for a period of at least about six months, or at least about 1 year, or at least about 2 years, to the extent necessary for storage, sale, and use of the formulation.

The term ''tablet-in-tablet" formulation refers to a composition comprising at least two active ingredients, where a tablet comprising an active ingredient completely or partially surrounds a tablet comprising another active ingredient.
The formulations are useful in treating patients with unstable angina, myocardial infarction without ST-segment elevation, stroke, myocardial infarction with ST-segment elevation, as well as those undergoing angioplasty and stenting.
The pharmaceutical formulations ot the Invention are usually prepared following conventional methods and are administered in pharmaceutically suitable forms such as solid formulations for oral administration, e.g. tablets and capsules, and liquid formulations for oral administration, e.g., syrups, emulsions and suspensions.

Therapeutically effective amounts of active ingredient can be provided in the form of pharmaceutical formulations in the form of tablets, capsules, granules (synonymously, "beads" or "particles" or "pellets"), suspensions, emulsions, powders, dry syrups, and the like, following conventional methods for immediate release of the pharmaceutically active compound. They may also be formulated so as to provide delayed or rate-controlled release of the active ingredient therein using release retarding polymers in varying proportions to provide the desired release profile.

Certain dosage forms according to the present invention are tablets. Tablets can be prepared by direct compression techniques, using powder blends, or can be prepared using granules. Granules can be formed by any processes, using operations such as one or more of dry granulation, wet granulation, extrusion-spheronization, and the like. In an embodiment, the granulation of an active, optionally with one or more pharmaceutically acceptable excipients like diluents or fillers, carried out in equipment such as planetary mixers, rapid mixer granulators. (RMG), fluid bed processors (FBP), and the like. The granules obtained may further be compressed into tablets or filled into capsules using techniques known in the art.

Alternatively powder blends can be compacted using a roller compactor and then milled to produce granules that are suitable for compression.

In one aspect of the invention, the granules formed by a wet granulation process have bulk densities ranging from about 0.4 to 0.6 g/ml, tapped densities ranging from about 0.6 to 0.8 g/ml and Carr indexes ranging from about 20 to 40%.

Aspirin formulations are prepared using aspirin particles having particle sizes ranging from about 100 urn to about 850 urn, or from about 150 urn to about 700 urn.

Clopidogrel formulations are prepared using clopidogrel compound particles having mean particle sizes of about 50 urn to about 400 urn. Such particles of the active ingredient exhibit required micromeritic properties such as, but not limited to, bulk density, tapped density, angle of repose, Carr index, compressibility ratio, and the like.

As used herein, the term "mean particle size" refers to a distribution of particles wherein about 50 volume percent of all particles measured have particle sizes less than the defined mean particle size value, and about 50 volume percent of all measurable particles measured have particle sizes greater than the defined mean particle size value; this can be denoted by the term "D50." Similarly, a particle size distribution where 90 volume percent of the particles have sizes less than a specified size is referred to as "D90" and a distribution where 10 volume percent of particles have sizes less than a specified size is referred to as "D10." A desired particle size range material can be obtained directly from a synthesis process or any known particle size reduction processes can be used, such as but not limited to sifting, milling, micronization, fluid energy milling, bail milling, and the like. Methods for determining D10 D50 and D90 include laser light diffraction, such as using equipment from Malvern Instruments Ltd. (Malvern, Worcestershire, United Kingdom).

Aspirin is known to be moisture sensitive and thermolabile, leading to its decomposition into acetic acid and salicylic acid. Hence, dosage forms containing aspirin need to be processed, packaged, and stored carefully, due to stability concerns. The combination of aspirin with other active principles is likely to suffer from instability during long-term storage, resulting in shortening of the shelf life of the product.
Due to the instability of aspirin in combination with a base salt, impurities may be generated during processing to prepare pharmaceutical formulations or during stability testing.

However, surprisingly and unexpectedly, it is possible, according to the invention, to prepare pharmaceutical compositions in an unit galenic form containing aspirin in combination with a base salt, such as clopidogrel bisulfate, by using various manufacturing methods and techniques.

In an embodiment, the invention includes antiplatelet formulations comprising aspirin in the form of enteric-coated tablets and clopidogrel bisulfate in the form of tablets, which are filled Into a hard gelatin capsule.

In an embodiment, the invention includes stable formulations comprising aspirin in the form of enteric-coated tablets and clopidogrel bisulfate in the form of tablets filled into a hard gelatin capsule, wherein a moisture content of the formulation is less than about 5% w/w.
In an embodiment, the invention includes stable formulations comprising aspirin in the form of enteric-coated tablets and clopidogrel bisulfate in the form of tablets filled into a hard gelatin capsule, wherein total impurities are less than about 2%, or less than about 1 %, by weight of the initial drug content. Certain known impurities are described in compendia, such as United States Pharmacopeia 29, United States Pharmacopeia! Convention, Rockville, Maryland, 2005 ("USP").

The dose administered may vary from about 1 to 500 mg per day of clopidogrel and 1 to 500 mg per day of aspirin. Certain exemplary formulations contain about 75 mg of clopidogrel bisulfate and about 75 mg of aspirin.
In the context of the present invention, during the processing of the pharmaceutical formulations into finished dosage forms, one or more pharmaceutically acceptable excipients may optionally be included, such as, but not limited to, diluents, binders, disintegrants, lubricants, glidants, coloring agents, film-forming agents, and others. Diluents:
Various useful fillers or diluents include but are not limited to starches, lactose, cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV) and others. Different starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation) and starch 1500, starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, PH-112 microcrystalline cellulose 114, and microcrystalline cellulose 112, silicified microcrystalline cellulose (e.g., Prosolv™ supplied by JRS Pharma). Other useful diluents include but are not limited to carmeltose, sugar alcohols such as mannitol (e.g., Pearlitol™ 200 SD), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate. Binders:
Various useful binders include but are not limited to hydroxypropyl celluloses, also called HPC (Klucel™ LF, Klucel EXF) and useful in various grades, hydroxypropyl methylcelluloses, also called hypromelloses or "HPMC (Methocel™) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP-K29, PVP-K30, and PVP-K90), Plasdone™ S 630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (Carbopol™), methylcelluloses, polymethacrylates, and starches.

Disintearants:

Various useful disintegrants include but are not limited to carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di-sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, XI-10, and INF-10 [manufactured by ISP Inc. (USA)], and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcellulose include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.

Lubricants:

An effective amount of any pharmaceutically acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof.

Glidants:

One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variation, can be used. Useful glidants include but are not limited to silicon dioxide, talc and combinations thereof. Coloring Agents:
Coloring agents can be used to color code the formulations, for example, to indicate the type and dosage of the therapeutic agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, iron oxides, silicon dioxide, and zinc oxide, combinations thereof, and the like. Film-forming agents:

Various film-forming agents that are useful for coating dosage forms include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl celluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc., insoluble cellulose derivative such as ethyl celluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polymethacrylates and derivatives thereof (Eudragit™ products), chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. Useful enteric coating materials include but are not limited to materials such as cellulosic polymers like cellulose acetate phthalates, cellulose acetate trimellitates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, etc., methacrylic acid polymers and copolymers (Eudragit™), and the like, and mixtures thereof.

Some excipients are frequently used as adjuvants for the coating processes, including plasticizers, opacifiers, antiadhesives, polishing agents, etc. Various useful plasticizers include but are not limited to castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, and mixtures thereof. An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating.

Antiadhesives are frequently used in the film coating process to avoid sticking effects during film formation and drying. An example of a useful antiadhesive for this purpose is talc. The antiadhesive is frequently present in the film coating in an amount of about 5% (w/w) to 15% (w/w) based upon the total weight of the coating.

Suitable polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax).
In addition to the above coating ingredients, sometimes pre-formulated coating products such as OPADRY™ products (supplied by Colorcon) or TABCOAT™ products will be used. OPADRY formulations generally comprise polymer, plasticizer and, if desired, pigment in a dry concentrate. OPADRY products produce attractive, elegant coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures. Products sold in a dry form generally require only dispersion in a liquid before use.

Other useful additives for coating include but are not limited to plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.

Various useful plasticizers include but are not limited to substances such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. An opacifier like titanium dibxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating.
When coloured tablets are desired, the colour is normally applied in the coating. Consequently, colouring agents and pigments may be present in the film coating. Various colouring agents include but not limited to iron oxides, which can be red, yellow, black or blends thereof.
Polymers that can be used in the present invention include hydrophilic and hydrophobic substances, and combinations thereof. Suitable polymers include, but are not limited to, cellulose ethers, e.g., hydroxypropyl methylcelluloses or hypromelloses (HPMC), ethylcelluloses, hydroxypropylcelluloses (HPC), hydroxyethylcelluloses and carboxymethylcellulose sodium, polyvinylpyrrolidones, including noncross-linked polyvinylpyrrolidones, carboxymethylstarch, polyethylene glycols, polyoxyethylenes, poloxamers (polyoxyethylene-polyoxypropylene copolymers), polyvinylalcohols, glucanes (glucans), carrageenans, scleroglucanes (scleroglucans), mannans, galactomannans, gellans, alginic acid and derivatives (e.g., sodium or calcium alginate, propylene glycol alginate), polyaminoacids (e.g., gelatin), methyl vinyl ether/maleic anhydride copolymers, polysaccharides (e.g., carageenan, guar gum, xanthan gum, tragacanth and ceratonia); alpha, beta or gamma cyclodextrins, and dextrin derivatives (e.g., dextrin), polymethacrylates (e.g., copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups); cellulose esters (e.g. cellulose acetate); acrylic acid polymers (e.g., carbomers); chitosan and derivatives thereof, shellac and derivatives thereof.
Sugar coating can be performed using various processes and excipients, as are known to a person skilled in the art.
Equipment suitable for processing the pharmaceutical formulations of the present invention include rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, homogenizers, blenders, roller compacters, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans; tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multimills, fluid energy nfliHs, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen.
In some embodiments, the invention includes use of packaging materials such as containers and lids of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, glassine foil, aluminum pouches, and blisters or strips composed of aluminum or high-density polypropylene, polyvinyl chloride, polyvinylidene dichloride, etc.
Mention of aspirin and clopidogrel is intended to include any of the alternative forms in which aspirin and clopidogrel can be administered, such as salts, esters, hydrates, solvates, crystalline or amorphous polymorphs, racemic mixtures, enantiomeric isomers, etc.
The following examples further describe certain specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given for purposes of illustration only and are not intended to limit the scope of the invention in any manner.
EXAMPLES

EXAMPLE 1: Capsule formulation containing aspirin and clopidogrel. (A) Aspirin 75 mq delaved-release tablets.
Ingredient I mg/Tablet
Granular aspirin 75
Starch 1500 145
Citric acid 2
Aerosif™ 200 W 05
Stearic acid 2
Core Weight 94
Sub-coating
HPMC 6 cps 1.9
Propylene glycol 0.19
Titanium dioxide 0.1
Talc 0.16
Isopropyl alcohol q.s.
Methylene chloride q.s.
Sub-coated Weight 96.35
Enteric Coating
Eudragit™ L100-55* 45
Polyethylene glycol 4000 0.45
Talc 0.45
Isopropyl alcohol q.s.
Methylene chloride q.s.
Total Weight 101.75
* Evaporates during processing.
* Eudragit L-100-55 is an anionic methacrylic acid/methacrylate polymer that is soluble above pH 5.5, and is sold by Evonik Industries, Germany.

** Aerosil®200 W is manufactured by Degussa. Manufacturing process:

1. Sift granular aspirin, starch 1500, Aerosil, citric acid and stearic acid through an ASTM #20 mesh sieve.

2. Blend the sifted materials of step 1.

3. Sift stearic acid through an ASTM #80 mesh sieve.

4. Blend materials of step 2 and step 3 and mix for 5 minutes.

5. Compress the blend of step 4 into tablets, using 6 mm round normal concave punches.

6. Dissolve HPMC 6 cps and propylene glycol in methylene chloride, disperse titanium dioxide and talc in isopropyl alcohol, and mix together.

7. Coat the compressed tablets of step 5 using dispersion of step 6 until a 2.5% weight increase is obtained.

8. Dissolve Eudragit L100-55 and polyethylene glycol in methylene chloride, disperse titanium dioxide and talc in isopropyl alcohol, and mix together.

9. Coat the sub-coated tablets of step 7 using the dispersion of step 8 until a 5.6% weight increase is obtained.

(B) Clopidoarel 75 mo tablets.
Ingredient mg/Tablet
Clopidogrel bisulfate* 98.07
Microcrystalline cellulose 140.43
Mannitol 45
Croscarmellose sodium 12
Hydrogenated castor oil 4.5
Core Weight 300
Film Coating
Opadry™ Pink 03B54202 12
Water q.s.
Total Weight 312

* Corresponds to 75 mg clopidogrel base. t Evaporates during processing Manufacturing process:

1. Sift clopidogrel bisulfate, microcrystalline cellulose, mannitol and croscarmellose sodium through an ASTM #20 mesh sieve.

2. Blend the sifted materials of step 1.

3. Sift hydrogenated castor oil through an ASTM #80 mesh sieve.

4. Blend materials of step 2 and step 3, and mix for 5 minutes.

5. Compress the blend of step 4 using 13 mm*5.5 mm capsule-shaped normal concave punches.

6. Mix Opadry Pink 03B54202 with water and coat the compressed tablets of step 5 until a 4% weight increase is obtained. C. Dosage Form Preparation.

1. An aspirin delayed-release tablet and a clopidogrel tablet are filled into a hard gelatin capsule.

The capsules are packaged in blister packages made of aluminum and aluminum lidding foil as a backing and stored at 40°C and 75% relative humidity (RH) conditions for 6 months, and are analyzed initially and during storage to evaluate the extent of impurity formation. Except for water, impurity compound values in the table below are percentages of the label content of the related drug, with salicylic acid being an aspirin-related impurity.

Impurity I Initial [ 1 Month I 2 Months 3 Months I 6 Months
Water (%) 2.4 2.5 2.6 3.2 3.7
Salicylic acid 0.04 0.14 0.32 0.63 0.54
IMP-1 0.01 0.02 0.02 0.14 0.17
MP-2 0.07 0.09 0.05 0.05 ND
lMP-3 ND ND ND ND ND

IMP-4 ND 0.04 0.10 0.05 0.05
R-isomer 0.05 0.08 0.10 0.14 0.17
Total 0.21 0.31 0.54 0.52 0.60
ND=Not detected.

IMP-1 is(+)-(s)-(o-chlorophenyl)-6,7-dihydrothieno-[3,2-c]Pyridine-5(4H)-acetic acid (USP clopidogrel related compound A).

IMP-2 is Thieno-[3,2-c-]-4,5,6,7-tetrahydropyridine hydrochloride ("Impurity
A").

IMP-3 is 2-chloro-a-[[2-(2-thienyl) ethyl) amino] benzene acetic acid methyl ester bisulfate ("Impurity C").

IMP-4 is 6,7-dihydrothieno [3,2-c]pyridine-4(5H)-one.

R-isomer is RS Methyl-(-)-(R)-o-chlorophenyl)-6p7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, hydrogen sulfate (USP clopidogrel related compound C).

EXAMPLE 2: Tablet-in-tablet formulation comprising aspirin and clopidogrel. (A) Aspirin 75 ma delaved-release tablets.
Ingredient mg/Tablet
Granular aspirin 75
Starch 1500 14.5
Citric acid 2
Aerosil 200 W 0.5
Stearic acid 2
Core Weight 94
Sub-coating
HPMC 6 cps 19
Propylene glycol 0.19
Titanium dioxide 0.1
Talc 016
Isopropyl alcohol q.s.
Methylene chloride q.s.
Sub-coated Weight 96.35
Enteric Coating
Eudragit 100-55 4.5
Polyethylene glycol 4000 0.45
Talc 0.45
Isopropyl alcohol q.s.
Methylene chloride q.s.
Total Weight 101.75

$ Evaporates during processing. Manufacturing process:

1. Sift granular aspirin, starch 1500, Aerosil, citric acid and stearic acid through an ASTM #20 mesh sieve.

2. Blend the sifted materials of step 1.

3. Sift stearic acid through an ASTM #80 mesh sieve.

4. Blend materials of steps 2 and 3 and mix for 5 minutes.

5. Compress the blend of step 4 into tablets, using 6 mm round normal concave punches.

6. Dissolve HPMC 6 cps and propylene glycol in methylene chloride, disperse titanium dioxide and talc in isopropyl alcohol, and mix together.

7. Coat the compressed tablets of step 5 using dispersion of step 7 until a 2.5% weight increase is obtained.

8. Dissolve Eudragit L100-55 and polyethylene glycol in methylene chloride, disperse titanium dioxide and talc in isopropyl alcohol, and mix together.

9. Coat the sub-coated tablets of step 7 using dispersion of step 9 until a 5.6% weight increase is obtained.

(B) Clopidoarel blend.
Ingredient I mg/Tablet
Clopidogrel bisulfate* 98.07
Microcrystalline cellulose 278.93
Mannitol 90
Croscarmellose sodium 24
Hydrogenated castor oil 9
Core Weight 500
Film Coating
Opadry Pink 03B54202 I 20
Water* q.s.
Total Weight 520

* Corresponds to 75 mg clopidogrel base. t Evaporates during processing. Manufacturing process:

1. Sift clopidogrel bisulfate, microcrystalline cellulose, mannitol and croscarmellose sodium through an ASTM #20 mesh sieve.

2. Blend the sifted materials of step 1.

3. Sift hydrogenated castor oil through an ASTM #80 mesh sieve.

4. Blend materials of steps 2 and 3 and mix for 5 minutes.

C. Dosage Form Preparation.

1. Fill a small amount of the clopidogrel-containing blend into the die of a bilayer compression machine, place an enteric-coated aspirin tablet on the blend, fill the remaining quantity of blend into the die, and compress using capsule shaped normal concave punches, so that the clopidogrel layer completely surrounds the enteric-coated aspirin tablet.

2. Combine Opadry Pink 03B54202 with water and coat the compressed tablets of step 5 until a 4% weight increase is obtained.

Film coated tablet-in-tablet formulations can optionally be filled into hard gelatin capsules.

CLAIMS:

1. A pharmaceutical formulation for oral administration comprising aspirin and clopidogrel, wherein aspirin is in the form of an enteric-coated tablet.

2. A pharmaceutical formulation according to claim 1, wherein enteric-coated aspirin and a clopidogrel composition are filled into a hard gelatin capsule.

3. A pharmaceutical formulation according to either of claims 1 or 2, comprising 75 mg of clopidogrel and 75 mg of aspirin.

4. A pharmaceutical formulation according to any of claims 1-3, wherein clopidogrel is in the form of clopidogrel bisulfate.

5. A pharmaceutical formulation according to any of claims 1-4, wherein the composition further comprises one or more pharmaceutical excipients such as diluents, binders, disintegrants, lubricants, etc.

6. A pharmaceutical formulation according to any of claims 1-5, wherein the tablets are prepared by a process comprising wet granulation, dry granulation, or direct compression.

7. A pharmaceutical formulation according to any of claims 1-6, having a moisture content less than about 5% w/w.

8. A pharmaceutical formulation according to any of claims 1-7, wherein the composition is used for treating a pathology induced by platelet aggregation.

9. A pharmaceutical formulation according to any of claims 1-8, prepared using aspirin having particle sizes ranging from about 100 urn to about 850 urn, or from about 150 µm to about 700 µrn, and clopidogrel having particle sizes ranging from about 50 µm to about 400 µm.

10. A stable pharmaceutical formulation for oral administration comprising aspirin and clopidogrel or a pharmaceutically acceptable salt thereof, wherein the total drug-related impurities are less than about 2%, or less than about 1%, by weight of the initial drug content.