PHARMACEUTICAL COMPOSITIONS COMPRISING DIPYRIDAMOLE AND
ASPIRIN

INTRODUCTION

Aspects of the present application relate to pharmaceutical formulations comprising dipyridamole and aspirin, and processes to prepare such compositions. Aspects of the present invention also relate to methods of using pharmaceutical compositions for the treatment of diseases and disorders. In particular aspects, the present invention relates to multi-particulate systems comprising dipyridamole and tablets comprising aspirin, contained in a capsule, and processes for preparing the same. Aspects of the invention further relate to therapeutic uses and methods of treatment employing such formulations comprising dipyridamole and aspirin.

Dipyridamole has a chemical name 2,2',2",2'"-[(4,8-dipiperidinopyrimido[5,4-d] pyrimidine-2,6-diyl)dinitrilo]-tetraethanol and is structurally represented as Formula A. It is commercially available in the form of oral tablets of 25, 50 and 75 mg strengths sold as PERSANTINE™ and as extended release capsules of 200 mg strength sold as PERSANTIN RETARD™. It is also available as a combination product of an immediate release aspirin 25 mg tablet and extended release dipyridamole 200 mg, contained in capsules and sold as AGGRENOX™.

Formula A

The antiplatelet agent aspirin (acetylsalicylic acid) has a chemical name benzoic acid, 2-(acetyloxy)-, and is structurally represented as formula B.

Formula B

AGGRENOX capsules contain the following inactive ingredients: acacia, aluminum stearate, colloidal silicon dioxide, corn starch, dimethicone, hypromellose, hypromellose phthalate, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, povidone, stearic acid, sucrose, talc, tartaric acid, titanium dioxide, and triacetin. Each capsule shell contains gelatin, red iron oxide and yellow iron oxide, titanium dioxide, and water.

U.S. Patent No. 4,361,546 describes a gelatin capsule dosage form that contains an easily disintegrating tablet comprising dipyridamole and having a water-soluble coating, plus five "retard" tablets, each containing a mixture of dipyridamole and tartaric acid and further having an insoluble lacquer coating.

U.S. Patent No. 4,367,217 describes a sustained release composition comprising spheroidal particles prepared by granulating a mixture of dipyridamole and a carboxylic acid, and are surrounded with a dialysis membrane that consists essentially of acid-insoluble lacquer.

U.S. Patent No. 6,015,577 describes pharmaceutical combinations of dipyridamole or mopidamol with acetylsalicylic acid, which release the two components simultaneously in the gastrointestinal tract.

International Application Publication No. WO 2010/036975 discloses a pharmaceutical formulation comprising pellets comprising dipyridamole and acetylsalicylic acid, wherein these two pellets are physically separated.

U.S. Patent Application Publication No. 2007/0184110 discloses extended release formulations of dipyridamole formed in a tablet solid form having diameters about 1.5 mm and about 3 mm, and an immediate release formulation of acetylsalicylic acid, wherein the extended release and the immediate release formulations are combined in a capsule.

Formulations having a number of active substances risk interactions between them, resulting in formulations which are unstable or contain unacceptable amounts of degradants, often limiting the activity of the active ingredients.

There remains a need for improved pharmaceutical formulations containing dipyridamole and aspirin.

SUMMARY

In aspects, the present invention relates to a pharmaceutical formulation comprising:

a) Dipyridamole in extended release composition and

b) Aspirin in immediate release composition.

Embodiments of the present invention relate to pharmaceutical formulations, comprising extended release composition of dipyridamole in the form of pellets and immediate release composition of aspirin in the form of tablet.

Embodiments of the present invention relate to extended release pellets of dipyridamole comprising core having one or more seal coating comprising a hydrocolloid;

a dipyridamole layer over the seal coating;

an outer coating comprising a drug release modifying substance; and

optionally, a seal coating layer covering the drug release modifying coating.

In embodiments, the seal coating prevents direct contact between dipyridamole and a core; and comprises of hydrophilic or hydrophobic materials, or combinations thereof.

The seal coating may be present in amounts about 5% to about 30% by weight of the core.

In embodiments, the core comprise of an organic acid selected from tartaric acid, citric acid, ascorbic acid, malic acid, succinic acid, and the like.

In embodiments, dipyridamole extended release pellets and aspirin immediate release tablet are filled together into a capsule.

In embodiments, the present invention provides processes for preparing dipyridamole extended release compositions and aspirin immediate release compositions.

In embodiments, the present invention provides a process for preparing a pharmaceutical composition comprising:

a) applying one or more seal coating of same or different pharmaceutically acceptable excipients or mixtures thereof over pharmaceutically inert core;

b) applying a coating comprising dipyridamole and optionally one or more pharmaceutical acceptable excipients upon coated core;

c) applying a coating comprising at least one drug release modifying substance, upon pellets coated with dipyridamole;

d) compressing aspirin with other pharmaceutically acceptable excipients in the form of tablets;

e) filling dipyridamole pellets and aspirin tablet into capsules.

In embodiments, pharmaceutical formulations comprise extended release compositions containing dipyridamole, wherein about 5% to about 40% of the dipyridamole is released in about 1 hour, following immersion in 900 mL of 0.1 N HCI and at least 40% dipyridamole is released into a neutral pH buffer in about 12 hours.

In embodiments, dosage forms of the present invention comprise extended release dipyridamole pellets and immediate release aspirin tablet, when subjected to in vitro dissolution testing using 0.1 N hydrochloric acid for 1 hour, followed by pH 5.5 phosphate buffer, release less than about 50% of the dipyridamole within about 1 hour, from about 20% to about 70% of the dipyridamole within about 1.5 hours, and about 50% to about 100% of the dipyridamole being released within about 12 hours.

In embodiments, the present invention relates to pharmaceutical formulations comprising:

a) Dipyridamole in extended release composition and

b) Aspirin in immediate release composition that are used to reduce the risk of stroke in patients who have had transient ischemia of the brain or complete ischemic stroke due to thrombosis.

DETAILED DESCRIPTION

Aspects of the present invention relate to pharmaceutical compositions containing dipyridamole and aspirin. In embodiments the dipyridamole is present in extended release form and the aspirin is present in immediate release form.

The extended release dipyridamole may be formulated in the form of multiparticulates.
In various embodiments, multi-particulates according to the present invention may be in the form of granules, pellets, spheroids, extrudates, mini-tablets, and the like.

Embodiments of the present invention relate to pharmaceutical formulations containing dipyridamole, which comprise at least one core having an intermediate coating, a dipyridamole layer thereupon, and an outer drug release-modifying layer.

Embodiments of the present invention relate to pharmaceutical formulations containing dipyridamole, which comprise at least one core covered with a coating layer comprising dipyridamole and a drug release modifying substance.

In the context of the present invention, the term "cores" refers to pharmacologically inert particles that may be in the form of beads, spheroids, granules, pellets, etc.

In the context of the present invention, the terms "layer" or "coating" or "deposit" are used synonymously.

Embodiments of the present invention relates to pharmaceutical formulations, comprising:

cores having an intermediate coating comprising a hydrocolloid;

a dipyridamole layer over the intermediate layer;

an outer layer comprising a drug release modifying substance; and

optionally, a seal coating layer covering the drug release modifying layer.

Embodiments of the present invention relate to pharmaceutical formulations, comprising:

cores having an intermediate coating comprising a hydrocolloid;

a dipyridamole layer containing a drug release modifying substance, over the intermediate layer; and

optionally, a seal coating layer covering the dipyridamole layer.

In embodiments, an intermediate coating that prevents direct contact between dipyridamole and a core comprises a hydrocolloid, optionally with other hydrophilic or hydrophobic materials, or combinations thereof. An intermediate coating can be formed as one or more layers of pharmaceutically acceptable excipients.

In embodiments, a core is coated with an intermediate coating and then layered with a dipyridamole coating. In embodiments, more than one intermediate coating between the core and the dipyridamole layer are also contemplated as being within the scope of the present invention.

In embodiments, pharmaceutically inert cores are layered with an organic acid, coated with an intermediate coating, and then layered with a dipyridamole coating. The organic acid can optionally be sprayed onto cores as a solution in a suitable solvent or solvent system

An aspect of the present invention provides processes for preparing pharmaceutical formulations of the invention embodiments comprising:

providing an intermediate layer coating over cores, optionally with other pharmaceutically acceptable excipients, using techniques such as powder coating, spray coating, dip coating, fluidized bed coating, and the like;

providing a dipyridamole coating, optionally with other pharmaceutically acceptable excipients, over the intermediate layer;

providing a coating of a drug release modifying substance, such as a cellulose polymer, cellulose phthalate polymer or a derivative thereof, methacrylic acid alkyl ester or a copolymer thereof, and the like, including any mixtures thereof; and

filling into capsules or compressing into tablets, optionally with other pharmaceutically acceptable excipients.

In embodiments of the present invention, seal coated cores can be layered or coated with dipyridamole by:

layering dipyridamole as a powder, together with a solvent system, optionally comprising a binder; or

layering dipyridamole as a suspension or solution, with or without a binder, using equipment such as a fluid bed processor.

Cores that are useful in the context of present invention include, but are not limited to: water-soluble cores such as sucrose spheres, lactose, organic acids such as tartaric acid, citric acid, ascorbic acid, malic acid, succinic acid, and the like; and water-insoluble cores such as microcrystalline cellulose, silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, and the like. Mixtures of any two or more thereof are contemplated.

In embodiments, dipyridamole extended release compositions and aspirin immediate release compositions are filled together into a capsule.

In embodiments, immediate release compositions include aspirin, which may be in the form of a pharmacologically acceptable salt. Pharmacologically acceptable salts of aspirin are those with pharmacologically acceptable cations such as metal, ammonium, amine, or quaternary ammonium cations.

The term "hydrocolloid" in the context of the present invention refers to hydrophilic colloidal substances such as acacia gum (also known as gum Arabic), tragacanth, xanthan gum, carboxymethyl cellulose sodium, hydroxyethyl celluloses, hydroxypropyl methylcelluloses (hypromellose or "HPMC"), hydroxypropyl celluloses, poly(N-vinylpyrrolidone) (povidones), polyvinyl acetates ("PVA"), chitosan, and the like, including any combinations thereof.

Various materials that may be used in an intermediate coating include, but are not limited to: hydrophilic materials such as homopolymers or copolymers of N-vinylpyrrolidone, cellulose derivatives such as hydroxypropyl methylcelluloses, vinyl and acrylic polymers, polyacrylic acid, and the like; hydrophobic substances such as cellulose derivatives like ethyl celluloses, low substituted hydroxylpropyl celluloses (L-HPC), cellulose acetates, cellulose propionates (lower, medium, or higher molecular weight), cellulose acetate propionates, cellulose acetate butyrates, cellulose acetate phthalates; polyalkyl methacrylates; polyalkyi acrylates; crosslinked vinylpyrrolidone polymers; hydrogenated castor oil; and the like. Other classes of rate controlling substances or their mixtures in various ratios as required are also within the purview of this invention without limitation.

The intermediate layer (or seal coating) may be coated over the cores using techniques such as powder coating, spray coating, dip coating, fluidized bed coating, and the like.

In embodiments of the present invention, an intermediate coating comprises one or more layers of different hydrophilic or hydrophobic materials, or combinations thereof.

In embodiments, pharmaceutical formulations of the present invention comprise an immediate-release aspirin composition, wherein the aspirin composition is optionally coated with an immediate release coating.

Immediate release coatings include coatings that dissolve quickly to release the aspirin including, but not limited to, gastro-soluble compositions for film-coating of moisture sensitive solid particles. Typically, the immediate release coating is present in amounts of about 1% to about 8% by weight of the aspirin composition. In embodiments, the immediate release coating is present in amounts about 2% to about 5% by weight of the aspirin composition.

In embodiments, preparation processes include mixing aspirin and at least one diluent, disintegrant, and/or lubricant, compressing the mixture into tablets, coating the tablets with an immediate release coating, and filling a capsule with an extended release dipyridamole composition and the coated aspirin composition.

In the context of the present invention, during the preparation of the pharmaceutical compositions and finished dosage forms, one or more pharmaceutically acceptable excipients may optionally be used, including, but not limited to: diluents such as microcrystalline cellulose (MCC), silicified MCC (e.g., Prosolv™ HD 90), microfine cellulose, lactose, starches, pregelatinized starches, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, and the like; binders such as acacia, guar gum, alginic acid, dextrin, maltodextrin, methyl celluloses, ethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses (e.g., KLUCEL® products), hydroxypropyl methylcelluloses (e.g., METHOCEL® products), carboxymethyl cellulose sodium, povidones (e.g., various grades of KOLLIDON® and PLASDONE® products), starches, and the like; disintegrants such as carboxymethyl cellulose sodium (e.g. Ac-Di-Sol® and Primellose® products), crospovidones (e.g. Kollidon®, Polyplasdone®), povidone K-30, polacrilin potassium, starches, pregelatinized starches, sodium starch glycolate (e.g. Explotab®) and the like; surfactants including anionic surfactants such as chenodeoxycholic acid, 1-octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxycholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium cholate hydrate, sodium dodecyl sulfate (SDS or SLS), cationic surfactants such as cetylpyridinium chloride monohydrate and hexadecyl- trimethylammonium bromide, nonionic surfactants such as N-decanoyl-N-methylglucamine, octyl a-D-glucopyranoside, n-Dodecyl b-D-maltoside (DDM), sorbitan esters, polyoxyethylene sorbitan esters like polysorbates, and the like; plasticizers such as acetyl tributyl citrate, phosphate esters, phthalate esters, amides, mineral oils, fatty acids and esters, glycerin, triacetin or sugars, fatty alcohols, polyethylene glycol, ethers of polyethylene glycol, fatty alcohols such as cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol and the like. Solvents that may be used in processing steps such as granulation, layering, and coating include water, alcohols like ethanol, isopropanol, mixtures of water with an alcohol in any ratio, and organic solvents like acetone, methylene chloride, dichloromethane, and the like.

Pharmaceutical compositions of the present invention may further include any one or more of pharmaceutical acceptable glidants, lubricants, opacifiers, colorants, and other commonly used excipients.

Various pharmaceutically acceptable excipients that may be used as drug release modifying substances include, but are not limited to, cellulosic polymers such as hydroxypropylmethyl cellulose phthalates, hydroxypropylcellulose phthalates, hydroxypropyl methylcellulose hexahydrophthalates, cellulose acetate phthalates, cellulose ester-ether phthalates, alkali salts of cellulose acetate phthalates, alkaline earth salts of cellulose acetate phthalates, cellulose acetate hexahydrophthalates, acrylic acid polymers and copolymers, such as methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl esters; copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate with a terpolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride, such as Eudragit® RS, Eudragit® S100, Eudragit® L100, etc., vinyl polymers and copolymers such as polyvinyl acetates, polyvinyl acetate phthalates, vinyl acetate crotonic acid copolymers and ethylene-vinyl acetate copolymers, shellac, ammoniated shellac, shellac-acetyl alcohol and shellac n-butyl stearate and the like, and any mixtures thereof. Other classes of polymers, copolymers of these polymers, and their mixtures in various ratios as desired are within the scope of this invention without limitation.

The foregoing lists of excipients are representative of the substances that can be used, and are not exhaustive. Those skilled in the art will be aware of other useful substances, and their uses in the present invention are also contemplated.

Many of the drug release modifying substances are generally insoluble in acidic environments such as gastric fluids, but are soluble in higher-pH environments such as the duodenum and lower areas of the gastrointestinal tract. These "enteric polymers" thus delay release of the drug substance contained inside a dosage form, by preventing contact of the drug-containing compositions and fluids until higher-pH conditions are encountered. By selecting appropriate polymers, drug release from a dosage form can be obtained in a desired portion of the digestive system.

The different physicochemical properties of the active ingredient, and as well as of excipients, are to be considered, as these properties affect the processing and formulation properties of the compound. Various important physicochemical properties include, but are not limited to, particle sizes, density (bulk density and tapped density), compressibility index, Hausner's ratio, angle of repose, etc.

Particle sizes of active pharmaceutical ingredient can affect a solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by drug particle sizes and size distributions. This can be critical for low-dose drugs, and satisfactory dosage units of low doses are difficult to manufacture from a drug that does not meet certain particle size and size distribution requirements. Also, particle sizes can play an important role in the dissolution of active ingredient from the final dosage form for certain drugs, because of their poor solubility. Hence, these physicochemical properties not only affect the processes of preparing the pharmaceutical compositions, but also affect the performance of pharmaceutical products, both in vitro and in vivo.

The selection of appropriate particles sizes of dipyridamole and aspirin, as well as of excipients, is within the scope of the invention. The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 is a size for which at least 90 volume percent of the particles have sizes smaller than the said value. Likewise D10 refers to 10 volume percent of the particles having sizes smaller than the given value. D50 refers to at least 50 volume percent of the particles having sizes smaller than the given value, and D[4,3] refers to the mean particle size. Methods for determining D10, D50, D90, and D[4,3] include laser diffraction techniques, such as using equipment sold by Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom, or by Horiba.

In embodiments, the formulations of the present invention comprise dipyridamole, or a pharmaceutically acceptable form of dipyridamole, having a particle size distribution such that: D90 is about 1 μm to about 200 μm, or about 1 μm to about 75 μm, or about 10 urn to about 60 urn; and D50 is from about 1 μm to about 100 urn, or about 1 μm to about 50 urn, or about 1 μm to about 25 μm.

Flowability of materials is measured and represented using the Carr Index. The Carr Index is the percentage ratio of the difference between tapped density and bulk density to tapped density, calculated as:

Carr Index = [(Tapped density-Bulk density) Tapped density] * 100.

Carr Index values below about 15% represent materials with very good flow properties and values above about 40% represent materials with very poor flow properties.

ln embodiments, pellets containing dipyridamole and granules of aspirin compositions have Carr Index values substantially lower than the 40% described for products with poor flow properties. Values of Carr Index for dipyridamole pellets of the present invention are generally less than about 40%, or less than about 30%. This indicates superior handling capabilities during processing into pharmaceutical dosage forms.

Values of Carr Index for aspirin granules of the present invention are generally less than about 40%, or less than about 30%. This indicates superior handling capabilities during processing into pharmaceutical dosage forms.

The densities can be determined using standard test method 616 "Bulk Density and
Tapped Density" from United States Pharmacopeia 32, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2009.

The dosage forms of the present invention can be subjected to in vitro dissolution testing, such as according to Test 711 "Dissolution" in United States Pharmacopeia 32, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2009 ("USP"), to determine the rate at which the active substance is released from the dosage forms, and content of active substance can be determined in dissolution media using techniques such as high performance liquid chromatography (HPLC).

An environment that a dosage form is likely to encounter when administered to a human (in vivo) can be correlated to in vitro dissolution studies conducted using dissolution media, such as, but not limited to, simulated gastric fluid (SGF) with or without pepsin, simulated intestinal fluid (SIF) with or without pancreatin, 0.01 N hydrochloric acid, pH 1.2, 4.5, 5.5, 6.0, 6.8, 7.2, and 7.4 buffers, pH 2.1 SGF, pH 5.0 and 4.5 acetate buffers, pH 4.5 ammonium acetate buffer, pH 5.0 fed state simulated intestinal fluid (FeSSIF), pH 6.5 fasted state simulated intestinal fluid (FASSIF), pH 6.8 phosphate buffer, with or without sodium lauryl sulphate (SLS), pH 1.5 HCI buffer, and the like.

In embodiments, the pharmaceutical compositions comprise of extended release formulation of dipyridamole, wherein about 5% to about 40% of the dipyridamole of the capsule is released in about 1 hour following immersion into 900 mL of 0.1 N HCI.
About 40-99% of dipyridamole is released after subsequent immersion into a higher-pH buffer stage within about 12 hours.

In embodiments, dosage forms of the present invention comprising extended release dipyridamole multiparticulates and a immediate release aspirin tablet are subjected to in vitro dissolution testing using 0.1 N hydrochloric acid (HCI) for the first hour, followed by pH 5.5 phosphate buffer. The dosage forms release less than about 50% of dipyridamole within about 1 hour, from about 20% to about 70% of dipyridamole within about 1.5 hours, and about 50% to about 100% within about 12 hours.

Among the dipyridamole-related degradants and impurities that may be present in a dipyridamole-containing formulation are those identified as the compounds having Formulas l-VI.

Formula I: 2,2'-[[4,6,8-tri(piperidin-1-yl)-pyrimido[5,4-d]pyrimidin-2-yl]nitrilo]diethanol.

Formula II: 2,2,,2",2'",2"",2"",-[[8-(Piperidin-1-yl)-pyrimido[5,4-d]pyrimidine-2,4,6-triyl]trinitrilo]hexaethanol.

Formula III: 2,2'-[[6-[(2-hydroxyethyl)amino]-4,8-di(piperidin-1-yl)pyrimido[5,4-d] pyrimidin-2-yl]nitrilo]diethanol.

Formula IV: 2,2,,2",2",-[[6,8-di(piperidin-1 -yl)pyrimido[5,4-c/]pyrimidine-2,4-iyl]dinitrilo]tetraethanol.

Formula V: 2,3-Dihydroxy-succinic acid mono-{2-[{6-[bis-(2-hydroxyethyl)amino]-4-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-2-yl}-(2-hydroxyethyl)amino]ethyl} ester.


Formula VI: 2,6-Bis-[(bis-2-hydroxyethylamino)]-8-piperidine-1-yl-pyrimido [5,4-d]pyrimidin-4-ol.

The impurities can be analyzed in dipyridamole compositions using high performance liquid chromatography (HPLC) analytical procedures, such as the procedure described below.

Buffer preparation: potassium dihydrogen phosphate (1.36 g) is dissolved in 1 L of Milli-Q water with sonication, followed by adjusting pH to 3 using orthophosphoric acid and filtration through a 0.45 urn Durapore PVDF hydrophilic membrane filter.

Mobile phase A: buffer solution is degassed in a sonicator for 10 minutes and used as Mobile phase A.

Mobile phase B: methanol is degassed in a sonicator for 10 minutes and used as Mobile phase B.

Elution gradient program:

Minutes % Mobile Phase A % Mobile Phase B
0 50 50
4 50 50
25 5 95
28 5 95
30 50 50
35 50 50

Detector wavelength 295 nm.

Column: Inertsil ODS 2, 150 mmx4.6 mm, 5 urn.

Column temperature: 45°C.

Flow rate: 1.0 mL/minute.

Injection volume: 10 μL

Diluent: Buffer solution: Dissolved 1.36 g of potassium dihydrogen phosphate in 1000 ml of water and the pH was adjusted to 3.0 with dilute orthophosphoric acid solution. This buffer solution and methanol were mixed in the ratio of 40:60 (v/v) respectively.

Standard preparation: 80 mg of Dipyridamole working standard was accurately weighed and transferred into a 100 mL volumetric flask, added about 70 mL of diluent and sonicated to dissolve the material completely. Adjusted the volume and mixed well.
Pipetted out 5.0 mL of the resultant solution into a 50 mL volumetric flask, diluted to volume with diluent and mix. Pipetted out 5.0 mL of the resultant solution into a 50 mL volumetric flask, diluted to volume with diluent and mix.

Preparation of impurity stock solution: Transferred an accurately weighed amount of about 2.0 mg of each impurity A, B, C, D and E into a 25 ml volumetric flask. Dissolved and diluted up to the mark with diluent.

Preparation of System suitability solution: Transferred an accurately weighed amount of about 40.0 mg of Dipyridamole working standard into a 25 ml volumetric flask and added 17 ml of diluent and sonicated to dissolve the material completely and then added 1 ml of impurity stock solution and adjusted the volume with the diluent.

Test preparation: Dipyridamole pellets from 20 capsules were taken in a poly bag and mixed well. Dipyridamole pellets equivalent to 80 mg of Dipyridamole were transferred into a 50 ml volumetric flask, added about 30 ml of diluent, shaken on a rotary shaker for 50 minutes at 200 RPM. The volume was adjusted with the diluent and mixed well. The above solution was centrifuged at 4000 RPM for 5 minutes and the supernatant liquid was used for analysis.

Typical relative retention times observed for impurities l-VI and dipyridamole are 1.54, 0.52, 0.97, 1.16, 0.24, and 1, respectively.

Typical relative response factor values observed for impurities l-VI and dipyridamole are 1.03, 0.91, 0.61, 0.55, 0.63, 0.36, and 1.0, respectively.

Among the aspirin-related degradants and impurities that may be present in an aspirin-containing composition are those identified as the compounds having Formulas l-V.
Formula I: 4-Hydroxybenzoic acid.

OH Formula II: 4-Hydroxyisophthalic acid (or) 4-hydroxybenzene-1,3-dicarboxylic
acid.

Formula III: Salicylic acid.

Formula IV: Acetylsalicylsalicylic acid (or) 2-[[2-(acetyloxy)benzoyl]oxy]benzoicacid.

Formula V: Salicylsalicylic acid (or) 2-[(2-hydroxybenzoyl)oxy]benzoic acid.

The impurities can be analyzed in aspirin-containing formulations using high performance liquid chromatography, such as with the procedure below.

Mobile phase: mix orthophosphoric acid, acetonitrile, and water in the volume ratio of 2:400:600. Filter through a 0.45 urn Nylon 66 membrane filter and degas in a sonicatorfor 10 minutes.

Detector wavelength 237 nm.

Column: Inertsil ODS-3V, 250x4.6 mm, 5 urn.

Column temperature: 25°C.

Flow rate: 1.0 mL/minute.

Injection volume: 20 μL

Run time: 45 minutes.

Diluent solution: 1000 ml of water was transferred in a beaker and the pH was adjusted to 2.3 ± 0.05 with formic acid (98%-100%) and degassed in a sonicator. Acetonitrile and Diluent-1 were mixed in the ratio of 50:50 (v/v) and degassed in a sonicatorfor 10min.
Standard preparation: Accurately weighed about 50 mg of Acetylsalicylic acid working standard into a 100 ml volumetric flask and dissolved in a diluent solution and the volume was adjusted with diluent solution. Pipetted out 5.0ml of resultant solution into a 100 ml volumetric flask and diluted to the volume with diluent solution and mixed well. Pipetted out 2ml of the above solution in to 50ml and diluted to volume with diluent solution and mixed well.

Test preparation: Acetylsalicylic acid tablet from 20 capsules were taken and weighed.
The tablets were crushed to fine powder in mortar with pestle. Accurately weighed and transferred tablet powder equivalent to 50mg of Acetylsalicylic acid into a 100ml volumetric flask. 25 ml of diluent solution was added and sonicated for 10 minutes with intermediate shaking, maintain the temperature of sonicator below 15°C. Diluted to volume with diluent solution and mixed. A portion of the above sample was centrifuged at about 3000 RPM for 10 minutes.

Typical relative retention times observed for impurities l-V and aspirin are 0.615, 0.732, 1.489, 3.019, 4.536, and 1, respectively.

Typical relative response factor values observed for impurities l-V and aspirin are 1.68, 1.54, 1.97, 1.68, 2.04, and 1, respectively.

In embodiments, the invention includes the use of formulation packaging materials, such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE), polypropylene, and/or glass, and blisters or strips composed of moisture resistant aluminum, high-density polypropylene, polyvinyl chloride and/or polyvinylidene dichloride.

In embodiments, the invention provides packages suitable for commercial sale, which provide stability during storage, transportation, and use.

Pharmaceutical formulations of the present invention are useful to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.

The following examples are provided to further illustrate certain specific aspects and embodiments of the invention in greater detail, and should not be regarded as limiting the scope of the invention in any manner.

EXAMPLES

EXAMPLE 1: Capsule formulation containing dipyridamole 200 mg extended release multi-particulates and an aspirin 25 mg tablet. Dipyridamole Multi-particulates:

* Evaporates during processing.

Aspirin Tablet:

* Evaporates during processing.

Manufacturing process (dipyridamole multi-particulates):

1. HPMC 15 cps is dissolved in isopropyl alcohol and methylene chloride is added.

2. Tartaric acid pellets are coated using the coating solution of step 1. After drying, the pellets are sifted through a #30 mesh sieve and then a #40 mesh sieve. Pellets retained on the #40 mesh sieve are progressed.

3. Acacia, HPMC 15 cp, and talc are dispersed in water. The pellets of step 2 are coated using this coating dispersion. After drying, the pellets are sifted through #30 mesh and #40 mesh sieves, and pellets retained on the 40 mesh sieve are progressed.

4. Povidone K-30 and HPMC 15 cp were mixed with isopropyl alcohol and methylene chloride is added. Dipyridamole is sifted through a #50 mesh sieve and dissolved in the solution.

5. The pellets from step 3 are coated with the solution of step 4. After drying, pellets passing through a #20 mesh sieve and retained on a #40 mesh sieve are progressed.

6. Eudragit® S 100, HPMC phthalate, HPMC 5 cp, stearic acid, triacetin, dimethicone, and talc are dispersed in a mixture of isopropyl alcohol and acetone.

7. The pellets of step 5 are coated using the coating dispersion of step 6. After drying, final pellets pass through a #20 mesh sieve and are retained on a #40 mesh sieve.

Manufacturing procedure (aspirin tablet):

1. Aspirin is sifted through a #30 mesh sieve.

2. Microcrystalline cellulose, lactose anhydrous, pregelatinized starch, and colloidal silicon dioxide are sifted through a #30 mesh sieve and blended.

3. Stearic acid is sifted through a #60 mesh sieve and blended with the material from step 2.

4. The material from step 3 is compressed into 5 mm tablets.

5. Opadry® AMB Yellow is dispersed in water and used to coat the tablets.

Encapsulation: dipyridamole enteric coated pellets and an aspirin film coated tablet are filled into a size '0' gelatin capsule.

An in vitro dissolution study is performed using the prepared capsules and the following conditions, and the results are shown in Table 1:

Media: 900 mL of 0.1 N HCI for the first hour, then 900 mL of pH 5.5 phosphate buffer.

Apparatus: USP type 1 (basket).

Rotation speed: 100 rpm.

Temperature: 37.0±0.5°C.

Table 1

Prepared capsules are packaged in HDPE 120 cc containers with 2 molecular sieve desiccant pouches and 38 mm child resistant closures and stored under the accelerated stability testing conditions of 40°C and 75% relative humidity (RH) for 3 months. The samples are analyzed for drug content and the impurities of Formula I-VI before, during, and after the storage, and results are shown in the tables below, where values are percentages of the label drug content. Analyses of dipyridamole and aspirin components for 1 month (1M), 2 months (2M) and 3 months (3M) of storage are reported in Tables 3A and 3B, respectively.

Table 3A: Dipyridamole Results

* ND: not detected.
Table 3B: Aspirin Results

Time Drug
Assay

EXAMPLE 2: Capsule formulations containing dipyridamole 200 mg extended release multi-particulates and an aspirin 25 mg tablet.
Dipyridamole Multi-particulates:

* Evaporates during processing. Aspirin Tablet:

* Evaporates during processing.

Manufacturing process (dipyridamole multi-particulates):

1. HPMC 15 cp is dissolved in isopropyl alcohol and methylene chloride is added.

2. Tartaric acid pellets are coated using the coating solution of step 1. After drying, the pellets are sifted through #30 mesh and #40 mesh sieves, and pellets retained on the #40 mesh sieve are progressed.

3. Acacia, HPMC 15 cp, and talc are dispersed in water and used to coat the pellets of step 2. After drying, the pellets were sifted through #30 mesh and #40 mesh sieves, and pellets retained on the #40 mesh sieve are progressed.

4. Povidone K-30 and HPMC 15 cp are mixed with isopropyl alcohol and methylene chloride is added. Dipyridamole is sifted through a #50 mesh sieve and dissolved in the solution.

5. The pellets from step 3 are coated with the solution of step 5. After drying, the pellets passing through a #20 mesh sieve and retained on a #40 mesh sieve are progressed.

6. Eudragit® RS (for 2A) or Eudragit® L100 (for 2B), HPMC phthalate, HPMC 5 cp, stearic acid, triacetin, dimethicone, and talc are dispersed in a mixture of isopropyl alcohol and acetone.

7. The pellets of step 5 are coated using the dispersion of step 6. After drying, final pellets pass through a #20 mesh sieve and are retained on a #40 mesh sieve.

Manufacturing procedure (aspirin tablet):

1. Aspirin is sifted through a #30 mesh sieve.

2. Microcrystalline cellulose (for 2A) or lactose monohydrate (for 2B), pregelatinized starch (for 2A) or povidone K-30 (for 2B), and colloidal silicon dioxide are sifted through a #30 mesh sieve and blended.

3. Magnesium stearate is sifted through a #60 mesh sieve and blended with the materials from step 2.

4. The material from step 3 is compressed into 5 mm tablets.

5. Opadry® AMB Yellow is dispersed in water and used to coat the tablets.
Encapsulation: dipyridamole modified release pellets and an aspirin film coated tablet are filled into a size '0' gelatin capsule.

EXAMPLE 3: Capsule formulations containing dipyridamole 200 mg extended release multi-particulates and an aspirin 25 mg tablet. Dipyridamole Multi-particulates:

Evaporates during processing.
Aspirin Tablet:

* Evaporates during processing.

Manufacturing process (dipyridamole multi-particulates):

1. HPMC 15 cp is dissolved in isopropyl alcohol and methylene chloride is added.

2. Tartaric acid pellets are coated using the coating solution of step 1. After drying, the pellets are sifted through #30 mesh and #40 mesh sieves, and pellets retained on the #40 mesh sieve are progressed.

3. Acacia, HPMC 15 cp, and talc are dispersed in water and used to coat the pellets of step 2. After drying, the pellets are sifted through #30 mesh and #40 mesh sieves and pellets retained on the #40 mesh sieve are progressed.

4. Povidone K-30 and HPMC 15 cp are mixed with isopropyl alcohol and methylene chloride is added. Dipyridamole is sifted through a #50 mesh sieve and dissolved in the
solution.

5. The pellets from step 3 are coated with the solution of step 4. After drying, pellets passing through a #20 mesh sieve and retained on a #40 mesh sieve are progressed.

6. Eudragit® S 100 (for 3A) or Eudragit® S 100 and Eudragit® L 100 (for 3B), HPMC phthalate, HPMC 5 cp, stearic acid, triacetin, dimethicone, and talc are dispersed in a mixture of isopropyl alcohol and acetone.

7. The pellets of step 5 are coated using the dispersion of step 6. After drying, final pellets pass through a #20 mesh sieve and are retained on a #40 mesh sieve.

Manufacturing procedure (aspirin tablet):

1. Aspirin is sifted through a #30 mesh sieve.

2. Microcrystalline cellulose, lactose anhydrous, pregelatinized starch (for 3A) or
Hypromellose 15 cp (for 3B), and colloidal silicon dioxide are sifted through a #30 mesh sieve and blended.

3. Magnesium stearate is sifted through a #60 mesh sieve and blended with the material from step 2.

4. The material from step 3 is compressed into 5 mm tablets.

5. Opadry® AMB Yellow is dispersed in isopropyl alcohol and used to coat the tablets.

Encapsulation: dipyridamole modified release pellets and an aspirin film coated tablet are filled into a size '0' extra-elongated capsule.

We claim:

1. A pharmaceutical formulation comprising:

a) Dipyridamole in extended release composition and

b) Aspirin in immediate release composition.

2. The pharmaceutical formulation of claim 1, wherein extended release composition of dipyridamole is in the form of pellets and immediate release composition of aspirin is in the form of tablet.

3. The pharmaceutical formulation of claim 2, wherein extended release composition of dipyridamole comprise of: a core having one or more seal coating comprising a hydrocolloid; a dipyridamole layer over the seal coating; an outer coating comprising a drug release modifying substance; and optionally, a seal coating layer covering the drug release modifying coating.

4. The pharmaceutical formulation of claim 3, wherein the seal coating comprises of hydrophilic and/or hydrophobic materials.

5. The pharmaceutical formulation of claim 3, wherein the seal coating may be present in amounts about 5% to about 30% by weight of core.

6. The pharmaceutical formulation of claim 3, wherein the core comprises of organic acid selected from tartaric acid, citric acid, ascorbic acid, malic acid, and succinic acid.

7. The pharmaceutical formulation of claim 1, wherein dipyridamole extended release composition and aspirin immediate release composition are filled into capsule.

8. The pharmaceutical formulation of claim 1, wherein a process for preparing a pharmaceutical formulation comprises the steps of:

a) applying one or more seal coating of same or different pharmaceutically acceptable excipients or mixtures thereof over pharmaceutically inert core;

b) applying a coating comprising dipyridamole and optionally one or more pharmaceutically acceptable excipients upon coated core;

c) applying a coating comprising at least one drug release modifying substance, upon pellets coated with dipyridamole;

d) compressing aspirin with other pharmaceutically acceptable excipients in the form of tablets; and

e) filling dipyridamole pellets and aspirin tablet into capsules.

9. The pharmaceutical formulation of claim 1, comprising

a) Dipyridamole in extended release composition and

b) Aspirin in immediate release composition used to reduce the risk of stroke in patients who have had transient ischemia of the brain or complete ischemic stroke due to thrombosis.

10. A pharmaceutical formulation and process of preparation thereof as described and illustrated in the examples herein.