FIELD OF THE INVENTION

The present invention relates to a pharmaceutical capsule formulation comprising the compound pellets consisting of Dipyridamole and Acetyl salicylic acid comprising (i) a core comprising the organic acid (ii) a Seal coating layer comprising the binder wherein the Seal coating layer encompasses the core (iii) a drug layer comprising the Dipyridamole wherein the drug layer comprising Dipyridamole encompasses the Seal coating layer iv) an extended release layer wherein the extended release layer encompasses the drug layer comprising the Dipyridamole v) a drug layer comprising the Acetyl salicylic acid wherein the drug layer comprising the Acetyl salicylic acid encompasses the extended release layer and vi) an optional coating layer comprising the binder encompassing the Acetyl salicylic acid layer.

BACKGROUND OF THE INVENTION

Dipyridamole is an antiplatelet agent chemically described as 2, 2',2",2"'-[(4,8- Dipiperidinopyrimido[5,4-c(]pyrimidine-2,6-diyl)dinitrilo]-tetra ethanol with the structural formula as follows

Dipyridamole exhibits a relatively short biological half-life of less than one hour. Therefore extended release formulations of Dipyridamole which provide a continual administration of Dipyridamole over time are preferred. Dipyridamole is soluble in acidic mediums with a pH below 4 and is practically insoluble in water. Therefore

Dipyridamole is readily absorbed more in the acidic regions of the upper gastrointestinal tract, but remains insoluble in the more basic regions of the intestine.

Dipyridamole can be administered with other active ingredients such as Aspirin. Aspirin (Acetyl salicylic acid) is an inhibitory substance which counteracts the aggregation of human blood platelets by inhibiting cyclooxygenase thereby inhibiting the biosynthesis of the aggregation promoting thromboxane A2.The combination of Dipyridamole and Aspirin can be administered as an anti-thrombotic agent which inhibits blood platelet aggregation in humans and animals; the combination prevents the formation and persistence of venous and arterial blood clots and thus prevents temporary ischemic episodes that helps in preventing cardiac infarction and strokes. The combination of Dipyridamole and Aspirin is also highly suitable for preventing the formation and persistence of clots in the case of arteriosclerosis or after operative intervention and conditions which involve a tendency of thrombosis.

The Antiplatelet agent Aspirin (acetyl salicylic acid) is chemically known as benzoic acid, 2-(acetyloxy)-, and has the following structural formula

Aspirin is an odorless white needle-like crystalline or powdery substance. When exposed to moisture. Aspirin hydrolyzes into salicylic and acetic acids and gives off a vinegary odor. It is highly lipid soluble and slightly soluble in water.

Dipyridamole is available as a combination product of Aspirin and Dipyridamole {25mg/200mg) in the form of extended release capsules under the brand name AGGRENOX®.

U.S. Patent. No. 4,367,217 (the '217 patent) describes a sustained release composition of Dipyridamole which comprises spheroidal particles comprised of Dipyridamole or crystallized salts thereof and a coating surrounding the said spheroidal particles, said coating comprising the acid insoluble lacquers soluble in intestinal juices. While preparing the composition similar to those described in the '217 patent it was observed that high levels of impurities are generated. This was ascribed to an incompatibility between Dipyridamole and acidic components which is believed to generate high level of impurities.

U.S. Patent. No. 6,105,577 ("the '577 patent") describes the pharmaceutical composition of the Acetyl salicylic acid and Dipyridamole. The example given by the '577 patent include Dipyridamole in the form of pellets or granules with a coating which is insoluble in gastric juices but soluble in the intestinal juices and the acetyl salicylic acid cores or tablets with a coating which is resistant to acetic acid and quickly dissolved in the gastric juices. Further examples of '577 patent include Dipyridamole granulate, separating granulate and acetyl salicylic acid granulate compressed into the three layered tablets; Dipyridamole granulate packed into a capsule together with a coated Aspirin tablet provided with the protective coating, or a film-coated tablet containing acetyl salicylic acid; and compressed tablets of the acetyl salicylic acid with a film coating combined with the Dipyridamole pellets that has been coated. The '577 patent states that acetyl salicylic acid is not free from the traces of acetic acid which are formed by the cleavage of the acetyl salicylic acid during the storage. The free acetic acid reacts with the Dipyridamole to form hygroscopic salts and Dipyridamole acetic acid esters which cause the Dipyridamole to degrade. Therefore the tablet is coated with a coating suspension comprising sucrose, gum Arabic and talc the purpose being to separate the two APIs and so prevent the degradation of the Dipyridamole over storage.

Co pending US Patent application Ser.No. 11/353,498, published as U.S. Patent Application No. US20070184110 discloses the extended release formulations of Dipyridamole formed in the solid form having a diameter of 1.5mm and about 3mm and an immediate release formulation of acetyl salicylic acid wherein the extended release and the immediate release formulations are combined in a capsule.

Co pending US Patent application Ser.No. 61/194,473 published as U.S. Patent Application 20100080846 discloses the pharmaceutical formulation comprising the pellets comprising the Dipyridamole and pellets comprising the Acetyl salicylic acid wherein the components of the Dipyridamole and Acetyl salicylic acid are physically separated.

Thus there is a need for a dosage form to be developed that can overcome the difficulties of the prior art. The development of the pharmaceutical compositions as described in the context of the present invention will be a significant improvement in the field of pharmaceutical technology.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical capsule formulation comprising the compound pellets consisting of Dipyridamole and Acetyl salicylic acid comprising (i) a core comprising the organic acid (ii) a Seal coating layer comprising the binder wherein the Seal coating layer encompasses the core (iii) a drug layer comprising the Dipyridamole wherein the drug layer comprising Dipyridamole encompasses the Seal coating layer iv) an extended release layer wherein the extended release layer encompasses the drug layer comprising the Dipyridamole v) a drug layer comprising the Acetyl salicylic acid wherein the drug layer comprising the Acetyl salicylic acid encompasses the extended release layer and vi) an optional coating layer comprising the binder encompassing the Acetyl salicylic acid layer.

In an embodiment the organic cores of the invention comprise tartaric acid, citric acid, ascorbic acid, malic acid, succinic acid or mixtures thereof.

In some embodiments the binder in the Seal coating layer encompassing the core are independently selected from polyvinylpyrrolidone (e.g.. Povidone), copolymers of vinylpyrrolidone and vinyl acetate (e.g., Copovidone), hydroxypropyl cellulose. Hydroxy ethyl methyl cellulose, methyl cellulose. Hydroxy butyl cellulose, Hydroxy butyl methyl cellulose. Hydroxy ethyl cellulose. Hydroxy methyl cellulose. Hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose. Gum acacia, tragacanth, Xanthan gum or combinations thereof.

The present invention is also directed to a process for preparing a pharmaceutical capsule formulation comprising the compound pellets consisting of Dipyridamole and Acetyl salicylic acid (A) (i) depositing the Seal coating layer onto a core comprising an organic acid wherein the Seal coating layer comprises a binder that is compatible with the organic acid; (ii) depositing onto the Seal coating layer a drug layer comprising the Dipyridamole; (iii) depositing onto the drug layer comprising the Dipyridamole an extended release layer; (iv) depositing onto the extended release layer a drug layer comprising the Acetyl salicylic acid; (v) depositing an optional coating layer comprising the binder encompassing the Acetyl salicylic acid layer; (B) adding the compound pellets consisting of Dipyridamole and Acetyl salicylic acid to a pharmaceutical capsule and (C) Sealing the pharmaceutical capsule.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanied drawings which are incorporated herein and form part of the specification illustrate one or more embodiments of the present invention and, together with the description, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention.

FIG.1. depicts a schematic representation of compound pellets consisting of Dipyridamole and Acetyl salicylic acid.
FIG.2. depicts the dissolution profile of Dipyridamole in combination Dipyridamole/acetyl salicylic acid capsules of the present invention and in acetyl salicylic acid/extended release Dipyridamole 25mg/200mg capsules sold under the trade name Aggrenox®.

FIG.3. depicts the dissolution profile of Acetyl salicylic acid in combination Dipyridamole/acetyl salicylic acid capsules of the present invention and in acetyl salicylic acid/extended release Dipyridamole 25mg/200mg capsules sold under the trade name Aggrenox®.

DETAILED DESCRIPTION OF THE INVENTION

The specification discloses one or more embodiments that incorporate the features of the invention. The disclosed embodiment(s) merely exemplify the invention. The scope of the invention is not limited to the disclosed embodiment(s).The invention is defined by the claims appended hereto.

As used herein the "compound pellets consisting of Dipyridamole and Acetyl salicylic acid" refers to the particles that are non-compressed for example a granule or a sphere comprising (i) a core comprising the organic acid (ii) a Seal coating layer comprising the binder wherein the Seal coating layer encompasses the core (iii) a drug layer comprising the Dipyridamole wherein the drug layer comprising Dipyridamole encompasses the Seal coating layer iv) an extended release layer wherein the extended release layer encompasses the drug layer comprising the Dipyridamole v) a drug layer comprising the Acetyl salicylic acid wherein the drug layer comprising the Acetyl salicylic acid encompasses the extended release layer and vi) an optional coating layer comprising the binder encompassing the Acetyl salicylic acid layer.

As used herein "Pharmaceutical capsule" refers to a capsule useful for administering the pellets of Aspirin and Dipyridamole to a subject in need thereof. In some embodiments, the pharmaceutical capsules can be, but are not limited to soft or hard gelatin capsules.

As used herein the term "stable" in the context of a Dipyridamole/acetyl salicylic acid pharmaceutical formulation refers to a formulation in which the Dipyridamole degradants, whether the chemical structure is known or not known is not more than 1.0% based on the initial weight of the Dipyridamole in the formulation, and in which each of acetyl salicylic acid degradants includes salicylic acid and any unknown degradants, has the weight that is not more than 3.0% (if the degradant is known) and not more than 0.2% (if the degradant is unknown) based on the initial weight of the salicylic acid after a storage at accelerated conditions of 40°C/75%RH for six months

The present invention relates to a pharmaceutical capsule comprising the compound pellets consisting of Dipyridamole and Acetyl salicylic acid comprising (i) a core comprising the organic acid (ii) a Seal coating layer comprising the binder wherein the Seal coating layer encompasses the core (iii) a drug layer comprising the Dipyridamole wherein the drug layer comprising Dipyridamole encompasses the Seal coating layer iv) an extended release layer wherein the extended release layer encompasses the drug layer comprising the Dipyridamole v) a drug layer comprising the Acetyl salicylic acid wherein the drug layer comprising the Acetyl salicylic acid encompasses the extended release layer vi) an optional coating layer comprising the binder encompassing the Acetyl salicylic acid layer.

FIG.1 provides the cross-sectional representation of compound pellets consisting of Dipyridamole and Aspirin of present invention referring to FIG.1 the pellet, 100, comprises a core 101, having the Seal coating layer thereon 102, the pellet further includes the drug layer of Dipyridamole thereon the Seal layer 103, the extended release layer comprising the extended release polymer 104 thereon the drug layer comprising the Dipyridamole, the aspirin drug layer 105 thereon the extended release layer comprising the extended release polymer.

In some embodiments the organic cores of the invention comprise tartaric acid, citric acid, ascorbic acid, malic acid, succinic acid or mixtures thereof.

In some embodiments the core has the at least one lateral dimensions of lOOpm to about 1000pm, about 3OOpm to about 700pm, about 400pm to about 800pm or about 400pm to about 800pm.

In some embodiments the core comprises the acidic substance which is an organic acid crystal. Without being bound to any particular theory, the crystalline nature of the organic acid in the core enhances the absorption of the Dipyridamole in the gastrointestinal tract. A crystalline organic acid core will solubilize more readily and lower the internal pH of the pellet. As the internal pH of the pellet drops, the Dipyridamole is protonated, solubilizing the drug for absorption in the gastrointestinal tract.
In some embodiments the binder in the Seal layer is selected from polyvinylpyrrolidone (e.g., Povidone), poly vinyl alchol, copolymers of vinylpyrrolidone and vinyl acetate (e.g., Copovidone), hydroxypropyl cellulose. Hydroxy ethyl methyl cellulose, methyl cellulose. Hydroxy butyl cellulose, Hydroxy butyl methyl cellulose. Hydroxy ethyl cellulose. Hydroxy methyl cellulose. Hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose, Gum acacia, tragacanth, Xanthan gum or combinations thereof.

Extended release layers are the layers that extend or "slow down" the release of the coated substance such as Dipyridamole and/or organic acid. The extended release layers may comprises the (i) polymers that resist dissolving in the gastric juices of the stomach and are more soluble at the pH normally found in the intestine. These polymers are known as enteric coating polymers as they are used to prevent the dissolution of the active material Dipyridamole before reaching the intestine (ii) polymers that have pH-independent solubility/swellabiiity.

In some embodiments of the present invention in the compound pellets consisting of Dipyridamole and Aspirin, the Aspirin releases immediately upon the contact with the gastric juices and get absorbed and Dipyridamole is released by an extended release mechanism which solubilize in the gastric and intestinal fluids.
In some embodiments of the present invention the compound pellets consisting of Dipyridamole and Aspirin comprises the enteric coating polymers in the Seal coating layer.
In any embodiment of the present invention the pharmaceutical capsule may be hard or soft gelatin capsules or any pharmaceutically acceptable capsule known in the art.

Preferably the amount of the Dipyridamole is between about 10% to about 75%, preferably about 20% to about 60%, more preferably of about 30 to 50%, and most preferably of about 35% to 45% by weight of the final pellets of Dipyridamole and Aspirin.

Preferably in a core comprising the organic acid, the amount of organic acid is between about 10% to about 100%, preferably to about 20 to about 90%, more preferably about 30% to about 85%, and most preferably about 40% to about 80% by weight of the core and the reminder of the core is made up of pharmaceutically acceptable excipients.

The drug layer of Dipyridamole may be present in an amount of about 10% to about 80%, preferably about 15% to about 70%, more preferably about 20% to about 60%, and more preferably about 30% to about 50%, by weight of the final pellets comprising Aspirin and Dipyridamole.

Preferably, the extended release layer is applied on top of the drug layer of Dipyridamole. The extended release layer may be present in an amount of about 0.5% to about 20%, preferably about 1% to about 18%, more preferably about 1% to about 15%, and most preferably about 1% to about 10%, by weight of the final pellets comprising Aspirin and Dipyridamole. Preferably, the amount of the extended release layer is about 1.5% to about 7%, more preferably about 2% to about 6%, by weight of the final pellet.

The extended release layer and/or the enteric coating layer allow(s) a certain amount of the active material Dipyridamole to be dissolved in the jejunum and continue to be released at a defined rate on reaching the intestine. This is preferably achieved by controlling the amount of organic acid released from the core at different pHs so that in acidic conditions the organic acid is not released from inner core, while at increased pH the organic acid is to be released from core, and consequently increases the solubility of the Dipyridamole in the drug layer.

In any embodiment of the present invention, the extended release layer may comprise at least one extended release polymer that include, but are not limited to, known extended release polymers and hydrophobic agents used in pharmaceutical formulations, for example, ethyl cellulose polymers (for example, those sold under the trade name Ethocel.RTM.), hydroxypropyl methylcellulose polymers, polyvinylpyrrolidone polymers, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer (for example, Eudragit.RTM. S or L), hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, ethyl cellulose phthalate, hydroxypropylmethylcellulose succinate, cellulose acetate succinate, hydroxypropyl methyl cellulose hexahydrophthalate, cellulose acetate hexahydrophthalate, hydroxypropyl methyl cellulose trimellitate, and combinations thereof.
Preferably, the extended release layer comprises about 50% to about 100%, preferably about 60% to about 95%, more preferably about 65% to about 85%, and most preferably about 70% to about 80% by weight extended release polymer(s) and the remainder of the extended release layer is made up with at least one pharmaceutical excipient.

Preferably, the extended release layer comprise(s) at least one pharmaceutically acceptable excipient, preferably a plasticizer. Suitable plasticizers used in the formulation include, but are not limited to, acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, triacetin, tributyl citrate, and Triethyl citrate. Preferably, the plasticizer is triethyl citrate.

Preferably, the plasticizer is present in an amount of about 15% to about 30%, preferably about 20% to about 27%, more preferably about 20% by weight of the extended release layer.

In one of the embodiment Aspirin is coated onto the extended release coated layer of Dipyridamole. Preferably the amount of the aspirin is between about 1 to about 20%, more preferably about 1% to about 10%, most preferably of about 1 to 6%, by weight of the final pellets of Dipyridamole and Aspirin.

In one embodiment the present invention is also directed to a process for preparing a pharmaceutical capsule comprising the compound pellets consisting of Dipyridamole and Acetyl salicylic acid (A) (i) depositing the Seal coating layer onto a core comprising an organic acid wherein the Seal coating layer comprises a binder that is compatible with the organic acid; (ii) depositing onto the Seal coating layer a drug layer comprising the Dipyridamole; (iii) depositing onto the drug layer comprising the Dipyridamole an extended release layer (iv) depositing onto the extended release layer a drug layer comprising the Acetyl salicylic acid; (B) adding the compound pellets consisting of Dipyridamole and Acetyl salicylic acid to a pharmaceutical capsule and (C) Sealing the pharmaceutical capsule.

The Seal coating layer may be applied to the core comprising the organic acid by any conventional method. Preferably, the Seal coat is applied on top of the core comprising the organic acid by using a coating solution comprising at least one binder. The coating process is performed by using a fluidized bed coater or a solid drug layering machine.

The drug layer comprising Dipyridamole may be applied using any conventional method. Preferably, the drug layer comprising Dipyridamole is applied on top of the Seal coating layer, by using a hydro or hydro-alcoholic dispersion of Dipyridamole and at least one pharmaceutical acceptable excipient, preferably a binder. The coating process is performed by using a fluidized bed coater or a solid drug layering machine.

The extended release layer may be applied to the drug layer by any conventional method. Preferably, the extended release layer is applied using a solution of at least one extended release polymer and at least one pharmaceutical acceptable excipient, preferably a plasticizer.

The drug layer comprising Aspirin may be applied using any conventional method. Preferably, the drug layer comprising Aspirin is applied on top of the extended release layer by using a hydro or hydro-alcoholic dispersion of Aspirin and at least one pharmaceutical acceptable excipient, preferably a binder. The coating process is preferably performed using a fluidized bed coater or a Solid drug layering machine.

In any of the final formulations of any embodiment of the present invention, the weight ratio of Dipyridamole to acetylsalicylic acid may preferably be between about 10 and about 0.5, more preferably between about 8 and about 1. For example, in one embodiment, the Dipyridamole is present in 200 mg and the acetyl salicylic acid is present in 25 mg in the formula.
Selection of excipients and the amounts to use can be readily determined by an experienced formulation scientist in view of standard procedures and reference works known in the art.
Excipients used in any formulation of the invention include, but are not limited to, binders, diluent, disintegrants, lubricants, glidants, extended release polymers (as described above), sweetening agent, coloring agent, flavoring agent, and plasticizer (as described above).
Suitable binders for formulation include polyvinylpyrrolidne (e.g., Povidone), copolymers of vinylpyrrolidne and vinyl acetate (e.g., Copovidone), hydroxypropyl cellulose. Hydroxy ethyl methyl cellulose, methyl cellulose. Hydroxy butyl cellulose, Hydroxy butyl methyl cellulose. Hydroxy ethyl cellulose. Hydroxy methyl cellulose, Hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose. Gum acacia, tragacanth, Xanthan gum or combinations thereof. Preferred binders include hydroxypropyl cellulose, polyvinylpyrrolidone, and copovidone.
Preferably, in any embodiment of the present invention, the binder is present in an amount of about 1% to about 40%, more preferably about 5% to about 30%, for example, about 25%, by weight of the compound pellets consisting of Dipyridamole and Aspirin.
Suitable lubricants which can optionally be used in the formulation include, but are not limited to, sodium lauryl sulfate, calcium stearate, Glyceryl behenate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. Preferred lubricants include sodium lauryl sulfate, magnesium stearate, and stearic acid and talc. Preferably, in any embodiment of the present invention, the lubricant is present in an amount of about 1% to about 6%, more preferably about 1% to about 4% by weight of the compound pellets consisting of Dipyridamole and Aspirin.
Suitable disintegrants which can optionally be used in the formulation include, but are not limited to, alginic acid, microcrystalline cellulose, croscarmellose sodium, crospovidone, maltose, polacrilin potassium, sodium starch glycolate, and starch. Preferably, the Disintegrant is crospovidone. Preferably, in any embodiment of the
j
present invention, tlie Disintegrant is present in an amount of about 1% to about 4%, of the compound pellets consisting of Dipyridamole and Aspirin.
Suitable glidants which can optionally be used in the formulation include, but are not limited to, talc, kaolin, glycerol monostearate, silicic acid, magnesium stearate, and titanium dioxide.
In one embodiment, about 5% to about 30% by weight of the Dipyridamole in the formulations of the present invention dissolves within about 60 minutes, after being mixed at 37°C in a dissolution medium of 900 ml of 0.01 N HCI in a USP Apparatus I (basket), under a mixing speed of 100 rpm followed by a second medium (medium II, 900 ml buffer, preferably Phosphate buffer having a pH of 5.5) for 1 to 12 hours. Particularly preferred dissolution profiles are as follows
Suggested dissolution profile of Dipyridamole:

in one embodiment, about 60% to about 90% by weight acetylsalicylic acid in the formulations of the present invention dissolves within 20 minutes, after being mixed in a USP Apparatus I (basket), under a mixing speed of 100 rpm at 37°C. in a dissolution medium of 900 ml 0.01 N HCI. Particularly preferred dissolution profiles are as follows
Suggested dissolution profile of Acetyl salicylic acid:

Dissolution studies of the capsules of the present invention demonstrated that compound pellets consisting of Aspirin and Dipyridamole exhibit a similar dissolution profile to the commercially available Aggrenox®. According to its label each Aggrenox® hard gelatin capsule contains 200 mg Dipyridamole in an extended- release form and 25 mg aspirin as an immediate-release sugar-coated tablet. In addition, each capsule contains the following inactive ingredients: acacia, aluminium 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.
For example, capsules filled with the compound pellets consisting of Dipyridamole and Aspirin of the present invention were tested for dissolution of Dipyridamole. The method used a USP Apparatus I, with a mixing speed of 100 rpm and at a temperature of 37°c in a first medium (medium-l, 900 ml 0.01 N HCI) for 1 hour, with samples of dissolution medium taken at 1 hour and analyzed; and a second medium (medium II, 900 ml buffer, preferably Phosphate buffer having a pH of 5.5) for 1 to 8 hours. The Dipyridamole release in the compound pellets consisting of Aspirin and Dipyridamole filled into capsules of the present invention has a similar dissolution profile to the Dipyridamole pellets in Aggrenox®.
The Pellets of Aspirin and Dipyridamole filled into to the capsule as per this invention is found to be stable and within the limits as per the ICH Guidelines (refer Table 4).
Examples
Example-1 Example-IA
Preparation of the Seal coating layer
Povidone, Copovidone and Talc were added slowly to a Mixture of Isopropyl alcohol and Purified water under stirring to form a Seal coating dispersion.
Example-IB
Preparation of the Dipyridamole coating layer
Povidone was added to the Purified water under stirring to form a clear dispersion. Dipyridamole was added slowly and mixed to produce a Dipyridamole coating solution.
Example-1 C
Preparation of the extended release coating layer
Eudragit-SlOO, Hydroxy propyl methyl cellulose phthalate and Hydroxy propyl methyl cellulose was added to Isopropyl alchol to form a uniform dispersion under stirring. Purified water was then added slowly until a clear solution was obtained, Triethyl citrate. Talc was added to produce an extended release coating dispersion.
Preparation of Aspirin coating layer
Polyvinyl pyrrolidone and aspirin was added to the mixture of dichloromethane and isopropyl alcohol under stirring to form a clear solution.
Example-2
Preparation of the Compound pellets consisting of Dipyridamole and Aspirin
A seal coating layer (Example-1A) was applied to the core (e.g., tartaric acid crystals) by the dispersion coating on the fluid bed at about 35°C to 50°C and screened through US standard Sieve 30# to produce the core having the seal coating layer.
The Dipyridamole coating layer (Example-IB) was applied onto the seal coated pellets by dispersion coating on fluid bed at about 35°C to 50°C and screened through US standard sieve 30# to produce the Dipyridamole coated pellets.
An extended release layer (Example-1 C) was applied onto the Dipyridamole coated pellets by dispersion coating on fluid bed at about 35°C to 40°C and screened through US standard sieve 25# to produce the extended release Dipyridamole pellets.
Aspirin coating layer (Example-ID) was applied onto the extended release pellets by dispersion coating on fluid bed at about 35°C to 40°C to obtain the compound pellets consisting of Dipyridamole and Aspirin. For specific gram quantities per dose see Table 1.

*Alcohol, Purified water and dichlorometlnane are not present in the final pellets
Dissolution comparison between the compound Pellets consisting of Dipyridamole and Aspirin of the Present Invention and Aggrenox®.
Dissolution conditions
Stage 1 (Relevant to both aspirin and Dipyridamole)
A USP Apparatus I (basket) with a mixing speed of lOOrpm at 37°C for 1 hour in a dissolution medium of 0.01 N Hcl (Medium I) was used. Samples of the dissolution medium were taken over the course of 1 hour and analyzed.
Stage 2 (Relevant to Dipyridamole)
The Medium I described above is pumped out from the vessel followed by the addition of 900ml of NaH2p04 buffer having a pH of 5.5 (medium II) for 1 to 8 hours when a mixing speed of lOOrpm at 37°C was used. Samples of the dissolution medium were taken over the course of 2 to 8 hours and analyzed.
The results are listed in Table 2, 3 and the dissolution profiles are shown in Fig.2 and Fig.3.


Stability of Dipyridamole and Acetyl salicylic acid in Aggrenox® in comparison to those of Dipyridamole and Acetyl salicylic acid in formulation of the present invention.
The stability of Aspirin and Dipyridamole capsules of the present invention packed in the HDPE bottles with silica canisters was kept at 40°C/75% RH for 3 months and analyzed by the HPLC method. The results presented in the Table 4 shows a clear advantage of the formulation of the invention, in terms of Dipyridamole and aspirin stability. According to the specification of International Conference on Harmonization (ICH) there should not be more than 0.2% by weight of unknown impurity of Dipyridamole. After stability testing at the accelerated conditions (40°C/75%RH for three months) the degradants of the Dipyridamole are within the limits of the ICH specification. For acetyl salicylic acid tested under the same conditions the known main degradant salicylic acid was within the limits allowed by the ICH specification 3.0% as allowed for the formulation of the present invention.

We Claim

1. A pharmaceutical capsule formulation comprising the compound pellets consisting of Dipyridamole and Acetyl salicylic acid comprising (i) a core comprising the organic acid (ii) a Seal coating layer comprising the binder wherein the Seal coating layer encompasses the core (iii) a drug layer comprising the Dipyridamole wherein the drug layer comprising Dipyridamole encompasses the Seal coating layer iv) an extended release layer wherein the extended release layer encompasses the drug layer comprising the Dipyridamole v) a drug layer comprising the Acetyl salicylic acid wherein the drug layer comprising the Acetyl salicylic acid encompasses the extended release layer and vi) an optional coating layer comprising the binder encompassing the Acetyl salicylic acid layer.

2. The pharmaceutical capsule formulation of claim 1 wherein the seal coating layer comprises the binder selected from the polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, hydroxypropyl cellulose, hydroxy ethyl methyl cellulose, methyl cellulose, hydroxy butyl cellulose and combinations thereof.

3. The pharmaceutical capsule formulation of claim 1 wherein the extended release layer comprises the extended release polymers selected from the group consisting of ethyl cellulose polymers, methacrylic acid-ethyl acrylate copolymers, methacrylic acid-methyl methacrylate copolymers, cellulose acetate polymers, hydroxypropyl methyl cellulose polymers, poly vinyl pyrrolidone polymers and combinations thereof.

4. The pharmaceutical capsule formulation of claim 3 wherein the extended release layer further comprises at least one plasticizer.

5. The pharmaceutical capsule formulation of claim 4 wherein the plasticizer is selected from the group consisting of acetyl triethyl citrate, acetyl tributyl citrate, castor oil, di acetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, triacetin, tributyl citrate, triethyl citrate or combinations thereof.

6. A process for preparing a pharmaceutical capsule formulation comprising the compound pellets consisting of Dipyridamole and Acetyl salicylic acid (A) (i) depositing the Seal coating layer onto a core comprising an organic acid wherein the Seal layer comprises a binder that is compatible with the organic acid; (ii) depositing onto the Seal coating layer a drug layer comprising the Dipyridamole; (ill) depositing onto the drug layer comprising the Dipyridamole an extended release layer (iv) depositing onto the extended release layer a drug layer comprising the Acetyl salicylic acid and (v) depositing an optional coating layer comprising the binder encompassing the Acetyl salicylic acid layer.; (B) adding the compound pellets consisting of Dipyridamole and Acetyl salicylic acid to a pharmaceutical capsule and (C) Sealing the pharmaceutical capsule

7. A process for preparing a pharmaceutical capsule formulation as per claim 6 wherein the seal coating layer comprises the binder selected from the polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, hydroxypropyl cellulose, hydroxy ethyl methyl cellulose, methyl cellulose, hydroxy butyl cellulose and combinations thereof.

8. A process for preparing a pharmaceutical capsule formulation as per claim 6 wherein the extended release layer comprises the extended release polymers selected from the group consisting of ethyl cellulose polymers, methacrylic acid-ethyl acrylate copolymers, methacrylic acid-methyl methacrylate copolymers, cellulose acetate polymers, hydroxypropyl methyl cellulose polymers, poly vinyl pyrrolidone polymers and combinations thereof.

9. A process for preparing a pharmaceutical capsule formulation as per claim 8 wherein the extended release layer further comprises at least one plasticizer selected from the group consisting of acetyl triethyl citrate, acetyl tributyl citrate, castor oil, di acetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, triacetin, tributyl citrate, triethyl citrate or combinations thereof.