FIELD OF INVENTION

The present invention relates to extended release compositions comprising dipyridamole or its pharmaceutically acceptable salts in combination with aspirin or its pharmaceutically acceptable salts and other pharmaceutically acceptable excipients and to processes of their preparation.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Dipyridamole is chemically (2, 6-bis-(diethanolamino)-4, 8-dipiperidino-(5, 4-d)-pyrimidine) and is clinically found to show antithrombotic and antiaggregatory activities. It is an organic base having moderate solubility in acidic pH and remains unabsorbed in alkaline pH. Mostly the drug gets absorbed in stomach but remains unabsorbed in intestine. To get a synergistic effect it can be used in combination with aspirin.

Aspirin is chemically acetyl salicylic acid and counter acts the aggregation of human blood platelets. It is weekly acidic having a poor solubility. The combination of dipyridamole with aspirin is commercially available in the United States and other countries as extended release capsules under the brand name of Aggrenox ™.

The problem that exists in formulating a combination product of dipyridamole and aspirin is chemical incompatibility between the two active agents, which can be solved by developing novel formulations like three layered tablets, making separate tablets or minitablets of one active ingredient and granules of other the active ingredient (or similar approaches) and filling them in capsules.

A number of prior art are cited below which discloses compositions comprising combined dosage form of dipyridamole and aspirin.

U.S. Patent No. 6,015,577 discloses a combination of dipyridamole and/or mopidamol or the physiologically acceptable salts thereof and acetylsalicylic acid or the physiologically acceptable salts thereof, containing the two components in a weight ratio of more than 4.5, preferably more than 5, and which releases the two components simultaneously in the gastrointestinal tract significantly reduces or prevents clotting and at the same time will dissolve any clot already present more rapidly than would occur through natural thrombolysis. According to this patent, the first component drug is in the form of granules and the second component drug is in the form of tablet, both finally placed in a capsule.

U.S. Patent No. 4,694,024 discloses successive administration of dipyridamole and 0-acetyl-salicylic acid with a time interval in a particular sequence shows an extremely great improvement in the therapy of diseases which are caused or characterized by impaired blood functions or impaired constituents of blood. To get the effective therapeutic action the ratio between dipyridamole and 0-acetyl-salicylic acid should be greater than 0.5.

U.S. Patent No. 4,367,217 discloses composition where dipyridamole and carboxylic acid are combined together into spheroid particles which are surrounded with a dialysis membrane consisting essentially of acid-insoluble lacquers soluble in intestinal juices.

U.S. Patent Application No. 2007/0184110 relates to pharmaceutical combinations consisting of dipyridamole or mopidamole and acetyl salicylic acid. According to this application, the first component drug is in the form of mini tablets and the second component drug is in the form of tablet.

US Patent application No. 20100080846 claims pharmaceutical formulation comprising: (i) pellets comprising dipyridamole, and (ii) pellets comprising acetylsalicylic acid, wherein both the components are physically separated. The invention uses two different capsules (i.e. a capsule within a capsule) for the separation of pellets.

J. Microencapsulation, 1996, Vol.13, No. 4, page-385-394 and 396-405 discloses a combination of dipyridamole and aspirin in a single pellet formulation.

Though the above prior arts disclose a number of extended release formulations of dipyridamole in combination with acetylsalicylic acid, the dosage form of the present invention are significantly different to those described above, in that present invention contains two different types of pellets, where one pellet comprises aspirin and the other comprises dipyridamole and both the pellets are enclosed in a single capsule dosage form without physical separation and the composition is thus prepared by an efficient process which is less time consuming and also economic as it avoids tableting and multiple capsule filling process.

The dosage form of the present invention has a comparable dissolution profile with the commercially available Aggrenox™.

SUMMARY AND OBJECTIVES OF THE INVENTION

The present invention relates to extended release compositions comprising dipyridamole or its pharmaceutically acceptable salts in combination with aspirin or its pharmaceutically acceptable salts and other pharmaceutically acceptable excipients.

More particularly, the present invention relates to extended release compositions comprising dipyridamole or its pharmaceutically acceptable salts in combination with aspirin or its pharmaceutically acceptable salts, wherein said compositions comprise two different types of pellets where one pellet comprises aspirin and the other comprises dipyridamole and both the pellets are enclosed in a single capsule dosage form without physical separation.

In one aspect, the present invention provides extended release pellets comprising dipyridamole or its pharmaceutically acceptable salts in combination with other pharmaceutically acceptable excipients and a process to prepare these pellets.

In another aspect, the present invention provides pellets comprising aspirin or its pharmaceutically acceptable salts in combination with other pharmaceutically acceptable excipients and a process to prepare these pellets.

In yet another aspect, the above two types of pellets are filled in capsules, without any physical separation.

In another aspect, the present invention provides an extended release composition comprising dipyridamole or its pharmaceutically acceptable salts in combination with aspirin or its pharmaceutically acceptable salts, wherein the in vitro dissolution release profile matches with the commercially available Aggrenox ™.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to extended release compositions comprising dipyridamole or its pharmaceutically acceptable salts in combination with aspirin or its pharmaceutically acceptable salts and other pharmaceutically acceptable excipients.

More particularly, the present invention relates to extended release compositions comprising dipyridamole or its pharmaceutically acceptable salts in combination with aspirin or its pharmaceutically acceptable salts, wherein said compositions comprise two different types of pellets where one pellet comprises aspirin and the other comprises dipyridamole and both the pellets are enclosed in a single capsule dosage form without physical separation.

The term "composition" as used herein refers to equivalents thereof, including but not limited to: cores, coated cores, pellets, micro-pellets, pills, compressed tablets, granules, spheres, capsules and the like.

The term "without physical separation" as used herein refers to that, the two different pellets comprising different drugs are enclosed in a single enclosure.

It is known in the art that there exists a chemical incompatibility between dipyridamole and acidic excipients generating high level of impurities. The interactions can be avoided by coating the core of dipyridamole with seal coat.

The dipyridamole pellets of the present invention comprise cores of organic acids. The organic acids are in the form of pellets and may include tartaric acid, citric acid, ascorbic acid, malic acid, succinic acid or mixtures thereof

The composition of the present invention can be formulated as solid compositions for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferably, the composition is in the form of tablets or capsules.

The composition of the present invention may comprise one or more pharmaceutically acceptable excipients which include, but are not limited to binders, diluents, disintegrants, extended release polymers, lubricants, film former, plasticizers, coloring agent, flavoring agents, sweetening agent, viscosity enhancers, preservatives, antioxidants and the like.

Binders used include, but not limited to acacia, alginic acid, carbomer copolymer, copovidone, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, glucose (liquid), guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyethylene oxide, polyvinylpyrrolidone, povidone, starch, or sodium carboxymethylcellulose and the like.

Extended release polymers include both hydrophilic and hydrophobic polymers. More preferred extended release polymers are enteric polymers including, but not limited to, at least one of methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer (Eudragit™ S), hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, ethylcellulose phthalate, hydroxypropylmethylcellulose succinate, or cellulose acetate succinate.

Plasticizers used in the invention include, but are not limited to, acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, triacetin, tributyl citrate, or triethyl citrate.

The seal coat may comprise hydrophilic or hydrophobic materials, or a combination thereof The hydrophilic materials include homopolymers or copolymers of N-vinylpyrrolidone, cellulose derivatives such as hydroxypropyl methyl cellulose, vinyl and acrylic polymers; polyacrylic acid and the like. The hydrophobic substances such as celluloses like ethyl cellulose, low substituted hydroxylpropyl cellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, polyalkyl methacrylates, polyalkyl acrylates; crosslinked vinylpyrrolidone polymers, hydrogenated castor oil and the like.

The aspirin pellets comprise inert cores wherein, said inert cores can be from a water soluble or a water insoluble substance. Examples of inert cores used in the present invention include but not limited to microcrystalline cellulose, sugar spheres, carboxymethylcellulose, sucrose, mannitol, sorbitol, lactose, starch or mixtures thereof

The pellets may optionally be coated with a film coat, which provides an aesthetic appeal or can also provide some functional role such as moisture protection, taste masking etc. The film coat may comprise polymers for example cellulose and cellulose derivatives, such as one which is commercially available as Opadry™.

The pellets of the present invention can be made by various known techniques. The main techniques are, e.g. high shear pelletization, fluid bed pelletization, hot-melt and extrusion-spheronization. Suitable equipment for producing pellets for the product of the invention comprises high-shear mixer/granulators, and fluid bed granulator.

Acceptable diluents include, but not limited to microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like; disintegrants which include, but not limited to cros-povidone, sodium starch glycolate, starch and its derivatives, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose and the like; lubricants which include, but not limited to colloidal silicon dioxide, talc, stearic acid and its salts.

In one embodiment, the present invention also relates to a process of preparing a composition comprising dipyridamole and aspirin wherein the process comprises:

1) Preparation of sub-coated tartaric acid pellets
i) preparation of a suitable solvent system
ii) dissolving required quantity of polymer in said solvent system
iii) coating tartaric acid core with the step (ii) solution

2) Coating of Dipyridamole on sub-coated tartaric acid pellets
i) preparing a binder solution containing the drug dispersed in it. ii) coating said sub-coated tartaric acid core with step (ii) dispersion

3) Extended release polymer coating on drug coated tartaric acid core

i) preparation of a suitable solvent system
ii) dissolving required quantity of extended release polymers in said solvent system
iii) adding required quantity of other auxiliary excipients such as binder, anti-tacking agent, plasticizer, pore-formers etc., to the above extended release polymer solution
iv) coating the drug coated tartaric acid core with the above extended release polymer dispersion

4) Preparation of Aspirin coated pellets
i) preparing a binder solution containing the drug dispersed in it ii) coating inert cores with above dispersion

5) Coating said pellets by a film coat

(i) preparing a solution/ dispersion comprising the film former [Opadry™] in a suitable solvent system

(ii) coating drug coated aspirin pellets with the above solution/ dispersion

6) Encapsulation: filling of the prepared dipyridamole and aspirin pellets in hard gelatin capsules.

In another embodiment, the present invention relates to a process of preparing a composition comprising dipyridamole and aspirin wherein the process comprises:

1) Preparation of sub-coated tartaric acid pellets
i) preparation of a suitable solvent system

ii) dissolving required quantity of polymer in said solvent system

iii) coating tartaric acid core with the step (ii) solution

2) Coating of Dipyridamole on sub-coated tartaric acid pellets
i) preparing a binder solution containing the drug dispersed in it. ii) coating said sub-coated tartaric acid core with step (ii) dispersion

3) Extended release polymer coating on drug coated tartaric acid core

i) preparation of a suitable solvent system

ii) dissolving required quantity of extended release polymers in said solvent system

iii) adding required quantity of other auxiliary excipients such as binder, anti-tacking agent, plasticizer, pore-formers etc., to the above extended release polymer solution

iv) coating the drug coated tartaric acid core with the above extended release polymer dispersion

4) Preparation of over-coat on drug coated pellets
i) preparation of a suitable solvent system
ii) dissolving required quantity of polymer in said solvent system
iii) coating drug coated pellets with the above polymer solution

5) Preparation of Aspirin coated pellets
i) preparing a binder solution containing the drug dispersed in it ii) coating inert cores with above dispersion

6) Coating said pellets by a film coat
(i) preparing a solution/ dispersion comprising the film former [Opadry™] in a suitable solvent system
(ii) coating drug coated aspirin pellets with the above solution/ dispersion

7) Encapsulation: filling of the prepared dipyridamole and aspirin pellets in hard gelatin capsules.

Further embodiment of the invention provides for oral pharmaceutical compositions of dipyridamole in combination with aspirin wherein the in vitro dissolution release profile matches with the commercially available Aggrenox™.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Example 1
Unit Composition:
Dipyridamole Pel ets Aspirin Pel ets
Ingredient mg/capsule Ingredient mg/capsule
Tartaric acid | 200.0 Sugar Spheres 70.00
Seal Coating Acetyl salicyclic acid 25.00
Hypromellose 10.0 Polyvinyl pyrrolidone 5.00
Isopropyl alcohol q.s Ethanol q.s.
Methylene chloride q.s Film coating
Active Layer Opadry™ I 10.00
Dipyridamole 200.0 Methylene chloride q.s.
Hypromellose 3.0 Isopropyl alcohol q.s.
Isopropyl alcohol q.s
Extended Release coating
Eudragit™S100 6.2 ~
Hypromellose Phthalate 55 12.4
Triethyl citrate 2^8
Purified talc 2.8 "
Isopropyl alcohol q.s
Acetone q.s

Brief Manufacturing Process:

1) Preparation of sub-coated tartaric acid pellets
i) preparation of a solvent system of isopropyl alcohol and water
ii) dissolving required quantity of hypromellose in said solvent system
iii) coating tartaric acid core with the step (ii) solution

2) Coating of Dipyridamole on sub-coated tartaric acid pellets
(i) dissolving a required quantity of hypromellose in isopropyl alcohol with continuous stirring
(ii) adding required quantity of dipyridamole to step (i) and stirring up to 15 minutes
(iii) coating the sub-coated tartaric acid core with step (ii) dispersion

3) Extended release polymer coating on drug coated tartaric acid core
(i) preparing a solvent system with isopropyl alcohol and acetone

(ii) dissolving required quantity of Eudragit™ SI00 to the prepared solvent system with continuous stirring up to 45-60 minutes

(iii) adding required quantity of hypromellose in step (ii) with stirring up to 30 minutes followed by addition of triacetin with stirring up to 15 minutes

(iv) adding required quantity of talc to step (iii) with stirring up to 10 minutes (v) coating the drug coated tartaric acid core with the prepared dispersion of step (iv)

4) Preparation of aspirin drug coated pellets
(i) dissolving required quantity of polyvinyl pyrrolidone in ethanol (ii) adding required amount of aspirin in step (i) (iii) coating sugar sphere with step (ii) dispersion

5) Coating said pellets by a film coat [Opadry™]
(i) preparing a solvent system of isopropyl alcohol and water and adding opadry to it
(ii) coating drug coated aspirin pellets with step (i)

6) Encapsulation: filling of the prepared dipyridamole and aspirin pellets in hard gelatin capsules.

Example 2
Unit Composition:
Dipyridamole Pellets Aspirin Pel ets
Ingredient mg/capsule Ingredient mg/capsule
Tartaric acid 200.0 Sugar Spheres 70.00
Seal Coating Acetyl salicyclic acid 25.00
Hypromellose 30.0 Polyvinyl pyrrolidone 5.00
Isopropyl alcohol q.s. ~Ethanol | q.s.
Methylene chloride q.s Film coating
Active Layer Opadry™ I 12.00
Dipyridamole 200.0 Methylene chloride q.s.
Polyvinyl pyrrolidone 3.0 Isopropyl alcohol q.s.
Isopropyl alcohol q.s
Seal Coating
Hypromellose 10.0
Iso propyl alcohol q.s
Methylene chloride q.s
Extended Release coating
Eudragit™ SI00 I 6.2
Hypromellose Phthalate 55 12.4
Triethyl citrate 2.8
Purified talc 2.8
Isopropyl alcohol q.s
Acetone q.s
Seal Coating
Hypromellose 1_0.0
Iso propyl alcohol q.s
Methylene chloride q.s

Brief Manufacturing Process:

1) Preparation of sub-coated tartaric acid pellets
i) preparation of a solvent system of isopropyl alcohol and methylene chloride
ii) dissolve required quantity of hypromellose in the said solvent system
iii) coat the tartaric acid core with the step (ii) dispersion

2) Coating of Dipyridamole on sub coated tartaric acid pellets
(i) dissolve a required quantity of polyvinyl pyrrolidone and hypromellose in isopropyl alcohol and methylene chloride with continuous stirring

(ii) add required quantity of dipyridamole to step (i) and stir up to 15 minutes

(iii) coat the sub-coated tartaric acid core with step(ii) dispersion

3) Preparation of seal coated drug coated pellets
(i) preparing a solvent system with isopropyl alcohol and water
(ii) dissolving required quantity of hypromellose in the prepared solvent with continuous stirring
(iii) coating the drug coated pellets with step (ii) dispersion

4) Extended release polymer coating on drug coated pellets
(i) preparation of a solvent system of isopropyl alcohol and acetone
(ii) adding required quantity of Eudragit™ SI00 to the solvent with continuous stirring up to 45-60 minutes
(iii) adding required quantity of hypromellose phthalate 55 to step (ii) with stirring up to 30 minutes
(iv) adding triacetin to step (iii) with stirring up to 15 minutes
(v) adding required quantity of talc to step (iv) with stirring up to 10 minutes
(vi) coating the drug coated tartaric acid core with the step (v) dispersion

5) Preparation of seal coated extended release pellets
(i) preparing a solvent system with isopropyl alcohol and water
(ii) dissolving required hypromellose in the prepared solvent with continuous stirring
(iii) adding required quantity of talc in step (ii) with continuous stirring
(iv) coating polymer coated pellets with step (iii) dispersion

6) Preparation of aspirin coated pellets
(i) dissolving required quantity of polyvinyl pyrrolidone in ethanol/water (ii) adding required amount of aspirin to step (i) (iii) coating the sugar spheres with step (ii) solution

7) Coating said pellets by a film coat [Opadry™]
(i) preparing a solvent system of isopropyl alcohol and water (ii) coating aspirin coated pellets with step (i) dispersion

8) Encapsulation: filling of the prepared dipyridamole and aspirin pellets in hard gelatin capsules.

Dissolution Study:
The compositions prepared according to example 1 are studied for drug release profile under following conditions.

Dissolution study for dipyridamole was carried out in 900 ml of O.OIN HCl at 100 rpm for 1 hr followed by 900 ml of phosphate buffer of pH 5.5 at 100 rpm using USP apparatus I and the results are tabulated in table-1 &2 respectively.

Dissolution study for aspirin was carried out in 900 ml of phosphate buffer of pH 4.5 at 100 rpm using USP apparatus I and results are tabulated in table-3.

Table-1

In 0.01 N HCl I % drug released in
l_hr.
Aggrenox (Reference Product) 23
Test 21
Table-2
Cumulative release
In pH 5.5 Phosphate Time in hrs
Buffer 1 2 5 7 I 8
Aggrenox 55 68 82 86 88
(Reference Product)
Test 47 62 88 90 | 90

Table-3
In pH 4.5 Acetate buffe Time in Minutes
15 20 30 45 60
Aggrenox 40 58 81 94 97
(Reference Product)
Test 50 66 82 89 91

We Claim:

1. An extended release composition comprising dipyridamole or its pharmaceutically acceptable salts in combination with aspirin or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients wherein said composition comprises two different types of pellets where one pellet comprises aspirin or its pharmaceutically acceptable salts and the other comprises dipyridamole or its pharmaceutically acceptable salts and both the
pellets are enclosed in a single capsule dosage form without physical separation.

2. The composition of claim l, wherein said pellets comprising dipyridamole are in extended release form.

3. The composition of claim l, wherein said pellets comprising aspirin are in immediate release form.

4. The composition of claim 1, wherein said pharmaceutically acceptable excipients include diluents, disintegrants, binders, glidants, lubricants, extended release polymers, and optionally outer coating ingredients.

5. The composition of claim 4, wherein said extended release polymer includes methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, ethylcellulose phthalate, hydroxypropylmethylcellulose succinate, or cellulose acetate succinate.

6. The composition of claim 1, wherein said pellets comprising dipyridamole comprises (i) sub coated organic acid pellets (ii) drug coat (iii) extended release coat.

7. The composition of claim 1, wherein said pellets comprising dipyridamole comprise (i) sub coated organic acid pellets (ii) drug coat (iii)seal coat (iii) extended release coat (iv) seal coat.

8. The composition of claim 1, wherein said pellets comprising aspirin comprise (i) inert core (ii) drug coat (iii) film coat.

9. A process for preparing compositions comprising dipyridamole or its pharmaceutically acceptable salts in combination with aspirin or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients wherein the process comprises

(i) sub-coating a tartaric acid core to get the tartaric acid pellets

(ii) coating the pellets of step (i) with a dipyridamole dispersion

(iii) coating the pellets of step (ii) with an extended release coating

(iv) coating inert sugar spheres with aspirin dispersion followed by film coating

(v) filling the dipyridamole and aspirin pellets in a single hard gelatin capsule.

10. A process for preparing compositions comprising dipyridamole or its pharmaceutically acceptable salts in combination with aspirin or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients wherein, the process comprising

(i) sub coating the tartaric acid core to get the tartaric acid pellets

(ii) coating the pellets of step i with dipyridamole dispersion

(iii) coating the drug coated pellets obtained in step ii with a seal coat

(iv) coating the pellets of step iii with extended release coat

(v) coating the extended release pellets obtained in step iv with a seal coat

(vi) coating inert sugar spheres with aspirin dispersion followed by film coating

(vii) filling the prepared dipyridamole and aspirin pellets in a single hard gelatin capsule.