Form 2
THE PATENTS ACT, 197

(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"Novel stable pharmaceutical composition of Clopidogrel Bisulfate and
process of preparation thereof
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.
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Technical field of the invention:
The present invention relates to a novel stable oral pharmaceutical composition comprising the active ingredient Clopidogrel bisulfate Form I along with pharmaceutically acceptable excipients and a novel process of preparation thereof. Particularly, according to the said process of preparation the Clopidogrel bisulfate Form I is coated with an hydrophilic polymer thereby providing an increased physical and chemical stability to the composition with improved dissolution.
Background and Prior art:
Clopidogrel is a dextro-rotatory enantiomer of methyl alpha-5-(4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate . Clopidogrel is useful as a medicine for prophylaxis and treatment of thrombotic events such as coronary artery disease, peripheral vascular disease and cerebrovascular disease by acting as a platelet aggregation inhibitor.
US 4,847, 265 for the first time disclosed the dextro-rotatory enantiomer of methyl alpha-5-(4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetatc (Clopidogrel) and its process of preparation and compositions using the same.
Clopidogrel bisulfate as a platelet aggregation inhibitor was described for the first time in EP 281459. No reference was made to the specific polymorphic forms of Clopidogrel bisulfate in EP 281459. The synthetic process claimed in EP 281459 lead to the preparation of Clopidogrel bisulfate which is called Form I but was later revealed in US 6,429,210. EP 281459 specifically claimed that the dextrorotatory isomer possessed excellent platelet aggregation inhibiting activity in comparison to
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the levorotatory isomer which is less active and less well tolerated.
However, it was discovered in US 6,429,210 that Clopidogrel bisulfate can exist in different polymorphic crystalline forms which differ from each other in terms of stability, physical properties, spectral characteristics and the process for their preparation. The novel polymorph disclosed in US 6,429,210 was named Crystalline Form II. In addition, the method of preparing the novel polymorph was disclosed in US 6,429,210. According to this process, it is more time consuming to synthesize Form II than to synthesize Form I.
Tablets of Clopidogrel that are commercially available [Plavix(R)] contains the crystalline Form II of Clopidogrel bisulfate. Plavix(R) is administered as an oral tablet at a recommended dose of 75mg once daily.
US 6914141 discloses pharmaceutical tablet comprising clopidogrel along with a lubricant selected from zinc stearate, stearic acid and sodium stearyl fumarate to prevent the sticking of the tablets to the punches during compression.
US 20050031691 discloses a composition with the advantages of easy administration combined with rapid dissolution of the active agent; achieved using nanoparticulate active agent and a gel forming substance.
However, all the above formulations fail to provide both together, satisfactory physical and chemical stability at accelerated conditions of stability.
Thus, there exists a need for pharmaceutical compositions which are stable physically
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as well as chemically.
In view of the drawbacks associated with the prior art compositions, the present inventors have developed a formulation using Clopidogrel bisulfate Form I which will provide both stability under accelerated storage conditions and improved solubility.
Object of the Invention:
The main object of the present invention is to provide novel stable oral pharmaceutical compositions comprising the active ingredient Clopidogrel bisulfate Form I along with pharmaceutically acceptable excipients wherein Clopidogrel bisulfate Form I is coated with an hydrophilic polymer thereby providing an increased physicochemical stability to the composition.
Another object of the present invention is to provide formulations with increased solubility facilitated by using hydrophilic polymers.
Summary of the invention:
The present invention discloses a novel stable pharmaceutical composition comprising Clopidogrel Bisulfate Form I along with pharmaceutically acceptable excipients wherein the the Clopidogrel bisulphate Form I is coated with an hydrophilic polymer to provide stable composition having improved solubility. The said composition may further comprise an antioxidant, a chelating agent, a lubricant and any other pharmaceutically acceptable excipients. The invention further discloses a novel process for the preparation of the said stable composition.
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Detailed Description:
The present invention describes a novel stable pharmaceutical composition comprising Clopidogrel Bisulfate Form I along with pharmaceutically acceptable excipients wherein the the Clopidogrel bisulphate Form I is coated with a hydrophilic polymer which provides a highly stable composition with improved dissolution. The invention further describes a novel process for the preparation of the said composition.
Clopidogrel bisulfate Form I is unstable in the presence of moisture and elevated temperatures. It converts spontaneously into Form II. Furthermore, Form I bulk solid is less compact and much more electrostatic than Form II and hence cannot be readily subjected to any treatment under the usual conditions of pharmaceutical technology. Moreover, Form I is practically insoluble in water and significant bioavailability can be a problem. Despite its above mentioned drawbacks, considering the advantages of reduced number of steps in the synthesis of Clopidogrel Bisulfate Form I and the time involved, a stable formulation with improved solubility and industrial feasibility has been developed using Crystalline Clopidogrel Bisulfate Form I .
In the pharmaceutical composition as per the present invention, the amount of Clopidogrel Bisulfate Form I is in the range of about 20 to about 70 % by weight and the amount of hydrophilic polymer is in the range of about 2 to about 50 % by weight. In addition, the pharmaceutical composition may further comprise an antioxidant, a chelating agent, a lubricant and other pharmaceutically acceptable excipients such as fillers, binders, glidants and coating agents can be used in the formulation.
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The hydrophilic polymers can be selected from a group consisting of cellulose polymers which include one or more of hydroxypropylmethyl cellulose. hydroxypropyl cellulose and hydroxyethyl cellulose or a mixture thereof. Polymers having viscosity in the range of 3 to 50cps are used.
The antioxidants used as per the present invention are selected from a group consisting of sodium salts of bisulphite, sulphite, metabisulphite, thiosulphate, formaldehyde sulphoxylate, 1 and d Ascorbic acid, Cysteine, Acetylcysteine, Thioglycerol, Thioglycollic acid, Thiolactic acid, Thiourea, Dithithreitol, Glutathione. Oil soluble antioxidants are selected from a group consisting of Propyl gallate, Butylated hydroxy anisole, Butylated hydroxy toluene, Ascorbyl palmitate, Nordihydroguaiaretic acid and Alpha- Tocopherol or a mixture thereof. The amount of antioxidant used is in the range of about 0.01 to about 1.00 % by weight.
The chelating or sequestering agents are selected from a group consisting of Edctic acids and its salts, beta-hydroxyethylenediamine triacetic acid, Diethylcne triaminepentacaetic acid and Nitrilotriacetate or a mixture thereof. The amount of chelating agent used is in the range of about 0.01 to about 1.00 % by weight.
The pharmaceutically acceptable carriers or diluents that are used for tabletting are are selected from a group consisting of lactose monohydrate, microcrystalline cellulose, mannitol and sugars or a mixture thereof. The amount of diluents used is in the range of about 20 to about 90 % by weight.
The lubricants which are used are selected from a group consisting of hydrogenated vegetable oil and siliconised talc or a mixture thereof. The amount of lubricants used
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is in the range of about 1 to about 10 % by weight.
The inventors of the present invention conducted a research to improve the stability of Clopidogrel bisulfate form I and discovered that when Form I is formulated by coating or loading with a hydrophilic polymer, the resulting coated particles, granules or pellets exhibited improved stability at accelerated storage conditions of stability.
Hydrophilic polymers improve the stability and the solubility of the resultant formulation by reducing the contact angle and thus improves the dissolution of the formulation.
The hydrophilic polymers which are used as per the present invention are selected from a group consisting of cellulose polymers which include one or more of hydroxypropylmefhyl cellulose, hydroxypropyl cellulose and hydroxyethyl cellulose or a mixture thereof. Polymers having viscosity in the range of 3 to 50cps arc used.
The polymer coated granules are further compressed with other pharmaceutically acceptable excipients and then film coated with a suitable coating agent. The amount of coating material may be in the range from about 2% to about 5%.
The presence of further additives like antioxidants and chelating agents helps to minimise the impurity formation caused by degradation of Clopidogrel bisulfate and thus improves the stability of the formulation.
Diluents that are used in the formulation are anhydrous with below 3% moisture content which minimizes the chances of degradation. This invention results in a
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formulation which has a moisture content below 3% .
The composition of the present invention is preferably formulated into a tablet. A method of formulating the tablets can be dry granulation, wet granulation or even direct compression. The coating can be performed according to any of the conventional methods of coating using suitable coating agents and alcoholic or hydroalcoholic solvents.
The following examples are offered by way of illustration and not by way of limitation. The disclosures of all citations in the specification are expressely incorporated herein by reference.
Examples
Example 1:
97.875 mg of Clopidogrel bisulphate (Form I), 1.00 mg of Sodium metabisulphite & 2.00 mg of Disodium edetate are mixed in a suitable equipment. The mix is granulated or coated using 10.00 mg of hydrophilic polymers. The wet mass is then dried and sized. Sized granules are then mixed with 106.625 mgs of Microcrystalline cellulose and 15 mg of Crospovidone. The blend is then lubricated with 10 mg of Siliconised Talc and 7.5 mg of Hydrogenated Vegetable Oil. The said blend is compressed into tablets onto rotary tablet press. The compressed tablets are coated with Opadry dispersion in water, hydroalcoholic or nonaqueous solvents.
Example 2:
97.875 gm of Clopidogrel Bisulfate, , 4 gm of Disodium EDTA, 0.2 gm of Sodium metabisulfite are mixed and 5 gm of Hydroxypropylmethyl Cellulose was dissolved
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in purified water and used for granulation of above dry mix. The wet mass is dried in fluid bed drier and sized to get the granules. Sized granules are mixed with Microcrystalline cellulose , sodium starch glycollate & lubricated using siliconised talc as lubricant. The lubricated blend is compressed on tablet press to get the tablets. The tablets are coated using nonaqueous dispersion of Opadry pink .
Example 3:
97.875 gm of Clopidogrel Bisulfate, 196.825 gm of Microcrystalline Cellulose, 10 gm of Crospovidone were mixed in kenwood mixer, 0.1 gm of Propyl gallate, 0.2 gm of BHA and 5 gm of Hydroxypropyl Cellulose were mixed in purified water in combination with isopropyl alcohol and used for granulation of above dry mix. The wet mass is dried in fluid bed drier and sized to get the granules. Sized granules arc lubricated using poloxamer 407 as lubricant. The lubricated blend is compressed on tablet press to get the tablets. The tablets are coated using aqueous dispersion of Opadry pink .
Example 4:
97.875 gm of Clopidogrel Bisulfate, 181.825 gm of Mannitol, 10 gm of Crospovidone were mixed in kenwood mixer. 0.3 gm of sodium metabisulfite and 5 gm of Hydroxypropyl Cellulose were mixed in purified water in combination with isopropyl alcohol and used for granulation of above dry mix. The wet mass is dried in fluid bed drier and sized to get the granules. Sized granules are lubricated using 5.0 gm of hydrogenated vegetable oil as lubricant. The lubricated blend is compressed on tablet press to get the tablets. The tablets are coated using aqueous dispersion of Opadry pink .
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The tablets prepared according to the example no.l and Plavix tablets are subjected to accelerated stability testing at 40°C/ 75% RH and the contents of the active ingredients and the impurities contained in the respective tablets were analysed and the results obtained is shown in Table 1.
Table 1

Total impurities Dissolution(% release)
10mins 20 mins 30 mins 45 mins
Plavix tablet 0.880 % 57.5 86.9 94.1 96.5
Example 1 0.516% 57.6 90.1 94.5 95.4
The tablets prepared according to the example no.l is subjected to accelerated stability testing at 40°C/ 75% RH and the impurities contained in the respective tablets were analysed and the results obtained are shown in Table 2.
Table 2

Example 1 Impurities
Single impurity (unknown%) Total impurity (%)
Initial 0.084 0.516
3M at 45°C/ 75%RH 0.092 0.768
While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the
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appended claims.
Brief Description of Drawings:
Fig 1 describes comparative dissolution profile of Plavix and Example
Dated this the 9th day of April, 2007

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