EP2086510A1

EP2086510A1 - Preparation of a free flowing molecular dispersion of clopidogrel base

Info

Publication number: EP2086510A1
Application number: EP07827489A
Authority: EP
Inventors: Venkateswarlu Guntuka; Bhumireddy Chennakesava Reddy; Harish Chandra Pandey
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-11-27
Filing date: 2007-04-30
Publication date: 2009-08-12
Also published as: WO2008065674A8; WO2008065674A1

Abstract

A solid free flowing molecular dispersion comprising clopidogrel base, at least one pharmaceutically acceptable polymer, at least one pharmaceutically acceptable excipient and optionally surfactant. A process for preparing a solid dispersion comprising dissolving clopidogrel base into a solid pharmaceutically acceptable polymer, or a mixture of polymers or a mixture of a polymer and a surfactant and removing solvent by spraying this solution onto a substrate comprising of a pharmaceutically acceptable excipient, in a fluid-bed processor.

Description

PREPARATION OF A FREE FLOWING MOLECULAR DISPERSION OF

CLOPIDOGREL BASE

TECHNICAL FIELD

The present invention relates to a free flowing molecular dispersion of clopidogrel base comprising clopidogrel base, a polymer, such as, hydroxypropylmethylcellulose or a mixture of polymers, such as, hydroxypropylmethylcellulose and ethyl cellulose, pharmaceutically acceptable excipients and optionally surfactant and a process for preparing the same.

BACKGROUND

Clopidogrel is an inhibitor of induced platelet aggregation and acts by inhibiting the binding of adenosine diphosphate to its receptor. Clopidogrel is metabolized by the liver into active form. Its antiplatelet activity is extended in that it stops any platelet activity even up to ten days after administration. Chemically clopidogrel is methyl (+)- ([pound])-[deg.]c-(o-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate.

U.S. Pat. No. 4,529,596 (EP 99802, JP 59027895), 6,258,961, 5,036,156 (EP 420706, JP 3120286), 6,080,875 (EP 971915, JP 2001513806) and 6,180,793 (EP 981529, JP 2001525829) disclose clopidogrel. Clopidogrel's ability to inhibit platelet aggregation makes it an effective drug for reducing the incidence of ischemic strokes, heart attacks or claudication due to vascular diseases such as atherosclerosis. Clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks.

In U.S. Pat. No. 5,576,328, a method of preventing the occurrence of a secondary ischemic event by administration of clopidogrel is described.

Clopidogrel is presently used as its bisulphate or hydrogensulphate salt. However, the hydrogensulphate salt has the disadvantage that concentrated sulfuric acid is required to prepare it, and that corresponding products have a very strong acidic reaction because of the acidic proton. These acidic properties have an adverse effect on compatibility with many pharmaceutical excipients and thus the stability of dosage forms made from it.

EP1310245 describes that there is an interaction between platelet aggregation inhibitor clopidogrel and magnesium stearate where magnesium stearate causes degradation of clopidogrel. This invention purports to overcome this problem by using zinc stearate, stearic acid, sodium stearyl fumarate as lubricant instead of magnesium stearate. US5520928 relates to use of stearic acid, WO0001364 relates to use of PEG and talc instead of magnesium stearate. US4591592 relates to use of a chelating agent such as stearic acid, benzoic acid, tartaric acid or fumaric acid and an antioxidant together with magnesium stearate. WO/2005/070464 decribes a stable pharmaceutical formulation of clopidogrel bisulphate wherein hydrogenated vegetable oil is used as lubricant.

Various salts of clopidogrel, other than the bisulphate, have been tried with the objective of preparing a stable and bioavailable tablet formulation. However, most of this exercise has been fruitless due to instability and hygroscopicity of these salts.

Clopidogrel base has not been used for formulation because it exists as an oil that is contaminated with solvents and clopidogrel acid. There is, therefore, an urgent need to make clopidogrel base that can be of use in pharmaceutical formulations.

WO 2006031847 provides processes for preparing clopidogrel base substantially free of solvents and suitable for use in pharmaceutical formulations. However, due to its physical nature, there is still a problem of formulating the base in a stable and bioavailable formulation. The reports in the literature about clopidogrel are focussed on the development of either novel polymorphs of clopidogrel bisulphate or the development of amorphous clopidogrel bisulphate. The use of clopidogrel base as an active pharmaceutical ingredient for developing a pharmaceutical dosage form has not been explored. This is due to the fact that clopidogrel base occurs as an amorphous semisolid paste-like mass and, therefore, is not conducive to being converted into an acceptable solid oral formulation.

The use of clopidogrel base as an active pharmaceutical ingredient in pharmaceutical dosage forms thus requires that the clopidogrel base be processed so as to render it suitable for further processing to develop a dosage form.

WO 2006/044548 relates to premixes comprising clopidogrel and a pharmaceutically acceptable excipient, and processes for the preparation of these compositions. In this invention, a composition containing clopidogrel is prepared by adsorbing a solution containing clopidogrel base onto a pharmaceutical excipient or a mixture of pharmaceutical excipients and then removing solvent. However, this invention can have the problems of poor flowability and stability. This approach also has limitation of the maximum content of clopidogrel possible in these compositions. The flowability of the material is a limiting factor and it is generally difficult to make a composition with a clopidogrel content of more than 30 percent.

There is, thus, a need for stable forms of clopidogrel which are easy to purify and easy to process with various pharmaceutical excipients such as diluents, carriers and other additives.

All the reports in the literature to date about clopidogrel are centered on the development of either novel polymorphs of clopidogrel bisulphate or the development of amorphous clopidogrel bisulphate. The use of clopidogrel base as an active pharmaceutical ingredient for developing a pharmaceutical dosage form has not been explored due to the inherent problems associated with the physical state in which clopidogrel base occurs. Clopidogrel base occurs as an amorphous semisolid paste-like mass. Hence the utilization of clopidogrel base as an active pharmaceutical ingredient in pharmaceutical dosage forms requires that it be processed so as to render it suitable for further processing to prepare a dosage form.

Conversion of clopidogrel base into a free-flowing powder with predefined characteristics suitable for its direct use as a medicament or which would allow its use in processing into pharmaceutical compositions has been a major challenge faced by those involved in development of pharmaceutical formulations.

The present inventors have found that clopidogrel base when processed to form a molecular dispersion or a solid solution in certain pharmaceutically acceptable polymers allows the formation of a free flowing granular powder containing clopidogrel base, with enhanced flowability,dissolution and stability.

OBJECTS OF THE INVENTION

Thus an object of the invention is to provide clopidogrel base in powder form which is free flowing and has enhanced stability and adequate dissolution.

Another object is to provide clopidogrel base which is easily and conveniently processed into pharmaceutical compositions.

A further object is to provide a process of preparation of clopidogrel base in powder form which is free flowing and has enhanced stability. SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided a molecular dispersion comprising clopidogrel base and a pharmaceutically acceptable polymer, pharmaceutically acceptable excipients and optionally a surfactant.

According to another aspect of the present invention there is provided a molecular dispersion comprising clopidogrel base, a pharmaceutically acceptable polymer, pharmaceutically, acceptable excipients, substrate of inert component and optionally a surfactant.

According to another aspect of the present invention there is provided a process for the preparation of the same.

According to further aspect of the present invention there is provided pharmaceutical dosage forms, medicaments and products containing the clopidogrel molecular dispersion blend and process for its preparation.

According to further aspect of the present invention there is provided use of the clopidogrel molecular dispersion blend and the pharmaceutical dosage forms containing the premix in the treatment of disease conditions.

DETAILED DESCRIPTION

A formulation of clopidogrel needs to have sufficient flowability and compressibility to be converted into a tablet or to be filled into capsules. However, clopidogrel being an oily liquid, can not be processed either in a tablet or a capsule. Its conversion into a molecular dispersion affords a granular solid material that can be conveniently subjected to unit operations like size reduction and granulation that may be required to impart flowability and compressibility. If a dispersion does not form ciopidogrel will remain a liquid mixed with excipients and will not acquire properties needed for formulation into a tablet or a capsule.

The blend of present invention is easily isolated in the form of stable, free-flowing granules, which exhibit good processing characteristics and can be easily and conveniently processed into pharmaceutical compositions (such as, for example, tablets, capsules, and the like).

"Blend" as in this application refers to a solid composition, comprising generally of powders or granules, of clopidogrel base coated as a molecular dispersion in a water-soluble or insoluble polymer and a surfactant, onto at least one pharmaceutically acceptable excipient that is compatible with clopidogrel base to form a tertiary "molecular dispersion" or a "solid solution or dispersion".

The term solid dispersion refers to the dispersion of one or more active ingredient in an inert carrier or matrix at solid state prepared by melting (fusion), solvent, or the melting solvent method.

Such drug-carrier combinations can also be prepared through coprecipitation of the two or more compounds from a common solvent. The present invention is about a similar process using a fluid bed processor to accomplish coprecipitation of the drug- polymer- surfactant coprecipitate from a common solvent on to a pharmaceutically acceptable excipient or excipient mixture. The approach involves a fluidized bed coating system, wherein a drug-carrier solution is sprayed onto the granular surface of excipients to produce either granules ready for tableting or drug-coated granules for encapsulation in one step. The method has been applied for both controlled- and immediate-release solid dispersions.

The invention describes a molecular dispersion containing clopidogrel prepared by spraying a solution comprising clopidogrel base and a pharmaceutically acceptable polymer, either alone or in combination with another polymer, onto a pharmaceutical excipient or a mixture of pharmaceutical excipients and then removing solvent in a fluid-bed processor. The molecular dispersion of clopidogrel thus prepared can be used directly, or used in combination with additional excipients to prepare desired pharmaceutical dosage forms.

The process can be carried out in a fluid bed processor using a bottom spray, a top spray or a tangential spray attachment. The flowability, processability and other characteristics of the clopidogrel base dispersion of the invention can be readily controlled through the choice of appropriate pharmaceutically acceptable excipients onto which the clopidogrel-polymer solution is coated; and by varying the process variables like the spray rate and the degree of fluidization. Further control on the particle size distribution can be exercised by subjecting the molecular dispersion obtained from the process to a size-reduction step.

The flowability of the clopidogrel base is significantly enhanced by its conversion into the molecular dispersion blend according to this application. Such a significant improvement in the flow properties of a material indicates superior handling capabilities during processing into pharmaceutical dosage forms.

Another important solid-state property of a pharmaceutical compound is its rate of dissolution in an aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach or in intestinal fluids can have therapeutic consequences because it affects the rate at which an orally-administered active ingredient reaches the bloodstream. The development of solid dispersions as a practically viable method to enhance bioavailability of poorly water-soluble drugs overcame the limitations of previous approaches such as salt formation, solubilization by cosolvents, and particle size reduction. Once the solid dispersion is exposed to aqueous media & the carrier dissolved, the dispersed drug is released as very fine, colloidal particles. Because of greatly enhanced surface area obtained in this way, the dissolution rate and the bioavailability of poorly water-soluble drugs are generally expected to be high. The commercial use of such systems, however, has been limited primarily because of manufacturing problems with solid dispersion systems.

For successful formulation of certain solid dosage forms, the components are required to be in a finely divided form. The clopidogrel molecular dispersion blend of the present invention can be subject to operations such as size reduction, particle size classification, such as, by sieving, blending with other components, and the like, without substantial alteration of the flow properties and other important features of the blend.

Incorporation of surfactants in a molecular dispersion has been reported to significantly improve dissolution properties of the active drug moiety being converted into a molecular dispersion. In this invention, polysorbate 80 and sodium lauryl sulphate have been used in the dispersion.

The solid-state physical properties of clopidogrel base such as for example, the flowability and handling of the semisolid mass, are significantly modified. Clopidogrel base occurs as a semisolid mass which is difficult to handle and to process into a pharmaceutical formulation. The flowability of the clopidogrel base is significantly enhanced by its conversion into the dispersion according to this invention.

According to another aspect the clopidogrel formulation of the invention is preferably based on compositions having a substrate forming inert component which may comprise of microcrystalline cellulose, a cyclodextrine or an ion-exchange resin. The substrate forming inert component is coated with a formulation which comprises clopidogrel, a water soluble polymer (either alone or in combination with another polymer) and a surface active agent, dissolved in a suitable solvent or a solvent mixture. The substrate forming inert component is typically in a concentration of 20- 50% of the final product weight. The substrate forming component is granulated with a pharmaceutically acceptable binder to provide uniformly sized granules to facilitate coating in a fluid bed processor. Clopidogrel may comprise from 10 to 40 weight % and preferably 30 to 40 wt % of the final formulation.

Polymers, to form the molecular dispersion, are selected from water soluble polymers like hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose; either alone or in combination with ethylcellulose. These polymers are used at a level of 10 to 100% of the clopidogrel weight.

The surface active agent is any pharmaceutically acceptable, non-toxic surfactant. Suitable surface active agents include sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and the like. The surface active agent are present at a level of from 0.1 to 5 wt % and preferably 0.25 to 2.5 wt % based on the total weight of the drug-polymer composition.

The drug-polymer solution is prepared in a solvent mixture which consists of one or more solvents from isopropanol, ethanol, dichloromethane, acetone and water.

The molecular dispersion is formed by spraying the substrate granules with an aqueous or non-aqueous solution which contains the clopidogrel, the polymer(s) and the surface active agent.

After the drug polymer solution is completely coated on to the substrate granules, the material is dried in the same coater till the moisture content is reduced to a level below 2%. The dried material is powdered using a suitable size-reduction equipment to get a material of the desired size distribution. This is further combined with commonly used excipients to make the desired pharmaceutical dosage form. The clopidogrel molecular dispersion blend of the invention can be further processed, either alone or with other active agents into various pharmaceutical dosage forms as is, or by combining with pharmaceutically acceptable excipients. The different pharmaceutical dosage forms where the clopidogrel molecular dispersion blend of the invention finds utility include, for example, tablets, capsules (hard and soft gelatin), granules, lozenges, sachets, pills, oral solutions, suspensions, and the like. Other pharmaceutically acceptable additives may be used as required for conversion of the blend into the final pharmaceutical dosage form and may include diluents, lubricants, glidants, disintegrating agents, wetting agents, and the like.

The clopidogrel molecular dispersion blend renders clopidogrel base amenable for processing into a pharmaceutical dosage forms. This blend offers numerous advantages to the formulator. It occurs as free flowing granules and thereby allows itself to be directly compressed. Consequently, various unit operations as granulation, drying, milling, sieving and the like can be avoided. The enhanced flow property and density enables compression of clopidogrel molecular dispersion blend into tablets, with or without granulation, and filling into capsules or sachets.

The invention is now described with reference to the following non limiting illustrative examples.

EXAMPLE 1

A clopidogrel base molecular dispersion blend was prepared, using the following:

Manufacturing process:

1. Microcrystalline cellulose is granulated by mixing with a 12 percent solution of polyvinylpyrrolidone in isopropanol. This mixture is dried in a draught of air.

The dried material is powdered and the 18 to 40 mesh size fraction is collected for coating with the clopidogrel molecular dispersion. 2. 360 g of clopidogrel base is dissolved in a solution of 272.5g of hydroxypropylmethylcellulose and 7g of Polysorbate 80 in 5054g of isopropanol and 720 g of water, with stirring.

3. Granulated microcrystalline cellulose is loaded in to a bottom spray attachment of a fluid bed processor.

4. Microcrystalline cellulose granules are coated with the clopidogrel:HPMC:Polysorbate 80 solution.

5. The coated material is dried at 40-45° until a loss on drying at 105° of 1-2 percent by weight is achieved. 6. The dried granules are sifted through a 40 ASTM mesh sieve.

7. Tablets containing 75 mg of clopidogrel were prepared from the following:

Manufacturing process: a. 17O g of clopidogrel dispersion(equivalent to 75 mg clopidogrel) is blended with 3.5 g microcrystallinene cellulose, 2.5 g of sodium bicarbonate, 3.75 g of crosscarmellose sodium and 0.875 g of colloidal silicone dioxide. b. 0.25 g of magnesium stearate is added to the above and blended. c. The blend is compressed into tablets using a round, biconvex tooling of 8.5 mm size. d. The tablets made above are coated with a 5 percent solution of hydroxypropylmethylcellulose (6 cps) in a mixture of isopropanol and water, further comprising of titanium dioxide and red ferric oxide as pigments, triethylcitrate as the plasticizer and talc and lactose as the antitack.

The tablets were evaluated for dissolution of clopidogrel as follows:

Dissolution

The dissolution of clopidogrel from the tablets made from the molecular dispersion blend as described above and the pure clopidogrel was determined in various dissolution medium in a paddle type dissolution tester. The amount of clopidogrel dissolved at regular intervals till one hour was estimated by using a UV specrophotometric method.

Dissolution of the pure clopidogrel base and its dissolution from tablets made from 5 its molecular dispersion in hydroxypropylmethylcellulose is given below. The enhancement in dissolution is obvious.

Stability

Both the granular molecular dispersion and the tablets made from it, along with tablets made from the clopidogrel hydrogensulphate, were subjected to a forced degradation study to understand the probable degradation pathways

The results of this study showed that, though the drug undergoes degradation under acidic and basic conditions, oxidation and dry heat treatment, stability of tablets made from complexes of clopidogrel is comparable to; and in some case even better than that of, tablets made from clopidogrel hydrogensulphate.

Results from an accelerated stability study conducted on these samples supported the conclusions drawn from the forced degradation study.

All of the components which are used in the present invention are used in amounts which are effective for the intended purpose for which the component is employed.

While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skilled in the art. Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof which do not depart from the spirit and scope of the invention.

The flowability of the mixtures of clopidogrel molecular dispersion was ascertained by density measurements and computation of Carr's Index, which is an excellent indicator of flow properties of granular materials. This was found, for all the formulations studied including those described above, to be in the range of 10 to 15%, which is indicative of good to very good flow properties. This observation was further supported by the excellent flow of the material from the hopper and on the turret during the tablet compression operation.

Claims

1. A solid free flowing molecular dispersion comprising clopidogrel base, at least one pharmaceutically acceptable polymer, at least one pharmaceutically acceptable excipient and optionally surfactant.

2. A solid dispersion comprising clopidogrel base, at least one pharmaceutically acceptable polymer, at least one pharmaceutically acceptable excipients and a substrate forming inert component and optionally surfactant.

3. The solid dispersion as claimed in claim 1or 2, wherein a pharmaceutical polymer comprises a water soluble cellulose derivative, either alone or in combination with a water insoluble cellulose derivative.

4. The solid dispersion as claimed in claim 1or 2, wherein the weight ratio of clopidogrel to pharmaceutical polymer is about 5 :1 to about 1 :1.

5. The solid dispersion as claimed in claim 1 or 2, wherein the clopidogrel content is of 20 to 50 weight percent.

6. The solid dispersant as claimed in any preceding claim wherein the pharmaceutical excipients is hydroxypropylmethyl cellulose.

7. The solid dispersant as claimed in claim 6 wherein the pharmaceutical excipients is present in amount of 10% to 50 weight % of the final composition.

8. The solid dispersion as claimed in claim 2, wherein the weight ratio of pharmaceutical polymer to the surfactant is about 20 :1 to about 10 :1.

9. The solid dispersion as claimed in any of preceding claim wherein surface active agents is selected from sodium laurγl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and the like.

10. The solid dispersion as claimed in claim 10 wherein the surface active agent is present in amount of from 0.1 to 5 wt %, preferably 0.25 to 2.5 wt%.

11. The solid dispersion as claimed in claim 2 wherein the substrate forming inert component is present in amount of 20-50% of total.

12. The solid dispersion as claimed in claim 11 , wherein the substrate is a cellulose derivative.

13. The solid dispersion as claimed in claim 11 , wherein the substrate is a cyclodextrine.

14. The solid dispersion as claimed in claim 11, wherein the substrate is an ion- exchange resin.

15.A process for preparing a solid dispersion comprising: a) dissolving clopidogrel base into a solid pharmaceutically acceptable polymer, or a mixture of polymers or a mixture of a polymer and a surfactant; and b) removing solvent by spraying this solution onto a pharmaceutically acceptable excipient, in a fluid-bed processor.

16. A process for preparing a solid dispersion comprising:, a) dissolving clopidogrel base into a solid pharmaceutically acceptable polymer, or a mixture of polymers or a mixture of a polymer and a surfactant; and b) removing solvent by spraying this solution onto a substrate comprising of a pharmaceutically acceptable excipient, in a fluid-bed processor.

17. The process as claimed in claim 15 or 16 wherein the drug-polymer solution is prepared in a solvent mixture which consists of one or more solvents from isopropanol, ethanol, dichloromethane, acetone and water.

18. The process as claimed in claim 17 after spraying of the drug polymer solution on to excipient, the material is dried in the same coater till the moisture content is reduced to a level below 2% and is then is powdered using a suitable size-reduction equipment to get a material of the desired size distribution.

19. A pharmaceutical composition, comprising the solid dispersion of claim any of claim 1 to 14 and at least one pharmaceutically acceptable excipient.

20. The pharmaceutical composition as claimed in claim 17 wherein the composition is in the form of a tablet, capsule, powder or sachet.

21. A method for treatment of the human or animal body by administering a pharmaceutical composition incorporating the solid dispersion of claim 1.

22. The method of claim 19, further comprising administering a second therapeutic agent for the treatment of thrombotic disorders.