WO2008072939A1

WO2008072939A1 - Inclusion complex containing clopidogrel with improved storage stability

Info

Publication number: WO2008072939A1
Application number: PCT/KR2007/006599
Authority: WO
Inventors: Jae-Sun Kim; Nam Ho Kim; Jin Young Lee; Nam Kyu Lee; Joon Gyo Oh; Ji Young Shin; Tae-Kon Kim; Mi-Sun Yoon; Jin-Heung Sung; Yoon-Jung Lee; Yeo-Jin Park; Key An Um
Original assignee: Sk Chemicals Co., Ltd.
Priority date: 2006-12-15
Filing date: 2007-12-17
Publication date: 2008-06-19
Also published as: KR20080055356A

Abstract

The present invention relates to an inclusion complex containing clopidogrel with superior storage stability, more particularly to a pharmaceutically stable and suitable inclusion complex obtained by reacting S-(+)-clopidogrel [methyl (+)-(S)-α- (o-chlorophenyl)-6/7-dihydrothieno[3,2-c]pyridin-5(4H)-acetate] represented by the formula (1) below with β-cyclodextrin at a specific equivalence ratio, and an antiplatelet agent composition comprising the same as an active ingredient:

Description

[DESCRIPTION] [Invention Title]

INCLUSION COMPLEX CONTAINING CLOPIDOGREL WITH IMPROVED STORAGE STABILITY

[Technical Field]

The present invention relates to an inclusion complex containing clopidogrel with superior storage stability, more particularly to a pharmaceutically stable and suitable inclusion complex obtained by reacting S-(+)-clopidogrel [methyl (+)-(S)-α- (o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-acetate] represented by the formula (1) below with β-cyclodextrin at a specific equivalence ratio, and an antiplatelet agent composition comprising the same as an active ingredient:

CO₂CH₃

[Background Art]

According to recent researches, it has been reported that clopidogrel is more effective than aspirin in blocking platelet aggregation even at lower dosage, with less gastrointestinal distress. Hence, it makes a very effective antiplatelet agent. Clopidogrel is marketed under the trade name Plavix. A tablet contains about 98 mg of clopidogrel hydrogen sulfate, which includes 75 mg of clopidogrel base as an active ingredient.

European Patent No. 0281459 proposes the use of an inorganic salt of (S)-(+)- clopidogrel, more specifically (S)-(+)-clopidogrel hydrogen sulfate for pharmaceutical preparations. Since the active ingredient clopidogrel base is an oily liquid, it has to be transformed into a pharmaceutically acceptable salt for simple pharmaceutical preparations. The above patent mentions, along with hydrogen sulfate, taurocholate, hydrochloride and bromochloride as salts of clopidogrel acceptable for pharmaceutical preparations. The patent also mentions organic salts of clopidogrel, but the organic salts are non-crystalline and/ or hygroscopic and difficult to purify.

Other patents published thereafter state that particularly a sulfonate has stability almost comparable to that of the hydrogen sulfate. WO 2004/072084 and 2004/072085 suggest that sulfonate, particularly benzosulfonate, which is described in European Patent No. 0281459 as unsuitable for pharmaceutical preparations, is acceptable for pharmaceutical preparation under a specific condition. It is mentioned that as crystalline clopidogrel besylate, a solvate form including toluene or dioxane solvent is preferable and that non-crystalline clopidogrel besylate is obtained by further drying and removing the solvent. WO 2005/103059 and Korean Patent Publication No. 2005-0099445 mention a novel crystalline salt clopidogrel napadisilate, a polymorphic crystal form, a hydrate and a solvate thereof, which are optically pure, thermally stable and non- hygroscopic. However, such a sulfonate salt of clopidogrel has very low solubility as compared to existing hydrogen sulfate and the clopidogrel base may be precipitated as oil in aqueous solution. Further, optical stability tends to be poor.

An especially important factor in the clopidogrel salt is hygroscopicity. High hygroscopicity may affect physical and chemical properties of active ingredient and excipient and cause problems in drug formulations. Accordingly, the control of hygroscopicity in pharmaceutical preparations is an important factor, along with packaging or storage. In particular, the clopidogrel base is an oily liquid and even the hydrogen sulfate, which is known as the most preferable salt form, may be hydrolyzed or racemized by external environment to produce impurities. The most commonly produced impurities are the hydrolysis product (2) of the methyl ester and the R-(-)-isomer of clopidogrel (3) resulting from racemization:

(2)

An adequate control is required in preparing and processing pharmaceuticals in large quantity to reduce these impurities below a certain level. Also, the packaging and storage need to be managed properly.

[Disclosure] [Technical Problem]

The present inventors have found that an inclusion complex prepared by reacting clopidogrel with cyclodextrin at a specific equivalence ratio has outstanding stability as free base, not as acid addition salt, and properties appropriate for drug manufacture.

[Technical Solution]

Accordingly, an object of the present invention is to provide an inclusion complex containing clopidogrel having superior storage stability and a use thereof.

[Advantageous Effects] The inclusion complex containing clopidogrel according to the present invention has outstanding storage stability against temperature and humidity.

Therefore, it can be stored for a long period of time, easily prepared into preparation forms and endure the temperature and humidity of the production process without being decomposed.

[Description of Drawings]

Figure 1 illustrates the inclusion of one clopidogrel molecule with two β- cyclodextrin molecules. Figure 2 shows the powder X-ray diffractogram of the clopidogrel inclusion complex prepared in Example 1.

Figure 3 compares the dissolution rate of the tablet containing clopidogrel inclusion complex prepared in Example 11 with that of a commercially available tablet.

[Best Mode]

In an aspect, the present invention provides an inclusion complex containing clopidogrel having superior storage stability comprising clopidogrel represented by the formula (1) below and β-cyclodextrin at an equivalence ratio from 1 : 2.0 to 1 : 2.5, and a preparation method thereof. CO₂CH₃

In another aspect, the present invention provides an antiplatelet agent composition comprising the inclusion complex as an active ingredient.

Hereunder is given a more detailed description of the present invention.

The present invention relates to a pharmaceutically stable and suitable inclusion complex obtained by reacting S-(+)-clopidogrel [methyl (+)-(S)-α-(o-chlorophenyl)-

6_/7-dihydrothieno[3_/2-c]pyridin-5(4H)-acetate] represented by the formula (1) with (3-cyclodextrin at a specific equivalence ratio, and an antiplatelet agent composition comprising the same as an active ingredient:

First, the preparation procedure of the inclusion complex containing clopidogrel according to present invention will be described in detail.

1) Clopidogrel is dissolved in a mixture of an organic solvent and an acidic solution or in distilled water. The acidic solution may be an organic or inorganic acid. Preferably, hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid is used. The organic solvent may be at least one selected from acetone, ethanol, isopropanol and butanol.

The clopidogrel used in the present invention may be a clopidogrel free base or a clopidogrel salt. The clopidogrel salt may be clopidogrel bisulfate, clopidogrel hydrochloride, clopidogrel bromide or clopidogrel benzenesulfonate. Further, other forms of clopidogrel, for example, a mixture (premix or adsorbate) of a clopidogrel free base with a pharmaceutically acceptable additive or excipient, may be used. The substance remaining without being dissolved is removed by filtering, and the filtrate, or an acidic solution of clopidogrel, is used in later steps.

2) Stirring is performed at 30 to 70 ⁰C, preferably at 40 to 60 ⁰C, while adding β-cyclodextrin to the solution prepared in step 1). When the temperature is below 30 ⁰C, more solvent is needed to dissolve cyclodextrin and inclusion efficiency may decrease. And, when the temperature exceeds 70 ⁰C, clopidogrel may be decomposed.

3) The reaction mixture is neutralized by adding a base. The base may be an alkali metal hydroxide, e.g., sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide. The neutralization is performed at 0 to 50 ⁰C, more preferably at 10 to 40 ⁰C. When the neutralization temperature is lower than 0 ⁰C, impurities other than the inclusion complex or unincluded cyclodextrin may be precipitated concurrently due to overcooling. And, when the temperature exceeds 50⁰C, the amount of impurities may increase.

4) The reaction mixture is filtered, washed and dried to obtain the wanted inclusion complex. The final inclusion complex can be obtained in high yield by washing the filtrate several times with a small quantity of water and drying. In step 2), a water-soluble polymer compound may be added. Preferably, the water-soluble polymer compound is at least one selected from polyethylene glycol

(PEG), polyvinylpyrrolidone (PVP), carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl ethyl cellulose (HPEC).

The β-cyclodextrin used in the present invention includes derivatives of β- cyclodextrin, as well as β-cyclodextrin itself. Preferably, β-cyclodextrin or a derivative thereof having a cavity diameter ranging from 6.0 to 6.5 A is selected.

Preferably, β-cyclodextrin is used in an amount from 2.0 to 2.5 equivalents, based on 1 equivalent of clopidogrel. The present inventors examined inclusion efficiencies at various equivalence ratios of clopidogrel and β-cyclodextrin. It was found that the inclusion efficiency is maximized and a stable inclusion complex is obtained when β-cyclodextrin is used in an amount of 2.0 or more equivalents, based on 1 equivalent of clopidogrel. As can be seen from Figure 1, which illustrates the inclusion of one clopidogrel molecule with two β-cyclodextrin molecules, each part of the thienopyridone and the chlorobenzene portions of clopidogrel is included as a rather stable structure by one β-cyclodextrin molecule. Accordingly, an optimal stability is attained when the proportion of clopidogrel and β-cyclodextrin is maintained at 1 : 2. However, when β-cyclodextrin is used in an amount exceeding 2.5 equivalents, there is a problem that the tablet volume increases. In order to limit the content of β-cyclodextrin required to obtain the inclusion complex to 2.5 equivalents or smaller, based on 1 (molar) equivalent of clopidogrel, the present inventors adjusted the amount of β-cyclodextrin, the amount of distilled water, and the amount of the base required for neutralization, and could attain a high inclusion efficiency with an equivalence ratio from 1 : 2.0 to 1 : 2.5.

The powder X-ray diffractogram (PXRD) of the clopidogrel inclusion complex shows a characteristic diffraction pattern. The PXRD was taken using M18XHF22 (Mac Science) under the condition of 20 mA, 40 kV and 203-35 °. Thus obtained inclusion complex of the present invention has outstanding storage stability against high temperature and humidity. Therefore, it can be stored for a long period of time, easily prepared into preparation forms and endure the temperature and humidity of the production process without being decomposed.

The present inventors performed studies in order to find a better clopidogrel composition than existing clopidogrel salts, using β-cyclodextrin. As a result, they developed a novel inclusion complex of clopidogrel having superior physical and chemical properties and pharmaceutical availability under a specific reaction condition. Whereas only limited acidic salts were obtained as stable salt of clopidogrel base, which is an oily liquid, in the prior art, the present invention has proven that a composition suitable for pharmaceutical preparations can be obtained through inclusion. Unexpectedly, thus obtained inclusion complex has very superior stability without any noticeable hygroscopicity, and is thus suitable for pharmaceutical preparations.

The requirements needed for an ideal clopidogrel containing composition are as follows.

First, it needs to be non-hygroscopic. The present inventors have prepared various clopidogrel salts. Since the clopidogrel base is an oily liquid, the reaction itself was not easy. In many cases, salt was not precipitated at all or, even when it did, the salt was discolored by absorbing moisture. Further, when clopidogrel absorbs moisture, impurities including hydrolysis product [formula (2)] and R- isomer [(formula 3)] may be generated. Thus, the inclusion composition needs to be non-hygroscopic.

Second, superior stability over a long period of time is required. Superior physical and chemical properties are advantageous not only in formulation studies, but also in packaging, storage and production. The present inventors measured storage stability of the inventive composition over a long period of time. They also observed the generation of hydrolysis products and R-isomers, which are important impurities needed to be controlled, and the content changes thereof, and compared them with those of known salts. Further, they tested the stability of the inclusion complex of clopidogrel and β-cyclodextrin under various harsh conditions and compared the result with those of known salts.

Third, a good handlability is required for large-scale preparation and formulation studies. For this purpose, the composition needs to be non- hygroscopic and have good stability, as mentioned above. Also, it needs to be easy to prepare and purify.

The inclusion complex containing clopidogrel according to the present invention satisfies all these requirements, and provides very good yield and purity.

The present invention further provides an antiplatelet agent comprising the inclusion complex as an active ingredient. The antiplatelet agent may be prepared into an oral administration form, preferably tablet, hard capsule, powder or granule, by mixing the inclusion complex with a pharmaceutically acceptable diluent, binder, disintegrant, lubricant, coating agent, etc. Examples of the pharmaceutically acceptable diluent include noncrystalline cellulose, corn starch, and so forth. The binder may be selected from a commonly used binder, including povidone, copovidone, cellulose, and the like. Preferably, the disintegrant may be croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose calcium, etc. The lubricant may be selected from a commonly used lubricant, including sodium stearyl fumarate, magnesium stearate, talc, glyceryl fatty acid ester, glycerol dibehenate, etc. And, the pharmaceutically acceptable coating agent includes polyvinyl alcohol, hydroxypropyl methyl cellulose, methylcellulose, ethylcellulose, and the like.

Effective dose of the clopidogrel containing inclusion complex may vary depending on the age of patient, severity of disease, and the like. Normally, based on the clopidogrel base, a daily dose of 30 to 300 mg, preferably 30 to 150 mg, more preferably 75 mg, may be employed.

[Mode for Invention]

The present invention is explained in more detail with reference to the following examples. However, they should not be construed as limiting the scope of the present invention.

Example 1: Preparation of inclusion complex of clopidogrel and β-cyclodextrin

1.6 g (5 mmol) of clopidogrel base was dissolved in 5 mL of acetone. 0.3 mL of strong sulfuric acid was added, and stirring was performed slowly at room temperature for 5 minutes. While slowly stirring at 60 ⁰C after adding 160 mL of distilled water, 12.8 g of β-cyclodextrin was added and stirring was performed at 60

⁰C for 3 hours. After adding 2 mL of 2.5 N NaOH solution and stirring at room temperature for 3 hours, the resultant solid was filtered and washed with 16 mL of distilled water. The product was dried in vacuum for 20 hours to obtain 7.79 g of white solid compound. The compound was identified as an inclusion complex of clopidogrel and β-cyclodextrin by HLPC analysis. X-ray diffraction measurement showed characteristic diffraction angles 20 at 5.96 ° and 12.98 ° [Figure 2].

Clopidogrel : β-cyclodextrin = 1 : 2.0 (equivalence ratio)

¹H-NMR (300 MHz, DMSOd₆) δ (ppm): 7.57-7.60 (m, IH), 7.48-7.52 (m, IH), 7.36-7.41 (m, 2H), 7.26 (d, IH, J = 5.1 Hz), 6.76 (d, IH, J = 5.1 Hz), 5.74 (d, 14H), 5.67 (d, 14H), 4.86 (s, IH), 4.83 (d, 14H), 4.45 (t, 14H), 3.70 (s, 3H), 3.50-3.69 (m, 58H), 3.26- 3.38 (m, 36H), 2.77-2.84 (m, 4H)

Example 2: Preparation of inclusion complex of clopidogrel and β-cyclodextrin 2.1 g (5 mmol) of clopidogrel bisulfate was dissolved in 5 mL of distilled water.

195 mL of distilled water was further added at room temperature to completely dissolve the clopidogrel bisulfate. Then, after adding 12.8 g of β-cyclodextrin and gradually heating to 60 ⁰C, stirring was performed for 3 hours. After gradually cooling to room temperature, adding 2 mL of 2.5 N NaOH solution and stirring at room temperature for 5 hours, the resultant solid was filtered and washed with 20 mL of distilled water. The product was dried in vacuum for 20 hours to obtain 7.80 g of white solid compound. The compound was identified as an inclusion complex of clopidogrel and β-cyclodextrin by HLPC analysis.

Clopidogrel : β-cyclodextrin = 1 : 2.05 (equivalence ratio) Example 3: Preparation of inclusion complex of clopidogrel and β-cyclodextrin

2.1 g (5 mmol) of clopidogrel bisulfate dissolved in 5 mL of distilled water was added to a suspension of 12.8 g of β-cyclodextrin and 195 mL of distilled water.

After gradually heating to 60 ⁰C, stirring was performed for 3 hours. Then, after gradually cooling to room temperature, adding 2 mL of 2.5 N NaOH solution and stirring at room temperature for 5 hours, the resultant solid was filtered and washed with 20 mL of distilled water. The product was dried in vacuum for 20 hours to obtain 8.30 g of white solid compound. The compound was identified as an inclusion complex of clopidogrel and β-cyclodextrin by HLPC analysis. Clopidogrel : β-cyclodextrin = 1 : 2.07 (equivalence ratio)

Examples 4: Preparation of inclusion complex of clopidogrel and β-cyclodextrin

1.6 g (5 mmol) of clopidogrel base was dissolved in 5.0 mL of acetone. After adding 0.3 mL of strong sulfuric acid, stirring was performed slowly at room temperature for 5 minutes. After adding 200 mL of aqueous 1 % HPMC solution and adding 14.08 g of β-cyclodextrin while stirring slowly at 60 ⁰C, stirring was performed at 60 ⁰C for 3 hours. Then, after adding 2 mL of 2.5 N NaOH solution and stirring at room temperature for 3 hours, the resultant solid was filtered and washed with 20 mL of distilled water. The product was dried in vacuum for 20 hours to obtain 9.53 g of white solid compound. The compound was identified as an inclusion complex of clopidogrel and β-cyclodextrin by HLPC analysis. Clopidogrel : β-cyclodextrin = 1 : 2.09 (equivalence ratio)

Examples 5: Preparation of inclusion complex of clopidogrel and β-cyclodextrin 1.6 g (5 mmol) of clopidogrel base was dissolved in 5.0 mL of acetone. After adding 0.3 mL of strong sulfuric acid, stirring was performed slowly at room temperature for 5 minutes. After adding 200 mL of aqueous 1 % PVP solution and adding 14.08 g of β-cyclodextrin while stirring slowly at 60 ⁰Q stirring was performed at 60 ⁰C for 3 hours. Then, after adding 2 mL of 2.5 N NaOH solution and stirring at room temperature for 3 hours, the resultant solid was filtered and washed with 20 mL of distilled water. The product was dried in vacuum for 20 hours to obtain 10.72 g of white solid compound. The compound was identified as an inclusion complex of clopidogrel and β-cyclodextrin by HLPC analysis.

Clopidogrel : β-cyclodextrin = 1 : 2.11 (equivalence ratio)

Test Example 1: Stability test

Stability test was performed for the clopidogrel inclusion complexes prepared in

Examples 1 to 5 and clopidogrel bisulfate (Dr. Reddy's), under the condition of 40 ⁰C and 75 % RH. The amount of impurities - that is, hydrolysis product [formula (2)] and racemization product R-isomer [formula (3)] - was measured and is given in Table 1 below.

Chiral HPLC was performed to identify the impurities and optical purities, under the following conditions:

Stationary phase: Ultron ES-OVM column, 5 μm (4.6 mm X 150 mm i.d.)

Mobile phase: 25 % acetonitrile + 75 % 0.01 M potassium dihydrogen phosphate solution (v/v)

Flow rate: 1 mL/min

Column temperature: 17⁰C

UV detection wavelength: 220 nm

Injection volume: 10 μL

Table 1 - Stability test (after 3 weeks)

As shown in Table 1, the inclusion complexes prepared in Examples 1 to 5 exhibited better stability than clopidogrel bisulfate (Plavix), with fewer impurities. Test Example 2: Blood level measurement after oral administration to rats

The inclusion complex prepared in Example 1 (Compound 1) and clopidogrel bisulfate (Compound 2) were orally administered to Sprague-Dawley rats weighing 250 to 270 g at a dose of 30 mg/kg (base). After 0.5, 1, 2, 4, 6, 8, 10 and 24 hours, blood sample were taken using a pipette treated with heparin. The blood sample was centrifuged at 12,000 rpm for 2 minutes. To 0.1 niL of thus obtained blood plasma, 100 μL of internal standard solution was added, and 0.6 mL of diethyl ether- hexane (80:20, v/v) mixture solvent was added. After extracting by shaking for about 5 minutes, the sample was centrifuged at 2,000 g for 10 minutes. The organic solvent layer was transferred to a clean test tube, and the organic solvent was evaporated under nitrogen flow. 50 μL of the mobile phase was added to the remainder, and 20 μL was taken and injected into the HPLC column. Liquid chromatography was performed, and blood level was measured from the peak area ratio of clopidogrel to the internal standard.

Table 2 - Blood levels and pharmacokinetic parameters after oral administration to rats at a dose of 30 mg/kg

a Numbers are expressed in average + standard deviation (n = 4)

As seen in Table 2, the inclusion complex of the present invention (Compound

1) exhibited comparable to or better pharmacokinetic parameters compared to

Compound 2, following oral administration to rats.

Examples 6-9: Preparation of film-coated tablet containing inclusion complex The ingredients and excipients listed in Table 3 below were prepared into granules using a high-shear mixer (SM-5, Sejong Machinery). Thus obtained granules were passed through a 30 mesh sieve, mixed with a lubricant, and compressed using a single punch press (Erweka) to produce round tablets. The rounded tablets were coated with coating base dissolved in purified water using a coating machine (SFC-30N, Sejong Machinery) to produce film-coated tablets. Table 3

Examples 10-11: Preparation of film-coated tablet containing inclusion complex

The ingredients and excipients of Examples 6 and 8 in Table 3 were prepared into granules using a fluidized-bed granulator (DPL-I, Mendel Korea) The temperatures at the inlet and outlet of the granulator were around 65 ⁰C and around

40⁰C, respectively. The spraying quantity and the spraying pressure were adjusted to 10 mL/min and 0.8 kg/ cm², respectively. Thus obtained granules were passed through a 30 mesh sieve, mixed with a lubricant, and compressed using a single punch press (Erweka) to produce round tablets. The rounded tablets were coated with coating base dissolved in purified water using a coating machine (SFC--30N, Sejong Machinery) to produce film-coated tablets.

Test Example 3: Stability test The clopidogrel inclusion complex tablets prepared in Examples 6, 8 and 10 and commercially available Plavix tablet (Sanofi-Synthelabo Korea) were subjected to stability tests. The test conditions were the same as described in the ICH (International Conference on Harmonization) guideline. That is, a long-term test was performed at 25 ⁰C and 60 % RH, and an accelerated test was performed at 40 ⁰C and 75 % RH as open test.

Analysis was performed according to USP (United States Pharmacopoeia) 3215- 3216. Most of the impurities were ascertained to be hydrolysis product (RRT 0.5, impurity A) and R-enantiomer (RRT 2.0, impurity C) in terms of RRT (relative retention time). USP recommended that impurity A, impurity C, unknown impurity and total impurity should be below 0.2 %, 1.0 %, 0.1 % and 1.2 %, respectively. The increased amounts of the impurities were calculated relative to initial values, and provided in Table 4 below.

Table 4 - Stability test (open test, 3 weeks)

As seen in Table 4, the tablets prepared in Examples exhibited superior stability than commercially available Plavix tablet, with less increase in impurities A and C.

Test Example 4: Dissolution test The clopidogrel inclusion complex containing tablet prepared in Example 8 and commercially available Plavix 75 mg tablet (Sanofi-Synthelabo Korea) were subjected to the dissolution test according to method II paddle test as described in the Korean Pharmacopoeia. The dissolution test was performed at pH 2.0 as recommended in USP 29, and media was 1000 mL and paddle rotation speed was 50 rpm.

4 mL of the sample was taken at 5, 10, 15, 30 and 45 minutes, and filtered through 0.45-μm membrane filter. The solution was analyzed by absorption spectrophotometry at a detection wavelength of 240 nm. As shown in Figure 3, the tablet prepared in accordance with the present invention showed comparable dissolution rate to that of commercially available Plavix. [Industrial Applicability]

As set forth above, the inclusion complex containing clopidogrel according to the present invention has outstanding storage stability against high temperature and humidity. Therefore, it can be stored for a long period of time, be easily prepared into preparation forms and endure the temperature and humidity of the production process without being decomposed. When compared with existing drugs, it is expected to provide a longer shelf life and better quality of drugs, while maintaining dissolution rate.

The present invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of the disclosure, may make modifications and improvements within the scope and spirit of the invention.

Claims

[CLAIMS] [Claim 1]

An inclusion complex containing clopidogrel having superior storage stability comprising clopidogrel represented by the formula (1) below and β-cyclodextrin at an equivalence ratio from 1 : 2.0 to 1 : 2.5:

CO₂CH₃

[Claim 2]

A method of preparing an inclusion complex containing clopidogrel comprising:

1) dissolving clopidogrel in a mixture of an organic solvent and an acidic solution or in distilled water;

2) stirring the resultant at 30 to 70 ⁰C, while adding 2.0 to 2.5 equivalents of β- cyclodextrin based on 1 equivalent of clopidogrel;

3) neutralizing the resultant product with an alkali metal hydroxide at 0 to 50 o 'rC-;- and

4) filtering, washing and drying the resultant product to obtain an inclusion complex. [Claim 3]

The method according to claim 2, wherein said clopidogrel is a clopidogrel base or a clopidogrel salt.

[Claim 4]

The method according to claim 3, wherein said clopidogrel salt is clopidogrel bisulfate, clopidogrel hydrochloride, clopidogrel bromide or clopidogrel benzenesulf onate .

[Claim 5]

The method according to claim I₁ wherein a water-soluble polymer is added in step 2).

[Claim 6]

An antiplatelet agent composition comprising the inclusion complex according to claim 1 as an active ingredient.