WO2008072836A1

WO2008072836A1 - Inclusion complex comprising clopidogrel

Info

Publication number: WO2008072836A1
Application number: PCT/KR2007/005321
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: 2007-10-26
Publication date: 2008-06-19
Also published as: KR20080055355A

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 COMPRISING CLOPIDOGREL

[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 nig 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.

According to other patents published thereafter, state that particularly a sulfonate has stability almost comparable to that of the hydrogen sulfate.

International Patent Publication 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. International Patent Publication 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 an aqueous solution. Further, optical stability tends to be poor.

An especially important factor in the clopidogrel salt is hygroscopicity. High hygroscopicity may affect physicochemical properties of active ingredient and excipient and cause problems in drug making. Accordingly, the control of hygroscopicity in drug making 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 hydrolysis product of methyl ester (2) and R-(-)-isomer of clopidogrel (3) resulting from racemization:

An adequate control is required in preparing and processing drugs 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 a free base, not as an acid addition salt, and properties suitable 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, be easily prepared into preparation forms and endure the temperature and humidity of the production process without being decomposed.

[Description of Drawings]

Figure 1 shows the powder X-ray diffractogram of the clopidogrel inclusion complex prepared in Example 1. Figure 2 shows the powder X-ray diffractogram of the clopidogrel inclusion complex prepared in Example 2.

Figure 3 shows the powder X-ray diffractogram of the clopidogrel inclusion complex prepared in Example 3.

Figure 4 compares the dissolution rate of the tablet containing clopidogrel inclusion complex prepared in Example 5 with that of a commercially available tablet.

[Best Mode]

The present invention provides an inclusion complex containing clopidogrel free base having superior storage stability which comprises clopidogrel represented by the formula (1) below and β-cyclodextrin at an equivalence ratio from 1 : 1 to 1 : 2, and a method of its preparation thereof.

CO₂CH₃

Further, 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-(ø-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-acetate] represented by the formula (1) with β-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.

The present inventors have found an inclusion complex of clopidogrel in free base form with β-cyclodextrin can be prepared by reacting a clopidogrel base or a clopidogrel salt with β-cyclodextrin in a liquid phase to induce inclusion, and then neutralizing with a base. When the amount of β-cyclodextrin was less than 1 equivalent based on 1 equivalent of clopidogrel, a uniform inclusion complex was not obtained, and the resultant substance had very poor stability. The present inventors have tried various inclusion reactions, varying the amount of β-cyclodextrin from 1 to 2 equivalents, based on 1 equivalent of clopidogrel. On the whole, either the stability was not good or the experimental reproducibility was not obtained, when less β- cyclodextrin was used and when the amount of β-cyclodextrin included in the inclusion complex was smaller. However, since it was occasionally possible to obtain a uniform and stable inclusion complex with a low degree of β-cyclodextrin inclusion, the optimization and standardization of inclusion processes were tried under the condition of low degree of β-cyclodextrin inclusion. They have found that, under strict conditions, a stable inclusion complex is obtained when β- cyclodextrin is used less than 2 equivalents, particularly 1.6 equivalents or less, based on 1 equivalent of clopidogrel. A smaller degree of inclusion is commercially very important, particularly when the administration dose is not small as in clopidogrel (75 mg), because the total volume of the drug with the above mentioned inclusion complex can be reduced.

Hereunder is given a more detailed description of each step of the inclusion reaction.

1) Clopidogrel is dissolved in distilled water or acidic aqueous solution. The acidic solution may be an organic or inorganic acid. Preferably, hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid is used.

The clopidogrel used in the present invention may be a clopidogrel base or a clopidogrel salt. The clopidogrel base may be a free base, a premix, an adsorbate or a solid dispersion of clopidogrel. Preferably, the clopidogrel salt may be clopidogrel bisulfate, clopidogrel hydrochloride, clopidogrel bromide or clopidogrel benzenesulfonate. The substance remaining without being dissolved is removed by filtering, and the filtrate, or an acidic solution of clopidogrel, is used in the later steps.

2) The solution prepared in step 1) is slowly added to distilled water or acidic aqueous solution containing β-cyclodextrin, and stirring is performed while heating. The stirring is performed at a temperature range from 30 to 70 ⁰C, preferably from 40 to 60 ⁰C. 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, the resultant drug may be decomposed. The clopidogrel containing acidic aqueous solution is added slowly to the β-cyclodextrin containing acidic aqueous solution for a period of about 30 minutes. It is to obtain a uniform inclusion complex by increasing inclusion efficiency. When the solutions are mixed too quickly, some of oily liquid may be precipitated and coagulated or clopidogrel may be decomposed.

The β-cyclodextrin used in the present invention includes derivatives of β- cyclodextrin, as well as β-cyclodextrin. 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 of from 1.0 equivalent to 2 equivalents, more preferably from 1.0 to 1.6 equivalents, based on 1 equivalent of clopidogrel. When too much β-cyclodextrin is used, an intended effect may not be obtained. And, when β-cyclodextrin is used less than 1.0 equivalent, appropriate stability may not be obtained.

3) The reaction mixture is neutralized by adding a base. The base may be 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 40⁰C. When the temperature is lower than 0⁰C, impurities other than the inclusion complex or unincluded cyclodextrin may be precipitated concurrently due to overcooling. And, when the temperature exceeds 50 ⁰C, the amount of impurities may increase.

4) The reaction mixture is filtered, washed and dried to obtain an 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.

Thus obtained inclusion complex was confirmed to be comparable to or better clopidogrel bisulfate (Plavix) in stability and rate of absorption when orally administered to rat. The powder X-ray diffractogram (PXRD) of the clopidogrel inclusion complex shows a characteristic diffraction pattern. PXRD was taken using M18XHF22 (Mac Science) under the condition of 20 mA, 40 kV and 3-352Θ.

The inclusion complex of the present invention has outstanding storage stability against 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.

Whereas only limited acidic salts were obtained as stable salt of clopidogrel base, which is a oily liquid, in the prior art, the present invention has proven that a composition suitable for drug making can be obtained by inclusion. Further, it has been found that, rather than the structurally most stable proportion of 1 : 2, a stable inclusion complex can be obtained with a proportion from 1 : 1 to 1 : 2.0, particularly from 1 : 1 to 1 : 1.6. Surprisingly, such an inclusion complex obtained with the above mentioned proportion is suitable for drug making, with superior stability and without hygroscopicity. The requirements needed for an ideal clopidogrel containing composition are as follows.

First, it is essential 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 turned grey 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 for a long period of time is required. Superior physical and chemical properties are advantageous not only in drug making, 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 product and R-isomer, which are important impurities needed to be controlled, and the content change thereof, and compared them with known salts. Further, they tested the stability of the inclusion complex of clopidogrel and (3-cyclodextrin under various harsh conditions and compared the result with that of known salts.

Third, a good handlability is required for large-scale preparation and drug design research. For this purpose, the composition needs to be non-hygroscopic and have good stability, as mentioned above. Also, it needs 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 common diluent, binder, disintegrant, surfactant, coating agent, etc. Examples of pharmaceutically acceptable diluent include non-crystalline 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 surfactant may be selected from a commonly used surfactant, including sodium stearyl fumarate, magnesium stearate, talc, glyceryl fatty acid ester, glycerol dibehenate, etc. And, pharmaceutically acceptable coating agent includes polyvinyl alcohol, hydroxypropylmethylcellulose, 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 based on 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

90 g of clopidogrel free base was put in a 1-L beaker, and a solution of 350 mL distilled water and 15 mL sulfuric acid was added. The mixture was dissolved by stirring at room temperature. Undissolved remainder was removed with filter paper. In a 10-L reactor containing 7 L of distilled water and 15 mL of sulfuric acid,

480.5 g of β-cyclodextrin was added. The mixture was dissolved by stirring, while heating to 60 ⁰C. After cooling to 50 ⁰C, the filtrate, that is, the clopidogrel sulfuric acid solution was slowly added for 30 minutes. After stirring for 3 hours at 50 ⁰C, the temperature was decreased to 30 ⁰C. While stirring, the mixture was neutralized by slowly adding 1.12 L of 1 N NaOH solution for 30 minutes. After stirring at room temperature for 18 hours, the resultant solid was filtered under reduced pressure and washed with 700 mL of distilled water. The product was dried in vacuum for 24 hours to obtain 360 g of white solid compound [Figure I].

Clopidogrel : β-cyclodextrin = 1 : 1.2 (equivalence ratio)

¹H-NMR (300 MHz, DMSO-d₆) 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), 5.72 (d, 8.4H), 5.67 (d, 8.4H), 4.86 (s, IH), 4.83 (d, 8.4H), 4.45 (t, 8.4H), 3.70 (s, 3H), 3.50-3.69 (m, 36H), 3.26-3.38 (m, 30H), 2.77-2.84 (m, 4H) Example 2: Preparation of inclusion complex of clopidogrel and β-cyclodextrin

10 g (19 %) of clopidogrel premix (Dr. Reddy's Premix) was put in a 100-mL flask, and a solution of 8.5 mL distilled water and 0.35 mL sulfuric acid was added. After stirring at room temperature for 30 minutes, undissolved remainder was removed with filter paper. In a 250-mL flask containing 150 mL of distilled water and 0.35 mL of sulfuric acid, 10.13 g of β-cyclodextrin was added. The mixture was dissolved by stirring, while heating to 60 ⁰C. After cooling to 50⁰C, the filtrate, that is, the clopidogrel sulfuric acid solution was slowly added for 30 minutes. After stirring for 3 hours at 50⁰C, the temperature was decreased to 30⁰C. While stirring, the mixture was neutralized by slowly adding 23.64 mL of 1 N NaOH solution for 30 minutes. After stirring at room temperature for 18 hours, the resultant solid was filtered under reduced pressure and washed with 15 mL of distilled water. The product was dried in vacuum for 24 hours to obtain 7.4 g of white solid compound [Figure 2].

Clopidogrel : β-cyclodextrin = 1 : 1.5 (equivalence ratio)

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 7.58-7.61 (m, IH), 7.49-7.51 (m, IH), 7.35-7.42 (m, 2H), 7.26 (d, IH, J = 5.1 Hz), 6.76 (d, IH, J = 5.1 Hz), 5.72 (d, 10.5H), 5.68 (d, 10.5H), 4.87 (s, IH), 4.82 (d, 10.5H), 4.45 (t, 10.5H), 3.70 (s, 3H), 3.50-3.69 (m, 44H), 3.26-3.38 (m, 33H), 2.76-2.84 (m, 4H) Example 3: Preparation of inclusion complex of clopidogrel and β-cyclodextrin

126.0 g of clopidogrel bisulfate was dissolved in 300 mL of distilled water. In a

10-L reactor containing 6.9 L of distilled water, 460.8 g of β-cyclodextrin was added. The mixture was dissolved by stirring, while heating to 50 ⁰C. Then, the clopidogrel solution was slowly added for 30 minutes. After stirring for 3 hours at

50 ⁰C, the temperature was decreased to 25 ⁰C. While stirring, the mixture was neutralized by slowly adding 240 mL of 2.5 N NaOH solution for 30 minutes. After stirring at room temperature for 10 hours, the resultant solid was filtered under reduced pressure and washed with 700 mL of distilled water. The product was dried in vacuum for 24 hours to obtain 382.94 g of white solid compound [Figure 3].

Clopidogrel : β-cyclodextrin = 1 : 1.0 (equivalence ratio)

¹H-NMR (300 MHz, DMSO-d₆) 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), 5.72 (d, 7H), 5.67 (d, 7H), 4.86 (s, IH), 4.83 (d, 7H), 4.45 (t, 7H), 3.70 (s, 3H), 3.50-3.69 (m, 30H), 3.26-3.38 (m, 26H), 2.77-2.84 (m, 4H)

Examples 4-7: Preparation of inclusion complex containing film-coated tablet The ingredients and excipients listed in Table 1 below were prepared into granule using a roller compactor (TF-LABO, Freund). Thus obtained granule was passed through a No. 18 sieve, mixed with surfactant, and prepared into circular tablet using a single tablet press making machine (Erweka). The coating agent was dissolved in purified and coated using a coating machine (SFC-30N, Sejong Machinery) to obtain a film-coated tablet. [Table 1]

Experimental Example 1: Stability test

Stability test was performed for the clopidogrel inclusion complexes prepared in Examples 1 to 3 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 racernization product R-isomer [formula (3)] - is given in Table 2 below.

Chiral HPLC was performed to identify the impurities and optical purity, 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 2]

Stability test (3 weeks)

As shown in Table 1, the inclusion complexes prepared in Examples 1 to 3 exhibited better stability than clopidogrel bisulfate (Plavix), with fewer impurities. Experimental Example 2: Blood level measurement after oral administration to rats

The inclusion complex prepared in Example 1 [formula (I)] and clopidogrel bisulfate [formula (2)] were orally administered to Sprague-Dawley rats (250 to 270 g) at a dose of 30 mg/kg (base). After 0.5₇ 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 mL 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 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 HPLC column. Liquid chromatography was performed, and blood level was measured from the peak area ratio of clopidogrel to the internal standard.

[Table 3] Blood level after oral administration to rats at a dose of 30 mg/kg

0.5 4.8 + 1.8 3.2 + 1.3

1 5.7 ± 2.5 2.8 ± 1.0

2 3.6 + 1.0 2.0 + 0.7

4 5.2 + 2.0 2.4 + 0.9

6 4.2 ± 1.2 1.7 + 0.7

8 2.9 ± 1.2 1.5 + 0.5

10 2.8 ± 1.4 1.2 + 0.5

24 0.5 ± 0.2 0.4 ± 0.1

AUCo-inf 61.94 ± 23.67 33.20 + 11.53

⁽—max 6.08 ± 2.26 3.20 + 1.25

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

As shown in Table I₁ the inclusion complex of the present invention exhibited comparable to or better pharmacological parameters compared to clopidogrel bisulfate, following oral administration to rats.

Experimental Example 3: Stability test

Stability test was performed for the clopidogrel inclusion complex tablets prepared in Examples 5 and 6 and commercially available Plavix tablet (Sanofi- Synthelabo Korea). In accordance with the ICH (International Conference on

Harmonization) guideline, long-term storage test was performed at 25 ⁰C and 60 % RH_x and accelerated test (open) at 40⁰C and 75 % RH.

Analysis was performed according to USP 3215-3216. Most of the impurities were hydrolysis product (RRT 0.5, impurity A) and R-isomer (RRT 2.0, impurity C) (RRT: relative retention time). USP states that impurity A should be less than 0.2 %, impurity C less than 1.0 %, unknown impurity less than 0.1 %, and total impurities less than 1.2 %. The increase of impurities from the initial value is presented in Table 4 below. [Table 4] Stability test (open, 3 weeks)

As shown in Table 4, the tablets prepared in Examples 5 and 6 exhibited superior stability than commercially available Plavix tablet, with less increase in impurities A and C.

Experimental Example 4: Dissolution rate test The clopidogrel inclusion complex containing tablet prepared in Example 5 and commercially available Plavix 75 mg tablet (Sanofi-Synthelabo Korea) were tested according to dissolution test method described in Korean Pharmacopoeia (the paddle method). Dissolution test was performed under pH 2.0 condition as described in United States Pharmacopoeia (USP 29). Volume of the effluent was 1000 L and the paddle rpm was 50 rpm.

Dissolution test was performed for 5, 10, 15, 30 and 45 minutes. 4 mL of the eluate was taken and passed through 0.45-μm membrane filter to be sued as test solution. Analysis was performed by absorption spectrophotometry. Detection wavelength was 240 nm. As shown in Figure 2, the tablet prepared in accordance with the present invention showed comparable dissolution rate to that of commercially available Plavix.

[Industrial Applicability] As stated above, 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 can endure the variations of temperature and humidity of the production process without being decomposed. When compared with existing drugs, it is expected to extend the life cycle and product 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 : 1.0 to 1 : 2.0:

CO₂CH₃

[Claim 2]

A method of preparing an inclusion complex containing clopidogrel comprising:

1) dissolving clopidogrel in distilled water or acidic aqueous solution;

2) adding the resultant solution to distilled water or acidic aqueous solution containing 1.0 to 2 equivalents of β-cyclodextrin based on 1 equivalent of clopidogrel at 30 to 70 ⁰C while stirring;

3) neutralizing the resultant product with alkali metal hydroxide at 0 to 50 ⁰C; 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 base is a free base, a premix, an adsorbate or a solid dispersion of clopidogrel.

[Claim 5]

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

[Claim 6]

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