KR20080055356A - Inclusion complex of clopidogrel and beta-cyclodextrin - Google Patents

Abstract

An inclusion complex of clopidogrel with high hygroscopy is provided to improve storage stability of clopidogrel by using beta-cyclodextrin, so that clopidogrel is easily formulated to inhibit aggregation of platelet. An inclusion complex of clopidogrel represented by the formula(1) contains the clopidogrel and beta-cyclodextrin in an equivalent ratio of 1:2.0-2.5, and is prepared by (1) solubilizing clopidogrel in a mixed solution of organic solvent and acidic solution or distilled water; (2) adding 2.0-2.5 equivalent based on 1 equivalent of clopidogrel of beta-cyclodextrin into the solution of step (1), and stirring the mixture at 30-70 deg. C, (3) neutralizing the reaction product with hydroxide of alkali metal at 0-50 deg. C, and (4) filtering, washing and drying the reaction product, wherein in the step (2), water-soluble polymer is added. An anti-platelet aggregation composition comprises the inclusion complex of clopidogrel and beta-cyclodextrin. Further, the clopidogrel is clopidogrel base or clopidogrel salt.

Description

Inclusion complex of clopidogrel and beta-cyclodextrin}

1 shows inclusion of one molecule of clopidogrel and two molecules of beta cyclodextrin.

Figure 2 shows a powder X-ray diffraction pattern of the clopidogrel clathrate of Example 1 (Powder X-ray Diffractogram),

3 is a graph comparing the dissolution rate of the clopidogrel clathrate complex-containing tablet of Example 11 and a commercially available formulation.

The present invention relates to a clopidogrel-containing clathrate complex having excellent storage stability, and more particularly, S-(+)-clopidogrel (methyl (+)-(S) -α- (o-chlorophenyl)) represented by the following Chemical Formula 1 -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate) reacts with beta cyclodextrin in a specific equivalent ratio to form a pharmaceutical formulation that is pharmaceutically stable and suitable for formulation formulation. And a platelet aggregation inhibitor composition containing the same as an active ingredient.

Recent studies have reported that clopidogrel is a very effective platelet aggregation inhibitor with a greater effect of blocking platelet aggregation and less effect on the gastrointestinal tract at lower doses than aspirin. Clopidogrel is currently sold under the trade name Flavix, which contains about 98 mg of clopidogrel hydrogen sulfate and contains 75 mg of the active ingredient clopidogrel base.

European Patent No. 0281459 proposes the use of (S)-(+)-clopidogrel-hydrogen sulfate in pharmaceutical formulations more specifically in inorganic salts of (S)-(+)-clopidogrel. Since the active ingredient clopidogrel base is an oily liquid, it is necessary to convert it into a pharmaceutically acceptable salt in order to prepare a convenient formulation. The patent mentions taurocholate, hydrogen chloride and bromate as salts suitable for the preparation of clopidogrel formulations with hydrogen sulphate. The patent also discloses organic salts of clopidogrel, but these organic salts are described as being amorphous and / or hygroscopic as well as difficult to purify.

However, other patents published later claim that sulfonic acid can be prepared as a salt whose stability is secured to a level close to hydrogen sulfate.

International published patents 2004/072084 and 2004/072085 suggest that it is suitable for the preparation of pharmaceutical preparations under certain conditions in sulfonic acids, in particular benzosulfonic acids, of organic salts which are mentioned in European Patent No. 0281459 as not suitable for formulation. It is mentioned that solvates containing toluene or dioxane solvents are preferred as crystalline clopidogrel besylate, and that further drying to remove the solvent breaks the crystal structure, resulting in an amorphous clopidogrel besylate. .

International Patent Publication No. 2005/103059 and Korean Patent Publication No. 2005-0099445 disclose clopidogrel napadisilate, a novel crystalline salt of clopidogrel, which is optically pure, heat stable, and non-hygroscopic, or polycrystalline polyhydrate thereof. And solvates. However, these sulfonic acid salts of clopidogrel have a very low solubility or a phenomenon that clopidogrel base is precipitated as an oil in aqueous solution, and has a disadvantage of poor light stability compared to conventional hydrogen sulfates.

A particularly important factor in dealing with salts of clopidogrel is hygroscopicity. The high hygroscopicity of pharmaceutical ingredients can affect the physicochemical properties of the active ingredient and excipients, which in turn can cause problems in formulation formulation. Therefore, control of hygroscopicity in formulation preparation should be managed as an important factor along with packaging or storage methods. Especially in the case of clopidogrel, even if the base itself is an oily liquid and made of hydrogen sulfate, which is known as the most preferred salt, impurities may be produced by hydrolysis or racemization by the external environment. In general, the most commonly produced impurities are those produced by hydrolysis of methyl esters (Formula 2) and racemization reactions to increase the content of R-(-)-isomers of Clopidogrel (Formula 3).

These flexible materials should be well managed to ensure that their contents are below the appropriate standards in a series of processes for the manufacture and processing of pharmaceutical raw materials in large quantities, and should be important for formulation, packaging and storage.

Accordingly, the present inventors have studied to solve the hygroscopicity and stability problems of clopidogrel raw material itself, and as a result, by reacting clopidogrel with cyclodextrin in a specific equivalent ratio to prepare an inclusion complex (inclusion complex) by the free base (not acid-addition salt) The present invention was completed by demonstrating excellent stability as a free base and providing suitable physical properties for formulation formulation.

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

The present invention is characterized by a clopidogrel-containing clathrate complex and a method for producing the same having excellent storage stability including clopidogrel and beta cyclodextrin represented by the following formula (1) in an equivalent ratio of 1: 2.0 to 2.5.

[Formula 1]

In addition, the platelet aggregation inhibitor composition containing the inclusion complex as an active ingredient.

The present invention will be described in detail as follows.

The present invention relates to S-(+)-clopidogrel (methyl (+)-(S) -α- (o-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine represented by Formula 1). -5 (4H) -acetate) is reacted with beta cyclodextrin in a specific equivalent ratio to a pharmaceutical composition which is pharmaceutically stable and suitable for preparation of a formulation and its use as an platelet aggregation inhibitor composition containing it as an active ingredient.

First, the process of preparing a clopidogrel-containing clathrate complex according to the present invention will be described in detail.

Step 1) dissolves clopidogrel using a mixture of an organic solvent and an acidic solution or distilled water. The acidic solution used here is an organic acid and an inorganic acid, preferably hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid. The organic solvent uses one or two or more selected from acetone, ethanol, isopropanol and butanol.

Clopidogrel used in the present invention means clopidogrel free base or clopidogrel salt, and clopidogrel salt includes clopidogrel bisulfate, clopidogrel hydrochloride, clopidogrel bromate, or clopidogrel benzenesulfonate Etc. are preferable. Clopidogrel as used herein is also possible in another form of clopidogrel, such as a mixture of clopidogrel free base or clopidogrel salt with pharmaceutically usable additives and excipients (Premix or Adsorbate). In this step, the insoluble and precipitated additives are removed by filtration, and then the reaction is performed using the filtrate, Clopidogrel acid solution.

 Step 2) is stirred at 30-70 ° C. while adding beta cyclodextrin. The stirring is carried out in a temperature range of 30 to 70 ℃, preferably at 40 to 60 ℃. If the stirring temperature is less than 30 ℃ the amount of the solvent for dissolving the cyclodextrin is increased and there is a disadvantage that the inclusion efficiency is lowered, when the temperature exceeds 70 ℃ is not preferable because there is a problem that the drug is decomposed.

Step 3) neutralizes the base by adding a base to the reactant. As a base material, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide are used. At this time, the neutralization reaction is carried out at 0 to 50 ℃, more preferably 10 to 40 ℃. When the neutralization temperature is less than 0 ℃, there is a problem that the supercooled to precipitate together with the impurities other than the inclusions or cyclodextrin in the non-inclusion state, there is a problem that the content of the flexible material is higher than 50 ℃.

Step 4) is a step of preparing the inclusion complex by filtration, washing and drying the reactants. The filtrate obtained by filtration is washed several times with a small amount of cold water and dried to obtain the final inclusion complex in high yield.

In step 2), a water-soluble polymer compound may be included and dissolved. Such water-soluble polymer compounds include polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), carboxymethyl cellulose (CMC), and hydroxypropyl cellulose (HPC). , One or two or more selected from hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropylmethyl cellulose (HPMC) and hydroxypropylethyl cellulose (HPEC).

The beta cyclodextrin used in the present invention includes all of the beta cyclodextrin derivatives in addition to the beta cyclodextrin, and preferably, beta cyclodextrin or a derivative thereof having a pupil diameter of 6.0 to 6.5 mm 3 is suitable.

As for beta cyclodextrin, it is preferable to use 2.0-2.5 equivalents with respect to 1 equivalent of clopidogrel. The present inventors attempted to confirm the optimum inclusion ratio through the inclusion experiments of various equivalent ratios of clopidogrel and beta cyclodextrin. When beta cyclodextrin is used more than twice as much as the equivalent of clopidogrel base, the efficiency of the inclusion reaction is maximized to make it uniform and stable. It was found that the inclusion of the state was formed. This is because the thienopyridine part and the chlorobenzene part of clopidogrel may be structurally enclosed with one molecule of the beta cyclodextrin, as shown in FIG. 1, which shows the inclusion of one molecule of clopidogrel and two molecules of beta cyclodextrin. This is because cyclodextrin can ensure optimum stability when the ratio of 1: 2 is maintained.

However, it has been pointed out that when the amount of beta cyclodextrin exceeds 2.5 equivalents, the amount of beta cyclodextrin is excessively large compared to the clopidogrel base having pharmacological activity, thus greatly increasing the total volume when preparing the tablet. Accordingly, the present inventors made the ratio of beta cyclodextrin to drug based on the molar ratio of clopidogrel base to the amount of beta cyclodextrin required for inclusion to be 1: 2.5 or less. Through a series of procedures, when the amount of beta cyclodextrin, distilled water, and the amount of base required for neutralization reaction is properly adjusted, it is possible to obtain a clathrate close to 1: 2.0 to 2.5 in high yield. Confirmed.

The clopidogrel inclusion complex was confirmed to have a characteristic diffraction pattern when measured by a powder X-ray diffraction (PXRD) instrument. PXRD was used as M18XHF22 from Mac science, and measured under the condition of 20 mA, 40 kV, 3 ~ 35 2θ.

The inclusion complex thus obtained has excellent storage stability against temperature and humidity of the raw material itself, so that it can be stored for a long time, is easy to manufacture a formulation, and can withstand the effects of temperature and humidity that may occur during the production process without being degraded. It could be confirmed.

We conducted various inclusion studies using beta cyclodextrins to find a composition that is superior to known salts of clopidogrel. Through this process, the present inventors confirmed that the inclusion complex obtained when appropriate reaction conditions are satisfied and maintained is a novel composition of clopidogrel which is excellent in physicochemical properties and is pharmaceutically useful even if it is not in the form of a salt. This is in contrast to previous results, where clopidogrel base was an oily liquid and was able to form a stable form of salt only by extremely limited acid salts, demonstrating that it is possible to prepare a composition suitable for formulation formulation even if it is not a salt by inclusion reaction. will be. In addition, the inclusion complexes thus obtained are unexpectedly excellent in stability and not hygroscopic, which makes them suitable for preparing the formulation of clopidogrel.

The present inventors have determined the following items as conditions to be provided as an optimal clopidogrel-containing composition and tried to identify them.

First, there should be no hygroscopicity. As a result of preparing various types of clopidogrel salts prior to the present invention, the clopidogrel base itself is an oily liquid, which is difficult to react, and in many cases, it does not precipitate as a salt even under various solvent conditions. Many cases of discoloration or melting were observed. In addition, if it is hygroscopic, clopidogrel is hygroscopic after being formed into a composition by a clathrate reaction because various flexible materials can be produced, including the hydrolyzate (formula 2) and R-isomer (formula 3), which are the main flexible materials. It is preferable not to have

Second, long-term storage stability should be good. The excellent physical and chemical properties of the raw materials themselves are not only beneficial for formulation studies, but also have many advantages at each stage of pharmaceutical manufacturing, including packaging and storage. We measured long term storage stability for the compositions invented. At the same time, the formation and content changes of hydrolysates and R-isomers, which are important soft substances to be managed, were compared and compared with known salts and clathrates of clopidogrel and beta cyclodextrin proposed by the present invention. In addition, stability tests under various harsh conditions were made and compared with known salts.

Third, it should be easy to handle in mass manufacturing and formulation studies. To this end, as mentioned above, the hygroscopicity and stability should be good, and the preparation should be easy and the purification process should be easy.

When formulated using the clopidogrel-containing clathrate complex according to the present invention satisfying the above conditions, it was confirmed that the yield and purity of the precipitated clathrate were very high and both physical and chemical properties mentioned above were satisfied.

Therefore, the method for preparing a platelet aggregation inhibitor composition containing the inclusion complex according to the present invention as an active ingredient is as follows.

A pharmaceutical preparation for oral administration may be prepared by mixing a conventionally acceptable pharmaceutically acceptable diluent, binder, disintegrant, lubricant, coating agent, etc., preferably as tablets, hard capsules, powders, and granules. Is possible. The pharmaceutically acceptable diluent includes microcrystalline cellulose, corn starch and the like, and the binder may be appropriately selected from among commonly used binders such as povidone, copovidone, and celluloses. In addition, the disintegrant is preferably croscarmellose sodium, sodium starch glycolate, calcium carboxymethyl cellulose, and the like, and the lubricant is stearyl sodium fumarate, magnesium stearate, talc, glyceryl fatty acid esters, glycerol dibehenate, etc. These are generally appropriately selected from the glidants used. In addition, the pharmaceutically acceptable coating agent preferably contains polyvinyl alcohol, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose and the like.

Effective dosages of clopilogrel-containing clathrate complexes vary depending on the patient's age, degree of disease, etc., but are generally administered at a dose of 30 to 300 mg, preferably 30 to 150 mg, more preferably 75 mg, based on the clopidogrel base per day. Can be.

Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1 Preparation of Inclusions of Clopidogrel and Beta Cyclodextrin

1.6 g (5 mmol) of clopidogrel base was dissolved in 5 ml of acetone, 0.3 ml of concentrated sulfuric acid was added, and the mixture was slowly stirred at room temperature for 5 minutes. 160 ml of distilled water was added and 12.8 g of beta cyclodextrin was added slowly with stirring at 60 ° C. and stirred at 60 ° C. for 3 hours. 2 ml of 2.5 N NaOH solution was added thereto, stirred at room temperature for 3 hours, and the resulting solid was filtered and washed with 16 ml of distilled water. The product was vacuum dried for 20 hours to give 7.79 g of a white solid compound. This compound was analyzed by HPLC to confirm that it is an inclusion complex of clopidogrel and beta cyclodextrin. In addition, X-ray diffraction pattern measurement results showed a characteristic diffraction angle at 5.96, 12.98 2θ [Fig. 2].

Clopidogrel: Beta Cyclodextrin = 1: 2.0 Equivalent Ratio

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 7.57-7.60 (m, 1H), 7.48-7.52 (m, 1H), 7.36-7.41 (m, 2H), 7.26 (d, 1H, J = 5.1 Hz), 6.76 (d, 1H, J = 5.1 Hz), 5.74 (d, 14H), 5.67 (d, 14H), 4.86 (s, 1H), 4.83 (d, 14H), 4.45 (t, 14H), 3.70 (s, 3H), 3.50-3.69 (m, 58H), 3.26-3.38 (m, 36H), 2.77-2.82 (m, 4H)

Example 2 Preparation of Inclusions of Clopidogrel and Beta Cyclodextrin

2.1 g (5 mmol) clopidogrel bisulfate is dissolved in 5 ml of distilled water, and 195 ml of distilled water is added to dissolve at room temperature. 12.8 g of beta cyclodextrin was added thereto, and the temperature was gradually raised to 60 ° C. and stirred for 3 hours. After slowly lowering the temperature to room temperature, 2 ml of 2.5 N NaOH solution was added thereto, stirred at room temperature for 5 hours, and the resulting solid was filtered and washed with 20 ml of distilled water. The product was vacuum dried for 20 hours to obtain 7.80 g of a white solid compound. This compound was analyzed by HPLC to confirm that it is an inclusion complex of clopidogrel and beta cyclodextrin.

Clopidogrel: Beta Cyclodextrin = 1: 2.05 Equivalent Ratio

Example 3 Preparation of Inclusions of Clopidogrel and Beta Cyclodextrin

5 ml of distilled water was dissolved in 2.1 g (5 mmol) clopidogrel bisulfate, and the solution was dissolved in 12.8 g of beta cyclodextrin and 195 ml of distilled water suspension, and the temperature was gradually raised to 60 ° C and stirred for 3 hours. After slowly lowering the temperature to room temperature, 2 ml of 2.5 N NaOH solution was added thereto, stirred at room temperature for 5 hours, and the resulting solid was filtered and washed with 20 ml of distilled water. The product was vacuum dried for 20 hours to obtain 8.30 g of a white solid compound. This compound was analyzed by HPLC to confirm that it is an inclusion complex of clopidogrel and beta cyclodextrin.

Clopidogrel: Beta Cyclodextrin = 1: 2.07 Equivalent Ratio

Example 4 Preparation of Inclusions of Clopidogrel and Beta Cyclodextrin

1.6 g (5 mmol) of clopidogrel base was dissolved in 5.0 ml of acetone, 0.3 ml of concentrated sulfuric acid was added, and the mixture was slowly stirred at room temperature for 5 minutes. 200 ml of 1% HPMC aqueous solution was added and 14.08 g of beta cyclodextrin was added slowly with stirring at 60 ° C., and stirred at 60 ° C. for 3 hours. 2 ml of 2.5 N NaOH solution was added and stirred at room temperature for 3 hours. The resulting solid was filtered and washed with 20 ml of distilled water. The product was vacuum dried for 20 hours to obtain 9.53 g of a white solid compound. This compound was analyzed by HPLC to confirm that it is an inclusion complex of clopidogrel and beta cyclodextrin.

Clopidogrel: Beta Cyclodextrin = 1: 2.09 Equivalent Ratio

Example 5: Preparation of Inclusions of Clopidogrel and Beta Cyclodextrin

1.6 g (5 mmol) of clopidogrel base was dissolved in 5.0 ml of acetone, 0.3 ml of concentrated sulfuric acid was added, and the mixture was slowly stirred at room temperature for 5 minutes. 200 ml of 1% PVP aqueous solution was added thereto, and 14.08 g of beta cyclodextrin was added thereto while stirring slowly at 60 ° C., and stirred at 60 ° C. for 3 hours. 2 ml of 2.5 N NaOH solution was added and stirred at room temperature for 3 hours. The resulting solid was filtered and washed with 20 ml of distilled water. The product was vacuum dried for 20 hours to give 10.72 g of a white solid compound. This compound was analyzed by HPLC to confirm that it is an inclusion complex of clopidogrel and beta cyclodextrin.

Clopidogrel: Beta Cyclodextrin = 1: 2.11 Equivalent Ratio

Test Example 1: Stability Test

The raw material stability test was carried out for the clopidogrel inclusion complex of Examples 1 to 5 and clopidogrel bisulfate (Doctor Ready), and a comparative test was conducted at 40 ° C. and 75% RH. The contents of the hydrolyzate (Chemical Formula 2), the R-isomer produced by racemization (Chemical Formula 3), and the total analogues, which are the main analogues of clopidogrel, are measured and shown in Table 1 below.

In this experiment, chiral HPLC using the following conditions was used to view the analog and the optical purity.

STILL PHASE: ULTRON ES-OVM Column, 5 μm (4.6 mm × 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: 17 ℃

UV detection wavelength: 220 nm

Injection volume: 10 μl

As shown in Table 1, it was confirmed that the clathrate composite material of Examples 1 to 5 has a superior effect on stability by reducing the total amount of the flexible material compared to clopidogrel bisulfate which is a raw material of the plavix.

Test Example 2 Measurement of Blood Level after Oral Administration of Test Substances in Rats

The clathrate complex (Compound 1) and Clopidogrel bisulfate (Compound 2) of Example 1 were orally administered to Sprague-Dawley rats (250 to 270 g) at a dose of 30 mg / kg (base) 0.5, 1 Blood samples were collected with heparin-treated pipettes at 2, 4, 6, 8, 10 and 24 hours. The collected blood was immediately centrifuged at 12,000 rpm for 2 minutes to obtain plasma, and 100 mL of internal standard solution was added to 0.1 mL of plasma, followed by 0.6 mL of diethyl ether-hexane (80:20, v / v). ), A mixed solvent was added. The extract was shaken for about 5 minutes and then centrifuged at 2,000 g for 10 minutes. The organic solvent layer was taken, transferred to a clean test tube, and the organic solvent was volatilized under a nitrogen stream. 50 μl of the mobile phase was added to the residue, 20 μl of the composition was recombined, injected into an HPLC column, tested by liquid chromatography, and blood concentration was measured using the peak area ratio of clopidogrel to the peak area of the internal standard obtained therein.

As shown in Table 2 above, Compound 1 obtained more than or equal to Compound 2 in pharmacokinetic parameters after oral administration to rats.

Examples 6 to 9: Preparation of Film Coating Tablet Containing Inclusion Composite

Next, the granules were prepared using a high-shear mixer [SM-5, Sejong Machinery Co., Ltd.] using the ingredients and the excipient composition and contents of Table 3, and the granules obtained by drying them were used as the No. 30 sieve. After the lubricant was mixed, a circular tablet was obtained using a single tablet press (ERWEKA). The coating base was dissolved in purified water and coated using a coating machine [SFC-30N, Sejong Machinery] to obtain a film coating tablet.

Examples 10 to 11: Preparation of film-coated tablets containing clathrate composite

With the same raw materials and excipient composition and content as in Example 6 and Example 8 of Table 3, the inlet temperature of the fluidized bed granulator [DPL-1, Mendel Korea] was about 65 ° C and the outlet temperature was about 40 ° C. While maintaining, the spray amount was adjusted to 10 ml / min, and the spray pressure was 0.8 kg / cm ² to obtain granules. The obtained granules were sized in No. 30 and used, and after lubricating agent was mixed, circular tablets were obtained using a single tablet press (ERWEKA). The coating base was dissolved in purified water and coated using a coating machine [SFC-30N, Sejong Machinery] to obtain a film coating tablet.

Test Example 3: Stability Test

The stability test of the clopidogrel clathrate tablets of Examples 6, 8, and 10 and the commercially available Flavix tablet [Sanopy-Sinderabo Korea] were conducted, and the conditions were long-term preservation tests in the same manner as the International Conference on Harmonization (ICH) guidelines. Was carried out at 25 ℃, 60% RH conditions, accelerated test was carried out by an open test at 40 ℃, 75% RH conditions.

The analytical method was carried out using the method of USP 3215 ~ 3216, and the flexible material was hydrolyzate (RRT 0.5, Impurity A) and R-isomer (RRT 2.0, Impurity C) when compared with relative holding time (RRT). ) Is found in most lead substances, the USP states that impurity A should occur below 0.2%, impurity C below 1.0%, unknown impurity below 0.1%, and total lead below 1.2%. The results are shown in Table 4 as the amount of increase in lead substances relative to the initial value.

As shown in Table 4, it was confirmed that the tablet of the Example has an excellent effect on stability by decreasing the amount of increase in impurity A and C than the tablet of the commercial formulation. That is, it was found that the storage stability was improved in the case of the preparation according to the present invention than the commercial preparation.

Test Example 4: Dissolution rate test

The clopidogrel clathrate complex containing tablet of Example 8 and the commercially available Flavix 75 mg tablet [Sanopy-Sinderabo Korea] were tested in accordance with the Korean Pharmacopoeia Dissolution Test Method 2 method paddle method. The dissolution test was carried out under the pH 2.0 condition of the US Pharmacopeia (USP 29), the eluent was used for 1000 ㎖, the paddle rotation speed was carried out at 50 rpm.

The dissolution test was performed for 5, 10, 15, 30 and 45 minutes, and 4 ml of the eluate was taken and filtered using a 0.45 μm membrane filter to obtain a sample solution. The assay was tested according to the absorbance spectrometry and the wavelength was measured at 240 nm. As shown in Figure 3, through the dissolution test with a commercial formulation, the formulation of the present invention also demonstrated that the dissolution rate is equivalent.

As described above, the clopidogrel-containing clathrate composite according to the present invention can be stored for a long time by ensuring excellent storage stability of the raw material itself, easy to manufacture the formulation, and does not decompose under the influence of temperature and humidity that may occur during the production process. It can withstand the effect. In addition, existing formulations and drug dissolutions will remain the same, resulting in longer product warranty and longer product value.

Claims (6)

A clopidogrel-containing clathrate having excellent storage stability, characterized in that it comprises clopidogrel and beta cyclodextrin represented by the following formula (1) in an equivalent ratio of 1: 2.0 to 2.5. [Formula 1]

1) dissolving clopidogrel in a mixed solution of an organic solvent and an acidic solution or distilled water; 2) stirring at 30 to 70 ° C. while adding beta cyclodextrin in a ratio of 2.0 to 2.5 equivalents based on 1 equivalent of clopidogrel to obtain a reactant; 3) neutralizing the reactant with a hydroxide of an alkali metal at 0 to 50 ° C .; And 4) A method for producing a clopidogrel-containing clathrate complex, comprising the step of filtering, washing and drying the reactant to produce a clathrate complex. The method of claim 2, wherein the clopidogrel is a clopidogrel base or clopidogrel salt. 4. The inclusion complex according to claim 3, wherein the clopidogrel salt is clopidogrel bisulfate, clopidogrel hydrochloride, clopidogrel bromate, or clopidogrel benzenesulfonate. The method according to claim 2, wherein the water-soluble polymer is added in 2). Platelet aggregation inhibitor composition comprising the inclusion complex of claim 1 as an active ingredient.

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