KR20070002702A - Composition containing clopidogrel free base - Google Patents

Abstract

A composition containing a clopidogrel free base is provided to enhance the release rate and stability of clopidogrel free base at high pH by using acid and pharmaceutically acceptable diluents, so that bioavailability of clopidogrel free base is improved and arteriosclerotic symptoms are treated. The composition contains a clopidogrel free base, an acid and a pharmaceutically acceptable diluent, wherein the composition further contains antioxidant selected from BHT(butylated hydroxytoluene), BHA(butylated hydroxyanisole), ascorbic acid, EDTA(ethylene diamine tetra-acetic acid) and sodium pyrosulfite; the clopidogrel free base and acid are in a type of solid dispersion prepared by dissolving and drying them; the acid is fumaric acid, citric acid, malic acid, oxalic acid, succinic acid or adipic acid; and the diluents is colloidal silica for adsorbing the clopidogrel free base.

Description

Clopidogrel free base containing composition {Composition containing clopidogrel free base}

The present invention relates to a composition containing clopidogrel free base.

Clopidogrel is the generic name for methyl (+)-(S)-(2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate, or stroke, myocardial infarction or It is used to improve atherosclerotic symptoms in patients with peripheral arterial disease. The free base of clopidogrel has a problem in absorption (bioavailability) because the solubility decreases rapidly as the pH of the medium rises, so that it is almost insoluble in purified water and pH 4.0 buffer, and in some cases, the clopidogrel free base is in the oil phase. There is a problem that handling and formulation are not easy because it is obtained.

Considering the results of studies that typically have an intragastric pH range of about 1 to 3.5 in normal adults and about 16% of adults having an intragastric pH above pH 3, the formulation should be designed so that the solubility of clopidogrel does not change significantly even with normal intragastric pH fluctuations. The design and evaluation of controlled release systems for the gastro-intestinal tract, In advances in drug delivery systems, Amsterdam, 1986, pp. 27-38). In other words, in order to improve the bioavailability of clopidogrel, it is necessary to design a composition which does not degrade the solubility even in the normal gastric pH fluctuation with the increase in the solubility of the drug itself.

The present this problem is to some extent overcome the pharmaceutically acceptable acid addition salt of clopidogrel is clopidogrel hydrogen sulphate as Plavix ^® - it is commercially available in the trade name (Co., Sanofi sinderabo, South Korea). However, it is important to minimize potential side effects when taking medications, and from this point of view it is not desirable to take clopidogrel with hydrogen sulfate, which forms a salt. In addition, clopidogrel hydrogen sulfate is usually prepared through an additional reaction to the clopidogrel free base has the disadvantage of requiring the formation of a salt containing a problem of increasing the manufacturing cost, wherein the salt is isolated for analytical evaluation of the finished formulation containing There is a hassle to do.

Therefore, the technical problem to be achieved by the present invention is to provide a clopidogrel free base-containing composition having a high dissolution rate, easy to mass production, and secured stability using a clopidogrel free base.

In order to achieve the above technical problem, the present invention provides a clopidogrel free base-containing composition comprising a clopidogrel free base, an acid and a pharmaceutically acceptable excipient (diluent). .

More preferably, the present invention provides a clopidogrel free base-containing composition, characterized in that the composition further comprises an antioxidant.

More preferably, the present invention is characterized in that the antioxidant is selected from the group consisting of BHT (butylated hydroxy toluene), BHA (butylated hydroxy anisole), ascorbic acid, EDTA and sodium pyrosulfite It provides a clopidogrel free base-containing composition, characterized in that any one or more.

More preferably, the present invention provides a clopidogrel free base-containing composition, characterized in that the clopidogrel free base and acid are dissolved together and dried to form a solid dispersion.

More preferably, the present invention provides a clopidogrel free base-containing composition, characterized in that the acid is any one or more selected from the group consisting of fumaric acid, citric acid, malic acid, oxalic acid, succinic acid and adipic acid.

More preferably, the present invention provides a clopidogrel free base-containing composition, wherein the acid is citric acid, succinic acid or a mixture thereof.

More preferably, the present invention provides a clopidogrel free base-containing composition, wherein the excipient is colloidal silica for adsorbing clopidogrel free base.

Hereinafter, the clopidogrel free base containing composition of this invention is demonstrated more concretely.

The present invention provides a clopidogrel free base-containing composition, characterized in that it contains clopidogrel free base, an acid and a pharmaceutically acceptable excipient. The clopidogrel free base has a sharp drop in solubility as the pH of the medium rises. The acid present in the composition of the present invention makes the surrounding environment of the clopidogrel free base to maintain a high dissolution rate even in a solution having a relatively high pH.

Acids contained in the composition of the present invention include fumaric acid, citric acid, malic acid, oxalic acid, succinic acid, adipic acid, tartaric acid, lactic acid, ascorbic acid, maleic acid, aspartic acid, glutamic acid, palmitic acid, chitosan, alginic acid, and manic acid. One or more organic acids and inorganic acids such as hydrochloric acid, phosphoric acid and acetic acid may be used, but is not limited thereto.

Difficulty aspects of preparation, taking into account the smell of acid (eg hydrochloric acid), solubility (eg manic acid), viscosity (eg chitosan and alginic acid); Safety aspects taking into account safety (eg, propionic acid, sulfuric acid and salicylic acid), and the like; Degree of dissolution rate improvement of the clopidogrel free base-containing composition (eg, boric acid); And fumaric acid, citric acid, malic acid, succinic acid, adipic acid or mixtures thereof are preferred in view of the stability (eg, tartaric acid) of the clopidogrel free base containing composition. In addition, citric acid, succinic acid, or mixtures thereof are more preferable in consideration of the problems of solvent selection (eg fumaric acid, adipic acid, etc.) and the properties of the composition (eg malic acid).

The excipients used in the present invention are used for the purpose of dilution or increase in order to adsorb clopidogrel free base or mixed with clopidogrel free base to facilitate handling, and to prepare tablets, capsules and the like. Pharmaceutically acceptable excipients may include, but are not limited to, starch, microcrystalline cellulose, sorbitol, mannitol, sucrose, silicon dioxide, spray dried lactose, anhydrous lactose, calcium dihydrogen phosphate, anhydrous dibasic calcium phosphate, or mixtures thereof. It is not. As the excipient, silicon dioxide having high adsorptivity, particularly colloidal silica, is preferable.

As a result of confirming the stability of the clopidogrel free base-containing composition having the same ingredients and contents except for the adsorption excipient, the composition obtained by adsorbing clopidogrel free base using only colloidal silica was used simultaneously with microcrystalline cellulose and / or hydroxypropylmethylcellulose. It was superior in stability to the composition adsorbed by. When the prepared composition was adsorbed using only colloidal silica when stored at 40 ° C. and 75% RH for 6 weeks, the content did not decrease at all, whereas the composition adsorbed using additional microcrystalline cellulose was initially compared after 6 weeks. The content of 6.4%, adsorbed with the addition of microcrystalline cellulose and hydroxypropylmethylcellulose, decreased the content of 10.3% after 6 weeks. These results indicate that microcrystalline cellulose and hydroxypropylmethylcellulose may adversely affect the contents of clopidogrel free base, whereas colloidal silica plays a role in maintaining stability of the clopidogrel free base containing composition of the present invention. do.

The clopidogrel free base and acid of the present invention are preferably contained in the composition of the present invention in the form of a solid dispersion. That is, the present invention provides a composition comprising a clopidogrel free base-containing solid dispersion, wherein the clopidogrel free base and the acid are uniformly dispersed therein. The acid is uniformly distributed around the clopidogrel free base in the solid dispersion of the present invention to maintain the microenvironment in an acidic state, and maintain the microenvironment in the dissolution medium to maintain a high dissolution rate even in a high pH solution. For this reason, the composition of the present invention containing clopidogrel free base and acid in the form of a solid dispersion has a higher dissolution rate than a simple physical mixture, and also has a high dissolution rate at a certain time.

The clopidogrel free base-containing composition of the present invention may further include a polymer which helps to maintain the form of the solid dispersion for a long time. Examples of the polymer that can be used in the solid dispersion of the present invention include hydroxypropyl cellulose and hydride. Roxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose , Hydroxyethylmethylcellulose, carboxymethylcellulose, polyvinylacetate, polyalkene oxide, polyalkeneglycol, polyoxyethylene-polyoxypropylene polymer (poloxamer ™), zein, shellac, diethylaminoacetate (AEA ™) , Aminoalkylmethacrylate copolymers (Euradgit E ™), sodium alginate, Acid, gelatin, gum (Gum), poly -L- lysine or a mixture thereof, but may be used, and the like. Considering the solubility of polymers and the ease of solid dispersion formation, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol airborne Preference is given to using coalescing or mixtures thereof.

More preferably, the present invention provides a clopidogrel free base-containing composition, characterized in that it contains clopidogrel free base, an acid, an antioxidant and a pharmaceutically acceptable excipient.

Specifically, the present invention provides the fact that the clopidogrel free base contained in the composition of the present invention is unstable under certain conditions such as heat, moisture, and the like, and that the instability can be improved by adding an antioxidant. In particular, the clopidogrel-containing composition has a problem in that the dissolution rate is lowered when a certain amount of heat and moisture are applied as well as the content decrease during storage.

Antioxidants that can be used in the compositions of the present invention include BHT (butylated hydroxy toluene), BHA (butylated hydroxy anisole), ascorbic acid, EDTA, sodium pyrosulfite or mixtures thereof May be used, but is not limited thereto.

Clopidogrel free base-containing compositions of the present invention, in addition to the components described above, conventional disintegrating agents, excipients, flavoring agents, coloring agents, for preparing oral dosage forms (e.g. tablets, granules, capsules, pellets), It may further include excipients such as lubricants, fillers.

In the clopidogrel free base-containing composition of the present invention, when the clopidogrel free base and an acid are included in the form of a solid dispersion, the solid dispersion may include preparing a solution in which the clopidogrel free base and the acid are dissolved; It may be prepared by a manufacturing method comprising a; and drying the prepared solution. As a solvent for preparing the solution, water, ethanol, methanol, isopropyl alcohol, dichloromethane, chloroform, acetone, or a mixture thereof may be used, but is not limited thereto. The drying may be used a conventional drying method using hot air, spray drying is preferred in terms of mass production. Spray drying may be performed using a fluidized bed granulator, spray dryer, C / F granulator, or the like.

The present invention also provides a step of preparing a solution in which (S1) clopidogrel free base and acid are dissolved; (S2) adsorbing the solution to colloidal silica to prepare a mixture; (S3) drying the mixture; And (S4) mixing the dried mixture with a pharmaceutically acceptable excipient to formulate a clopidogrel free base-containing composition.

More preferably, the present invention provides a method for producing a clopidogrel-containing composition, characterized in that the antioxidant is further dissolved in the solution of step (S1).

More preferably, the present invention provides a method for producing a clopidogrel free base-containing composition, further comprising the step of concentrating a reduced pressure solution of the clopidogrel free base and an acid in between (S1) and (S2). do.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the scope of the present invention is not limited by the following embodiments, and the following embodiments are provided by way of example to describe the present invention more specifically to those skilled in the art. Will be.

<Production of Comparative Example 1>

An acid-free clopidogrel freebase containing composition was prepared. After mixing 10 g of clopidogrel and 1.5 g of colloidal silica in 20 ml of ethanol, 15 g of microcrystalline cellulose was further mixed thereto. The mixture was then dried at 40 ° C. until the loss on drying was about 2%. After drying, it is established as a 30 mesh sieve, and 3 g of sodium starch glycolate and 0.2 g of magnesium stearate are added and mixed evenly, followed by content evaluation by the following method. 75 mg of clopidogrel free base per tablet is obtained. It was contained, and tableted with a tableting machine (KI-1300, Kisan Machinery, Korea) to have a hardness of about 10 Kp.

In the content test, a solution of 27.2 mg of hydrogen sulfate clopidogrel standard was accurately taken as a standard solution, dissolved in methanol, and the total amount was adjusted to 50 ml. Finally, 10 ml of this solution was diluted to 50 ml with methanol. Was used. The content of clopidogrel free base included in the sample was measured and calculated relative to the standard solution using liquid chromatography (HPLC). The sample solution was prepared by taking 20 tablets, turning it to powder, dissolving about 320 mg accurately, dissolving it in methanol, and then adding the total amount to 200 ml. Finally, 10 ml of this solution was added to make 50 ml. Hereinafter, all content evaluations were performed using the same content test standards in a similar manner.

<Evaluation of Commercial Preparation Agent and Comparative Example 1>

The dissolution rate of Flavix ^® (Sanopy-Cinderabo, Korea) and Comparative Example 1, which are clopidogrel hydrogen sulfate salts, were evaluated by the following method. The elution medium was dissolved in water, pH 2.0 buffer [0.157 g of KCl, 119 ml of 0.1 M HCl, 1,000 ml of water] and pH 4.0 buffer [700 g of 6.8 g of KH ₂ PO ₄ , dissolved in phosphoric acid]. The pH was adjusted to 4.0 and then 1,000 ml of water was used. The test was conducted under paddle (50 rpm) and elution mass of 900 ml according to the KEPCO dissolution test method.

After the content was measured, the amount of clopidogrel free base eluted at each time compared to the initial content was set forth in Table 1 as an initial content of 100.

(unit: %) Commercially available Comparative Example 1 pH 2.0 pH 4.0 water pH 2.0 pH 4.0 water 30 minutes 94.1 64.8 71.0 101.0 15.9 6.2 120 minutes - 74.2 81.4 - 40.7 13.5 240 minutes - 76.8 83.0 - 54.8 15.6

As shown in Table 1, commercial preparations containing clopidogrel hydrogen sulfate showed a good dissolution rate in the dissolution test using pH 2.0 buffer, pH 4.0 buffer and water as the medium, whereas the composition of Comparative Example 1 was in pH 2.0 buffer Contrary to the high dissolution rate of, the dissolution rate was low in pH 4.0 buffer and water.

Preparation of Example 1-3

Examples 1 to 3 were prepared with the ingredients and contents shown in Table 2 below. Specifically, raw materials 1 and 2 were added to about 40 ml of ethanol and mixed well, followed by concentration under reduced pressure at a temperature of 40 ° C. until the total volume was reduced by about 50%. To this, raw materials 3 and 4 were added and mixed evenly, and the mixture was dried at 40 ° C. until the loss on drying was about 2%. After drying, the mixture was stipulated as a 30 mesh sieve, and then the raw materials 5 and 6 were mixed and mixed well. In the acid (equivalent) means the equivalent of the acid contained relative to the content of the clopidogrel free base as the main component.

(Unit: g) Example 1 Example 2 Example 3 One Clopidogrel 10 10 10 2 Fumaric acid 7.2 (2 equivalents) - - Tartaric acid - 9.3 (2 equivalents) - Citric acid - - 6.0 (1 equivalent) 3 Hydroxypropylmethylcellulose 15 - - Microcrystalline cellulose - 15 15 4 Colloidal silica 1.5 1.5 1.5 5 Sodium starch glycolate 3 3 3 6 Magnesium stearate 0.2 0.2 0.2

<Elution evaluation of Example 1-3>

The clopidogrel free base-containing tablet prepared in Example 1-3 was subjected to the dissolution test in the same manner as the dissolution test method of Comparative Example 1. The results are shown in Table 3.

(unit:%) Example 1 Example 2 Example 3 pH 2.0 pH 4.0 water pH 2.0 pH 4.0 water pH 2.0 pH 4.0 water 30 minutes 98.1 42.9 48.2 96.9 68.1 68.5 102.4 67.4 62.2 120 minutes - 66.9 74.5 - 81.3 80.8 - 81.9 74.1 240 minutes - 74.6 83.9 - 83.1 84.2 - 82.5 76.0

As shown in Table 3, the clopidogrel free base-containing composition of the present invention showed a dissolution rate far superior to that of Comparative Example 1 containing no acid, and particularly, when water was used as the dissolution medium, the dissolution rate improvement effect was excellent.

Preparation of Example 4-10

To prepare Examples 4-10 with the ingredients and contents shown in Table 4. Specifically, 1st raw material, 2nd raw material (2 equivalents to clopidogrel free base) and 3rd raw material were added to 40 ml of ethanol and mixed evenly, and then concentrated under reduced pressure at a temperature of 40 ° C. until the total volume was reduced by about 50%. It was. Raw material No. 4 and raw material No. 5 were added thereto and mixed evenly, and the mixture was dried at 40 ° C. until the loss on drying content was about 2%. After drying, the mixture was stipulated as a 30 mesh sieve, and then 6 and 7 raw materials were mixed and mixed well.

(Unit: g) Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 One Clopidogrel 10 10 10 10 10 10 10 2 Tartaric acid 9.3 - - - - - - Citric acid - 12.0 - - - - - Malic acid - - 8.34 - - - - Oxalic acid - - - 7.8 - - - Succinic acid - - - - 7.3 - - Adipic acid - - - - - 9.1 - Phosphoric Acid - - - - - - 7.2 3 BHT 0.5 0.5 - 0.5 0.5 0.5 0.5 Ascorbic acid - - 0.5 - - - - 4 HPMC 15 - - - - - - MCC - 15 5 5 5 5 5 5 SiO ₂ 1.5 1.5 10 10 10 10 10 6 Disintegrant 3 3 3 3 3 3 3 7 Mg-stearate 0.2 0.2 0.2 0.2 0.2 0.2 0.2 BHT: Butylated hydroxy toluene (antioxidant) HPMC: Hydroxypropylmethylcellulose (excipient) MCC: Microcrystalline cellulose (excipient) SiO ₂ : Colloidal silica Disintegrant: Sodium starch glycolate mg-stearate: Magnesium stearate

<Elution evaluation of Example 4-10>

The clopidogrel free base-containing tablet prepared in Example 4-10 was subjected to the dissolution test in the same manner as the dissolution test method of Comparative Example 1. The results are shown in Table 3.

unit:% Example 4 Example 5 Example 6 pH 2.0 pH 4.0 water pH 2.0 pH 4.0 water pH 2.0 pH 4.0 water 30 minutes 97.6 66.7 68.7 101.9 70.1 73.2 103.9 - 69.2 120 minutes - 81.4 80.8 - 81.0 83.2 - - 80.8 240 minutes - 82.5 82.6 - 84.4 83.3 - - 81.9 Example 7 Example 8 Example 9 pH 2.0 pH 4.0 water pH 2.0 pH 4.0 water pH 2.0 pH 4.0 water 30 minutes 99.1 - 75.7 105.3 - 54.4 102.0 - 37.7 120 minutes - - 84.1 - - 67.1 - - 51.1 240 minutes - - 84.6 - - 68.5 - - 53.2 Example 10 pH 2.0 pH 4.0 water 30 minutes 102.7 - 72.0 120 minutes - - 79.7 240 minutes - - 86.2

As shown in Table 5, the clopidogrel free base-containing composition of the present invention using various kinds of acids showed an excellent dissolution rate compared to Comparative Example 1. However, the dissolution rate improvement effect was different according to the type of acid added. The use of adipic acid showed the least effect of dissolution rate improvement.

In addition, when comparing the dissolution test results of Example 2 and the dissolution test results of Example 4 of Table 3, it can be seen that the addition of antioxidant has little effect on the dissolution rate.

Preparation of Example 11-16

In order to evaluate the degree of dissolution improvement according to the amount of acid contained compared to clopidogrel free base, Examples 11-16 were prepared using the ingredients and contents shown in Table 6 below. Specifically, the first raw material and the second raw material were added to 40 ml of ethanol and mixed evenly, and then concentrated under reduced pressure at a temperature of 40 ° C. until the total volume was reduced by about 50%. To this, raw materials 3 and 4 were added and mixed evenly, and the mixture was dried at 40 ° C. until the loss on drying was about 2%. After drying, the mixture was stipulated as a 30 mesh sieve, and then the raw materials 5 and 6 were mixed and mixed well.

(Unit: g) Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 One Clopidogrel 10 10 10 10 10 10 2 Citric acid 12 6 3 1.8 1.2 0.6 3 MCC 5 5 5 5 5 - 4 SiO ₂ 10 10 10 10 10 10 5 Disintegrant 3 3 3 3 3 3 6 Mg-streate 0.2 0.2 0.2 0.2 0.2 0.2 MCC: microcrystalline cellulose (excipient) SiO ₂ : colloidal silica disintegrant: sodium starch glycolate mg-stearate: magnesium stearate

<Elution evaluation of Example 11-16>

The clopidogrel free base-containing tablet prepared in Example 11-16 was subjected to the dissolution test in the same manner as the dissolution test method of Comparative Example 1. The results are shown in Tables 7 and 8.

<pH 2.0> Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 30 minutes 103.5 102.2 106.2 99.3 101.6 100.3

<Water> Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 30 minutes 79.3 61.6 47.2 35.8 29.7 24.1 120 minutes 90.3 73.6 51.3 37.5 32.7 24.4 240 minutes 91.5 76.2 51.2 37.0 32.1 24.3

As shown in Table 8, the dissolution rate in water also decreased as the amount of citric acid contained decreased.

Preparation of Example 17-18

In order to evaluate the degree of dissolution improvement according to the amount of acid contained compared to clopidogrel free base, Examples 17-18 were prepared using the ingredients and contents shown in Table 9 below. Example 17-18 was prepared by the same method as the preparation method used in Example 4.

(Unit: g) Example 10 Example 17 Example 18 One Clopidogrel 10 10 10 2 Phosphoric Acid 22.4 11.2 5.6 3 BHT 0.5 0.5 0.5 4 MCC 5 5 5 5 SiO ₂ 10 10 10 6 Disintegrant 3 3 3 7 Mg-stearate 0.2 0.2 0.2 BHT: Butylated hydroxy toluene (antioxidant) MCC: Microcrystalline cellulose (excipient) SiO ₂ : Colloidal silica Disintegrant: Sodium starch glycolate mg-stearate: Magnesium stearate

<Elution evaluation of Examples 10, 17 and 18>

The clopidogrel free base-containing tablets prepared in Examples 10, 17 and 18 were subjected to the dissolution test in the same manner as the dissolution test method of Comparative Example 1. The results are shown in Table 10 and Table 11.

<pH 2.0> Example 10 Example 17 Example 18 30 minutes 102.7 104.8 104.9

<Water> Example 10 Example 17 Example 18 30 minutes 72.0 53.3 35.9 120 minutes 84.9 62.8 40.2 240 minutes 86.2 64.5 41.7

As shown in Table 11, the dissolution rate in water also decreased as the amount of phosphoric acid contained decreased.

Preparation of Example 19-23

Examples 19-23 were prepared to evaluate the effects of antioxidants and the effects of preparation methods. Examples 19-21 were prepared by the same method as the preparation method used in Example 4.

Examples 22 and 23 were prepared as follows. Raw material No. 1 was evenly mixed with raw material No. 4 and raw material No. 5, and the mixture was dried at 40 ° C. until loss on drying was about 2.0%. After drying, the mixture was stipulated as a 30 mesh sieve, and then the raw material No. 2, the No. 6 material and the No. 7 material were added, mixed well, and then compressed into tablets as in Comparative Example 1 to obtain 75 mg of clopidogrel free base per tablet.

(Unit: g) Example 6 Example 19 Example 20 Example 21 Example 22 Example 23 One Clopidogrel 10 10 10 10 10 10 2 Malic acid 8.34 8.34 8.34 - - 8.34 Citric acid - - - 9.0 9.0 - 3 BHA - - 0.3 - - - Na ₂ S ₂ O ₅ - 0.3 - - - - Ascorbic acid 0.5 - _- 0.5 - _- 4 MCC 15 15 5 5 5 5 5 SiO ₂ 3 3 10 10 10 10 6 Disintegrant 3 3 3 3 3 3 7 Mg-stearate 0.2 0.2 0.2 0.2 0.2 0.2 BHA: Butylated hydroxy toluene (antioxidant) Na ₂ S ₂ O ₅ : Sodium pyrosulfite (antioxidant) MCC: Microcrystalline cellulose (excipient) SiO ₂ : Colloidal silica disintegrant: Sodium starch glycolate mg -stearate: magnesium stearate

<Elution evaluation of Example 6 and 19-23>

The clopidogrel free base-containing tablets prepared in Examples 6 and 19-23 were subjected to the dissolution test using water as the dissolution medium in the same manner as the dissolution test method of Comparative Example 1. The results are shown in Table 13.

<Water> Example 6 Example 19 Example 20 Example 21 Example 22 Example 23 30 minutes 69.2 67.8 72.9 61.8 41.4 41.8 120 minutes 80.8 79.4 84.6 74.7 62.4 62.0 240 minutes 81.9 80.2 84.9 76.6 70.8 70.1

As shown in Table 13, when comparing Examples 6, 19 and 20, there was little difference in dissolution rate according to the type of antioxidant. However, as can be seen by comparison between Example 21 and Example 22, or Example 6 and Example 23, dissolution rate is higher when dissolving clopidogrel free base and acid together to prepare a solid dispersion by drying it Good to know. This is believed to form a solid dispersion in which the acid is finely distributed around the clopidogrel free base during dissolution and drying process, and thus, it shows a better dissolution rate even in the case of a composition having similar components.

Preparation of Example 24-31

To evaluate the effect of antioxidants on the stability of clopidogrel freebase-containing compositions according to the present invention, the compositions of Examples 24-31 were prepared according to the ingredients and contents shown in Table 14 below. Specifically, the first raw material, the second raw material and the third raw material were added to 40 ml of ethanol, and the mixture was evenly mixed and concentrated under reduced pressure at a temperature of 40 ° C. until the total volume was reduced by about 50%. The raw material was added thereto 4 times, mixed evenly, and the mixture was dried at 40 ° C until the loss on drying content was about 2%. After drying, the mixture was stipulated as a 30 mesh sieve, and then 5 and 6 raw materials were mixed and tableted as in Comparative Example 1 to obtain 75 mg of clopidogrel free base per tablet.

(Unit: g) Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 One Clopidogrel 10 10 10 10 10 10 10 10 2 Citric acid 9 9 9 9 - - - - Succinic acid - - - - 7.3 7.3 7.3 7.3 3 BHT 0.5 0.1 0.5 0.2 0.5 0.1 0.5 0.2 4 SiO ₂ 11 11 11 11 11 11 11 11 5 Disintegrant 3 3 3 3 3 3 3 3 6 Lubricant 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 BHT: Butylated hydroxy toluene (antioxidant) MCC: Microcrystalline cellulose (excipient) SiO ₂ : Colloidal silica Disintegrant: Sodium starch glycolate Glidant: Magnesium stearate

<Stability Evaluation of Example 24-31>

The clopidogrel free base-containing composition prepared in Example 24-31 was subjected to stability experiments under severe conditions (60 ° C., 75% relative humidity). The results are shown in Table 15 below. The content of clopidogrel free base remaining at each time point is expressed in% relative to the initial content.

Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 3 days 95.2 84.8 84.8 84.7 - 97.3 92.9 86.3 9th 90.8 63.0 61.5 62.1 97.6 95.4 90.5 82.6 14 days 72.6 51.2 50.5 51.6 95.6 92.3 85.3 80.2

As shown in Table 14, as the amount of antioxidant increased, the stability under severe conditions also increased.

In addition, it can be seen from the results of Table 14 that the stability of the clopidogrel free base-containing composition varies depending on the type of acid, and the stability of the composition using succinic acid is better than that of the composition using citric acid.

Preparation of Example 32-34

The effect of antioxidants on the dissolution rate stability of clopidogrel containing compositions was evaluated. Examples 32-34 were prepared using the same preparation method as Example 24 with the ingredients and contents shown in Table 16 below.

(Unit: g) Example 32 Example 33 Example 34 One Clopidogrel 10 10 10 2 Citric acid 9 - - Malic acid - 8.3 - Succinic acid - - 7.3 3 BHT 0.5 0.5 0.5 4 SiO ₂ 11 11 11 5 Disintegrant 3 3 3 6 Lubricant 0.2 0.2 0.2 BHT: Butylated hydroxy toluene (antioxidant) SiO ₂ : Colloidal silica disintegrant: Sodium starch glycolate lubricant: Magnesium stearate

<Elution Evaluation of Examples 32-34 and Plavix ^®>

Dissolution experiments were carried out in the same manner as in Comparative Example 1 after storing the composition of the present invention prepared in Examples 32-34 and Flavix ^® at 60 ° C., 75% relative humidity for 4 weeks. The results are shown in Table 17 and Table 18.

<pH 2.0> Example 32 Example 33 Example 34 Flavix 30 minutes 55.6 24.9 84.7 22.7

<Water> Example 32 Example 33 Example 34 Flavix 30 minutes 31.9 17.6 33.5 17.6 120 minutes 41.6 20.6 48.5 34.0 240 minutes 45.7 21.7 54.6 35.8

As can be seen from the results of Tables 16 and 17, the compositions of the present invention showed a better dissolution rate than the commercially available Flavix ^® even after storage for 4 weeks in harsh conditions. When comparing the dissolution rates of Examples 5 (using citric acid), Example 6 (using citric acid) and Example 8 (using zucchini acid) with similar prescription, the dissolution rate stability of the clopidogrel free base-containing composition of the present invention using succinic acid was excellent. It was.

Preparation of Example 35-40

To evaluate the effect of the type of antioxidant on the stability of the clopidogrel free base-containing composition according to the present invention, the composition of Example 35-40 was prepared using the same preparation method as in Example 24 with the ingredients and contents shown in Table 19 below. Prepared.

(Unit: g) Example 35 Example 36 Example 37 Example 38 Example 39 Example 40 One Clopidogrel 10 10 10 10 10 10 2 Malic acid 8.3 8.3 8.3 8.3 8.3 8.3 3 BHT 0.3 - - - - - BHA - 0.3 - - - - Ascorbic acid - - 0.3 - - - EDTA - - - 0.3 - - SP - - - - 0.3 - 4 SiO ₂ 11 11 11 11 11 11 5 Disintegrant 3 3 3 3 3 3 6 Lubricant 0.2 0.2 0.2 0.2 0.2 0.2 BHT: Butylated hydroxy toluene (antioxidant) BHA: Butylated hydroxy anisole (antioxidant) SP: Sodium pyrosulfite (antioxidant) MCC: Microcrystalline cellulose (excipient) SiO ₂ : Colloidal silica boron Release: Sodium starch glycolate Glidant: Magnesium stearate

<Stability Evaluation of Example 35-40>

Stability experiment was performed under the conditions of acceleration (40 ° C., 75% RH) with the clopidogrel free base-containing composition prepared in Example 35-40. The results are shown in Table 20 below. The content of clopidogrel free base remaining at each time point is expressed in% relative to the initial content.

Example 35 Example 36 Example 37 Example 38 Example 39 Example 40 start 100 100 100 100 100 100 1 week 96.6 96.8 97.1 96.9 96.5 90.1 2 weeks 95.6 94.2 96.5 95.8 95.2 83.1

As shown in Table 20, it can be seen that the composition of Example 35-40 to which the antioxidant is added is much more stable than Example 40 to which the antioxidant is not added. From these results, it can be seen that the clopidogrel free base-containing composition improves stability by adding an antioxidant.

The present invention provides a clopidogrel free base, a composition containing clopidogrel free base, an acid and a pharmaceutically acceptable excipient, and more preferably clopidogrel free base, an acid, an antioxidant and a pharmaceutically acceptable excipient. It provides a clopidogrel free base-containing composition comprising a. The clopidogrel free base-containing composition of the present invention not only has a good dissolution rate but also excellent stability in a medium having a high pH.

Claims (7)

A clopidogrel free base containing composition, characterized in that it contains clopidogrel free base, an acid and a pharmaceutically acceptable excipient. The clopidogrel free base-containing composition of claim 1, wherein the composition further comprises an antioxidant. The method of claim 2 wherein the antioxidant is selected from the group consisting of BHT (butylated hydroxy toluene), BHA (butylated hydroxy anisole), ascorbic acid, EDTA and sodium pyrosulfite Clopidogrel free base-containing composition, characterized in that one or more. The clopidogrel free base-containing composition according to claim 1, wherein the clopidogrel free base and the acid are dissolved together and dried to be contained in the form of a solid dispersion. The clopidogrel free base-containing composition according to claim 1, wherein the acid is at least one selected from the group consisting of fumaric acid, citric acid, malic acid, oxalic acid, succinic acid, and adipic acid. The clopidogrel free base-containing composition according to claim 5, wherein the acid is citric acid, succinic acid or a mixture thereof. 2. The clopidogrel free base-containing composition according to claim 1, wherein the excipient is colloidal silica for adsorbing clopidogrel free base.