KR20130013157A - Solid dispersion containing cilostazol and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a solid dispersion of cilostazol and a polymethacrylate copolymer, comprising: a solid dispersion that significantly increases the solubility of a water-soluble drug cilostazol; And pharmaceutical compositions containing the same. The pharmaceutical composition can achieve high bioavailability by rapidly releasing cilostazol from the beginning in the physiological aqueous medium, thus reducing the dosage and thus high safety can be expected.

Description

Solid dispersion containing cilostazol and pharmaceutical composition comprising the same {Solid dispersion containing cilostazol and pharmaceutical composition comprising the same}

The present invention relates to a solid dispersion containing cilostazol and a pharmaceutical composition comprising the same, and more particularly, to a solid dispersion of cilostazol and a polymethacrylate copolymer, which is a water-soluble drug. Solid dispersions that significantly increase the solubility of stazoles; And to pharmaceutical compositions containing the same. The pharmaceutical composition can achieve high bioavailability by rapidly releasing cilostazol from the beginning in a physiological aqueous medium, thus reducing the dosage and thus high safety can be expected.

Cilostazol has a structure of formula (1), the chemical name of which is 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) -butoxy] -3,4-dihydro-2 (1H) ) Quinolinone. Cilostazol is a representative inhibitor of the activity of cAMP PDE (cyclic AMP phosphodiesterase) in cells, has the effect of inhibiting platelet aggregation and promoting blood vessel relaxation, and exhibits antitumor action, antihypertensive action and anti-inflammatory action. Therefore, it is widely used as an antithrombotic agent, central blood circulation improver, anti-inflammatory agent, anti-tumor agent, blood pressure lowering agent, anti-asthma agent, and is also used for prevention and treatment of cerebral infarction and improvement of brain circulation.

≪ Formula 1 >

On the other hand, cilostazol is a representative water-soluble drug having a solubility in aqueous solution of 3.34 μg / mL and an octanol / water partition coefficient of about 200, and is a BCS (Biopharmaceutics Classification System) Class II, that is, low solubility and high permeability. Drugs classified into a group of drugs having a. Accordingly, there is a need in the art for pharmaceutical methods to improve low dissolution rates in aqueous media, particularly physiological aqueous media, due to the poorly water-soluble properties of cilostazol.

For example, US Pat. No. 6,388,080 discloses various polymorphic and amorphous forms for improving the physicochemical properties of the cilostazol raw material itself (API). Since the sol raw material itself requires complicated treatment such as temperature raising / cooling, it is difficult to apply the sol raw material itself at the production site.

As a pharmaceutical method for improving the water-solubility property of cilostazol, Patel and Rajput et al. Have disclosed preparation of clathrate compounds using cyclodextrins (Patel, SG and Rajput, SJ (2009) Enhancement of Oral bioavailability of cilostazol by forming its inclusion complexes, AAPS Pharm SciTech. 10 (2), 660-669), dissolution rate of cilostazol is only twice that of the raw material, which is still unsatisfactory.

In addition, the Republic of Korea Patent Publication No. 10-2009-0122344 prepared a solubilizer such as sodium lauryl sulfate and cilostazol as solid dispersion granules to improve the wettability of cilostazol, and then, such as hydroxypropylmethylcellulose A cilostazol controlled release formulation dispersed in an erosive hydrogel forming material has been disclosed. However, the Republic of Korea Patent Publication No. 10-2009-0122344 design a solid dispersion granules form to improve the wettability, that is, control the release rate of the drug, there is a limit in improving the fundamental water-soluble properties of cilostazol.

In addition, Korean Patent Publication No. 10-2010-0027337 and Korean Patent Publication No. 10-2007-0024254 disclose a sustained-release tablet using hydroxypropylmethylcellulose or the like as a release control agent.

The present inventors have tried various pharmaceutical methods to develop a method for increasing the solubility of cilostazol, and as a result, the cilostazol is converted into a solid dispersion form using a specific copolymer, that is, a polymethacrylate copolymer. When prepared, it was found that the solubility in physiological aqueous media (eg, aqueous buffer at pH6.8) can be increased up to 14 times or more. In addition, the pharmaceutical composition formulated with the solid dispersion obtained as described above can achieve high bioavailability by rapidly releasing cilostazol from the beginning in a physiological aqueous medium, thus reducing the dosage and thus high safety. It was found that can be expected.

Accordingly, an object of the present invention is to provide a solid dispersion of cilostazol and a polymethacrylate copolymer having high solubility.

In addition, an object of the present invention is to provide an oral pharmaceutical composition comprising the solid dispersion.

According to one aspect of the invention, a solid dispersion of cilostazol and a polymethacrylate copolymer is provided.

The polymethacrylate copolymer may be a copolymer of methacrylic acid and methyl methacrylate; Copolymers of methacrylic acid and ethyl acrylate; Ammonio methacrylate copolymers; And butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, and copolymers of methyl methacrylate. Preferably, the polymethacrylate copolymer is a copolymer of 1 part by weight of methacrylic acid and 1 part by weight of methyl methacrylate; Copolymers of 1 part by weight of methacrylic acid and 2 parts by weight of methyl methacrylate; And a copolymer of 1 part by weight of butyl methacrylate, 2 parts by weight of (2-dimethylaminoethyl) methacrylate, and 1 part by weight of methyl methacrylate, and more preferably meta And a copolymer of 1 part by weight of methacrylic acid and 1 part by weight of methyl methacrylate and a copolymer of 1 part by weight of methacrylic acid and 2 parts by weight of methyl methacrylate. In the solid dispersion according to the present invention, the weight ratio of the cilostazol and the polymethacrylate copolymer may be in the range of 1: 0.5 to 20.

Solid dispersion of the present invention is hydroxypropyl methyl cellulose; Polyvinylpyrrolidone; Crospovidone; And a polymer selected from the group consisting of a copolymer of vinylpyrrolidone and vinyl acetate, and may further include a copolymer of vinylpyrrolidone and vinyl acetate.

According to another aspect of the present invention, there is provided an oral pharmaceutical composition comprising the solid dispersion and a pharmaceutically acceptable additive.

The cilostazol-containing solid dispersion according to the invention can increase the solubility of cilostazol in a physiological aqueous medium (eg, an aqueous buffer at pH6.8) by up to 14 times or more. In addition, the solid dispersion exhibits excellent stability by maintaining the amorphous form without changing the cilostazol in the solid dispersion into a crystalline form at all even if stored for a long time. In particular, the oral pharmaceutical composition containing the solid dispersion can achieve high bioavailability by rapidly releasing cilostazol from the beginning in the physiological aqueous medium, thus reducing the dosage and thus high safety. You can expect.

1 is a result of evaluating the thermal properties using DSC of the solid dispersion (Example 5), the physical mixture (Comparative Example 1) and the cilostazol raw material powder according to the present invention.
Figure 2 is a result of measuring the change in the endothermic peak using DSC while storing the solid dispersion (Example 5) according to the invention at room temperature for 1 month, 2 months, 5 months, 6 months.
3 is a tablet prepared from a solid dispersion according to the present invention (Example 7), a tablet prepared from a physical mixture (Comparative Example 9), a tablet prepared from a sodium lauryl sulfate-containing solid dispersion (Comparative Example 10) , And commercially available formulations ("Pretal tablet (cilostazol: 100 mg)", Otsuka Pharmaceutical Co., Ltd.) are the results of dissolution test in physiological aqueous medium.

The present invention provides a solid dispersion of cilostazol and a polymethacrylate copolymer.

It has been found by the present invention that cilostazol can form a solid dispersion with a polymethacrylate copolymer, and furthermore, that cilostazol in the solid dispersion does not change into a crystalline form at all and maintains an amorphous form stably. It turned out. In particular, the solid dispersion can increase the solubility of cilostazol in a physiological aqueous medium (eg, an aqueous buffer at pH6.8) by up to 14 times or more.

In the present specification, the term "solid dispersion" refers to a form in which cilostazol is in an amorphous form and evenly dispersed in a polymethacrylate copolymer, and is a simple form of cilostazol and polymethacrylate copolymer. It is distinguished from the mixture. The solid dispersion may be prepared using a conventional solid dispersion production method, for example, a melting method or a solvent evaporation method, preferably by a solvent evaporation method. Preparation of the solid dispersion by the solvent evaporation method may be performed by dissolving cilostazol and polymethacrylate copolymer in an appropriate solvent, for example, an organic solvent such as methanol, and then drying by spray drying or the like. have.

In the present invention, the cilostazol may be in the form of a pharmaceutically acceptable salt, and unless otherwise stated herein, "cilostazol" refers to pharmaceutically acceptable cilostazol as well as cilostazol. Possible salts are included. In the solid dispersion according to the present invention, the cilostazol may be used in a therapeutically effective amount, for example in a unit dosage form (ie, an oral pharmaceutical composition containing the solid dispersion). The sugar may be used in the range of 25 to 200 mg, but is not limited thereto. In addition, pharmaceutical compositions formulated using the solid dispersions according to the invention can achieve high bioavailability by rapidly releasing cilostazol from the outset, so even at low dosages (i.e., low content per unit dosage form). It can exhibit the same level of bioavailability as the conventional formulation. Those skilled in the art will be able to readily determine the amount of cilostazol used in the solid dispersions and pharmaceutical compositions comprising the same, in consideration of the desired level of bioavailability.

The polymethacrylate copolymer is a copolymer of methacrylic acid and methyl methacrylate (copolymer of methacrylic acid and methyl methacrylate); Copolymers of methacrylic acid and ethyl acrylate; Ammonio methacrylate copolymer; And butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, and a copolymer of methyl methacrylate (copolymer of butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate). Can be selected. Preferably, the polymethacrylate is a copolymer of methacrylic acid and 1 part by weight of methyl methacrylate 1 parts by weight of a copolymer [e.g., Eudragit ^TM L100 (Eudragit ^TM L100), etc.]; Methacrylic acid 1 part by weight and 2 parts by weight of methyl methacrylate copolymer [e.g., Eudragit ^TM S100 (S100 Eudragit ^TM), etc.]; And 1 part by weight of butyl methacrylate, (2-dimethylaminoethyl) methacrylate, 2 parts by weight of methyl methacrylate and 1 part by weight of the copolymer [e.g., Eudragit E100 ^{TM (TM} Eudragit E100) and so on; It may be selected from the group consisting of one or more. More preferably, the polymethacrylate copolymer is methacrylic acid, 1 part by weight of methyl methacrylate 1 parts by weight of a copolymer [e.g., Eudragit ^TM L100 (Eudragit ^TM L100), etc.] and methacrylic acid 1 parts by weight of methyl methacrylate, 2 parts by weight of the copolymer [e.g., Eudragit ^TM E100 (Eudragit ^TM E100), etc.] may be a mixture, the mixing ratio (by weight) from 1: 0.5 to 1.5, preferably It may range from about 1: 1.

In the solid dispersion according to the present invention, the weight ratio of the cilostazol and the polymethacrylate copolymer may be in the range of 1: 0.5 to 20, preferably 1: 2 to 10. When the weight of the polymethacrylate copolymer is less than 0.5 part by weight based on 1 part by weight of cilostazol, it is difficult to expect improvement in the solubility of cilostazol, and when the amount exceeds 20 parts by weight, the resulting formulation (solid dispersion and The pharmaceutical composition containing the same) may be too large in size and amount, resulting in poor patient compliance.

The solid dispersions of the present invention may also comprise additional polymers, which may contribute to the solubility improvement of cilostazol as needed. That is, the solid dispersion of the present invention is in addition to the polymethacrylate copolymer hydroxypropyl methyl cellulose; Polyvinylpyrrolidone; Crospovidone; And a polymer selected from the group consisting of a copolymer of vinylpyrrolidone and vinyl acetate, and may further include a copolymer of vinylpyrrolidone and vinyl acetate. The amount of the additional polymer used may range from 1: 0.5 to 10, preferably from 1: 1 to 5, based on 1 part by weight of cilostazol.

The present invention also provides an oral pharmaceutical composition comprising the solid dispersion and a pharmaceutically acceptable additive. The oral pharmaceutical composition may include solid dosage forms such as granules, capsules, and tablets, and may be preferably in tablet form.

Such pharmaceutically acceptable additives include excipients (diluents), disintegrants, binders, glidants and the like conventionally used in the pharmaceutical arts.

For example, the excipient (diluent) is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, gelatinized starch, synthetic aluminum silicate, hydroxypropyl methyl cellulose, polyoxyl 40 hardened castor oil, polyethylene glycol 6000, polyethylene glycol 4000, poloxamer, povidone, glucose, pectin, talc, sodium bicarbonate, magnesium carbonate, sodium carbonate, crospovidone, crosscarboxymethylcellulose sodium, copovidone, kaolin, carboxymethylcellulose calcium, sodium carboxymethylcellulose, Carboxymethyl Cellulose, Precipitated Calcium Carbonate, Pregelatinized Starch, Sodium Starch Glyconate, Starch, Low Substituted Hydroxypropyl Cellulose, Xylitol, Sucrose Fatty Ester, Calcium Phosphate, Calcium Hydrogen Phosphate, Silicon Dioxide, Lactose, Corn Starch, Ethyl Cellulose, D-sorbitol, cellulose, polyethylene oxide, Magnesium oxide, xanthan gum, beta-cyclodextrin, white sugar, microcrystalline cellulose, D-mannitol, rudipress, dextrin, glyceryl behenate, magnesium aluminate silicate, magnesium silicate, citric acid, hard silicic anhydride or crystalline cellulose do.

The disintegrant is crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium , Cross-linked carboxymethylcellulose sodium, microcrystalline cellulose, sodium gluconate, crystalline cellulose, hydroxypropyl cellulose, gelatinized starch, polyethylene glycol 6000, povidone and the like.

The binder is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, gelatinized starch, hydroxypropylmethylcellulose phthalate, polyethylene glycol 6000, polyethylene glycol 4000, polyvinyl alcohol, poloxamer, povidone , Crospovidone, crosscarboxymethylcellulose sodium, copovidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose, gelatin, pregelatinized starch, starch glyconate, starch, low-substituted hydroxy Propyl cellulose, corn starch, ethyl cellulose, gum arabic, white sugar, microcrystalline cellulose, methacrylic acid copolymer, methyl cellulose, meglumine, mannitol, honey, glycerin, or crystalline cellulose It includes.

The lubricant is magnesium stearate, stearic acid, talc, synthetic aluminum silicate, sodium stearyl fumarate, kaolin, silicon dioxide, silicon fluid 350 centistokes, simethicone , Magnesium silicate, or light silicic anhydride.

In addition, if necessary, the pharmaceutical composition of the present invention may contain a coloring agent such as titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide or aluminum lake.

Hereinafter, the present invention will be described in more detail through Examples and Test Examples. However, these Examples and Test Examples are for illustrating the present invention, and the scope of the present invention is not limited to these Examples and Test Examples.

Example  1 to 6. Cilostazol  Containing Of the solid dispersion  Produce

To prepare a solid dispersion in the component and content shown in Table 2. That is, after dissolving each component in methanol, the resulting solution was spray-dried using a spray dryer (Buchi, B-290) to prepare a solid dispersion. Conditions of the spray dryer is shown in Table 1 below.

Condition Suction Temperature (Inlet temp.) (℃) 75 Spray flow (l / h) 538 Feed flow (ml / min) 1.5 Aspirator (%) 75 Nozzle diameter (mm) 0.7

ingredient Example (mg) One 2 3 4 5 6 Cilostazol 10 10 10 10 10 10 Methacrylic acid-methyl methacrylate (1: 1) copolymer
(Eudragit ^TM L100, Degussa) 50 25 25 Methacrylic acid-methyl methacrylate (1: 2) copolymer
(Eudragit ^TM S100, Degussa Co.)
50 25 25 Butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate (1: 2: 1) copolymer [Eudragit ^™ E100, Degussa Corporation] 50 Vinylpyrrolidone-Vinyl Acetate Copolymer
(Kollidon VA64, BASF Corporation) 25 25 Methanol (mL) 10 10 10 10 10 10 Gross weight 60 60 60 60 60 60

Comparative example  1. Preparation of physical mixture

In order to compare the solubility with the solid dispersion of the present invention, a mixture of cilostazol and Eudragit ^™ L100 (Degussa) and Eudragit ^™ S100 (Degussa) was prepared in the same ratio as in Example 5.

Comparative example  2 to 8.

Water-soluble polymers such as hydroxypropylmethylcellulose, carbopol 971NF, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, vinylpyrrolidone vinyl acetate copolymer (collidone VA64), polyvinylacetate, polyethylene glycol 3400, and the like In the same manner as in Examples 1 to 6, the solid dispersion was prepared with the ingredients and contents shown in Table 3 below.

ingredient Comparative Example (mg) 2 3 4 5 6 7 8 Cilostazol 10 10 10 10 10 10 10 Hydroxypropylmethylcellulose 50 Carbopol 971NF 50 Polyvinylpyrrolidone K30 50 Polyvinylpyrrolidone K90 50 Vinylpyrrolidone Vinyl Acetate Copolymer
(Collidon VA64) 50 Polyvinylacetate 50 Polyethylene Glycol 3400 50 Methanol (mL) 10 10 10 10 10 10 10 Gross weight 60 60 60 60 60 60 60

Test Example  1. Solubility test

The solubility in the aqueous medium of the solid dispersions and the physical mixtures prepared in Examples 1 to 6 and Comparative Examples 1 to 8 was evaluated. As the aqueous medium, a pH 6.8 phosphate buffer, which is a physiological aqueous medium, was used. Specifically, a sample containing 1 mg of cilostazol was placed in 1 mL of pH 6.8 phosphate buffer, stirred at room temperature for 24 hours, filtered, and quantified by high performance liquid chromatography. In the quantitative analysis, three samples (n = 3) were used, and high-speed liquid chromatography analysis conditions were as follows.

<Method: high speed liquid chromatography method>

Column: Gemini 5μ c18

Mobile phase: water / acetonitrile = 45/55 (v / v)

Injection volume: 20 μL

Flow rate: 1 mL / min

Detector: 254 nm

Column temperature: 25 ℃

The solubility of each sample in the physiological aqueous medium analyzed as above is shown in Table 4 below.

sample Solubility (µg / mL) Example 1 29.05 ± 2.25 Example 2 25.34 ± 3.46 Example 3 25.23 ± 3.38 Example 4 25.71 ± 0.50 Example 5 45.91 ± 2.70 Example 6 32.97 ± 3.18 Comparative Example 1 4.97 ± 0.03 Comparative Example 2 10.09 ± 1.36 Comparative Example 3 6.32 ± 0.49 Comparative Example 4 5.70 ± 0.06 Comparative Example 5 7.48 ± 0.30 Comparative Example 6 10.34 ± 1.04 Comparative Example 7 3.77 ± 0.10 Comparative Example 8 5.88 ± 0.67 Cilostazol Raw Material 3.23 ± 0.20

As can be seen from the results of Table 4, all of the solid dispersions obtained according to the present invention significantly increased the solubility of cilostazol, in particular 1 part by weight of methacrylic acid and 1 part by weight of methyl methacrylate The solid dispersion prepared using a mixture of copolymer (Eudragit ^TM L100), copolymer of 1 part by weight of methacrylic acid and 2 parts by weight of methyl methacrylate (Eudragit ^TM S100) is about 14 compared to the cilostazol raw material (powder). It exhibited a solubility higher than twice. On the other hand, other water-soluble polymers such as hydroxypropylmethylcellulose, carbopol 971NF, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, vinylpyrrolidone vinyl acetate copolymer (collidone VA64), polyvinylacetate, polyethylene Solid dispersions prepared using glycol 3400 and the like showed solubility of only 3.77 to 10.34 μg / mL.

Test Example  2. Of the solid dispersion  Thermal characteristic evaluation

Changes in endothermic peaks were measured for the solid dispersion of Example 5, the physical mixture of Comparative Example 1, and the cilostazol raw material (powder) using a differential scanning calorimeter (DSC). Same as FIG. 1.

As can be seen in Figure 1, unlike the physical mixture (Comparative Example 1) and the cilostazol raw material, the solid dispersion prepared according to the present invention (Example 5) is near the melting point of cilostazol at 159.6 ℃ There was no endothermic peak, indicating that cilostazol is in amorphous form in the solid dispersion.

Test Example  3. Stability Evaluation

The solid dispersion of Example 5 was stored at room temperature for 1 month, 2 months, 5 months, and 6 months, and the change in endothermic peak was measured using DSC in the same manner as in Test Example 2, and the results are shown in FIGS. same. From the results of FIG. 2, it can be seen that the solid dispersion prepared according to the present invention does not convert cilostazol to a crystalline form even when stored for a long time and stably maintains an amorphous state.

Example  7 to 14. Preparation of Pharmaceutical Composition in Tablet Form

Tablets were prepared with the ingredients and contents in Table 5 below. Table 5 shows the content per tablet. That is, the solid dispersion prepared in Example 5 and each additive were mixed and then tableted with a single tablet tablet to prepare a tablet.

ingredient Example (mg) 7 8 9 10 11 12 13 14 Solid dispersion of Example 5 600 600 600 600 600 600 600 600 Microcrystalline cellulose 196 156 156 156 156 156 156 156 Sodium alginate - 40 - - - - - - Hydroxypropylmethylcellulose - - 40 - - - - - Hydroxymethylcellulose - - - 40 - - - - Methylcellulose - - - - 40 - - - Polyethylene glycol - - - - - 40 - - Povidone K-90 - - - - - - 40 - Polyvinyl alcohol - - - - - - - 40 Magnesium stearate 4 4 4 4 4 4 4 4 Gross weight 800 800 800 800 800 800 800 800

Comparative example  9. Preparation of Tablets Using Physical Mixtures

Tablets were prepared in the same manner as in Example 7 using the physical mixture obtained in Comparative Example 1, and the dissolution test of Test Example 4 was performed.

Comparative example  10. Lauryl  Sodium sulfate-containing Solid dispersion  Preparation of Tablets Containing

In the same manner as in Example 10 of Korean Patent Publication No. 10-2009-0122344, a tablet (cilostazol content: 100 mg) containing a solid dispersion prepared using sodium lauryl sulfate was prepared.

Test Example  4. Dissolution test

For the tablet of Example 7, the tablet of Comparative Example 9, the tablet of Comparative Example 10, and the commercial preparation ("Pretal tablet (cilostazol: 100 mg)", Otsuka Pharmaceutical, Korea), The dissolution test was performed under the same conditions.

<Elution test condition>

Dissolution Test Equipment: DST-810 (Labfine Inc.)

Eluent: pH 6.8 phosphate buffer, 500 mL

Eluent temperature: 37 ± 0.5 ℃

Paddle speed: 75 rpm

Dissolution test results performed as described above are as shown in FIG. From the results of FIG. 3, the tablet obtained from the solid dispersion according to the present invention (Example 7) showed a remarkably excellent dissolution rate compared to other formulations. When a physiological aqueous medium containing no surfactant was used as the eluent, the tablets obtained according to the present invention showed a significantly better dissolution rate of at least four times that of conventional formulations. In contrast, tablets containing solid dispersion prepared with sodium lauryl sulfate (cilostazol content: 100 mg) have an effect of improving dissolution rate when using a physiological aqueous medium containing no surfactant as eluent. Hardly appeared. Thus, tablets according to the present invention can be expected to achieve rapid efficacy and at least equivalent bioavailability when administered to the human body, even if the dosage of the drug (ie, content in the formulation) is reduced.

Claims (8)

Solid dispersion of cilostazol and polymethacrylate copolymer. The method of claim 1, wherein the polymethacrylate copolymer is a copolymer of methacrylic acid and methyl methacrylate; Copolymers of methacrylic acid and ethyl acrylate; Ammonio methacrylate copolymers; And a copolymer selected from the group consisting of butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, and copolymers of methyl methacrylate. 3. The method of claim 2, wherein the polymethacrylate copolymer comprises: 1 part by weight of methacrylic acid and 1 part by weight of methyl methacrylate; Copolymers of 1 part by weight of methacrylic acid and 2 parts by weight of methyl methacrylate; And at least one copolymer selected from the group consisting of 1 part by weight of butyl methacrylate, 2 parts by weight of (2-dimethylaminoethyl) methacrylate, and 1 part by weight of methyl methacrylate. . 4. The method of claim 3, wherein the polymethacrylate copolymer is a mixture of a copolymer of 1 part by weight of methacrylic acid and 1 part by weight of methyl methacrylate and a copolymer of 1 part by weight of methacrylic acid and 2 parts by weight of methyl methacrylate. Solid dispersion, characterized in that. The solid dispersion according to claim 1, wherein the weight ratio of the cilostazol and the polymethacrylate copolymer is 1: 0.5 to 20. The compound of claim 1, further comprising hydroxypropylmethylcellulose; Polyvinylpyrrolidone; Crospovidone; And at least one polymer selected from the group consisting of a copolymer of vinylpyrrolidone and vinyl acetate. The solid dispersion according to claim 6, wherein the polymer is a copolymer of vinylpyrrolidone and vinyl acetate. An oral pharmaceutical composition comprising the solid dispersion according to any one of claims 1 to 7 and a pharmaceutically acceptable additive.

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