TWI725442B - Pharmaceutical composition comprising cilostazol and statin derivatives - Google Patents

Abstract

The present invention relates to a sustained-release combined preparation containing a statin-based drug which is an HMG-CoA reductase inhibitor and cilostazol as active ingredients, the sustained-release combined preparation includes an HMG-CoA reductase inhibitor mixed part containing an HMG-CoA reductase inhibitor and a cilostazol mixed part containing cilostazol, and the cilostazol mixed part includes immediate-release granules and sustained-release granules, and the sustained-release combined preparation has rapid pharmacological activity and less side effects and a sustained release to render a sufficient pharmacological effect by only one administration a day.

Description

Pharmaceutical composition containing cilostazol and statin derivatives

The present invention relates to a sustained-release combined preparation containing statins and cilostazol as active ingredients, and the statins are HMG-CoA reductase inhibitors.

Cilostazol is used to inhibit the primary aggregation of platelets caused by ADP, epinephrine and their analogs in platelets isolated from mice, rats, rabbits, dogs and humans, and to dissociate platelet aggregation. In addition, cilostazol is used to inhibit platelet aggregation induced by ADP and collagen when administered orally to MiGru dogs, and it is also administered orally to patients with chronic arterial occlusive disease (Buerger's disease (Buerger's disease (Buerger's disease)). Disease), arteriosclerosis obliterans, diabetic peripheral vascular disease, etc.) inhibit platelet aggregation induced by ADP, collagen, arachidonic acid, and epinephrine in platelets isolated from the patient. The effect of cilostazol in inhibiting platelet aggregation was immediately apparent after the administration of cilostazol, and was maintained by repeated administration of cilostazol. When the administration of cilostazol was suspended, the inhibited platelet aggregation returned to its original level, and its concentration in the plasma decreased without rebound phenomenon (increased aggregation).

The mechanism of action of cilostazol is as follows. Cilostazol is used to inhibit the release of serotonin in rabbit platelets, but has no effect on the migration of serotonin and adenosine to platelets. In addition, cilostazol is used to inhibit platelet aggregation caused by thromboxane A2 (TXA2) without affecting the metabolism of arachidonic acid in platelets. This indicates that cilostazol is used to inhibit platelets and vascular smooth muscle AMP phosphodiesterase (cyclic AMP phosphodiesterase, cAMP-PDE) activity, thereby exhibiting antiplatelet effects and vasodilator effects.

The disadvantage of conventional cilostazol formulations is that they have poor patient compliance when administered twice daily. In addition, the immediate release cilostazol formulation has the disadvantage that the drug is released quickly and irregularly when administered orally. Therefore, it is known that as the concentration of cilostazol in the blood increases sharply, these cilostazol preparations cause side effects such as headache, severe dizziness, and tachycardia (see Am J Cardiol 2001; 87 (Supplement): 28D- 33D and US 2002/0058066 A1). Since cilostazol is poorly water-soluble and also has a reduced absorption rate in the lower small intestine, the conventional release control formulation using cilostazol has the disadvantage that its bioavailability may deteriorate as a whole. In addition, WO 2000/57881 discloses a method for improving the absorption rate of cilostazol in the lower small intestine using a preparation in which cilostazol in a fine powder form is dispersed and/or dissolved together with a dispersant and/or solubilizer.

【Related Literature】

【Patent Literature】

(Patent Document 1) KR 10-1008540 B1

The present invention relates to a sustained-release combination preparation that improves the disadvantages of conventional cilostazol sustained-release formulations with large solubility deviations. It is prepared in the form of lozenges to significantly increase productivity and is inhibited by the addition of HMG-CoA reductase. The agent as an active ingredient further improves the bioavailability.

The present invention provides a sustained-release combination preparation, which comprises an HMG-CoA reductase inhibitor mixed part containing an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; and a mixed part containing cilostazol or its A pharmaceutically acceptable salt is the mixed part of cilostazol as the active ingredient. At the same time, the mixed part of cilostazol includes release modifiers to control activity. The amount of cilostazol dissolved in the body of the sex ingredient, and relative to 100 parts by weight of the active ingredient cilostazol, the content of the release regulator may be 3 to 9 parts by weight.

The pharmaceutical composition according to the present invention is a combined preparation containing cilostazol and an HMG-CoA reductase inhibitor, which has a very excellent effect on bioavailability, and by adjusting the cilostazol-containing facilostazol The content of the release regulator in the azole mixed part can be administered only once a day to have sufficient suspension release, and the side effects of cilostazol are reduced.

Here, when the content of the release modifier is less than 3 parts by weight relative to 100 parts by weight of the active ingredient cilostazol, since the initial release amount of cilostazol is too much, it may not exhibit sufficient sustained release, and may Side effects such as headaches occur. On the other hand, when the content of the release modifier is greater than 9 parts by weight relative to 100 parts by weight of the active ingredient cilostazol, the dissolution of the active ingredient cilostazol is too delayed to obtain sufficient pharmacological effects.

The HMG-CoA reductase inhibitor used in the present invention can be selected from rosuvastatin (rosuvastatin), simvastatin (simvastatin), atorvastatin (atorvastatin), pitavastatin (pitavastatin), pravastatin (pravastatin) One or two or more of the group consisting of fluvastatin, fluvastatin and lovastatin, the content of the active ingredient in the mixed part of the HMG-CoA reductase inhibitor can be 3 to 40 mg, and The content of the active ingredient of the mixed part of lotazol may be 160 to 240 mg.

When the active ingredient content of the HMG-CoA reductase inhibitor mixed part is less than 3 mg or the active ingredient content of the cilostazol mixed part is less than 160 mg, sufficient pharmacological activity may not be exhibited, and when HMG-CoA is reduced When the content of the active ingredient of the enzyme inhibitor mixed part is greater than 40 mg or the content of the active ingredient of the cilostazol mixed part is greater than 240 mg, the blood concentration of the active ingredient may be too high, and therefore side effects may occur.

Meanwhile, in the cilostazol mixing part of the sustained-release combination preparation according to the present invention, a mixture of hypromellose and carbomer may be used as a release modifier, and in this case, the viscosity is 75,000 to 140,000 cp The hypromellose and carbomer are preferably 1:1 to 2.5:1 weight ratio mixed use. When the mixing ratio of the release modifier exceeds the above range, the stability of the sustained release matrix may be reduced.

In addition, the mixed part of cilostazol may include immediate-release particles, which include cilostazol as an active ingredient, a disintegrant, and a binder; and sustained-release particles, which include cilostazol as an active ingredient, a release modifier, and Binder. Based on the content of the active ingredient of the immediate-release granule, the content of the active ingredient of the sustained-release granule is preferably 50 to 90% by weight, and more preferably 60 to 80% by weight.

As mentioned above, when the immediate-release particles and sustained-release particles (each containing cilostazol) are prepared and mixed together and used, they can exhibit the rapid pharmacological activity of the immediate-release particles and the sustained action of the sustained-release particles, and can Reduce side effects. Here, the content ratio of the active ingredient of the immediate release part and the sustained release part is very important, and when the content of the active ingredient of the immediate release part is too much, side effects caused by too fast dissolution may occur. At the same time, in the case of the sustained release part, in order to continue the pharmacological action for a long time, the dissolution characteristics should be considered and the content of the active ingredient should be adjusted relative to the release regulator. As a result of repeated research, the applicant was able to find the optimal content ratio of the active ingredient in the immediate release part and the sustained release part as described above, and considering the active ingredient content in each mixed part containing the active ingredient, the disintegrant , The type and content of the binder and release modifier reach the maximum to adjust the dissolution rate uniformly. Therefore, long-term durability and reduced side effects and rapid pharmacological activity can be achieved.

As the disintegrant, one or two or more selected from the group consisting of calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, 1-hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone can be used. Many kinds, and as a binder, can be selected from hydroxypropyl cellulose, hydroxy cellulose, hydroxypropyl methyl cellulose, hydroxypropyl starch, polyvinyl alcohol, hydroxymethyl cellulose and polyvinylpyrrolidone One or two or more of the group. In addition, as a release modifier, hypromellose and carbomer can be used alone or in combination. However, as mentioned above, the best results are obtained when a mixture of hypromellose and carbomer is used.

The active ingredient contained in the cilostazol mixed part of the sustained-release combination preparation according to the present invention has the characteristics of satisfying the dissolution profile, wherein according to the dissolution test method II (stirring paddle method) in the Korean Pharmacopoeia, cilostazol is 30 minutes later 20% or less of the total weight of the active ingredients in the mixed part, 20-50% of the total weight of the active ingredients in the cilostazol mixed part after 90 minutes, and the total weight of the active ingredients in the cilostazol mixed part after 300 minutes 80% or more is dissolved in 0.4% sodium lauryl sulfate dissolving solution. Therefore, a formulation that exhibits rapid pharmacological activity, reduction of side effects caused by excessive dissolution, and dissolution of almost all active ingredients after 300 minutes is completed.

In addition, the immediate release particles and sustained release particles according to the present invention have a diameter ranging from 350 to 450 μm, which affects the dissolution characteristics. Therefore, when the diameter exceeds the above range, the dissolution may be too fast or may not show sufficient pharmacological effects.

Meanwhile, the sustained-release combination preparation of the present invention preferably has a diameter of 5 to 10 mm and a total weight of 350 to 550 mg. When the diameter is less than 5 mm, the formulation may collapse in tablet making, and when the diameter is greater than 10 mm, the patient's convenience in drug treatment may be reduced. In addition, when the total weight is less than 350 mg, the stability may be reduced due to insufficient addition of excipients, and when the total weight is greater than 550 mg, the formulation may become too large, so the patient's convenience in drug treatment may be reduced.

The hardness of the sustained-release combination preparation of the present invention may be 10 to 30 kg/cm ² , and when the hardness is less than 10 kg/cm ² , the formulation may collapse or decrease in stability during tableting, and when the hardness is greater than 30 kg/cm ² , The dissolution delay exceeds the expected problem.

The sustained-release combination preparation according to the present invention includes an HMG-CoA reductase inhibitor mixed part containing an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; and a mixed part containing cilostazol or a pharmaceutical thereof The above acceptable salt is the mixed part of cilostazol as the active ingredient. When the preparation is prepared in the form of a double-layer single lozenge, the double-layer single lozenge includes a first layer formed by the HMG-CoA reductase inhibitor mixed part; and a second layer formed by the cilostazol mixed part, It can be mass-produced quickly and has excellent stability, and therefore it is in terms of productivity and It is preferable in terms of preservation.

At the same time, the sustained-release combination preparation containing HMG-CoA reductase inhibitor and cilostazol according to the present invention can be prepared by the following steps: Prepare HMG-CoA reductase inhibitor mixed granules by mixing HMG-CoA reductase inhibitor, excipients, binders and disintegrants; prepare immediate-release granules by mixing cilostazol, excipients and binders ; Prepare sustained-release granules by mixing cilostazol, excipients, release modifiers, binders and lubricants; prepare cilostazol mixed granules containing cilostazol by mixing immediate-release granules and sustained-release granules ; And by preparing a sustained-release combination preparation by mixing the HMG-CoA reductase inhibitor mixed granules and cilostazol mixed granules into a tablet. The preparation sequence of the HMG-CoA reductase inhibitor mixed part and the cilostazol mixed part and the preparation sequence of the immediate release part and the sustained release granule can be changed.

The present invention relates to a sustained-release combination preparation comprising an HMG-CoA reductase inhibitor and cilostazol, which has rapid pharmacological activity and fewer side effects and sustained release, and sufficient pharmacological effects can be produced by only administration once a day Learn the role.

Since the pharmaceutical composition of the present invention includes immediate-release particles containing cilostazol as an active ingredient, a sufficient amount of the active ingredient cilostazol to exhibit pharmacological activity after oral administration is quickly dissolved in the body. Therefore, the initial blood concentration increases rapidly to achieve rapid pharmacological effects. In addition, when the pharmaceutical composition includes sustained-release particles containing cilostazol, sufficient long-term pharmacological activity can be exhibited by administering only once a day.

In addition, when an HMG-CoA reductase inhibitor is contained as an active ingredient, the bioavailability is further improved compared to cilostazol alone. As a statin, The HMG-CoA reductase inhibitor may be one or two or more selected from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin and lovastatin Many kinds, in consideration of pharmacological effects, long-term storage stability, and marketability, preferably one or two or more selected from the group consisting of Russellstatin, Simvastatin and Atorvastatin, and more preferably Russell Statin.

<Method for preparing sustained-release combination preparation>

According to an exemplary embodiment of the present invention, the sustained-release combination preparation according to the present invention is prepared according to the tablet portion generally prescribed in the Korean Pharmacopoeia, which includes: by mixing HMG-CoA reductase inhibitors, excipients, and Preparation of HMG-CoA reductase inhibitor mixed granules by mixing cilostazol, excipients and binders; preparation of immediate release granules by mixing cilostazol, excipients and release regulators , Binders and lubricants to prepare sustained-release particles; form cilostazol-containing mixed particles of cilostazol by mixing immediate-release particles and sustained-release particles; and by mixing HMG-CoA reductase inhibitors with particles and cilostazol Lostazol mixed granules tableting to prepare sustained-release combination preparations, and can change the tableting sequence of the HMG-CoA reductase inhibitor mixed part and the cilostazol mixed part, as well as the preparation sequence of immediate release and sustained release granules.

In addition, in each of the following examples and comparative examples, reference is made to a specific composition including the type and content of the raw materials used in each step, and the formulation of each combination preparation is prepared in a double-layer tablet via a direct tableting method .

Design of the content and composition of the release regulator

In order to reduce the side effects of cilostazol and statins in the oral administration and improve the bioavailability, it was concluded that the best composition for preparing a sustained-release combination preparation that showed sufficient effects by administering only once a day, As shown in the examples and comparative examples in Table 1 below, the sustained release combination preparation was prepared by changing the content and composition of the release modifier to adjust the amount of other excipients.

<Experiment 1> Measurement of the dissolution rate of the active ingredient cilostazol

The dissolution rates of the examples and comparative examples over time were measured according to the dissolution test method of the 11th edition of the Korean Pharmacopoeia, and are listed in Table 1 below. A 0.4% SLS aqueous solution was used as the dissolving solution, a stirring paddle method was used as the dissolution method, and 900 mL of the dissolving solution was used for dissolution at a stirring speed of 75 rpm and a dissolution temperature of 37±0.5°C.

discuss

In Examples 1 to 3, 30 minutes after cilostazol was administered to the dissolving solution, 20% or less of the active ingredient was dissolved, and then a constant amount of the drug was continuously dissolved. On the other hand, in the case of Comparative Example 1, due to the decrease in sustained release, the active ingredient was dissolving too quickly, and the blood concentration increased rapidly. Therefore, side effects may occur due to the rapid increase in blood concentration. In the case of Comparative Example 2, since the dissolution is too slow and the drug does not exhibit sufficient pharmacological activity when it stays in the body, the effect may be reduced.

In addition, in Examples 1 to 3, about 20 to 50% of the active ingredient was dissolved after 90 minutes, and 80% or more of the active ingredient was dissolved after 300 minutes. In these cases, when the formulation is administered orally, it is expected to show a better dissolution profile in the body for a long time, which is a different environment from the dissolution solution including the surfactant.

<Experiment 2> Measurement of the dissolution rate of the active ingredient statin

The pharmaceutical composition according to the present invention is a sustained-release combination preparation containing two different types of active ingredients, and due to the combination characteristics or formulation characteristics of the active ingredients with different characteristics, it is possible to change the dissolution rate of the active ingredients.

Therefore, in order to verify whether the characteristics of the formulation of the combination or sustained-release combination preparation with cilostazol affect the dissolution of the statin component, the applicant prepared a single lozenge according to Comparative Examples 3 to 5, which contains the statin drugs rosuvastatin, xin Each of Vastatin and Atorvastatin can be used as a control. At the same time, except for the statin type, Example 4 with the same composition as Example 2 was prepared And 5, compare the dissolution profiles of the statin component of the combined preparations according to Examples 2, 4, and 5 and the single tablets according to Comparative Examples 3 to 5.

Preparation Comparative Examples 3 to 5: Single formulation containing statin

As a control for comparing the dissolution rate of statin components, a single lozenge containing rosuvastatin, simvastatin or atorvastatin as an active ingredient was prepared according to the content of the components shown in Table 3 below.

Examples 2, 4 and 5: Sustained release combination preparations containing cilostazol and statins

According to the component contents shown in Table 4 below, the sustained release combination preparations of Examples 4 and 5 were prepared in the same manner as described in Example 2 using components other than statins.

Comparison of dissolution profiles of Examples 2, 4 and 5 and Comparative Examples 3 to 5

The dissolution rates of the active ingredient statin in the statin single tablets according to Comparative Examples 3 to 5 and the sustained release combination preparations according to Examples 2, 4, and 5 are shown in Tables 5 to 7 below.

A pH 6.6 and pH 7.0 buffered aqueous solution and water were used as the dissolution solution, and the stirring paddle method was used as the dissolution method. Use 900 mL of the dissolving solution to dissolve at a stirring speed of 50 rpm and a dissolution temperature of 37 ± 0.5°C.

discuss

As shown in Tables 5 to 7, the dissolution rates of the sustained-release combination preparation according to the present invention and the statin single tablet are very similar and substantially the same. Therefore, it can be seen that although the formula and composition are different from those of the control group containing a single-component statin, the sustained-release combination preparation according to the present invention quickly shows an effect without affecting the dissolution of the contained statin component in the body.

Therefore, when the dissolution rate of cilostazol shown in Table 2 and the results of the dissolution rate of rosistatin shown in Tables 5 to 7 are integrated together, the sustained-release combination preparation according to the present invention shows two The best dissolution profile of different types of active ingredients, and is suitable for sustained-release combination preparations administered once a day.

<Experiment 3> An experiment comparing the dissolution of a combined preparation formed by a single lozenge

The single tablet shown in Table 8 below (Comparative Examples 6 to 8) was prepared by simply mixing all cilostazol sustained-release particles, immediate-release particles, and statin components together, and dissolved in 0.4% SLS The dissolution rate of the active ingredient was compared with the sustained-release combination formulations (Examples 2, 4, and 5) according to the present invention in 120 minutes under solution conditions. The results are shown in Table 9 below.

discuss

Although the sustained-release combination preparation of the present invention exhibits excellent initial dissolution rate of all active ingredients, in the case of a simple mixed single lozenge, the active ingredient statin hardly dissolves in the early stage due to the viscosity of the sustained-release matrix. Therefore, it can be seen that the sustained-release combination preparation of the present invention formed in two layers containing statin and cilostazol in different layers is a formulation with excellent initial dissolution rate of the contained active ingredient and excellent sustained release Things.

<Experiment 4> Experiment on the dissolution deviation of the active ingredient cilostazol relative to the control drug

At the same time, in order to verify that the dissolution deviation effect of cilostazol (the sustained-release active ingredient of the sustained-release combination preparation of the present invention) is minimized, the dissolution rate between the formulation of Example 2 of the present invention and Pletaal SR capsule as a control drug was compared , And the results are shown in Table 10 below.

discuss

As shown in Table 10, the formulation of Example 2 of the present invention has a significantly smaller deviation than the conventional Pletaal SR, showing excellent pharmacological activity and a significant reduction in side effects.

<Experiment 5> Dissolution experiment of the active ingredient cilostazol in a sustained-release combination preparation containing 10 mg of the active ingredient statin

As another formulation of the sustained-release combination preparation according to the present invention, a formulation of a sustained-release combination preparation containing 10 mg of statins (10.4 mg rosstatin calcium) was designed, and the active ingredient cilostazol Dissolution experiment.

The compositions of the examples and comparative examples are shown in Table 11 below.

According to the dissolution test method of the 11th edition of the Korean Pharmacopoeia, the dissolution rates of the examples and comparative examples were measured over time, and the results are listed in Table 12 below. A 0.4% SLS aqueous solution was used as the dissolving solution, and the stirring paddle method was used as the dissolving method. Use 900 mL of the dissolving solution to dissolve at a stirring speed of 75 rpm and a dissolution temperature of 37 ± 0.5°C.

discuss

In Examples 6 to 8, as shown in Examples 1 to 3 described in Experiment 1, a better dissolution profile was shown, and in Comparative Examples 9 and 10, the dissolution was too fast or too slow.

<Experiment 6> Measurement of the dissolution rate of the active ingredient statin

For the sustained-release combination preparation containing 10 mg of the active ingredient statin shown in Experiment 5, the statins were replaced with rosuvastatin, simvastatin, and atorvastatin, respectively, and the experiment was performed in the same manner as described in Experiment 2. .

Preparation comparative examples 11 to 13: a single formulation containing statins

As a control for comparing the dissolution rate of statin components, a single tablet containing rosuvastatin, simvastatin and atorvastatin as active ingredients was prepared according to the content of the components in Table 13 below.

Examples 7, 9 and 10: Sustained release combination preparations containing cilostazol and statins

According to the component contents shown in Table 14 below, the sustained-release combination preparations of Examples 9 and 10 were prepared in the same manner as described in Example 7 using components other than statins.

Comparison of dissolution profiles of Examples 7, 9 and 10 and Comparative Examples 11 to 13

The dissolution rates of the active ingredient statin in the statin single tablets according to Comparative Examples 11 to 13 and the sustained release combination preparations according to Examples 7, 9 and 10 are shown in Tables 15 to 17 below.

Use pH 6.6 and pH 7.0 buffered aqueous solutions and water as the dissolving solution. The dissolving method is the stirring paddle method, and 900 mL of the dissolving solution is used for dissolution at a stirring speed of 50 rpm and a dissolution temperature of 37 ± 0.5°C.

[Table 16]

discuss

As shown in Tables 15 to 17, the dissolution rates of the sustained-release combination preparation of the present invention and the single statin tablet are very similar and substantially the same. Therefore, it can be seen that although the sustained-release combination preparation according to the present invention is different in formula and composition from the control containing a single-component statin, it has no effect on the dissolution of the contained statin component in the body and therefore quickly exhibits an effect .

Therefore, the same results as in Experiment 2 were shown, and the sustained-release combination preparation according to the present invention showed the best dissolution profile of two different types of active ingredients, and was suitable for a sustained-release combination preparation administered once a day.

<Experiment 7> An experiment comparing the dissolution of a combined preparation formed by a single lozenge

A single lozenge (Comparative Examples 14 to 16) shown in Table 18 below was prepared by simply mixing together all cilostazol sustained-release particles, immediate-release particles, and statin components, and Comparative Examples 7 and 9 And 10, the formula of the sustained-release combination preparation according to the present invention and the dissolution rate of the active ingredient in 120 minutes under the condition of 0.4% SLS dissolving solution, and the results are shown in Table 19 below.

discuss

As described in Experiment 3, in the case of a simple mixed single lozenge, due to the viscosity of the sustained release matrix, there is a problem that the active ingredient statin hardly dissolves in the early stage.

<Experiment 8> Experiment on the dissolution deviation of the active ingredient cilostazol relative to the control drug

At the same time, in order to verify that the dissolution deviation effect of the sustained release active ingredient cilostazol of the sustained release combination preparation according to the present invention is minimized, the dissolution rate between the formulation of Example 7 of the present invention and the Pletaal SR capsule as a control drug was compared. Deviations, and the results are shown in Table 20 below.

discuss

As shown in Table 20, the formulation of Example 7 of the present invention has significantly smaller deviations than the conventional Pletaal SR capsule, which proves to show excellent pharmacological activity and significantly reduce side effects.

Claims (15)

A sustained-release combination preparation, comprising: a HMG-CoA reductase inhibitor mixed part containing the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; and a cilostazol mixed part , Which contains cilostazol or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the cilostazol mixed part contains 3 to 9 parts by weight relative to 100 parts by weight of the active ingredient cilostazol A release modifier, wherein the release modifier contains hypromellose and carbomer with a viscosity of 75,000 to 140,000 cp, and the weight ratio of the two is 1:1 to 2.5:1. The combination preparation as described in item 1 of the scope of patent application, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin and One or two or more of the group consisting of lovastatin. The combined preparation as described in item 1 of the scope of the patent application, wherein the content of the active ingredient in the mixed part of the HMG-CoA reductase inhibitor is 3 to 40 mg. The combined preparation as described in item 1 of the scope of the patent application, wherein the content of the active ingredient of the mixed part of cilostazol is 160 to 240 mg. The combination preparation according to the first item of the patent application, wherein the cilostazol mixed part comprises: immediate-release granules, which comprise cilostazol as active ingredients, a disintegrant and a binder; and sustained-release granules , Which contains cilostazol as an active ingredient, a release modifier and a binder, and based on the content of the active ingredient of the immediate-release granule, the activity of the sustained-release granule The content of the ingredients is 50 to 90% by weight. The combined preparation according to item 5 of the scope of patent application, wherein the disintegrant is selected from the group consisting of calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, 1-hydroxypropyl cellulose and cross-linked polyvinylpyrrolidine One or two or more of the group of ketones. The combined preparation according to item 5 of the scope of patent application, wherein the binder is selected from the group consisting of hydroxypropyl cellulose, hydroxy cellulose, hydroxypropyl methyl cellulose, hydroxypropyl starch, polyvinyl alcohol, hydroxymethyl One or two or more of the group consisting of base cellulose and polyvinylpyrrolidone. The combined preparation according to item 5 of the scope of patent application, wherein the release modifier is one or two or more selected from the group consisting of hypromellose and carbomer. The combination preparation according to the first item of the patent application, wherein the active ingredient contained in the cilostazol mixed part of the sustained-release combination preparation satisfies the dissolution profile in a 0.4% sodium lauryl sulfate dissolving solution. profiles), wherein according to the dissolution test method II (stirring paddle method) in the Korean Pharmacopoeia, 20% or less of the total weight of the active ingredients in the cilostazol mixed portion dissolves after 30 minutes, the cilostazol 20 to 50% of the total weight of the active ingredients in the azole mixing part dissolves after 90 minutes, and 80% or more of the total weight of the active ingredients in the cilostazol mixing part dissolves after 300 minutes. The combined preparation as described in item 5 of the scope of the patent application, wherein the diameters of the immediate-release particles and the sustained-release particles are in the range of 350 to 450 μm. The combined preparation described in item 1 of the scope of the patent application has a diameter of 5 to 10 mm. The combined preparation described in item 1 of the scope of the patent application, wherein the total weight of the sustained-release combined preparation is 350 to 550 mg. The combined preparation as described in item 1 of the scope of patent application, wherein the hardness of the sustained-release combined preparation is 10 to 30 kg/cm ² . The combination preparation according to item 1 of the scope of patent application, wherein the sustained-release combination preparation is prepared in the form of a double-layer lozenge, and the double-layer lozenge comprises: a mixed part of an HMG-CoA reductase inhibitor The first layer; and a second layer composed of mixed parts of cilostazol. A method for preparing a sustained-release combination preparation containing an HMG-CoA reductase inhibitor and cilostazol, which comprises: preparing HMG-CoA reductase inhibitors, excipients, binders and disintegrants by mixing HMG-CoA reductase inhibitors, excipients, binders, and disintegrants. CoA reductase inhibitor mixed granules; by mixing cilostazol, excipients and binders to prepare immediate release granules; by mixing cilostazol, excipients, release regulators, binders and lubricants to prepare continuous Release particles; preparing cilostazol mixed particles containing cilostazol by mixing the immediate release particles and the sustained release particles; and by mixing the HMG-CoA reductase inhibitor mixed particles and the cilostazol Lostazol mixed granules are made into tablets to prepare a sustained-release combination preparation ; wherein the cilostazol mixed granules contain 3 to 9 parts by weight of a release modifier relative to 100 parts by weight of the cilostazol, and the release modifier The agent contains hypromellose and carbomer with a viscosity of 75,000 to 140,000 cp, and the weight ratio of the two is 1:1 to 2.5:1.