WO2016195154A1 - Oral sustained-release preparation - Google Patents

Abstract

The present invention relates to a sustained-release cilostazol preparation, the sustained-release preparation of the present invention showing an elution profile that can effectively maintain drug concentration in vivo while showing an adequate early elution rate, thereby enabling the effects of maintaining the medicinal effect of cilostazol through one intake per day while decreasing the expression of side effects, and also improving medication compliance.

Description

Oral sustained release preparations

The present invention relates to oral sustained release preparations containing cilostazol.

Cilostazol is 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) -butoxy] -3,4-dihydro- which is a quinolinone compound represented by the following formula (1): 2 (1H) -quinolinone, which is a selective inhibitor of representative intracellular cAMP PDE type III (cyclic AMP phosphodiesterase type III).

[Formula 1]

Cilostazol inhibits PDE activity upon body absorption, inhibits platelet aggregation and dilates blood vessels, thereby inhibiting blood coagulation, improving central blood circulation, anti-inflammatory, anti-ulcer, lowering blood pressure, preventing and treating asthma and cerebral infarction, brain circulation Since it exhibits an action such as improvement, it is widely used as an antithrombotic agent, brain circulation improving agent, anti-inflammatory agent, anti-tumor agent, antihypertensive agent, and anti-asthma agent.

Conventional cilostazol formulations are administered orally twice a day, the patient's compliance with the medication is poor, causing oral administration, causing a rapid rise in blood drug concentrations, causing side effects such as headache, headache, tachycardia, etc. It is known. In addition, cilostazol is a poorly water-soluble drug having a water solubility of 1 μg / ml or less, and is mainly absorbed in the upper gastrointestinal tract and decreases absorption toward the lower intestine. Thus, the general bioavailability of the conventional release control formulation is decreased. It may decrease. Therefore, in order to solve the above problem, various studies for preparing a sustained release or controlled release formulation of cilostazol have been conducted.

Specifically, WO 97/48382 discloses a cilostazol sustained release preparation in a multi-unit form containing at least two mini-tablets using hydroxypropylmethylcellulose as the main matrix base. Sustained-release tablets in the form of a matrix can be prepared simply by conventional manufacturing techniques and equipment, but once the matrix structure is collapsed, there is a problem that the drug is rapidly released and the blood concentration is temporarily increased, such as cilostazol. In the case of highly insoluble drugs, some of the drugs may remain undissolved even after the matrix structure is collapsed, which is uneconomical. In addition, there is a side that the initial release rate is low due to the nature of the matrix structure, which may act as a disadvantage in the situation where rapid expression is required, it is difficult to secure the advantages as a sustained release formulation. To overcome this, in WO 00/57881 and US 2002/0058066, the outer layer of the tablet in the upper gastrointestinal tract (small intestine) causes a sustained release of the drug, and in the lower intestine and in the large intestine the nucleus of the tablet Although preparations have been shown to disintegrate to produce immediate release of the drug, it also stimulates and damages the intestinal mucosa due to rapid drug release in the lower intestine and in the large intestine. Dissolution may occur irregularly, so the absorption rate and absorption rate is irregular, and because it consists of an immediate release core tablet and the outer layer surrounding it has a disadvantage in that the manufacturing process is complicated and the overall tablet size is increased, thereby reducing the patient's dose compliance.

As such, the existing cilostazol preparations have a great need for the development of sustained-release preparations in order to reduce the incidence of adverse effects due to high dissolution rates immediately after taking them. There is a need for the development of cilostazol sustained-release preparations that exhibit a constant dissolution rate as well as a delayed release.

Accordingly, the present inventors have diligently studied to solve the problem of sustained-release formulation of poorly soluble cilostazol, using a mixture of a hydrophilic polymer and a carbomer and a solubilizing agent as a sustained-release carrier. In formulating, the use of cilostazol having a specific range of average particle diameters and the wet granulated granules with fine control of the amount of ethanol solvent can effectively maintain the drug concentration in the body while exhibiting an appropriate initial dissolution rate. It was confirmed that the provision of a sustained release formulation having an elution profile was possible and completed the present invention.

The present invention has been made to solve the problems of the prior art for cilostazol sustained-release tablet, and aims to provide a sustained-release formulation having an elution profile that can effectively maintain the drug concentration in the body while showing an appropriate initial dissolution rate.

The sustained release formulation for oral administration according to the present invention exhibits an early dissolution rate and an elution profile that can effectively maintain the drug concentration in the body. Thus, once-daily dosing reduces the expression of side effects while maintaining the efficacy of cilostazol. It is also possible to improve medication compliance.

BRIEF DESCRIPTION OF THE DRAWINGS It is a figure which shows the elution profile of a cilostazol sustained-release formulation with the average particle diameter of cilostazol.

2 is a diagram showing an elution profile of a cilostazol sustained release formulation according to the amount of ethanol solvent.

In order to attain the above object, in one aspect, the present invention provides a sustained release formulation for oral administration in which a composition comprising a cilostazol, a sustained release carrier which is a mixture of a hydrophilic polymer and a carbomer, and a solubilizing agent is formed as an active ingredient. ,

When the dissolution test (37 ± 0.5 ℃, 0.5% sodium lauryl sulfate solution, 50rpm) according to the KEPCO dissolution test method 2 (paddle method) provides an extended release formulation for oral administration characterized in that the following dissolution profile do:

1) 20-30% of the total weight of cilostazol is eluted at 2 hours after the start of the test;

2) 50-70% of the total weight of cilostazol is eluted at 5 hours after the start of the test;

3) More than 85% of the total weight of cilostazol elutes at 10 hours after the start of the test.

In the sustained release preparation according to the present invention, the composition may be wet granulated granules with an ethanol solvent.

The ethanol solvent may be used in an amount of 40 to 75 parts by weight based on 100 parts by weight of cilostazol.

According to the present invention, the active ingredient cilostazol may be one having an average particle diameter of 12 μm or less.

In the present invention, the hydrophilic polymer that can be used as a sustained release carrier is hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanta, acacia gum, It may be at least one selected from the group consisting of locust bean gum, xanthan gum, alginate, polyvinyl alcohol and polyvinylpyrrolidone.

The hydrophilic polymer may have a viscosity of 50,000 to 150,000 cps.

The solubilizer used in accordance with the present invention is one selected from the group consisting of sodium lauryl sulfate, polysorbate 80, oleoyl macrogolglycerides, linoleoyl macrogolglycerides, and caprylocaproyl polyoxyglycerides. It may be abnormal.

The sustained-release preparation according to the present invention may include 10 to 30 parts by weight of a hydrophilic polymer, 3 to 10 parts by weight of carbomer, and 5 to 20 parts by weight of a solubilizer based on 100 parts by weight of cilostazol.

Sustained release formulations according to the invention may further comprise fillers, binders, and glidants.

Specifically, the filler may be included in an amount of 30 to 70 parts by weight, 1 to 10 parts by weight, and 2 to 10 parts by weight of a lubricant, based on 100 parts by weight of cilostazol.

The filler used according to the invention may be at least one selected from the group consisting of microcrystalline cellulose, starch, lactose, mannitol, sorbitol, and colloidal silicon dioxide.

The binder used according to the present invention may be at least one selected from the group consisting of polyvinylpyrrolidone, copolymers of vinylpyrrolidone / vinyl derivatives, and starch.

The glidants used in accordance with the present invention may be one or more selected from the group consisting of magnesium stearate, talc, and amorphous silica.

In another aspect, the present invention provides a sustained release carrier, a mixture of 5 to 20 parts by weight solubilizer, a mixture of 100 parts by weight of cilostazol, 10 to 30 parts by weight of hydroxypropylmethylcellulose and 3 to 10 parts by weight of carbomer As a sustained-release formulation for oral administration in which a composition comprising 30 to 70 parts by weight, 1 to 10 parts by weight of a binder, and 2 to 10 parts by weight of a lubricant is molded,

When the dissolution test (37 ± 0.5 ℃, 0.5% sodium lauryl sulfate solution, 50rpm) according to the KEPCO dissolution test method 2 (paddle method) provides an extended release formulation for oral administration characterized in that the following dissolution profile do:

1) 20-30% of the total weight of cilostazol is eluted at 2 hours after the start of the test;

2) 50-70% of the total weight of cilostazol is eluted at 5 hours after the start of the test;

3) More than 85% of the total weight of cilostazol elutes at 10 hours after the start of the test.

In the sustained release formulation, the composition may be a wet granulated granule with ethanol solvent.

Specifically, the ethanol solvent may be used in an amount of 40 to 75 parts by weight based on 100 parts by weight of cilostazol.

In addition, cilostazol may have an average particle diameter of 12 μm or less.

Specifically, the solubilizer is sodium lauryl sulfate, the filler is a mixture of microcrystalline cellulose and colloidal silicon dioxide, the binder is polyvinylpyrrolidone, and the lubricant is magnesium stearate.

According to one embodiment of the present invention, there is provided a sustained release formulation for oral administration in which a composition comprising a sustained release carrier which is a mixture of cilostazol, a hydrophilic polymer and a carbomer, and a solubilizer is formed as an active ingredient,

When the dissolution test (37 ± 0.5 ℃, 0.5% sodium lauryl sulfate solution, 50rpm) according to the method of the Korean Pharmacopoeia dissolution test method (paddle method) provides an extended release formulation for oral administration, characterized in that the following dissolution profile do:

1) 20-30% of the total weight of cilostazol is eluted at 2 hours after the start of the test;

2) 50-70% of the total weight of cilostazol is eluted at 5 hours after the start of the test;

3) More than 85% of the total weight of cilostazol elutes at 10 hours after the start of the test.

The sustained-release preparation according to the present invention is formulated into a sustained-release matrix tablet using a mixture of a hydrophilic polymer and a carbomer and a solubilizing agent as a sustained-release carrier. By using the wet granulated granules with fine control of the amount of ethanol solvent, the dissolution profile can effectively exhibit the drug concentration in the body while showing an appropriate initial dissolution rate.

The elution profile of the sustained release formulation according to the invention is the elution profile at 2, 5 and 10 hour time points obtained in a suitable in vitro dissolution test. Suitable dissolution test can be carried out using a 0.5% sodium lauryl sulfate solution as the dissolution test medium at a 50rpm rotation speed at 37 ± 0.5 ℃ dissolution temperature according to the method of the Korean Pharmacopoeia dissolution test method (paddle method), It can be carried out with some variation in here to the extent well known to those skilled in the art.

Specifically, the sustained-release preparation according to the present invention dissolves 20 to 30% of the total weight of cilostazol at 2 hours after the start of the test, and 50 to 70% of the total weight of cilostazol at 5 hours after the start of the test. Elution and at least 85% of the total weight of cilostazol elute at 10 hours after the start of the test.

If the above dissolution profile is satisfied, it shows an appropriate early dissolution rate, which can reduce the onset of side effects without delaying the expression of the drug, and can effectively maintain the concentration of drug in the body for a certain period of time. It is possible to maintain the efficacy of the sol to improve medication compliance.

According to the present invention, the active ingredient cilostazol may be one having an average particle diameter of 12 μm or less. If the average particle size is larger than 12 µm, the initial dissolution rate is significantly lowered, the release is delayed, and it is difficult to maintain the effective concentration in the blood. Although a minimum is not specifically limited, 5 micrometers is preferable.

According to one embodiment of the present invention, by using cilostazol having an average particle diameter in the above range, 20 to 30% of the total weight of cilostazol is eluted at 2 hours after the start of the test, and 5 hours after the start of the test. 50 to 70% of the total weight of cilostazol is eluted, and showed an elution profile in which more than 85% of the total weight of cilostazol is eluted at 10 hours after the start of the test (FIG. 1, Experimental Example 1).

According to the present invention, a composition comprising as an active ingredient a slow release carrier which is a mixture of cilostazol, a hydrophilic polymer and a carbomer, and a solubilizer can be molded after wet granulation. Preferably, the composition may be wet granulated granules with ethanol solvent.

In order to achieve the object of the present invention, the ethanol solvent may be used in an amount of 40 to 75 parts by weight based on 100 parts by weight of cilostazol. When the amount of the ethanol solvent is less than 40 parts by weight, the finely produced granules are fine, there is no strength of the granulated particles, the fluidity is poor during tableting, a slight capping phenomenon occurs, and the manufacturing efficiency is low, the hardness after tableting is low, and the initial dissolution rate is low. This is a problem that a product having a high dissolution rate of 2 hours and 5 hours does not meet the standard, and when the amount of use exceeds 75 parts by weight, the produced granules are wetting due to poor fluidity, and the strength of the particles is so good that the tablets are compressed after tableting. Since the hardness is too high, the initial dissolution is low, there is a problem that the product is not suitable for 2 hours dissolution rate standards.

According to one embodiment of the present invention, by using the granules using an amount of ethanol that satisfies the above range, it exhibits fluidity suitable for tableting, and satisfies the commercialization of tablets with tablet hardness of 11-13 Kg / cm 2 after tableting Smooth hardness can be achieved, and the dissolution profile was found to be improved (Table 4, FIG. 2, Experimental Examples 2 and 3).

In the present invention, a mixture of a hydrophilic polymer and a carbomer is used as a sustained release carrier. Carbomer is present in a sol state in the stomach in acidic conditions, drug release is maintained by the hydrophilic polymer, in the small intestine in alkaline conditions is present in the hydrogel state to control the release of the drug. In addition, when used with a hydrophilic polymer, it has the effect of strengthening the matrix in the drug, and the expansion of the tablet to maintain the form, by maintaining the matrix of the tablet to prevent the tablet from falling off to maintain a constant dissolution rate.

In the present invention, the hydrophilic polymer that can be used as a sustained release carrier is hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanta, acacia gum, It may be one or more selected from the group consisting of locust bean gum, xanthan gum, alginate, polyvinyl alcohol, and polyvinylpyrrolidone, but is not limited thereto. For example, it may be hydroxypropylmethylcellulose.

The hydrophilic polymer may have a viscosity of 50,000 to 150,000 cps. Preferably, it has a viscosity of 80,000 to 120,000 cps. If the viscosity is less than 50,000 cps, a large amount of hydrophilic polymer is required and the size of the tablet becomes large. If the viscosity exceeds 150,000 cps, uniform mixing with the active ingredient becomes difficult. Even if the viscosity is the same, the particle crushing degree is more uniform, and the physical shape of the product having excellent dispersion is used.

In the present invention, the sustained release carrier may be used in an amount of 10 to 30 parts by weight of the hydrophilic polymer and 3 to 10 parts by weight of carbomer based on 100 parts by weight of cilostazol. Here, when the amount of carbomer is used less than the weight ratio of 1 to 1 compared to the hydrophilic polymer, it is difficult to form a matrix in the tablet, the effect of delaying drug release is reduced, when used in excess of 10: 1, alkaline conditions The dissolution rate of cilostazol decreases and it is difficult to uniformly mix the cilostazol and the water-soluble polymer.

The solubilizer used in accordance with the present invention is a component that aids in the dissolution of the poorly soluble drug cilostazol, sodium lauryl sulfate, polysorbate 80, oleoyl macrogolglycerides, linoleoyl macrogolglycerides, and It may be one or more selected from the group consisting of caprylocaproyl polyoxyglycerides, but is not limited thereto. For example, it may be sodium lauryl sulfate.

The content of the solubilizer may be 5 to 20 parts by weight with respect to 100 parts by weight of cilostazol, and below the range, the drug does not reach the critical micelle concentration, thereby reducing the dissolution rate, making it difficult to exhibit a sufficient pharmacological effect. If it exceeds, there is a fear that the concentration of the free drug decreases and the absorption of the drug decreases.

The sustained-release preparation according to the present invention may include 10 to 30 parts by weight of a hydrophilic polymer, 3 to 10 parts by weight of carbomer, and 5 to 20 parts by weight of a solubilizer based on 100 parts by weight of cilostazol.

Sustained release formulations according to the invention may further comprise fillers, binders, and glidants.

In the case of further comprising a filler, a binder, and a lubricant, the filler may include 30 to 70 parts by weight, 1 to 10 parts by weight, and 2 to 10 parts by weight of the lubricant, based on 100 parts by weight of cilostazol. This is not restrictive.

The filler used according to the present invention may be at least one selected from the group consisting of microcrystalline cellulose, starch, lactose, mannitol, sorbitol, and colloidal silicon dioxide, but is not limited thereto. For example, it may be a mixture of microcrystalline cellulose and colloidal silicon dioxide.

The binder used according to the present invention may be at least one selected from the group consisting of polyvinylpyrrolidone, a copolymer of vinylpyrrolidone / vinyl derivative, and starch, but is not limited thereto. For example, it may be polyvinylpyrrolidone, such as povidone K-30.

The lubricant used according to the present invention may be one or more selected from the group consisting of magnesium stearate, talc, and amorphous silica, but is not limited thereto. For example, it may be magnesium stearate.

According to another embodiment of the present invention, a sustained release carrier which is a mixture of 100 parts by weight of cilostazol, 10 to 30 parts by weight of hydroxypropylmethylcellulose and 3 to 10 parts by weight of carbomer, and 5 to 20 parts by weight of a solubilizer As a sustained-release formulation for oral administration in which a composition comprising 30 to 70 parts by weight of a filler, 1 to 10 parts by weight of a binder, and 2 to 10 parts by weight of a lubricant is molded,

When the dissolution test (37 ± 0.5 ℃, 0.5% sodium lauryl sulfate solution, 50rpm) according to the method of the Korean Pharmacopoeia dissolution test method (paddle method) provides an extended release formulation for oral administration, characterized in that the following dissolution profile do:

1) 20-30% of the total weight of cilostazol is eluted at 2 hours after the start of the test;

2) 50-70% of the total weight of cilostazol is eluted at 5 hours after the start of the test;

3) More than 85% of the total weight of cilostazol elutes at 10 hours after the start of the test.

In this embodiment, the composition may be wet granulated granules with ethanol solvent.

Specifically, the ethanol solvent may be used in an amount of 40 to 75 parts by weight based on 100 parts by weight of cilostazol.

In addition, cilostazol may have an average particle diameter of 12 μm or less.

Specifically, the solubilizer is sodium lauryl sulfate, the filler is a mixture of microcrystalline cellulose and colloidal silicon dioxide, the binder is polyvinylpyrrolidone, the lubricant is magnesium stearate.

Sustained release formulations according to the invention may be formulated according to conventional methods such as granulation, mixing, compression molding. In particular, the sustained release formulations according to the invention can be prepared by a wet granulation process. After cilostazol and excipients are sufficiently mixed as an active ingredient, water-soluble polymers and carbomers and solubilizers are added to a powder mixer as a sustained release carrier, and the mixture is uniformly mixed to prepare wet granules. The amount of ethanol used may be used in an amount of 40 to 75 parts by weight based on 100 parts by weight of cilostazol. If necessary, a small amount of sustained release carrier can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder. The granules thus prepared may be prepared by sufficiently drying in an oven at 60 ° C., then milling evenly, further mixing magnesium stearate for shaping the formulation by post-mixing, and tableting using a rotary tablet machine.

Hereinafter, the configuration and effects of the present invention will be described in more detail with reference to Examples, Comparative Examples and Experimental Examples. However, the following Examples, Comparative Examples and Experimental Examples are provided only for the purpose of illustration in order to facilitate understanding of the present invention, and the scope and scope of the present invention are not limited thereto.

Examples 1-2 and Comparative Examples 1-4: Cilostazol Indeed star according to the particle size of the sol producing a sustained-release preparation

1) Example 1

According to the mixing ratio of Table 1, as the active ingredient, cilostazol having an average particle diameter of 8.61 μm and each excipient are sufficiently mixed, and in addition to the above, hydroxypropylmethylcellulose is added to a powder mixer with a water-soluble polymer, and then uniformly mixed with ethanol. Wet granules were prepared. In wet granulation, ethanol was used in an amount equivalent to 55 parts by weight based on 100 parts by weight of cilostazol. The granules thus prepared are sufficiently dried in an oven at 60 ° C. and then milled evenly, further mixed with magnesium stearate for shaping of the formulation by post-mixing, containing 200 m of cilostazol per tablet using a rotary tablet machine. Tablets were prepared by tableting.

ingredient	Mixing ratio
Cilostazol	100 parts by weight
Carbomer	5 parts by weight
Hydroxypropylmethylcellulose	15 parts by weight
Sodium Lauryl Sulfate	10 parts by weight
Microcrystalline cellulose	50 parts by weight
Povidone K-30	3 parts by weight
Colloidal silicon dioxide	5 parts by weight
Magnesium stearate	4 parts by weight

2) Example 2

A cilostazol sustained-release preparation was prepared in the same manner as in Example 1 except that cilostazol having an average particle diameter of 11.42 μm was used.

3) Comparative Examples 1 to 4

The cilostazol sustained-release preparation was prepared in the same manner as in Example 1 except that cilostazol having an average particle diameter of 12.81 μm, 13.85 μm, 15.43 μm, and 15.65 μm was used, respectively.

The average particle diameter of the cilostazol used in Examples 1 to 2 and Comparative Examples 1 to 4 is as described in Table 2.

	Example 1	Example 2	Comparative Example 1	Comparative Example 2	Comparative Example 3	Comparative Example 4
Average particle size (㎛)	8.61	11.42	12.81	13.85	15.43	15.65

Comparative Examples 5 to 6: Preparation of cilostazol sustained release formulation according to the amount of ethanol solvent

The cilostazol sustained-release preparation was prepared in the same manner as in Example 1 except that 35 parts by weight and 80 parts by weight of ethanol were used for 100 parts by weight of cilostazol in wet granulation.

The amount of ethanol solvent used in Example 1 and Comparative Examples 5 to 6 is as described in Table 3.

	Example 1	Comparative Example 5	Comparative Example 6
Ethanol Consumption	55 parts by weight	35 parts by weight	80 parts by weight

Experimental Example 1: Dissolution test of cilostazol sustained release formulation according to cilostazol particle diameter

A dissolution test was carried out to evaluate the dissolution rate of the cilostazol sustained release formulations of Examples 1 to 2 and Comparative Examples 1 to 4 prepared by varying the average particle diameter of cilostazol.

In the dissolution test, 900 ml of sodium lauryl sulfate (0.5%) solution was used as the dissolution test medium, and 50 revolutions per minute and the dissolution temperature were 37 ± 0.5 ° C. according to the Korean Chemical Dissolution Test No. 2 method (paddle method). . After starting the dissolution test, take 5 ml of the eluate from each container at 0, 15, 30, 60, 90, 120, 180, 300, 360, 480, 600 minutes specified in the test standard, and filter with 0.45 μm membrane filter. This solution was used as the sample solution, and the absorbance At and As were measured at 257 nm using UV (spectrophotometer, Shimadzu, Japan). The dissolution test results are shown in FIG. 1.

As shown in FIG. 1, in Examples 1 and 2 having an average particle diameter of cilostazol of 12 μm or less, 20 to 30% of the total weight of cilostazol was eluted at 2 hours after the start of the test. At time points, 50-70% of the total weight of cilostazol is eluted, and at 10 hours after the start of the test, more than 85% of the total weight of cilostazol is eluted. On the other hand, in Comparative Examples 1 to 4 with an average particle diameter of cilostazol exceeding 12 μm, the mixture was eluted with less than 20% at 2 hours, less than 50% at 5 hours, and less than 85% at 10 hours. The dissolution rate was low and the drug concentration in the body was not effectively maintained over time, and thus it was found to be not suitable as a sustained release preparation.

Experimental Example 2: Dissolution test of cilostazol sustained release formulation according to the amount of ethanol solvent

A dissolution test was carried out to evaluate the dissolution rate of the cilostazol sustained release formulations of Example 1 and Comparative Examples 5 to 6 prepared by varying the amount of ethanol.

In the dissolution test, 900 ml of sodium lauryl sulfate (0.5%) solution was used as the dissolution test medium, and 50 revolutions per minute and the dissolution temperature were 37 ± 0.5 ° C. according to the Korean Chemical Dissolution Test No. 2 method (paddle method). . After starting the dissolution test, take 5 ml of the eluate from each container at 0, 15, 30, 60, 90, 120, 180, 300, 360, 480, 600 minutes specified in the test standard, and filter with 0.45 μm membrane filter. This solution was used as the sample solution, and the absorbance At and As were measured at 257 nm using UV (spectrophotometer, Shimadzu, Japan). The dissolution test results are shown in FIG. 2.

As shown in Figure 2, Example 1 elutes 20-30% of the total weight of cilostazol at 2 hours after the start of the test, and 50-70% of the total weight of cilostazol at 5 hours after the start of the test. Was eluted and showed an elution profile at least 85% of the total weight of cilostazol at 10 hours after the start of the test. On the contrary, in Comparative Example 5, the dissolution rate exceeded 30% at 2 hours and exceeded 70% at 5 hours, so that the initial dissolution rate was excessive and there was a risk of causing side effects. In Comparative Example 6, the dissolution rate at 20 hours was 20%. It was confirmed that less than early dissolution was not suitable for proper drug expression.

Experimental Example 3: Evaluation of Physical Properties of Sustained Release Formulations According to Ethanol Consumption in Granulation

In order to evaluate the physical properties of the cilostazol sustained release preparations of Examples 1 and Comparative Examples 5 to 6 prepared by varying the amount of ethanol solvent, the angle of repose and the hardness of the tablets of the granules prepared by wet granulation were measured.

The angle of repose was measured directly through the funnel of the granules prepared by wet granulation and the angle of repose (θ), which is the angle of the deposited slope.

In the hardness test, 10 tablets were taken for each tablet, and hardness was measured using an ERWEKA hardness tester.

The angle of repose and hardness measurements are shown in Table 4.

	Example 1	Comparative Example 5	Comparative Example 6
Hardness (Kg / ㎠)	11-13	5 ~ 8	18-20
Repose angle (°)	39-42	40-43	≥57

As shown in Table 4, in the case of Example 1, the angle of repose (39 ~ 42 °) showed a suitable fluidity for tableting, the tablet hardness after tableting is 11 ~ 13 Kg / ㎠ to achieve a satisfactory hardness for commercialization It was confirmed that it can. On the other hand, in Comparative Example 5 the strength of the granules were a lot of fine powder was generated, there is no strength in the particles and the angle of repose of the granules showed more than 50 ~ 55 ° fluidity not suitable for tableting. In addition, a low hardness (5 ~ 8 Kg / ㎠) and some capping phenomenon occurred after tableting.

In the case of Comparative Example 6, the amount of ethanol added during the preparation of the granules was too high, the granule dough properties were too high, and the hardness of the prepared granules was also so strong that the tablets had a high hardness of 18-20 Kg / cm 2 after tableting. Due to the hardness, elution of the main component did not occur smoothly, and the repose angle of the granules also showed a fluidity that was unable to proceed smooth tableting above 57 °.

Claims (18)

1. As an oral sustained release preparation in which a composition comprising a sustained release carrier which is a mixture of cilostazol, a hydrophilic polymer and a carbomer, and a solubilizing agent is formed as an active ingredient,

   Sustained release preparation for oral administration which shows the following dissolution profile in the dissolution test (37 ± 0.5 ° C., 0.5% sodium lauryl sulfate solution, 50rpm) according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method):

   1) 20-30% of the total weight of cilostazol is eluted at 2 hours after the start of the test;

   2) 50-70% of the total weight of cilostazol is eluted at 5 hours after the start of the test;

   3) More than 85% of the total weight of cilostazol elutes at 10 hours after the start of the test.
2. The sustained-release preparation for oral administration according to claim 1, wherein the composition is a wet granulated granule with ethanol solvent.
3. The sustained-release preparation for oral administration according to claim 2, wherein the ethanol solvent is used in an amount of 40 to 75 parts by weight based on 100 parts by weight of cilostazol.
4. The sustained-release preparation for oral administration according to claim 1, wherein the cilostazol has an average particle diameter of 12 µm or less.
5. The method of claim 1, wherein the hydrophilic polymer is hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanta, acacia gum, locust bean gum, xanthan gum The sustained-release preparation for oral administration which is at least one selected from the group consisting of alginate, polyvinyl alcohol and polyvinylpyrrolidone.
6. The sustained-release preparation for oral administration according to claim 1, wherein the hydrophilic polymer has a viscosity of 50,000 to 150,000 cps.
7. The solubilizer of claim 1 wherein the solubilizer is selected from the group consisting of sodium lauryl sulfate, polysorbate 80, oleoyl macrogolglycerides, linoleoyl macrogolglycerides, and caprylocaproyl polyoxyglycerides. Sustained release preparation for oral administration that is at least one species.
8. The sustained-release preparation for oral administration according to claim 1, comprising 10 to 30 parts by weight of a hydrophilic polymer, 3 to 10 parts by weight of carbomer, and 5 to 20 parts by weight of a solubilizer based on 100 parts by weight of cilostazol.
9. The sustained-release preparation for oral administration according to claim 1, further comprising a filler, a binder, and a lubricant.
10. The sustained-release preparation for oral administration according to claim 9, wherein the filler is 30 to 70 parts by weight, the binder is 1 to 10 parts by weight, and the lubricant is 2 to 10 parts by weight based on 100 parts by weight of cilostazol.
11. The sustained-release preparation for oral administration according to claim 9, wherein the filler is at least one selected from the group consisting of microcrystalline cellulose, starch, lactose, mannitol, sorbitol, and colloidal silicon dioxide.
12. The sustained-release preparation for oral administration according to claim 9, wherein the binder is at least one selected from the group consisting of polyvinylpyrrolidone, a copolymer of vinylpyrrolidone / vinyl derivative, and starch.
13. The sustained-release preparation for oral administration according to claim 9, wherein the lubricant is at least one selected from the group consisting of magnesium stearate, talc, and amorphous silica.
14. Sustained release carrier which is a mixture of 100 parts by weight of cilostazol, 10 to 30 parts by weight of hydroxypropylmethylcellulose and 3 to 10 parts by weight of carbomer, 5 to 20 parts by weight of solubilizer, 30 to 70 parts by weight of filler, binder As a sustained release preparation for oral administration in which the composition containing 1-10 weight part and 2-10 weight part of lubricants is shape | molded,

    Sustained release preparation for oral administration which shows the following dissolution profile in the dissolution test (37 ± 0.5 ° C., 0.5% sodium lauryl sulfate solution, 50rpm) according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method):

    1) 20-30% of the total weight of cilostazol is eluted at 2 hours after the start of the test;

    2) 50-70% of the total weight of cilostazol is eluted at 5 hours after the start of the test;

    3) More than 85% of the total weight of cilostazol elutes at 10 hours after the start of the test.
15. The sustained-release preparation for oral administration according to claim 14, wherein the composition is a wet granulated granule with ethanol solvent.
16. The sustained-release preparation for oral administration according to claim 15, wherein the ethanol solvent is used in an amount of 40 to 75 parts by weight based on 100 parts by weight of cilostazol.
17. The sustained-release preparation for oral administration according to claim 14, wherein the cilostazol has an average particle diameter of 12 µm or less.
18. 15. The oral dosage form of claim 14, wherein the solubilizer is sodium lauryl sulfate, the filler is a mixture of microcrystalline cellulose and colloidal silicon dioxide, the binder is polyvinylpyrrolidone, and the lubricant is magnesium stearate. Sustained release preparations.

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