PH12015000296A1

PH12015000296A1 - Oral sustained release formulation

Info

Publication number: PH12015000296A1
Application number: PH12015000296A
Authority: PH
Inventors: Choi Youn Woong; Min Byung Gu; Cho Sang Min; Jang Jae Sang; Choi Ji Hyun
Original assignee: Korea United Pharm Inc
Priority date: 2015-05-29
Filing date: 2015-09-03
Publication date: 2017-03-13
Also published as: TWI732762B; RU2017140447A; AR134066A2; RU2696870C2; WO2016195154A1; RU2017140447A3; KR101748215B1; AR104811A1; KR20160141253A; PH12015000296B1; TW201707688A

Abstract

Provided is an oral sustained release formulation, in which the sustained release formulation of the present invention exhibits a proper initial dissolution rate and a dissolution profile capable of effectively maintaining the drug concentration in the body, thereby reducing generation of side effects while maintaining efficacy of cilostazol even through taken once daily, and also improving drug compliance.

Description

LL

ORAL SUSTAINED RELEASE FORMULATION o

Ia .

BACKGROUND OF THE INVENTION = 1. Field of the Invention

The present invention relates to an oral sustained release formulation including cilostazol. 2. Description of the Related Art =

Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-butoxy]-3,4-dihydro-2(1H)- - quinolinone which is a quinolinone-based compound represented by the following

Chemical Formula 1, and is a representative intracellular cAMP PDE type III (cyclic

AMP phosphodiesterase type III) inhibitor. [Chemical Formula 1] Crm pap errs

Wt por ert

LI

0” N 7

Cilostazol plays roles in suppression of blood coagulation, promotion of central blood circulation, anti-inflammation and anti-ulcer actions, depression of blood pressure, prevention and treatment of asthma and cerebral infarction, and improvement of cerebral circulation by suppressing platelet coagulation and dilating the arteries through the inhibition of PDE activity when absorbed into the body. Therefore, cilostazol has been widely used as a thrombolytic agent, a cerebral circulation improving agent, an anti- phlogistic drug, an anti-tumor agent, a hypotensive agent, and an anti-asthmatic agent.

Conventional cilostazol preparations are orally administered twice daily, and disadvantageous in that they have poor patient compliance, and they cause side effects such as headache, heavy headedness and tachycardia with a sudden increase in the blood drug concentration when administered orally. Cilostazol is a poorly soluble drug oo © having a water-solubility of 1 pg/mL or less, and it has been demonstrated that cilostazol - is absorbed mainly in the upper gastrointestinal tract and its absorption decreases as it ~ moves to the lower intestinal tract. Therefore, it is apprehended that an ordinary © controlled release formulation of cilostazol has poor bioavailability. Accordingly, there “1 have been numerous attempts to develop a sustained or controlled release formulation of - cilostazol that is free from the above problems. | ne cote on )

In detail, International Patent Publication No.W097/48382 discloses a sustained _ release formulation of cilostazol of a multiple unit form including at least 2 mini tablets = prepared using hydroxypropylmethylcellulose as a main matrix. This matrix-type C sustained release tablet can be easily prepared using a typical preparation technique and equipment. However, once the matrix structure is disintegrated, rapid release of the drug occurs, causing a transient increase in the blood drug concentration. Further, poorly soluble drugs such as cilostazol may not be fully dissolved even after the matrix structure is disintegrated, resulting in uneconomical problems. Moreover, they have low initial release rates due to characteristics of the matrix structure, which becomes a drawback when a rapid release is required. Thus, it is difficult to obtain an advantage as a sustained release formulation. In order to solve these problems, International

Patent Publication No.WO00/57881 and US Patent Publication No.2002/0058066 have suggested a formulation including an external layer and a core, in which the external layer slowly releases the drug in the upper gastrointestinal tract (the small intestine) and the core disintegrates and releases the drug rapidly in the lower small intestine and the colon. However, this formulation has the problems that rapid drug release in the lower small intestine and the colon may cause irritation and damage of the colonic mucosal layer, and irregular dissolution of the poorly soluble drug may occur in the colon where the water content is relatively low, leading to an irregular absorption rate and absorption ratio, the preparation process thereof is very complicated because the formulation consists of a rapid release core and an external layer surrounding the core, and the large volume of the tablet reduces patients’ drug compliance. a :

be typ : IR wdmaet fondo ledion

Ts

Accordingly, it is necessary to develop a sustained release formulation in order to i reduce side effects caused by a high dissolution rate of the conventional cilostazol . formulations immediately after taken. However, in the case of the sustained release ~ formulations under development, drug release is still difficult to control. Thus, there is oe a need to develop a sustained release cilostazol formulation which simply delays release = of the drug and also exhibits a stable dissolution rate when taken once daily. 4

Accordingly, the present inventors have made many efforts to solve the problems ol of the sustained release formulation of the poorly soluble cilostazol, and as a result, they - found that when cilostazol is formulated into a sustained release matrix tablet using a mixture of a hydrophilic polymer and a carbomer as a sustained release carrier and a solubilizing agent, cilostazol having an average particle size within a particular range is ~~ » used and granules wet-granulated by precisely controlling an amount of ethanol solvent are used so as to prepare a sustained release formulation having a proper initial dissolution rate and a dissolution profile capable of effectively maintaining the drug concentration in the body, thereby completing the present invention.

SUMMARY OF THE INVENTION

In order to solve the problems of the conventional sustained release cilostazol tablets, an object of the present invention is to provide a sustained release formulation having a proper initial dissolution rate and a dissolution profile capable of effectively maintaining the drug concentration in the body.

In order to achieve the above object, an aspect of the present invention provides an oral sustained release formulation which is prepared by molding a composition including cilostazol as an active ingredient, a mixture of a hydrophilic polymer and a carbomer as a sustained release carrier, and a solubilizing agent, characterized in that the oral sustained release formulation exhibits the following dissolution profile when it is subjected to a dissolution test according to the second method of Korean Pharmacopoeia ©

Dissolution Test (a paddle method) (37£0.5°C, 0.5% sodium lauryl sulfate solution, 50 ® pm): - 1) 20% to 30% of the total weight of cilostazol is released at the time point of 2 - hours after initiation of the test; . 2) 50% to 70% of the total weight of cilostazol is released at the time point of 5 = hours after initiation of the test; and 0 3) at least 85% of the total weight of cilostazol is released at the time point of 10 = hours after initiation of the test. x =

In the sustained release formulation according to the present invention, the composition may be a granule that is wet-granulated using an ethanol solvent.

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

According to the present invention, the active ingredient cilostazol may have an average particle size of 12 um or less.

In the present invention, the hydrophilic polymer used as the sustained release carrier may be one or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanth, arabic gum, locust bean gum, xanthan gum, alginate, polyvinyl alcohol, and polyvinyl pyrrolidone.

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

The solubilizing agent used according to the present invention may be one or © more selected from the group consisting of sodium lauryl sulfate, polysorbate 80, oleoyl = macrogolglyceride, linoleoyl macrogolglyceride, and caprylocaproyl polyoxylglyceride. "

The sustained release formulation according to the present invention may include ~ parts by weight to 30 parts by weight of the hydrophilic polymer, 3 parts by weight to + 10 parts by weight of the carbomer, and 5 parts by weight to 20 parts by weight of the J solubilizing agent, based on 100 parts by weight of cilostazol. = = 10 The sustained release formulation according to the present invention may further = include a filler, a binder and a lubricant.

Specifically, the sustained release formulation may include 30 parts by weight to 70 parts by weight of the filler, 1 part by weight to 10 parts by weight of the binder, and 2 parts by weight to 10 parts by weight of the lubricant, based on 100 parts by weight of cilostazol.

The filler used according to the present invention may be one or more 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 one or more selected from the group consisting of polyvinyl pyrrolidone, a copolymer of a vinyl pyrrolidone/vinyl derivative, and starch.

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.

Another aspect of the present invention provides an oral sustained release 2 formulation prepared by molding a composition including 100 parts by weight of © diostazol as an active ingredient, a mixture of 10 parts by weight to 30 parts by weight oO of | hydroxypropylmethylcellulose and 3 parts by weight to 10 parts by weight of - carbomer as a sustained release carrier, 5 parts by weight to 20 parts by weight of the . solubilizing agent, 30 parts by weight to 70 parts by weight of the filler, 1 part by weight He to 10 parts by weight of the binder, and 2 parts by weight to 10 parts by weight of the 0 lubricant, characterized in that the oral sustained release formulation exhibits the eT following dissolution profile when it is subjected to a dissolution test according to the y second method of Korean Pharmacopoeia Dissolution Test (a paddle method) (37+0.5°C, o 0.5% sodium lauryl sulfate solution, 50 rpm): 1) 20% to 30% of the total weight of cilostazol is released at the time point of 2 hours after initiation of the test; 2) 50% to 70% of the total weight of cilostazol is released at the time point of 5 hours after initiation of the test; and 3) at least 85% of the total weight of cilostazol is released at the time point of 10 hours after initiation of the test.

In the sustained release formulation, the composition may be a granule that is wet-granulated using an ethanol solvent.

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

Further, cilostazol may have an average particle size of 12 um or less.

Specifically, the solubilizing agent may be sodium laiiryl sulfate, the filler may be a mixture of microcrystalline cellulose and colloidal silicon dioxide, the binder may be polyvinyl pyrrolidone, and the lubricant may be magnesium stearate,’

An oral sustained release formulation according to the present invention exhibits = a proper initial dissolution rate and a dissolution profile capable of effectively . maintaining the drug concentration in the body, thereby reducing generation of side ~ effects while maintaining efficacy of cilostazol even though taken once daily, and also - improving drug compliance. + 7

BRIEF DESCRIPTION OF THE DRAWINGS =

FIG. 1 shows a dissolution profile of a sustained release cilostazol formulation ~ according to an average particle size of cilostazol; and >

FIG. 2 shows a dissolution profile of a sustained release cilostazol formulation according to an amount of ethanol solvent.

DETAILED DESCRIPTION OF THE PREF ERRED EMBODIMENTS

According to a specific embodiment of the present invention, provided is an oral sustained release formulation prepared by molding a composition including cilostazol as an active ingredient, a mixture of a hydrophilic polymer and a carbomer as a sustained release carrier, and a solubilizing agent, characterized in that the oral sustained release formulation exhibits the following dissolution profile when it is subjected to a dissolution test according to the second method of Korean Pharmacopoeia Dissolution

Test (a paddle method) (37+0.5°C, 0.5% sodium lauryl sulfate solution, 50 rpm): ; 1) 20% to 30% of the total weight of cilostazol is released at the time point of 2 hours after initiation of the test; 2) 50% to 70% of the total weight of cilostazol is released at the time point of 5 hours after initiation of the test; and 3) at least 85% of the total weight of cilostazol is released at the time point of 10 hours after initiation of the test. :

In the sustained release formulation according to the present invention, a mixture + of the hydrophilic polymer and carbomer as a sustained release carrier and the = solubilizing agent may be used to formulate cilostazol into a sustained release matrix ~ tablet, in which cilostazol having an average particle size within a particular range is ~ used and granules wet-granulated by precisely controlling an amount of ethanol solvent pos are used, whereby the sustained release formulation has a proper initial dissolution rate : and a dissolution profile capable of effectively maintaining the drug concentration in the ~ body. 5 fo

LI

The dissolution profile of the sustained release formulation according to the - present invention is a dissolution profile at the time points of 2 hours, 5 hours, and 10 hours, which is obtained by a suitable in-vitro dissolution test. The suitable dissolution test may be performed at a dissolution temperature of 37+0.5°C using a 0.5% sodium lauryl sulfate solution as a dissolution test medium at a rotation speed of 50 rpm according to the second method of Korean Pharmacopoeia Dissolution Test (a paddle method), and a partial modification as known to those skilled in the art may be made hereto.

Specifically, from the sustained release formulation according to the present invention, 20% to 30% of the total weight of cilostazol is released at the time point of 2 hours after initiation of the test, 50% to 70% of the total weight of cilostazol is released at the time point of 5 hours after initiation of the test, and at least 85% of the total weight of cilostazol is released at the time point of 10 hours after initiation of the test.

If the sustained release formulation satisfies such dissolution profile, it exhibits a proper initial dissolution rate, and thus incidence of side-effects may be reduced without delay of efficacy, and the drug concentration in the body may be maintained for a predetermined time. Consequently, efficacy of cilostazol may be maintained even © when taken once a day, leading to improvement of drug compliance. o v

According to the present invention, the active ingredient cilostazol may have an i

Lr average particle size of 12 um or less. If the average particle size is larger than 12 pm, in the initial dissolution rate is remarkably decreased, resulting in delayed drug release. Ne . ’ Thus, it is difficult to maintain the effective drug concentration in the blood. The lower 7 limit is not particularly limited, but preferably, is 5 um. wo o 10 According to an embodiment of the present invention, when cilostazol having an we average particle size within the above range was used, the formulation exhibited the following dissolution profile: 20% to 30% of the total weight of cilostazol was released at the time point of 2 hours after initiation of the test, 50% to 70% of the total weight of cilostazol was released at the time point of 5 hours after initiation of the test, and 85% at least of the total weight of cilostazol was released at the time point of 10 hours after initiation of the test (FIG. 1, Experimental Example 1).

According to the present invention, a composition including cilostazol as an active ingredient, a mixture of the hydrophilic polymer and carbomer as a sustained release carrier, and the solubilizing agent may be wet-granulated and then molded.

Preferably, the composition may be a granule prepared by wet-granulation using an ethanol solvent.

In order to achieve the object of the present invention, the ethanol solvent may be used in an amount of 40 parts by weight to 75 parts by weight, based on 100 parts by weight of cilostazol. If the amount of the ethanol solvent is less than 40 parts by weight, fine powder of the granule is produced in a large amount, the granule particles become weak, and fluidity is poor and slight capping occurs during tableting so as to reduce the

SE - Cg | : i - = preparation efficiency, and after tableting, hardness is low and initial dissolution rate is & high. Thus, there is a problem in that a product fails to meet the dissolution rate at 2 = hours and 5 hours. If the amount of the ethanol solvent is more than 75 parts by weight, the produced granules are too wet to have good fluidity and the particles are strong, and = after tableting, hardness is too high and initial dissolution rate becomes low. Thus, . there is a problem in that a product fails to meet the dissolution rate at 2 hours. = 7

According to an embodiment of the present invention, when granules prepared by om using ethanol in an amount satisfying the above range were used, fluidity suitable for © tableting was obtained, and the tablet had hardness of 11 kg/cm? to 13 kg/cm? after © tableting, so as to obtain a product of satisfactory hardness, and the dissolution profile was also improved (Table 4, FIG. 2, Experimental Examples 2 and 3).

In the present invention, a mixture of the hydrophilic polymer and the carbomer is used as a sustained release carrier. The carbomer is present in a sol state in the stomach under acidic conditions so that the drug release can be maintained by the hydrophilic polymer. The carbomer is present in a hydrogel state in the small intestine under alkaline conditions so that the drug release can be controlled. When the carbomer is used together with the hydrophilic polymer, the carbomer functions to solidly form a matrix in the tablet, maintain the shape of the matrix due to swelling of the tablet, and prevent erosion of the tablet, which makes it possible to maintain a constant dissolution rate. Cal yo

In the present invention, the hydrophilic polymer used as the sustained release carrier may be one or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanth, arabic gum, locust bean gum, xanthan gum, alginate, polyvinyl alcohol, and polyvinyl pyrrolidone, but is not limited thereto. For example, the hydrophilic polymer may be © ‘hydroxypropylmethyleellulose. o ¥

The hydrophilic polymer may have a viscosity of 50,000 cps to 150,000 cps, and ~ preferably, 80,000 cps to 120,000 cps. If the viscosity is less than 50,000 cps, a large ~ amount of hydrophilic polymer is required, which leads to an increase in the tablet size. =

If the viscosity exceeds 150,000 cps, the active ingredient may not be uniformly mixed 2 therewith. Although having the same viscosity, a product having consistent particle © uniformity, excellent dispersibility, and a good physical form may be used. ~ fed

In the present invention, 10 parts by weight to 30 parts by weight of the hydrophilic polymer and 3 parts by weight to 10 parts by weight of the carbomer may be used as the sustained release carrier, based on 100 parts by weight of cilostazol. Here, if the weight ratio of carbomer to hydrophilic polymer is less than 1:1, a matrix may not be easily formed in the tablet, and thus the delay of drug release may not work properly.

If the weight ratio exceeds 10:1, a dissolution rate of cilostazol under alkaline conditions may be decreased, and the cilostazol and the hydrophilic polymer may not be mixed uniformly.

The solubilizing agent used according to the present invention is a component that assists in dissolution of the poorly soluble drug cilostazol and it may be one or more selected from the group. consisting of sodium lauryl sulfate, polysorbate 80, oleoyl macrogolglyceride, linoleoyl macrogolglyceride, and caprylocaproyl polyoxylglyceride, but is not limited thereto. For example, the solubilizing agent may be sodium lauryl sulfate.

The content of the solubilizing agent may be 5 parts by weight to 20 parts by weight, based on 100 parts by weight of cilostazol. If the content is lower than the 11 1 above range, the drug does not reach a critical micelle concentration to reduce the o dissolution rate, and thus it is difficult to obtain sufficient pharmaceutical effects. On © the contrary, if the content exceeds the above range, the concentration of the released y drug may be decreased to reduce absorption of the drug. - ; ;

The sustained release formulation according to the present invention may include be parts by weight to 30 parts by weight of the hydrophilic polymer, 3 parts by weight to . 10 parts by weight of the carbomer, 5 parts by weight to 20 parts by weight of the = solubilizing agent, based on 100 parts by weight of cilostazol. ro 10 -

The sustained release formulation according to the present invention may further include a filler, a binder, and a lubricant.

If the sustained release formulation according to the present invention may further include a filler, a binder, and a lubricant, it may include 30 parts by weight to 70 parts by weight of the filler, 1 part by weight to 10 parts by weight of the binder, 2 parts by weight to 10 parts by weight of the lubricant, based on 100 parts by weight of cilostazol, but is not limited thereto.

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

The binder used according to the present invention may be one or more selected from the group consisting of polyvinyl pyrrolidone, a copolymer of a vinyl pyrrolidone/vinyl derivative, and starch, but is not limited thereto. For example, the binder may be polyvinyl pyrrolidone such as Povidone K-30.

rin

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

Ja

According to another specific embodiment of the present invention, provided is . an oral sustained release formulation, prepared by molding a composition including 100 parts by weight of cilostazol as an active ingredient, a mixture of 10 parts by weight to = 30 parts by weight of hydroxypropylmethylcellulose and 3 parts by weight to 10 parts by 5 weight of the carbomer as a sustained release carrier, 5 parts by weight to 20 parts by - weight of the solubilizing agent, 30 parts by weight to 70 parts by weight of the filler, 1 part by weight to 10 parts by weight of the binder, and 2 parts by weight to 10 parts by weight of the lubricant, characterized in that the oral sustained release formulation exhibits the following dissolution profile when it is subjected to a dissolution test according to the second method of Korean Pharmacopoeia Dissolution Test (a paddle method) (37+0.5°C, 0.5% sodium lauryl sulfate solution, 50 rpm): 1) 20% to 30% of the total weight of cilostazol is released at the time point of 2 hours after initiation of the test; 2) 50% to 70% of the total weight of cilostazol is released at the time point of 5 hours after initiation of the test; and 3) at least 85% of the total weight of cilostazol is released at the time point of 10 hours after initiation of the test.

In the specific embodiment, the composition may be a granule that is wet- granulated using an ethanol solvent.

FE

Further, cilostazol may have an average particle size of 12 um or less. =

Specifically, the solubilizing agent may be sodium lauryl sulfate, the filler may ~ be a mixture of microcrystalline cellulose and colloidal silicon dioxide, the binder may } be polyvinyl pyrrolidone, and the lubricant may be magnesium stearate. =

O

The sustained release formulation according to the present invention may be @ formulated by a conventional method such as granulation, mixing, and compression 2 molding. Specifically, the sustained release formulation according to the present invention may be prepared by a wet-granulation process. Cilostazol as an active ni. iviinicu ingredient and excipients are sufficiently mixed, and then a mixture of a hydrophilic wa polymer and a carbomer as a sustained release carrier, and a solubilizing agent are Cr uniformly mixed with each other in a powder mixer. Ethanol is added thereto to . prepare wet granules. The amount of ethanol used may be 40 parts by weight to 75 N parts by weight, based on 100 parts by weight of cilostazol. If necessary, a small amount of the sustained release carrier is dissolved in water or a mixed solvent of alcohol, and used for granulation of powder. The prepared granules are sufficiently dried in an Co oven at 60°C, and uniformly milled. Magnesium stearate is further mixed for molding the formulation, and tableting is performed using a rotary tabletter.

Hereinafter, the constitution and effect 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 for illustrative purposes only, and the scope and range of the present invention are not intended to be limited thereto.

Examples 1 to 2 and Comparative Examples 1 to 4: Preparation of sustained release cilostazol formulations by varying particle size of cilostazol “

1) Example 1 ~

According to a mixing ratio of Table 1, cilostazol having an average particle size = ! of 8.61 um as an active ingredient and respective excipients were sufficiently mixed. o

Then, hydroxypropylmethylcellulose as a hydrophilic polymer was further added thereto, - and they were uniformly mixed in a powder mixer. Thereafter, wet granules were Nn prepared using ethanol. Upon wet granulation, 55 parts by weight of ethanol was used, . based on 100 parts by weight of cilostazol. The prepared granules were sufficiently - dried in an oven at 60°C, and uniformly milled. Magnesium stearate was further mixed & for molding of the formulation, and tableting was performed using a rotary tabletter so as > to prepare tablets containing 200 mg of cilostazol per tablet. [Table 1] oy 2) Example 2

A sustained release cilostazol formulation was prepared in the same manner as in

Example 1, except that cilostazol having an average particle size of 11.42 um was used. 3) Comparative Examples 1 to 4 oo

A sustained release cilostazol formulation was prepared in the same manner as in -

Lo

Example 1, except that cilostazol having an average particle size of 12.81 pm, 13.85 pm, w

Fon! 15.43 pum, or 15.65 um was used. = [a . . foe

The average particle size of cilostazol used in Examples 1 to 2 and Comparative I

Examples 1 to 4 is as given in Table 2. Lr [Table 2] 5

Comparative| Comparative Comparative | Comparative on

Example 1|Example 2

Example 1 | Example 2 | Example 3 | Example 4

Average particle 8.61 11.42 12.81 13.85 15.43 15.65 size (um)

Comparative Example 5 to 6: Preparation of sustained release cilostazol formulations by varying amount of ethanol solvent

Example 1, except that upon wet granulation, 35 parts by weight or 80 parts by weight of ethanol was used based on 100 parts by weight of cilostazol.

The amounts of ethanol solvent used in Example 1 and Comparative Examples 5 to 6 are as given in Table 3. [Table 3]

Comparative Comparative

Example 1

Example 5 Example 6

Amount of ethanol | 55 parts by weight | 35 parts by weight | 80 parts by weight

©

La

Experimental Example 1: Dissolution test of sustained release cilostazol = formulations prepared by varying particle sizes of cilostazol -

To evaluate the dissolution rates of the sustained release cilostazol formulations - prepared by varying the average particle size of cilostazol in Examples 1 to 2 and .

Comparative Examples 1 to 4, a dissolution test was performed.

The dissolution test was performed using 900 mL of sodium lauryl sulfate (0.5%) = solution as a dissolution test medium at a rotation speed of 50 rpm and a dissolution > temperature of 37+0.5°C according to the second method of Korean Pharmacopoeia -

Dissolution Test (a paddle method). Each 5 mL of dissolution medium was sampled at predetermined time points of 0, 15, 30, 60, 90, 120, 180, 300, 360, 480, and 600 minutes after initiation of the dissolution test, and filtered using a 0.45 um membrane filter. The resulting solutions were used as test solutions. The absorbances (At and As) of test and standard solutions at 257 nm were determined using a UV spectrophotometer (Shimadzu,

Japan). The results of the dissolution test are given in FIG. 1.

As shown in FIG. 1, when cilostazol having an average particle size of 12 pm or less was used in Examples 1 and 2, the formulations exhibited a dissolution profile in which 20% to 30% of the total weight of cilostazol was released at the time point of 2 hours after initiation of the test, 50% to 70% of the total weight of cilostazol was released at the time point of 5 hours after initiation of the test, and at least 85% of the total weight of cilostazol was released at the time point of 10 hours after initiation of the test. On the contrary, when cilostazol having an average particle size of more than 12 um was used in Comparative Examples 1 to 4, a dissolution rate was less than 20% at the time point of 2 hours, less than 50% at the time point of 5 hours, and less than 85% at the time point of 10 hours, and their initial dissolution rate was low and the drug concentrations in the body were not effectively maintained over time, indicating that - these formulations are not suitable as sustained release formulations. c

Experimental Example 2: Dissolution test of sustained release cilostazol ~~ 5 formulations prepared by varying amount of ethanol solvent .

To evaluate the dissolution rates of the sustained release cilostazol formulations a prepared by varying the amount of ethanol solvent in Example 1 and Comparative 0

Examples 5 to 6, a dissolution test was performed.

The dissolution test was performed using 900 mL of sodium lauryl sulfate (0.5%) . solution as a dissolution test medium at a rotation speed of 50 rpm and a dissolution ~ temperature of 37+0.5°C according to the second method of Korean Pharmacopoeia

Japan). The results of the dissolution test are given in FIG. 2.

As shown in FIG. 2, Example 1 exhibited a dissolution profile in which 20% to 30% of the total weight of cilostazol was released at the time point of 2 hours after initiation of the test, 50% to 70% of the total weight of cilostazol was released at the time point of 5 hours after initiation of the test, and at least 85% of the total weight of cilostazol was released at the time point of 10 hours after initiation of the test. On the contrary, Comparative Example 5 showed a dissolution rate of more than 30% at the time point of 2 hours and a dissolution rate of more than 70% at the time point of S hours, indicating an excessively high initial dissolution rate and high risk of side effects.

Comparative Example 6 showed a dissolution rate of less than 20% at the time point of 2 ,

hours, indicating that its initial dissolution hardly occurred and this formulation is not o suitable to obtain proper efficacy. = y

Experimental Example 3: Test of physical properties of sustained release ~ formulations prepared by varying amount of ethanol upon granulation ~

To evaluate the physical properties of the sustained release cilostazol i” formulations prepared by varying the amount of ethanol solvent in Example 1 and 7

Comparative Examples 5 to 6, an angle of repose of granules prepared by wet © granulation and hardness of tablets were determined.

To determine the angle of repose, granules prepared by wet granulation were oe passed through a funnel, and the angle of repose (0) which is an angle of a ridge line of the granules deposited was directly measured.

In the hardness test, hardness of each of 10 tablets was measured using an

ERWEKA hardness tester.

Results of measuring an angle of repose and hardness are given in Table 4. [Table 4] eT

Example 1

Example 5 Example 6

As shown in Table 4, Example 1 showed an angle of repose of 39° to 42°, indicating that the fluidity is suitable for tableting, and showed a tablet hardness of 11 kg/cm? to 13 kg/cm? after tableting, indicating that a product of satisfactory hardness can be obtained. On the contrary, in Comparative Example 5, granules showed low hardness to generate a large amount of fine powder, and particles were weak and granules showed an angle of repose of 50° to 55° or higher, indicating that the fluidity is o not suitable for tableting. Further, low hardness (5 kg/cm? to 8 kg/cm?) and slight @ capping were observed after tableting.

In Comparative Example 6, excessive ethanol was injected during granulation so = that the granule paste became too watery, and the prepared granules were too hard, such . that tablets had high hardness of 18 kg/cm? to 20 kg/cm? after tableting. Therefore, the = active ingredient was not easily released, and granules showed an angle of repose of 57° J or higher, indicating that the fluidity is not suitable for tableting. CE > 0 2