TWI732762B - Oral sustained release formulation - Google Patents

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 though taken once daily, and also improving drug compliance.

Description

Oral sustained release formulations

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

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

When absorbed into the body, the role of cilostazol is to suppress blood coagulation, promote central blood circulation, anti-inflammatory and anti-ulcer effects, lower blood pressure, prevent and treat asthma and cerebral infarction, and suppress platelet coagulation and inhibit PDE activity. Expand arteries and improve central circulation. Therefore, cilostazol is widely used as a thrombolytic agent, a cerebral circulation improving agent, an anti-inflammatory agent, an antitumor agent, a blood pressure lowering agent, and an antiasthmatic agent.

The traditional cilostazol preparation is orally administered twice a day, and its The disadvantage is that patients have poor compliance and cause side effects such as headache, heavy head and tachycardia that suddenly increase the concentration of the drug in the blood during oral administration. Cilostazol is a poorly soluble drug having a water solubility of 1 μg/mL or less, and it has been confirmed that cilostazol is mainly absorbed in the upper digestive tract, and the absorption decreases when it moves to the lower intestinal tract. Therefore, there is a concern that the bioavailability of the general regulated release formulation of cilostazol is poor. Accordingly, there have been many attempts to develop sustained or controlled release formulations of cilostazol that do not have the above-mentioned problems.

In detail, International Patent Publication No. WO97/48382 discloses a multi-unit form of cilostazol sustained-release formulation, which contains at least two mini-tablets prepared using hydroxypropyl methylcellulose as the main matrix. This matrix-type sustained-release lozenge can be easily prepared using general manufacturing techniques and equipment. However, once the matrix structure disintegrates, rapid drug release occurs, resulting in a transient increase in blood drug concentration. Furthermore, poorly soluble drugs such as cilostazol may not be completely dissolved even after the matrix structure is disintegrated, leading to uneconomical problems. Furthermore, due to the characteristics of the matrix structure, it has a low initial release rate, which becomes a disadvantage when rapid release is required. Therefore, the advantage as a sustained-release formulation cannot be obtained. In order to solve these problems, International Patent Publication No. WO00/57881 and US Patent Publication No. 2002/0058066 have proposed a formulation that includes an outer layer and a core, wherein the outer layer is slowly released in the upper digestive tract (small intestine) The drug and the core disintegrate in the lower part of the small intestine and colon and release the drug quickly. However, this formulation has the following problems: the rapid release of drugs in the lower part of the small intestine and colon may cause irritation and damage to the colonic mucosa, and irregular dissolution of insoluble drugs may occur in the colon with relatively low water content. And cause irregular sucking The recovery rate and absorption ratio, because the formulation is composed of a fast-release core and an outer layer surrounding the core, the preparation method is very complicated, and the large volume of the lozenge reduces the patient's medication compliance.

Accordingly, in order to reduce the side effects caused by the high dissolution rate of traditional cilostazol formulations immediately after administration, it is necessary to develop sustained-release formulations. However, in the case of developing sustained-release formulations, it is still difficult to control drug release. Therefore, there is a need to develop sustained-release cilostazol formulations that simply delay drug release and exhibit a stable dissolution rate when taken once a day.

Accordingly, the inventors of the present invention have made many efforts to solve the problem of sustained-release formulations of insoluble cilostazol. As a result, they found that a mixture of hydrophilic polymers and carbomers was used as a sustained-release formulation. When cilostazol is formulated into a sustained-release matrix tablet as a carrier and cosolvent, it is made by using cilostazol with an average particle size within a specific range and using a wet granulation method that finely adjusts the amount of ethanol solvent Thus, the sustained-release formulation with proper initial dissolution rate and dissolution profile can be prepared to effectively maintain the drug concentration in the body, thereby completing the present invention.

In order to solve the problems of traditional sustained-release cilostazol tablets, the purpose of the present invention is to provide a sustained-release formulation that has an appropriate initial dissolution rate and dissolution profile and can effectively maintain the drug concentration in the body.

In order to achieve the above object, one aspect of the present invention is to provide an oral sustained-release formulation prepared by molding a composition, the composition comprising cilostazol as an active ingredient and a hydrophilic sustained-release carrier as the active ingredient. A mixture of a synthetic polymer and carbomer, and a co-solvent, which is characterized by dissolving according to the second method of the Korean Pharmacopoeia dissolution test (paddle method) (37±0.5°C, 0.5% sodium lauryl sulfate solution, 50 rpm) During the test, the oral sustained-release formulation showed the following dissolution profile: 1) 20% to 30% of the total weight of cilostazol was released at a time point of 2 hours after the start of the test; 2) 50% of the total weight of cilostazol Up to 70% was released at a time point of 5 hours after the start of the test; and 3) At least 85% of the total weight of cilostazol was released at a time point of 10 hours after the start of the test.

In the sustained-release formulation according to the present invention, the composition may be particles made by wet granulation using an ethanol solvent.

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

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

In the present invention, the hydrophilic polymer used as a sustained-release carrier may be one or more selected from the group consisting of: hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl Cellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanth gum, acacia gum, locust bean gum, sanxian gum, alginate, polyvinyl alcohol and polyvinylpyrrolidone.

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

The co-solvent used according to the present invention can be selected from the following One or more of the group consisting of: sodium lauryl sulfate, polysorbate 80, oleyl polyethylene glycol glycerides, linoleic polyethylene glycol glycerides, and caprylyl hexyl glycerides Base polyoxyglyceride (caprylocaproyl polyoxylglyceride).

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

The sustained-release formulation according to the present invention may further include fillers, binders and lubricants.

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

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 silica.

The binder used according to the present invention may be one or more selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone/ethylene derivative copolymer 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 formulation prepared by molding a composition, the composition comprising as an active ingredient 100 parts by weight of cilostazol, a mixture of 10 parts by weight to 30 parts by weight of hydroxypropyl methylcellulose 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 Co-solvent, 30 parts by weight to 70 parts by weight of filler, 1 part by weight to 10 parts by weight of binder, and 2 parts by weight to 10 parts by weight of lubricant, characterized by the second method of dissolution test according to the Korean Pharmacopoeia (paddle method) (37±0.5°C, 0.5% sodium lauryl sulfate solution, 50rpm) and the dissolution test, the oral sustained release formulation showed the following dissolution profile: 1) 20% to 30% of the total weight of cilostazol It was released at a time point of 2 hours after the start of the test; 2) 50% to 70% of the total weight of cilostazol was released at a time point of 5 hours after the start of the test; and 3) At least 85% of the total weight of cilostazol was in the test Release at a time point of 10 hours after the start.

In the sustained-release formulation, the composition may be particles made by wet granulation using an ethanol solvent.

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

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

Specifically, the co-solvent can be sodium lauryl sulfate, the filler can be a mixture of microcrystalline cellulose and colloidal silica, the binder can be polyvinylpyrrolidone, and the lubricant can be magnesium stearate.

The sustained release formulations according to the present invention exhibit proper initial The initial dissolution rate and dissolution curve can effectively maintain the drug concentration in the body even if the drug is taken once a day, thereby reducing the occurrence of side effects while maintaining the efficacy of cilostazol, and improving medication compliance.

Figure 1 shows the dissolution profile of the sustained-release cilostazol formulation based on the average particle size of cilostazol; and Figure 2 shows the dissolution profile of the sustained-release cilostazol formulation based on the amount of ethanol solvent.

According to a specific embodiment of the present invention, there is provided an oral sustained-release formulation prepared by molding a composition, the composition comprising cilostazol as an active ingredient, a hydrophilic polymer as a sustained-release carrier, and carbomer A mixture of mol and co-solvent, characterized in that when the dissolution test is carried out according to the second method of the Korean Pharmacopoeia dissolution test (paddle method) (37±0.5°C, 0.5% sodium lauryl sulfate solution, 50 rpm), the oral administration continues The release formulation showed the following dissolution profile: 1) 20% to 30% of the total weight of cilostazol was released at the time point 2 hours after the start of the test; 2) 50% to 70% of the total weight of cilostazol was released at the start of the test Release at a time point of the last 5 hours; and 3) At least 85% of the total weight of cilostazol is released at a time point of 10 hours after the start of the test.

In the sustained-release formulation according to the present invention, it can be used as Cilostazol is formulated into a sustained-release matrix tablet for sustained release of a mixture of hydrophilic polymer and carbomer as a carrier and a co-solvent, wherein cilostazol and cilostazol having an average particle size within a specific range are used The granules made by the wet granulation method that finely regulates the amount of ethanol solvent are used, so that the sustained-release formulation has an appropriate initial dissolution rate and dissolution profile, and can effectively maintain the drug concentration in the body.

The dissolution curves of the sustained-release formulations according to the present invention are dissolution curves at 2 hours, 5 hours, and 10 hours, which are obtained from an appropriate in vitro dissolution test. This appropriate in vitro dissolution test can be performed at 37±0.5°C dissolution temperature, using 0.5% sodium lauryl sulfate solution as the dissolution test medium, rotating at 50 rpm, according to the Korean Pharmacopoeia dissolution test second method (paddle method), and Partial modifications can be made here as known to those skilled in the art.

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

If the sustained-release formulation conforms to such a dissolution profile, it will exhibit an appropriate initial dissolution rate, thereby reducing the incidence of side effects without delaying efficacy, and maintaining the drug concentration in the body for a predetermined period of time. Therefore, the efficacy of cilostazol can be maintained even if the drug is taken once a day, resulting in improved medication compliance.

According to the present invention, the active ingredient cilostazol may have 12μ m or smaller average particle size. If the average particle size is greater than 12 μm, the initial dissolution rate is significantly reduced, resulting in delayed drug release. Therefore, it is difficult to maintain an effective drug concentration in the blood. The lower limit is not particularly limited, but it is preferably 5 μm.

According to a specific example of the present invention, when using cilostazol with an average particle size within the above range, the formulation exhibits the following dissolution profile: 20% to 30% of the total weight of cilostazol within 2 hours after the start of the test 50% to 70% of the total weight of cilostazol is released at a time point of 5 hours after the start of the test, and at least 85% of the total weight of cilostazol is released at a time point of 10 hours after the start of the test (1st Figure, experimental example 1).

According to the present invention, a composition comprising cilostazol as an active ingredient, a mixture of a hydrophilic polymer and carbomer as a sustained release carrier, and a co-solvent can be granulated by wet granulation and then molded. Preferably, the composition may be particles made by wet granulation using ethanol solvent.

In order to achieve the purpose of the present invention, the amount of ethanol solvent used is based on 100 parts by weight of cilostazol, which may be 40 parts by weight to 75 parts by weight. If the amount of the ethanol solvent is less than 40 parts by weight, a large number of fine powder particles will be produced, the particles will become weak, the fluidity will be poor, and slight capping will occur during ingot making, which will reduce the production efficiency, and the hardness will be low and initial High dissolution rate. Therefore, there is a problem that the product cannot satisfy the dissolution rate in 2 hours and 5 hours. If the amount of ethanol solvent exceeds 75 parts by weight, the particles produced are too wet to have good fluidity and the particles are firm, after ingot manufacturing, the hardness is too high and the initial dissolution rate becomes low. Therefore, there is a problem that the product cannot satisfy the dissolution rate within 2 hours.

According to a specific example of the present invention, when the amount of ethanol meets the above-mentioned range of ethanol to prepare granules, the fluidity suitable for tableting is obtained, and the tablet has a hardness of ^{11kg/cm 2} to 13kg/cm ^{2 after the tableting.} A product with satisfactory hardness was obtained, and the dissolution curve was improved (Table 4, Figure 2, Experimental Examples 2 and 3).

In the present invention, a mixture of a hydrophilic polymer and carbomer is used as a sustained release carrier. Carbomer exists in the stomach under acidic conditions in a sol state, thereby making it possible to maintain drug release via the hydrophilic polymer. Carbomer exists in the small intestine under alkaline conditions in the state of hydrogel, thereby making it possible to regulate drug release. When carbomer is used together with a hydrophilic polymer, the carbomer acts in the lozenge to form a strong matrix, maintain the shape of the matrix due to the swelling of the lozenge, and prevent the lozenge from corroding, which makes it possible to maintain a constant dissolution Rate.

In the present invention, the hydrophilic polymer used as a sustained-release carrier may be one or more selected from the group consisting of: hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl Cellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanth gum, acacia gum, locust bean gum, trixian gum, alginate, polyvinyl alcohol, and polyvinylpyrrolidone, but not limited thereto. For example, the hydrophilic polymer may be hydroxypropyl methylcellulose.

The hydrophilic polymer may have a viscosity of 50,000 cps to 150,000 cps, 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 size of the lozenge. If the viscosity exceeds 150,000cps, it may not be uniformly mixed with the active ingredients. Although it has the same viscosity, it is possible to use Consistent particle uniformity, excellent dispersibility and good physical form.

In the present invention, 10 parts by weight to 30 parts by weight of hydrophilic polymer and 3 parts by weight to 10 parts by weight of carbomer based on 100 parts by weight of cilostazol may be used as a sustained release carrier. Here, if the weight ratio of the carbomer to the hydrophilic polymer is less than 1:1, it may not be easy to form a matrix in the lozenge, and therefore it may not be possible to appropriately delay the drug release. If the weight ratio exceeds 10:1, the dissolution rate of cilostazol under alkaline conditions may be reduced, and cilostazol and the hydrophilic polymer may not be uniformly mixed.

The cosolvent used according to the present invention is a component that assists the dissolution of the poorly soluble drug cilostazol and may be one or more selected from the group consisting of: sodium lauryl sulfate, polysorbate 80. Oleoyl polyethylene glycol glycerides, linoleic polyethylene glycol glycerides, and caprylic hexyl polyoxyglycerides, but are not limited thereto. For example, the co-solvent may be sodium lauryl sulfate.

The content of the co-solvent may be 5 parts by weight to 20 parts by weight based on 100 parts by weight of cilostazol. If the content is less than the above range, the drug cannot reach the critical micromicelle concentration and the dissolution rate is reduced, so it is difficult to obtain sufficient pharmaceutical effects. Conversely, if the content exceeds the above range, the concentration of the released drug may decrease and the absorption of the drug may be reduced.

The sustained-release formulation according to the present invention may comprise 10 parts by weight to 30 parts by weight of hydrophilic polymer based on 100 parts by weight of cilostazol, 3 parts by weight to 10 parts by weight of carbomer, and 5 parts by weight to 20 parts by weight of Co-solvent.

The sustained release formulation according to the present invention may further comprise Fillers, binders and lubricants.

If the sustained-release formulation according to the present invention may further comprise fillers, binders and lubricants, it may comprise 30 parts by weight to 70 parts by weight of fillers based on 100 parts by weight of cilostazol, and 1 part by weight to 10 parts by weight. Binder, 2 parts by weight to 10 parts by weight of lubricant, but not limited thereto.

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

The binder used according to the present invention may be one or more selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone/ethylene derivative copolymers, and starch, but is not limited thereto. For example, the binder 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, the lubricant may be magnesium stearate.

According to another specific embodiment of the present invention, provided is an oral sustained-release formulation, which is prepared by molding the composition, the composition comprising 100 parts by weight of cilostazol as an active ingredient, as A mixture of 10 parts by weight to 30 parts by weight of hydroxypropyl methylcellulose and 3 parts by weight to 10 parts by weight of carbomer, 5 parts by weight to 20 parts by weight of co-solvent, 30 parts by weight to 70 parts by weight of sustained release carrier Parts of filler, 1 part by weight to 10 parts by weight of binder, and 2 parts by weight to 10 parts by weight A lubricant, characterized in that when the dissolution test is performed according to the second method of the Korean Pharmacopoeia dissolution test (paddle method) (37±0.5°C, 0.5% sodium lauryl sulfate solution, 50 rpm), the oral sustained-release formulation Show the following dissolution profile: 1) 20% to 30% of the total weight of cilostazol is released at a time point of 2 hours after the start of the test; 2) 50% to 70% of the total weight of cilostazol is released 5 hours after the start of the test And 3) At least 85% of the total weight of cilostazol was released at a time point of 10 hours after the start of the test.

In a specific embodiment, the composition may be particles made by a wet granulation method using an ethanol solvent.

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

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

Specifically, the co-solvent can be sodium lauryl sulfate, the filler can be a mixture of microcrystalline cellulose and colloidal silica, the binder can be polyvinylpyrrolidone, and the lubricant can be magnesium stearate.

The sustained-release formulations according to the present invention can be formulated through traditional methods such as granulation, mixing, and compression molding. Specifically, a wet granulation method can be used to prepare the sustained release formulation according to the present invention. Cilostazol as the active ingredient and excipients are thoroughly mixed in a powder mixer, and then a mixture of hydrophilic polymer and carbomer as a sustained release carrier, and auxiliary The solvents are uniformly mixed with each other. Ethanol is added thereto to prepare wet granules. The amount of ethanol used is based on 100 parts by weight of cilostazol, and may be 40 parts by weight to 75 parts by weight. If necessary, dissolve a small amount of sustained-release carrier in a mixed solvent of water or ethanol and use it for powder granulation. The prepared particles were fully dried in an oven at 60° C. and ground uniformly. Magnesium stearate is then mixed to mold the formulation, and tableting is performed using a rotary tablet press.

Hereinafter, the structure 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 for illustrative purposes only, and are not intended to limit the scope of the present invention.

[Example]

Examples 1 to 2 and Comparative Examples 1 to 4: Preparation of sustained-release cilostazol formulations by changing the particle size of cilostazol

1) Example 1

According to the mixing ratio of Table 1, cilostazol having a particle size of 8.61 μm as an active ingredient and each excipient were thoroughly mixed. Then, hydroxypropyl methyl cellulose as a hydrophilic polymer is added here, and mixed uniformly in a powder mixer. After that, ethanol was used to prepare wet granules. In the wet granulation method, 55 parts by weight of ethanol based on 100 parts by weight of cilostazol was used. The prepared particles were fully dried in an oven at 60° C. and ground uniformly. Magnesium stearate was then mixed to mold the formulation, and tableting was performed using a rotary tablet press, thereby preparing tablets containing 200 mg of cilostazol per tablet.

2) Example 2

A sustained-release cilostazol formulation was prepared in the same manner as in Example 1, except that cilostazol having a particle size of 11.42 μm was used.

3) Comparative examples 1 to 4

A sustained-release cilostazol formulation was prepared in the same manner as in Example 1, except that cilostazol having a particle size of 12.81 μm, 13.85 μm, 15.43 μm, or 15.65 μm was used.

The average particle size of cilostazol used in Examples 1 to 2 and Comparative Examples 1 to 4 is shown in Table 2.

Comparative Examples 5 to 6: Preparation of sustained-release cilostazol formulations by changing the amount of ethanol solvent

The sustained-release cilostazol formulation was prepared in the same manner as in Example 1, except that when the wet granulation method was performed, 35 parts by weight or 80 parts by weight of ethanol based on 100 parts by weight of cilostazol were used.

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

Experimental example 1: Dissolution test of sustained-release cilostazol formulation prepared by changing the particle size of cilostazol

A dissolution test was performed to evaluate the dissolution rate of the sustained-release cilostazol formulations prepared by changing the particle size of cilostazol in Examples 1 to 2 and Comparative Examples 1 to 4.

According to the second method of the Korean Pharmacopoeia dissolution test (paddle method), 900 mL of sodium lauryl sulfate (0.5%) solution was used as the dissolution test medium The dissolution test was carried out at a rotation speed of 50rpm and a dissolution temperature of 37±0.5℃. At predetermined time points of 0, 15, 30, 60, 90, 120, 180, 300, 360, 480, and 600 minutes after the start of the dissolution test, 5 mL of the dissolving medium was sampled and filtered using a 0.45 μm membrane filter. The resulting solution was used as the test solution. A UV spectrometer (Shimadzu, Japan) was used to measure the absorbance (At and As) of the test and standard solutions at 257 nm. Figure 1 shows the results of the dissolution test.

As shown in Figure 1, when cilostazol with an average particle size of 12 μm or less was used in Examples 1 and 2, the formulation exhibited a dissolution curve in which 20% to 30% of the total weight of cilostazol was tested. Released at a time point of 2 hours after the start, 50% to 70% of the total weight of cilostazol was released at a time point of 5 hours after the start of the test, and at least 85% of the total weight of cilostazol was released 10 hours after the start of the test Time to release. In contrast, when cilostazol having an average particle diameter exceeding 12 μm was used in Comparative Examples 1 to 4, the dissolution rate was less than 20% at the time of 2 hours, less than 50% at the time of 5 hours, and The 10-hour time point is less than 85%, and their initial dissolution rate is low and the drug concentration in the body cannot be effectively maintained for a period of time, indicating that these formulations are not suitable as sustained-release formulations.

Experimental Example 2: Dissolution test of sustained-release cilostazol formulation prepared by changing the amount of ethanol solvent

A dissolution test was performed to evaluate the dissolution rate of the sustained-release cilostazol formulations prepared by changing the amount of ethanol solvent in Example 1 and Comparative Examples 5 to 6.

According to the second method of the Korean Pharmacopoeia dissolution test (paddle method), Using 900 mL of sodium lauryl sulfate (0.5%) solution as the dissolution test medium, the dissolution test was carried out at a rotation speed of 50 rpm and a dissolution temperature of 37 ± 0.5°C. At predetermined time points of 0, 15, 30, 60, 90, 120, 180, 300, 360, 480, and 600 minutes after the start of the dissolution test, 5 mL of the dissolving medium was sampled and filtered using a 0.45 μm membrane filter. The resulting solution was used as the test solution. A UV spectrometer (Shimadzu, Japan) was used to measure the absorbance (At and As) of the test and standard solutions at 257 nm. Figure 2 shows the results of the dissolution test.

As shown in Figure 2, Example 1 exhibits a dissolution profile in which 20% to 30% of the total weight of cilostazol is released at a time point 2 hours after the start of the test, and 50% to 70% of the total weight of cilostazol is in It was released at a time point of 5 hours after the start of the test, and at least 85% of the total weight of cilostazol was released at a time point of 10 hours after the start of the test. On the contrary, Comparative Example 5 showed a dissolution rate of more than 30% at the time of 2 hours and a dissolution rate of more than 70% at the time of 5 hours, indicating an excessively high initial dissolution rate and a 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 the initial dissolution is difficult to occur and this formulation is not suitable for obtaining proper performance.

Experimental example 3: Physical property test of sustained-release formulation prepared by changing the amount of ethanol solvent during granulation

The angle of repose and the hardness of the tablets prepared by the wet granulation method were measured to evaluate the physical properties of the sustained-release cilostazol formulations prepared by varying the amount of ethanol solvent in Example 1 and Comparative Examples 5 to 6.

When measuring the angle of repose, the particles made by the wet granulation method are passed through the funnel, and the angle of repose (θ) is directly measured. The angle of repose is the ridge line of the deposited particles Of the horns.

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

Table 4 shows the results of measuring the angle of repose and hardness.

As shown in Table 4, Example 1 shows an angle of repose of 39° to 42°, indicating that the fluidity is suitable for ingot making, and shows that the hardness of the tablet after ingot making is 11kg/cm ² to 13kg/cm ² , indicating that it can Satisfied with the hardness of the product. In contrast, in Comparative Example 5, the particles showed low hardness to produce a large amount of fine powder, the particles were weak and the particles showed an angle of repose of 50° to 55° or higher, indicating that the fluidity was not suitable for ingot making. Furthermore, low hardness (5 kg/cm ² to 8 kg/cm ² ) and slight capping were observed after ingot manufacturing.

In Comparative Example 6, excessive ethanol was injected during the granulation, thereby making the granular paste too thin and the prepared granules too hard, so that the tablet after tableting had a high hardness of ^{18 kg/cm 2} to 20 kg/cm ^2. Therefore, the active ingredient is not easily released, and the particles show an angle of repose of 57° or higher, indicating that the fluidity is not suitable for tablet making.

Since the picture in this case is experimental data, it is not a representative picture of this case. Therefore, there is no designated representative diagram in this case.

Claims (11)

An oral sustained-release formulation prepared by molding a composition comprising 100 parts by weight of cilostazol as an active ingredient and 10 parts by weight to 30 parts by weight of a hydrophilic polymer as a sustained-release carrier A mixture of 3 parts by weight to 10 parts by weight of carbomer, and 5 parts by weight to 20 parts by weight of co-solvent, according to the second method of Korean Pharmacopoeia dissolution test (paddle method) (37±0.5°C, 0.5% dodecane) Sodium sulphate solution, 50rpm) and the dissolution test, the oral sustained-release formulation showed the following dissolution profile: 1) 20% to 30% of the total weight of cilostazol was released at a time point of 2 hours after the start of the test; 2 ) 50% to 70% of the total weight of cilostazol is released at a time point of 5 hours after the start of the test; and 3) At least 85% of the total weight of cilostazol is released at a time point of 10 hours after the start of the test, wherein the The composition is based on 100 parts by weight of cilostazol, using 40 parts by weight to 75 parts by weight of ethanol solvent wet granulation method, and wherein the cilostazol has an average particle diameter of 12 μm or less. The oral sustained-release formulation according to item 1 of the scope of patent application, wherein the hydrophilic polymer is one or more selected from the group consisting of: hydroxypropyl methylcellulose, hydroxyethyl Cellulose, hydroxypropyl cellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanth gum, acacia gum, locust bean gum, trixian gum, alginate, polyvinyl alcohol and Polyvinylpyrrolidone. The oral sustained-release formulation described in item 1 of the scope of the patent application, wherein the hydrophilic polymer has a viscosity of 50,000 cps to 150,000 cps. The oral sustained-release formulation according to item 1 of the scope of patent application, wherein the co-solvent is one or more selected from the group consisting of: sodium lauryl sulfate, polysorbate 80, Oleoyl polyethylene glycol glycerides, linoleic polyethylene glycol glycerides, and caprylic hexyl polyoxyglycerides. The oral sustained-release formulation as described in item 1 of the scope of patent application further includes fillers, binders and lubricants. The oral sustained-release formulation described in item 5 of the scope of the patent application includes 30 to 70 parts by weight of filler based on 100 parts by weight of cilostazol, 1 to 10 parts by weight of binder, and 2 parts by weight To 10 parts by weight of lubricant. The oral sustained-release formulation according to claim 5, wherein the filler is one or more selected from the group consisting of: microcrystalline cellulose, starch, lactose, mannitol, sorbitol And colloidal silica. The oral sustained-release formulation according to item 5 of the patent application, wherein the binder is one or more selected from the group consisting of: polyvinylpyrrolidone, vinylpyrrolidone/ethylene derivative copolymer And starch. The oral sustained-release formulation as described in item 5 of the scope of patent application, which The lubricant is one or more selected from the group consisting of magnesium stearate, talc and amorphous silica. An oral sustained-release formulation prepared by molding a composition, the composition comprising 100 parts by weight of cilostazol as an active ingredient, and 10 parts by weight to 30 parts by weight of hydroxypropyl as a sustained-release carrier A mixture of methyl cellulose and 3 parts by weight to 10 parts by weight of carbomer, 5 parts by weight to 20 parts by weight of co-solvent, 30 parts by weight to 70 parts by weight of fillers, 1 part by weight to 10 parts by weight of binder, and 2 parts by weight to 10 parts by weight of lubricant, wherein when the dissolution test is carried out according to the second method of the Korean Pharmacopoeia dissolution test (paddle method) (37±0.5°C, 0.5% sodium lauryl sulfate solution, 50rpm), the oral The sustained release formulation exhibits the following dissolution profile: 1) 20% to 30% of the total weight of cilostazol is released at a time point of 2 hours after the start of the test; 2) 50% to 70% of the total weight of cilostazol is in the test Released at a time point of 5 hours after the start; and 3) At least 85% of the total weight of cilostazol was released at a time point of 10 hours after the start of the test, wherein the composition was based on 100 parts by weight of cilostazol, using 40 parts by weight Part to 75 parts by weight of the particles produced by the wet granulation method of ethanol solvent, and wherein cilostazol has an average particle diameter of 12 μm or less. The oral sustained-release formulation described in item 10 of the scope of patent application, wherein the co-solvent is sodium lauryl sulfate, and the filler is microcrystalline cellulose A mixture with colloidal silica, the binder is polyvinylpyrrolidone, and the lubricant is magnesium stearate.

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