KR102138253B1 - Sustained release preparation of cilostazol - Google Patents

Abstract

The present invention relates to a cilostazol sustained release formulation comprising a neutral water insoluble methacrylic acid copolymer as cilostazol or a pharmaceutically acceptable salt thereof and a sustained release matrix base.

Description

Silostazol sustained release formulation {SUSTAINED RELEASE PREPARATION OF CILOSTAZOL}

The present invention relates to a cilostazol sustained release formulation comprising a neutral water insoluble methacrylic acid copolymer as cilostazol or a pharmaceutically acceptable salt thereof and a sustained release matrix base.

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

[Formula 1]

Cilostazol inhibits platelet aggregation by inhibiting the activity of PDE upon absorption by the body and expands blood vessels, thereby inhibiting blood clotting, improving central blood circulation, preventing and treating anti-inflammatory, anti-ulcer, lowering blood pressure, asthma and cerebral infarction, and brain circulation. Since it exhibits actions such as improvement, it has been widely used as an antithrombotic agent, brain circulation improving agent, anti-inflammatory agent, anti-tumor agent, anti-hypertensive agent, and anti-asthma agent.

Existing cilostazol formulations are administered orally twice a day, and the patient's compliance with the medication is poor, and when taken orally, there is a problem of causing side effects such as headache, weight sensation, tachycardia, etc. It is known. In addition, cilostazol is a poorly soluble drug having a water solubility of 1 μg/ml or less, and is mainly absorbed from the upper portion of the gastrointestinal tract and has a characteristic of decreasing absorption toward the lower intestinal tract. It may decrease.

Accordingly, in order to solve the above problems, various studies for preparing sustained-release or controlled-release preparations of cilostazol have been conducted, and various studies have been made to improve the solubility and absorption of cilostazol.

As a technique for releasing the drug from the sustained release formulation even when it reaches the lower part of the digestive tract, a matrix formulation known as a sustained release formulation using a methacrylic acid enteric polymer is known (Japanese Patent Publication (Pyeong)4(1992)-43049) Publication, Japanese Patent Publication (Pyeong) 6(1994)-199657 publication, U.S. Patent No. 4,968,508 specification, U.S. Patent Publication 2006/0159753 publication), these formulations have low surface area, solubility is low, poor solubility with slow dissolution rate In the case of a preparation containing a drug, there are cases in which a drug release is impaired.

In addition, in International Patent Publication Nos. WO00/057881 and U.S. Patent Publication No. 2002/0058066, the outer layer of the tablet causes sustained-release drug release in the upper gastrointestinal tract (small intestine), while in the small intestine and in the large intestine, the tablets disintegrate and disintegrate A formulation in the form of causing release of a releasing drug is proposed, and International Patent Publication No. WO2005/023225 dissolves cilostazol in an organic solvent and then contains the additives such as microcrystalline cellulose, lactose, mannitol, and croscarmellose sodium. Although it suggests a sustained-release preparation of cilostazol obtained by adsorption on a porous inert carrier to increase the solubility of the drug and then mix it with a sustained-release polymer, the size of the whole tablet is increased due to the complicated manufacturing process or a large amount of additives. There is a disadvantage that can cause discomfort.

On the other hand, in Korean Patent No. 10-1008540, carbomer and hydroxypropylmethylcellulose are used to formulate a sustained-release matrix to achieve a dissolution rate suitable for once-a-day administration, but there is a problem that the dissolution rate between individual tablets is large. .

The present inventors showed a dissolution rate while showing a dissolution rate suitable for once-a-day administration when a neutral water-insoluble methacrylic acid copolymer was used as a sustained-release matrix base in order to solve the problem of slow-release formulation of cilostazol, which is very poorly soluble in water. It is not only very advantageous as a sustained-release preparation due to a small variation in it, it is possible to uniformly mix with an excipient during formulation using a wet granulation method, thereby increasing the fluidity and finding that it has an effect suitable for mass production and completed the present invention.

Accordingly, an object of the present invention is to provide a cilostazol sustained release formulation comprising a neutral water insoluble methacrylic acid copolymer as cilostazol or a pharmaceutically acceptable salt thereof and a sustained release matrix base.

In addition, the present invention provides a cilostazol sustained release formulation comprising a mixture of a neutral water insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose as a cilostazol or a pharmaceutically acceptable salt and sustained release matrix base thereof. It is aimed at.

According to the above object, the present invention provides a cilostazol sustained release formulation comprising a neutral water insoluble methacrylic acid copolymer as cilostazol or a pharmaceutically acceptable salt thereof and a sustained release matrix base.

The neutral water-insoluble methacrylic acid copolymer is composed of a poly(ethylacrylate-methylmethacrylate) copolymer, a poly(ethylacrylate-methylmethacrylate-trimethylaminoethylmethacrylate chloride) copolymer, and mixtures thereof. It may be selected from the group.

The poly(ethyl acrylate-methyl methacrylate) copolymer may be a copolymer having a weight ratio of ethyl acrylate and methyl methacrylate of about 2:1.

The poly(ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate chloride) copolymer has a weight ratio of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride of about 1:2:0.2 or about It may be a 1:2:0.1 copolymer.

The neutral water-insoluble methacrylic acid copolymer is Eudragit NE 30D, Eudragit NE 40D, Eudragit NE 40D, Eudragit NM 30D, Eudragit M 30D, Eudragit RL 100 RL 100), Eudragit RL PO (Eudragit RL PO), Eudragit RL 30D, Eudragit RL 12.5, Eudragit RL 12.5, Eudragit RS 100, Eudragit RS 100 It may be one or more selected from the group consisting of Eudragit RS PO, Eudragit RS 30D, and Eudragit RS 12.5.

The sustained release preparation may include about 10 to 40 parts by weight based on 100 parts by weight of the cilostazol, and preferably about 13 to 33 parts by weight of the neutral water-insoluble methacrylic acid copolymer. When the content of the neutral water-insoluble methacrylic acid copolymer is less than about 10 parts by weight, the matrix of the tablet is partially damaged and the tablet disintegrates. When the content of the neutral water-insoluble methacrylic acid copolymer exceeds about 40 parts by weight, the hardness of the tablet is excessively lowered.

According to another object of the present invention, the present invention is a neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose (hypromellose, HPMC) as cilostazol or a pharmaceutically acceptable salt and sustained release matrix base thereof. It provides a sustained-release formulation cilostazol comprising a mixture of.

The neutral water-insoluble methacrylic acid copolymer is composed of a poly(ethylacrylate-methylmethacrylate) copolymer, a poly(ethylacrylate-methylmethacrylate-trimethylaminoethylmethacrylate chloride) copolymer, and mixtures thereof. It may be selected from the group.

The poly(ethyl acrylate-methyl methacrylate) copolymer may be a copolymer in which the weight ratio of ethyl acrylate and methyl methacrylate is about 2:1.

The poly(ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate chloride) copolymer has a weight ratio of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride of about 1:2:0.2 or about It may be a 1:2:0.1 copolymer.

The neutral water-insoluble methacrylic acid copolymer is Eudragit NE 30D, Eudragit NE 40D, Eudragit NE 40D, Eudragit NM 30D, Eudragit M 30D, Eudragit RL 100 RL 100), Eudragit RL PO (Eudragit RL PO), Eudragit RL 30D, Eudragit RL 12.5, Eudragit RL 12.5, Eudragit RS 100, Eudragit RS 100 It may be one or more selected from the group consisting of Eudragit RS PO, Eudragit RS 30D, and Eudragit RS 12.5.

The sustained release preparation may include about 15 to 40 parts by weight of a mixture of a neutral water insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose based on 100 parts by weight of cilostazol, preferably about 19 to 33 parts by weight It can contain. When the content of the mixture is less than about 15 parts by weight, the release time of cilostazol is shortened, and the amount of elution per unit time increases, which may cause side effects. On the other hand, when the content of the mixture exceeds about 40 parts by weight, the cilostazol release time becomes longer, and accordingly, the elution amount of the drug per unit time decreases, so it is difficult to expect sufficient efficacy.

The sustained release preparation may include a mixture of a neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose in a weight ratio of about 1:0.6 to 1:4.2.

The hydroxypropyl methyl cellulose may have a viscosity of about 80,000 to 120,000 cps. When the viscosity is less than about 80,000 cps, the required amount of hydroxypropylmethylcellulose increases, resulting in an excessively large tablet size, and when the viscosity is greater than about 120,000 cps, it cannot be uniformly mixed with cilostazol and other excipients. .

The sustained-release preparation according to the present invention includes tablets; Granules; Pellets; Mini tablets; And capsules filled with granules, pellets or minitablets.

The sustained-release preparation of the present invention uses a neutral water-insoluble methacrylic acid copolymer as a sustained-release matrix base, thereby enabling uniform mixing with excipients during formulation using a wet granulation method, thereby increasing fluidity and being suitable for mass production. It is effective, and exhibits a dissolution rate suitable for once-a-day administration, but it is very advantageous as a sustained-release preparation due to little variation in dissolution rate.

1 is a graph showing the dissolution test results of the sustained-release preparations of Examples 1 to 3 of the present invention using a neutral water-insoluble methacrylic acid copolymer (Eudragit) as a sustained release base.
Figure 2 is a graph showing the dissolution test results of the sustained-release preparations of Examples 4 and 5 of the present invention using a neutral water-insoluble methacrylic acid copolymer (Eudragit) and hydroxypropylmethylcellulose as a sustained release base.
3 is a graph showing the dissolution test results of a cilostazol sustained-release tablet (comparative example) using carbomer and hydroxypropylmethylcellulose as a sustained-release base.

In one aspect of the present invention, there is provided a cilostazol sustained release formulation comprising a neutral water insoluble methacrylic acid copolymer as cilostazol or a pharmaceutically acceptable salt thereof and a sustained release matrix base.

Various methacrylic acid copolymers are available from Evonik Industries of Germany under the trade name Eudragit. Since Eudragit was first introduced as a drug coating base in 1953 due to its properties that are soluble in alkaline and resistant to gastric juice, Eudragit has been introduced with anionic, cationic, and neutral properties. These polymers exhibit various solubility profiles depending on pH/independently, and have been applied as a matrix of tablets in general direct or granulation processes as well as coating bases having various properties.

Cilostazol is a BCS Ⅱ group drug and is a drug with low solubility and high permeability. In addition, it is known that the absorption rate of the cilostazol drug itself is higher in the upper small intestine than in the lower small intestine. Accordingly, it is important to maintain the matrix form of cilostazol for a long time and deliver the drug to the lower intestine. The present inventors have a neutral water-insoluble methacrylic acid copolymer with low permeability to water, which is particularly suitable as a sustained-release matrix base for sustained release of cilostazol, showing a dissolution rate suitable for once-a-day administration, but less variation in dissolution rate. It has been found that it is advantageous for sustained release of cilostazol, and it is possible to uniformly mix with excipients during formulation using a wet granulation method, thereby increasing fluidity and being suitable for mass production. The present invention is based on this.

In the present invention, a neutral water-insoluble methacrylic acid copolymer that can be used as a sustained release matrix base is a poly(ethylacrylate-methylmethacrylate) copolymer, poly(ethylacrylate-methylmethacrylate-trimethylaminoethylmethacryl Rate chloride) copolymers and mixtures thereof.

The poly(ethyl acrylate-methyl methacrylate) copolymer that can be used as a sustained release matrix base material in the present invention may be a copolymer having a weight ratio of ethyl acrylate and methyl methacrylate of about 2:1.

The poly(ethylacrylate-methylmethacrylate-trimethylaminoethylmethacrylate chloride) copolymer which can be used as a sustained release matrix base material in the present invention comprises ethyl acrylate, methylmethacrylate and trimethylaminoethylmethacrylate chloride. It may be a copolymer having a weight ratio of about 1:2:0.2 or about 1:2:0.1.

The neutral water-insoluble methacrylic acid copolymer is Eudragit NE 30D, Eudragit NE 40D, Eudragit NE 40D, Eudragit NM 30D, Eudragit M 30D, Eudragit RL 100 Eudragit RL PO, Eudragit RL 30D, Eudragit RL 30D, Eudragit RL 12.5, Eudragit RS 100, Eudragit RS 100 It may be one or more selected from the group consisting of Eudragit RS PO, Eudragit RS 30D, and Eudragit RS 12.5. Especially preferred is Eudragit RS 100, Eudragit RS PO, Eudragit RS 30D, or Eudragit RS 12.5. Can.

The sustained release preparation may include about 10 to 40 parts by weight of the neutral water-insoluble methacrylic acid copolymer based on 100 parts by weight of cilostazol, and more preferably about 13 to 33 parts by weight. When the content of the neutral water-insoluble methacrylic acid copolymer is less than about 10 parts by weight, the matrix of the tablet is partially damaged and the tablet disintegrates. When the content of the neutral water-insoluble methacrylic acid copolymer exceeds about 40 parts by weight, the hardness of the tablet is excessively lowered.

As a result of the dissolution test of Examples 1 to 3 using only Eudragit, a neutral water-insoluble methacrylic acid copolymer, as a sustained release base, the variation in dissolution rate was compared to a comparative formulation using carbomer and hydroxypropylmethylcellulose as the sustained release base. It was found that it can be reduced, and exhibited a dissolution rate pattern equivalent to that of the comparative formulation (Experimental Example 1).

In another aspect of the invention, a cilostazol sustained-release preparation comprising cilostazol or a pharmaceutically acceptable salt thereof and a mixture of a neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose as a sustained release matrix base is provided. Is provided.

When the neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose are used together, there is an effect of strengthening the matrix in the sustained-release tablet, and the tablet expansion maintains its shape, and the tablet falls off by maintaining the matrix of the tablet (erosion ) To maintain a constant dissolution rate.

In the present invention, the neutral water-insoluble methacrylic acid copolymer is a poly (ethyl acrylate-methyl methacrylate) copolymer, poly (ethyl acrylate-methyl methacrylate-trimethylamino ethyl methacrylate chloride) copolymer and its It may be selected from the group consisting of mixtures.

In the present invention, the poly(ethyl acrylate-methyl methacrylate) copolymer may be a copolymer in which the weight ratio of ethyl acrylate and methyl methacrylate is about 2:1.

In the present invention, the poly(ethylacrylate-methylmethacrylate-trimethylaminoethylmethacrylate chloride) copolymer has a weight ratio of ethylacrylate, methylmethacrylate and trimethylaminoethylmethacrylate chloride of about 1:2: 0.2 or about 1:2:0.1.

The neutral water-insoluble methacrylic acid copolymer is Eudragit NE 30D, Eudragit NE 40D, Eudragit NE 40D, Eudragit NM 30D, Eudragit M 30D, Eudragit RL 100 RL 100), Eudragit RL PO (Eudragit RL PO), Eudragit RL 30D, Eudragit RL 12.5, Eudragit RL 12.5, Eudragit RS 100, Eudragit RS 100 It may be one or more selected from the group consisting of Eudragit RS PO, Eudragit RS 30D, and Eudragit RS 12.5. Especially preferred is Eudragit RS 100, Eudragit RS PO, Eudragit RS 30D, or Eudragit RS 12.5. Can.

The sustained-release preparation may include about 15 to 40 parts by weight of a mixture of a neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose based on 100 parts by weight of cilostazol, more preferably about 19 to 33 parts by weight It can contain. When the content of the mixture of the neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose is less than about 15 parts by weight, the release time of cilostazol is shortened, and the amount of elution per unit time increases, which may cause side effects. On the other hand, when the content of the mixture exceeds about 40 parts by weight, the cilostazol release time becomes longer, and accordingly, the elution amount of the drug per unit time decreases, so it is difficult to expect sufficient efficacy.

The sustained release preparation may include a mixture of a neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose in a weight ratio of about 1:0.6 to 1:4.2. When the weight ratio is less than about 1:0.6, it is difficult to form a matrix in the tablet, so the delaying effect of drug release decreases. When the weight ratio exceeds about 1:4.2, the dissolution rate of cilostazol decreases and cilostazol and neutral water-insoluble methacrylic acid Homogeneous mixing between copolymers is difficult. Preferably, mixing of about 1:0.8 to 1:3.5 is possible.

The hydroxypropyl methyl cellulose may have a viscosity of 80,000 to 120,000 cps. Preferably, it may be 90,000 to 110,000 cps. If the viscosity is less than 80,000 cps, a large amount of hydroxypropylmethylcellulose is required to increase the size of the tablet, and when the viscosity exceeds 120,000 cps, uniform mixing with cilostazol becomes difficult. Even at the same viscosity, it is preferable to use a product having a more uniform physical pulverization and good physical form with excellent dispersion.

The neutral water-insoluble methacrylic acid copolymer as a sustained release base was obtained by dissolution test results of Examples 4 and 5 using Eudragit and hydroxypropylmethylcellulose together, compared with carbomer and hydroxypropylmethylcellulose as a sustained release base. It was found that the deviation of the dissolution rate can be reduced compared to the formulation, and the dissolution rate pattern of the same level as the comparative formulation was shown (Experimental Example 1).

The sustained-release preparation according to the present invention includes tablets; Granules; Pellets; Mini tablets; And capsules filled with granules, pellets or minitablets.

The sustained release preparation according to the present invention may further include a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipients may include diluents, binders, lubricants, disintegrants, solubilizers, and the like.

The diluent serves to increase the volume of the preparation, and is one or more from the group consisting of lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate anhydrous, calcium carbonate, sugars, and mixtures thereof. The selected one can be used, but is not limited thereto.

The binder can be used by dissolving it in a solvent, and serves to increase the binding power of the formulation, polyvinylpyrrolidone (povidone), copovidone, gelatin, starch, sucrose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, One or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl alkyl cellulose, and mixtures thereof may be used, but is not limited thereto. Specifically, povidone may be used as the binder, povidone K-15, K-30, or K-90 is preferred, and povidone K-30 is more preferred.

The lubricant improves the fluidity of the granular material, thereby increasing the filling property to a die, which is the lower part of the tableting machine, and reducing friction between the granules and between the powder and the punch-die, which is the upper portion of the tableting machine. It is a component that facilitates compression and release of tablets, and as lubricants, stearates such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, glyceryl monostearate, sodium stearyl fumarate, talc, Corn starch, carnauba wax, colloidal silicon dioxide, magnesium silicate, synthetic aluminum silicate, hardened oil, platinum, titanium oxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, and mixtures thereof One or more selected from the group consisting of can be used, but is not limited thereto.

The disintegrant is used to improve the dissolution of the drug by absorbing moisture to promote disintegration of the formulation, as crosscammellose sodium, sodium starch glycolate, pregelatinized star Pregelatinized starch, microcrystalline cellulose, crospovidone, cross-linked povidone, other commercially available polyvinylpyrrolidone (PVP, Povidone), carboxymethylcellulose calcium, carboxymethylcellulose sodium , Hydoxypropylcellulose, low substituted, alginic acid, colloidal silicon dioxide, powdered cellulose, starch, sodium alginate, one or more selected from mixtures thereof It can be used, but is not limited thereto.

The solubilizing agent is intended to assist dissolution of poorly soluble drugs, and may be polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, colloidal silicon dioxide, etc., but is not limited thereto.

Preferably, the pharmaceutically acceptable excipients are lactose, sucrose, dextrin, mannitol, sorbitol, microcrystalline cellulose, povidone, copovidone, methylcellulose, ethylcellulose, hydroxypropylalkylcellulose, croscarmellose sodium, carboxymethylcellulose Calcium, carboxymethylcellulose sodium, sodium lauryl sulfate, crospovidone, starch, dextrin, pregelatinized starch, colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, calcium stearate, glyceryl monostearate, sodium Stearyl fumarate, talc and may be selected from one or more selected from the group consisting of mixtures thereof, but is not limited thereto.

Hereinafter, the present invention will be described in more detail through examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.

Example 1 to 3: neutral Water insoluble Methacrylic acid copolymer Western painting Preparation of sustained-release preparations used as matrix bases

The sustained-release tablet was prepared using the following manufacturing method according to each component and content shown in Table 1 below. First, povidone K-30 was dissolved in 100% ethanol, and Eudragit RS PO was dispersed in 90% ethanol aqueous solution to make a 20 w/w% solution. Next, after mixing well with cilostazol, microcrystalline cellulose, sodium lauryl sulfate, and colloidal silicon dioxide using a speed mixer, cylindrical granulator using povidone K-30 binding solution and 20% Eudragit solution prepared earlier Was wet granulated at. After drying the granules prepared in a drying oven (40° C.) for 12 hours or more and sizing with a 20 mesh sieve, Table 1 was further mixed with Eudragit RS PO (excluding Example 1) and magnesium stearate in the semi-finished product. It was tabletted according to the weight per tablet described in the above.

division
Ingredient name
Example 1 Example 2 Example 3 Content (mg) Content (mg) Content (mg) chief ingredient Cilostazol 200.0 200.0 200.0 Excipient Microcrystalline cellulose 100.0 100.0 100.0 Excipient Sodium lauryl sulfate 20.0 20.0 20.0 Excipient Colloidal silicon dioxide 10.0 10.0 10.0 Western medicine Eudragit RS PO 26.4 38.8 64.8 Binder Povidone K-30 6.0 6.0 6.0 Lubricant Magnesium stearate 8.0 8.0 8.0 1 tablet total weight 370.4 382.8 408.8

Example 4 to 5: neutral Water insoluble Methacrylic acid copolymer and Hydroxypropylmethylcellulose Western painting Preparation of sustained-release preparations used as matrix bases

The sustained-release tablet was prepared using the following manufacturing method according to each component and content shown in Table 2 below. First, povidone K-30 was dissolved in 100% ethanol, and Eudragit RS PO was dispersed in a 90% aqueous ethanol solution. Next, using a speed mixer, mix well with cilostazol, microcrystalline cellulose, sodium lauryl sulfate, colloidal silicon dioxide, and 100,000 cps hypromellose, and then prepare the povidone K-30 binding solution and Eudragit solution prepared earlier. Wet granulation was performed in a cylindrical granulator. The granules thus prepared were dried in a dry oven (40° C.) for 12 hours or more and sized with a 20 mesh sieve, then further mixed with magnesium stearate in the sized semi-finished product and tabletted to the weight per tablet described below.

division
Ingredient name
Example 4 Example 5 Content (mg) Content (mg) chief ingredient Cilostazol 200.00 200.00 Excipient Microcrystalline cellulose 100.00 100.00 Excipient Sodium lauryl sulfate 20.00 20.00 Excipient Colloidal silicon dioxide 10.00 10.00 Western medicine Hypromellose (100,000 cps) 30.00 30.00 Western medicine Eudragit RS PO 8.70 34.80 Binder Povidone K-30 6.00 6.00 Lubricant Magnesium stearate 8.00 8.00 1 tablet total weight 382.70 408.80

Comparative example 1 to 3: Western painting As a basis Carbomer And Hydroxypropylmethylcellulose Preparation of sustained-release preparations using the mixture

The sustained-release tablet was prepared using the following manufacturing method according to the components and contents listed in Table 3. First, povidone K-30 was dissolved in ethanol. Next, using a speed mixer, mix well with cilostazol, microcrystalline cellulose, sodium lauryl sulfate, colloidal silicon dioxide, 100,000 cps hypromellose, and carbomer, and then use the previously prepared povidone K-30 binding solution Wet granulation was performed in a cylindrical granulator. The granules thus prepared were dried in a dry oven (40° C.) for 12 hours or more and sized with a 20 mesh sieve, then further mixed with magnesium stearate in the sized semi-finished product and tabletted to the weight per tablet described below.

division
Ingredient name
Comparative Example 1 Comparative Example 2 Comparative Example 3 Content (mg) Content (mg) Content (mg) chief ingredient Cilostazol 200.0 200.00 200.0 Excipient Microcrystalline cellulose 120 110 100 Excipient Sodium lauryl sulfate 15.0 22.0 24.0 Excipient Colloidal silicon dioxide 15.0 8.0 6.0 Western medicine Hypromellose (100,000 cps) 28.0 32.0 34.0 Western medicine Carbomer 12.0 8.0 6.0 Binder Povidone K-30 6.0 8.0 10.0 Lubricant Magnesium stearate 10.0 10.0 10.0 1 tablet total weight 406.0 398.0 390.0

Experimental Example 1: Dissolution test of cilostazol sustained-release preparation

A certain amount of cilostazol sustained-release tablets prepared in Examples and Comparative Examples was tested for elution by the Korean Pharmacopoeia Dissolution Test Method. As an eluent, an aqueous solution of 0.4 W/W% sodium lauryl sulfate was used. The elution method was a paddle method, an eluate was 900 ml, a stirring speed of 75 rpm, and an elution temperature of 37±0.5°C. At 1.5, 2, 4, 5, 6, 10 and 24 hours, 5 ml of the sample was taken and the same amount of eluate was added. As for the analysis conditions, the liquid obtained by the above elution test was filtered with a 0.45 μm membrane filter, and cilostazol was quantified using a UV/Vis spectrophotometer. The analysis wavelength was 257 nm.

time
(hr)
Dissolution rate (%) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 1.5 6.3(0.8) 12(1.2) 16.2(1.3) 16.2 (0.4) 12.7 (0.8) 16.3 (1.8) 14.0 (2.2) 14.1 (2.3) 2 18.8 (0.3) 24.4 (0.7) 26.4 (2.0) 30.0 (2.1) 25.7 (0.5) 27.5 (3.0) 26.4 (2.7) 24.4 (2.0) 4 25.5 (2.1) 34.6 (1.5) 36.2 (0.7) 42.4 (0.5) 39.2 (0.7) 42.5 (3.1) 36.6 (3.5) 36.2 (2.7) 5 28(1.3) 36.4 (0.6) 40.4 (0.5) 57.7 (1.4) 53.3 (3.5) 57.7 (5.0) 52.0(4.8) 50.8 (4.5) 6 34(1.1) 45.2 (1.0) 49.3 (0.9) 75.8 (0.6) 69.4 (1.1) 72.4(4.1) 65.2 (3.0) 63.3(2.1) 10 54.2 (2.4) 66.4 (1.3) 74.6 (1.4) 95.3 (2.7) 99.1(0.5) 95.9 (1.4) 85.3 (4.3) 84.3(3.4) 24 74.3 (2.5) 84.9(0.9) 87.7 (1.5) 99.5 (0.9) 99.5 (0.4) 99.5 (0.5) 98.4 (0.9) 97.4 (1.5)

* The standard deviation of the individual dissolution rate in parentheses

As a result of the dissolution test of Examples 1 to 3 using Eudragit only as a sustained release base, Examples 1 to 3 had a smaller variation in dissolution rate than Comparative Examples 1 to 3, but a dissolution rate pattern equivalent to that of Comparative Examples 1 to 3 It was found that indicates.

In addition, the results of the dissolution test of Examples 4 and 5 using HPMC and Eudragit together as a sustained release mechanism, Examples 4 and 5, the variation of the dissolution rate was reduced than Comparative Examples 1 to 3, Comparative Examples 1 to 3 and It was found that the dissolution rate pattern was at a comparable level.

Experimental Example 2: Evaluation of physical properties of sustained-release preparations

For evaluation of the properties of Examples 1 to 5 and Comparative Examples 1 to 3, the hardness and thickness of the tablets were measured. For the hardness test, 10 tablets each were taken and the hardness was measured using a PTB-411 hardness tester manufactured by ERWEKA Hardness Pharma Test. Table 5 shows the results of the hardness measurement.

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative example 3 Hardness (Kpa) 9.5 9.3 7.8 9.5 9.4 9.5 9.4 9.3 Thickness(mm) 4.43 4.67 4.9 4.85 4.95 4.67 4.68 4.70

As a result of the measurement, it was confirmed that in the hardness and thickness of each sustained-release preparation, there was practically no difference and was suitable as a sustained-release preparation.

Claims (15)

A cilostazol sustained-release preparation comprising a neutral water-insoluble methacrylic acid copolymer as cilostazol or a pharmaceutically acceptable salt thereof and a sustained-release matrix base material, wherein the neutral water-insoluble methacrylic acid copolymer is Eudragit NE 30D (Eudragit NE 30D), Eudragit NE 40D (Eudragit NE 40D), Eudragit NM 30D, Eudragit RS 100, Eudragit RS 100 (Eudragit RS PO) , Eudragit RS 30D (Eudragit RS 30D), and Eudragit RS 12.5 (Eudragit RS 12.5) selected from the group consisting of at least one cilostazol sustained-release preparation.
delete delete delete delete The cilostazol sustained-release preparation according to claim 1, wherein the neutral water-insoluble methacrylic acid copolymer contains 10 to 40 parts by weight based on 100 parts by weight of cilostazol.
A cilostazol sustained-release preparation comprising cilostazol or a pharmaceutically acceptable salt thereof and a mixture of a neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose as a sustained-release matrix base, wherein the neutral water-insoluble methacrylic Acid copolymers are Eudragit NE 30D, Eudragit NE 40D, Eudragit NE 40D, Eudragit NM 30D, Eudragit RS 100, Eudragit RS 100 A cilostazol sustained-release preparation having at least one selected from the group consisting of Eudragit RS PO, Eudragit RS 30D, and Eudragit RS 12.5.
delete delete delete delete The cilostazol sustained-release preparation according to claim 7, comprising 15 to 40 parts by weight based on 100 parts by weight of cilostazol, the mixture of the neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose.
The cilostazol sustained-release preparation according to claim 7, comprising a mixture of the neutral water-insoluble methacrylic acid copolymer and hydroxypropylmethylcellulose in a weight ratio of 1:0.6 to 1:4.2.
8. The cilostazol sustained-release preparation according to claim 7, wherein the hydroxypropylmethylcellulose has a viscosity of 80,000 to 120,000 cps.
The method according to any one of claims 1, 6, 7, and 12 to 14, wherein the tablet; Granules; Pellets; Mini tablets; And a sustained release preparation selected from the group consisting of capsules filled with granules, pellets or minitablets.

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