WO2006112596A1

WO2006112596A1 - Controlled-release formulation containing tamsulosin hydrochloride

Info

Publication number: WO2006112596A1
Application number: PCT/KR2006/000489
Authority: WO
Inventors: Hong-Ryeol Jeon; Do-Woo Kwon; Bong-Sang Lee
Original assignee: CTC BIO Inc
Current assignee: CTC BIO Inc
Priority date: 2005-02-11
Filing date: 2006-02-10
Publication date: 2006-10-26
Anticipated expiration: 2007-08-11
Also published as: KR20060091036A; KR100678421B1; CN101128190A

Abstract

The present invention relates to a controlled-release preparation containing tamsulosin hydrochloride. The preparation of the present invention can release tamsulosin hydrochloride at zero-order rate regardless of ambient conditions of stomach and small intestine, and therefore can reduce several side effects and maintain the effect of the drug constantly. In addition, the tamsulosin hydrochloride-containing controlled-release preparation of the present invention is simple to manufacture and cost-effective, and can be made with conventional tabletting machine and coating machine used usually so that it does not need a specific equipment.

Description

CONTROLLED-RELEASE FORMULATION CONTAINING TAMSULOSIN HYDROCHLORIDE

Technical Field

[1] The present invention relates to a controlled-release formulation containing tamsulosin hydrochloride, and more particularly, to a controlled release formulation that can release tamsulosin hydrochloride at zero-order rate regardless of ambient in vivo condition. Background Art

[2] Tamsulosin hydrochloride is an alpha (α) 1 blocker that is selective to prostatic smooth muscle. Tamsulosin hydrochloride is a drug useful for the treatment of obstructive urinary tract disorders due to benign prostate enlargement. The usual daily dose of tamsulosin hydrochloride is 0.2-0.8 mg. Tamsulosin hydrochloride has greater selectivity for prostatic smooth muscle and acts weakly on blood vessels, unlike other alpha 1 blockers such as doxazosin and terazosin, thereby greatly decreasing occurrences of side effects such as orthostatic hypotension. However, despite the high selectivity for prostatic smooth muscle, since tamsulosin hydrochloride is highly potent, a very low dose is required. Also, excessive increase of blood concentration of tamsulosin hydrochloride due to fast absorption into the body may cause side effects such as orthostatic hypotension.

[3] In view of these problems, U.S. Patent No. 4,772,475 discloses a controlled release formulation containing tamsulosin hydrochloride. According to this patent, tamsulosin hydrochloride is mixed with at least 50% by weight of a unit-forming substance selected from the group consisting of crystalline cellulose, chitin and chitosan. Then, to the mixture, a release-controlling agent selected from the group consisting of acrylic acid polymers, acrylic acid copolymers and mixtures thereof is added, followed by granulation, to produce sustained-release granules containing tamsulosin hydrochloride.

[4] However, the controlled-release formulation according to the above patent does not show enough controlled-release property. For example, 16.2 to 60.4% of the drug is released from said formulation within one hour after start of release in a first acidic solution (pH: about 1.2), and more than 90% of the drug is released within one hour after start of release in the second neutral solution when release is carried out in a second neutral solution (pH: about 6.8) after the release in the first acid solution (See Korean patent application No. 10-2003-0015391).

[5] Because of these problems, orthostatic hypotension, the main side effect of tamsulosin hydrochloride, often happens within 4 hours after administration, and 8.4% (when 0.4mg of tamsulosin hydrochloride is administered) and 18.1% (when 0.8mg of tamsulosin hydrochloride is administered) of patients have side effects such as abnormal ejaculation [Prescription Drug Reference(PDR), 2002]. Therefore, there is a need to design a sustained-release preparation that can efficiently control the release of tamsulosin hydrochloride, that is, a sustained-release preparation that can release the drug at steady rate regardless of ambient in vivo condition. In more detail, it is important to reduce the side effects caused by the large amount of absorption of tamsulosin hydrochloride during short time, through release control from stomach to intestine (through release control with zero-order rate).

[6] Most conventional sustained-release preparations containing tamsulosin hydrochloride are using an enteric polymer to control the release of the drug. Therefore, it is possible in stomach to efficiently sustain the drug release because of the enteric polymer, but when the preparation passes on into small intestine over time, there may be a problem that the large amount of the drug is released because of the rapid increase of solubility of the enteric polymer. That is, many conventional preparations using only enteric polymers to control the release of tamsulosin hydrochloride, for example made by coating the core material with a solution or suspension comprising a enteric polymer and tamsulosin hydrochloride, are a problem that the large amount of the drug are released simultaneously when the preparation passes on into small intestine.

[7] Commercially available products containing tamsulosin hydrochloride (Harnal™,

Yamanouchi Co. Ltd.; Flomax™, Boehringer Ingelheim) also exhibit distinct pH- dependent drug release property. It is reported that administration of these products into human before food intake results in 30% increase of bioavailability and 40-70% increase of maximum drug concentration in bloods (Cmax), as compared to after food intake (Physicians Desk Reference 2002). This report demonstrates that food intake influences the mobility of the gastric intestinal tract and the ambient pH of a drug- containing preparation.

[8] In addition, most commercially available sustained-release products are using granule type to control easily the drug release instead of tablet type, the most-used type as medicinal preparation. However, this granule type of preparations made by making granules and coating the granules are complex to manufacture and not cost-effective, and need a specific equipment to coat the granules. Disclosure of Invention Technical Problem

[9] Therefore, the object of the present invention is to provide a tamsulosin hydrochloride -containing controlled-release preparation that releases constantly the drug irrespective of ambient in vivo pH, that is that releases the drug at regular rate (zero-order rate) from stomach to small intestine. In other words, the object of the present invention is to provide a tamsulosin hydrochloride-containing preparation that maintains the effect of tamsulosin hydrochloride longer and reduces side effects such as orthostatic hypotension and abnormal ejaculation, which are caused by the large amount of absorption of tamsulosin hydrochloride during short time. Technical Solution

[10] To achieve the object, the present invention provides a tamsulosin hydrochloride- containing controlled-release preparation, wherein the preparation comprises:

[11] (A) a core tablet comprising tamsulosin hydrochloride; a binder selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low- viscosity hydroxypropylmethylcellulose, low- viscosity hydroxypropylcellulose and their mixtures; a diluent selected from the group consisting of lactose anhydrous, lactose hydrous, microcrystalline cellulose and their mixtures; low-viscosity hydroxypropylmethylcellulose for controlling drug release; and a disintegrator selected from the group consisting of sodium starch glycolate, croscarmellose sodium and their mixture, and

[12] (B) a coated membrane comprising an enteric polymer; a pore-maker selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low- viscosity hydroxypropylmethylcellulose, low-viscosity hydroxypropylcellulose and their mixtures; and a surfactant for coating.

[13] More preferably, the present invention provides said tamsulosin hydrochloride- containing controlled-release preparation, wherein the preparation comprises:

[14] (A) a core tablet comprising 0.03-0.14% by weight of tamsulosin hydrochloride;

0.5-7% by weight of binder; 45-75% by weight of diluent; 10-27% by weight of low- viscosity hydroxypropylmethylcelmlose for controlling drug release; and 5-15% by weight of disintegrator, and

[15] (B) a coated membrane comprising 3-8% by weight of enteric polymer; 0.5-3% by weight of pore-maker; and 0.5-2% by weight of surfactant for coating,

[16] based on the total weight of the preparation including the core tablet and the coated membrane.

[17] Unlike conventional tamsulosin hydrochloride-containing preparations made by coating with only enteric polymer or mixing tamsulosin hydrochloride with enteric polymer, the present invention makes the core tablet itself control drug release by using appropriate ratio of mixture comprising low- viscosity hydroxypropylmethylcellulose (pH- independent polymer for controlling drug release), binder, diluent, etc., and in addition thereto, makes the preparation release tamsulosin hydrochloride at zero-order rate irrespective of ambient condition of stomach and small intestine by coating the core tablet with appropriate ratio of mixture comprising enteric polymer, pore-maker and surfactant.

[18] Furthermore, most commercially available sustained-release products are using granule type to control easily drug release instead of tablet type, the most-used type as medicinal preparation. This granule type of preparations made by making granules and coating the granules are complex to manufacture and not cost-effective, and need a specific equipment to coat the granules. However, the controlled-release preparation of the present invention is tablet type which is used frequently, and the preparation of the present invention has merits that its manufacturing is simple and cost-effective, and does not also need specific equipment for coating process.

[19] Hereinafter, tamsulosin hydrochloride-containing controlled-release preparation according to the present invention will be described in detail.

[20] The present invention provides a tamsulosin hydrochloride-containing controlled- release preparation, wherein the preparation comprises:

[21] (A) a core tablet comprising tamsulosin hydrochloride; a binder selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low- viscosity hydroxypropylmethylcellulose, low- viscosity hydroxypropylcellulose and their mixtures; a diluent selected from the group consisting of lactose anhydrous, lactose hydrous, microcrystalline cellulose and their mixtures; low-viscosity hydroxypropylmethylcellulose for controlling drug release; and a disintegrator selected from the group consisting of sodium starch glycolate, croscarmellose sodium and their mixture, and

[22] (B) a coated membrane comprising an enteric polymer; a pore-maker selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low- viscosity hydroxypropylmethylcellulose, low-viscosity hydroxypropylcellulose and their mixtures; and a surfactant for coating.

[23] More preferably, the present invention provides said tamsulosin hydrochloride- containing controlled-release preparation, wherein the preparation comprises:

[24] (A) a core tablet comprising 0.03-0.14% by weight of tamsulosin hydrochloride;

0.5-7% by weight of binder; 45-75% by weight of diluent; 10-27% by weight of low- viscosity hydroxypropylmethylcellulose for controlling drug release; and 5-15% by weight of disintegrator, and

[25] (B) a coated membrane comprising 3-8% by weight of enteric polymer; 0.5-3% by weight of pore-maker; and 0.5-2% by weight of surfactant for coating,

[26] based on the total weight of the preparation including the core tablet and the coated membrane.

[27] The core tablet (A) of the present invention comprises comprising 0.03-0.14% by weight of tamsulosin hydrochloride; 0.5-7% by weight of binder selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low- viscosity hydroxypropylmethylcellulose, low- viscosity hydroxypropylcellulose and their mixtures; 45-75% by weight of diluent selected from the group consisting of lactose anhydrous, lactose hydrous, microcrystalline cellulose and their mixtures; 10-27% by weight of low-viscosity hydroxypropylmethylcellulose for controlling drug release; and 5-15% by weight of disintegrator selected from the group consisting of sodium starch glycolate, croscarmellose sodium and their mixture based on the total weight of the preparation including the core tablet and the coated membrane.

[28] The controlled-release preparation of the present invention comprises a binder for binding powders to make granules for tabletting and controlling release of tamsulosin hydrochloride. Preferable binder of the present invention includes polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low-viscosity hydroxypropylmethylcellulose, low-viscosity hydroxypropylcellulose and their mixtures. Polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer and their mixture are more preferable in view of easy manufacturing of granules for tabletting and easy controlling property of drug release pattern. Preferable content of the binder is 0.5-7% by weight and more preferable content of the binder is 1.5-4% by weight based on the total weight of the preparation. In case that the content of the binder is less than 0.5% by weight, it is difficult to make enough strong granules for tabletting. In case that the content of the binder is more than 7% by weight, drug release rate may be severely delayed because the binder itself blocks integration of the preparation and drug release from the preparation.

[29] The controlled-release preparation of the present invention comprises a diluent for giving the preparation enough volume for administration and drawing proper amount of water into the core tablet during dissolution of the preparation. As a result, the diluent has close relations with the other ingredients. Preferable diluent of the present invention includes lactose anhydrous, lactose hydrous, microcrystalline cellulose and their mixtures. Preferable content of the diluent is 45-75% by weight and more preferable content of the diluent is 50-70% by weight based on the total weight of the preparation. Diluent consisting of 30-45% by weight of lactose and 15-30% by weight of microcrystalline cellulose is most preferable in view of easy manufacturing of the tablet. In case that the content of the diluent is less than 45% or more than 75% by weight, it is difficult to maintain good drug release rate.

[30] The controlled-release preparation of the present invention comprises low- viscosity hydroxypropylmethylcellulose playing an important role in controlling the release of tamsulosin hydrochloride. More specifically, the low- viscosity hydroxypropylmethylcellulose of the present invention plays its role in controlling the drug release even after the preparation passes on into small intestine where the coated membrane of enteric polymer dissolves out. The low- viscosity hydroxypropylmethylcellulose is not the only ingredient for controlling the release of tamsulosin hydrochloride, but the other ingredients contained in the preparation of the present invention, consisting of the core tablet and the coated membrane, play their roles in controlling the release of tamsulosin hydrochloride. That is, all ingredients have relations with each other in controlling the release of tamsulosin hydrochloride. Preferable content of low-viscosity hydroxypropylmethylcellulose is 10-27% by weight based on the total weight of the preparation. In case that the content is less than 10% by weight, it is difficult to control the release of tamsulosin hydrochloride. In case that the content is more than 27% by weight, the release of tamsulosin hydrochloride is too slow to get a desirable release pattern.

[31] The "low- viscosity" in low-viscosity hydroxypropylmethylcellulose and low- viscosity hydroxypropylcellulose means that the viscosity of 2% water solution made with each polymer is from 20 to 150 cps at 2O⁰C, and more preferably, from 70 to 130 cps.

[32] The controlled-release preparation of the present invention comprises a disintegrator. Preferable disintegrator includes sodium starch glycolate, croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium) and their mixture. Preferable content of the disintegrator is 5-15% by weight based on the total weight of the preparation. In case that the content is less than 5% by weight, it is difficult to get a desirable release pattern. In case that the content is more than 15% by weight, the release of tamsulosin hydrochloride is too fast because of fast disintegration.

[33] The controlled-release preparation of the present invention may further comprise a lubricant such as colloidal silica, talc, magnesium stearate and their mixtures to improve flowability of granules for tabletting and tabletting property within the scope not to obstruct the object of the present invention.

[34] The core tablet (A) of the present invention is enclosed by membrane comprising an enteric polymer; a pore-maker selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low-viscosity hydroxypropylmethylcellulose, low-viscosity hydroxypropylcellulose and their mixtures; and a surfactant for coating. The coated membrane of the present invention performs a role controlling the release in stomach.

[35] The controlled-release preparation of the present invention comprises in the coated membrane an enteric polymer that does not dissolve in stomach so that the preparation of the present invention can control the release of tamsulosin hydrochloride in stomach. Preferable enteric polymer includes hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate and their mixtures. Preferable content of the enteric polymer is 3-8% by weight based on the total weight of the preparation. In case that the content is less than 3% by weight, the drag release in stomach is too fast. In case that the content is more than 8% by weight, the drug release in stomach is too slow and the difference of the drug release between stomach condition and small intestine condition is too big, that is, the large amount of tamsulosin hydrochloride is released and absorbed during short time, which may cause many side effects.

[36] The controlled-release preparation of the present invention comprises a pore-maker in the coated membrane. A material used as this pore-maker is dissolved in stomach and makes a pore in the membrane. Through this pore, tamsulosin hydrochloride is suitably released in stomach. Preferable pore-maker includes polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low-viscosity hydroxypropylmethyl- cellulose, low-viscosity hydroxypropylcellulose and their mixtures. Preferable content of the pore-maker is 0.5-3% by weight based on the total weight of the preparation. In case that the content of the pore-maker is less than 0.5% by weight, it is difficult to release tamsulosin hydrochloride in stomach. In case that the content is more than 3% by weight, the release of tamsulosin hydrochloride in stomach is too fast to get a desirable release pattern.

[37] The controlled-release preparation of the present invention comprises a surfactant for coating in the coated membrane to give plasticity to the enteric polymer. Preferable surfactant for coating includes dibutylsebacate, triethylcitrate, propylene glycol, poly ethylenegly col and their mixtures. More preferable surfactant is polyethyleneglycol and most preferable surfactant is polyethyleneglycolβOOO. Preferable content of the surfactant is 05-2% by weight based on the total weight of the preparation. The surfactant for coating according to the present invention performs an accessory role making a pore in the membrane comprising, for example, hydrox- ypropylmethylcellulose phthalate by being dissolved out in stomach, as well as a main role giving plasticity to the enteric polymer. That is, like the pore-maker, the surfactant controls the release of tamsulosin hydrochloride in stomach. In case that the content of the surfactant is less than 0.5% by weight, it is difficult to get a desirable plasticity for coating. In case that the content is more than 2% by weight, the release of the drag is too fast in stomach.

[38] The coated membrane (B) according to the present invention may further comprise a lubricant (for example, talc), an agent for blocking light (for example, titanium oxide) and so on.

[39] Tamsulosin hydrochloride-containing controlled-release preparation according to the present invention can be made by a method known well to one of ordinary skill in the art. For example, a controlled-release preparation according to the present invention can be made by the following method, but the manufacturing method for the preparation of the present invention is not limited thereto.

[40] Firstly, tamsulosin hydrochloride and a binder are dissolved in adequate amount of solvent (for example, water, methanol, ethanol, isopropanol, acetone, methylene chloride and their mixtures) to make a binding solution, and then granules having appropriate size for tabletting are prepared with the binding solution and a diluent. The granules, low- viscosity hydroxypropylmethylcellulose, a disintegrator, lubricant and so on are mixed and tabletted by using tabletting machine to make a core tablet. Then, coating process is performed as follows: an enteric polymer, a pore-maker, surfactant etc. are dissolved in adequate amount of solvent (for example, water, methanol, ethanol, isopropanol, acetone, methylene chloride and their mixtures) to make a coating solution. A conventional tablet-coating machine is used with the core tablet and the coating solution to make a tamsulosin hydrochloride-containing controlled release preparation of the present invention. Brief Description of the Drawings

[41] Figure 1 shows the results of dissolution tests for controlled-release preparations according to one example of the present invention and commercially-available products.

[42] Figure 2 shows the results of dissolution tests for controlled-release preparations according to one example of the present invention and comparative examples. Mode for the Invention

[43] Hereinafter, a preferred embodiment of the present invention will be described in detail. Prior to the description, it should be understood that various modifications are possible to the embodiments of the present invention, and it should be understood that the scope of the invention is not limited to the following embodiments.

[44]

[45] <Manufacturing of examples 1-4 and comparative examples 1~4>

[46] Examples and comparative examples were manufactured with ingredients and contents shown in the below table 1. Almost 10,000 tablets were prepared at a time per each example. That is, 10,000 times amount of weight of each ingredient was measured and used to make each preparation. For example, example 1 was manufactured as follows: 2 g of tamsulosin hydrochloride and 50 g of polyvinylpyrrolidone were dissolved in 600 ml of ethanol to make a binding solution. The binding solution was combined with 936 g of lactose and 530 g of microcrystalline cellulose to make granules. The granules were dried (6O⁰C, 4 hours) and sieved to make adequate size of granules, and then 440 g of low-viscosity hydroxypropylmethylcellulose, 220 g of sodium starch glycolate and 22 g of magnesium stearate were added to the granules. The mixture was mixed well and tabletted with a tabletting machine (TMI 1400, Kisan, South Korea). After tabletting, 119 g of hydroxypropylmethylcellulose phthalate, 24 g of polyvinylpyrrolidone, 26 g of polyethyleneglycol6000, 4 g of titanium oxide and 3 g of talc were dissolved or suspended in the mixture of 1,400 ml of ethanol and 1,000 ml of methylene chloride to make a coating solution. The above manufactured tablets were coated with the coating solution with a conventional coating machine (KC400SF, Kisan, South Korea). More amount of the coating solution than needed was manufactured to supplement the loss in the coating process.

[47] Examples 2-4 and comparative examples 1-4 were manufactured according to the same method as used in example 1. [48] Table 1

[49] In table 1, HPMC and HPMCP mean hydroxypropylmethylcellulose and hydroxypropylmethylcellulose phthalate, respectively. [50] [51] <Dissolution tests of examples, comparative examples and commercially available products>

[52] Dissolution tests were performed with the above manufactured examples 1-4, comparative examples 1-4 and commercially available products [TAMSNAL™(Yuhan Corp., South Korea), URONAL™(KyungDong Pharm. Co. Ltd., South Korea) and HARNAL™(Yamanouchi Korea Co. Ltd., South Korea)] according to the paddle method of the dissolution test method of Korea Pharmacopoeia. The paddle was rotated at a rate of 100 rpm and the temperature of dissolution medium was 37±0.5°C. 500 ml of pH 1.2 solution [2.0 g of NaCl was dissolved in 7.0 ml of hydrochloric acid, and then distilled water was added to make the volume 1 liter], to which 1 ml of polysorbate 80 solution (3→200) was added, was used as dissolution medium until 2 hours after the start of the test, and then the pH 1.2 solution was immediately replaced with 500 ml of pH 7.2 phosphate buffered solution. The amount of tamsulosin hydrochloride dissolved into dissolution medium at each time was measured by the below described HPLC method.

[53] [Analysis condition] [54] Detector: UV- Visible spectrophotometer (detection wavelength 225 nm) [55] Column: Commosil C (ODS) or a similar column [56] Mobile phase: 8.7 ml of perchloric acid and 3.0 g of NaOH were dissolved in 1,900 ml of water to make a solution. pH of the solution was adjusted to 2.0 with NaOH solution and water was added to make the volume 2,000 ml. 1 ,400 ml of the solution and 600 ml of acetonitrile were mixed to make a mobile phase.

[57] Table 2

[58] As shown in table 2, example 2 showed a desirable release pattern even if a little less amount of the coated membrane and a little more amount of low- viscosity hydrox- ypropylmethylcellulose than example 1 were used. Example 3 showed a desirable Table release pattern even if a little more amount of the coated membrane and a little less amount of low- viscosity hydroxypropylmethylcellulose were used. Example 4, wherein the amounts of low- viscosity hydroxypropylmethylcellulose and hydroxypropylmethylcellulose phthalate are in boundary of the preferable scope of the present invention, showed a little slow release pattern.

[59] As shown in figure 1 , unlike the examples of the present invention, the commercially available products released more amount of tamsulosin hydrochloride between 120 minutes and 150 minutes when the dissolution medium was changed from pH 1.2 to pH 7.2 (that is, the preparation is passed on into small intestine from stomach), which may cause several side effects. However, the examples of the present invention showed a constant release pattern (zero-order rate release) irrespective of ambient condition.

[60] As shown in figure 2, comparative example 1 showed a fast release pattern because the content of the low- viscosity hydroxypropylmethylcellulose is less than the preferable scope of the present invention. Comparative example 2 could not properly control the release of tamsulosin hydrochloride because the content of the disintegrator was too high. Comparative example 3 showed very slow release pattern because of the large amount of coating. Comparative example 4 could not properly control the release of tamsulosin hydrochloride because of the large amount of the pore-maker.

[61]

[62] <Manufacturing of examples 5 and 6>

[63] Examples 5 and 6 were manufactured as shown in the below table 3 according to the same method as used in example 1.

[64] Table 3

[65] In table 3, HPMC means hydroxypropylmethylcellulose, and Acryl-EZE™ is a methacrylic acid co-polymer, an example of the enteric polymer, which can be purchased from Colorcon, Inc., and AQOAT™ is hydroxypropylmethylcellulose acetate succinate, an example of the enteric polymer, which can be purchased from Shin-Etsu Chemical Co., Ltd. Water and mixture of ethanol and water were used for coating medium of Acryl-EZE™ and AQOAT™, respectively.

[66] [67] <Dissolution tests of examples 5 and 6> [68] Dissolution tests on examples 5 and 6 were performed according to the same method as used in dissolution test on example 1. Results were shown in table 4.

[69] Table 4

[70] As shown in table 4, Examples 5 and 6 using methacrylic acid co-polymer and hy- droxypropylmethylcellulose acetate succinate, respectively, instead of hydroxypropyl- methylcellulose phthalate of the enteric polymer of example 1 showed zero-order release of tamsulosin hydrochloride like the result of example 1. Industrial Applicability

[71] The present invention provides a tamsulosin hydrochloride-containing controlled- release preparation that can maintain the effect of the drug longer and reduce side effects such as orthostatic hypotension and abnormal ejaculation by releasing constantly the drug irrespective of ambient in vivo pH, that is, releasing the drug at regular rate (zero-order rate) from stomach to small intestine. In addition, the tamsulosin hydrochloride-containing controlled-release preparation of the present invention is simple to manufacture and cost-effective, and can be made with conventional tabletting machine and coating machine used usually so that it does not need a specific equipment for coating granules.

Claims

[1] A tamsulosin hydrochloride-containing controlled-release preparation, wherein the preparation comprises:

(A) a core tablet comprising tamsulosin hydrochloride; a binder selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low-viscosity hydroxypropylmethylcellulose, low-viscosity hydrox- ypropylcellulose and their mixtures; a diluent selected from the group consisting of lactose anhydrous, lactose hydrous, microcrystalline cellulose and their mixtures; low- viscosity hydroxypropylmethylcellulose for controlling drug release; and a disintegrator selected from the group consisting of sodium starch glycolate, croscarmellose sodium and their mixture, and

(B) a coated membrane comprising an enteric polymer; a pore-maker selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low-viscosity hydroxypropylmethylcellulose, low-viscosity hydrox- ypropylcellulose and their mixtures; and a surfactant for coating.

[2] The tamsulosin hydrochloride-containing controlled-release preparation of claim

1, wherein the preparation comprises:

(A) a core tablet comprising 0.03-0.14% by weight of tamsulosin hydrochloride; 0.5-7% by weight of binder; 45-75% by weight of diluent; 10-27% by weight of low-viscosity hydroxypropylmethylcellulose for controlling drug release; and 5-15% by weight of disintegrator, and

(B) a coated membrane comprising 3-8% by weight of enteric polymer; 0.5-3% by weight of pore-maker; and 0.5-2% by weight of surfactant for coating, based on the total weight of the preparation including the core tablet and the coated membrane.

[3] The tamsulosin hydrochloride-containing controlled-release preparation of claim

2, wherein the diluent consists of 30-45% by weight of lactose and 15-30% by weight of microcrystalline cellulose.

[4] The tamsulosin hydrochloride-containing controlled-release preparation of claim

1, wherein the enteric polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer and hydroxypropylmethylcellulose acetate succinate.

[5] The tamsulosin hydrochloride-containing controlled-release preparation of claim

1 , wherein the surfactant for coating is polyethyleneglycol.

[6] The tamsulosin hydrochloride-containing controlled-release preparation of claim

1 , wherein the binder is polyvinylpyrrolidone or vinylpyrrolidone-vinylacetate copolymer. [7] The tamsulosin hydrochloride-containing controlled-release preparation of claim

1 , wherein the pore-maker is polyvinylpyrrolidone or vinylpyrrolidone- vinylacetate copolymer.