MXPA06009141A - Composition for oral administration of tamsulosin hydrochloride and controlled release granule formulation comprising same - Google Patents

Abstract

A composition for oral administration of tamsulosin hydrochloride and a controlled release granule formulation comprising the same exhibited excellent stability and sustained release characteristics of tamsulosin hydrochloride regardless of pH changes for an extended period of time.

Description

COMPOSITION FOR THE ORAL ADMINISTRATION OF TAMSULOSIN CHLORHYDRATE AND CONTROLLED RELEASE GRANULATE FORMULATION COMPRISING THE SAME Field of the Invention The present invention relates to a composition for the oral administration of tamsulosin hydrochloride, which exhibits excellent stability and sustained release of tamsulosin hydrochloride, and a controlled release granule formulation comprising the same.

Description of the Prior Art Tamsulosin hydrochlorides are currently available to treat benign prostatic hypertrophy, and many attempts have been made to develop a controlled release formulation of tamsulosin hydrochloride that has good stability and a prolonged release rate. For example, European Patent Publication No. 80341A discloses an oral formulation for the controlled release of tamsulosin containing multiple drug preparations; and Korean Patent Publication No. 1993-7245 discloses a controlled release formulation for oral use comprising the drug, an aggregate forming agent such as cellulose, chitin and chitosan, and an insoluble polymer. However, the stability and release characteristics of these formulations fluctuate in an unsatisfactory manner depending on the retained food or the pH changes in the gastroenteric organs. Efforts have been made to develop a composition having good stability and sustained release characteristics of tamsulosin hydrochloride under any digestive condition; and it has been unexpectedly discovered that a composition comprising tamsulosin hydrochloride, polyvinyl acetate and a water-soluble hydroxypropyl methylcellulose is particularly suitable for oral administration.

SUMMARY OF THE INVENTION Accordingly, it is a primary object of the present invention to provide a novel tamsulosin hydrochloride composition which exhibits high stability and satisfactory sustained release characteristics of tamsulosin hydrochloride in oral administration. Another object of the present invention is to provide a controlled release granule formulation comprising the aforementioned composition. In accordance with one aspect of the present invention, there is provided a composition for the oral administration of tamsulosin hydrochloride comprising tamsulosin hydrochloride, polyvinyl acetate, and a water-soluble hydroxypropyl methylcellulose. According to another aspect of the present invention, a sustained release granule of tamsulosin hydrochloride comprising tamsulosin hydrochloride, polyvinyl acetate, a water soluble hydroxypropyl methylcellulose, and a granulating agent is provided.

BRIEF DESCRIPTION OF THE DRAWINGS The foregoing and other objects and features of the present invention will become apparent from the following description of the invention, when taken together with the accompanying drawings, which show respectively: FIGURE 1: Dissolution profiles of tamsulosin hydrochloride observed for the hard capsule prepared in Example 17 and the Harnal capsule (Jeil Pharm., Korea); FIGURES 2A and 2B: The dissolution profiles of tamsulosin hydrochloride observed for the hard capsule prepared in Example 17 (A) and the Harnal capsule (B) after storage for 10 days under the condition of Test Example 2; and FIGURES 3A and 3B: The microscopic photographs of the coated granule prepared in Example 15 (A) and the granule of the Harnal capsule (B).

Detailed Description of the Invention The composition of the present invention comprises tamsulosin hydrochloride, polyvinyl acetate, and a water-soluble hydroxypropyl methylcellulose. The inventive composition may further comprise various granulation agents, coating materials, and pharmaceutically acceptable additives. Each ingredient of the inventive composition and the formulation of granules are described in detail as follows: Tamsulosin Hydrochloride Tamsulosin hydrochloride, the active ingredient of the inventive composition, has a low solubility in water. A typical daily dose of tamsulosin hydrochloride in the case of treating a urinary disorder accompanied by benign prostatic hypertrophy ranges from 0.2 to 0.8 mg, and should be administered once a day 30 minutes before a meal. However, it should be understood that the dose of tamsulosin hydrochloride should be determined in view of several relevant factors including the condition to be treated, the severity of the patient's symptoms, the route of administration, or the physiological form of the antineoplastic agent; and therefore, the dose suggested above should not be construed to limit the scope of the invention in any way.

Polyvinyl Acetate Polyvinyl acetate plays an important role in assisting the granulation agent in the process of granule formation and maintenance of pores formed in the granules for some period of time after the inventive granule formulation dissolves in a medium aqueous. Accordingly, the polyvinyl acetate gives the composition of the inventive composition the sustained release capacity of the active ingredient for a prolonged period of time without taking into account the pH of the aqueous medium. In the inventive composition, the polyvinyl acetate can be used alone or in the form of a mixture with other pharmaceutically acceptable materials, preferably in the form of a powder or a suspension containing more than 30% by weight or more of polyvinyl acetate . For example, Kollidon SRß (BASF), a powder prepared by mixing polyvinyl acetate and polyvinylpyrrolidone in a ratio of 8: 2 (w / w) and by spray drying the mixture, and Kollicoat SR30D18 (solid content: 30%, BASF ), a suspension (or a dilute aqueous solution) prepared by mixing polyvinyl acetate, polyvinyl pyrrolidone and sodium lauryl sulfate, and suspending the mixture in water, can be used in the present invention as a source of polyvinyl acetate. In addition, any pharmaceutically acceptable material can be used as a source of polyvinyl acetate insofar as it contains 30% by weight or more of polyvinyl acetate. The polyvinyl acetate can be used in the inventive composition in an amount ranging from 20 to 1000 parts by weight, preferably 40 to 600 parts by weight, and most preferably 50 to 300 parts by weight based on 1 part by weight of hydrochloride of tamsulosin.

Water-soluble hydroxypropyl methylcellulose A water-soluble hydroxypropyl methylcellulose (HPMC) controls the initial phase of release of the active ingredient by forming pores, through which the active ingredient is released. To obtain a desired sustained release pattern, it is preferable to employ a water-soluble HPMC having a high viscosity, and the desired effect may not be achieved when a low viscosity water-soluble HPMC is employed. Therefore, water-soluble HPMC having a high viscosity of more than 10,000 cps, preferably 15,000 to 100,000 cps, is used in the present invention, and representative examples therein include METOLOSE 60SH, 65SH and 90SH (Shin -Etsu) The water-soluble HPMC can be used in an amount ranging from 0.1 to 500 parts by weight, preferably 1 to 100 parts by weight, and most preferably 2 to 50 parts by weight based on 1 part by weight of tamsulosin hydrochloride. A controlled release granule formulation prepared by using the inventive composition may further comprise the following ingredients.

Granulation Agent The inventive granulation formulation may comprise a granulating agent and examples thereof include microcrystalline cellulose, lactose and inorganic carrier such as dibasic calcium phosphate, calcium dibasic phosphate dihydrate and tribasic calcium phosphate, wherein microcrystalline cellulose and dibasic calcium phosphate (for example, A-ab®, Rhodia). The granulating agent may be used in an amount ranging from 1 to 2000 parts by weight, preferably 10 to 1000 parts by weight based on 1 part by weight of tamsulosin hydrochloride.

Coating material The inventive granules formulation of tamsulosin hydrochloride can also be coated with a conventional enteric coating material or a polymeric coating material for the purpose of accurately controlling the absorption of the active ingredient in the gastrointestinal treatment. Examples of the enteric coating material include hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, shellac, methacrylate-methyl methacrylate copolymer and ethyl acrylate methacrylate copolymer. Examples of the polymeric coating material include hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, polyvinyl acetate and a mixture thereof. The coating material can be used in an amount ranging from 0.2 to 100 parts by weight, preferably 1 to 50 parts by weight based on the amount 1 part by weight of tamsulosin hydrochloride.

Pharmaceutically Acceptable Additives The inventive granule formulation may further comprise conventional pharmaceutically acceptable additives for preparation in various formulations, and a pharmaceutically acceptable exemplary additive includes a conventional plasticizer, lubricant and other auxiliaries. The pharmaceutically acceptable additive may be employed in an amount ranging from 0.1 to 500 parts by weight, preferably 1 to 200 parts by weight, and most preferably 2 to 50 parts by weight based on 1 part by weight of tamsulosin hydrochloride. The inventive composition of tamsulosin hydrochloride can be formulated into a granule formulation by a conventional method comprising the steps of (i) mixing the composition with a granulating agent, and (ii) subjecting the mixture to wet grinding, molding compression and spheronization to obtain a wet granule. The granule can also be coated with a coating material dissolved in water to obtain a coated granule. If necessary, the granule can further be mixed with pharmaceutically acceptable additives and filled into a hard gelatin capsule to obtain a capsule formulation. The following Examples are intended to further illustrate the present invention without limiting its scope.

I. Preparation of a controlled release granules formulation of tamsulosin hydrochloride EXAMPLE 1 0.2 parts by weight of tamsulosin hydrochloride, 21.0 parts by weight of Kollicoat SR30D (BASF, polyvinyl acetate), 5.5 parts by weight of METOLOSE 90SH (water-soluble HPMC, viscosity: 100,000) were placed in a high-speed mixer. cps), and 123.5 parts by weight of microcrystalline cellulose (granulating agent), and an appropriate amount of water was added thereto. The mixture was mixed for 10 to 15 minutes and treated with a wet rectifier to obtain a ground material, which was passed through a compression mold equipped with a 0.8 mm mesh, and granulated with a spheronizer to obtain a desired granule.

Example 2 The procedure of Example 1 was repeated except that 133.5 parts by weight of dibasic calcium phosphate was used as a granulating agent, to obtain a desired granule.

Example 3 The procedure of Example 1 was repeated except that 95.5 parts by weight of dibasic calcium phosphate dihydrate was used as a granulating agent, to obtain a desired granule.

Example 4 The procedure of Example 1 was repeated except that 128.5 parts by weight of lactose was used as a granulating agent, to obtain a desired granule.

Example 5 The procedure of Example 1 was repeated except that a mixture of 60 parts by weight of lactose and 68.5 parts by weight of microcrystalline cellulose as a granulating agent was used to obtain a desired granule.

Example 6 The procedure of Example 1 was repeated except that 3.8 parts by weight of METOLOSE 65SH (viscosity: 4,000 cps) was used instead of METOLOSE 90SH, to obtain a desired granule.

Example 7 The procedure of Example 1 was repeated except that 4.5 parts by weight of METOLOSE 65SH was used in place of METOLOSE 90SH, to obtain a desired granule.

Example 8 The procedure of Example 1 was repeated except that 70.0 parts by weight of Kollidon SR was used instead of Kollicoat SR30D, and 34.5 parts by weight of METOLOSE 65SH instead of METOLOSE 90SH, to obtain a desired granule.

Example 9 The procedure of Example 1 was repeated except that 78.0 parts by weight of Kollidon SR was used instead of Kollicoat SR30D, and 55.5 parts by weight of microcrystalline cellulose instead of 123.5 parts by weight, to obtain a desired granule.

II. Preparation of the controlled coating release granule of tamsulosin hydrochloride Example 10 150.0 parts by weight of the controlled release granule of tamsulosin hydrochloride obtained in Example 1 were placed in a fluidized bed (DALTON) NQ-160 and the bottom was sprayed with a coating solution comprising 9.7 parts by weight of Kollicoat SR30D (solid content: 2.9 parts by weight, a coating material), a mixture of 0.56 parts by weight of polyvinylpyrrolidone and 0.43 parts by weight of propylene glycol (a plasticizer), and 18.0 parts by weight of distilled water, to obtain a granule desired coating. During the coating, the inlet temperature was 36 to 39 ° C, the outlet temperature was 26 to 28 ° C, the injection rate of the coating solution was 0.7 to 0.8 ml / min, and the pressure of atomized air was 45 to 55 psi.

Example 11 The procedure of Example 10 was repeated except that 3.4 parts by weight of ethylcellulose (IPI) and 7.6 parts by weight of hydroxypropyl methylcellulose (Shin-Etsu) were used as a coating material, to obtain a desired coated granule.

Example 12 The procedure of Example 10 was repeated except that a coating solution comprising 12.0 parts by weight of Eudragit L30D-55 (ethyl acrylate methacrylate copolymer, solid content: 3.6 parts by weight, Roehm) was used as a coating material. coating, 0.54 parts by weight of triacetin as a plasticizer and 21.8 parts by weight of water in place of the coating solution of Example 10, to obtain a desired coated granule.

Example 13 The procedure of Example 10 was repeated except that 0 parts by weight of hydroxypropyl methylcellulose phthalate (solid content: 3.6 parts by weight, Roehm) was used as a coating material, to obtain a desired coated granule.

Example 14 The procedure of Example 10 was repeated except that 9.0 parts by weight of Eudragit E-100 (methyl methacrylate-methacrylate copolymer, solid content: 3.6 parts by weight, Roehm) was used as a coating material, to obtain a desired coated granule.

Example 15 The procedure of Example 10 was repeated except that 153.9 parts by weight of the coated granule obtained in Example 10 was used in place of the granule obtained in Example 1, and a coating solution comprising 12.0 parts by weight of Eudragit L30D- 55 (ethyl acrylate methacrylate copolymer, solid content: 3.6 parts by weight, Roehm) as a coating material, 0.54 parts by weight of triacetin as a plasticizer and 21.8 parts by weight of water in place of the coating solution of Example 10, to obtain a desired coated granule.

III. Preparation of a hard capsule comprising a controlled release granule of tamsulosin hydrochloride EXAMPLE 16 158.14 parts by weight of the coated granule obtained in Example 13, 0.5 parts by weight of talc, and 0.5 parts by weight of calcium stearate were mixed, and a hard capsule was filled with the mixture to obtain a desired hard capsule.

Example 17 158.14 parts by weight of the coated granule obtained in Example 15, 0.5 parts by weight of talc, and 0.5 parts by weight of calcium stearate were mixed, and a hard capsule was filled with the mixture to obtain a desired hard capsule. .

Test Example 1: Dissolution Test A dissolution test for tamsulosin hydrochloride was performed using the capsule obtained in Example 17 and the Harnal capsule (Jeil Pharm.) As a comparative preparation in the following manner. 500 ml of artificial gastric juice (pH 1.2) containing 1 ml of Tween 80 was used as a test solution (1) . Each treated capsule was added to the test solution (1), the mixture was stirred at 37 + 0.5 ° C and 100 rpm for 2 hours, and a 10 ml sample of the test solution (1) was taken.

Then, the test solution (1) was changed for the test solution (2), 500 ml of a phosphate buffer (pH 7.2), the same stirring procedure was repeated, and 10 ml samples of the solution were taken. of test (2) at hour 1 and 3 after the start of agitation, respectively. The sample taken from the test solution (1) was mixed with 2.0 ml of an internal standard (propyl parahydroxybenzoate dissolved in a water: acetonitrile = 7: 3 mixture), while each sample taken from the test solution (2). ) was mixed with the mixture of 0.5 N HCl and 2.0 ml of the internal standard. The resulting mixture was filtered through a 0.5 μm membrane filter, and subjected to liquid chromatography (column: Cosmosil (ODS) (4.6x150 mm, 5 μm) C? 8; temperature: 40 ° C; Mobile phase: aqueous HC104 (adjusted to pH 2.0 using NaOH): acetonitrile = 7: 3; flow rate: 1.0 ml / min; injection volume: 500 μl; and wavelength: 225 mm) to analyze the amount of time-dependent release of tamsulosin hydrochloride. The results are shown in FIGURE 1. As shown in FIGURE 1, the capsule of the present invention and the Harnal capsule exhibited similar tamsulosin hydrochloride release patterns regardless of pH.

Test Example 2: Stability Test Each of 12 of the hard capsules obtained in Example 17 and 12 Harnal capsules (Jeil Pharm.) Was placed in an HDPE bottle. Then, the bottle was sealed, and kept at 60 ° C, or at 40 ° C and 75% relative humidity (a forced condition). At day 0, 10 or 30 of this treatment, each residual percentage of inventive tamsulosin hydrochloride or Harnal capsule was analyzed using liquid chromatography, and the results are listed in Table 1.

Table 1 In addition, the procedure of the Example of Test 1 using the inventive capsule and Harnal maintained for 10 days under the previous forced condition. The results are shown in FIGURES 2A (the inventive capsule) and 2B (Harnal capsule). As the results show, the inventive capsule of tamsulosin hydrochloride exhibits high stability and good sustained release characteristics of tamsulosin hydrochloride, compared to the Harnal capsule.

Test Example 3: Sphericity Test The particles of 10 granules of the coated granule obtained in Example 15 and those of the Harnal capsule were examined using a microscope (Nik on SMZ800). In each microscopic photograph, a minimum circumscribed circle was drawn, and the distance from the circumcenter and surface of the granule was measured to obtain the minimum distance (A) and maximum distance (B). The sphericity of each granule was evaluated by A / B, and the results are listed in Table II.

Table II The results in Table II suggest that the granule of the present invention is more spherical than the Harnal granule, since the average A / B of the inventive granule was closer to 1 than the comparative granule. In this way, the composition of the present invention is capable of forming uniform granules. As can be seen from the foregoing, the inventive composition for the oral administration of tamsulosin hydrochloride having high stability, a good sustained release rate of the active ingredient and the ability to form uniform granules can be used advantageously in various fields including medical sciences and pharmaceutical chemistry. Although the invention has been described with respect to the specific embodiments, it should be recognized that various changes and modifications can be made by those skilled in the art for the invention which also falls within the scope of the invention as defined by the appended claims.

Claims (11)

1. CLAIMS 1. A composition for the oral administration of tamsulosin hydrochloride comprising tamsulosin hydrochloride, polyvinyl acetate, and a water-soluble hydroxypropyl methylcellulose. The composition of claim 1, wherein the polyvinyl acetate is in the form of a powder or suspension comprising polyvinyl acetate and a pharmaceutically acceptable additive. The composition of claim 1, wherein the amount of polyvinyl acetate ranges from 20 to 1000 parts by weight based on 1 part by weight of tamsulosin hydrochloride. The composition of claim 1, wherein the water-soluble hydroxypropyl methylcellulose has a viscosity ranging from 10,000 to 100,000 cps. The composition of claim 1, wherein the amount of water-soluble hydroxypropyl methylcellulose ranges from 0.1 to 500 parts by weight based on 1 part by weight of tamsulosin hydrochloride. 6. A sustained release granule of tamsulosin hydrochloride comprising tamsulosin hydrochloride, polyvinyl acetate, a water-soluble hydroxypropyl methylcellulose, and a granulating agent. The granule of claim 6, wherein the granulating agent is selected from the group consisting of lactose, microcrystalline cellulose, calcium dibasic phosphate, calcium dibasic phosphate dihydrate, tribasic calcium phosphate and a mixture thereof. 8. The granule of claim 6, wherein the amount of the granulating agent varies from 1 to 2000 parts by weight based on 1 part by weight of tamsulosin hydrochloride. 9. The granule of claim 6, which is coated with a coating material. The granule of claim 9, wherein the coating material is a polymeric or enteric coating material. The granule of claim 9, wherein the amount of the coating material ranges from 0.2 to 100 parts by weight based on 1 part by weight of tamsulosin hydrochloride.