KR20110113940A - A pharmaceutical composition comprising an enteric sustained release pellet portion and immediate release portion containing tamsulosin or a pharmaceutically acceptable salt thereof as an active ingredient - Google Patents

Abstract

The present invention provides a compound comprising a sustained release portion comprising an enteric sustained-release pellet portion containing tamsulosin or a pharmaceutically acceptable salt thereof and an immediate release portion including a fast disintegrating granule.
In addition, the present invention is to prepare an enteric sustained-release pellet portion in a multi-layer composition consisting of (a) drug layer, (b) sustained release layer, (c) enteric layer and (d) sweetening layer using a multilayer coating method, The immediate release portion is prepared by granules containing immediate release excipients and then mixed to provide a method for preparing a simple and stable oral dosage form by a direct stroke process.

Description

Pharmaceutical composition comprising of immediate-release parts and enteric coated controlled-release pellets containing tamsulosin or its pharmaceutical acceptable salts}

The present invention relates to a pharmaceutical composition comprising an enteric sustained-release pellet portion and immediate disintegration portion containing tamsulosin as an active ingredient.

Tablets that disintegrate rapidly in the oral cavity have been developed in various forms to make it easy to take water without difficulty in swallowing elderly or pediatric patients. In recent years, in accordance with the demand of various drug applications, it is required to impart sustained-release function to tablets that disintegrate rapidly in the oral cavity.

U.S. Patent Nos. 4,371,516 and 5,501,816 disclose methods for preparing porous fast disintegrating tablets, which comprise adding a small amount of solvent to sugars, alcohols to obtain a purification mixture and removing the solvent therefrom. . However, these preparation methods may deform the properties of the drug in the step of removing the solvent and have a disadvantage of affecting the stability.

In Korean Patent Nos. 0530546 and 0386391, after preparing sustained-release microparticles, in order to prepare fast disintegrating formulations, granules are prepared by sugars and granulation and tableted to prepare tablets, such as a humidification process, a heating process and a cooling process. This is posted. However, these manufacturing methods require a complicated manufacturing process, and there is a problem that can affect the stability of the drug by a humidification process and a heating process.

Republic of Korea Patent Publication No. 2002-0077548 relates to a method for producing a tablet having a porosity by mixing the water-soluble sugars, disintegrants and foaming material to prepare a tablet, and then contact the water with water to dry the tablet. This may result in disintegration of the tablet by the effervescent material when stored in moisture or air.

Therefore, there is a demand for development of a formulation that is more stable than a conventional drug and has a simple manufacturing method.

Accordingly, an object of the present invention is characterized in that it comprises an enteric sustained-release pellet portion containing tamsulosin or a pharmaceutically acceptable salt thereof and a rapid release portion containing an immediate release excipient and is stable while rapidly disintegrating in the oral cavity. It is to provide an oral composition.

Another object of the present invention is to provide a method for preparing the composition by a simple direct process.

The present invention provides a compound comprising a sustained release portion comprising an enteric sustained-release pellet portion containing tamsulosin as an active ingredient and a rapid release portion including a fast disintegrating granule.

In addition, the present invention is to prepare an enteric sustained-release pellet portion in a multi-layer composition consisting of (a) drug layer, (b) sustained release layer, (c) enteric layer and (d) sweetening layer using a multilayer coating method, The immediate release portion provides a method of easily tableting a composition composed of granules including an immediate release excipient by a direct stroke process.

According to the composition and the manufacturing method according to the present invention, it is possible to manufacture very simply by a simple direct process to facilitate mass production, and to obtain oral fast disintegrating oral pharmaceutical formulations with improved stability.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound comprising a sustained release portion comprising an enteric sustained-release pellet portion containing tamsulosin or a pharmaceutical salt thereof as an active ingredient, and a rapid release portion including fast disintegrating granules.

The enteric sustained release pellet portion according to the present invention comprises: (a) a pellet core; (b) a drug coating layer coated with tamsulosin or a pharmaceutical salt thereof on the pellet core; (c) a sustained release coating layer coated with a water insoluble polymer and / or a water soluble polymer on the drug coating layer; (d) an enteric coating layer coated with an enteric polymer and / or a water insoluble polymer on the sustained release coating layer; (e) providing an enteric sustained-release pellet portion containing tamsulosin or a pharmaceutical salt thereof, comprising forming a sweetening layer coated with a coating liquid containing an enteric polymer and a sugar or a sugar alcohol on the enteric coating layer.

The pellet core may be used as sugar spheres such as water-soluble or non-water-soluble cores, non-Pareil ^TM , Nu-Core ^TM , Nu-Pareil ^TM , which are commonly used in pellet production, and corn starch, lactose, and the like. Mixed sugar spheres may also be used. In addition, it is also possible to use a cell sphere (Cellet Sphere) mixed with microcrystalline cellulose, starch, mannitol, povidone, lactose, canavawax. The size of the pellet core is 300 um or less, preferably 100-200 um and can be used by appropriately adjusting the size as necessary. The weight of the pellet core is preferably about 70.0% by weight or less relative to the total weight of the enteric sustained release pellet portion, more preferably 55.0 to 65.0% by weight.

The drug coating layer comprises tamsulosin or a pharmaceutical salt thereof and a water soluble polymer and / or a water insoluble polymer. As the water-soluble polymer and / or the water-insoluble polymer, a polymer commonly used in the pharmaceutical field may be used. Preferred examples are hydroxypropyl methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, methacrylate copolymer (Eudragit ^TM And the like, or polyvinyl acetal diethylamino acetate (AEA) and the like, and more preferably hydroxypropyl methylcellulose. The coating liquid used to form the drug coating layer may include about 0.1 to 10.0% by weight of tamsulosin or a pharmaceutical salt thereof based on the total weight of the enteric sustained-release pellet portion, and preferably 0.5 to 1.0% by weight. It may include. The water-soluble polymer and / or the water-insoluble polymer may comprise 0.1 to 10.0 wt%, and preferably 0.5 to 1.0 wt%, based on the total weight of the enteric sustained release pellet portion. The drug coating layer may further include a pharmaceutically acceptable plasticizer, a lubricant and the like. The plasticizer and / or glidant may comprise 1.0 to 10.0 wt%, preferably 0.1 to 5.0 wt%, based on the total weight of the enteric sustained release pellet portion. Forming the drug coating layer may be carried out using conventional methods such as fluid bed granulators known to those skilled in the art.

The sustained release coating layer of the present invention includes a water insoluble polymer and / or a water soluble polymer. Ethyl cellulose, cellulose acetate or hydroxyethyl cellulose may be used as the water-insoluble polymer, and hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, plasmon, polyvinyl alcohol, xanthan gum or Gellan and the like can be used. More preferably, ethyl cellulose, which is a water-insoluble polymer, and hydroxypropyl methyl cellulose, which is a water-soluble polymer, may be mixed and used. The sustained release coating layer may further include a plasticizer. In order to form the sustained-release coating layer, the water-insoluble polymer and the water-soluble polymer may each contain about 1.0 to 10.0 wt% with respect to the total weight of the enteric sustained-release pellet portion, preferably 5.0 to 7.0 wt% of the water insoluble polymer, The water-soluble polymer may comprise 1.0 to 3.0% by weight. Forming the sustained release coating layer may be carried out using conventional methods such as a fluidized bed granulator known to those skilled in the art.

The enteric coating layer of the present invention comprises an enteric polymer and / or a water insoluble polymer. Preferably, two or more kinds of materials may be mixed and used in the enteric polymer and the water insoluble polymer. The enteric polymer may be an enteric polymer commonly used in the pharmaceutical field, for example, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC AS) or Eudragit L 30D. Methacrylic acid and ethyl acrylate copolymer (1: 1) of -55 ^TM (Eudragit L 30D-55) and the like can be used. As the water-insoluble polymer, ethyl cellulose, aqua coat ^TM , ethyl acrylate, methyl methacrylate, methyl methacrylate copolymer dispersion (Euragit RS), acrylic acid ethyl methyl methacrylate copolymer dispersion (Euragit NE 30D) Polymers, such as these, can be used. To form the enteric coating layer may comprise about 1.0 to 50.0% by weight of the enteric polymer and / or water-insoluble polymer relative to the total weight of the enteric sustained-release pellet portion. Preferably about 15.0 to 30.0 wt% may be included. The enteric coating layer may further include a pharmaceutically acceptable plasticizer. Forming the sustained release coating layer may be carried out using conventional methods such as a fluidized bed granulator known to those skilled in the art.

The sweetening layer of the present invention may comprise conventional materials known to those skilled in the art. It may preferably comprise an enteric polymer and a sugar or sugar alcohol. The enteric polymer may be a component commonly used in the pharmaceutical field, for example, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC AS) or Eudragit L 30D- Methacrylic acid and ethyl acrylate copolymer (1: 1) of 55 ^TM (Eudragit L 30D-55) and the like can be used. Preferably Eudragit L 30D-55 ^™ can be used. As the sugar or sugar alcohol, erythritol, mannitol, maltitol, maltodextrin, xylitol, isomalt, white sugar, sorbitol, gelatin and the like can be used. Preferably, erythritol, a saccharide sugar alcohol, can be used. It may include about 5.0 to 60.0% by weight of the sweetening layer component relative to the total weight of the enteric sustained-release pellet portion to form the sweetening layer, preferably about 5.0 to 20.0% by weight of the enteric polymer and about 20.0 of sugar or sugar alcohol And 40.0 weight percent. Forming the sustained release coating layer may be carried out using conventional methods such as a fluidized bed granulator known to those skilled in the art.

The immediate release portion of the present invention may include conventional excipient components, and may preferably include rudiflash spray dried mannitol.

Formulations according to the invention may further comprise pharmaceutically acceptable lubricants, disintegrants and the like. Disintegrating agents may include sodium starch glycolate, croscarmellose sodium, crospovidone and mixtures thereof. Preferably may comprise crospovidone. In addition, the lubricant may include colloidal silicon dioxide, magnesium stearate, calcium stearate, talc, magnesium trisilicate or mixtures thereof. Preferably, talc and calcium stearate may be mixed and used.

Although this invention is demonstrated in more detail based on an Example and a test example below, this invention is not limited to these Examples.

Example  One

Step 1. Preparation of the drug coating layer

10.0 mg of 50-200 μm Selesphere spheres were placed in a fluidized bed coater and coated with a coating solution prepared by dispersing 0.2 mg of tamsulosin hydrochloride and 0.2 mg of hydroxypropyl methylcellulose in a mixed solution of 3.2 mL of purified water and 7.0 mL of methanol. A coating layer was prepared. Coating conditions were performed at a spray air of 2.4 to 2.7 bar, an outlet air temperature of 25 to 35 ° C, an inlet air temperature of 38 to 40 ° C, and a flow of 28.

Step 2. Preparation of the slow release layer

The pellet coated with the drug coating layer obtained in step 1 was coated with a coating solution prepared by dispersing in a mixed solution of 1.1 mg of ethyl cellulose, 0.4 mg of hydroxypropyl methylcellulose, 1.6 mL of purified water and 29.9 mL of methanol in a fluidized bed coater to prepare a sustained release coating layer. It was. Coating conditions were carried out at a spray air 2.5bar, outlet air temperature 25 ~ 35 ℃, inlet air temperature 38 ~ 40 ℃, Flow (Flow) 30.

Step 3. Preparation of Enteric Coating Layer

The pellet coated with the drug coating layer and the sustained release layer obtained in step 2 was coated with a coating liquid prepared by dispersing 11.3 mg of Eudragit L30D-55, 2.7 mg of Eudragit NE 303, and 7.7 mg of Aquacoat in a 22.9 mL of purified water in a fluidized bed coater. An enteric coating layer was prepared. Coating conditions were carried out at spray air 2.2 ~ 2.5bar, outlet air temperature 24 ~ 28 ℃, inlet air temperature (40 ~ 43 ℃), Flow (Flow) 28 ~ 32.

Step 4. Preparation of Sweetener Layer

The pellet obtained in step 3 was coated with a coating solution prepared by dispersing 11.6 mg of Eudragit L30D-55 and 11.0 mg of erythritol in 10.0 mL of purified water in a fluidized bed coater to prepare a sweet layer. Coating conditions were carried out at spray air 2.4bar, outlet air temperature 30 ~ 40 ℃, inlet air temperature 50 ~ 55 ℃, Flow 29 ~ 31.

Step 5. Preparation of Immediate Release Containing Enteric Sustained Release Pellets

In the enteric sustained-release pellet portion obtained in step 4, ruditol spray-dried mannitol, crospovidone, calcium stearate, and talc were mixed in a mixer so as to have a total weight of 200 mg. Tablets containing 0.2 mg of tamsulosin hydrochloric acid per tablet were prepared by tableting at 6 kp.

Example  2

In the pellet prepared in step 1 of Example 1, a sustained release coating layer was prepared by coating with a coating solution prepared by dispersing in a mixed solution of 0.9 mg of ethyl cellulose, 0.3 mg of hydroxypropylmethyl cellulose, 1.3 mL of purified water and 24.0 mL of methanol. Preparation steps 3, 4, and 5 were carried out in the same manner as in Example 1.

Example  3

In the pellet prepared in Step 1 of Example 1, a sustained release coating layer was prepared by coating with a coating solution prepared by dispersing in a mixed solution of 1.4 mg of ethyl cellulose, 0.5 mg of hydroxypropyl methyl cellulose, 1.9 mL of purified water and 35.9 mL of ethanol, Preparation steps 3, 4, and 5 were carried out in the same manner as in Example 1.

Comparative example

5 g of tamsulosin hydrochloric acid and 470 g of crystalline cellulose were sufficiently mixed, and purified water was added to 83.3 g of Eudragit L30D-55 (25 g as a solid component) to make 500 g, followed by mixing and stirring. Talc and magnesium stearate were mixed with the obtained granules to prepare 0.2 mg of tamsulosin hydrochloride per tablet.

Test Example : Stability Test

The change in content was measured after 6 months under accelerated conditions of 40 ° C. and 75% relative humidity for Examples 1 to 3 and Comparative Examples. PTP + Al-Bag was used as the packaging container, and the content analysis method was performed as follows.

Diluent: 1.36 g of potassium dihydrogen phosphate was dissolved in water to make 1000 mL, and the pH was adjusted to 7.0 ± 0.05 with 2 mol / L sodium hydroxide solution. The obtained liquid and acetonitrile were mixed in the same amount.

Standard solution: 2 mg of tamsulosin hydrochloride standard was precisely weighed, placed in a 100 mL flask, filled with diluent to the mark, mixed, and sonicated for 10 minutes. 5 mL of this solution was accurately taken, and a diluted solution was added to make 100 mL to obtain a standard solution.

Test solution: Take about 20 tablets from the prepared Examples 1 to 3 and Comparative Examples, weigh the contents, weigh 0.2 mg as tamsulosin hydrochloric acid, put into a 200 mL flask, add 150 mL of diluent, and shake for 60 minutes. It was. The diluent was added to the mark and mixed well for 60 minutes to prepare a sample solution.

The test results are shown in Table 1 below. According to the test results, Examples 1 to 3 can be confirmed that the formulation is high in stability because the content change is smaller than the comparative example.

Content test 1 month later 2 months later 4 months later 6 months later Example 1 101.2% 100.8% 101.5% 99.8% Example 2 101.1% 101.0% 100.8% 100.3% Example 3 100.9% 100.5% 100.1% 99.7% Comparative example 98.5% 96.1% 93.3% 91.0%

Claims (6)

Pharmaceutical composition consisting of enteric sustained release pellets and immediate disintegrating parts containing tamsulosin or a pharmaceutically acceptable salt thereof as an active ingredient The method of claim 1, wherein the enteric sustained release pellet portion comprises: (a) a pellet core; (b) a drug coating layer coated with tamsulosin or a pharmaceutically acceptable salt thereof on the pellet core; (c) a sustained release coating layer coated on the drug coating layer with a water-insoluble polymer, a water-soluble polymer, or a mixture thereof; (d) a pharmaceutical composition comprising an enteric coating layer coated on the sustained release coating layer with an enteric polymer, a water insoluble polymer, or a mixture thereof The composition of claim 1 wherein the immediate disintegrating portion consists of granules comprising an immediate release excipient.       The pharmaceutical composition according to claim 2, further comprising coating the sweetening layer.       The method of claim 1, further comprising: (a) a pellet core; (b) a drug coating layer comprising tamsulosin or a pharmaceutically acceptable salt thereof; (c) a sustained release coating layer; (d) Method of manufacturing by coating in order of enteric coating layer       The method of claim 5, wherein the sweetening layer is further coated.