JP2018083809A - Production method of silodosin-containing particles and production method of orally disintegrating tablet containing silodosin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide production methods of silodosin-containing particles in which the bitterness of silodosin is suppressed and production of analogues is suppressed, and to provide production methods of orally disintegrating tablet containing silodosin.SOLUTION: The production method of silodosin-containing particles according to one embodiment of the present invention is characterized by that a powder mixture comprising silodosin is kneaded with water to obtain a kneaded product, 125 parts by mass or more to 800 parts by mass or less of powder of aminoalkyl methacrylate copolymer E is added to the kneaded products with respect to 100 parts by mass of the silodosin and is mixed, and an obtained mixture is heated at a higher temperature than the glass transition point of the aminoalkyl methacrylate copolymer E.SELECTED DRAWING: Figure 1

Description

The present invention relates to a method for producing silodosin-containing particles and a method for producing silodosin-containing orally disintegrating tablets. In particular, the present invention relates to a method for producing silodosin-containing particles that suppresses the bitterness of silodosin and suppresses the formation of related substances, and a method for producing a silodosin-containing orally disintegrating tablet.

Silodosin ((-)-1- (3-Hydroxypropyl) -5-[(2R) -2-([2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino) propyl] -2, 3-dihydro-1H-indole-7-carboxamide) binds with high selectivity of the α _1A receptor subtypes in the prostate, urethra and bladder triangles and blocks sympathetic transmission. Thereby, silodosin alleviates the tension of the lower urinary tract tissue smooth muscle, suppresses the increase in the urethral pressure, and improves dysuria associated with prostatic hypertrophy.

Since patients with benign prostatic hyperplasia are aged, there is an increasing demand for orally disintegrating tablets that are easy for patients to take. Orally disintegrating tablets are solid preparations that disintegrate rapidly in the oral cavity and can be taken with oral saliva or a small amount of water. However, since silodosin has a bitter taste, masking of the bitter taste is necessary to obtain an orally disintegrating tablet that is easy to take.

As an orally disintegrating tablet masking the bitter taste of silodosin, for example, Patent Documents 1 and 2 granulate or coat drug particles containing fine powder of cidocosin with a coating agent containing a non-enteric polymer. And the non-enteric polymer content is 80 mass parts-400 mass parts with respect to 100 mass parts of silodosin, and the orally disintegrating tablet containing the masking particles is described. Patent Documents 1 and 2 describe that ethyl cellulose, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, or the like is contained as a non-enteric polymer.

Patent Document 3 describes a pharmaceutical product for oral administration containing a mixture of silodosin or a pharmaceutically acceptable salt thereof and Eudragit (registered trademark) E as a basic copolymer. Patent Document 3 describes that the pharmaceutical preparation for oral administration contains Eudragit E to mask bitterness and improve storage stability under the action of light and temperature.

For such bitterness masking, a methacrylic acid copolymer such as Eudragit E is generally used as described in Patent Document 4. In Patent Document 4, it is described that a drug having an unpleasant taste and carmellose calcium and a methacrylic acid copolymer are used in combination.

International Publication No. 2014/157137 International Publication No. 2016/051782 Special table 2013-53651 gazette JP 2011-162458 A

In silodosin-containing orally disintegrating tablets, not only bitterness masking but also silodosin stabilization is an important issue. Patent Document 3 describes that Eudragit E is contained to mask bitterness and improve storage stability under the action of light and temperature, but there is no description of Examples. For this reason, it is not clear how Patent Document 3 improves storage stability. In Patent Document 3, silodosin or a pharmaceutically acceptable salt thereof and a basic copolymer are mixed with a) a further pharmaceutically acceptable additive added as necessary in the presence of a solvent, and then prepared. Granulating, drying the granulated product as necessary, and sieving the dried granulated product as necessary, b) further pharmaceutically acceptable added if necessary Processing with a step of dissolving in a solvent together with the additive and then spray drying the solution, or c) melt extruding with additional pharmaceutically acceptable additives as required, and as necessary Although a manufacturing method is described in which a further pharmaceutically acceptable additive is added and the product of step a), b) or c) is formulated into a unit dosage form, bitterness masking and storage by the manufacturing method is described. On the impact on stability There is not mentioned.

Patent Documents 1 and 2 only describe bitterness masking, and do not mention the stability of silodosin. Patent Document 1 discloses (a) a step of preparing drug particles by mixing or granulating a fine powder of silodosin and an additive, and (b) a non-enteric polymer on the drug particles obtained in step (a). Is coated with a high-speed mixed stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, etc., and the non-enteric polymer content is 100 parts by weight of silodosin. The manufacturing method including the process of preparing masking particle | grains which are 80 mass parts-400 mass parts is described. In Patent Document 2, (a) a step of preparing a drug particle by mixing or granulating a drug having a bitter taste and an additive, and (b) methyl methacrylate-methacrylic acid on the drug particle obtained in the step (a). A coating agent containing diethylaminoethyl acid copolymer, granulated or coated by nuclear granule coating method, granulation matrix method, granulation coating method, etc., and the methyl methacrylate-diethylaminoethyl methacrylate copolymer content is The manufacturing method including the process of preparing masking particle | grains which are 80 mass parts-400 mass parts with respect to 100 mass parts of chemical | medical agents which have a bitter taste is described.

Patent Document 4 discloses that either or both of carmellose calcium and methacrylic acid copolymer need to be uniformly mixed with the main agent, and the main agent, carmellose calcium and methacrylic acid copolymer are stirred and granulated. It is also possible to use those previously granulated by the method, fluidized bed granulation method, rolling granulation method, compression granulation method, extrusion granulation method, melt granulation method, spray granulation method, etc. However, it does not mention the influence of the manufacturing method on the masking of bitterness.

On the other hand, it is known that silodosin is extremely insoluble in water, and the dissolution property of silodosin is one of the important issues in orally disintegrating tablets.

One object of the present invention is to provide a method for producing silodosin-containing particles that suppresses the bitterness of silodosin and suppresses the formation of related substances and a method for producing a silodosin-containing orally disintegrating tablet. Another object of the present invention is to provide a method for producing silodosin-containing particles and a method for producing silodosin-containing orally disintegrating tablets that improve the dissolution of silodosin.

According to one embodiment of the present invention, a mixed powder containing silodosin is kneaded with water to obtain a kneaded product, and an aminoalkyl methacrylate copolymer having a mass of 125 to 800 parts by mass with respect to 100 parts by mass of the silodosin. A method for producing silodosin-containing particles, wherein the powder of E is added to the kneaded material and mixed, and the resulting mixture is heated at a temperature higher than the glass transition point of the aminoalkyl methacrylate copolymer E. Is provided.

In the method for producing silodosin-containing particles, a mixed powder containing silodosin may be kneaded with water using a mixing kneader.

In the method for producing silodosin-containing particles, the mixed powder containing silodosin is selected from the group consisting of partially pregelatinized starch, D-mannitol, lactose, precipitated calcium carbonate, cumulite, low-substituted hydroxypropylcellulose, and corn starch. One or more may be included.

Moreover, according to one embodiment of the present invention, the silodosin-containing orally disintegrating tablet is characterized by mixing any of the silodosin-containing particles and a predetermined additive, and tableting the obtained mixture. A manufacturing method is provided.

According to one embodiment of the present invention, there are provided a method for producing silodosin-containing particles that inhibits the bitterness of silodosin and suppresses the production of related substances and a method for producing an orally disintegrating tablet containing silodosin. Moreover, according to one Embodiment of this invention, the manufacturing method of the silodosin containing particle | grains which improve the dissolution property of silodosin, and the manufacturing method of a silodosin containing orally disintegrating tablet are provided.

It is a figure which shows the evaluation result of the silodosin containing orally disintegrating tablet which concerns on the Example of this invention.

Hereinafter, a method for producing silodosin-containing particles and a method for producing silodosin-containing orally disintegrating tablets according to the present invention will be described. However, the method for producing silodosin-containing particles and the method for producing silodosin-containing orally disintegrating tablets of the present invention are not construed as being limited to the description of the embodiments and examples shown below.

As a result of investigations by the present inventors, it has been clarified that the silodosin-containing orally disintegrating tablets of Patent Documents 1 and 2 generate an indole as a related substance when stored under high temperature and high humidity conditions. Since the aminoalkyl methacrylate copolymer E is effective in suppressing the bitter taste of silodosin, as a result of further studies, the present inventors granulated silodosin-containing particles by a stirring granulation method using a mixing kneader. It was found that the formation of a related substance can be suppressed by heating at a temperature higher than the glass transition point of the aminoalkyl methacrylate copolymer E to form a film of the aminoalkyl methacrylate copolymer E on the surface of the granulated product.

(Silodosin-containing particles)
The silodosin-containing particle according to the present invention includes silodosin and aminoalkyl methacrylate copolymer E in one embodiment. The aminoalkyl methacrylate copolymer E is a basic copolymer composed of methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate. For example, Eudragit (registered trademark) EPO of Evonik Nutrition & Care GmbH can be used.

In one embodiment, the silodosin-containing particle according to the present invention is preferably 125 parts by mass or more and 800 parts by mass or less, more preferably 200 parts by mass of aminoalkyl methacrylate copolymer E, with respect to 100 parts by mass of silodosin. More than 600 parts by mass can be contained.

In one embodiment, the silodosin-containing particles according to the present invention include, as an excipient, one selected from the group consisting of D-mannitol, lactose, precipitated calcium carbonate, cumulite, low-substituted hydroxypropylcellulose, and corn starch. Including. These excipients are preferred because they do not affect the dissolution properties of silodosin in silodosin-containing orally disintegrating tablets.

In addition, in one embodiment, the silodosin-containing particles according to the present invention, as an excipient, in addition to the additive described as a disintegrant, for example, magnesium aluminate metasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, silicic acid Examples thereof include calcium, calcium lactate, lactose, fructose, D-mannisyl, erythryl, xylyl, maltose, D-sorbyl and multi-malls. Examples of the binder include starches, crystalline cellulose, hydroxip oral pill cellulose, hippo melose, povidone, dextrins, gelatin, fulleran, polyvinyl alcohol, sodium alginate, polyethylene glycol and the like. Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous silicic acid, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, glyceryl monostearate and the like.

In one embodiment, the silodosin-containing particles according to the present invention may contain, for example, aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, acesulfame potassium, sucralose and the like as a sweetener. As a sour agent, for example, citric acid, tartaric acid, malic acid, ascorbic acid and the like can be added. As the foaming agent, for example, sodium hydrogen carbonate, sodium carbonate, calcium carbonate and the like can be added. As a flavoring agent, for example, L-aspartic acid, sodium chloride, magnesium chloride, sodium citrate, calcium citrate, sodium L-glutamate, sodium hydrogen carbonate and the like can be added. Examples of flavors that can be added include strawberry, yogurt, banana, pineapple, orange, lemon, menthol, peach, apple, chocolate, cocoa, vanilla, black tea, matcha tea, and the like. As the colorant, for example, edible dyes such as edible yellow No. 5, edible red No. 2 and edible blue No. 2, yellow ferric oxide, ferric oxide, caramel dye, titanium oxide, and the like can be added.

(Method for producing silodosin-containing particles)
In one embodiment, the silodosin-containing particles according to the present invention are obtained by kneading a mixed powder containing silodosin with water to obtain a kneaded product, and adding a powder of aminoalkyl methacrylate copolymer E to the kneaded product and mixing them. The resulting mixture is then heated at a temperature above the glass transition point of the aminoalkyl methacrylate copolymer E.

In the fluidized bed granulation described in Patent Documents 1 and 2, the aminoalkyl methacrylate copolymer E uniformly covers the surface of silodosin-containing particles to suppress bitterness. Furthermore, sugar or sugar alcohol is overcoated on silodosin-containing particles by fluidized bed granulation. It is considered that related substances are generated in the fluidized bed granulation described in Patent Documents 1 and 2 by such a long manufacturing process. Although shown in the comparative example mentioned later, according to the fluidized-bed granulation described in patent document 1 and 2, even if only the silodosin inside a silodosin containing particle | grain is uniformly coat | covered, the bitter taste of silodosin cannot be suppressed.

Moreover, in the fluid bed granulation described in Patent Documents 1 and 2, the dissolution rate of silodosin in the silodosin-containing orally disintegrating tablet is lowered.

As a result of the study by the present inventors, silodosin-containing particles are granulated by a kneading method using a mixing kneader, and heated at a temperature higher than the glass transition point of the aminoalkyl methacrylate copolymer E. By forming a film of the alkyl methacrylate copolymer E, it is possible to suppress the formation of related substances.

In one embodiment, the mixed powder includes one selected from the group consisting of partially pregelatinized starch, D-mannitol, lactose, precipitated calcium carbonate, cumulite, low substituted hydroxypropylcellulose, corn starch. Moreover, the excipient | filler, binder, and lubricant which were mentioned above can be included.

It is preferable to use purified water for kneading the mixed powder. Purified water is added to the mixed powder and kneaded using a mortar. The aminoalkyl methacrylate copolymer E is added to the obtained kneaded material as a powder and mixed. In the present invention, Eudragit EPO is preferably used as the aminoalkyl methacrylate copolymer E. Eudragit EPO, which is a powder, is generally used as an aqueous dispersion, but in the present invention, Eudragit EPO is adhered to the surface of the kneaded material in a powder state.

The mixture in which the powdered aminoalkyl methacrylate copolymer E is adhered to the surface of the kneaded material is heated at a temperature higher than the glass transition point of the aminoalkyl methacrylate copolymer E. For example, since Eudragit EPO has a glass transition point of 48 ° C., the mixture is heated at a higher temperature to dry the mixture. In one Embodiment, it is preferable that the heating temperature of a mixture is 50 degreeC or more and 70 degrees C or less. By heating the aminoalkyl methacrylate copolymer E at a temperature higher than the glass transition point, the aminoalkyl methacrylate copolymer E on the surface of the mixture is vitrified and the surface of the mixture is coated.

For this reason, in the method for producing silodosin-containing particles according to the present invention, in one embodiment, the aminoalkyl methacrylate copolymer E is preferably 125 parts by mass or more and 800 parts by mass or less, more preferably amino acid, with respect to 100 parts by mass of silodosin. 200 parts by mass or more and 600 parts by mass or less of alkyl methacrylate copolymer E is added. In the method for producing silodosin-containing particles according to the present invention, the bitter taste of silodosin can be suppressed by adding the aminoalkyl methacrylate copolymer E at the above-described addition ratio to coat the surface of the mixture.

Silodosin-containing particles according to the present invention can be produced by sizing the obtained dried product with a pulverizer.

In the method for producing silodosin-containing particles according to the present invention, since silodosin-containing particles are produced by a kneading method using a mixing kneader, the production time is short, and the production of indole, which is a related substance of silodosin, is suppressed. Is done. In addition, since the film of aminoalkyl methacrylate copolymer E is formed on the surface of silodosin-containing particles by heating at a temperature higher than the glass transition point of aminoalkyl methacrylate copolymer E, the dissolution properties of silodosin in silodosin-containing orally disintegrating tablets are improved. Can be made.

(Silodosin-containing orally disintegrating tablets)
The silodosin-containing orally disintegrating tablet according to the present invention is produced by mixing silodosin-containing particles and a predetermined additive selected from the additives used for silodosin-containing particles, and tableting the resulting mixture. be able to. In one embodiment, the silodosin-containing orally disintegrating tablet according to the present invention contains 2 mg or 4 mg of silodosin per tablet, but the present invention is not limited thereto.

Since the silodosin-containing orally disintegrating tablet according to the present invention produces silodosin-containing particles by a kneading method using a mixing kneader, the production time is short, and the production of indole, which is a related substance of silodosin, is suppressed. The In addition, since the film of aminoalkyl methacrylate copolymer E is formed on the surface of silodosin-containing particles by heating at a temperature higher than the glass transition point of aminoalkyl methacrylate copolymer E, the dissolution properties of silodosin in silodosin-containing orally disintegrating tablets are improved. Can be made. In the silodosin-containing orally disintegrating tablet according to the present invention, the aminoalkyl methacrylate copolymer E is 125 parts by mass or more and 800 parts by mass or less, more preferably 200 parts by mass or more and 600 parts by mass with respect to 100 parts by mass of silodosin. Silodosin-containing particles can be produced by adding a part or less, and the bitter taste of silodosin can be sufficiently masked.

Example 1
As Example 1 of the present invention, silodosin-containing particles were produced. 20 g silodosin, 73.5 g PC-10 from Asahi Kasei Co., Ltd. as partially pregelatinized starch, 10 g Neusilin (registered trademark) FH2 from Fuji Chemical Industry Co., Ltd. as magnesium metasilicate, 5 g talc from Fuji Talc In addition, 25 g of HPC (SSL) manufactured by Nippon Soda Co., Ltd. was mixed in a plastic bag as hydroxypropylcellulose, and sieved with sieve No. 30.

Purified water was added to the sieved mixed powder, and kneaded using a high speed mixer (LFS-GS-2J, Fukae Pautech Co., Ltd.). 40 g of Eudragit (registered trademark) EPO from Evonik Nutrition & Care GmbH was added to the kneaded mixture and mixed. The obtained mixture was dried by heating at 60 ° C. for 3 hours in a mini-jet oven (Fujimac Co., Ltd.).

The dried mixture was sized with a power mill φ1 mm (Dalton Co., Ltd.) to obtain silodosin-containing particles of Example 1.

Next, the orally disintegrating tablet of Example 1 was produced using the silodosin-containing particles of Example 1. 154.3 g of ROQUETTE PHARMA Pearlitol (registered trademark) Flash, 6 g of Neusilin (registered trademark) FH2 from Fuji Chemical Industry Co., Ltd., 1.6 g of yellow iron sesquioxide, 34.7 g of silodosin-containing particles of Example 1 0.4 g of iron sesquioxide and 3 g of magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were mixed to obtain a pre-tablet powder. The pre-tablet powder was tableted using a tableting machine (Kikusui Seisakusho, model: VELA5) to obtain an orally disintegrating tablet of Example 1 weighing 200 mg.

(Example 2)
In Example 1, Eudragit EPO was added so that it might become 200 mass parts with respect to 100 mass parts of silodosin. In Example 2, silodosin-containing particles were produced in the same manner as in Example 1 except that 25 g of Eudragit EPO was added so as to be 125 parts by mass with respect to 100 parts by mass of silodosin. Also, the oral cavity of Example 2 having a weight of 200 mg was obtained in the same manner as Example 1 except that 31.7 g of silodosin-containing particles of Example 2 were used and 157.3 g of ROQUETTE PHARMA Pearlitol (registered trademark) Flash was added. An internally disintegrating tablet was produced.

(Example 3)
In Example 3, silodosin-containing particles were produced in the same manner as in Example 1 except that 80 g of Eudragit EPO was added to 400 parts by mass with respect to 100 parts by mass of silodosin. In addition, the oral cavity of Example 3 having a weight of 200 mg was used in the same manner as Example 1, except that 42.7 g of silodosin-containing particles of Example 3 were used and 146.3 g of ROQUETTE PHARMA Pearlitol (registered trademark) Flash was added. An internally disintegrating tablet was produced.

Example 4
In Example 4, silodosin-containing particles were produced in the same manner as in Example 1 except that 85 g of Eudragit EPO was added to 425 parts by mass with respect to 100 parts by mass of silodosin. In addition, the oral cavity of Example 4 having a weight of 200 mg was obtained in the same manner as Example 1 except that 43.7 g of silodosin-containing particles of Example 4 were used and 145.3 g of ROQUETTE PHARMA Pearlitol (registered trademark) Flash was added. An internally disintegrating tablet was produced.

(Example 5)
In Example 5, silodosin-containing particles were produced in the same manner as in Example 1 except that 120 g of Eudragit EPO was added so as to be 600 parts by mass with respect to 100 parts by mass of silodosin. Also, the oral cavity of Example 5 having a weight of 200 mg was used in the same manner as Example 1 except that 58.3 g of silodosin-containing particles of Example 5 were used and 138.3 g of ROQUETTE PHARMA Pearlitol (registered trademark) Flash was added. An internally disintegrating tablet was produced.

(Example 6)
In Example 6, silodosin-containing particles were produced in the same manner as in Example 1 except that 160 g of Eudragit EPO was added so as to be 800 parts by mass with respect to 100 parts by mass of silodosin. Also, the oral cavity of Example 6 having a weight of 200 mg was obtained in the same manner as Example 1 except that 58.7 g of silodosin-containing particles of Example 6 were used and 130.3 g of ROQUETTE PHARMA Pearlitol (registered trademark) Flash was added. An internally disintegrating tablet was produced.

(Comparative Example 1)
As Comparative Example 1, silodosin-containing particles were produced according to the example of Patent Document 1. 40 g of silodosin, 147 g of Asahi Kasei's PC-10 as partially pregelatinized starch, and 10 g of talc from Fuji Talc as talc were mixed in a plastic bag, and sieved through sieve No. 30.

As a hydroxypropyl cellulose, 3.0 g of SSL manufactured by Nippon Soda Co., Ltd. was dissolved in purified water to prepare a granulation liquid. The granulated liquid was sprayed on the sieved mixed powder, fluidized bed granulated with a fluidized bed granulator (Freund Sangyo Co., Ltd., model: MP-01), and dried to obtain a granulated product. The obtained granulated product was sized using a power mill φ1 mm (Dalton Co., Ltd.).

A coating agent was prepared by adding 70 g of Eudragit (registered trademark) EPO, 25 g of talc from Fuji Talc as a talc, 7 g of sodium lauryl sulfate from Kao Indonesia Chemical, 10 g of stearic acid from AVANTOR, and purified water. A coating agent was sprayed onto the sized product, and fluidized bed granulation was performed using a fluidized bed granulator (Freund Sangyo Co., Ltd., model: MP-01), followed by drying.

Further, a coating agent was prepared by adding 30 g of Mannit P of Mitsubishi Corporation Foodtech Co., Ltd. as purified D-mannitol to purified water. The obtained film-coated granule was sprayed with a coating agent and overcoated with a fluidized bed granulator (Freund Sangyo Co., Ltd., model: MP-01) to obtain silodosin-containing particles of Comparative Example 1.

Next, the orally disintegrating tablet of Comparative Example 1 was produced using the silodosin-containing particles of Comparative Example 1. 34.2 g of silodosin-containing particles of Comparative Example 1, 143.4 g of ROQUETTE PHARMA's Pearlitol (registered trademark) Flash, 14 g of xx16w of Nippon Food & Chemicals Co., Ltd. as corn starch, and Saneigen FFI Co., Ltd. as sucralose P of 2g, 2g of Freund Sangyo Co., Ltd. Adsolider (registered trademark) 101 as light anhydrous silicic acid, 0.2g of orange oil, 0.2g of yellow iron sesquioxide and magnesium stearate (Taihei Chemical Industrial Co., Ltd.) 4 g was mixed to obtain a powder before tableting. The pre-tabletting powder was tableted using a tableting machine (Kikusui Seisakusho, model: VELA5) to obtain an orally disintegrating tablet of Comparative Example 1 having a weight of 200 mg.

(Comparative Example 2)
As Comparative Example 2, silodosin-containing particles were produced in one fluidized bed granulation step. 20 g of silodosin, 73.5 g of PC-10 from Asahi Kasei Corporation as partially pregelatinized starch, 10 g of Neusilin (registered trademark) FH2 from Fuji Chemical Industry Co., Ltd. as magnesium metasilicate, and talc from Fuji Talc as talc 5 g and 85 g of Eudragit (registered trademark) EPO from Evonik Nutrition & Care GmbH, 1.5 g of yellow iron sesquioxide and 0.5 g of iron sesquioxide, were mixed in a plastic bag and sieved through sieve No. 30.

As a hydroxypropyl cellulose, 5 g of SSL manufactured by Nippon Soda Co., Ltd. was dissolved in purified water to prepare a granulation liquid. The granulated liquid was sprayed on the sieved mixed powder, fluidized bed granulated with a fluidized bed granulator (Freund Sangyo Co., Ltd., model: MP-01), and dried to obtain a granulated product. The obtained granulated product was sized with a power mill φ1 mm (Dalton Co., Ltd.) to obtain silodosin-containing particles of Comparative Example 2.

Next, the orally disintegrating tablet of Comparative Example 2 was produced using the silodosin-containing particles of Comparative Example 2. To 40.1 g of silodosin-containing particles of Comparative Example 2, 149.3 g of ROQUETTE PHARMA's Pearlitol (registered trademark) Flash, 6 g of Neusilin (registered trademark) FH2 from Fuji Chemical Co., Ltd., 1.6 g of yellow ferric oxide, 0.4 g of iron sesquioxide and 3 g of magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were mixed to obtain a pre-tablet powder. The pre-tablet powder was tableted using a tableting machine (VELA5, Kikusui Seisakusho, model: VELA5) to obtain an orally disintegrating tablet of Comparative Example 2 weighing 200.4 mg.

(Comparative Example 3)
As Comparative Example 3, silodosin-containing particles were produced by a kneading method using a mortar. In Comparative Example 3, unlike Example 1, Eudragit EPO was added to the mixed powder and kneaded. 20 g of silodosin, 73.5 g of PC-10 from Asahi Kasei Corporation as partially pregelatinized starch, 10 g of Neusilin (registered trademark) FH2 from Fuji Chemical Industry Co., Ltd. as magnesium metasilicate, and talc from Fuji Talc as talc 5 g, 1.5 g of yellow iron sesquioxide, 0.5 g of iron sesquioxide, 5 g of SSL from Nippon Soda Co., Ltd. as hydroxypropylcellulose and 85 g of Eudragit (registered trademark) EPO from Evonik Nutrition & Care GmbH in a plastic bag And sieved with sieve No. 30.

Purified water was added to the sieved mixed powder and kneaded using a mortar. The obtained kneaded material was dried by heating at 60 ° C. for 3 hours in a mini-jet oven (Fujimac Co., Ltd.).

The dried mixture was sized with a power mill φ1 mm (Dalton Co., Ltd.) to obtain silodosin-containing particles of Comparative Example 3.

Next, the orally disintegrating tablet of Comparative Example 3 was produced using the silodosin-containing particles of Comparative Example 3. To 40.1 g of silodosin-containing particles of Comparative Example 3, 149.3 g of ROQUETTE PHARMA's Pearlitol (registered trademark) Flash, 6 g of Neusilin (registered trademark) FH2 from Fuji Chemical Co., Ltd., 1.6 g of yellow ferric oxide, 0.4 g of iron sesquioxide and 3 g of magnesium stearate (Taihei Chemical Industrial Co., Ltd.) were mixed to obtain a pre-tablet powder. The powder before tableting was tableted using a tableting machine (Kikusui Seisakusho, model: VELA5) to obtain an orally disintegrating tablet of Comparative Example 3 having a weight of 200.4 mg.

(Comparative Example 4)
In Comparative Example 4, silodosin-containing particles were produced in the same manner as in Example 1 except that 15 g of Eudragit EPO was added to 75 parts by mass with respect to 100 parts by mass of silodosin. Also, the oral cavity of Comparative Example 4 having a weight of 200 mg was used in the same manner as Example 1 except that 29.7 g of silodosin-containing particles of Comparative Example 4 were used and 159.3 g of ROQUETTE PHARMA Pearlitol (registered trademark) Flash was added. An internally disintegrating tablet was produced.

(Comparative Example 5)
In Comparative Example 5, polyvinyl acetal diethylaminoacetate (AEA (registered trademark) of Mitsubishi Chemical Foods), which is a non-enteric polymer, was used as a bitter taste masking agent. Silodosin-containing particles were produced in the same manner as in Example 6 except that 160 g of AEA was added to 100 parts by mass of silodosin. However, AEA could not be sufficiently adhered to the kneaded material and separated during sizing, and the silodosin-containing particles of Comparative Example 5 could not be produced.

(Comparative Example 6)
In Comparative Example 6, polyvinyl acetal diethylaminoacetate (AEA (registered trademark) of Mitsubishi Chemical Foods), which is a non-enteric polymer, was used as a bitter taste masking agent. Silodosin-containing particles were produced in the same manner as in Example 1 except that 40 g of AEA was added to 100 parts by mass of silodosin. However, AEA could not be sufficiently adhered to the kneaded product and separated during granulation, and the silodosin-containing particles of Comparative Example 6 could not be produced.

As polymers that can be used for bitterness masking, methacrylic acid copolymer L, methacrylic acid copolymer S, ammonio alkyl methacrylate copolymer, and ethyl cellulose are known. However, since it is desirable for silodosin to elute quickly in the stomach, the enteric polymers methacrylic acid copolymer L and methacrylic acid copolymer S cannot rapidly elute silodosin in the stomach and enter the body. Since absorption is delayed, it is not preferable for the silodosin-containing particles according to the present invention. In addition, an ammonioalkyl methacrylate copolymer and ethyl cellulose, which are polymers exhibiting pH-independent sustained release properties, are also not preferable for the silodosin-containing particles according to the present invention because they delay the absorption into the body. For example, silodosin-containing particles can be produced in the same manner as in Example 6 using ethyl cellulose (Nisshin Kasei Co., Ltd., Etocel 7FP). Although bitterness is suppressed by using ethyl cellulose, it is an enteric polymer, and thus is not suitable for silodosin-containing particles and orally disintegrating tablets according to the present invention.

(Evaluation of bitterness)
The bitterness was evaluated about the silodosin containing orally disintegrating tablet of Examples 1-6 mentioned above and Comparative Examples 1-4. The bitterness was evaluated by a sensory test. The evaluation results are shown in FIG.

(Stability test)
Stability was evaluated about the silodosin containing orally disintegrating tablet of Examples 1-6 mentioned above and Comparative Examples 1-4. The stability was evaluated by conducting a purity test using liquid chromatography for the initial state (initial), storage at 60 ° C. and 60% humidity for 1 week and 2 weeks, and using indole as a related substance. The percentage was calculated. The evaluation results are shown in FIG.

(Dissolution test)
For the silodosin-containing orally disintegrating tablets of Examples 1 to 6 and Comparative Examples 1 to 4 described above, the dissolution rate per 15 minutes of silodosin, which is the active ingredient, was measured according to the 16th revised Japanese Pharmacopoeia Dissolution Test Method did. Using purified water and second solution for dissolution test (1 volume of water was added to 1 volume of pH 6.8 phosphate buffer) as the dissolution test solution, the elution rate at 15 minutes was measured. The measurement results are shown in FIG.

From the results of FIG. 1, it is clear that the orally disintegrating tablet of Comparative Example 1 according to the example of Cited Document 1 can suppress the bitter taste of silodosin but produces an indole. In addition, it was revealed that the orally disintegrating tablet of Comparative Example 1 has low solubility in water. Moreover, it became clear that the bitter taste of silodosin cannot be suppressed in the orally disintegrating tablet of Comparative Example 2 in which fluidized bed granulation was performed in one step.

Even in the orally disintegrating tablet of Comparative Example 3 produced by a kneading method using a mortar, it became clear that when Eudragit EPO was added to a mixed powder of silodosin and kneaded, the bitter taste of silodosin could not be suppressed.

On the other hand, in the orally disintegrating tablets of Examples 1 to 6 of the present invention, the bitter taste of silodosin was suppressed and the production of indole was also suppressed. Further, in the dissolution test, the dissolution performance was excellent for purified water and the second dissolution test solution, and the dissolution performance of silodosin was improved as compared with the orally disintegrating tablet of Comparative Example 1.

In the orally disintegrating tablet of Comparative Example 4 using the same production method as Example 1 of the present invention, it was revealed that the bitter taste of silodosin cannot be suppressed because the amount of Eudragit EPO added is lower than the ratio of the present application. .

Claims (4)

A mixed powder containing silodosin is kneaded with water to obtain a kneaded product,
125 parts by mass or more and 800 parts by mass or less of aminoalkyl methacrylate copolymer E powder is added to the kneaded product with respect to 100 parts by mass of silodosin, and mixed.
A method for producing silodosin-containing particles, characterized in that the obtained mixture is heated at a temperature higher than the glass transition point of the aminoalkyl methacrylate copolymer E. The method for producing silodosin-containing particles according to claim 1, wherein the mixed powder containing silodosin is kneaded with water using a mixing kneader. The mixed powder containing silodosin contains at least one selected from the group consisting of partially pregelatinized starch, D-mannitol, lactose, precipitated calcium carbonate, cumulite, low-substituted hydroxypropylcellulose, and corn starch. The method for producing silodosin-containing particles according to claim 1 or 2. Mixing the silodosin-containing particles according to any one of claims 1 to 3 and a predetermined additive,
A method for producing a silodosin-containing orally disintegrating tablet, comprising tableting the obtained mixture.

Images