JP2009179604A - Orally rapidly disintegrating tablets - Google Patents

Abstract

Provided is an intraorally rapidly disintegrating tablet having a good mouthfeel.
SOLUTION: An intraoral quick disintegrating tablet in which a granulated product containing a pharmaceutical ingredient having an odd taste is coated with a coating agent, crospopidone and sugar alcohol are blended as a powder, and compression molded. The granulated product is 8 to 29.5% by mass in the tablet, crospovidone is 0.5 to 22% by mass in the tablet, sugar alcohol is 70 to 91.5% by mass in the tablet, and the coating agent is an aminoalkyl methacrylate copolymer. Orally rapidly disintegrating tablet.
[Selection figure] None

Description

  The present invention relates to an intraoral rapidly disintegrating tablet.

  In recent years, in the treatment of diseases, the development of pharmaceutical preparations with pharmacological ingenuity has been actively promoted for the purpose of improving the quality of life (QOL) of patients, and the oral disintegrating tablets are the most frequently developed preparations. is there. Intraoral rapidly disintegrating tablets are instantly disintegrable even with a small amount of saliva in the oral cavity, and are easy to take, and are the best preparation for elderly people and children who are difficult to swallow with ordinary tablets. Moreover, since it can be taken without water, it has the advantage that the place and time for taking are not limited.

However, for drugs with an odd taste, application to the orally rapidly disintegrating tablets is limited to drugs with weak bitterness. As a device for reducing off-flavors, a method of adding a flavor or a sweetener is known. However, it has been difficult to suppress off-flavors only by adding flavors and sweeteners.

An object of the present invention is to provide an intraorally rapidly disintegrating tablet having a good mouthfeel.

  As a result of intensive studies to solve the above problems, the present inventors have formulated a pharmaceutical ingredient into a granulated product coated with a coating agent, and formulated crospovidone and sugar alcohol as a powder outside the granulated product. As a result, the present inventors have found that the object can be achieved.

That is, the present invention
(1) An orally rapidly disintegrating tablet, in which a granulated product containing a pharmaceutical ingredient having an odd taste is coated with a coating agent, crospopidone and sugar alcohol are blended as a powder, and compression molded,
(2) The oral cavity according to (1), wherein the granulated product is 8 to 29.5% by mass in the tablet, crospovidone is 0.5 to 22% by mass in the tablet, and sugar alcohol is 70 to 91.5% by mass in the tablet. Internal disintegrating tablets,
(3) The present invention relates to a rapidly disintegrating tablet in the oral cavity according to (2), wherein the coating agent is an aminoalkyl methacrylate copolymer.

  According to the present invention, it is possible to provide an orally rapidly disintegrating tablet having a good mouthfeel.

The present invention will be described in detail below. In the present specification, an intraoral rapidly disintegrating tablet means about 90 seconds, preferably about 60 seconds, more preferably 40 seconds without chewing in the presence of saliva in the oral cavity. A solid pharmaceutical preparation that disintegrates in a shorter time.

In the present invention, the pharmaceutical ingredient having a different taste is not particularly limited as long as it is an orally administered pharmaceutical ingredient and has an unpleasant taste such as a bitter taste or astringent taste. For example, antipyretic analgesics, antihistamines, antiallergic agents, sympathomimetic agents, parasympathomimetic blockers, central stimulants, H ₂ blockers, antacids, anti-inflammatory enzymes, anti-inflammatory agents, bronchodilators, antibacterial agents, antitussives , Expectorants, anticholinergic agents, antispasmodics, hypnotic sedatives, antihypertensives, antihypertensives, skeletal muscle relaxants, motion sickness prevention / treatment drugs, vitamins, herbal medicines and the like. The granulation method of the pharmaceutical ingredient-containing granule is a dry granulation method, agitation granulation method, extrusion granulation method, fluidized bed granulation method, rolling fluidized bed granulation method, spray granulation method, etc., preferably fluidized Layer granulation method, rolling fluidized bed granulation method. The average particle size of the granulated product is preferably 0.1 to 350 μm, more preferably 50 to 200 μm.
The medicinal component-containing granulated product can contain components other than the medicinal component as long as the effects of the present invention are not impaired. Examples thereof include excipients and binders. Excipients and binders can be blended with additives that can be used in the manufacture of pharmaceutical formulations. Specifically, those described in the Pharmaceutical Additives Dictionary [Japan Pharmaceutical Additives Association, Yakuji Nippo (2007)] can be used.

A granulated product containing a pharmaceutical ingredient having a different taste is coated with a coating agent to mask the taste. The coating agent that can be used in the present invention is not particularly limited as long as it can be used for the production of pharmaceutical preparations. Examples of the water-soluble coating agent include pH-independent coating agents such as povidone and hypromellose, and hydrophobic coatings. Ethyl cellulose, stearyl alcohol, ammonio methacrylate copolymer, etc. are used as agents, aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate are used as gastric coating agents, and methacrylic acid copolymers (L, S) are used as enteric coating agents. And so on.

The amount of the coating agent for coating the granulated product is not particularly limited, but is preferably about 0.001 to 10 parts by mass, more preferably about 0.01 to 1 part by mass with respect to 1 part by mass of the granulated product, Particularly preferred is about 0.05 to 0.5 parts by mass. The coating method using a coating agent is not particularly limited as long as it is a method that can be used for production of a pharmaceutical preparation. The amount of the granulated product after coating is not particularly limited, but is preferably 8% by mass or more, more preferably 10 to 29.5% by mass, particularly preferably 10% by mass or more in the intraoral quick disintegrating tablet from the viewpoint of tablet content uniformity. Is 12 to 25% by mass.

Moreover, it is preferable to use an aminoalkyl methacrylate copolymer as a coating agent from the point which suppresses the time-dependent fall of the hardness of an intraoral quick disintegrating tablet. Examples of the aminoalkyl methacrylate copolymer include aminoalkyl methacrylate copolymer E (trade name: Eudragit E100 or EPO), aminoalkyl methacrylate copolymer RS, and RL (trade name: Eudragit RS or RL). The addition amount of the aminoalkyl methacrylate copolymer is preferably 0.2 to 10% in the intraoral rapidly disintegrating tablet.

In the oral disintegrating tablet of the present invention, crospovidone is blended as a disintegrant and sugar alcohol is blended as an excipient from the viewpoint of ease of drinking. Examples of the sugar alcohol that can be used in the present invention include D-mannitol, erythritol, xylitol, maltitol, sorbitol, and the like, preferably D-mannitol. Moreover, you may mix | blend sugar alcohol combining 1 type or 2 types or more. Crospopidone and sugar alcohol are blended as a powder (non-granulated material) outside the granulated material so as to spread in the oral cavity immediately after taking. It is preferable that the compounding quantity of sugar alcohol is 50-91.5 mass% in an intraoral quick disintegrating tablet, More preferably, it is 70-88 mass%, Most preferably, it is 75-85 mass%. Moreover, it is preferable that the compounding quantity of a crospovidone is 0.5-22 mass% in an intraoral quick disintegrating tablet, More preferably, it is 1-10 mass%, Especially preferably, it is 2-6 mass%.

The oral rapidly disintegrating tablet can be blended with additives that can be used in the production of pharmaceutical preparations, if necessary. Specifically, those described in the Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nippo (2007)] can be used, for example, stearic acid and its metal salts as lubricants, talc, Light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester, etc., sugars, sugar alcohols, aspartame, saccharin and salts thereof, glycyrrhizic acid and salts thereof, stevia, acesulfame potassium, etc. as sweeteners, citric acid as a flavoring agent Sodium citrate, succinic acid, tartaric acid, fumaric acid, and the like, iron sesquioxide, yellow sesquioxide, caramel, riboflavin, and aluminum lake as coloring agents, and menthol and orange oil as fragrances.

  In the present invention, the shape of the tablet to be molded is not particularly limited as long as the effect of the present invention is not impaired. For example, special shapes such as hollows, polygons, and concave shapes can be used. In addition, a flat tablet with a thin tablet thickness and a large tablet diameter to increase the contact area of the tablet on the tongue, rapidly penetrate the oral cavity into the tablet, and enhance the rapid disintegration of the oral cavity. It can also be formed into.

For mixing the additive components, a normal mixing method can be used. For example, a V-shaped mixer or the like can be used. About compression molding, a normal tableting method can be used, for example, a rotary tableting machine etc. can be used.

Hereinafter, the present invention will be described more specifically with reference to examples, comparative examples and comparative tests of the present invention.
In addition, the evaluation method of an imidafenacin containing granulated material and a coating granule is as follows.
[Particle size distribution measurement] The particle size distribution was measured using a sieve having a mesh size of 75, 106, 150, 180, 212, and 355 μm with a sieve type particle size distribution analyzer (ATM, Sonic Shifter).
The average particle size (50% size) was calculated from the particle size distribution measurement.
Evaluation method of intraoral rapidly disintegrating tablet [Hardness test] The hardness was measured using a tablet hardness tester (Okada Seiko Co., Ltd.). The test is performed with 5 tablets, and the average value is shown.
[Disintegration test] Measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.). The test is performed with 6 tablets, and the average value is shown. The test solution was water, and the time until the tablet completely disintegrated and dissolved was measured.

Example 1
4.0 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixture of 118.2 g of purified water and 257.8 g of ethanol. 394 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 22.5 g / min, spraying air pressure 0. 1 MPa, air supply temperature 70 ° C.) and an imidafenacin-containing granulated product was obtained. Separately, 90 g of Eudragit EPO (Rohm GmbH & Co. KG) and 45 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 409.5 g of purified water and 955.5 g of ethanol. 300 g of imidafenacin-containing granulated material is charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution is coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.1 MPa, supply (Gas temperature 75 ° C.) and coated granules were obtained.
Furthermore, after mixing 145 g of this coated granule, 1579 g of Pearitol (ROQUETTE JAPAN), 54 g of Kollidon CL-F (BASF) and 4 g of Carplex # 67 (DSL Japan), 18 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.0 kg (n = 5) and a disintegration time of 10 seconds (n = 6).

Example 2
25.0 g of imidafenacin and 12.5 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 738.75 g of purified water and 1723.75 g of ethanol. Starch 1500G (Nihon Colorcon) 4962.5g was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) A supply temperature of 70 ° C.), and an imidafenacin-containing granulated product was obtained (average particle size: 128 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 117 μm).
Furthermore, after mixing 2600g of this coated granule, 14640g of Pairitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 9 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.3 kg (n = 5) and a disintegration time of 12 seconds (n = 6).

Example 3
20.0 g of imidafenacin and 10.0 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 591 g of purified water and 1379 g of ethanol. Charge 4970g of Starch 1500G (Nihon Colorcon) to a fluidized bed granulator (Freund Sangyo, FL-5), and coat this solution by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa, supply And an imidafenacin-containing granulated product was obtained (average particle size: 124 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 120 μm).
Further, 3250 g of this coated granule, 13990 g of Pearitol (ROQUETTE JAPAN), 540 g of Kollidon CL-F (BASF) and 40 g of Carplex # 67 (DSL Japan) were mixed, and then 180 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 9 kN using a rotary tableting machine. The obtained tablet had a hardness of 4.9 kg (n = 5) and a disintegration time of 10 seconds (n = 6).

Example 4
16.7 g of imidafenacin and 8.3 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 483.5 g of purified water and 1151.5 g of ethanol. Starch 1500G (Nihon Colorcon) 4975g was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa, supply And an imidafenacin-containing granulated product was obtained (average particle size: 119 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 115 μm).
Furthermore, after mixing 3900g of this coated granule, 13340g of Pearitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 9 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.2 kg (n = 5) and a disintegration time of 16 seconds (n = 6).

Example 5
25.0 g of imidafenacin and 12.5 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 738.75 g of purified water and 1723.75 g of ethanol. Charge 2500 g of Starch 1500G (Nihon Colorcon) and 2462.5 g of Theolas PH-301 (Asahi Kasei Chemicals) into a fluidized bed granulator (Freund Sangyo, FL-5), and coat this solution by the top spray method (spray solution) An amount of 100 g / min, a spraying air pressure of 0.3 MPa, a supply air temperature of 70 ° C., and an imidafenacin-containing granulated product were obtained (average particle size: 85 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply Temperature 80 ° C.), and coated granules were obtained (average particle size: 118 μm).
Furthermore, after mixing 2600g of this coated granule, 14640g of Pairitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 7.7 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.2 kg (n = 5) and a disintegration time of 12 seconds (n = 6).

Example 6
20.0 g of imidafenacin and 10.0 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 591 g of purified water and 1379 g of ethanol. Starch 1500G (Nihon Colorcon) 2500g and Theolas PH-301 (Asahi Kasei Chemicals) 2470g were charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spray liquid volume 120g) / Min, spraying air pressure 0.3 MPa, supply air temperature 70 ° C.), and imidafenacin-containing granulated product was obtained (average particle size: 80 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply Temperature 80 ° C.), and coated granules were obtained (average particle size: 123 μm).
Further, 3250 g of this coated granule, 13990 g of Pairitol (ROQUETTE JAPAN), 540 g of Kollidon CL-F (BASF) and 40 g of Carplex # 67 (DSL Japan) were mixed, and then 180 g of magnesium stearate plant (Tahei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 7.2 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.5 kg (n = 5) and a disintegration time of 15 seconds (n = 6).

Example 7
16.7 g of imidafenacin and 8.3 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 483.5 g of purified water and 1151.5 g of ethanol. Starch 1500G (Nihon Colorcon) 2500g and Theolas PH-301 (Asahi Kasei Chemicals) 2475g were charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (amount of spray liquid 160g / Min, spraying air pressure 0.3 MPa, supply air temperature 70 ° C.), and imidafenacin-containing granulated product was obtained (average particle size: 87 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 99 μm).
Furthermore, 3900 g of this coated granule, 13340 g of Pearitol (ROQUETTE JAPAN), 540 g of Kollidon CL-F (BASF) and 40 g of Carplex # 67 (DSL Japan) were mixed, and then 180 g of magnesium stearate plant (Tahei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 7.2 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.4 kg (n = 5) and a disintegration time of 12 seconds (n = 6).

Example 8
25.0 g of imidafenacin, 125 g of Eudragit EPO (Rohm GmbH & Co. KG) and 62.5 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 915 g of purified water and 1372.5 g of ethanol. 4787.5g of starch 1500G (Nihon Colorcon) was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) A supply temperature of 70 ° C.) and an imidafenacin-containing granulated product was obtained (average particle size: 115 μm). Separately, 940 g of Eudragit EPO (Rohm GmbH & Co. KG) and 470 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 5702.8 g of purified water and 8554.2 g of ethanol. 4700 g of imidafenacin-containing granulated product is charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution is coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply Temperature 80 ° C.), and coated granules were obtained (average particle size: 123 μm).
Furthermore, after mixing 2600g of this coated granule, 14640g of Pairitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8.6 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.6 kg (n = 5) and a disintegration time of 12 seconds (n = 6).

Comparative Example 1
4.0 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 197 g of purified water and 197 g of ethanol. 394 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, A supply temperature of 50 ° C.) and an imidafenacin-containing granulated product were obtained (average particle size: 134 μm).
Furthermore, 25 g of this imidafenacin-containing granulated product, 172 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant (Taihei Chemical Industry) ) After adding 4.5 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 800 kg using a rotary tableting machine were produced. The obtained tablet had a hardness of 4.7 kg (n = 5).

Comparative Example 2
4.0 g of imidafenacin and 4 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 196 g of purified water and 196 g of ethanol. 392 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, A supply temperature of 50 ° C.) and an imidafenacin-containing granulated product was obtained.
Furthermore, 25 g of this imidafenacin-containing granulated product, 172 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant (Taihei Chemical Industry) ) After adding 4.5 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 1000 kg using a rotary tableting machine were produced. The obtained tablet had a hardness of 7.1 kg (n = 5).

Comparative Example 3
4.0 g of imidafenacin and 4 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 196 g of purified water and 196 g of ethanol. 392 g of Peeritol (ROQUETTE JAPAN) was charged into a rolling fluidized bed granulator (Dalton NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, supply Gas temperature 50 ° C.), and imidafenacin-containing granulated product was obtained.
Furthermore, 25 g of this imidafenacin-containing granulated product, 172 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant (Taihei Chemical Industry) ) After adding 4.5 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 1000 kg using a rotary tableting machine were produced. The obtained tablet had a hardness of 7.2 kg (n = 5).

Comparative Example 4
2.0 g of imidafenacin was dissolved in a mixed solution of 100 g of purified water and 100 g of ethanol. 200 g of Neusilin US2 (Fuji Chemical Industry) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa) A supply temperature of 50 ° C.) and an imidafenacin-containing granulated product was obtained.
Furthermore, 25 g of this imidafenacin-containing granulated product, 172 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant (Taihei Chemical Industry) ) After adding 4.5 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 700 kg using a rotary tableting machine were produced. The obtained tablet had a hardness of 7.2 kg (n = 5).

Comparative Example 5
4.0 g of imidafenacin and 40 g of polyplastidone XL-10 (ISP) were dissolved in a mixed solution of 178 g of purified water and 178 g of ethanol. 356 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, A supply temperature of 50 ° C.) and an imidafenacin-containing granulated product was obtained.
Furthermore, 25 g of this imidafenacin-containing granulated product, 172 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant (Taihei Chemical Industry) ) After adding 4.5 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 850 kg using a rotary tableting machine. The obtained tablet had a hardness of 4.8 kg (n = 5).

Comparative Example 6
4.0 g of imidafenacin and 40 g of HPC-SSL (Nippon Soda) were dissolved in a mixed solution of 178 g of purified water and 178 g of ethanol. 356 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, A supply temperature of 50 ° C.) and an imidafenacin-containing granulated product was obtained.
Furthermore, 25 g of this imidafenacin-containing granulated product, 172 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant (Taihei Chemical Industry) ) After adding 4.5 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 1000 kg using a rotary tableting machine were produced. The obtained tablet had a hardness of 6.7 kg (n = 5).

Comparative Example 7
3.0 g of imidafenacin and 9 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 144 g of purified water and 144 g of ethanol. 288 g of polyplastidone XL-10 (ISP) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0 0.1 MPa, supply air temperature 50 ° C.), an imidafenacin-containing granulated product was obtained.
Furthermore, 25 g of this imidafenacin-containing granulated product, 172 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant (Taihei Chemical Industry) ) After adding 4.5 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 1000 kg using a rotary tableting machine were produced. The obtained tablet had a hardness of 6.7 kg (n = 5).

Comparative Example 8
0.45 g of imidafenacin and 3.375 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 73.1 g of purified water and 73.1 g of ethanol. 460.6 g of Peeritol (ROQUETTE JAPAN) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 10 g / min, spraying air pressure 0.1 MPa) A supply temperature of 70 ° C.) and an imidafenacin-containing granulated product was obtained.
Furthermore, 206.4 g of this imidafenacin-containing granulated product, 54 g of Peeritol (ROQUETTE JAPAN), Theolas PH-102 (Asahi Kasei Chemicals), 6 g of Kollidon CL-F (BASF) and 0.6 g of Carplex # 67 (DSL Japan) are mixed. Thereafter, 3 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed, and then a 150 mg tablet containing 0.1 mg of imidafenacin per tablet was produced at a tableting pressure of 500 kg using a rotary tableting machine. The obtained tablet had a hardness of 4.6 kg (n = 5).

In addition, what was used for the Example and the comparative example is as follows.
1． Product name Starch 1500G (Nihon Colorcon): Partially pregelatinized starch
2． Product name Theolas PH-301 and PH-102 (Asahi Kasei Chemicals): Crystalline cellulose
3． Product name Kollidon 90F (BASF): Popidon
Four. Product name Eudragit EPO and E100 (Rohm GmbH & Co. KG): aminoalkyl methacrylate copolymer E
Five. Product name Magnesium stearate vegetable (Taihei Chemical Industry)
6． Product name Pairitol (ROQUETTE JAPAN): D-mannitol
7． Product name Kollidon CL-F (BASF): Cross Popidon
8． Product Name Polyplusdon XL-10 (ISP): Crospopidone
9. Product name Carplex # 67 (DSL Japan): Hydrous silicon dioxide
10. Product name Neusilin US2 (Fuji Chemical Industry): Magnesium aluminate metasilicate
11. Product name HPC-SSL (Nippon Soda): Hydroxypropylcellulose

The formulation of Examples 1 to 8 in which the pharmaceutical ingredients having a different taste were contained in the granulated product, and the granulated product was an orally rapidly disintegrating tablet coated with an aminoalkyl methacrylate copolymer, had a good mouthfeel. . On the other hand, the formulation of Comparative Examples 1 to 8, which contains a pharmaceutical ingredient having an odd taste in the granulated product, and the granulated product is an orally rapidly disintegrating tablet that is not coated with an aminoalkyl methacrylate copolymer, is poor in mouthfeel. Met.

Test example 1
A content uniformity test was performed on the formulations of Examples 2-4.
Content uniformity test Ten test preparations were collected, and the content of imidafenacin was evaluated by high performance liquid chromatography (HPLC method). Calculate the content of the main drug (ratio (%) with respect to the displayed amount (100%)) and its average value, and the standard deviation (see formula (1) below) and content uniformity judgment value according to the calculation method described in the Japanese Pharmacopoeia (See the following formula (2)).

(Wherein S is the standard deviation, n is the total number of samples tested (10), and X _i is the content of the main drug contained in each tested sample (ratio to the indicated amount (%)). shown .A is the average value of each content from X ₁ to X _n)
Determination value = | 100−A | + S × 2.2 (2)
(In the formula, A and S are the same as the formula (1)).

Moreover, when the “judgment value is 0-15%” and the “standard deviation is 0-3.5%”, it can be considered that there is little variation in the drug content in the prepared tablets and no segregation occurs. , "Uniformity of drug content is ensured". Further, when the “judgment value is 0-15%” and the “standard deviation is not 0-3.5%”, it can be considered that the variation in drug content is large and segregation occurs, and “the content uniformity is poor. It can be said. The appropriate range of the standard deviation in the present invention, that is, “standard deviation is 0-3.5%” is a numerical value considered necessary for quality assurance, and indicates that a composition containing a certain amount of drug can be obtained. It is shown.

HPLC method column: octadecylsilylated silica gel (average particle size 3 μm, inner diameter 4.6 mm × length 50 mm) (GL Science Co., Ltd., trade name Inertsil ODS-3)
Mobile phase: Dissolve 1.08 g of sodium 1-octanesulfonate in diluted phosphoric acid (1 → 1000) to make 1000 mL. Add 300 mL of acetonitrile for liquid chromatography to 700 mL of this solution.
Detector: UV
Measurement wavelength: 220 nm

From Table 1, it was confirmed that the preparations of Examples 2 to 4 had a standard deviation of 3.5 and a judgment value of not more than 15.0 and good content uniformity.

According to the present invention, it is possible to provide an orally rapidly disintegrating tablet having a good mouthfeel.

Claims (3)

  An orally rapidly disintegrating tablet in which a granulated product containing a pharmaceutical ingredient having an odd taste is coated with a coating agent, crospovidone and sugar alcohol are blended as a powder, and compression molded. The intraoral rapid disintegration according to claim 1, wherein the granulated product is 8 to 29.5% by mass in the tablet, crospovidone is 0.5 to 22% by mass in the tablet, and sugar alcohol is 70 to 91.5% by mass in the tablet. Sex tablets. The tablet according to claim 1 or 2, wherein the coating agent is an aminoalkyl methacrylate copolymer.