JP5452050B2 - Orally disintegrating tablets containing imidafenacin - Google Patents

Description

  The present invention relates to an intraoral quick disintegrating tablet containing imidafenacin as an active ingredient.

Imidafenacin is a compound having a muscarinic receptor M3 and M1 antagonistic action (Patent Document 1) and is provided as a therapeutic agent for overactive bladder (Non-Patent Document 1). Known pharmaceutical formulations containing imidafenacin as a main component include oral solid preparations containing imidafenacin, transdermal absorption agents, and the like (Patent Documents 2 and 3).
Patent Document 2 describes that imidafenacin preparations are unstable to light, so that light stabilization is achieved by coating tablets with a coating solution containing titanium oxide and iron sesquioxide.

Meanwhile, the patient's QOL (Quality
For the purpose of improving (of Life), development of pharmaceutical preparations with pharmacological ingenuity is in progress, and intraoral quick disintegrating tablets are the most frequently developed preparations. Intraoral rapidly disintegrating tablets disintegrate instantaneously even with a small amount of saliva in the oral cavity, and thus 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, it is difficult to coat the tablet with titanium / iron sesquioxide while maintaining the disintegration property of the intraoral quick disintegrating tablet, and there has been no report on the light stable imidafenacin-containing intraoral quick disintegrating tablet.

JP-A-7-215943 WO01 / 34147 A1 brochure WO2006 / 082888 A1 brochure

The present invention provides an imidafenacin-containing intraoral quick disintegrating tablet that can be taken without ingesting water and is excellent in light stability.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have adjusted the concentration of imidafenacin in granules and added an iron sesquioxide to provide an orally rapidly disintegrating tablet excellent in photostability and disintegration. As a result, the present invention was completed.

  That is, the present invention relates to a preparation for compression-molding imidafenacin-containing granules, the concentration of imidafenacin in the granules is 0.001 to 3% by mass, and the tablet contains 0.05% by mass or more of iron sesquioxide. Orally disintegrating tablets.

  According to the present invention, an imidafenacin-containing intraoral quick disintegrating tablet excellent in oral disintegration and photostability can be provided, and administration to elderly and pediatric patients who are difficult to swallow is facilitated.

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

Imidafenacin, which is an active ingredient in the intraorally rapidly disintegrating tablet of the present invention, is 4- (2-methyl-1-imidazolyl) -2, which is a therapeutic agent for pollakiuria and urinary incontinence having a selective anticholinergic action on the bladder. 2-diphenylbutyramide.

The concentration of imidafenacin is preferably 0.001% by mass or more, more preferably 0.005% by mass or more, more preferably 0.01% by mass or more, and still more preferably 0.05% in the granule from the viewpoint of light stability. It is preferably at least 0.1% by mass, particularly preferably at least 0.2% by mass. Further, from the viewpoint of content uniformity, the content is preferably 3% by mass or less, more preferably 2% by mass or less, more preferably 1% by mass or less, still more preferably 0.8% by mass or less, and particularly preferably 0.8% by mass or less. 6% by mass or less.

Granulation methods of imidafenacin-containing granules include dry granulation method, stirring granulation method, extrusion granulation method, fluidized bed granulation method, rolling fluidized bed granulation method, spray granulation method, etc., preferably fluidized bed It is a granulation method or a 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. As long as the effect of this invention is not impaired, a granulated material can mix | blend components other than a pharmaceutical ingredient and an excipient | filler. From the viewpoint of light stability, the excipient to be blended in the granulated product is preferably starch, more preferably partially pregelatinized starch.
The imidafenacin-containing granulated product can also be dried after granulation from the viewpoint of the stability of pharmaceutical components and the ease of production of tablets. The drying method is not particularly limited as long as it is a method that can be used for producing a pharmaceutical preparation.

Also, blended with iron sesquioxide for light stabilization. The iron sesquioxide used in the present invention is yellow iron sesquioxide or red iron sesquioxide, and these can be used alone or in combination.
The content of iron sesquioxide is preferably 0.001% by mass or more in the tablet, more preferably 0.005% by mass or more, more preferably 0.01% by mass or more, and particularly preferably 0.05% by mass or more. .

The intraoral quick disintegrating tablet of the present invention contains an excipient and a disintegrating agent separately from imidafenacin particles. The excipients used here are not particularly limited as long as they can be used for the production of pharmaceutical preparations. For example, they are described in the Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nippo (2007)]. Can be used. Examples thereof include sugars such as lactose and glucose, sugar alcohols such as D-sorbitol and mannitol, celluloses such as crystalline cellulose, starches such as partially pregelatinized starch and corn starch. A sugar alcohol is preferred.

The disintegrant used in the present invention is not particularly limited as long as it can be used for the production of pharmaceutical preparations. Can be used. For example, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, cellulose such as methylcellulose, crospovidone, etc. can be used, and crospovidone can be used from the viewpoint of ease of drinking (feel good to the mouth). It is preferable to use it. 1-10 mass% is preferable in a tablet, and, as for the compounding quantity of a disintegrating agent, More preferably, it is 2-6 mass%.

The intraoral quick disintegrating tablet can be blended with additives that can be used for the production of pharmaceutical preparations, if necessary. Specifically, those described in the Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nipposha (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., saccharides, sugar alcohols, aspartame, saccharin and salts thereof, glycyrrhizic acid and salts thereof, stevia, acesulfame potassium, etc. Sodium citrate, succinic acid, tartaric acid, fumaric acid, and the like, iron sesquioxide, yellow sesquioxide, caramel, riboflavin, aluminum lake, and the like 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 increase 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 test examples of the present invention.

The evaluation method of imidafenacin-containing granulated product and coated 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 meter (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.

In addition, the compound shown by the brand name used for the following Examples and Comparative Examples is as follows.
1. Product name Kollidon 90F (BASF): Povidone Product name Starch 1500G (Japan Colorcon): Partially pregelatinized starch Product name Pairitol (ROQUETTE JAPAN): D-mannitol Trade name: Polyplastidone XL-10 (ISP): Crospovidone Product name Carplex # 67 (DSL Japan): Hydrous silicon dioxide Product name Magnesium stearate vegetable (Taihei Chemical Industry)
7). Product name Kollidon 25 (BASF): Povidone

Example 1
4.0 g of imidafenacin, 4 g of Kollidon 90F (BASF) and 4 g of iron sesquioxide (Hana Kasei) were dissolved and dispersed in a mixture of 194 g of purified water and 194 g of ethanol. 388 g of starch 1500G (Nihon Colorcon) was charged into a 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, air supply A temperature of 70 ° C.) and an imidafenacin-containing granulated product was obtained (average particle size: 159 μm). Further, 25 g of this granulated product, 374.5 g of Pearitol (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 850 kgf were produced using a rotary tableting machine. The obtained tablet had a hardness of 5 kg (n = 5).

Example 2
4.0 g of imidafenacin, 4 g of Kollidon 90F (BASF) and 20 g of iron sesquioxide (Hana Kasei) were dissolved and dispersed in a mixed solution of 186 g of purified water and 186 g of ethanol. 372 g of starch 1500G (Nihon Colorcon) was charged into a 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, air supply Temperature 70 ° C.) and imidafenacin-containing granules were obtained (average particle size: 166 μm). Further, 25 g of this granulated product, 374.5 g of Pearitol (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 850 kgf were produced using a rotary tableting machine. The obtained tablet had a hardness of 5 kg (n = 5).

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 starch 1500G (Nihon Colorcon) was charged into a 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, air supply Temperature 50 ° C.) and an imidafenacin-containing granulated product was obtained (average particle size: 192 μm). Separately, 3 g of Kollidon 25 (BASF) and 3 g of iron sesquioxide (Hana Kasei) were dissolved and dispersed in a mixed solution of 47 g of purified water and 47 g of ethanol. 294 g of imidafenacin-containing granulated material is charged into a fluidized bed granulator (Dalton, NQ-160), and this solution is coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, supply air temperature 75 ° C.) to obtain coated granules (average particle size: 191 μm).
Further, 25.5 g of this coated granule, 374 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) are 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 730 kgf were produced using a rotary tableting machine. The obtained tablet had a hardness of 4.4 kg (n = 5).

Example 4
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 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, air supply Temperature 50 ° C.) and an imidafenacin-containing granulated product was obtained (average particle size: 192 μm). Separately, 15 g of Kollidon 25 (BASF) and 15 g of iron sesquioxide (Hana Kasei) were dissolved and dispersed in a mixture of 235 g of purified water and 235 g of ethanol. 270 g of imidafenacin-containing granulated product is charged into a fluidized bed granulator (Dalton, NQ-160), and this solution is coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, supply air temperature 75 ° C.) to obtain coated granules.
Further, 22.4 g of this coated granule, 297.2 g of Pairitol (ROQUETTE JAPAN), 36 g of Polyplastidone XL-10 (ISP) and 0.8 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant ( Taihei Chemical Industry) After adding 3.6 g and mixing, 180 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 720 kgf using a rotary tableting machine. The obtained tablet had a hardness of 4.2 kg (n = 5).

Comparative Example 1
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 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, air supply Temperature 50 ° C.) and an imidafenacin-containing granulated product was obtained (average particle size: 192 μm). Further, 25 g of this granulated product, 374.5 g of Pearitol (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 kgf using a rotary tableting machine were produced. The obtained tablet had a hardness of 7.1 kg (n = 5).

Test example 1
A purity test was performed on the preparations of Examples 1 to 5 and Comparative Example 1. Table 1 shows the results of the amount of decomposition products before and after irradiation with light. The degradation product was evaluated by liquid chromatography (HPLC method).

HPLC method column: octadecylsilylated silica gel (average particle size 5 μm, inner diameter 4.6 mm × length 250 mm) (GL Sciences Inc., trade name Inertsil ODS-3)
Liquid A: Add diethylamine to diluted phosphoric acid (1 → 200) and adjust the pH to 6.0.
Liquid B: acetonitrile for liquid chromatography
Liquid C: Methanol solution for liquid chromatography: Concentration control is performed by changing the mixing ratio of liquid A, liquid B and liquid C.
Detector: UV
Measurement wavelength: 220 nm

顆粒中に三二酸化鉄を配合した実施例１〜３の製剤や顆粒を三二酸化鉄でコーティングした実施例４，５の製剤は、三二酸化鉄を配合していない比較例１と比べて光線照射による分解物の生成量は小さかった。

The preparations of Examples 1 to 3 in which iron sesquioxide was blended in the granules and the preparations of Examples 4 and 5 in which the granules were coated with iron sesquioxide were irradiated with light compared to Comparative Example 1 in which no ferric sesquioxide was blended. The amount of degradation products produced by the was small.

Claims (2)

In a preparation for compression-molding imidafenacin-containing granules, the concentration of imidafenacin in the granules is 0.001 to 3% by mass, and the tablet contains 0.05% by mass or more of iron sesquioxide. Disintegrating tablets. The orally disintegrating tablet according to claim 1, wherein the granulation method is a fluidized bed granulation method or a rolling fluidization granulation method.