JP5452051B2 - An orally disintegrating tablet 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

An object of the present invention is to provide an imidafenacin-containing intraoral quick disintegrating tablet having a uniform content and excellent light stability.

  As a result of intensive studies to solve the above problems, the present inventors have found that an intraoral rapidly disintegrating tablet excellent in light stability and disintegration can be obtained by coating imidafenacin with iron sesquioxide and an antistatic agent. The headline and the present invention were completed.

  That is, the present invention relates to an orally disintegrating tablet characterized by directly tableting particles obtained by dry coating imidafenacin with ferric sesquioxide and an antistatic agent.

  According to the present invention, it is possible to provide an imidafenacin-containing intraoral quick disintegrating tablet that ensures content uniformity and is excellent in light stability, and can be easily administered to elderly and pediatric patients who are difficult to swallow.

  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.

Imidafenacin particles are coated 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. is there.

An antistatic agent is used for dry coating with iron sesquioxide. By using an antistatic agent, it becomes easy to provide a preparation in which the content uniformity of the drug is ensured. Examples of the antistatic agent include hydrous silicon dioxide, light anhydrous silicic acid, talc and the like. The antistatic agent is preferably 0.5 parts by mass or more, preferably 0.8 parts by mass or more with respect to 1 part by mass of imidafenacin, from the viewpoint of preventing adhesion to the apparatus during dry coating and the uniformity of drug content. More preferably, it is 1.8 parts by mass or more.

The dry coating used in the present invention is a mechanochemical coating method in which fine particles are used using an apparatus having a large mechanical shearing force.

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.

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 Carplex # 100 (DSL Japan): Hydrous silicon dioxide Product name Pairitol (ROQUETTE JAPAN): D-mannitol Trade name: Polyplusdon XL-10 (ISP): Crospovidone Product name Carplex # 67 (DSL Japan): Hydrous silicon dioxide Product name PH-102 (Asahi Kasei Chemicals): Crystalline cellulose

Example 1
Imidafenacin 10.0 g, Carplex # 100 (DSL Japan) 10 g, and iron sesquioxide (Hana Kasei) 20 g were mixed with a high-speed stirring mixer (Osaka Chemical, Wonder Blender) to obtain imidafenacin-containing coated particles. Further, after mixing 4 g of this imidafenacin-containing coating particle, 1595 g of Pearitol (ROQUETTE JAPAN), 180 g of Polyplastidone XL-10 (ISP) and 3 g of Carplex # 67 (DSL Japan), the magnesium stearate plant (Taihei Chemical Industry) After adding 18 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 1000 kgf using a rotary tableting machine. The obtained tablet had a hardness of 6.2 kg (n = 5).

Example 2
Imidafenacin 5.0 g, Carplex # 100 (DSL Japan) 15 g, and iron sesquioxide (Hana Kasei) 5 g were mixed with a high-speed stirring mixer (Osaka Chemical, Wonder Blender) to obtain imidafenacin-containing coated particles. Furthermore, after mixing 5 g of this imidafenacin-containing coating particle, 1596 g of Pearitol (ROQUETTE JAPAN), 180 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan), the magnesium stearate plant (Taihei Chemical Industry) After adding 18 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 800 kgf using a rotary tableting machine. The obtained tablet had a hardness of 5.6 kg (n = 5) and a disintegration time of 16 seconds (n = 6).

Comparative Example 1
Imidafenacin 5.0 g and Carplex # 100 (DSL Japan) 20 g were mixed with a high-speed stirring mixer (Osaka Chemical, Wonder Blender) to obtain imidafenacin-containing particles. Furthermore, after mixing 5 g of this imidafenacin-containing particles, 1597 g of Pearitol (ROQUETTE JAPAN) and 180 g of Polyplastidone XL-10 (ISP), 18 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed, and then a single tablet machine was used. A 180 mg tablet containing 0.1 mg imidafenacin per tablet was produced at a tableting pressure of 800 kgf. The obtained tablet had a hardness of 5.2 kg and a disintegration time of 15 seconds (n = 6).

Comparative Example 2
Imidafenacin 5.0 g, polyplastidone XL-10 (ISP) 85 g, and iron sesquioxide (Hana Kasei) 10 g were mixed with a high-speed stirring mixer (Osaka Chemical, Wonder Blender) to obtain imidafenacin-containing particles. Further, 20 g of this imidafenacin-containing particle, 1595 g of Pearitol (ROQUETTE JAPAN), 163 g of Polyplastone XL-10 (ISP) and 4 g of Carplex # 67 (DSL Japan) are mixed, and then 18 g of magnesium stearate plant (Tahei Chemical Industry) After mixing, 180 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 800 kgf using a single tableting machine. The obtained tablet had a hardness of 5.3 kg.

Comparative Example 3
Imidafenacin 5.0 g, PH-102 (Asahi Kasei Chemicals) 85 g and iron sesquioxide (Hana Kasei) 10 g were mixed with a high-speed stirring mixer (Osaka Chemical, Wonder Blender) to obtain imidafenacin-containing particles. Furthermore, 20 g of this imidafenacin-containing particles, 1578 g of Pearitol (ROQUETTE JAPAN), 180 g of Polyplastone XL-10 (ISP) and 4 g of Carplex # 67 (DSL Japan) are mixed, and then 18 g of magnesium stearate plant (Tahei Chemical Industry) After mixing, 180 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 800 kgf using a single tableting machine. The obtained tablet had a hardness of 5.4 kg and a disintegration time of 13 seconds (n = 6).

Test example 1
A purity test was performed on the preparations of Examples 1 and 2 and Comparative Examples 1 to 3. 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

As shown in Table 1, preparations containing ferric sesquioxide of Examples 1 and 2 produced a smaller amount of decomposition products by irradiation with light than preparations containing no ferric sesquioxide of Comparative Example 1.

Test example 3
A content uniformity test was performed on the preparations of Examples 1 and 2 and Comparative Examples 1 to 3.
Content uniformity test Ten tablets of the test preparation 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)
(Equation 2)
Determination value = | 100−A | + S × 2.2
... (2)
(In the formula, A and S are the same as the formula (1)).

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

As shown in Table 2, the formulation containing the antistatic agent of Examples 1 and 2 has a smaller judgment value and excellent drug content uniformity than the formulation of Comparative Examples 1 and 2 not containing the antistatic agent. I understood.

Claims (5)

Intraoral , characterized in that particles containing imidafenacin , iron sesquioxide and antistatic agent are obtained by a mechanochemical coating method using a device having a large mechanical shear force, and the obtained particles are directly compressed. Disintegrating tablets. The orally disintegrating tablet according to claim 1, wherein the antistatic agent is 0.5 parts by mass or more with respect to 1 part by mass of imidafenacin. The orally disintegrating tablet according to claim 1 or 2, wherein the device is a Wonder Blender (trademark). The orally disintegrating tablet according to any one of claims 1 to 3, comprising 0.1 mg of the imidafenacin per tablet. Particles containing imidafenacin, ferric sesquioxide and an antistatic agent obtained by a mechanochemical coating method by using a device having a high mechanical shear force.