JP6423034B2 - Imidafenacin-containing tablets - Google Patents

Description

The present invention relates to a tablet containing imidafenacin.

Imidafenacin is an anticholinergic agent that selectively inhibits muscarinic M1 and M3 receptors and is widely used as a therapeutic agent for urgency, frequent urination and urge urinary incontinence in overactive bladder. Currently, film-coated tablets (FC tablets) and orally disintegrating tablets (OD tablets) are commercially available as pharmaceuticals containing imidafenacin as an active ingredient (Non-patent Document 1).

Patent Document 1 discloses an FC tablet containing imidafenacin as an active ingredient and a method for producing the same. Patent Documents 2 to 8 disclose an OD tablet containing imidafenacin as an active ingredient and a method for producing the same. Patent Documents 2 to 3 and 6 describe that light stability is improved by coating an imidafenacin granulated product with a specific non-cellulosic excipient. Patent Document 6 describes that the production of decomposition products in the production process can be suppressed by granulating aminoalkyl methacrylate copolymer E, tocopherol and the like together with imidafenacin. Patent Document 7 describes an OD tablet in which a granulated product containing imidafenacin and tocopherol is mixed with an excipient such as mannitol and then compression-molded, and describes the light stabilization effect of tocopherol.

However, Patent Documents 1 to 8 do not disclose the use of granulated products containing imidafenacin, tocopherol and the like together with cellulose-based excipients for FC tablets.

Uritos Tablets 0.1 mg, Uritos OD Tablets 0.1 mg Package insert, revised in June 2014 (11th edition)

Japanese Patent No. 4610834 Japanese Patent No. 4656672 Japanese Patent No. 4524502 Japanese Patent No. 5545050 Japanese Patent No. 5452051 Japanese Patent No. 5713544 Japanese Patent No. 5658511 JP 2014-172855 A

An object of this invention is to provide the imidafenacin containing tablet excellent in photostability.

As a result of intensive studies, the present inventors have added a cellulose-based excipient to a granulated product containing tocopherol or a tocopherol derivative and imidafenacin, and mixed, and the tablet obtained by compression molding has a high light stabilizing effect. I found out that That is, the present invention includes the following inventions.
[1] A tablet containing a granulated product containing tocopherol or a tocopherol derivative and imidafenacin, and a cellulose-based excipient.
[2] The tablet according to [1], wherein the granulated product containing imidafenacin is not coated with a coating agent.
[3] The tablet according to [1], wherein the tablet is a plain tablet or a film-coated tablet, and the tablet according to [1] or [2] [4] The tablet is a plain tablet.

According to the present invention, an imidafenacin tablet excellent in light stability can be provided.

In the present invention, imidafenacin represents 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide.
In the present invention, the content of imidafenacin in the tablet is preferably 0.025 to 2 mg, more preferably 0.05 to 0.25 mg, and particularly preferably 0.1 mg.

In the present invention, examples of the tocopherol or tocopherol derivative include dl-α-tocopherol (vitamin E), d-σ-tocopherol, tocopherol acetate, tocopherol phosphate, tocopherol sulfate, tocopherol glycosyl ester and salts thereof. . The content of tocopherol is preferably 0.05% by mass or more, more preferably 0.05% by mass or more and 10% by mass or less, further preferably 0.08% by mass or more and 5% by mass or less, in the imidafenacin-containing granulated product. More preferably, they are 1 mass% or more and 3 mass% or less, Especially preferably, they are 1.5 mass% or more and 3 mass% or less.

In the present invention, the cellulose-based excipient is an excipient containing cellulose or a derivative thereof as a constituent component. Examples of the cellulose-based excipient include crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, etc. Among these, one or more of them Cellulosic excipients can be used. As the cellulose-based excipient contained in the tablet of the present embodiment, crystalline cellulose is preferable in that the light stabilization effect is high and that high hardness can be obtained when it is formed into a tablet. The cellulose-based excipient is preferably 1% by mass or more, more preferably 2% by mass or more and 50% by mass or less, 5% by mass or more and 30% by mass or less, and further preferably 7% by mass with respect to 1 part by mass of the imidafenacin-containing granulated product. The mass is 15% by mass or more.

In the present invention, a tablet means a tablet described in the Japanese Pharmacopoeia 16 General Rules for Preparations. That is, it means a solid preparation of a certain shape for oral administration. Tablets include, for example, FC tablets and the like that maintain the shape at the time of oral administration (hereinafter also referred to as normal tablets), OD tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc. Although a special preparation is contained, a tablet is usually preferable in that a preparation excellent in light stability can be obtained.

Examples of normal tablets include plain tablets, FC tablets, sugar-coated tablets, multilayer tablets, and dry-coated tablets. More preferred are uncoated tablets or FC tablets, and even more preferred are uncoated tablets.

In the present invention, the coating agent is an additive for coating the granulated product or tablet surface, and examples thereof include a cellulose-based coating agent and a non-cellulosic coating agent. Examples of the cellulose-based coating agent include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, carmellose calcium, carmellose sodium, carboxymethylethylcellulose, crystalline cellulose, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate. Non-cellulose coating agents such as aminoalkyl methacrylate copolymers (E, RS), methacrylic acid copolymers (L, S, LD), acrylic polymer materials such as ethyl acrylate / methyl methacrylate copolymer dispersions, povidone, stearyl alcohol And polyvinyl acetal diethylaminoacetate.

The granule of the present invention or the tablet containing the granule can contain any pharmaceutically acceptable additive. The additive represents an ingredient other than the active ingredient (imidafenacin), and those described in the Pharmaceutical Additives Dictionary [Japan Pharmaceutical Additives Association, Yakuji Nipposha (2016)] can be used as appropriate. For example, excipients, disintegrants, binders, lubricants, coating agents, colorants, brighteners, sweeteners, corrigents, fragrances and the like can be mentioned.

In the present invention, pharmaceutically acceptable excipients include sugars such as lactose and sucrose, sugar alcohols such as D-sorbitol and mannitol, crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose Examples thereof include celluloses such as sodium, carboxymethylcellulose calcium and low-substituted hydroxypropylcellulose, starches such as partially pregelatinized starch and corn starch. In the present invention, crystalline cellulose, starches, or sugar alcohols are preferred.

Moreover, the excipient | filler used in a granulated material and the excipient | filler used outside a granulated material may use the same or different excipient | filler. The excipient used in the granulated product is preferably celluloses or starches, more preferably crystalline cellulose or partially pregelatinized starch, more preferably partially pregelatinized starch. The excipient used outside the granulated material is preferably celluloses or starches, more preferably crystalline cellulose or partially pregelatinized starch. Tablets obtained by using a cellulosic excipient outside the granulated product are preferred in that they have a high light stabilizing effect and that a high hardness can be obtained when they are formed into tablets.

In the present invention, pharmaceutically acceptable disintegrants include carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, cellulose such as croscarmellose sodium and methylcellulose, starch such as partially pregelatinized starch and corn starch. And crospovidone. More preferred is partially pregelatinized starch.

In the present invention, pharmaceutically acceptable binders include crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, celluloses such as ethylcellulose and methylcellulose, povidone, polyvinyl acetal diethylaminoacetate, and a completely saponified polyvinyl alcohol. , Polyvinyl alcohol partial saponification products, carboxyvinyl polymers, vinyl polymer materials such as polyvinyl chloride, aminoalkyl methacrylate copolymers (E, RS), methacrylic acid copolymers (L, S, LD), ethyl acrylate / methyl methacrylate Acrylic polymer materials such as copolymer dispersions, stearyl alcohol, gelatin, dextrin, gum arabic, pullulan, macrogow , Starch, and the like. More preferably, polyvinylpyrrolidone is mentioned.

In the present invention, pharmaceutically acceptable lubricants include stearic acid and its metal salts, talc, hydrogenated oil, light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester and the like. More preferably, hydrous silicon dioxide or magnesium stearate is used, and magnesium stearate is more preferable.

In the present invention, a high light stabilization effect can be exhibited by a combination of tocopherol or a derivative thereof present in the granulated product and a cellulose-based excipient present outside the granulated product. Therefore, it is not always necessary to coat the imidafenacin-containing granulated product with a coating agent with the aim of the light stabilization effect.
In the present invention, examples of the pharmaceutically acceptable colorant include titanium oxide, iron sesquioxide, and yellow iron sesquioxide.
In the present invention, examples of the pharmaceutically acceptable brightener include carnauba wax.

In the present invention, pharmaceutically acceptable sweeteners include sugars, sugar alcohols, aspartame, saccharin and salts thereof, glycyrrhizic acid and salts thereof, stevia, and acesulfame potassium.

In the present invention, pharmaceutically acceptable flavoring agents include citric acid, sodium citrate, succinic acid, tartaric acid, fumaric acid and the like.

In the present invention, menthol, orange oil and the like are listed as pharmaceutically acceptable fragrances.

The tablet containing the granule of the present invention can be produced by a method commonly used in the art. For example, the granules produced by the above method can be produced by compression molding using an arbitrary tableting machine.
When making the tablet of this invention into a film coating tablet, it can carry out by the method as described in international publication WO2001 / 034147, for example.

EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited by these Examples.
The evaluation method of the intraoral quick disintegrating tablet is as follows.
[Hardness test] The hardness was measured using a tablet hardness tester (Okada Seiko Co., Ltd.). The test is performed with 5 and 10 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 (for example, refer to Pharmaceutical Additives Dictionary 2016 (published by Yakuji Nippo)).
1. Product name Starch 1500G (Japan Colorcon): Partially pregelatinized starch Product name Kollidon 90F (BASF): Povidone 3. Product name dl-α-tocopherol (BASF): Tocopherol4. Product name Eudragit E100 (Evonik): Aminoalkyl methacrylate copolymer E
5. Product name Magnesium stearate vegetable (Taihei Chemical Industry): Magnesium stearate Product name Theolas PH-301 (Asahi Kasei): crystalline cellulose Product name Pairitol (Rocket Japan): D-mannitol8. Product name Kollidon CL-F (BASF): Crospovidone Product name Carplex # 67 (DSL Japan): Hydrous silicon dioxide

Table 1 shows the tablets of the present invention.

Example 1
4 g of imidafenacin, 2 g of Kollidon 90F (BASF) and 20 g of dl-α-tocopherol (BASF) were dispersed in a mixed solution of 37.4 g of purified water and 336.6 g of ethanol. 774 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 20 g / min, spraying air pressure 0.13 MPa, A supply temperature of 60 ° C.) and an imidafenacin granulated product were obtained. Furthermore, 20.0 g of this imidafenacin granulated product, 211.15 g of Theolas PH-301 (Asahi Kasei) and 7.05 g of starch 1500 G (Nihon Colorcon) were mixed, and then 1.8 g of magnesium stearate plant (Tahei Chemical Industry) was added. After mixing, 240 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 4.5 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.4 kg (n = 5).
(Comparative Example 1)
4 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixed solution of purified water 157.6 g and ethanol 236.4 g. 794 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 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Furthermore, 20.0 g of this imidafenacin granulated product, 211.65 g of Theolas PH-301 (Asahi Kasei) and 6.55 g of starch 1500G (Nihon Colorcon) were mixed, and then 1.8 g of magnesium stearate plant (Taihei Chemical Industry) was added. After mixing, 240 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 4.5 kN using a rotary tableting machine. The obtained tablet had a hardness of 6.3 kg (n = 6).
(Comparative Example 2)
4 g of imidafenacin, 20 g of Eudragit E100 (Evonik) and 10 g of magnesium stearate plant (Taihei Chemical Industry) were dispersed in a mixed solution of purified water 146.4 g and ethanol 219.6 g. 766 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 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Furthermore, 20.0 g of this imidafenacin granulated product, 210.95 g of Theolas PH-301 (Asahi Kasei), 7.25 g of Starch 1500 G (Nihon Colorcon) were mixed, and 1.8 g of magnesium stearate plant (Tahei Chemical Industry) was added. After mixing, 240 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 4.5 kN using a rotary tableting machine. The obtained tablet had a hardness of 6.1 kg (n = 5).
(Comparative Example 3)
4 g of imidafenacin, 2 g of Kollidon 90F (BASF) and 20 g of dl-α-tocopherol (BASF) were dispersed in a mixed solution of 37.4 g of purified water and 336.6 g of ethanol. 774 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 20 g / min, spraying air pressure 0.13 MPa, A supply temperature of 60 ° C.) and an imidafenacin granulated product were obtained. Further, 60.0 g of this imidafenacin granulated product, 457.3 g of Pairitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan) were mixed, and then a magnesium stearate plant. After adding 5.4 g of property (Taihei Chemical Industry), 180 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 8.5 kN using a rotary tableting machine. The obtained tablet had a hardness of 3.7 kg (n = 10) and a disintegration time of 12 seconds (n = 6).
(Test example)
The photostability test was carried out on the granulated products and tablets of Example 1 and Comparative Examples 1-3. Tables 2 and 3 show the results of the amount of decomposed product produced in a D65 lamp of 4000 lux × about 14 days. In addition, quantification of the decomposition 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 150 mm) (GL Sciences Inc. trade name Inertsil ODS-3)
Solution A: Dissolve 1.08 g of sodium 1-octanesulfonate in 1000 mL of diluted phosphoric acid (1 → 1000).
Liquid B: Acetonitrile for liquid chromatography Liquid transfer: The concentration gradient is controlled by changing the mixing ratio of liquid A and liquid B.
Detector: UV
Measurement wavelength: 220 nm

As can be seen by comparing the results of Example 1 in Table 2 and Table 3, in the case of the granulated product containing tocopherol, a high light stabilization effect is exhibited both in the granulated state and in the tablet state. On the other hand, in the case of a granulated product containing aminoalkyl methacrylate copolymer E, although there is a high light stabilization effect in the state of the granulated product (Table 2 Comparative Example 2), when a cellulose excipient is added and tableted This effect attenuates (Table 3 Comparative Example 2).

The present inventors have so far found that OD tablets can be produced using imidafenacin granules containing aminoalkyl methacrylate copolymer E (Patent Document 6 discloses that mannitol is used as an excipient. OD tablets compressed and molded after mixing are described). This time, in order to manufacture FC tablets, the excipient mixed with the granulated product was changed to a cellulose-based excipient, and compression molding, a new effect that the stabilizing action of the aminoalkyl methacrylate copolymer E was attenuated. A challenge has arisen. Cellulose-based excipients are inexpensive and can be used when producing ordinary tablets such as FC tablets because they can give high hardness when molded into tablets.

In the present invention, when a granulated product containing tocopherol or a tocopherol derivative is used, even when a cellulosic excipient is used, the light stabilizing effect such as the aminoalkyl methacrylate copolymer E is not reduced. It is the feature that it discovered that the tablet excellent in stability was obtained.

As can be seen from the values after light irradiation in Table 3, the tocopherol-containing formulation (Example 1) is a formulation that does not contain tocopherol (Comparative Example 1), and a formulation that contains aminoalkyl methacrylate copolymer E instead of tocopherol ( Compared to Comparative Example 2), the total amount of photodecomposition products is suppressed to 1/10 or less. It can be seen that by blending tocopherol in the imidafenacin granulated product, a high light stabilization effect is exhibited.

Moreover, although the comparative example 3 uses the imidafenacin granulation containing the same tocopherol as Example 1, it is an orally disintegrating tablet, and it is implemented using mannitol as a main component outside the granulation. Different from Example 1.

Compared to Example 1 (ordinary tablet) using crystalline cellulose as the main component outside the granulated product, the total amount of photodegradation product produced is large, 1.2%. It can be seen that, by using crystalline cellulose as an excipient to be used outside the granulated product, it is possible to provide a normal tablet having excellent light stability by molding into a normal tablet.

ADVANTAGE OF THE INVENTION According to this invention, the imidafenacin containing tablet excellent in light stability can be provided, and it is industrially useful.

Claims (4)

A granule containing tocopherol or a tocopherol derivative and imidafenacin, and a cellulose system selected from the group consisting of crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium and low-substituted hydroxypropylcellulose A tablet containing an excipient , wherein the tocopherol or tocopherol derivative is dl-α-tocopherol, d-σ-tocopherol, tocopherol acetate, tocopherol phosphate, tocopherol sulfate and tocopherol glycosyl ester and salts thereof A tablet selected from the group consisting of: The tablet according to claim 1, wherein the granulated product containing tocopherol or a tocopherol derivative and imidafenacin is not coated with a coating agent. The tablet according to claim 1 or 2, wherein the tablet is an uncoated tablet or a film-coated tablet. The tablet according to claim 1, wherein the tablet is an uncoated tablet.