JP6303045B1 - Method for producing imidafenacin-containing preparation using stirring granulation method - Google Patents

Abstract

An object of the present invention is to provide a new method for producing a preparation containing imidafenacin. [MEANS FOR SOLVING PROBLEMS] It has been found that by using agitation granulation method, a preparation with excellent light stability of imidafenacin in the preparation can be produced, and the present invention has been completed. [Selection figure] None

Description

  The present invention relates to a novel method for producing a preparation 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.

  However, Patent Documents 1 to 8 disclose only a method of producing a granulated product containing imidafenacin by a fluidized bed granulation method and tableting using this, and using other granulation methods. There are no reports of preparations containing imidafenacin.

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 JP 2010-229075 A JP 2010-229076 A JP 2011-32183 A JP 2011-68640 A JP 2014-172855 A

  So far, it has not been known whether or not a production method other than fluidized bed granulation can be used for production of a preparation containing imidafenacin. Accordingly, it is an object of the present invention to provide a new method for producing a preparation containing imidafenacin.

As a result of intensive studies, the present inventors have found that a preparation with excellent light stability of imidafenacin in the preparation can be produced by using the stirring granulation method, and the present invention has been completed. That is, the present invention includes the following inventions.
[1] (i) a step of dissolving or suspending imidafenacin in a pharmaceutically acceptable solvent to produce a solution or suspension;
(Ii) adding the solution or suspension to one or more stirred pharmaceutically acceptable excipients and pharmaceutically acceptable binders to produce a granulated product; and iii) A method for producing a granulated product containing imidafenacin, comprising a step of drying the granulated product.
[2] (i) a step of dissolving or suspending imidafenacin and a pharmaceutically acceptable binder in a pharmaceutically acceptable solvent to produce a solution or suspension;
(Ii) adding the solution or suspension to one or more pharmaceutically acceptable excipients that have been stirred to produce a granulated product; and (iii) drying the granulated product. The manufacturing method of the granulated material containing imidafenacin including a process.
[3] The pharmaceutically acceptable binder is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol and polyvinylpyrrolidone, and the pharmaceutically acceptable solvent is purified water and / or alcohol. The production method according to [1] or [2], wherein the pharmaceutically acceptable excipient is partially pregelatinized starch and / or crystalline cellulose.
[4] (iv) A mixed powder obtained by mixing a granulated product containing imidafenacin obtained by the production method according to any one of [1] to [3] and a pharmaceutically acceptable additive. And (v) a method for producing an imidafenacin-containing tablet, comprising the step of compression molding the mixed powder.
[5] The production method according to [4], wherein the pharmaceutically acceptable additive is a pharmaceutically acceptable excipient and / or lubricant.
[6] The production method according to [5], wherein the pharmaceutically acceptable excipient is crystalline cellulose and the pharmaceutically acceptable lubricant is magnesium stearate.
[7] The production method according to any one of [1] to [3], including a step of sizing the dried granulated product after the step (iii).

  According to the present invention, a preparation with excellent light stability of imidafenacin in the preparation can be produced by using the stirring granulation method.

  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.

  The granulates and tablets of the present invention 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 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 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 and / or partially pregelatinized starch are preferred. When both crystalline cellulose and partially pregelatinized starch are blended, the blending ratio of crystalline cellulose and partially pregelatinized starch is from the viewpoint of flowability and moldability. 4: 1 is preferred.

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

  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. In the present invention, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol and / or polyvinylpyrrolidone are preferable, and hydroxypropylcellulose is particularly preferable.

  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. In the present invention, magnesium stearate is preferred.

  In the present invention, pharmaceutically acceptable coating agents include hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, carmellose calcium, carmellose sodium, carboxymethylethylcellulose, crystalline cellulose, hydroxypropylmethylcellulose acetate succinate and hydroxy Celluloses such as propylmethylcellulose phthalate, aminoalkyl methacrylate copolymers (E, RS), methacrylic acid copolymers (L, S, LD), acrylic polymer materials such as ethyl acrylate / methyl methacrylate copolymer dispersions, povidone, stearyl Examples thereof include alcohol and polyvinyl acetal diethylaminoacetate.

  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, the pharmaceutically acceptable solvent is not particularly limited as long as it is a solvent that can be used when a preparation is produced. Examples thereof include purified water, an organic solvent, and a mixed solvent of purified water and an organic solvent. In the present invention, purified water and / or alcohol is preferable, purified water and / or ethanol is more preferable, and a mixed solvent of purified water and ethanol is particularly preferable.

  The granulated product of the present invention is pharmaceutically acceptable, for example, with one or more pharmaceutically acceptable excipients obtained by stirring a solution of imidafenacin dissolved in a pharmaceutically acceptable solvent. It can granulate by adding to a binder, and can manufacture by drying the obtained granulated material. In addition, a solution prepared by dissolving imidafenacin and a pharmaceutically acceptable binder in a pharmaceutically acceptable solvent is added to one or more pharmaceutically acceptable excipients that are stirred. It can be produced by granulating and drying the resulting granulated product. The dried granulated product is preferably used for the production of the following tablets after sizing.

  For the tablet of the present invention, for example, a granulated product produced by the above method is mixed with a pharmaceutically acceptable additive to produce a mixed powder, and this is compressed using an arbitrary tableting machine. Can be manufactured.

  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.

Example 1
After 200 mg of imidafenacin was dissolved in 106.8 g of ethanol (95), 106.8 g of purified water was added to prepare a solution. 211.4 g of crystalline cellulose, 52.8 g of partially pregelatinized starch, and 2.8 g of hydroxypropyl cellulose were mixed for 30 seconds using a high speed mixer (trade name) (LFS-GA-2J, Fukae Pautech). The resulting mixture was kneaded for 4 minutes using a high speed mixer (trade name) (LFS-GA-2J, Fukae Pautech) while adding the entire amount of the above solution. The obtained kneaded product was dried at 65 ° C. for 75 minutes using a ventilation dryer (30C, manufactured by Fuji Paudal). The obtained dried product was sized using a comil (trade name) (QC-197S, manufactured by Paulek) to obtain 241.1 g of a granulated product.

(Example 2)
To 133.6 g of the granulated product obtained in Example 1, 104.6 g of crystalline cellulose and 1.8 g of magnesium stearate were added and mixed in a polyethylene bag. The obtained mixture was tableted using a tableting machine (VELA5, Kikusui Seisakusho, mortar with a diameter of 9 mm, R facet with a radius of curvature of 12 mm) to a mass of 240 mg per tablet to obtain 810 tablets. .

(Comparative Example 1)
0.2 g of imidafenacin, 211.4 g of crystalline cellulose, 52.8 g of partially pregelatinized starch and 2.8 g of hydroxypropylcellulose were taken and mixed for 1 minute using a Wonder Blender (trade name) (WB-1, Osaka Chemical). The obtained mixed product was granulated using a roller compactor (trade name) (TF-MINI, Freund Industries, roll shape: DPS, roll pressure: 50 kgf · cm ² ). The obtained granulated product was sized using a roll granulator (trade name) (GRN-T54S, Nippon Granulator). The obtained sized product was sieved using a stainless sieve (mesh 710 μm) to obtain 243.5 g of a granulated product.

(Comparative Example 2)
To 133.6 g of the granulated product obtained in Comparative Example 1, 104.6 g of crystalline cellulose and 1.8 g of magnesium stearate were added and mixed in a polyethylene bag. The obtained mixture was tableted using a tableting machine (VELA5, Kikusui Seisakusho, mortar with a diameter of 9 mm, R facet with a radius of curvature of 12 mm) to a mass of 240 mg per tablet to obtain 788 tablets. .

(Comparative Example 3)
After 800 mg of imidafenacin was dissolved in 274 g of ethanol (95), 274 g of purified water was added and mixed. 11.2 g of hydroxypropylcellulose was dissolved in the resulting solution to prepare a binding solution. 211.4 g of crystalline cellulose and 52.8 g of partially pregelatinized starch were mixed in a polyethylene bag. The obtained mixture was sprayed with 140 g of a binding solution using a Numeralizer (trade name) (NQ-160, Fuji Powder) to obtain 254.6 g of a granulated product.

(Comparative Example 4)
To 133.6 g of the granulated product obtained in Comparative Example 3, 104.6 g of crystalline cellulose and 1.8 g of magnesium stearate were added and mixed in a polyethylene bag. The obtained mixture was tableted using a tableting machine (VELA5, Kikusui Seisakusho, mortar with a diameter of 9 mm, R facet with a radius of curvature of 12 mm) to a mass of 240 mg per tablet to obtain 756 tablets. .

(Content uniformity test)
The granules obtained in Example 1 and Comparative Examples 1 and 3 were subjected to a content uniformity test in accordance with the content uniformity test of the 16th revised Japanese Pharmacopoeia. However, the content was calculated by accurately weighing 103.6 sets of granulated product 133.6 mg as one set and correcting the weight.

(Light stability test)
A photostability test was performed on the preparations of Examples 1 and 2 and Comparative Examples 1 to 4. The ratio of impurities at the start of the test and when irradiated with D65 lamp 4000 lux × about 14 days was measured. The quantification of impurities 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 Science Co., Ltd. trade name Inertsil ODS-3)
Liquid A: Liquid B prepared by adding diethylamine to diluted phosphoric acid (1 → 200) and adjusting pH to 6.0 Liquid B: Acetonitrile C for liquid chromatography: Methanol detector for liquid chromatography: UV
Measurement wavelength: 220 nm

  Formulation of granulated products obtained in Example 1 and Comparative Examples 1 and 3 (units of each component: mg / tablet) and granulation method, and results of content uniformity test and light stability test Is shown in Table 1. In the table, HPC represents hydroxypropylcellulose.

As is clear from Table 1, the granulated product obtained by the stirring granulation method is better than the granulated product obtained by other granulation methods (dry granulation method, fluidized bed granulation method). It showed good content uniformity and light stability.

  Table 2 shows the formulation of the tablets obtained in Example 2 and Comparative Examples 2 and 4 (units of amounts of each component: mg / tablet), the granulation method, and the results of the photostability test thereof. In the table, HPC represents hydroxypropylcellulose.

As is clear from Table 2, the granulation obtained by the stirring granulation method as compared with the tablet containing the granulated product obtained by other granulation methods (dry granulation method, fluidized bed granulation method). Tablets containing granules showed good light stability.

  According to the present invention, a preparation with excellent light stability of imidafenacin in the preparation can be produced by using the stirring granulation method.

Claims (6)

(I) a step of dissolving or suspending imidafenacin in a pharmaceutically acceptable solvent to produce a solution or suspension;
(Ii) adding the solution or suspension to one or more stirred pharmaceutically acceptable excipients and pharmaceutically acceptable binders to produce a granulated product; and iii) A method for producing a granulated product containing imidafenacin, comprising a step of drying the granulated product. (I) dissolving or suspending imidafenacin and a pharmaceutically acceptable binder in a pharmaceutically acceptable solvent to produce a solution or suspension;
(Ii) adding the solution or suspension to one or more pharmaceutically acceptable excipients that have been stirred to produce a granulated product; and (iii) drying the granulated product. The manufacturing method of the granulated material containing imidafenacin including a process.   The pharmaceutically acceptable binder is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol and polyvinylpyrrolidone, the pharmaceutically acceptable solvent is purified water and / or alcohol, The process according to claim 1 or 2, wherein the pharmaceutically acceptable excipient is partially pregelatinized starch and / or crystalline cellulose. (Iv) a step of mixing a granulated product containing imidafenacin obtained by the production method according to any one of claims 1 to 3 and a pharmaceutically acceptable additive to produce a mixed powder; And (v) a method for producing a tablet containing imidafenacin, comprising a step of compression-molding the mixed powder.   The production method according to claim 4, wherein the pharmaceutically acceptable additive is a pharmaceutically acceptable excipient and / or lubricant.   The production method according to claim 5, wherein the pharmaceutically acceptable excipient is crystalline cellulose, and the pharmaceutically acceptable lubricant is magnesium stearate.