JP2018168107A - Granulated material containing imidafenacin having less production process decomposed product - Google Patents

Abstract

An object of the present invention is to provide a preparation containing imidafenacin with little degradation product of new process.
[Solution]
A method for producing a granulated product containing imidafenacin,
A method for producing a granulated product obtained through the following steps a) and b) via the drying step of either step c) -1 or c) -2. .
a) Step of producing a solution or suspension by dissolving or suspending imidafenacin in a pharmaceutically acceptable solvent b) One or more types of pharmaceutically acceptable fluidized in a fluid bed granulator Step c) -1 of spraying the excipient or the solution or suspension obtained in step a) to produce a granulated product Step c) of drying the granulated product obtained in step b) under reduced pressure -2 Step of drying the granulated product obtained in step b) in a fluidized bed granulator within 100 minutes [selection figure] None

Description

The present invention relates to a granulated product containing imidafenacin with little degradation product.

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. And patent document 6 describes that the production | generation of a manufacturing process decomposition product can be suppressed by granulating tocopherol etc. with imidafenacin.

However, Patent Document 6 does not disclose that the decomposition product of the production process can be suppressed by drying the imidafenacin granulated product under certain conditions.

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

The inventors have studied mass production of granulated products containing imidafenacin. When imidafenacin granulation was produced using a fluidized bed granulator, it was not generated in the case of a small scale (about 10,000 tablets) that has been conventionally performed, and is represented by the following general formula (1). It was found that a new process degradation product (degradation product A) occurs on a large scale (about 100,000 to 750,000 tablets). Further, it has been found that the decomposition product A is generated mainly in the drying step of the granulated product. It is a problem to be solved by the present invention to provide an imidafenacin-containing granulated product with less generation of the decomposition product A.

As a result of intensive studies, the present inventors have found that the production of a novel process decomposition product (decomposition product A) can be suppressed by drying the imidafenacin-containing granulated product under specific conditions, thereby completing the present invention. . That is, the present invention includes the following inventions.
[1] A method for producing a granulated product containing imidafenacin,
A method for producing a granulated product obtained through the following steps a) and b) via the drying step of either step c) -1 or c) -2. .
a) Step of dissolving or suspending imidafenacin in a pharmaceutically acceptable solvent to produce a solution or suspension b) One or more types of pharmaceutically acceptable fluidized in a fluid bed granulator Step c) -1 of spraying the solution or suspension obtained in step a) onto the excipient to produce a granulated product Step c) drying the granulated product obtained in step b) under reduced pressure ) -2 The process according to [1], wherein the granulated product obtained in step b) is dried in a fluid bed granulator within 100 minutes [2] The drying step is c) -1. .
[3] The production method according to [2], wherein drying under reduced pressure is performed under a condition of −0.15 MPaG or more and −0.05 MPaG or less.
[4] The production method according to [2] or [3], wherein the loss on drying at the end of drying is 2% or more and 7% or less.
[5] Drying under reduced pressure is performed using a vibration dryer, and the set temperature range of the heat medium in the vibration dryer is 60 ° C. or higher and 90 ° C. or lower, according to [2] to [4]. Production method.
[6] The production method according to [5], wherein the set temperature range of the heat medium is 80 ° C. or higher and 90 ° C. or lower and the drying time is within 60 minutes.
[7] The drying step is step c) -2, the supply temperature in the drying step is 75 ° C. or more and 100 ° C. or less, and the drying time of the granulated product is 60 minutes or less. Production method.
[8] The production method according to [1] to [7], wherein a pharmaceutically acceptable binder is used in the solution or suspension of step a).
[9] A method for producing a tablet containing imidafenacin by mixing the granulated product obtained in [1] to [8] and a pharmaceutically acceptable additive, followed by compression molding.

ADVANTAGE OF THE INVENTION According to this invention, the formulation by which the production | generation of the novel process decomposition product (decomposition product A) was suppressed can be manufactured by drying the imidafenacin containing granulated material on specific conditions.

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 from 0.025 mg to 2 mg, more preferably from 0.05 mg to 0.25 mg, particularly preferably 0.1 mg.

In the present invention, the pharmaceutically acceptable solvent is not particularly limited as long as it is a solvent that can be used when producing a preparation. For example, water, an organic solvent, or a mixed solution of water and an organic solvent can be used. Examples of the organic solvent include methanol, ethanol, isopropanol, acetone and the like, preferably ethanol. More preferred is a mixed solution of water and ethanol.

In the present invention, the pharmaceutically acceptable excipient includes a cellulosic excipient or a non-cellulosic excipient.

In the present invention, examples of the cellulose-based excipient include cellulose-based excipients such as crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, and low-substituted hydroxypropylcellulose. . By using the cellulosic excipient in the granulated product, the tablet hardness increases when the granulated product is tableted.

In the present invention, pharmaceutically acceptable non-cellulosic excipients include sugars such as lactose and sucrose, sugar alcohols such as D-sorbitol and mannitol, and starches such as partially pregelatinized starch and corn starch. Is mentioned.
In the present invention, a combination of cellulosic excipients and starches is preferable from the viewpoint of good moldability. More preferred is a combination of crystalline cellulose and partially pregelatinized starch.
From the viewpoint of fluidity and moldability, the cellulosic excipient is 1 part by mass or more and 10 parts by mass or less, more preferably 2 parts by mass or more and 7 parts by mass or less, more preferably 1 part by mass of starch. 3 parts by mass or more and 5 parts by mass or less, more preferably 4 parts by mass is used.

In the present invention, pharmaceutically acceptable binders include crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, celluloses such as ethylcellulose and methylcellulose, povidone, polyvinyl acetal diethylaminoacetate, and 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, macrogol, Pung, and the like. Preferably, celluloses or vinyl polymers are used. More preferably, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol completely saponified product or polyvinyl alcohol partial saponified product is used. More preferred is povidone.

In the present invention, the pharmaceutically acceptable additive is preferably a lubricant. Examples of the lubricant 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 magnesium stearate.

In the present invention, the drying step is performed in a short time in the step c) -1 of drying under reduced pressure (hereinafter, also referred to as a vacuum drying method) or the fluidized bed granulator c) -2. Drying is performed under any of the conditions of the process. The reduced-pressure drying method of c) -1 is preferable in that the generation of the decomposition product A can be further suppressed.

c) In the case of the vacuum drying method of -1, for example, a vibration dryer, a stirring dryer, a drum dryer, a shelf dryer, a rotary dryer (a cylindrical rotary dryer, a double cone rotary dryer), a disk dryer, Drying is performed under reduced pressure using a conductive electric heat dryer such as a vacuum macro wave dryer, a paddle dryer, or a stirring shaft dryer. A vibration dryer is preferable in that the generation of the decomposition product A can be further suppressed, and a vibration dryer VU type (Chuo Kako Co., Ltd.) is more preferable.

In the present invention, the conduction electric heat dryer means that a metal plate (for example, a wall surface inside the device, a rotating plate, a heating plate, a stirring blade, etc.) in the apparatus is heated and the sample touches the metal plate. In this type of dryer, heat is transferred from the metal plate to the sample, and the sample is dried.
When drying under reduced pressure, it is preferable to dry under heating conditions in terms of shortening the drying time. In many cases of conduction electric heat dryers, a metal plate inside the apparatus is indirectly heated by passing a heated gas or liquid through a jacket portion provided in the dryer. A gas or liquid that mediates heating of the sample through the jacket portion is referred to as a “heating medium”. The heat medium is preferably water (including warm water and water vapor). The set temperature range of the heat medium is preferably 60 ° C. or higher and 90 ° C. or lower. More preferably, it is 80 ° C. or higher and 90 ° C. or lower, more preferably 83 ° C. or higher and 85 ° C. or lower, in that the drying time can be shortened without generating a process decomposition product.

In the present invention, “reduced pressure” means less than atmospheric pressure, preferably −0.30 MPaG or more and −0.01 MPaG or less, more preferably −0.20 MPaG or more and −0.02 MPaG or less, and further preferably −0. 15 MPaG or more and -0.05 MPaG or less are mentioned. There are two types of pressure notation: absolute pressure notation with zero absolute vacuum and gauge pressure notation with atmospheric pressure zero. In this specification, the latter gauge pressure notation is used.
When drying under reduced pressure of c) -1, it is preferable to adjust the loss on drying to 2% or more and 7% or less in that a granulated product with high content uniformity can be obtained. Furthermore, the loss on drying is more preferably 3% or more and 5% or less. Loss on drying is a value that indicates how much the weight after drying is reduced compared to the weight before drying when a sample of a certain weight is dried, and is calculated by the following formula. .

c) When drying in the fluidized bed granulator of -2, for example, flow coater (Freund industry)
, Etc. can be used. When drying in a fluidized bed granulator, drying is performed by blowing air to the fluidized granulated product. The temperature of the air sprayed on the granulated product (hereinafter also referred to as the supply air temperature) is preferably 50 ° C. or higher, more preferably 60 ° C. or higher and 100 ° C. or lower, and even more preferably 75 ° C. or higher and 100 ° C. or lower.

The granulated product or tablet of the present invention may 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 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.
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, 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 granulated product or tablet of the present invention can be produced by a method commonly used in the art. For example, it is possible to produce a mixed powder by mixing the granulated product produced by the above method with a pharmaceutically acceptable additive, and compressing it using an arbitrary tableting machine. it can.

  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.
(Comparative Example 1)
For each tablet, 26.4 mg of partially pregelatinized starch and 105.7 mg of crystalline cellulose are taken (19.8 kg of partially pregelatinized starch and 79.275 kg of crystalline cellulose are taken as a scale of 750,000 tablets), and a fluidized bed granulator (Pneumatic) A riser NQ-750, Dalton) was sprayed with an aqueous ethanol solution equivalent to 0.1 mg of imidafenacin (spraying liquid speed of about 896 mL / min) to obtain a granulated product before imidafenacin before drying. In the same apparatus, drying was performed for 210 minutes (supply temperature 40 ° C., initial air volume 42 m ³ / min, late air volume 37 m ³ / min) to obtain a granulated product after imidafenacin drying. The loss on drying at the end of drying was 7.6%.
Example 1
For each tablet, 26.4 mg of partially pregelatinized starch and 105.7 mg of crystalline cellulose are taken (19.8 kg of partially pregelatinized starch and 79.275 kg of crystalline cellulose are taken as a scale of 750,000 tablets), and a fluidized bed granulator (Pneumatic) A riser NQ-750, Dalton) was sprayed with an aqueous ethanol solution equivalent to 0.1 mg of imidafenacin (spraying liquid speed: about 833 mL / min) to obtain a granulated product before imidafenacin before drying. In the same apparatus, drying was performed for 58 minutes (a supply temperature of 80 ° C., an initial air volume of 40 m ³ / min, a late air volume of 34 m ³ / min), and a granulated product was obtained after drying imidafenacin. The loss on drying at the end of drying was 7.9%.
(Example 2)
For each tablet, 26.4 mg of partially pregelatinized starch and 105.7 mg of crystalline cellulose are taken (19.8 kg of partially pregelatinized starch and 79.275 kg of crystalline cellulose are taken as 750,000 tablets per operation), and fluidized bed construction Using an agglomerator (pneumaticizer NQ-750, Dalton), an ethanol aqueous solution equivalent to 0.1 mg of imidafenacin was sprayed (spraying liquid speed of about 833 mL / min) to obtain a granulated product before imidafenacin before drying. In the same apparatus, drying was performed for 55 minutes (supplying temperature 100 ° C., initial air volume 37 m ³ / min, late air volume 31 m ³ / min), and a granulated product was obtained after drying imidafenacin. The loss on drying at the end of drying was 5.4%.
(Test Example 1) Purity Test The following purity test was performed on the granulated product after drying obtained in Comparative Example 1 and Examples 1-2. The results are shown in Table 2.
After drying, approximately 2.672 g of granulated material (amount corresponding to 2 mg of imidafenacin (C ₂₀ H ₂₁ N ₃ O)) was precisely measured and diluted with phosphoric acid (1 → 1000) / acetonitrile mixture for liquid chromatography (7: 3) Add 10 mL accurately and shake for 60 minutes. This solution is centrifuged (3000 rpm for 20 minutes), and the supernatant is filtered through a membrane filter having a pore size of 0.45 μm, and the filtrate is used as a sample solution. Separately, weigh accurately about 20 mg of imidafenacin standard product (measure moisture separately) and dissolve in diluted phosphoric acid (1 → 1000) / acetonitrile mixture for liquid chromatography (7: 3) to make exactly 100 mL. Use standard stock solution. Pipet 2 mL of this solution and add diluted phosphoric acid (1 → 1000) / acetonitrile mixture for liquid chromatography (7: 3) to make exactly 20 mL. Pipet 5 mL of this solution, add diluted phosphoric acid (1 → 1000) / acetonitrile mixture for liquid chromatography (7: 3) to make exactly 100 mL, and use this solution as the standard solution. 20 μL each of the sample solution and the standard solution were accurately taken and tested by liquid chromatography under the following conditions, and each peak area of each solution was measured by an automatic integration method.

試験条件

Test conditions

Detector: UV absorptiometer (measurement wavelength: 220 nm)

Column: Each stainless steel tube with an inner diameter of 4.6 mm, a length of 5 mm, an inner diameter of 4.6 mm, and a length of 25 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography to form a guard column and a separation column, respectively (GL Cart and Inertsil ODS-3, manufactured by GL Sciences).
Column temperature: Constant temperature around 40 ° C. Mobile phase A: Add diethylamine to diluted phosphoric acid (1 → 200) and adjust pH to 6.0.
Mobile phase B: Acetonitrile mobile phase for liquid chromatography C: Methanol mobile phase for liquid chromatography Liquid transfer: Concentration control is performed by changing the mixing ratio of mobile phase A, mobile phase B, and mobile phase C as shown in Table 1 .

Flow rate: 1.0 mL per minute
Under this condition, imidafenacin has a retention time of about 32 minutes. Compound A has a relative retention time of about 1.2 relative to the imidafenacin peak.
Area measurement range: The range after the solvent peak is about 1.5 times the retention time of imidafenacin, except for the placebo-derived peaks (relative retention times for imidafenacin; about 0.38 and 0.39).

As can be seen from Table 2, when the imidafenacin granulated product is dried in a fluidized bed granulator, the amount of compound A produced increases as the drying time increases. In order to shorten the drying time, it is preferable to set the supply air temperature as high as 75 ° C. or higher, for example.
Example 4
For each tablet, 26.4 mg of partially pregelatinized starch and 105.7 mg of crystalline cellulose are taken (1848 g of partially pregelatinized starch and 7399 g of crystalline cellulose are taken as 70,000 tablets per operation), and fluidized bed granulator (flow Using an coater FLO-15, Freund Sangyo Co., Ltd., an aqueous ethanol solution equivalent to 0.1 mg of imidafenacin was sprayed (spraying liquid rate: 205 mL / min) to obtain a granulated product before imidafenacin before drying. (This was equally divided into two, and one was used in Example 5.) In the same apparatus, drying was performed for 32 to 34 minutes (supply temperature 75 ° C., initial air flow rate 2.7 m ³ / min, Late air volume 1.9 m ³ / min), imidafenacin dried granulation was obtained. The same operation was performed 8 times.
(Example 5)
The obtained granulated product (each twice the pre-dried granulated product divided in Example 4) was transferred to a vibration dryer (vibration dryer VU-45, Chuo Kogyo Co., Ltd.) under the following conditions. Then, drying was performed for 80 to 90 minutes to obtain a granulated product after drying imidafenacin. The loss on drying at the end of drying was 3.0 to 4.5%. The same operation was performed 4 times.
Drying conditions Warm water set temperature: 75 ° C
Dryer side valve opening: Fully open vibration: Always (Test example 2) Purity test 2
A purity test was performed on the granulated products obtained in Examples 4 and 5. The purity test method was the same as in Test Example 1. The results are shown in Table 3.

ND: Not detected, as shown in Table 3, 0.05 to 0.47% of compound A was produced in Example 4 where no drying under reduced pressure was carried out, but the production of compound A was highly suppressed by drying under reduced pressure. can do. Further, in Example 4, the amount of compound A produced varies from lot to lot, but in Example 5, such variation does not occur, and no compound A was detected in any lot.
(Example 6)
Except that the hot water set temperature was 82 ° C., the same procedure as in Example 5 was performed, and when the loss on drying reached 4%, the drying was finished. The drying time was about 50 minutes.
As can be seen from Example 5 and Example 6, the drying time can be shortened from 80 to 90 minutes to 50 minutes by raising the warm water set temperature from 75 ° C. to 82 ° C. By increasing the hot water set temperature, the production amount of Compound A did not increase, and an imidafenacin granulated product equivalent in quality was successfully produced in a short time.

  ADVANTAGE OF THE INVENTION According to this invention, the formulation by which the production | generation of the novel process decomposition product was suppressed can be manufactured by drying imidafenacin containing granulated material on specific conditions.

EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited by these Examples.
(Comparative Example 1)
For each tablet, 26.4 mg of partially pregelatinized starch and 105.7 mg of crystalline cellulose are taken (19.8 kg of partially pregelatinized starch and 79.275 kg of crystalline cellulose are taken as a scale of 750,000 tablets), and a fluidized bed granulator (Pneumatic) A riser NQ-750, Dalton) was sprayed with an aqueous ethanol solution equivalent to 0.1 mg of imidafenacin (spraying liquid speed: about 896 mL / min) to obtain a granulated product before imidafenacin before drying. In the same apparatus, drying was performed for 210 minutes (supply temperature 40 ° C., initial air volume 42 m ³ / min, late air volume 37 m ³ / min) to obtain a granulated product after imidafenacin drying. The loss on drying at the end of drying was 7.6%.
( Reference Example 1 )
For each tablet, 26.4 mg of partially pregelatinized starch and 105.7 mg of crystalline cellulose are taken (19.8 kg of partially pregelatinized starch and 79.275 kg of crystalline cellulose are taken as a scale of 750,000 tablets), and a fluidized bed granulator (Pneumatic) A riser NQ-750, Dalton) was sprayed with an aqueous ethanol solution equivalent to 0.1 mg of imidafenacin (spraying liquid speed of about 833 mL / min) to obtain a granulated product before imidafenacin before drying. In the same apparatus, drying was performed for 58 minutes (a supply temperature of 80 ° C., an initial air volume of 40 m ³ / min, a late air volume of 34 m ³ / min), and a granulated product was obtained after drying imidafenacin. The loss on drying at the end of drying was 7.9%.
( Reference Example 2)
For each tablet, 26.4 mg of partially pregelatinized starch and 105.7 mg of crystalline cellulose are taken (19.8 kg of partially pregelatinized starch and 79.275 kg of crystalline cellulose are taken as 750,000 tablets per operation), and fluidized bed construction Using an agglomeration apparatus (Numeralizer NQ-750, Dalton), an ethanol aqueous solution equivalent to 0.1 mg of imidafenacin was sprayed on this (spraying liquid speed of about 833 mL / min) to obtain a granulated product before imidafenacin before drying.
In the same apparatus, drying was performed for 55 minutes (supplying temperature 100 ° C., initial air volume 37 m ³ / min, late air volume 31 m ³ / min), and a granulated product was obtained after drying imidafenacin. The loss on drying at the end of drying was 5.4%.
(Test Example 1) Purity Test The following purity test was performed on the granulated product after drying obtained in Comparative Example 1 and Reference Examples 1-2.
The results are shown in Table 2.
After drying, approximately 2.672 g of granulated material (amount corresponding to 2 mg of imidafenacin (C ₂₀ H ₂₁ N ₃ O)) was precisely measured and diluted with phosphoric acid (1 → 1000) / acetonitrile mixture for liquid chromatography (7: 3) Add 10 mL accurately and shake for 60 minutes. This solution is centrifuged (3000 rpm for 20 minutes), and the supernatant is filtered through a membrane filter having a pore size of 0.45 μm, and the filtrate is used as a sample solution. Separately, weigh accurately about 20 mg of imidafenacin standard product (measure moisture separately) and dissolve in diluted phosphoric acid (1 → 1000) / acetonitrile mixture for liquid chromatography (7: 3) to make exactly 100 mL. Use standard stock solution. Pipet 2 mL of this solution and add diluted phosphoric acid (1 → 1000) / acetonitrile mixture for liquid chromatography (7: 3) to make exactly 20 mL. Pipet 5 mL of this solution, add diluted phosphoric acid (1 → 1000) / acetonitrile mixture for liquid chromatography (7: 3) to make exactly 100 mL, and use this solution as the standard solution. 20 μL each of the sample solution and the standard solution were accurately taken and tested by liquid chromatography under the following conditions, and each peak area of each solution was measured by an automatic integration method.

Flow rate: 1.0 mL per minute
Under this condition, imidafenacin has a retention time of about 32 minutes. Degradation product A has a relative retention time of about 1.2 relative to the peak of imidafenacin.
Area measurement range: The range after the solvent peak is about 1.5 times the retention time of imidafenacin, except for the placebo-derived peaks (relative retention times for imidafenacin; about 0.38 and 0.39).

As can be seen from Table 2, when the imidafenacin granulated product is dried in the fluidized bed granulator, the generation amount of the decomposition product A increases as the drying time increases. In order to shorten the drying time, it is preferable to set the supply air temperature as high as 75 ° C. or higher, for example.
( Reference Example 4 )
For each tablet, 26.4 mg of partially pregelatinized starch and 105.7 mg of crystalline cellulose are taken (1848 g of partially pregelatinized starch and 7399 g of crystalline cellulose are taken as 70,000 tablets per operation), and fluidized bed granulator (flow Using an coater FLO-15, Freund Sangyo Co., Ltd., an aqueous ethanol solution equivalent to 0.1 mg of imidafenacin was sprayed (spraying liquid rate: 205 mL / min) to obtain a granulated product before imidafenacin before drying. (This was equally divided into two, and one was used in Example 5.) In the same apparatus, drying was performed for 32 to 34 minutes (supply temperature 75 ° C., initial air flow rate 2.7 m ³ / min, Late air volume 1.9 m ³ / min), imidafenacin dried granulation was obtained. The same operation was performed 8 times.
(Example 5)
The obtained granulated product (each twice the pre-dried granulated product divided in Example 4) was transferred to a vibration dryer (vibration dryer VU-45, Chuo Kogyo Co., Ltd.) under the following conditions. Then, drying was performed for 80 to 90 minutes to obtain a granulated product after drying imidafenacin. The loss on drying at the end of drying was 3.0 to 4.5%. The same operation was performed 4 times.
Drying conditions Warm water set temperature: 75 ° C
Dryer side valve opening: Fully open vibration: Always (Test example 2) Purity test 2
The granule obtained in Reference Example 4 and Example 5 was subjected to a purity test. The purity test method was the same as in Test Example 1. The results are shown in Table 3.

ND: Not detected, as shown in Table 3, 0.05 to 0.47% decomposition product A was generated in Reference Example 4 where vacuum drying was not performed. However, by performing drying under reduced pressure, the generation of decomposition product A is highly advanced. Can be suppressed.
Furthermore, in Reference Example 4 , the amount of the decomposed product A produced varies from lot to lot, but in Example 5, there was no such variation, and the result was that the decomposed product A was not detected in any lot.
(Example 6)
Except that the hot water set temperature was 82 ° C., the same procedure as in Example 5 was performed, and when the loss on drying reached 4%, the drying was finished. The drying time was about 50 minutes.
As can be seen from Example 5 and Example 6, the drying time can be shortened from 80 to 90 minutes to 50 minutes by raising the warm water set temperature from 75 ° C. to 82 ° C. By increasing the hot water set temperature, the amount of decomposition product A did not increase, and an imidafenacin granulated product having the same quality was successfully produced in a short time.

Claims (9)

A method for producing a granulated product containing imidafenacin,
A method for producing a granulated product obtained through the following steps a) and b) via the drying step of either step c) -1 or c) -2. .
a) Step of dissolving or suspending imidafenacin in a pharmaceutically acceptable solvent to produce a solution or suspension b) One or more types of pharmaceutically acceptable fluidized in a fluid bed granulator Step c) -1 of spraying the solution or suspension obtained in step a) onto the excipient to produce a granulated product Step c) drying the granulated product obtained in step b) under reduced pressure ) -2 Step of drying the granulated product obtained in step b) within 100 minutes in a fluidized bed granulator The manufacturing method of Claim 1 whose drying process is c) -1. The production method according to claim 2, wherein drying under reduced pressure is performed under a condition of −0.15 MPaG or more and −0.05 MPaG or less. The production method according to claim 2 or 3, wherein the loss on drying at the end of drying is 2% or more and 7% or less. Drying under reduced pressure is performed using a vibration drier, The manufacturing method of Claim 2 thru | or 4 whose preset temperature range of a heat medium in a vibration drier is 60 degreeC or more and 90 degrees C or less. The manufacturing method according to claim 5, wherein the set temperature range of the heat medium is 80 ° C or higher and 90 ° C or lower, and the drying time is within 60 minutes. The manufacturing method according to claim 1, wherein the drying step is step c) -2, the supply temperature in the drying step is 75 ° C or higher and 100 ° C or lower, and the drying time of the granulated product is within 60 minutes. The production method according to claim 1, wherein a pharmaceutically acceptable binder is used in the solution or suspension of step a). A method for producing a tablet containing imidafenacin by mixing the granulated product obtained in claims 1 to 8 and a pharmaceutically acceptable additive, followed by compression molding.