JP6435363B2 - Method for producing granulated product containing imidafenacin by wet granulation method - Google Patents

Description

The present invention relates to a novel method for producing a granulated product 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.
Although the granulated material containing imidafenacin and a cellulosic excipient is disclosed in Patent Documents 1 to 3, all have a step of spraying a binder solution.

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 the present invention is to obtain an imidafenacin and a cellulose-based excipient-containing granulated product excellent in light stability by a simple method.

As a result of intensive studies, the inventors of the present invention can obtain a granulated product with excellent light stability without mixing or spraying a binder solution by mixing imidafenacin and a specific excipient in the presence of a solvent. As a result, the present invention has been completed. This production method is simple because the addition / spraying step of the binder solution can be omitted, and the addition / spraying binder does not need to be used separately, and is an inexpensive production method. The present invention includes the following inventions.
[1] A method for producing a granulated product containing imidafenacin,
The manufacturing method includes:
a) mixing imidafenacin, a cellulosic excipient, one or more pharmaceutically acceptable non-cellulosic excipients, and a pharmaceutically acceptable solvent;
b) does not include adding or spraying a pharmaceutically acceptable binder solution or suspension;
The manufacturing method of the said granulated material.
[2] The production method according to [1], wherein the step a) according to [1] includes the following step a) -1, step a) -2 and step a) -3.
a) -1 Dissolving or suspending imidafenacin in a pharmaceutically acceptable solvent to produce an imidafenacin solution or suspension;
a) -2 Step of mixing a cellulosic excipient and one or more pharmaceutically acceptable non-cellulosic excipients to obtain a powder mixture a) -3 During fluid bed granulation, a) Step a) according to Step [3] [1], in which the powder mixture obtained in -2 is fluidized and the imidafenacin solution or suspension obtained in Step a) -1 is added or sprayed thereto. The production method a) -4 imidafenacin, cellulosic excipient, and one or more pharmaceutically acceptable non-containing substances according to [1], comprising the following steps a) -4 and a) -5 Step a) -5 of mixing a cellulosic excipient to obtain a powder mixture In a fluidized bed granulator, the powder mixture obtained in a) -4 is fluidized and a pharmaceutically acceptable solvent is added thereto. Or spraying step [4] imidafenacin, starches, cellulosic excipients, and A granulated product consisting only of antioxidants.
[5] A granulated product comprising only imidafenacin, partially pregelatinized starch, crystalline cellulose and an antioxidant.
[6] An oral solid preparation containing a granulated product composed of imidafenacin, partially pregelatinized starch, crystalline cellulose and an antioxidant, and coated with a coating agent containing iron sesquioxide.

According to the present invention, it is not necessary to spray the binder solution, and a granulated product having excellent light stability can be produced by a simpler method than the conventionally known wet 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 0.025 to 0.25 mg, and particularly preferably 0.1 mg.

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. Etc.
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 viewpoints of fluidity and moldability, the cellulose-based excipient is 1 to 10 parts by weight, more preferably 2 to 7 parts by weight, still more preferably 3 to 5 parts by weight, with respect to 1 part by weight of starches. More preferably, 4 parts by mass are used.

In the present invention, pharmaceutically acceptable binders include crystalline cellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, celluloses such as ethylcellulose and methylcellulose, povidone, polyvinyl acetal diethylaminoacetate, saponified polyvinyl alcohol, polyvinyl alcohol moiety. 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 copolymer dispersions, etc. Acrylic polymer materials such as stearyl alcohol, gelatin, dextrin, gum arabic, pullulan, macrogol, starch, etc.

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.

In this invention, an antioxidant is a substance added in order to suppress the oxidation of a component, and prevents oxidation of a component by being oxidized on its behalf. For example, tocopherol derivatives such as tocopherol, d-δ-tocopherol, or tocopherol acetate hydroquinone, hydroquinone, sodium sulfite, ascorbic acid, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, alpha thioglycerin, sodium edetate, Erythorbic acid, cysteine hydrochloride, dry sodium sulfite, citric acid hydrate, potassium dichloroisocyanurate, dibutylhydroxytoluene (BHT), soy lecithin, sodium thioglycolate, sodium thiomalate, natural vitamin E, concentrated mixed tocopherol, Ascorbic palmitate, sodium pyrosulfite, butylhydroxyanisole, 1,3-butylene glycol, benzotriazole, penta Risurichiru - tetrakis (3- (3,5-di -t- butyl-4-hydroxyphenyl) propionate), propyl gallate, 2-mercaptobenzimidazole, L- cysteine, sodium citrate. In view of exhibiting the photostability effect of imidafenacin, tocopherol derivatives, hydroquinone, and BHT are preferable, and hydroquinone is more preferable.

The granulated product of the present invention can be produced by a wet granulation method. By producing by a wet granulation method, an imidafenacin-containing granulated product having excellent light stability can be obtained. In the present invention, the wet granulation method is a method in which a pharmaceutically acceptable solvent is added or sprayed to a pharmaceutical mixture, the pharmaceutical particles are aggregated, granulated, dried, classified and granulated. In general, when a granulated product is produced by a wet granulation method, it is often necessary to add or spray a binder solution or suspension, but in the case of the present invention, it is not necessary to use a binder solution. It is.

By producing an imidafenacin granulated product by a wet granulation method, a decrease in the content of imidafenacin can be suppressed. Examples of the wet granulation method include a fluidized bed granulation method, an agitation granulation method, an extrusion granulation method, a rolling granulation method, a pulverization granulation method, and a spray drying granulation method depending on the granulation mechanism. The fluidized bed granulation method is preferable in that a preparation that does not change in color tone and disintegration immediately after production is obtained.

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

When it is set as the tablet containing the granulated material of this invention, arbitrary pharmaceutically acceptable additives can be included. 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, an excipient | filler, a disintegrating agent, a lubricant agent, a coating agent, a coloring agent, a brightener, a sweetening agent, a corrigent, a fragrance | flavor, etc. are 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 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, hydroxypropylmethylcellulose is preferred.
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.

EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited by these Examples.
(Production Example 1)
The raw powder of imidafenacin was pulverized using a jet mill (Jet Mill 100AS) under the following conditions to obtain a pulverized imidafenacin. Table 1 shows the particle size distribution measurement results of imidafenacin (unground product) before pulverization and imidafenacin (ground product) after pulverization.
Grinding conditions During raw powder supply: Amount of pulverized gas using sieve (aperture 1700 μm): 63 to 64 Nm ² / h
Grinding pressure: 4.5-5.0 kg / cm ²
Bulk powder supply pressure: 5.7 kg / cm ²

(Comparative Example 1)
For each tablet, 0.025 mg of imidafenacin (ground product) and 15.945 mg of partially pregelatinized starch were added and mixed, and 63.79 mg of crystalline cellulose was added and mixed. Furthermore, 0.24 mg of magnesium stearate was added and mixed, and tableted to obtain an uncoated tablet. The obtained uncoated tablet was coated with 4 mg of hydroxypropylmethylcellulose 2910, and 0.002 mg of carnauba wax was added and mixed to obtain a film-coated tablet.
Example 1
For each tablet, 19.2 mg of partially pregelatinized starch, 76.475 mg of crystalline cellulose and 0.025 mg of imidafenacin (unground product) are taken, and using a fluidized bed granulator (Flow coater FGB-1, Freund Sangyo), This was sprayed with an aqueous ethanol solution (spraying liquid speed of about 50 mL / min) to obtain an imidafenacin granulated product. After this imidafenacin granulated product was sieved and sized, 0.3 mg of magnesium stearate was added and mixed, and tableted to obtain an uncoated tablet. The obtained uncoated tablet was coated with 4 mg of hydroxypropylmethylcellulose 2910, and 0.002 mg of carnauba wax was added and mixed to obtain a film-coated tablet.
(Example 2)
Take 19.2 mg of partially pregelatinized starch and 76.475 mg of crystalline cellulose per tablet, and use a fluidized bed granulator (Flow coater FGB-1, Freund Sangyo) to add imidafenacin (unground product) 0.025 mg A corresponding ethanol aqueous solution was sprayed (spraying liquid speed of about 50 mL / min) to obtain an imidafenacin granulated product. After this imidafenacin granulated product was sieved and sized, 0.3 mg of magnesium stearate was added and mixed, and tableted to obtain an uncoated tablet. The obtained uncoated tablet was coated with 4 mg of hydroxypropylmethylcellulose 2910, and 0.002 mg of carnauba wax was added and mixed to obtain a film-coated tablet.
Example 3
Take 19.2 mg of partially pregelatinized starch and 76.225 mg of crystalline cellulose per tablet and use a fluidized bed granulator (Flow Coater FGB-1, Freund Sangyo) to add it to 0.25 mg of hydroquinone and imidafenacin (not yet) Grinded product) An aqueous ethanol solution equivalent to 0.025 mg was sprayed (spraying liquid speed of about 50 mL / min) to obtain an imidafenacin granulated product. After this imidafenacin granulated product was sieved and sized, 0.3 mg of magnesium stearate was added and mixed, and tableted to obtain an uncoated tablet. The obtained uncoated tablet was coated with 4 mg of hydroxypropylmethylcellulose 2910, and 0.002 mg of carnauba wax was added and mixed to obtain a film-coated tablet.
(Example 4)
Take 19.2 mg of partially pregelatinized starch and 76.225 mg of crystalline cellulose per tablet and use a fluidized bed granulator (Flow coater FGB-1, Freund Sangyo) to add 0.25 mg of dibutylhydroxytoluene and imidafenacin (Unground product) An aqueous ethanol solution equivalent to 0.025 mg was sprayed (spraying liquid speed of about 50 mL / min) to obtain an imidafenacin granulated product. After this imidafenacin granulated product was sieved and sized, 0.3 mg of magnesium stearate was added and mixed, and tableted to obtain an uncoated tablet. The obtained uncoated tablet was coated with 4 mg of hydroxypropylmethylcellulose 2910, and 0.002 mg of carnauba wax was added and mixed to obtain a film-coated tablet.
(Example 5)
Take 19.2 mg of partially pregelatinized starch and 75.975 mg of crystalline cellulose per tablet and use a fluid bed granulator (Flow coater FGB-1, Freund Sangyo) to add 0.5 mg of dibutylhydroxytoluene and imidafenacin (Unground product) An aqueous ethanol solution equivalent to 0.025 mg was sprayed (spraying liquid speed of about 50 mL / min) to obtain an imidafenacin granulated product. After this imidafenacin granulated product was sieved and sized, 0.3 mg of magnesium stearate was added and mixed, and tableted to obtain an uncoated tablet. The obtained uncoated tablet was coated with 4 mg of hydroxypropylmethylcellulose 2910, and 0.002 mg of carnauba wax was added and mixed to obtain a film-coated tablet.
(Example 6)
For each tablet, 19.2 mg of partially pregelatinized starch and 76.225 mg of crystalline cellulose are taken, and using a fluid bed granulator (Flow coater FGB-1, Freund Sangyo), this is equivalent to 0.25 mg of tocopherol acetate and imidafenacin ( (Unground product) An aqueous ethanol solution equivalent to 0.025 mg was sprayed (spraying liquid speed: about 50 mL / min) to obtain an imidafenacin granulated product. After this imidafenacin granulated product was sieved and sized, 0.3 mg of magnesium stearate was added and mixed, and tableted to obtain an uncoated tablet. The obtained uncoated tablet was coated with 4 mg of hydroxypropylmethylcellulose 2910, and 0.002 mg of carnauba wax was added and mixed to obtain a film-coated tablet.
(Example 7)
For each tablet, 19.2 mg of partially pregelatinized starch and 75.975 mg of crystalline cellulose are taken, and using a fluidized bed granulator (Flow coater FGB-1, Freund Sangyo), this is equivalent to 0.5 mg of tocopherol acetate and imidafenacin ( (Unground product) An aqueous ethanol solution equivalent to 0.025 mg was sprayed (spraying liquid speed: about 50 mL / min) to obtain an imidafenacin granulated product. After this imidafenacin granulated product was sieved and sized, 0.3 mg of magnesium stearate was added and mixed, and tableted to obtain an uncoated tablet. The obtained uncoated tablet was coated with 4 mg of hydroxypropylmethylcellulose 2910, and 0.002 mg of carnauba wax was added and mixed to obtain a film-coated tablet.
(Example 8)
Take 19.2 mg of partially pregelatinized starch and 76.475 mg of crystalline cellulose per tablet, and use a fluidized bed granulator (Flow coater FGB-5, Freund Sangyo) to add 0.025 mg of imidafenacin (unground product). A corresponding ethanol aqueous solution was sprayed (spraying liquid speed of about 50 mL / min) to obtain an imidafenacin granulated product. After this imidafenacin granulated product was sieved and sized, 0.3 mg of magnesium stearate was added and mixed, and tableted to obtain an uncoated tablet. The obtained uncoated tablet was coated with 4 mg of hydroxypropylmethylcellulose 2910, and 0.002 mg of carnauba wax was added and mixed to obtain a film-coated tablet.
Example 9
The plain tablet obtained in Example 8 was coated with an aqueous suspension containing hydroxypropyl methylcellulose 2910 equivalent to 7.2 mg and titanium oxide equivalent to 0.8 mg, 0.002 mg of carnauba wax was added and mixed, and film coating was performed. I got a tablet.
(Example 10)
The plain tablet obtained in Example 8 was coated with an aqueous suspension containing 7.2 mg of hydroxypropylmethylcellulose 2910 and 0.8 mg of iron sesquioxide, and 0.002 mg of carnauba wax was added and mixed to form a film. Coated tablets were obtained.
(Test Example 1) Light Stability Test For the tablets of Examples 1 to 10 and Comparative Example 1, degradation products up to 1,200,000 Lux · hr of light irradiation were measured by a high performance liquid chromatograph method without packaging. The quantification of the decomposed product was evaluated by liquid chromatography (HPLC method).
Storage condition Light source: White fluorescent lamp Illuminance: 4200 Lux
Storage form: glass petri dish (with lid)
Temperature and humidity: Naruki HPLC condition detector: UV absorptiometer (measurement wavelength: 227 nm)
Column: Octadecylsilylated silica gel (average particle size 5 μm, inner diameter 5 mm × length 150 mm) (Wakosil-II 5C18HG)
Column humidity: Constant temperature mobile phase around 40 ° C:
Liquid A: 6 mmol / L dilute phosphoric acid (1 → 1000) / acetonitrile mixture (7: 3) containing sodium 1-octanesulfonate
B liquid: Acetonitrile 0-40 minutes from A liquid 90% B liquid 10% to A liquid 60% B liquid 40% After linear gradient 40 minutes, B liquid 100%
(Test example 2) Content uniformity test About the tablet of Examples 1-2 and the comparative example 1, it carried out according to the content uniformity test as described in the 13th revision Japanese Pharmacopoeia.
Table 2 summarizes the results of Test Examples 1 and 2 for Comparative Example 1 and Examples 1-2.

As can be seen from Table 2, imidafenacin is very unstable when directly compressed, and a decomposition product of 13% or more is produced (Comparative Example 1). On the other hand, by carrying out wet granulation using a solvent, the light stability of imidafenacin is remarkably improved, and the amount of the main degradation product of imidafenacin can be suppressed to 1/4 compared with the case of direct tableting (Example 1). ~ 2). In addition, imidafenacin is dissolved in an aqueous ethanol solution and sprayed onto the excipient rather than being mixed with the excipient in a powder state (Example 1) in that a preparation with good content uniformity is obtained (Example 1). Example 2) is preferred. In addition, when wet granulation is usually performed, a step of adding or spraying a binder solution is necessary, but in the present invention, such a step is unnecessary.
The results of Test Example 1 are summarized in Table 3 for Examples 2-7.

As can be seen from Table 3, by further adding an antioxidant such as hydroquinone (Example 3), dibutylhydroxytoluene (Examples 4 to 5), tocopherol acetate (Examples 6 to 7), an excellent light stabilization effect Demonstrate.
The results of Test Example 1 are summarized in Table 4 for Examples 8-10.

As can be seen from Table 4, when the coating is performed with iron sesquioxide (Example 10), the light stabilization effect is more excellent than when the coating is performed with titanium oxide (Example 9).

According to the present invention, imidafenacin and cellulosic excipient granule excellent in photostability can be produced by a simpler method than the conventionally known wet granulation method, which is industrially useful. is there.

Claims (6)

A method for producing a granulated product containing imidafenacin,
The manufacturing method includes:
a) mixing imidafenacin, a cellulosic excipient, one or more pharmaceutically acceptable non-cellulosic excipients, and a pharmaceutically acceptable solvent;
b) a solution or suspension of a pharmaceutically acceptable binding agent, free of added or sprayed to step,
Here, the cellulose-based excipient is selected from the group consisting of crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium and low-substituted hydroxypropylcellulose,
The non-cellulosic excipient is selected from the group consisting of lactose, sucrose, D-sorbitol, mannitol, partially pregelatinized starch and corn starch;
The binder is crystalline cellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, ethylcellulose, methylcellulose, povidone, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol completely saponified product, polyvinyl alcohol partial saponified product, carboxyvinyl polymer, polyvinyl chloride, aminoalkyl methacrylate. Copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer S, methacrylic acid copolymer LD, ethyl acrylate / methyl methacrylate copolymer dispersion, stearyl alcohol, gelatin, dextrin, gum arabic, pullulan, macrogol and Selected from the group consisting of starch,
The manufacturing method of the said granulated material. The production method according to claim 1, wherein step a) comprises the following step a) -1, step a) -2 and step a) -3 .
a) -1 Dissolving or suspending imidafenacin in a pharmaceutically acceptable solvent to produce an imidafenacin solution or suspension;
a) -2 Step of mixing a cellulosic excipient and one or more pharmaceutically acceptable non-cellulosic excipients to obtain a powder mixture ,
a) -3 In the fluidized bed granulation, the powder mixture obtained in a) -2 is fluidized, and the imidafenacin solution or suspension obtained in step a) -1 is added or sprayed thereto . The production method according to claim 1, wherein step a) comprises the following steps a) -4 and a) -5 ;
a) -4 A step of mixing imidafenacin , a cellulosic excipient, and one or more pharmaceutically acceptable non-cellulosic excipients to obtain a powder mixture ,
a) -5 Flowing the powder mixture obtained in a) -4 in a fluidized bed granulator and adding or spraying a pharmaceutically acceptable solvent thereto . A group consisting of imidafenacin and starches selected from the group consisting of partially pregelatinized starch and corn starch , crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium and low-substituted hydroxypropylcellulose cellulosic excipients selected from, as well as granules consisting only of antioxidants. A granulated product consisting of imidafenacin, partially pregelatinized starch, crystalline cellulose and an antioxidant. An oral solid preparation containing a granulated product composed of imidafenacin, partially pregelatinized starch, crystalline cellulose and an antioxidant, and coated with a coating agent containing iron sesquioxide.