JP7093473B2 - Small tablets with excellent manufacturability and elution - Google Patents

Description

The present invention relates to a pharmaceutical composition containing imeglimin or a pharmaceutically acceptable salt thereof, which is a small tablet having excellent manufacturability and elution.

There are many patients with diabetes all over the world, and according to the 2017 IDF (International Diabetes Federation) announcement, one in 11 adults in the world is currently diabetic, and the total number of patients in 2015. The number will increase by 10 million to 425 million, and is expected to increase to about 700 million by 2045. In Japan, in particular, most diabetic patients are type 2 diabetic patients, and it is estimated that there are 3,166,000 diabetic patients.

Imeglimin is widely known as a therapeutic agent for diabetes and is used for the treatment of type 2 diabetes. However, it is necessary to orally administer a large amount of 200 to 4000 mg daily (Patent Document 1), and there is a problem in the method of oral administration thereof. was there.

Patent Document 1 discloses a film-coated tablet having an imeglimin content of 83.4% as an orally-administered preparation of imeglimin, but does not disclose a specific production method thereof. Further, Patent Document 2 discloses a tablet having an imeglimin content of 87.0%, which is produced on a 1 kg scale by using a direct tableting method in which a prescription component is mixed and tableted as an orally administered preparation of imeglimin. There is. However, although the direct tableting method is easy to manufacture on a small scale, the powder compression time during tableting decreases as the manufacturing scale increases, and if the drug's compression moldability is poor, tableting problems may occur. It may occur and it may be difficult to lock. Therefore, a method capable of stably producing an oral tablet of imeglimin on a large scale has not been substantially known.

WO2011 / 154497 WO2010 / 06632

The subject of the present invention is a miniaturized tablet containing a high content of imeglimin per tablet and having excellent elution in the administration of imeglimin having a very large daily dose, and production thereof that can be stably supplied. To provide a method.

As a result of diligent studies, the present inventors showed excellent elution by using a disintegrant and a high proportion of hydroxypropyl cellulose, polyvinyl alcohol or / and hydroxypropylmethyl cellulose as a water-soluble binder. Moreover, it was found that a very miniaturized imeglimin tablet can be stably produced. It was also found that the fluidized bed granulation method is used as the production method.

That is, the present invention is as follows.

[Item 1]
One or more binders selected from the group consisting of (1) imeglimin or a pharmaceutically acceptable salt thereof in an amount of 84 to 95 wt%, (2) hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose, and a binder thereof. (3) Tablets containing a disintegrant.

[Item 2]
(1) The tablet according to Item 1, which contains 88 to 95 wt% of imeglimin or a pharmaceutically acceptable salt thereof.
Or [Item 2']
One or more binders selected from the group consisting of (1) imeglimin or a pharmaceutically acceptable salt thereof in an amount of 88 to 95 wt%, (2) hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose, and a binder thereof. (3) Tablets containing a disintegrant.

[Item 3]
(1) The tablet according to Item 1, which contains 90 to 95 wt% of imeglimin or a pharmaceutically acceptable salt thereof.

[Item 4]
(1) The tablet according to Item 1 or 2, which contains 90 to 92 wt% of imeglimin or a pharmaceutically acceptable salt thereof.

[Item 5]
(3) The tablet according to Item 1 or 2, which contains 0.2 to 7.5 wt% of a disintegrant.

[Item 6]
(3) The tablet according to any one of Items 1 to 5, which contains 0.2 to 5.0 wt% of a disintegrant.

[Item 7]
(3) The tablet according to any one of Items 1 to 6, which contains 0.2 to 4.0 wt% of a disintegrant.

[Item 8]
(3) The tablet according to any one of Items 1 to 7, which contains 0.2 to 3.0 wt% of a disintegrant.

[Item 9]
(3) The tablet according to any one of Items 1 to 8, which contains 0.2 to 2.0 wt% of a disintegrant.

[Item 10]
(3) The tablet according to Item 1 or 2, which contains 0.5 to 7.5 wt% of a disintegrant.

[Item 11]
(3) The tablet according to any one of Items 1 to 4 and 10, which contains 0.5 to 5.0 wt% of a disintegrant.

[Item 12]
(3) The tablet according to any one of Items 1 to 4, 10 and 11, which contains 0.5 to 4.0 wt% of a disintegrant.

[Item 13]
(3) The tablet according to any one of Items 1 to 4, 10 to 12, which contains 0.5 to 3.0 wt% of a disintegrant.

[Item 14]
(3) The tablet according to any one of Items 1 to 4, 10 to 13, which contains 0.5 to 2.0 wt% of a disintegrant.

[Item 15]
(2) Any one of Items 1 to 14 containing 4.5 to 7.0 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose. The tablets described in.

[Item 16]
(2) Any one of Items 1 to 15 containing 4.5 to 6.0 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose. The tablets described in.

[Item 17]
(2) Any one of Items 1 to 16 containing 4.5 to 5.5 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose. The tablets described in.

[Item 18]
(2) Item 1 to Item 17 containing 4.8 to 5.5 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose. The tablets described in.

[Item 19]
Item 6. The tablet according to any one of Items 1 to 18, wherein the hydroxypropyl cellulose has a viscosity of 2.0 to 400 mPa · s.

[Item 20]
Item 6. The tablet according to any one of Items 1 to 19, wherein the hydroxypropyl cellulose has a viscosity of 6.0 to 400 mPa · s.

[Item 21]
Item 6. The tablet according to any one of Items 1 to 20, wherein the polyvinyl alcohol has a viscosity of 3.4 to 9.2 mPa · s.

[Item 22]
Item 6. The tablet according to any one of Items 1 to 21, wherein the polyvinyl alcohol has a viscosity of 4.3 to 5.8 mPa · s.

[Item 23]
Item 6. The tablet according to any one of Items 1 to 22, wherein the viscosity of hydroxypropylmethyl cellulose is 4.0 to 12.0 mPa · s.

[Item 24]
Item 6. The tablet according to any one of Items 1 to 23, wherein the viscosity of hydroxypropylmethyl cellulose is 4.0 to 6.0 mPa · s.

[Item 25]
Item 6. The tablet according to any one of Items 1 to 24, wherein the viscosity of hydroxypropylmethyl cellulose is 4.5 to 6.0 mPa · s.

[Item 26]
Items 1 to 19 contain hydroxypropyl cellulose having a viscosity of 2.0 to 2.9 mPa · s in the range of 3.5 wt% or less and hydroxypropyl cellulose having a viscosity of 150 to 400 mPa · s in the range of 1.5 wt% or less. The tablet according to any one of 21 to 25.

[Item 27]
(2) The tablet according to any one of Items 1 to 22, 26, wherein the binder is one or two selected from the group consisting of hydroxypropyl cellulose and polyvinyl alcohol.

[Item 28]
(2) The tablet according to any one of Items 1 to 20 and 23 to 26, wherein the binder is one or two selected from the group consisting of hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

[Item 29]
(2) The tablet according to any one of Items 1 to 20 and 26 to 28, wherein the binder is hydroxypropyl cellulose.

[Item 30]
(3) The tablet according to any one of Items 1 to 29, wherein the disintegrant is one or more selected from the group consisting of sodium croscarmellose, sodium starch glycolate and crospopidone.

[Item 31]
(3) The tablet according to any one of Items 1 to 30, wherein the disintegrant is croscarmellose sodium.

[Item 32]
Item 2. The tablet according to any one of Items 1 to 31, which is produced by using a fluidized bed granulation method.

[Item 33]
Item 6. The method for producing a tablet according to any one of Items 1 to 31, which is produced by using a fluidized bed granulation method.

[Item 34]
Item 6. The tablet according to any one of Items 1 to 18, which is produced by using a fluidized bed granulation method.

[Item 35]
Item 6. The method for producing a tablet according to any one of Items 1 to 18, which is produced by using a fluidized bed granulation method.

[Item 36]
(1) Imeglycin or a pharmaceutically acceptable salt thereof, (2) one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose, and (3) disintegrant. Item 3. The method for producing a tablet according to Item 35, which comprises a step of producing granulated granules containing the above-mentioned granules by using a fluidized bed granulation method.

[Item 37]
One or two selected from the group consisting of (2) hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose in a powder containing (1) imeglycin or a pharmaceutically acceptable salt thereof and (3) a disintegrant. Item 3. The method for producing a tablet according to Item 36, which comprises a step of adding the above binder and producing by using a fluidized layer granulation method.

[Item 38]
Item 6. The production method according to Item 36 or 37, further comprising a tableting step or a film coating step.

[Item 39]
Item 38. The production method according to Item 38, wherein any of the fluidized bed granulation step, the tableting step, and the film coating step is manufactured with a production amount of 10 kg or more.

[Item 40]
Item 38. The production method according to Item 38, wherein any of the fluidized bed granulation step, the tableting step, and the film coating step is manufactured with a production amount of 30 kg or more.

[Item 41]
Item 38. The production method according to Item 38, wherein any of the fluidized bed granulation step, the tableting step, and the film coating step is manufactured with a production amount of 50 kg or more.

The imeglimin composition in the present invention has poor compression moldability by being produced by a fluidized bed granulation method using a disintegrant and a large amount of hydroxypropyl cellulose, polyvinyl alcohol or / and hydroxypropyl methyl cellulose as a binder. Despite the extremely high content of imeglimin, it has manufacturability that enables stable supply on a production scale. In addition, the imeglimin composition in the present invention has good dissolution property, and it is possible to provide an oral preparation having excellent bioavailability. Furthermore, the imeglimin composition in the present invention has a very high content of imeglimin, so that it is possible to provide a miniaturized tablet that can be easily taken.

Hereinafter, the present invention will be described in more detail.

(A) Tablets The tablets of the present invention are uncoated tablets, film-coated tablets in which the surface of the uncoated tablets is coated with a film (sometimes referred to as FC tablets in the present specification), and the surface of the uncoated tablets is coated with sugar. It contains a sugar-coated tablet-like form, and is preferably an uncoated tablet or a film-coated tablet. The uncoated tablet contains an imeglimin-containing composition, and may optionally contain other additives to the extent that the function of the present invention is not lost. The imeglimin-containing composition is selected from the group consisting of (1) imeglimin or a pharmaceutically acceptable salt thereof, and (2) hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose as a water-soluble polymer binder 1). Seeds or two or more, (3) containing disintegrants, optionally containing excipients and lubricants, and optionally other additives to the extent that they do not impair the functionality of the invention. It may be included. The film coating contains a film coating agent, and may optionally contain other additives to the extent that the function of the present invention is not lost.

(B) Imeglimin "Imeglimin" in the present invention is a compound known as a therapeutic agent for diabetes, and its chemical names are (6R) ^-N2 , ^N2 , 6-trimethyl-3,6-dihydro-1. , 3,5-Triazine-2,4-Diamine (CAS Registry Number: 775351-65-0) and has the following chemical structure. In addition, "imeglimin" is (6S) -N ² , N ² , 6-trimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine (CAS registry number: 1251468-04-8). Also includes.

The present invention includes all forms of imeglimin (eg, tautomers, amorphous, crystalline, various crystalline polymorphs, etc.), including optical isomers thereof or mixtures thereof. The R-form of the mixture is preferably contained in an amount of 90 wt% or more, 95 wt% or more, 97 wt% or more, and 99 wt% or more.
The imeglimin used in the present invention may be pulverized to a desired particle size, if necessary. The average particle size (50% particle size, D50) based on the volume ratio may be, for example, in the range of 11 to 274 μm, preferably 11 μm to 169 μm.

The composition ratio of imeglimin in the tablet of the present invention is 84 wt% or more, preferably 88 wt% or more, and 90 wt% or more. The composition ratio of imeglimin in the present invention is preferably 90 wt% or less, 92 wt% or less, and 95 wt% or less. The content of imeglimin or a pharmaceutically acceptable salt thereof contained in one tablet of the tablet of the present invention is preferably 500 mg.

Pharmaceutically acceptable salts of imeglimin include, but are not limited to, acid addition salts. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate and phosphate, or citrate, oxalate and phthalate. Fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonic acid Examples thereof include organic acid salts such as salts and camphor sulfonates, and further include amino acid salts with acidic amino acids. The pharmaceutically acceptable salt of imeglimin is preferably hydrochloride.

(C) Hydroxypropyl Cellulose The viscosity of hydroxypropyl cellulose in the present invention is not particularly limited, but has 2.0 to 400 mPa · s, preferably 6.0 to 400 mPa · s.
The composition ratio of hydroxypropyl cellulose in the tablet of the present invention is not particularly limited, but hydroxypropyl cellulose having a viscosity of 2.0 to 2.9 mPa · s is 3.5 wt% or less and 150 to 400 mPa · s. It is preferable to contain hydroxypropyl cellulose in the range of 1.5 wt% or less.
Hydroxypropyl cellulose is preferably contained in an amount of 4.5 wt% or more, 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. Hydroxypropyl cellulose is preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less%, 5 7.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, 6.0 wt% or less, 6.1 wt% or less, 6.2 wt% or less, 6.3 wt% or less, 6.4 wt% or less, 6.5 wt % Or less, 6.6 wt% or less, 6.7 wt% or less, 6.8 wt% or less, 6.9 wt% or less, 7.0 wt% or less.
Hydroxypropyl cellulose is more preferably contained in an amount of 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. Hydroxypropyl cellulose is more preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less, It includes 5.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, and 6.0 wt% or less.
Hydroxypropyl cellulose is most preferably contained in an amount of 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. Hydroxypropyl cellulose is most preferably contained in an amount of 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, and 5.5 wt% or less.

(D) Polyvinyl alcohol (polyvinyl alcohol-based resin)
The polyvinyl alcohol in the present invention is a polyvinyl alcohol-based resin and contains a polyvinyl alcohol derivative. It is preferably polyvinyl alcohol (PVA). Although not particularly limited, it is preferable to use a partially saponified product for polyvinyl alcohol (PVA). note that. A saponification degree of 97 mol% or more is called a complete saponification, and a saponification degree of 79 to 96 mol% is called a partial saponification.
The polyvinyl alcohol in the present invention is not particularly limited, but has 3.4 to 9.2 mPa · s, preferably 4.3 to 5.8 mPa · s, and more preferably 4.8 to 5.8 mPa · s. Have.
The polyvinyl alcohol in the tablet of the present invention preferably contains, for example, 4.5 wt% or more, 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. .. Polyvinyl alcohol is preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt%, 5.6 wt% or less, 5.7 wt. % Or less, 5.8 wt% or less, 5.9 wt% or less, 6.0 wt% or less, 6.1 wt% or less, 6.2 wt% or less, 6.3 wt% or less, 6.4 wt% or less, 6.5 wt% or less , 6.6 wt% or less, 6.7 wt% or less, 6.8 wt% or less, 6.9 wt% or less, 7.0 wt% or less.
Polyvinyl alcohol is more preferably contained in an amount of 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. Polyvinyl alcohol is more preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less%, 5 It includes 7.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, and 6.0 wt% or less.
Polyvinyl alcohol is most preferably contained in an amount of 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. Polyvinyl alcohol is most preferably contained in an amount of 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, and 5.5 wt% or less.
The polyvinyl alcohol-based resin in the present invention also includes, for example, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol graft copolymer and the like.

(E) Hydroxypropyl Methyl Cellulose The viscosity of hydroxypropylmethyl cellulose in the present invention is not particularly limited, but has 4.0 to 12.0 mPa · s, and is preferably 4.0 to 6.0 mPa · s. It has 5 to 6.0 mPa · s.
The hydroxypropylmethyl cellulose in the tablet of the present invention preferably contains 4.5 wt% or more, 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. The hydroxypropylmethyl cellulose is preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less, 5 7.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, 6.0 wt% or less, 6.1 wt% or less, 6.2 wt% or less, 6.3 wt% or less, 6.4 wt% or less, 6.5 wt % Or less, 6.6 wt% or less, 6.7 wt% or less, 6.8 wt% or less, 6.9 wt% or less, 7.0 wt% or less.
The hydroxypropylmethyl cellulose is more preferably contained in an amount of 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. The hydroxypropylmethyl cellulose is more preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less, It includes 5.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, and 6.0 wt% or less.
The hydroxypropylmethyl cellulose is most preferably contained in an amount of 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. The hydroxypropylmethyl cellulose is most preferably contained in an amount of 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, and 5.5 wt% or less.

(F) Disintegrant The disintegrant used in the present invention is necessary to prevent the drug from absorbing water and dissolving or solidifying during wet granulation, and to exhibit good fluidity in the manufacturing apparatus during granulation. .. In order to achieve miniaturization of tablets, it is desirable to show good water absorption and disintegration after tableting even when the content in the tablets is low.
The disintegrant used in the present invention is not particularly limited, but a disintegrant usually used in the formulation can be used. For example, starches, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, crospovidone, croscarmellose sodium, sodium carboxymethyl starch (also referred to as sodium starch glycolate) and the like can be mentioned. Further, two or more kinds of disintegrants may be used.
It is preferably crospovidone, croscarmellose sodium, carboxymethyl starch sodium, and more preferably croscarmellose sodium. The disintegrant in the tablet of the present invention preferably contains 0.1 wt% or more, 0.2 wt% or more, 0.5 wt% or more, 1.0 wt% or more, and 1.5 wt% or more. The disintegrant is preferably 7.5 wt% or less, 7.4 wt% or less, 7.3 wt% or less, 7.2 wt% or less, 7.1 wt% or less, 7.0 wt% or less, 6.9 wt% or less, 6. 8 wt% or less, 6.7 wt% or less, 6.6 wt% or less, 6.5 wt% or less, 6.4 wt% or less, 6.3 wt% or less, 6.2 wt% or less, 6.1 wt% or less, 6.0 wt% Below, 5.9 wt% or less, 5.8 wt% or less, 5.7 wt% or less, 5.6 wt% or less, 5.5 wt% or less, 5.0 wt% or less, 4.5 wt% or less, 4.0 wt% or less, It includes 3.5 wt% or less, 3.0 wt% or less, 2.5 wt% or less, and 2.0 wt% or less.

(G) Excipient The excipient used in the present invention is not particularly limited, but an excipient usually used in the formulation can be used. For example, crystalline cellulose, sugar, sugar alcohol and the like can be mentioned. Examples of the sugar or sugar alcohol include mannitol, erythritol, xylitol, maltitol, sorbitol, lactose, sucrose, trehalose and the like. In addition, the excipient may be used alone or in combination of two or more.
The content of the excipient is preferably 0.1 wt% or more, 0.5 wt% or more, 1.0 wt% or more, and 2.0 wt% or more. The content of the excipient is preferably 7.5 wt% or less, 7.4 wt% or less, 7.3 wt% or less, 7.2 wt% or less, 7.1 wt% or less, 7.0 wt% or less, 6.9 wt. % Or less, 6.8 wt% or less, 6.7 wt% or less, 6.6 wt% or less, 6.5 wt% or less, 6.4 wt% or less, 6.3 wt% or less, 6.2 wt% or less, 6.1 wt% or less , 6.0 wt% or less, 5.9 wt% or less, 5.8 wt% or less, 5.7 wt% or less, 5.6 wt% or less, 5.5 wt% or less, 5.0 wt% or less, 4.5 wt% or less, 4 .0 wt% or less, 3.5 wt% or less, 3.0 wt% or less, 2.5 wt% or less, 2.0 wt% or less.

(H) Lubricants In the present invention, a lubricant can be added. Lubricants prevent the drug substance and granules from adhering to the mortar at the time of tableting depending on the type of drug substance and granules, and are expected to efficiently produce tablets. The lubricant may be mixed with other components before tableting, or may be sprayed onto the mortar at the time of tableting. The lubricant used in the present invention is not particularly limited, and examples thereof include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, carnauba wax, and sucrose fatty acid ester. These lubricants can be used alone or in combination of two or more. The lubricant used in the present invention is preferably magnesium stearate.
The content of the lubricant is preferably 0.1 wt% or more, 0.2 wt% or more, 0.4 wt% or more, 0.6 wt%, 0.8 wt% or more, and 1.0 wt% or more. The content of the lubricant is preferably 4.0 wt% or less, 3.5 wt% or less, 3.0 wt% or less, 2.5 wt% or less, 2.0 wt% or less, 1.8 wt% or less, 1.6 wt. % Or less, 1.4 wt% or less, 1.2 wt% or less, 1.0 wt% or less.
The content of the lubricant is more preferably 0.4 wt% or more, 0.6 wt%, 0.8 wt% or more, and 1.0 wt% or more. The content of the lubricant is more preferably 2.0 wt% or less, 1.8 wt% or less, 1.6 wt% or less, 1.4 wt% or less, 1.2 wt% or less, and 1.0 wt% or less.

(I) Other Additives In addition to the above, other additives can be added to the tablets of the present invention to the extent that the functions of the present invention are not lost. Other additives include, for example, sweeteners, flavoring agents, flavoring agents, fragrances, fluidizing agents (eg Aerosil), antistatic agents, colorants, plasticizers, anti-aggregating agents, brightening agents (eg carnauba wax). , Talc), etc., but is not limited to these.

(J) Film coating agent Examples of the film coating agent used for film coating include hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol graft copolymer, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacryl. A combination of a base material such as acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer and a plasticizer such as polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin and glycerin fatty acid ester is However, it is not limited to this. Further, additives such as titanium oxide, iron oxide, talc, and a colorant can be added. Preferably, the base material is hypromellose, hydroxypropyl cellulose and polyvinyl alcohol, and the plasticizers are polyethylene glycol, propylene glycol and triethyl citrate.

"Excellent elution"
Excellent dissolution is preferably 80% or more, 85% or more, 90 at 30 minutes when the dissolution test of the prototype formulation is carried out under the following dissolution test conditions in accordance with the second method of the Japanese Pharmacopoeia dissolution test. It shows an elution rate of% or more and 95% or more, and preferably 97% or more, 98% or more, and 99% or more elution rate at 60 minutes. Further, at 60 minutes, the elution rate is preferably 103% or less, 102% or less, and 100% or less.
Test solution: Japanese Pharmacopoeia dissolution test 2nd solution Paddle rotation speed: 50 rpm
Test solution: 900 mL

"Manufacturing on a large scale"
The large-scale production in the present invention means that any one of the granulation step, the tableting step, and the film coating step is preferably 10 kg or more, 15 kg or more, 20 kg or more, 25 kg or more, 30 kg or more, 35 kg or more, 40 kg. As mentioned above, it is manufactured with a production amount (charged amount) of 45 kg or more and 50 kg or more.

"viscosity"
The viscosity of the polymer in the present invention refers to the viscosity when measuring a 2 wt% polymer aqueous solution at 20 ° C. using a B-type viscometer.
As a method for producing an imeglimin-containing composition contained in a tablet of the present invention, a granulation method capable of producing granules having excellent compression moldability in order to prevent tableting trouble and obtain a tablet having an appropriate hardness. Is desirable. For example, a fluidized bed granulation method can be mentioned, preferably a fluidized bed granulation method in which a binder solution is sprayed, but a fluidized bed granulation method in which a binder is partially added as a powder may be used.
The present invention is not limited to these, but the following is an example of a process for producing a film-coated tablet by, for example, a fluidized bed granulation method.

(1) Preparation of Hydroxypropyl Cellulose Aqueous Solution Hydroxypropyl cellulose is dissolved in purified water. The amount of hydroxypropyl cellulose is selected from, for example, 1 to 20 wt%, preferably 2 to 6.5 wt% with respect to the amount of purified water.

(2) Production of imeglimin-containing composition (fluidized bed granulation step)
Imeglimin, Aerosil and a disintegrant are charged in a fluidized bed granulator, and granulated while spraying the water-soluble polymer aqueous solution prepared in the above step (1).

(3) Drying of imeglimin-containing composition The above granulated product is dried under reduced pressure or normal pressure. This drying is performed so that the drying weight loss value measured at 80 ° C. with an infrared moisture meter or a halogen type moisture meter is, for example, within 3 wt%, preferably within 2 wt%.

(4) Blending of lubricant (mixing process)
A fluidizing agent and a lubricant are added to the imeglimin-containing composition dried in (3) above and mixed. For mixing, for example, a mixer classified as a stirring mixer is used. Specific examples thereof include a tumbler blender, a V blender, a double cone, and a bin tumbler. However, it is not limited to these.

(5) Locking (locking process)
The above mixture is beaten to prepare an uncoated tablet. Examples of the locking device include a locking machine classified as a rotary type.

(6) Film coating (film coating process)
A film coat is applied to the above-mentioned uncoated lock. Examples of the coating device include a device classified as a coating pan. Devices are preferably classified as a ventilated coating system.

(7) Drying the film-coated lock The film-coated lock is dried. Drying is carried out under reduced pressure or normal pressure so that the drying weight loss value measured at 80 ° C. with an infrared moisture meter or a halogen type moisture meter is, for example, 3 wt% or less, preferably 2 wt% or less.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Unless otherwise specified, the following agents and additives were used in the present examples and test examples.
Imeglycin hydrochloride: Dainippon Sumitomo Pharmaceutical Co., Ltd. Crystalline cellulose (Theoras ^TM PH-101): Asahi Kasei Co., Ltd. Light anhydrous silicic acid (AEROSIL ^TM 200): Nippon Aerosil Co., Ltd. Croscarmellose sodium (Ac-Di-Sol ^TM SD-) 711): FMC Health and Nutrition
Hydroxypropyl cellulose (HPC-SSL / 2.0-2.9 mPa · s ^{Note 1)} ): Nippon Soda Co., Ltd. Hydroxypropyl cellulose (HPC-L / 6.0-10.0 mPa · s ^{Note 1} )): Nippon Soda Hydroxypropyl Cellulose Co., Ltd. (HPC-M / 150-400 mPa · s ^{Note 1)} ): Nippon Soda Co., Ltd. Hypromellose (Hydroxypropyl Methyl Cellulose) (TC-5R ^TM / 6 mPa · s ^{Note 2)} ): Shinetsu Chemical Industry Co., Ltd. Povidon (Kollidon ^TM K30 / 5.5-8.5 mPa · s ^{Note 3)} ): BASF
Polyvinyl alcohol (Gohsenol ^TM EG-05P / 4.8-5.8 mPa · s ^{Note 4)} ): Mitsubishi Chemical Corporation Magnesium stearate (magnesium stearate (vegetable)): Taihei Chemical Corporation OPADRY ^TM tm 07F28588 WHITE : Japan Talc GK (luxury talc MSP): Japan Talc Co., Ltd. Cross Povidon (Kollidon ^TM CL): BASF
Sodium Starch Glycolate (Primogel ^TM ): DFE Pharma
Note 1) Manufacturer's catalog value at 20 ° C and 2% solution.
Note 2) Manufacturer's catalog value at 20 ° C and 2% solution.
Note 3) Manufacturer's catalog value at 20 ° C and 10% solution.
Note 4) Manufacturer's catalog value at 20 ° C and 4% solution.

Example 1: Tablet containing 500 mg of imeglimin hydrochloride (1)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 1-1 were produced.

B. Production Method (1) Preparation of 5 wt% Hydroxypropyl Cellulose Solution (1) 1900 g of purified water was placed in a beaker made of SUS, and 100 g of HPC-L was gradually added and dissolved while stirring. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 5 wt% hydroxypropyl cellulose solution (1).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 1-2 and the production conditions shown in Table 1-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 1-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type manufactured by Paulek Co., Ltd.) and exhausted. Mixing was carried out while flowing until the temperature reached 35 ° C. Subsequently, the 5 wt% hydroxypropyl cellulose solution (1) of the charged amount shown in Table 1-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 1-4. Granulated granules containing the amount of imeglimin hydrochloride shown in Table 1-4 are added to the V10 type container, and then the amount of light anhydrous silicic acid shown in Table 1-4 is added to the mixer ( Using Tsutsui Rikagaku Kikai Co., Ltd., S-5 type), mixing was performed at 40 rpm for 10 minutes. Subsequently, magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 1-5. It was locked and an uncoated tablet was manufactured.

Example 2: Tablet containing 500 mg of imeglimin hydrochloride (2)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 2-1 were produced.

B. Production Method (1) Preparation of 5 wt% Hydroxypropyl Cellulose Solution (2) 1900 g of purified water was placed in a beaker made of SUS, and 100 g of HPC-L was gradually added and dissolved while stirring. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 5 wt% hydroxypropyl cellulose solution (2).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 2-2 and the production conditions shown in Table 2-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 2-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type manufactured by Paulek Co., Ltd.) and exhausted. Mixing was carried out while flowing until the temperature reached 35 ° C. Subsequently, the 5 wt% hydroxypropyl cellulose solution (2) of the charged amount shown in Table 2-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.9 mm and a rotation speed of 900 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 2-4. Granulated granules containing the imeglimin hydrochloride in the amount shown in Table 2-4 are put into a V2 type container, and then the light anhydrous silicic acid in the amount shown in Table 2-4 is added to the mixer ( Using Tsutsui Rikagaku Kikai Co., Ltd., S-3 type), mixing was performed at 40 rpm for 10 minutes. Subsequently, magnesium stearate was put into a V2 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-3 type).

(4) Manufacture of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locking machine (manufactured by Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 2-5. It was locked and an uncoated tablet was manufactured.

Example 3: Tablets containing 500 mg of imeglimin hydrochloride (3)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 3-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (1) Take 1920 g of purified water in a beaker made of SUS, gradually add 56 g of HPC-SSL while stirring, and then add 24 g of HPC-M. And dissolved. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (1).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 3-2 and the production conditions shown in Table 3-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 3-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type manufactured by Paulek Co., Ltd.) and exhausted. Mixing was carried out while flowing until the temperature reached 35 ° C. Subsequently, the 4 wt% hydroxypropyl cellulose solution (1) of the charged amount shown in Table 3-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 3-4. Granulated granules containing the imeglimin hydrochloride in the amount shown in Table 3-4 are put into a V10 type container, and then the light anhydrous silicic acid in the amount shown in Table 3-4 is added to the mixer ( Using Tsutsui Rikagaku Kikai Co., Ltd., S-5 type), mixing was performed at 40 rpm for 10 minutes. Subsequently, magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).

(4) Manufacture of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locking machine (manufactured by Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 3-5. It was locked and an uncoated tablet was manufactured.

Example 4: Tablets containing 500 mg of imeglimin hydrochloride (4)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 4-1 were produced.

B. Production Method (1) Preparation of 6.5 wt% Hydroxypropyl Cellulose Solution (1) 1870 g of purified water was placed in a beaker made of SUS, and 130 g of HPC-L was gradually added and dissolved while stirring. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 6.5 wt% hydroxypropyl cellulose solution (1).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 4-2 and the production conditions shown in Table 4-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 4-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type manufactured by Paulek Co., Ltd.) and exhausted. Mixing was carried out while flowing until the temperature reached 35 ° C. Subsequently, the 6.5 wt% hydroxypropyl cellulose solution (1) of the charged amount shown in Table 4-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 4-4. Granulated granules containing the imeglimin hydrochloride in the amount shown in Table 4-4 are put into a V10 type container, and then the light anhydrous silicic acid in the amount shown in Table 4-4 is added to the mixer ( Using Tsutsui Rikagaku Kikai Co., Ltd., S-5 type), mixing was performed at 40 rpm for 10 minutes. Subsequently, magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locking machine (manufactured by Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 4-5. It was locked and an uncoated tablet was manufactured.

Example 5: Tablet containing 500 mg of imeglimin hydrochloride (5)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 5-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (2) Take 64.8 kg of purified water in a beaker made of SUS, gradually add 2.43 kg of HPC-L while stirring, and then 0.27 kg. HPC-M was gradually added and dissolved. Two of these solutions were prepared, allowed to stand for a whole day and night, and then stirred again to prepare a total of 135 kg of a 4 wt% hydroxypropyl cellulose solution (2).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 5-2 and the production conditions shown in Table 5-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 5-2 were put into a fluidized bed granulation dryer (NFLO-120SJC type manufactured by Freund Sangyo Co., Ltd.), and the exhaust temperature was increased. Was mixed while flowing until the temperature reached 60 ° C. Subsequently, the 4 wt% hydroxypropyl cellulose solution (2) of the charged amount shown in Table 5-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 5-4. Granulated granules containing the amount of imeglimin hydrochloride shown in Table 5-4 are put into an 800 L container, and then the amount of light anhydrous silicic acid shown in Table 5-4 is added to the container mixer. (Tumbler blender manufactured by Yamazaki Metal Machinery Co., Ltd.) was used to mix at 12 rpm for 5 minutes. Subsequently, magnesium stearate was put into an 800 L container, and further mixed at 12 rpm for 5 minutes using a container mixer (manufactured by Yamazaki Metal Machinery Co., Ltd., tumbler blender).

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 5-5. It was locked and an uncoated tablet was manufactured.

Example 6: Tablet containing 500 mg of imeglimin hydrochloride (6)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 6-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (3) Take 64.8 kg of purified water in a beaker made of SUS, gradually add 2.16 kg of HPC-L while stirring, and then 0.54 kg. HPC-M was gradually added and dissolved. Two of these solutions were prepared, allowed to stand for a whole day and night, and then stirred again to prepare a total of 135 kg of a 4 wt% hydroxypropyl cellulose solution (3).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 6-2 and the production conditions shown in Table 6-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 6-2 were put into a fluidized bed granulation dryer (NFLO-120SJC type manufactured by Freund Sangyo Co., Ltd.), and the exhaust temperature was increased. Was mixed while flowing until the temperature reached 55 ° C. Subsequently, the 4 wt% hydroxypropyl cellulose solution (3) of the charged amount shown in Table 6-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 6-4. In an 800 L container, put the granulated granules containing the imeglimin hydrochloride in the amount shown in Table 6-4, and then lightly add the light anhydrous silicic acid and magnesium stearate in the amount shown in Table 6-4. The mixture was added and mixed using a container mixer (manufactured by Yamazaki Metal Machinery Co., Ltd., tumbler blender) at 12 rpm for 5 minutes.

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 6-5. It was locked and an uncoated tablet was manufactured.

(5) Preparation of film coating liquid (1) 55.2 kg of purified water was placed in a SUS tank, and 4.8 kg of OPADRY ^TM tm 07F28588 WHITE was gradually added while stirring to disperse and dissolve. This liquid was passed through a screen having an opening of 106 μm to obtain a film coating liquid (1).

(6) Production of Film-Coated Tablets Containing 500 mg of Imeglimin Hydrochloride A film-coated tablet containing 500 mg of imeglimin hydrochloride was produced under the conditions shown in Table 6-6. First, an 82.5 kg uncoated lock is put into a coating machine (AQC-170FS type manufactured by Freund Sangyo Co., Ltd.), and the exhaust temperature becomes 50 ° C. under the conditions shown in Table 6-6 while rotating the coating pan. It was warmed up to. Subsequently, while rotating the coating pan at 4 rpm, the film coating liquid (1) was sprayed under the conditions shown in Table 6-6, and the film was coated until the film amount became about 14 mg. Then, the coating pan was rotated at 2 rpm and dried until the exhaust temperature reached 55 ° C., and 21.38 g of talc was sprayed.

Example 7: Tablet containing 500 mg of imeglimin hydrochloride (7)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 7-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (4) Take 23284.9 g of purified water in a beaker made of SUS, gradually add 679.0 g of HPC-L while stirring, and then 291.2 g. HPC-M was gradually added and dissolved. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (4).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 7-2 and the production conditions shown in Table 7-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 7-2 were put into a fluidized bed granulation dryer (NFLF-30 type manufactured by Freund Sangyo Co., Ltd.), and the exhaust temperature was increased. Was mixed while flowing until the temperature reached 35 ° C. Subsequently, the 4 wt% hydroxypropyl cellulose solution (4) of the charged amount shown in Table 7-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 7-4. Granulated granules containing the amount of imeglimin hydrochloride shown in Table 7-4 are put into a 110 L container, and then the amount of light anhydrous silicic acid shown in Table 7-4 is added to the container mixer. Mixing was performed at 20 rpm for 10 minutes using (Picks Blender, manufactured by Pickstecnica). Subsequently, magnesium stearate was put into a 110 L container, and the mixture was further mixed at 20 rpm for 5 minutes using a container mixer (Pix Blender manufactured by Pickstechnica).

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 7-5. It was locked and an uncoated tablet was manufactured.

Example 8: Tablets containing 500 mg of imeglimin hydrochloride (8)
A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 8-1 were produced.

B. Production Method (1) Preparation of 6.5 wt% Hydroxypropyl Cellulose Solution (2) 1870 g of purified water was placed in a beaker made of SUS, and 130 g of HPC-L was gradually added and dissolved while stirring. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 6.5 wt% hydroxypropyl cellulose solution (2).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 8-2 and the production conditions shown in Table 8-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 8-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type manufactured by Paulek Co., Ltd.) and exhausted. Mixing was carried out while flowing until the temperature reached 36 ° C. Subsequently, the 6.5 wt% hydroxypropyl cellulose solution (2) of the charged amount shown in Table 8-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 8-4. Granulated granules containing the imeglimin hydrochloride in the amount shown in Table 8-4 are put into a V10 type container, and then the light anhydrous silicic acid in the amount shown in Table 8-4 is added to the mixer ( Using Tsutsui Rikagaku Kikai Co., Ltd., S-5 type), mixing was performed at 40 rpm for 10 minutes. Subsequently, magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 8-5. It was locked and an uncoated tablet was manufactured.

Example 9: Tablet containing 500 mg of imeglimin hydrochloride (9)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 9-1 were produced.

B. Production Method (1) Preparation of 4 wt% Hypromellose Solution (1) 1920 g of purified water was placed in a beaker made of SUS, and 80 g of TC- ^5RTM was gradually added and dissolved while stirring. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% hypromellose solution (2).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 9-2 and the production conditions shown in Table 9-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 9-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while flowing for 2 minutes. did. Subsequently, the 4 wt% hypromellose solution (1) of the charged amount shown in Table 9-2 was sprayed while mixing. Further, after drying, granules containing imeglimin hydrochloride were prepared through a granulator (Comil 194S type manufactured by Paulek) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 9-4. The amount of light anhydrous silicic acid shown in Table 9-4 was added to a plastic bag containing the granulated granules containing the amount of imeglimin hydrochloride shown in Table 9-4, and the mixture was shaken for 2 minutes. Then, the charged amount of magnesium stearate shown in Table 9-4 was added, and the mixture was further shaken for 1 minute to mix.

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 9-5. It was locked and an uncoated tablet was manufactured.

Example 10: Tablets containing 500 mg of imeglimin hydrochloride (10)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 10-1 were produced.

B. Production method (1) Preparation of 4 wt% polyvinyl alcohol solution (1) 1920 g of purified water was placed in a beaker made of SUS and heated to a boil. 80 g of Gohsenol ^TM EG-05P was gradually added and dissolved while stirring the heated purified water. After allowing to stand for a whole day and night, the mixture was stirred again, purified water was added to adjust the solution to 2000 g, and a 4 wt% polyvinyl alcohol solution (1) was prepared.

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 10-2 and the production conditions shown in Table 10-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 10-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while flowing for 3 minutes. did. Subsequently, the 4 wt% polyvinyl alcohol solution (1) of the charged amount shown in Table 10-2 was sprayed while mixing. Further, after drying, granules containing imeglimin hydrochloride were prepared through a granulator (Comil 194S type manufactured by Paulek) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 10-4. The amount of light anhydrous silicic acid shown in Table 10-4 was added to a plastic bag containing the granulated granules containing the amount of imeglimin hydrochloride shown in Table 10-4, and the mixture was shaken for 2 minutes. Then, the amount of magnesium stearate shown in Table 10-4 was added, and the mixture was further shaken for 1 minute to mix.

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 10-5. It was locked and an uncoated tablet was manufactured.

Example 11: Tablet containing 500 mg of imeglimin hydrochloride (11)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 11-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (5) Take 2880 g of purified water in a beaker made of SUS, gradually add 95.99 g of HPC-L while stirring, and then add 24 g of HPC-M. Was gradually added and dissolved. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (5).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 11-2 and the production conditions shown in Table 11-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and crospovidone shown in Table 11-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type manufactured by Paulek Co., Ltd.), and the exhaust temperature was adjusted. Mixing was carried out while flowing until the temperature reached 38 ° C. Subsequently, the 4 wt% hydroxypropyl cellulose solution (5) of the charged amount shown in Table 11-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 11-4. Granulated granules containing the amount of imeglimin hydrochloride shown in Table 11-4 are put into a polyethylene bag, and then the amount of light anhydrous silicic acid shown in Table 11-4 is added, and the hands are added for 2 minutes. Mixed. Subsequently, magnesium stearate was added and manually mixed for 1 minute.

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 11-5. It was locked and an uncoated tablet was manufactured.

Example 12: Tablets containing 500 mg of imeglimin hydrochloride (12)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 12-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (6) Take 2880 g of purified water in a beaker made of SUS, gradually add 95.99 g of HPC-L while stirring, and then add 24 g of HPC-M. Was gradually added and dissolved. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (6).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 12-2 and the production conditions shown in Table 12-3. First, the charged amounts of imeglycin hydrochloride, light anhydrous silicic acid, and sodium starch glycolate shown in Table 12-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type manufactured by Paulek Co., Ltd.) and exhausted. Mixing was carried out while flowing until the temperature reached 39 ° C. Subsequently, the 4 wt% hydroxypropyl cellulose solution (6) of the charged amount shown in Table 12-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 12-4. Granulated granules containing the amount of imeglimin hydrochloride shown in Table 12-4 are put into a polyethylene bag, and then the amount of light anhydrous silicic acid shown in Table 12-4 is added, and the hands are added for 2 minutes. Mixed. Subsequently, magnesium stearate was added and manually mixed for 1 minute.

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 12-5. It was locked and an uncoated tablet was manufactured.

Example 13: Tablets containing 500 mg of imeglimin hydrochloride (13)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 13-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (7) Take 2880 g of purified water in a beaker made of SUS, gradually add 95.99 g of HPC-L while stirring, and then add 24 g of HPC-M. Was gradually added and dissolved. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (7).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 13-2 and the production conditions shown in Table 13-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 13-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type manufactured by Paulek Co., Ltd.) and exhausted. Mixing was carried out while flowing until the temperature reached 35 ° C. Subsequently, the 4 wt% hydroxypropyl cellulose solution (7) of the charged amount shown in Table 13-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were made into granulated granules containing imeglimin hydrochloride through a granulator (manufactured by Paulek, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 13-4. Granulated granules containing the amount of imeglimin hydrochloride shown in Table 13-4 are put into a polyethylene bag, and then the amount of light anhydrous silicic acid shown in Table 13-4 is added, and the hands are added for 2 minutes. Mixed. Subsequently, magnesium stearate was added and manually mixed for 1 minute.

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 13-5. It was locked and an uncoated tablet was manufactured.

Comparative Example 1: Tablet containing 167 mg of imeglimin hydrochloride (14)
A. Formulation of Uncoated Tablets Containing 167 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 14-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (8) Take 1920 g of purified water in a beaker made of SUS, gradually add 64 g of HPC-L while stirring, and then gradually add 16 g of HPC-M. It was put into the water and dissolved. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (8).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 14-2 and the production conditions shown in Table 14-3. First, the charged amounts of imeglimin hydrochloride, crystalline cellulose, light anhydrous silicic acid, and croscarmellose sodium shown in Table 14-2 were put into a fluidized bed granulator / dryer (Multiplex MP-01 type) and flowed for 3 minutes. It was mixed while letting it. Subsequently, the 4 wt% hydroxypropyl cellulose solution (8) of the charged amount shown in Table 14-2 was sprayed while mixing. Further, after drying, granules containing imeglimin hydrochloride were prepared through a granulator (Comil 194S type manufactured by Paulek) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 14-4. The amount of light anhydrous silicic acid shown in Table 14-4 was added to a plastic bag containing the granulated granules containing the amount of imeglimin hydrochloride shown in Table 14-4, and the mixture was shaken for 2 minutes. Then, the charged amount of magnesium stearate shown in Table 14-4 was added, and the mixture was further shaken for 1 minute to mix.

(4) Production of uncoated tablets containing 167 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 167 mg of imeglimin hydrochloride under the conditions shown in Table 14-5. It was locked and an uncoated tablet was manufactured.

Comparative Example 2: Tablets containing 500 mg of imeglimin hydrochloride (15)
A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 15-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (9) Take 1152 g of purified water in a beaker made of SUS, gradually add 36 g of HPC-L while stirring, and then gradually add 12 g of HPC-M. It was put into the water and dissolved. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (9).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 15-2 and the production conditions shown in Table 15-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 15-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while flowing for 3 minutes. did. Subsequently, the 4 wt% hydroxypropyl cellulose solution (9) of the charged amount shown in Table 15-2 was sprayed while mixing. Further, after drying, granules containing imeglimin hydrochloride were obtained through a granulator (Comil 194S type manufactured by Paulec) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 15-4. Granulated granules containing the amount of imeglimin hydrochloride shown in Table 15-4 are put into a V10 type container, and then the amount of light anhydrous silicic acid shown in Table 15-4 is added to the mixer ( Using Tsutsui Rikagaku Kikai Co., Ltd., S-5 type), mixing was performed at 40 rpm for 10 minutes. Subsequently, magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locking machine (manufactured by Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 15-5. It was locked and an uncoated tablet was manufactured.

Comparative Example 3: Tablets containing 500 mg of imeglimin hydrochloride (16)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 16-1 were produced.

B. Production Method (1) Preparation of 5 wt% Hydroxypropyl Cellulose Solution (3) 1900 g of purified water was placed in a beaker made of SUS, and 100 g of HPC-L was gradually added and dissolved while stirring. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 5 wt% hydroxypropyl cellulose solution (3).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 16-2 and the production conditions shown in Table 16-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 16-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type), and the exhaust temperature became 31 ° C. It was mixed until it became. Subsequently, the 5 wt% hydroxypropyl cellulose solution (3) of the charged amount shown in Table 16-2 was sprayed while mixing. Further, after drying, the granules were sized by a granulator (Comil 194S type manufactured by Paulec) set to an opening of 1.4 mm and a rotation speed of 1400 rpm to obtain granulated granules containing imeglimin hydrochloride. Two of these granulated granules were produced.

(3) Production of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 16-4. Granulated granules containing the amount of imeglimin hydrochloride shown in Table 16-4 are put into a V10 type container, and then the amount of light anhydrous silicic acid shown in Table 16-4 is added to the mixer ( Using Tsutsui Rikagaku Kikai Co., Ltd., S-5 type), mixing was performed at 40 rpm for 10 minutes. Subsequently, magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (Kikusui Seisakusho, AQUARIUS type 3) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 16-5. It was locked and an uncoated tablet was manufactured.

Comparative Example 4: Tablets containing 500 mg of imeglimin hydrochloride (17)
A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 17-1 were produced.

B. Production method (1) Preparation of 4 wt% povidone solution (1) 1920 g of purified water was placed in a beaker made of SUS, and 80 g of Kollidon ^TM K30 was gradually added and dissolved while stirring. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% povidone solution (1).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 17-2 and the production conditions shown in Table 17-3. First, the charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium shown in Table 17-2 were put into a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while flowing for 3 minutes. did. Subsequently, the 4 wt% povidone solution (1) of the charged amount shown in Table 17-2 was sprayed while mixing. Further, after drying, the granules containing imeglimin hydrochloride are passed through a sieve having an opening of 1000 μm and then through a granulator (Paulec, Comil 194S type) set to an opening of 1.4 mm and a rotation speed of 1400 rpm. And said.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 17-4. The amount of light anhydrous silicic acid shown in Table 17-4 was added to a plastic bag containing the granulated granules containing the amount of imeglimin hydrochloride shown in Table 17-4, and the mixture was shaken for 2 minutes. Then, the charged amount of magnesium stearate shown in Table 17-4 was added, and the mixture was further shaken for 1 minute to mix.

(4) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 17-5. It was locked and an uncoated tablet was manufactured.

Comparative Example 5: Tablet containing 500 mg of imeglimin hydrochloride (18)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 18-1 were produced.

B. Production Method (1) Production of Granulated Granules Containing Imeglimin Hydrochloride The amount of imeglimin hydrochloride, light anhydrous silicic acid, hydroxypropyl cellulose (3.32 g HPC-M and 13.3 g) shown in Table 18-1. HPC-L) was put into a high-speed stirring granulator (FM-VG-05 type manufactured by Paulek Co., Ltd.) and mixed for 2 minutes under the conditions shown in Table 18-3. Subsequently, while mixing, the charged amounts of purified water shown in Table 18-2 were sprayed using a Paulek standard spray gun, and then mixed for 2 minutes. Take out from a stirring granulator (Maurek Co., Ltd., FM-VG-05 type), pass through a sieve with a mesh opening of 1000 μm, and then pass through a fluidized bed granulator dryer (Paurek Co., Ltd., multiplex MP-01 type). I put it in. Drying was carried out while flowing under the conditions shown in Table 18-2, and granules containing imeglimin hydrochloride were obtained through a sieve having an opening of 710 μm.

(2) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 18-4. Put the light anhydrous silicic acid and croscarmellose sodium in the amount shown in Table 18-4 into a plastic bag containing the granulated granules containing the imeglimin hydrochloride in the amount shown in Table 18-4. Shake for minutes. Then, the charged amount of magnesium stearate shown in Table 18-4 was added, and the mixture was further shaken for 1 minute to mix.

(3) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 18-5. It was locked and an uncoated tablet was manufactured.

Comparative Example 6: Tablet containing 500 mg of imeglimin hydrochloride (19)
A. Formulation of Uncoated Tablets Containing 500 mg of Imeglimin Hydrochloride A mixed powder and uncoated tablets having the composition shown in Table 19-1 were produced.

B. Production Method (1) Production of Mixed Powder Containing Imeglimin Hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 19-2. The charged amounts of imeglimin hydrochloride, light anhydrous silicic acid, hydroxypropyl cellulose, and croscarmellose sodium shown in Table 19-2 were placed in a plastic bag and shaken for 2 minutes. Then, the charged amount of magnesium stearate shown in Table 19-2 was added, and the mixture was further shaken for 1 minute to mix.

(2) Production of uncoated tablets containing 500 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 500 mg of imeglimin hydrochloride under the conditions shown in Table 19-3. It was locked and an uncoated tablet was manufactured.

Comparative Example 7: Tablet containing 388 mg of imeglimin hydrochloride (20)
A. Formulation of Uncoated Tablets Containing 388 mg of Imeglimin Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 20-1 were produced.

B. Production method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (10) Take 1920 g of purified water in a beaker made of SUS, gradually add 64 g of HPC-L while stirring, and then gradually add 16 g of HPC-M. It was put into the water and dissolved. After allowing to stand for a whole day and night, the mixture was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (10).

(2) Production of Granulated Granules Containing Imeglimin Hydrochloride Granulated granules containing imeglimin hydrochloride were produced under the charging amount shown in Table 20-2 and the production conditions shown in Table 20-3. First, the charged amounts of imeglimin hydrochloride, crystalline cellulose, light anhydrous silicic acid, and croscarmellose sodium shown in Table 20-2 were put into a fluidized bed granulator / dryer (Multiplex MP-01 type) and flowed for 3 minutes. It was mixed while letting it. Subsequently, the 4 wt% hydroxypropyl cellulose solution (10) of the charged amount shown in Table 20-2 was sprayed while mixing. Further, after drying, granules containing imeglimin hydrochloride were prepared through a granulator (Comil 194S type manufactured by Paulek) set to an opening of 1.4 mm and a rotation speed of 1400 rpm.

(3) Production of mixed powder containing imeglimin hydrochloride The mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 20-4. The amount of light anhydrous silicic acid shown in Table 20-4 was added to a plastic bag containing the granulated granules containing the amount of imeglimin hydrochloride shown in Table 20-4, and the mixture was shaken for 2 minutes. Then, the charged amount of magnesium stearate shown in Table 20-4 was added, and the mixture was further shaken for 1 minute to mix.

(4) Production of uncoated tablets containing 388 mg of imeglimin hydrochloride Using a rotary locker (manufactured by Kikusui Seisakusho, VELA2 type) so that one tablet contains 388 mg of imeglimin hydrochloride under the conditions shown in Table 20-5. It was locked and an uncoated tablet was manufactured.

Test Example 1: Bulk Density of Mixed Powder The bulk density of the mixed powder was measured for Examples 1 to 13 and Comparative Examples 1, 2, 4 to 7. The bulk density was calculated from the following formula by gently pouring about 10 g of mixed powder into a 25 mL graduated cylinder or a 50 mL graduated cylinder, reading the scale of the powder surface height. The results are shown in Table 21.
<Calculation formula for bulk density>
Bulk density (g / mL) = Sampling volume (g) / Powder surface height scale (mL)

表２２より、実施例１～１３は良好な強度を示しており、医薬品として流通させるに十分にたる強度を有していることが明らかとなった。一方で、比較例２及び比較例３はキャッピング錠が発生しており、日本薬局方の錠剤の摩損度試験法の判定基準における物理的強度の指標である１．０％以下を満たすことができず、錠剤として市場に提供することが困難であることが明らかとなった。なお、比較例４～６についてはキャッピングにより打錠することができなかった。この結果から、イメグリミンは圧縮成形性が悪く、錠剤中の薬物含有割合が高くなると打錠障害（キャッピング）が発生しやすいことが分かった。また、錠剤の高薬物含量化させる際に通常選択される攪拌造粒法を用いて製造すると、キャッピングが発生しやすいことが分かった。通常、流動層造粒法は薬物含有割合が高くなると、流動層造粒機内で流動不良が起こり、造粒が難しくなるため、薬物高含有化させる際には用いられない。一方で、イメグリミンでは、処方中に崩壊剤を添加することで、高薬物含有量処方でも流動層造粒機内で流動させることが出来た。また、水溶性高分子結合剤は多量に使用すると、粗大粒が発生し、打錠性や錠剤の溶出性が悪化することが知られているが、あえて水溶性高分子結合剤であるヒドロキシプロピルセルロース、ポリビニルアルコールまたはヒドロキシプロピルメチルセルロースを比較的多量用いることにより、打錠障害が起きない小型化錠剤を製造することが出来た。 Test Example 2: Evaluation of tableting property and measurement of shape, hardness, and abrasion degree of uncoated tablet For Examples 1 to 13 and Comparative Examples 1 to 7, the tableting property was evaluated, and the thickness, hardness, and abrasion degree of the uncoated tablet were evaluated. Was measured. For the thickness and hardness of the uncoated tablets, MultiCheck 5 manufactured by ERWEKA was used, and the average value of 5 tablets or 10 tablets was described. The abrasion degree test of the tablet was measured using a FRIABILATOR TFT-1200 manufactured by Toyama Sangyo in accordance with the test method described in the Japanese Pharmacopoeia. The measurement results are shown in Table 22.

From Table 22, it was clarified that Examples 1 to 13 showed good strength and had sufficient strength to be distributed as a pharmaceutical product. On the other hand, in Comparative Example 2 and Comparative Example 3, capping tablets are generated, and can satisfy 1.0% or less, which is an index of physical strength in the judgment criteria of the tablet abrasion degree test method of the Japanese Pharmacopoeia. However, it became clear that it was difficult to provide it to the market as a tablet. In addition, Comparative Examples 4 to 6 could not be locked by capping. From this result, it was found that imeglimin has poor compression moldability, and when the drug content in the tablet is high, tableting disorder (capping) is likely to occur. It was also found that capping is likely to occur when manufactured using the stirring granulation method usually selected for increasing the drug content of tablets. Normally, the fluidized bed granulation method is not used for increasing the drug content because when the drug content ratio is high, flow failure occurs in the fluidized bed granulator and granulation becomes difficult. On the other hand, with imeglimin, by adding a disintegrant during the formulation, even a high drug content formulation could be fluidized in the fluidized bed granulator. Further, it is known that when a large amount of a water-soluble polymer binder is used, coarse particles are generated and the tableting property and the elution property of the tablet are deteriorated. However, hydroxypropyl, which is a water-soluble polymer binder, is intentionally used. By using a relatively large amount of cellulose, polyvinyl alcohol or hydroxypropylmethyl cellulose, it was possible to produce a miniaturized tablet that does not cause tableting trouble.

表２３に示されるように、本願により、明らかに一日当たりの投与製剤数を減らすことができ、これにより、生産性の向上及び服薬アドヒアランスの向上が見込まれる。 Test Example 3: Assumed number of administered preparations per day Table 23 shows the assumed number of administered preparations per day. Since the comparative example could not be locked stably due to capping, it was calculated from the following formula assuming that the mixed powder was filled in a capsule. The calculated number of pharmaceutical products was calculated by rounding up to the first decimal place.
<Calculation formula for the number of capsules to be administered>
Number of pharmaceutical products to be administered = mass of mixed powder corresponding to 2000 mg / bulk density (g / mL) / volume of capsule body (mL)
<Capsule size>
Volume 1 capsule body (mL): Approximately 0.50
Overall length (mm) at the time of bonding: Approximately 19.4
Body outer diameter (mm): Approximately 6.63
Volume 2 capsule body (mL): Approximately 0.37
Overall length (mm) at the time of bonding: Approximately 18.0
Body outer diameter (mm): Approximately 6.07

As shown in Table 23, the present application can clearly reduce the number of pharmaceutical formulations administered per day, which is expected to improve productivity and medication adherence.

Test Example 4: Dissolution Test The tablets produced in Examples 1 to 13 and Comparative Example 7 were subjected to a dissolution test under the following conditions in accordance with the Japanese Pharmacopoeia general test method dissolution test method.
<Dissolution test conditions>
Method: Dissolution test method of the Japanese Pharmacopoeia general test method (rotary basket method)
Rotation speed: 100 rpm
Test solution volume: 900 mL
Test solution temperature: 37 ° C ± 0.5 ° C
Test solution: Dissolution test second solution
Number of tests: N = 3 or more <Preparation of sample solution>
Put the tablet in a tester containing 900 mL of the test solution, collect 5 mL of the test solution using a 10 mL syringe 30 minutes after the start of the test, and slowly filter using a Millipore membrane filter (Millex LG 0.2 μm × 25 mm). This was used as a sample of the sample solution except for 1 mL or more of the initial filtrate.
<Preparation of standard solution>
27.78 mg of imeglimin hydrochloride was weighed in a 50 mL volumetric flask and dissolved using the second solution of the dissolution test. This was used as a sample of the standard solution.
<High Performance Liquid Chromatography Analysis Conditions>
High Performance Liquid Chromatography Equipment: UFLC-XR manufactured by Shimadzu Corporation
Detection wavelength: 240nm
Column: Phenomenex, Luna PFP (2) 150 mm x 4.6 mm ID Particle size 3 μm
Mobile phase: Water / methanol / trifluoroacetic acid mixed solution (1000/250/1)
Analysis time: 6 minutes Flow rate: 1.2 mL / min
Column temperature: 40 ° C
Injection volume: 2 μL
Sample cooler temperature: 25 ° C
Syringe cleaning solution: Methanol / water mixture (1/4)

表２４に示したとおり、本発明の素錠またはＦＣ錠の溶出は速やかであり、生体内での高い吸収性が見込まれる。また、フィルムコーティングの有無は溶出性に影響しなかった。水溶性高分子結合剤は多量に使用すると、粗大粒が発生し、打錠性や錠剤の溶出性が悪化することが知られているが、本発明ではあえて水溶性高分子結合剤であるヒドロキシプロピルセルロース、ポリビニルアルコールまたはヒドロキシプロピルメチルセルロースを比較的多量に用いることにより、打錠障害が起きない良好な溶出性を示す小型化錠剤を製造することが出来た。The dissolution test results are shown in Table 24.

As shown in Table 24, the uncoated tablet or FC tablet of the present invention is rapidly eluted and is expected to be highly absorbable in vivo. In addition, the presence or absence of film coating did not affect the elution property. It is known that when a large amount of a water-soluble polymer binder is used, coarse particles are generated and the tableting property and the elution property of the tablet are deteriorated. However, in the present invention, hydroxy, which is a water-soluble polymer binder, is intentionally used. By using a relatively large amount of propyl cellulose, polyvinyl alcohol or hydroxypropyl methyl cellulose, it was possible to produce a miniaturized tablet showing good dissolution without causing tableting trouble.

Manufactured using a fluidized bed granulation method and containing a disintegrant and one or more selected from the group consisting of a high proportion of hydroxyprocellulose, polyvinyl alcohol and hydroxypropylmethylcellulose as a water-soluble binder. It has been found that the present invention characterized by the above can stably produce imeglimin tablets which are small in size and have excellent elution. As a result, it becomes possible to stably provide tablets that are more effective and bring about a higher dose continuation rate, and it becomes possible to provide better treatment for diabetes.

Claims (36)

(1) 84-95 wt% of imeglimin or a pharmaceutically acceptable salt thereof, and (2) one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose . A tablet containing 5.5 to 6.0 wt% and (3) a disintegrant and manufactured using a fluidized bed granulation method . (1) The tablet according to claim 1, which contains 88 to 95 wt% of imeglimin or a pharmaceutically acceptable salt thereof. (1) The tablet according to claim 1, which contains 90 to 95 wt% of imeglimin or a pharmaceutically acceptable salt thereof. (1) The tablet according to claim 1 or 2, which contains 90 to 92 wt% of imeglimin or a pharmaceutically acceptable salt thereof. (3) The tablet according to claim 1 or 2, which contains 0.2 to 7.5 wt% of a disintegrant. (3) The tablet according to any one of claims 1 to 5, which contains 0.2 to 5.0 wt% of a disintegrant. (3) The tablet according to any one of claims 1 to 6, which contains 0.2 to 4.0 wt% of a disintegrant. (3) The tablet according to any one of claims 1 to 7, which contains 0.2 to 3.0 wt% of a disintegrant. (3) The tablet according to any one of claims 1 to 8, which contains 0.2 to 2.0 wt% of a disintegrant. (3) The tablet according to claim 1 or 2, which contains 0.5 to 7.5 wt% of a disintegrant. (3) The tablet according to any one of claims 1 to 4 and 10, which contains 0.5 to 5.0 wt% of a disintegrant. (3) The tablet according to any one of claims 1 to 4, 10 and 11, which contains 0.5 to 4.0 wt% of a disintegrant. (3) The tablet according to any one of claims 1 to 4, 10 to 12, which contains 0.5 to 3.0 wt% of a disintegrant. (3) The tablet according to any one of claims 1 to 4, 10 to 13, which contains 0.5 to 2.0 wt% of a disintegrant. (2) Any one of claims 1 to 14 containing 4.5 to 6.0 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose. The tablets described in the section. (2) Any one of claims 1 to 15 containing 4.5 to 5.5 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose. The tablets described in the section. (2) Any one of claims 1 to 16 containing 4.8 to 5.5 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose. The tablets described in the section. The tablet according to any one of claims 1 to 17 , wherein the hydroxypropyl cellulose has a viscosity of 2.0 to 400 mPa · s. The tablet according to any one of claims 1 to 18 , wherein the hydroxypropyl cellulose has a viscosity of 6.0 to 400 mPa · s. The tablet according to any one of claims 1 to 19 , wherein the polyvinyl alcohol has a viscosity of 3.4 to 9.2 mPa · s. The tablet according to any one of claims 1 to 20 , wherein the polyvinyl alcohol has a viscosity of 4.3 to 5.8 mPa · s. The tablet according to any one of claims 1 to 21 , wherein the viscosity of hydroxypropylmethyl cellulose is 4.0 to 12.0 mPa · s. The tablet according to any one of claims 1 to 22 , wherein the viscosity of hydroxypropylmethyl cellulose is 4.0 to 6.0 mPa · s. The tablet according to any one of claims 1 to 23 , wherein the viscosity of hydroxypropylmethyl cellulose is 4.5 to 6.0 mPa · s. Claims 1 to 18 include hydroxypropyl cellulose having a viscosity of 2.0 to 2.9 mPa · s in the range of 3.5 wt% or less and hydroxypropyl cellulose having a viscosity of 150 to 400 mPa · s in the range of 1.5 wt% or less. , 20-24 . The tablet according to any one of Items . (2) The tablet according to any one of claims 1 to 21 , 25 , wherein the binder is one or two selected from the group consisting of hydroxypropyl cellulose and polyvinyl alcohol. (2) The tablet according to any one of claims 1 to 19 and 22 to 25 , wherein the binder is one or two selected from the group consisting of hydroxypropyl cellulose and hydroxypropyl methyl cellulose. (2) The tablet according to any one of claims 1 to 19 and 25 to 27 , wherein the binder is hydroxypropyl cellulose. (3) The tablet according to any one of claims 1 to 28 , wherein the disintegrant is one or more selected from the group consisting of sodium croscarmellose, sodium starch glycolate and crospopidone. (3) The tablet according to any one of claims 1 to 29, wherein the disintegrant is sodium croscarmellose. (1) Imeglycin or a pharmaceutically acceptable salt thereof, (2) one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose, and (3) disintegrant. The method for producing a tablet according to claim 1 , which comprises a step of producing granulated granules containing the above-mentioned granules by using a fluidized bed granulation method. One or two selected from the group consisting of (2) hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose in a powder containing (1) imeglycin or a pharmaceutically acceptable salt thereof and (3) a disintegrant. The production method according to claim 31 , which comprises a step of adding the above binder and producing using the fluidized bed granulation method. The production method according to claim 31 or 32 , further comprising a tableting step or a film coating step. The production method according to claim 33 , wherein any of the fluidized bed granulation step, the tableting step, and the film coating step is manufactured with a production amount of 10 kg or more. The production method according to claim 33 , wherein any of the fluidized bed granulation step, the tableting step, and the film coating step is manufactured with a production amount of 30 kg or more. The production method according to claim 33 , wherein any of the fluidized bed granulation step, the tableting step, and the film coating step is manufactured with a production amount of 50 kg or more.