Small tablets with excellent manufacturability and dissolution properties

Abstract

To provide a small tablet containing a high content of imeglimin per tablet and having excellent dissolution properties when administering imeglimin at a very high daily dose, and to provide a method for producing the same that enables stable supply. [Solution] By using a disintegrant and a high proportion of hydroxypropyl cellulose, polyvinyl alcohol, and / or hydroxypropyl methylcellulose as a water-soluble binder, it is possible to stably produce very small imeglimin tablets that exhibit excellent dissolution properties. Furthermore, the manufacturing method is a fluidized bed granulation method.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition comprising imeglimin or a pharma- ceutical acceptable salt thereof, which is a mini-tablet having excellent manufacturability and dissolution properties. [Background technology]

[0002] There are many diabetes patients around the world, and in 2017 the International Diabetes Federation (IDF) announced that currently, one in eleven adults in the world is diabetic, an increase of 10 million from the total number of patients in 2015 to 425 million, and predicted that this number will increase to approximately 700 million by 2045. In Japan in particular, most diabetic patients are type 2 diabetes patients, and there are an estimated 3.166 million diabetic patients.

[0003] Imeglimin is widely known as a therapeutic drug for diabetes and is used to treat type 2 diabetes, but it needs to be orally administered in large amounts of 200 to 4,000 mg per day (Patent Document 1), and there were issues with the method of oral administration.

[0004] Patent Document 1 discloses a film-coated tablet containing 83.4% imeglimin as an oral formulation of imeglimin, but does not disclose a specific manufacturing method. Patent Document 2 discloses a tablet containing 87.0% imeglimin, which is manufactured on a 1 kg scale by a direct compression method of mixing and compressing the prescription ingredients, as an oral formulation of imeglimin. However, although the direct compression method is easy to manufacture on a small scale, as the manufacturing scale increases, the powder compression time during tableting decreases, and if the drug has poor compression moldability, tableting problems may occur, making tableting difficult. Therefore, a method for stably manufacturing oral tablets of imeglimin on a large scale has been substantially unknown. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2011 / 154497 [Patent Document 2] WO2010 / 066326 Summary of the Invention [Problem to be solved by the invention]

[0006] The objective of the present invention is to provide small tablets that contain a high content of imeglimin per tablet and have excellent dissolution properties when administering imeglimin at a very large daily dose, and to provide a manufacturing method that enables a stable supply of the same. [Means for solving the problem]

[0007] As a result of intensive research, the present inventors have found that by using a disintegrant and further using a high proportion of hydroxypropyl cellulose, polyvinyl alcohol and / or hydroxypropyl methylcellulose as a water-soluble binder, it is possible to stably produce very small imeglimin tablets that exhibit excellent dissolution properties, and also to use a fluidized bed granulation method as a manufacturing method thereof.

[0008] That is, the present invention is as follows.

[0009] [Section 1] A tablet containing (1) 84 to 95 wt% of imeglimin or a pharma- ceutically acceptable salt thereof, (2) one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose, and (3) a disintegrant.

[0010] [Section 2] (1) The tablet according to item 1, containing 88 to 95 wt% of imeglimin or a pharma- ceutically acceptable salt thereof. or [Term 2'] A tablet containing (1) 88 to 95 wt% of imeglimin or a pharma- ceutically acceptable salt thereof, (2) one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose, and (3) a disintegrant.

[0011] [Section 3] (1) The tablet according to item 1, containing 90 to 95 wt% of imeglimin or a pharma- ceutically acceptable salt thereof.

[0012] [Section 4] (1) The tablet according to item 1 or 2, containing 90 to 92 wt% of imeglimin or a pharma- ceutically acceptable salt thereof.

[0013] [Section 5] (3) The tablet according to item 1 or 2, containing 0.2 to 7.5 wt % of a disintegrant.

[0014] [Section 6] (3) The tablet according to any one of items 1 to 5, comprising 0.2 to 5.0 wt % of a disintegrant.

[0015] [Section 7] (3) The tablet according to any one of items 1 to 6, containing 0.2 to 4.0 wt % of a disintegrant.

[0016] [Section 8] (3) The tablet according to any one of items 1 to 7, comprising 0.2 to 3.0 wt % of a disintegrant.

[0017] [Section 9] (3) The tablet according to any one of items 1 to 8, comprising 0.2 to 2.0 wt % of a disintegrant.

[0018] [Section 10] (3) The tablet according to item 1 or 2, containing 0.5 to 7.5 wt % of a disintegrant.

[0019] [Section 11] (3) The tablet according to any one of items 1 to 4 and 10, containing 0.5 to 5.0 wt % of a disintegrant.

[0020] [Section 12] (3) The tablet according to any one of items 1 to 4, 10, and 11, containing 0.5 to 4.0 wt% of a disintegrant.

[0021] [Section 13] (3) The tablet according to any one of items 1 to 4 and 10 to 12, containing 0.5 to 3.0 wt % of a disintegrant.

[0022] [Section 14] (3) The tablet according to any one of items 1 to 4 and 10 to 13, containing 0.5 to 2.0 wt % of a disintegrant.

[0023] [Section 15] (2) The tablet according to any one of items 1 to 14, comprising 4.5 to 7.0 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose.

[0024] [Section 16] (2) The tablet according to 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 methylcellulose.

[0025] [Section 17] (2) The tablet according to any one of items 1 to 16, comprising 4.5 to 5.5 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose.

[0026] [Section 18] (2) The tablet according to any one of items 1 to 17, comprising 4.8 to 5.5 wt% of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose.

[0027] [Section 19] Item 19. The tablet according to any one of items 1 to 18, wherein the viscosity of the hydroxypropyl cellulose is 2.0 to 400 mPa·s.

[0028] [Section 20] Item 20. The tablet according to any one of Items 1 to 19, wherein the viscosity of the hydroxypropyl cellulose is 6.0 to 400 mPa·s.

[0029] [Section 21] 21. The tablet according to any one of items 1 to 20, wherein the viscosity of the polyvinyl alcohol is 3.4 to 9.2 mPa·s.

[0030] [Section 22] 22. The tablet according to any one of items 1 to 21, wherein the viscosity of the polyvinyl alcohol is 4.3 to 5.8 mPa·s.

[0031] [Section 23] 23. The tablet according to any one of items 1 to 22, wherein the viscosity of the hydroxypropyl methylcellulose is 4.0 to 12.0 mPa·s.

[0032] [Section 24] 24. The tablet according to any one of items 1 to 23, wherein the viscosity of the hydroxypropyl methylcellulose is 4.0 to 6.0 mPa·s.

[0033] [Section 25] 25. The tablet according to any one of items 1 to 24, wherein the viscosity of the hydroxypropyl methylcellulose is 4.5 to 6.0 mPa·s.

[0034] [Section 26] Item 1 to 19, 21 to 25, the tablet according to any one of items 1 to 19 and 21 to 25, containing hydroxypropyl cellulose having a viscosity of 2.0 to 2.9 mPa s in an amount of 3.5 wt% or less and hydroxypropyl cellulose having a viscosity of 150 to 400 mPa s in an amount of 1.5 wt% or less.

[0035] [Section 27] (2) The tablet according to any one of items 1 to 22 and 26, wherein the binder is one or two selected from the group consisting of hydroxypropyl cellulose and polyvinyl alcohol.

[0036] [Section 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 methylcellulose.

[0037] [Section 29] (2) The tablet according to any one of items 1 to 20 and 26 to 28, wherein the binder is hydroxypropyl cellulose.

[0038] [Section 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 croscarmellose sodium, sodium starch glycolate and crospovidone.

[0039] [Section 31] (3) The tablet according to any one of items 1 to 30, wherein the disintegrant is croscarmellose sodium.

[0040] [Section 32] Item 32. The tablet according to any one of items 1 to 31, which is produced using a fluidized bed granulation method.

[0041] [Section 33] Item 32. The method for producing the tablet according to any one of items 1 to 31, wherein the tablet is produced using a fluidized bed granulation method.

[0042] [Section 34] Item 19. The tablet according to any one of items 1 to 18, which is produced using a fluidized bed granulation method.

[0043] [Section 35] Item 19. The method for producing the tablet according to any one of items 1 to 18, wherein the tablet is produced using a fluidized bed granulation method.

[0044] [Section 36] Item 36. A method for producing a tablet according to Item 35, comprising the step of producing granules containing (1) imeglimin or a pharma- ceutically acceptable salt thereof, (2) one or more binders selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, and hydroxypropylmethylcellulose, and (3) a disintegrant, by a fluidized bed granulation method.

[0045] [Section 37] Item 37. A method for producing a tablet according to Item 36, comprising the steps of adding (2) one or more binders selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, and hydroxypropylmethylcellulose to a powder containing (1) imeglimin or a pharma- ceutical acceptable salt thereof and (3) a disintegrant, and producing the tablet by a fluidized bed granulation method.

[0046] [Section 38] Item 36 or 37, the method according to item 36 or 37, further comprising a tableting step or a film coating step.

[0047] [Section 39] Item 39. The method according to Item 38, wherein any one of the steps of the fluidized bed granulation step, the tableting step, and the film coating step is carried out in an amount of 10 kg or more.

[0048] [Section 40] Item 39. The method according to Item 38, wherein any one of the steps of the fluidized bed granulation step, the tableting step, and the film coating step is carried out in an amount of 30 kg or more.

[0049] [Section 41] Item 39. The method according to Item 38, wherein any one of the steps of the fluidized bed granulation step, the tableting step, and the film coating step is carried out in an amount of 50 kg or more. Effect of the Invention

[0050] The imeglimin composition of the present invention is produced by fluidized bed granulation using a disintegrant and a large amount of hydroxypropyl cellulose, polyvinyl alcohol and / or hydroxypropyl methylcellulose as a binder, and has manufacturability that allows stable supply on a production scale despite a very high content of imeglimin, which has poor compression moldability. In addition, the imeglimin composition of the present invention has good dissolution properties, making it possible to provide an oral preparation with excellent bioavailability. Furthermore, since the imeglimin composition of the present invention has a very high content of imeglimin, it is possible to provide a small tablet that makes it easy to continue taking the medication. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] The present invention will now be described in further detail.

[0052] (a) Tablets The tablet of the present invention includes forms such as plain tablets, film-coated tablets (sometimes referred to as FC tablets in this specification) in which a film coat is applied to the surface of a plain tablet, and sugar-coated tablets in which a sugar coat is applied to the surface of a plain tablet, and is preferably a plain tablet or a film-coated tablet. The plain tablet contains an imeglimin-containing composition, and may further contain other additives as long as the function of the present invention is not lost. The imeglimin-containing composition contains (1) imeglimin or a pharma- ceutically acceptable salt thereof, (2) one or more water-soluble polymer binders selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, and hydroxypropylmethylcellulose, and (3) a disintegrant, and may further contain an excipient and a lubricant as desired, and may further contain other additives as long as the function of the present invention is not lost. The film coat contains a film coating agent, and may further contain other additives as long as the function of the present invention is not lost.

[0053] (b) Imeglimin In the present invention, "imeglimin" is a compound known as a therapeutic agent for diabetes, and its chemical name is (6R)-N 2 ,N 2 ,6-trimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine (CAS Registry Number: 775351-65-0) and has the following chemical structure. 2 ,N 2 ,6-trimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine (CAS registration number: 1251468-04-8). [ka]

[0054] The present invention encompasses all forms of imeglimin (e.g., tautomers, amorphous, crystalline, various polymorphs, etc.), including optical isomers thereof, or mixtures thereof, in which the R isomer of the mixture preferably accounts for 90 wt% or more, 95 wt% or more, 97 wt% or more, or 99 wt% or more. Imeglimin used in the present invention may be pulverized to a desired particle size as necessary. The average particle size by volume (50% particle size, D50) is, for example, in the range of 11 to 274 μm, preferably 11 to 169 μm.

[0055] The composition ratio of imeglimin in the tablet of the present invention is 84 wt% or more, preferably 88 wt% or more, 90 wt% or more. The composition ratio of imeglimin in the present invention is preferably 90 wt% or less, 92 wt% or less, 95 wt% or less. In addition, the content of imeglimin or a pharma- ceutically acceptable salt thereof in one tablet of the present invention is preferably 500 mg.

[0056] Pharmaceutically acceptable salts of imeglimin include, but are not limited to, acid addition salts. Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, and camphorsulfonate, and further include amino acid salts with acidic amino acids. A preferred pharma-ceutically acceptable salt of imeglimin is hydrochloride.

[0057] (c) Hydroxypropyl cellulose The viscosity of the hydroxypropyl cellulose in the present invention is not particularly limited, but is from 2.0 to 400 mPa·s, and preferably from 6.0 to 400 mPa·s. Furthermore, the composition ratio of hydroxypropyl cellulose in the tablet of the present invention is not particularly limited, but it is preferable that the tablet contains hydroxypropyl cellulose having a viscosity of 2.0 to 2.9 mPa·s in an amount of 3.5 wt% or less and hydroxypropyl cellulose having a viscosity of 150 to 400 mPa·s in an amount of 1.5 wt% or less. Hydroxypropyl cellulose is preferably contained in an amount of 4.5wt% or more, 4.6wt% or more, 4.7wt% or more, 4.8wt% or more, 4.9wt% or more, or 5.0wt% or more. Hydroxypropyl cellulose is preferably contained in an amount of 5.0wt% or less, 5.1wt% or less, 5.2wt% or less, 5.3wt% or less, 5.4wt% or less, 5.5wt% or less, 5.6wt% or less, 5.7wt% or less, 5.8wt% or less, 5.9wt% or less, 6.0wt% or less, 6.1wt% or less, 6.2wt% or less, 6.3wt% or less, 6.4wt% or less, 6.5wt% or less, 6.6wt% or less, 6.7wt% or less, 6.8wt% or less, 6.9wt% or less, or 7.0wt% or less. Hydroxypropyl cellulose is more preferably contained at 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, or 5.0 wt% or more. Hydroxypropyl cellulose is more preferably contained at 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 wt% or less, 5.8 wt% or less, 5.9 wt% or less, or 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, or 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, or 5.5 wt% or less.

[0058] (d) Polyvinyl alcohol (polyvinyl alcohol resin) The polyvinyl alcohol in the present invention is a polyvinyl alcohol-based resin, and includes polyvinyl alcohol derivatives. Polyvinyl alcohol (PVA) is preferable. Although not particularly limited, it is preferable to use a partially saponified polyvinyl alcohol (PVA). Note that a saponification degree of 97 mol% or more is called a completely saponified product, and a saponification degree of 79 to 96 mol% is called a partially saponified product. The polyvinyl alcohol in the present invention has a viscosity of, but is not particularly limited to, 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. The polyvinyl alcohol in the tablet of the present invention is preferably contained in an amount of, for example, 4.5wt% or more, 4.6wt% or more, 4.7wt% or more, 4.8wt% or more, 4.9wt% or more, or 5.0wt% or more. The polyvinyl alcohol is preferably contained in an amount of 5.0wt% or less, 5.1wt% or less, 5.2wt% or less, 5.3wt% or less, 5.4wt% or less, 5.5wt%, 5.6wt% or less, 5.7wt% or less, 5.8wt% or less, 5.9wt% or less, 6.0wt% or less, 6.1wt% or less, 6.2wt% or less, 6.3wt% or less, 6.4wt% or less, 6.5wt% or less, 6.6wt% or less, 6.7wt% or less, 6.8wt% or less, 6.9wt% or less, or 7.0wt% or less. The 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, or 5.0 wt% or more. The polyvinyl alcohol is more 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, 5.5 wt% or less, 5.6 wt% or less, 5.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, or 6.0 wt% or less. The polyvinyl alcohol is most preferably contained in an amount of 4.8 wt% or more, 4.9 wt% or more, or 5.0 wt% or more. The 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, or 5.5 wt% or less. The polyvinyl alcohol 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.

[0059] (e) Hydroxypropyl methylcellulose The viscosity of the hydroxypropyl methylcellulose in the present invention is not particularly limited, but is from 4.0 to 12.0 mPa·s, preferably from 4.0 to 6.0 mPa·s, and more preferably from 4.5 to 6.0 mPa·s. Hydroxypropyl methylcellulose in the tablet of the present invention is preferably 4.5wt% or more, 4.6wt% or more, 4.7wt% or more, 4.8wt% or more, 4.9wt% or more, 5.0wt% or more. Hydroxypropyl methylcellulose is preferably 5.0wt% or less, 5.1wt% or less, 5.2wt% or less, 5.3wt% or less, 5.4wt% or less, 5.5wt% or less, 5.6wt% or less, 5.7wt% or less, 5.8wt% or less, 5.9wt% or less, 6.0wt% or less, 6.1wt% or less, 6.2wt% or less, 6.3wt% or less, 6.4wt% or less, 6.5wt% or less, 6.6wt% or less, 6.7wt% or less, 6.8wt% or less, 6.9wt% or less, 7.0wt% or less. Hydroxypropyl methylcellulose is more preferably contained at 4.6wt% or more, 4.7wt% or more, 4.8wt% or more, 4.9wt% or more, or 5.0wt% or more. Hydroxypropyl methylcellulose is more preferably contained at 5.0wt% or less, 5.1wt% or less, 5.2wt% or less, 5.3wt% or less, 5.4wt% or less, 5.5wt% or less, 5.6wt% or less, 5.7wt% or less, 5.8wt% or less, 5.9wt% or less, or 6.0wt% or less. Hydroxypropyl methylcellulose is most preferably contained in an amount of 4.8 wt% or more, 4.9 wt% or more, or 5.0 wt% or more.Hydroxypropyl methylcellulose 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, or 5.5 wt% or less.

[0060] (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 provide good fluidity in the manufacturing equipment during granulation. In order to achieve small tablet size, it is desirable for the disintegrant to provide good water absorption and disintegration after tableting even when the content in the tablet is low. The disintegrant used in the present invention is not particularly limited, but disintegrants used in normal formulations can be used. For example, starches, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, crospovidone, croscarmellose sodium, sodium carboxymethyl starch (also called sodium starch glycolate), etc. may be used. Two or more disintegrants may be used. Preferred are crospovidone, croscarmellose sodium, and sodium carboxymethylstarch, and more preferred is croscarmellose sodium. The disintegrant in the tablet of the present invention is preferably contained in an amount of 0.1 wt% or more, 0.2 wt% or more, 0.5 wt% or more, 1.0 wt% or more, or 1.5 wt% or more. The disintegrant is preferably contained in an amount of 7.5wt% or less, 7.4wt% or less, 7.3wt% or less, 7.2wt% or less, 7.1wt% or less, 7.0wt% or less, 6.9wt% or less, 6.8wt% or less, 6.7wt% or less, 6.6wt% or less, 6.5wt% or less, 6.4wt% or less, 6.3wt% or less, 6.2wt% or less, 6.1wt% or less, 6.0wt% or less, 5.9wt% or less, 5.8wt% or less, 5.7wt% or less, 5.6wt% or less, 5.5wt% or less, 5.0wt% or less, 4.5wt% or less, 4.0wt% or less, 3.5wt% or less, 3.0wt% or less, 2.5wt% or less, 2.0wt% or less.

[0061] (g) Excipients The excipient used in the present invention is not particularly limited, and excipients used in normal formulations can be used. For example, crystalline cellulose, sugar or sugar alcohol, etc. can be mentioned. For example, sugar or sugar alcohol, mannitol, erythritol, xylitol, maltitol, sorbitol, lactose, sucrose, trehalose, etc. can be mentioned. In addition, one or more excipients can be used in combination. The content of the excipient is preferably 0.1 wt% or more, 0.5 wt% or more, 1.0 wt% or more, or 2.0 wt% or more. The content of the excipient is preferably 7.5wt% or less, 7.4wt% or less, 7.3wt% or less, 7.2wt% or less, 7.1wt% or less, 7.0wt% or less, 6.9wt% or less, 6.8wt% or less, 6.7wt% or less, 6.6wt% or less, 6.5wt% or less, 6.4wt% or less, 6.3wt% or less, 6.2wt% or less, 6.1wt% or less, 6.0wt% or less, 5.9wt% or less, 5.8wt% or less, 5.7wt% or less, 5.6wt% or less, 5.5wt% or less, 5.0wt% or less, 4.5wt% or less, 4.0wt% or less, 3.5wt% or less, 3.0wt% or less, 2.5wt% or less, or 2.0wt% or less.

[0062] (h) Lubricants In the present invention, a lubricant can be added. The lubricant prevents the drug substance or granules from adhering to the punch and die during tableting depending on the type of drug substance or granules, and is expected to efficiently manufacture tablets. The lubricant may be mixed with other ingredients before tableting, or may be sprayed onto the punch and die during tableting. The lubricant used in the present invention is not particularly limited, but examples thereof include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, carnauba wax, and sucrose fatty acid esters. 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 lubricant content 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, or 1.0 wt% or more.The lubricant content 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, or 1.0 wt% or less. The lubricant content is more preferably 0.4 wt% or more, 0.6 wt% or more, 0.8 wt% or more, or 1.0 wt% or more.The lubricant content 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, or 1.0 wt% or less.

[0063] (i) Other additives In addition to the above, other additives may be added to the tablet of the present invention to the extent that the functions of the present invention are not lost. Examples of other additives include, but are not limited to, sweeteners, flavorings, odorants, flavorings, flow agents (e.g., Aerosil), antistatic agents, colorants, plasticizers, anti-aggregating agents, and gloss agents (e.g., carnauba wax, talc).

[0064] (j) Film coating agents Examples of the film coating agent used for film coating include, but are not limited to, combinations of substrates such as hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, and plasticizers such as polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, and glycerin fatty acid esters. In addition, additives such as titanium oxide, iron oxide, talc, and colorants can also be added. Preferably, the substrates are hypromellose, hydroxypropyl cellulose, and polyvinyl alcohol, and the plasticizers are polyethylene glycol, propylene glycol, and triethyl citrate.

[0065] "Excellent dissolution" Excellent dissolution properties refer to a dissolution rate of preferably 80% or more, 85% or more, 90% or more, or 95% or more at 30 minutes, a dissolution rate of preferably 97% or more, 98% or more, or 99% or more at 60 minutes, and a dissolution rate of preferably 103% or less, 102% or less, or 100% or less at 60 minutes, when a dissolution test of a prototype preparation is carried out according to the Japanese Pharmacopoeia Dissolution Test Method 2 under the following dissolution test conditions. Test solution: Japanese Pharmacopoeia dissolution test second solution Paddle rotation speed: 50 rpm Test solution: 900mL

[0066] Large-scale manufacturing In the present invention, large-scale production means production in any one of the granulation process, the tabletting process, and the film coating process, preferably in a production amount (charge amount) of 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 or more, 45 kg or more, or 50 kg or more.

[0067] "viscosity" The viscosity of the polymer in the present invention refers to the viscosity when a 2 wt % aqueous polymer solution at 20° C. is measured using a Brookfield viscometer. The method for producing the imeglimin-containing composition contained in the tablet of the present invention is preferably a granulation method capable of producing granules with excellent compression moldability in order to prevent tableting problems and obtain tablets with appropriate hardness. For example, a fluidized bed granulation method is mentioned, and preferably, a fluidized bed granulation method in which a binder solution is sprayed is preferable, but a fluidized bed granulation method in which a binder is added in part as a powder may also be used. Although the present invention is not limited thereto, examples of steps for producing film-coated tablets, for example, by fluidized bed granulation, are given below.

[0068] (1) Preparation of hydroxypropyl cellulose aqueous solution Hydroxypropyl cellulose is dissolved in purified water. The amount of hydroxypropyl cellulose is selected, for example, from the range of 1 to 20 wt %, preferably from the range of 2 to 6.5 wt %, relative to the amount of purified water.

[0069] (2) Production of Imeglimin-Containing Composition (Fluidized Bed Granulation Process) Imeglimin, Aerosil and a disintegrant are charged into a fluidized bed granulator, and granulated while spraying the aqueous solution of the water-soluble polymer prepared in the above step (1).

[0070] (3) Drying of the Imeglimin-Containing Composition The granules are dried under reduced pressure or normal pressure until the loss on drying measured at 80° C. with an infrared moisture meter or a halogen moisture meter is, for example, within 3 wt %, preferably within 2 wt %.

[0071] (4) Blending of lubricants (mixing process) A flow 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 an agitation mixer is used. Specific examples include a tumbler blender, a V blender, a double cone, a bin tumbler, etc., but are not limited to these.

[0072] (5) Tableting (tableting process) The mixture is compressed into uncoated tablets. Examples of the compression device include rotary type compression machines.

[0073] (6) Film coat (film coating process) The above-mentioned plain tablets are then film-coated. Examples of the coating apparatus include those classified as coating pans. Preferably, the coating apparatus is classified as an aerated coating system.

[0074] (7) Drying of film-coated tablets The film-coated tablets are dried under reduced pressure or normal pressure so that the loss on drying measured at 80° C. with an infrared moisture meter or halogen moisture meter is, for example, 3 wt % or less, preferably 2 wt % or less. EXAMPLES

[0075] The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited to these.

[0076] Unless otherwise specified, the following drugs and additives were used in the Examples and Test Examples. Imeglimin hydrochloride: Sumitomo Dainippon Pharma Co., Ltd. Crystalline cellulose (Ceolas TM PH-101): Asahi Kasei Corporation 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 / 2.0~2.9mPa·s 注1) ): Nippon Soda Co., Ltd. Hydroxypropyl cellulose (HPC-L / 6.0~10.0mPa·s 注1 )): Nippon Soda Co., Ltd. Hydroxypropyl cellulose (HPC-M / 150~400mPa·s 注1) ): Nippon Soda Co., Ltd. Hypromellose (hydroxypropyl methylcellulose) (TC-5R TM / 6mPa·s 注2) ): Shin-Etsu Chemical Co., Ltd. Povidone (Kollidon TM K30 / 5.5~8.5mPa·s 注3) ):BASF Polyvinyl alcohol (Gohsenol TM EG-05P / 4.8~5.8mPa·s 注4) ): Mitsubishi Chemical Corporation Magnesium stearate (Magnesium stearate (vegetable)): Taihei Chemical Industry Co., Ltd. OPADRY TM tm 07F28588 WHITE: Japan Colorcon LLC Talc (High-grade talc MSP): Nippon Talc Co., Ltd. Crospovidone (Kollidon TM CL):BASF Sodium starch glycolate (Primojel TM ):DFE Pharma Note 1) Manufacturer catalog values ​​for a 2% solution at 20°C. Note 2) Manufacturer catalog values ​​for a 2% solution at 20°C. Note 3) Manufacturer catalogue value for 10% solution at 20℃. Note 4) Manufacturer catalogue value at 20℃, 4% solution.

[0077] Example 1: Tablet containing 500 mg of imeglimin hydrochloride (1) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 1-1 were produced. TIFF0007671265000002.tif73155

[0078] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (1) 1900 g of purified water was placed in a SUS beaker, and 100 g of HPC-L was gradually added while stirring to dissolve. After leaving it to stand overnight, it was stirred again to prepare a 5 wt% hydroxypropyl cellulose solution (1).

[0079] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions shown in Table 1-3 under the amounts listed in Table 1-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (Powrex Corporation, Multiplex MP-01 type) in the amounts listed in Table 1-2, and mixed while fluidizing until the exhaust temperature reached 35°C. Next, 5 wt% hydroxypropylcellulose solution (1) in the amount listed in Table 1-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (Powrex Corporation, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000003.tif42155 TIFF0007671265000004.tif62155

[0080] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 1-4. Granules containing imeglimin hydrochloride in the amount shown in Table 1-4 were added to a V10 container, followed by the addition of light anhydrous silicic acid in the amount shown in Table 1-4, and mixing was performed for 10 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). Magnesium stearate was then added to the V10 container, followed by further mixing for 5 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). TIFF0007671265000005.tif34155

[0081] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 1-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000006.tif39155

[0082] Example 2: Tablet containing 500 mg of imeglimin hydrochloride (2) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 2-1 were produced. TIFF0007671265000007.tif73155

[0083] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (2) 1900 g of purified water was placed in a SUS beaker, and 100 g of HPC-L was gradually added while stirring to dissolve. After leaving it to stand overnight, it was stirred again to prepare a 5 wt% hydroxypropyl cellulose solution (2).

[0084] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions described in Table 2-3 under the amounts listed in Table 2-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (Powrex Corporation, Multiplex MP-01 type) in the amounts listed in Table 2-2, and mixed while fluidizing until the exhaust temperature reached 35°C. Next, 5 wt% hydroxypropylcellulose solution (2) in the amount listed in Table 2-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (Powrex Corporation, Comil 194S type) set to a mesh size of 1.9 mm and a rotation speed of 900 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000008.tif40155 TIFF0007671265000009.tif63155

[0085] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 2-4. Granules containing imeglimin hydrochloride in the amount shown in Table 2-4 were added to a V2 container, followed by the addition of light anhydrous silicic acid in the amount shown in Table 2-4, and mixing was performed for 10 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-3 model). Magnesium stearate was then added to the V2 container, followed by further mixing for 5 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-3 model). TIFF0007671265000010.tif34155

[0086] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 2-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000011.tif34155

[0087] Example 3: Tablet containing 500 mg of imeglimin hydrochloride (3) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 3-1 were produced. TIFF0007671265000012.tif73155

[0088] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (1) 1920 g of purified water was placed in a SUS beaker, and 56 g of HPC-SSL was gradually added while stirring, followed by 24 g of HPC-M, which was dissolved. After leaving the mixture to stand overnight, it was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (1).

[0089] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions described in Table 3-3 under the amounts listed in Table 3-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (Powrex Corporation, Multiplex MP-01 type) in the amounts listed in Table 3-2, and mixed while fluidizing until the exhaust temperature reached 35°C. Next, 4 wt% hydroxypropylcellulose solution (1) in the amount listed in Table 3-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (Powrex Corporation, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000013.tif40155 TIFF0007671265000014.tif63155

[0090] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 3-4. Granules containing imeglimin hydrochloride in the amount shown in Table 3-4 were added to a V10 container, followed by the addition of light anhydrous silicic acid in the amount shown in Table 3-4, and mixing was performed for 10 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). Magnesium stearate was then added to the V10 container, followed by further mixing for 5 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). TIFF0007671265000015.tif34155

[0091] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 3-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000016.tif34155

[0092] Example 4: Tablet containing 500 mg of imeglimin hydrochloride (4) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 4-1 were produced. TIFF0007671265000017.tif73155

[0093] B. Manufacturing method (1) Preparation of 6.5 wt% hydroxypropyl cellulose solution (1) 1870g of purified water was placed in a SUS beaker, and 130g of HPC-L was gradually added while stirring to dissolve. After leaving it to stand overnight, it was stirred again to prepare a 6.5wt% hydroxypropyl cellulose solution (1).

[0094] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions described in Table 4-3 under the amounts listed in Table 4-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (Powrex Corporation, Multiplex MP-01 type) in the amounts listed in Table 4-2, and mixed while fluidizing until the exhaust temperature reached 35°C. Next, 6.5 wt% hydroxypropylcellulose solution (1) in the amount listed in Table 4-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (Powrex Corporation, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000018.tif40155 TIFF0007671265000019.tif62155

[0095] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 4-4. Granules containing imeglimin hydrochloride in the amount shown in Table 4-4 were added to a V10 container, followed by the addition of light anhydrous silicic acid in the amount shown in Table 4-4, and mixing was performed for 10 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). Magnesium stearate was then added to the V10 container, followed by further mixing for 5 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). TIFF0007671265000020.tif34155

[0096] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 4-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000021.tif34155

[0097] Example 5: Tablet containing 500 mg of imeglimin hydrochloride (5) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 5-1 were produced. TIFF0007671265000022.tif73155

[0098] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (2) 64.8 kg of purified water was placed in a SUS beaker, and 2.43 kg of HPC-L was gradually added while stirring, followed by 0.27 kg of HPC-M, which was gradually added and dissolved. Two of these solutions were prepared, left to stand overnight, and then stirred again to prepare a total of 135 kg of 4 wt% hydroxypropyl cellulose solution (2).

[0099] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions described in Table 5-3 under the amounts listed in Table 5-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (manufactured by Freund Corporation, NFLO-120SJC type) in the amounts listed in Table 5-2, and mixed while fluidizing until the exhaust temperature reached 60°C. Next, 4 wt% hydroxypropylcellulose solution (2) in the amount listed in Table 5-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (manufactured by Powrex, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000023.tif40155 TIFF0007671265000024.tif57155

[0100] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 5-4. Granules containing imeglimin hydrochloride in the amount shown in Table 5-4 were added to an 800 L container, followed by the addition of light anhydrous silicic acid in the amount shown in Table 5-4, and mixing was performed for 5 minutes at 12 rpm using a container mixer (Yamazaki Metal Machinery, tumbler blender). Magnesium stearate was then added to the 800 L container, followed by further mixing for 5 minutes at 12 rpm using a container mixer (Yamazaki Metal Machinery, tumbler blender). TIFF0007671265000025.tif34155

[0101] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 5-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000026.tif34155

[0102] Example 6: Tablet containing 500 mg of imeglimin hydrochloride (6) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 6-1 were produced. TIFF0007671265000027.tif73155

[0103] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (3) 64.8 kg of purified water was placed in a SUS beaker, and 2.16 kg of HPC-L was gradually added while stirring, followed by 0.54 kg of HPC-M, which was gradually added and dissolved. Two of these solutions were prepared, left to stand overnight, and then stirred again to prepare a total of 135 kg of 4 wt% hydroxypropyl cellulose solution (3).

[0104] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions shown in Table 6-3 under the amounts listed in Table 6-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (manufactured by Freund Corporation, NFLO-120SJC type) in the amounts listed in Table 6-2, and mixed while fluidizing until the exhaust temperature reached 55°C. Next, 4 wt% hydroxypropylcellulose solution (3) in the amount listed in Table 6-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (manufactured by Powrex, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000028.tif40155 TIFF0007671265000029.tif57155

[0105] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was manufactured in the amount shown in Table 6-4. Granules containing imeglimin hydrochloride in the amount shown in Table 6-4 were charged into an 800 L container, and then light anhydrous silicic acid and magnesium stearate in the amounts shown in Table 6-4 were added with light mixing, and mixed for 5 minutes at 12 rpm using a container mixer (Tumbler Blender, manufactured by Yamazaki Metal Machinery Co., Ltd.). TIFF0007671265000030.tif34155

[0106] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 6-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000031.tif34155

[0107] (5) Preparation of film coating solution (1) 55.2 kg of purified water was placed in a stainless steel tank and stirred with 4.8 kg of OPADRY. TM tm 07F28588 WHITE was gradually added and dispersed / dissolved. This liquid was passed through a screen with 106 μm openings to obtain film coating liquid (1).

[0108] (6) Manufacture of film-coated tablets containing 500 mg of imeglimin hydrochloride Film-coated tablets containing 500 mg of imeglimin hydrochloride were produced under the conditions described in Table 6-6. First, 82.5 kg of plain tablets were placed in a coating machine (Freund Corporation, AQC-170FS type), and the coating pan was heated under the conditions of Table 6-6 until the exhaust temperature reached 50° C. while rotating the coating pan at 4 rpm. Next, the film coating liquid (1) was sprayed under the conditions of Table 6-6 while rotating the coating pan at 4 rpm, and film-coated until the coating amount reached about 14 mg. After that, the coating pan was dried while rotating at 2 rpm until the exhaust temperature reached 55° C., and 21.38 g of talc was sprayed. TIFF0007671265000032.tif68155

[0109] Example 7: Tablet containing 500 mg of imeglimin hydrochloride (7) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 7-1 were produced. TIFF0007671265000033.tif73155

[0110] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (4) 23284.9 g of purified water was placed in a SUS beaker, and 679.0 g of HPC-L was gradually added while stirring, followed by 291.2 g of HPC-M, which was gradually added and dissolved. After leaving the mixture to stand overnight, it was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (4).

[0111] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions shown in Table 7-3 under the amounts listed in Table 7-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (manufactured by Freund Corporation, NFLF-30 type) in the amounts listed in Table 7-2, and mixed while fluidizing until the exhaust temperature reached 35°C. Next, 4 wt% hydroxypropylcellulose solution (4) in the amount listed in Table 7-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (manufactured by Powrex, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000034.tif40155 TIFF0007671265000035.tif57155

[0112] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was manufactured in the amount shown in Table 7-4. Granules containing imeglimin hydrochloride in the amount shown in Table 7-4 were added to a 110 L container, followed by the addition of light anhydrous silicic acid in the amount shown in Table 7-4, and mixing was performed for 10 minutes at 20 rpm using a container mixer (Pix Blender, manufactured by Pick Technica). Magnesium stearate was then added to the 110 L container, followed by further mixing for 5 minutes at 20 rpm using a container mixer (Pix Blender, manufactured by Pick Technica). TIFF0007671265000036.tif34155

[0113] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 7-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000037.tif34155

[0114] Example 8: Tablet containing 500 mg of imeglimin hydrochloride (8) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 8-1 were produced. TIFF0007671265000038.tif73155

[0115] B. Manufacturing method (1) Preparation of 6.5 wt% hydroxypropyl cellulose solution (2) 1870 g of purified water was placed in a SUS beaker, and 130 g of HPC-L was gradually added while stirring to dissolve. After leaving it to stand overnight, it was stirred again to prepare a 6.5 wt% hydroxypropyl cellulose solution (2).

[0116] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions described in Table 8-3 under the amounts listed in Table 8-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (Powrex Corporation, Multiplex MP-01 type) in the amounts listed in Table 8-2, and mixed while fluidizing until the exhaust temperature reached 36°C. Next, 6.5 wt% hydroxypropyl cellulose solution (2) in the amount listed in Table 8-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (Powrex Corporation, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000039.tif40155 TIFF0007671265000040.tif62155

[0117] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 8-4. Granules containing imeglimin hydrochloride in the amount shown in Table 8-4 were added to a V10 container, followed by the addition of light anhydrous silicic acid in the amount shown in Table 8-4, and mixing was performed for 10 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). Magnesium stearate was then added to the V10 container, followed by further mixing for 5 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). TIFF0007671265000041.tif34155

[0118] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 8-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000042.tif34155

[0119] Example 9: Tablet containing 500 mg of imeglimin hydrochloride (9) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 9-1 were produced. TIFF0007671265000043.tif73155

[0120] B. Manufacturing method (1) Preparation of 4 wt% hypromellose solution (1) Put 1920g of purified water into a SUS beaker and add 80g of TC-5R while stirring. TM After leaving it to stand overnight, it was stirred again to prepare a 4 wt% hypromellose solution (2).

[0121] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced using the amounts listed in Table 9-2 and the production conditions listed in Table 9-3. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium in the amounts listed in Table 9-2 were added to a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while fluidizing for 2 minutes. Next, 4 wt% hypromellose solution (1) in the amount listed in Table 9-2 was sprayed while mixing. After drying, the mixture was passed through a granulator (Powrex, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000044.tif40155 TIFF0007671265000045.tif62155

[0122] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 9-4. A light anhydrous silicic acid in the amount shown in Table 9-4 was added to a plastic bag containing granules containing imeglimin hydrochloride in the amount shown in Table 9-4, and the bag was shaken for 2 minutes. Then, magnesium stearate in the amount shown in Table 9-4 was added, and the bag was shaken for another 1 minute. TIFF0007671265000046.tif34155

[0123] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 9-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000047.tif34155

[0124] Example 10: Tablet containing 500 mg of imeglimin hydrochloride (10) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 10-1 were produced. TIFF0007671265000048.tif73155

[0125] B. Manufacturing method (1) Preparation of 4 wt% polyvinyl alcohol solution (1) 1920g of purified water was placed in a SUS beaker and heated to boiling. 80g of Gohsenol was added to the heated purified water while stirring. TM EG-05P was gradually added and dissolved. After leaving it to stand overnight, it was stirred again and purified water was added to adjust the solution to 2000 g, to prepare a 4 wt % polyvinyl alcohol solution (1).

[0126] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced using the amounts listed in Table 10-2 and the production conditions listed in Table 10-3. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium in the amounts listed in Table 10-2 were added to a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while fluidizing for 3 minutes. Next, 4 wt% polyvinyl alcohol solution (1) in the amount listed in Table 10-2 was sprayed while mixing. After drying, the mixture was passed through a granulator (Powrex, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000049.tif40155 TIFF0007671265000050.tif62155

[0127] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was manufactured in the amount shown in Table 10-4. A light anhydrous silicic acid in the amount shown in Table 10-4 was added to a plastic bag containing granules containing imeglimin hydrochloride in the amount shown in Table 10-4, and the mixture was shaken for 2 minutes. Then, magnesium stearate in the amount shown in Table 10-4 was added, and the mixture was shaken for another minute. TIFF0007671265000051.tif34155

[0128] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 10-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000052.tif34155

[0129] Example 11: Tablet containing 500 mg of imeglimin hydrochloride (11) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 11-1 were produced. TIFF0007671265000053.tif73155

[0130] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (5) 2880 g of purified water was placed in a SUS beaker, and 95.99 g of HPC-L was gradually added while stirring, followed by 24 g of HPC-M, which was gradually added and dissolved. After leaving it to stand overnight, it was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (5).

[0131] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions described in Table 11-3 under the amounts listed in Table 11-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and crospovidone in the amounts listed in Table 11-2 were added to a fluidized bed granulation dryer (Powrex Corporation, Multiplex MP-01 type) and mixed while fluidizing until the exhaust temperature reached 38°C. Next, 4 wt% hydroxypropyl cellulose solution (5) in the amount listed in Table 11-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (Powrex Corporation, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000054.tif40155 TIFF0007671265000055.tif62155

[0132] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was manufactured in the amount shown in Table 11-4. Granules containing imeglimin hydrochloride in the amount shown in Table 11-4 were placed in a polyethylene bag, followed by the addition of light anhydrous silicic acid in the amount shown in Table 11-4 and mixing by hand for 2 minutes. Magnesium stearate was then added and mixed by hand for 1 minute. TIFF0007671265000056.tif34155

[0133] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 11-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000057.tif34155

[0134] Example 12: Tablet containing 500 mg of imeglimin hydrochloride (12) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 12-1 were produced. TIFF0007671265000058.tif73155

[0135] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (6) 2880 g of purified water was placed in a SUS beaker, and 95.99 g of HPC-L was gradually added while stirring, followed by 24 g of HPC-M, which was gradually added and dissolved. After leaving the mixture to stand overnight, it was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (6).

[0136] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions described in Table 12-3 under the amounts listed in Table 12-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and sodium starch glycolate in the amounts listed in Table 12-2 were added to a fluidized bed granulation dryer (Powrex Corporation, Multiplex MP-01 type) and mixed while fluidizing until the exhaust temperature reached 39°C. Next, 4 wt% hydroxypropylcellulose solution (6) in the amount listed in Table 12-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (Powrex Corporation, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000059.tif40155 TIFF0007671265000060.tif62155

[0137] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 12-4. Granules containing imeglimin hydrochloride in the amount shown in Table 12-4 were placed in a polyethylene bag, followed by the addition of light anhydrous silicic acid in the amount shown in Table 12-4 and mixing by hand for 2 minutes. Magnesium stearate was then added and mixed by hand for 1 minute. TIFF0007671265000061.tif34155

[0138] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 12-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000062.tif34155

[0139] Example 13: Tablet containing 500 mg of imeglimin hydrochloride (13) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 13-1 were produced. TIFF0007671265000063.tif73155

[0140] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (7) 2880 g of purified water was placed in a SUS beaker, and 95.99 g of HPC-L was gradually added while stirring, followed by 24 g of HPC-M, which was gradually added and dissolved. After leaving it to stand overnight, it was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (7).

[0141] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions described in Table 13-3 under the amounts listed in Table 13-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (Powrex Corporation, Multiplex MP-01 type) in the amounts listed in Table 13-2, and mixed while fluidizing until the exhaust temperature reached 35°C. Next, 4 wt% hydroxypropyl cellulose solution (7) in the amount listed in Table 13-2 was sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were passed through a granulator (Powrex Corporation, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000064.tif40155 TIFF0007671265000065.tif62155

[0142] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was manufactured in the amount shown in Table 13-4. Granules containing imeglimin hydrochloride in the amount shown in Table 13-4 were placed in a polyethylene bag, followed by the addition of light anhydrous silicic acid in the amount shown in Table 13-4 and mixing by hand for 2 minutes. Magnesium stearate was then added and mixed by hand for 1 minute. TIFF0007671265000066.tif34155

[0143] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 13-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000067.tif34155

[0144] Comparative Example 1: Tablet containing 167 mg of imeglimin hydrochloride (14) A. Formulation of uncoated tablets containing 167 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 14-1 were produced. TIFF0007671265000068.tif79155

[0145] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (8) 1920 g of purified water was placed in a SUS beaker, and 64 g of HPC-L was gradually added while stirring, followed by 16 g of HPC-M, which was gradually added and dissolved. After leaving it to stand overnight, it was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (8).

[0146] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced using the amounts listed in Table 14-2 and the production conditions listed in Table 14-3. First, imeglimin hydrochloride, crystalline cellulose, light anhydrous silicic acid, and croscarmellose sodium in the amounts listed in Table 14-2 were added to a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while fluidizing for 3 minutes. Next, a 4 wt% hydroxypropyl cellulose solution (8) in the amount listed in Table 14-2 was sprayed while mixing. After drying, the mixture was passed through a granulator (Powrex, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000069.tif45155 TIFF0007671265000070.tif62155

[0147] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was manufactured in the amount shown in Table 14-4. A light anhydrous silicic acid in the amount shown in Table 14-4 was added to a plastic bag containing granules containing imeglimin hydrochloride in the amount shown in Table 14-4, and the bag was shaken for 2 minutes. Then, magnesium stearate in the amount shown in Table 14-4 was added, and the bag was shaken for another 1 minute. TIFF0007671265000071.tif34155

[0148] (4) Manufacturing of uncoated tablets containing 167 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 14-5 to produce uncoated tablets so that each tablet contained 167 mg of imeglimin hydrochloride. TIFF0007671265000072.tif34155

[0149] Comparative Example 2: Tablet containing 500 mg of imeglimin hydrochloride (15) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 15-1 were produced. TIFF0007671265000073.tif73155

[0150] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (9) 1152 g of purified water was placed in a SUS beaker, and 36 g of HPC-L was gradually added while stirring, followed by 12 g of HPC-M, which was gradually added and dissolved. After leaving it to stand overnight, it was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (9).

[0151] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced using the amounts listed in Table 15-2 and the production conditions listed in Table 15-3. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium in the amounts listed in Table 15-2 were added to a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while fluidizing for 3 minutes. Next, a 4 wt% hydroxypropyl cellulose solution (9) in the amount listed in Table 15-2 was sprayed while mixing. After drying, the mixture was passed through a granulator (Powrex, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000074.tif40160 TIFF0007671265000075.tif62155

[0152] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was manufactured in the amount shown in Table 15-4. Granules containing imeglimin hydrochloride in the amount shown in Table 15-4 were added to a V10 container, followed by the addition of light anhydrous silicic acid in the amount shown in Table 15-4, and mixing was performed for 10 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). Magnesium stearate was then added to the V10 container, followed by further mixing for 5 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). TIFF0007671265000076.tif34155

[0153] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 15-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000077.tif34155

[0154] Comparative Example 3: Tablet containing 500 mg of imeglimin hydrochloride (16) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 16-1 were produced. TIFF0007671265000078.tif73155

[0155] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (3) 1900 g of purified water was placed in a SUS beaker, and 100 g of HPC-L was gradually added while stirring to dissolve. After leaving it to stand overnight, it was stirred again to prepare a 5 wt% hydroxypropyl cellulose solution (3).

[0156] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced under the manufacturing conditions shown in Table 16-3 under the amounts listed in Table 16-2. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium were added to a fluidized bed granulation dryer (Multiplex MP-01 type) in the amounts listed in Table 16-2, and mixed until the exhaust temperature reached 31°C. Next, a 5 wt% hydroxypropylcellulose solution (3) in the amount listed in Table 16-2 was sprayed while mixing. After drying, the mixture was sized using a granulator (Powrex, Comil 194S type) with a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. Two of these granules were produced. TIFF0007671265000079.tif40161 TIFF0007671265000080.tif62155

[0157] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 16-4. Granules containing imeglimin hydrochloride in the amount shown in Table 16-4 were added to a V10 container, followed by the addition of light anhydrous silicic acid in the amount shown in Table 16-4, and mixing was performed for 10 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). Magnesium stearate was then added to the V10 container, followed by further mixing for 5 minutes at 40 rpm using a mixer (Tsutsui Rikagaku Kikai Co., Ltd., S-5 model). TIFF0007671265000081.tif34155

[0158] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (Kikusui Seisakusho, AQUARIUS3) under the conditions shown in Table 16-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000082.tif34155

[0159] Comparative Example 4: Tablet containing 500 mg of imeglimin hydrochloride (17) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 17-1 were produced. TIFF0007671265000083.tif73155

[0160] B. Manufacturing method (1) Preparation of 4 wt% povidone solution (1) Put 1920g of purified water into a SUS beaker and add 80g of Kollidon while stirring. TM K30 was gradually added and dissolved. After standing overnight, the mixture was stirred again to prepare a 4 wt% povidone solution (1).

[0161] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced using the amounts listed in Table 17-2 and the production conditions listed in Table 17-3. First, imeglimin hydrochloride, light anhydrous silicic acid, and croscarmellose sodium in the amounts listed in Table 17-2 were added to a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while fluidizing for 3 minutes. Next, 4 wt% povidone solution (1) in the amount listed in Table 17-2 was sprayed while mixing. After drying, the mixture was passed through a sieve with a mesh size of 1000 μm, and then passed through a sieve (Powrex, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000084.tif40160 TIFF0007671265000085.tif62155

[0162] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amount shown in Table 17-4. A light anhydrous silicic acid in the amount shown in Table 17-4 was added to a plastic bag containing granules containing imeglimin hydrochloride in the amount shown in Table 17-4, and the bag was shaken for 2 minutes. Then, magnesium stearate in the amount shown in Table 17-4 was added, and the bag was shaken for another 1 minute. TIFF0007671265000086.tif34155

[0163] (4) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 17-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000087.tif34155

[0164] Comparative Example 5: Tablet containing 500 mg of imeglimin hydrochloride (18) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Granules, mixed powders and plain tablets having the compositions shown in Table 18-1 were produced. TIFF0007671265000088.tif73155

[0165] B. Manufacturing method (1) Production of granules containing imeglimin hydrochloride The amounts of imeglimin hydrochloride, light anhydrous silicic acid, and hydroxypropylcellulose (3.32 g of HPC-M and 13.3 g of HPC-L) listed in Table 18-1 were charged into a high-speed stirring granulator (Powrex Corporation, FM-VG-05 type) and mixed for 2 minutes under the conditions listed in Table 18-3. Subsequently, the amount of purified water listed in Table 18-2 was sprayed using a Powrex standard spray gun while mixing, and then mixed for 2 minutes. The mixture was taken out of the stirring granulator (Powrex Corporation, FM-VG-05 type), passed through a sieve with an opening of 1000 μm, and then put into a fluidized bed granulation dryer (Powrex Corporation, Multiplex MP-01 type). The mixture was dried while being fluidized under the conditions listed in Table 18-2, and passed through a sieve with an opening of 710 μm to obtain granules containing imeglimin hydrochloride. TIFF0007671265000089.tif45160 TIFF0007671265000090.tif57158

[0166] (2) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was manufactured in the amounts shown in Table 18-4. The amounts of light anhydrous silicic acid and croscarmellose sodium shown in Table 18-4 were added to a plastic bag containing granules containing imeglimin hydrochloride in the amounts shown in Table 18-4, and the bag was shaken for 2 minutes. Then, the amount of magnesium stearate shown in Table 18-4 was added, and the bag was shaken for another minute. TIFF0007671265000091.tif40155

[0167] (3) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 18-5 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000092.tif34155

[0168] Comparative Example 6: Tablet containing 500 mg of imeglimin hydrochloride (19) A. Formulation of uncoated tablets containing 500 mg of imeglimin hydrochloride Mixed powders and uncoated tablets having the compositions shown in Table 19-1 were prepared. TIFF0007671265000093.tif62155

[0169] B. Manufacturing method (1) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was produced in the amounts listed in Table 19-2. Imeglimin hydrochloride, light anhydrous silicic acid, hydroxypropyl cellulose, and croscarmellose sodium in the amounts listed in Table 19-2 were added to a plastic bag and shaken for 2 minutes. Then, magnesium stearate in the amount listed in Table 19-2 was added and further shaken for 1 minute. TIFF0007671265000094.tif45155

[0170] (2) Manufacturing of uncoated tablets containing 500 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 19-3 to produce uncoated tablets so that each tablet contained 500 mg of imeglimin hydrochloride. TIFF0007671265000095.tif34155

[0171] Comparative Example 7: Tablet (20) containing 388 mg of imeglimin hydrochloride A. Formulation of uncoated tablets containing 388 mg of imeglimin hydrochloride Granulated granules, mixed powders and plain tablets having the compositions shown in Table 20-1 were produced. TIFF0007671265000096.tif79155

[0172] B. Manufacturing method (1) Preparation of 4 wt% hydroxypropyl cellulose solution (10) 1920 g of purified water was placed in a SUS beaker, and 64 g of HPC-L was gradually added while stirring, followed by 16 g of HPC-M, which was gradually added and dissolved. After leaving it to stand overnight, it was stirred again to prepare a 4 wt% hydroxypropyl cellulose solution (10).

[0173] (2) Production of granules containing imeglimin hydrochloride Granules containing imeglimin hydrochloride were produced using the amounts listed in Table 20-2 and the production conditions listed in Table 20-3. First, imeglimin hydrochloride, crystalline cellulose, light anhydrous silicic acid, and croscarmellose sodium in the amounts listed in Table 20-2 were added to a fluidized bed granulation dryer (Multiplex MP-01 type) and mixed while fluidizing for 3 minutes. Next, a 4 wt% hydroxypropyl cellulose solution (10) in the amount listed in Table 20-2 was sprayed while mixing. After drying, the mixture was passed through a granulator (Powrex, Comil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm to produce granules containing imeglimin hydrochloride. TIFF0007671265000097.tif45158 TIFF0007671265000098.tif62155

[0174] (3) Manufacture of mixed powder containing imeglimin hydrochloride A mixed powder containing imeglimin hydrochloride was manufactured in the amount shown in Table 20-4. A light anhydrous silicic acid in the amount shown in Table 20-4 was added to a plastic bag containing granules containing imeglimin hydrochloride in the amount shown in Table 20-4, and the bag was shaken for 2 minutes. Then, magnesium stearate in the amount shown in Table 20-4 was added, and the bag was shaken for another 1 minute. TIFF0007671265000099.tif34155

[0175] (4) Manufacturing of uncoated tablets containing 388 mg of imeglimin hydrochloride The mixture was compressed using a rotary tablet press (VELA2 type, manufactured by Kikusui Seisakusho) under the conditions shown in Table 20-5 to produce uncoated tablets so that each tablet contained 388 mg of imeglimin hydrochloride. TIFF0007671265000100.tif34155

[0176] 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, and 4 to 7. The bulk density was calculated by slowly pouring about 10 g of the mixed powder into a 25 mL or 50 mL graduated cylinder, reading the scale of the powder surface height, and using the following formula. The results are shown in Table 21. <Bulk density calculation formula> Bulk density (g / mL) = sample amount (g) / scale of powder surface height (mL) TIFF0007671265000101.tif130155

[0177] Test Example 2: Evaluation of tableting properties and measurement of shape, hardness, and friability of uncoated tablets Tableting properties were evaluated for Examples 1 to 13 and Comparative Examples 1 to 7, and the thickness, hardness, and friability of the uncoated tablets were measured. The thickness and hardness of the uncoated tablets were measured using MultiCheck 5 manufactured by ERWEKA, and the average values ​​of 5 or 10 tablets were recorded. The friability test of the tablets was performed according to the test method described in the Japanese Pharmacopoeia, using FRIABILATOR TFT-1200 manufactured by Toyama Sangyo. The measurement results are shown in Table 22. TIFF0007671265000102.tif189158 From Table 22, it was revealed that Examples 1 to 13 showed good strength and had sufficient strength for distribution as pharmaceuticals. On the other hand, in Comparative Example 2 and Comparative Example 3, capping occurred, and it was not possible to satisfy the physical strength index of 1.0% or less in the judgment criteria of the tablet friability test method of the Japanese Pharmacopoeia, and it was revealed that it was difficult to provide them to the market as tablets. In addition, it was not possible to tablet Comparative Examples 4 to 6 due to capping. From this result, it was found that imeglimin has poor compression moldability, and tableting trouble (capping) is likely to occur when the drug content ratio in the tablet is high. In addition, it was found that capping is likely to occur when produced using the stirring granulation method that is usually selected when increasing the drug content of tablets. Usually, when the drug content ratio is high, the fluidized bed granulation method is not used when increasing the drug content because poor flow occurs in the fluidized bed granulator and granulation becomes difficult. On the other hand, in the case of imeglimin, by adding a disintegrant during formulation, it was possible to fluidize even a high drug content formulation in a fluidized bed granulator. In addition, it is known that using a large amount of a water-soluble polymer binder generates coarse particles, which deteriorates the tableting properties and dissolution properties of the tablets. However, by deliberately using a relatively large amount of a water-soluble polymer binder such as hydroxypropyl cellulose, polyvinyl alcohol or hydroxypropyl methylcellulose, it was possible to produce small tablets that do not cause tableting problems.

[0178] Test Example 3: Estimated number of formulations administered per day The expected number of formulations to be administered per day is shown in Table 23. For the comparative example, stable tableting was not possible due to capping, so calculations were made using the following formula assuming that the mixed powder was filled into capsules. The calculated number of formulations to be administered was rounded up to the first decimal place and calculated as an integer. <Formula for calculating the number of capsules to be administered> Number of doses = mass of powder mixture equivalent to 2000 mg (g) / bulk density (g / mL) / volume of capsule body (mL) <Capsule size> Capsule No. 1 Body volume (mL): approx. 0.50 Total length when combined (mm): Approx. 19.4 Outer diameter of body (mm): Approx. 6.63 Capsule No. 2 Body volume (mL): approx. 0.37 Total length when combined (mm): Approx. 18.0 Outer diameter of body (mm): Approx. 6.07 TIFF0007671265000103.tif136155 As shown in Table 23, the present application clearly enables a reduction in the number of formulations administered per day, which is expected to improve productivity and medication adherence.

[0179] Test Example 4: Dissolution test For the tablets produced in Examples 1 to 13 and Comparative Example 7, a dissolution test was carried out under the following conditions in accordance with the dissolution test method of the general test method of the Japanese Pharmacopoeia. <Dissolution test conditions> Method: Dissolution test method according to the Japanese Pharmacopoeia general test method (rotating basket method) Rotation speed: 100 rpm Test liquid volume: 900mL Test liquid temperature: 37℃±0.5℃ Test fluid: Dissolution test second fluid Number of tests: N=3 or more <Preparation of sample solution> A tablet was placed in a test vessel containing 900 mL of test solution, and 30 minutes after the start of the test, 5 mL of the test solution was taken using a 10 mL syringe and slowly filtered using a Millipore membrane filter (Millex LG 0.2 μm × 25 mm). At least 1 mL of the initial filtrate was removed, and this was used as the specimen for the sample solution. <Preparation of standard solutions> 27.78 mg of imeglimin hydrochloride was weighed into a 50 mL measuring flask and dissolved in the second dissolution test solution. This was used as a sample for the standard solution. <High performance liquid chromatography analysis conditions> High-performance liquid chromatography device: Shimadzu UFLC-XR 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 mixture (1000 / 250 / 1) Analysis time: 6 minutes Flow rate: 1.2mL / min Column temperature: 40℃ Injection volume: 2μL Sample cooler temperature: 25℃ Syringe cleaning solution: methanol / water mixture (1 / 4)

[0180] The dissolution test results are shown in Table 24. TIFF0007671265000104.tif107153 As shown in Table 24, the dissolution of the plain tablet or FC tablet of the present invention is rapid, and high absorption in vivo is expected. In addition, the presence or absence of film coating did not affect the dissolution. It is known that the use of a large amount of water-soluble polymer binder generates coarse particles, which deteriorates the tableting properties and dissolution properties of the tablet. However, in the present invention, a relatively large amount of water-soluble polymer binder such as hydroxypropyl cellulose, polyvinyl alcohol, or hydroxypropyl methylcellulose was deliberately used, and it was possible to produce a miniaturized tablet that shows good dissolution properties without tableting problems. [Industrial Applicability]

[0181] It has been found that the present invention, which is characterized by being produced using a fluidized bed granulation method and containing a disintegrant and one or more water-soluble binders selected from the group consisting of a high proportion of hydroxypropylcellulose, polyvinyl alcohol, and hydroxypropylmethylcellulose, makes it possible to stably produce small imeglimin tablets with excellent dissolution properties. This makes it possible to stably provide tablets that are more effective and result in a higher rate of continued medication, enabling better diabetes treatment.

Claims

1. A granule containing (1) imeglimin or a pharma- ceutically acceptable salt thereof, (2) one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose, and (3) a disintegrant, and produced by a fluidized bed granulation method, wherein a tablet produced from the granules and a mixed component containing (4) a fluidizer and (5) a lubricant has a composition ratio of (1) of 84 to 95 wt % and a composition ratio of (2) of 4.5 to 6.0 wt % relative to the tablet.

2. The granule according to claim 1, wherein the tablet contains (1) 88 to 95 wt % of imeglimin or a pharma- ceutically acceptable salt thereof.

3. The granule according to claim 1, wherein the tablet contains (1) 90 to 95 wt % of imeglimin or a pharma- ceutically acceptable salt thereof.

4. The granule according to claim 1, wherein the tablet contains (1) 90 to 92 wt % of imeglimin or a pharma- ceutically acceptable salt thereof.

5. The granules according to claim 1 or 2, wherein the tablet contains (3) a disintegrant in an amount of 0.2 to 7.5 wt %.

6. The granules according to any one of claims 1 to 4, wherein the tablet contains (3) a disintegrant in an amount of 0.2 to 5.0 wt %.

7. The granules according to any one of claims 1 to 4, wherein the tablet contains (3) a disintegrant in an amount of 0.2 to 4.0 wt %.

8. The granules according to any one of claims 1 to 4, wherein the tablet contains (3) a disintegrant in an amount of 0.2 to 3.0 wt %.

9. The granule according to any one of claims 1 to 4, wherein the tablet contains (3) a disintegrant in an amount of 0.2 to 2.0 wt %.

10. The granules according to claim 1 or 2, wherein the tablet contains (3) a disintegrant in an amount of 0.5 to 7.5 wt %.

11. The granules according to any one of claims 1 to 4, wherein the tablet contains (3) a disintegrant in an amount of 0.5 to 5.0 wt %.

12. The granules according to any one of claims 1 to 4, wherein the tablet contains (3) a disintegrant in an amount of 0.5 to 4.0 wt %.

13. The granules according to any one of claims 1 to 4, wherein the tablet contains (3) a disintegrant in an amount of 0.5 to 3.0 wt %.

14. The granules according to any one of claims 1 to 4, wherein the tablet contains (3) a disintegrant in an amount of 0.5 to 2.0 wt %.

15. The granule according to any one of claims 1 to 14, wherein the tablet contains (2) 4.5 to 5.5 wt % of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose.

16. The granule according to any one of claims 1 to 14, wherein the tablet contains (2) 4.8 to 5.5 wt % of one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose.

17. The granule according to any one of claims 1 to 16, wherein the viscosity of the hydroxypropyl cellulose is 2.0 to 400 mPa·s.

18. The granule according to any one of claims 1 to 16, wherein the viscosity of the hydroxypropyl cellulose is 6.0 to 400 mPa·s.

19. The granule according to any one of claims 1 to 18, wherein the viscosity of the polyvinyl alcohol is 3.4 to 9.2 mPa·s.

20. The granule according to any one of claims 1 to 18, wherein the viscosity of the polyvinyl alcohol is 4.3 to 5.8 mPa·s.

21. The granule according to any one of claims 1 to 20, wherein the viscosity of the hydroxypropyl methylcellulose is 4.0 to 12.0 mPa·s.

22. The granule according to any one of claims 1 to 20, wherein the viscosity of the hydroxypropyl methylcellulose is 4.0 to 6.0 mPa·s.

23. The granule according to any one of claims 1 to 20, wherein the viscosity of the hydroxypropyl methylcellulose is 4.5 to 6.0 mPa·s.

24. The tablet contains 3.5 wt % or less of hydroxypropyl cellulose having a viscosity of 2.0 to 2.9 mPa s and 1.5 wt % or less of hydroxypropyl cellulose having a viscosity of 150 to 400 mPa s. The granule according to any one of claims 1 to 17 and 19 to 23.

25. (2) The granule according to any one of claims 1 to 20 and 24, wherein the binder is one or two selected from the group consisting of hydroxypropyl cellulose and polyvinyl alcohol.

26. (2) The granule according to any one of claims 1 to 18 and 21 to 24, wherein the binder is one or two selected from the group consisting of hydroxypropyl cellulose and hydroxypropyl methylcellulose.

27. (2) The granule according to any one of claims 1 to 18 and 24 to 26, wherein the binder is hydroxypropyl cellulose.

28. (3) The granule according to any one of claims 1 to 27, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and crospovidone.

29. (3) The granule according to any one of claims 1 to 28, wherein the disintegrant is croscarmellose sodium.

30. 2. The method for producing the granulated granules according to claim 1, comprising a step of producing granulated granules containing (1) imeglimin or a pharma- ceutical acceptable salt thereof, (2) one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose, and (3) a disintegrant, by using a fluidized bed granulation method.

31. The method for producing the composition according to claim 30, comprising the steps of adding (2) one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and hydroxypropyl methylcellulose to a powder containing (1) imeglimin or a pharma- ceutical acceptable salt thereof and (3) a disintegrant, and producing the composition by using a fluidized bed granulation method.

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