Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

• the present invention relates to a pharmaceutical composition containing imegrimin or a pharmaceutically acceptable salt thereof, which is a small tablet having excellent manufacturability and dissolution property.
• Imegrimin is widely known as a therapeutic agent for diabetes mellitus and is used for the treatment of type 2 diabetes. However, it is necessary to orally administer a large amount of 200 to 4000 mg per day (Patent Document 1), and there is a problem in the method of oral administration thereof. was there.
• Patent Document 1 discloses a film-coated tablet having an imegrimin content of 83.4% as an orally-administered preparation of imegrimin, but does not disclose a specific manufacturing method thereof.
• Patent Document 2 discloses a tablet having an imegrimin content of 87.0%, which is produced on a 1 kg scale by using a direct tableting method in which a prescription component is mixed and tableted as an orally-administered preparation of imegrimin.
• the direct tableting method is easy to manufacture on a small scale, the powder compression time at the time of tableting decreases as the manufacturing scale increases, and if the compression moldability of the drug is poor, there may be a locking disorder. It may occur and it may be difficult to lock. Therefore, a method capable of stably producing an oral tablet of imegrimin on a large scale has not been substantially known.
• the subject of the present invention is a miniaturized tablet containing a high content of imegrimin per tablet and having excellent dissolution property for administration of imegrimin in a very large daily dose, and production thereof that can be stably supplied. To provide a method.
• the present inventors showed excellent elution by using a disintegrant and a high proportion of hydroxypropyl cellulose, polyvinyl alcohol or / and hydroxypropyl methyl cellulose as a water-soluble binder. Moreover, it was found that a very miniaturized imagerimin tablet can be stably produced. It was also found that the fluidized bed granulation method is used as the production method.
• the present invention is as follows.
• One or more binders selected from the group consisting of (1) 84-95 wt% of imeglycin or a pharmaceutically acceptable salt thereof, (2) hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose, and (3) Tablets containing a disintegrant.
• [Item 2] (1) The tablet according to Item 1, which contains 88 to 95 wt% of imeglycin or a pharmaceutically acceptable salt thereof.
• [Item 2'] One or more binders selected from the group consisting of (1) 88-95 wt% of imeglycin or a pharmaceutically acceptable salt thereof, (2) hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose, and (3) Tablets containing a disintegrant.
• Item 19 The tablet according to any one of Items 1 to 18, wherein the hydroxypropyl cellulose has a viscosity of 2.0 to 400 mPa ⁇ s.
• Item 20 The tablet according to any one of Items 1 to 19, wherein the hydroxypropyl cellulose has a viscosity of 6.0 to 400 mPa ⁇ s.
• Item 21 The tablet according to any one of Items 1 to 20, wherein the polyvinyl alcohol has a viscosity of 3.4 to 9.2 mPa ⁇ s.
• Item 22 The tablet according to any one of Items 1 to 21, wherein the polyvinyl alcohol has a viscosity of 4.3 to 5.8 mPa ⁇ s.
• Item 6 The tablet according to any one of Items 1 to 22, wherein the viscosity of hydroxypropyl methylcellulose is 4.0 to 12.0 mPa ⁇ s.
• Item 6 The tablet according to any one of Items 1 to 23, wherein the viscosity of hydroxypropyl methylcellulose is 4.0 to 6.0 mPa ⁇ s.
• Item 6 The tablet according to any one of Items 1 to 24, wherein the viscosity of hydroxypropyl methylcellulose is 4.5 to 6.0 mPa ⁇ s.
• Item 32 The tablet according to any one of Items 1 to 31, which is produced by using a fluidized bed granulation method.
• Item 8 The method for producing a tablet according to any one of Items 1 to 31, which is produced by using a fluidized bed granulation method.
• Item 34 Item 2. The tablet according to any one of Items 1 to 18, which is produced by using a fluidized bed granulation method.
• Item 8 The method for producing a tablet according to any one of Items 1 to 18, which is produced by using a fluidized bed granulation method.
• Imeglycin or a pharmaceutically acceptable salt thereof (2) one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose, and (3) disintegrant.
• the method for producing a tablet according to Item 35 which comprises a step of producing granulated granules containing the above using a fluidized bed granulation method.
• Item 37 One or two selected from the group consisting of (2) hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose in a powder containing (1) imeglycin or a pharmaceutically acceptable salt thereof and (3) a disintegrant.
• Item 3 The method for producing a tablet according to Item 36, which comprises a step of adding the above binder and producing using the fluidized bed granulation method.
• Item 38 Item 3. The production method according to Item 36 or 37, further comprising a tableting step or a film coating step.
• Item 38 The production method according to Item 38, wherein any of the fluidized bed granulation step, the tableting step, and the film coating step is manufactured in a production amount of 10 kg or more.
• Item 38 The production method according to Item 38, wherein any of the fluidized bed granulation step, the tableting step, and the film coating step is manufactured in a production amount of 30 kg or more.
• Item 38 The production method according to Item 38, wherein any of the fluidized bed granulation step, the tableting step, and the film coating step is manufactured in a production amount of 50 kg or more.
• the imegrimin composition in the present invention has poor compressibility by being produced by a fluidized bed granulation method using a disintegrant and a large amount of hydroxypropyl cellulose, polyvinyl alcohol or / and hydroxypropyl methyl cellulose as a binder.
• imegrimin has a manufacturability that enables stable supply on a production scale.
• the imegrimin composition in the present invention has good dissolution property, and it is possible to provide an oral preparation having excellent bioavailability.
• the imegrimin composition in the present invention has a very high content of imegrimin, so that it is possible to provide a miniaturized tablet that can be easily taken.
• the tablets of the present invention are uncoated tablets, film-coated tablets in which the surface of the uncoated tablets is film-coated (sometimes referred to as FC tablets in the present specification), and sugar-coated surfaces of the uncoated tablets. It contains a sugar-coated tablet-like form, and is preferably an uncoated tablet or a film-coated tablet.
• the uncoated tablet contains an imeglycin-containing composition, and may optionally contain other additives to the extent that the function of the present invention is not lost.
• the imeglycin-containing composition is selected from the group consisting of (1) imegrimin or a pharmaceutically acceptable salt thereof, and (2) hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methyl cellulose as a water-soluble polymer binder 1 Seeds or two or more, (3) containing disintegrants, optionally containing excipients and lubricants, and optionally other additives to the extent that the functionality of the invention is not lost. It may be included.
• the film coating contains a film coating agent, and may optionally contain other additives to the extent that the functions of the present invention are not lost.
• Imegrimin in the present invention is a compound known as a therapeutic agent for diabetes, and its chemical names are (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.
• "Imeglycin” is (6S) -N 2 , N 2 , 6-trimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine (CAS Registry Number: 1251468-04-8). Also includes.
• the present invention includes all forms of imegrimin (eg, tautomers, amorphous, crystalline, various crystalline polymorphs, etc.), including optical isomers thereof or mixtures thereof.
• the R form of the mixture is preferably contained in an amount of 90 wt% or more, 95 wt% or more, 97 wt% or more, 99 wt% or more.
• the imegrimin used in the present invention may be pulverized to a desired particle size, if necessary.
• the average particle size (50% particle size, D50) by volume ratio includes, for example, a range of 11 to 274 ⁇ m, preferably 11 ⁇ m to 169 ⁇ m.
• the composition ratio of imeglycin 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 imegrimin in the present invention is preferably 90 wt% or less, 92 wt% or less, and 95 wt% or less.
• the content of imegrimin or a pharmaceutically acceptable salt thereof contained in one tablet of the tablet of the present invention is preferably 500 mg.
• a pharmaceutically acceptable salt of imegrimin includes, but is not limited to, an acid addition salt.
• the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate and phosphate, or citrate, oxalate and phthalate. Fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonic acid Examples thereof include organic acid salts such as salts and camphor sulfonates, and further include amino acid salts with acidic amino acids.
• the pharmaceutically acceptable salt of imegrimine is preferably hydrochloride.
• (C) Hydroxypropyl Cellulose The viscosity of hydroxypropyl cellulose in the present invention is not particularly limited, but has 2.0 to 400 mPa ⁇ s, preferably 6.0 to 400 mPa ⁇ s.
• the composition ratio of hydroxypropyl cellulose in the tablet of the present invention is not particularly limited, but the content of hydroxypropyl cellulose showing a viscosity of 2.0 to 2.9 mPa ⁇ s is 3.5 wt% or less and 150 to 400 mPa ⁇ s. It is preferable to contain hydroxypropyl cellulose in the range of 1.5 wt% or less.
• Hydroxypropyl cellulose is preferably contained in an amount of 4.5 wt% or more, 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more.
• Hydroxypropyl cellulose is preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less%, 5 7.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, 6.0 wt% or less, 6.1 wt% or less, 6.2 wt% or less, 6.3 wt% or less, 6.4 wt% or less, 6.5 wt% % Or less, 6.6 wt% or less, 6.7 wt% or less, 6.8 wt% or less, 6.9 wt% or less, 7.0 wt% or less.
• Hydroxypropyl cellulose is more preferably contained in an amount of 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more.
• Hydroxypropyl cellulose is more preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less, It includes 5.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, and 6.0 wt% or less.
• Hydroxypropyl cellulose is most preferably contained in an amount of 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more. Hydroxypropyl cellulose is most preferably contained in an amount of 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, and 5.5 wt% or less.
• the polyvinyl alcohol in the present invention is a polyvinyl alcohol-based resin and contains a polyvinyl alcohol derivative.
• Polyvinyl alcohol (PVA) is preferred.
• PVA partially saponified product of polyvinyl alcohol (PVA).
• a saponification degree of 97 mol% or more is called a complete saponification, and a saponification degree of 79 to 96 mol% is called a partial saponification.
• the polyvinyl alcohol in the present invention is not particularly limited, but has 3.4 to 9.2 mPa ⁇ s, preferably 4.3 to 5.8 mPa ⁇ s, and more preferably 4.8 to 5.8 mPa ⁇ s.
• the polyvinyl alcohol in the tablet of the present invention preferably contains, for example, 4.5 wt% or more, 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, 5.0 wt% or more. ..
• Polyvinyl alcohol is preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt%, 5.6 wt% or less, 5.7 wt.
• Polyvinyl alcohol is more preferably contained in an amount of 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more.
• Polyvinyl alcohol is more preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less%, 5 It includes 7.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, and 6.0 wt% or less.
• Polyvinyl alcohol is most preferably contained in an amount of 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more.
• Polyvinyl alcohol is most preferably contained in an amount of 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, and 5.5 wt% or less.
• the polyvinyl alcohol-based resin in the present invention also includes, for example, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol graft copolymer and the like.
• the viscosity of hydroxypropyl methylcellulose in the present invention is not particularly limited, but has 4.0 to 12.0 mPa ⁇ s, and is preferably 4.0 to 6.0 mPa ⁇ s. It has 5 to 6.0 mPa ⁇ s.
• the hydroxypropyl methylcellulose in the tablet of the present invention preferably contains 4.5 wt% or more, 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more.
• the hydroxypropyl methylcellulose is preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less, 5 7.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, 6.0 wt% or less, 6.1 wt% or less, 6.2 wt% or less, 6.3 wt% or less, 6.4 wt% or less, 6.5 wt% % Or less, 6.6 wt% or less, 6.7 wt% or less, 6.8 wt% or less, 6.9 wt% or less, 7.0 wt% or less.
• the hydroxypropyl methylcellulose is more preferably contained in an amount of 4.6 wt% or more, 4.7 wt% or more, 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more.
• the hydroxypropyl methylcellulose is more preferably 5.0 wt% or less, 5.1 wt% or less, 5.2 wt% or less, 5.3 wt% or less, 5.4 wt% or less, 5.5 wt% or less, 5.6 wt% or less, It includes 5.7 wt% or less, 5.8 wt% or less, 5.9 wt% or less, and 6.0 wt% or less.
• the hydroxypropyl methylcellulose is most preferably contained in an amount of 4.8 wt% or more, 4.9 wt% or more, and 5.0 wt% or more.
• the 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, 5.5 wt% or less.
• the disintegrant used in the present invention is necessary to prevent the drug from absorbing water and dissolving or solidifying during wet granulation, and to exhibit good fluidity in the manufacturing apparatus during granulation. .. In order to achieve miniaturization of tablets, it is desirable to show good water absorption and disintegration after tableting even when the content in the tablets is low.
• the disintegrant used in the present invention is not particularly limited, but a disintegrant usually used in the formulation can be used.
• starches low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, crospovidone, croscarmellose sodium, sodium carboxymethyl starch (also referred to as sodium starch glycolate) and the like can be mentioned.
• two or more kinds of disintegrants may be used. It is preferably crospovidone, croscarmellose sodium, carboxymethyl starch sodium, and more preferably croscarmellose sodium.
• the disintegrant in the tablet of the present invention preferably contains 0.1 wt% or more, 0.2 wt% or more, 0.5 wt% or more, 1.0 wt% or more, and 1.5 wt% or more.
• the disintegrant is preferably 7.5 wt% or less, 7.4 wt% or less, 7.3 wt% or less, 7.2 wt% or less, 7.1 wt% or less, 7.0 wt% or less, 6.9 wt% or less, 6.
• the excipient used in the present invention is not particularly limited, but an excipient usually used in the formulation can be used.
• an excipient usually used in the formulation can be used.
• crystalline cellulose, sugar, sugar alcohol and the like can be mentioned.
• sugar or sugar alcohol include mannitol, erythritol, xylitol, maltitol, sorbitol, lactose, sucrose, trehalose and the like.
• the excipient may be used alone or in combination of two or more.
• the content of the excipient is preferably 0.1 wt% or more, 0.5 wt% or more, 1.0 wt% or more, and 2.0 wt% or more.
• the content of the excipient is preferably 7.5 wt% or less, 7.4 wt% or less, 7.3 wt% or less, 7.2 wt% or less, 7.1 wt% or less, 7.0 wt% or less, 6.9 wt.
• a lubricating agent can be added. Depending on the type of drug substance and granules, the lubricant prevents the drug substance and granules from adhering to the mortar at the time of tableting, and efficient production of tablets is expected.
• the lubricant may be mixed with other components before tableting, or may be sprayed onto the mortar at the time of tableting.
• the lubricant used in the present invention is not particularly limited, and examples thereof include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, carnauba wax, and sucrose fatty acid ester. These lubricants can be used alone or in combination of two or more.
• the lubricant used in the present invention is preferably magnesium stearate.
• the content of the lubricant is preferably 0.1 wt% or more, 0.2 wt% or more, 0.4 wt% or more, 0.6 wt%, 0.8 wt% or more, and 1.0 wt% or more.
• the content of the lubricant is preferably 4.0 wt% or less, 3.5 wt% or less, 3.0 wt% or less, 2.5 wt% or less, 2.0 wt% or less, 1.8 wt% or less, 1.6 wt. % Or less, 1.4 wt% or less, 1.2 wt% or less, 1.0 wt% or less.
• the content of the lubricant is more preferably 0.4 wt% or more, 0.6 wt%, 0.8 wt% or more, and 1.0 wt% or more.
• the content of the lubricant is more preferably 2.0 wt% or less, 1.8 wt% or less, 1.6 wt% or less, 1.4 wt% or less, 1.2 wt% or less, and 1.0 wt% or less.
• additives can be added to the tablets of the present invention to the extent that the functions of the present invention are not lost.
• Other additives include, for example, sweeteners, flavoring agents, flavoring agents, fragrances, fluidizing agents (eg Aerosil), antistatic agents, colorants, plasticizers, anti-aggregating agents, brightening agents (eg carnauba wax). , Talc), etc., but is not limited to these.
• film coating agent examples include hypromerose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid.
• a combination of a base material such as acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer, and a plasticizer such as polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, and glycerin fatty acid ester is available.
• a plasticizer such as polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, and glycerin fatty acid ester
• additives such as titanium oxide, iron oxide, talc, and a colorant can be added.
• the base material is hypromellose, hydroxypropyl cellulose and polyvinyl alcohol
• the plasticizer is polyethylene glycol, propylene glycol and triethyl citrate.
• Excellent elution Excellent dissolution means preferably 80% or more, 85% or more, 90 at 30 minutes when the dissolution test of the prototype product is carried out under the following dissolution test conditions in accordance with the second method of the Japanese Pharmacopoeia dissolution test. It shows an elution rate of% or more and 95% or more, and preferably 97% or more, 98% or more, and 99% or more at 60 minutes. Further, at 60 minutes, the elution rate is preferably 103% or less, 102% or less, and 100% or less.
• Test solution Japanese Pharmacopoeia dissolution test 2nd solution Paddle rotation speed: 50 rpm
• Test solution 900 mL
• the large-scale production in the present invention means that any of the granulation step, the tableting step, and the film coating step is preferably performed in an 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. As mentioned above, the production is carried out with a production amount (preparation amount) of 45 kg or more and 50 kg or more.
• viscosity refers to the viscosity when measuring a 2 wt% polymer aqueous solution at 20 ° C. using a B-type viscometer.
• a granulation method capable of producing granules having excellent compression moldability in order to prevent tableting obstacles and obtain a tablet having an appropriate hardness. Is desirable.
• a fluidized bed granulation method can be mentioned, preferably a fluidized bed granulation method in which a binder solution is sprayed, but a fluidized bed granulation method in which a part of the binder is added as a powder may also be used.
• the present invention is not limited to these, but the following is an example of a process for producing a film-coated tablet by, for example, a fluidized bed granulation method.
• Hydroxypropyl Cellulose Aqueous Solution Hydroxypropyl cellulose is dissolved in purified water.
• the amount of hydroxypropyl cellulose is selected from, for example, 1 to 20 wt%, preferably 2 to 6.5 wt% with respect to the amount of purified water.
• a fluidizing agent and a lubricant are added to the imeglycin-containing composition dried in (3) above and mixed.
• a mixer classified as a stirring mixer is used for mixing.
• Specific examples include a tumbler blender, a V blender, a double cone, and a bin tumbler. However, it is not limited to these.
• Locking (locking process)
• the above mixture is tableted to prepare an uncoated tablet.
• the locking device include a locking machine classified as a rotary type.
• Film coating (film coating process) A film coat is applied to the uncoated lock.
• the coating device include a device classified as a coating pan. Devices are preferably classified as a ventilated coating system.
• Drying the film-coated tablet The film-coated tablet is dried. Drying is carried out under reduced pressure or normal pressure so that the drying weight loss value measured at 80 ° C. with an infrared moisture meter or a halogen type moisture meter is, for example, 3 wt% or less, preferably 2 wt% or less.
• Imeglycin hydrochloride Sumitomo Dainippon Pharma Co., Ltd. Crystalline cellulose (Theoras TM PH-101): Asahi Kasei Co., Ltd. Light anhydrous silicic acid (AEROSIL TM 200): Japan Aerosil Co., Ltd. Croscarmellose sodium (Ac-Di-Sol TM SD-) 711): FMC Health and Nutrition Hydroxypropyl cellulose (HPC-SSL / 2.0 to 2.9 mPa ⁇ s Note 1) ): Nippon Soda Co., Ltd.
• Hydroxypropyl cellulose (HPC-L / 6.0 to 10.0 mPa ⁇ s Note 1 )): Nippon Soda Hydroxypropyl Cellulose Co., Ltd. (HPC-M / 150-400 mPa ⁇ s Note 1) ): Nippon Soda Co., Ltd.
• Hypromellose (Hydroxypropyl Methyl Cellulose) (TC-5R TM / 6 mPa ⁇ s Note 2) ): Shin-Etsu Chemical Co., Ltd.
• Povidon (Kollidon TM K30 / 5.5-8.5 mPa ⁇ s Note 3) ): BASF Polyvinyl alcohol (Gohsenol TM EG-05P / 4.8-5.8 mPa ⁇ s Note 4) ): Mitsubishi Chemical Co., Ltd. Magnesium stearate (magnesium stearate (vegetable)): Taihei Chemical Industry Co., Ltd. OPADRY TM tm 07F28588 WHITE : Japan Talc GK (luxury talc MSP): Japan Talc Co., Ltd.
• Cross Povidon (Kollidon TM CL): BASF Sodium Starch Glycolate (Primogel TM ): DFE Pharma Note 1) Manufacturer's catalog value at 20 ° C and 2% solution. Note 2) Manufacturer's catalog value at 20 ° C and 2% solution. Note 3) Manufacturer's catalog value at 20 ° C and 10% solution. Note 4) Manufacturer's catalog value at 20 ° C and 4% solution.
• Example 1 Tablet containing 500 mg of imegrimine hydrochloride (1)
• A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride
• Granulated granules, mixed powders and uncoated tablets having the compositions shown in Table 1-1 were produced.
• magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).
• Example 2 Tablets containing 500 mg of imegrimine hydrochloride (2) A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride Granulated granules, mixed powder and uncoated tablets having the composition shown in Table 2-1 were produced.
• magnesium stearate was put into a V2 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-3 type).
• Example 3 Tablets containing 500 mg of imegrimine hydrochloride (3)
• A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride
• Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 3-1 were produced.
• magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).
• Example 4 Tablets containing 500 mg of imegrimine hydrochloride (4) A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 4-1 were produced.
• magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).
• Example 5 Tablets containing 500 mg of imegrimine hydrochloride (5)
• Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 5-1 were produced.
• the 4 wt% hydroxypropyl cellulose solution (2) of the charged amount shown in Table 5-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were passed through a granulator (manufactured by Paulec, Comil 194S type) set to have an opening of 1.4 mm and a rotation speed of 1400 rpm to obtain granulated granules containing imegrimine hydrochloride.
• a granulator manufactured by Paulec, Comil 194S type
• a mixed powder containing imegrimine hydrochloride was produced in the amount shown in Table 5-4.
• Granulated granules containing the amount of imegrimine hydrochloride shown in Table 5-4 are put into an 800 L container, and then the amount of light anhydrous silicic acid shown in Table 5-4 is added to the container mixer. (Tumbler blender manufactured by Yamazaki Metal Machinery Co., Ltd.) was used to mix at 12 rpm for 5 minutes. Subsequently, magnesium stearate was put into an 800 L container, and further mixed at 12 rpm for 5 minutes using a container mixer (manufactured by Yamazaki Metal Machinery Co., Ltd., tumbler blender).
• Example 6 Tablet containing 500 mg of imegrimine hydrochloride (6)
• A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride
• Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 6-1 were produced.
• the 4 wt% hydroxypropyl cellulose solution (3) of the charged amount shown in Table 6-2 was sprayed while flowing. Then, it was dried while flowing until the exhaust temperature reached 45 ° C., and then taken out from the container. Further, the granules taken out were passed through a granulator (manufactured by Paulec, Comil 194S type) set to have an opening of 1.4 mm and a rotation speed of 1400 rpm to obtain granulated granules containing imegrimine hydrochloride.
• a granulator manufactured by Paulec, Comil 194S type
• the mixed powder containing imegrimine hydrochloride was produced in the amount shown in Table 6-4.
• the granulated granules containing the amount of imegrimine hydrochloride shown in Table 6-4 are charged, and then the amounts of light anhydrous silicic acid and magnesium stearate shown in Table 6-4 are lightly added.
• the mixture was added and mixed using a container mixer (manufactured by Yamazaki Metal Machinery Co., Ltd., tumbler blender) at 12 rpm for 5 minutes.
• a film-coated tablet containing 500 mg of Imegrimine Hydrochloride was produced under the conditions shown in Table 6-6.
• a coating machine (AQC-170FS type manufactured by Freund Sangyo Co., Ltd.), and the exhaust temperature becomes 50 ° C. under the conditions shown in Table 6-6 while rotating the coating pan. Warmed up to.
• the film coating liquid (1) was sprayed under the conditions shown in Table 6-6, and the film was coated until the film amount became about 14 mg.
• the coating pan was dried at 2 rpm until the exhaust temperature reached 55 ° C., and 21.38 g of talc was sprayed.
• Example 7 Tablets containing 500 mg of imegrimine hydrochloride (7)
• A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride
• the mixed powder containing imegrimine hydrochloride was produced in the amount shown in Table 7-4.
• Granulated granules containing the amount of imegrimine hydrochloride shown in Table 7-4 are put into a 110 L container, and then the amount of light anhydrous silicic acid shown in Table 7-4 is added to the container mixer.
• Mixing was carried out at 20 rpm for 10 minutes using (Pix Blender, manufactured by Pick Steknica). Subsequently, magnesium stearate was put into a 110 L container, and the mixture was further mixed at 20 rpm for 5 minutes using a container mixer (Pix Blender, manufactured by Pixtecnica).
• Example 8 Tablets containing 500 mg of imegrimine hydrochloride (8)
• A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride
• Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 8-1 were produced.
• magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).
• Example 9 Tablets containing 500 mg of imegrimine hydrochloride (9)
• A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride
• Granulated granules, mixed powders and uncoated tablets having the compositions shown in Table 9-1 were produced.
• granules containing imegrimine hydrochloride were prepared through a granulator (manufactured by Paulec, Comil 194S type) set to have an opening of 1.4 mm and a rotation speed of 1400 rpm.
• Example 10 Tablet (10) containing 500 mg of imegrimine hydrochloride A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride Granulated granules, mixed powders and uncoated tablets having the compositions shown in Table 10-1 were produced.
• granules containing imegrimine hydrochloride were prepared through a granulator (manufactured by Paulec, Comil 194S type) set to have an opening of 1.4 mm and a rotation speed of 1400 rpm.
• the mixed powder containing imegrimine hydrochloride was produced in the amount shown in Table 10-4.
• the amount of light anhydrous silicic acid shown in Table 10-4 was put into a plastic bag containing the granulated granules containing the amount of imegrimine hydrochloride shown in Table 10-4, and the mixture was shaken for 2 minutes. Then, the amount of magnesium stearate shown in Table 10-4 was added, and the mixture was further shaken for 1 minute to mix.
• Example 11 Tablets containing 500 mg of imegrimine hydrochloride (11) A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride Granulated granules, mixed powders and uncoated tablets having the compositions shown in Table 11-1 were produced.
• Example 12 Tablets containing 500 mg of imegrimine hydrochloride (12)
• A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride
• Granulated granules, mixed powders and uncoated tablets having the compositions shown in Table 12-1 were produced.
• Example 13 Tablets containing 500 mg of imegrimine hydrochloride (13) A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride Granulated granules, mixed powders and uncoated tablets having the compositions shown in Table 13-1 were produced.
• Comparative Example 1 Tablets containing 167 mg of imegrimine hydrochloride (14)
• Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 14-1 were produced.
• granules containing imegrimine hydrochloride were prepared through a granulator (manufactured by Paulec, Comil 194S type) set to have an opening of 1.4 mm and a rotation speed of 1400 rpm.
• the mixed powder containing imegrimine hydrochloride was produced in the amount shown in Table 14-4.
• the amount of light anhydrous silicic acid shown in Table 14-4 was put into a plastic bag containing the granulated granules containing the amount of imegrimine hydrochloride described in Table 14-4, and the mixture was shaken for 2 minutes. Then, the amount of magnesium stearate shown in Table 14-4 was added, and the mixture was further shaken for 1 minute to mix.
• Comparative Example 2 Tablet (15) containing 500 mg of imegrimine hydrochloride A. Formulation of uncoated tablets containing 500 mg of imeglycin hydrochloride Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 15-1 were produced.
• granules containing imegrimine hydrochloride were prepared through a granulator (manufactured by Paulec, Comil 194S type) set to have an opening of 1.4 mm and a rotation speed of 1400 rpm.
• magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).
• Comparative Example 3 Tablet (16) containing 500 mg of imegrimine hydrochloride A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 16-1 were produced.
• the granules were sized with a granulator (manufactured by Paulec, Comil 194S type) set to have an opening of 1.4 mm and a rotation speed of 1400 rpm to obtain granulated granules containing imegrimine hydrochloride. Two of these granulated granules were produced.
• a granulator manufactured by Paulec, Comil 194S type
• magnesium stearate was put into a V10 type container, and further mixed at 40 rpm for 5 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type).
• Comparative Example 4 Tablet (17) containing 500 mg of imegrimine hydrochloride A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 17-1 were produced.
• the granules containing imegrimine hydrochloride are passed through a sieve having a mesh size of 1000 ⁇ m and then passed through a granulator (Paulec, Komil 194S type) set to a mesh size of 1.4 mm and a rotation speed of 1400 rpm. And said.
• Comparative Example 5 Tablet (18) containing 500 mg of imegrimine hydrochloride A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride Granulated granules, mixed powders and uncoated tablets having the composition shown in Table 18-1 were produced.
• Comparative Example 6 Tablet containing 500 mg of imegrimine hydrochloride (19) A. Formulation of Uncoated Tablets Containing 500 mg of Imegrimine Hydrochloride A mixed powder and uncoated tablets having the compositions shown in Table 19-1 were produced.
• a mixed powder containing imegrimine hydrochloride was produced in the amount shown in Table 19-2.
• the amounts of imegrimine hydrochloride, light anhydrous silicic acid, hydroxypropyl cellulose, and croscarmellose sodium shown in Table 19-2 were put into a plastic bag and shaken for 2 minutes. Then, the amount of magnesium stearate shown in Table 19-2 was added, and the mixture was further shaken for 1 minute to mix.
• Comparative Example 7 Tablet (20) containing 388 mg of imegrimine hydrochloride A. Formulation of Uncoated Tablets Containing 388 mg of Imegrimine Hydrochloride Granulated granules, mixed powders and uncoated tablets having the compositions shown in Table 20-1 were produced.
• granules containing imegrimine hydrochloride were prepared through a granulator (manufactured by Paulec, Comil 194S type) set to have an opening of 1.4 mm and a rotation speed of 1400 rpm.
• the mixed powder containing imegrimine hydrochloride was produced in the amount shown in Table 20-4.
• the amount of light anhydrous silicic acid shown in Table 20-4 was put into a plastic bag containing the granulated granules containing the amount of imegrimine hydrochloride described in Table 20-4, and the mixture was shaken for 2 minutes. Then, the amount of magnesium stearate shown in Table 20-4 was added, and the mixture was further shaken for 1 minute to mix.
• Test Example 1 Bulk Density of Mixed Powder
• the bulk density of the mixed powder was measured for Examples 1 to 13 and Comparative Examples 1, 2, 4 to 7.
• Test Example 2 Evaluation of tableting property and measurement of shape, hardness, and abrasion degree of uncoated tablet For Examples 1 to 13 and Comparative Examples 1 to 7, the tableting property was evaluated, and the thickness, hardness, and abrasion degree of the uncoated tablet were evaluated. Was measured.
• the thickness and hardness of the uncoated tablets MultiCheck 5 manufactured by ERWEKA was used, and the average value of 5 tablets or 10 tablets was described.
• the tablet abrasion degree test was measured using a FRIABILATOR TFT-1200 manufactured by Toyama Sangyo in accordance with the test method described in the Japanese Pharmacopoeia. The measurement results are shown in Table 22.
• Test Example 3 Estimated number of administered preparations per day Table 23 shows the estimated number of administered preparations per day. Since the comparative example could not be locked stably due to capping, it was calculated from the following formula assuming that the mixed powder was filled in the capsule. The calculated number of administered preparations was calculated as an integer by rounding up the first decimal place.
• Number of pharmaceutical products to be administered mass of mixed powder (g) / bulk density (g / mL) / volume of capsule body (mL) corresponding to 2000 mg ⁇ Capsule size> Volume 1 capsule body (mL): Approximately 0.50 Overall length (mm) at the time of connection: Approximately 19.4 Body outer diameter (mm): Approximately 6.63 Volume 2 capsule body (mL): Approximately 0.37 Overall length (mm) at the time of connection: Approximately 18.0 Body outer diameter (mm): Approximately 6.07 As shown in Table 23, the present application can clearly reduce the number of dosages administered per day, which is expected to improve productivity and medication adherence.
• Test Example 4 Dissolution Test The tablets produced in Examples 1 to 13 and Comparative Example 7 were subjected to a dissolution test under the following conditions in accordance with the Japanese Pharmacopoeia General Test Method Dissolution Test Method.
• a Millipore membrane filter Millipore membrane filter
• the dissolution test results are shown in Table 24.
• Table 24 the uncoated tablet or FC tablet of the present invention is rapidly eluted and is expected to be highly absorbable in vivo.
• the presence or absence of film coating did not affect the elution property.
• hydroxy which is a water-soluble polymer binder, is intentionally used.

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