WO2019146642A1 - METHOD FOR IMPROVING CHEMICAL STABILITY OF γ-AMINOBUTYRIC ACID DERIVATIVE- CONTAINING TABLET - Google Patents

METHOD FOR IMPROVING CHEMICAL STABILITY OF γ-AMINOBUTYRIC ACID DERIVATIVE- CONTAINING TABLET Download PDF

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WO2019146642A1
WO2019146642A1 PCT/JP2019/002083 JP2019002083W WO2019146642A1 WO 2019146642 A1 WO2019146642 A1 WO 2019146642A1 JP 2019002083 W JP2019002083 W JP 2019002083W WO 2019146642 A1 WO2019146642 A1 WO 2019146642A1
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tablet
acid derivative
aminobutyric acid
weight
preferable
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PCT/JP2019/002083
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French (fr)
Japanese (ja)
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浩人 寺田
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大原薬品工業株式会社
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Priority to JP2019567115A priority Critical patent/JP7138666B2/en
Publication of WO2019146642A1 publication Critical patent/WO2019146642A1/en

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a preparation containing a ⁇ -aminobutyric acid derivative (mainly pregabalin) as a drug substance, and discloses a detailed method for improving the chemical stability of the drug substance under storage conditions of chewing It is
  • Pregabalin (common name) is a derivative of ⁇ -aminobutyric acid (GABA) whose chemical name is written as (3S) -3-aminomethyl-5-methylhexanoic acid.
  • GABA ⁇ -aminobutyric acid
  • Pregabalin is an agent useful for treating neuropathic pain and pain associated with fibromyalgia. (Reference to Non-Patent Document 1, etc.).
  • pregabalin is provided to medical sites in Japan in the form of a capsule or orally disintegrating tablet.
  • the formulation and manufacturing method of tablets containing pregabalin are introduced in the following Patent Documents 1 to 3, and the like.
  • Example 7 of Patent Document 1 there is described the formulation and manufacturing method of an orally disintegrating tablet containing pregabalin, calcium silicate and the like.
  • An orally disintegrating tablet is a dosage form developed in recent years, and it is generally known that the convenience at the time of taking it is higher than that of a normal tablet because it has the property of disintegrating quickly with a small amount of water like saliva.
  • the number of documents introduced about the technology of orally disintegrating tablets containing pregabalin is scarce.
  • orally disintegrating tablets have technical differences with ordinary tablets, and it is often difficult to guarantee the quality such as the stability of the drug substance. Therefore, the present inventor aimed to develop a new technique for improving the chemical stability of ⁇ -aminobutyric acid derivatives such as pregabalin contained in the preparation.
  • the ⁇ -aminobutyric acid derivative is known to form a lactam by dehydration.
  • An object of the present invention is to provide a technical means for producing a tablet (in particular, an orally disintegrating tablet) in which the chemical stability and the like of the ⁇ -aminobutyric acid derivative are improved.
  • the present inventor found that the chemical stability of the ⁇ -aminobutyric acid derivative is in the tablet containing the ⁇ -aminobutyric acid derivative which does not contain the silicic acid based additive. I found it to be excellent. Based on the findings, the present inventor has further intensively studied to complete the present invention described below.
  • the present invention relates to a tablet or the like containing a ⁇ -aminobutyric acid derivative, and preferred configurations are described in (1) to (7) below.
  • a tablet containing a ⁇ -aminobutyric acid derivative (in particular, an orally disintegrating tablet), which is characterized by containing no silicic acid additive.
  • Silicate-based additives are silicon dioxide (including light anhydrous silicic acid, hydrous silicon dioxide etc.), calcium silicate, magnesium aluminosilicate, magnesium aluminometasilicate, magnesium silicate, aluminum silicate (1) or (2) selected from (including natural aluminum silicate, synthetic aluminum silicate, colloidal hydrous aluminum silicate and the like), and magnesium aluminum silicate (including synthetic magnesium sodium silicate and the like); The tablet as described in 2.).
  • the silicic acid based additive is selected from silicon dioxide, calcium silicate and magnesium aluminometasilicate.
  • ⁇ -aminobutyric acid derivative and the appropriate additive based on the total weight of the tablet (most preferably the ⁇ -aminobutyric acid derivative and the appropriate addition Tablets (in particular, uncoated tablets), wherein said suitable additives are the following additives (each additive below is an excipient, a disintegrant, a binder, a fluidizer, a lubricant, and The other additives are exemplified to belong to any kind of additives, but to use in other kinds which are not the kind to which they belong (example: using crystalline cellulose belonging to an excipient as a disintegrant) is used.
  • Excipients lactose, crystalline cellulose, trehalose, D-mannitol, isomalt, erythritol, corn starch, cyclodextrin Disintegrators: hydroxypropyl starch, low substituted hydroxypropyl cellulose, sodium starch glycolate, partially pregelatinized starch, carmellose Calcium, croscarmellose sodium, crospovidone Binder: hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol graft copolymer, carmellose sodium, pregelatinized starch
  • Fluidizing agent talc Lubricant: glycerin fatty acid Ester, magnesium stearate, calcium stearate, sodium stearyl fumarate, Hardened oil
  • Other additives orally disintegrating tablets containing calcium hydrogen phosphate hydrate
  • Flavoring agent An orally disintegrating tablet containing aspartame, sucralose, sodium saccharin (7) ⁇ -aminobutyric acid derivative, wherein the flavoring agent is a granulated product (preferably a dry granulated product, more preferably a ⁇ -aminobutyric acid derivative)
  • a granulated product preferably a dry granulated product, more preferably a ⁇ -aminobutyric acid derivative
  • An orally disintegrating tablet containing a ⁇ -aminobutyric acid derivative, wherein the flavoring agent is contained in the dry granulated product (preferably a melt granulated product) together with the ⁇ -aminobutyric acid derivative and a low melting point oil and fat The tablet according to (6) or (7) above, characterized in that
  • a tablet in particular, an orally disintegrating tablet
  • the chemical stability and the like of the ⁇ -aminobutyric acid derivative are improved.
  • FIG. 1 shows the results of analyzing the crystal form of pregabalin used in the examples by powder X-ray diffractometry.
  • the tablet according to one embodiment of the present invention is characterized by containing a ⁇ -aminobutyric acid derivative and a suitable additive.
  • the tablet according to the present embodiment contains a ⁇ -aminobutyric acid derivative as a drug substance.
  • ⁇ -aminobutyric acid derivative examples include 1 to 4 aliphatic hydrocarbon groups (preferably having a carbon number of the same or different types) on the carbon atom (preferably on the carbon atom at position 3).
  • ⁇ -aminobutyric acid derivative are, for example, selected from the group consisting of ⁇ -aminobutyric acid (GABA; 4-aminobutanoic acid), pregabalin, atagabalin, mirogabalin and pharmaceutically acceptable salts thereof One or more may be mentioned, and pharmaceutically acceptable salts of pregabalin or navel are preferred.
  • GABA ⁇ -aminobutyric acid
  • pregabalin atagabalin
  • mirogabalin mirogabalin
  • pharmaceutically acceptable salts of pregabalin or navel are preferred.
  • ⁇ -aminobutyric acid derivative in the present embodiment includes any of its free form (zwitter ion) and pharmaceutically acceptable complexes, salts, solvates, hydrates and polymorphs thereof.
  • the form of the ⁇ -aminobutyric acid derivative of Salts include, but are not limited to, acid addition salts and base addition salts, including hemisalts.
  • Pharmaceutically acceptable acid addition salts include those derived from inorganic acids (eg, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.)
  • inorganic acids eg, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.
  • Nontoxic salts and nontoxic salts obtained from organic acids eg, aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Potentially useful salts include acetates, aspartates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, besylates, bicarbonates, carbonates, bisulfates, Sulfate, pyrosulfate, bisulfite, sulfite, borate, camsylate, caprylate, citrate, edylate, esylate, formate, fumarate, gluceptate, gluconate, Glucuronate, hexafluorophosphate, hibenzate, hydrochloride, chloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, isobutyrate, lactate, malate Salt, maleate, malonate, mandelicate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • Pharmaceutically acceptable base addition salts may include non-toxic salts obtained from bases including metal cations (eg, alkali metal cations or alkaline earth metal cations) and amines.
  • bases including metal cations (eg, alkali metal cations or alkaline earth metal cations) and amines.
  • potentially useful salts include aluminum, arginine, N, N'-dibenzylethylenediamine, calcium, chloroprocaine, choline, diethanolamine, diethylamine, dicyclohexylamine, ethylenediamine, glycine, lysine, magnesium, N-methylgulene.
  • These include, but are not limited to, kamin, olamine, potassium, procaine, sodium, tromethamine, zinc and the like.
  • the cumulative 10% particle diameter (d10) of the ⁇ -aminobutyric acid derivative in volume-based measurement is preferably 3.0 ⁇ m or more, more preferably 5.0 ⁇ m or more, from the viewpoint of the chemical stability of the ⁇ -aminobutyric acid derivative, etc.
  • the thickness is preferably 6.0 ⁇ m or more, more preferably 7.0 ⁇ m or more. Further, from the practical viewpoint of tablet production and the like, 50.0 ⁇ m or less is preferable, 45.0 ⁇ m or less is more preferable, 35.0 ⁇ m or less is more preferable, and 25.0 ⁇ m or less is particularly preferable.
  • the cumulative 50% particle diameter (d50) of the ⁇ -aminobutyric acid derivative in volume-based measurement is preferably 9.0 ⁇ m or more, more preferably 15.0 ⁇ m or more from the viewpoint of the chemical stability of the ⁇ -aminobutyric acid derivative, etc.
  • the thickness is preferably 20.0 ⁇ m or more, more preferably 30.0 ⁇ m or more, and particularly preferably 40.0 ⁇ m or more. Further, from the practical viewpoint of tablet production and the like, 250.0 ⁇ m or less is preferable, 220.0 ⁇ m or less is more preferable, 150.0 ⁇ m or less is more preferable, and 100.0 ⁇ m or less is particularly preferable.
  • the cumulative 90% particle size (d90) of the ⁇ -aminobutyric acid derivative in volume-based measurement is preferably 30.0 ⁇ m or more, more preferably 50.0 ⁇ m or more, from the viewpoint of the chemical stability of the ⁇ -aminobutyric acid derivative 80.0 ⁇ m or more is more preferable, 110.0 ⁇ m or more is more preferable, and 140.0 ⁇ m or more is particularly preferable. Further, from the practical viewpoint of tablet production and the like, 600.0 ⁇ m or less is preferable, 550.0 ⁇ m or less is more preferable, 400.0 ⁇ m or less is more preferable, and 300.0 ⁇ m or less is particularly preferable.
  • the volume average diameter of the ⁇ -aminobutyric acid derivative is preferably 13.0 ⁇ m or more, more preferably 22.0 ⁇ m or more, and still more preferably 45.0 ⁇ m or more from the viewpoint of the chemical stability of the ⁇ -aminobutyric acid derivative, etc. 57.0 micrometers or more are especially preferable. Further, from the practical viewpoint of tablet production and the like, 400.0 ⁇ m or less is preferable, 350.0 ⁇ m or less is more preferable, 290.0 ⁇ m or less is more preferable, and 200.0 ⁇ m or less is particularly preferable.
  • the ⁇ -aminobutyric acid derivative used in the present embodiment preferably has any of the particle size distribution or volume average diameter described above, and more preferably d50 and d90 described above.
  • the particle size distribution and the volume average diameter can be measured by a laser diffraction / scattering method, and the detailed measurement conditions of soot are described in the following examples. It is possible to follow things.
  • the ⁇ -aminobutyric acid derivative is preferably 10.0 to 90.0% by weight, more preferably 20.0 to 80.0% by weight, still more preferably 20% by weight, based on the total weight of the tablet (preferably uncoated). It is contained in the tablet in the range of 0 to 60.0% by weight, more preferably 25.0 to 50.0% by weight, particularly preferably 25.0 to 40.0% by weight.
  • the content of the ⁇ -aminobutyric acid derivative per tablet includes, for example, 25 mg, 75 mg and 150 mg.
  • the form of the tablet according to the present embodiment is preferably a plain tablet compression-molded by tableting or the like, or alternatively, the plain tablet may be coated with a film coating layer containing a coating agent to form a film-coated tablet. It is possible after appropriate examination.
  • the shape of the tablet of the present invention may be any shape such as a circular tablet, a circular R tablet, a circular corner corner tablet, a circular two-tiered R tablet and a modified tablet (such as an oval tablet).
  • the dosage form of the tablet is preferably an orally disintegrating tablet, and an orally disintegrating tablet, which is an uncoated tablet, is more preferable.
  • An orally disintegrating tablet is provided as a tablet that disintegrates rapidly in the oral cavity, as distinguished from ordinary tablets, and the oral disintegration time is less than 60 seconds, preferably less than 40 seconds.
  • the tablet according to the present embodiment preferably has a total content of silicic acid additives of less than 3.0% by weight, more preferably less than 1.0% by weight, still more preferably less than 0.5% by weight, and further preferably May be less than 0.1% by weight, and it is particularly preferred not to contain a silicic acid additive.
  • the silicic acid based additive is an additive used as a fluidizing agent, a lubricant or an excipient.
  • siliceous additives include silicon dioxide (including light anhydrous silicic acid and hydrous silicon dioxide), calcium silicate, magnesium aluminosilicate, magnesium aluminometasilicate, magnesium silicate and silicate Aluminum (including natural aluminum silicate, synthetic aluminum silicate, colloidal hydrous aluminum silicate and the like), magnesium aluminum silicate (including synthetic magnesium sodium silicate and the like), etc. are mentioned; in particular, silicon dioxide, silica Examples include calcium acid and magnesium aluminometasilicate.
  • Additives such as excipients, binders, disintegrants, fluidizers, lubricants, flavoring agents, coating agents and the like generally used in the manufacture of pharmaceuticals to produce the tablet according to the present embodiment Can also be used. Moreover, it is preferable to use low melting point fats and oils as an additive. In the present specification, interpretation of the terms of various additives (excipients, binders, disintegrants, fluidizers, lubricants, flavoring agents, coating agents, low melting point oils and fats, etc.) is often formulated.
  • excipient examples include lactose (lactose hydrate, anhydrous lactose and the like), crystalline cellulose, sugar alcohol (D-mannitol, isomalto, erythritol and the like), trehalose, corn starch, cyclodextrin and the like; Preferably, it is selected from lactose, microcrystalline cellulose, sugar alcohol, corn starch and cyclodextrin; more preferably, it is selected from microcrystalline cellulose, sugar alcohol and corn starch; more preferably the above options to include sugar alcohol Particularly preferably selected from the above options to include D-mannitol and / or erythritol. These excipients may be used alone or in combination of two or more.
  • the content of the excipient with respect to the total weight of the tablet is preferably 10.0% by weight or more, more preferably 20.0% by weight or more, still more preferably 25.0% by weight or more, and 30. 0 weight% or more is more preferable, and 40.0 weight% or more is especially preferable.
  • the content is preferably 90.0 wt% or less, more preferably 80.0 wt% or less, still more preferably 75.0 wt% or less, still more preferably 70.0 wt% or less, and 65.0 wt%. % Or less is particularly preferred.
  • disintegrant examples include hydroxypropyl starch, low substituted hydroxypropyl cellulose, sodium starch glycolate, partially pregelatinized starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone and the like; Selected from hydroxypropyl starch, low substituted hydroxypropyl cellulose, sodium starch glycolate, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, and crospovidone; more preferably hydroxypropyl starch, low substituted hydroxypropyl Selected from cellulose, sodium starch glycolate and crospovidone; more preferably from the above options to include crospovidone Barrel.
  • These disintegrants may be used alone or in combination of two or more. When the tablet is an orally disintegrating tablet, it is preferable to contain a disintegrant.
  • the content of the disintegrant based on the total weight of the tablet is preferably 1.0% by weight or more, more preferably 2.0% by weight or more, still more preferably 2.5% by weight or more, 3.0 % By weight or more is particularly preferred. Moreover, 20.0 weight% or less is preferable, as for this content, 15.0 weight% or less is more preferable, 12.0 weight% or less is still more preferable, 10.0 weight% or less is especially preferable.
  • ⁇ Binder> As a binder, specifically, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), methyl cellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol graft copolymer, carmellose sodium And preferably selected from hydroxypropyl cellulose, hypromellose, methylcellulose, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol graft copolymer, carmellose sodium, and pregelatinized starch; more preferably hydroxypropyl; Cellulose, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol Lumpur graft polymer, carmellose sodium, and selected from pregelatinized starch; more preferably, hydroxypropylcellulose, selected polyvinyl alcohol, and carmellose sodium.
  • These binders may be used alone or in combination of two or more.
  • 0.1 weight% or more is preferable, as for content of the binder with respect to the total weight of a tablet (preferably uncoated tablet), 0.2 weight% or more is more preferable, 0.5 weight% or more is still more preferable, 1.0 % By weight or more is particularly preferred.
  • the content is preferably 10.0% by weight or less, more preferably 8.0% by weight or less, still more preferably 5.0% by weight or less, and particularly preferably 4.0% by weight or less.
  • content of a binder may be less than 1.0 weight% (preferably less than 0.1 weight%). And may not contain a binder.
  • Fluidizer Specific examples of the fluidizing agent include talc and the like, with preference given to talc.
  • 0.1 weight% or more is preferable, as for content of the fluidizer with respect to the total weight of a tablet (preferably uncoated tablet), 0.2 weight% or more is more preferable, 0.5 weight% or more is more preferable, and 0. 8 weight% or more is more preferable, and 1.0 weight% or more is especially preferable.
  • the content is preferably 5.0% by weight or less, more preferably 4.0% by weight or less, still more preferably 3.0% by weight or less, still more preferably 2.0% by weight or less, 1.5% by weight % Or less is particularly preferred.
  • lubricant examples include glycerin fatty acid ester, sucrose fatty acid ester, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated oil and the like; preferably, glycerin fatty acid ester, magnesium stearate, stear It is selected from calcium phosphate, sodium stearyl fumarate, and hydrogenated oils; more preferably, selected from the above options to include magnesium stearate. These lubricants may be used alone or in combination of two or more.
  • 0.1 weight% or more is preferable, as for content of the lubricant with respect to the total weight of a tablet (preferably uncoated tablet), 0.2 weight% or more is more preferable, 0.3 weight% or more is more preferable, 0. 4 weight% or more is more preferable, and 0.5 weight% or more is especially preferable.
  • the content is preferably 5.0% by weight or less, more preferably 4.0% by weight or less, still more preferably 3.0% by weight or less, still more preferably 2.0% by weight or less, 1.5% by weight % Or less is particularly preferred.
  • flavoring agent specifically, ascorbic acid, L-aspartic acid, citric acid, tartaric acid, malic acid, aspartame, sucralose, acesulfame potassium, saccharin sodium (including water hydrate), saccharin, thaumatin, neotame etc. Is preferably selected from aspartame, sucralose and saccharin sodium; more preferably sucralose.
  • sweetening agents may be used alone or in combination of two or more.
  • the tablet is an orally disintegrating tablet, it is preferable to contain a flavoring agent. In particular, good disintegratability can be obtained by incorporating a flavoring agent together with the ⁇ -aminobutyric acid derivative in the granulated product.
  • the content of the flavoring agent relative to the total weight of the tablet is preferably 0.1% by weight or more, more preferably 0.5% by weight or more, still more preferably 1.0% by weight or more, 1.2 % By weight or more is more preferable, and 1.5% by weight or more is particularly preferable.
  • the content is preferably 10.0% by weight or less, more preferably 9.0% by weight or less, still more preferably 8.0% by weight or less, still more preferably 7.0% by weight or less, 6.0% by weight % Or less is particularly preferred.
  • the low melting point fats and oils used in this embodiment preferably have a melting point of 20 to 90 ° C., more preferably 30 to 85 ° C., still more preferably 40 to 80 ° C., and further preferably 45 to 69 ° C. Particularly preferred.
  • the low melting point fats and oils can be blended uniformly with the active ingredient as compared with the high melting point fats and oils. As a result, it is possible to obtain a more stable tablet in which the decomposition and the like of the ⁇ -aminobutyric acid derivative which is the active ingredient is suppressed.
  • low melting point fats and oils include, for example, higher fatty acids (for example, 10 to 40, preferably 12 to 26 carbon atoms) and salts of persimmon, higher alcohols (for example, 10 to 40, preferably 12 to 26 carbon atoms).
  • Hydrocarbons paraffin wax, microcrystalline wax, etc.
  • fatty acid ester fatty acid ester
  • hydrogenated oil cured castor oil, hydrogenated soybean oil, cured rapeseed oil, cured cottonseed oil, etc.
  • polymer of alkylene oxide polyethylene glycol, polypropylene glycol etc.
  • fatty acid esters and / or hydrogenated oils are preferred, and fatty acid esters of polyhydric alcohols are more preferred.
  • These low melting point fats and oils may be used alone or in combination of two or more.
  • these low melting point fats and oils may function as the above-mentioned binder, lubricant and the like.
  • fatty acid ester of polyhydric alcohol means a compound in which part or all of the hydroxyl groups of polyhydric alcohol are esterified with a fatty acid (preferably a fatty acid having 12 to 26 carbon atoms).
  • polyhydric alcohol moiety of the "fatty acid ester of polyhydric alcohol” include alkylene glycols such as ethylene glycol, propylene glycol, butanediol and pentanediol; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; glycerin, sorbitol, sorbitan, penta Examples thereof include saccharides such as erythritol and sucrose and the like, and glycerin is preferable.
  • fatty acid ester of polyhydric alcohol examples include ethylene glycol fatty acid ester, propylene glycol fatty acid ester, glycerin fatty acid ester, polyoxyalkylene fatty acid ester, sorbitan fatty acid ester, polyoxyalkylene sorbitan fatty acid ester, polyoxyalkylene Sorbitol fatty acid ester, sucrose fatty acid ester and the like are mentioned, glycerin fatty acid ester is preferable, mono fatty acid (C12-26) glyceryl is more preferable, and glycerin monostearate is particularly preferable. These fatty acid esters of polyhydric alcohols may be used alone or in combination of two or more.
  • 0.1 weight% or more is preferable, 0.5 weight% or more is more preferable, 0.5 weight% or more is more preferable, and, as for content of the low melting fats and oils with respect to the total weight of a tablet (preferably uncoated tablet), 0.8 weight% or more is more preferable 0 weight% or more is more preferable, and 1.2 weight% or more is especially preferable.
  • the content is preferably 10.0% by weight or less, more preferably 8.0% by weight or more, still more preferably 6.0% by weight or less, still more preferably 5.0% by weight or less, and 4.5% by weight % Or less is particularly preferred.
  • additives include titanium oxide and calcium hydrogen phosphate (calcium hydrogen phosphate hydrate, anhydrous calcium hydrogen phosphate etc.), preferably calcium hydrogen phosphate .
  • Other additives (inorganic salts) can be used as a coating agent, an excipient, or a fluidizing agent after appropriate examination.
  • the tablet according to the present embodiment is preferably one containing a granulated product (granules) containing a ⁇ -aminobutyric acid derivative (preferably, an additive such as a flavoring agent is also added).
  • the granulated material is preferably 10.0 to 90.0% by weight, more preferably 20.0 to 80.0% by weight, still more preferably 30.
  • the tablet is contained in the range of 0 to 70.0% by weight, particularly preferably 35.0 to 60.0% by weight.
  • the granulated material containing the ⁇ -aminobutyric acid derivative is preferably 70.0 to 99.0% by weight, more preferably 75.0 to 98.0% by weight, further preferably, based on the total weight of the granulated product. Is obtained so as to contain 80.0 to 97.0% by weight, more preferably 85.0 to 96.0% by weight, particularly preferably 90.0 to 95.0% by weight of the ⁇ -aminobutyric acid derivative.
  • Granulation method In the production of the tablet according to the present embodiment, it is preferable that granulation is performed using a ⁇ -aminobutyric acid derivative having any of the above particle diameter distribution or volume average diameter.
  • a dry granulation method a crushing granulation method, a melt granulation method, etc.
  • a wet granulation method a fluid bed granulation method, a stirring granulation method, an extrusion granulation method, etc.
  • the dry granulation method is suitably used, and the melt granulation method is more preferable.
  • a ⁇ -aminobutyric acid derivative and a low melting point fat and oil are uniformly blended by the above granulation method, and a granulated product (preferably a dry granulated product, more preferably a melt granulated product It is mentioned as a preferable aspect to form a substance.
  • a granulated product containing the ⁇ -aminobutyric acid derivative and the low melting point fat and oil it is possible to produce a tablet in which the chemical stability of the ⁇ -aminobutyric acid derivative is further improved.
  • the dry granulation method is characterized in that granulation is performed without adding a solution such as water or alcohol.
  • the drug substance ⁇ -aminobutyric acid derivative
  • low melting point fats and oils are charged into a stirring granulator, a fluidized bed granulator, etc.
  • other additives such as a flavoring agent may be charged.
  • the low melting point fats and oils are dissolved by heating while mixing them, and a granulated material is formed by finally cooling.
  • melt granulation At the time of melt granulation, it is heated to a temperature (generally 40 to 100 ° C., preferably 50 to 90 ° C., more preferably 60 to 80 ° C., further preferably 70 to 80 ° C.) above the melting point of the low melting point fat.
  • a temperature generally 40 to 100 ° C., preferably 50 to 90 ° C., more preferably 60 to 80 ° C., further preferably 70 to 80 ° C.
  • the low melting point fats and oils are preferably 1.0 to 30.0% by weight, more preferably 1.5 to 20.0% by weight, still more preferably 2.0 to 18.0% by weight based on the total weight of the granulated product. %, More preferably 2.5 to 14.0%, particularly preferably 3.0 to 9.0%.
  • the flavoring agent is preferably 1.0 to 30.0% by weight, more preferably 1.5 to 20.0% by weight, still more preferably 2.0 to 18.0%, based on the total weight of the granulated product. It is more preferably contained in the granulate in a range of 2.5 to 14.0%, particularly preferably 3.0 to 9.0%.
  • 0.010 or more is preferable, and 0.015 or more is preferable for the blending amount of low melting point fats and oils (blending amount of low melting point fats and oils / blending amount of ⁇ -aminobutyric acid derivative) relative to the blending amount of ⁇ -aminobutyric acid derivative in the granulated product
  • 0.020 or more is further preferable, 0.025 or more is further preferable, and 0.030 or more is particularly preferable.
  • the blending amount of low melting point fats and oils (blending amount of low melting point fats and oils / blending amount of ⁇ -aminobutyric acid derivative) with respect to the blending amount of ⁇ -aminobutyric acid derivative in the granulated product is preferably 0.40 or less .20 or less is more preferable, 0.18 or less is further preferable, 0.14 or less is more preferable, 0.090 or less is particularly preferable.
  • 0.010 or more is preferable and 0.015 or more of the compounding amount of the flavoring agent (compounding amount of the flavoring agent / compounded amount of the ⁇ -aminobutyric acid derivative) with respect to the compounding amount of the ⁇ -aminobutyric acid derivative in the granulated material More preferably, 0.020 or more is further preferable, 0.025 or more is further preferable, and 0.030 or more is particularly preferable.
  • the blending amount of the flavoring agent (blending amount of the flavoring agent / blending amount of the ⁇ -aminobutyric acid derivative) with respect to the blending amount of the ⁇ -aminobutyric acid derivative in the granulated product is preferably 0.40 or less, 0.20 The following is more preferable, 0.18 or less is further preferable, 0.14 or less is more preferable, 0.090 or less is particularly preferable.
  • the tablet according to the present embodiment can be produced by a general production method, for example, can be produced by the following production method.
  • melt granulation is carried out by heating while stirring the drug substance and low melting point fats and oils (optionally, additives such as flavoring agents) to produce a granulated product. Then, after granulating the obtained granulated product, it is mixed with an excipient, a disintegrant, a lubricant and the like, and compression molded by a tableting machine to make a tablet (uncoated tablet).
  • the batting pressure at the time of tableting and manufacturing the uncoated tablet is preferably selected from any value within the range of 600 to 1400 kgf.
  • the obtained uncoated tablet may be provided with a film coating layer.
  • the tablet according to the present embodiment is a ⁇ -aminobutyric acid derivative and suitable additives (excipients, binders, disintegrants, fluidizers, lubricants and other additives described above (tablets according to the present embodiment
  • suitable additives excipients, binders, disintegrants, fluidizers, lubricants and other additives described above
  • the additive mentioned preferably in any column of “(a flavoring agent is also included)” is preferably 90.0% by weight, more preferably 95% based on the total weight of the tablet. And more preferably at least 98.0% by weight, most preferably consisting only of ⁇ -aminobutyric acid derivatives and appropriate additives.
  • a PTP sheet product including a tablet according to the present embodiment can be obtained by sandwiching and covering the tablet with a sheet for packaging and aluminum foil or the like and heat sealing.
  • materials used for the packaging sheet include polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene and the like.
  • a PTP sheet product is manufactured using a material having a drying function, an aluminum pillow package of the PTP sheet product, a desiccant It is possible to use known methods, such as sealing in bottles with tablets.
  • the results of powder X-ray analysis measurement of the pregabalin are shown in FIG.
  • Glycerine monostearate Rikemar S-100P (melting point: 63-68 ° C) manufactured by Riken Vitamin Co., Ltd.
  • Excipient 1 PEARLITOL (registered trademark) 100SD (an additive comprising D-mannitol) manufactured by Rocket Japan Co., Ltd.
  • Excipient 2 PEARLITOL (registered trademark) Flash (available from D-mannitol and corn starch) manufactured by Rocket Japan Co., Ltd.
  • Excipient 3 Theorus (registered trademark) UF-711 (crystalline cellulose) manufactured by Asahi Kasei Co., Ltd.
  • Flavoring agent 1 Sucralose P (Sucralose) manufactured by San-Ei Gen F.F.I.
  • Flavoring agent 2 Ajinomoto Healthy Assortment KK Ajinomoto KK aspartame (aspartame)
  • Flavoring agent 3 Saccharin sodium hydrate Crospovidone manufactured by Daiwa Kasei Co., Ltd .: Kollidone (registered trademark) CL-SF manufactured by BASF Japan Ltd.
  • the tablet of the present invention is one in which the chemical stability of ⁇ -aminobutyric acid derivative such as pregabalin is sufficiently improved.
  • the production amount of the pregabalin-derived analogue after storage is sufficiently low.
  • the obtained sized particles, excipients 1 to 3 and crospovidone are mixed in a polyethylene bag, and then magnesium stearate (made by Taihei Kagaku Sangyo Co., Ltd.) is added and mixed to obtain a mixture.
  • the This mixture is tableted using a rotary tableting machine (Vera 5 / manufactured by Kikusui Seisakusho Ltd.) at a striking pressure of 1300 kgf, and the tablet weight is 420.0 mg, a tablet having a diameter of 10.5 mm and a thickness of 5.7 mm ( An uncoated tablet, an orally disintegrating tablet, and a round two-stage R tablet) were obtained.
  • the drug substance and each additive were used in the above-mentioned production in such an amount that the tablet was formulated as shown in Table 5 below.
  • Test Example 4 Measurement of intraoral disintegration time of orally disintegrating tablet With respect to the tablet of tablet example A, the test liquid: water (manufactured by Higuchi Shokai Co., Ltd.) using the orally disintegrating tablet testing machine (OD-mate / Co., Ltd.) The time to disintegrate the tablet was measured at 37 ° C.). The results are shown in Table 6 below.
  • the orally disintegrating tablet of the present invention is one in which the chemical stability of a ⁇ -aminobutyric acid derivative such as pregabalin is sufficiently improved.

Abstract

This γ-aminobutyric acid derivative-containing tablet is characterized by not containing a silicic acid-based additive.

Description

γ－アミノ酪酸誘導体含有錠剤の化学的安定性を改善する方法Method for improving the chemical stability of tablets containing .gamma.-aminobutyric acid derivative
　本発明は、原薬としてγ－アミノ酪酸誘導体（主にプレガバリン）を含有する製剤に関するものであり、其の保存条件下における原薬の化学的な安定性を改善するための詳細な方法を開示するものである。 The present invention relates to a preparation containing a γ-aminobutyric acid derivative (mainly pregabalin) as a drug substance, and discloses a detailed method for improving the chemical stability of the drug substance under storage conditions of chewing It is
　プレガバリン（一般名）は、化学名が（３Ｓ）－３－アミノメチル－５－メチルヘキサン酸と記される、γ－アミノ酪酸（ＧＡＢＡ）の誘導体である。プレガバリンは、神経障害性疼痛、線維筋痛症に伴う疼痛の治療に有用な薬剤である。（非特許文献１等参考）。 Pregabalin (common name) is a derivative of γ-aminobutyric acid (GABA) whose chemical name is written as (3S) -3-aminomethyl-5-methylhexanoic acid. Pregabalin is an agent useful for treating neuropathic pain and pain associated with fibromyalgia. (Reference to Non-Patent Document 1, etc.).
　現在、プレガバリンはカプセル剤又は口腔内崩壊錠の剤形で日本国内の医療現場に提供されている。プレガバリンを含有する錠剤の処方や製造方法は、以下の特許文献１～３等で紹介されている。例えば、特許文献１の実施例７には、プレガバリン及びケイ酸カルシウム等を含有する口腔内崩壊錠の処方及び製造方法が記載されている。 Currently, pregabalin is provided to medical sites in Japan in the form of a capsule or orally disintegrating tablet. The formulation and manufacturing method of tablets containing pregabalin are introduced in the following Patent Documents 1 to 3, and the like. For example, in Example 7 of Patent Document 1, there is described the formulation and manufacturing method of an orally disintegrating tablet containing pregabalin, calcium silicate and the like.
　口腔内崩壊錠は近年開発された剤形であり、唾液程度の少量の水で素早く崩壊する性質をもつことから、普通錠に比べて服用時の利便性が高いことが一般に知られる。しかしながら、プレガバリンを含有する口腔内崩壊錠の技術について紹介した文献の数は乏しいのが現状である。一般的に、口腔内崩壊錠は普通錠と技術的な相違点を有しており、原薬の安定性等の品質を保証することが困難である場合が多い。そこで本発明者は、製剤中に含まれるプレガバリン等のγ－アミノ酪酸誘導体の化学的な安定性を改善する新たな技術の開発を目指した。 An orally disintegrating tablet is a dosage form developed in recent years, and it is generally known that the convenience at the time of taking it is higher than that of a normal tablet because it has the property of disintegrating quickly with a small amount of water like saliva. However, at present the number of documents introduced about the technology of orally disintegrating tablets containing pregabalin is scarce. In general, orally disintegrating tablets have technical differences with ordinary tablets, and it is often difficult to guarantee the quality such as the stability of the drug substance. Therefore, the present inventor aimed to develop a new technique for improving the chemical stability of γ-aminobutyric acid derivatives such as pregabalin contained in the preparation.
特表２０１０－５２４９９１号公報Japanese Patent Publication No. 2010-524991 特表２０１４－５２１６３９号公報Japanese Patent Application Publication No. 2014-521639 特許第４３３４６１０号公報Patent No. 4334610
　γ－アミノ酪酸誘導体は、脱水によりラクタム体を生成することが知られている。本発明は、γ－アミノ酪酸誘導体の化学的な安定性等が改善された錠剤（特に口腔内崩壊錠）を製造するための技術的手段を提供することを目的とするものである。 The γ-aminobutyric acid derivative is known to form a lactam by dehydration. An object of the present invention is to provide a technical means for producing a tablet (in particular, an orally disintegrating tablet) in which the chemical stability and the like of the γ-aminobutyric acid derivative are improved.
　本発明者は、上記課題を解決するための検討を鋭意重ねた結果、ケイ酸系添加剤を含まないγ－アミノ酪酸誘導体を含有する錠剤において、γ－アミノ酪酸誘導体の化学的な安定性が優れていることを見出した。本発明者はその知見に基づいて更に鋭意検討を重ね、下記の本発明を完成するに至った。 As a result of intensive investigations for solving the above problems, the present inventor found that the chemical stability of the γ-aminobutyric acid derivative is in the tablet containing the γ-aminobutyric acid derivative which does not contain the silicic acid based additive. I found it to be excellent. Based on the findings, the present inventor has further intensively studied to complete the present invention described below.
　本発明は、γ－アミノ酪酸誘導体を含有する錠剤等に関するものであって、好ましい構成は以下（１）～（７）において記述されるものである。
（１）γ－アミノ酪酸誘導体を含有する錠剤（特に口腔内崩壊錠）であって、ケイ酸系添加剤が含有されていないことを特徴とする、錠剤。
（２）γ－アミノ酪酸誘導体がプレガバリンである、前記（１）に記載の錠剤。
（３）ケイ酸系添加剤が、二酸化ケイ素（軽質無水ケイ酸、含水二酸化ケイ素等を含む。）、ケイ酸カルシウム、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、ケイ酸アルミニウム（天然ケイ酸アルミニウム、合成ケイ酸アルミニウム、コロイド性含水ケイ酸アルミニウム等を含む。）、及びケイ酸マグネシウムアルミニウム（合成ケイ酸マグネシウムナトリウム等を含む。）から選ばれる、前記（１）又は（２）に記載の錠剤。
（４）ケイ酸系添加剤が、二酸化ケイ素、ケイ酸カルシウム、及びメタケイ酸アルミン酸マグネシウムから選ばれる、前記（１）又は（２）に記載の錠剤。
（５）γ－アミノ酪酸誘導体及び適切な添加剤を錠剤全重量に対して９０．０重量％（好ましくは９５．０重量％）以上含有する（最も好ましくはγ－アミノ酪酸誘導体及び適切な添加剤のみからなる）錠剤（特に素錠）であって、前記適切な添加剤が以下の添加剤（以下の各添加剤は賦形剤、崩壊剤、結合剤、流動化剤、滑沢剤及びその他添加剤のいずれかの種類に属するように例示しているが、当該属する種類ではない他の種類で使用すること（例：賦形剤に属する結晶セルロースを崩壊剤として使用すること。）は制限されない。）から選ばれることを特徴とする、前記（１）～（４）のいずれかに記載の錠剤。
　賦形剤：乳糖、結晶セルロース、トレハロース、Ｄ－マンニトール、イソマルト、エリスリトール、トウモロコシデンプン、シクロデキストリン
　崩壊剤：ヒドロキシプロピルスターチ、低置換度ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、部分アルファー化デンプン、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン
　結合剤：ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ポリビニルアルコール、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー、カルメロースナトリウム、アルファー化デンプン
　流動化剤：タルク
　滑沢剤：グリセリン脂肪酸エステル、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、硬化油
　その他添加剤：リン酸水素カルシウム水和物、無水リン酸水素カルシウム
（６）γ－アミノ酪酸誘導体を含有する口腔内崩壊錠であって、前記適切な添加剤が以下の矯味剤からも選ばれることを特徴とする、前記（５）に記載の錠剤。
矯味剤：アスパルテーム、スクラロース、サッカリンナトリウム
（７）γ－アミノ酪酸誘導体を含有する口腔内崩壊錠であって、矯味剤がγ－アミノ酪酸誘導体と共に造粒物（好ましくは乾式造粒物、より好ましくは溶融造粒物）中に含有されていることを特徴とする、前記（６）に記載の錠剤。
（８）γ－アミノ酪酸誘導体を含有する口腔内崩壊錠であって、矯味剤がγ－アミノ酪酸誘導体及び低融点油脂と共に乾式造粒物（好ましくは溶融造粒物）中に含有されていることを特徴とする、前記（６）又は（７）に記載の錠剤。 The present invention relates to a tablet or the like containing a γ-aminobutyric acid derivative, and preferred configurations are described in (1) to (7) below.
(1) A tablet containing a γ-aminobutyric acid derivative (in particular, an orally disintegrating tablet), which is characterized by containing no silicic acid additive.
(2) The tablet according to (1) above, wherein the γ-aminobutyric acid derivative is pregabalin.
(3) Silicate-based additives are silicon dioxide (including light anhydrous silicic acid, hydrous silicon dioxide etc.), calcium silicate, magnesium aluminosilicate, magnesium aluminometasilicate, magnesium silicate, aluminum silicate (1) or (2) selected from (including natural aluminum silicate, synthetic aluminum silicate, colloidal hydrous aluminum silicate and the like), and magnesium aluminum silicate (including synthetic magnesium sodium silicate and the like); The tablet as described in 2.).
(4) The tablet according to (1) or (2) above, wherein the silicic acid based additive is selected from silicon dioxide, calcium silicate and magnesium aluminometasilicate.
(5) 90.0% by weight (preferably 95.0% by weight) or more of the γ-aminobutyric acid derivative and the appropriate additive based on the total weight of the tablet (most preferably the γ-aminobutyric acid derivative and the appropriate addition Tablets (in particular, uncoated tablets), wherein said suitable additives are the following additives (each additive below is an excipient, a disintegrant, a binder, a fluidizer, a lubricant, and The other additives are exemplified to belong to any kind of additives, but to use in other kinds which are not the kind to which they belong (example: using crystalline cellulose belonging to an excipient as a disintegrant) is used. The tablet according to any one of the above (1) to (4), which is selected from, but not limited to).
Excipients: lactose, crystalline cellulose, trehalose, D-mannitol, isomalt, erythritol, corn starch, cyclodextrin Disintegrators: hydroxypropyl starch, low substituted hydroxypropyl cellulose, sodium starch glycolate, partially pregelatinized starch, carmellose Calcium, croscarmellose sodium, crospovidone Binder: hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol graft copolymer, carmellose sodium, pregelatinized starch Fluidizing agent: talc Lubricant: glycerin fatty acid Ester, magnesium stearate, calcium stearate, sodium stearyl fumarate, Hardened oil Other additives: orally disintegrating tablets containing calcium hydrogen phosphate hydrate, anhydrous calcium hydrogen phosphate (6) γ-aminobutyric acid derivative, wherein the appropriate additive is also obtained from the following flavoring agents The tablet according to (5) above, characterized in that it is selected.
Flavoring agent: An orally disintegrating tablet containing aspartame, sucralose, sodium saccharin (7) γ-aminobutyric acid derivative, wherein the flavoring agent is a granulated product (preferably a dry granulated product, more preferably a γ-aminobutyric acid derivative) The tablet according to the above (6), which is contained in a melt-granulated product).
(8) An orally disintegrating tablet containing a γ-aminobutyric acid derivative, wherein the flavoring agent is contained in the dry granulated product (preferably a melt granulated product) together with the γ-aminobutyric acid derivative and a low melting point oil and fat The tablet according to (6) or (7) above, characterized in that
　本発明によれば、γ－アミノ酪酸誘導体の化学的な安定性等が改善された錠剤（特に口腔内崩壊錠）を提供することができる。 According to the present invention, it is possible to provide a tablet (in particular, an orally disintegrating tablet) in which the chemical stability and the like of the γ-aminobutyric acid derivative are improved.
図１は、実施例で使用されたプレガバリンの結晶形態を粉末Ｘ線回折測定法によって解析した結果を表したものである。FIG. 1 shows the results of analyzing the crystal form of pregabalin used in the examples by powder X-ray diffractometry.
　本発明の一実施形態に係る錠剤は、γ－アミノ酪酸誘導体及び適切な添加剤を含有することを特徴とする。以下に、該錠剤及び其の製造方法について詳細に説明する。但し、以下の記載は本発明を説明するための例示であり、本発明の技術的範囲をこの記載範囲にのみ限定する趣旨ではない。尚、本明細書において、「～」を用いて数値範囲を示す場合、その両端の数値を含むものとする。 The tablet according to one embodiment of the present invention is characterized by containing a γ-aminobutyric acid derivative and a suitable additive. Below, the manufacturing method of this tablet and chewing is demonstrated in detail. However, the following description is an illustration for explaining the present invention, and the technical scope of the present invention is not intended to be limited only to this description range. In the present specification, when a numerical range is indicated using “to”, numerical values at both ends thereof are included.
＜原薬＞
　本実施形態に係る錠剤は、原薬としてγ－アミノ酪酸誘導体を含有する。本実施形態における「γ－アミノ酪酸誘導体」としては、例えば、炭素原子上（好ましくは３位の炭素原子上）に同種または異種の１～４個の脂肪族炭化水素基（好ましくは炭素数が１～１０の脂肪族炭化水素基）が置換されていてもよいγ－アミノ酪酸（４－アミノブタン酸）又は其の製薬学的に許容される塩が挙げられる。ここにおいて、２つの脂肪族炭化水素基が同一の炭素原子（好ましくは３位の炭素原子）に結合している場合には、その炭素原子と一緒になって飽和または一部不飽和の炭化水素環（該炭化水素環は脂肪族炭化水素基で置換されていてもよい）を形成してもよい。「γ－アミノ酪酸誘導体」の具体例としては、例えば、γ－アミノ酪酸（ＧＡＢＡ；４－アミノブタン酸）、プレガバリン、アタガバリン、ミロガバリンおよびそれらの製薬学的に許容される塩からなる群から選ばれる１以上が挙げられ、プレガバリン又は其の製薬学的に許容される塩が好ましい。 <Active drug>
The tablet according to the present embodiment contains a γ-aminobutyric acid derivative as a drug substance. Examples of the “γ-aminobutyric acid derivative” in the present embodiment include 1 to 4 aliphatic hydrocarbon groups (preferably having a carbon number of the same or different types) on the carbon atom (preferably on the carbon atom at position 3). And pharmaceutically acceptable salts of 其 -aminobutyric acid (4-aminobutanoic acid) or 其 with which 1 to 10 aliphatic hydrocarbon groups may be substituted. Here, in the case where two aliphatic hydrocarbon groups are bonded to the same carbon atom (preferably, the carbon atom at position 3), saturated or partially unsaturated hydrocarbon together with the carbon atom It may form a ring (the hydrocarbon ring may be substituted with an aliphatic hydrocarbon group). Specific examples of the “γ-aminobutyric acid derivative” are, for example, selected from the group consisting of γ-aminobutyric acid (GABA; 4-aminobutanoic acid), pregabalin, atagabalin, mirogabalin and pharmaceutically acceptable salts thereof One or more may be mentioned, and pharmaceutically acceptable salts of pregabalin or navel are preferred.
　本実施形態における「γ－アミノ酪酸誘導体」としては、その遊離形態（両性イオン）並びにその製薬学的に許容される錯体、塩、溶媒和物、水和物、及び多型体を含む、任意のγ－アミノ酪酸誘導体の形態を利用し得る。塩には、ヘミ塩（ｈｅｍｉｓａｌｔｓ）を含む、酸付加塩及び塩基付加塩が含まれるがこれらに限定されない。 The “γ-aminobutyric acid derivative” in the present embodiment includes any of its free form (zwitter ion) and pharmaceutically acceptable complexes, salts, solvates, hydrates and polymorphs thereof. The form of the γ-aminobutyric acid derivative of Salts include, but are not limited to, acid addition salts and base addition salts, including hemisalts.
　製薬学的に許容される酸付加塩には、無機酸（例えば、塩酸、硝酸、リン酸、硫酸、臭化水素酸、ヨウ化水素酸、フッ化水素酸、亜リン酸等）から得られる非毒性塩、並びに有機酸（例えば、脂肪族モノ－及びジカルボン酸、フェニル置換アルカン酸、ヒドロキシアルカン酸、アルカン二酸、芳香族酸、脂肪族及び芳香族スルホン酸等）から得られる非毒性塩が含まれ得る。潜在的に有用な塩には、酢酸塩、アスパラギン酸塩、安息香酸塩、クロロ安息香酸塩、メチル安息香酸塩、ジニトロ安息香酸塩、ベシル酸塩、重炭酸塩、炭酸塩、重硫酸塩、硫酸塩、ピロ硫酸塩、亜硫酸水素塩、亜硫酸塩、ホウ酸塩、カンシル酸塩、カプリル酸塩、クエン酸塩、エジシル酸塩、エシレート、ギ酸塩、フマル酸塩、グルセプテート、グルコン酸塩、グルクロン酸塩、ヘキサフルオロリン酸塩、ヒベンズ酸塩、塩酸塩、塩化物、臭化水素酸塩、臭化物、ヨウ化水素酸塩、ヨウ化物、イセチオン酸塩、イソ酪酸塩、乳酸塩、リンゴ酸塩、マレイン酸塩、マロン酸塩、マンデル酸塩、メシル酸塩、メチル硫酸塩、ナフチル酸塩、２－ナプシレート、ニコチン酸塩、硝酸塩、オロチン酸塩、シュウ酸塩、パルミチン酸塩、パモエート、リン酸塩、リン酸水素塩、リン酸二水素塩、メタリン酸塩、ピロリン酸塩、フタル酸塩、プロピオン酸塩、サッカリン酸塩、セバシン酸塩、ステアリン酸塩、スベリン酸塩、コハク酸塩、酒石酸塩、トシレート、トリフルオロ酢酸塩等が含まれる。 Pharmaceutically acceptable acid addition salts include those derived from inorganic acids (eg, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.) Nontoxic salts and nontoxic salts obtained from organic acids (eg, aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.) May be included. Potentially useful salts include acetates, aspartates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, besylates, bicarbonates, carbonates, bisulfates, Sulfate, pyrosulfate, bisulfite, sulfite, borate, camsylate, caprylate, citrate, edylate, esylate, formate, fumarate, gluceptate, gluconate, Glucuronate, hexafluorophosphate, hibenzate, hydrochloride, chloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, isobutyrate, lactate, malate Salt, maleate, malonate, mandelicate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, Phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, phthalate, propionate, saccharinate, sebacate, stearate, suberinate, succinate Tartrate, tosylate, trifluoroacetate and the like.
　製薬学的に許容される塩基付加塩には、金属カチオン（例えば、アルカリ金属カチオン又はアルカリ土類金属カチオン）及びアミンを含む塩基から得られる非毒性塩が含まれ得る。潜在的に有用な塩の例には、アルミニウム、アルギニン、Ｎ，Ｎ'－ジベンジルエチレンジアミン、カルシウム、クロロプロカイン、コリン、ジエタノールアミン、ジエチルアミン、ジシクロヘキシルアミン、エチレンジアミン、グリシン、リジン、マグネシウム、Ｎ－メチルグルカミン、オラミン、カリウム、プロカイン、ナトリウム、トロメタミン、亜鉛等が含まれるがこれらに限定されない。 Pharmaceutically acceptable base addition salts may include non-toxic salts obtained from bases including metal cations (eg, alkali metal cations or alkaline earth metal cations) and amines. Examples of potentially useful salts include aluminum, arginine, N, N'-dibenzylethylenediamine, calcium, chloroprocaine, choline, diethanolamine, diethylamine, dicyclohexylamine, ethylenediamine, glycine, lysine, magnesium, N-methylgulene. These include, but are not limited to, kamin, olamine, potassium, procaine, sodium, tromethamine, zinc and the like.
　γ－アミノ酪酸誘導体の、体積基準測定における累積１０％粒子径（ｄ１０）は、γ－アミノ酪酸誘導体の化学的な安定性等の観点から、３．０μｍ以上が好ましく、５．０μｍ以上がより好ましく、６．０μｍ以上が更に好ましく、７．０μｍ以上が特に好ましい。また、錠剤の製造上等の実用的な面からは、５０．０μｍ以下が好ましく、４５．０μｍ以下がより好ましく、３５．０μｍ以下が更に好ましく、２５．０μｍ以下が特に好ましい。 The cumulative 10% particle diameter (d10) of the γ-aminobutyric acid derivative in volume-based measurement is preferably 3.0 μm or more, more preferably 5.0 μm or more, from the viewpoint of the chemical stability of the γ-aminobutyric acid derivative, etc. The thickness is preferably 6.0 μm or more, more preferably 7.0 μm or more. Further, from the practical viewpoint of tablet production and the like, 50.0 μm or less is preferable, 45.0 μm or less is more preferable, 35.0 μm or less is more preferable, and 25.0 μm or less is particularly preferable.
　γ－アミノ酪酸誘導体の、体積基準測定における累積５０％粒子径（ｄ５０）は、γ－アミノ酪酸誘導体の化学的な安定性等の観点から、９．０μｍ以上が好ましく、１５．０μｍ以上がより好ましく、２０．０μｍ以上が更に好ましく、３０．０μｍ以上が更に好ましく、４０．０μｍ以上が特に好ましい。また、錠剤の製造上等の実用的な面からは、２５０．０μｍ以下が好ましく、２２０．０μｍ以下がより好ましく、１５０．０μｍ以下が更に好ましく、１００．０μｍ以下が特に好ましい。 The cumulative 50% particle diameter (d50) of the γ-aminobutyric acid derivative in volume-based measurement is preferably 9.0 μm or more, more preferably 15.0 μm or more from the viewpoint of the chemical stability of the γ-aminobutyric acid derivative, etc. The thickness is preferably 20.0 μm or more, more preferably 30.0 μm or more, and particularly preferably 40.0 μm or more. Further, from the practical viewpoint of tablet production and the like, 250.0 μm or less is preferable, 220.0 μm or less is more preferable, 150.0 μm or less is more preferable, and 100.0 μm or less is particularly preferable.
　γ－アミノ酪酸誘導体の、体積基準測定における累積９０％粒子径（ｄ９０）は、γ－アミノ酪酸誘導体の化学的な安定性等の観点から、３０．０μｍ以上が好ましく、５０．０μｍ以上がより好ましく、８０．０μｍ以上が更に好ましく、１１０．０μｍ以上が更に好ましく、１４０．０μｍ以上が特に好ましい。また、錠剤の製造上等の実用的な面からは、６００．０μｍ以下が好ましく、５５０．０μｍ以下がより好ましく、４００．０μｍ以下が更に好ましく、３００．０μｍ以下が特に好ましい。 The cumulative 90% particle size (d90) of the γ-aminobutyric acid derivative in volume-based measurement is preferably 30.0 μm or more, more preferably 50.0 μm or more, from the viewpoint of the chemical stability of the γ-aminobutyric acid derivative 80.0 μm or more is more preferable, 110.0 μm or more is more preferable, and 140.0 μm or more is particularly preferable. Further, from the practical viewpoint of tablet production and the like, 600.0 μm or less is preferable, 550.0 μm or less is more preferable, 400.0 μm or less is more preferable, and 300.0 μm or less is particularly preferable.
　γ－アミノ酪酸誘導体の体積平均径は、１３．０μｍ以上が好ましく、γ－アミノ酪酸誘導体の化学的な安定性等の観点から、２２．０μｍ以上がより好ましく、４５．０μｍ以上が更に好ましく、５７．０μｍ以上が特に好ましい。また、錠剤の製造上等の実用的な面からは、４００．０μｍ以下が好ましく、３５０．０μｍ以下がより好ましく、２９０．０μｍ以下が更に好ましく、２００．０μｍ以下が特に好ましい。 The volume average diameter of the γ-aminobutyric acid derivative is preferably 13.0 μm or more, more preferably 22.0 μm or more, and still more preferably 45.0 μm or more from the viewpoint of the chemical stability of the γ-aminobutyric acid derivative, etc. 57.0 micrometers or more are especially preferable. Further, from the practical viewpoint of tablet production and the like, 400.0 μm or less is preferable, 350.0 μm or less is more preferable, 290.0 μm or less is more preferable, and 200.0 μm or less is particularly preferable.
　本実施形態において使用されるγ－アミノ酪酸誘導体は、上記の粒子径分布又は体積平均径のいずれかを有することが好ましく、上記のｄ５０およびｄ９０を有することがより好ましい。尚、本実施形態において、上記粒子径分布及び体積平均径は、レーザー回析・散乱法によって測定することが可能であり、其の詳細な測定条件は、下記実施例に記載される乾式測定のものに従うことが可能である。 The γ-aminobutyric acid derivative used in the present embodiment preferably has any of the particle size distribution or volume average diameter described above, and more preferably d50 and d90 described above. In the present embodiment, the particle size distribution and the volume average diameter can be measured by a laser diffraction / scattering method, and the detailed measurement conditions of soot are described in the following examples. It is possible to follow things.
　γ－アミノ酪酸誘導体は、錠剤（好ましくは素錠）の全重量に対して、好ましくは１０．０～９０．０重量％、より好ましくは２０．０～８０．０重量％、更に好ましくは２０．０～６０．０重量％、更に好ましくは２５．０～５０．０重量％、特に好ましくは２５．０～４０．０重量％の範囲内で当該錠剤中に含有される。１錠あたりのγ－アミノ酪酸誘導体の含有量としては、例えば、２５ｍｇ、７５ｍｇ、１５０ｍｇが挙げられる。 The γ-aminobutyric acid derivative is preferably 10.0 to 90.0% by weight, more preferably 20.0 to 80.0% by weight, still more preferably 20% by weight, based on the total weight of the tablet (preferably uncoated). It is contained in the tablet in the range of 0 to 60.0% by weight, more preferably 25.0 to 50.0% by weight, particularly preferably 25.0 to 40.0% by weight. The content of the γ-aminobutyric acid derivative per tablet includes, for example, 25 mg, 75 mg and 150 mg.
＜錠剤の形態＞
　本実施形態に係る錠剤の形態は、打錠等により圧縮成形した素錠のままであることが好ましいが、或いはコーティング剤を含むフィルムコーティング層で素錠を被覆してフィルムコーティング錠とすることも必要な検討を適宜行った上で可能である。本発明の錠剤の形状は、円形錠、円形Ｒ錠、円形隅角錠、円形２段Ｒ錠や異形錠（楕円錠等）等のいずれの形状であってもよい。 <Form of tablet>
The form of the tablet according to the present embodiment is preferably a plain tablet compression-molded by tableting or the like, or alternatively, the plain tablet may be coated with a film coating layer containing a coating agent to form a film-coated tablet. It is possible after appropriate examination. The shape of the tablet of the present invention may be any shape such as a circular tablet, a circular R tablet, a circular corner corner tablet, a circular two-tiered R tablet and a modified tablet (such as an oval tablet).
　錠剤の剤形は、口腔内崩壊錠であることが好ましく、素錠である口腔内崩壊錠がより好ましい。口腔内崩壊錠は、口腔内で迅速に崩壊する錠剤として普通錠と区別して提供されるものであって、口腔内崩壊時間が６０秒未満のものであり、４０秒未満のものが好ましい。 The dosage form of the tablet is preferably an orally disintegrating tablet, and an orally disintegrating tablet, which is an uncoated tablet, is more preferable. An orally disintegrating tablet is provided as a tablet that disintegrates rapidly in the oral cavity, as distinguished from ordinary tablets, and the oral disintegration time is less than 60 seconds, preferably less than 40 seconds.
＜ケイ酸系添加剤＞
　本実施形態に係る錠剤は、ケイ酸系添加剤の合計含有量を、好ましくは３．０重量％未満、より好ましくは１．０重量％未満、更に好ましくは０．５重量％未満、更に好ましくは０．１重量％未満とすることができ、ケイ酸系添加剤を含有しないことが特に好ましい。本実施形態において、ケイ酸系添加剤は、流動化剤、滑沢剤又は賦形剤等として用いられる添加剤である。ケイ酸系添加剤として具体的には、二酸化ケイ素（軽質無水ケイ酸、含水二酸化ケイ素等を含む。）、ケイ酸カルシウム、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、ケイ酸アルミニウム（天然ケイ酸アルミニウム、合成ケイ酸アルミニウム、コロイド性含水ケイ酸アルミニウム等を含む。）、ケイ酸マグネシウムアルミニウム（合成ケイ酸マグネシウムナトリウム等を含む。）等が挙げられ；特に、二酸化ケイ素、ケイ酸カルシウム、及びメタケイ酸アルミン酸マグネシウムが挙げられる。 <Silica-based additive>
The tablet according to the present embodiment preferably has a total content of silicic acid additives of less than 3.0% by weight, more preferably less than 1.0% by weight, still more preferably less than 0.5% by weight, and further preferably May be less than 0.1% by weight, and it is particularly preferred not to contain a silicic acid additive. In the present embodiment, the silicic acid based additive is an additive used as a fluidizing agent, a lubricant or an excipient. Specific examples of the siliceous additives include silicon dioxide (including light anhydrous silicic acid and hydrous silicon dioxide), calcium silicate, magnesium aluminosilicate, magnesium aluminometasilicate, magnesium silicate and silicate Aluminum (including natural aluminum silicate, synthetic aluminum silicate, colloidal hydrous aluminum silicate and the like), magnesium aluminum silicate (including synthetic magnesium sodium silicate and the like), etc. are mentioned; in particular, silicon dioxide, silica Examples include calcium acid and magnesium aluminometasilicate.
＜添加剤＞
　本実施形態に係る錠剤を製造するために、医薬品の製造において一般的に使用されている賦形剤、結合剤、崩壊剤、流動化剤、滑沢剤、矯味剤、コーティング剤等の添加剤も使用することができる。また、添加剤として低融点油脂を使用することが好ましい。尚、本明細書において、各種添加剤（賦形剤、結合剤、崩壊剤、流動化剤、滑沢剤、矯味剤、コーティング剤、低融点油脂等）の語句の解釈は其々、製剤化において其の添加剤としての役割を発揮することが必須に期待されて使用されるものであって、結果的にも其の添加剤としての役割が発揮されたものと解することが好ましい。また当然であるが、本明細書における添加剤の語句の解釈において原薬が含まれることはない。 <Additives>
Additives such as excipients, binders, disintegrants, fluidizers, lubricants, flavoring agents, coating agents and the like generally used in the manufacture of pharmaceuticals to produce the tablet according to the present embodiment Can also be used. Moreover, it is preferable to use low melting point fats and oils as an additive. In the present specification, interpretation of the terms of various additives (excipients, binders, disintegrants, fluidizers, lubricants, flavoring agents, coating agents, low melting point oils and fats, etc.) is often formulated. In the above, it is preferable to use and be expected to exert the role of the soot additive as an additive, and as a result, it is preferable to understand that the role as the soot additive is also exhibited. It is also understood that the drug substance is not included in the interpretation of the term of the additive herein.
＜賦形剤＞
　賦形剤として、具体的には、乳糖（乳糖水和物、無水乳糖等）、結晶セルロース、糖アルコール（Ｄ－マンニトール、イソマルト、エリスリトール等）、トレハロース、トウモロコシデンプン、シクロデキストリン等が挙げられ；好ましくは、乳糖、結晶セルロース、糖アルコール、トウモロコシデンプン、及びシクロデキストリンから選ばれ；より好ましくは、結晶セルロース、糖アルコール、及びトウモロコシデンプンから選ばれ；更に好ましくは糖アルコールを含むように前記の選択肢から選ばれ；特に好ましくは、Ｄ－マンニトール及び／又はエリスリトールを含むように前記の選択肢から選ばれる。これらの賦形剤は、１種単独で用いてもよく、２種以上を併用してもよい。 <Excipient>
Specific examples of the excipient include lactose (lactose hydrate, anhydrous lactose and the like), crystalline cellulose, sugar alcohol (D-mannitol, isomalto, erythritol and the like), trehalose, corn starch, cyclodextrin and the like; Preferably, it is selected from lactose, microcrystalline cellulose, sugar alcohol, corn starch and cyclodextrin; more preferably, it is selected from microcrystalline cellulose, sugar alcohol and corn starch; more preferably the above options to include sugar alcohol Particularly preferably selected from the above options to include D-mannitol and / or erythritol. These excipients may be used alone or in combination of two or more.
　錠剤（好ましくは素錠）の全重量に対する賦形剤の含有量は、１０．０重量％以上が好ましく、２０．０重量％以上がより好ましく、２５．０重量％以上が更に好ましく、３０．０重量％以上が更に好ましく、４０．０重量％以上が特に好ましい。また、該含有量は、９０．０重量％以下が好ましく、８０．０重量％以下がより好ましく、７５．０重量％以下が更に好ましく、７０．０重量％以下が更に好ましく、６５．０重量％以下が特に好ましい。 The content of the excipient with respect to the total weight of the tablet (preferably uncoated tablet) is preferably 10.0% by weight or more, more preferably 20.0% by weight or more, still more preferably 25.0% by weight or more, and 30. 0 weight% or more is more preferable, and 40.0 weight% or more is especially preferable. The content is preferably 90.0 wt% or less, more preferably 80.0 wt% or less, still more preferably 75.0 wt% or less, still more preferably 70.0 wt% or less, and 65.0 wt%. % Or less is particularly preferred.
＜崩壊剤＞
　崩壊剤として、具体的には、ヒドロキシプロピルスターチ、低置換度ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、部分アルファー化デンプン、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン等が挙げられ；好ましくは、ヒドロキシプロピルスターチ、低置換度ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、部分アルファー化デンプン、カルメロースカルシウム、クロスカルメロースナトリウム、及びクロスポビドンから選ばれ；より好ましくはヒドロキシプロピルスターチ、低置換度ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、及びクロスポビドンから選ばれ；更に好ましくは、クロスポビドンを含むように前記の選択肢から選ばれる。これらの崩壊剤は、１種単独で用いてもよく、２種以上を併用してもよい。尚、錠剤が口腔内崩壊錠である場合は、崩壊剤を含有することが好ましい。 <Disintegrant>
Specific examples of the disintegrant include hydroxypropyl starch, low substituted hydroxypropyl cellulose, sodium starch glycolate, partially pregelatinized starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone and the like; Selected from hydroxypropyl starch, low substituted hydroxypropyl cellulose, sodium starch glycolate, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, and crospovidone; more preferably hydroxypropyl starch, low substituted hydroxypropyl Selected from cellulose, sodium starch glycolate and crospovidone; more preferably from the above options to include crospovidone Barrel. These disintegrants may be used alone or in combination of two or more. When the tablet is an orally disintegrating tablet, it is preferable to contain a disintegrant.
　錠剤（好ましくは素錠）の全重量に対する崩壊剤の含有量は、１．０重量％以上が好ましく、２．０重量％以上がより好ましく、２．５重量％以上が更に好ましく、３．０重量％以上が特に好ましい。また、該含有量は、２０．０重量％以下が好ましく、１５．０重量％以下がより好ましく、１２．０重量％以下が更に好ましく、１０．０重量％以下が特に好ましい。 The content of the disintegrant based on the total weight of the tablet (preferably uncoated tablet) is preferably 1.0% by weight or more, more preferably 2.0% by weight or more, still more preferably 2.5% by weight or more, 3.0 % By weight or more is particularly preferred. Moreover, 20.0 weight% or less is preferable, as for this content, 15.0 weight% or less is more preferable, 12.0 weight% or less is still more preferable, 10.0 weight% or less is especially preferable.
＜結合剤＞
　結合剤として、具体的には、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース（ヒプロメロース）、メチルセルロース、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー、カルメロースナトリウム、アルファー化デンプン等が挙げられ；好ましくは、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ポリビニルアルコール、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー、カルメロースナトリウム、及びアルファー化デンプンから選ばれ；より好ましくは、ヒドロキシプロピルセルロース、ポリビニルアルコール、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー、カルメロースナトリウム、及びアルファー化デンプンから選ばれ；更に好ましくは、ヒドロキシプロピルセルロース、ポリビニルアルコール、及びカルメロースナトリウムから選ばれる。これらの結合剤は、１種単独で用いてもよく、２種以上を併用してもよい。 <Binder>
As a binder, specifically, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), methyl cellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol graft copolymer, carmellose sodium And preferably selected from hydroxypropyl cellulose, hypromellose, methylcellulose, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol graft copolymer, carmellose sodium, and pregelatinized starch; more preferably hydroxypropyl; Cellulose, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol Lumpur graft polymer, carmellose sodium, and selected from pregelatinized starch; more preferably, hydroxypropylcellulose, selected polyvinyl alcohol, and carmellose sodium. These binders may be used alone or in combination of two or more.
　錠剤（好ましくは素錠）の全重量に対する結合剤の含有量は、０．１重量％以上が好ましく、０．２重量％以上がより好ましく、０．５重量％以上が更に好ましく、１．０重量％以上が特に好ましい。また、該含有量は、１０．０重量％以下が好ましく、８．０重量％以下がより好ましく、５．０重量％以下が更に好ましく、４．０重量％以下が特に好ましい。尚、錠剤が乾式造粒法（好ましくは溶融造粒法）によって製造される場合は、結合剤の含有量は１．０重量％未満（好ましくは０．１重量％未満）であってもよく、結合剤を含有しなくてもよい。 0.1 weight% or more is preferable, as for content of the binder with respect to the total weight of a tablet (preferably uncoated tablet), 0.2 weight% or more is more preferable, 0.5 weight% or more is still more preferable, 1.0 % By weight or more is particularly preferred. The content is preferably 10.0% by weight or less, more preferably 8.0% by weight or less, still more preferably 5.0% by weight or less, and particularly preferably 4.0% by weight or less. In addition, when a tablet is manufactured by the dry granulation method (preferably melt granulation method), content of a binder may be less than 1.0 weight% (preferably less than 0.1 weight%). And may not contain a binder.
＜流動化剤＞
　流動化剤として、具体的にはタルク等を挙げる事ができ、好ましくはタルクである。 Fluidizer
Specific examples of the fluidizing agent include talc and the like, with preference given to talc.
　錠剤（好ましくは素錠）の全重量に対する流動化剤の含有量は、０．１重量％以上が好ましく、０．２重量％以上がより好ましく、０．５重量％以上が更に好ましく、０．８重量％以上が更に好ましく、１．０重量％以上が特に好ましい。また、該含有量は、５．０重量％以下が好ましく、４．０重量％以下がより好ましく、３．０重量％以下が更に好ましく、２．０重量％以下が更に好ましく、１．５重量％以下が特に好ましい。 0.1 weight% or more is preferable, as for content of the fluidizer with respect to the total weight of a tablet (preferably uncoated tablet), 0.2 weight% or more is more preferable, 0.5 weight% or more is more preferable, and 0. 8 weight% or more is more preferable, and 1.0 weight% or more is especially preferable. In addition, the content is preferably 5.0% by weight or less, more preferably 4.0% by weight or less, still more preferably 3.0% by weight or less, still more preferably 2.0% by weight or less, 1.5% by weight % Or less is particularly preferred.
＜滑沢剤＞
　滑沢剤として、具体的には、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、硬化油等が挙げられ；好ましくは、グリセリン脂肪酸エステル、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、及び硬化油から選ばれ；より好ましくは、ステアリン酸マグネシウムを含むように前記の選択肢から選ばれる。これらの滑沢剤は、１種単独で用いてもよく、２種以上を併用してもよい。 <Lubricant>
Specific examples of the lubricant include glycerin fatty acid ester, sucrose fatty acid ester, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated oil and the like; preferably, glycerin fatty acid ester, magnesium stearate, stear It is selected from calcium phosphate, sodium stearyl fumarate, and hydrogenated oils; more preferably, selected from the above options to include magnesium stearate. These lubricants may be used alone or in combination of two or more.
　錠剤（好ましくは素錠）の全重量に対する滑沢剤の含有量は、０．１重量％以上が好ましく、０．２重量％以上がより好ましく、０．３重量％以上が更に好ましく、０．４重量％以上が更に好ましく、０．５重量％以上が特に好ましい。また、該含有量は、５．０重量％以下が好ましく、４．０重量％以下がより好ましく、３．０重量％以下が更に好ましく、２．０重量％以下が更に好ましく、１．５重量％以下が特に好ましい。 0.1 weight% or more is preferable, as for content of the lubricant with respect to the total weight of a tablet (preferably uncoated tablet), 0.2 weight% or more is more preferable, 0.3 weight% or more is more preferable, 0. 4 weight% or more is more preferable, and 0.5 weight% or more is especially preferable. In addition, the content is preferably 5.0% by weight or less, more preferably 4.0% by weight or less, still more preferably 3.0% by weight or less, still more preferably 2.0% by weight or less, 1.5% by weight % Or less is particularly preferred.
＜矯味剤＞
　矯味剤として、具体的には、アスコルビン酸、Ｌ－アスパラギン酸、クエン酸、酒石酸、リンゴ酸、アスパルテーム、スクラロース、アセスルファムカリウム、サッカリンナトリウム（其の水和物を含む。）、サッカリン、ソーマチン、ネオテーム等が挙げられ；好ましくは、アスパルテーム、スクラロース、及びサッカリンナトリウムから選ばれ；より好ましくはスクラロースである。これらの矯味剤は、１種単独で用いてもよく、２種以上を併用してもよい。尚、錠剤が口腔内崩壊錠である場合は、矯味剤を含有することが好ましい。特に、矯味剤をγ－アミノ酪酸誘導体と共に造粒物中に含有することにより、良好な崩壊性を得ることができる。 <Flavor>
As the flavoring agent, specifically, ascorbic acid, L-aspartic acid, citric acid, tartaric acid, malic acid, aspartame, sucralose, acesulfame potassium, saccharin sodium (including water hydrate), saccharin, thaumatin, neotame etc. Is preferably selected from aspartame, sucralose and saccharin sodium; more preferably sucralose. These flavoring agents may be used alone or in combination of two or more. When the tablet is an orally disintegrating tablet, it is preferable to contain a flavoring agent. In particular, good disintegratability can be obtained by incorporating a flavoring agent together with the γ-aminobutyric acid derivative in the granulated product.
　錠剤（好ましくは素錠）の全重量に対する矯味剤の含有量は、０．１重量％以上が好ましく、０．５重量％以上がより好ましく、１．０重量％以上が更に好ましく、１．２重量％以上が更に好ましく、１．５重量％以上が特に好ましい。また、該含有量は、１０．０重量％以下が好ましく、９．０重量％以下がより好ましく、８．０重量％以下が更に好ましく、７．０重量％以下が更に好ましく、６．０重量％以下が特に好ましい。 The content of the flavoring agent relative to the total weight of the tablet (preferably uncoated tablet) is preferably 0.1% by weight or more, more preferably 0.5% by weight or more, still more preferably 1.0% by weight or more, 1.2 % By weight or more is more preferable, and 1.5% by weight or more is particularly preferable. The content is preferably 10.0% by weight or less, more preferably 9.0% by weight or less, still more preferably 8.0% by weight or less, still more preferably 7.0% by weight or less, 6.0% by weight % Or less is particularly preferred.
＜低融点油脂＞
　本実施形態において使用される低融点油脂は、融点が２０～９０℃のものが好ましく、３０～８５℃のものがより好ましく、４０～８０℃のものが更に好ましく、４５～６９℃のものが特に好ましい。低融点油脂は高融点油脂と比べて有効成分と均一に配合可能なものであり、その結果、有効成分であるγ－アミノ酪酸誘導体の分解等が抑制されたより安定な錠剤を得ることができる。低融点油脂の具体例としては、例えば、高級脂肪酸（炭素数が例えば１０～４０、好ましくは１２～２６）及び其の塩、高級アルコール（炭素数が例えば１０～４０、好ましくは１２～２６）、炭化水素類（パラフィンワックス、マイクロクリスタリンワックス等）、脂肪酸エステル、硬化油（硬化ヒマシ油、硬化大豆油、硬化ナタネ油、硬化綿実油等）、アルキレンオキサイドの重合体（ポリエチレングリコール、ポリプロピレングリコール等）等が挙げられ、脂肪酸エステル及び／又は硬化油が好ましく、多価アルコールの脂肪酸エステルがより好ましい。これらの低融点油脂は、１種単独で用いてもよく、２種以上を併用してもよい。また、これらの低融点油脂は、前記の結合剤、滑沢剤等として機能するものであってもよい。 <Low melting point fats and oils>
The low melting point fats and oils used in this embodiment preferably have a melting point of 20 to 90 ° C., more preferably 30 to 85 ° C., still more preferably 40 to 80 ° C., and further preferably 45 to 69 ° C. Particularly preferred. The low melting point fats and oils can be blended uniformly with the active ingredient as compared with the high melting point fats and oils. As a result, it is possible to obtain a more stable tablet in which the decomposition and the like of the γ-aminobutyric acid derivative which is the active ingredient is suppressed. Specific examples of low melting point fats and oils include, for example, higher fatty acids (for example, 10 to 40, preferably 12 to 26 carbon atoms) and salts of persimmon, higher alcohols (for example, 10 to 40, preferably 12 to 26 carbon atoms). Hydrocarbons (paraffin wax, microcrystalline wax, etc.), fatty acid ester, hydrogenated oil (cured castor oil, hydrogenated soybean oil, cured rapeseed oil, cured cottonseed oil, etc.), polymer of alkylene oxide (polyethylene glycol, polypropylene glycol etc.) And the like, and fatty acid esters and / or hydrogenated oils are preferred, and fatty acid esters of polyhydric alcohols are more preferred. These low melting point fats and oils may be used alone or in combination of two or more. In addition, these low melting point fats and oils may function as the above-mentioned binder, lubricant and the like.
　本明細書において「多価アルコールの脂肪酸エステル」とは、多価アルコールの有する水酸基の一部又は全部が脂肪酸（好ましくは炭素数が１２～２６の脂肪酸）でエステル化された化合物を意味する。「多価アルコールの脂肪酸エステル」の多価アルコール部分としては、エチレングリコール、プロピレングリコール、ブタンジオール、ペンタンジオール等のアルキレングリコール；ポリエチレングリコール、ポリプロピレングリコール等のポリアルキレングリコール；グリセリン、ソルビトール、ソルビタン、ペンタエリスリトール、ショ糖等の糖類等が挙げられ、グリセリンが好ましい。「多価アルコールの脂肪酸エステル」の具体例としては、例えば、エチレングリコール脂肪酸エステル、プロピレングリコール脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシアルキレン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシアルキレンソルビタン脂肪酸エステル、ポリオキシアルキレンソルビトール脂肪酸エステル、ショ糖脂肪酸エステル等が挙げられ、グリセリン脂肪酸エステルが好ましく、モノ脂肪酸（Ｃ１２－２６）グリセリルがより好ましく、モノステアリン酸グリセリンが特に好ましい。これらの多価アルコールの脂肪酸エステルは、１種単独で用いてもよく、２種以上を併用してもよい。 In the present specification, “fatty acid ester of polyhydric alcohol” means a compound in which part or all of the hydroxyl groups of polyhydric alcohol are esterified with a fatty acid (preferably a fatty acid having 12 to 26 carbon atoms). Examples of the polyhydric alcohol moiety of the "fatty acid ester of polyhydric alcohol" include alkylene glycols such as ethylene glycol, propylene glycol, butanediol and pentanediol; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; glycerin, sorbitol, sorbitan, penta Examples thereof include saccharides such as erythritol and sucrose and the like, and glycerin is preferable. Specific examples of "fatty acid ester of polyhydric alcohol" include ethylene glycol fatty acid ester, propylene glycol fatty acid ester, glycerin fatty acid ester, polyoxyalkylene fatty acid ester, sorbitan fatty acid ester, polyoxyalkylene sorbitan fatty acid ester, polyoxyalkylene Sorbitol fatty acid ester, sucrose fatty acid ester and the like are mentioned, glycerin fatty acid ester is preferable, mono fatty acid (C12-26) glyceryl is more preferable, and glycerin monostearate is particularly preferable. These fatty acid esters of polyhydric alcohols may be used alone or in combination of two or more.
　錠剤（好ましくは素錠）の全重量に対する低融点油脂の含有量は、０．１重量％以上が好ましく、０．５重量％以上がより好ましく、０．８重量％以上が更に好ましく、１．０重量％以上が更に好ましく、１．２重量％以上が特に好ましい。また、該含有量は、１０．０重量％以下が好ましく、８．０重量％以上がより好ましく、６．０重量％以下が更に好ましく、５．０重量％以下が更に好ましく、４．５重量％以下が特に好ましい。 0.1 weight% or more is preferable, 0.5 weight% or more is more preferable, 0.5 weight% or more is more preferable, and, as for content of the low melting fats and oils with respect to the total weight of a tablet (preferably uncoated tablet), 0.8 weight% or more is more preferable 0 weight% or more is more preferable, and 1.2 weight% or more is especially preferable. In addition, the content is preferably 10.0% by weight or less, more preferably 8.0% by weight or more, still more preferably 6.0% by weight or less, still more preferably 5.0% by weight or less, and 4.5% by weight % Or less is particularly preferred.
＜その他添加剤＞
　その他添加剤（無機塩）として、具体的には、酸化チタン、リン酸水素カルシウム（リン酸水素カルシウム水和物、無水リン酸水素カルシウム等）等が挙げられ、好ましくはリン酸水素カルシウムである。その他添加剤（無機塩）は、適宜の検討の上、コーティング剤、賦形剤又は流動化剤として用いることが可能である。 <Other additives>
Specific examples of other additives (inorganic salts) include titanium oxide and calcium hydrogen phosphate (calcium hydrogen phosphate hydrate, anhydrous calcium hydrogen phosphate etc.), preferably calcium hydrogen phosphate . Other additives (inorganic salts) can be used as a coating agent, an excipient, or a fluidizing agent after appropriate examination.
＜造粒物＞
　本実施形態に係る錠剤は、γ－アミノ酪酸誘導体（好ましくは矯味剤等の添加剤も併せて）を含む造粒物（顆粒）を含有するものであることが好ましい。当該造粒物は、錠剤（好ましくは素錠）の全重量に対して、好ましくは１０．０～９０．０重量％、より好ましくは２０．０～８０．０重量％、更に好ましくは３０．０～７０．０重量％、特に好ましくは３５．０～６０．０重量％の範囲で錠剤中に含有される。 Granules
The tablet according to the present embodiment is preferably one containing a granulated product (granules) containing a γ-aminobutyric acid derivative (preferably, an additive such as a flavoring agent is also added). The granulated material is preferably 10.0 to 90.0% by weight, more preferably 20.0 to 80.0% by weight, still more preferably 30. The tablet is contained in the range of 0 to 70.0% by weight, particularly preferably 35.0 to 60.0% by weight.
　γ－アミノ酪酸誘導体を含む造粒物は、当該造粒物の全重量に対して、好ましくは７０．０～９９．０重量％、より好ましくは７５．０～９８．０重量％、更に好ましくは８０．０～９７．０重量％、更に好ましくは８５．０～９６．０重量％、特に好ましくは９０．０～９５．０重量％のγ－アミノ酪酸誘導体を含有するように得られる。 The granulated material containing the γ-aminobutyric acid derivative is preferably 70.0 to 99.0% by weight, more preferably 75.0 to 98.0% by weight, further preferably, based on the total weight of the granulated product. Is obtained so as to contain 80.0 to 97.0% by weight, more preferably 85.0 to 96.0% by weight, particularly preferably 90.0 to 95.0% by weight of the γ-aminobutyric acid derivative.
＜造粒方法＞
　本実施形態に係る錠剤の製造においては、上記の粒子径分布又は体積平均径のいずれかを有するγ－アミノ酪酸誘導体を用いて造粒がなされることが好ましい。本実施形態に係る造粒方法として乾式造粒法（破砕造粒法、溶融造粒法等）又は湿式造粒法（流動層造粒法、攪拌造粒法、押出し造粒法等）が挙げられる。なかでも乾式造粒法が好適に用いられ、溶融造粒法がより好ましい。 Granulation method
In the production of the tablet according to the present embodiment, it is preferable that granulation is performed using a γ-aminobutyric acid derivative having any of the above particle diameter distribution or volume average diameter. As a granulation method according to the present embodiment, a dry granulation method (a crushing granulation method, a melt granulation method, etc.) or a wet granulation method (a fluid bed granulation method, a stirring granulation method, an extrusion granulation method, etc.) is mentioned. Be Among them, the dry granulation method is suitably used, and the melt granulation method is more preferable.
　前記の造粒方法によって、γ－アミノ酪酸誘導体及び低融点油脂（更に任意で矯味剤等の添加剤）を均一に配合し、造粒物（好ましくは乾式造粒物、より好ましくは溶融造粒物）を形成することが好ましい態様として挙げられる。γ－アミノ酪酸誘導体と低融点油脂とを含む造粒物を形成することにより、γ－アミノ酪酸誘導体の化学的安定性がより改善された錠剤を製造することができる。 A γ-aminobutyric acid derivative and a low melting point fat and oil (more optionally, an additive such as a flavoring agent) are uniformly blended by the above granulation method, and a granulated product (preferably a dry granulated product, more preferably a melt granulated product It is mentioned as a preferable aspect to form a substance. By forming a granulated product containing the γ-aminobutyric acid derivative and the low melting point fat and oil, it is possible to produce a tablet in which the chemical stability of the γ-aminobutyric acid derivative is further improved.
　乾式造粒法は、湿式造粒法とは異なり、水やアルコール等の溶液を加えずに造粒することを特徴とするものである。溶融造粒法は、撹拌造粒機や流動層造粒機等に原薬（γ－アミノ酪酸誘導体）及び低融点油脂を投入（併せて矯味剤等の他の添加剤を投入してもよい。）し、これを混合しながら加温することによって低融点油脂を溶解させ、最後に冷却することで造粒物を形成するものである。溶融造粒時には、低融点油脂の融点以上の温度（通常４０～１００℃、好ましくは５０～９０℃、より好ましくは６０～８０℃、更に好ましくは７０～８０℃）まで加温される。 Unlike the wet granulation method, the dry granulation method is characterized in that granulation is performed without adding a solution such as water or alcohol. In the melt granulation method, the drug substance (γ-aminobutyric acid derivative) and low melting point fats and oils are charged into a stirring granulator, a fluidized bed granulator, etc. (In combination, other additives such as a flavoring agent may be charged. The low melting point fats and oils are dissolved by heating while mixing them, and a granulated material is formed by finally cooling. At the time of melt granulation, it is heated to a temperature (generally 40 to 100 ° C., preferably 50 to 90 ° C., more preferably 60 to 80 ° C., further preferably 70 to 80 ° C.) above the melting point of the low melting point fat.
　低融点油脂は、造粒物の全重量に対して、好ましくは１．０～３０．０重量％、より好ましくは１．５～２０．０重量％、更に好ましくは２．０～１８．０％、更に好ましくは２．５～１４．０％、特に好ましくは３．０～９．０％の範囲で当該造粒物中に含有される。 The low melting point fats and oils are preferably 1.0 to 30.0% by weight, more preferably 1.5 to 20.0% by weight, still more preferably 2.0 to 18.0% by weight based on the total weight of the granulated product. %, More preferably 2.5 to 14.0%, particularly preferably 3.0 to 9.0%.
　矯味剤は、造粒物の全重量に対して、好ましくは１．０～３０．０重量％、より好ましくは１．５～２０．０重量％、更に好ましくは２．０～１８．０％、更に好ましくは２．５～１４．０％、特に好ましくは３．０～９．０％の範囲で当該造粒物中に含有される。 The flavoring agent is preferably 1.0 to 30.0% by weight, more preferably 1.5 to 20.0% by weight, still more preferably 2.0 to 18.0%, based on the total weight of the granulated product. It is more preferably contained in the granulate in a range of 2.5 to 14.0%, particularly preferably 3.0 to 9.0%.
　造粒物中の、γ－アミノ酪酸誘導体の配合量に対する低融点油脂の配合量（低融点油脂の配合量／γ－アミノ酪酸誘導体の配合量）は、０．０１０以上が好ましく、０．０１５以上がより好ましく、０．０２０以上が更に好ましく、０．０２５以上が更に好ましく、０．０３０以上が特に好ましい。また、造粒物中の、γ－アミノ酪酸誘導体の配合量に対する低融点油脂の配合量（低融点油脂の配合量／γ－アミノ酪酸誘導体の配合量）は、０．４０以下が好ましく、０．２０以下がより好ましく、０．１８以下が更に好ましく、０．１４以下が更に好ましく、０．０９０以下が特に好ましい。 0.010 or more is preferable, and 0.015 or more is preferable for the blending amount of low melting point fats and oils (blending amount of low melting point fats and oils / blending amount of γ-aminobutyric acid derivative) relative to the blending amount of γ-aminobutyric acid derivative in the granulated product The above is more preferable, 0.020 or more is further preferable, 0.025 or more is further preferable, and 0.030 or more is particularly preferable. Also, the blending amount of low melting point fats and oils (blending amount of low melting point fats and oils / blending amount of γ-aminobutyric acid derivative) with respect to the blending amount of γ-aminobutyric acid derivative in the granulated product is preferably 0.40 or less .20 or less is more preferable, 0.18 or less is further preferable, 0.14 or less is more preferable, 0.090 or less is particularly preferable.
　造粒物中の、γ－アミノ酪酸誘導体の配合量に対する矯味剤の配合量（矯味剤の配合量／γ－アミノ酪酸誘導体の配合量）は、０．０１０以上が好ましく、０．０１５以上がより好ましく、０．０２０以上が更に好ましく、０．０２５以上が更に好ましく、０．０３０以上が特に好ましい。また、造粒物中の、γ－アミノ酪酸誘導体の配合量に対する矯味剤の配合量（矯味剤の配合量／γ－アミノ酪酸誘導体の配合量）は、０．４０以下が好ましく、０．２０以下がより好ましく、０．１８以下が更に好ましく、０．１４以下が更に好ましく、０．０９０以下が特に好ましい。 0.010 or more is preferable and 0.015 or more of the compounding amount of the flavoring agent (compounding amount of the flavoring agent / compounded amount of the γ-aminobutyric acid derivative) with respect to the compounding amount of the γ-aminobutyric acid derivative in the granulated material More preferably, 0.020 or more is further preferable, 0.025 or more is further preferable, and 0.030 or more is particularly preferable. Further, the blending amount of the flavoring agent (blending amount of the flavoring agent / blending amount of the γ-aminobutyric acid derivative) with respect to the blending amount of the γ-aminobutyric acid derivative in the granulated product is preferably 0.40 or less, 0.20 The following is more preferable, 0.18 or less is further preferable, 0.14 or less is more preferable, 0.090 or less is particularly preferable.
＜錠剤の製造方法＞
　本実施形態に係る錠剤は、一般的な製造方法によって作成することが可能であり、例えば以下の製造方法によって作成することが可能である。 <Method for producing tablets>
The tablet according to the present embodiment can be produced by a general production method, for example, can be produced by the following production method.
　まず、原薬及び低融点油脂（更に任意で矯味剤等の添加剤）を攪拌しながら加温することで溶融造粒を行い、造粒物を製造する。そして、得られた造粒物を整粒した後に、賦形剤、崩壊剤及び滑沢剤等と混合して打錠機によって圧縮成形して錠剤（素錠）とする。素錠を打錠して製造する際の打圧は、好ましくは６００～１４００ｋｇｆの範囲内の任意の数値から選ばれる。更に所望によって、得られた素錠にフィルムコーティング層を施してもよい。 First, melt granulation is carried out by heating while stirring the drug substance and low melting point fats and oils (optionally, additives such as flavoring agents) to produce a granulated product. Then, after granulating the obtained granulated product, it is mixed with an excipient, a disintegrant, a lubricant and the like, and compression molded by a tableting machine to make a tablet (uncoated tablet). The batting pressure at the time of tableting and manufacturing the uncoated tablet is preferably selected from any value within the range of 600 to 1400 kgf. Furthermore, if desired, the obtained uncoated tablet may be provided with a film coating layer.
＜錠剤の処方＞
　本実施形態に係る錠剤は、γ－アミノ酪酸誘導体並びに適切な添加剤（上記の賦形剤、結合剤、崩壊剤、流動化剤、滑沢剤及びその他添加剤（本実施形態に係る錠剤が口腔内崩壊錠である場合、好ましくは矯味剤も併せて）のいずれかの欄で好ましく挙げられた添加剤）を、錠剤の全重量に対して好ましくは９０．０重量％、より好ましくは９５．０重量％以上、更により好ましくは９８．０重量％以上含有し、最も好ましくはγ－アミノ酪酸誘導体及び適切な添加剤のみからなる。 <Formulation of tablets>
The tablet according to the present embodiment is a γ-aminobutyric acid derivative and suitable additives (excipients, binders, disintegrants, fluidizers, lubricants and other additives described above (tablets according to the present embodiment In the case of an orally disintegrating tablet, preferably the additive mentioned preferably in any column of “(a flavoring agent is also included)” is preferably 90.0% by weight, more preferably 95% based on the total weight of the tablet. And more preferably at least 98.0% by weight, most preferably consisting only of γ-aminobutyric acid derivatives and appropriate additives.
　また、包装用シートとアルミ箔等で錠剤を挟んで覆い、加熱シールすることで、本実施形態に係る錠剤を含むＰＴＰシート製品を得ることができる。前記包装用シートに使用される具体的な素材としては、ポリ塩化ビニル、ポリプロピレン、ポリ塩化ビニリデン、ポリクロロトリフルオロエチレン等が挙げられる。尚、湿度に対する本実施形態に係る錠剤の安定性を改善するためには、乾燥機能を有した素材を用いてＰＴＰシート製品を製造したり、ＰＴＰシート製品をアルミピロー包装したり、乾燥剤を錠剤と共に瓶に封入する等の周知の方法を使用することが可能である。 Moreover, a PTP sheet product including a tablet according to the present embodiment can be obtained by sandwiching and covering the tablet with a sheet for packaging and aluminum foil or the like and heat sealing. Specific examples of materials used for the packaging sheet include polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene and the like. In addition, in order to improve the stability of the tablet according to the present embodiment with respect to humidity, a PTP sheet product is manufactured using a material having a drying function, an aluminum pillow package of the PTP sheet product, a desiccant It is possible to use known methods, such as sealing in bottles with tablets.
　以下に実施例等により本発明を説明するが、本発明はこれらの実施例等に限定されるものではない。以下の錠剤製造において、プレガバリンは事前にその粒子径分布がｄ１０＝８．０μｍ、ｄ５０＝４４．８μｍ、ｄ９０＝１５２．７μｍ｛レーザー回析・散乱法によって測定（体積基準）｝であるもの（体積平均径：６３．６μｍ）を使用した。当該プレガバリンを粉末Ｘ線解析測定した結果を図１に示す。 EXAMPLES The present invention will be described by way of examples and the like below, but the present invention is not limited to these examples and the like. In the following tablet production, pregabalin has a particle size distribution of d10 = 8.0 μm, d50 = 44.8 μm, d90 = 152.7 μm {measured by laser diffraction / scattering method (volume basis)} in advance Volume average diameter: 63.6 μm) was used. The results of powder X-ray analysis measurement of the pregabalin are shown in FIG.
　以下、実施例において用いる各種薬品をまとめて示す。
モノステアリン酸グリセリン：理研ビタミン（株）製のリケマールＳ－１００Ｐ（融点：６３～６８℃）
賦形剤１：ロケットジャパン（株）製のＰＥＡＲＬＩＴＯＬ（登録商標）１００ＳＤ（Ｄ－マンニトールから成る添加剤）
賦形剤２：ロケットジャパン（株）製のＰＥＡＲＬＩＴＯＬ（登録商標）Ｆｌａｓｈ（Ｄ－マンニトールとトウモロコシデンプンから成る添加剤）
賦形剤３：旭化成（株）製のセオラス（登録商標）ＵＦ－７１１（結晶セルロース）
矯味剤１：三栄源エフ・エフ・アイ（株）製のスクラロースＰ（スクラロース）
矯味剤２：味の素ヘルシーサプライ（株）製の味の素　ＫＫ　アスパルテーム（アスパルテーム）
矯味剤３：大和化成（株）製のサッカリンナトリウム水和物
クロスポビドン：ＢＡＳＦジャパン（株）製のＫｏｌｌｉｄｏｎｅ（登録商標）ＣＬ－ＳＦ Hereinafter, various medicines used in an example are summarized.
Glycerine monostearate: Rikemar S-100P (melting point: 63-68 ° C) manufactured by Riken Vitamin Co., Ltd.
Excipient 1: PEARLITOL (registered trademark) 100SD (an additive comprising D-mannitol) manufactured by Rocket Japan Co., Ltd.
Excipient 2: PEARLITOL (registered trademark) Flash (available from D-mannitol and corn starch) manufactured by Rocket Japan Co., Ltd.
Excipient 3: Theorus (registered trademark) UF-711 (crystalline cellulose) manufactured by Asahi Kasei Co., Ltd.
Flavoring agent 1: Sucralose P (Sucralose) manufactured by San-Ei Gen F.F.I.
Flavoring agent 2: Ajinomoto Healthy Assortment KK Ajinomoto KK aspartame (aspartame)
Flavoring agent 3: Saccharin sodium hydrate Crospovidone manufactured by Daiwa Kasei Co., Ltd .: Kollidone (registered trademark) CL-SF manufactured by BASF Japan Ltd.
［試験例１］プレガバリンと各種汎用添加剤との配合試験
　プレガバリンと一の各添加剤（表１、２記載）を質量比１：１でポリ袋中で混合した各混合物の其々を、製造直後及び５０℃相対湿度７５％開放条件下で１７日間保存した後で、プレガバリン由来の主な類縁体であるラクタム体の生成量｛プレガバリン及び其の総類縁体の全体量に対する割合（％）で示す。｝を、高速液体クロマトグラフィー法（定量方法は面積百分率法を使用した。）によって測定した。上記の測定結果を基に、保存前後における総類縁体の増加量（％）（差分）を求めた結果（小数点第４位以下は四捨五入した。）を下記の表１に示す。 [Test Example 1] Formulation Test of Pregabalin and Various General-purpose Additives Each of the mixtures prepared by mixing Pregabalin and one of the respective additives (described in Tables 1 and 2) in a plastic bag at a mass ratio of 1: 1 is manufactured. Immediately after and after storage at 50 ° C. and 75% relative humidity for 17 days, the amount of lactam that is the main analogue from pregabalin {% of total amount of pregabalin and salmon total analogues Show. } Was measured by high performance liquid chromatography (the quantitative method used the area percentage method). Based on the measurement results described above, the increase (%) (difference) in the amount of increase in total analogues before and after storage (Results rounded to the fourth decimal place) are shown in Table 1 below.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表２より、ケイ酸系添加剤（二酸化ケイ素、ケイ酸カルシウム、ケイ酸アルミン酸マグネシウム）を含有する混合物において保存後のプレガバリンの総類縁体の生成量が驚くほどに並外れて多いことが分かった。一方、表１、表２に記載のケイ酸系添加剤以外の添加剤との混合物は、ケイ酸系添加剤を含有する混合物と比べて、保存後のプレガバリンの総類縁体の生成量が相対的に低いことが分かった。表１、表２において、賦形剤、結合剤、崩壊剤、流動化剤、滑沢剤及びその他添加剤の各欄毎に保存後のプレガバリンの総類縁体の生成量が相対的に多いものを下線で示す。 From Table 2, it was found that in the mixture containing the siliceous additives (silicon dioxide, calcium silicate, magnesium aluminosilicate), the production amount of the total analogue of pregabalin after storage was surprisingly extraordinarily high. . On the other hand, in the mixture with additives other than the siliceous additives described in Table 1 and Table 2, the amount of the total analogue of pregabalin after storage is relative to that of the mixture containing the siliceous additives. It turned out that it was very low. In Table 1 and Table 2, relatively large amounts of total pregabalin analogues are stored after storage for each column of excipient, binder, disintegrant, fluidizer, lubricant and other additives Is underlined.
［錠剤例α、β、γ、ε］プレガバリン含有錠剤の試作製造例
　プレガバリン、モノステアリン酸グリセリンの粉末を撹拌造粒機に投入し、加温・攪拌した後に冷却して溶融造粒物を得た。得られた溶融造粒物、賦形剤２、及び各矯味剤（錠剤例αの場合は除く。）をポリエチレン製の袋にて混合した後、更にステアリン酸マグネシウムを加えて混合して混合物を得た。この混合物を打錠し、１錠質量が２００．０ｍｇの各錠剤（錠剤例α、β、γ、ε）を得た。尚、原薬並びに各添加剤は、当該各錠剤が下記表３に示す処方となるような量で上記製造に用いた。 [Tablet Example α, β, γ, ε] Preparation Example of Pregabalin-Containing Tablet A powder of pregabalin and glyceryl monostearate is charged into a stirring granulator, heated and stirred, and then cooled to obtain a melt granulated product. The The resulting melt-granulated product, Excipient 2, and each flavoring agent (except in the case of tablet example α) are mixed in a polyethylene bag, and then magnesium stearate is further added and mixed to obtain a mixture. Obtained. The mixture was compressed into tablets to give tablets each having a weight of 200.0 mg (tablet examples α, β, γ, ε). In addition, the drug substance and each additive were used in the above-mentioned production in such an amount that the respective tablets were formulated as shown in Table 3 below.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
［試験例２］錠剤中の薬物の化学的安定性試験
　錠剤例α、β、γ、εの、製造直後及び５０℃相対湿度７５％開放条件下で７日間保存した後の、プレガバリン由来の類縁体（ラクタム体）の生成量｛プレガバリン及び其の総類縁体の全体量に対する割合（％）で示す。｝を、高速液体クロマトグラフィー法（定量方法は面積百分率法を使用した。）によって測定した。上記の測定結果を基に、保存前後における総類縁体の増加量（％）（差分）を求めた結果（小数点第４位以下は四捨五入した。）を下記の表４に示す。 [Test Example 2] Chemical stability test of drug in tablet Pregabaline-derived affinity of tablet examples α, β, γ, ε immediately after production and after storage at 50 ° C and 75% relative humidity for 7 days The amount of production of a body (lactam body) {% of total amount of pregabalin and total analogue of salmon is shown. } Was measured by high performance liquid chromatography (the quantitative method used the area percentage method). Based on the measurement results described above, the increase (%) (difference) in the amount of increase in total analogues before and after storage was determined. The results (rounded off to the fourth decimal place) are shown in Table 4 below.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　表４より、ケイ酸系添加剤を含有せず、適切な添加剤から主に構成される錠剤（錠剤例α、β、γ、ε）においては、保存後のプレガバリン由来の類縁体の生成量がいずれも十分に低いことが確認された。よって、本発明の錠剤はプレガバリン等γ－アミノ酪酸誘導体の化学的な安定性が十分に改善されたものであることが示された。また口腔内崩壊錠用の矯味剤を添加した錠剤（錠剤例β、γ、ε）であっても保存後のプレガバリン由来の類縁体の生成量が十分に低いことが分かった。 According to Table 4, in tablets (tablet examples α, β, γ, ε) mainly containing appropriate additives, which do not contain silicic acid additives, the production amount of pregabalin-derived analogues after storage It was confirmed that all were sufficiently low. Therefore, it was shown that the tablet of the present invention is one in which the chemical stability of γ-aminobutyric acid derivative such as pregabalin is sufficiently improved. In addition, it was found that, even with tablets (tablet examples β, γ, ε) added with a flavoring agent for orally disintegrating tablets, the production amount of the pregabalin-derived analogue after storage is sufficiently low.
［錠剤例Ａ］プレガバリン含有口腔内崩壊錠の製造例
　プレガバリン、モノステアリン酸グリセリン及び矯味剤１の粉末を撹拌造粒機（ＶＧ０１型／（株）パウレック製）に投入し、温度７０℃になるまで加温してモノステアリン酸グリセリンを融解させ、当該温度を維持しながら５分間攪拌（ブレード回転数：２９０回転／分、クロススクリュー回転数：３５００回転／分）させ、その後温度４０℃になるまで冷却し、溶融造粒物を得た。得られた溶融造粒物は２４メッシュの篩で整粒した。
　得られた整粒物、賦形剤１～３、及びクロスポビドンをポリエチレン製の袋にて混合した後、更にステアリン酸マグネシウム（太平化学産業（株）製）を加えて混合して混合物を得た。この混合物をロータリー式打錠機（Ｖｅｒａ５／（株）菊水製作所製）を用いて打圧１３００ｋｇｆで打錠し、１錠質量が４２０．０ｍｇ、直径１０．５ｍｍ、厚さ５．７ｍｍの錠剤（素錠、口腔内崩壊錠、円形・２段Ｒ錠）を得た。尚、原薬並びに各添加剤は、当該錠剤が下記表５に示す処方となるような量で上記製造に用いた。 [Tablet Example A] Production Example of Pregabalin-Containing Orally Disintegrating Tablet Powder of pregabalin, glycerin monostearate and flavoring agent 1 is charged into a stirring granulator (type VG01 / made by Powrex Corp.), and the temperature reaches 70 ° C. The mixture is heated to the maximum temperature to melt glyceryl monostearate, stirred for 5 minutes while maintaining the temperature (blade rotation speed: 290 rpm, cross screw rotation speed: 3500 rpm), and then the temperature becomes 40 ° C. The mixture was cooled to obtain molten granules. The obtained melt-granulated product was sieved with a 24 mesh screen.
The obtained sized particles, excipients 1 to 3 and crospovidone are mixed in a polyethylene bag, and then magnesium stearate (made by Taihei Kagaku Sangyo Co., Ltd.) is added and mixed to obtain a mixture. The This mixture is tableted using a rotary tableting machine (Vera 5 / manufactured by Kikusui Seisakusho Ltd.) at a striking pressure of 1300 kgf, and the tablet weight is 420.0 mg, a tablet having a diameter of 10.5 mm and a thickness of 5.7 mm ( An uncoated tablet, an orally disintegrating tablet, and a round two-stage R tablet) were obtained. In addition, the drug substance and each additive were used in the above-mentioned production in such an amount that the tablet was formulated as shown in Table 5 below.
［錠剤例Ｂ］
「１錠質量が４２０．０ｍｇ、直径１０．５ｍｍ、厚さ５．７ｍｍの錠剤（素錠、口腔内崩壊錠、円形・２段Ｒ錠）を得た。」を「１錠質量が２１０．０ｍｇ、直径８．０ｍｍ、厚さ４．７ｍｍの錠剤（素錠、口腔内崩壊錠、円形・２段Ｒ錠）を得た。」に、「打圧１３００ｋｇｆ」を「打圧９００ｋｇｆ」に代替したこと以外は錠剤Ａの製造例と同様にして錠剤を得た。 [Tablet Example B]
"One tablet weight is 420.0 mg, diameter 10.5 mm, thickness 5.7 mm tablet (uncoated tablet, orally disintegrating tablet, round two-stage R tablet)", "one tablet mass is 210. "A strike pressure of 1300 kgf" is replaced with a strike pressure of 900 kgf "to 0 mg, a diameter of 8.0 mm and a tablet of 4.7 mm thickness (uncoated tablet, orally disintegrating tablet, round 2 step R tablet)." Tablets were obtained in the same manner as in the production example of tablet A except for the above.
［錠剤例Ｃ］
「１錠質量が４２０．０ｍｇ、直径１０．５ｍｍ、厚さ５．７ｍｍの錠剤（素錠、口腔内崩壊錠、円形・２段Ｒ錠）を得た。」を「１錠質量が７０．０ｍｇ、直径６．０ｍｍ、厚さ３．２ｍｍの錠剤（素錠、口腔内崩壊錠、円形・２段Ｒ錠）を得た。」に、「打圧１３００ｋｇｆ」を「打圧６００ｋｇｆ」に代替したこと以外は錠剤Ａの製造例と同様にして錠剤を得た。 [Tablet Example C]
"One tablet weight is 420.0 mg, diameter 10.5 mm, thickness 5.7 mm tablet (uncoated tablet, orally disintegrating tablet, round two-stage R tablet)" is obtained. Replaced “1 pounding force 1300 kgf” with “0 pounding force 600 kgf” to “0 mg, 6.0 mm diameter, 3.2 mm thick tablet (uncoated tablet, orally disintegrating tablet, round 2 step R tablet)”. Tablets were obtained in the same manner as in the production example of tablet A except for the above.
　錠剤例Ａ、Ｂ、及びＣで得られる各錠剤の処方を下記の表５に一覧して示す（数値単位はｍｇ）。表５中の数値は小数点第２位以下を四捨五入した。 The formulations of each tablet obtained in Tablet Examples A, B and C are listed in Table 5 below (numerical units are in mg). The numbers in Table 5 were rounded to the first decimal place.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
［包装例Ａ］
　錠剤例Ａ、Ｂ、Ｃの錠剤を其々のポリエチレン製ボトルに４０錠投入し、シリカと共に封入した。シリカと共に封入することで保存時の錠剤の硬度の低下の顕著な抑制効果が期待される。 [Packaging example A]
Tablets of tablet examples A, B and C were charged into 40 polyethylene bottles and sealed with silica. It is expected that the sealing with the silica significantly suppresses the reduction in hardness of the tablet during storage.
［試験例３］錠剤中の薬物の化学的安定性試験
　錠剤例Ａの、製造直後及び４０℃相対湿度７５％開放条件下で１１日間保存した後の、プレガバリン由来の類縁体（ラクタム体）の生成量｛プレガバリン及び其の総類縁体の全体量に対する割合（％）で示す。｝を、高速液体クロマトグラフィー法（定量方法は面積百分率法を使用した。）によって測定した。上記の測定結果を基に、保存前後における総類縁体の増加量（％）（差分）を求めた結果（小数点第４位以下は四捨五入した。）を下記の表６に示す。 [Test Example 3] Chemical stability test of drug in tablet Tablet Example A of the analogue (lactam) derived from pregabalin immediately after production and after storage for 11 days under 40 ° C relative humidity 75% open conditions The amount of production {% of total amount of pregabalin and total analogue of salmon is shown. } Was measured by high performance liquid chromatography (the quantitative method used the area percentage method). Based on the measurement results described above, the results of determining the increase (%) (difference) in the total analogue before and after storage (the fourth decimal place and lower are rounded off) are shown in Table 6 below.
［試験例４］口腔内崩壊錠の口腔内崩壊時間の測定
　錠剤例Ａの錠剤について、口腔内崩壊錠試験機（ＯＤ－ｍａｔｅ／（株）樋口商会製）を用いて、試験液：水（３７℃）の条件にて錠剤が崩壊する時間を測定した。結果を下記の表６に示す。 [Test Example 4] Measurement of intraoral disintegration time of orally disintegrating tablet With respect to the tablet of tablet example A, the test liquid: water (manufactured by Higuchi Shokai Co., Ltd.) using the orally disintegrating tablet testing machine (OD-mate / Co., Ltd.) The time to disintegrate the tablet was measured at 37 ° C.). The results are shown in Table 6 below.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　表６より、ケイ酸系添加剤を含有せず、適切な添加剤から主に構成される口腔内崩壊錠（錠剤例Ａ）においても、保存後のプレガバリン由来の類縁体の生成量が十分に低いことが確認された。よって、本発明の口腔内崩壊錠はプレガバリン等のγ－アミノ酪酸誘導体の化学的な安定性が十分に改善されたものであることが示された。 According to Table 6, even in the orally disintegrating tablet (tablet example A) mainly containing appropriate additives without containing a siliceous additive, the production amount of the pregabalin-derived analogue after storage is sufficient. It was confirmed to be low. Therefore, it was shown that the orally disintegrating tablet of the present invention is one in which the chemical stability of a γ-aminobutyric acid derivative such as pregabalin is sufficiently improved.
　表６より、口腔内崩壊錠（錠剤例Ａ）は口腔内崩壊時間についても十分に問題ないものであることが確認された。 From Table 6, it was confirmed that the orally disintegrating tablet (Tablet Example A) is not a problem with the oral disintegration time.
　本発明により、過酷な保存条件下における錠剤（特に口腔内崩壊錠）中のγ－アミノ酪酸誘導体の化学的な安定性等が顕著に改善することが期待され、高品質な当該錠剤が医療現場に提供されることも併せて期待される。 According to the present invention, it is expected that the chemical stability etc. of the γ-aminobutyric acid derivative in tablets (especially orally disintegrating tablets) under severe storage conditions is expected to be significantly improved It is also expected to be provided to

Claims (6)

  1. γ－アミノ酪酸誘導体を含有する錠剤であって、ケイ酸系添加剤が含有されていないことを特徴とする、錠剤。 A tablet comprising a γ-aminobutyric acid derivative, wherein the tablet is characterized by containing no silicic acid based additive.
  2. ケイ酸系添加剤が、二酸化ケイ素、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウムから選ばれる、請求項１に記載の錠剤。 The tablet according to claim 1, wherein the siliceous additive is selected from silicon dioxide, calcium silicate and magnesium aluminometasilicate.
  3. γ－アミノ酪酸誘導体及び下記から選ばれる１以上の添加剤を、錠剤全重量の９０．０重量％以上含有することを特徴とする、請求項２に記載の錠剤。
    　賦形剤：乳糖、結晶セルロース、トレハロース、Ｄ－マンニトール、イソマルト、エリスリトール、トウモロコシデンプン、シクロデキストリン
    　崩壊剤：ヒドロキシプロピルスターチ、低置換度ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、部分アルファー化デンプン、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン
    　結合剤：ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ポリビニルアルコール、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー、カルメロースナトリウム、アルファー化デンプン
    　流動化剤：タルク
    　滑沢剤：グリセリン脂肪酸エステル、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、硬化油
    　その他添加剤：リン酸水素カルシウム水和物、無水リン酸水素カルシウム     The tablet according to claim 2, wherein the γ-aminobutyric acid derivative and one or more additives selected from the following are contained in 90.0% by weight or more of the total weight of the tablet.
    Excipients: lactose, crystalline cellulose, trehalose, D-mannitol, isomalt, erythritol, corn starch, cyclodextrin Disintegrators: hydroxypropyl starch, low substituted hydroxypropyl cellulose, sodium starch glycolate, partially pregelatinized starch, carmellose Calcium, croscarmellose sodium, crospovidone Binder: hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol graft copolymer, carmellose sodium, pregelatinized starch Fluidizing agent: talc Lubricant: glycerin fatty acid Ester, magnesium stearate, calcium stearate, sodium stearyl fumarate, Hardened oil Other additives: calcium hydrogen phosphate hydrate, anhydrous calcium hydrogen phosphate
  4. γ－アミノ酪酸誘導体を含有する口腔内崩壊錠であって、前記添加剤が以下の矯味剤からも選ばれることを特徴とする、請求項３に記載の錠剤。
    　矯味剤：アスパルテーム、スクラロース、サッカリンナトリウム     An orally disintegrating tablet containing a γ-aminobutyric acid derivative, wherein the additive is also selected from the following flavoring agents:
    Flavoring agents: aspartame, sucralose, saccharin sodium
  5. γ－アミノ酪酸誘導体を含有する口腔内崩壊錠であって、矯味剤がγ－アミノ酪酸誘導体と共に造粒物中に含有されていることを特徴とする、請求項４に記載の錠剤。 An orally disintegrating tablet containing a γ-aminobutyric acid derivative, wherein the flavoring agent is contained in the granulated product together with the γ-aminobutyric acid derivative.
  6. γ－アミノ酪酸誘導体を含有する口腔内崩壊錠であって、矯味剤がγ－アミノ酪酸誘導体及び低融点油脂と共に乾式造粒物中に含有されていることを特徴とする、請求項４又は５に記載の錠剤。 An orally disintegrating tablet containing a γ-aminobutyric acid derivative, wherein the flavoring agent is contained in the dry granulation together with the γ-aminobutyric acid derivative and the low melting point oil and fat. The tablets described in.
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CN112971150A (en) * 2021-04-06 2021-06-18 北京菲瑞阳林医药技术研发有限公司 Gamma-aminobutyric acid sugar-containing freeze-dried flash-release tablet and preparation method thereof
JP7458085B2 (en) 2021-07-28 2024-03-29 株式会社三協 Disintegrant for tablets and tablets using the same

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