WO2023176783A1 - Solid composition - Google Patents

Solid composition Download PDF

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Publication number
WO2023176783A1
WO2023176783A1 PCT/JP2023/009651 JP2023009651W WO2023176783A1 WO 2023176783 A1 WO2023176783 A1 WO 2023176783A1 JP 2023009651 W JP2023009651 W JP 2023009651W WO 2023176783 A1 WO2023176783 A1 WO 2023176783A1
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WO
WIPO (PCT)
Prior art keywords
acid
composition
ascorbic acid
solid composition
tablet
Prior art date
Application number
PCT/JP2023/009651
Other languages
French (fr)
Japanese (ja)
Inventor
倫有 加茂
Original Assignee
第一三共ヘルスケア株式会社
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Publication of WO2023176783A1 publication Critical patent/WO2023176783A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention generally relates to solid compositions containing nicotinamide, ascorbic acid, and tranexamic acid.
  • Nicotinamide which is a type of vitamin B group
  • ascorbic acid which is vitamin C
  • Nicotinamide and ascorbic acid exhibit a white color when mixed in a solid state, but when granulated with water, alcohol, or a mixture thereof, the color changes to yellow. Therefore, when nicotinamide and ascorbic acid are included in a solid composition that undergoes a manufacturing process in which the ingredients are exposed to water, alcohol, or a mixture thereof, such as wet granulation, it is not possible to provide the solid composition in a white state. This has traditionally been difficult.
  • the problem to be solved by the present invention is to provide a solid composition that is resistant to yellowing and contains nicotinic acid amide and ascorbic acid.
  • tranexamic acid prevents yellowing even under conditions where the combination of nicotinamide and ascorbic acid causes discoloration, leading to the completion of the present invention.
  • a solid composition containing nicotinamide, ascorbic acid, and tranexamic acid [2] The solid composition according to [1], further comprising calcium pantothenate. [3] The solid composition according to [1] or [2], further comprising pyridoxine hydrochloride. [4] The solid composition according to any one of [1] to [3], containing 6 mg to 400 mg of nicotinic acid amide, 10 mg to 3000 mg of ascorbic acid, and 50 mg to 3000 mg of tranexamic acid, per composition administered per day. .
  • the content of nicotinic acid amide is 1% by mass to 5% by mass, the content of ascorbic acid is 5% to 30% by mass, and the content of tranexamic acid is 20% to 60% by mass.
  • the solid composition according to any one of [1] to [5] which is in the form of a tablet.
  • this embodiment will be described, but the scope of the present invention should not be interpreted as being limited to the following embodiments.
  • composition a solid composition containing nicotinamide, ascorbic acid, and tranexamic acid is provided.
  • Nicotinic acid amide blended into the composition is originally a white solid, and is also called niacinamide or vitamin B3. Although nicotinamide is incorporated into cosmetics and the like in anticipation of its whitening effect, the use of the composition of the present invention is not particularly limited.
  • the blending amount of nicotinic acid amide is appropriately adjusted depending on the use of nicotinic acid amide in the composition, the symptoms, age, weight, sex, etc. of the subject to be administered.
  • the daily amount of nicotinamide administered to adults is adjusted within the range of 1 mg to 500 mg, preferably 6 mg to 400 mg, and more preferably 10 mg to 200 mg. obtain.
  • "adult” refers to men and women aged 15 years or older.
  • the composition of the present invention is not limited to being taken by adults, but may be taken by children under 15 years of age. When taken by children, the dose can be reduced to 1/2 or 2/3 of the daily dose for adults, depending on the age category.
  • the above dosages are exemplary, and examples of amounts of nicotinamide per composition in which the weight administered per day is from about 1000 mg to about 4000 mg, preferably from about 1500 mg to about 1800 mg, are from about 10 mg to about 70 mg. , about 15 mg to about 65 mg, about 20 mg to about 60 mg, about 25 mg to about 55 mg, about 30 mg to about 50 mg, about 35 mg to about 45 mg, and the like.
  • the weight and dosage of the above composition are the daily dosage (daily dose), but the same amount is administered to the subject multiple times a day, for example, 2 or 3 times, preferably divided into 2 times. You may. The same applies to components other than nicotinamide. Furthermore, since each dose is a total amount, the content of each component contained in the composition may vary depending on the single dose, the dosage form of the composition, etc.
  • the composition is a tablet and the above dosage is the amount of the ingredient contained in 4, 6 or 8 tablets, preferably the amount of the ingredient in 4 tablets.
  • the single dose for adults (15 years and older) is 2, and the single dose is 2 tablets, 3 tablets or 4 tablets, preferably the single dose is 2 tablets. It is.
  • Ascorbic acid blended into the composition is originally a white or pale yellow solid.
  • Ascorbic acid as used herein is the L form, which is also referred to as vitamin C.
  • Ascorbic acid is added to foods for its antioxidant effect, and it is also added to cosmetics to suppress the production of melanin to prevent age spots and melasma.
  • Ascorbic acid may be in the form of a salt or a derivative.
  • the salt of ascorbic acid include mineral acid salts such as hydrochloride, nitrate, and sulfate, alkali metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt, and alkaline earth metal salts.
  • ascorbic acid examples include ascorbic acid; ascorbate salts such as sodium ascorbate, magnesium ascorbate, potassium ascorbate, and calcium ascorbate; ascorbic acid monostearate, ascorbic acid monopalmitate, ascorbic acid; Ascorbyl acid monoalkyl or monoalkenyl esters such as monooleate; ascorbic acid dialkyl or dialkenyl esters such as ascorbic acid distearate, ascorbyl acid dipalmitate, ascorbyl acid dioleate; ascorbic acid tristearate, ascorbic acid tripalmitate, ascorbic acid trioleate Ascorbyl trialkyl or trialkenyl esters such as ascorbyl sulfate, sodium ascorbyl sulfate, potassium ascorbyl sulfate, magnesium ascorbyl sulfate, calcium ascorbyl sulfate and other ascorbyl sulfate esters; ascorbic acid; ascorbate salts
  • the amount of ascorbic acid to be blended is appropriately adjusted depending on the use of ascorbic acid in the composition, the symptoms, age, weight, sex, etc. of the subject to whom it is administered.
  • the daily amount of ascorbic acid administered to adults is 1 mg to 5000 mg, preferably 10 mg to 3000 mg, and more preferably 20 mg to 2000 mg. can be adjusted within the range of
  • the above dosages are exemplary, and examples of the amount of ascorbic acid per composition in which the weight administered per day is from about 1000 mg to about 4000 mg, preferably from about 1500 mg to about 1800 mg, from about 50 mg to about 2000 mg; Examples include about 75 mg to about 1750 mg, about 100 mg to about 1500 mg, about 200 mg to about 1000 mg, about 250 mg to about 350 mg, and the like.
  • Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) blended into the composition is originally a white solid. Tranexamic acid is added to medicines for its anti-inflammatory effects, and is also added to cosmetics to prevent the symptoms of age spots and melasma.
  • Tranexamic acid may be in the form of a salt.
  • tranexamic acid as used herein also includes salts of tranexamic acid.
  • Salts of tranexamic acid include mineral acid salts such as hydrochloride, nitrate, and sulfate, organic acid salts such as methanesulfonate, alkali metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt, and alkaline earth salts. Examples include metal salts.
  • the amount of tranexamic acid is adjusted as appropriate depending on the amount of nicotinamide and ascorbic acid and the desired degree of discoloration inhibiting effect, but it is added to prevent yellowing and at the same time to have other medicinal effects.
  • the dosage may be adjusted as appropriate depending on the use of tranexamic acid in the composition, the symptoms, age, weight, sex, etc. of the subject to whom it is administered.
  • the daily amount of tranexamic acid administered to adults can be adjusted within the range of 5 mg to 5000 mg, preferably 50 mg to 3000 mg, and more preferably 100 mg to 2000 mg. .
  • the above dosages are examples, and examples of amounts of tranexamic acid per composition in which the weight administered per day is about 1000 mg to about 4000 mg, preferably about 1500 mg to about 1800 mg, include about 500 mg to about 1000 mg; Examples include about 550 mg to about 950 mg, about 600 mg to about 900 mg, about 650 mg to about 850 mg, about 700 mg to about 800 mg, and the like.
  • compositions for oral administration include dosage forms such as tablets, granules, pills, and powders.
  • composition for parenteral administration parenteral administration preparation
  • parenteral administration preparation is also not particularly limited as long as it is in a solid dosage form.
  • composition may optionally contain other ingredients, such as known carriers and additives, as long as the effects of tranexamic acid are not impaired.
  • formulation additives include, for example, excipients, binders, disintegrants, disintegration aids, lubricants, stabilizers, surfactants, antioxidants, buffers, pH adjusters, dispersants, and solubilizers.
  • Auxiliary agents, fluidizing agents, brighteners, flavoring agents, sweeteners, cooling agents, colorants, flavoring agents, fragrances, adsorbents, sugar coating agents, coating agents, suspending agents, antistatic agents, plasticizers, and fragrances, etc. can be exemplified without limitation.
  • excipients include crystalline cellulose, lactose hydrate, refined white sugar, glucose, powdered sugar, fructose, maltose, reduced maltose starch syrup, powdered cellulose, Corn starch (corn starch), potato starch, sugar alcohols (mannitol, xylitol, sorbitol, erythritol, etc.), trehalose, inorganic salts, dextran, dextrin, ⁇ -cyclodextrin, sucrose fatty acid ester, soybean lecithin, tragacanth powder, gum arabic, Pullulan, kaolin, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, magnesium aluminate metasilicate, methylcellulose, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate Hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, sodium
  • the mass of the composition is 100% by mass
  • the proportion of excipients contained therein is not limited as long as it does not adversely affect the effect of tranexamic acid, but for example, 0.1% by mass to 70% by mass.
  • the range of can be exemplified. It is preferably in the range of 0.5% to 50% by weight, more preferably 1% to 40% by weight.
  • the excipient preferably contains one or more components selected from the group consisting of mannitol, crystalline cellulose, and corn starch.
  • binders include gum arabic, gelatin, pregelatinized starch, alginic acid, sodium alginate, carboxyvinyl polymer, agar, pullulan, dextrin, shellac, and sucrose, but are not limited as long as they do not impair the effects of tranexamic acid.
  • tragacanth tragacanth powder, xanthan gum, pectin, sodium polyacrylate, guar gum, corn starch, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, copolyvidone, hypromellose (2208), hypromellose (2906), hypromellose (2910) , hypromellose acetate succinate, hypromellose phthalate (200731), hypromellose phthalate (220824), povidone (K25), povidone (K30), povidone (K90), polyvinyl alcohol (completely saponified) , polyvinyl alcohol (partially saponified product), methylcellulose, magnesium aluminate metasilicate, and the like.
  • the proportion of the binder contained therein is not limited as long as it does not adversely affect the effect of tranexamic acid, but for example, from 0.1% to 10% by mass. Examples of ranges can be given. It is preferably in the range of 0.5% to 8% by weight, more preferably 1% to 5% by weight.
  • Disintegrants include, but are not limited to, as long as they do not impair the effectiveness of tranexamic acid, such as corn starch, potato starch, partially pregelatinized starch, hydroxypropyl starch, sodium starch glycolate, sodium carboxymethyl starch, and low degree of substitution.
  • examples include sodium carboxymethyl starch, carmellose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crystalline cellulose, powdered cellulose, crospovidone, carmellose sodium, agar powder, sodium bicarbonate, and carmellose.
  • the proportion of the disintegrant contained therein is not limited as long as it does not adversely affect the effect of tranexamic acid, but for example, from 0.1% to 30% by mass. Examples of ranges can be given. It is preferably in the range of 0.5% to 20% by weight, more preferably 1% to 15% by weight.
  • the lubricant is not limited as long as it does not impair the effect of tranexamic acid, but examples include magnesium stearate, calcium stearate, stearic acid, talc, sucrose fatty acid ester, sodium stearyl fumarate, carnauba wax, glycerin fatty acid ester, Examples include calcium stearate, light anhydrous silicic acid, and magnesium aluminate metasilicate.
  • flavoring agent examples include, but are not limited to, organic acids such as citric acid, tartaric acid, and malic acid, sodium glutamate, sodium 5'-inosinate, sodium 5-guanylate, sodium aspartate, and caramel.
  • sweeteners include, but are not limited to, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, Lacanca, thaumatin, acesulfame potassium, sucralose, sucrose, fructose, glucose, lactose hydrate, anhydrous lactose, maltose, sorbitol, maltitol. , mannitol, xylitol, erythritol, glycerol, inositol, reduced maltose starch syrup, palatinose, coupling sugar, and honey.
  • Coating agents include, but are not limited to, ethyl acrylate/methyl methacrylate copolymer dispersion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer E, gum arabic, gum arabic powder, ammonioalkyl methacrylate copolymer, ethyl cellulose, ethyl cellulose water dispersion.
  • compositions may include tablets, granules, pills and powders.
  • the composition is preferably a tablet or granule, more preferably a tablet or granule obtained via a mixing process in the presence of water, such as wet granulation.
  • the tablet may be composed of a single layer or may have a multilayer structure of two or more layers.
  • tablets examples include bare tablets, uncoated tablets, sugar-coated tablets, orally disintegrating tablets, film-coated tablets, and chewable tablets.
  • the tablet may be a multilayer tablet obtained by stacking two or three or more layers of powders or granules with different compositions and compressing them.
  • the film can be imparted with properties such as immediate dissolution, slow dissolution, gastric solubility, and enteric coating depending on the desired composition.
  • the diameter thereof can be in the range of about 2 mm to about 15 mm. Preferably it is about 3 mm to about 12 mm. Further, the thickness thereof is not limited, and may be in the range of about 3 mm to about 10 mm.
  • the composition may be a solid preparation for internal use. Such solid preparations may be once packaged in bottle packaging, PTP packaging, pouch packaging, stick packaging, or SP packaging for airtight storage. Furthermore, they may be wrapped in pillows or stored in a box or the like.
  • the material used for pillow packaging is not particularly limited, and for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, and aluminum foil attached to these resin films can be used.
  • resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, and aluminum foil attached to these resin films can be used.
  • a desiccant or the like may be stored at the same time in the bottle packaging or pillow packaging.
  • the solid preparation for internal use may be in the form of the above-mentioned orally administrable tablets, granules, pills, and powders.
  • the composition of the present invention can exist as a pharmaceutical composition, beauty composition, cosmetic composition, food/beverage composition, etc. that are expected to exhibit a white color as a final product.
  • the composition preferably has a white color, but if the discoloration suppressing effect of tranexamic acid is not sufficient, such as when the amount of tranexamic acid in the composition is small, the composition may have a slightly yellowish white color, a pale yellowish white color, a slightly yellowish color, or a yellowish color. It may be white or pale yellow in color.
  • the composition is intended to be provided as a cosmetic composition, preferably an internally administered cosmetic composition.
  • the composition further contains calcium pantothenate and pyridoxine hydrochloride.
  • the amount of calcium pantothenate is 1 mg to 1200 mg, preferably 5 mg per composition administered per day. ⁇ 600 mg, more preferably 10 mg to 100 mg, and the amount of pyridoxine hydrochloride is 0.5 mg to 200 mg, preferably 1 mg to 100 mg, more preferably 2 mg to 50 mg per composition administered per day.
  • whitening refers to pigmentation disorders such as age spots (including melasma, senile pigment spots, etc.), freckles, sunburn, dark skin, and skin melanization caused by drugs such as steroids. Including prevention and/or treatment.
  • the composition of the present invention may further contain a known component that exhibits a whitening effect or a component that enhances the whitening effect.
  • these components include, for example, L-cysteine or its derivatives (N-acetyl-L-cysteine, L-homocysteine, L-cysteic acid, L-homocysteic acid, L-cysteinesulfinic acid, S-sulfino-L-cysteine, - Cysteine, S-sulfo-L-cysteine, cystine (dimer of cysteine), pantothenic acid, its derivatives, or their salts (pantothenic acid; pantothenic acid salts such as sodium pantothenate, calcium pantothenate; pantetheine, pantethine) , phosphopantetheine, etc.), hydroquinone or its derivatives (hydroquinone; hydroquinone glycosides
  • calcium pantothenate is preferred, and can also be used as calcium pantothenate type S (trade name), which is a granulated product of calcium pantothenate and calcium lactate.
  • These components may be blended alone or in combination of two or more.
  • the whitening composition (whitening agent) may further contain components other than the known components exhibiting a whitening effect and the components enhancing the whitening effect.
  • the blending amounts of these components are not particularly limited as long as the effects of tranexamic acid are not impaired.
  • nicotinamide 6 mg to 400 mg of nicotinamide, 10 mg to 3000 mg of ascorbic acid, and 50 mg to 3000 mg of tranexamic acid are included per composition.
  • compositions are examples of daily doses, and if the composition is administered multiple times a day, these doses can be divided into multiple doses, for example 2 to 4 doses.
  • the content of nicotinic acid amide is 1% to 5% by weight, the content of ascorbic acid is 5% to 30% by weight, and the content of tranexamic acid is 20% by weight per composition. ⁇ 60% by mass.
  • a method for producing a solid composition comprising contacting nicotinamide, ascorbic acid, and tranexamic acid in the presence of water.
  • the timing of addition of each component is not particularly limited.
  • tranexamic acid may be added before the start of discoloration, or may be added at an appropriate time after the start of discoloration. From the viewpoint of keeping the color of the composition white, it is preferable that water is added after blending tranexamic acid with a combination of nicotinamide and ascorbic acid and thoroughly mixing the mixture.
  • nicotinic acid amide is about 10 mg to about 70 mg, about 15 mg to about 65 mg, about 20 mg to about 60 mg, about 25 mg to about 55 mg, about 30 mg to about 50 mg, or about 35 mg to about 45 mg
  • ascorbic acid is about 50 mg to about 2000 mg, about 75 mg to about 1750 mg, about 100 mg to about 1500 mg, about 200 mg to about 1000 mg, about 250 mg to about 350 mg
  • the amount of tranexamic acid is 500 mg to about 1000 mg, about 550 mg to about 950 mg, It is adjusted as appropriate within the range of about 600 mg to about 900 mg, about 650 mg to about 850 mg, or about 700 mg to about 800 mg.
  • the above blending amount is an example, and the amount of tranexamic acid added can be increased or decreased depending on the desired degree of discoloration inhibiting effect.
  • Formulation additives include excipients, binders, disintegrants, disintegration aids, lubricants, stabilizers, surfactants, antioxidants, buffers, pH adjusters, dispersants, dissolution aids, and flow agents. coloring agents, brighteners, flavoring agents, sweeteners, cooling agents, coloring agents, flavoring agents, fragrances, adsorbents, sugar coating agents, coating agents, suspending agents, antistatic agents, plasticizers, fragrances, etc.
  • the formulation additives may be appropriately selected and added in appropriate amounts within a range that does not impair the effects of tranexamic acid.
  • the composition can be manufactured using a general solid preparation manufacturing method.
  • Granulation granules are an example of such a manufacturing method, and examples thereof include wet granulation methods such as high-speed stirring granulation method and fluidized bed granulation method.
  • Ascorbic acid is a highly adhesive component, so if the amount of ascorbic acid in the composition is large, granules are used to reduce the surface area in order to avoid tableting problems when making tablets. It is preferable to do so. This allows the granules containing the drug to be sufficiently covered with the lubricant, and also makes it possible to reduce contact between the drug and the die during tabletting.
  • the manufacturing method comprises wet granulating nicotinamide, ascorbic acid, and tranexamic acid with water or an aqueous solution or dispersion of a binder, and optionally, manufacturing a solid composition.
  • a wet granulation method commonly used mixing stirring granulation method, high speed stirring granulation method, fluidized bed granulation method, or rolling granulation method can be used, but preferably high speed stirring granulation method, or The method is a fluidized bed granulation method, and more preferably a fluidized bed granulation method.
  • any process such as a drying process or sizing may be carried out after granulation.
  • composition can also be made into a tablet by mixing granules obtained by wet granulation and compression molding. Furthermore, granules and tablets can be sugar-coated or film-coated using known methods.
  • Coating with sugar coating or film can be carried out, for example, by a pan coating method, a fluidized bed coating method, a rolling coating method, a dry coating method, or a combination of these methods.
  • the sugar coating component and film component may be dissolved or dispersed in water or an organic solvent (ethanol, etc.) and spray coated according to the standard method, or the film component may be directly sprayed and dry coated by applying heat or pressure. You can also do that.
  • Sugar coating components used for sugar coating formation include, but are not limited to, monosaccharides and disaccharides such as sucrose (white sugar, refined white sugar), fructose, glucose, lactose hydrate, anhydrous lactose, and trehalose; erythritol and mannitol. , sorbitol, xylitol, maltitol, powdered reduced maltose starch syrup, reduced lactose, and other sugar alcohols.
  • monosaccharides and disaccharides such as sucrose (white sugar, refined white sugar), fructose, glucose, lactose hydrate, anhydrous lactose, and trehalose
  • erythritol and mannitol erythritol and mannitol.
  • sorbitol xylitol
  • maltitol powdered reduced maltose starch syrup
  • reduced lactose and other sugar alcohols.
  • the sugar coating liquid also contains gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, carmellose sodium, stearic acid, polyoxyl stearate 40, purified gelatin, purified shellac, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, hydroxypropyl.
  • Examples of the film coating agent include water-soluble polymer compounds, gastric-soluble polymer compounds, and enteric-coated polymer compounds.
  • water-soluble polymer compounds include, but are not limited to, methylcellulose, hypromellose (2208), hypromellose (2906), hypromellose (2910), hydroxypropylcellulose, polyethylene glycol, polyvinyl alcohol (completely saponified), polyvinyl alcohol (partially saponified).
  • polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer examples include polyethylene glycol graft copolymers.
  • gastric soluble polymer compounds include, but are not limited to, polyvinyl acetal polymers such as polyvinyl acetal diethylaminoacetate, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, and methyl methacrylate-diethylaminoethyl methacrylate.
  • Examples include gastric soluble methacrylic acid-based polymer compounds such as copolymers.
  • Examples of the enteric polymer compound include, but are not limited to, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid copolymer S, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, etc. enteric-coated methacrylic acid-based polymer compounds; enteric-coated cellulose-based polymer compounds such as cellulose acetate phthalate, hypromellose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, and carboxymethylethyl cellulose.
  • the coating liquid contains talc, titanium oxide, gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, carmellose sodium, stearic acid, polyoxyl stearate 40, purified gelatin, purified shellac, gelatin, shellac, talc, precipitated calcium carbonate.
  • the produced composition exhibits a white color, but if the discoloration inhibiting effect of tranexamic acid is not sufficient, such as when the amount of tranexamic acid in the composition is small, it may have a slightly yellowish white color, a pale yellowish white color, or a slightly yellowish white color. It may be yellow, yellow-white, or pale yellow.
  • Discoloration suppression method in a third aspect, there is provided a method for inhibiting discoloration of a solid composition, comprising the step of contacting nicotinic acid amide, ascorbic acid, and tranexamic acid in the presence of water.
  • nicotinamide and ascorbic acid can change its color from white to pale yellow-white, pale yellow-white, pale yellow, yellow-white, pale yellow, and yellow, but tranexamic acid prevents such yellowing. It can be used as an active ingredient for The amount of tranexamic acid as an active ingredient of the discoloration inhibitor is appropriately adjusted depending on the amounts of nicotinamide and ascorbic acid.
  • nicotinic acid amide is about 10 mg to about 70 mg, about 15 mg to about 65 mg, about 20 mg to about 60 mg, about 25 mg to about 55 mg, about 30 mg to about 50 mg, or about 35 mg to about 45 mg
  • ascorbic acid is about 50 mg to about 2000 mg, about 75 mg to about 1750 mg, about 100 mg to about 1500 mg, about 200 mg to about 1000 mg, about 250 mg to about 350 mg
  • the amount of tranexamic acid is 500 mg to about 1000 mg, about 550 mg to about 950 mg, It is adjusted as appropriate within the range of about 600 mg to about 900 mg, about 650 mg to about 850 mg, or about 700 mg to about 800 mg.
  • the above blending amount is an example, and the amount of tranexamic acid added can be increased or decreased depending on the desired discoloration inhibiting effect.
  • tranexamic acid may be added before the start of discoloration, or may be added at an appropriate time after the start of discoloration. From the viewpoint of keeping the color of the composition white, it is preferable that water is added after blending tranexamic acid with a combination of nicotinamide and ascorbic acid and thoroughly mixing the mixture.
  • the discoloration suppressing effect is confirmed in the mixture immediately after mixing the three components of nicotinic acid amide, ascorbic acid, and tranexamic acid, and in the granules and molded products obtained thereafter.
  • the discoloration suppression method may further include an arbitrary step. For example, from the viewpoint of maintaining the effect of suppressing discoloration, it is preferable to store the granulated material and the like in an airtight container with reduced moisture permeability at a temperature below room temperature.
  • an "airtight container” is one that does not allow solid or liquid foreign matter to enter during transportation or storage, resulting in loss of the medicinal product, efflorescence, deliquescence, or means a container that can prevent evaporation.
  • An example of such an airtight container is a common pill bottle.
  • Nicotinic acid amide manufactured by DSM
  • ascorbic acid manufactured by DSM
  • operation 1 Nicotinic acid amide
  • operation 2 Ascorbic acid
  • operation 3 After dropping and granulating (operation 2), drying was performed in a constant temperature chamber at 60° C. for 1 hour to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
  • Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), and corn starch (manufactured by Matsutani Chemical Industry Co., Ltd.) are mixed in an agate mortar in the proportions shown in Table 1 (operation 1), and the total mass of the mixture is After performing granulation by dropping 7% by mass of purified water (operation 2), drying was performed in a constant temperature chamber at 60° C. for 1 hour to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
  • Example 1 Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), and tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) were mixed in an agate mortar in the proportions shown in Table 1 (operation 1), and the total mass of the mixture was After performing granulation by dropping 3% by mass of purified water (operation 2), drying was performed in a constant temperature chamber at 60° C. for 1 hour to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
  • Example 2 Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and calcium pantothenate (calcium pantothenate type S: BASF Japan) in the proportions shown in Table 1.
  • (Procedure 1) was mixed in an agate mortar (Procedure 1), and granulated by dropping 3% by mass of purified water based on the total mass of the mixture (Procedure 2), and then dried in a constant temperature chamber at 60°C for 1 hour. was carried out to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
  • Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and pyridoxine hydrochloride (manufactured by DSM) were mixed in an agate mortar at the proportions shown in Table 1.
  • (Operation 1) After performing granulation by dropping 3% by mass of purified water based on the total mass of the mixture (Operation 2), drying was carried out for 1 hour in a constant temperature chamber at 60 ° C. to obtain granules. (Operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
  • Example 4 Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical), and calcium pantothenate (calcium pantothenate type S: BASF Japan) in the proportions shown in Table 1.
  • (manufactured by DSM) and pyridoxine hydrochloride (manufactured by DSM) were mixed in an agate mortar (operation 1), and granulation was performed by dropping 3% by mass of purified water based on the total mass of the mixture (operation 2). Drying was performed in a constant temperature chamber at 60° C. for 1 hour to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
  • Example 5 Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and mannitol (D-mannitol, manufactured by Bussan Food Science) were added to agate in the proportions shown in Table 1. After mixing in a mortar (operation 1), dropping 3% by mass of purified water based on the total mass of the mixture to perform granulation (operation 2), drying in a constant temperature chamber at 60 ° C. for 1 hour, Granules were obtained (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
  • Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and corn starch (manufactured by Matsutani Chemical Industry Co., Ltd.) were mixed in an agate mortar at the proportions shown in Table 1. After (operation 1), granulation was performed by dropping 5% by mass of purified water based on the total mass of the mixture (operation 2), and then drying was performed in a constant temperature chamber at 60 ° C. for 1 hour to obtain granules. (Operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
  • Example 7 Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei) were added to agate in the proportions shown in Table 1. After mixing in a mortar (operation 1) and performing granulation by dropping 5% by mass of purified water based on the total mass of the mixture (operation 2), drying was performed in a constant temperature chamber at 60 ° C. for 1 hour, Granules were obtained (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
  • the color tone change was evaluated as the degree of change in the color tone of the sample at the time of operation 3 compared to the color tone of the sample at time of operation 1, -: no change, ⁇ : very slight change (from white to slightly yellowish white), It was performed in 5 stages: +: slight change (from white to pale yellow-white or slightly yellow), ++: clear change (from white to yellow-white or pale yellow), +++: marked change (from white to yellow).
  • the evaluation results for each example are shown in Table 1.
  • Formulation examples of a solid composition containing nicotinic acid amide, ascorbic acid, and tranexamic acid, and a solid composition containing nicotinic acid amide and ascorbic acid as a reference example are shown in the table below.

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Abstract

The present invention provides a solid composition comprising nicotinic acid amide, ascorbic acid, and tranexamic acid.

Description

固形組成物solid composition
　本発明は広く、ニコチン酸アミドと、アスコルビン酸と、トラネキサム酸とを含有する固形組成物に関するものである。 The present invention generally relates to solid compositions containing nicotinamide, ascorbic acid, and tranexamic acid.
　ビタミンＢ群の一種であるニコチン酸アミドと、ビタミンＣであるアスコルビン酸はサプリメントや化粧品等に一般的に配合される成分であるが、この２つの組合せを溶解した場合、水溶液は黄色を呈し、また、冷却すると黄色針状結晶が析出することが知られている（非特許文献１）。 Nicotinamide, which is a type of vitamin B group, and ascorbic acid, which is vitamin C, are ingredients commonly added to supplements and cosmetics, but when a combination of these two is dissolved, the aqueous solution takes on a yellow color. Furthermore, it is known that yellow needle-like crystals precipitate when cooled (Non-Patent Document 1).
　ニコチン酸アミドとアスコルビン酸は固体状態で混合すると白色を呈するが、水やアルコール又はその混液で造粒すると黄色へと変色してしまう。そのため、製造工程において湿式造粒のように成分を水、アルコール又はその混液に晒す工程を経る固形組成物にニコチン酸アミドとアスコルビン酸を含める場合、固形組成物を白色の状態で提供することは従来困難であった。 Nicotinamide and ascorbic acid exhibit a white color when mixed in a solid state, but when granulated with water, alcohol, or a mixture thereof, the color changes to yellow. Therefore, when nicotinamide and ascorbic acid are included in a solid composition that undergoes a manufacturing process in which the ingredients are exposed to water, alcohol, or a mixture thereof, such as wet granulation, it is not possible to provide the solid composition in a white state. This has traditionally been difficult.
　本発明が解決しようとする課題は、ニコチン酸アミドと、アスコルビン酸とを含有する、黄変し難い固形組成物を提供することにある。 The problem to be solved by the present invention is to provide a solid composition that is resistant to yellowing and contains nicotinic acid amide and ascorbic acid.
　本発明者らは、驚くべきことに、ニコチン酸アミドとアスコルビン酸の組み合わせが変色する条件でもトラネキサム酸が存在することで黄変が防止されることを見出し、本発明を完成させるに至った。 Surprisingly, the present inventors have found that the presence of tranexamic acid prevents yellowing even under conditions where the combination of nicotinamide and ascorbic acid causes discoloration, leading to the completion of the present invention.
　すなわち、本願は以下の発明を包含する。
［１］
　ニコチン酸アミドと、アスコルビン酸と、トラネキサム酸とを含有する固形組成物。
［２］
　更にパントテン酸カルシウムを含む、［１］に記載の固形組成物。
［３］
　更にピリドキシン塩酸塩を含む、［１］又は［２］に記載の固形組成物。
［４］
　１日に投与される組成物あたり、ニコチン酸アミドを６ｍｇ～４００ｍｇ、アスコルビン酸を１０ｍｇ～３０００ｍｇ、トラネキサム酸を５０ｍｇ～３０００ｍｇ含有する、［１］～［３］のいずれかに記載の固形組成物。
［５］
　組成物あたり、ニコチン酸アミドの含有量が１質量％～５質量％、アスコルビン酸の含有量が５質量％～３０質量％であり、トラネキサム酸の含有量が２０質量％～６０質量％である、［１］～［３］のいずれかに記載の固形組成物。
［６］
　錠剤の形態である、［１］～［５］のいずれかに記載の固形組成物。
［７］
　錠剤が裸錠、素錠、糖衣錠、口腔内崩壊錠、フィルムコーティング錠又はチュアブル錠である、［１］～［６］のいずれかに記載の固形組成物。
［８］
　更に、結晶セルロース、マンニトール及びトウモロコシデンプンから成る群から選択される１又は複数の成分を含む、［１］～［７］のいずれかに記載の固形組成物。
［９］
　ニコチン酸アミドと、アスコルビン酸と、トラネキサム酸との組み合わせが白色を呈する、［１］～［８］のいずれかに記載の固形組成物。 That is, the present application includes the following inventions.
[1]
A solid composition containing nicotinamide, ascorbic acid, and tranexamic acid.
[2]
The solid composition according to [1], further comprising calcium pantothenate.
[3]
The solid composition according to [1] or [2], further comprising pyridoxine hydrochloride.
[4]
The solid composition according to any one of [1] to [3], containing 6 mg to 400 mg of nicotinic acid amide, 10 mg to 3000 mg of ascorbic acid, and 50 mg to 3000 mg of tranexamic acid, per composition administered per day. .
[5]
Per composition, the content of nicotinic acid amide is 1% by mass to 5% by mass, the content of ascorbic acid is 5% to 30% by mass, and the content of tranexamic acid is 20% to 60% by mass. , the solid composition according to any one of [1] to [3].
[6]
The solid composition according to any one of [1] to [5], which is in the form of a tablet.
[7]
The solid composition according to any one of [1] to [6], wherein the tablet is a bare tablet, uncoated tablet, sugar-coated tablet, orally disintegrating tablet, film-coated tablet, or chewable tablet.
[8]
The solid composition according to any one of [1] to [7], further comprising one or more components selected from the group consisting of crystalline cellulose, mannitol, and corn starch.
[9]
The solid composition according to any one of [1] to [8], wherein the combination of nicotinamide, ascorbic acid, and tranexamic acid exhibits a white color.
　本発明によれば、トラネキサム酸を配合するのみでニコチン酸アミドとアスコルビン酸の組み合わせの黄変を防ぐことが可能になる。 According to the present invention, it is possible to prevent yellowing of the combination of nicotinic acid amide and ascorbic acid simply by blending tranexamic acid.
　以下、本発明の実施の形態（以下、「本実施形態」という。）について説明するが、本発明の範囲は以下の実施形態に限定して解釈されない。 Hereinafter, embodiments of the present invention (hereinafter referred to as "this embodiment") will be described, but the scope of the present invention should not be interpreted as being limited to the following embodiments.
（組成物）
　第一の態様において、ニコチン酸アミドと、アスコルビン酸と、トラネキサム酸とを含有する固形組成物が提供される。 (Composition)
In a first aspect, a solid composition containing nicotinamide, ascorbic acid, and tranexamic acid is provided.
　組成物に配合されるニコチン酸アミドは本来白色の固体であり、ナイアシンアミド、ビタミンＢ３とも称される。ニコチン酸アミドはその美白効果を期待して化粧料等に配合されるが、本発明の組成物の用途は特に限定されない。 Nicotinic acid amide blended into the composition is originally a white solid, and is also called niacinamide or vitamin B3. Although nicotinamide is incorporated into cosmetics and the like in anticipation of its whitening effect, the use of the composition of the present invention is not particularly limited.
　ニコチン酸アミドの配合量は、組成物におけるニコチン酸アミドの用途、投与される対象の症状、年齢、体重、性別等に応じて適宜調節される。例えば、ニコチン酸アミドが美白目的で配合される場合、成人に投与されるニコチン酸アミドの１日あたりの量は１ｍｇ～５００ｍｇ、好ましくは６ｍｇ～４００ｍｇ、より好ましくは１０ｍｇ～２００ｍｇの範囲で調整され得る。本発明において「成人」とは１５歳以上の男女を意味する。但し、本発明の組成物は成人が服用するためのものに限定されるものではなく、１５歳未満の小児が服用するものであってもよい。小児が服用する場合、各年齢区分に応じて成人が１日に服用する量の１／２や２／３等に減量して用いることができる。 The blending amount of nicotinic acid amide is appropriately adjusted depending on the use of nicotinic acid amide in the composition, the symptoms, age, weight, sex, etc. of the subject to be administered. For example, when nicotinamide is formulated for skin whitening purposes, the daily amount of nicotinamide administered to adults is adjusted within the range of 1 mg to 500 mg, preferably 6 mg to 400 mg, and more preferably 10 mg to 200 mg. obtain. In the present invention, "adult" refers to men and women aged 15 years or older. However, the composition of the present invention is not limited to being taken by adults, but may be taken by children under 15 years of age. When taken by children, the dose can be reduced to 1/2 or 2/3 of the daily dose for adults, depending on the age category.
　上記の投与量は一例であり、一日に投与される重量が約１０００ｍｇ～約４０００ｍｇ、好ましくは約１５００ｍｇ～約１８００ｍｇである組成物あたりのニコチン酸アミドの量の例として、約１０ｍｇ～約７０ｍｇ、約１５ｍｇ～約６５ｍｇ、約２０ｍｇ～約６０ｍｇ、約２５ｍｇ～約５５ｍｇ、約３０ｍｇ～約５０ｍｇ、約３５ｍｇ～約４５ｍｇ等が挙げられる。 The above dosages are exemplary, and examples of amounts of nicotinamide per composition in which the weight administered per day is from about 1000 mg to about 4000 mg, preferably from about 1500 mg to about 1800 mg, are from about 10 mg to about 70 mg. , about 15 mg to about 65 mg, about 20 mg to about 60 mg, about 25 mg to about 55 mg, about 30 mg to about 50 mg, about 35 mg to about 45 mg, and the like.
　上記の組成物の重量及び投与量は１日あたりの投与量（１日分量）であるが、同量を１日複数回、例えば２回又は３回、好ましくは２回に分けて対象に投与してもよい。ニコチン酸アミド以外の成分についても同様である。また、各投与量は合計量であるため、１回量や組成物の剤形等によって組成物に含まれる各成分の含量は変動し得る。 The weight and dosage of the above composition are the daily dosage (daily dose), but the same amount is administered to the subject multiple times a day, for example, 2 or 3 times, preferably divided into 2 times. You may. The same applies to components other than nicotinamide. Furthermore, since each dose is a total amount, the content of each component contained in the composition may vary depending on the single dose, the dosage form of the composition, etc.
　特定の実施形態において、組成物は錠剤であり、上記の投与量は、４錠、６錠又は８錠中に含まれる成分の量であり、好ましくは４錠中の成分量である。この実施形態において、成人（１５歳以上）の１回の服用量は２回であり、１回の服用量は２錠、３錠又は４錠であり、好ましくは１回の服用量は２錠である。 In certain embodiments, the composition is a tablet and the above dosage is the amount of the ingredient contained in 4, 6 or 8 tablets, preferably the amount of the ingredient in 4 tablets. In this embodiment, the single dose for adults (15 years and older) is 2, and the single dose is 2 tablets, 3 tablets or 4 tablets, preferably the single dose is 2 tablets. It is.
　組成物に配合されるアスコルビン酸は本来白色又は淡黄色の固体である。本明細書で使用する場合のアスコルビン酸はＬ体であり、これはビタミンＣとも称される。アスコルビン酸はその酸化防止効果を期待して食品等に配合されるほか、メラニンの生成を抑制するため、シミや肝斑の症状を防ぐ目的で化粧料等に配合される。 Ascorbic acid blended into the composition is originally a white or pale yellow solid. Ascorbic acid as used herein is the L form, which is also referred to as vitamin C. Ascorbic acid is added to foods for its antioxidant effect, and it is also added to cosmetics to suppress the production of melanin to prevent age spots and melasma.
　アスコルビン酸は塩又は誘導体の形態であってもよい。アスコルビン酸の塩としては、塩酸塩、硝酸塩、硫酸塩等の鉱酸塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等のアルカリ金属塩、アルカリ土類金属塩等を挙げることができる。アスコルビン酸、その誘導体又はそれらの塩としては、アスコルビン酸；アスコルビン酸ナトリウム、アスコルビン酸マグネシウム、アスコルビン酸カリウム、アスコルビン酸カルシウム等のアスコルビン酸塩；アスコルビン酸モノステアレート、アスコルビン酸モノパルミテート、アスコルビン酸モノオレエート等のアスコルビン酸モノアルキル又はモノアルケニルエステル類；アスコルビン酸ジステアレート、アスコルビン酸ジパルミテート、アスコルビン酸ジオレエート等のアスコルビン酸ジアルキル又はジアルケニルエステル類；アスコルビン酸トリステアレート、アスコルビン酸トリパルミテート、アスコルビン酸トリオレエート等のアスコルビン酸トリアルキル又はトリアルケニルエステル類；アスコルビル硫酸、アスコルビル硫酸ナトリウム、アスコルビル硫酸カリウム、アスコルビル硫酸マグネシウム、アスコルビル硫酸カルシウム等のアスコルビン酸硫酸エステル類；アスコルビルリン酸、アスコルビルリン酸ナトリウム、アスコルビルリン酸カリウム、アスコルビルリン酸マグネシウム、アスコルビルリン酸カルシウム等のアスコルビン酸リン酸エステル類など；アスコルビン酸グリコシド等のアスコルビン酸配糖体などを挙げることができる。 Ascorbic acid may be in the form of a salt or a derivative. Examples of the salt of ascorbic acid include mineral acid salts such as hydrochloride, nitrate, and sulfate, alkali metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt, and alkaline earth metal salts. Examples of ascorbic acid, derivatives thereof, or salts thereof include ascorbic acid; ascorbate salts such as sodium ascorbate, magnesium ascorbate, potassium ascorbate, and calcium ascorbate; ascorbic acid monostearate, ascorbic acid monopalmitate, ascorbic acid; Ascorbyl acid monoalkyl or monoalkenyl esters such as monooleate; ascorbic acid dialkyl or dialkenyl esters such as ascorbic acid distearate, ascorbyl acid dipalmitate, ascorbyl acid dioleate; ascorbic acid tristearate, ascorbic acid tripalmitate, ascorbic acid trioleate Ascorbyl trialkyl or trialkenyl esters such as ascorbyl sulfate, sodium ascorbyl sulfate, potassium ascorbyl sulfate, magnesium ascorbyl sulfate, calcium ascorbyl sulfate and other ascorbyl sulfate esters; ascorbyl phosphoric acid, sodium ascorbyl phosphate, ascorbyl phosphate Examples include ascorbic acid phosphate esters such as potassium, magnesium ascorbyl phosphate, and calcium ascorbyl phosphate; and ascorbic acid glycosides such as ascorbic acid glycoside.
　アスコルビン酸の配合量は組成物におけるアスコルビン酸の用途、投与される対象の症状、年齢、体重、性別等に応じて適宜調節される。例えば、アスコルビン酸がシミや肝斑の症状を防ぐ目的で配合される場合、成人に投与されるアスコルビン酸の１日あたりの量は１ｍｇ～５０００ｍｇ、好ましくは１０ｍｇ～３０００ｍｇ、より好ましくは２０ｍｇ～２０００ｍｇの範囲で調整され得る。 The amount of ascorbic acid to be blended is appropriately adjusted depending on the use of ascorbic acid in the composition, the symptoms, age, weight, sex, etc. of the subject to whom it is administered. For example, when ascorbic acid is formulated to prevent age spots and melasma symptoms, the daily amount of ascorbic acid administered to adults is 1 mg to 5000 mg, preferably 10 mg to 3000 mg, and more preferably 20 mg to 2000 mg. can be adjusted within the range of
　上記の投与量は一例であり、一日に投与される重量が約１０００ｍｇ～約４０００ｍｇ、好ましくは約１５００ｍｇ～約１８００ｍｇである組成物あたりのアスコルビン酸の量の例として、約５０ｍｇ～約２０００ｍｇ、約７５ｍｇ～約１７５０ｍｇ、約１００ｍｇ～約１５００ｍｇ、約２００ｍｇ～約１０００ｍｇ、約２５０ｍｇ～約３５０ｍｇ等が挙げられる。 The above dosages are exemplary, and examples of the amount of ascorbic acid per composition in which the weight administered per day is from about 1000 mg to about 4000 mg, preferably from about 1500 mg to about 1800 mg, from about 50 mg to about 2000 mg; Examples include about 75 mg to about 1750 mg, about 100 mg to about 1500 mg, about 200 mg to about 1000 mg, about 250 mg to about 350 mg, and the like.
　組成物に配合されるトラネキサム酸（トランス－４－アミノメチルシクロヘキサンカルボン酸）は本来白色の固体である。トラネキサム酸は抗炎症作用を期待して医薬等に配合されるほか、シミや肝斑の症状を防ぐ目的で化粧料等に配合される。 Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) blended into the composition is originally a white solid. Tranexamic acid is added to medicines for its anti-inflammatory effects, and is also added to cosmetics to prevent the symptoms of age spots and melasma.
　トラネキサム酸は塩の形態であってもよい。特に断らない限り、本明細書で使用する場合のトラネキサム酸にはトラネキサム酸の塩も含まれる。トラネキサム酸の塩としては、塩酸塩、硝酸塩、硫酸塩等の鉱酸塩、メタンスルホン酸塩等の有機酸塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等のアルカリ金属塩、アルカリ土類金属塩等を挙げることができる。 Tranexamic acid may be in the form of a salt. Unless otherwise specified, tranexamic acid as used herein also includes salts of tranexamic acid. Salts of tranexamic acid include mineral acid salts such as hydrochloride, nitrate, and sulfate, organic acid salts such as methanesulfonate, alkali metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt, and alkaline earth salts. Examples include metal salts.
　トラネキサム酸の配合量は、ニコチン酸アミドとアスコルビン酸の配合量や所望とする変色抑制効果の程度に応じて適宜調節されるが、黄変を防ぐと同時にその他の薬効を期待して添加される場合、組成物におけるトラネキサム酸の用途、投与される対象の症状、年齢、体重、性別等に応じて適宜調節される。例えば、シミや肝斑の症状を防ぐ目的の場合、成人に投与されるトラネキサム酸の１日あたりの量は５ｍｇ～５０００ｍｇ、好ましくは５０ｍｇ～３０００ｍｇ、より好ましくは１００ｍｇ～２０００ｍｇの範囲で調整され得る。 The amount of tranexamic acid is adjusted as appropriate depending on the amount of nicotinamide and ascorbic acid and the desired degree of discoloration inhibiting effect, but it is added to prevent yellowing and at the same time to have other medicinal effects. In this case, the dosage may be adjusted as appropriate depending on the use of tranexamic acid in the composition, the symptoms, age, weight, sex, etc. of the subject to whom it is administered. For example, for the purpose of preventing age spots and melasma symptoms, the daily amount of tranexamic acid administered to adults can be adjusted within the range of 5 mg to 5000 mg, preferably 50 mg to 3000 mg, and more preferably 100 mg to 2000 mg. .
　上記の投与量は一例であり、一日に投与される重量が約１０００ｍｇ～約４０００ｍｇ、好ましくは約１５００ｍｇ～約１８００ｍｇである組成物あたりのトラネキサム酸の量の例として、約５００ｍｇ～約１０００ｍｇ、約５５０ｍｇ～約９５０ｍｇ、約６００ｍｇ～約９００ｍｇ、約６５０ｍｇ～約８５０ｍｇ、約７００ｍｇ～約８００ｍｇ等が挙げられる。 The above dosages are examples, and examples of amounts of tranexamic acid per composition in which the weight administered per day is about 1000 mg to about 4000 mg, preferably about 1500 mg to about 1800 mg, include about 500 mg to about 1000 mg; Examples include about 550 mg to about 950 mg, about 600 mg to about 900 mg, about 650 mg to about 850 mg, about 700 mg to about 800 mg, and the like.
　本発明の組成物は、経口的又は非経口的に投与（服用）すればよい。経口的に投与する組成物（経口投与製剤）としては、錠剤、顆粒剤、丸剤、散剤等の剤形を挙げることができる。非経口的に投与する組成物（非経口投与製剤）も固形の剤形であれば特に限定されない。 The composition of the present invention may be administered (taken) orally or parenterally. Compositions for oral administration (oral administration preparations) include dosage forms such as tablets, granules, pills, and powders. The composition for parenteral administration (parenteral administration preparation) is also not particularly limited as long as it is in a solid dosage form.
　組成物は、トラネキサム酸の効果を損なわない範囲で、更に他の成分、例えば公知の担体や添加剤等の製剤添加物を任意に配合することができる。これらの製剤添加物としては、例えば、賦形剤、結合剤、崩壊剤、崩壊補助剤、滑沢剤、安定剤、界面活性剤、抗酸化剤、緩衝剤、ｐＨ調整剤、分散剤、溶解補助剤、流動化剤、光沢剤、矯味剤、甘味料、清涼化剤、着色剤、矯臭剤、香料、吸着剤、糖衣剤、コーティング剤、懸濁化剤、静電防止剤、可塑剤、及び芳香剤等を、制限なく、例示することができる。 The composition may optionally contain other ingredients, such as known carriers and additives, as long as the effects of tranexamic acid are not impaired. These formulation additives include, for example, excipients, binders, disintegrants, disintegration aids, lubricants, stabilizers, surfactants, antioxidants, buffers, pH adjusters, dispersants, and solubilizers. Auxiliary agents, fluidizing agents, brighteners, flavoring agents, sweeteners, cooling agents, colorants, flavoring agents, fragrances, adsorbents, sugar coating agents, coating agents, suspending agents, antistatic agents, plasticizers, and fragrances, etc. can be exemplified without limitation.
　賦形剤としては、トラネキサム酸の効果を損なわないことを限度として制限されないものの、例えば、結晶セルロース、乳糖水和物、精製白糖、ぶどう糖、粉糖、果糖、マルトース、還元麦芽糖水あめ、粉末セルロース、トウモロコシデンプン（コーンスターチ）、バレイショデンプン、糖アルコール（マンニトール、キシリトール、ソルビトール、エリスリトール等）、トレハロース、無機塩、デキストラン、デキストリン、β－シクロデキストリン、ショ糖脂肪酸エステル、大豆レシチン、トラガント末、アラビアガム、プルラン、カオリン、無水乳糖、無水リン酸水素カルシウム、無水リン酸水素カルシウム造粒物、メタケイ酸アルミン酸マグネシウム、メチルセルロース、リン酸水素カルシウム水和物、リン酸水素カルシウム造粒物、リン酸水素ナトリウム水和物、リン酸二水素カリウム、リン酸二水素カルシウム水和物、リン酸二水素ナトリウム、ケイ酸アルミン酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、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、粉末還元麦芽糖水アメ、カルメロース、カルメロースカルシウム、カルメロースナトリウム等を挙げることができる。これらは１種単独又は２種以上を任意に組み合わせて使用することができる。組成物の質量を１００質量％とした場合、それに含まれる賦形剤の割合は、トラネキサム酸の効果に悪影響を及ぼさない範囲であるかぎり制限されないものの、例えば、０．１質量％～７０質量％の範囲を例示することができる。好ましくは０．５質量％～５０質量％、より好ましくは１質量％～４０質量％の範囲である。組成物の色調を白色に維持する観点からは、賦形剤はマンニトール、結晶セルロース及びトウモロコシデンプンから成る群から選択される１又は複数の成分を含むことが好ましい。 Examples of excipients include crystalline cellulose, lactose hydrate, refined white sugar, glucose, powdered sugar, fructose, maltose, reduced maltose starch syrup, powdered cellulose, Corn starch (corn starch), potato starch, sugar alcohols (mannitol, xylitol, sorbitol, erythritol, etc.), trehalose, inorganic salts, dextran, dextrin, β-cyclodextrin, sucrose fatty acid ester, soybean lecithin, tragacanth powder, gum arabic, Pullulan, kaolin, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, magnesium aluminate metasilicate, methylcellulose, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate Hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate, magnesium aluminate silicate, calcium silicate, magnesium silicate, light silicic anhydride, low-substituted hydroxypropylcellulose , sodium starch glycolate, powdered reduced maltose starch syrup, carmellose, carmellose calcium, carmellose sodium, and the like. These can be used alone or in any combination of two or more. When the mass of the composition is 100% by mass, the proportion of excipients contained therein is not limited as long as it does not adversely affect the effect of tranexamic acid, but for example, 0.1% by mass to 70% by mass. The range of can be exemplified. It is preferably in the range of 0.5% to 50% by weight, more preferably 1% to 40% by weight. From the viewpoint of maintaining a white color tone of the composition, the excipient preferably contains one or more components selected from the group consisting of mannitol, crystalline cellulose, and corn starch.
　結合剤としては、トラネキサム酸の効果を損なわないことを限度として制限されないものの、例えば、アラビアゴム、ゼラチン、アルファー化デンプン、アルギン酸、アルギン酸ナトリウム、カルボキシビニルポリマー、寒天、プルラン、デキストリン、セラック、ショ糖、トラガント、トラガント末、キサンタンガム、ペクチン、ポリアクリル酸ナトリウム、グァーガム、トウモロコシデンプン、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、コポリビドン、ヒプロメロース（２２０８）、ヒプロメロース（２９０６）、ヒプロメロース（２９１０）、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル（２００７３１）、ヒプロメロースフタル酸エステル（２２０８２４）、ポビドン（Ｋ２５）、ポビドン（Ｋ３０）、ポビドン（Ｋ９０）、ポリビニルアルコール（完全けん化物）、ポリビニルアルコール（部分けん化物）、メチルセルロース、メタケイ酸アルミン酸マグネシウム等を挙げることができる。組成物の質量を１００質量％とした場合、それに含まれる結合剤の割合は、トラネキサム酸の効果に悪影響を及ぼさない範囲であるかぎり制限されないものの、例えば、０．１質量％～１０質量％の範囲を例示することができる。好ましくは０．５質量％～８質量％、より好ましくは１質量％～５質量％の範囲である。 Examples of binders include gum arabic, gelatin, pregelatinized starch, alginic acid, sodium alginate, carboxyvinyl polymer, agar, pullulan, dextrin, shellac, and sucrose, but are not limited as long as they do not impair the effects of tranexamic acid. , tragacanth, tragacanth powder, xanthan gum, pectin, sodium polyacrylate, guar gum, corn starch, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, copolyvidone, hypromellose (2208), hypromellose (2906), hypromellose (2910) , hypromellose acetate succinate, hypromellose phthalate (200731), hypromellose phthalate (220824), povidone (K25), povidone (K30), povidone (K90), polyvinyl alcohol (completely saponified) , polyvinyl alcohol (partially saponified product), methylcellulose, magnesium aluminate metasilicate, and the like. When the mass of the composition is 100% by mass, the proportion of the binder contained therein is not limited as long as it does not adversely affect the effect of tranexamic acid, but for example, from 0.1% to 10% by mass. Examples of ranges can be given. It is preferably in the range of 0.5% to 8% by weight, more preferably 1% to 5% by weight.
　崩壊剤としては、トラネキサム酸の効果を損なわないことを限度として制限されないものの、例えばコーンスターチ、バレイショデンプン、部分アルファー化デンプン、ヒドロキシプロピルスタ－チ、デンプングリコール酸ナトリウム、カルボキシメチルスターチナトリウム、低置換度カルボキシメチルスターチナトリウム、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、結晶セルロース、粉末セルロース、クロスポビドン、カルメロースナトリウム、カンテン末、炭酸水素ナトリウム、カルメロース等を挙げることができる。組成物の質量を１００質量％とした場合、それに含まれる崩壊剤の割合は、トラネキサム酸の効果に悪影響を及ぼさない範囲であるかぎり制限されないものの、例えば、０．１質量％～３０質量％の範囲を例示することができる。好ましくは０．５質量％～２０質量％、より好ましくは１質量％～１５質量％の範囲である。 Disintegrants include, but are not limited to, as long as they do not impair the effectiveness of tranexamic acid, such as corn starch, potato starch, partially pregelatinized starch, hydroxypropyl starch, sodium starch glycolate, sodium carboxymethyl starch, and low degree of substitution. Examples include sodium carboxymethyl starch, carmellose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crystalline cellulose, powdered cellulose, crospovidone, carmellose sodium, agar powder, sodium bicarbonate, and carmellose. When the mass of the composition is 100% by mass, the proportion of the disintegrant contained therein is not limited as long as it does not adversely affect the effect of tranexamic acid, but for example, from 0.1% to 30% by mass. Examples of ranges can be given. It is preferably in the range of 0.5% to 20% by weight, more preferably 1% to 15% by weight.
　滑沢剤としては、トラネキサム酸の効果を損なわないことを限度として制限されないものの、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸、タルク、ショ糖脂肪酸エステル、フマル酸ステアリルナトリウム、カルナウバロウ、グリセリン脂肪酸エステル、ステアリン酸カルシウム、軽質無水ケイ酸、メタケイ酸アルミン酸マグネシウム等を挙げることができる。 The lubricant is not limited as long as it does not impair the effect of tranexamic acid, but examples include magnesium stearate, calcium stearate, stearic acid, talc, sucrose fatty acid ester, sodium stearyl fumarate, carnauba wax, glycerin fatty acid ester, Examples include calcium stearate, light anhydrous silicic acid, and magnesium aluminate metasilicate.
　矯味剤としては、制限されないものの、例えばクエン酸、酒石酸、リンゴ酸等の有機酸、グルタミン酸ナトリウム、５’－イノシン酸ナトリウム、５－グアニル酸ナトリウム、アスパラギン酸ナトリウム、カラメルを例示することができる。 Examples of the flavoring agent include, but are not limited to, organic acids such as citric acid, tartaric acid, and malic acid, sodium glutamate, sodium 5'-inosinate, sodium 5-guanylate, sodium aspartate, and caramel.
　甘味料としては、制限されないものの、例えばサッカリンナトリウム、グリチルリチン酸ジカリウム、アスパルテーム、ステビア、ラカンカ、ソーマチン、アセスルファムカリウム、スクラロース、ショ糖、果糖、ブドウ糖、乳糖水和物、無水乳糖、麦芽糖、ソルビトール、マルチトール、マンニトール、キシリトール、エリスリトール、グリセロール、イノシトール、還元麦芽糖水アメ、パラチノース、カップリングシュガー、ハチミツ等の高甘味度甘味料を例示することができる。 Examples of sweeteners include, but are not limited to, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, Lacanca, thaumatin, acesulfame potassium, sucralose, sucrose, fructose, glucose, lactose hydrate, anhydrous lactose, maltose, sorbitol, maltitol. , mannitol, xylitol, erythritol, glycerol, inositol, reduced maltose starch syrup, palatinose, coupling sugar, and honey.
　コーティング剤としては、制限されないものの、例えばアクリル酸エチル・メタクリル酸メチルコポリマー分散液、アセチルグリセリン脂肪酸エステル、アミノアルキルメタクリレートコポリマーＥ、アラビアゴム、アラビアゴム末、アンモニオアルキルメタクリレートコポリマー、エチルセルロース、エチルセルロース水分散液、オクチルデシルトリグリセリド、カルナウバロウ、カルメロースカルシウム、カルメロースナトリウム、含水二酸化ケイ素、乾燥水酸化アルミニウムゲル、乾燥メタクリル酸コポリマーＬＤ、クエン酸トリエチル、グリセリン、グリセリン脂肪酸エステル、ケイ酸マグネシウム、軽質無水ケイ酸、軽質無水ケイ酸含有ヒドロキシプロピルセルロース、合成ケイ酸アルミニウム、合成ヒドロタルサイト、酸化チタン、酸化マグネシウム、ジメチルアミノエチルメタアクリレート・メチルメタアクリレートコポリマー、ショ糖脂肪酸エステル、水酸化アルミニウムゲル、ステアリルアルコール、ステアリン酸、ステアリン酸アルミニウム、ステアリン酸カルシウム、ステアリン酸ポリオキシル４０、ステアリン酸マグネシウム、精製ゼラチン、精製セラック、精製白糖、ゼラチン、セラック、Ｄ－ソルビトール、Ｄ－ソルビトール液、タルク、炭酸カルシウム、炭酸マグネシウム、沈降炭酸カルシウム、低置換度ヒドロキシプロピルセルロース、濃グリセリン、白色セラック、白糖、パラフィン、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２９１０・酸化チタン・マクロゴール混合物、ヒプロメロース（２２０８）、ヒプロメロース（２９０６）、ヒプロメロース（２９１０）、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル（２００７３１）、ヒプロメロースフタル酸エステル（２２０８２４）、フマル酸・ステアリン酸・ポリビニルアセタールジエチルアミノアセテート・ヒドロキシプロピルメチルセルロース２９１０混合物、プルラン、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油６０、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリソルベート８０、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール（完全けん化物）、ポリビニルアルコール（部分けん化物）、マクロゴール３００、マクロゴール４００、マクロゴール６００、マクロゴール１５００、マクロゴール１５４０、マクロゴール４０００、マクロゴール６０００、マクロゴール６０００ＥＰ、マクロゴール２００００、マクロゴール３５０００、マンニトール、無水クエン酸、無水ケイ酸水和物、無水フタル酸、無水リン酸水素カルシウム、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＳ、メタケイ酸アルミン酸マグネシウム、メチルメタクリレート・メタアクリル酸・メチルメタアクリレートコポリマー、モノステアリン酸アルミニウム、モノステアリン酸グリセリン、モノステアリン酸ソルビタン、モノラウリン酸ソルビタン、硫酸カルシウム、フマル酸及びＤＬ－リンゴ酸等を挙げることができる。 Coating agents include, but are not limited to, ethyl acrylate/methyl methacrylate copolymer dispersion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer E, gum arabic, gum arabic powder, ammonioalkyl methacrylate copolymer, ethyl cellulose, ethyl cellulose water dispersion. liquid, octyldecyl triglyceride, carnauba wax, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dry aluminum hydroxide gel, dry methacrylic acid copolymer LD, triethyl citrate, glycerin, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid , hydroxypropyl cellulose containing light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, magnesium oxide, dimethylaminoethyl methacrylate/methyl methacrylate copolymer, sucrose fatty acid ester, aluminum hydroxide gel, stearyl alcohol, Stearic acid, aluminum stearate, calcium stearate, polyoxyl stearate 40, magnesium stearate, purified gelatin, purified shellac, purified white sugar, gelatin, shellac, D-sorbitol, D-sorbitol liquid, talc, calcium carbonate, magnesium carbonate, sedimentation Calcium carbonate, low-substituted hydroxypropylcellulose, concentrated glycerin, white shellac, white sugar, paraffin, hydroxypropylcellulose, hydroxypropylmethylcellulose 2910/titanium oxide/macrogol mixture, hypromellose (2208), hypromellose (2906), hypromellose (2910) , hypromellose acetate succinate, hypromellose phthalate (200731), hypromellose phthalate (220824), fumaric acid/stearic acid/polyvinyl acetal diethylaminoacetate/hydroxypropyl methylcellulose 2910 mixture, pullulan, polyoxyethylene Hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polysorbate 80, polyvinyl acetal diethylamino acetate, polyvinyl Alcohol (completely saponified), polyvinyl alcohol (partially saponified), Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macrogol 6000EP, Macrogol 20000 , macrogol 35000, mannitol, citric acid anhydride, silicic anhydride hydrate, phthalic anhydride, calcium hydrogen phosphate anhydride, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminate metasilicate, methyl Examples include methacrylate/methacrylic acid/methyl methacrylate copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, fumaric acid, and DL-malic acid.
　組成物は固体形状を有する。そのような組成物としては、錠剤、顆粒剤、丸剤及び散剤を挙げることができる。組成物は、好ましくは錠剤又は顆粒剤、より好ましくは湿式造粒のような水の存在下で混合する工程を経由して得られる錠剤又は顆粒剤である。なお、錠剤は単層からなるものであっても、２層以上の複層構造を有するものであってもよい。 The composition has a solid form. Such compositions may include tablets, granules, pills and powders. The composition is preferably a tablet or granule, more preferably a tablet or granule obtained via a mixing process in the presence of water, such as wet granulation. Note that the tablet may be composed of a single layer or may have a multilayer structure of two or more layers.
　錠剤の例としては、裸錠、素錠、糖衣錠、口腔内崩壊錠、フィルムコーティング錠又はチュアブル錠が挙げられる。錠剤は、組成の異なる粉末又は顆粒を２層又は３層以上に積み重ねて圧縮成形した多層錠であってもよい。フィルムには、所望とする組成物に応じて即溶性、遅溶性、胃溶性、及び腸溶性といった特性を付与することができる。 Examples of tablets include bare tablets, uncoated tablets, sugar-coated tablets, orally disintegrating tablets, film-coated tablets, and chewable tablets. The tablet may be a multilayer tablet obtained by stacking two or three or more layers of powders or granules with different compositions and compressing them. The film can be imparted with properties such as immediate dissolution, slow dissolution, gastric solubility, and enteric coating depending on the desired composition.
　錠剤（裸錠・素錠）の大きさは、例えば円形の錠剤（円柱状）に成形した場合、その直径は、約２ｍｍ～約１５ｍｍの範囲を挙げることができる。好ましくは約３ｍｍ～約１２ｍｍである。またその厚みは、制限されないもの、約３ｍｍ～約１０ｍｍの範囲を挙げることができる。 Regarding the size of the tablet (uncoated tablet), for example, when it is formed into a circular tablet (cylindrical shape), the diameter thereof can be in the range of about 2 mm to about 15 mm. Preferably it is about 3 mm to about 12 mm. Further, the thickness thereof is not limited, and may be in the range of about 3 mm to about 10 mm.
　組成物は、内服用固形製剤であってもよい。そのような固形製剤を、瓶包装、ＰＴＰ包装、パウチ包装、スティック包装、ＳＰ包装により一旦包装して気密保存してもよい。さらにそれらをピロー包装してもよく、それらを箱等に格納してもよい。ピロー包装に用いられる材料としては、特に限定されず、例えば、ポリプロピレンフィルム、ポリエチレンテレフタレートフィルム、ポリエチレンフィルム等の樹脂フィルムやこれら樹脂フィルムにアルミニウム箔を付着させたものを用いることができる。なお、吸湿性が懸念される場合には乾燥剤等を瓶包装内やピロー包装内に同時に保存してもよい。 The composition may be a solid preparation for internal use. Such solid preparations may be once packaged in bottle packaging, PTP packaging, pouch packaging, stick packaging, or SP packaging for airtight storage. Furthermore, they may be wrapped in pillows or stored in a box or the like. The material used for pillow packaging is not particularly limited, and for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, and aluminum foil attached to these resin films can be used. In addition, if hygroscopicity is a concern, a desiccant or the like may be stored at the same time in the bottle packaging or pillow packaging.
　内服用固形製剤は、上述した経口投与可能な錠剤、顆粒剤、丸剤及び散剤のような形態であってもよい。 The solid preparation for internal use may be in the form of the above-mentioned orally administrable tablets, granules, pills, and powders.
　本発明の組成物は最終製品として白色を呈することが期待される医薬組成物、美容組成物、化粧品組成物、飲食品組成物等として存在し得る。組成物は白色を呈していることが好ましいが、組成物中のトラネキサム酸の量が少ない場合など、トラネキサム酸の変色抑制効果が十分でない場合には微黄白色、淡黄白色、微黄色、黄白色又は淡黄色を呈することもある。 The composition of the present invention can exist as a pharmaceutical composition, beauty composition, cosmetic composition, food/beverage composition, etc. that are expected to exhibit a white color as a final product. The composition preferably has a white color, but if the discoloration suppressing effect of tranexamic acid is not sufficient, such as when the amount of tranexamic acid in the composition is small, the composition may have a slightly yellowish white color, a pale yellowish white color, a slightly yellowish color, or a yellowish color. It may be white or pale yellow in color.
　ニコチン酸アミド、アスコルビン酸、トラネキサム酸が共通して奏する美白効果から、組成物は美容組成物、好ましくは内服の美容組成物として提供されることが意図される。組成物が美容用途に供される場合、パントテン酸カルシウムやピリドキシン塩酸塩を更に含むことが好ましい。これらの化合物の含有量は当業者によって適宜調節されるため、限定することを意図するものではないが、パントテン酸カルシウムの量は、１日に投与される組成物あたり１ｍｇ～１２００ｍｇ、好ましくは５ｍｇ～６００ｍｇ、より好ましくは１０ｍｇ～１００ｍｇであり、ピリドキシン塩酸塩の量は、１日に投与される組成物あたり０．５ｍｇ～２００ｍｇ、好ましくは１ｍｇ～１００ｍｇ、より好ましくは２ｍｇ～５０ｍｇである。 Because of the whitening effect that nicotinamide, ascorbic acid, and tranexamic acid commonly exhibit, the composition is intended to be provided as a cosmetic composition, preferably an internally administered cosmetic composition. When the composition is used for cosmetic purposes, it is preferable that the composition further contains calcium pantothenate and pyridoxine hydrochloride. Although the content of these compounds is appropriately adjusted by those skilled in the art and is not intended to be limiting, the amount of calcium pantothenate is 1 mg to 1200 mg, preferably 5 mg per composition administered per day. ~600 mg, more preferably 10 mg to 100 mg, and the amount of pyridoxine hydrochloride is 0.5 mg to 200 mg, preferably 1 mg to 100 mg, more preferably 2 mg to 50 mg per composition administered per day.
　本明細書で使用する場合、美白とは、シミ（肝斑、老人性色素斑等を含む）、そばかす、日やけ、色黒やステロイド等の薬物による皮膚の黒化症などの色素沈着症の予防及び／又は治療を包含する。 As used herein, whitening refers to pigmentation disorders such as age spots (including melasma, senile pigment spots, etc.), freckles, sunburn, dark skin, and skin melanization caused by drugs such as steroids. Including prevention and/or treatment.
　美白効果を奏する組成物として提供される場合、本発明の組成物は更に公知の美白効果を示す成分や美白効果を増強する成分を含んでもよい。これらの成分としては、例えば、Ｌ－システイン又はその誘導体（Ｎ－アセチル－Ｌ－システイン、Ｌ－ホモシステイン、Ｌ－システイン酸、Ｌ－ホモシステイン酸、Ｌ－システインスルフィン酸、Ｓ－スルフィノ－Ｌ－システイン、Ｓ－スルホ－Ｌ－システイン、シスチン（システインの二量体）など、パントテン酸、その誘導体又はそれらの塩（パントテン酸；パントテン酸ナトリウム、パントテン酸カルシウム等のパントテン酸塩；パンテテイン、パンテチン、ホスホパンテテインなど）、ハイドロキノン又はその誘導体（ハイドロキノン；ハイドロキノン－β－Ｄ－グルコース（アルブチン）等のハイドロキノン配糖体など）、グルコサミン又はその誘導体（グルコサミン；アセチルグルコサミン等のグルコサミンエステル類；グルコサミンメチルエーテル等のグルコサミンエーテル類など）、ヒノキチオール又はその誘導体（ヒノキチオール；ヒノキチオールグルコシド等のヒノキチオール配糖体など）、アゼライン酸、その誘導体又はそれらの塩（アゼライン酸；アゼライン酸モノアルキルエステル等のアゼライン酸モノエステル類；アゼライン酸ジアルキルエステル等のアゼライン酸ジエステル類など）、トコフェロール類（α－トコフェロール、β－トコフェロール、γ－トコフェロール、δ－トコフェロール、コハク酸ｄ－α－トコフェロールなど）、ユビキノン類（コエンザイムＱ６（ＣｏＱ６）、コエンザイムＱ７（ＣｏＱ７）、コエンザイムＱ８（ＣｏＱ８）、コエンザイムＱ９（ＣｏＱ９）、コエンザイムＱ１０（ＣｏＱ１０）など）、カロテノイド（カロテン、ルテイン、ビオラキサンチン、スピリロキサンチン、スフェロイデンなど）、フラボン類（フラボン、アピゲニン、ルテオリン及びこれらの配糖体など）、イソフラボン又はその誘導体（イソフラボン；イソフラボン配糖体など）、フラバノン又はその誘導体（ナリンゲニン、エリオジクチオール、ナリンギンなど）、カテキン類（カテキン、カテキンガラート、ガロカテキンなど）、フラボノール類（ケンフェロール、クエルセチン、ミリセチン及びこれらの配糖体など）、グリチルリチン酸、その誘導体又はそれらの塩（グリチルリチン酸；グリチルリチン酸ジカリウム、グリチルリチン酸モノアンモニウム等のグリチルリチン酸塩など）、グリチルリチン酸、その誘導体又はそれらの塩（グリチルリチン酸；グリチルリチン酸ステアリル等のグリチルリチン酸アルキルエステル類など）、コウジ酸、その誘導体又はそれらの塩（コウジ酸；コウジ酸モノブチレート、コウジ酸モノカプレート、コウジ酸モノパルミテート、コウジ酸モノステアレート等のコウジ酸モノアルキルエステル類；コウジ酸ジブチレート、コウジ酸ジパルミテート、コウジ酸ジステアレート、コウジ酸ジオレエート等のコウジ酸ジアルキルエステル類など）、エラグ酸、その誘導体又はそれらの塩（エラグ酸；エラグ酸テトラメチルエーテル等のエラグ酸エーテル類；エラグ酸テトラアセタート、エラグ酸テトラベンゾアート等のエラグ酸アシル誘導体など）、グルタチオン、その誘導体又はそれらの塩（グルタチオン；Ｓ－ラクトイルグルタチオン等のＳ－アシルグルタチオン類；Ｎ，Ｓ－ジオクタノイルグルタチオンジステアリル、Ｎ，Ｓ－ジパルミトイルグルタチオンジセチル等のＮ，Ｓ－ジアシルグルタチオンジエステル類など）、レゾルシノール又はその誘導体（レゾルシノール；４－ｎ－ブチルレゾルシノール、４－イソアミルレゾルシノール、４－シクロヘキシルレゾルシノール、５－メチルレゾルシノール等のアルキル化レゾルシノール；４－クロロレゾルシノール、４－ブロモレゾルシノール等のハロゲン化レゾルシノールなど）、グリコーゲン；ヨクイニン、ハマメリス、ユキノシタ、ジンコウ、チャ、イタドリ、メリッサ、タイム、カワラヨモギ、セイヨウノコギリソウ、オトギリソウ、セイヨウオトギリ、シャクヤク、ボタン、スペインカンゾウ、カンゾウ、クワ、マグワ、シマグワ、クララ、ウワウルシ、ヘラヤハズ、ハリアミジ、ヒジキ、フシツナギ、イワヒゲ、ダルス、ヤナギモク（オオバモク）、エゾノネジモク、フシスジモク、イシモズク、モウセンゴケ、コモウセンゴケ、ラベンダー、オウレン、ハトムギ、イワナシ、アメリカイワナシ、パッション・フラワー、クダモノトケイ、ウォーターレモン、トケイソウ、月葉西番蓮、蛇王藤、杯葉西番蓮、ワイルドパンジー、ニオイスミレ、スミレ、コスミレ、ノジスミレ、ニョイスミレ、ツクシスミレ、シロスミレ、エゾノタチツボスミレ、ネパールスミレ、シロバナスミレ、マルバケスミレ、フキスミレ、タチツボスミレ、地草果、スミレサイシン、ツボスミレ、威霊仙、テッセン、カザグルマ、センニンソウ、杜仲、トゲミノマサキ、ツリバナ、アスパラガス、イブキトラノオ、エンドウ豆、エイジツ、オウゴン、オノニス、キイチゴ、クジン、ケイケットウ、ゴカヒ、サイシン、サンザシ、サンペンズ、シラユリ、センプクカ、ソウハクヒ、大豆、茶、トウキ抽出物、糖蜜、ビャクレン、ブナノキ、ブドウ種子、フローデマニータ、ホップ、マイカイカ、モッカ、羅漢果、アロエ、アルテア、アルニカ、アシタバ、インチンコウ、イラクサ、ウコン、オウバク、カミツレ、キンギンカ、クレソン、コンフリー、サルビア、シコン、シソ、シラカバ、トウキンセンカ、ニワトコ、ホオウ、ムクロジ、レンゲソウ、ヨモギ、ユーカリ、ノイバラ、イチョウ、ヤシャジツ、ジコッピ、ミクロメルム  ミヌツム（Ｍｉｃｒｏｍｅｌｕｍ  ｍｉｎｕｔｕｍ）、ミクロメルム  プベセンス（Ｍｉｃｒｏｍｅｌｕｍ  ｐｕｂｅｓｃｅｎｓ）、バハクジ、ボウカ、スズメウリ、ラズベリー、カキョク又はそれらの抽出物；胎盤抽出物等を挙げることができるが、上記のもののみに限定されるべきものではない。しかしながら、パントテン酸カルシウムが好ましく、パントテン酸カルシウムと乳酸カルシウムの造粒物であるパントテン酸カルシウムタイプＳ（商品名）としても利用できる。これらの成分は１つのもののみを配合してもよく、また、２種以上のものを組み合わせて配合してもよい。美白用組成物（美白剤）には、公知の美白効果を示す成分や美白効果を増強する成分以外の成分を、さらに加えてもよい。これら成分の配合量は、トラネキサム酸の効果を損なわない限り、特に限定されない。 When provided as a composition that exhibits a whitening effect, the composition of the present invention may further contain a known component that exhibits a whitening effect or a component that enhances the whitening effect. These components include, for example, L-cysteine or its derivatives (N-acetyl-L-cysteine, L-homocysteine, L-cysteic acid, L-homocysteic acid, L-cysteinesulfinic acid, S-sulfino-L-cysteine, - Cysteine, S-sulfo-L-cysteine, cystine (dimer of cysteine), pantothenic acid, its derivatives, or their salts (pantothenic acid; pantothenic acid salts such as sodium pantothenate, calcium pantothenate; pantetheine, pantethine) , phosphopantetheine, etc.), hydroquinone or its derivatives (hydroquinone; hydroquinone glycosides such as hydroquinone-β-D-glucose (arbutin), etc.), glucosamine or its derivatives (glucosamine; glucosamine esters such as acetylglucosamine; glucosamine methyl glucosamine ethers such as ethers), hinokitiol or its derivatives (hinokitiol; hinokitiol glycosides such as hinokitiol glucoside, etc.), azelaic acid, derivatives thereof, or salts thereof (azelaic acid; azelaic acid monoalkyl esters, etc.) Esters; azelaic acid diesters such as azelaic acid dialkyl ester, etc.), tocopherols (α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, d-α-tocopherol succinate, etc.), ubiquinones (coenzyme Q6 (CoQ6), coenzyme Q7 (CoQ7), coenzyme Q8 (CoQ8), coenzyme Q9 (CoQ9), coenzyme Q10 (CoQ10), etc.), carotenoids (carotene, lutein, violaxanthin, spiryloxanthin, spheroiden, etc.), flavones ( flavones, apigenin, luteolin and their glycosides, etc.), isoflavones or their derivatives (isoflavones; isoflavone glycosides, etc.), flavanones or their derivatives (naringenin, eriodictyol, naringin, etc.), catechins (catechin, catechin, etc.) lat, gallocatechin, etc.), flavonols (kaempferol, quercetin, myricetin, and their glycosides, etc.), glycyrrhizic acid, its derivatives, or their salts (glycyrrhizic acid; glycyrrhizic acid salts such as dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.) etc.), glycyrrhizic acid, its derivatives, or their salts (glycyrrhizic acid; glycyrrhizic acid alkyl esters such as stearyl glycyrrhizinate, etc.), kojic acid, its derivatives, or their salts (kojic acid; kojic acid monobutyrate, kojic acid monocaprate), , kojic acid monoalkyl esters such as kojic acid monopalmitate and kojic acid monostearate; kojic acid dialkyl esters such as kojic acid dibutyrate, kojic acid dipalmitate, kojic acid distearate, kojic acid dioleate, etc.), ellagic acid, Derivatives thereof or salts thereof (ellagic acid; ellagic acid ethers such as ellagic acid tetramethyl ether; ellagic acid acyl derivatives such as ellagic acid tetraacetate, ellagic acid tetrabenzoate, etc.), glutathione, its derivatives or salts thereof (Glutathione; S-acylglutathiones such as S-lactoylglutathione; N,S-diacylglutathione diesters such as N,S-dioctanoylglutathione distearyl, N,S-dipalmitoylglutathione dicetyl, etc.), resorcinol or derivatives thereof (resorcinol; alkylated resorcinols such as 4-n-butylresorcinol, 4-isoamylresorcinol, 4-cyclohexylresorcinol, 5-methylresorcinol; halogenated resorcinols such as 4-chlororesorcinol, 4-bromoresorcinol, etc.), Glycogen; Glycogen, hamamelis, saxifrage, jinkou, tea, Japanese knotweed, melissa, thyme, mugwort, yarrow, hypericum, hypericum, peony, peony, Spanish daylily, daylily, mulberry, magwa, shimaguwa, clara, sumac, Japanese knotweed, harlequin , Hijiki, Bulbasaur, Selaginella, Dulse, Willow moss (Ovamoku), Ezononespinum, Fushisium moss, Ishimozuku, Mosengoke, Coix moss, Lavender, Orensis, Coix moss, Sardine, American sardine, Passion flower, Kudamon tokei, Water lemon, Passiflora, Tsukiha Nishiban Lotus, snake king wisteria, cup-leafed western lotus, wild pansy, smelly violet, violet, black violet, white violet, white violet, horsetail violet, white violet, Japanese violet, Nepalese violet, white violet, red violet, Japanese butterbur violet, white violet, ground herb, violet Saishin, Violet violet, Eireisen, Tessen, Kazaguruma, Senninso, Mori zhong, Togeminomasaki, Asparagus, Asparagus, Ibukitranoo, Pea, Eijitsu, Scutellariae, Ononis, Rubus, Kujin, Keikethorn, Gokahi, Saishin, Hawthorn, Sunpens, White lily, Sempucca, soybean, tea, ginger extract, molasses, sandalwood, beech, grape seed, flodemanita, hops, mica squid, mocca, luo han guo, aloe, althea, arnica, reedica, quincea, stinging nettle, turmeric, aracula, chamomile , Kinginka, Cresson, Cresson, Saleson, Salvia, Sicon, Sicon, Polar, Toukinsenka, Niwatoko, Niwatco, Huo, Huo, Rogi, Homogue, Yomogi, Euchargi, Neukari, Gliks, Gifts, Zicoppi, Zicoppi, Micromerum Minutum (Micromelum Minutum (Micromelum Minutum) ), Micromelm Pubesense (Micromelum examples thereof include, but are not limited to, the above-mentioned ones. However, calcium pantothenate is preferred, and can also be used as calcium pantothenate type S (trade name), which is a granulated product of calcium pantothenate and calcium lactate. These components may be blended alone or in combination of two or more. The whitening composition (whitening agent) may further contain components other than the known components exhibiting a whitening effect and the components enhancing the whitening effect. The blending amounts of these components are not particularly limited as long as the effects of tranexamic acid are not impaired.
　特定の実施形態において、組成物あたり、ニコチン酸アミドは６ｍｇ～４００ｍｇ、アスコルビン酸は１０ｍｇ～３０００ｍｇ、トラネキサム酸は５０ｍｇ～３０００ｍｇ配合される。 In certain embodiments, 6 mg to 400 mg of nicotinamide, 10 mg to 3000 mg of ascorbic acid, and 50 mg to 3000 mg of tranexamic acid are included per composition.
　上記の配合量は一日量の例示であり、組成物が１日に複数回投与される場合、これらの量を複数回、例えば２回～４回に分けることもできる。 The above formulation amounts are examples of daily doses, and if the composition is administered multiple times a day, these doses can be divided into multiple doses, for example 2 to 4 doses.
　特定の実施形態において、組成物あたり、ニコチン酸アミドの含有量は１質量％～５質量％、アスコルビン酸の含有量は５質量％～３０質量％であり、トラネキサム酸の含有量は２０質量％～６０質量％である。 In certain embodiments, the content of nicotinic acid amide is 1% to 5% by weight, the content of ascorbic acid is 5% to 30% by weight, and the content of tranexamic acid is 20% by weight per composition. ~60% by mass.
（製造方法）
　第二の態様において、水の存在下で、ニコチン酸アミドと、アスコルビン酸と、トラネキサム酸とを接触させる工程を含む、固形組成物の製造方法が提供される。各成分の添加の時期は特に限定されない。例えば、トラネキサム酸は変色開始前に添加してもよいし、変色が始まってから適当な時期に添加してもよい。組成物の色を白色に維持する観点から、水は、ニコチン酸アミドとアスコルビン酸の組み合わせにトラネキサム酸を配合し、十分混合してから添加されることが好ましい。 (Production method)
In a second aspect, there is provided a method for producing a solid composition comprising contacting nicotinamide, ascorbic acid, and tranexamic acid in the presence of water. The timing of addition of each component is not particularly limited. For example, tranexamic acid may be added before the start of discoloration, or may be added at an appropriate time after the start of discoloration. From the viewpoint of keeping the color of the composition white, it is preferable that water is added after blending tranexamic acid with a combination of nicotinamide and ascorbic acid and thoroughly mixing the mixture.
　トラネキサム酸の量は、ニコチン酸アミドとアスコルビン酸の量に応じて適宜調整される。例えば、ニコチン酸アミドが約１０ｍｇ～約７０ｍｇ、約１５ｍｇ～約６５ｍｇ、約２０ｍｇ～約６０ｍｇ、約２５ｍｇ～約５５ｍｇ、約３０ｍｇ～約５０ｍｇ又は約３５ｍｇ～約４５ｍｇであり、また、アスコルビン酸が、約５０ｍｇ～約２０００ｍｇ、約７５ｍｇ～約１７５０ｍｇ、約１００ｍｇ～約１５００ｍｇ、約２００ｍｇ～約１０００ｍｇ、約２５０ｍｇ～約３５０ｍｇである場合、トラネキサム酸の量は、５００ｍｇ～約１０００ｍｇ、約５５０ｍｇ～約９５０ｍｇ、約６００ｍｇ～約９００ｍｇ、約６５０ｍｇ～約８５０ｍｇ又は約７００ｍｇ～約８００ｍｇの範囲で適宜調整される。 The amount of tranexamic acid is adjusted as appropriate depending on the amounts of nicotinamide and ascorbic acid. For example, nicotinic acid amide is about 10 mg to about 70 mg, about 15 mg to about 65 mg, about 20 mg to about 60 mg, about 25 mg to about 55 mg, about 30 mg to about 50 mg, or about 35 mg to about 45 mg, and ascorbic acid is about 50 mg to about 2000 mg, about 75 mg to about 1750 mg, about 100 mg to about 1500 mg, about 200 mg to about 1000 mg, about 250 mg to about 350 mg, the amount of tranexamic acid is 500 mg to about 1000 mg, about 550 mg to about 950 mg, It is adjusted as appropriate within the range of about 600 mg to about 900 mg, about 650 mg to about 850 mg, or about 700 mg to about 800 mg.
　上記の配合量は例示であり、所望とする変色抑制効果の程度に応じてトラネキサム酸の添加量を増減せることができる。 The above blending amount is an example, and the amount of tranexamic acid added can be increased or decreased depending on the desired degree of discoloration inhibiting effect.
　組成物中には適当な製剤添加物を加えることができる。製剤添加物としては、賦形剤、結合剤、崩壊剤、崩壊補助剤、滑沢剤、安定剤、界面活性剤、抗酸化剤、緩衝剤、ｐＨ調整剤、分散剤、溶解補助剤、流動化剤、光沢剤、矯味剤、甘味料、清涼化剤、着色剤、矯臭剤、香料、吸着剤、糖衣剤、コーティング剤、懸濁化剤、静電防止剤、可塑剤、及び芳香剤等を挙げることができ、製剤添加物は、トラネキサム酸の効果を損なわない範囲で適宜選択して、適当量を加えればよい。 Appropriate formulation additives can be added to the composition. Formulation additives include excipients, binders, disintegrants, disintegration aids, lubricants, stabilizers, surfactants, antioxidants, buffers, pH adjusters, dispersants, dissolution aids, and flow agents. coloring agents, brighteners, flavoring agents, sweeteners, cooling agents, coloring agents, flavoring agents, fragrances, adsorbents, sugar coating agents, coating agents, suspending agents, antistatic agents, plasticizers, fragrances, etc. The formulation additives may be appropriately selected and added in appropriate amounts within a range that does not impair the effects of tranexamic acid.
　組成物の製造は、一般的な固形製剤の製造方法を用いて行うことができる。そのような製造方法として造粒顆粒があり、その例として、高速撹拌造粒法や流動層造粒法等に代表される湿式造粒法が挙げられる。 The composition can be manufactured using a general solid preparation manufacturing method. Granulation granules are an example of such a manufacturing method, and examples thereof include wet granulation methods such as high-speed stirring granulation method and fluidized bed granulation method.
　アスコルビン酸は付着性が高い成分であるため、組成物中におけるアスコルビン酸の配合量が多い場合、錠剤化の際には打錠障害を回避するために、造粒顆粒を採用して表面積を低減することが好ましい。これにより、薬物を含む顆粒が滑沢剤に十分に覆われるようになり、また打錠時の薬物と臼杵への接触を低減することが可能となる。 Ascorbic acid is a highly adhesive component, so if the amount of ascorbic acid in the composition is large, granules are used to reduce the surface area in order to avoid tableting problems when making tablets. It is preferable to do so. This allows the granules containing the drug to be sufficiently covered with the lubricant, and also makes it possible to reduce contact between the drug and the die during tabletting.
　特定の実施形態において、製造方法は、ニコチン酸アミド、アスコルビン酸及びトラネキサム酸を水、又は結合剤の水溶液もしくは分散液を用いて湿式造粒する工程、そして任意に、固形組成物を製造するのに当業界で一般的に採用されているその他の工程を含んでもよい。湿式造粒法としては一般に用いられる混合撹拌造粒法、高速撹拌造粒法、流動層造粒法、又は転動造粒法などを用いることができるが、好ましくは高速撹拌造粒法、又は流動層造粒法であり、より好ましくは流動層造粒法である。所望の造粒物、更にはその成形物を製造するために、造粒後に乾燥工程や整粒等の任意の工程を実施してもよい。 In certain embodiments, the manufacturing method comprises wet granulating nicotinamide, ascorbic acid, and tranexamic acid with water or an aqueous solution or dispersion of a binder, and optionally, manufacturing a solid composition. may include other steps commonly employed in the industry. As the wet granulation method, commonly used mixing stirring granulation method, high speed stirring granulation method, fluidized bed granulation method, or rolling granulation method can be used, but preferably high speed stirring granulation method, or The method is a fluidized bed granulation method, and more preferably a fluidized bed granulation method. In order to produce a desired granulated product or even a molded product thereof, any process such as a drying process or sizing may be carried out after granulation.
　湿式造粒により得られた顆粒剤を混合し、圧縮成形することで組成物を錠剤の形態にすることもできる。更に、顆粒剤や錠剤を、公知の方法にて、糖衣又はフィルムコーティングすることも可能である。 The composition can also be made into a tablet by mixing granules obtained by wet granulation and compression molding. Furthermore, granules and tablets can be sugar-coated or film-coated using known methods.
　糖衣やフィルムによる被覆（コーティング）は、例えばパンコーティング法、流動層コーティング法、転動コーティング法、ドライコーティング法、又はこれらの方法を組み合わせることで実施することができる。この際、定法に従って、糖衣成分やフィルム成分を水や有機溶媒（エタノール等）に溶解又は分散させてスプレーコーティングすることや、またフィルム成分を直接噴霧して、熱や圧力をかけてドライコーティングすることもできる。 Coating with sugar coating or film can be carried out, for example, by a pan coating method, a fluidized bed coating method, a rolling coating method, a dry coating method, or a combination of these methods. At this time, the sugar coating component and film component may be dissolved or dispersed in water or an organic solvent (ethanol, etc.) and spray coated according to the standard method, or the film component may be directly sprayed and dry coated by applying heat or pressure. You can also do that.
　糖衣形成のために使用される糖衣成分としては、制限されないものの、ショ糖（白糖、精製白糖）、果糖、ブドウ糖、乳糖水和物、無水乳糖、トレハロースなどの単糖類や二糖類；エリスリトール、マンニトール、ソルビトール、キシリトール、マルチトール、粉末還元麦芽糖水飴、還元乳糖などの糖アルコール等の糖類を挙げることができる。また糖衣液には、アラビアゴム、アラビアゴム末、エチルセルロース、カルナウバロウ、カルメロースナトリウム、ステアリン酸、ステアリン酸ポリオキシル４０、精製ゼラチン、精製セラック、ゼラチン、セラック、タルク、沈降炭酸カルシウム、白色セラック、ヒドロキシプロピルセルロース、ヒプロメロース（２２０８）、ヒプロメロース（２９０６）、ヒプロメロース（２９１０）、プルラン、ポビドン（Ｋ２５）、ポビドン（Ｋ３０）、ポビドン（Ｋ９０）、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール、ポリビニルアルコール（部分けん化物）、マクロゴール１５００、マクロゴール４０００、マクロゴール６０００、マンニトール、リン酸一水素カルシウム、リン酸水素カルシウム、リン酸二水素カルシウム、硫酸カルシウム、乳酸カルシウム、カオリン、酸化チタン、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄銅、クロロフィリンナトリウム、銅クロロフィル、リボフラビン、リボフラビン酪酸エステル、リボフラビンリン酸エステルナトリウムなどが含まれていてもよい。 Sugar coating components used for sugar coating formation include, but are not limited to, monosaccharides and disaccharides such as sucrose (white sugar, refined white sugar), fructose, glucose, lactose hydrate, anhydrous lactose, and trehalose; erythritol and mannitol. , sorbitol, xylitol, maltitol, powdered reduced maltose starch syrup, reduced lactose, and other sugar alcohols. The sugar coating liquid also contains gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, carmellose sodium, stearic acid, polyoxyl stearate 40, purified gelatin, purified shellac, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, hydroxypropyl. Cellulose, hypromellose (2208), hypromellose (2906), hypromellose (2910), pullulan, povidone (K25), povidone (K30), povidone (K90), polyoxyethylene (105) polyoxypropylene (5) glycol, polyvinyl alcohol (partially saponified product), macrogol 1500, macrogol 4000, macrogol 6000, mannitol, calcium monohydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium sulfate, calcium lactate, kaolin, titanium oxide, sesquioxide Iron, yellow iron sesquioxide, copper black iron oxide, sodium chlorophyllin, copper chlorophyll, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, etc. may be contained.
　フィルムコーティング剤としては、例えば水溶性高分子化合物、胃溶性高分子化合物、及び腸溶性高分子化合物を挙げることができる。水溶性高分子化合物としては、制限されないものの、例えばメチルセルロース、ヒプロメロース（２２０８）、ヒプロメロース（２９０６）、ヒプロメロース（２９１０）、ヒドロキシプロピルセルロース、ポリエチレングリコール、ポリビニルアルコール（完全けん化物）、ポリビニルアルコール（部分けん化物）、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、ポリビニルピロリドン、マクロゴール３００、マクロゴール４００、マクロゴール６００、マクロゴール１５００、マクロゴール１５４０、マクロゴール４０００、マクロゴール６０００、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などを挙げることができる。胃溶性高分子化合物としては、制限されないものの、例えばポリビニルアセタールジエチルアミノアセテート等のポリビニルアセタール系高分子、メタクリル酸メチル－メタクリル酸ブチル－メタクリル酸ジメチルアミノエチル共重合体、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体等の胃溶性メタクリル酸系高分子化合物を挙げることができる。腸溶性高分子化合物としては、制限されないものの、例えばメタクリル酸－アクリル酸エチル共重合体、メタクリル酸－メタクリル酸メチル共重合体、メタクリル酸コポリマーＳ、アクリル酸メチル－メタクリル酸メチル－メタクリル酸コポリマー等の腸溶性メタクリル酸系高分子化合物；酢酸フタル酸セルロース、ヒプロメロースフタレート、ヒプロメロースアセテートサクシネート、ポリビニルアセテートフタレート、カルボキシメチルエチルセルロース等の腸溶性セルロース系高分子化合物を挙げることができる。また、コーティング液には、タルク、酸化チタン、アラビアゴム、アラビアゴム末、エチルセルロース、カルナウバロウ、カルメロースナトリウム、ステアリン酸、ステアリン酸ポリオキシル４０、精製ゼラチン、精製セラック、ゼラチン、セラック、タルク、沈降炭酸カルシウム、白色セラック、プルラン、ポビドン（Ｋ２５）、ポビドン（Ｋ３０）、ポビドン（Ｋ９０）、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール、マクロゴール１５００、マクロゴール４０００、マクロゴール６０００、マンニトール、リン酸一水素カルシウム、リン酸水素カルシウム、リン酸二水素カルシウム、硫酸カルシウム、乳酸カルシウム、カオリン、酸化チタン、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄銅、クロロフィリンナトリウム、銅クロロフィル、リボフラビン、リボフラビン酪酸エステル、リボフラビンリン酸エステルナトリウムなどが含まれていてもよい。 Examples of the film coating agent include water-soluble polymer compounds, gastric-soluble polymer compounds, and enteric-coated polymer compounds. Examples of water-soluble polymer compounds include, but are not limited to, methylcellulose, hypromellose (2208), hypromellose (2906), hypromellose (2910), hydroxypropylcellulose, polyethylene glycol, polyvinyl alcohol (completely saponified), polyvinyl alcohol (partially saponified). compound), polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyvinylpyrrolidone, macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, polyvinyl alcohol Examples include polyethylene glycol graft copolymers. Examples of gastric soluble polymer compounds include, but are not limited to, polyvinyl acetal polymers such as polyvinyl acetal diethylaminoacetate, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, and methyl methacrylate-diethylaminoethyl methacrylate. Examples include gastric soluble methacrylic acid-based polymer compounds such as copolymers. Examples of the enteric polymer compound include, but are not limited to, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid copolymer S, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, etc. enteric-coated methacrylic acid-based polymer compounds; enteric-coated cellulose-based polymer compounds such as cellulose acetate phthalate, hypromellose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, and carboxymethylethyl cellulose. In addition, the coating liquid contains talc, titanium oxide, gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, carmellose sodium, stearic acid, polyoxyl stearate 40, purified gelatin, purified shellac, gelatin, shellac, talc, precipitated calcium carbonate. , white shellac, pullulan, povidone (K25), povidone (K30), povidone (K90), polyoxyethylene (105) polyoxypropylene (5) glycol, macrogol 1500, macrogol 4000, macrogol 6000, mannitol, phosphorus Calcium monohydrogen acid, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium sulfate, calcium lactate, kaolin, titanium oxide, iron sesquioxide, yellow iron sesquioxide, copper black iron oxide, sodium chlorophyllin, copper chlorophyll, riboflavin, riboflavin Butyrate ester, sodium riboflavin phosphate, etc. may be included.
　製造される組成物は白色を呈していることが好ましいが、組成物中のトラネキサム酸の量が少ない場合など、トラネキサム酸の変色抑制効果が十分でない場合には微黄白色、淡黄白色、微黄色、黄白色又は淡黄色を呈することもある。 It is preferable that the produced composition exhibits a white color, but if the discoloration inhibiting effect of tranexamic acid is not sufficient, such as when the amount of tranexamic acid in the composition is small, it may have a slightly yellowish white color, a pale yellowish white color, or a slightly yellowish white color. It may be yellow, yellow-white, or pale yellow.
（変色抑制方法）
　第三の態様において、水の存在下で、ニコチン酸アミドと、アスコルビン酸と、トラネキサム酸とを接触させる工程を含む、固形組成物の変色抑制方法が提供される。 (Discoloration suppression method)
In a third aspect, there is provided a method for inhibiting discoloration of a solid composition, comprising the step of contacting nicotinic acid amide, ascorbic acid, and tranexamic acid in the presence of water.
　ニコチン酸アミドとアスコルビン酸の組み合わせは、その色が白色から微黄白色、淡黄白色、微黄色、黄白色、淡黄色、黄色へと変化し得るが、トラネキサム酸はそのような黄変を防ぐための有効成分として使用することができる。変色抑制剤の有効成分としてのトラネキサム酸の量は、ニコチン酸アミドとアスコルビン酸の量に応じて適宜調整される。例えば、ニコチン酸アミドが約１０ｍｇ～約７０ｍｇ、約１５ｍｇ～約６５ｍｇ、約２０ｍｇ～約６０ｍｇ、約２５ｍｇ～約５５ｍｇ、約３０ｍｇ～約５０ｍｇ又は約３５ｍｇ～約４５ｍｇであり、また、アスコルビン酸が、約５０ｍｇ～約２０００ｍｇ、約７５ｍｇ～約１７５０ｍｇ、約１００ｍｇ～約１５００ｍｇ、約２００ｍｇ～約１０００ｍｇ、約２５０ｍｇ～約３５０ｍｇである場合、トラネキサム酸の量は、５００ｍｇ～約１０００ｍｇ、約５５０ｍｇ～約９５０ｍｇ、約６００ｍｇ～約９００ｍｇ、約６５０ｍｇ～約８５０ｍｇ又は約７００ｍｇ～約８００ｍｇの範囲で適宜調整される。 The combination of nicotinamide and ascorbic acid can change its color from white to pale yellow-white, pale yellow-white, pale yellow, yellow-white, pale yellow, and yellow, but tranexamic acid prevents such yellowing. It can be used as an active ingredient for The amount of tranexamic acid as an active ingredient of the discoloration inhibitor is appropriately adjusted depending on the amounts of nicotinamide and ascorbic acid. For example, nicotinic acid amide is about 10 mg to about 70 mg, about 15 mg to about 65 mg, about 20 mg to about 60 mg, about 25 mg to about 55 mg, about 30 mg to about 50 mg, or about 35 mg to about 45 mg, and ascorbic acid is about 50 mg to about 2000 mg, about 75 mg to about 1750 mg, about 100 mg to about 1500 mg, about 200 mg to about 1000 mg, about 250 mg to about 350 mg, the amount of tranexamic acid is 500 mg to about 1000 mg, about 550 mg to about 950 mg, It is adjusted as appropriate within the range of about 600 mg to about 900 mg, about 650 mg to about 850 mg, or about 700 mg to about 800 mg.
　上記の配合量は例示であり、所望とする変色抑制効果に応じてトラネキサム酸の添加量を増減せることができる。 The above blending amount is an example, and the amount of tranexamic acid added can be increased or decreased depending on the desired discoloration inhibiting effect.
　各成分の添加の時期は特に限定されない。例えば、トラネキサム酸は変色開始前に添加してもよいし、変色が始まってから適当な時期に添加してもよい。組成物の色を白色に維持する観点から、水は、ニコチン酸アミドとアスコルビン酸の組み合わせにトラネキサム酸を配合し、十分混合してから添加されることが好ましい。 The timing of addition of each component is not particularly limited. For example, tranexamic acid may be added before the start of discoloration, or may be added at an appropriate time after the start of discoloration. From the viewpoint of keeping the color of the composition white, it is preferable that water is added after blending tranexamic acid with a combination of nicotinamide and ascorbic acid and thoroughly mixing the mixture.
　変色抑制効果はニコチン酸アミド、アスコルビン酸及びトラネキサム酸の三成分を混合した直後の混合物、その後に得られる造粒物やその成形品において確認される。変色抑制方法は、更に任意の工程を含んでもよい。例えば変色抑制効果を維持する観点から、造粒物等を透湿性が抑えられた気密容器において、室温以下の温度で保管することが好ましい。ここで、「気密容器」とは、第十八改正日本薬局方　通則において定義されるとおり、運搬又は保存状態において、固形又は液状の異物が侵入せず、内容医薬品の損失、風解、潮解又は蒸発を防ぐことができる容器を意味する。そのような気密容器として、一般的な錠剤瓶が挙げられる。 The discoloration suppressing effect is confirmed in the mixture immediately after mixing the three components of nicotinic acid amide, ascorbic acid, and tranexamic acid, and in the granules and molded products obtained thereafter. The discoloration suppression method may further include an arbitrary step. For example, from the viewpoint of maintaining the effect of suppressing discoloration, it is preferable to store the granulated material and the like in an airtight container with reduced moisture permeability at a temperature below room temperature. As defined in the General Rules of the 18th Edition of the Japanese Pharmacopoeia, an "airtight container" is one that does not allow solid or liquid foreign matter to enter during transportation or storage, resulting in loss of the medicinal product, efflorescence, deliquescence, or means a container that can prevent evaporation. An example of such an airtight container is a common pill bottle.
　以下に実施例及び比較例を挙げて本発明をさらに詳しく説明するが、本発明はこれらに限定されるものではない。 The present invention will be explained in more detail with reference to Examples and Comparative Examples below, but the present invention is not limited thereto.
（比較例１）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）とアスコルビン酸（ＤＳＭ社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して３質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Comparative example 1)
Nicotinic acid amide (manufactured by DSM) and ascorbic acid (manufactured by DSM) are mixed in an agate mortar at the ratio of the amounts shown in Table 1 (operation 1), and 3% by mass of purified water is added to the total mass of the mixture. After dropping and granulating (operation 2), drying was performed in a constant temperature chamber at 60° C. for 1 hour to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（比較例２）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）とマンニトール（Ｄ－マンニトール：物産フードサイエンス社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して３質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Comparative example 2)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), and mannitol (D-mannitol: manufactured by Bussan Food Science) were mixed in an agate mortar at the ratio of the amounts shown in Table 1 (operation 1), and the mixture was mixed. After performing granulation by dropping 3% by mass of purified water based on the total mass of (operation 2), drying was performed for 1 hour in a constant temperature chamber at 60° C. to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（比較例３）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）とトウモロコシデンプン（松谷化学工業社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して７質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Comparative example 3)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), and corn starch (manufactured by Matsutani Chemical Industry Co., Ltd.) are mixed in an agate mortar in the proportions shown in Table 1 (operation 1), and the total mass of the mixture is After performing granulation by dropping 7% by mass of purified water (operation 2), drying was performed in a constant temperature chamber at 60° C. for 1 hour to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（比較例４）
表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）と結晶セルロース（セオラスＰＨ－１０１：旭化成社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して１２質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Comparative example 4)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM) and crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei) are mixed in an agate mortar at the ratio of the amounts shown in Table 1 (operation 1), and the mixture is mixed. After performing granulation by dropping 12% by mass of purified water based on the total mass of (operation 2), drying was performed for 1 hour in a constant temperature chamber at 60° C. to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（実施例１）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）とトラネキサム酸（Ｈｕｎａｎ　Ｄｏｎｇｔｉｎｇ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して３質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Example 1)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), and tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) were mixed in an agate mortar in the proportions shown in Table 1 (operation 1), and the total mass of the mixture was After performing granulation by dropping 3% by mass of purified water (operation 2), drying was performed in a constant temperature chamber at 60° C. for 1 hour to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（実施例２）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）、トラネキサム酸（Ｈｕｎａｎ　Ｄｏｎｇｔｉｎｇ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ社製）とパントテン酸カルシウム（パントテン酸カルシウム・タイプＳ：ＢＡＳＦジャパン社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して３質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Example 2)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and calcium pantothenate (calcium pantothenate type S: BASF Japan) in the proportions shown in Table 1. (Procedure 1) was mixed in an agate mortar (Procedure 1), and granulated by dropping 3% by mass of purified water based on the total mass of the mixture (Procedure 2), and then dried in a constant temperature chamber at 60°C for 1 hour. was carried out to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（実施例３）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）、トラネキサム酸（Ｈｕｎａｎ　Ｄｏｎｇｔｉｎｇ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ社製）とピリドキシン塩酸塩（ＤＳＭ社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して３質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Example 3)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and pyridoxine hydrochloride (manufactured by DSM) were mixed in an agate mortar at the proportions shown in Table 1. (Operation 1) After performing granulation by dropping 3% by mass of purified water based on the total mass of the mixture (Operation 2), drying was carried out for 1 hour in a constant temperature chamber at 60 ° C. to obtain granules. (Operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（実施例４）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）、トラネキサム酸（Ｈｕｎａｎ　Ｄｏｎｇｔｉｎｇ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ社製）、パントテン酸カルシウム（パントテン酸カルシウム・タイプＳ：ＢＡＳＦジャパン社製）とピリドキシン塩酸塩（ＤＳＭ社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して３質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Example 4)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical), and calcium pantothenate (calcium pantothenate type S: BASF Japan) in the proportions shown in Table 1. (manufactured by DSM) and pyridoxine hydrochloride (manufactured by DSM) were mixed in an agate mortar (operation 1), and granulation was performed by dropping 3% by mass of purified water based on the total mass of the mixture (operation 2). Drying was performed in a constant temperature chamber at 60° C. for 1 hour to obtain granules (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（実施例５）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）、トラネキサム酸（Ｈｕｎａｎ　Ｄｏｎｇｔｉｎｇ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ社製）とマンニトール（Ｄ－マンニトール：物産フードサイエンス社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して３質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Example 5)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and mannitol (D-mannitol, manufactured by Bussan Food Science) were added to agate in the proportions shown in Table 1. After mixing in a mortar (operation 1), dropping 3% by mass of purified water based on the total mass of the mixture to perform granulation (operation 2), drying in a constant temperature chamber at 60 ° C. for 1 hour, Granules were obtained (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（実施例６）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）、トラネキサム酸（Ｈｕｎａｎ　Ｄｏｎｇｔｉｎｇ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ社製）とトウモロコシデンプン（松谷化学工業社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して５質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Example 6)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and corn starch (manufactured by Matsutani Chemical Industry Co., Ltd.) were mixed in an agate mortar at the proportions shown in Table 1. After (operation 1), granulation was performed by dropping 5% by mass of purified water based on the total mass of the mixture (operation 2), and then drying was performed in a constant temperature chamber at 60 ° C. for 1 hour to obtain granules. (Operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
（実施例７）
　表１の配合量の比率にてニコチン酸アミド（ＤＳＭ社製）、アスコルビン酸（ＤＳＭ社製）、トラネキサム酸（Ｈｕｎａｎ　Ｄｏｎｇｔｉｎｇ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ社製）と結晶セルロース（セオラスＰＨ－１０１：旭化成社製）をメノウ乳鉢で混合し（操作１）、混合物の合計質量に対して５質量％の精製水を滴下して造粒を行った後（操作２）、６０℃の恒温チャンバーで１時間乾燥を実施し、顆粒を得た（操作３）。操作１、操作２、操作３の各時点においてサンプルの色調を観察した。 (Example 7)
Nicotinic acid amide (manufactured by DSM), ascorbic acid (manufactured by DSM), tranexamic acid (manufactured by Hunan Dongting Pharmaceutical) and crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei) were added to agate in the proportions shown in Table 1. After mixing in a mortar (operation 1) and performing granulation by dropping 5% by mass of purified water based on the total mass of the mixture (operation 2), drying was performed in a constant temperature chamber at 60 ° C. for 1 hour, Granules were obtained (operation 3). The color tone of the sample was observed at each time point of Operation 1, Operation 2, and Operation 3.
　色調変化の評価は、操作１時点でのサンプルの色調と比較した操作３時点でのサンプルの色調の変化の程度として、－：変化なし、±：ごくわずかな変化（白から微黄白色）、＋：軽微な変化（白から淡黄白色又は微黄色）、＋＋：明確な変化（白から黄白色又は淡黄色）、＋＋＋：顕著な変化（白から黄）の５段階で行った。各例の評価結果は表１に示すとおりである。 The color tone change was evaluated as the degree of change in the color tone of the sample at the time of operation 3 compared to the color tone of the sample at time of operation 1, -: no change, ±: very slight change (from white to slightly yellowish white), It was performed in 5 stages: +: slight change (from white to pale yellow-white or slightly yellow), ++: clear change (from white to yellow-white or pale yellow), +++: marked change (from white to yellow). The evaluation results for each example are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　ニコチン酸アミドと、アスコルビン酸と、トラネキサム酸とを含有する固形組成物と、参考例としてのニコチン酸アミドとアスコルビン酸とを含む固形組成物の製剤例を以下の表に示す。
Figure JPOXMLDOC01-appb-T000002
  
Figure JPOXMLDOC01-appb-T000003
 Formulation examples of a solid composition containing nicotinic acid amide, ascorbic acid, and tranexamic acid, and a solid composition containing nicotinic acid amide and ascorbic acid as a reference example are shown in the table below.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003

Claims (9)

  1. 　ニコチン酸アミドと、アスコルビン酸と、トラネキサム酸とを含有する固形組成物。 A solid composition containing nicotinamide, ascorbic acid, and tranexamic acid.
  2. 　更にパントテン酸カルシウムを含む、請求項１に記載の固形組成物。 The solid composition according to claim 1, further comprising calcium pantothenate.
  3. 　更にピリドキシン塩酸塩を含む、請求項１又は２に記載の固形組成物。 The solid composition according to claim 1 or 2, further comprising pyridoxine hydrochloride.
  4. 　１日に投与される組成物あたり、ニコチン酸アミドを６ｍｇ～４００ｍｇ、アスコルビン酸を１０ｍｇ～３０００ｍｇ、トラネキサム酸を５０ｍｇ～３０００ｍｇ含有する、請求項１～３のいずれか一項に記載の固形組成物。 The solid composition according to any one of claims 1 to 3, containing 6 mg to 400 mg of nicotinic acid amide, 10 mg to 3000 mg of ascorbic acid, and 50 mg to 3000 mg of tranexamic acid, per composition administered per day. .
  5. 　組成物あたり、ニコチン酸アミドの含有量が１質量％～５質量％、アスコルビン酸の含有量が５質量％～３０質量％であり、トラネキサム酸の含有量が２０質量％～６０質量％である、請求項１～３のいずれか一項に記載の固形組成物。 Per composition, the content of nicotinic acid amide is 1% by mass to 5% by mass, the content of ascorbic acid is 5% to 30% by mass, and the content of tranexamic acid is 20% to 60% by mass. , the solid composition according to any one of claims 1 to 3.
  6. 　錠剤の形態である、請求項１～５のいずれか一項に記載の固形組成物。 The solid composition according to any one of claims 1 to 5, which is in the form of a tablet.
  7. 　錠剤が裸錠、素錠、糖衣錠、口腔内崩壊錠、フィルムコーティング錠又はチュアブル錠である、請求項１～６のいずれか一項に記載の固形組成物。 The solid composition according to any one of claims 1 to 6, wherein the tablet is a bare tablet, plain tablet, sugar-coated tablet, orally disintegrating tablet, film-coated tablet, or chewable tablet.
  8. 　更に、結晶セルロース、マンニトール及びトウモロコシデンプンから成る群から選択される１又は複数の成分を含む、請求項１～７のいずれか一項に記載の固形組成物。 The solid composition according to any one of claims 1 to 7, further comprising one or more components selected from the group consisting of crystalline cellulose, mannitol, and corn starch.
  9. 　ニコチン酸アミドと、アスコルビン酸と、トラネキサム酸との組み合わせが白色を呈する、請求項１～８のいずれか一項に記載の固形組成物。 The solid composition according to any one of claims 1 to 8, wherein the combination of nicotinic acid amide, ascorbic acid, and tranexamic acid exhibits a white color.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010016509A1 (en) * 2008-08-06 2010-02-11 第一三共ヘルスケア株式会社 Stable pharmaceutical composition containing tranexamic acid and ascorbic acid
WO2011049093A1 (en) * 2009-10-20 2011-04-28 第一三共ヘルスケア Film-coated tablet which is suppressed in discoloration and odor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010016509A1 (en) * 2008-08-06 2010-02-11 第一三共ヘルスケア株式会社 Stable pharmaceutical composition containing tranexamic acid and ascorbic acid
WO2011049093A1 (en) * 2009-10-20 2011-04-28 第一三共ヘルスケア Film-coated tablet which is suppressed in discoloration and odor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OKAZAKI, YUKO ET AL.: "Polarographic behavior of nicotinamide and ascorbic acid mixture", ANALYTICAL CHEMISTRY, vol. 17, no. 10, 1968, pages 1228 - 1233, XP009548874 *

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