Non-aqueous preparation having excellent stability

Abstract

Provided is a non-aqueous preparation which contains 5-ALA, a derivative thereof, or a salt of 5-ALA or a derivative thereof, and which has excellent stability of 5-ALA, a derivative thereof, or a salt of 5-ALA or a derivative thereof. This non-aqueous preparation contains: a compound represented by general formula (I) or a salt thereof # imgabs0 # [in general formula (I), R1 represents a hydrogen atom or an acyl group, and R2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group]; a sugar or sugar alcohol; and at least one selected from the group consisting of fatty acids, fatty acid esters, aliphatic hydrocarbons, and aliphatic alcohols, the fatty acids, fatty acid esters, aliphatic hydrocarbons, and aliphatic alcohols having a melting point of 30 DEG C to 100 DEG C.

Description

Technical Field

[0001] The present invention relates to a non-aqueous preparation having excellent stability. Background Art

[0002] Aminolevulinic acid (5-ALA), its derivatives and their salts are used as photodynamic diagnostic agents, which are used for visualization of non-muscle-invasive bladder cancer (muscle-infiltrative non-invasive bladder cancer) during transurethral bladder tumor resection, health foods, etc. In addition, Patent Documents 1 to 3 disclose preventive and / or therapeutic agents for side effects of anticancer agents containing ALA (Patent Document 1), hangover preventive and / or therapeutic agents containing ALA (Patent Document 2), cancer anemia improving agents and preventive agents containing ALA (Patent Document 3), etc.

[0003] Generally, useful compounds such as active ingredients in pharmaceuticals or nutrients in health foods are formulated with additives such as excipients, binders, disintegrants, and lubricants, and taken as tablets or granules that are easy to orally administer. In such preparations, it is extremely important to ensure the storage stability of the active ingredients and nutrients in the preparations from the perspectives of exerting the expected efficacy, avoiding unexpected side effects, and preventing the reduction of commercial value due to discoloration.

[0004] However, there is a problem that the decomposition of 5-ALA over time is induced by the form of the preparation and the type of additives in preparations containing 5-ALA. For example, Patent Document 4 describes that when developing preparations containing ALAs, if ALAs and iron compounds coexist in a preparation containing water, the stability of ALAs in the preparation is reduced, and the concentration of ALA decreases in a short period of time. Therefore, it is difficult to develop preparations containing 5-ALA, and a non-aqueous preparation with excellent stability of 5-ALA is not yet known. Prior art literature Patent Literature

[0005] Patent Document 1: International Publication No. 2013 / 054756 Patent Document 2: International Publication No. 2013 / 084816 Patent Document 3: International Publication No. 2013 / 054770 Patent Document 4: International Publication No. 2018 / 043240 Patent Document 5: Japanese Patent Application Publication No. 2014-189492 Non-patent literature

[0006] Non-patent document 1: Bunke, A., et al., Degradation Mechanism and Stability of 5-Aminolevulinic Acid, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 10, October 2000, pp. 1335-1341 Summary of the invention Technical Problems to be Solved by the Invention

[0007] An object of the present invention is to provide a non-aqueous preparation containing 5-ALA or a derivative thereof or a salt thereof, wherein the 5-ALA or a derivative thereof or a salt thereof has excellent stability. Technical means to solve technical problems

[0008] The present invention provides the following aspects [1]~[9].

[0009] [1] A non-aqueous preparation, wherein the non-aqueous preparation contains: A compound represented by the following general formula (I) or a salt thereof, [Chemistry 1] [Where R 1 represents a hydrogen atom or an acyl group, R 2 represents a hydrogen atom, a straight-chain or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group]; Sugar or sugar alcohols; At least one selected from the group consisting of fatty acids, fatty acid esters, aliphatic hydrocarbons and aliphatic alcohols, wherein the melting point of the fatty acids, fatty acid esters, aliphatic hydrocarbons and aliphatic alcohols is 30°C to 100°C. [2] The non-aqueous preparation according to [1], wherein The sugar or sugar alcohol is at least one selected from the group consisting of D-mannitol, erythritol, xylitol, sorbitol, lactose, trehalose, isomalt hydrate and maltitol. [3] The non-aqueous preparation according to [1] or [2], wherein The fatty acid esters are fatty acid esters of polyols. [4] The non-aqueous preparation according to [1] to [3], wherein The fatty acid ester is one or more selected from the group consisting of sucrose fatty acid esters and glycerol fatty acid esters. [5] The non-aqueous preparation according to any one of [1] to [4], wherein Fatty acids are saturated fatty acids with 10 to 24 carbon atoms. [6] The non-aqueous preparation according to any one of [1] to [5], wherein The content of the compound represented by the general formula (I) or a salt thereof is 5% by mass to 80% by mass based on the total amount of the non-aqueous preparation. [7] A product comprising the non-aqueous preparation according to any one of [1] to [6] and a package for storing the non-aqueous preparation in a dry state. [8] The product as described in [7], wherein The non-aqueous preparation has the shape of tablets, capsules, powders, granules, or fine granules. [9] The product as described in [7] or [8], wherein The non-aqueous preparation is dried by a desiccant, wherein the desiccant is one or more selected from the group consisting of silica gel, silica-alumina colloid (alophane, etc.), natural zeolite, synthetic zeolite, calcium chloride, quicklime (calcium oxide), bentonite (montmorillonite, montmorillonite, etc.), magnesium chloride, magnesium oxide, calcium sulfate, activated alumina, alumina, bauxite, anhydrous calcium sulfate, water-absorbing clay, and a mixture of these components and activated carbon. Beneficial Effects

[0010] According to the present invention, a non-aqueous preparation containing 5-ALA or a derivative thereof or a salt thereof, wherein 5-ALA or a derivative thereof or a salt thereof is excellent in stability, can be provided. DETAILED DESCRIPTION

[0011] Hereinafter, some embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0012] The non-aqueous preparation according to one embodiment contains a compound represented by the following general formula (I) or a salt thereof. [Chemistry 2] In the formula, R 1 represents a hydrogen atom or an acyl group, R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group.

[0013] Hereinafter, the compound represented by the general formula (I) or a salt thereof may be collectively referred to as a "5-ALA compound". The compound represented by the general formula (I) is composed of 5-ALA (5-aminolevulinic acid, 5-aminolevulinic acid) and a 5-ALA derivative (a compound represented by the general formula (I) other than 5-ALA). Therefore, the 5-ALA compound may also be 5-ALA or a 5-ALA derivative or a salt thereof.

[0014] First, 5-ALA (5-aminolevulinic acid) is described. 5-ALA is 1 and R 2 A compound consisting entirely of hydrogen atoms, a type of amino acid.

[0015] Next, the 5-ALA derivatives are described. The 5-ALA derivatives may be R 1 is a hydrogen atom, and R 2 is a straight-chain or branched alkyl, cycloalkyl, aryl or aralkyl group, and may also be R 1 is an acyl group, and R 2 It is a hydrogen atom, a straight-chain or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group.

[0016] As R 1 The acyl group in the formula (I) includes a linear or branched alkanoyl group having 1 to 8 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, benzylcarbonyl, etc.; and an aromatic acyl group having 7 to 14 carbon atoms, such as benzoyl, 1-naphthoyl, 2-naphthoyl, etc.

[0017] As R 2 The alkyl group in the above-mentioned group includes a linear or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl.

[0018] As R 2 The cycloalkyl group in the above-mentioned group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 1-cyclohexenyl and other saturated or partially unsaturated cycloalkyl groups having 3 to 8 carbon atoms.

[0019] As R 2 The aryl group in the formula (a) includes aryl groups having 6 to 14 carbon atoms such as phenyl, naphthyl, anthracenyl and phenanthrenyl.

[0020] As R 2 The aralkyl group in the aryl group may be exemplified in the same manner as the above aryl group, and the alkyl group may be exemplified in the same manner as the above alkyl group, and specifically, aralkyl groups having 7 to 15 carbon atoms such as benzyl, phenylethyl, phenylpropyl, phenylbutyl, diphenylmethyl, triphenylmethyl, naphthylmethyl and naphthylethyl may be mentioned.

[0021] As 5-ALA derivatives, R 1 is a compound of formyl, acetyl, propionyl, or butyryl. In addition, R 2A compound in which R is methyl, ethyl, propyl, butyl, pentyl or the like. As the 5-ALA derivative, preferably, the above R 1 With R 2 The combination of is a compound of a combination of a formyl group and a methyl group, an acetyl group and a methyl group, a propionyl group and a methyl group, a butyryl group and a methyl group, a formyl group and an ethyl group, an acetyl group and an ethyl group, a propionyl group and an ethyl group, and a butyryl group and an ethyl group.

[0022] The 5-ALA derivative may be a prodrug of 5-ALA. A prodrug of 5-ALA is a compound that generates 5-ALA by metabolism in the body. Examples of prodrugs of 5-aminolevulinic acid include R 1 is a hydrogen atom, R 2 The ester of 5-aminolevulinic acid is a linear or branched C1-C5 alkyl group, wherein the ester of 5-aminolevulinic acid is methyl 5-aminolevulinic acid, ethyl 5-aminolevulinic acid, propyl 5-aminolevulinic acid, butyl 5-aminolevulinic acid, pentyl 5-aminolevulinic acid, and the like.

[0023] Next, the salt of 5-ALA or a 5-ALA derivative is described. The salt of 5-ALA or a 5-ALA derivative can be any pharmacologically acceptable salt. As salts, for example, acid addition salts, metal salts, ammonium salts, organic amine addition salts, etc. can be cited. As examples of acid addition salts, inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, phosphates, nitrates, and sulfates can be cited; and organic acid addition salts such as formate, acetate, propionate, toluenesulfonate, succinate, oxalate, lactate, tartrate, glycolate, methanesulfonate, butyrate, valerate, citrate, fumarate, maleate, and malate can be cited. As examples of metal salts, alkali metal salts such as lithium salts, sodium salts, and potassium salts can be cited; alkaline earth metal salts such as magnesium salts and calcium salts; and aluminum salts, zinc salts, etc. As examples of ammonium salts, alkylammonium salts such as ammonium salts and tetramethylammonium salts can be cited. Examples of organic amine addition salts include triethylamine salts, piperidine salts, morpholine salts, and toluidine salts.

[0024] The 5-ALA compound is preferably at least one selected from the group consisting of 5-ALA and 5-ALA esters (5-ALA methyl ester, 5-ALA ethyl ester, 5-ALA propyl ester, 5-ALA butyl ester, 5-ALA pentyl ester, etc.), and their hydrochlorides, phosphates, and sulfates. The 5-ALA compound is more preferably 5-ALA hydrochloride and / or 5-ALA phosphate.

[0025] Based on the total amount of the non-aqueous preparation, the content of the 5-ALA compound may be 5% by mass or more, 20% by mass or more, or 40% by mass or more, and may be 80% by mass or less, 70% by mass or less, or 65% by mass or less. Based on the total amount of the non-aqueous preparation, the content of the 5-ALA compound is preferably 5% by mass to 80% by mass, more preferably 20% by mass to 70% by mass, and particularly preferably 40% by mass to 65% by mass.

[0026] In addition to the above-mentioned 5-ALA compound, the non-aqueous preparation of one embodiment may contain a sugar or a sugar alcohol. The sugar or sugar alcohol may be one or more selected from the group consisting of monosaccharides, disaccharides, oligosaccharides (sugars with a molecular weight of 300 to 3000, but excluding those equivalent to disaccharides), and sugar alcohols thereof.

[0027] Examples of monosaccharides include glucose and fructose, and examples of sugar alcohols of monosaccharides (also referred to as “monosaccharide alcohols”) include D-mannitol, erythritol, xylitol, and sorbitol.

[0028] Examples of disaccharides include lactose (e.g., lactose hydrate, anhydrous lactose, spray-dried lactose, fluidized bed granulated lactose, and isomerized lactose), sucrose, trehalose, and maltose, and examples of disaccharide alcohols (also referred to as "disaccharide alcohols") include isomalt hydrate, lactitol (reduced lactose), and maltitol. Disaccharides may be contained as refined white sugar, white sugar, and the like. In addition, refined white sugar and white sugar contain sucrose. In addition, disaccharide alcohols may be contained as reduced maltose syrup (reduced maltose syrup), and the like. In addition, reduced maltose syrup contains monosaccharide alcohols, disaccharide alcohols (maltitol), and oligosaccharide alcohols (also referred to as "oligosaccharide alcohols (oligosaccharide syrups)"). When the non-aqueous preparation contains reduced maltose syrup, it can be said that the reduced maltose syrup contains monosaccharide alcohol and oligosaccharide alcohol in addition to disaccharide alcohol.

[0029] Oligosaccharides are sometimes referred to as oligosaccharides. Examples of oligosaccharides include oligofructose and the like. Oligosaccharides may be sugars in which three or more and ten or less monosaccharides are linked.

[0030] The non-aqueous preparation may contain only one of these sugars or sugar alcohols, or may contain two or more. Sugar or sugar alcohol is preferably at least one selected from the group consisting of monosaccharides, disaccharides, oligosaccharides and their sugar alcohols, more preferably at least one selected from the group consisting of monosaccharide sugar alcohols, disaccharide sugar alcohols and oligosaccharide sugar alcohols. In addition, sugar or sugar alcohol may be at least one selected from the group consisting of D-mannitol, erythritol, xylitol, sorbitol, lactose, trehalose, isomalt hydrate, and maltitol.

[0031] Based on the total amount of the non-aqueous preparation, the content of sugar or sugar alcohol can be 10% by mass or more, 20% by mass or more, 30% by mass or more, or 33% by mass or more, and can be 95% by mass or less, 80% by mass or less, 70% by mass or less, or 60% by mass or less. Based on the total amount of the non-aqueous preparation, the content of sugar or sugar alcohol can be 10% by mass to 95% by mass, preferably 20% by mass to 80% by mass, more preferably 30% by mass to 70% by mass, and further preferably 33% by mass to 60% by mass.

[0032] In addition to the above-mentioned 5-ALA compound, the non-aqueous preparation of one embodiment may contain at least one selected from the group consisting of fatty acids, fatty acid esters, aliphatic hydrocarbons and aliphatic alcohols, wherein the melting point of the fatty acids, fatty acid esters, aliphatic hydrocarbons and aliphatic alcohols is 30°C to 100°C (hereinafter also referred to as "low melting point compounds"). Here, the melting point can be measured by the method described in "The Eighteenth Revised Japanese Pharmacopoeia General Test Methods 2. Physical Test Methods 2.60 Melting Point Determination Method (The Eighteenth Revised Japanese Pharmacopoeia General Test Methods 2. Physical Test Methods 2.60 Melting Point Determination Method)". The low melting point compound may be water-insoluble or poorly water-soluble.

[0033] The fatty acid of the low melting point compound is a fatty acid having a melting point of 30°C to 100°C. The melting point of the fatty acid may be above 40°C or above 50°C, may be below 90°C or below 80°C. The fatty acid is preferably a saturated fatty acid having 10 to 24 carbon atoms, and the carbon number of the saturated fatty acid may be 12 to 24 or 14 to 18. Examples of saturated fatty acids having 10 to 24 carbon atoms include decanoic acid (decanoic acid), dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), heptadecanoic acid (pearl acid), octadecanoic acid (stearic acid), eicosanoic acid (arachidic acid), docosanoic acid (behenic acid) and lignoceric acid (lignoceric acid). The fatty acid is particularly preferably stearic acid. The fatty acid may be contained as Japan wax (wood wax).

[0034] The fatty acid ester of the low melting point compound is a fatty acid ester having a melting point of 30°C to 100°C. The melting point of the fatty acid ester may be above 40°C or above 50°C, below 90°C or below 80°C. The fatty acid ester may be, for example, a fatty acid ester of a polyol. Examples of fatty acid esters of polyols include sucrose fatty acid esters, glycerol fatty acid esters, propylene glycol fatty acid esters, and sorbitan fatty acid esters. The fatty acid ester of a polyol is particularly preferably a sucrose fatty acid ester or a glycerol fatty acid ester or a mixture thereof.

[0035] Sucrose fatty acid ester is an ester of a hydrophilic group, i.e. sucrose, and a lipophilic group, i.e. a fatty acid from a plant oil, and is also called a sugar ester. Sucrose (シュガーエステル) is also called sucrose, and is a sugar formed by two monosaccharides, glucose and fructose, and has eight hydroxyl groups. Sucrose fatty acid ester is an ester in which one or more of the hydroxyl groups of sucrose are replaced by fatty acids. Sucrose fatty acid ester may be a monoester in which one of the hydroxyl groups of sucrose is replaced by fatty acids, or an ester in which two or more and eight or less of the hydroxyl groups are replaced by fatty acids (diester, triester, octaester, etc.), or a mixture thereof.

[0036] The fatty acid constituting the sucrose fatty acid ester may be a saturated fatty acid or an unsaturated fatty acid. In addition, it may be a straight chain or a branched chain. The fatty acid constituting the sucrose fatty acid ester may be a fatty acid having 10 to 24 carbon atoms, preferably a fatty acid having 12 to 22 carbon atoms or 18 to 22 carbon atoms. Examples of fatty acids having 18 to 22 carbon atoms include octadecanoic acid (stearic acid), eicosanoic acid (arachidic acid), docosanoic acid (behenic acid), and erucic acid.

[0037] Glycerol fatty acid ester is an ester of glycerol and fatty acid. Glycerol is a trivalent sugar alcohol having three hydroxyl groups. Glycerol fatty acid ester is an ester in which one or more of the hydroxyl groups of glycerol are replaced by fatty acids. Glycerol fatty acid ester is preferably a monoester in which one of the hydroxyl groups of glycerol is replaced by fatty acids. Glycerol fatty acid ester can be contained as fats and oils. Examples of fats and oils include vegetable fats such as cocoa butter, and hydrogenated vegetable oils such as hydrogenated rapeseed oil and hydrogenated castor oil. Hydrogenated vegetable oils are vegetable fats and oils that are liquid at room temperature because they contain a large amount of unsaturated fatty acids with a low melting point, and the proportion of saturated fatty acids with a higher melting point is increased, thereby solidifying at room temperature.

[0038] The aliphatic hydrocarbon of the low melting point compound is an aliphatic hydrocarbon having a melting point of 30°C to 100°C. The melting point of the aliphatic hydrocarbon can be 40°C or higher, or 50°C or higher, and can be 90°C or lower, or 80°C or lower. The aliphatic hydrocarbon can be a saturated aliphatic hydrocarbon. The aliphatic hydrocarbon can be contained as a mineral oil. Mineral oil is a hydrocarbon refined from petroleum and minerals. As an example of the mineral oil, paraffin wax (petroleum), microcrystalline wax (petroleum), and ceresin wax (ceresine, earth wax) can be cited.

[0039] The aliphatic alcohol of the low melting point compound is an aliphatic alcohol having a melting point of 30°C to 100°C. The melting point of the aliphatic alcohol can be 40°C or higher, or 50°C or higher, and can be 90°C or lower, or 80°C or lower. The aliphatic alcohol can be a saturated aliphatic alcohol or an unsaturated aliphatic alcohol. In addition, the aliphatic alcohol can be linear or branched. The number of carbon atoms of the aliphatic alcohol can be 14 to 24 or 15 to 20. As an example of the aliphatic alcohol, cetyl alcohol and stearyl alcohol can be cited.

[0040] The low melting point compound can be contained as a vegetable or animal wax. As an example of the vegetable wax, carnauba wax (carnauba palm wax) can be cited. As an example of the animal wax, beeswax can be cited.

[0041] The low melting point compound can be at least one selected from the group consisting of fatty acid esters of polyhydric alcohols and fatty acids, wherein the melting points of the fatty acid esters of polyhydric alcohols and the fatty acids are 30°C to 100°C.

[0042] Based on the total amount of the non-aqueous preparation, the low melting point compound can be 0.1% by mass or more, 0.5% by mass or more, or 1% by mass or more, and can be 20% by mass or less, 10% by mass or less, or 5% by mass or less. Based on the total amount of the non-aqueous preparation, the content of the low melting point compound can be 0.1% by mass to 20% by mass, preferably 0.5% by mass to 10% by mass, and more preferably 1% by mass to 5% by mass.

[0043] The non-aqueous preparation can contain a binder. As an example of the binder, hydroxyalkyl celluloses such as crystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose; and gum arabic can be cited. The non-aqueous preparation can contain one of these binders or two or more thereof. Based on the total amount of the non-aqueous preparation, the content of the binder can be 0.1% by mass or more, 0.5% by mass or more, or 1% by mass or more, and can be 20% by mass or less, 10% by mass or less, or 5% by mass or less. The content of the binder can be 0.1% by mass to 20% by mass, preferably 0.5% by mass to 10% by mass, and more preferably 1% by mass to 5% by mass.

[0044] As long as the effect of the present invention is not affected, the non-aqueous preparation may further contain other additives commonly used in the field of preparations. Examples of other additives include excipients, disintegrants, lubricants, buffers, glidants, antioxidants, stabilizers, surfactants, sweeteners, flavoring agents, fragrances, colorants, and film coating agents. The non-aqueous preparation may contain one or more of these additives.

[0045] Examples of the excipient include magnesium aluminum metasilicate, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, calcium silicate, calcium lactate, precipitated calcium carbonate, calcium silicate, and calcium lactate.

[0046] Examples of the disintegrant include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and sodium starch glycolate.

[0047] Examples of the lubricant include stearates such as magnesium stearate and calcium stearate. The melting point of stearates is generally 100° C. or higher.

[0048] Examples of the buffer include carboxylic acids (succinic acid, fumaric acid, citric acid, tartaric acid, etc.), amino acids (glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine, etc.), organic acids such as ascorbic acid (excluding fatty acids having a melting point of 30°C to 100°C), and salts thereof; inorganic acids such as phosphoric acid and boric acid, and salts thereof; metal hydroxides such as magnesium hydroxide; metal oxides such as magnesium oxide and zinc oxide, and the like.

[0049] Examples of the glidant include anhydrous calcium silicate, hydrated silicon dioxide, stearic acid, magnesium stearate, calcium stearate, and talc.

[0050] Examples of the antioxidant include citric acid, sodium nitrite, ascorbic acid, L-ascorbyl stearate, sodium hydrogen nitrite, sodium nitrite, α-thioglycerol, sodium edetate, isoascorbic acid, cysteine ​​hydrochloride, dried sodium sulfite, potassium dichloroisocyanurate, soybean lecithin, sodium thioglycolate, sodium thiomalate, natural vitamin E, tocopherol, d-δ-tocopherol, tocopherol acetate, concentrated mixed tocopherols, antioxidants, and the like. Ascorbyl palmitate, sodium metabisulfite, butylhydroxyanisole, 1,3-butanediol, benzotriazole, pentaerythritol-tetrakis [3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate] (pentaerythritol-tetrakis [3-(3,5-di-t-butyl-4-hydroxyphenyl) propionate]), 2-mercaptobenzimidazole, propyl gallate, butylated hydroxytoluene, etc.

[0051] Examples of the stabilizer include citric acid and salts thereof (citric acid, citric acid hydrate, calcium citrate, sodium citrate hydrate, sodium dihydrogen citrate, disodium citrate, and the like).

[0052] Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil), and the like.

[0053] Examples of the sweetener include saccharin sodium, glycyrrhizic acid, aspartame, stevia, and thaumatin.

[0054] Examples of the flavoring agent include citric acid, tartaric acid, malic acid, and the like.

[0055] Examples of the flavor include lemon, lemon-lime, orange, and menthol.

[0056] Examples of the coloring agent include ferric oxide, yellow ferric oxide, edible tar pigment and its aluminum lake, riboflavin, and sodium copper chlorophyllin.

[0057] Examples of the film coating agent include hypromellose, polyvinyl alcohol, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, ammonioalkyl methacrylate copolymers, and ethyl cellulose.

[0058] The non-aqueous preparation may contain one other additive, or may contain two or more additives in combination. They may be added in appropriate amounts. The content of other additives may be appropriately adjusted within the range that does not affect the effect of the present invention, for example, based on the total amount of the non-aqueous preparation, it may be 0.5% by mass or less.

[0059] The non-aqueous preparation may contain a certain amount of water. Specifically, based on the total amount of the non-aqueous preparation, the water content of the non-aqueous preparation is 20% by mass or less, preferably 7% by mass or less, more preferably 3% by mass or less, and further preferably 1% by mass or less.

[0060] The non-aqueous preparation may be in the form of, for example, fine granules, granules, tablets (e.g., plain tablets, film-coated tablets, chewable tablets, orally disintegrating tablets), capsules, powders, or dry syrups. The non-aqueous preparation is preferably a tablet. In addition, the non-aqueous preparation may be taken with water when taken. The non-aqueous preparation may be taken directly with water, or may be taken after being added to water to form a solution or suspension.

[0061] The non-aqueous preparation of the present invention may be a formulation further containing other active ingredients different from the 5-ALA compound. In this case, the dosage form of the non-aqueous preparation may be a regular tablet, a laminated tablet, a core tablet (core tablet), a tablet or granule containing coated particles, a coated tablet containing the main drug in the film layer, etc. The laminated tablet may be a double-layer tablet consisting of the first layer and the second layer, or a multi-layer tablet (three-layer tablet, four-layer tablet, five-layer tablet, etc.) having one or more intermediate layers disposed between the first layer and the second layer on the basis of the first layer and the second layer. The core tablet may be a core tablet having only an inner core and an outer layer, or a core tablet having an inner core, an outer layer, and an intermediate layer disposed between the inner core and the outer layer. In these formulations, the 5-ALA compound, sugar or sugar alcohol, and at least one selected from the group consisting of fatty acid esters of polyols and fatty acids having a melting point of 30°C or more may be contained only in a part of the layer, the inner core, or the outer shell.

[0062] The non-aqueous preparation of one embodiment can be produced, for example, by a method including a pulverizing step, a mixing step, a granulating step, a drying step, a molding (tabletting) step, a film coating step, a crystallization step, etc. The method for producing the non-aqueous preparation may be a method including some of these steps or a method including all of them.

[0063] In the pulverizing step, the raw materials of the non-aqueous preparation are pulverized. The raw materials of the non-aqueous preparation include at least one of a 5-ALA compound, a sugar or a sugar alcohol, a low melting point compound, and one or more selected from the group consisting of other additives added as needed. There is no particular limitation on the pulverizing device and means. Examples of the pulverizing device include a hammer mill, a ball mill, a jet mill, a colloid mill, and the like. The pulverizing conditions can be appropriately selected.

[0064] In the mixing step, the raw materials are mixed. The mixing step is not particularly limited to any device or means as long as the components can be uniformly mixed, and the mixing step may be performed after the pulverizing step or simultaneously with the pulverizing step.

[0065] In the granulation process, the raw material is granulated. There is no particular limitation on the granulation device and means. The granulation process may be a wet granulation process using a solvent such as water or ethanol, or may be a dry granulation process. In the wet granulation process, ethanol is preferably used as a solvent, and 90% or more ethanol is particularly preferably used. As a granulation method for wet granulation, for example, a high-speed stirring granulation method, a crushing (crushing) granulation method, a fluidized bed granulation method, an extrusion granulation method, a tumbling granulation method, a spray drying granulation method, etc. may be cited. In the granulation process, a high-speed stirring granulation method is preferably used.

[0066] In the drying process, for example, the granulated material obtained in the granulation process is dried. As the drying device and means, commonly used devices and means can be used. In the drying process, it is preferred to dry under reduced pressure and / or in an environment below 60° C. As the drying device, for example, a ventilated dryer, a reduced pressure dryer, a vacuum dryer, a fluidized bed granulation dryer, etc. can be cited. The drying process can include a process of sieving (sizing) the granulated material using a sieve, a coal mill, etc. after drying.

[0067] In the molding (tabletting) process, for example, the raw materials after the mixing process or the granulated material obtained by the granulation process are molded. In this case, a lubricant can be added to the granulated material before molding. There are no particular restrictions on the molding device and means. In the molding process, for example, compression molding is performed using tableting devices such as a rotary tablet press and an oil press. The tableting conditions can be appropriately adjusted. The hardness of the tablet obtained by the molding process can be, for example, 40N to 200N as long as it is not damaged during the manufacturing and circulation process.

[0068] In the film coating step, for example, film coating is applied to the surface of the tablet obtained by the molding step. Examples of the film coating method include pan coating, immersion coating, and the like. In the film coating step, for example, one or more of the above-mentioned film coating agents may be added to the tablet. The coating rate (content of the film coating agent) of the non-aqueous preparation after the film coating step may be, for example, 1% to 10% by mass based on the total amount of the non-aqueous preparation. For the film coating step, the tablet may be dried during and after the film coating.

[0069] In the crystallization process, the crystallization of the 5-ALA compound is promoted. When making a preparation, the proportion of crystals of the 5-ALA compound is sometimes reduced. In this case, it is preferred to implement this crystallization process. As a method for promoting crystallization, for example, microwave, low-frequency and other radio wave irradiation treatments, thermal electron irradiation treatments, etc. can be cited. For radio wave irradiation treatment, for example, 10MHz~25GHz radio waves can be irradiated. In this case, the treatment time can be appropriately adjusted according to the initial crystal ratio, the type of additive, etc., for example, it can be 10 seconds to 60 minutes. For radio wave irradiation treatment, 10kHz~600kHz radio waves can also be irradiated. In this case, the treatment time can be appropriately adjusted according to the initial crystal ratio, the type of additive, etc., for example, it can be 10 seconds to 24 hours. Radio wave irradiation can be performed continuously or intermittently.

[0070] The non-aqueous preparation described above contains at least one of a 5-ALA compound, a sugar or a sugar alcohol, and a low melting point compound, so the 5-ALA compound has excellent stability. The present inventors have found that by including at least one of a 5-ALA compound, a sugar or a sugar alcohol, and / or a low melting point compound in a non-aqueous preparation, the 5-ALA compound in the non-aqueous preparation is stabilized. Therefore, the non-aqueous preparation described above can also be referred to as a stabilized non-aqueous preparation. In addition, one embodiment of the present invention is also a method for stabilizing a non-aqueous preparation, the method comprising including at least one of a 5-ALA compound, a sugar or a sugar alcohol, and / or a low melting point compound in a non-aqueous preparation.

[0071] The non-aqueous preparation may be contained in a package. Another embodiment of the present invention is a product comprising a non-aqueous preparation and a package containing the non-aqueous preparation in a dry state.

[0072] The package can be a package that can inhibit the substantial intrusion of moisture from the outside of the package during normal use, transportation or storage, including "containers", such as the "airtight container" and "sealed container" defined in the 18th revised Japanese Pharmacopoeia Reference Information G0. Basic matters related to the quality of pharmaceutical products (The 18th revised Japanese Pharmacopoeia Reference Information G0. Basic matters related to the quality of pharmaceutical products). The shape of the package can be a fixed container such as a bottle (ビン) or a bottle (ボトル), or it can be an indefinite shape such as an SP (strip packaging) package, a PTP (Press Through Packaging) package, a bag-shaped package (such as a pillow-shaped package, and a stick package). In the product, these packages can be used alone or in combination of two or more. For example, in the product, a non-aqueous preparation can be contained in a primary package (such as a PTP package), and the primary package containing the non-aqueous preparation can be further contained in a secondary package (such as a pillow-shaped package).

[0073] From the viewpoint of protecting the product from the influence of moisture, the material of the package is preferably a material that is substantially impermeable to moisture or has a moisture-proof function. Here, substantially impermeable to moisture means that the amount of moisture that affects the non-aqueous preparation contained in the package is not permeable. As the material of the package, the material used for packaging of contents that are intolerant to moisture in the fields of pharmaceuticals and foods can be appropriately used.

[0074] As the material of a bottle, examples include glass; resins such as polyester, polypropylene, polyethylene (including low-density polyethylene (LDPE) and high-density polyethylene (HDPE)), polycarbonate, and polystyrene; those containing a desiccant in such resins (resins containing a desiccant); metals such as aluminum, etc. In addition, the bottle may have a stopper or a cap. As the material of the stopper or the cap, examples include plastics such as polyester, polyethylene, polycarbonate, polystyrene, and polypropylene; metals such as aluminum, etc. A bottle made of plastic掺有干燥剂的塑料 is also called a bottle with a moisture absorption function (a bottle with a moisture absorption function).

[0075] As the material of SP packaging, PTP packaging, and bag-like packaging (such as pillow packaging and stick packaging), examples include biaxially stretched polypropylene (OPP), biaxially stretched polyester (PET), glucose-modified PET (PET-G), biaxially stretched nylon (ONy, PA), polyethylene (including low-density polyethylene (LDPE) and linear low-density polyethylene (L-LDPE)), ethylene-vinyl acetate copolymer (EVA), unstretched polypropylene (CPP, IPP), ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially stretched polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic olefin copolymer (COC), unstretched nylon (CNy), polycarbonate (PC), polystyrene (PS), rigid polyvinyl chloride (VSC), etc.; those containing a desiccant in such resins (resins containing a desiccant); metals such as aluminum (Al); cellophane; paper, etc.

[0076] The material of the packaging can be used alone or in combination of two or more. The packaging can be, for example, a laminate, which laminates two or more layers made of different materials. As a laminate with a two-layer structure, examples include laminates of the above-mentioned metal, cellophane, or paper and the above-mentioned resin or resin containing a desiccant. The laminate can have a moisture-proof layer that inhibits moisture penetration as an outer layer or an intermediate layer, or can have an absorption layer with a drying function as an inner layer or an intermediate layer. As an example of the material constituting the absorption layer with a drying function, a resin containing a desiccant can be cited.

[0077] In a product of one embodiment, the packaging houses the non-aqueous preparation in a dry state. "Housing in a dry state" here means a state in which the non-aqueous preparation is kept in a dry state by the packaging, including cases where the packaging itself is made of a non-moisture-permeable and non-water-permeable material, and cases where the non-aqueous preparation is packaged together with a desiccant. As those where the packaging itself is non-moisture-permeable and non-water-permeable, in addition to the packaging made of metal, a laminate can also be cited, which is a laminate of metal, cellophane, or paper and a resin containing a desiccant.

[0078] The desiccant may be a desiccant that can be generally used for preparations. The desiccant may be one or more selected from the group consisting of silica gel, silica-alumina colloid (alphite, etc.), natural zeolite, synthetic zeolite, calcium chloride, quicklime (calcium oxide), bentonite (montmorillonite, montmorillonite, etc.), magnesium chloride, magnesium oxide, calcium sulfate, activated alumina, alumina, bauxite, anhydrous calcium sulfate, water-absorbing clay, and a mixture of these components and activated carbon. The desiccant is preferably one or more selected from the group consisting of silica gel, silica-alumina colloid (alphite, etc.), synthetic zeolite, and calcium chloride. From the viewpoint of suppressing the interaction between the 5-ALA compound and water, synthetic zeolite is more preferably used.

[0079] The shape of the desiccant may be, for example, a sheet type such as a plate or bag, or a cylindrical (tablet) shape. In addition, the desiccant may be used as a film integrated with the resin.

[0080] For example, the product can be manufactured by a method including a packaging process after manufacturing the non-aqueous preparation, and the packaging process is a packaging process in which the non-aqueous preparation and, if necessary, the desiccant are contained in the package. In the packaging process, devices and means corresponding to the non-aqueous preparation and the form of the package can be appropriately used. The method of containing the non-aqueous preparation and the desiccant as needed in the package can be, for example, a method of arranging the non-aqueous preparation and the desiccant as needed in the package, or a method of arranging the non-aqueous preparation in a package with a lid (e.g., a bottle (ビン)) and attaching the desiccant (preferably a cylindrical (tablet-shaped) desiccant) to the lid. In addition, it can also be a method in which the non-aqueous preparation is arranged in a primary package (e.g., a PTP package), and the primary package containing the non-aqueous preparation and the desiccant (e.g., a bag-shaped or sheet-shaped desiccant) are further arranged in a secondary package (e.g., a pillow-shaped package). Example

[0081] The present invention will be further specifically described below with reference to formulation examples, but the present invention is not limited to these formulation examples.

[0082] Preparation Examples 1 to 40 used the following ingredients. 5-ALA hydrochloride: 5-aminolevulinic acid hydrochloride (ingredient A) A-1: Isomalt hydrate (manufactured by BENEO-Palatinit) A-2: D-mannitol (Merck) A-3: Anhydrous lactose (manufactured by DFE Fiamma Co., Ltd.) A-4: Lactose hydrate (manufactured by Froton Industrial Co., Ltd.) A-5: Sorbitol (Merck) A-6: Trehalose (manufactured by Hayashihara Co., Ltd.) A-7: Reduced maltose syrup (manufactured by Mitsubishi Commercial Corporation) a-1: Crystalline cellulose (manufactured by Asahi Kasei Corporation) a-2: Corn starch (manufactured by Japan Cosmetics Co., Ltd.) a-3: Low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) (ingredient B) B-1: Sucrose fatty acid ester (Mitsubishi Chemical Co., Ltd., melting point 58°C to 64°C) B-2: Glyceryl fatty acid ester (manufactured by Riken Biomin Co., Ltd., melting point 68°C to 73°C) B-3: Stearic acid (manufactured by NOF Corporation, melting point 56°C~72°C) B-4: Hydrogenated rapeseed oil ("Rapura (registered trademark)" manufactured by Froton Industry Co., Ltd., 69℃~86℃) b-1: Magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) b-2: Calcium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) b-3: Sodium stearyl fumarate (manufactured by DuPont) (Ingredient C) C-1: Hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) C-2: Hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.)

[0083] [Manufacture of non-aqueous preparations and products] <Preparation Examples 1 to 10, Preparation Examples 14 to 23, Preparation Examples 27 to 40> After the amount of aminolevulinic acid hydrochloride (5-ALA hydrochloride) shown in Tables 2 to 5 and the type and amount of component A shown in Tables 2 to 5 were put into a plastic bag and mixed, the type and amount of component B shown in Tables 2 to 5 were added and further mixed, and the tablets (non-aqueous preparations) of Formulation Examples 1 to 10, Formulation Examples 14 to 23, and Formulation Examples 27 to 40 were formed by using an automatic tablet tester (Auto-Tab-200TR model, manufactured by Ichibashi Seiki Co., Ltd.). The tablets were placed in a polyethylene bag (PE bag), and for the tablets of Formulation Examples 1 to 10 and Formulation Examples 27 to 33, only the PE bag containing the tablets was placed in an aluminum bag (aluminum bag), and for the tablets of Formulation Examples 14 to 23 and Formulation Examples 34 to 40, the PE bag containing the tablets and the desiccant were placed in an aluminum bag (aluminum bag), thereby manufacturing the products. Preparation Examples 27 to 40 are comparative examples.

[0084] <Preparation Example 11, Preparation Example 24> The amounts of 5-ALA hydrochloride, component A and component C shown in Tables 2 and 3 were put into a vertical granulator (FM-VG-10, Pawleck), and 99.5% ethanol was added for stirring and granulation. After that, the granules were sized by a power mill (Pawmill) (D-80 type, Dalton), and dried at 50°C by a constant temperature air dryer (WFO-1020 type, Tokyo Rikkō Kikai). After drying, the granules were sized by a sieve with a mesh size of 850 μm to obtain granulated particles. In addition to using the granulated particles prepared by the above method, tablets (non-aqueous preparations) of Preparation Examples 11 and 24 were prepared by the same method as Preparation Examples 1 to 10 and Preparation Examples 14 to 23, and the obtained tablets were stored in PE bags. For the tablets of Preparation Example 11, only the PE bag containing the tablets was placed in an aluminum bag, and for the tablets of Preparation Example 24, the PE bag containing the tablets and the desiccant were placed in an aluminum bag to produce products.

[0085] <Preparation Example 12, Preparation Example 13, Preparation Example 25, Preparation Example 26> The 5-ALA hydrochloride, component A and component C in the amounts shown in Tables 2 and 3 were put into a vertical granulator (FM-VG-10, Puleck), and 99.5% ethanol was added for stirring and granulation. After that, the granules were granulated by a power mill (D-80 type, Dulton) and dried at 50°C by a constant temperature air dryer (WFO-1020 type, Tokyo Rikkō Kikai). After drying, the granules were granulated by a sieve with a mesh of 850 μm to obtain granulated particles. The granulated particles prepared by the above method and the component B of the type and amount shown in Tables 2 and 3 were put into a plastic bag for mixing, and then formed by a circular tablet mold with a diameter of 5 mm using an automatic tablet tester (Auto-Tab-200TR type, manufactured by Ichibashi Seiki Co., Ltd.), thereby preparing tablets (non-aqueous preparations) of Preparation Example 12, Preparation Example 13, Preparation Example 25, and Preparation Example 26. The obtained tablets were placed in a PE bag. For the tablets of Preparation Examples 12 and 13, the PE bag containing the tablets was placed in an aluminum bag. For the tablets of Preparation Examples 25 and 26, the PE bag containing the tablets and the desiccant were placed in an aluminum bag, thereby manufacturing products.

[0086] [Time-dependent stability test] The non-aqueous preparation of each preparation example was stored as a product at 40°C and 75% RH for 2 months, and the content of the compound represented by the following formula (II) (also referred to as compound (II)), which is a representative analog of 5-ALA, after storage was measured by liquid chromatography. It is known that the decomposition pathway of 5-ALA (see Non-Patent Document 1) and the generation of compound (II) from 5-ALA increase as an impurity (see Patent Document 5). [Chemistry 3] The conditions for liquid chromatography were as follows. Detector: UV absorption spectrophotometer (measurement wavelength 260nm) Column: A stainless steel tube having an inner diameter of 3.0 mm and a length of 15.0 mm was filled with 3 μm reverse phase and strong cation exchange silica gel for liquid chromatography. Column temperature: Constant temperature around 40°C Mobile phase A: 0.3% formic acid in water Mobile phase B: 0.2 M ammonium formate solution (water / acetonitrile (volume ratio) = 700 / 300) Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed according to Table 1 below to control the concentration gradient. [Table 1] Flow rate: 0.4mL / min Injection volume: 20 μL Sample cooler temperature: 5°C

[0087] The peak area (ATI) of the compound represented by the general formula (I) and the peak area (ATII) of the compound represented by the formula (II) 25 minutes after the sample solution was injected were determined, and the amount of the compound represented by the formula (II) was calculated by the following formula. The results are shown in Tables 2 to 5. Content of compound (II) (%) = (ATII / ATI) × 100 / 165 In addition, in the above formula, 165 is the sensitivity coefficient.

[0088] [Table 2]

[0089] [Table 3]

[0090] [Table 4]

[0091] [Table 5]

Claims

1. A non-aqueous preparation, wherein The non-aqueous formulation contains: A compound represented by the following general formula (I) or a salt thereof, [Chemistry 1] In the formula, R 1 represents a hydrogen atom or an acyl group, R 2 represents a hydrogen atom, a straight-chain or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group; Sugar or sugar alcohols; At least one selected from the group consisting of fatty acids, fatty acid esters, aliphatic hydrocarbons and aliphatic alcohols, wherein the melting point of the fatty acids, fatty acid esters, aliphatic hydrocarbons and aliphatic alcohols is 30°C to 100°C.

2. The non-aqueous preparation according to claim 1, wherein The sugar or sugar alcohol is at least one selected from the group consisting of D-mannitol, erythritol, xylitol, sorbitol, lactose, trehalose, isomalt hydrate and maltitol.

3. The non-aqueous preparation according to claim 1, wherein The fatty acid ester is a fatty acid ester of a polyol.

4. The non-aqueous preparation according to claim 1, wherein The fatty acid ester is one or more selected from the group consisting of sucrose fatty acid esters and glycerol fatty acid esters.

5. The non-aqueous preparation according to claim 1, wherein The fatty acid is a saturated fatty acid having 10 to 24 carbon atoms.

6. The non-aqueous preparation according to claim 1, wherein The content of the compound represented by the general formula (I) or a salt thereof is 5% by mass to 80% by mass based on the total amount of the non-aqueous preparation.

7. A product, wherein The product comprises the non-aqueous preparation according to any one of claims 1 to 6 and a package for storing the non-aqueous preparation in a dry state.

8. The product of claim 7, wherein: The non-aqueous preparation has the shape of tablets, capsules, powders, granules, or fine particles.

9. The product of claim 7, wherein: The non-aqueous preparation is dried by a desiccant, and the desiccant is one or more selected from the group consisting of silica gel, silica-alumina gel, natural zeolite, synthetic zeolite, calcium chloride, quicklime, bentonite, magnesium chloride, magnesium oxide, calcium sulfate, activated alumina, alumina, bauxite, anhydrous calcium sulfate, water-absorbent clay, and a mixture of these components and activated carbon.

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