Pharmaceutical preparations

Abstract

To provide new means for suppressing the adsorption of a tocopherol onto a polyolefin resin container.SOLUTION: A pharmaceutical preparation contains a liquid or semisolid composition containing following components (A), (B) and (C): (A) a tocopherol; (B) polyoxyalkylene fatty acid ester; and (C) polyoxyalkylene hydrogenated castor oil, the composition housed in a polyolefin resin container.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to pharmaceutical preparations and the like. [Background technology]

[0002] Tocopherols, typified by dl-α-tocopherol acetate, are components with useful pharmacological effects such as antioxidant effect, anti-inflammatory effect, and blood circulation promoting effect, and are incorporated into various liquid and semi-solid compositions, including eye drops. However, tocopherols are fat-soluble components, and are known to be adsorbed to containers made of polyolefin resins such as polyethylene and polypropylene, and the content decreases over time during storage (e.g., Non-Patent Document 1, etc.). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Home Medicine Research, No. 8, pp. 24-30, 1989 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a new means for suppressing the adsorption of tocopherols to polyolefin resin containers. [Means for solving the problem]

[0005] The present inventors have conducted intensive research to solve the above-mentioned problems and have found that by further incorporating a combination of a polyoxyalkylene fatty acid ester and a polyoxyalkylene hydrogenated castor oil into a liquid or semi-solid composition containing tocopherols, the adsorption of tocopherols to polyolefin resin containers is suppressed, resulting in a pharmaceutical formulation with improved content stability, and have completed the present invention.

[0006] That is, the present invention relates to a composition comprising the following components (A), (B) and (C): (A) Tocopherols; (B) polyoxyalkylene fatty acid ester; (C) polyoxyalkylene hydrogenated castor oil; The present invention provides a pharmaceutical preparation comprising a liquid or semi-solid composition containing the above in a polyolefin resin container. Effect of the Invention

[0007] According to the present invention, it is possible to suppress the adsorption of tocopherols to polyolefin resin containers, and improve the stability of the tocopherol content in a composition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Hereinafter, in this specification, "w / v %" means percentage by mass to volume, specifically, the mass (g) of each component contained per 100 mL of the composition. <Component (A)> In the present invention, the term "tocopherols" refers to one or more selected from tocopherol, tocotrienol, and their derivatives (e.g., esterified derivatives such as acetate, succinate, and nicotinate) and their salts (e.g., alkaline earth metal salts such as calcium salt and magnesium salt). Here, the tocopherol may be any of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, with α-tocopherol being preferred. In addition, the tocotrienol may be any of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, with α-tocotrienol being preferred. In the present invention, one or more selected from the group consisting of α-tocopherol, α-tocopherol acetate, α-tocopherol succinate, and α-tocopherol nicotinate, and their salts, are preferred. In addition, although optical isomers may exist in tocopherols and tocotrienols, in the present invention, all isomers are included unless otherwise specified. In other words, in the present invention, unless a specific optical isomer is specified as the component name of tocopherols, such component notation includes all of the various optical isomers alone and their mixtures in any ratio, and may be a single optical isomer or a mixture of various optical isomers in any ratio (for example, the description of "acetate ester of α-tocopherol" includes both acetate ester of dl-α-tocopherol and acetate ester of d-α-tocopherol). In addition, as the tocopherols of the present invention, "tocopherol", "tocopherol succinate calcium", "tocopherol acetate", "tocopherol nicotinate", etc. listed in the 17th revised Japanese Pharmacopoeia can be suitably used. These tocopherols are known compounds and may be produced by known methods, or commercially available products may be used.

[0009] In the present invention, the tocopherols are preferably one or more selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof, more preferably one or more selected from the group consisting of tocopherol, tocopherol succinate calcium, tocopherol acetate, and tocopherol nicotinate, even more preferably one or more selected from the group consisting of d-α-tocopherol, d-α-tocopherol succinate calcium, d-α-tocopherol acetate, and d-α-tocopherol nicotinate, and particularly preferably d-α-tocopherol acetate.

[0010] The content of tocopherols in the composition is not particularly limited and may be determined appropriately depending on the purpose of use, etc., but it is preferably 0.00001 to 1 w / v% relative to the total volume of the composition, more preferably 0.0001 to 0.5 w / v%, even more preferably 0.001 to 0.1 w / v%, and particularly preferably 0.005 to 0.05 w / v%.

[0011] <Ingredient (B)> In the present invention, the term "polyoxyalkylene fatty acid ester" means an ester of a polyalkylene glycol and a fatty acid, and in the present invention, a single type of ester or a mixture of multiple types of esters can be used. The fatty acid in the polyoxyalkylene fatty acid ester may be a linear or branched saturated or unsaturated fatty acid, and from the viewpoint of suppressing the adsorption of tocopherols, a linear saturated fatty acid is preferred. The number of carbon atoms is not particularly limited, but from the viewpoint of suppressing the adsorption of tocopherols, it is preferably 12 to 30, more preferably 14 to 28, and particularly preferably 16 to 26. Specific examples of such fatty acids include lauric acid, myristic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, linolenic acid, linolenic acid, eleostearic acid, behenic acid, and hexacosanoic acid. In the present invention, the fatty acid in the polyoxyalkylene fatty acid ester is preferably a fatty acid having 12 to 30 carbon atoms, more preferably a linear saturated fatty acid having 16 to 26 carbon atoms, and particularly preferably stearic acid, from the viewpoint of suppressing adsorption of tocopherols. In the present invention, the ester is not particularly limited, and may be a monoester or a diester.

[0012] In the polyoxyalkylene fatty acid ester, the oxyalkylene group forming the repeating unit is not particularly limited, and may be a straight or branched alkylene group. The number of carbon atoms is not particularly limited, but from the viewpoint of suppressing the adsorption of tocopherols, it is preferably 2 to 6, more preferably 2 to 4, and particularly preferably 2 to 3. Specific examples of such oxyalkylene groups include oxyethylene group, oxypropylene group, oxybutylene group, and oxypentylene group. The number of repeating units (average number of moles added) of the oxyalkylene group in the polyoxyalkylene fatty acid ester is not particularly limited as long as it is a positive integer, but from the viewpoint of suppressing the adsorption of tocopherols, it is preferably 2 to 70, more preferably 3 to 65, even more preferably 4 to 60, and particularly preferably 4 to 50. The multiple oxyalkylene groups forming the repeating units may be the same or different from each other. Specifically, for example, the repeating units may be formed only with oxyethylene, such as a polyoxyethylene group, or the repeating units may be formed with multiple different types of oxyalkylene groups, such as polyoxyethylene polyoxypropylene. These polyoxyalkylene fatty acid esters are known compounds and may be produced by known methods, or commercially available products may be used.

[0013] In the present invention, the polyoxyalkylene fatty acid ester preferably has an HLB value calculated by Griffin's formula of 4 to 20, more preferably 7 to 17, and particularly preferably 10 to 14, from the viewpoint of suppressing adsorption of tocopherols.

[0014] In the present invention, examples of the polyoxyalkylene fatty acid ester include the following (note that the numbers indicate the number of repeating units of the polyoxyalkylene (average number of moles added)). Monoesters of ethylene glycol and stearic acid, such as ethylene glycol monostearate; Monoesters of polyethylene glycol and stearic acid, such as polyethylene glycol(2) monostearate, polyethylene glycol(5) monostearate, polyethylene glycol(10) monostearate, polyethylene glycol(20) monostearate, polyethylene glycol(30) monostearate, polyethylene glycol(40) monostearate, polyethylene glycol(50) monostearate, and polyethylene glycol(55) monostearate; Diesters of polyethylene glycol and stearic acid, such as polyethylene glycol(2) distearate, polyethylene glycol(4) distearate, polyethylene glycol(6) distearate, polyethylene glycol(8) distearate, and polyethylene glycol(12) distearate; Monoesters of polyethylene glycol and oleic acid, such as polyethylene glycol (6) monooleate and polyethylene glycol (10) monooleate; Diesters of polyethylene glycol and oleic acid, such as polyethylene glycol(2) dioleate, polyethylene glycol(4) dioleate, polyethylene glycol(6) dioleate, polyethylene glycol(8) dioleate, and polyethylene glycol(12) dioleate; Monoesters of polyethylene glycol and isostearate, such as polyethylene glycol(3) monoisostearate, polyethylene glycol(6) monoisostearate, polyethylene glycol(8) monoisostearate, polyethylene glycol(10) monoisostearate, polyethylene glycol(12) monoisostearate, and polyethylene glycol(20) monoisostearate; Diesters of polyethylene glycol and isostearic acid, such as polyethylene glycol (2) diisostearate, polyethylene glycol (4) diisostearate, polyethylene glycol (6) diisostearate, polyethylene glycol (8) diisostearate, and polyethylene glycol (12) diisostearate. In the present invention, from the viewpoint of inhibiting adsorption of tocopherols, polyoxyethylene fatty acid esters are preferred, esters of fatty acids having 12 to 30 carbon atoms and polyoxyethylene having an average number of added moles of 4 to 60 (polyoxyethylene (4-60) C12-30 fatty acid esters) are more preferred, esters of fatty acids having 12 to 30 carbon atoms and polyoxyethylene having an average number of added moles of 4 to 50 (polyoxyethylene (4-55) C12-30 fatty acid esters) are even more preferred, and polyoxyethylene (4-55) monostearate is particularly preferred.

[0015] The content of the polyoxyalkylene fatty acid ester in the composition is not particularly limited and may be determined by appropriate consideration. From the viewpoint of suppressing adsorption of tocopherols, however, the content is preferably 0.001 to 5 w / v%, more preferably 0.01 to 3 w / v%, and particularly preferably 0.1 to 1 w / v%, relative to the total volume of the composition.

[0016] The mass ratio of tocopherols and polyoxyalkylene fatty acid ester contained in the composition is not particularly limited, but from the viewpoint of suppressing adsorption of tocopherols, the composition preferably contains 0.1 to 35 parts by mass of polyoxyalkylene fatty acid ester per 1 part by mass of tocopherols, more preferably 1 to 25 parts by mass, and particularly preferably 3 to 15 parts by mass.

[0017] <Ingredient (C)> In the present invention, "polyoxyalkylene hydrogenated castor oil" means an ester of a hydrogenated oil obtained by adding hydrogen to a polyalkylene glycol and castor oil, and in the present invention, a single type of ester or a mixture of multiple types of esters can be used. In the polyoxyalkylene hydrogenated castor oil, the oxyalkylene group forming the repeating unit is not particularly limited, and may be a straight or branched alkylene group. The number of carbon atoms is not particularly limited, but from the viewpoint of suppressing the adsorption of tocopherols, it is preferably 2 to 6, more preferably 2 to 4, and particularly preferably 2 to 3. Specific examples of such oxyalkylene groups include oxyethylene group, oxypropylene group, oxybutylene group, and oxypentylene group. The number of repeating units (average number of moles added) of the oxyalkylene group in the polyoxyalkylene hydrogenated castor oil is not particularly limited as long as it is a positive integer, but from the viewpoint of suppressing the adsorption of tocopherols, it is preferably 2 to 150, more preferably 3 to 120, and particularly preferably 4 to 100. The multiple oxyalkylene groups forming the repeating units may be the same or different from each other. Specifically, for example, the repeating units may be formed only with oxyethylene, such as a polyoxyethylene group, or the repeating units may be formed with multiple different types of oxyalkylene groups, such as polyoxyethylene polyoxypropylene. These polyoxyalkylene fatty acid esters are known compounds and may be produced by known methods, or commercially available products may be used.

[0018] In addition, in the present invention, the polyoxyalkylene hydrogenated castor oil preferably has an HLB value, calculated by Griffin's formula, of 4 to 20, more preferably 7 to 17, and particularly preferably 10 to 14, from the viewpoint of suppressing adsorption of tocopherols.

[0019] In the present invention, examples of the polyoxyalkylene hydrogenated castor oil include the following (note that the numbers indicate the number of repeating units of the oxyalkylene (average number of moles added)): Polyoxyethylene hydrogenated castor oils such as polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil and polyoxyethylene (100) hydrogenated castor oil. In the present invention, from the viewpoint of suppressing adsorption of tocopherols, polyoxyethylene hydrogenated castor oil is preferred, polyoxyethylene (5-100) hydrogenated castor oil is more preferred, and polyoxyethylene (20-80) hydrogenated castor oil is particularly preferred.

[0020] The content of polyoxyalkylene hydrogenated castor oil in the composition is not particularly limited and may be determined through appropriate consideration. From the viewpoint of suppressing adsorption of tocopherols, however, it is preferably contained in an amount of 0.001 to 5 w / v%, more preferably 0.01 to 3 w / v%, and particularly preferably 0.05 to 1 w / v%, relative to the total volume of the composition.

[0021] The mass ratio of tocopherols to polyoxyalkylene hydrogenated castor oil in the composition is not particularly limited, but from the viewpoint of suppressing adsorption of tocopherols, the composition preferably contains 0.01 to 30 parts by mass of polyoxyalkylene hydrogenated castor oil per 1 part by mass of tocopherols, more preferably 0.1 to 20 parts by mass, and particularly preferably 1 to 15 parts by mass.

[0022] The mass ratio of the polyoxyalkylene fatty acid ester to the polyoxyalkylene hydrogenated castor oil in the composition is not particularly limited, but from the viewpoint of suppressing adsorption of tocopherols, the composition preferably contains 0.001 to 12 parts by mass of polyoxyalkylene hydrogenated castor oil per part by mass of polyoxyalkylene fatty acid ester, more preferably 0.01 to 8 parts by mass, and particularly preferably 0.1 to 4 parts by mass.

[0023] In the present invention, the properties of the "liquid or semi-solid composition" are not particularly limited as long as they can be contained in a container described later, and may be any of liquid (solution, colloidal solution (sol (suspension or emulsion))), semi-solid (ointment, gel), etc. Furthermore, the type and properties of the solvent or base are not particularly limited, and they may be hydrophilic or hydrophobic such as oily, and further, multiple different types of solvents and bases may be appropriately mixed, emulsified, etc. and used. Specific examples of such solvents and bases include the components exemplified as additives described later.

[0024] From the viewpoint of the feeling when using the composition, the liquid or semi-solid composition preferably contains water (Note that in this specification, a liquid or semi-solid composition containing water is referred to as a "water-containing composition.") Here, the water in the water-containing composition may be, for example, purified water, water for injection, sterilized purified water, or the like. The content of water in the water-containing composition is not particularly limited, but is preferably 5% by mass or more, more preferably 20% by mass or more, even more preferably 50% by mass or more, even more preferably 90% by mass or more, and particularly preferably 90 to 97% by mass.

[0025] In addition to the above, the composition may contain additives used in pharmaceuticals, quasi-drugs, etc., depending on the dosage form. Examples of such additives include inorganic salts, isotonicity agents, chelating agents, stabilizers, pH regulators, preservatives, antioxidants, thickening agents, surfactants, solubilizers, suspending agents, refreshing agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, etc.

[0026] Specific examples of such additives include sodium hydrogen sulfite, benzyl benzoate, fennel oil, ethanol, ethylene-vinyl acetate copolymer, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, alkyldiaminoethylglycine hydrochloride solution, fructose, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, xylitol, glycerin, creatinine, chlorobutanol, geraniol, sodium chondroitin sulfate, titanium oxide, dibutylhydroxytoluene, potassium bromide, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, sorbitol, taurine, sodium hydrogen carbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, tyloxapol, sodium dehydroacetate, trometamol, white petrolatum, peppermint water, peppermint oil, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, and propyl parahydroxybenzoate. , methyl parahydroxybenzoate, human serum albumin, sodium pyrosulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalkonium chloride, benzyl alcohol, povidone, polyoxyethylene (200) polyoxypropylene glycol (70), sodium polystyrene sulfonate, polysorbate 80, d-borneol, macrogol 100, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 20000, macrogol 35000, mannitol, methanesulfonic acid, l-menthol, monoethanolamine, aluminum monostearate, eucalyptus oil, potassium iodide, oxyquinoline sulfate, liquid paraffin, ryunou, and petrolatum, and one or more of these can be blended.

[0027] In addition to the above, the composition may contain an appropriate medicinal ingredient according to its intended use (application).Specific examples of such medicinal ingredients include epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, neostigmine methylsulfate, epsilon-aminocaproic acid, allantoin, berberine chloride, berberine sulfate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme chloride, diphenhydramine hydrochloride, chlorpheniramine maleate, sodium flavin adenine dinucleotide, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, potassium L-aspartate, Examples include calcium L-aspartate, magnesium and potassium L-aspartate (mixture of equal parts), aminoethylsulfonic acid, sodium chondroitin sulfate, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, potassium chloride, calcium chloride, sodium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methylcellulose, glucose, methylcellulose, alkyl polyaminoethyl glycine, boric acid, and the like, and one or more of these can be blended.

[0028] The pH (25° C.) of the composition is not particularly limited, but is preferably 3 to 9, more preferably 3.5 to 8, further preferably 4 to 7, and particularly preferably 5 to 6. The osmotic pressure ratio to physiological saline is not particularly limited, but is preferably 0.6 to 3, and particularly preferably 0.6 to 2.

[0029] The pharmaceutical preparation of the present invention is prepared in a container made of a polyolefin resin. In this specification, the term "container" refers to a package that directly contains the composition. The term "container" is a concept that encompasses any of "sealed containers," "airtight containers," and "sealed containers" defined in the General Rules of the Japanese Pharmacopoeia, 17th Edition.

[0030] The shape of the container is not particularly limited as long as it can accommodate the composition, and may be appropriately selected and set depending on the dosage form, use of the pharmaceutical preparation, etc. Specific examples of such container shapes include containers for injections, containers for inhalants, containers for sprays, bottle-shaped containers, tube-shaped containers, containers for eye drops, containers for nasal drops, containers for ear drops, bag containers, etc. The container is preferably an eye drop container, from the viewpoint of advantageously utilizing the pharmacological action of tocopherols.

[0031] In this specification, the term "polyolefin resin container" refers to a container in which at least the portion of the container that comes into contact with the liquid or semi-solid composition is "made of polyolefin resin". Therefore, for example, a container in which a polyolefin resin layer is provided as an inner layer that comes into contact with the liquid or semi-solid composition and a resin of another material is laminated on the outside of the inner layer, or a container that includes a container body and an inner plug having a discharge port, in which the inner plug is disposed so as to come into contact with the liquid or semi-solid composition and the surface material of the inner plug is a polyolefin resin, also falls under the category of "polyolefin resin container". Here, the polyolefin resin is not particularly limited, and may be a polymer (homopolymer) of a single type of monomer or a copolymer (copolymer) of multiple types of monomers. In addition, in the case of a copolymer, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited. Specific examples of such polyolefin resins include polyethylene (more specifically, for example, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, etc.), polypropylene, cyclic polyolefin, poly(4-methylpentene), polytetrafluoroethylene, ethylene-propylene copolymer, ethylene-α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, etc., and one or more of these can be used in combination. As the polyolefin resin, from the viewpoint of suppressing adsorption of tocopherols, polyethylene, polypropylene, and cyclic polyolefin are preferred, and polyethylene and polypropylene are more preferred. In this specification, "made of polyolefin-based resin" means that at least a portion of the material contains polyolefin-based resin; for example, a mixture of two or more resins, that is, a polyolefin-based resin and another resin (polymer alloy), is also included in "made of polyolefin-based resin".

[0032] It is preferable that the inside of the polyolefin resin container is visible (observable) with the naked eye. If the inside is visible, there are advantages such as enabling inspection for the presence or absence of foreign matter in the manufacturing process of the pharmaceutical preparation, and enabling users of the pharmaceutical preparation to check the remaining amount of the contents (composition). Here, visibility only needs to be ensured on at least a part of the container surface (for example, even if the side of an eye drop container is obscured by a shrink film or the like, it can be said to be visible as long as the bottom surface is visible). If the inside is visible on a part of the container surface, this allows the composition in the container to be confirmed.

[0033] The means for storing the composition in the polyolefin resin container is not particularly limited, and the composition may be filled in a conventional manner according to the shape of the container.

[0034] The pharmaceutical preparation or liquid or semi-solid composition can be made into various dosage forms according to known methods described in, for example, the General Provisions for Preparations of the 17th Edition of the Japanese Pharmacopoeia. Examples of dosage forms include injections, inhalation liquids, eye drops, eye ointments, ear drops, nasal drops, enemas, external liquids, sprays, ointments, gels, oral liquids, syrups, etc. From the viewpoint of advantageously utilizing the pharmacological action of tocopherols, the dosage form is preferably an agent for eye diseases, specifically eye drops and eye ointments, and more preferably eye drops.

[0035] The indications for the pharmaceutical preparation are not particularly limited, and may be appropriately selected depending on the pharmacological action of the tocopherols, etc. Specifically, the pharmaceutical preparation of the present invention can be suitably used as a medicine having efficacy or effects such as eye fatigue, conjunctival congestion, prevention of eye diseases (after swimming, when dust or sweat gets into the eyes, etc.), eye inflammation caused by ultraviolet rays or other light (snow blindness, etc.), blepharitis (sore eyelids), discomfort when wearing hard or soft contact lenses, itchy eyes, blurred vision (when there is a lot of eye mucus, etc.), conjunctivitis (pink eye), styes, assistance with tears (dry eyes), facilitating the wearing of hard or soft contact lenses, and eye cleaning.

[0036] When the composition or pharmaceutical preparation is used as eye drops or eye ointment, it may be administered in an appropriate amount, for example, about 1 to 3 times a day.

[0037] The present invention also provides a composition comprising the following component (A): (A) Tocopherols; A liquid or semi-solid composition comprising the following components (B) and (C): (B) polyoxyalkylene fatty acid ester; (C) polyoxyalkylene hydrogenated castor oil; and containing the composition in a polyolefin resin container. In this case, the order of each step is not particularly limited, as long as a liquid or semi-solid composition containing components (A), (B), and (C) is ultimately produced in a state in which it is contained in a polyolefin resin container. Further, the present invention relates to a composition comprising the following component (A): (A) Tocopherols; A liquid or semi-solid composition comprising the following components (B) and (C): (B) polyoxyalkylene fatty acid ester; (C) polyoxyalkylene hydrogenated castor oil; and housing the composition in a polyolefin resin container. In this case, the order of each step is not particularly limited, as long as a liquid or semi-solid composition containing components (A), (B), and (C) is ultimately produced in a state in which it is contained in a polyolefin resin container.

[0038] The present specification discloses, for example, embodiments of the following aspects, but is in no way limited thereto. [1A] The following components (A), (B) and (C): (A) Tocopherols; (B) polyoxyalkylene fatty acid ester; (C) polyoxyalkylene hydrogenated castor oil; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above in a polyolefin resin container. [2A] The pharmaceutical formulation according to [1A], wherein component (A) is one or more members selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof. [3A] The pharmaceutical formulation according to [1A] or [2A], wherein component (B) is a polyoxyethylene fatty acid ester. [4A] The pharmaceutical formulation according to any one of [1A] to [3A], wherein component (B) is a polyoxyethylene (4-60) C12-30 fatty acid ester. [5A] The pharmaceutical formulation according to any one of [1A] to [4A], wherein the fatty acid constituting component (B) is one or more selected from the group consisting of lauric acid, myristic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, linolenic acid, linolenic acid, eleostearic acid, behenic acid, and hexacosanoic acid. [6A] The pharmaceutical formulation according to any one of [1A] to [5A], wherein the component (B) is polyoxyethylene (4-60) monostearate. [7A] The pharmaceutical formulation according to any one of [1A] to [6A], wherein component (B) is polyethylene glycol (55) monostearate. [8A] The pharmaceutical formulation according to any one of [1A] to [7A], wherein the component (C) is polyoxyethylene (2-150) hydrogenated castor oil. [9A] The pharmaceutical formulation according to any one of [1A] to [8A], wherein the component (C) is one or more selected from the group consisting of polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil, and polyoxyethylene (100) hydrogenated castor oil. [10A] The pharmaceutical formulation according to any one of [1A] to [9A], wherein the component (C) is polyoxyethylene (60) hydrogenated castor oil. [11A] The pharmaceutical formulation according to any one of [1A] to [10A], wherein the composition is a water-containing composition. [12A] The pharmaceutical formulation according to any one of [1A] to [11A], wherein the dosage form is an injection, an inhalation liquid, eye drops, eye ointment, ear drops, nasal solution, enema, external liquid, spray, ointment, gel, oral liquid, or syrup.

[0039] [1B] The following component (A): (A) Tocopherols; A liquid or semi-solid composition comprising the following components (B) and (C): (B) polyoxyalkylene fatty acid ester; (C) polyoxyalkylene hydrogenated castor oil; and housing the composition in a polyolefin resin container. [2B] The method according to [1B], wherein component (A) is one or more members selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof. [3B] The method according to [1B] or [2B], wherein component (B) is a polyoxyethylene fatty acid ester. [4B] The method according to any one of [1B] to [3B], wherein the component (B) is a polyoxyethylene (4-60) C12-30 fatty acid ester. [5B] The method according to any one of [1B] to [4B], wherein the fatty acid constituting component (B) is one or more selected from the group consisting of lauric acid, myristic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, linolenic acid, linolenic acid, eleostearic acid, behenic acid, and hexacosanoic acid. [6B] The method according to any one of [1B] to [5B], wherein the component (B) is polyoxyethylene (4-60) monostearate. [7B] The method according to any one of [1B] to [6B], wherein the component (B) is polyethylene glycol (55) monostearate. [8B] The method according to any one of [1B] to [7B], wherein the component (C) is polyoxyethylene (2-150) hydrogenated castor oil. [9B] The method according to any one of [1B] to [8B], wherein the component (C) is one or more selected from the group consisting of polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil, and polyoxyethylene (100) hydrogenated castor oil. [10B] The method according to any one of [1B] to [9B], wherein the component (C) is polyoxyethylene (60) hydrogenated castor oil. [11B] The method according to any one of [1B] to [10B], wherein the composition is a water-containing composition. [12B] The method according to any one of [1B] to [11B], wherein the dosage form is an injection, an inhalation liquid, eye drops, eye ointment, ear drops, nasal solution, enema, external liquid, spray, ointment, gel, oral liquid, or syrup.

[0040] [1C] The following component (A): (A) Tocopherols; A liquid or semi-solid composition comprising the following components (B) and (C): (B) polyoxyalkylene fatty acid ester; (C) polyoxyalkylene hydrogenated castor oil; and housing the composition in a polyolefin resin container. [2C] The method according to [1C], wherein component (A) is one or more members selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof. [3C] The method according to [1C] or [2C], wherein component (B) is a polyoxyethylene fatty acid ester. [4C] The method according to any one of [1C] to [3C], wherein the component (B) is a polyoxyethylene (4-60) C12-30 fatty acid ester. [5C] The method according to any one of [1C] to [4C], wherein the fatty acid constituting component (B) is one or more selected from the group consisting of lauric acid, myristic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, linolenic acid, linolenic acid, eleostearic acid, behenic acid and hexacosanoic acid. [6C] The method according to any one of [1C] to [5C], wherein the component (B) is polyoxyethylene (4-60) monostearate. [7C] The method according to any one of [1C] to [6C], wherein the component (B) is polyethylene glycol (55) monostearate. [8C] The method according to any one of [1C] to [7C], wherein the component (C) is polyoxyethylene (2-150) hydrogenated castor oil. [9C] The method according to any one of [1C] to [8C], wherein the component (C) is one or more selected from the group consisting of polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil, and polyoxyethylene (100) hydrogenated castor oil. [10C] The method according to any one of [1C] to [9C], wherein the component (C) is polyoxyethylene (60) hydrogenated castor oil. [11C] The method according to any one of [1C] to [10C], wherein the composition is a water-containing composition. [12C] The method according to any one of [1C] to [11C], wherein the dosage form is an injection, an inhalation liquid, eye drops, eye ointment, ear drops, nasal solution, enema, external liquid, spray, ointment, gel, oral liquid, or syrup. EXAMPLES

[0041] The present invention will now be described in further detail with reference to examples, but the present invention is not limited to these in any way.

[0042] [Test Example 1] Adsorption suppression test In order to investigate means for suppressing the adsorption of tocopherols onto polyolefin resin containers, a liquid or semi-solid composition containing tocopherols was placed in a container made of polyethylene resin and stored for a certain period of time, and the decrease in the tocopherol content was evaluated.

[0043] That is, various liquid aqueous compositions shown in Table 1 were prepared by a conventional method, and then placed in a general-purpose eye drop container (body material: polyethylene terephthalate) with a part of the container (inner stopper) made of polyethylene, to obtain various pharmaceutical preparations. Each of the obtained pharmaceutical preparations was stored for one week at 60° C. in such a way that the water-containing composition in the container was in contact with the inner stopper. In order to confirm the decrease in the content of d-α-tocopherol acetate after storage, the concentration of d-α-tocopherol acetate in the water-containing composition in each pharmaceutical preparation was measured before and after storage. The concentration of d-α-tocopherol acetate in the aqueous composition was calculated by measuring the ratio of the peak area in the aqueous composition to the peak area of ​​a solution of d-α-tocopherol acetate of known concentration using HPLC. Then, the residual rate (%) of d-α-tocopherol acetate was evaluated based on the concentration of d-α-tocopherol acetate in the obtained water-containing composition according to the following formula.

[0044] Residual rate (%) = {(concentration of d-α-tocopherol acetate in the aqueous composition after storage) / (concentration of d-α-tocopherol acetate in the aqueous composition before storage)} x 100 The results are shown in Table 1.

[0045] [Table 1]

[0046] The results shown in Table 1, comparing Example 1 with Examples 2 and 3, reveal that when a hydrous composition containing d-α-tocopherol acetate is combined with polyethylene glycol monostearate (55 E.O.) and polyoxyethylene hydrogenated castor oil 60 and stored in a polyolefin resin container, the residual rate of d-α-tocopherol acetate after storage at 60°C for one week is significantly improved compared to when either polyethylene glycol monostearate (55 E.O.) or polyoxyethylene hydrogenated castor oil 60 is used alone.

[0047] From the above test results, it has become clear that by further adding a combination of a polyoxyalkylene fatty acid ester and a polyoxyalkylene hydrogenated castor oil to a liquid or semi-solid composition containing tocopherols, the decrease in content (adsorption) that may occur when the composition is stored in a polyolefin resin container is relatively suppressed.

[0048] Formulation example 1 (eye drops) A liquid composition (eye drops) containing the following ingredients and amounts per 100 mL was prepared by a conventional method and placed in a container (bottle: polypropylene, inner stopper: polyethylene). Naphazoline hydrochloride 0.0015g Neostigmine methylsulfate 0.004g Zinc sulfate hydrate 0.2g d-α-tocopherol acetate 0.05g Potassium L-aspartate 1.0g l-Menthol, dl-camphor, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol (55) monostearate, ethanol, concentrated benzalkonium chloride solution 50, chlorobutanol, boric acid, sodium citrate, dilute hydrochloric acid, sodium chloride, sodium edetate and purified water (as needed)

[0049] Manufacturing Example 2 (eye drops) A liquid composition (eye drops) containing the following ingredients and amounts per 100 mL was prepared by a conventional method and placed in a container (bottle: polypropylene, inner stopper: polyethylene). Neostigmine methylsulfate 0.003g Chlorpheniramine maleate 0.02g Retinol palmitate 50,000 units d-α-tocopherol acetate 0.045g Sodium chondroitin sulfate 0.5g l-Menthol, dl-camphor, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol (55) monostearate, ethanol, concentrated benzalkonium chloride solution 50, chlorobutanol, boric acid, sodium citrate, dilute hydrochloric acid, sodium chloride, sodium edetate and purified water (as needed)

[0050] Manufacturing Example 3 (eye drops) A liquid composition (eye drops) containing the following ingredients and amounts per 100 mL was prepared by a conventional method and placed in a container (bottle: polypropylene, inner stopper: polyethylene). Tetrahydrozoline hydrochloride 0.04g Neostigmine methylsulfate 0.003g Epsilon-aminocaproic acid 1.0g Chlorpheniramine maleate 0.02g Cyanocobalamin 0.02g d-α-tocopherol acetate 0.05g Magnesium and potassium L-aspartate (mixture of equal parts) 2.0g l-Menthol, dl-camphor, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol (55) monostearate, ethanol, concentrated benzalkonium chloride solution 50, chlorobutanol, boric acid, sodium citrate, dilute hydrochloric acid, sodium chloride, sodium edetate and purified water (as needed)

[0051] Manufacturing Example 4 (eye drops) A liquid composition (eye drops) containing the following ingredients and amounts per 100 mL was prepared by a conventional method and placed in a container (bottle: polypropylene, inner stopper: polyethylene). Neostigmine methylsulfate 0.002g Allantoin 0.15g Chlorpheniramine maleate 0.015g Retinol palmitate 50,000 units Pyridoxine hydrochloride 0.03g d-α-tocopherol acetate 0.035g Taurine 1.0g l-Menthol, dl-camphor, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol (55) monostearate, ethanol, concentrated benzalkonium chloride solution 50, chlorobutanol, boric acid, sodium citrate, dilute hydrochloric acid, sodium chloride, sodium edetate and purified water (as needed)

[0052] Production Example 5 (eye drops) A liquid composition (eye drops) containing the following ingredients and amounts per 100 mL was prepared by a conventional method and placed in a container (bottle: polypropylene, inner stopper: polyethylene). Tetrahydrozoline hydrochloride 0.05g Neostigmine methylsulfate 0.005g Allantoin 0.3g Dipotassium glycyrrhizinate 0.15g Zinc sulfate hydrate 0.1g Chlorpheniramine maleate 0.03g Pyridoxine hydrochloride 0.05g Panthenol 0.1g d-α-tocopherol acetate 0.025g Magnesium and potassium L-aspartate (mixture of equal parts) 2.0g Taurine 0.5g Sodium chondroitin sulfate 0.25g l-Menthol, dl-camphor, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol (55) monostearate, ethanol, concentrated benzalkonium chloride solution 50, chlorobutanol, boric acid, sodium citrate, dilute hydrochloric acid, sodium chloride, sodium edetate and purified water (as needed)

[0053] Production Example 6 (eye drops) A liquid composition (eye drops) containing the following ingredients and amounts per 100 mL was prepared by a conventional method and placed in a container (bottle: polypropylene, inner stopper: polyethylene). Naphazoline hydrochloride 0.003g Neostigmine methylsulfate 0.004g Allantoin 0.15g Dipotassium glycyrrhizinate 0.1g Zinc sulfate hydrate 0.15g Chlorpheniramine maleate 0.03g Flavin adenine dinucleotide sodium salt 0.025g Panthenol 0.1g d-α-tocopherol acetate 0.025g Potassium L-aspartate 1.0g Taurine 0.3g Sodium chondroitin sulfate 0.25g l-Menthol, dl-camphor, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol (55) monostearate, ethanol, concentrated benzalkonium chloride solution 50, chlorobutanol, boric acid, sodium citrate, dilute hydrochloric acid, sodium chloride, sodium edetate and purified water (as needed) [Industrial Applicability]

[0054] INDUSTRIAL APPLICABILITY According to the present invention, a pharmaceutical preparation having excellent stability can be provided, which can be suitably used in the pharmaceutical industry and the like.

Claims

1. The following components (A), (B) and (C): (A) tocopherols; (B) polyethylene glycol (55) monostearate; (C) polyoxyethylene (2-150) hydrogenated castor oil; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above in a polyolefin resin container.

2. 2. The pharmaceutical formulation according to claim 1, wherein the component (A) is one or more members selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof.

3. 3. The pharmaceutical formulation according to claim 1 or 2, wherein the component (C) is one or more selected from the group consisting of polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil and polyoxyethylene (100) hydrogenated castor oil.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the dosage form is an injection, an inhalation solution, an eye drop, an eye ointment, an ear drop, a nasal solution, an enema, a liquid for external application, a spray, an ointment, a gel, an oral liquid, or a syrup.

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