JP7663370B2 - Pharmaceutical preparations - Google Patents

Description

The present invention relates to pharmaceutical preparations, etc.

Tocopherols, such as dl-α-tocopherol acetate, are components that have useful pharmacological effects, such as antioxidant, anti-inflammatory, and blood circulation promoting effects, 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, resulting in a decrease in their content over time during storage (e.g., Non-Patent Document 1, etc.).

Home Medicine Research, No. 8, pp. 24-30, 1989

The objective of the present invention is to provide a new means for suppressing the adsorption of tocopherols to polyolefin resin containers.

The inventors conducted extensive research to solve the above problems and discovered 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 preparation with improved content stability, and thus completing the present invention.

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.

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 the composition.

Hereinafter, in this specification, "w/v %" means percentage by mass to volume, and specifically means 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 derivatives thereof (e.g., esterified derivatives such as acetate, succinate, and nicotinate), and salts thereof (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 salts thereof, 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 mixtures of them in any ratio, and may be a single optical isomer or a mixture of various optical isomers in any ratio (for example, the description "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.

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 calcium succinate, tocopherol acetate, and tocopherol nicotinate, even more preferably one or more selected from the group consisting of d-α-tocopherol, d-α-tocopherol calcium succinate, d-α-tocopherol acetate, and d-α-tocopherol nicotinate, and particularly preferably d-α-tocopherol acetate.

The amount of tocopherols contained in the composition is not particularly limited and may be determined appropriately depending on the intended use, etc., but it is preferable that the amount is 0.00001 to 1 w/v% of 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%.

<Component (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.

In the polyoxyalkylene fatty acid ester, the oxyalkylene group forming the repeating unit is not particularly limited, and may be a straight-chain or branched-chain 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 an oxyethylene group, an oxypropylene group, an oxybutylene group, and an 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 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.

In addition, 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.

In the present invention, examples of the polyoxyalkylene fatty acid ester include the following (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 isostearic acid, 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 ester) 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 ester) are even more preferred, and polyoxyethylene (4-55) monostearate is particularly preferred.

The content of polyoxyalkylene fatty acid ester in the composition is not particularly limited and may be determined through appropriate consideration, but from the viewpoint of suppressing adsorption of tocopherols, it is preferable that the content be 0.001 to 5 w/v% of the total volume of the composition, more preferably 0.01 to 3 w/v%, and particularly preferably 0.1 to 1 w/v%.

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, it is preferable that the composition 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.

<Component (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-chain or branched-chain 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 an oxyethylene group, an oxypropylene group, an oxybutylene group, and an oxypentylene group.
In the polyoxyalkylene hydrogenated castor oil, the number of repeating units of the oxyalkylene group (average number of moles added) is not particularly limited as long as it is a positive integer, but from the viewpoint of suppressing 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 from oxyethylene, such as a polyoxyethylene group, or the repeating units may be formed from 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.

In addition, in the present invention, from the viewpoint of suppressing the adsorption of tocopherols, 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.

In the present invention, examples of the polyoxyalkylene hydrogenated castor oil include the following (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 inhibiting 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.

The content of polyoxyalkylene hydrogenated castor oil in the composition is not particularly limited and may be determined through appropriate consideration, but from the viewpoint of suppressing the adsorption of tocopherols, it is preferable that the content be 0.001 to 5 w/v% of the total volume of the composition, more preferably 0.01 to 3 w/v%, and particularly preferably 0.05 to 1 w/v%.

The mass ratio of tocopherols and polyoxyalkylene hydrogenated castor oil in the composition is not particularly limited, but from the viewpoint of suppressing adsorption of tocopherols, it is preferable that the composition 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.

The mass ratio of the polyoxyalkylene fatty acid ester and polyoxyalkylene hydrogenated castor oil in the composition is not particularly limited, but from the viewpoint of suppressing the adsorption of tocopherols, it is preferable that the composition contains 0.001 to 12 parts by mass of polyoxyalkylene hydrogenated castor oil per 1 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.

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 below, 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 multiple different types of solvents and bases may be appropriately mixed and emulsified for use. Specific examples of such solvents and bases include the components exemplified as additives described below.

From the viewpoint of the feeling when using the composition, the liquid or semi-solid composition preferably contains water (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.

In addition to the above, the composition may contain additives used in pharmaceuticals and quasi-drugs 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, cooling agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, etc.

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 paraoxybenzoate, 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, petrolatum, etc. are examples, and one or more of these can be blended.

In addition to the above, the composition may contain an appropriate medicinal ingredient depending on the purpose (application) of use. 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, sodium sulfamethoxazole, sulfisoxazole, sodium sulfisomidine, 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, hydroxypropylmethylcellulose, glucose, methylcellulose, alkylpolyaminoethylglycine, boric acid, etc., and one or more of these can be blended.

The pH (25°C) of the composition is not particularly limited, but is preferably 3 to 9, more preferably 3.5 to 8, even more 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.

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" encompasses any of the terms "sealed container", "airtight container" and "sealed container" defined in the General Rules of the Japanese Pharmacopoeia, 17th Edition.

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.

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 arranged 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 polyolefins, 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 these can be used alone or in combination of two or more. As the polyolefin resin, from the viewpoint of suppressing adsorption of tocopherols, polyethylene, polypropylene, and cyclic polyolefins 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, and 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".

It is preferable that the inside of a polyolefin resin container is visible (observable) with the naked eye. If the inside is visible, there are advantages such as making it possible to inspect for the presence of foreign matter during the manufacturing process of the pharmaceutical preparation, and allowing 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 portion 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 portion of the container surface, this makes it possible to check the composition inside the container.

There are no particular limitations on the means for storing the composition in the polyolefin resin container, and the composition may be filled in a conventional manner according to the shape of the container.

Pharmaceutical preparations or liquid or semi-solid compositions can be made into various dosage forms, for example, according to known methods described in the General Provisions for Preparations of the 17th Revised Japanese Pharmacopoeia. Dosage forms include, for example, injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal drops, enemas, external solutions, sprays, ointments, gels, oral solutions, and syrups. From the viewpoint of advantageously utilizing the pharmacological action of tocopherols, preferred dosage forms are preparations for eye diseases, specifically eye drops and eye ointments, with eye drops being particularly preferred.

The indications for the pharmaceutical preparation are not particularly limited, and may be appropriately selected depending on the pharmacological action of the tocopherols. 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 discharge, etc.), conjunctivitis (pink eye), styes, supplementation of tears (dry eyes), facilitating the wearing of hard or soft contact lenses, and eye cleaning.

When the composition or pharmaceutical preparation is used as eye drops or eye ointments, it is sufficient to administer an appropriate amount, for example, 1 to 3 times a day.

The present invention also relates to 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 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.

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 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 component (C) is polyoxyethylene (2-150) hydrogenated castor oil.
[9A] The pharmaceutical formulation according to any one of [1A] to [8A], wherein 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 solution, eye drops, eye ointment, ear drops, nasal solution, enema, external solution, spray, ointment, gel, oral solution, or syrup.

[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 the 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 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, linoleic acid, linolenic acid, eleostearic acid, behenic acid, and hexacosanoic acid.
[6B] The method according to any one of [1B] to [5B], wherein component (B) is polyoxyethylene (4-60) monostearate.
[7B] The method according to any one of [1B] to [6B], wherein component (B) is polyethylene glycol (55) monostearate.
[8B] The method according to any one of [1B] to [7B], wherein component (C) is polyoxyethylene (2-150) hydrogenated castor oil.
[9B] The method according to any one of [1B] to [8B], wherein 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 solution, eye drops, eye ointment, ear drops, nasal solution, enema, external solution, spray, ointment, gel, oral solution, or syrup.

[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 the 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 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 component (B) is polyoxyethylene (4-60) monostearate.
[7C] The method according to any one of [1C] to [6C], wherein 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 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 solution, eye drops, eye ointment, ear drops, nasal solution, enema, external solution, spray, ointment, gel, oral solution, or syrup.

Next, the present invention will be further explained by way of examples, but the present invention is not limited to these in any way.

[Test Example 1] Adsorption suppression test In order to examine a means for suppressing the adsorption of tocopherols to 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.

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) having a part (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 manner 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 a known concentration using HPLC.
The residual rate (%) of d-α-tocopherol acetate was evaluated from the concentration of d-α-tocopherol acetate in the obtained water-containing composition according to the following formula.

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)}×100
The results are shown in Table 1.

The results shown in Table 1, comparing Example 1 with Examples 2 and 3, reveal that by combining polyethylene glycol monostearate (55 E.O.) and polyoxyethylene hydrogenated castor oil 60 in a water-containing composition containing d-α-tocopherol acetate and storing it 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.

The above test results show that by further incorporating a combination of polyoxyalkylene fatty acid ester and polyoxyalkylene hydrogenated castor oil into 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.

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)

Production 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)

Production 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) 2.0 g
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)

Production 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)

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) 2.0 g
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)

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)

The present invention provides a pharmaceutical preparation with excellent stability, which can be suitably used in the pharmaceutical industry, etc.

Claims (4)

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. The pharmaceutical preparation according to claim 1, wherein component (A) is one or more selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof. 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. The pharmaceutical preparation according to any one of claims 1 to 3 , which is in the form of an injection, an inhalation liquid, 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.