JP2005314353A - Pranoprofen-containing composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To inhibit the decomposition of pranoprofen by light. <P>SOLUTION: The subject pranoprofen-containing composition capable of markedly being stabilized against light is provided by containing the pranoprofen or its salt and a vitamin B<SB>12</SB>. Further, in an aqueous composition, it is possible to maintain its appearance in a good state over a long period since it is possible to keep it a clear state without forming precipitated materials or insoluble materials. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a composition in which degradation of pranoprofen by light is suppressed.

Planoprofen is known as a highly safe propionic acid-based acidic non-steroidal anti-inflammatory agent with excellent anti-inflammatory, analgesic, and antipyretic effects. Eye drops, tablets, capsules, and syrups Although it is widely used in the form of internal preparations such as, it is necessary to store it in the dark because it decomposes over time when exposed to light. In particular, in the presence of water, it becomes extremely unstable and insoluble matter is likely to be produced. When stored for a long period of time, aqueous compositions such as eye drops impair the clarity of the solution and deteriorate the appearance. .
For this reason, various aqueous compositions in which pranoprofen is stabilized have been studied. For example, carbonate (Patent Document 1), organic amine (Patent Document 2), antioxidant (Patent Document 3), propylene glycol (Patent Document) Although it has been reported that ingredients such as 4) are blended, the sufficient light stabilizing effect of pranoprofen or the maintenance of the clarity of the composition has not been achieved.
On the other hand, vitamin B ₁₂ has a pharmacological action against pernicious anemia, neurological disease, hepatic sclerosis, and eye strain, and is known to be unstable to light and heat. The effect on it is not known.

JP-A-5-186349 JP-A-8-291065 Japanese Patent Laid-Open No. 7-304670 Japanese Patent Laid-Open No. 10-236951

The objective of this invention is providing the composition which can suppress decomposition | disassembly of pranoprofen or its salt, especially decomposition | disassembly by light. Furthermore, it is an object of the aqueous composition to maintain clarity without producing precipitates or insolubilized materials even when stored for a long period of time.
Another object of the present invention is to provide a method for stabilizing a composition containing pranoprofen or a salt thereof.

The present inventors have revealed that intensive studies to solve the above problems, by formulating vitamin B ₁₂ compound in compositions containing pranoprofen or a salt thereof, the stability of pranoprofen, stability especially against light The present invention was completed by finding that the properties were remarkably improved and that the aqueous composition maintained a clear state without the formation of precipitates or insolubilized materials.

That is, this invention is a composition hung up to the following (1)-(11).
(1) pranoprofen or a composition containing the salt and vitamin B ₁₂ compound.
(2) The composition according to (1), wherein the vitamin B ₁₂ is cyanocobalamin, mecobalamin, hydroxocobalamin, hydroxocobalamin hydrochloride, or hydroxocobalamin acetate.
(3) The composition according to (1) or (2), further comprising at least one selected from a nonionic surfactant, a chelating agent, a preservative, a buffer, and a pH adjuster.
(4) The composition according to any one of (1) to (3), wherein the composition is an aqueous composition.
(5) The aqueous composition according to any one of (1) to (4), which is contained in a container having an average absorbance of 340 nm to 380 nm of 1.0 or more.
(6) The container is a container composed of any one of polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, and polyethylene, a copolymer polyester thereof, or a mixture of two or more kinds. Aqueous composition.
(7) The aqueous composition according to (5), wherein the container is a container composed of polyethylene naphthalate, polyarylate, or a copolymer polyester thereof.
(8) The container is a container composed of a mixture of at least one of polyethylene naphthalate, polyarylate, or a copolymerized polyester thereof, and at least one of polyethylene terephthalate, polypropylene, and polyethylene (5 ).
(9) Material in which a container is added or coated with an ultraviolet blocking agent to one or a mixture of two or more selected from polyethylene naphthalate, polyarylate, copolymerized polyesters thereof, polyethylene terephthalate, polypropylene and polyethylene (5) The aqueous composition according to (5).
(10) The aqueous composition according to any one of (5) to (9), wherein the container is a container to which an ultraviolet blocking agent is added or coated.
(11) The aqueous composition according to any one of (1) to (10), wherein the aqueous composition is an eye drop, a nose drop, an eye wash, a nose wash, or a contact lens preparation.
The present invention also includes a method for stabilizing light of pranoprofen.
(12) pranoprofen or characteristics to the optical method for stabilizing pranoprofen that blending a salt thereof, and a vitamin B ₁₂ compounds in the composition.

The present invention, by containing pranoprofen or a salt thereof and vitamin B ₁₂ compounds, can be remarkably stabilized pranoprofen to light.
Furthermore, in an aqueous composition, since a clear state can be maintained without the formation of precipitates or insolubilized materials, the appearance can be maintained in a good state over a long period of time.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, unless otherwise specified,% means w / v%. Further, the term “contact lens” is used in the meaning of including all types of contact lenses such as hard, oxygen-permeable hard, and soft unless otherwise specified.
In the present specification, “salt” means a pharmacologically or physiologically acceptable salt.
Furthermore, in the present specification, the aqueous composition means a composition containing at least 5% by weight, preferably 20% by weight or more, more preferably 50% by weight or more of water in the composition.

  Planoprofen, that is, α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid contained in the composition of the present invention is a known compound and can be synthesized by a known method. It can also be obtained as a commercial product.

The salt of pranoprofen is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such salts include salts with inorganic bases [eg, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, etc.] and salts with organic bases [eg, methylamine, triethylamine, diethylamine, And salts with organic bases such as triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline] and the like.
Planoprofen or a salt thereof can also be used in the form of a hydrate.

  These pranoprofen and its salt can be used individually by 1 type or in combination of 2 or more types. Pranoprofen is preferred.

  In the composition of the present invention, the proportion of pranoprofen or a salt thereof to be blended is not particularly limited as long as the effects of the present invention are obtained. For example, in the case of an aqueous composition, 0.0001 to 2 w / v%, preferably It is about 0.0005 to 0.2 w / v%, particularly preferably about 0.001 to 0.1 w / v%. Specifically, in the case of eye drops, 0.01 to 0.1 w / v%, preferably about 0.01 to 0.05 w / v%, and in the case of eyewashes, 0.001 to 0.01 w / v%, preferably 0.001 to 0.005 w. In the case of a syrup, it is 0.1 to 2 w / v%, preferably 0.5 to 1.5 w / v%. Moreover, in the case of a solid preparation for internal use (tablet), it is about 20 to 100 mg, preferably about 30 to 80 mg per tablet (100 to 250 mg).

Vitamin B ₁₂ contained in the composition of the present invention is a known compound, and may be synthesized by a known method or obtained as a commercial product.
The vitamin B ₁₂ include, for example, cyanocobalamin, mecobalamin, hydroxocobalamin, hydrochloric hydroxocobalamin acetate, etc. hydroxocobalamin and the like. In the case of an aqueous composition, cyanocobalamin is preferable.

In the composition of the present invention, the ratio of vitamin B _{12 to be} blended is not particularly limited as long as the effects of the present invention are obtained. For example, in the case of an aqueous composition, 0.00001 to 0.05 w / v%, preferably 0.00005. ˜0.03 w / v%, particularly preferably about 0.0001 to 0.02 w / v%. Specifically, in the case of eye drops, 0.002 to 0.02 w / v%, preferably about 0.004 to 0.02 w / v%, and in the case of eye wash, 0.0001 to 0.002 w / v%, preferably 0.0002 to 0.002 w. In the case of a syrup, it is about 0.001 to 0.1 w / v%, preferably 0.01 to 0.05 w / v%. In the case of a solid preparation for internal use (tablet), it is 1 to 2000 μg, preferably about 10 to 1500 μg per tablet (100 to 250 mg).

In the composition of the present invention, the blending ratio of pranoprofen and vitamin B ₁₂ is not particularly limited as long as the effects of the present invention can be obtained. For example, in the case of an aqueous composition, 1 weight of pranoprofen or a salt thereof. The amount of vitamin B ₁₂ is 0.001 to 20 parts by weight, preferably 0.01 to 5 parts by weight, more preferably 0.04 to 2 parts by weight, and particularly preferably 0.1 to 0.4 parts by weight.
Also, when the inner dose solid dosage (tablets), with respect to vitamin B ₁₂ compound 1 part by weight, pranoprofen or a salt 1-100 parts by weight, preferably 5 to 80 parts by weight, particularly preferably 10 to 50 weight Part.

  In the composition of the present invention, for the purpose of enhancing or supplementing the stability of the formulation of the present invention, one or more nonionic surfactants, chelating agents, preservatives, buffers, and pH adjusting agents are further added. It can mix | blend in combination.

The nonionic surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. For example, polyoxyethylene (POE) -polyoxypropylene (POP) block copolymers (eg, poloxamer 407, poloxamer 235, poloxamer 188, etc.); polyoxyethylene-polyoxypropylene block copolymer adducts of ethylenediamine (eg, poloxamine); POE sorbitan fatty acid esters such as monolauric acid POE (20) sorbitan (polysorbate 20), monooleic acid POE (20) sorbitan (polysorbate 80), polysorbate 60; POE cured castor oil such as POE (60) cured castor oil; POE (9) POE alkyl ethers such as lauryl ether; POE (20) POP (4) POE alkyl ethers such as cetyl ether; POE (10) POE alkyl phenyl ethers such as nonyl phenyl ether; POE (10 ) POE alkylphenyl ethers such as nonylphenyl ether . Of these, poloxamer 407, polysorbate 80, POE (60) hydrogenated castor oil, particularly preferably polysorbate 80 are preferred. The numbers in parentheses indicate the number of added moles.
These nonionic surfactants may be used alone or in any combination of two or more.

  In the composition of the present invention, the ratio of the nonionic surfactant to be blended is, for example, 0.001 to 2 w / v%, preferably 0.01 to 2 w / v%, more preferably 0.05 to 1 w / w in the case of an aqueous composition. Examples are v%, particularly preferably 0.15 to 0.5 w / v%.

Examples of the chelating agent include ethylenediaminetetraacetic acid, ascorbic acid, citric acid, phytic acid, polyphosphoric acid, metaphosphoric acid, succinic acid, and salts thereof. Among these, ethylenediaminetetraacetic acid, citric acid or a salt thereof is preferable, and ethylenediaminetetraacetic acid or a salt thereof is particularly preferable.
The salt of ethylenediaminetetraacetic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. For example, sodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, ethylenediaminetetraacetate Mention may be made of alkali metal salts such as tetrasodium acetate.
Ethylenediaminetetraacetic acid or a salt thereof can also be used in the form of a hydrate. Specific examples of the hydrate form include disodium ethylenediaminetetraacetate (hereinafter also referred to as sodium edetate).
These chelating agents may be used alone or in any combination of two or more.

  In the composition of the present invention, the ratio of the chelating agent to be added is, for example, 0.0005 to 0.5 w / v%, preferably 0.001 to 0.2 w / v%, more preferably 0.004 to 0.1 w / v in the case of an aqueous composition. %, Particularly preferably 0.01 to 0.05 w / v%.

Preservatives include sorbic acid or salts thereof, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sodium dehydroacetate, methyl parahydroxybenzoate, paraoxybenzoic acid Examples thereof include ethyl, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), glowkill (trade name, manufactured by Rhodia), and the like. Of these, sorbic acid or a salt thereof, benzalkonium chloride, alkyldiaminoethylglycine hydrochloride, particularly preferably sorbic acid or a salt thereof.
Examples of sorbic acid salts include salts with inorganic bases [for example, ammonium salts; alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), and aluminum salts. And salts with organic bases (for example, salts with organic bases such as methylamine, triethylamine, diethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), particularly sodium salts, A potassium salt is preferred.
These preservatives may be used alone or in any combination of two or more.

  In the composition of the present invention, the proportion of the preservative to be blended is, for example, 0.001 to 2 w / v%, preferably 0.005 to 0.5 w / v%, more preferably 0.005 to 0.3 w / v% in the case of an aqueous composition. Particularly preferably, 0.01 to 0.2 w / v% is exemplified.

Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aminoethylsulfonic acid, aspartic acid, aspartate and the like. Among these, a borate buffer and a phosphate buffer are preferable, and a borate buffer is particularly preferable.
Specific examples of the boric acid buffer include boric acid and salts thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.), and boric acid and borax are particularly preferable.
Specific examples of phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer include citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, boric acid, borax, Examples thereof include disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like.

  In the composition of the present invention, the ratio of the buffering agent to be blended varies depending on the type of buffering agent used and the expected effect and cannot be uniformly defined.For example, in the case of an aqueous composition, 0.01% -3 w / v%, preferably 0.1-2 w / v%, more preferably 0.3-2 w / v%, particularly preferably 0.5-2 w / v%.

  Examples of the pH adjuster include hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, borax, triethanolamine, monoethanolamine and the like. Of these, hydrochloric acid and sodium hydroxide are particularly preferred.

In the composition of the present invention, the appropriate pH varies depending on the application site, dosage form and the like of the aqueous composition, but is usually 6.0 to 9.0, preferably 6.5 to 8.5, more preferably 6.8 to 8.2, particularly preferably about 7.0 to 8.0. It is. A significant deviation from these ranges is undesirable because it may reduce the chemical stability of pranoprofen or a salt thereof and is not acceptable to the living body.
The pH adjustment can be performed by a method known in the art using the buffer, the pH adjuster, or the like.

  The aqueous composition of the present invention is preferably contained in a container having an absorbance of 340 nm to 380 nm of 1.0 or more because pranoprofen can be further stabilized. A container having an absorbance of 340 nm to 380 nm of 1.0 or more is a container having an average absorbance of 340 nm, 350 nm, 360 nm, 370 nm, and 380 nm of 1.0 or more. It is preferably 2.0 or more, more preferably 2.5 or more, particularly preferably 3.0 or more, and still more preferably 3.5 or more.

The absorbance in the container containing the aqueous composition of the present invention is measured by the following method in accordance with the 14th revision Japanese Pharmacopoeia “Plastic Drug Container Test 4. Transparency Test Method”.
UV absorption spectrum measurement cells filled with water, each of 5 pieces cut to a size of 2 to 4 cm in length and 0.9 to 1.1 cm in width, taking a portion with as little curvature as possible from the container body. Absorbance is measured by the UV-visible absorbance measurement method for each measurement wavelength, using a cell immersed in water and filled with water alone as a control.

The container for storing the aqueous composition of the present invention can be used as long as the aforementioned absorbance is achieved, for example, among plastic containers or glass containers.
Examples of plastic container materials include olefin resins (polyethylene, polypropylene, etc.), polyethylene terephthalate resins, polyethylene naphthalate resins, polyarylate resins, polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins. Examples thereof include synthetic resins such as resins, polyamide resins, rigid vinyl chloride resins, styrene resins (polystyrene, acrylonitrile-styrene copolymers (AS resins), etc.), cellulose acetates, etc. Any one of these synthetic resins Or the container etc. which were comprised with 2 or more types of mixtures are mentioned.

Of the containers containing the aqueous composition of the present invention, the plastic container is preferably made of any one of polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, a copolymer polyester thereof, or two or more thereof. The mixture of these is mentioned.
The copolyester is a copolyester mainly comprising any one of ethylene-2,6-naphthalate unit, arylate unit, ethylene terephthalate unit, propylene unit, and ethylene unit, and other polyester units. Examples of the acid component include terephthalic acid, isophthalic acid, hexahydroterephthalic acid, naphthalene-2,6-dicarboxylic acid, and adipic acid. Examples of the copolymer glycol component include 1,3-propanediol. , Tetramethylene glycol, 1,4-cyclohexanedimethanol, neopentyl glycol, propylene glycol, 1,4-butanediol, diethylene glycol and the like.

Among the containers for storing the aqueous composition of the present invention, the following three kinds of containers are particularly preferable as plastic containers.
First, a container composed of polyethylene naphthalate, polyarylate or a copolymer polyester thereof, and second, any one or more of polyethylene naphthalate or polyarylate and any one of polyethylene terephthalate, polypropylene, polyethylene Containers composed of the above mixture are mentioned, preferably containers composed of a mixture of polyethylene naphthalate and polyethylene terephthalate, third, polyethylene naphthalate, polyarylate, copolymerized polyesters thereof, polyethylene terephthalate, Examples thereof include a container made of a material obtained by adding or coating an ultraviolet blocking agent to one or a mixture selected from polypropylene and polyethylene. The ultraviolet blocking agent is as described later.

  The container containing the aqueous composition of the present invention may be a container to which an ultraviolet blocking agent is added or coated. For example, a container molded after adding an ultraviolet blocking agent to glass or synthetic resin, or a container formed by processing a synthetic resin into a sheet and then coated with an ultraviolet blocking agent, and then molded, or glass or synthetic resin And a container coated with an ultraviolet light blocking agent after being molded into a final container shape. Further, a sheet-like synthetic resin to which an ultraviolet blocking agent is added or coated may be shrink-wrapped in a molded container.

As UV-blocking agents, zinc oxide, titanium oxide, triazole compounds, benzoate compounds, substituted acrylonitrile compounds, cyanoacrylate compounds, triazine compounds, oxalic anilide compounds, nickel complex compounds, trade name Tinuvin (R ) Benzotriazole compounds such as 328, Tinuvin (R) 384-2, Tinuvin (R) 400, Tinuvin (R) 400-2, Tinuvin (R) 900, Tinuvin (R) 928, Tinuvin (R) 1130; Methyl cinnamate, sinoxate, diparamethoxycinnamate mono-2-ethylhexanoate glyceryl, paramethoxycinnamate isopropyl diisopropylcinnamate mixture, paramethoxycinnamate 2-ethylhexyl, cinnamate benzyl, etc. Cinnamate UV absorbers; oxybenzone, hydroxymethoxybenzophenone sulfo Acid, sodium hydroxymethoxybenzophenonesulfonate, dihydroxydimethoxybenzophenone, dihydroxydimethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, tetrahydroxybenzophenone and other benzophenone UV absorbers; paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, paradimethyl Benzoic acid ester UV absorbers such as amyl aminobenzoate, 2-ethylhexyl paradimethylaminobenzoate, ethyl 4- [N, N-di (2-hydroxypropyl) amino] benzoate; ethylene glycol salicylate, octyl salicylate, Salicylic acid UV such as dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, methyl salicylate Absorbent, guaiazulene, dimethoxybenzylidenedioxoimidazolidinepropionate 2-ethylhexyl, 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] 1,3,5-triazine, parahydroxyanisole, 2- (2-hydroxy-5-methylphenyl) benzotriazole, 4-tert-butyl-4′-methoxydibenzoylmethane, phenylbenzimidazolesulfonic acid, 2- (4-diethylamino-2-hydroxybenzoyl) -benzoic acid hexyl, etc. Is mentioned. Riboflavin, anthraquinone dyes (1-amino-4-methylanthraquinone, 1,4-diaminoanthraquinone, anthraquinone yellow, etc.), phthalocyanine dyes (phthalocyanine blue (CI Pigment Blue 15; CI 74160; blue 404)), A colorant having absorption at 340 nm to 380 nm such as phthalocyanine green (CI Pigment Green 7) may be used.
Preferably zinc oxide, titanium oxide, Tinuvin (R) 328, Tinuvin (R) 384-2, Tinuvin (R) 400, Tinuvin (R) 400-2, Tinuvin (R) 900, Tinuvin (R) 928, Tinuvin ( R) 1130, 2-methoxyhexyl paramethoxycinnamate, glyceryl mono-2-ethylhexanoate diparamethoxycinnamate, 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] 1,3 , 5-triazine, phenylbenzimidazolesulfonic acid, 2- (4-diethylamino-2-hydroxybenzoyl) -hexyl benzoate, dimethoxybenzylidenedioxoimidazolidinepropionate 2-ethylhexyl, particularly preferably zinc oxide, oxidation Titanium, Tinuvin (R) 328, Tinuvin (R) 384-2, Tinuvin (R) 400, Tinuvin (R) 400-2, Tinuvin (R) 900, Tinuvin (R) 928, Tinuvin (R) 1130 . Zinc oxide and titanium oxide may be further coated with silica, silicon, zinc silicate or the like.

Specific examples include containers in which polyethylene oxide is added or coated with zinc, containers in which polypropylene is added or coated with zinc oxide, containers in which zinc oxide is added or coated on polyethylene terephthalate, and preferably polyethylene terephthalate. A container in which zinc oxide is added or coated.
In the container containing the aqueous composition of the present invention, the proportion of the ultraviolet blocking agent to be added is, for example, 0.05 to 5.0% by weight, preferably 0.1 to 3.0% by weight.

  In the container containing the aqueous composition of the present invention, a container coated with an ultraviolet blocking agent is manufactured by, for example, applying a coating paint containing an ultraviolet absorber to a molded container or a synthetic resin sheet. Can do. Here, the coating paint is transparent and is a radical polymerization type acrylic type (for example, polyester polyacrylate, urethane polyacrylate, epoxy polyacrylate, polyether polyacrylate, side chain acryloyl type acrylic resin, etc.), Thiolene type (for example, polythiol acrylic type oligomer, polythiol spiroacetal type, etc.), unsaturated polyester, or cationic polymerization type epoxy resin can be used.

Moreover, the container which accommodates the aqueous composition of this invention may shape | mold from the sheet | seat which extended the raw material which comprises a container in the shape of a film, and adhere | attached and laminated | stacked this film.
In addition, the absorbance at 450 nm is 1.0 or less, preferably 0.8 or less, more preferably 0.6 or less, particularly preferably 0.4 or less, and still more preferably 0.2 or less because the foreign matter test of the contents or confirmation of the remaining capacity can be performed. .

  In the composition of the present invention, the osmotic pressure ratio can be adjusted within a range that is acceptable to a living body, if necessary. The appropriate osmotic pressure ratio varies depending on the application site, dosage form and the like of the aqueous composition, but is usually 0.3 to 4.2, preferably 0.3 to 2.1, more preferably 0.5 to 1.8, and particularly preferably about 0.8 to 1.5. The adjustment of the osmotic pressure can be performed by a method known in the art using an inorganic salt and a polyhydric alcohol, a sugar alcohol, a saccharide or the like.

  The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 0.9 w / v% sodium chloride aqueous solution based on the 14th revised Japanese pharmacopoeia. Use to measure. In addition, the osmotic pressure of the standard solution for measuring the osmotic pressure ratio is measured before and after the measurement of the test sample, and the osmotic pressure ratio is calculated using the actually measured value obtained at this time. The standard solution for measuring the osmotic pressure ratio was sodium chloride (Japanese Pharmacopoeia standard reagent) dried at 500-650 ° C for 40-50 minutes, then allowed to cool in a desiccator (silica gel), accurately weighed 0.900 g and purified. Dissolve in water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

  The composition of this invention is not limited to a specific form, According to the objective, a liquid agent, a semi-solid agent, or a solid agent, Preferably a liquid agent or a solid agent can be mention | raise | lifted. Specifically, liquids, semisolids (ointments), tablets (including intraoral quick disintegrating tablets, chewable tablets, dry tablets, multilayer tablets, effervescent tablets, lozenges, jelly-like drops, etc.), Granules, fine granules, powders, hard capsules, soft capsules, gels, jelly agents and the like can be exemplified, and liquids, tablets, granules, hard capsules or soft capsules are particularly preferable. These preparations are obtained by a conventional method, and in this case, in addition to the above-mentioned components, conventional additives corresponding to the preparation can be used.

The liquid agent may be a uniform solution, a suspension, or a composition used by mixing or dissolving. Specifically, eye drops (liquid) [however, eye drops include eye drops (liquid) that can be applied while wearing contact lenses], eye wash (liquid) [however, eye drops are used when wearing contact lenses. Eyewash (liquid), nasal drops (liquid), nasal rinse (liquid), contact lens preparation [contact lens mounting liquid, contact lens care liquid (contact lens disinfectant, contact lens) Preservatives, contact lens cleaning agents, contact lens cleaning preservatives, etc.], syrups, drinks, and the like. Among these, eye drops (liquid), eye wash (liquid), syrup, and drink are preferable, and eye drops (liquid) and eye wash (liquid) are more preferable.
The agent for contact lenses can be applied to all contact lenses including hard contact lenses and soft contact lenses, but is particularly preferably applied to oxygen permeable hard contact lenses or soft contact lenses.

  The composition of the present invention can contain various components (including pharmacologically active components and physiologically active components) in combination with the above components as long as the effects of the present invention are achieved. There are no particular restrictions on the types of such components, for example, decongesting components, ophthalmic modifier components, anti-inflammatory components or astringent components, antihistamine components or antiallergic components, vitamins, amino acids, antibacterial agents Ingredients, bactericidal ingredients, macromolecular compounds such as sugars, gums, polysaccharides, cellulose or its derivatives or their salts, local anesthetic ingredients, steroid ingredients, glaucoma treatment ingredients, cataract treatment ingredients, antipyretic analgesics ingredients, sedation A hypnotic component, an antitussive component, a bronchodilator component or a sympathomimetic component, an expectorant component, a crude drug component and the like can be exemplified. Examples of suitable components in the present invention include the following components.

  Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate. These may be d-form, l-form or dl-form.

  Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien, and the like.

  Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, sodium azulenesulfonate, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, diclofenac sodium, bromfena Sodium chloride, berberine chloride, berberine sulfate, piroxicam, etc.

  Antihistamine component or antiallergic component: for example, acitazanolast, amlexanox, ibudilast, pemirolast, tazanolast, tranilast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, potassium pemirolast, chlorpheniramine maleate , Iproheptin, isothipentyl, dipheterol, diphenylpyralin, triprolidine, tripelenamine, tondilamine, promethazine, methodirazine, carbinoxamine, alimemazine, promethazine, mebuhydrolin, phenetadine, oxatomide, mequitazine, terfenadine, epinastine, chincetazine , Clemastine fumarate, hydrochloric acid Such as Rasuchin.

  Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, sodium flavin adenine dinucleotide, pyridoxal phosphate, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate.

  Amino acids: For example, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, potassium aspartate, magnesium aspartate, magnesium / aspartate mixture, sodium glutamate, sodium chondroitin sulfate and the like. These may be d-form, l-form or dl-form.

  Antibacterial or bactericidal component: for example, aminodeoxykanamycin sulfate, kanamycin sulfate, gentamicin sulfate, sisomycin sulfate, streptomycin sulfate, tobramycin, micronomycin sulfate, alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, Sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomethazole sodium, sulfisomidine sodium, tetracycline hydrochloride, oxytetracycline hydrochloride, ofloxacin, Norfloxacin, Levofloxacin, Lomefloxacin hydrochloride, Sulbenicin sodium, Cefmenoxime hydrochloride, Benzylpenicillin potassium, Bell sulfate Phosphorus, berberine chloride, colistin sodium metasulfonate, erythromycin, erythromycin lactobionate, kitasamycin, spiramycin, fradiomycin sulfate, polymyxin sulfate, dibekacin, amikacin, amikacin sulfate, acyclovir, iododeoxycytidine, idoxuridine, cyclocydine Tidine, cytosine arabinoside, trifluorothymidine, bromodeoxyuridine, polyvinyl alcohol iodine, iodine, amphotericin B, isoconazole, econazole, clotrimazole, nystatin, pimaricin, fluorocytosine, miconazole.

Sugars: for example glucose, fructose, galactose, mannose, ribose, allose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, glucobiose, vicyanose, rutinose, lactose, pullulan, lactulose, raffinose, maltitol , Stachyose and so on.
High molecular compounds such as gum and polysaccharides: for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guayac fat, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran , Garagenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, ceramide, polyvinyl alcohol (complete, Or partially saponified product), polyvinylpyrrolidone, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deo Such Shiribo nucleic acids, and the like pharmaceutically acceptable salts.
Cellulose or a derivative thereof or a salt thereof: for example, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose and the like.

  Local anesthetic components: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride.

  Steroid component: For example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, sodium dexamethasone metasulfobenzoate, sodium dexamethasone sulfate Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.

  Glaucoma treatment components: for example, isopropyl unoprostone, epinephrine, apraclonidine hydrochloride, carteolol hydrochloride, dipivefrin hydrochloride, dorzolamide hydrochloride, pilocarpine hydrochloride, bunazosin hydrochloride, bupranolol hydrochloride, betaxolol hydrochloride, befnolol hydrochloride, carbachol, levobunolol hydrochloride, epinephrine hydrochloride , Distigmine bromide, nipradilol, timolol maleate, latanoprost and the like.

  Cataract treatment component: for example, glutathione, pirenoxine, sodium 5,12-dihydroazapentacene disulfonate and the like.

Antipyretic analgesic component: for example, acetylsalicylic acid, acetaminophen, lactylphenetidine and the like.
Sedative hypnotic ingredients: for example, bromvalerylurea, allylisopropylacetylurea, etc.
Antitussive ingredients: achloramide, cloperastine, pentoxyberine (carbetapentane), tipepidine, dibutate, dextromethorphan, codeine, dihydrocodeine, noscapine and their pharmacologically acceptable salts (eg cloperastine hydrochloride, tipepidine hibenzate) Dextromethorphan hydrobromide, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, etc.).

Bronchodilator component or sympathomimetic component: ephedrine, methylephedrine, pseudoephedrine, trimethquinol, methoxyphenamine and pharmacologically acceptable salts thereof (for example, ephedrine hydrochloride, methylephedrine hydrochloride, pseudoephedrine hydrochloride) , Trimethquinol hydrochloride, methoxyphenamine hydrochloride, etc.).
Expectorant ingredient: sodium guaiacol sulfonate, guaifenesin, etc.
Herbal medicine ingredients: licorice, kikyo, fennel, chamomile, keihi, kakkonto, etc.

  For the composition of the present invention, the blending amounts of these components are appropriately selected according to the type of formulation, the type of active ingredient, etc., and the blending amounts of various components in ophthalmic preparations, internal preparations, etc. Known in the field. For example, it can be selected from a range of about 0.0001 to 30 w / v%, preferably about 0.001 to 10 w / v% with respect to the whole preparation.

  In addition, in the composition of the present invention, various components and additives used for pharmaceuticals, quasi drugs and the like are appropriately selected depending on the use and form as long as the effects of the invention are not impaired. It is possible to formulate it in combination. For example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of liquids, thickeners, sugars, sugar alcohols, surfactants, tonicity agents, fragrances or refreshing Examples of solid agents such as an agent, a stabilizer, a solubilizer, and a base include various additives such as a binder, an excipient, a lubricant, a disintegrant, and a foaming agent. Examples of suitable components in the present invention include the following components.

  Thickeners: for example, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate and the like.

Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.

  Surfactant: For example, glycine-type amphoteric surfactant such as alkyldiaminoethylglycine; alkyl quaternary ammonium salt (specifically, cationic surfactant such as benzalkonium chloride and benzethonium chloride).

  Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.

  Perfume or refreshing agent: for example, camphor, geraniol, borneol, menthol, leopard, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. These may be d-form, l-form or dl-form.

  Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.

  Solubilizer, base: octyldodecanol, olive oil, sesame oil, titanium oxide, potassium bromide, soybean oil, camellia oil, corn oil, rapeseed oil, paraffin, castor oil, plastibase, peanut oil, lanolin, petrolatum and the like.

Binder: Hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like.
Excipients: Sucrose, lactose, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.
Lubricant: polyethylene glycol, magnesium stearate, etc.
Disintegrants: methylcellulose, polysorbate 80, croscarmellose sodium, etc.
Foaming agent: sodium bicarbonate and the like.

The composition of this invention can be manufactured by a well-known method. For example, in eye drops or eyewashes, pranoprofen and vitamin B ₁₂ are dissolved using distilled water or purified water and additives, adjusted to a predetermined osmotic pressure and pH, and filtered and sterilized in an aseptic environment. And can be manufactured by aseptically filling a container that has been sterilized by washing.

The present invention also includes a method for stabilizing light of pranoprofen. In the method of the present invention, a light stabilizer of pranoprofen it can be achieved by combined use of pranoprofen or a salt thereof and vitamin B ₁₂ compound. Pranoprofen or a salt thereof and vitamin B ₁₂ include, in the method of the present invention, as well as its mixing ratio, including the amount is the same as that used in the composition.

  In the light stabilization method of the present invention, various components (including pharmacologically active components and physiologically active components) may be contained in combination as long as the effects of the invention are not impaired. The kind of such components is not particularly limited, but specific examples are the same as those for the above-described composition.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

Test Example 1 Light stability test
According to the formulation described in Table 1, each component was dissolved in purified water to prepare a test solution with a total volume of 100 mL.
Each test solution was filled into a transparent glass screw tube (capacity 10 mL) by 7 mL, and these were used as test samples (n = 3). For this test sample, light stability test equipment ("Light-Tron LT-120 D3CJ type", manufactured by Nagano Kagaku Co., Ltd.) is used. Was continuously irradiated for 6 hours, and the test solution was exposed to light with an integrated dose of 30,000 lx · hr. The concentration of pranoprofen in the test sample before and after light irradiation was measured by high performance liquid chromatography. From the measured pranoprofen concentration of each test sample, the residual ratio (%) of pranoprofen was calculated according to the following formula.
Residual rate (%) = planoprofen concentration after light irradiation × 100 / planoprofen concentration before light irradiation Further, the properties (degree of cloudiness) of each test sample after light irradiation were visually observed according to the following evaluation criteria. evaluated.
<Evaluation criteria>
++++: Severely cloudy, ++: Slightly cloudy, +: Slightly cloudy, −: No cloudiness, clear results are shown in Table 1.

In Comparative Examples 1 to 4, it was confirmed that pranoprofen was decomposed to about half and became cloudy and the clarity was impaired. On the other hand, in Examples 1 to 4, the residual ratio of pranoprofen was 97% or more, especially in Example 3, the light stability was drastically improved to 99.5%, maintaining a clear state, and appearance. It was confirmed that can be maintained well.
In Examples 1 to 4, when the concentration of cyanocobalamin in the test samples before and after the light irradiation was measured by high performance liquid chromatography, the residual ratio was almost 100%, and it was said that it was unstable to light. It was confirmed that cyanocobalamin is present stably.
Thus, since pranoprofen that becomes extremely unstable in the presence of water can be stabilized in an aqueous solution, the effect of light stabilization can be expected even in solid preparations such as tablets.

The formulation examples are given below. The osmotic pressure ratio was adjusted to 0.8 to 2.0.
The compounding amounts in the following examples all represent weights in the case of appropriate amounts or those not particularly described. In Examples 5 to 18 and 21 to 27, containers of a mixture of 10% polyethylene naphthalate and 90% polyethylene terephthalate (absorbance of 340 nm to 380 nm of 3.0 or more) were filled.

Example 19 Tablet: 1 tablet of pranoprofen 75 mg
Hydroxocobalamin 0.1mg
Hydroxypropylcellulose 17mg
Magnesium stearate 2mg
Crystalline cellulose
180mg total

Example 20 Tablet: 1 tablet Planoprofen 35 mg
Hydroxocobalamin 0.06mg
Hydroxypropylcellulose 17mg
Magnesium stearate 2mg
Crystalline cellulose
180mg total

  Further, according to the formulations of Examples 5 to 18 and 21 to 27, each component was dissolved in purified water to prepare test solutions 5 to 18 and 21 to 27. Each test solution was filled in a polyethylene terephthalate container, and the test solution It was set as Examples 28-48 in order from 5.

Test Example 2 Light stability test using a container of a mixture of polyethylene naphthalate and polyethylene terephthalate
In accordance with the formulations of Examples 1 to 4 shown in Table 1, each component was dissolved in purified water to prepare test solutions 1 to 4 with a total amount of 100 mL.
30 mL of each test solution was filled into a container (capacity 30 mL) of a mixture of 10% polyethylene naphthalate and 90% polyethylene terephthalate, and Examples 49 to 52 were sequentially formed from Test Solution 1, and these were used as test samples (n = 3). For this test sample, light stability test equipment ("Light-Tron LT-120 D3CJ type", manufactured by Nagano Kagaku Co., Ltd.) is used. Was continuously irradiated for 6 hours, and the test solution was exposed to light having an accumulated irradiation amount of 30,000 lx · hr. The concentration of pranoprofen in the test sample before and after light irradiation was measured by high performance liquid chromatography. From the measured pranoprofen concentration of each test sample, the residual ratio (%) of pranoprofen was calculated according to the following formula.
Residual rate (%) = planoprofen concentration after light irradiation × 100 / planoprofen concentration before light irradiation In addition, the property (degree of cloudiness) of each test sample after light irradiation was visually in accordance with the following evaluation criteria. evaluated.
<Evaluation criteria> ++++: Severely cloudy, ++: Slightly cloudy, +: Slightly cloudy,-: No cloudiness, clear

As a result, in all of Examples 49 to 52, it was confirmed that the degradation rate of pranoprofen was 5% or less, the light stability was improved, the clear state was maintained, and the appearance was satisfactorily maintained.
Moreover, when the light absorbency of 340 nm-380 nm of the container used for this test was measured, it was 3.0 or more.

Claims (7)

Pranoprofen or a composition containing the salt and vitamin B ₁₂ compound. The composition according to claim 1, wherein the vitamin B ₁₂ is cyanocobalamin, mecobalamin, hydroxocobalamin, hydroxocobalamin hydrochloride, or hydroxocobalamin acetate. The composition according to claim 1 or 2, wherein the composition is an aqueous composition. The composition according to any one of claims 1 to 3, wherein the composition is contained in a container having an absorbance of 340 nm to 380 nm of 1.0 or more. The composition according to claim 4, wherein the container is a container composed of any one of polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, a copolymer polyester thereof, or a mixture of two or more thereof. . The composition according to claim 4 or 5, wherein the container is a container to which an ultraviolet blocking agent is added or coated. Pranoprofen or characteristics to the optical method for stabilizing pranoprofen that blending a salt thereof, and a vitamin B ₁₂ compounds in the composition.