JP5575100B2 - Planoprofen-containing composition - Google Patents

Description

The present invention, pranoprofen or a salt thereof, and to the improvement of eyestrain due to vitamin B ₂ compounds.

  In recent years, as the number of people who complain of eye fatigue has increased, a solution has been desired. For example, eye drops and internal medicines, products that give warmth and coolness, massage machines around the eyes, etc. Products to be taken have been developed.

  Causes of eye fatigue include reading, gazing, and observation due to overuse of the eye and mental tension. Eyes due to VDT (Visual Display Terminal) work, which has increased rapidly with the spread of personal computers. The tiredness of has become very much. In particular, many contact lens wearers complain of eye fatigue due to VDT work. Patients who complain of eye fatigue usually have symptoms such as pain in the back of the eye, blurred vision, dry eyes, stiff shoulders, and head weight. When the eyestrain is severe, nausea and nausea May also accompany. It has been pointed out that these symptoms are caused by the ciliary muscles becoming excessively tense due to long-term gaze work and the like, and the regulation function of the eyes is lowered.

Many eye drops for improving eye fatigue include vitamin B ₂ and other vitamins and amino acids. Flavin adenine dinucleotide is inter alia coenzyme vitamin B ₂ such, recovered eye fatigue, ocular tissue, in particular known to activate the metabolism of the cornea (Patent Document 1). Furthermore, flavin adenine dinucleotide is also known to have anti-allergic / anti-inflammatory action (Patent Document 2), uveitis treatment action (Patent Document 3), improvement of dry eyes (Patent Document 4), and the like.

  On the other hand, pranoprofen is known as a highly safe acidic non-steroidal anti-inflammatory agent of propionic acid type with excellent anti-inflammatory, analgesic and antipyretic effects, and is an eye drop, tablet, capsule, syrup Although it is widely used in the form of an internal medicine such as an agent, the effect on eye fatigue has not been known so far. Furthermore, since pranoprofen decomposes with time when exposed to light, it needs to be stored in the dark. 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. .

Japanese Unexamined Patent Publication No. 08-104636 JP 63-188627 A Japanese Unexamined Patent Publication No. 08-225451 Japanese Patent Laid-Open No. 11-263729

  An object of the present invention is to provide a composition having a high effect of improving eye fatigue.

The present inventors diligently studied to solve the above problems, and the effect of improving eye fatigue becomes remarkable by adding vitamin B ₂ to a composition containing pranoprofen or a salt thereof. The present invention has been completed.

That is, this invention is a composition hung up to the following (1)-(15).
(1) A composition containing pranoprofen or a salt thereof, and vitamin B ₂ .
(2) The composition according to (1), wherein the vitamin B ₂ is flavin adenine dinucleotide or a salt thereof.
(3) The composition according to (1) or (2), further comprising a monoterpenoid.
(4) Furthermore, 1 type or 2 types or more selected from the group which consists of a thickener, a nonionic surfactant, a chelating agent, a preservative, a buffering agent, and a pH adjuster are contained (1)-(3 ).
(5) A composition for improving eye fatigue, comprising pranoprofen.
(6) The composition according to any one of (1) to (5), wherein the composition is an eye drop, a nose drop, an eye wash, a contact lens preparation, or an internal preparation.
(7) The composition according to any one of (1) to (6), wherein the composition is an aqueous composition.
(8) The composition according to any one of (1) to (5), wherein the composition is an ophthalmic composition.
(9) The composition according to any one of (1) to (4), wherein the composition is an eye drop or eye wash for improving eye fatigue.
(10) The composition according to any one of (1) to (9), which is contained in a container having an average absorbance of 340 nm to 380 nm of 1.0 or more.
(11) The container is a container composed mainly of any one of polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, a copolymer polyester thereof, or a mixture of two or more kinds (10 ).
(12) The composition according to (10), wherein the container is a container composed mainly of polyethylene naphthalate, polyarylate, or a copolymer polyester thereof.
(13) A container in which a main raw material is a mixture of at least one of polyethylene naphthalate, polyarylate, or a copolymer polyester thereof, and at least one of polyethylene terephthalate, polypropylene, and polyethylene. The composition according to (10).
(14) The container is composed of one or more selected from polyethylene naphthalate, polyarylate, copolymerized polyesters thereof, polyethylene terephthalate, polypropylene, and polyethylene, and a UV blocking agent is added as a main raw material. The aqueous composition according to (10), which is a container composed of a coated material.
(15) The composition according to any one of (10) to (14), wherein the container is a container to which an ultraviolet blocking agent is added or coated.

The present invention can remarkably improve eye fatigue by containing pranoprofen or a salt thereof and vitamin B ₂ .

  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 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 nasal drops, eyewashes or contact lens preparations, 0.001 to 0.01 w / v. v%, preferably 0.001 to 0.005 w / v%, and in the case of syrup, 0.1 to 2 w / v%, preferably 0.5 to 1.5 w / v%.

  Moreover, in the case of a solid composition, it is 8 to 90 weight%, Preferably it is 12 to 80 weight%. Specifically, in the case of a tablet, it may be within the range of 20 to 100 mg, preferably about 30 to 80 mg per tablet (100 to 250 mg) and included in the above-mentioned weight%. The daily dose for an adult may be within a range of, for example, about 0.1 to 10,000 mg, preferably about 1 to 1000 mg.

The vitamin B ₂ 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.

Examples of vitamin B ₂ include riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, and flavin mononucleotide. Vitamin B ₂ may be a salt with an inorganic base such as sodium salt or potassium salt, and examples thereof include sodium riboflavin phosphate and sodium flavin adenine dinucleotide. Among these vitamin B ₂ types, riboflavin phosphate, riboflavin sodium phosphate, riboflavin butyrate, flavin adenine dinucleotide, and flavin adenine dinucleotide sodium are preferable, and flavin adenine dinucleotide sodium is particularly preferable.

In the composition of the present invention, the proportion of vitamin B _{2 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, 0.0005 to 0.1 w / v%, preferably 0.001. It is about ~ 0.05w / v%. Specifically, in the case of eye drops, 0.005 to 0.1 w / v%, preferably about 0.01 to 0.05 w / v%, and in the case of nasal drops, eyewashes or contact lens agents, 0.0005 to 0.01 w / v. v%, preferably about 0.001 to 0.005 w / v%, and in the case of a syrup, it is 0.01 to 0.1 w / v%, preferably 0.01 to 0.05 w / v%.

  Moreover, in the case of a solid composition, it is 4 to 50 weight%, Preferably it is 8 to 45 weight%. Specifically, in the case of a tablet, it may be in the range of 1 to 50 mg, preferably about 2 to 45 mg per tablet (100 to 250 mg) and included in the weight%. The daily dose for an adult may be within a range of, for example, about 0.1 to 10,000 mg, preferably about 1 to 1000 mg.

In the composition of the present invention, the compounding ratio of pranoprofen or a salt thereof and vitamin B ₂ is not particularly limited as long as the effect of the present invention is obtained, but with respect to 1 part by weight of pranoprofen or a salt thereof, Vitamin B ₂ is 0.001 to 100 parts by weight, preferably 0.05 to 10 parts by weight, particularly preferably 0.2 to 5 parts by weight.

  The composition of the present invention may further contain a monoterpenoid in order to improve the effect of improving eye fatigue.

  Monoterpenoids include cyclic groups such as menthol, camphor, borneol, limonene, cineol, terpinene, ferrandrene, menthone, terpineol, carvone, perylaldehyde, thymol, p-cymene, carvacrol, cuminal, pinene, camphene, tuyon, and karen. Examples thereof include chain monoterpenoids such as monoterpenoid, geraniol, nerol, linalool, citral, citronellol, citronellal, myrcene and ocimene, and preferred are menthol, camphor, borneol, limonene, cineol, geraniol and linalool. The three-dimensional structure of these monoterpenoids may be d-form, l-form or dl-form, or (+)-form, (-)-form or (±) -form. Among these, d-menthol, l-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, d-limonene, l-limonene, dl-limonene, d-linalool L-linalool, particularly preferably l-menthol, d-camphor and d-borneol.

  Monoterpenoids may be blended as a mixture of essential oils, such as eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, mint oil, cypress oil, turpentine oil, cedar oil, camphor oil, chromodi oil. , Rose oil, geranium oil, lemon oil, orange oil, orange peel oil, salamander oil, thyme oil, lavender oil, citronella oil, lemongrass oil, eucalyptus oil, peppermint water and the like.

  These monoterpenoids may be used alone or in any combination of two or more.

  In the composition of the present invention, the proportion of the monoterpenoid to be blended is, for example, 0.00005 to 5 w / v%, preferably 0.0001 to 1 w / v%, particularly preferably 0.0002 to 0.1 w / v% in the case of an aqueous composition. Illustrated.

  In the composition of the present invention, for the purpose of enhancing or supplementing the stability of the preparation of the present invention, a thickener, chelating agent, nonionic surfactant, preservative, buffer, and pH adjuster Or it can mix | blend in combination of 2 or more types.

  Examples of the thickener include polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, polyoxyethylene-polyoxypropylene block copolymer (BASF Wyandotte Coproration, Pluronic, Tronic, etc.), cellulose derivatives [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208,2906,2910 etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or their salts], macrogol (300,400, 1500,4000, etc.), chondroitin sodium sulfate, gum arabic, tragacanth, dextran 70, glucose, sorbitol, etc. Alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), cellulose derivatives (methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208,2906,2910, etc.), carboxymethylcellulose or their Salt), Macrogol 300, Macrogol 400, and Dextran 70.

  These thickening agents may be used alone or in any combination of two or more.

  In the composition of the present invention, for example, in the case of an aqueous composition, the proportion of the thickening agent to be blended is 0.0005 to 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 or physiologically acceptable. For example, sodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, etc. The alkali metal salt of can be mentioned.

  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%.

  The nonionic surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically 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%.

  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.), glow kill (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 added 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 composition of the present invention can be used locally or systemically to improve eye fatigue. Since the effect of the present invention is exhibited by the coexistence of pranoprofen or a salt thereof and vitamins, it is preferable that the administration be local administration that facilitates cooperation at the site of action after administration.
Moreover, it is desirable that it is an aqueous composition which tends to exhibit an effect quickly in an action site.

  The composition of this invention is not limited to a specific form, According to the objective, a liquid agent, a semisolid agent, or a solid agent (solid composition), Preferably a liquid agent or a solid agent can be mention | raise | lifted. Specifically, liquids, semi-solid preparations (ointments), tablets (including intraoral quick disintegrating tablets, chewable tablets, dry tablets, multilayer tablets, effervescent tablets, lozenges, jelly-like drops, etc.), Examples thereof include granules, fine granules, powders, hard capsules, soft capsules, gels, and jelly agents.

  A liquid, tablet, granule, hard capsule or soft capsule is preferable, and a liquid is particularly preferable.

  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), contact lens preparation [contact lens mounting liquid, contact lens care preparation (contact lens disinfectant, contact lens preservative, contact lens use] Cleaning agents, contact lens cleaning preservatives etc.)], syrups, drinks and the like. Among these, eye drops, eye wash, nasal drops, and contact lens agents, preferably for topical administration, more preferably ophthalmic compositions such as eye drops, eye wash, contact lens agents, and the like. is there.

  The contact lens agent can be applied to all contact lenses including hard contact lenses and soft contact lenses, but it is particularly preferable to apply the contact lens agent to soft contact lenses that are said to be prone to eye fatigue.

  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 use of the composition of the present invention, an anti-inflammatory based on pharmacological effects inherent in pranoprofen and vitamin B _2, addition, metabolic disorder improving include improvement of eye fatigue. Of the compositions of the present invention, eye drops or eye washes are suitable for improving eye fatigue.

  The 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 according to the 14th revised Japanese Pharmacopoeia “Plastic drug container test method 4. Transparency test”.

  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. Resin, polyamide resin, hard vinyl chloride resin, styrene resin (polystyrene, acrylonitrile-styrene copolymer (AS resin), etc.), synthetic resins such as cellulose acetate can be exemplified, and as a main raw material constituting a plastic container, An olefin resin or a polyester resin is preferable. The “main raw material” refers to a raw material that occupies 50% by weight or more, preferably 70% by weight or more, of all constituent raw materials of the plastic container.

  Of the containers containing the aqueous composition of the present invention, the main raw material constituting the plastic container is preferably polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, a copolymer polyester thereof, or 2 or more types of mixtures are 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 mainly of polyethylene naphthalate, polyarylate or a copolymer polyester thereof, and second, any one or more of polyethylene naphthalate or polyarylate and any of polyethylene terephthalate, polypropylene and polyethylene Or a container composed mainly of a mixture of at least one kind, preferably a container composed mainly of a mixture of polyethylene naphthalate and polyethylene terephthalate, and thirdly, polyethylene naphthalate, polyarylate, Containers made of a material obtained by adding or coating an ultraviolet blocking agent using one or a mixture of two or more selected from these copolymerized polyesters, polyethylene terephthalate, polypropylene, and polyethylene as main raw materials are listed. . 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 For example, a container coated with an ultraviolet 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 hydroxymethoxybenzophenone sulfonate, dihydroxydimethoxybenzophenone, dihydroxydimethoxybenzophenone sodium disulfonate, benzophenone UV absorbers such as dihydroxybenzophenone, tetrahydroxybenzophenone; 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-ethylhexyl 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) -benzoyl hexyl, 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 zinc oxide is added or coated on polyethylene, containers in which zinc oxide is added or coated on polypropylene, 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 oligomer, polythiol spiroacetal type, etc.), unsaturated polyester, cationic polymerization type epoxy resin, or the like can be used.

  Moreover, the container which accommodates the 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 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 0.6 to 1.5. The osmotic pressure can be adjusted by a method known in the art using an inorganic salt and a polyhydric alcohol, sugar alcohol, 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. 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 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 exhibited. The type of such component is not particularly limited, and examples thereof include a decongestant component, an ocular muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial agents. Drug component, bactericidal component, local anesthetic component, steroid component, glaucoma treatment component, cataract treatment component, antipyretic analgesic component, sedative hypnotic component, antitussive component, bronchodilator component or sympathomimetic component, expectorant Ingredients, herbal medicine ingredients 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 agent 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, chinemethadine, rostemadine , 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.

  Antimicrobial component 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.

  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, in the case of an aqueous composition, it can be selected from the range of about 0.0001 to 30 w / v%, preferably about 0.001 to 10 w / v% with respect to the whole preparation. In the case of a preparation for internal use, the daily dose for adults can be selected from a range of 0.01 to 10000 mg, preferably about 0.1 to 1000 mg.

  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, gums, polymer compounds such as polysaccharides, saccharides, sugar alcohols, surfactants, etc. Solid agents such as tonicity agents, fragrances or refreshing agents, stabilizers, solubilizers, bases, and the like can include various additives such as binders, excipients, lubricants, disintegrants, and foaming agents. . Examples of suitable components in the present invention include the following components.

  High molecular compounds such as gums and polysaccharides: for example, Karaya gum, xanthan gum, carob gum, guar gum, guayac fat, quince seed, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, cyclodextrin, dextran, garaginan , Gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, ceramide, polyvinyl methacrylate, polyacrylic acid, polyethyleneimine Ribonucleic acid, deoxyribonucleic acid and the like, and pharmaceutically acceptable salts thereof.

  Sugars: for example fructose, galactose, mannose, ribose, allose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, glucobiose, vicyanose, lutinose, lactose, pullulan, lactulose, raffinose, maltitol, stachyose Such.

  Sugar alcohols: For example, xylitol, mannitol and the like.

  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, anethole, eugenol, ryuunou, fennel oil, bonito perfume oil, clove oil, anise oil, cinnamon oil and the like.

  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.

  Excipients: Sucrose, lactose, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.

  Lubricant: Magnesium stearate, etc.

  Disintegrant: croscarmellose sodium and the like.

  Foaming agent: sodium bicarbonate and the like.

The composition of this invention can be manufactured by a well-known method. For example, in an eye drop or eye wash, pranoprofen or a salt thereof and vitamin B ₂ are dissolved using distilled water or purified water and additives, adjusted to a predetermined osmotic pressure and pH, It can be manufactured by sterilizing by filtration and aseptically filling containers that have been sterilized by washing.

  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 Fatigue self-assessment 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.

  For 4 healthy subjects, the test solution of Comparative Example 1 was instilled into both eyes before VDT work, 1 hour after the start of VDT work, and 2 hours later, and after 2 hours of instillation, self-assessment of fatigue was performed. It was. The evaluation criteria and evaluation items are 18 evaluation items according to the following five-step evaluation criteria according to Yoshiko Nakamura, “Diagnosis and Countermeasures for Eye Fatigue”, New Ophthalmology, Vol. 14, No. 9, pages 1319–1326. The subject was given a score for and the total score was taken as the fatigue level. Similarly, the fatigue strength of the test solutions of Comparative Examples 2 and 3 and Example 1 was also evaluated.

  From the degree of fatigue evaluated for each test solution, a self-evaluation improvement value was calculated according to the following formula on the basis of one eye point after Comparative Example.

Self-assessment improvement value = Fatigue degree (after 1 instillation of Comparative Example) −Fatigue degree (after instillation of test solution)
<Evaluation criteria>
0: No 1: Symptom is not enough to worry 2: Symptom is worrisome, but is left as it is 3: Cannot be left as it is, so I would like to consult someone 4: Need treatment <Assessment>
Eyes are tired, back of eyes hurts, eyes are blurred, tears are born, blood is congested, eyes are hot, eyes are dull / heavy / compressed, eyes are dry, dazzling, eyes are open Painful, blurry, double-looking, foreign body sensation, out of focus as distance changes, headache, dizziness / dizziness, stiff shoulders / backache, heavy head The results are shown in Table 1.

  From Comparative Examples 2 and 3, it can be seen that pranoprofen or flavin adenine dinucleotide sodium also has an effect of slightly improving the self-evaluation of the fatigue degree, but both pranoprofen and flavin adenine dinucleotide sodium are contained. In Example 1, it was confirmed that the self-evaluation of the fatigue degree significantly improved.

Test example 2 Focus adjustment speed measurement test
Immediately after the evaluation of Test Example 1 was completed, the far index set within the focus adjustment force range (4 to 5D) of the four subjects using the focus adjustment force measuring instrument (Accomodometer AR3-SV6: manufactured by Nidec Co.). And the near index are stared as alternate presentations for 5 seconds (step method), and the tension velocity (GRAD value (cm / sec)) of the ciliary muscle when moving from the far index to the near index is measured three times. The average value was obtained. Large tension speed (large absolute value of GRAD value) indicates fast focus adjustment speed. From the measured GRAD value of each test sample, the adjustment speed improvement rate (%) was calculated according to the following formula, based on the eyedrop after the first eyedrop of Comparative Example.

Adjustment rate improvement rate (%) = GRAD value (average value after instillation of test solution) / GRAD value (average value after instillation of 1 comparative example) × 100
The results are shown in Table 2.

  From Comparative Examples 2 and 3, it can be seen that pranoprofen or flavin adenine dinucleotide sodium also has an effect of increasing the focus control rate, but in Example 1 containing both pranoprofen and flavin adenine dinucleotide sodium, It was confirmed that the focus adjustment speed was significantly improved.

  The formulation examples are given below.

  The compounding amounts in the following examples all represent w / v% in the case of an appropriate amount or a unit not particularly described. In Examples 2 to 19, a container of a mixture of 10% polyethylene naphthalate and 90% polyethylene terephthalate (absorbance of 340 nm to 380 nm of 3.0 or more) was filled, and light at 50,000 lx was applied at 25 ° C. for 6 hours. When continuously irradiated and exposed to light with an integrated irradiation amount of 30,000 lx · hr, in all of Examples 2 to 19, the residual ratio of pranoprofen was maintained at 90% or more.

Example 20 Tablet: 1 tablet of pranoprofen 75 mg
Flavin adenine dinucleotide sodium 2mg
Hydroxypropylcellulose 17mg
Magnesium stearate 2mg
Crystalline cellulose
180mg total
According to the Japanese Pharmacopoeia General Rules for Preparation, “Tablets”, 180 mg tablets (tablets taken 1 tablet 3 times a day) were manufactured. More specifically, ingredients other than magnesium stearate are mixed and granulated. Thereafter, magnesium stearate was mixed until uniform, and then tableted to produce tablets.

Example 21 Tablet: 1 tablet of pranoprofen 35 mg
Riboflavin sodium phosphate 2mg
Hydroxypropylcellulose 17mg
Magnesium stearate 2mg
Crystalline cellulose
180mg total
According to the Japanese Pharmacopoeia General Rules for Preparation, “Tablets”, 180 mg tablets (tablets taken 1 tablet 3 times a day) were manufactured. More specifically, ingredients other than magnesium stearate are mixed and granulated. Thereafter, magnesium stearate was mixed until uniform, and then tableted to produce tablets.

Claims (4)

(A) For 1 part by weight of pranoprofen or a salt thereof,
(B) 0.05-10 parts by weight of at least one selected from the group consisting of riboflavin, flavin adenine dinucleotide, flavin mononucleotide and salts thereof,
(A) component content is 0.01-0.1 w / v%, (B) component content is 0.005-0.1 w / v%, and
An eye drop characterized by being contained in a container having an average absorbance of 340 nm to 380 nm of 1.0 or more. The eye drop according to claim 1, wherein the component (B) is a flavin adenine dinucleotide or a salt thereof. Container, polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene Pi Ren, any one port triethylene, these copolyesters, or two or more mixture of the a configuration containers as main components, The eye drop according to claim 1 or 2. The eye drop according to any one of claims 1 to 3, comprising 0.2 to 5 parts by weight of the component (B) with respect to 1 part by weight of the component (A).