JP2006232822A - Pranoprofen-containing composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a composition having a high ameliorating effect on eyestrain. <P>SOLUTION: The composition for remarkably ameliorating eyestrain comprises pranoprofen or its salt and neostigmine methyl sulfate. The composition is especially useful since it treats eyestrain (especially contact lens wearer) caused by overuse of eyes in a VDT (Visual Display Terminal) operation, reading, gaze operation, observation operation, etc. The addition of a specific viscous agent to the composition improves preparation stability. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to improvement of fatigue eyes by pranoprofen or a salt thereof and neostigmine methylsulfate.

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 work, observation work, and eye overuse and mental tension such as dry eye. Recently, VDT (Visual Display) has been increasing rapidly with the spread of personal computers. (Terminal) Eye fatigue caused by work is very high. 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 that improve eye fatigue include those containing neostigmine methyl sulfate, vitamins, amino acids, and the like. For example, Patent Document 1 discloses an ophthalmic solution for improving eye strain containing taurine and menthol, and Patent Document 2 discloses an ophthalmic disease preventive and therapeutic drug containing eye strain containing an L-ascorbic acid derivative. . However, these eye drops are not fully satisfactory for recovery from eye strain. In addition, neostigmine methyl sulfate inhibits the action of cholinesterase, which degrades acetylcholine, thereby stimulating the parasympathetic nerves and acting on ciliary muscles to improve eye regulation. It is used in eye drops for the purpose of alleviating fatigue (Non-patent Document 1). However, it cannot be said that neostigmine methylsulfate alone sufficiently suppresses eye fatigue. For example, as shown in Patent Document 3, attempts have been made to improve the effect in combination with various components such as vitamins and amino acids. 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. .
JP 9-40549 JP2004-75578 Japanese Patent Laid-Open No. 9-14964 OTC Handbook 2002-2003 Academic Information Distribution Center

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

  The inventors of the present invention have intensively studied to solve the above-mentioned problems, and that the effect of improving eye fatigue becomes remarkable by adding neostigmine methyl sulfate to a composition containing pranoprofen or a salt thereof. The headline and the present invention were completed.

That is, this invention is a composition hung up to the following (1)-(14).
(1) A composition containing pranoprofen or a salt thereof and neostigmine methylsulfate.
(2) The composition according to (1), which is used for improving eye fatigue.
(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) Further, it contains one or more selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose or a salt thereof, polyethylene glycol, and dextran. The composition according to any one of (1) to (4).
(6) The composition according to any one of (1) to (5), wherein the composition is an aqueous composition.
(7) The composition according to any one of (1) to (6), wherein the composition is for topical administration.
(8) The composition according to any one of (1) to (7), wherein the composition is an eye drop, a nose drop, an eye wash, or a contact lens preparation.
(9) The composition according to any one of (1) to (8), which is contained in a container having an average absorbance of 340 nm to 380 nm of 1.0 or more.
(10) 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 (9 ).
(11) The composition according to (9), wherein the container is a container composed mainly of polyethylene naphthalate, polyarylate, or a copolymer polyester thereof.
(12) A container in which one or more of polyethylene naphthalate, polyarylate or a copolymer polyester thereof and a mixture of at least one of polyethylene terephthalate, polypropylene, and polyethylene are used as a main raw material. The composition according to (9).
(13) The container is composed of one or a mixture selected from polyethylene naphthalate, polyarylate, copolymerized polyesters thereof, polyethylene terephthalate, polypropylene, and polyethylene, and a UV blocking agent is added thereto as a main raw material. The aqueous composition according to (9), which is a container composed of a coated material.
(14) The composition according to any one of (9) to (13), wherein the container is a container to which an ultraviolet blocking agent is added or coated.
The present invention also includes a method for stabilizing the formulation of a composition containing pranoprofen or a salt thereof and neostigmine methylsulfate.
(15) A composition containing pranoprofen or a salt thereof, and neostigmine methylsulfate is further added to polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or a salt thereof, polyethylene glycol, And a method for stabilizing a preparation by containing one or more selected from the group consisting of dextran.

  The present invention can significantly improve eye fatigue by containing pranoprofen or a salt thereof and neostigmine methylsulfate. Furthermore, the stability of a formulation can be improved by containing a specific thickener.

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 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%.
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 in 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 neostigmine methylsulfate 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.

  In the composition of the present invention, the ratio of neostigmine methylsulfate 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 to It is about 0.05w / v%. Specifically, in the case of eye drops, 0.001 to 0.005 w / v%, preferably about 0.003 to 0.005 w / v%, and in the case of nasal drops, eyewashes or contact lens agents, 0.0001 to 0.0005 w / v. It is v%, preferably about 0.0003 to 0.0005 w / v%.

  In the composition of the present invention, the blending ratio of pranoprofen or a salt thereof and methylostigmine sulfate is not particularly limited as long as the effect of the present invention can be obtained, but methyl per 1 part by weight of pranoprofen or a salt thereof. Neostigmine sulfate is 0.001 to 1 part by weight, preferably 0.02 to 0.5 part by weight, particularly preferably 0.05 to 0.2 part 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 menthol, camphor, borneol, limonene, cineol, geraniol and linalool are preferred. 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 product), polyvinylpyrrolidone (such as Kollidon (R) K25, Kollidon (R) K30, Kollidon (R) K90), carboxyvinyl polymer, polyoxyethylene-poly Oxypropylene block copolymer (BASF Wyandotte Coproration, Pluronic, Tetronic, etc.), cellulose derivatives [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208,2906,2910 etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose Or salts thereof], polyethylene glycol (eg, macrogol 300, macrogol 400, macrogol 1500, macrogol 4000), sodium chondroitin sulfate, Arabia , Tragant, dextran (40, 70, etc.), glucose, sorbitol, etc., preferably polyvinyl alcohol (completely or partially saponified), polyvinyl pyrrolidone (Kollidon (R) K25, Kollidon (R) K30, Kollidon (R) ) K90), cellulose derivatives (methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208,2906,2910), carboxymethylcellulose or salts thereof), polyethylene glycol (Macrogol 300, Macrogol 400), dextran ( 70), more preferably polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cell Or a salt thereof, polyethylene glycol, dextran, particularly preferably polyvinyl alcohol, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose or a salt thereof, polyethylene glycol, dextran, most preferably hydroxyethyl cellulose, sodium carboxymethyl cellulose It is.
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%. Specifically, for hydroxypropyl methylcellulose, it is usually 0.001 to 5 w / v%, preferably 0.01 to 1 w / v%, more preferably 0.1 to 0.5 w / v%, and for hydroxyethylcellulose, usually 0.001 to 5 w / v%, Preferably 0.01 to 1 w / v%, more preferably 0.05 to 0.5 w / v%. In sodium carboxymethyl cellulose, usually 0.001 to 5 w / v%, preferably 0.01 to 1 w / v%, more preferably 0.1 to 0.5 w / v. For dextran 70, usually 0.001 to 5 w / v%, preferably 0.01 to 3 w / v%, more preferably 0.1 to 1.5 w / v%. For polyvinylpyrrolidone, usually 0.01 to 5 w / v%, preferably 0.1 ~ 5w / v%, more preferably 0.5 ~ 5w / v%, polyvinyl alcohol usually 0.001 ~ 5w / v%, preferably 0.01 ~ 1w / v%, more preferably 0.05 ~ 0.5w / v%, polyethylene glycol Usually 0.001 to 5 w / v%, preferably 0.01 to 3 w / v%, more preferably 0. It is 1-1 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 is not limited to a specific form, and can include a liquid agent (including a syrup and a drink), a semi-solid agent or a solid agent, preferably a liquid agent or a solid agent, depending on the purpose. . Specifically, liquids, semi-solids (ointments), tablets (including dry tablets, multilayer tablets, effervescent tablets, etc.), granules, fine granules, powders, hard capsules, soft capsules, gels And jelly agents.
Preferred are aqueous compositions such as liquids, and solid compositions such as tablets, granules, hard capsules and soft capsules, and particularly preferred are aqueous compositions such as liquids.

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. Of these, ophthalmic solutions, eye drops, nasal drops, contact lens agents, and the like, preferably for topical administration, and more preferably ophthalmic aqueous solutions such as eye drops, eye washes, contact lens agents, and the like. It is a composition, and eye drops and eye wash are particularly preferable.
The contact lens agent can be applied to all contact lenses including hard contact lenses and soft contact lenses, but is particularly preferably applied to soft contact lenses 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.

  Uses of the composition of the present invention include anti-inflammation, foreign body sensation, conjunctival hyperemia, smooth eyes, and eye fatigue improvement based on the inherent pharmacological action of pranoprofen and neostigmine methylsulfate. Since the composition of the present invention has an enhanced effect on eye fatigue, it is used as a composition for improving eye fatigue, and an eye drop or eye wash is particularly preferred.

  The composition of the present invention is preferably used by topical administration in order to improve eye fatigue. In the present invention, since the effect is enhanced by the coexistence of pranoprofen or a salt thereof and neostigmine methyl sulfate, it is preferable that the local administration be more easily cooperated 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. Further, the inclusion of a thickening agent can enhance or supplement the effect of improving eye fatigue.

When a thickening agent is added for the purpose of enhancing or supplementing the effect of improving eye fatigue, examples of the thickening agent include polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (Kollidon (R) K25, Kollidon ( R) K30, Kollidon (R) K90, etc.), carboxyvinyl polymer, polyoxyethylene-polyoxypropylene block copolymer (BASF Wyandotte Coproration, Pluronic, Tetronic, etc.), cellulose derivatives [methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose , Hydroxypropylmethylcellulose (2208, 2906, 2910, etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or their salts], polyethylene glycol (Macrogol 300, Macrogol 400, Macrogow) 1500, Macrogol 4000, etc.), chondroitin sodium sulfate, gum arabic, tragacanth, dextran (40, 70, etc.), glucose, sorbitol, etc., preferably polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (corridone ( R) K25, Kollidon (R) K30, Kollidon (R) K90, etc.), cellulose derivatives (such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208,2906,2910), carboxymethylcellulose or salts thereof), polyethylene Glycol (Macrogol 300, Macrogol 400) and dextran (70), more preferably polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, hydroxypropylse Loose, hydroxypropylmethylcellulose, carboxymethylcellulose or a salt thereof, polyethylene glycol, dextran, particularly preferably polyvinyl alcohol, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose or a salt thereof, polyethyleneglycol, dextran, most preferably Hydroxyethyl cellulose and sodium carboxymethyl cellulose.
These thickening agents may be used alone or in any combination of two or more.
When a thickener is blended for the purpose of enhancing or supplementing the effect of improving eye fatigue, the ratio of the thickener is, for example, 0.0005 to 5 w / v% in the case of an aqueous composition. Specifically, for hydroxypropyl methylcellulose, it is usually 0.001 to 5 w / v%, preferably 0.01 to 1 w / v%, more preferably 0.1 to 0.5 w / v%, and for hydroxyethylcellulose, usually 0.001 to 5 w / v%, Preferably 0.01 to 1 w / v%, more preferably 0.05 to 0.5 w / v%. In sodium carboxymethyl cellulose, usually 0.001 to 5 w / v%, preferably 0.01 to 1 w / v%, more preferably 0.1 to 0.5 w / v. For dextran 70, usually 0.001 to 5 w / v%, preferably 0.01 to 3 w / v%, more preferably 0.1 to 1.5 w / v%. For polyvinylpyrrolidone, usually 0.01 to 5 w / v%, preferably 0.1 ~ 5w / v%, more preferably 0.5 ~ 5w / v%, polyvinyl alcohol usually 0.001 ~ 5w / v%, preferably 0.01 ~ 1w / v%, more preferably 0.05 ~ 0.5w / v%, polyethylene glycol Usually 0.001 to 5 w / v%, preferably 0.01 to 3 w / v%, more preferably 0. It is 1-1 w / v%.

  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 with reference 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 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-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 type oligomer, polythiol spiroacetal type, etc.), unsaturated polyester, or cationic polymerization type epoxy resin 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 agonist, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, and the like. 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, tropicamide, helenien sulfate atropine, 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, agitazanolast, 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.

  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.

  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.

  With respect to 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. Known in the field. For example, 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 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, guaiac gum, 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 neostigmine methyl sulfate, and in some cases a viscous agent are dissolved using distilled water or purified water and additives, and adjusted to a predetermined osmotic pressure and pH. Then, it can be manufactured by subjecting it to filtration sterilization in an aseptic environment and aseptically filling a container that has been washed and sterilized.

The present invention also includes a method for improving the formulation stability of a composition containing pranoprofen or a salt thereof and neostigmine methylsulfate. In the method of the present invention, the formulation stability improvement of a composition containing pranoprofen and neostigmine methylsulfate is polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyethylene glycol, This can be achieved by including one or more selected from the group consisting of dextran and their salts.
In the method of the present invention, pranoprofen, neostigmine methylsulfate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyethylene glycol, dextran, and the blending amounts thereof are the above-mentioned composition The same as that used in the above.

  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 persons, 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 then the self-evaluation of the degree of fatigue was performed. 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 eye of Comparative Example) −Fatigue degree (after eye drop 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 neostigmine methylsulfate also has an effect of slightly improving the self-evaluation of the degree of fatigue, respectively. Example 1 containing both pranoprofen and neostigmine methylsulfate Then, it was confirmed that the self-evaluation of the degree of fatigue significantly improved.

Test Example 2 Formulation stability test
According to the formulation described in Table 2, each component was dissolved in purified water to prepare a test solution with a total volume of 100 mL.
8 mL of each test solution was filled into a transparent glass screw tube (capacity 10 mL) with a styrene cap, and these were used as test samples (n = 2). For this test sample, using a light stability tester ("Light-Tron LT-120 D3CJ type", manufactured by Nagano Kagaku Co., Ltd.), using a D65 lamp as a light source at 25.degree. Was continuously irradiated for 2.5 hours, and the test solution was exposed to light having an accumulated irradiation amount of 15,000 lx · hr. The absorbance (420 nm) of each test solution before and after light irradiation was measured using a spectrophotometer (Hitachi spectrophotometer U-3010) to evaluate the stability of the preparation.
The results are shown in Table 2.

After light irradiation, the absorbance increased when testosterone 1-3 and pranoprofen and neostigmine methylsulfate coexisted, and the turbidity (degree of white turbidity) of the test solution deteriorated, making the formulation more unusable. Although it turns out that it has become stable, it turned out that a light absorbency falls rather than the test liquid 1 by coexisting a specific thickener from the test liquids 4-11, and the external appearance and formulation stability were improved. . In particular, when the absorbance of test solution 2 is 100, it is 20 or less for test solution 4, 10 or less for test solutions 7 and 9, and 20 or less for test solution 5 when the absorbance of test solution 3 is 100. It was confirmed that the stability of the formulation was improved. In addition, all the light absorbency of the test liquid before light irradiation was 0-0.01.
Moreover, when the pranoprofen density | concentration in the test liquid before and after light irradiation was measured by the high performance liquid chromatography, the residual ratio of the planoprofen of the test liquids 4-11 tends to become higher than the test liquids 1-3. Therefore, it is thought that it contributed to formulation stability by suppressing the production | generation of a pranoprofen degradation product.
Therefore, it has been clarified that the formulation of a composition containing pranoprofen and neostigmine methylsulfate is stabilized by the coexistence of a specific thickener.

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 Tables 3 and 4, carboxymethylcellulose sodium indicates cellogen (R) PR-S, polyvinylpyrrolidone K25 indicates corridone (R) K25, and hydroxypropyl methylcellulose 2906 indicates Metrolose (R) 65SH-4000.
In Examples 2 to 17, a container of a mixture of 10% polyethylene naphthalate and 90% polyethylene terephthalate (absorbance of 340 nm to 380 nm with an absorbance of 3.0 or more) was filled with light of 50,000 lx 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 17, the residual ratio of pranoprofen was maintained at 90% or more.

  In Examples 18 to 38, the osmotic pressure ratio was adjusted to 0.7 to 1.5. In Examples 18 to 38, 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 of 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 18 to 38, the residual ratio of pranoprofen was maintained at 90% or more.

Claims (6)

A composition comprising pranoprofen or a salt thereof and neostigmine methylsulfate. The composition according to claim 1, which is used for improving eye fatigue. Furthermore, it contains one or more selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose or salts thereof, polyethylene glycol, and dextran. The composition according to 1 or 2. The composition according to any one of claims 1 to 3, wherein the composition is an aqueous composition. The composition according to any one of claims 1 to 4, which is contained in a container having an average absorbance of 340 nm to 380 nm of 1.0 or more. A composition containing pranoprofen or a salt thereof and neostigmine methylsulfate comprises polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or a salt thereof, polyethylene glycol, and dextran The formulation stabilization method by containing 1 type, or 2 or more types selected from a group.