JP2008189677A - Washing agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an eye wash for persons wearing contact lenses having high anti-inflammatory activity and an excellent antipruritic effect. <P>SOLUTION: The eye wash for persons wearing contact lenses contains zinc or a zinc salt and an antihistamine. The zinc salt is preferably at least one selected from the group consisting of zinc sulfate, zinc lactate, zinc chloride, zinc gluconate, zinc citrate, zinc 2-oxoglutarate and zinc acetate. The antihistamine is preferably at least one selected from diphenhydramine, chlorpheniramine, ketotifen, emedastine, mequitazine or a pharmaceutically acceptable salt thereof. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to an eyewash or nasal rinse with enhanced anti-inflammatory effects.

Today, with changes in the environment and lifestyle, the number of people suffering from allergic diseases such as hay fever is increasing rapidly, and the development of more effective drugs is desired. For example, allergic keratoconjunctival diseases (eg, allergic conjunctivitis) are mainly caused by type I allergic reactions, which involve IgE and mast cells, and bind to IgE receptors on the surface of the conjunctival mast cells. And antigen bind to the surface of mast cells, degranulation releases active substances such as histamine. As a result, for example, histamine causes inflammatory effects such as increased capillary permeability and increased sensory nerve stimulation, causing allergic symptoms such as edema, hyperemia, pruritus, sneezing and mucosal secretion. Therefore, drugs that suppress the release of active substances such as histamine and antihistamines that act antagonistically against free histamine are often used as therapeutic agents for allergic diseases.

For example, eye drops containing antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate are used as preparations for allergic diseases in order to suppress or relieve itchy eyes. For eye washing, an eyewash containing these is used. However, with eye drops, the amount of liquid to be applied is small, it is not possible to wash away substances causing inflammation such as pollen and house dust, and it is possible to sufficiently suppress itchiness due to the short contact time. Moreover, there was a problem that the sustainability was weak.

On the other hand, eyewashes wash the ocular mucosa with a large amount of liquid, so that the causative agent of inflammation can be sufficiently washed away, so that a high antipruritic effect is obtained, but most of the tears are removed together with foreign substances etc. Furthermore, since mucosal protective components that take time to regenerate such as mucin and globulin are also removed, frequent eye washing is not desirable from the viewpoint of protecting the ocular mucosa. Therefore, a preparation having a high anti-inflammatory action and excellent durability has been desired.

Cytokines, which are glycoprotein bioactive substances, play a central role in the control of various allergic and inflammatory responses. Among them, IL-8 is a cytokine produced by monocytes, macrophages, fibroblasts, blood endothelial cells, skin keratinocytes, renal mesangial cells, intestinal tract and airway epithelial cells, liver parenchymal cells and various tumor cells. As production stimulating substances, IL-1, TNF, endotoxin derived from gram-negative bacteria, and the like are known. (Matsushima Tsunaharu, p. 88-93, 1994, Cytokine 94, from basics to the latest information, edited by Shinhei Kasakura, published by Nippon Medical Center). When various cells are treated with a stimulating substance such as IL-1 or TNFα in vitro, IL-8 production is observed after several hours. Similar effects are observed in vivo. It is also known that IL-8 is produced when conjunctival epithelial cells are stimulated with histamine (Allergy Immunology 115 p288-293).

The IL-8 action includes chemotactic activation action on neutrophils, T lymphocytes and basophils, neutrophil activation, histamine release promotion of basophils, monocyte vascular endothelium It is known to have effects such as promoting adhesion to cells (Kuno Kuno and Tsunaharu Matsushima, Immunopharmacology, 9, p197-205, 1991). In addition, eosinophils and neutrophils infiltrate in the keratoconjunctiva of allergic keratoconjunctivitis patients, causing tissue injury and contributing to worsening of symptoms. In such patients, there has been a correlation between the expression level of IL-8 in conjunctival epithelial cells and the level of neutrophil and eosinophil infiltration (Cornea 20 (7), p743-747, 2001).

An object of the present invention is to provide a cleaning agent for ocular mucosa and nasal mucosa with enhanced anti-inflammatory action. Furthermore, another object of the present invention is to provide a cleaning agent for ocular mucosa and nasal mucosa having an excellent antipruritic effect.

As a result of various investigations to obtain a cleansing agent for the ocular mucosa and nasal mucosa having a high antipruritic effect, the present inventors have surprisingly found that a cleansing agent containing zinc or a zinc salt and an antihistamine is an ocular mucosa or It was found to have an excellent antipruritic action in the nasal mucosa. Moreover, not only that zinc or zinc salt has an anti-inflammatory action by suppressing IL-8 production, but also zinc or zinc salt acts synergistically with antihistamines to enhance the anti-inflammatory action by suppressing IL-8 production. I found out. That is, the present invention includes (1) an ophthalmic mucosa or nasal mucosa eyewash characterized by containing zinc or a zinc salt and an antihistamine, and (2) a zinc salt comprising zinc sulfate, zinc lactate, zinc chloride, The cleaning agent according to (1), which is one or more selected from zinc gluconate, zinc citrate, zinc 2-oxoglutarate, and zinc acetate, and (3) an antihistamine is diphenhydramine, chlorpheniramine, ketotifen, emedastine , Mequitazine or one or more selected from pharmacologically acceptable thereof, the cleaning agent according to (1) or (2), (4) and further containing a cooling agent (1 The cleaning agent according to (4), wherein the cleaning agent according to (2) or (3) and (5) the refreshing agent are at least one selected from menthol, camphor, borneol, geraniol, and caffeine. (6) Detergent for allergic diseases containing zinc or zinc salt and antihistamine, (7) Detergent for ocular mucosa of contact lens wearer containing zinc or zinc salt and antihistamine, (8) IL-8 production inhibitor containing zinc or zinc salt as an active ingredient, and (9) A method for inhibiting IL-8 production comprising containing zinc or a zinc salt in a composition containing an antihistamine , Etc.

In the present specification, the “ocular mucosa or nasal mucosa cleaning agent” of the present invention is also referred to as “eyewash (eyewash)” and “nasal (nasal cleaner, nasal)”, respectively.

In the present specification, unless otherwise specified,% means w / v%. Further, the term “contact lens (CL)” is used in the meaning of including all types of contact lenses such as hard, oxygen-permeable hard, and soft unless otherwise specified.

The cleaning agent of the present invention contains zinc or a zinc salt and an antihistamine. Usable zinc salts include zinc sulfate, zinc lactate, zinc chloride, zinc nitrate, zinc gluconate, zinc citrate and zinc 2-oxoglutarate, zinc oxide, zinc phosphate, zinc aluminate, zinc fluoride, iodine Zinc halide, zinc hydroxide, zinc carbonate, zinc chromate, zinc benzoate, zinc acetate, zinc paraaminobenzoate, zinc paradimethylaminobenzoate, zinc paraphenolsulfonate, zinc paramethoxycinnamate, 2-mercaptopyridine-N -Zinc oxide, zinc picrate, zinc citrate, zinc aspartate, zinc naphthenate, zinc salicylate, zinc phenolsulfonate, zinc sebacate, sodium tripolyphosphate, zinc stearate, zinc caprate, zinc laurate, myristic Zinc acid, zinc palmitate, zinc oleate, polyphosphonic acid Lead, zinc chondroitin sulfate, zinc undecylenate, zinc ascorbate, zinc pyrithione, zinc hinokitiol, zinc dipicolinate, zinc glycerolate complex, bishistidine zinc complex, zinc complex such as zinc-3,4-dihydroxybenzoate complex, etc. . Among them, zinc sulfate, zinc lactate, zinc chloride, zinc gluconate, zinc citrate, zinc 2-oxoglutarate, zinc acetate and the like are preferable because zinc is less irritating, and zinc sulfate, zinc lactate, zinc chloride and the like are more preferable. . Zinc sulfate and zinc lactate are particularly preferred because of their high solubility in water and easy formulation. These zinc salts have been confirmed to be safe and are widely used in eye drops, and are preferable because of their high safety when used in the eyewash or nasal wash of the present invention. Hereinafter, the zinc or zinc salt used in the composition of the present invention may be referred to as a zinc salt or the like.

The amount of zinc salt used in the cleaning agent of the present invention varies depending on the composition, application method, compound type, etc., but is usually in the range of 0.0001 to 5%. Specifically, from the viewpoint of local irritation such as zinc salt and astringent action, in the case of nasal rinse, 0.0005-5%, preferably 0.001-2%, more preferably 0.01-0.5%. In the case of eyewash, it is in the range of 0.0001 to 5%, preferably 0.0005 to 2%, and more preferably 0.001 to 0.5%. Zinc salts can be used alone or in combination of two or more.

The antihistamine to be blended in the cleaning agent of the present invention may be any antihistamine as long as it has an antihistamine action. Olopatadine, mequitazine, loratadine, fexofenadine, cetirizine, pemirolast, and pharmacologically acceptable salts such as diphenhydramine hydrochloride, chlorpheniramine maleate, iproheptine hydrochloride, ketotifen fumarate, Emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, etc.). Of these, diphenhydramine, chlorpheniramine, ketotifen, emedastine, mequitazine, or a pharmacologically acceptable salt thereof is preferable. In particular, chlorpheniramine maleate, diphenhydramine hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate and the like are preferable from the viewpoint of safety. The concentration of the antihistamine in the composition of the present invention is 0.0001 to 1.0%, preferably 0.0005 to 0.5%, particularly preferably 0.0005 to 0.05%. Antihistamines can be used alone or in combination of two or more.

Furthermore, a cooling agent can also be mix | blended with the cleaning agent of this invention. The refreshing agent has an effect of enhancing allergic diseases and inflammatory diseases by suppressing the itch of allergic diseases and inflammatory diseases, and mitigating action (masking) of stimuli derived from medicinal components and base components. As the refreshing agent used in the present invention, a monoterpene or a xanthine derivative can be used, and at least one kind can be contained. Examples of the monoterpene contained in the cleaning agent of the present invention include menthol, camphor, borneol, geraniol, cineol, anethole, limonene, eugenol and the like. These monoterpenes may be either d-form, l-form or dl-form, but 1-menthol, d-menthol, dl-menthol, d-camphor from the aspect of safety and safety such as refreshing feeling and fragrance. Dl-camphor, d-borneol and dl-borneol are preferred. Geraniol, 1-menthol, d-camphor and d-borneol are particularly preferred. The monoterpene can be used in the state of being contained in an essential oil, and preferred essential oils are eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, and the like.

As a xanthine derivative contained in the cleaning agent of the present invention, the following formula (1):

（式中、Ｒ1、Ｒ2及びＲ3は、同一又は異なっていてもよく、それぞれ、水素原子又は置換されてもよいアルキル基を示す）で表される化合物またはその薬理学的に許容される塩などの化合物が挙げられる。例えば、カフェイン、ペントキシフィリン、テオフィリン、ジプロフィリン、テオブロミン、プロキシフィリンなどがあり、特に、刺激性の改善の面から、カフェインが好ましい。

(Wherein R1, R2 and R3 may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group) or a pharmacologically acceptable salt thereof, etc. The compound of this is mentioned. For example, caffeine, pentoxifylline, theophylline, diprofylline, theobromine, proxyphylline and the like are available, and caffeine is particularly preferable from the viewpoint of improving irritation.

These monoterpenes or xanthine derivatives may be used alone or in combination of two or more.

The concentration of the monoterpene or xanthine derivative in the detergent of the present invention varies depending on the composition mode, application method, type of compound, etc., but in the case of a monoterpene, it is usually 0.00001 to 0.1%, preferably 0.0001 to 0.05%. Range. In particular, in consideration of the monoterpene irritation, it is preferably 0.1% or less, and preferably 0.00001% or more from the viewpoint of obtaining an antipruritic action and a feeling of use improvement by monoterpene. As suitable ranges, for example, 0.0003 to 0.05% for eyewashes and 0.0001 to 0.03% for nasal rinses may be employed.

In the case of a xanthine derivative, it is usually in the range of 0.00001 to 2%, preferably 0.0001 to 1%. In particular, the concentration is preferably 1% or less from the viewpoint of the concentration that does not exert the stimulating property of the xanthine derivative, and is preferably 0.00001% or more from the viewpoint of improving the feeling of use. As a suitable range, for example, 0.003 to 0.5% is adopted for an eye wash, and 0.0001 to 0.3% is adopted for a nasal wash.

The cleaning agent of the present invention can be widely used as a mucosal composition for cleaning mucous membranes such as nasal mucosa (nasal cavity) and ocular mucosa (ocular tissue), and can be applied to all fields. For example, it can be used in a wide range of fields such as pharmaceuticals, quasi drugs, and miscellaneous goods. More specifically, examples include nasal wash and eye wash.

As long as the effects of the present invention are not hindered, the composition of the present invention combines various components (including pharmacologically active ingredients and physiologically active ingredients) in addition to the zinc, zinc salt, antihistamine, and cooling agent. May be contained. There are no particular limitations on the type of such ingredients, such as decongestants, anti-inflammatory ingredients, antibacterial or bactericidal ingredients, antiallergic ingredients, vitamins, amino acids, sugars, local anesthetic ingredients, steroid ingredients, etc. It can be illustrated. Examples of suitable components in the present invention include the following components.

Decongestant: For example, imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.) or pharmacologically acceptable salts thereof (for example, naphazoline hydrochloride, naphazoline nitrate) , Tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and organic acid salts such as epinephrine hydrogen tartrate).

Anti-inflammatory components: celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, pranoprofen, piroxicam, meloxicam, epsilon-aminocaproic acid, berberine or their pharmaceutically acceptable salts (For example, berberine chloride, berberine sulfate, etc.), lysozyme, lysozyme chloride, methyl salicylate, allantoin, glycyrrhizic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, and the like.

Antibacterial or bactericidal components: for example, sulfonamides [eg, sulfamethoxazole, sulfisoxazole, sulfisomidine or pharmacologically acceptable salts thereof (sulfamethoxazole sodium, sulfiso Such as sodium amidine), acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium, etc.) or pharmacologically acceptable salts thereof (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride) , Cetylpyridinium bromide, etc.), alkylpolyaminoethylglycine, new quinolones (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), biguanides (polyhexamethyle) Biguanides, chlorhexidine or salts thereof), berberine or salts thereof, polydronium chloride, Glokill (trade name, manufactured by Rhodia), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethrene Dichloride), parabens (such as methylparaben, ethylparaben or salts thereof).

Antiallergic drugs: for example, cromoglycic acid, sodium cromoglycate, tranilast, amlexanox, ibudilast, pemirolast.

Vitamins: for example, vitamin A [for example, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (for example, retinol acetate, retinol palmitate, etc.), vitamin B (E.g. thiamine hydrochloride, thiamine nitrate, bis-thiamine nitrate, thiamine disulfide, thiamine dicetyl nitrate ester salt, dicetiamine hydrochloride, flustiamine hydrochloride, octothiamine, chicotiamine, bisbutiamine, bisbentiamine, fursultiamine, pursultiamine , Benfotiamine, flavin adenine dinucleotide, riboflavin, sodium riboflavin phosphate, riboflavin butyrate, pyridoxine hydrochloride, pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxo acetate Baramin, cyanocobalamin, hydroxocobalamin, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, etc.), vitamin C [ascorbic acid and its derivatives, erythorbic acid and its derivatives and their pharmacology Acceptable salts (for example, sodium ascorbate, sodium erythorbate, etc.)], vitamin Ds (for example, ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaxosterol and theirs) Pharmacologically acceptable salts, etc.), vitamin E [for example, tocopherol and derivatives thereof, ubiquinone derivatives and pharmacologically acceptable salts thereof (tocopherol acetate, nico Tocopherol acid, tocopherol succinate, calcium tocopherol succinate etc.)], other vitamins [eg carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, hesperidin and their pharmacologically acceptable Salts (such as carnitine chloride)].

Amino acids: for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxy Lysine, glycylglycine, aminoethylsulfonic acid (taurine) or pharmacologically acceptable salts thereof (for example, potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.).

Sugars: monosaccharides (eg glucose), disaccharides (eg trehalose, lactose, fructose etc.), oligosaccharides (eg lactulose, raffinose, pullulan etc.), cellulose or derivatives thereof (eg methylcellulose, ethylcellulose, hydroxyethylcellulose) , Hydroxypropylcellulose, carboxymethylcellulose, carboxyethylcellulose, etc.), high molecular sugars (eg, alginic acid, chondroitin sulfate, hyaluronic acid, etc.) and pharmacologically acceptable salts thereof (eg, sodium alginate, chondroitin sulfate, hyaluronic acid) Sodium), sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.).

Local anesthetic ingredients: lidocaine, oxyprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilucaine and their salts (such as lidocaine hydrochloride and oxybuprocaine hydrochloride).

Steroid component: Hydrocortisone, prednisolone and their salts.

Other components: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, etc.

The blending amounts of these components in the cleaning agent of the present invention are appropriately selected according to the type of preparation, the type of active ingredient, etc., and the blending amounts of various components in the cleaning agent for ocular mucosa and nasal mucosa are known in the art. It is. For example, it can be selected from the range of about 0.00001 to 30%, preferably about 0.001 to 10% with respect to the whole preparation. More specifically, the content of each component in the cleaning agent is, for example, as follows.

Decongestant component (vasoconstrictor or sympathomimetic agent): For example, 0.00001 to 0.5%, preferably 0.0001 to 0.3%, more preferably about 0.001 to 0.1%.
Anti-inflammatory component: for example, 0.0001-10%, preferably 0.0001-5%.
Antibacterial or bactericidal component: for example, 0.00001 to 10%, preferably 0.0001 to 10%, more preferably 0.001 to 5%.
Antiallergic component: for example, 0.00001 to 10%, preferably 0.0001 to 5%.
Vitamins: For example, 0.0001 to 10%, preferably 0.0001 to 5%, more preferably 0.0001 to 1%.
Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%. Saccharides: For example, 0.0001 to 5%, preferably 0.001 to 5%, more preferably 0.01 to 2%.
Local anesthetic component: For example, 0.001-1%, preferably 0.01-1%.
Steroid component: For example, 0.0001 to 1%, preferably 0.001 to 1%.
Polyvinyl pyrrolidone, polyvinyl alcohol: For example, 0.001 to 10%, preferably 0.001 to 5%, more preferably 0.01 to 3%.

Further, in the cleaning agent of the present invention, various components and additives are appropriately selected according to conventional methods according to the use and form as long as the effects of the invention are not impaired, and one or more are used in combination. And may be contained. Examples of such components or additives include thickeners, surfactants, antiseptic / sterilizing / antibacterial agents, pH adjusters, tonicity agents, inorganic salts, chelating agents, buffers, solubilizing agents, and suspending agents. Various additives, such as an agent, an emulsifier, an antioxidant, and a fragrance | flavor, can be mentioned.

The following are exemplary components used in the composition of the present invention, but these are merely presentations.

Thickeners: for example, polysaccharides or derivatives thereof (gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guayac fat, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, Carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, etc., ceramide, cellulose derivative (methylcellulose) , Ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, Ruboxyethyl cellulose, cellulose, etc.), polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, and their drugs Examples include salts that are physically acceptable.

Surfactant: For example, polyoxyethylene (POE) -polyoxypropylene (POP) block copolymer (eg, poloxamer 407, poloxamer 235, poloxamer 188, etc.), ethylenediamine POE-POP block copolymer adduct (eg, poloxamine, etc.) POE sorbitan fatty acid esters such as monolauric acid POE (20) sorbitan (polysorbate 20) and monooleic acid POE (80) sorbitan (polysorbate 80), POE cured castor oil such as POE (60) castor oil, POE ( 9) Nonionic interfaces such as POE alkyl ethers such as lauryl ether, POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether, and POE alkyl phenyl ethers such as POE (10) nonylphenyl ether Activator, a Amphoteric surfactants such as glycine type such as killiaminoethylglycine, betaine acetate type such as lauryldimethylaminoacetic acid betaine, imidazoline type, POE alkyl ether phosphates such as POE (10) sodium lauryl ether phosphate and salts thereof, lauroyl N-acyl amino acid salts such as sodium methylalanine, alkyl ether carboxylates, N-acyl taurine salts such as sodium N-cocoylmethyl taurate, sulfonates such as sodium tetradecenesulfonate, alkyl sulfates such as sodium lauryl sulfate , POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, anionic surfactants such as α-olefin sulfonates, alkylamine salts, alkyl quaternary ammonium salts [benzalkoni chloride] , Benzethonium chloride, polydronium chloride, Glokill (trade name, for example, Glokill PQ, manufactured by Rhodia), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) trendyl chloride], polyethylene polyamine, dimethyl Amine epichlorohydrin polycondensates (trade names such as Busan 1157, manufactured by Bachman Laboratories, etc.), alkylpyridinium salts (such as cetylpyridium chloride and cetylpyridium bromide), chlorhexidine salts (such as chlorhexidine gluconate and chlorhexidine hydrochloride) Examples include cationic surfactants, etc. The numbers in parentheses indicate the number of moles added.

Antiseptic / antibacterial / bactericidal agents: For example, paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), sulfonamides (for example, sulfamethoxazole, sulf Isoxazole, sulfisomidine, and pharmacologically acceptable salts), new quinolones (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciproxacin hydrochloride, etc.), methylrosaniline chloride, quaternary ammonium compounds (eg, benza) Luconium, benzethonium, cetylpyridinium) and pharmacologically acceptable salts thereof (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide), chlor Xylidine, alkylpolyaminoethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, sulfur, zirconium phosphate silver, zinc, zinc oxide and other supports, silver zinc aluminosilicate, mercurochrome, povidone iodine, dehydro Acetic acid, chloroxylenol, cresol, chlorophene, phenol, resorcin, orthophenylphenol, isopropylmethylphenol, thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid , Propionic acid, sorbic acid, triclocarban sorbate, halocarban, thiabendazole, polymer Syn-B, 5-chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, polylysine, hydrogen peroxide, polydronium chloride (polyquarterium-1), Glokill ( Trade name, for example Glokill PQ, Rhodia, Unisense CP (trade name, poly (diallyldimethylammonium chloride), Senca), WSCP (trade name, poly [oxyethylene (dimethyliminio) ethylene- (dimethyli Minio) etrange dichloride] containing about 60% by weight, manufactured by Bachman Laboratories)), Cosmosil CQ (trade name, containing about 20% by weight polyhexamethylene biguanide hydrochloride, manufactured by Avicia).

pH adjuster: For example, inorganic salt (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acid (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid , Propionic acid, acetic acid, aspartic acid, epsilon aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic base (sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide) , Magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), borax, and pharmacologically acceptable salts thereof.

Isotonizing agents: for example, polyhydric alcohols such as glycerin and propylene glycol, saccharides (buty sugar, mannitol, sorbitol, etc.) and the like.

Chelating agents: for example, edetic acid, citric acid, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid and their drugs Examples include salts that are physically acceptable.

Inorganic salts: For example, sodium chloride, potassium chloride, sodium carbonate, sodium bicarbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulfate, sodium acetate, etc. It is done.

It is necessary to adjust the cleaning agent of the present invention to a pH and / or osmotic pressure within a range that is acceptable to a living body, if necessary. The appropriate pH depends on the site of application, dosage form, etc., although the osmotic pressure is usually 4.0 to 9.0 in the form at the time of use, preferably 4.0 to 8.0, particularly preferably for reducing irritation. pH 4.0 to 7.0; the osmotic pressure ratio to physiological saline is usually 0.4 to 4.0, preferably 0.5 to 2.5, particularly preferably 0.6 to 1.6 in order to reduce irritation. The pH or osmotic pressure can be adjusted using a buffer, the pH regulator, the isotonic agent, the inorganic salts, and the like.

Here, examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartate and the like. These buffering agents may be used in combination. Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer and citrate buffer. Particularly preferred buffering agents are borate buffer, citrate buffer or phosphate buffer. Examples of the borate buffer include borates such as alkali metal borate and alkaline earth metal borate. Examples of the citrate buffer include alkali metal citrate. Examples of the phosphate buffer include phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Further, borate, citrate or phosphate hydrate may be used as a borate buffer, citrate buffer or phosphate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or a salt thereof (sodium bicarbonate, sodium carbonate, etc.), citric acid or a salt thereof (sodium citrate, potassium citrate, etc.). When a borate buffer, a citrate buffer or a phosphate buffer is used as the buffer, the concentration of these buffers in the cleaning agent of the present invention is, for example, about 0.0001 to 10.0% by weight. is there.

The cleaning agent of the present invention can be used as an eyewash or nasal rinse because it can wash away inflammation-causing substances (allergy-causing substances) such as pollen and ticks and has an excellent antipruritic effect. In addition, allergic patients such as pollen have a strong itching sensation on the eye mucosa and nasal mucosa, and many contact lens wearers are also inflamed. Detergents are particularly preferred for patients with allergic diseases and contact lens wearers. Moreover, since the washing | cleaning agent of this invention can also wash away the inflammation causative substance sufficiently, a low concentration zinc or zinc salt, and an antihistamine can be mix | blended.

The cleaning agent of the present invention can be produced by a known method. The liquid preparation can be prepared by mixing each component. Furthermore, if necessary, a filtration sterilization treatment step, a filling step into a container, and the like can be added. The cleaning agent of the present invention can also be produced by the above-mentioned known methods. More specifically, for example, in the case of an eyewash, zinc or a zinc salt, an antihistamine, and other compounding ingredients are purified water. It can be produced by dissolving in a solution, adjusting to a predetermined osmotic pressure and pH, subjecting to filtration sterilization in an aseptic environment, and aseptically filling a container that has been sterilized by washing. Moreover, a nasal rinse can be manufactured by the same method. In the case of a preparation that can be dissolved at the time of use, it can be produced by a known method according to the dosage form, and is used by dissolving in water or an attached solution at the time of use.

Hereinafter, the present invention will be described in detail based on test examples and examples, but the present invention is not limited to these examples.

Test Example 1 histamine-induced IL-8 production inhibitory action test growth medium (10% fetal calf serum-containing F199 medium) was suspended in 1mL human conjunctival epithelial cell line 1-5c-4,5 × 10 ⁵ cells to 24-well plates Seeded and cultured overnight at 37 ° C., 5% CO ₂ . After aspirating the growth medium, 1 mL each of a growth medium containing 5 × 10 ⁻⁷ M chlorpheniramine maleate and 0.001 to 0.005% zinc sulfate was added. Only growth medium was added to the control. After culturing for 30 minutes, 25 μM histamine was added, and further cultured for 24 hours. The culture supernatant is collected, and the IL-8 concentration in each supernatant is quantified using an ELISA kit (trade name: QUANTIKINE human IL-8, manufactured by R & D SYSTEMS), and the inhibition rate of histamine-induced IL-8 production relative to the control Was obtained from the following equation.
Inhibition rate (%) = (1− (IL-8 amount in test example / IL-8 amount in control example)) × 100

The test results are shown in Table 1.
Test results

From the above results, the inhibition rate was 10 to 20% at zinc sulfate 0.001% to 0.005%. 50nM chlorpheniramine maleate and 0.001 to 0.005% zinc sulfate can be expected to suppress about 20% of histamine-induced IL-8 production, compared with chlorpheniramine maleate alone or zinc sulfate alone Clearly, a strong inhibitory effect was observed, and the effect was synergistic. The combined use of 0.0025% zinc sulfate and 50 nM chlorpheniramine maleate resulted in an inhibition rate of about 60%. From these results, it was revealed that the zinc compound and the antihistamine synergistically suppress the production of IL-8 in the ocular region.

In other words, pretreatment with a solution containing an antihistamine and zinc salt or the like suppresses IL-8 production even when allergy-causing substances and mast cells come into contact with each other and histamine is released. A detergent containing a drug and a zinc salt has anti-inflammatory action against allergic diseases and is expected to be very effective.

Example 1 and Comparative Example 1-3 Eyewash According to the formulation described in Table 2 below, each compounding component was dissolved in sterilized purified water, and after adjusting the osmotic pressure and pH, the total amount was 100 ml, and sterile filtered. The container was filled and an eyewash (eyewash) was prepared.

Test 2 Eyewash use test (1)
5 ml of the eyewash solution prepared in Example 1 and Comparative Examples 1 to 3 was placed in an eyewash cup, and a use test was conducted on hay fever patients. For 10 subjects, when itching was felt, both left and right eyes were used for 10 seconds. The itching after eye washing was evaluated over time according to the following criteria.
Evaluation criteria Presence or absence of pruritus:
-: No itching feeling is felt at all +: A slight itching feeling is felt ++: A very itching feeling is felt

The results are shown in Table 3.

From the above test results, it was confirmed that the detergent containing zinc or a zinc salt and an antihistamine is a composition having an excellent antipruritic effect.

Test 3 Eyewash use test (2)
5 ml of the eyewash prepared in Example 1 and Comparative Examples 1 to 3 was placed in an eyewash cup, and a use test was conducted on contact lens wearers. When ten subjects (5 oxygen-permeable hard contact lens wearers and 5 soft contact lens wearers) felt itching, they were used for 10 seconds for both eyes. The itching after eye washing was evaluated over time according to the following criteria.
Evaluation criteria Presence or absence of pruritus:
-: No itching feeling is felt at all +: A slight itching feeling is felt ++: A very itching feeling is felt

The results are shown in Table 4.

From the above test results, it was confirmed that the detergent containing zinc or a zinc salt and an antihistamine is a composition having an excellent antipruritic effect.

Example 2-13 Eyewash In accordance with the prescriptions in Table 5 and Table 6 below, each compounding component was dissolved in sterilized purified water, and after adjusting the osmotic pressure and pH, the total amount was 100 ml, sterilized and filtered. The eyewash (eyewash) was prepared.

Example 14-20 Nasal Washing Agent In accordance with the formulation shown in Table 7 below, each compounding component was dissolved in sterilized purified water, and after adjusting the osmotic pressure and pH, the total volume was adjusted to 100 ml, sterilized and filled into a container. And a nasal rinse (nasal rinse) was prepared.

According to the present invention, it is possible to obtain a nasal mucosa or ocular mucosa cleaning agent having a high anti-inflammatory action and an excellent antipruritic effect. INDUSTRIAL APPLICABILITY The present invention is particularly effective for patients with allergic diseases such as hay fever and contact lens wearers who tend to cause inflammation in the eye mucosa and nasal mucosa and also feel itching.

Claims (8)

An eyewash for contact lens wearers, comprising zinc or a zinc salt and an antihistamine. The zinc salt is at least one selected from the group consisting of zinc sulfate, zinc lactate, zinc chloride, zinc gluconate, zinc citrate, zinc 2-oxoglutarate, and zinc acetate. The eye wash described. The eyewash according to claim 1 or 2, wherein the antihistamine is at least one selected from diphenhydramine, chlorpheniramine, ketotifen, emedastine, mequitazine, or a pharmacologically acceptable salt thereof. . The eye wash according to any one of claims 1 to 3, further comprising a cooling agent. The eye wash according to any one of claims 1 to 4, wherein the content of zinc or zinc salt is 0.005 to 0.025 (w / v)%. The eye wash according to any one of claims 1 to 5, wherein the content of the antihistamine is 0.0006 to 0.005 (w / v)%. A method for enhancing the antipruritic action of the eyewash characterized by adding zinc or a zinc salt to an eyewash containing an antihistamine A method for maintaining the antipruritic action of the eyewash, which comprises adding zinc or a zinc salt to an eyewash containing an antihistamine.