JP2003146891A - Cleaning agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safe cleaning agent for eye and nose mucous membrane, having a high cell-protecting effect and easy to use. SOLUTION: This cleaning agent for the eye or nose mucous membrane is characterized by containing zinc or a zinc salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cleaning agent for ocular mucosa or nasal mucosa with improved cytotoxicity.

[0002]

2. Description of the Related Art The surfaces of the eyes and nose are in contact with the outside world through mucous membranes, which are protected by lacrimal fluid or nasal mucus. When eye drops or nasal drops are applied to the eyes or nose, the protection from tears and mucus is temporarily disturbed. However, these preparations have small doses and are rapidly diluted with tear fluid or nasal mucus, so that the mucous membranes rapidly recover their original protected state. However, in the case of detergents used for the eye mucosa and nasal mucosa such as eye wash and nasal wash (nasal wash), the purpose is to wash away foreign substances, etc. Liquid is used. Therefore, most of tears and nasal mucus are removed along with foreign substances, and further,
Mucosal protective components such as mucin and globulin, which take time to regenerate, are also removed. Moreover, the contact time between the mucous membrane and the detergent is much longer than that with the nasal drops and eye drops. Therefore, washing makes the ocular and nasal mucosa very susceptible to cell damage. In particular, in the case of the tear film, it has been pointed out that when the tear film is destroyed by washing the eye, the tearing time (breakup time) of the tear film is shortened and various disorders occur. Therefore, it is necessary to thoroughly study the cytotoxicity in selecting not only the active ingredient but also the ingredient to be added to the detergent.

For example, in the detergent, benzalkonium chloride, benzethonium chloride, and chlorhexidine gluconate, which are one of the cationic surfactants, are used as components (bactericidal agent and bacteriostatic agent) having a cleaning action and an antiseptic action. Used (eg, JP 2000-109425, JP 2001-247446, JP
2000-191529), it has been reported that these components damage corneal epithelial cells clinically and from basic experiments using experimental animals and cultured cells. Therefore, the use of an eye wash or a nasal wash containing these components may damage the mucous membrane.

In contact lens wearers, dry eye patients and aging patients whose lacrimal secretion function is reduced both quantitatively and qualitatively, or allergic patients such as pollen whose nasal mucosa and ocular mucosa are roughened. In many cases, cell damage such as corneal epithelial damage has occurred, and washing can further aggravate the cell damage. In order to avoid such an adverse effect, it was necessary to mix the cytotoxic component in a lower concentration, but there was a problem in that the effect of preservative of the preparation was maintained. In addition, the formulation of components having cytotoxicity is limited,
As a result, there is a problem that the types of components that can be contained and the range of compounding amounts are narrow. As described above, as a cleansing agent for ocular mucosa and nasal mucosa, a preparation having sufficient antiseptic properties, little cytotoxicity, and high safety to living bodies is required.

[0005]

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide a cleansing agent for ocular mucosa and nasal mucosa which has less cytotoxicity. Furthermore, the present invention also aims at providing a detergent having an improved feeling of use. The present invention also provides a detergent which can be selected from a wide range of components regardless of the presence or absence of cytotoxicity.

[0006]

Means for Solving the Problems As a result of various studies to obtain a detergent for ocular mucosa and nasal mucosa in which the cytotoxic effect due to washing is reduced, the present inventors have surprisingly found that zinc or a zinc salt. It has been found that the addition of the above suppresses the cytotoxicity of the detergent. Zinc salts such as zinc sulfate and zinc lactate have astringent and anti-inflammatory effects as their main effects, and are widely used in eye drops as astringents and anti-inflammatory agents. The effect of suppressing the damage to the epithelial cells of the eye and nose and the cytoprotective effect of washing have not been known. That is, the present invention provides (1) a cleansing agent for ocular mucosa or nasal mucosa, characterized by containing zinc or a zinc salt and a surfactant, and (2) a zinc salt containing zinc sulfate, zinc lactate, zinc chloride, One or more selected from zinc gluconate, zinc citrate, zinc 2-oxoglutarate, and zinc acetate, and the detergent according to (1), (3) the surfactant is a cationic surfactant. The cleaning agent according to (1) or (2), wherein (4) further contains a cooling agent, according to any one of (1) to (3). Washing soap. (5) A method for suppressing the cytotoxic effect of a detergent by adding zinc or a zinc salt to the detergent for the eye mucous membrane or the nasal mucous membrane, (6) For the detergent for the eye mucous membrane containing a surfactant, The present invention relates to a method of preventing the cytotoxic action of a detergent by adding zinc or a zinc salt, and the like.

[0007] In the present specification, the "cleansing agent for ocular mucosa or nasal mucosa" of the present invention is also referred to as "eye wash" and "nasal cleansing agent".

In this specification,% is w unless otherwise specified.
/ V%. The term contact lens (CL) is used to include all types of contact lenses such as hard, oxygen permeable hard, and soft, unless otherwise specified.

Zinc or a zinc salt is added to the detergent of the present invention. Examples of usable zinc salts are zinc sulfate, zinc lactate, zinc chloride, zinc nitrate, zinc gluconate, zinc citrate and zinc 2-oxoglutarate, zinc oxide, zinc phosphate, zinc aluminate, zinc fluoride, and iodide. Zinc oxide, 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, zinc tripolyphosphate, zinc stearate, zinc caprate, zinc laurate, myristin Zinc acid, zinc palmitate, zinc oleate, polyphosphonic acid Lead, zinc chondroitin sulfate, zinc undecylenate, zinc ascorbate, zinc pyrithione, hinokitiol zinc, zinc dipicolinate, zinc glycerolate complex, bishistidine zinc complex, zinc complex such as zinc-3,4-dihydroxybenzoic acid complex or zinc salt Is mentioned. Among them, zinc sulfate, zinc lactate, zinc chloride, zinc gluconate, zinc citrate, zinc 2-oxoglutarate, zinc acetate and the like are preferable, and zinc sulfate, zinc lactate, zinc chloride and the like are more preferable. Since it has high solubility in water and is easy to formulate,
Zinc sulfate and zinc lactate are particularly preferred. These zinc salts have been confirmed to be safe and are widely used in eye drops, and are highly safe and preferable when used in the eye wash and 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 the zinc salt or the like used in the detergent of the present invention varies depending on the mode of the composition, the method of application, the type of compound, etc., but is usually in the range of 0.0001 to 5%. Specifically, from the aspect of local irritation and astringent action of zinc salt, in the case of a nasal wash, 0.0005 to 5%, preferably 0.001 to 2
%, More preferably 0.01 to 0.5%, in the case of an eye wash, 0.0001 to 5%, preferably 0.0005 to 2%,
More preferably, it is in the range of 0.001 to 0.5%. The zinc salt and the like can be used alone or in combination of two or more kinds. In the case of the detergent of the present invention, even if a cytotoxic component is added due to the presence of a zinc salt or the like, it is possible to reduce or avoid the expression thereof, and conventionally it cannot be added due to the risk of cytotoxicity. The above components can also be blended, and the components and blending amounts that can be contained in a wide range.

The detergent of the present invention can contain a cytotoxic component since it suppresses the action of the cytotoxic component. Examples of such a cytotoxic component include a surfactant and the like. be able to. As the surface active agent, a cationic surface active agent, an anionic surface active agent, a zwitterionic surface active agent, or a nonionic surface active agent can be used. More specifically, polyoxyethylene (PO
E) -polyoxypropylene (POP) block copolymer (for example, poloxamer 407, poloxamer 235,
Poloxamer 188), polyoxyethylene-polyoxypropylene block copolymer adduct of ethylenediamine (eg poloxamine), monolauric acid PO
P such as E (20) sorbitan (polysorbate 20) and POE (20) sorbitan monooleate (polysorbate 80)
OE sorbitan fatty acid esters, POE (60) hydrogenated castor oil and other POE hydrogenated castor oil, POE (9) lauryl ether and other POE alkyl ethers, POE (20) P
OP (4) POE / POP alkyl ethers such as cetyl ether, non-ionic surfactants such as POE alkylphenyl ethers such as POE (10) nonylphenyl ether, glycine type such as alkyldiaminoethylglycine, lauryldimethylaminoacetic acid Betaine acetate, such as betaine, amphoteric surfactants such as imidazoline, P
PO such as OE (10) lauryl ether sodium phosphate
E Alkyl ether phosphates and salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl taurine salts such as sodium N-cocoylmethyl taurine, and sulfonic acids such as sodium tetradecene sulfonate Salt, alkyl sulphate such as sodium lauryl sulphate, POE (3) POE alkyl ether sulphate such as sodium lauryl ether sulphate, anionic surfactant such as α-olefin sulphonate, alkyl amine salt, alkyl quaternary ammonium salt (Benzalkonium chloride, benzethonium chloride, etc.), polydronium chloride, Glokill (trade name eg Glokill PQ, manufactured by Rhodia), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- Dimethyliminio) eth range chloride, polyethylene polyamine, dimethylamine epichlorohydrin polycondensate (trade name, for example Busa
n1157, manufactured by Bachmann Laboratories, and alkyl pyridinium salts (cetylpyridinium chloride, cetylpyridinium bromide, etc.), chlorhexidine salts (chlorhexidine gluconate, chlorhexidine hydrochloride, etc.), and cationic surfactants. The numbers in parentheses indicate the number of added moles.

It is preferable to suppress the cytotoxicity due to the alkyl quaternary ammonium salt and the chlorhexidine salt.
Among them, cationic surfactants such as benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate have high antibacterial activity and broad antibacterial spectrum,
It is preferable because it is easy to use in pharmaceutical preparations. In particular, benzalkonium chloride and benzethonium chloride are more preferable because they are excellent in solubility and antibacterial property and can be easily formulated into a formulation.

In the composition for cleaning mucous membranes, surfactants are used as solubilizing agents, preservatives, emulsifiers, dispersants, stabilizers and the like. The content is 0.0001 to 10%, preferably 0.0001 to 5%. When using a surfactant as a preservative, bactericide, antibacterial agent, preservative, disinfectant,
The content is preferably 0.0001 to 0.05%. Particularly, from the viewpoint of reducing irritation, 0.0001 to 0.02% is preferable. Especially 0.00
1 to 0.02% is preferable.

The ratio of the surfactant to the zinc salt or the like varies depending on the mode of the composition, the method of application, the kind of the compound, etc. Usually, the zinc salt or the like is added to 1 part by weight of the surfactant.
0.0001 to 100 parts by weight, preferably 0.0005 to 50 parts by weight, more preferably 0.002 to 20 parts by weight, particularly preferably 0.02
It can be used in a proportion of up to 10 parts by weight.

Further, the cleaning agent of the present invention may contain a cooling agent. The cooling agent is useful for improving the sensation of discomfort caused by zinc salt or the like and the surfactant and improving the feeling of use. As the cooling agent, a monoterpene or a caffeine derivative can be used, and at least one kind can be contained. Examples of the monoterpene to be contained in the detergent of the present invention include menthol, camphor, borneol, geraniol, cineol, anethole, limonene, eugenol and the like. These monoterpenes may be d-, l-, or dl-forms, but from the viewpoints of sensory aspects such as refreshing feeling and aroma and safety, 1-menthol, d-menthol, dl-menthol, d-camphor. , Dl-camphor, d-borneol and dl-borneol are preferred. Geraniol, 1-menthol, d-camphor and d-borneol are particularly preferred. The monoterpene can also be used in a state of being contained in an essential oil, and a preferable essential oil is
Eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil and the like.

The caffeine derivative contained in the detergent of the present invention is represented by the formula (1)

[Chemical 1] (Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group) or a pharmaceutically acceptable compound thereof. Examples of such compounds include salts. Specific examples thereof include caffeine, pentoxifylline, theophylline, diprophylline, theobromine, proxyphylline and the like, and caffeine is preferable from the viewpoint of improving irritation.
These monoterpenes or caffeine derivatives may be used alone or in combination of two or more.

The concentration of the monoterpene or caffeine derivative in the detergent of the present invention varies depending on the mode of composition, application method, kind of compound, etc., but in the case of monoterpene, it is usually 0.00001 to 0.1% by weight, preferably Is 0.0001 ~
It is in the range of 0.05% by weight. In particular, considering the irritating property of monoterpenes, it is preferably 0.1% by weight or less, and from the viewpoint of improving the stimulating property due to a zinc salt or the like and obtaining the effect of improving the feeling of use, it is 0.00001% by weight or more. Is preferred. A suitable range is, for example, 0.0003 for eye wash.
~ 0.05% by weight, 0.0001-0.03% by weight for nasal washes can be employed.

In the case of caffeine derivatives, usually 0.00
It is in the range of 001 to 2% by weight, preferably 0.0001 to 1% by weight. In particular, from the viewpoint of the concentration that does not exhibit the irritation of the caffeine derivative, it is preferably 1% by weight or less, from the viewpoint of improving the irritation by surfactants and zinc salts, and obtaining the effect of improving the feeling of use. It is preferably 0.00001% by weight or more. As a suitable range, for example,
0.0003 to 0.5% by weight for eye washes, 0.000 for nasal washes
1 to 0.3% by weight can be adopted. The ratio of the zinc salt and the like to the monoterpene varies depending on the mode of the composition, the application method, and the type of the compound, but usually the monoterpene is 0.005 to 50, preferably 0.05 to 1 part by weight of the zinc salt and the like. It is in the range of 10. The compounding ratio of the caffeine derivative with respect to the zinc salt and the like varies depending on the aspect of the composition, application method, and type of compound, but is usually 0.01 to 1000, preferably 0.05 to 50.
The range is 0.

The monoterpene or caffeine derivative is
A detergent with reduced irritation of a surfactant and improved usability can be provided. The ratio of the monoterpene or caffeine derivative and the surfactant is the composition aspect, the application method,
Although it depends on the type of compound, etc., usually surfactant 1
With respect to parts by weight, the monoterpene or caffeine derivative is 0.0001 to 100 parts by weight, preferably 0.0005 to 50 parts by weight.
It can be used in an amount of 0.002 to 10 parts by weight, particularly preferably 0.02 to 5 parts by weight.

The cleansing 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 (eye 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 items. More specifically, nasal wash, eye wash and the like can be mentioned.

The detergent of the present invention may be in any form provided that it can be prepared into a liquid at the time of use, and may be in the form of powder, jelly, liquid or the like depending on the purpose. For example, it may be a liquid formulation that can be used as it is or a formulation that can be prepared into a liquid at the time of use. It is preferable that it is a liquid agent from the viewpoint of ease of use.

The composition of the present invention contains various components (including a pharmacologically active ingredient and a physiologically active ingredient) in addition to the above-mentioned zinc salt, a surfactant and a cooling agent, as long as the effects of the present invention are not impaired.
May be contained in combination. The type of such components is not particularly limited, and examples include decongestant components, α-adrenergic agonist components, anti-inflammatory drug components, vitamins, amino acids, saccharides, local anesthetic components, steroid components, antihistamine drug components. Alternatively, an antiallergic drug component, cellulose or a derivative thereof or a salt thereof, a polysaccharide or a derivative thereof, and the like can be exemplified. Examples of suitable components in the present invention include the following components.

Decongestant components: epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof. α-adrenergic agonists: for example, imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and pharmaceutically or physiologically acceptable salts thereof (eg, Inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate).

Anti-inflammatory drug ingredient: celecoxib
b), rofecoxib, indomethacin,
Diclofenac, diclofenac sodium, pranoprofen, piroxicam, meloxica
m), epsilon-aminocaproic acid, berberine and pharmacologically acceptable salts (for example, berberine chloride, berberine sulfate), lysozyme, lysozyme chloride, methyl salicylate, allantoin, glycyrrhizinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, etc. )Such.

Antihistamine or antiallergic ingredients: for example, chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglic acid, tranilast, amlexanox, mequitazine, loratadine, loratadine, loratadine. Fexofenadine, cetirizin
e), ibudilast, splatast, pemirolast or salts thereof (for example, chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, clomoglitan hydrochloride). etc.

Vitamin: For example, vitamin A [eg retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (eg retinol acetate, retinol palmitate etc.)] , Vitamin Bs [thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl nitrate ester salt, dicetiamine hydrochloride, fursultiamine hydrochloride, octotiamine, shicothiamine, bis-ibutyamine, bisbentiamine, fursultiamine, pro Sultiamine, benfotiamine,
Flavin adenine dinucleotide sodium, riboflavin, sodium riboflavin phosphate, riboflavin butyrate, pyridoxine hydrochloride, pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin, hydroxocobalamin, nicotinic acid, nicotinic acid amide, panthenol, calcium pantothenate, Sodium pantothenate, biotin, etc.], vitamin C [ascorbic acid and its derivatives, erythorbic acid and its derivatives, and pharmacologically acceptable salts thereof (eg, sodium ascorbate, sodium erythorbate, etc.]], vitamin D [Eg ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaki Sterols and pharmaceutically acceptable salts thereof, etc.], vitamin Es [eg tocopherol and its derivatives, ubiquinone derivatives and pharmaceutically acceptable salts thereof (tocopherol acetate, tocopherol nicotinate, tocopherol succinate) , Tocopherol calcium succinate, etc.), and other vitamins [eg, carnitine, ferulic acid, γ-
Oryzanol, orotic acid, rutin, eriocitrin,
Hesperidin and its pharmacologically acceptable salts (carnitine chloride, etc.), etc.].

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, hydroxylysine, glycylglycine, aminoethyl sulfonic acid (taurine) or salts thereof (eg potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.) and the like.

Sugars: monosaccharides (eg glucose), disaccharides (eg trehalose, lactose, fructose etc.), oligosaccharides (eg lactulose, raffinose, pullulan etc.), cellulose or its derivatives (eg methylcellulose, ethylcellulose). , Hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, etc.), polymeric sugars (eg chondroitin sulfate, hyaluronic acid etc.) and their pharmacologically acceptable salts (eg sodium chondroitin sulfate, sodium hyaluronate etc.) )), Sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.) and the like.

Local anesthetic components: lidocaine, oxyprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilukaine, and salts thereof (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) and the like. Steroid ingredients: hydrocortisone, prednisolone,
And their salts etc.

Polysaccharides or derivatives thereof: gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin. , Collagen, pectin,
Starch, polygalacturonic acid (alginic acid), chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate or its salts (sodium alginate, sodium hyaluronate, sodium chondroitin sulfate) Other ingredients such as):
Polyvinyl alcohol (completely or partially saponified product), polyvinyl pyrrolidone, etc.

The content of these components in the detergent of the present invention is appropriately selected according to the type of formulation, the type of active ingredient, etc., and the content of various components in the detergent for the eye mucous membrane and nasal mucosa is the same as in the art. Known in the art. For example, 0.0001 to 30%, preferably 0.001-1 to 1 of the whole preparation
It can be selected from the range of about 0%. More specifically, the content of each component in the detergent is as follows, for example.

Decongestant component (vasoconstrictor or sympathomimetic): For example, 0.00001 to 0.5%, preferably 0.0001 to 0.3%, more preferably 0.0.
01-0.1%. Anti-inflammatory drug component or astringent drug component: For example, 0.0001-
10%, preferably 0.0001-5%. Antihistamine drug component or antiallergic drug component: For example,
0.00001-10%, preferably 0.0001-5
%. Vitamins: For example, 0.0001 to 1%, preferably 0.0001 to 0.5%. Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%. Sugar: For example, 0.0001 to 5
%, Preferably 0.001 to 5%, more preferably 0.01 to 2%. Local anesthetic component: For example, 0.0001 to 1%, preferably 0.001 to 1%. Cellulose or a derivative thereof or a salt thereof: For example,
0.001-5%, preferably 0.01-1%. Polysaccharide or its derivative: For example, 0.0001 to 2%,
Preferably 0.01 to 2%, more preferably 0.01
~ 1%. Polyvinylpyrrolidone, polyvinyl alcohol: For example, 0.001 to 10%, preferably 0.001 to 5
%, More preferably 0.01 to 3%.

Further, in the composition of the present invention, various components and additives are appropriately selected according to a conventional method according to the use and the form, as long as the effects of the invention are not impaired, and one or more of them are selected. The above may be contained in combination. As those components or additives, for example, thickeners, antiseptic / sterilizing / antibacterial agents,
Examples include various additives such as pH regulators, isotonic agents, inorganic salts, chelating agents, buffers, solubilizing agents, suspending agents, emulsifiers, antioxidants, and fragrances.

The typical components used in the composition of the present invention are illustrated below, but these are merely examples.

Thickeners: For example, polysaccharides or derivatives thereof (gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, quince seed, darman 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 Derivatives (methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl Cellulose, carboxyethyl cellulose, cellulose), polyvinyl alcohol (completely or partially saponified), polyvinyl pyrrolidone,
Examples thereof include macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid and the like, and pharmacologically acceptable salts thereof.

Sugars: for example, glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol, and the like. Examples thereof include pharmacologically acceptable salts.

Preservatives, bactericides or antibacterial agents: they may overlap with the above examples, for example, paraoxybenzoic acid ester (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.) ), Sulfonamides (eg, sulfamethoxazole, sulfisoxazole, sulfisomidine, and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.), new quinolone agents (lomefloxacin) , Levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride), acrinol, methylrosanilin chloride, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium) and Pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, etc.), biguanides (polyhexamethylene biguanide, chlorhexidine or its salts, etc.), berberine or its salts, alkylpolyamino Ethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, zirconium phosphate such as silver support, thimerosal, dehydroacetic acid, chlorxylenol, chlorophen, resorcin,
Thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, benzoic acid, propionic acid, halocarban, thiabendazole, polymyxin B, 5-chloro-2-methyl-4-isothiazoline-3 -One, 2-methyl-4-isothiazolin-3-one, polylysine, hydrogen peroxide, polydronium chloride, Gl
okill (Product name eg Glokill PQ, made by Rhodia),
Polydiallyldimethylammonium chloride, poly
[Oxyethylene (dimethyliminio) ethylene- (dimethyliminio) etrenedichloride, polyethylene polyamine, dimethylamine epichlorohydrin polycondensate (trade name, for example, Busan 1157, manufactured by Buckman Laboratories) and the like can be mentioned.

PH adjusters: For example, inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (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 bases (sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, etc.) ),
Examples thereof include organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), borax, and pharmacologically acceptable salts thereof.

Isotonic agents: polyhydric alcohols such as glycerin and propylene glycol, sugars (but sugar,
Mannitol, sorbitol, etc.) and the like.

Inorganic salts: For example, sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate,
Examples thereof include sodium thiosulfate and sodium acetate.

Fragrance or cooling agent: in some cases overlapping with the above examples, for example, menthol, camphor, borneol, geraniol, eucalyptus oil, bergamot oil, fennel oil, peppermint oil, cinnamon oil, rose oil, peppermint oil. And so on.

The detergent of the present invention needs to be adjusted to a pH and / or an osmotic pressure within a range acceptable for the living body, if necessary. The appropriate pH and osmotic pressure differ depending on the application site, dosage form, etc., but when used, the pH is usually 4.0 to 4.0.
9.0, preferably 4.0 to 8. to relieve irritation.
0, particularly preferably 4.0 to 7.0; the osmotic pressure ratio to physiological saline is usually 0.4 to 4.0, in order to reduce irritation, preferably 0.6 to 2.5, particularly preferably Is 0.
It is in the range of 8 to 1.6. The pH or osmotic pressure can be adjusted using a buffering agent, the pH adjusting agent, the tonicity adjusting agent, the inorganic salt, or the like.

Here, as the buffer, a borate buffer,
Examples thereof include phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartate and the like. These buffer agents may be used in combination. Preferred buffers are borate buffers, phosphate buffers, carbonate buffers and citrate buffers. Particularly preferred buffering agents are borate buffers, citrate buffers or phosphate buffers. Examples of the borate buffer include borate salts such as alkali metal borate and alkaline earth metal borate. Examples of the citrate buffer include citrate alkali metal salts and the like. As a phosphate buffer,
Examples thereof include phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Further, a borate, citrate or phosphate hydrate may be used as the 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 salts thereof (sodium hydrogen carbonate, sodium carbonate, etc.), citric acid or salts 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 aqueous composition of the present invention is, for example,
It is about 0.0001 to 10.0% by weight.

The detergent of the present invention is particularly useful for contact lens wearers, dry eye patients, the aged, or the nasal mucosa or ocular mucosa whose tear-secreting function is reduced both quantitatively and qualitatively. In allergic patients such as pollen, it is particularly preferable because washing causes cell damage.

The detergent 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 filter sterilization treatment step, a container filling step, and the like can be added. The detergent of the present invention can also be produced by the above-mentioned known method, but more specifically, for example, if it is an eyewash, a surfactant, a refreshing agent, a zinc salt and the like, and other compounding ingredients. Is dissolved in purified water, adjusted to a predetermined osmotic pressure and pH, filtered and sterilized in a sterile environment, and aseptically filled in a container that has been washed and sterilized. In addition, the nasal wash can be manufactured by the same method. Further, in the case of a preparation that can be dissolved at the time of use, it can be produced by a known method depending on the dosage form, and it is used by dissolving it in water or an attached solution at the time of use.

[0046]

EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

Test Example 1 Cytotoxicity inhibition test (1) Using a pore filter, rabbit corneal cells were cultured on the filter to prepare a simulated cornea, and the cytotoxicity was determined by the leakage amount of the fluorescent indicator from the simulated cornea. I checked. Specifically, the rabbit corneal epithelial cell line (SIRC) is a cell culture insert (Falcon, inner diameter 6 mm, pore diameter 0.4 μm).
A pseudo cornea was prepared by culturing on the PET micropore filter until the confluence was reached.

A cell culture insert in which a rabbit corneal epithelial cell line (SIRC) was cultured was allowed to stand still on a 24-well culture plate (manufactured by Falcon), 0.4 ml of a test solution in the cell culture insert, and a culture plate outside the cell culture insert. HBSS (Hanks equilibration buffer; 100
In ml, calcium chloride 0.014 g, potassium chloride 0.04 g,
0.006 g of potassium dihydrogen phosphate, 0.01 g of magnesium chloride hexahydrate, 0.8 g of sodium chloride, 0.035 g of sodium hydrogen carbonate, 0.0048 g of sodium dihydrogen phosphate, and 0.1 g of D-glucose) (0.6 ml) are added, Incubated at 37 ° C for 1 hour. After removing the test solution by suction, fluorescein
400 μl of 1 μg / ml HBSS is added. The concentration of fluorescein leaked to the lower surface of the filter was quantified every 10 minutes thereafter. The leakage rate of fluorescein per unit area was determined from the change over time in the amount of leaked fluoroscein. In addition, after the addition of fluorescein, no change in the liquid volume was observed inside or outside the cell culture insert by the end of the test.

The cytotoxicity was determined according to the following formula.

[Equation 1]

Cytotoxicity was tested using each of the samples listed in Table 1 below.

[Table 1]

The results are shown in Table 2. Test results

[Table 2]

The above test results show that the cytotoxicity due to the surfactant is suppressed by the zinc salt and the like,
It was confirmed that the composition containing the zinc salt or the like of the present invention is a composition with suppressed cytotoxicity.

Example 1-5 Eyewash According to the formulation shown in Table 3 below, each component was dissolved in sterilized purified water to adjust the osmotic pressure and pH.
The volume was adjusted to 0 mL, sterile filtered, and filled in a container to prepare an eye wash (agent).

[0054]

[Table 3]

Next, 5 ml of the eyewash solution prepared in Examples 1 to 5 and Comparative Example 1 was placed in an eyewash cup, and a usage test was carried out for soft contact lens wearers. The left and right eyes of 10 test subjects were used for 10 seconds, and the refreshing feeling, irritation, and overall feeling of use were evaluated according to the following criteria. Criteria for evaluation Presence / absence of refreshing feeling: -: No refreshing feeling is felt +: A little refreshing feeling is felt ++: Irritating sensation of feeling quite refreshing (unnaturalness other than refreshing feeling): -: No stimulation Not felt +: Slight irritation is felt ++: Very irritation is felt Evaluation of use (comprehensive): Good, normal, and bad results are shown in Table 4.

[0056]

[Table 4] As shown in Table 4, except for Comparative Example 1, there was no irritation and the feeling of use was good.

Examples 6-10 Nasal washes According to the formulations shown in Table 5 below, each compounding ingredient was dissolved in sterile purified water to adjust the osmotic pressure and pH, and then the total amount was adjusted to 10
The volume was adjusted to 0 mL, sterile filtered, and filled in a container to prepare a nasal rinse (agent).

[0058]

[Table 5]

The formulations prepared in Examples 6 to 10 and Comparative Example 2 were filled in aerosol containers to prepare nasal washes.
The nasal washes were tested for alleviation of symptoms, presence / absence of irritation, and feeling of use in allergic patients. After washing by nasal spray by 5 hay fever patients, evaluation was performed according to the following evaluation criteria. Evaluation Criteria Criteria: Alleviation of allergic symptoms (improvement of runny nose / stuffy nose): −: No improvement in runny nose / nasal congestion +: Some improvement in runny nose / nasal congestion ++: Significant runny nose / nasal congestion The presence or absence of improved irritation: -: No irritation is felt +: Some irritation is felt ++: Very irritation is felt Evaluation of usage (comprehensive): Good, normal, and bad results are shown in Table 6. Show.

[0060]

[Table 6] Clearly from the above table, in all cases except the comparative example, there was no irritation and the feeling of use was good.

Examples 11-22 (Eyewash) Eyewashes were prepared according to the formulations shown in Tables 7 and 8 below.

[Table 7]

[0062]

[Table 8]

Examples 23-29 (nasal wash) Nasal washes were prepared according to the formulations shown in Table 9 below.

[Table 9]

[0064]

EFFECTS OF THE INVENTION According to the present invention, the cytotoxicity of the cytotoxic component can be reduced, so that a highly safe detergent for the ocular and nasal mucosa can be obtained. Further, according to the present invention, since the presence or absence of cytotoxicity of the component is less likely to cause a problem, it is possible to select an effective component from a wide range of components,
A higher quality cleaning agent can be obtained. Further, according to the present invention, the feeling of use of the cleaning agent can be improved, and the compliance of the user is improved. Furthermore, the present invention is particularly effective for contact lens wearers who are susceptible to damage to the ocular and nasal mucosa and allergic patients such as hay fever.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/00 A61K 47/00 47/04 47/04 47/08 47/08 47/10 47/10 47 / 28 47/28 A61P 11/02 A61P 11/02 27/04 27/04 43/00 105 43/00 105 F term (reference) 4C076 AA12 BB24 BB25 CC03 CC31 DD16F DD30Z DD37T DD51 FF12 FF16 4C086 AA01 AA02 BC17 HA03 HA14 HA15 HA20 MA02 MA03 MA05 MA17 MA58 MA59 NA06 NA14 ZA33 ZA34 ZB21 ZB31 4C206 AA01 AA02 FA53 MA02 MA03 MA05 MA37 MA79 MA80 NA05 NA06 ZA33 ZA34 ZB21 ZB31

Claims (6)

[Claims] 1. A cleansing agent for ocular mucosa or nasal mucosa, which contains zinc or a zinc salt and a surfactant. 2. The zinc salt is one or more selected from zinc sulfate, zinc lactate, zinc chloride, zinc gluconate, zinc citrate, zinc 2-oxoglutarate, and zinc acetate. The cleaning agent according to. 3. The cleaning agent according to claim 1 or 2, wherein the surfactant is a cationic surfactant. 4. The cleaning agent according to any one of claims 1 to 3, further comprising a cooling agent. 5. A method for suppressing the cytotoxic action of a detergent by adding zinc or a zinc salt to the detergent for the ocular mucosa or nasal mucosa. 6. A method for preventing the cytotoxic action of a detergent by adding zinc or a zinc salt to the detergent for ocular mucosa containing a surfactant.