JP2004315517A - Ophthalmologic composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ophthalmologic composition enhanced in the effect of cooling a region to which it is applied and reduced in the initial stimulus when it is applied. <P>SOLUTION: The ophthalmologic composition comprises (A) a monocyclic monoterpenoid and (B) a monoterpene alcohol in such amounts that 0.01 to 2,000 pts.wt. (B) is present per 1 pt.wt. (A). This composition is enhanced in the effect of cooling a region to which it is applied because the surface temperature of the region is lowered, and the cooling effect is sustained, and is reduced in the initial stimulus when it is applied, and is excellent in functionality. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to an ophthalmic composition having improved organoleptic properties and a method for improving the organoleptic properties of an ophthalmic composition.

Pharmaceuticals, etc. are not based on the so-called medicinal approach, but by applying a refreshing feeling and a refreshing feeling at the time of application, to improve the functionality of the preparation and to be able to realize the effect more, as a refreshing agent, essential oils and Essential oil components are often included. Among them, compounds such as menthol, camphor and borneol are known to have a strong cooling effect (cooling effect), and are compounded in various preparations including ophthalmic compositions such as eye drops. The cooling effect of these cooling agents is expected to have an effect of improving the discomfort of the eyes and providing a relaxing feeling and a refreshing feeling, in addition to the effect of relieving eye fatigue. However, these cooling effects are not due to evaporation or vasodilation, but are reported to involve the cold-sensing nerve, but details are not clear. On the other hand, as a method of relieving eye fatigue, products that cool the eye with eye pillows are sold, or by lowering the temperature of the eye and its surrounding parts, the stress caused by dryness, hot flashes, and overuse of the eyes Although a technique for healing insomnia and the like (Patent Document 1) is disclosed, it is not easy to use at the time of use, and a refreshing sensation cannot be obtained.

On the other hand, menthol or the like, which is widely used as a cooling agent, has a strong cooling effect, but may be irritating when applied to the ocular mucosa at a high concentration. In ophthalmic compositions such as eye drops and eyewashes, there are so-called `` cooling-type '' compositions in which several types of cooling agents are blended to obtain a more refreshing or cooling sensation when applied. There is a tendency for a refreshing ophthalmic composition to demand a stronger cooling sensation and its persistence, or a stronger cooling effect such that a cooler sensation can be realized upon application. However, if the amount of the cooling agent in the composition is increased to satisfy the demand, eye irritation may appear when applied to the eyes. The so-called initial stimulus, such as burning sensation or pain, which is felt strongly immediately after application, especially among eye irritation, may lead to a decrease in user compliance. There is a need for a formulation having a feeling.

In order to reduce irritation during application of an ophthalmic composition containing menthol as a cooling agent, a specific amount of menthol and a specific ratio of camphors and borneols to this menthol are combined and combined. In this way, a strong cooling sensation, a technique that can enhance the persistence of a refreshing sensation and reduce eye irritation (Patent Document 2), or by combining menthols and cyclodextrins into eye drops A technique that can provide a strong refreshing feeling and reduce eye irritation (Patent Document 3) is known.

However, camphors and borneols also have a cooling effect and are also irritating, and even if the amounts and blending ratios of the respective components are controlled, their irritating effect is not sufficient. On the other hand, cyclodextrin, by including menthol, reduces the irritation of menthol, but masks a useful cooling effect and does not provide a sufficient refreshing feeling. No mention is made of a cooling function that allows the user to feel cold.

JP 2001-245915 A JP-A-9-132526 JP-A-10-306022

An object of the present invention is to provide an ophthalmic composition capable of enhancing the cooling effect of an ophthalmic composition containing a monoterpene alcohol such as menthol or borneol and suppressing initial irritation upon application. It is another object of the present invention to provide a method for enhancing the cooling effect of an ophthalmic composition containing a monoterpene-based alcohol and suppressing initial irritation.

The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, A) a monocyclic monoterpene-based hydrocarbon, a monocyclic monoterpene-based ketone, and a monocyclic monoterpene-based oxide One or more selected monocyclic monoterpenoids and A) at least one or more monoterpene-based alcohols in a weight ratio of A) to 1 part by weight and B) of 0.01 to 2000 parts by weight. By using an ophthalmic composition formulated in the range of, the temperature of the eyeball surface is reduced when applied to the eye, and the coldness is sustained, while the initial stimulus is suppressed, and the present invention is found. Was completed.

That is, the present invention is an ophthalmic composition described in the following (1) to (5).
(1) A) one or more monocyclic monoterpenoids selected from the group consisting of monocyclic monoterpene hydrocarbons, monocyclic monoterpene ketones and monocyclic monoterpene oxides, and B) at least An ophthalmic composition comprising at least one monoterpene alcohol in a weight ratio of A) to 1 part by weight and B) in a range of 0.01 to 2,000 parts by weight.
(2) The ophthalmic composition according to (1), further comprising at least one alcohol selected from the group consisting of lower alcohols and polyhydric alcohols.
(3) The ophthalmic composition according to any one of (1) and (2), which is a liquid composition.
(4) The ophthalmic composition according to (3), wherein the liquid composition is an eye drop, an eyewash, a contact lens mounting solution or a contact lens agent.
(5) The ophthalmic composition according to any one of (1) to (4), further comprising a thickening agent and having an absolute viscosity at 20 ° C of 2 to 200 mPa · s.
The present invention is a method described in the following (6) and (7).
(6) A) one or more monocyclic monoterpenoids selected from the group consisting of monocyclic monoterpene hydrocarbons, monocyclic monoterpene ketones and monocyclic monoterpene oxides, and B) at least A method in which one or more monoterpene alcohols are contained in a weight ratio of A) to 1 part by weight and B) in a range of 0.01 to 2000 parts by weight to enhance the cooling effect of the ophthalmic composition.
(7) A) one or more monocyclic monoterpenoids selected from the group consisting of monocyclic monoterpene hydrocarbons, monocyclic monoterpene ketones and monocyclic monoterpene oxides, and B) at least A method of containing one or more monoterpene alcohols in a weight ratio of A) to 1 part by weight and B) in a range of 0.01 to 2000 parts by weight to suppress the initial irritation of the ophthalmic composition. .

  Advantageous Effects of Invention According to the present invention, it has become possible to provide an ophthalmic composition that exhibits an enhanced cooling effect on an application site, suppresses initial irritation, and has an excellent feeling in use.

In this specification, unless otherwise specified,% means w / v%. The term contact lens (CL) is used to mean any type of contact lens, such as hard, oxygen-permeable hard, and soft, unless otherwise specified. In this specification, the ophthalmic composition may be simply referred to as “composition” or “formulation”.

In the present invention, the enhancement of the cooling action includes lowering the cooling temperature of the application site and maintaining the cooling action. The case where both of these enhanced actions are exhibited, or the case where only one of these actions is exhibited, is within the scope of the present invention.

In the present invention, the initial stimulus means a stimulus such as a burning sensation, an uncomfortable sensation, and a pain that is temporarily strongly felt on the eye immediately after the application of the ophthalmic composition.

Examples of the monocyclic monoterpene-based hydrocarbon of the present invention include limonene, terpinene, ferrandrene, pinene, and the like, and examples of the monocyclic monoterpene-based ketone include mentone, isomentone, carvone, piperidone, plegone, and the like. Examples of the monocyclic monoterpene-based oxide include cineol and the like. These can be appropriately added alone or in combination of two or more, and any of α, β, γ, d, l, dl and the like can be used. Preferred are menthone, carvone, limonene, ferrandrene, pinene, cineole, piperiton, and particularly preferred are menthone, carvone, pinene, limonene, cineole. Further, these compounds are preferably blended at a concentration that does not cause eye irritation, and are used in the range of 0.0001 to 0.1%. It is more preferably 0.0005 to 0.05%, particularly preferably 0.0005 to 0.01%. If the concentration deviates significantly from this concentration range, it becomes difficult to enhance the cooling effect in the present invention, and if the concentration deviates from a high concentration, the effect of suppressing the initial irritation in the present invention tends to be hardly obtained.

Examples of the monoterpene alcohol of the present invention include menthol, geraniol, borneol, nerol, citronellol, linalool, thymol, terpineol, isopulegol, and the like. These may be used alone or in combination of two or more. And any of α, β, γ, d, l, dl and the like can be used. Preferred are menthol, isopulegol, linalool, geraniol, borneol, and particularly preferred are menthol and borneol.

The monoterpene alcohol is preferably blended at a concentration that does not cause eye irritation, and is used in the range of 0.0001 to 0.1%. It is more preferably 0.001 to 0.05%, particularly preferably 0.005 to 0.05%. If the concentration deviates significantly from this concentration range, it becomes difficult to enhance the cooling effect in the present invention, and if the concentration deviates from a high concentration, the effect of suppressing the initial irritation in the present invention tends to be hardly obtained.

The monocyclic monoterpenoids can be used in a state where they are contained in essential oils, and can also be used as purified or synthesized components. As such essential oils, mint oil, peppermint oil, rose oil, fennel oil, eucalyptus oil, bergamot oil, cool mint and the like can be used.

In the composition of the present invention, the ratio of A) monocyclic monoterpenoids of monocyclic monoterpene hydrocarbons, monocyclic monoterpene ketones and monocyclic monoterpene oxides, and B) monoterpene alcohols The amount of A) is 1 part by weight, and the amount of B) is 0.01 to 2000 parts by weight, preferably 0.05 to 1000 parts by weight, and more preferably 0.05 to 500 parts by weight. If the value is significantly out of this range, the effect obtained by the present invention tends to decrease.

Furthermore, by adding alcohols to the ophthalmic composition of the present invention, the cooling effect that the present composition can exert can be further enhanced. The alcohol in the present invention is at least one or more alcohols selected from the group consisting of lower alcohols and polyhydric alcohols. Examples of lower alcohols include alcohols having 2 to 5 carbon atoms, for example, ethanol, propanol, butanol, pentanol and various modified alcohols. Examples of polyhydric alcohols include propylene glycol and glycerin. Among them, propylene glycol is preferred. The concentration of the alcohol in the ophthalmic composition is not particularly limited as long as the ophthalmic composition of the present invention has the effects of the present invention, but is preferably 0.001 to 2%. , 0.01 to 2% is more preferable, and particularly 0.05 to 1% is preferable. If it is less than 0.001%, the effect of enhancing the cooling effect in the present invention is hardly obtained, and if it exceeds 2%, eye irritation tends to occur.

Furthermore, by blending the ophthalmic composition of the present invention with a polymer compound as a thickening agent, the cooling action according to the present invention is maintained, and the cooling action is further strengthened. The stability over time of the ophthalmic composition containing the monoterpenoids B) can be ensured. In addition, the feeling of use can be improved without stickiness of the preparation when applied to the eye.

The thickening agent in the present invention is a polymer compound, preferably a cellulose or a derivative thereof or a salt thereof, a polymer polysaccharide and a salt or a derivative thereof or a salt thereof, and the like. The absolute viscosity at 20 ° C. is 2 to 200 mPa · s. In addition, as a high molecular compound, methylcellulose, carboxymethylcellulose and its salt, polyacrylic acid and its salt, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, carboxyvinyl polymer, hyaluronic acid Examples thereof include acids and salts thereof, dextran, polyoxyethylene polyoxypropylene block copolymer, and the like, as long as at least one of them is contained.

In the present invention, the compounding amount of the thickening agent varies depending on the molecular weight and type of the thickening agent, but the absolute viscosity of the ophthalmic agent of the present invention is 2 to 200 mPa · s at a temperature of 20 ° C., preferably 2 to 200 mPa · s. The amount of the thickening agent can be appropriately selected so as to be 150 mPa · s, more preferably 2 to 100 mPa · s.

Such an absolute viscosity can be measured by a method using a conical plate type rotary viscometer. In detail, the general test method described in the 14th revised Japanese Pharmacopoeia, 45. Viscosity measurement method, 2nd method Rotational viscometer method, (3) The method described in the section of conical flat plate type viscometer. The measurement can be performed using a commercially available conical plate-type rotary viscometer and a suitably selected rotor. Examples of such viscometers include E-type viscometers (Tokimec), synchro rheological PC type (Brookfield), Ferranti Shirley (Ferranty), Lord Visco (Haake), IGK High shear rheometer (Ishida Giken Co., Ltd.), Shimadzu rheometer (Shimadzu Corporation), mechanical spectrometer (Rheometrics) and the like. The rotors of these commercially available viscometers are appropriately selected, and each time a test sample is measured, a petroleum hydrocarbon oil (Newtonian fluid) specified by JIS Z 8809 is used as a calibration standard solution, and appropriately adjusted. At 20 ° C. can be measured.

  The viscosities of eye drops and eyewashes shown in Examples are as follows: TV-20 type viscometer (manufactured by Tokimec, model name: TVE-20L), which is a type of E-type viscometer, rotor: 1 ° 34 ′ × R24. It measured using. As measurement conditions, when the viscosity is less than 6 mPas, the rotation speed is 100 rpm, when the viscosity is less than 6 to 12 mPas, the rotation speed is 50 rpm, when the viscosity is less than 12 to 30 mPas, the rotation speed is 20 rpm, and the viscosity is less than 30 to 60 mPas. The measurement was performed at a rotation speed of 5 rpm for a rotation speed of 10 rpm and a viscosity of less than 60 to 120 mPa · s, and at a rotation speed of 2.5 rpm for a viscosity of less than 120 to 240 mPa · s.

Further, the ophthalmic composition of the present invention is preferably a liquid composition, particularly an eye drop (hereinafter also referred to as an eye drop, including an eye drop that can be used even while wearing a hard or soft contact lens), Eyewash (hereinafter also referred to as eyewash; also includes eyewash that can be used while wearing hard or soft contact lenses), contact lens mounting solution, contact lens agent (washing solution, preservative solution, cleaning preservative solution, disinfection Liquid, multi-purpose solution).

The ophthalmic composition of the present invention may further contain various components (including pharmacologically active components and physiologically active components) in combination as long as the effects of the present invention are not impaired. The types of such components are not particularly limited, and include, for example, decongestant components, α-adrenergic agonist components, anti-inflammatory drug components, vitamins, amino acids, saccharides, steroid components, antihistamine drug components, or antiallergic drug components. , Cellulose or a derivative thereof, a salt thereof, a polysaccharide or a derivative thereof, and the like. Examples of suitable components in the present invention include the following components.

Decongestant: epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof.
α-Adrenergic agonists: For example, imidazoline derivatives (eg, naphazoline, tetrahydrozoline), β-phenylethylamine derivatives (eg, phenylephrine, epinephrine, ephedrine, methylephedrine), 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; and organic acid salts such as epinephrine bitartrate).
Anti-inflammatory drug components: celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, planoprofen, piroxicam, meloxicam, epsilon-aminocaproic acid, berberine and pharmacologically acceptable salts (eg, , Berberine chloride, berberine sulfate), zinc salts (zinc sulfate, zinc lactate, zinc glycolate, zinc hydroxybutyrate, zinc glycerin, zinc malate, zinc tartrate, zinc citrate, etc.), lysozyme, lysozyme chloride, methyl salicylate, allantoin Glycyrrhizic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, etc.).
Antihistamine or antiallergic component: for example, chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglinic acid, tranilast, amlexanox, mequitazine, loratadine (loratadine), loratadine (loratadine) fexofenadine), cetirizine, ibudilast, splatast, pemirolast or a salt thereof (for example, chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, emedastin fumarate, clemastine fumarate, azelastine hydrochloride, levocabas hydrochloride, levocabastine hydrochloride Olopatadine, sodium cromoglycate, etc.).
Vitamins: For example, vitamins A (eg, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmaceutically acceptable salts thereof (eg, retinol acetate, retinol palmitate, etc.), vitamin B) (Thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, octiamine, sicotiamine, bisbutiamine, bisbenthamine, fursultiamine, prosultiamine, Benfotiamine, flavin adenine dinucleotide sodium, riboflavin, riboflavin sodium phosphate, riboflavin butyrate, pyridoxine hydrochloride, pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxy acetate Socobalamin, cyanocobalamin, hydroxocobalamin, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, etc., vitamin Cs [ascorbic acid and its derivatives, erythorbic acid and its derivatives and its pharmacological properties] Acceptable salts (eg, sodium ascorbate, sodium erythorbate, etc.), and vitamin Ds (eg, ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaxosterol and pharmacology thereof) Vitamin Es [eg, tocopherol and its derivatives, ubiquinone derivatives and its pharmacologically acceptable salts (tocopherol acetate, nicotine, etc.) And other vitamins [e.g., carnitine, ferulic acid, [gamma] -oryzanol, orotic acid, rutin, eriocitrin, hesperidin, and pharmacologically acceptable salts thereof.] [Tocopherol formate, tocopherol succinate, calcium tocopherol succinate, etc.] 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 a salt thereof (eg, potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.) and the like.
Saccharides: monosaccharides (eg, glucose, etc.), disaccharides (eg, trehalose, lactose, fructose, etc.), oligosaccharides (eg, lactulose, raffinose, pullulan, etc.), sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.) Such.
Steroid components: hydrocortisone, prednisolone, and salts thereof.
Polysaccharides or derivatives thereof: gum arabic, gum karaya, xanthan gum, carob gum, guar gum, guaiac fat, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, carrageenan, gelatin, collagen, pectin, Starch, polygalacturonic acid (alginic acid), chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, chondroitin sulfate or salts thereof (sodium alginate, sodium chondroitin sulfate, etc.)

  The amount of these components in the ophthalmic composition is appropriately selected depending on the type of the preparation, the type of the active ingredient, and the like, and is 0.0001 to 30%, preferably 0.001 to 10% based on the whole preparation. You can choose from a range of degrees. More specifically, the content of each component in the ophthalmic composition is, for example, as follows.

Decongestant (vasoconstrictor or sympathomimetics): For example, 0.0001 to 0.5%, preferably 0.0005 to 0.3%, more preferably 0.001 to 0.1%.
Anti-inflammatory or astringent components: for example, 0.0001 to 10%, preferably 0.0001 to 5%.
Antihistamine component or antiallergic component: for example, 0.0001 to 10%, preferably 0.001 to 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%.
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%.
Polysaccharide or derivative thereof: for example, 0.0001 to 2%, preferably 0.01 to 2%, more preferably 0.01 to 1%.
Polyvinyl pyrrolidone, polyvinyl alcohol: for example, 0.001 to 10%, preferably 0.001 to 5%, more preferably 0.01 to 3%.

Further, the ophthalmic composition of the present invention can contain an antibacterial component and a bactericide component, if desired. Specifically, examples of the antibacterial or bactericide component include sulfonamides (for example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and pharmacologically acceptable salts (sulfamethoxazole) Sodium, sulfisomidine sodium, etc.), acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium), and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetyl chloride) Pyridinium, cetylpyridinium bromide), alkyl polyaminoethyl glycine, new quinolones (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), biguanides (polyhexamethylene) Guanide, chlorhexidine or a salt thereof), berberine or a salt thereof, polydronium chloride, Glokill (trade name, manufactured by Rhodia), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethrene Dichloride], parabens (eg, methyl benzoate, ethyl aminobenzoate, etc.).

    The ophthalmic composition of the present invention may contain these antibacterial or bactericide components at a concentration of 0.001 to 10%, preferably 0.01 to 10%.

Hereinafter, typical components used in the ophthalmic composition of the present invention will be exemplified, but the present invention is not limited thereto.
Saccharides: for example, glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol and the like, and pharmacological properties thereof And the salts that are acceptable.
Surfactants: For example, polyoxyethylene-polyoxypropylene block copolymer adduct of ethylenediamine (for example, poloxamine), POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbita monooleate (polysorbate 80) POE sorbitan fatty acid esters such as POE (60) hydrogenated castor oil, POE hardened castor oil such as POE (9) lauryl ether, POE alkyl ethers such as POE (20) POP (4) cetyl ether, etc. Nonionic surfactants such as alkyl ethers and POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether; glycine type such as alkyl diaminoethyl glycine; betaine acetate type such as lauryl dimethylamino acetate betaine; imidazoline type; of POE (10) POE alkyl ether phosphoric acid and salts thereof such as sodium lauryl ether phosphate, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, sodium N-cocoyl methyl taurine and the like N-acyltaurine salts, sulfonates such as sodium tetradecenesulfonate, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, α-olefin sulfonate, etc. Cationic surfactants such as alkylamine salts, alkyl quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, etc.) and alkylpyridinium salts (cetylpyridinium chloride, cetylpyridinium bromide, etc.) Such as an active agent, and the like. The numbers in parentheses indicate the number of moles added.
Preservatives, bactericides or antibacterials: for example, sorbic acid or a salt thereof (sorbic acid, potassium sorbate, sodium sorbate, triclocarban sorbate, etc.), paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, Propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), acrinol, methylrosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, chlorhexidine, polyhexamethylene biguanide, alkylpolyaminoethyl glycine, benzyl alcohol, phenethyl Carriers such as alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, silver zirconium phosphate, thimerosal, dehydrovinegar Chlorxylenol, chlorophen, resorcin, thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid, propionic acid, halocarban, thiabendazole, polymyxin B, 5 -Chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, polylysine, hydrogen peroxide, polydronium chloride, Glokill (for example, Glokill PQ, manufactured by Rhodia), poly Diallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethlene dichloride, polyethylenepolyamine / dimethylamine epichlorohydrin polycondensate (trade name such as Bu san1157, manufactured by Bachman).
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, hydroxide) Calcium, magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), borax, and pharmacologically acceptable salts thereof.
Isotonicity agents: for example, sugars (such as sugar, mannitol, and sorbitol).
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, sodium thiosulfate, sodium acetate and the like.

The pH and the osmotic pressure of the ophthalmic composition of the present invention are adjusted, if necessary, within the range acceptable for a living body. The pH is between 3.0 and 10.0, preferably between 4.0 and 8.5, particularly preferably between 4.0 and 7.0. The osmotic pressure is 100 to 1200 mOsm, preferably about 100 to 600 mOsm, particularly preferably about 150 to 450 mOsm, and the osmotic pressure ratio to physiological saline is 0.3 to 4.1, preferably 0.3 to 2.1, Particularly preferably, it is about 0.5 to 1.4. The pH is adjusted using a buffer, the pH adjuster, and the osmotic pressure is adjusted using 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 buffers may be used in combination. Preferred buffers are borate, phosphate, carbonate and citrate buffers. Particularly preferred buffers are borate, citrate or phosphate buffers. Examples of the borate buffer include borates such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphates such as alkali metal phosphate and alkaline earth metal phosphate. Examples of the citrate buffer include alkali metal citrate. Further, a borate or a phosphate hydrate may be used as the borate buffer or the 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 (such as sodium hydrogen carbonate and sodium carbonate), and citric acid or a salt thereof (such as sodium citrate and potassium citrate). When a borate buffer or a phosphate buffer is used as the buffer, the concentration of these buffers in the ophthalmic composition of the present invention is, for example, about 0.0001 to 10.0% by weight.

The ophthalmic composition of the present invention can be produced by a known method. If necessary, a filtration sterilization step, a step of filling a container, and the like can be added.

In the present invention, there is also provided A) one or more monocyclic monoterpenoids selected from the group consisting of monocyclic monoterpene hydrocarbons, monocyclic monoterpene ketones and monocyclic monoterpene oxides. B) A method for enhancing the cooling effect of the ophthalmic composition by adding at least one or more monoterpene-based alcohols in the range of 0.01 to 2,000 parts by weight with respect to parts by weight, and initial stimulation at the time of application. It also includes a method for suppressing the property.

The usage and dosage of the ophthalmic composition of the present invention can be appropriately selected according to the symptoms of the user, the active ingredients contained in the composition, and the form of the preparation. For example, in the case of eye drops, it is usually applied about 1 to 6 times per day, and about 1 to 3 drops are applied at a time. In the case of eyewash, it is usually washed about 1 to 6 times per day, and 5 times per day. Use about 10 mL. In the case of a contact lens mounting solution, the contact lens is usually mounted on a contact lens after both surfaces of the contact lens are wetted with one or two drops, and then washed or washed once with water and then dropped on the inner surface of the lens. In addition, in the case of a contact lens agent, although it differs depending on the type of lens, for example, when used as a cleaning agent, an appropriate amount is dripped and scrubbed on both sides of the lens, or an appropriate amount is transferred to a lens case and the lens is immersed there. And pickle and wash. When used as a preservation and rinsing liquid, rinse both sides of the lens with an appropriate amount, or transfer an appropriate amount to a lens case or the like and immerse and store the lens therein.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

1. Ophthalmic test Test method According to the prescription described in Table 1, each component is dissolved in purified water, the osmotic pressure and the pH are adjusted, and the total amount is adjusted to 100 mL, sterilized by filtration, and sterilized plastic container (material / container body) : Polyethylene terephthalate, nozzle: polyethylene, cap: polypropylene) to prepare each test solution (eye drops).
This was instilled into 15 panelists, and the degree of coldness immediately after instillation, 5 minutes and 20 minutes after instillation of each test solution, pain felt immediately after instillation, presence or absence of stimulus such as burning sensation (initial irritation), stickiness The presence or absence was evaluated. The evaluation was performed by panelists according to the criteria described in the margins of each table. In addition, the eyeball surface temperature of each test solution immediately after instillation was measured using thermography (Thermal Vision LAIRD-S270 (manufactured by Nikon Corporation)), and the eyeball surface temperature when separately measured saline solution was instilled was measured. Using the measured values, the degree of decrease in the eyeball surface temperature was calculated according to the following equation 1.

Equation 1

なお、冷たさの評価については、パネラーの評価で最も多かったものを、点眼直後の初期刺激の有無については、刺激が無いと評価したパネラーの割合（％）を、各表の欄外に記載の基準に従い表中に示した。

In addition, about the evaluation of the coldness, what was the most in the evaluation of the panelists, about the presence or absence of the initial stimulus immediately after instillation, the ratio (%) of the panelists who evaluated that there was no irritation was described in the margin of each table. It is shown in the table according to the standard.

result

In the eye drops of Comparative Examples 1, 2, and 4 containing no mentone, which is a monocyclic monoterpene ketone, the cold was felt immediately after instillation, but almost disappeared 5 minutes after instillation. The proportion of panelists who felt the initial stimulus was also high. The same tendency was observed in the eye drops of Comparative Example 3 containing only mentone. In Comparative Example 4 containing hydroxypropyl methylcellulose as a thickening agent, some stickiness after instillation was also felt.
On the other hand, in Examples 1 to 3 in which menthol and menthol, a monoterpene-based alcohol, were mixed, the cold felt immediately after instillation was strong and continued even after 20 minutes from instillation. Also, the degree of decrease in the eyeball surface temperature was large as compared with Comparative Examples 1 to 4, and almost no initial stimulation was felt.
Therefore, by adding both menthol and menthol in the preparation, the cooling effect at the ophthalmic site can be enhanced and the initial irritation at the time of instillation can be suppressed. Furthermore, the same effect can be obtained even when a thickening agent is further added to the preparation, stickiness peculiar to the thickening agent is suppressed, and the sensory characteristics are improved.

According to the formulations described in Tables 2 to 5, each component was dissolved in purified water, and after adjusting the osmotic pressure and pH, the total amount was adjusted to 100 mL, sterilized by filtration, and filled in containers to prepare eye drops and eyewash.

Claims (6)

A) one or more monocyclic monoterpenoids selected from the group consisting of monocyclic monoterpene hydrocarbons, monocyclic monoterpene ketones, and monocyclic monoterpene oxides; and B) at least one or more monocyclic monoterpenoids. An ophthalmic composition comprising the monoterpene alcohol of the formula (I) in an amount of 0.01 to 2000 parts by weight of B) based on 1 part by weight of A). The ophthalmic composition according to claim 1, which is a liquid composition. The ophthalmic composition according to claim 2, wherein the liquid composition is an eye drop, an eyewash, a contact lens mounting solution, or a contact lens agent. The ophthalmic composition according to claim 1, further comprising a thickening agent, and having an absolute viscosity at 20 ° C. of 2 to 200 mPa · s. A) one or more monocyclic monoterpenoids selected from the group consisting of monocyclic monoterpene hydrocarbons, monocyclic monoterpene ketones, and monocyclic monoterpene oxides; and B) at least one or more monocyclic monoterpenoids. A method for enhancing the cooling effect of an ophthalmic composition, wherein the monoterpene alcohol is contained in an amount of 0.01 to 2000 parts by weight of B) per 1 part by weight of A). A) one or more monocyclic monoterpenoids selected from the group consisting of monocyclic monoterpene hydrocarbons, monocyclic monoterpene ketones, and monocyclic monoterpene oxides; and B) at least one or more monocyclic monoterpenoids. A method of suppressing the initial irritation of an ophthalmic composition by incorporating the monoterpene alcohol of the formula (I) in a range of 0.01 to 2000 parts by weight of B) with respect to 1 part by weight of A).