JP2023099870A - Refreshing composition for ophthalmology - Google Patents

Abstract

To provide a refreshing composition for ophthalmology, capable of imparting a sufficient refreshing effect even when soft contact lenses are worn.SOLUTION: A refreshing composition for ophthalmology for imparting the refreshing effect when the soft contact lenses are worn can be provided, which contains compounds especially selected from menthol, camphor, or borneol in refrigerants singly or in combination in the total amount in a limited range of at least 0.01 w/v% and less than 0.1 w/v%, and inorganic salts as essential components besides them, and further contains a specified polymer having a specific molecular weight in combination therewith.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to an ophthalmic cooling composition that can impart a sufficient cooling sensation even when a soft contact lens is worn by applying it to the eye while wearing the soft contact lens.

Cooling agents such as menthol are blended in ophthalmic cooling compositions. It is important to formulate the composition of the cooling agent so that it can provide a cooling sensation of a comfortable intensity without causing any unpleasant irritation. It is necessary to administer a high concentration of menthol that can provide a moderately strong cooling sensation even when worn. However, an excessively high concentration of menthol causes an excessively strong unpleasant stimulus that exceeds the cooling sensation immediately after instillation, so there is a limit to the amount of menthol that can be blended in ophthalmic cooling compositions.

Therefore, among ophthalmic cooling compositions, eye drops and contact lens wetting solutions containing terpenoids, water-soluble polymers (such as hydroxypropylmethylcellulose), and local anesthetics (such as chlorobutanol) provide a good cooling sensation. It is known that it can be formed, maintains a cool feeling, and has low irritation (Patent Document 1). In addition, by blending camphor and borneol at a certain ratio or more with respect to menthol, a method of suppressing eye irritation and maintaining a cool feeling is disclosed, and the stimulation of menthol with an upper limit of 0.015 w / v% is disclosed. It can be mitigated (Patent Document 2).

As described above, a method for maintaining a sufficient cooling sensation and improving the irritation of menthol without simply increasing the amount of a cooling agent such as menthol has been disclosed. However, these methods and eye drops have been developed mainly for the purpose of imparting a refreshing feeling to users who do not wear soft contact lenses, i.e., to users who wear unaided eyes or who regularly wear hard contact lenses. , no consideration is given to the unique challenges of wearing soft contact lenses.

By the way, there are the following specific problems in wearing soft contact lenses.
The cornea is a tissue rich in sensory nerves, and the density of nerves in the corneal epithelium is said to be about 300 to 600 times that of the skin. (Non-Patent Document 1). Therefore, whether or not the user feels a refreshing sensation is affected by the degree of contact of menthol with the corneal surface. The diameter of a hard contact lens is smaller than the diameter of the cornea, and even if a hard contact lens is worn, the corneal periphery is exposed, but the diameter of a soft contact lens is larger than the cornea. covered by the lens. For this reason, soft contact lens wearers are far less likely to feel coolness compared to the case with the naked eye.
In addition, while wearing a soft contact lens, the lacrimal fluid exchange rate between the posterior surface of the lens (cornea side) and the portion not covered with the lens (conjunctival surface) is extremely reduced. With hard contact lenses, the tear exchange rate at the best fitting is 25.6 ± 11.1 (%/min), which is similar to that of the tear meniscus of a healthy eye. , even the best fitting lacrimal fluid exchange rate shows a low value of 16.5±1.1 (%/min) (Non-Patent Document 2 Lens and decrease in lacrimal fluid exchange rate). Therefore, tear fluid exchange for menthol to reach the center of the cornea through the tear film in the gap between the soft contact lens and the ocular surface is remarkably slow, increasing the decrease in sensitivity to cool sensation.

Until now, no ophthalmic cooling composition has been known that can provide a sufficient cooling sensation even when applied to the eye while wearing a soft contact lens. Also, little is known about how to promote tear exchange on the posterior surface of the lens while wearing soft contact lenses. Thus, it has been extremely difficult to alleviate irritation while maintaining the required coolness for a certain period of time while wearing soft contact lenses.
Furthermore, cooling agents such as menthol, local anesthetics such as chlorobutanol, preservatives such as quaternary ammonium salts such as benzalkonium chloride, etc., vasoconstrictors such as tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, etc. Formulation design is limited if it contains ingredients that may adversely affect the soft contact lens (adsorption or deformation).

Japanese Patent Application Laid-Open No. 2003-183157 JP-A-9-132526

Literature on the perception of the corneal surface New Ophthalmology, 4(1), p11-20, 1987 Journal of Japan Contact Lens Society 45(1), p1-10, 2003

Accordingly, an object of the present invention is to provide a cooling composition capable of imparting a sufficient cooling sensation even while wearing soft contact lenses.

As a result of intensive studies for solving the problem, the present inventors have found that a) a compound selected from menthol, camphor or borneol is added in a total amount of 0.01 (w / v)% or more to 0.1 (w / v) less than %, b) inorganic salts, and c) hydroxyethyl cellulose with an average molecular weight of 200,000 to 2,500,000, methylcellulose with an average molecular weight of 50,000 to 500,000, polyvinylpyrrolidone with an average molecular weight of 10,000 to 150,000, average molecular weight at least one selected from chondroitin sulfate or a salt thereof having an average molecular weight of 50,000 to 500,000, hydroxypropyl methylcellulose having an average molecular weight of 50,000 to 500,000, and polyvinyl alcohol having an average molecular weight of 10,000 to 300,000. The present inventors have found that the containing ophthalmic cooling composition can provide a sufficient cooling sensation without irritation when applied to the eyes when wearing soft contact lenses, and have completed the present invention.

The present inventor was developed based on such knowledge.
That is, the present invention is an ophthalmic cooling composition described in (1) to (12) below.
(1) a) a compound selected from menthol, camphor, or borneol in a total amount of 0.01 w/v% or more and less than 0.1 w/v%;
b) inorganic salts, and c) hydroxyethyl cellulose with an average molecular weight of 200,000 to 2,500,000, methyl cellulose with an average molecular weight of 50,000 to 500,000, polyvinylpyrrolidone with an average molecular weight of 10,000 to 150,000, and an average molecular weight of 50,000 to 50,000. 10,000 hydroxypropyl methylcellulose, polyvinyl alcohol with an average molecular weight of 10,000 to 300,000, or chondroitin sulfuric acid with an average molecular weight of 50,000 to 500,000 or a salt thereof. An ophthalmic cooling composition for imparting a cooling sensation when wearing contact lenses,
(2) The ophthalmic cooling composition according to (1), containing 0.001 to 10 w/v% of hydroxyethyl cellulose having an average molecular weight of 200,000 to 2,500,000.
(3) The ophthalmic cooling composition according to (1), containing 0.001 to 10 w/v% of methylcellulose having an average molecular weight of 50,000 to 500,000.
(4) The ophthalmic cooling composition according to (1), containing 0.001 to 10 w/v% of polyvinylpyrrolidone having an average molecular weight of 10,000 to 150,000.
(5) The ophthalmic cooling composition according to (1), containing 0.001 to 10 w/v% of hydroxypropylmethylcellulose having an average molecular weight of 50,000 to 500,000.
(6) The ophthalmic cooling composition according to (1), containing 0.001 to 10 w/v% of polyvinyl alcohol having an average molecular weight of 10,000 to 300,000.
(7) The ophthalmic cooling composition according to (1), containing 0.001 to 10 w/v% of chondroitin sulfate or a salt thereof having an average molecular weight of 50,000 to 500,000.
(8) The ophthalmic cooling composition according to (1) to (7), further containing 0.001 to 5 w/v% of a nonionic surfactant,
(9) The ophthalmic cooling composition according to (1) to (8), further containing 0.0001 to 1 w/v% of edetic acid or a salt thereof;
(10) Furthermore, at least one component selected from aminoethylsulfonic acid, glutamic acid, potassium aspartate, magnesium aspartate, sodium glutamate, glucose or trehalose, in a total amount of 0.01 to 5 w/v% The ophthalmic cooling composition according to (1) to (9) containing
(11) The ophthalmic cooling composition according to (1) to (10), which is an eye drop or an eye wash,
(12) a) a compound selected from menthol, camphor or borneol in a total amount of 0.01 w/v% or more and less than 0.1 w/v%;
b) inorganic salts, and c) hydroxyethyl cellulose with an average molecular weight of 200,000 to 2,500,000, methyl cellulose with an average molecular weight of 50,000 to 500,000, polyvinylpyrrolidone with an average molecular weight of 10,000 to 150,000, and an average molecular weight of 50,000 to 50,000. 10,000 hydroxypropyl methylcellulose, polyvinyl alcohol with an average molecular weight of 10,000 to 300,000, or chondroitin sulfuric acid with an average molecular weight of 50,000 to 500,000 or a salt thereof. An ophthalmic cooling composition for regular contact lens wearers.
In this specification, unless otherwise specified, % means w/v %.

According to the ophthalmic cooling composition of the present invention, among cooling agents, compounds selected from menthol, camphor and borneol are used singly or in combination, and the total amount thereof is 0.01 w/v% or more and 0.1 w/v. A soft contact characterized by containing within a limited range of less than v%, containing an inorganic salt as an essential constituent, and further containing a combination of specific polymers having a specific molecular weight. It is possible to provide an ophthalmic cooling composition for imparting a cooling sensation when wearing lenses.
Until now, artificial tear type eye drops have been widely used as eye drops to be applied while wearing soft contact lenses. Conventional artificial tear-type eye drops contain a high concentration of menthol because the adsorption of cooling agents such as menthol to soft contact lenses poses a safety hazard, even if sufficient cooling sensation is desired. I couldn't. In addition, even if the adhesion problem is solved and the amount of menthol is increased, the cornea is not exposed in the eyes wearing soft contact lenses, and the lacrimal fluid exchange rate is low. However, it was difficult to impart a refreshing feeling.
According to the ophthalmic cooling composition of the present invention, a sufficient cooling sensation can be obtained immediately after application of the composition to the eyes, and the irritation is alleviated, so that the wearer of the soft contact lens is provided with a pleasant cooling sensation. It is possible to provide an ophthalmic cooling composition for Furthermore, according to the present invention, it is possible to provide an ophthalmologic cooling composition that can provide a sufficient cooling sensation even with a small amount of menthol and is non-irritating and highly safe.
Furthermore, the ophthalmic cooling composition of the present invention provides a cooling sensation without the stimulation of the cooling agent. It can also be used as an ophthalmic cooling composition for regular users of soft contact lenses to provide a cool feeling to the eyes not only while wearing the soft contact lenses but also after removing the soft contact lenses.

The ophthalmic cooling composition of the present invention contains one or more compounds selected from menthol, camphor and borneol in a total amount of 0.01% or more and less than 0.1%. The lower limit is preferably 0.012% or more, more preferably 0.014% or more, and particularly preferably 0.016% or more, and the upper limit is preferably 0.08% or less, more preferably 0.06% or less. Particularly preferably, it is 0.04% or less. If it is less than 0.01%, it is difficult to feel a sufficient cooling sensation immediately after applying the composition to the eyes, and if it is 0.1% or more, the cooling sensation immediately after applying the composition to the eyes is strong, and depending on the user, it may be warped. It is not recommended because it may cause irritation. These compounds are known compounds, commercially available ones can be used, and either d-form or l-form can be used.

The ophthalmic cooling composition of the present invention contains inorganic salts as essential ingredients. Such inorganic salts include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate. , and potassium dihydrogen phosphate. Among them, potassium chloride, calcium chloride, sodium chloride, sodium hydrogen carbonate, sodium carbonate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate are preferable, and potassium chloride and sodium chloride are particularly preferable. .

In the present invention, these inorganic salts in the ophthalmic cooling composition can be used singly or in combination of two or more, and the content thereof is preferably 0.01 to 10%, more preferably 0.01 to 10% as the total amount of inorganic salts. is about 0.1 to 10%, particularly preferably about 0.1 to 5%. When the inorganic salt content is less than 0.01%, it is difficult to feel a sufficient cooling sensation immediately after applying the composition to the eyes, and when it is 10 (w/v)% or more, the cooling sensation immediately after applying the composition to the eyes is strong. There is a tendency to become too much, and some users may feel irritation.

In the ophthalmic cooling composition of the present invention, it is essential to contain a combination of specific polymers having specific molecular weights. That is, in the present invention, hydroxyethyl cellulose with an average molecular weight of 200,000 to 2,500,000, methyl cellulose with an average molecular weight of 50,000 to 500,000, polyvinylpyrrolidone with an average molecular weight of 10,000 to 150,000, and an average molecular weight of 50,000 to 500,000. It is characterized by containing at least one selected from hydroxypropyl methylcellulose, polyvinyl alcohol with an average molecular weight of 10,000 to 300,000, and chondroitin sulfate with an average molecular weight of 50,000 to 500,000 or a salt thereof.

Hydroxyethyl cellulose used in the present invention is a known polymer compound, and hydroxyethyl cellulose having an average molecular weight of 200,000 to 2,500,000 is used, more preferably 500,000 to 2,000,000, and particularly preferably 800,000 to 1,500,000. use. Such hydroxyethyl cellulose can be commercially available, for example, HEC-CF-G (average molecular weight of about 400,000) and HEC-CF-H (average molecular weight of about 700,000) sold by Sumitomo Seika Co., Ltd. , HEC-CF-V (average molecular weight about 1 million), HEC-CF-W (average molecular weight about 1.3 million), HEC-CF-X (average molecular weight about 1.5 million), HEC-CF-Y (average molecular weight about 180 10,000) can be used.
In the present invention, the content of hydroxyethyl cellulose in the ophthalmic cooling composition is preferably about 0.001 to 10%, more preferably 0.005 to 5%, and particularly preferably about 0.01 to 3%.

Methylcellulose used in the present invention is a known polymer compound, and one having an average molecular weight of 50,000 to 500,000 is used. More preferably, methyl cellulose having an average molecular weight of 100,000 to 500,000, particularly preferably 200,000 to 500,000 is used. Such methyl cellulose can be commercially available, for example, SM-15 (average molecular weight of about 70,000), SM-25 (average molecular weight of about 90,000), sold by Shin-Etsu Chemical Co., Ltd. as Metroose SM series ), SM-50 (average molecular weight about 110,000), SM-100 (average molecular weight about 120,000), SM-400 (average molecular weight about 170,000), SM-1500 (average molecular weight about 290,000), SM-4000 (average molecular weight of about 360,000), etc. can be used.
In the present invention, the content of methylcellulose in the ophthalmic cooling composition is preferably about 0.001 to 10%, more preferably 0.005 to 5%, and particularly preferably about 0.01 to 3%.

Polyvinylpyrrolidone used in the present invention is a known polymer compound having an average molecular weight of 10,000 to 150,000. More preferably, polyvinylpyrrolidone having an average molecular weight of 20,000 to 150,000 is used. Commercially available polyvinylpyrrolidone can be used. For example, Kollidon 25 (average molecular weight: about 30,000), Kollidon 30 (average molecular weight: about 50,000), Kollidon 25 (average molecular weight: about 30,000), Kollidon 30 (average molecular weight: about 50,000), sold by BASF Corporation as Kollidon series. Kollidon 17PF (average molecular weight of about 90,000), Kollidon 90 (average molecular weight of about 120,000), etc. can be used.
In the present invention, the content of polyvinylpyrrolidone in the ophthalmic cooling composition is preferably about 0.001 to 10%, more preferably 0.01 to 5%, and particularly preferably about 0.1 to 3%.

Hydroxypropylmethylcellulose used in the present invention is a known polymer compound, and one having an average molecular weight of 50,000 to 500,000 is used. More preferably, hydroxypropylmethylcellulose having an average molecular weight of 100,000 to 500,000, particularly preferably 200,000 to 500,000 is used. Such hydroxypropyl methylcellulose can be commercially available, for example, 60SH-15 (average molecular weight of about 70,000), 60SH-25 (average molecular weight of about 70,000), 60SH-25 (average molecular weight of about 90,000), 60SH-50 (average molecular weight about 110,000), 60SH-100 (average molecular weight about 120,000), 60SH-400 (average molecular weight about 170,000), 60SH-1500 (average molecular weight about 290,000), 60SH- 4000 (average molecular weight of about 360,000) and the like can be used.
In the present invention, the content of hydroxypropylmethylcellulose in the ophthalmic cooling composition is preferably about 0.001 to 10%, more preferably 0.005 to 5%, and particularly preferably about 0.01 to 3%.

Polyvinyl alcohol used in the present invention is a known polymer compound having an average molecular weight of 10,000 to 300,000. More preferably, polyvinyl alcohol having an average molecular weight of 20,000 to 200,000, particularly preferably 20,000 to 150,000 is used. Commercially available polyvinyl alcohols can be used. For example, Gosenol EG05 (average molecular weight of about 30,000) and Gosenol EG40 (average molecular weight of about 120,000) sold by Nippon Synthetic Chemical Co., Ltd. as Gosenol series ) etc. can be used.
In the present invention, the content of polyvinyl alcohol in the ophthalmic cooling composition is preferably about 0.001 to 10%, more preferably 0.01 to 5%, and particularly preferably about 0.1 to 3%.

Chondroitin sulfate or a salt thereof used in the present invention is a known polymer compound having an average molecular weight of 50,000 to 500,000. Chondroitin sulfate or a salt thereof having an average molecular weight of 50,000 to 200,000, more preferably 50,000 to 100,000, and particularly preferably 50,000 to 40,000 is used. Such chondroitin sulfate or a salt thereof can be commercially available. For example, sodium chondroitin sulfate (average molecular weight: 10,000, etc.), sodium chondroitin sulfate (average molecular weight of about 7,000, etc.) sold by Maruha Co., Ltd., etc. can be used.
In the present invention, the content of chondroitin sulfate or a salt thereof in the ophthalmic cooling composition is preferably about 0.001 to 10%, more preferably 0.01 to 5%, and particularly preferably about 0.05 to 3%. be.

The refreshing effect of the present invention becomes remarkable when a nonionic surfactant is blended.

As the nonionic surfactant to be used in the present invention, those that are commonly available to those skilled in the art for ophthalmic cooling compositions can be used. (hereinafter also referred to as POP) block copolymers (e.g., poloxamer 407, poloxamer 235, poloxamer 188, etc.); POE-POP block copolymer adducts of ethylenediamines such as poloxamines; POE sorbitan fatty acid esters such as POE (20) sorbitan oleate (polysorbate 80), POE sorbitan monostearate (polysorbate 60), POE sorbitan tristearate (polysorbate 65); POE hydrogenated castor oil 5, POE hydrogenated castor oil 10 , POE hydrogenated castor oil 20, POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil 100; POE alkyl ethers such as POE (9) lauryl ether POE-POP alkyl ethers such as POE(20) POP(4) cetyl ether; POE alkylphenyl ethers such as POE(10) nonylphenyl ether; The numbers in parentheses indicate the number of added moles.

Among them, a nonionic surfactant selected from polyoxyethylene-polyoxypropylene block copolymers, POE sorbitan fatty acid esters or POE hydrogenated castor oils is particularly preferred, and polyoxyethylene-polyoxypropylene block is particularly preferred. Copolymer, Polysorbate 80, Polyoxyethylene Hydrogenated Castor Oil 60.

The content of the nonionic surfactant in the ophthalmic cooling composition of the present invention varies depending on the type of surfactant, and cannot be generally defined, but is usually 0.001 to 5%, preferably 0.001 to 1%. %, more preferably about 0.005 to 0.5%.

The effect of the present invention for imparting a refreshing sensation becomes even more pronounced when edetic acid or a salt thereof is blended into the ophthalmic refreshing composition. Moreover, it becomes more pronounced when edetic acid or a salt thereof and a nonionic surfactant are used in combination.

Examples of such edetic acid or salts thereof include edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), and the like. can be exemplified. These can be blended singly or in combination of two or more, and may be used as pharmacologically or physiologically acceptable salts (eg, sodium ethylenediaminetetraacetate, etc.). Of these, ethylenediaminetetraacetic acid or a salt thereof is preferred, such as disodium ethylenediaminetetraacetate and disodium ethylenediaminetetraacetate dihydrate (hereinafter also referred to as sodium edetate).

The content of edetic acid or a salt thereof in the ophthalmic cooling composition of the present invention varies depending on the molecular weight, type, etc., and cannot be categorically defined. 5%, particularly preferably about 0.001 to 0.3%.

The cooling sensation imparting effect of the present invention is obtained by adding at least one component selected from aminoethylsulfonic acid (taurine), glutamic acid, potassium aspartate, magnesium aspartate, sodium glutamate, glucose or trehalose to the ophthalmic cooling composition. becomes even more pronounced when blended with In this case, it becomes more pronounced when blended with the above-described edetic acid or its salt or a nonionic surfactant.

The total amount of these components in the ophthalmic cooling composition of the present invention is preferably 0.01 to 5%, more preferably about 0.05 to 3%.

The ophthalmic cooling composition of the present invention is desirably designed to have an appropriate viscosity from the viewpoint of imparting a cooling sensation. The viscosity at 20.degree. The lower limit is preferably designed to be 2 mPa·s or more, and the upper limit is 100 mPa·s. If the viscosity exceeds 100 mPa·s, there is a tendency that a refreshing sensation immediately after instillation is not sufficiently imparted.
Viscosity is measured by a method using a cone-plate rotary viscometer (described in the 14th revision of the Japanese Pharmacopoeia, general test methods, 45. Viscosity measurement method, second method rotary viscometer method, "(3) cone - Flat plate type rotational viscometer"). As an example, a TVE-20L viscometer cone plate type (manufactured by TOKIMEC, Toki Sangyo (Japan)), which is a type of E-type viscometer, can be used for measurement under the following measurement conditions. can.
A standard cone rotor (α = 1°34', radius (R) = 2.4 cm) attached to the TVE-20L viscometer cone-plate type was rotated through a spring with a full-scale torque of 67.37 × 10 ^-6 Nm. Rotate with a motor. At the time of measurement, the viscometer is installed so that the axis of rotation is perpendicular to the horizontal plane. 1 ml of the sample to be tested is placed on a predetermined plate position of the cone rotor and left until the temperature reaches 20°C. The device is then rotated at a speed corresponding to the viscosity of the sample to be tested, and after 4 minutes the indicated viscosity is read. In order to obtain highly accurate measurement results, a petroleum-based hydrocarbon oil (Newtonian fluid) specified by JIS Z 8809 is used as a calibration standard liquid before measurement of the test sample, and the measured value is the viscosity of the standard liquid. adjusted to match The rotor used during measurement, the number of revolutions, the amount of sample to be measured, etc. can be selected as appropriate.

The ophthalmic cooling composition of the present invention is not particularly limited as long as it can be applied to eyes wearing soft contact lenses or regular users of soft contact lenses. (eye washes) are preferred.
Soft contact lenses to which the ophthalmologic cooling composition of the present invention can be applied can be used regardless of the curve shape, edge shape, material, etc. of the soft contact lens. Provide a sufficient cooling sensation to any soft contact lens classified into Group I to Group IV according to the classification method of soft contact lenses in the examination of soft contact lenses and disinfectants for soft contact lenses by the Safety Bureau. can be done. For example, non-hydrous soft contact lenses, Group I (Medalist, registered trademark, Bausch & Lomb Japan Co., Ltd.), Group II (Menicon Soft S, registered trademark, Menicon Co., Ltd.), Group III (High Flow Ace, registered trademark, HOYA Healthcare Co., Ltd.), Group IV (2Week Acuvue, registered trademark, Johnson & Johnson Co., Ltd.) and other soft contact lenses.

The ophthalmic cooling composition of the present invention is suitable for containing various ingredients (including pharmacologically active ingredients and physiologically active ingredients) in combination. Examples include decongestants, eye-regulating agents, anti-inflammatory agents or astringent agents, antihistamines or anti-allergic agents, vitamins, amino acids, sugars and the like, which are commonly used in ophthalmic cooling compositions. Specifically, the following components can be exemplified.

Decongestant ingredients: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine bitartrate, naphazoline nitrate, and the like. These may be d-, l- or dl-isomers.
Ocular muscle modulating drug components: for example, cholinesterase inhibitors with active centers similar to acetylcholine, specifically neostigmine methyl sulfate, tropicamide, atropine helenien sulfate, and the like.
Anti-inflammatory or astringent ingredients: e.g. zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulene sulfonate, dipotassium glycyrrhizinate, diclofenac sodium, bromfena sodium chloride, berberine chloride, berberine sulfate, etc.
Antihistamine ingredients or antiallergic ingredients: For example, acitazanolast, amlexanox, ibudilast, tranilast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, pemirolast potassium, chlorpheniramine maleate, and the like.
Vitamins: For example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate, and the like.
Local anesthetic ingredients: e.g. chlorobutanol, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate hydrochloride, pipelocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, hydrochloric acid such as lidocaine.

In addition, in the ophthalmic cooling composition of the present invention, various ingredients and additives are appropriately selected in accordance with conventional methods according to the application and form within the range that does not impair the effects of the invention, and one or more of them are used in combination. may be contained as As components or additives thereof, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.), thickeners, sugars, surfactants, commonly used in the preparation of semi-solid agents and liquid agents, etc. Various additives such as antiseptics, bactericides or antibacterial agents, pH adjusters, tonicity agents, fragrances or cooling agents, buffers, and the like can be mentioned.

Typical ingredients used in the ophthalmic cooling composition of the present invention are exemplified below, but are not limited thereto.
Thickening agents: For example, carboxyvinyl polymer, alginic acid or its salt, macrogol, sodium hyaluronate, xanthan gum, sodium carboxymethylcellulose, glycerin, dextran, propylene glycol alginate and the like.
Sugars: For example, glucose, cyclodextrin, trehalose and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like.
Surfactants: for example, glycine type amphoteric surfactants such as alkyldiaminoethylglycine; alkyl quaternary ammonium salts (specifically, cationic surfactants such as benzalkonium chloride, benzethonium chloride, etc.) indicates the number of moles added.
Preservatives, bactericides or antibacterial agents: for example alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glokyl (manufactured by Rhodia) name), etc.
pH adjusters: for example hydrochloric acid, boric acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, borax, triethanolamine, monoethanolamine and the like.
Tonicity agent: for example, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol, etc.
Perfume or cooling agent: For example, geraniol, rhubarb, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc., other than menthol, camphor and borneol mentioned above . These may be d-, l- or dl-isomers.
Stabilizers: dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Rongalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.

The ophthalmic cooling composition of the present invention can contain various components and additives selected appropriately as described above, and can contain one or more of them in combination. Therefore, chlorobutanol (1,1,1-trichloro-2-methyl-2-propanol), benzalkonium chloride (alkylbenzyldimethylammonium chloride), parahydroxybenzoates such as methylparaben, ethylparaben, propylparaben, and butylparaben , tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, epinephrine, epinephrine hydrochloride, etc. In the case of containing a decongestant that may mask a serious illness, it is necessary to devise a formulation design. It is also possible to design formulations that are substantially free of these ingredients, and in some cases, ophthalmic cooling compositions that are substantially free of these ingredients are desirable.

The ophthalmic cooling composition of the present invention is used after being adjusted to an osmotic pressure within a range acceptable to living organisms, if necessary. The osmotic pressure is about 100-1200 mOsm, preferably 100-600 mOsm, particularly preferably about 150-400 mOsm, and the osmotic pressure ratio to physiological saline is usually 0.4-4.1, preferably 0.3-2. 1, particularly preferably about 0.5 to 1.4.

The ophthalmic cooling composition of the present invention is used after adjusting the osmotic pressure within the range applicable to the living body, if necessary. The pH is usually pH 5.0 to 10.0, preferably 6.0 to 9.0, particularly preferably 6.5 to 8.5. The pH can be adjusted using a buffering agent, the aforementioned pH adjuster, or the like.

The ophthalmic cooling composition of the present invention can be produced by a known method. For example, a liquid formulation can be prepared by mixing a base and each component. Furthermore, if necessary, a filtration sterilization process, a container filling process, and the like can be added.

In addition, the ophthalmic cooling composition of the present invention provides a cooling sensation without the stimulation of the cooling agent. It can also be used as an ophthalmic cooling composition for giving a refreshing feeling to the eyes of users who regularly wear soft contact lenses, not only while wearing the soft contact lenses but also after removing the soft contact lenses.
Among cooling agents, compounds selected from menthol, camphor and borneol are contained singly or in combination within a limited range of 0.01 w/v% or more and less than 0.1 w/v% as the total amount. contains inorganic salts as essential constituents, and further contains a combination of specific polymers having a specific molecular weight, so that regular use of soft contact lenses causes eye damage and irritation. Even when applied to eyes that have become sensitive, it is possible to provide a composition that imparts a sufficient cooling sensation immediately after application and that has an excellent feeling of use in which irritation is alleviated.

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

Preparation of Examples and Comparative Examples Preparations of Examples and Test Examples used in the tests were according to the recipes shown in Tables 1-6. Specifically, the preparation method of Example 1 described in Table 1 is shown. Hydroxyethyl cellulose (HEC-CF-G) was stirred and dissolved in about 100 mL of purified water (preparation solution A). Next, polysorbate 80, l-menthol, d-camphor and d-borneol were stirred and dissolved (adjustment solution B). Sodium edetate and sodium chloride were dissolved in 50 mL of purified water, adjusted solution A and prepared solution B were added, and further purified water was added to adjust the pH (pH=7.4) to make the total volume 200 ml. Further, according to Example 1, other examples and comparative examples were also prepared.

Refreshing feeling imparting test The test solution was sterilely filtered, 10 ml each was filled into an eyedropper container, and 20 special panelists who regularly use soft contact lenses were tested while wearing soft contact lenses or when they were naked (soft contact lenses). Immediately after the eye drops were removed), the cooling sensation was evaluated immediately after instillation, 5 minutes after instillation, and 10 minutes after instillation. Soft contact lenses of Group IV (2Week Acuvue (registered trademark), Johnson & Johnson Co., Ltd.) were used.
Each panelist was asked to evaluate the cooling sensation on a 7-point scale, with 0 points indicating no cooling sensation and 6 points indicating a sufficiently strong cooling sensation. Similarly, the subject was evaluated on a 7-point scale, with 6 points indicating no eye irritation and 0 points indicating strong irritation. Average the evaluation points of all panelists, and the average value is 0 to less than 2 points, △ from 2 points to less than 3 points, ○ from 3 points to less than 4 points, and ◎ from 4 points to 6 points. shows the results.

As a result of the test, in Examples of the present invention, it was shown that a sufficient cooling sensation was obtained immediately after applying the composition to the eyes, and that the composition was non-irritating and highly safe. Regular use of soft contact lenses is known to cause a decrease in tear fluid and some damage to the corneal surface. Especially immediately after removing soft contact lenses, the patient is extremely sensitive to the cooling sensation of menthol and other substances. However, it was confirmed that a sufficient cooling sensation can be imparted without irritation even to these extremely sensitive eyes.

As a result of the test, in Examples of the present invention, it was shown that a sufficient cooling sensation was obtained immediately after applying the composition to the eyes, and that the composition was non-irritating and highly safe. Regular use of soft contact lenses is known to cause a decrease in tear fluid and some damage to the corneal surface. Especially immediately after removing soft contact lenses, the patient is extremely sensitive to the cooling sensation of menthol and other substances. However, it was confirmed that a sufficient cooling sensation can be imparted without irritation even to these extremely sensitive eyes.

As a result of the test, in Examples of the present invention, it was shown that a sufficient cooling sensation was obtained immediately after applying the composition to the eyes, and that the composition was non-irritating and highly safe. Regular use of soft contact lenses is known to cause a decrease in tear fluid and some damage to the corneal surface. Especially immediately after removing soft contact lenses, the patient is extremely sensitive to the cooling sensation of menthol and other substances. However, it was confirmed that a sufficient cooling sensation can be imparted without irritation even to these extremely sensitive eyes.

As a result of the test, in the examples of the present invention containing polyvinylpyrrolidone (average molecular weight of about 30,000) or/and polyvinylpyrrolidone (average molecular weight of about 120,000) in combination with sodium chloride, the composition was sufficiently applied immediately after application to the eye. A refreshing feeling was obtained, and it was shown to be highly safe without irritation. Regular use of soft contact lenses is known to cause a decrease in tear fluid and some damage to the corneal surface. Especially immediately after removing soft contact lenses, the patient is extremely sensitive to the cooling sensation of menthol and other substances. However, it was confirmed that a sufficient cooling sensation can be imparted without irritation even to these extremely sensitive eyes.

As a result of the test, in the examples of the present invention containing polyvinyl alcohol (average molecular weight of about 30,000) or/and polyvinyl alcohol (average molecular weight of about 120,000) in combination with sodium chloride, sufficient A refreshing feeling was obtained, and it was shown to be highly safe without irritation. Regular use of soft contact lenses is known to cause a decrease in tear fluid and some damage to the corneal surface. Especially immediately after removing soft contact lenses, the patient is extremely sensitive to the cooling sensation of menthol and other substances. However, it was confirmed that a sufficient cooling sensation can be imparted without irritation even to these extremely sensitive eyes.

As a result of the test, in the examples of the present invention containing sodium chondroitin sulfate (average molecular weight of about 10,000) or/and sodium chondroitin sulfate (average molecular weight of about 20,000) in combination with sodium chloride, immediately after applying the composition to the eyes, It was shown that a sufficient refreshing feeling was obtained, and that it was highly safe without irritation. Regular use of soft contact lenses is known to cause a decrease in tear fluid and some damage to the corneal surface. Especially immediately after removing soft contact lenses, the patient is extremely sensitive to the cooling sensation of menthol and other substances. However, it was confirmed that a sufficient cooling sensation can be imparted without irritation even to these extremely sensitive eyes.

Claims (1)

a) a compound selected from menthol, camphor or borneol in a total amount of 0.01 w/v% or more and less than 0.1 w/v%;
b) inorganic salts, and c) hydroxyethyl cellulose with an average molecular weight of 200,000 to 2,500,000, methyl cellulose with an average molecular weight of 50,000 to 500,000, polyvinylpyrrolidone with an average molecular weight of 10,000 to 150,000, or an average molecular weight of 10,000 to An ophthalmic cooling composition for providing a cooling sensation when wearing a soft contact lens, containing at least one selected from 300,000 polyvinyl alcohols.