JP2020063235A - Eye drop - Google Patents

Abstract

To provide a method for relaxing stimulation of a refrigerant component in instillation time in application of an eye drop, and maintaining for a long term, a cool feeling and refreshing feeling.SOLUTION: There is provided an eye drop comprising: (a) a refrigerant component; and (b) at least one kind of a thickening agent which is selected from a group formed of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hyaluronate and salt of the hyaluronate, dextran, polyoxyethylene polyoxypropylene block copolymer, in the eye drop, absolute viscosity at temperature of 20°C is 3-15 mPa s.SELECTED DRAWING: None

Description

  The present invention relates to an eye drop containing a cooling component and a thickening agent, and a method for maintaining a refreshing feeling.

  The eye drops contain essential oils such as peppermint oil, fennel oil, rose oil, bergamot oil, and essential oil components such as menthol, camphor, and borneol for the purpose of imparting a refreshing and refreshing feeling to the eye drops. . Among these essential oils or essential oil components, compounds having a terpene structure such as menthol, camphor, borneol, etc., are widely used because they have a strong refreshing and refreshing feeling.

  However, although these essential oils and essential oil components impart a refreshing feeling and a refreshing feeling immediately after instillation, they are not persistent.

  Further, it is known that these components are accompanied by pain due to the irritating property of the essential oil or the essential oil component itself, although the user tends to seek a refreshing feeling or a refreshing feeling. Therefore, in JP-A-9-132526 (Patent Document 1), in an eye drop containing menthols, camphors and borneols, the total amount of (a) menthol, camphor and borneol is 0.01 to 0. 0.05% by weight, and (b) the blending ratio of camphor and borneol to menthol were 0.5 to 1.0, respectively, to give a strong cool sensation, enhance the sustainability of the refreshing sensation, and irritate the eyes. It is described that eye drops having extremely reduced properties can be obtained. However, with such a method, the effect of reducing irritation and the effect of sustaining a refreshing feeling and refreshing feeling are still insufficient.

  On the other hand, in recent years, people who complain of dry eyes and tired eyes due to dry air due to air conditioners, decrease in blink frequency due to staring at the screen of personal computer / TV (TV), wear of soft or hard contact lenses, etc. Is increasing. Therefore, for the purpose of alleviating such dry feeling, many artificial tear-drop type eye drops containing a thickening agent are commercially available. Of the eye drops, artificial tear-type eye drops are eye drops that supplement the tears that normally cover the cornea and resemble tears that have a main effect of moisturizing and moisturizing, and hard contact lenses (oxygen). (Including transparent hard contact lenses) and soft contact lenses. By blending a thickening agent with such an artificial tear-drop type eye drop, it is possible to eliminate the dry feeling of the eye due to the decrease of tear fluid and to supplement the moisturization of the eye. However, the tired eyes cannot be eliminated.

  As described above, with the conventional eye drops, although a refreshing feeling and a refreshing feeling can be imparted at the time of instillation, the sensory sensation does not last, and not only the dry feeling of eyes but also tired eyes cannot be eliminated.

JP-A-9-132526

  Therefore, an object of the present invention is to provide a method for alleviating the irritation of a refreshing component at the time of eye application by applying an eye drop and maintaining a refreshing feeling or a refreshing feeling for a long time.

  Another object of the present invention is to provide an eye drop which not only enhances user's compliance by maintaining refreshing feeling and refreshing feeling for a long time by applying the above method, but can also eliminate tired eyes. .

  The inventors of the present invention have conducted extensive studies to achieve the above-mentioned object, and used a combination of a cooling component and a thickening agent, and controlling the viscosity of the eye drops, the refreshing feeling and refreshing feeling by the application of the eye drops. It has been found that can be maintained for a long time, enhances user compliance, and eliminates tired eyes. Furthermore, they have also found that a refreshing component also has an effect of relieving irritation (pain) at the time of instillation, so that a highly safe eye drop without irritation can be obtained. The present invention was made based on these findings.

  That is, the eye drop of the present invention contains a cooling component and a thickening agent, and has an absolute viscosity of 3 to 15 mPa · s at a temperature of 20 ° C. The above-mentioned cooling component includes an essential oil component, an essential oil and the like.

Examples of the thickening agent include cellulose-based polymers (methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, etc.), vinyl-based polymers (polyvinylpyrrolidone, etc.), sugars (mucopolysaccharides such as hyaluronic acid and salts thereof, etc.), Examples thereof include polysaccharides such as dextran and cyclodextrin) and oxyalkylene polymers (polyoxyethylene polyoxypropylene block copolymer), and at least one thickening agent may be used. The molecular weight of the thickening agent can be selected from the range of, for example, the number average molecular weight of 0.5 × 10 ^{4 to} 100 × 10 ⁴ . The amount of the thickening agent used can be usually selected from the range of about 0.001 to 10% by weight (or (W / V)%), for example, 0.12 to 5% by weight (or (W / V)). %), Preferably about 0.13 to 3% by weight (or (W / V)%). Furthermore, the ratio of the cooling component with respect to the whole eye drop may be selected from the range of, for example, about 0.0001 to 0.1% by weight (or (W / V)%), and 0.007 to 0.1. Even if it is about wt% (or (W / V)%) or about 0.001 to 0.05 wt% (or (W / V)%), the irritation sensation associated with instillation can be reduced or alleviated.

  In a preferred embodiment of the present invention, the content of the thickening agent is 0.12 to 3% by weight (or (W / V)%), for example 0.15 to 0.5% by weight (or (W / V). )%) May be sufficient.

  The present invention also includes a method for maintaining a refreshing sensation in an eye drop containing a cooling component, which contains a thickening agent and has an absolute viscosity of 3 to 15 mPa · s at a temperature of 20 ° C.

  In addition, in this specification, "eye drops" is used to include "artificial tear-type eye drops" for soft or hard contact lenses.

  In the present invention, the refreshing feeling and refreshing feeling when applying the eye drop can be maintained for a long time, and the compliance of the user can be enhanced. In addition, tired eyes can be eliminated. Furthermore, it is non-greasy and has an excellent feeling of use, has no irritation when instilled, and is highly safe.

  The cooling component in the present invention is a component capable of imparting a refreshing feeling, and examples thereof include essential oils and / or essential oil components. Specifically, essential oils such as fennel oil, eucalyptus oil, bergamot oil, peppermint oil, rose oil, peppermint oil, cool mint oil, cinnamon oil, and essential oil components such as camphor, borneol, geraniol, menthol, citroneol, and limonene ( Especially terpenes) and the like. These can be appropriately added singly or in combination of two or more, and any of d-, l- and dl-forms can be used. Preferred cooling components include menthols (1-menthol, d-menthol, dl-menthol, etc.), camphors (d-camphor, dl-camphor, etc.), borneols (d-borneol, dl-borneol, etc.), geraniol. And essential oils containing many of these components (mint oil, peppermint oil, eucalyptus oil, etc.).

  The cooling component is usually blended in the eye drop at a concentration that does not cause eye irritation, and the ratio of the cooling component to the whole eye drop is, for example, 0.0001 to 0.1% by weight (or (W / V )%), Preferably 0.0005 to 0.07% by weight (or (W / V)%), more preferably 0.001 to 0.05% by weight (or (W / V)%), especially 0.1. It is from 01 to 0.05% by weight (or (W / V)%). If the concentration of the cooling component is less than 0.0001%, a refreshing sensation cannot be expected, and if it exceeds 0.1%, it causes eye irritation and causes pain, which is not preferable.

  In the present invention, even when the cooling component is contained in a high concentration, unpleasant eye irritation is reduced or alleviated by adjusting the viscosity within a specific viscosity range, the refreshing feeling is maintained, and tired eyes are relieved. There is an advantage that can be solved. Therefore, the present invention provides, for example, 0.007% to 0.1% by weight (or (W / V)%), especially 0.007 to 0.05% by weight (or (W / V)%) of cooling. It is also useful as an eye drop containing the components.

  The thickening agent means a compound that imparts viscosity to the eye drop and includes, for example, a cellulose-based polymer (or a water-soluble cellulose derivative), a vinyl-based polymer (or a water-soluble vinyl polymer), a saccharide (acid mucopolysaccharide). Saccharides, water-soluble polysaccharides, etc.), other components (oxyalkylene-based polymers, etc.), etc. are included.

  Examples of the cellulosic polymer in the thickening agent include, for example, alkyl celluloses [methyl celluloses (methyl cellulose, methyl ethyl cellulose, etc.), ethyl celluloses (ethyl cellulose, ethyl methyl cellulose, ethyl propyl cellulose, etc.)], hydroxyalkyl celluloses [ Hydroxyethylcelluloses (hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, hydroxyethylhydroxypropylcellulose, etc.), hydroxypropylcelluloses (hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, etc.), etc.], carboxyalkylcelluloses (carboxy Methyl cellulose, carboxy Chill cellulose, carboxymethyl cellulose or salts thereof (such as sodium salt)), and others. Examples of vinyl polymers include vinylpyrrolidone polymers (such as polyvinylpyrrolidone), vinyl alcohol polymers (such as polyvinyl alcohol), carboxyvinyl polymers, and vinyl alkyl ether polymers (such as polyvinyl methyl ether). it can. Examples of acidic mucopolysaccharides include hyaluronic acid and salts thereof (sodium hyaluronate, etc.), and examples of sugars (or polysaccharides) include dextran, cyclodextrin, etc. Furthermore, examples of the other component include polyoxyethylene glycol, polyoxyethylene-oxypropylene random copolymer, polyoxyethylene polyoxypropylene block copolymer (POE-POP block copolymer), and the like. These thickening agents can be used alone or in combination of two or more kinds.

  Preferred thickening agents are hydroxyalkyl celluloses (hydroxyethyl cellulose, hydroxypropylmethyl cellulose, etc.), vinylpyrrolidone-based polymers (polyvinylpyrrolidone, etc.), sugars (dextran, cyclodextrin), polyoxyethylene polyoxypropylene block copolymers. Alkyl celluloses (methyl cellulose, ethyl cellulose, etc.) are also preferable. Particularly preferred are cellulose-based polymers (hydroxyethyl cellulose, hydroxypropylmethyl cellulose), vinylpyrrolidone-based polymers (polyvinylpyrrolidone), and POE-POP block copolymers.

  When using a plurality of thickening agents, for example, a combination of a cellulosic polymer and a POE-POP block copolymer (for example, a combination of at least one selected from hydroxyethyl cellulose and hydroxypropylmethyl cellulose and a POE-POP block copolymer). ), A combination of cellulosic polymers (for example, a combination of hydroxyethylcellulose and hydroxypropylmethylcellulose), a combination of a vinylic polymer and a cellulosic polymer (for example, polyvinylpyrrolidone, and selected from hydroxyethylcellulose and hydroxypropylmethylcellulose). A combination of at least one of the above-mentioned vinyl polymers and a POE-POP block copolymer (for example, vinylpyrrolidone and a POE-POP block copolymer). The combination of the Rimmer) is preferred. Usually, at least a POE-POP block copolymer is often used in the combination of a plurality of thickening agents.

The molecular weight of these thickening agents is, for example, number average molecular weight of 0.5 × 10 ^{4 to} 100 × 10 ⁴ , preferably 1 × 10 ⁴ to 50 × 10 ⁴ , and more preferably 1 × 10 ⁴ to 10. It is about × 10 ⁴ . The average substitution degree (or etherification degree) of the cellulosic polymer is, for example, 0.5 to 2.5, preferably 0.7 to 2, and more preferably 0.7 to 1.5.

  In the present invention, the compounding amount of the thickening agent cannot be unconditionally specified because it varies depending on the molecular weight and the type of the thickening agent, and the viscosity of the eye drop of the present invention is 3 to 15 mPa · s at a temperature of 20 ° C. The blending amount of the thickening agent can be appropriately selected so that The amount of the thickening agent used can be selected according to the type and molecular weight of the thickening agent, and is usually 0.001 to 10% by weight (or (W / V)%), preferably 0.005 to 10%. The weight% (or (W / V)%) can be selected from the range of about 0.01 to 5% by weight (or (W / V)%). The content of the thickening agent is, for example, 0.12 to 3% by weight (or (W / V)%), preferably 0.13 to 2% by weight (or (W / V)%), particularly 0.1. 15 to 1.5% by weight (or (W / V)%), 0.13 to 1% by weight (or (W / V)%), particularly 0.15 to 0.5% by weight (or ( W / V)%) may be sufficient.

  The eye drop of the present invention has an absolute viscosity value of 3 to 15 mPa · s (kgm−1s−1), preferably 3 to 11 mPa · s (for example, 3 to 10 mPa · s) when measured at a temperature of 20 ° C. Yes, and particularly preferably adjusted to about 3 to 7 mPa · s. If the viscosity is too high, it has a moistening effect, but may cause discomfort such as warping and stickiness, and it is not preferable because it makes the filtration step for aseptic treatment of eye drops difficult. On the other hand, if the viscosity is too low, the effect will be insufficiently expressed.

  The absolute viscosity can be measured by a method using a conical plate type rotational viscometer. This method is a general test method described in the 13th revised Japanese Pharmacopoeia, 36. Viscosity measurement method, second method Rotational viscometer method, by the method described in the section of (3) conical plate type rotational viscometer. The measurement can be performed by using a commercially available cone-and-plate rotary viscometer and a rotor selected appropriately. An example of such a viscometer is an E-type viscometer (TOKIMEC). , Synchro Rhetoric PC type (Brookfield), Ferranti Shirley (Feranti), Lord Visco R (Haake), IGK Highshire rheometer (Ishida Giken Co., Ltd.), Shimadzu rheometer (Shimadzu), mechanical There are spectrometers (Rheometrics) etc. By appropriately selecting these commercially available viscometers and rotors, and appropriately adjusting by using petroleum hydrocarbon oil (Newtonian fluid) defined by JIS Z 8809 as a calibration standard solution for each measurement of a test sample. The absolute viscosity at 20 ° C can be measured.

  The viscosity of the eyedrops shown in the examples was measured using a TV-20 type viscometer (type name: TVE-20L), which is a type of E-type viscometer, and a rotor of 1 ° 34 ′ × R24. As the measurement conditions, the rotation speed was 100 rpm when the viscosity was less than 6 mPa · s, the rotation speed was 50 rpm when the viscosity was less than 6 to 12 mPa · s, and the rotation speed was 20 rpm when the viscosity was less than 12 to 30 mPa · s.

  The eye drop of the present invention further includes inorganic salts; active ingredients such as decongestants, ocular muscle regulators, antiphlogistic astringents, antihistamines, antiallergic agents, vitamins, amino acids, antibacterial agents; buffers, isotonic agents. Agents, chelating agents, stabilizers, pH regulators, surfactants, preservatives, etc. do not cause problems such as eye irritation, and artificial tear film eye drops do not have problems such as adsorption or accumulation on soft contact lenses It can be added as appropriate. When a drug as an active ingredient is mixed, the amount of the active ingredient used is, for example, 0.0001 to 30% by weight (or (W / V)%), preferably 0.0005 to 10% by weight (or ( W / V)%), and more preferably from 0.001 to 5% by weight (or (W / V)%).

  Examples of the inorganic salts include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dried sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. . These inorganic salts may be used as a buffer component or a tonicity component.

  Examples of the decongestant include epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, methylephedrine hydrochloride and the like.

  Examples of the eye muscle regulator include neostigmine methylsulfate and the like.

  Examples of antiphlogistic astringents include epsilon aminocaproic acid, allantoin, berberine chloride, berberine sulfate, sodium azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, and lysozyme chloride.

  As the anti-inflammatory (or anti-inflammatory) agent, pranoprofen, diclofenac, lomefloxane, norfloxacin, ofloxacin and the like may be used.

  Examples of the antihistamine include diphenhydramine hydrochloride and chlorpheniramine maleate.

  Examples of the antiallergic agent include cromoglycic acid, amlexanox, ibudilast, suplatast tosylate, pemirolast, tranilast, ketotifen fumarate and salts thereof (sodium cromoglycate, etc.) and the like.

  Examples of vitamins include flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, and tocopherol acetate.

  Examples of the amino acids include potassium L-aspartate, magnesium L-aspartate, magnesium / potassium L-aspartate (equal amount mixture), aminoethylsulfonic acid, sodium chondroitin sulfate and the like.

  Examples of the antibacterial agent include sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, ofloxacin, norfloxacin and the like.

  Furthermore, if necessary depending on the application, local anesthetics (oxybuprocaine, lidocaine, lidocaine hydrochloride, etc.), myopia treatment / prevention agents (tropicamide, cyclopentolate, endothelin, etc.), intraocular pressure-lowering agents (pilocarpine hydrochloride, Isopropyl unoprostone, distigmine bromide, carbacomal, carteolol hydrochloride, befnolol hydrochloride, timolol maleate, dipibefrine hydrochloride, ecothiopart iodide, diclofenamide, etc.), soothing agents (benzalkonium chloride, procaine hydrochloride, etc.), etc. Active ingredients may be used.

  Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, tartaric acid buffer, acetic acid buffer, epsilon aminocaproic acid, and aspartate. Preferred are borate buffer, phosphate buffer and carbonate buffer.

  Examples of the tonicity agent include sugars (sorbitol, glucose, mannitol, etc.), polyhydric alcohols (glycerin, polyethylene glycol, propylene glycol, etc.), inorganic salts (sodium chloride, potassium chloride, etc.) and the like.

  Examples of chelating agents include edetates (disodium edetate, calcium disodium edetate, trisodium edetate, tetrasodium edetate, calcium edetate, etc.), ethylenediaminetetraacetic acid salt, nitrilotriacetic acid or its salt, hexametaphosphoric acid. Examples include soda and citric acid.

  Examples of the stabilizer include edetates, sodium bisulfite, and the like.

  Examples of pH adjusters include bases (alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate), acids (organic acids such as acetic acid and citric acid, hydrochloric acid). , Inorganic acids such as phosphoric acid) and the like.

  Examples of the surfactant include nonionic surfactants, cationic surfactants, anionic surfactants and amphoteric surfactants. Specifically, non-ionic surfactants such as polysorbate, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene hydrogenated castor oil are mainly used. Furthermore, if necessary, a polyoxyethylene (POE) -polyoxypropylene (POP) block is added to a cationic surfactant (quaternary ammonium salt such as benzalkonium chloride or alkylenediamine (such as ethylenediamine)). POE-POP block-substituted alkylenediamine), anionic surfactants (alkylbenzenesulfonate, alkylsulfate, etc.) and amphoteric surfactants (alkylpolyaminoethylglycine hydrochloride, etc.) may be used.

  Examples of the preservatives include sorbic acid, potassium sorbate, paraoxybenzoic acid ester (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), chlorhexidine gluconate, and quaternary ammonium salt. (Benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, etc.), alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine and the like can be mentioned.

  Further, if necessary, sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol, sorbitol and the like may be added.

  The pH of the eye drop of the present invention is usually adjusted to 4 to 9, preferably 5 to 8.5, more preferably 5.5 to 7.5. The osmotic pressure is usually about 150 to 450 mOsm, and the osmotic pressure ratio to physiological saline is usually 0.6 to 2.0, preferably 0.7 to 1.7, and more preferably 0.8 to 1.5. It is a degree.

  The eye drop of the present invention is a conventional method using components such as the cooling component and the thickening agent, for example, dissolving or suspending the components with distilled water, adjusting to a predetermined osmotic pressure, and sterilizing by filtration. It can be prepared by treating.

  In the present invention, in an eye drop containing a cooling component (including an artificial tears type eye drop), a viscous agent is included to adjust the viscosity to the above-mentioned specific viscosity, thereby providing a refreshing feeling and a refreshing feeling of the eye drop. Can be sustained, the irritation of the refreshing component at the time of instillation can be alleviated, and the user's compliance can be improved. Moreover, not only the dry feeling of eyes but also tired eyes can be eliminated. Therefore, the present invention, by combining a cooling component and a thickening agent to a specific viscosity, a method of relaxing stimulation by the cooling component, a method of maintaining a refreshing feeling and refreshing feeling, eliminating tired eyes. The method of doing is also included.

  The usage and dose of the eye drop of the present invention can be appropriately selected according to the symptoms of the user, the active ingredient contained in the eye drop and the form of the preparation. Then, usually, about 1 to 6 times a day, and apply 1 to 3 drops at a time.

  Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto. In the following Examples and Reference Examples, "Fujichem HECR CF-V" was used as the hydroxyethyl cellulose, "Hydroxypropyl methylcellulose 2906 (Metroses R 65SH-4000)" was used as the hydroxypropyl methylcellulose, and polyoxyethylene polyoxypropylene was used. "Poloxamer 407" was used as the block copolymer, and "polyvinylpyrrolidone K90" was used as the polyvinylpyrrolidone.

Example 1 (artificial tear drop)
[Composition of 100 ml of eye drops]
Sodium chloride 0.44g
Potassium chloride 0.08g
Boric acid 0.30g
Borax 0.035g
Polysorbate 80 0.1g
l-menthol 0.005g
Hydroxyethyl cellulose 0.15g
Potassium sorbate 0.1g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 7.5, viscosity 3.5 mPa · s).

Example 2 (artificial tear type eye drop)
[Composition of 100 ml of eye drops]
Sodium chloride 0.44g
Potassium chloride 0.08g
L-potassium aspartate 0.10 g
Boric acid 0.30g
Borax 0.035g
Polysorbate 80 0.1g
l-menthol 0.001g
Hydroxyethyl cellulose 0.15g
Potassium sorbate 0.1g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 7.5, viscosity 3.5 mPa · s).

Example 3 (artificial tear type eye drop)
[Composition of 100 ml of eye drops]
Sodium chloride 0.44g
Potassium chloride 0.08g
Boric acid 0.30g
Borax 0.035g
Polysorbate 80 0.1g
l-menthol 0.005g
Hydroxypropyl methylcellulose 0.2g
Potassium sorbate 0.1g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 7.5, viscosity 4.6 mPa · s).

Example 4 (artificial tear type eye drop)
[Composition of 100 ml of eye drops]
Sodium chloride 0.5g
Boric acid 0.73g
Borax 0.05g
Polyoxyethylene polyoxypropylene block copolymer (poloxamer 407) 0.1 g
Polyvinylpyrrolidone 1.8g
l-menthol 0.01g
d-camphor 0.005g
Benzalkonium chloride 0.01g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 7.2, viscosity 7.5 mPa · s).

Example 5
[Composition of 100 ml of eye drops]
Naphazoline hydrochloride 0.003 g
Methyl sulfate neostigmine 0.005g
Allantoin 0.2g
Chlorpheniramine maleate 0.03g
L-potassium aspartate 1.0 g
Boric acid 0.9g
Borax 0.045g
Polysorbate 80 0.2g
Hydroxypropyl methylcellulose 0.2g
l-menthol 0.05g
Alkyl polyaminoethyl glycine 0.01g
Chlorobutanol 0.15g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 5.2, viscosity 4.6 mPa · s).

Example 6
[Composition of 100 ml of eye drops]
Methyl sulfate neostigmine 0.005g
Chlorpheniramine maleate 0.03g
L-potassium aspartate 1.0 g
Acetic acid d-α-tocopherol 0.05 g
Boric acid 0.8g
Borax 0.09g
Polysorbate 80 0.3g
Hydroxypropyl methylcellulose 0.2g
l-menthol 0.05g
Alkyl polyaminoethyl glycine 0.01g
Chlorobutanol 0.15g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 5.8, viscosity 4.6 mPa · s).

Example 7
[Composition of 100 ml of eye drops]
Tetrahydrozoline hydrochloride 0.050g
Methyl sulfate neostigmine 0.005g
Allantoin 0.2g
Chlorpheniramine maleate 0.03g
L-potassium aspartate 1.0 g
Pyridoxine hydrochloride 0.1 g
Boric acid 0.9g
Borax 0.045g
Polysorbate 80 0.2g
Hydroxypropyl methylcellulose 0.2g
l-menthol 0.05g
Alkyl polyaminoethyl glycine 0.01g
Chlorobutanol 0.15g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 5.2, viscosity 4.6 mPa · s).

Example 8
[Composition of 100 ml of eye drops]
Tetrahydrozoline hydrochloride 0.05g
Chlorpheniramine maleate 0.03g
Cyanocobalamin 0.01g
Boric acid 0.80g
Borax 0.09g
Polysorbate 80 0.2g
Hydroxyethyl cellulose 0.13g
l-menthol 0.03g
Benzalkonium chloride 0.01g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 5.8, viscosity 3.1 mPa · s).

Example 9
[Composition of 100 ml of eye drops]
Tetrahydrozoline hydrochloride 0.05g
Azulene sulfonate sodium 0.02g
Chlorpheniramine maleate 0.03g
Boric acid 1.80 g
Borax 0.035g
Polysorbate 80 0.2g
Hydroxyethyl cellulose 0.13g
l-menthol 0.03g
Alkyl polyaminoethyl glycine 0.01g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 7.2, viscosity 3.1 mPa · s).

Example 10
[Composition of 100 ml of eye drops]
Methyl sulfate neostigmine 0.005g
Chlorpheniramine maleate 0.02g
Flavin adenine dinucleotide sodium 0.05g
L-potassium aspartate 1.0 g
Boric acid 1.8g
Borax 0.05g
Polysorbate 80 0.2g
Hydroxypropyl methylcellulose 0.2g
l-menthol 0.01g
d-borneol 0.01 g
Benzalkonium chloride 0.01g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 5.8, viscosity 4.6 mPa · s).

Example 11
[Composition of 100 ml of eye drops]
Dipotassium glycyrrhizinate 0.10 g
Chlorpheniramine maleate 0.02g
Sulfamethoxazole sodium 4.00 g
Polysorbate 80 0.2g
Hydroxypropyl methylcellulose 0.2g
l-menthol 0.01g
d-borneol 0.01g
Benzalkonium chloride 0.01g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 8.5, viscosity 4.6 mPa · s).

Example 12
[Composition of 100 ml of eye drops]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800 g
Borax 0.050g
Polysorbate 80 0.200 g
l-menthol 0.010 g
Hydroxypropyl methylcellulose 0.180g
Benzalkonium chloride 0.01g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 6.3, viscosity 3.8 mPa · s).

Example 13
[Composition of 100 ml of eye drops]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800 g
Borax 0.050g
Polysorbate 80 0.200 g
l-menthol 0.030g
Hydroxypropyl methylcellulose 0.200g
Benzalkonium chloride 0.01g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 6.3, viscosity 4.6 mPa · s).

Example 14
[Composition of 100 ml of eye drops]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800 g
Borax 0.050g
Polysorbate 80 0.200 g
l-menthol 0.050g
Hydroxypropyl methylcellulose 0.200g
Benzalkonium chloride 0.01g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 6.3, viscosity 4.6 mPa · s).

Example 15
[Composition of 100 ml of eye drops]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800 g
Borax 0.050g
Polysorbate 80 0.200 g
l-menthol 0.050g
Hydroxypropyl methylcellulose 0.250g
Benzalkonium chloride 0.010g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 6.3, viscosity 6.1 mPa · s).

Example 16
[Composition of 100 ml of eye drops]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800 g
Borax 0.050g
Polysorbate 80 0.200 g
l-menthol 0.050g
Hydroxypropyl methylcellulose 0.350g
Benzalkonium chloride 0.01g
Hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Total amount 100 ml
The above components were aseptically prepared by a conventional method and filled in a container to obtain an eye drop (pH = 6.3, viscosity 10.2 mPa · s).

Examples 17-29 and Reference Examples 1-5
In addition, in Examples 22 to 29 and Reference Examples 4 to 5, artificial tear-drop type eye drops were examined.

Test example [Test method]
Eye drops were prepared by blending a cooling component (such as 1-menthol) and a thickening agent (such as hydroxypropylmethyl cellulose) at various concentrations shown in Tables 1 to 3. Eye drops were applied to a paneler who used and worked on a personal computer for two hours in a row, and the degree of coolness and refreshing feeling immediately after and 5 minutes after the eye drops, the presence or absence of irritation (pain) felt at the time of eye drops, and tired eyes caused by the eye drops Whether or not it was resolved was tested for the degree of discomfort (discomfort) due to stickiness of the eye drop.

  The results are shown in Table 1. Among the numerical values in the table, the degree of coolness immediately after instillation and 5 minutes after instillation, the degree of elimination of tired eyes, and the degree of discomfort (discomfort) due to stickiness of eye drops are from "1" to each panel. A three-level evaluation of "3" is performed, and the average value of seven panelists is shown. Regarding the presence or absence of irritation (pain) at the time of instillation, the percentage (%) of the panelists who evaluated that there is no irritation (pain) is shown.

  As a result, the eye drops of Reference Examples 1 to 5 did not retain a refreshing feeling after 5 minutes and had no effect of eliminating tired eyes. The eye drop of Reference Example 4 retains a refreshing sensation, but has discomfort due to stickiness, and since it has an irritating property, it also has a problem in safety. Further, it is difficult to filter with a membrane filter of 0.2 μm, which causes a problem in manufacturing.

  On the other hand, it can be seen that the eye drops of Examples 17 to 29 of the present invention retain the refreshing feeling even after 5 minutes from the instillation. It is also effective for eliminating tired eyes. Furthermore, it was shown to be a highly safe and comprehensively superior eye drop without irritation (pain).

  The effect of eliminating tired eyes depends on the sustaining effect of the cooling component, and it was confirmed that the effects were high in Examples 19 to 21 (containing 0.05% of 1-menthol).

  Furthermore, in the present invention, it was shown that the irritation at the time of instillation was reduced. As shown in Reference Example 2 (Table 1), an eye drop containing 0.05% of 1-menthol causes a strong irritation upon instillation and gives discomfort to the user, but is specified by containing a thickening agent. With the eye drops adjusted to the viscosity range of 1, the irritation feeling at the time of instillation is reduced or alleviated. The effect of reducing or alleviating the sensation of stimulus is the same in eye drops containing a cooling component other than 1-menthol. Therefore, the present invention is also useful for use in eye drops containing a high concentration of a cooling component. Furthermore, it was shown that the effect of eliminating fatigue eyes was higher when the polyoxyethylene polyoxypropylene block copolymer (poloxamer 407) was contained.

The following are examples of aspects of the present invention.
[1] An eye drop containing a cooling component and a thickening agent and having an absolute viscosity of 3 to 15 mPa · s at a temperature of 20 ° C.
[2] The eye drop according to claim 1, wherein the cooling component is an essential oil component or an essential oil.
[3] The thickening agent is at least selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hyaluronic acid and its salts, dextran, cyclodextrin, and polyoxyethylene polyoxypropylene block copolymer. The eye drop according to claim 1, which is a kind.
[4] A method of sustaining a refreshing feeling by using an eye drop containing a cooling component, which contains a thickening agent and has an absolute viscosity of 3 to 15 mPa · s at a temperature of 20 ° C.

Claims (1)

(a) a cooling component, and (b) at least one selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hyaluronic acid and its salts, dextran, polyoxyethylene polyoxypropylene block copolymer. An eye drop containing the thickening agent of 1. and an absolute viscosity at a temperature of 20 ° C. of 3 to 15 mPa · s.