JP2005247875A - Ophthalmic preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an ophthalmic preparation which can give a refreshing feeling over a long time and can refresh tired eyes. <P>SOLUTION: This ophthalmic preparation comprises a refreshing ingredient and a thickening agent, and has an absolute viscosity of 3 to 15 mPa s at a temperature of 20°C. The refreshing ingredient can include essential oil ingredients (menthol, and the like) and essential oils. The thickening agent can include ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, dextran, cyclodextrin, and polyoxyethylene polyoxypropylene block copolymer. When such the ophthalmic preparation is applied, the refreshing feeling can be kept over a long time to enhance the compliance of a user. <P>COPYRIGHT: (C)2005,JPO&NCIPI

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.

  Eye drops are formulated with essential oils such as peppermint oil, fennel oil, rose oil, bergamot oil, and essential oil ingredients such as menthol, camphor, and borneol for the purpose of imparting a refreshing and refreshing feeling when instilled. . Among these essential oils or essential oil components, compounds having a terpene structure such as menthol, camphor, and borneol are widely used because they have a strong refreshing feeling and refreshing feeling.

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

  Moreover, although a user tends to seek a refreshing feeling and a refreshing feeling, these components are known to be painful because of the irritation that the essential oil or the essential oil component itself has. In view of this, JP-A-9-132526 (Patent Document 1) discloses an ophthalmic solution containing menthols, camphors and borneols, wherein (a) the total amount of menthol, camphor and borneol is 0.01 to 0. .05% by weight, (b) When the mixing ratio of camphor and borneol to menthol is 0.5 to 1.0 as a weight ratio, respectively, the sensation of cooling is strong and the sustainability of the refreshing sensation is enhanced, and the irritation to the eyes It is described that it is possible to obtain eye drops with extremely reduced properties. However, with such a method, the stimulus reduction effect, the refreshing effect and the refreshing effect are not yet sufficient.

  On the other hand, people who complain of dry eyes and tired eyes due to air drying with an air conditioner, a decrease in the number of blinks due to staring on the screen of personal computers and televisions, and wearing of soft or hard contact lenses. Is increasing. Therefore, many artificial tear-type eye drops containing a thickening agent are commercially available for the purpose of alleviating such dry feeling. Among the eye drops, artificial tear type eye drops are usually eye drops that replenish the tears that cover the cornea and resemble tears that have a moisturizing and moisturizing effect. Instilled while wearing a soft contact lens). By adding a thickening agent to such an artificial tear type eye drop, it is possible to eliminate the dryness of the eyes accompanying the decrease in tears and to supplement the eyes with moisture. However, it is impossible to eliminate tired eyes.

As described above, the conventional eye drops can give a refreshing feeling and a refreshing feeling at the time of instillation, but the sensation is not maintained, and not only the eye dryness but also the tired eyes cannot be eliminated.
JP-A-9-132526

  Accordingly, an object of the present invention is to provide a method capable of alleviating stimulation of a refreshing component during application by applying an eye drop and maintaining a refreshing feeling and refreshing feeling for a long time.

  Another object of the present invention is to provide an eye drop that not only enhances user compliance by maintaining a refreshing feeling and refreshing feeling over a long period of time by applying the above method, but can also eliminate fatigue. .

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have used a combination of a refreshing component and a thickening agent, and when controlling the viscosity of the eye drop, a refreshing feeling and refreshing feeling can be achieved by applying the eye drop. Has been found to be able to sustain for a long time, improve user compliance and eliminate fatigue. Furthermore, since it also has the effect of relieving irritation (pain) during eye drops by the refreshing component, it has also been found that a highly safe eye drop without irritation can be obtained. The present invention has been made based on these findings.

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

Examples of the thickening agent include cellulosic polymers (methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, etc.), vinyl polymers (polyvinylpyrrolidone, etc.), saccharides (mucopolysaccharides such as hyaluronic acid and its salts, Examples thereof include polysaccharides such as dextran and cyclodextrin), oxyalkylene polymers (polyoxyethylene polyoxypropylene block copolymers), and the like, 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, a number average molecular weight of about 0.5 × 10 ^{4 to} 100 × 10 ⁴ . The amount of thickening agent used can usually be 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 to the whole eye drop may be selected from a range of about 0.0001 to 0.1% by weight (or (W / V)%), for example, 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 associated with eye drops 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)%), such as 0.15 to 0.5% by weight (or (W / V). )%).

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

  In the present specification, the term “eye drops” is used to mean “artificial tear liquid type eye drops” for soft or hard contact lenses.

  In this invention, the refreshing feeling and refreshing feeling at the time of application of eye drops can be maintained for a long time, and a user's compliance can be improved. It can also relieve fatigue. In addition, there is no stickiness, excellent usability, no irritation when instilled, and high safety.

  The refreshing component in this invention is a component which can provide a refreshing feeling, and an essential oil and / or an essential oil component etc. are mentioned. Specifically, essential oils such as fennel oil, eucalyptus oil, bergamot oil, peppermint oil, rose oil, peppermint oil, cool mint oil, and cinnamon oil, and essential oil ingredients such as camphor, borneol, geraniol, menthol, citronole, and limonene ( In particular, terpenes). These can be 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 (l-menthol, d-menthol, dl-menthol, etc.), camphors (d-camphor, dl-camphor, etc.), borneols (d-borneol, dl-borneol, etc.), geraniol And essential oils such as mint oil, peppermint oil, and eucalyptus oil that contain many of these components.

  The refreshing component is usually added to the eye drop at a concentration that does not cause eye irritation, and the ratio of the refreshing component to the total amount of the 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)%), in particular 0.8. 01 to 0.05% by weight (or (W / V)%). When the concentration of the refreshing component is less than 0.0001%, a refreshing feeling cannot be expected, and when it exceeds 0.1%, the eye irritation occurs and pain is accompanied, which is not preferable.

  In the present invention, even if the cooling component is contained in a high concentration, by adjusting to a specific viscosity range with a thickening agent, unpleasant eye irritation is reduced or alleviated, a refreshing feeling is maintained, There is an advantage that can be eliminated. Therefore, the present invention provides, for example, a cooling of 0.007% to 0.1% by weight (or (W / V)%), particularly 0.007 to 0.05% by weight (or (W / V)%). It is also useful as an eye drop containing ingredients.

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

  Among the thickening agents, examples of the cellulose-based polymer include alkylcelluloses [methylcelluloses (methylcellulose, methylethylcellulose, etc.), ethylcelluloses (ethylcellulose, ethylmethylcellulose, ethylpropylcellulose, etc.)], hydroxyalkylcelluloses [ Hydroxyethylcelluloses (hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, hydroxyethylhydroxypropylcellulose, etc.), hydroxypropylcelluloses (hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, etc.)], carboxyalkylcelluloses (carboxy Methylcellulose, carboxy Chill cellulose, carboxymethyl cellulose or salts thereof (such as sodium salt)), and others. Examples of vinyl polymers include vinyl pyrrolidone polymers (such as polyvinyl pyrrolidone), vinyl alcohol polymers (such as polyvinyl alcohol), carboxyvinyl polymers, vinyl alkyl ether polymers (such as polyvinyl methyl ether), and the like. it can. Examples of acidic mucopolysaccharides include hyaluronic acid and salts thereof (such as sodium hyaluronate), and examples of saccharides (or polysaccharides) include dextran and cyclodextrin. Furthermore, examples of other components 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.

  Preferred thickening agents are hydroxyalkylcelluloses (hydroxyethylcellulose, hydroxypropylmethylcellulose, etc.), vinylpyrrolidone polymers (polyvinylpyrrolidone, etc.), sugars (dextran, cyclodextrin), polyoxyethylene polyoxypropylene block copolymers Alkyl celluloses (such as methyl cellulose and ethyl cellulose) are also preferable. Particularly preferred are cellulose polymers (hydroxyethylcellulose, hydroxypropylmethylcellulose), vinylpyrrolidone polymers (polyvinylpyrrolidone), and POE-POP block copolymers.

  When a plurality of thickening agents are used, 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) ), Combinations of cellulose polymers (for example, combinations of hydroxyethyl cellulose and hydroxypropyl methylcellulose), combinations of vinyl polymers and cellulose polymers (for example, selected from polyvinylpyrrolidone, hydroxyethyl cellulose, and hydroxypropyl methylcellulose) A combination of a vinyl polymer and a POE-POP block copolymer (for example, vinyl pyrrolidone and POE-POP block copolymer). The combination of the Rimmer) is preferred. In the combination of a plurality of thickening agents, usually at least a POE-POP block copolymer is often used.

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

  In the present invention, the blending amount of the thickening agent varies depending on the molecular weight and type of the thickening agent and thus cannot be defined unconditionally. The viscosity of the eye drop of the present invention is 3 to 15 mPa · s at a temperature of 20 ° C. Thus, the blending amount of the thickening agent can be appropriately selected. The amount of 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%. It can be selected from the range of about wt% (or (W / V)%), more preferably about 0.01 to 5 wt% (or (W / V)%). The content of the thickening agent is, for example, from 0.12 to 3% by weight (or (W / V)%), preferably from 0.13 to 2% by weight (or (W / V)%), in particular from 0. 15 to 1.5% by weight (or (W / V)%), 0.13 to 1% by weight (or (W / V)%), especially 0.15 to 0.5% by weight (or ( W / V)%).

The eye drop of the present invention has an absolute viscosity value of 3 to 15 mPa · s (kgm ⁻¹ s ⁻¹ ), preferably 3 to 11 mPa · s (for example, 3 to 10 mPa · s) when measured at a temperature of 20 ° C. And particularly preferably adjusted to about 3 to 7 mPa · s. If the viscosity is too high, there is a moistening effect, but uncomfortable feelings such as stickiness may occur, and the filtration step for aseptic treatment of eye drops is difficult, which is not preferable. If the viscosity is too low, the effect will be insufficient.

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, (3) According to the method described in the section of conical plate type rotational viscometer. The measurement can be carried out using a commercially available conical plate type rotational viscometer and an appropriately selected rotor. Examples of such viscometers include an E-type viscometer (TOKIMEC). , Synchronic PC type (Brookfield), Ferranty Shirley (Feranti), Road Visco ^R (Hake), IGK Hisher Rheometer (Ishida Giken), Shimadzu Rheometer (Shimadzu Corporation), Mechanical There are spectrometers (rheometrics). By appropriately selecting these commercially available viscometers and rotors, and using petroleum-based hydrocarbon oils (Newtonian fluid) defined by JIS Z 8809 as calibration standard solutions for each test sample measurement The absolute viscosity at 20 ° C. can be measured.

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

  The eye drops of the present invention further include inorganic salts; active ingredients such as decongestants, eye muscle modifiers, anti-inflammatory agents, antihistamines, antiallergic agents, vitamins, amino acids, antibacterial agents; buffering agents, isotonicity Agents, chelating agents, stabilizers, pH regulators, surfactants, preservatives, etc., eye irritation, etc., and artificial tears-type eye drops have no problems such as adsorption or accumulation on soft contact lenses It can be added as appropriate. When a drug as an active ingredient is blended, 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)%), more preferably from about 0.001 to 5% by weight (or (W / V)%).

  Examples of inorganic salts include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dry 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 an isotonic agent 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 modifier include neostigmine methyl sulfate.

  Anti-inflammatory astringents include epsilon aminocaproic acid, allantoin, berberine chloride, berberine sulfate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme chloride, and the like.

  In addition, as an 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 antiallergic agents include cromoglycic acid, amlexanox, ibudilast, suplatast tosylate, pemirolast, tranilast, ketotifen fumarate and salts thereof (such as sodium cromoglycate).

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

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

  Antibacterial agents include sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, ofloxacin, norfloxacin and the like.

  In addition, local anesthetics (oxybuprocaine, lidocaine, lidocaine hydrochloride, etc.), myopia treatment / prevention agents (tropicamide, cyclopentrate, endothelin, etc.), intraocular pressure-lowering agents (pilocarpine hydrochloride, Various types such as isopropyl unoprostone, distigmine bromide, carbacomal, carteolol hydrochloride, befnolol hydrochloride, timolol maleate, dipivefrine hydrochloride, ecothiopart iodide, diclofenamide, etc.), soothing agents (benzalkonium chloride, procaine hydrochloride, etc.) Active ingredients may be used.

  Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, tartaric acid buffer, acetate buffer, epsilon aminocaproic acid, aspartate and the like. A borate buffer, a phosphate buffer, and a carbonate buffer are preferable.

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

  Chelating agents include edetates (disodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, calcium edetate, etc.), ethylenediaminetetraacetate, nitrilotriacetic acid or salts thereof, hexametaphosphate Examples include soda and citric acid.

  Examples of the stabilizer include edetate salts and sodium bisulfite.

  Examples of pH regulators 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) And inorganic acids such as phosphoric acid).

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

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

  If necessary, saccharides 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 about 5.5 to 7.5. The osmotic pressure is usually about 150 to 450 mOsm, and the osmotic pressure ratio with respect to physiological saline is usually 0.6 to 2.0, preferably 0.7 to 1.7, more preferably 0.8 to 1.5. Degree.

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

  In the present invention, in the eye drops containing a refreshing component (including artificial tears type eye drops), by adding a thickener and adjusting to the specific viscosity, the refreshing feeling and refreshing feeling of the eye drops Can be maintained, and the stimulation of the refreshing component at the time of instillation can be alleviated, and the user's compliance can be improved. Moreover, not only the dryness of the eyes but also the tired eyes can be eliminated. Therefore, the present invention combines a cooling component and a thickening agent to obtain a specific viscosity, thereby relieving irritation caused by the cooling component, a method for maintaining a refreshing feeling and a refreshing feeling, and eliminating fatigue. The method of carrying out is also included.

  The usage and dosage 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, it is usually instilled about 1 to 6 times a day, and about 1 to 3 drops are applied 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, “Fuji Chemi HEC ^R CF-V” is used as hydroxyethyl cellulose, and “Hydroxypropyl methyl cellulose 2906 (Metroise ^R 65SH-4000)” is used as hydroxypropyl methyl cellulose. “Polyxomer 407” was used as the propylene block copolymer, and “polyvinylpyrrolidone K90” was used as the polyvinylpyrrolidone.

Example 1 (artificial tear liquid type eye drops)
[Composition of eye drops 100 ml]
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 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 7.5, viscosity 3.5 mPa · s).

Example 2 (artificial tear drop)
[Composition of eye drops 100 ml]
Sodium chloride 0.44g
Potassium chloride 0.08g
L-potassium 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 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 7.5, viscosity 3.5 mPa · s).

Example 3 (artificial tear drop)
[Composition of eye drops 100 ml]
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 100ml
The above ingredients were prepared aseptically 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 liquid type eye drop)
[Composition of eye drops 100 ml]
Sodium chloride 0.5g
Boric acid 0.73g
Borax 0.05g
0.1 g of polyoxyethylene polyoxypropylene block copolymer (poloxamer 407)
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 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 7.2, viscosity 7.5 mPa · s).

Example 5
[Composition of eye drops 100 ml]
Naphazoline hydrochloride 0.003g
Methyl sulfate neostigmine 0.005g
Allantoin 0.2g
0.03 g chlorpheniramine maleate
L-potassium potassium aspartate 1.0 g
Boric acid 0.9g
Borax 0.045g
Polysorbate 80 0.2g
Hydroxypropyl methylcellulose 0.2g
l-Menthol 0.05g
0.01g alkylpolyaminoethylglycine
Chlorobutanol 0.15g
Hydrochloric acid appropriate amount sodium hydroxide appropriate amount sterilized purified water appropriate amount total amount 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 5.2, viscosity 4.6 mPa · s).

Example 6
[Composition of eye drops 100 ml]
Methyl sulfate neostigmine 0.005g
0.03 g chlorpheniramine maleate
L-potassium potassium aspartate 1.0 g
D-α-Tocopherol acetate 0.05 g
Boric acid 0.8g
Borax 0.09g
Polysorbate 80 0.3g
Hydroxypropyl methylcellulose 0.2g
l-Menthol 0.05g
0.01g alkylpolyaminoethylglycine
Chlorobutanol 0.15g
Hydrochloric acid appropriate amount sodium hydroxide appropriate amount sterilized purified water appropriate amount total amount 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 5.8, viscosity 4.6 mPa · s).

Example 7
[Composition of eye drops 100 ml]
Tetrahydrozoline hydrochloride 0.050 g
Methyl sulfate neostigmine 0.005g
Allantoin 0.2g
0.03 g chlorpheniramine maleate
L-potassium potassium aspartate 1.0 g
0.1 g of pyridoxine hydrochloride
Boric acid 0.9g
Borax 0.045g
Polysorbate 80 0.2g
Hydroxypropyl methylcellulose 0.2g
l-Menthol 0.05g
0.01g alkylpolyaminoethylglycine
Chlorobutanol 0.15g
Hydrochloric acid appropriate amount sodium hydroxide appropriate amount sterilized purified water appropriate amount total amount 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 5.2, viscosity 4.6 mPa · s).

Example 8
[Composition of eye drops 100 ml]
Tetrahydrozoline hydrochloride 0.05g
0.03 g chlorpheniramine maleate
Cyanocobalamin 0.01g
Boric acid 0.80g
Borax 0.09g
Polysorbate 80 0.2g
Hydroxyethylcellulose 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 100ml
The above ingredients were prepared aseptically by a conventional method and filled into a container to obtain an eye drop (pH = 5.8, viscosity 3.1 mPa · s).

Example 9
[Composition of eye drops 100 ml]
Tetrahydrozoline hydrochloride 0.05g
Sodium azulenesulfonate 0.02g
0.03 g chlorpheniramine maleate
1.80 g of boric acid
Borax 0.035g
Polysorbate 80 0.2g
Hydroxyethylcellulose 0.13g
l-Menthol 0.03g
0.01g alkylpolyaminoethylglycine
Hydrochloric acid appropriate amount sodium hydroxide appropriate amount sterilized purified water appropriate amount total amount 100ml
The above ingredients 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 eye drops 100 ml]
Methyl sulfate neostigmine 0.005g
Chlorpheniramine maleate 0.02g
Flavin adenine dinucleotide sodium 0.05g
L-potassium 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 100ml
The above ingredients were prepared aseptically by a conventional method and filled into a container to obtain an eye drop (pH = 5.8, viscosity 4.6 mPa · s).

Example 11
[Composition of eye drops 100 ml]
Dipotassium glycyrrhizinate 0.10g
Chlorpheniramine maleate 0.02g
Sulfamethoxazole sodium 4.00 g
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 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 8.5, viscosity 4.6 mPa · s).

Example 12
[Composition of eye drops 100 ml]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800g
Borax 0.050g
Polysorbate 80 0.200g
l-Menthol 0.010g
Hydroxypropyl methylcellulose 0.180g
Benzalkonium chloride 0.01g
Hydrochloric acid appropriate amount sodium hydroxide appropriate amount sterilized purified water appropriate amount total amount 100ml
The above ingredients 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 eye drops 100 ml]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800g
Borax 0.050g
Polysorbate 80 0.200g
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 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 6.3, viscosity 4.6 mPa · s).

Example 14
[Composition of eye drops 100 ml]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800g
Borax 0.050g
Polysorbate 80 0.200g
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 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 6.3, viscosity 4.6 mPa · s).

Example 15
[Composition of eye drops 100 ml]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800g
Borax 0.050g
Polysorbate 80 0.200g
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 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 6.3, viscosity 6.1 mPa · s).

Example 16
[Composition of eye drops 100 ml]
Methyl sulfate neostigmine 0.005g
Allantoin 0.100g
Boric acid 1.800g
Borax 0.050g
Polysorbate 80 0.200g
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 100ml
The above ingredients were aseptically prepared by a conventional method and filled into a container to obtain an eye drop (pH = 6.3, viscosity 10.2 mPa · s).

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

Test example [Test method]
Eye drops were prepared by blending a refreshing component (such as l-menthol) and a thickening agent (such as hydroxypropylmethylcellulose) at various concentrations shown in Tables 1 to 3. Eye drops on a paneler who used and worked on a personal computer for 2 hours continuously. The degree of refreshing and refreshing feeling immediately after instillation and after 5 minutes of instillation, the presence or absence of irritation (pain), and instillation The degree of discomfort (discomfort) due to the eyelash nebula was tested to see if it was resolved.

  The results are shown in Table 1. Among the numerical values in the table, the degree of refreshing feeling immediately after instillation and 5 minutes after instillation, the degree of relief from fatigued eyes, and the degree of discomfort (uncomfortable feeling) due to the eyedrops' discomfort are "1" to Three-stage evaluation of “3” is performed, and an average value of seven panelists is shown. About the presence or absence of irritation (pain) at the time of instillation, the percentage (%) of panelists evaluated as having no irritation (pain) is shown.

  As a result, the eye drops of Reference Examples 1 to 5 do not retain a refreshing feeling after 5 minutes and do not have an effect of eliminating fatigue eyes. In the eye drop of Reference Example 4, a refreshing feeling is maintained, but there is a feeling of discomfort due to the stickiness, and since it has irritation, there is also a problem in safety. Furthermore, it is difficult to filter with a 0.2 μm membrane filter, which has a problem in terms of manufacturing.

  On the other hand, in the eye drops of Examples 17 to 29 of the present invention, it can be seen that a refreshing feeling is maintained even after 5 minutes have passed after the eye drops. It is also effective in eliminating tired eyes. Furthermore, since there was no irritation (pain), it was shown that the eye drops are highly excellent in safety and high overall.

  The effect of relieving fatigue was dependent on the sustaining effect of the cooling component, and it was confirmed that Examples 19 to 21 (containing 1% menthol 0.05%) had a high effect.

  Furthermore, in this invention, it was shown that the irritation | stimulation at the time of instillation is relieved. As shown in Reference Example 2 (Table 1), an ophthalmic solution containing 0.05% of 1-menthol is accompanied by a strong irritation at the time of instillation and gives an unpleasant feeling to the user. In the eye drop adjusted to the above viscosity range, the irritation feeling during eye drop is reduced or alleviated. And the effect of reducing or alleviating this irritation is the same in eye drops containing a cooling component other than l-menthol. Therefore, this invention is useful also for the use to the eye drop containing a high concentration refreshing component. Furthermore, it has been shown that the effect of eliminating fatigue eyes becomes higher when a polyoxyethylene polyoxypropylene block copolymer (Polyxomer 407) is contained.

Claims (4)

  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.   The eye drop according to claim 1, wherein the refreshing component is an essential oil component or an essential oil.   The thickening agent is at least one selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hyaluronic acid and its salts, dextran, cyclodextrin, polyoxyethylene polyoxypropylene block copolymer The eye drop according to claim 1.   A method of maintaining a refreshing sensation by containing a thickening agent and an absolute viscosity at a temperature of 20 ° C. of 3 to 15 mPa · s in an eye drop containing a cooling component.