JP2002097129A - Eye lotion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an eye lotion that can retain refrigerant and refreshing feelings for hours and heal the tired eyes. SOLUTION: The objective eye drops include a refrigerant component and a thickening agent and have an absolute viscosity of 3-15 mPa.s at 20 deg.C. As a refrigerant, are cited essential oil components (menthol and the like) and essential oils, while ethylcellulose, hydroxyethylcellulose, hydroxypropylmethyl- cellulose, polyvinyl pyrrolidone, dextran, cyclodextrin, poly(oxyethylene)- poly(oxypropylene) block copolymer and the like can be used as a thickening agent. When the resultant eye drops are applied, the refrigerant and refreshing feelings are retained for hours and the compliance of the user can be increased.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Ophthalmic oils, mint oils, and mint oils have been used in eye drops for the purpose of imparting a refreshing or refreshing feeling when instilled.
Essential oils such as rose oil and bergamot oil, menthol,
Essential oil components such as camphor and borneol are blended.
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 and refreshing feeling.

[0003] However, these essential oils and essential oil components impart a refreshing sensation and a refreshing sensation immediately after instillation, but do not have long-lasting properties.

[0004] In addition, although users tend to demand a refreshing sensation and a refreshing sensation, these components are known to be painful due to the irritancy of the essential oil or the essential oil component itself. I have. Therefore, Japanese Patent Application Laid-Open No. Hei 9-132526 discloses an ophthalmic solution containing menthols, camphors and borneols, wherein (a) menthol,
The total amount of camphor and borneol is 0.01 to 0.05
% By weight, and (b) the blending ratio of camphor and borneol to menthol was 0.5 to 1.0, respectively, as a weight ratio.
It describes that an eye drop having a strong cooling sensation, enhancing the persistence of a refreshing sensation, and having extremely reduced irritation to the eyes can be obtained. However, in such a method, the effect of reducing irritation and the effect of maintaining a refreshing sensation and a refreshing sensation are not yet sufficient.

On the other hand, in recent years, dry eyes and fatigued eyes due to drying of air by an air conditioner or the like, reduction in the number of blinks caused by staring at the screen of a personal computer television (TV), wearing of soft or hard contact lenses, and the like. More people are complaining. 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 eye drops similar to tears, which mainly supplement the tears covering the cornea and have a moisturizing and moisturizing effect as a main effect, and include hard contact lenses (oxygen (Including permeable hard contact lenses) and soft contact lenses. By adding a thickening agent to such an artificial tear-type eye drop, it is possible to eliminate the feeling of dryness of the eyes due to the decrease in tears and to make the eyes moist. However, tired eyes cannot be eliminated.

[0006] As described above, the conventional eye drops can give a refreshing feeling and a refreshing feeling when instilled, but they do not maintain their sensuality and eliminate tired eyes as well as dry eyes. Can not.

[0007]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for alleviating the irritation of a refreshing ingredient at the time of instillation by applying an ophthalmic solution and maintaining a refreshing or refreshing feeling over a long period of time. It is in.

[0008] Another object of the present invention is to provide an eye drop which not only enhances the compliance of the user by maintaining the refreshing sensation and the refreshing sensation for a long time by applying the above method, but also can eliminate the tired eyes. It is in.

[0009]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and as a result, when using a combination of a cooling component and a thickening agent and controlling the viscosity of eye drops, It has been found that the application of the agent can maintain a refreshing sensation and a refreshing sensation over a long period of time, enhance user compliance, and eliminate fatigue eyes. Furthermore, they have also found that since they also have the effect of relieving irritation (pain) when instilled by the cooling component, highly safe eye drops without irritation can be obtained. The present invention has been made based on these findings.

That is, the ophthalmic solution of the present invention contains a cooling component and a thickening agent, and has an absolute viscosity at a temperature of 20 ° C. of 3 to 15 mPa · s. The cooling 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 (eg, polyvinylpyrrolidone), sugars (mucopolysaccharides such as hyaluronic acid and salts thereof, polysaccharides such as dextran, cyclodextrin), oxyalkylene polymers ( Polyoxyethylene polyoxypropylene block copolymer) and the like, and at least one kind of thickening agent may be used. The molecular weight of the thickener can be selected, for example, from the range of about 0.5 × 10 ^{4 to} 100 × 10 ⁴ number average molecular weight. The amount of the thickener used is usually 0.001
10 to 10% by weight (or (W / V)%), for example, 0.12 to 5% by weight (or (W / V)%).
%), Preferably 0.13 to 3% by weight (or (W / V)
%). Furthermore, the ratio of the cooling component to the whole eye drops may be selected, for example, from the range of about 0.0001 to 0.1% by weight (or (W / V)%), and 0.007 to 0.1. % By weight (or (W / V)%) or 0.001 to 0.05% by weight (or (W / V)
%), It is possible to reduce or alleviate the feeling of irritation caused by eye drops.

In a preferred embodiment of the present invention, the content of the thickener is 0.12 to 3% by weight (or (W / V)
%), For example, 0.15 to 0.5% by weight (or (W /
V)%).

According to the present invention, there is also provided a method of maintaining a refreshing feeling by adding a thickening agent to an eye drop containing a refreshing component and making the absolute viscosity at a temperature of 20 ° C. 3 to 15 mPa · s. included.

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

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The cooling component in the present invention is a component capable of imparting a refreshing sensation, and includes 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, cauliflower oil, and essential oil components such as camphor, borneol, geraniol, menthol, citroneol and limonene ( Particularly, terpenes). These may be one or two
More than one species can be added as appropriate, and d,
Both the l and dl forms can be used. Preferred refreshing ingredients include menthols (l-menthol, d-menthol, dl-menthol, etc.) and camphors (d-menthol).
Camphor, dl-camphor, etc.), borneols (d
-Borneol, dl-borneol, etc.), geraniols, and essential oils containing many of these components (eg, peppermint oil, peppermint oil, eucalyptus oil).

The cooling component is usually added to the eye drops at a concentration that does not cause eye irritation, and the ratio of the cooling component to the whole eye drops 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, it is 0.01 to 0.05% by weight (or (W / V)%). If the concentration of the refreshing component is less than 0.0001%, a refreshing feeling cannot be expected, and if it exceeds 0.1%, it is unfavorable because it causes eye irritation and pain.

In the present invention, even when a refreshing ingredient is contained in a high concentration, unpleasant eye irritation is reduced or alleviated by adjusting the viscosity to a specific viscosity range with a thickening agent, and the refreshing feeling is maintained. This has the advantage of eliminating eyestrain. Therefore, the present invention provides, for example, 0.007% to 0.1% by weight.
(Or (W / V)%), particularly useful as an eye drop containing 0.007 to 0.05% by weight (or (W / V)%) of a cooling component.

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

Examples of the cellulosic polymer among the thickening agents include, for example, alkylcellulose [methylcellulose (methylcellulose, methylethylcellulose, etc.), ethylcellulose (ethylcellulose, ethylmethylcellulose, ethylpropylcellulose, etc.)], hydroxyalkyl Cellulose [hydroxyethylcellulose (hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, hydroxyethylhydroxypropylcellulose, etc.), hydroxypropylcellulose (hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, etc.), carboxyalkylcellulose (Carboxymethylcellulose Carboxymethyl cellulose, carboxymethyl cellulose or salts thereof (such as sodium salt)), and others. Examples of the vinyl polymer include a vinyl pyrrolidone polymer (eg, polyvinyl pyrrolidone), a vinyl alcohol polymer (eg, polyvinyl alcohol), a carboxyvinyl polymer, and a vinyl alkyl ether polymer (eg, polyvinyl methyl ether). it can. Examples of the acidic mucopolysaccharide include hyaluronic acid and salts thereof (such as sodium hyaluronate), and examples of the saccharide (or polysaccharide) 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 thickeners can be used alone or in combination of two or more.

Preferred thickening agents are hydroxyalkyl celluloses (hydroxyethylcellulose, hydroxypropylmethylcellulose, etc.), vinylpyrrolidone-based polymers (polyvinylpyrrolidone, etc.), sugars (dextran, cyclodextrin), polyoxyethylene polyoxypropylene block. It is a copolymer, and alkylcelluloses (methylcellulose, ethylcellulose, etc.) are also preferable. Particularly preferred are a cellulose-based polymer (hydroxyethylcellulose, hydroxypropylmethylcellulose), a vinylpyrrolidone-based polymer (polyvinylpyrrolidone), and a POE-POP block copolymer.

When a plurality of thickeners are used, for example, a combination of a cellulosic polymer and a POE-POP block copolymer (for example, at least one selected from hydroxyethylcellulose and hydroxypropylmethylcellulose, and a POE-POP block copolymer) , A combination of cellulosic polymers (eg, a combination of hydroxyethylcellulose and hydroxypropylmethylcellulose), a combination of a vinyl polymer and a cellulosic polymer (eg, polyvinylpyrrolidone, hydroxyethylcellulose and hydroxypropyl) A combination of at least one selected from methylcellulose), a combination of a vinyl polymer and a POE-POP block copolymer (for example, vinylpyrrolidone and POE-PO The combination of block copolymers) are preferred. In a combination of a plurality of thickeners, usually at least a POE-POP block copolymer is often used.

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

In the present invention, the compounding amount of the thickening agent cannot be specified unconditionally because it differs depending on the molecular weight and type of the thickening agent, and the viscosity of the eye drop of the present invention is 3 to 15 mPa. The compounding amount of the thickener can be appropriately selected so that s is obtained. The amount of the thickening agent to be used can be selected according to the type and molecular weight of the thickening agent.
001 to 10% by weight (or (W / V)%), preferably 0.005 to 10% by weight (or (W / V)%), more preferably 0.01 to 5% by weight (or (W / V) )%) Range. 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%. About 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)%).

The ophthalmic solution of the present invention has an absolute viscosity of 3 to 15 mPa · s (kg) when measured at a temperature of 20 ° C.
m ⁻¹ s ⁻¹ ), preferably 3 to 11 mPa · s (for example,
3 to 10 mPa · s), and particularly preferably 3 to 7 m
It is adjusted to about Pa · s. If the viscosity is too high, although it has a wetting effect, it may cause discomfort such as warpage 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 manifestation of the effect becomes insufficient.

The absolute viscosity can be measured by a method using a conical plate type rotary viscometer. This method is based on the general test method described in the 13th revised Japanese Pharmacopoeia, 36. Viscosity measurement method, second method: Rotational viscometer method, (3) The method described in the section of conical flat plate type rotational viscometer. The measurement can be carried out using a commercially available conical plate-type rotary viscometer and an appropriately selected rotor, and an example of such a viscometer is an E-type viscometer (TOKIMEC). , Synchro rhetoric PC type (Brookfield), Ferranti Shirley (Ferranty), Lord Visco ^R (Haake), IGK Hi-Shear rheometer (Ishida Giken Co., Ltd.), Shimadzu rheometer (Shimadzu), mechanical There is a spectrometer (rheometrics) and the like. These commercially available viscometers and rotors are appropriately selected and adjusted appropriately using a petroleum hydrocarbon oil (Newtonian fluid) specified by JIS Z 8809 as a calibration standard solution for each test sample measurement. At 20 ° C. can be measured.

The viscosity of the ophthalmic solution shown in the examples was measured using a TV-20 type viscometer (model name: TVE-20) which is a kind of E type viscometer.
L), the rotor was measured using 1 ° 34 ′ × R24. As measurement conditions, the viscosity was measured at a rotation speed of 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 drops of the present invention further include inorganic salts; active ingredients such as decongestants, ocular muscle regulators, antiphlogistic astringents, antihistamines, antiallergic agents, vitamins, amino acids, and antibacterial agents; buffers. , Tonicity agents, chelating agents, stabilizers, pH regulators, surfactants, preservatives, etc., for problems such as eye irritation, and for artificial tears-type eye drops, such as adsorption or accumulation on soft contact lenses It can be appropriately added as long as there is no problem. When compounding a drug as an active ingredient, the amount of the active ingredient used is, for example, 0.0001 to 3
0% by weight (or (W / V)%), preferably 0.000%
It can be selected from the range of about 5 to 10% by weight (or (W / V)%), more preferably about 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. Is mentioned. 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 ocular muscle regulator include neostigmine methyl sulfate and the like.

Examples of the anti-inflammatory astringent include epsilon aminocaproic acid, allantoin, berberine chloride, berberine sulfate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme chloride and the like.

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

Examples of the antihistamine include diphenhydramine hydrochloride, chlorpheniramine maleate and the like.

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

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

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

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

Further, if necessary according to the application, if necessary, a local anesthetic (oxybuprocaine, lidocaine, lidocaine hydrochloride, etc.), an agent for treating or preventing myopia (tropicamide, cyclopentolate, endothelin, etc.), an intraocular pressure reducing agent ( Pilocarpine hydrochloride, isopropyl unoprostone, distigmine bromide, carbacomal, carteolol hydrochloride, befnolol hydrochloride, timolol maleate, dipivefrin hydrochloride, ecothiopart iodide, diclofenamide, etc.),
Soothing agents (benzalkonium chloride, procaine hydrochloride, etc.)
Various active ingredients may be used.

As the buffer, for example, borate buffer,
Phosphate buffer, carbonate buffer, citrate buffer, tartrate buffer, acetate buffer, epsilon aminocaproic acid, aspartate and the like. Preferably, they are a borate buffer, a phosphate buffer, and a carbonate buffer.

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

As the chelating agent, edetates (edetate disodium, edetate calcium disodium,
Trisodium edetate, tetrasodium edetate, calcium edetate, etc.), ethylenediaminetetraacetate, nitrilotriacetic acid or a salt thereof, sodium hexametaphosphate, citric acid and the like.

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

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

Examples of the surfactant include a nonionic surfactant, a cationic surfactant, an anionic surfactant and an amphoteric surfactant. Specifically, nonionic surfactants such as polysorbate, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene hydrogenated castor oil are mainly used. Further, if necessary, a cationic surfactant (a quaternary ammonium salt such as benzalkonium chloride, an alkylenediamine (such as ethylenediamine)) may be added to polyoxyethylene (POE)-
P added with polyoxypropylene (POP) block
OE-POP block-substituted alkylenediamines, anionic surfactants (such as alkyl benzene sulfonates and alkyl sulfates) and amphoteric surfactants (such as alkyl polyaminoethyl glycine hydrochloride) may be used.

Examples of preservatives include sorbic acid, potassium sorbate, paraoxybenzoic acid esters (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), chlorhexidine gluconate, Grade ammonium salts (benzalkonium chloride, benzethonium chloride,
Cetylpyridinium chloride), alkyl polyaminoethyl glycine, 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 4 to 9,
Preferably 5-8.5, more preferably 5.5-7.
It is adjusted to about 5. The osmotic pressure is usually between 150 and 450
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.

The ophthalmic solution of the present invention is prepared by dissolving or suspending the above-mentioned components in distilled water using the above-mentioned components such as a refreshing component and a thickening agent to a predetermined osmotic pressure. ,
It can be prepared by sterilizing by filtration.

In the present invention, the ophthalmic solution containing a refreshing component (including artificial tear type eye drops) is adjusted to the above-mentioned specific viscosity by adding a thickening agent, whereby the refreshing sensation of the ophthalmic solution is reduced. In addition, refreshing sensation can be maintained, irritation of the refreshing component at the time of instillation can be reduced, and user compliance can be improved. In addition, not only the feeling of dryness of eyes but also tired eyes can be eliminated. Therefore, the present invention provides a method for alleviating irritation caused by a cooling component, a method for maintaining a refreshing sensation and a refreshing sensation, and eliminating tired eyes by combining a cooling component and a thickening agent to a specific viscosity. It also includes the method of performing.

The usage and dosage of the ophthalmic solution of the present invention can be appropriately selected according to the symptoms of the user, the active ingredients contained in the ophthalmic solution and the form of the preparation. Then, it is usually instilled about 1 to 6 times per day, and about 1 to 3 drops are applied at a time.

[0050]

According to the present invention, the refreshing sensation and the refreshing sensation when applying the eye drops can be maintained for a long time, and the compliance of the user can be enhanced. Also, tired eyes can be eliminated. Furthermore, there is no stickiness and the feeling of use is excellent, and there is no irritation when instilled and the safety is high.

[0051]

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
In the following Examples and Reference Examples, as hydroxyethylcellulose "Fujikemi HEC ^R CF-V"
The use, using the "hydroxypropylmethylcellulose 2906 (Metolose ^R 65SH-4000)" as hydroxypropyl methylcellulose, using a "poloxamer 407" as polyoxyethylene polyoxypropylene block copolymers, using "Polyvinylpyrrolidone K90" as polyvinylpyrrolidone .

Example 1 (Artificial tear-type eye drops) [Composition of 100 ml of eye drops] Sodium chloride 0.44 g Potassium chloride 0.08 g Boric acid 0.30 g Borax 0.035 g Polysorbate 80 0.1 g l-menthol 0 0.005 g Hydroxyethylcellulose 0.15 g Potassium sorbate 0.1 g Hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs 100 ml Aseptically prepared using the above ingredients in a conventional manner, filled into a container, and filled into a container with eye drops (pH = 7.5, viscosity 3.5 mPa.
s) was obtained.

Example 2 (Artificial tear type eye drops) [Composition of eye drops 100 ml] Sodium chloride 0.44 g Potassium chloride 0.08 g L-potassium L-aspartate 0.10 g Boric acid 0.30 g Borax 0.035 g Polysorbate 80 0.1 g l-menthol 0.001 g hydroxyethylcellulose 0.15 g potassium sorbate 0.1 g hydrochloric acid suitable amount sodium hydroxide suitable amount sterile purified water proper amount total amount 100 ml And an eye drop (pH = 7.5, viscosity 3.5 mPa ·
s) was obtained.

Example 3 (Artificial tear type eye drop) [Composition of 100 ml of eye drop] Sodium chloride 0.44 g Potassium chloride 0.08 g Boric acid 0.30 g Borax 0.035 g Polysorbate 80 0.1 g l-menthol 0 0.0005 g Hydroxypropyl methylcellulose 0.2 g Potassium sorbate 0.1 g Hydrochloric acid suitable amount Sodium hydroxide suitable amount Sterile purified water proper amount total amount 100 ml The above components are aseptically prepared by a conventional method, filled into a container, and filled into a container with eye drops ( pH = 7.5, viscosity 4.6 mPa.
s) was obtained.

Example 4 (Artificial tear type eye drops) [Composition of eye drops 100 ml] Sodium chloride 0.5 g Boric acid 0.73 g Borax 0.05 g Polyoxyethylene polyoxypropylene block copolymer (poloxamer 407) 1 g polyvinylpyrrolidone 1.8 g l-menthol 0.01 g d-camphor 0.005 g benzalkonium chloride 0.01 g hydrochloric acid qs sodium hydroxide qs sterile purified water qs 100 ml Aseptically prepared using the above ingredients in a conventional manner And filled in a container, and eye drops (pH = 7.2, viscosity 7.5 mPa ·
s) was obtained.

Example 5 [Composition of 100 ml of eye drops] Naphazoline hydrochloride 0.003 g Neostigmine methyl sulfate 0.005 g Allantoin 0.2 g Chlorpheniramine maleate 0.03 g Potassium L-aspartate 1.0 g Boric acid 0.9 g Borate Sand 0.045g Polysorbate 80 0.2g Hydroxypropyl methylcellulose 0.2g l-menthol 0.05g Alkyl polyaminoethyl glycine 0.01g Chlorobutanol 0.15g Hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs 100ml Using the above components Formulated aseptically by a conventional method, filled in a container, and added to eye drops (pH = 5.2, viscosity 4.6 mPa ·
s) was obtained.

Example 6 Composition of 100 ml of eye drops Neostigmine methyl sulfate 0.005 g Chlorpheniramine maleate 0.03 g Potassium L-aspartate 1.0 g d-α-tocopherol acetate 0.05 g Boric acid 0.8 g Borate Sand 0.09 g Polysorbate 80 0.3 g Hydroxypropyl methylcellulose 0.2 g l-menthol 0.05 g Alkyl polyaminoethyl glycine 0.01 g Chlorobutanol 0.15 g Hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs 100 ml Using the above components Formulated aseptically by a conventional method, filled in a container, and added to eye drops (pH = 5.8, viscosity 4.6 mPa ·
s) was obtained.

Example 7 [Composition of 100 ml of eye drops] Tetrahydrozoline hydrochloride 0.050 g Neostigmine methyl sulfate 0.005 g Allantoin 0.2 g Chlorpheniramine maleate 0.03 g Potassium L-aspartate 1.0 g Pyridoxine hydrochloride 0.1 g Ho Acid 0.9g Borax 0.045g Polysorbate 80 0.2g Hydroxypropyl methylcellulose 0.2g l-menthol 0.05g Alkyl polyaminoethylglycine 0.01g Chlorobutanol 0.15g Hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs 100ml The above components are aseptically prepared by a conventional method, filled into a container, and added to eye drops (pH = 5.2, viscosity 4.6 mPa ·
s) was obtained.

Example 8 [Composition of 100 ml of eye drops] Tetrahydrozoline hydrochloride 0.05 g Chlorpheniramine maleate 0.03 g Cyanocobalamin 0.01 g Boric acid 0.80 g Borax 0.09 g Polysorbate 80 0.2 g Hydroxyethyl cellulose 0.13 g l-menthol 0.03 g benzalkonium chloride 0.01 g hydrochloric acid appropriate amount sodium hydroxide appropriate amount sterile purified water appropriate amount total amount 100 ml The above components are aseptically prepared by a conventional method, filled into a container, and filled into a container with eye drops (pH = 5.8, viscosity 3.1 mPa ·
s) was obtained.

Example 9 [Composition of 100 ml of eye drops] Tetrahydrozoline hydrochloride 0.05 g Sodium azulene sulfonate 0.02 g Chlorpheniramine maleate 0.03 g Boric acid 1.80 g Borax 0.035 g Polysorbate 80 0.2 g Hydroxyethyl cellulose 0.13 g l-menthol 0.03 g alkyl polyaminoethyl glycine 0.01 g hydrochloric acid qs sodium hydroxide qs sterile purified water qs 100 ml Aseptically prepared using the above ingredients in a conventional manner, filled into a container, filled with eye drops Agent (pH = 7.2, viscosity 3.1 mPa ·
s) was obtained.

Example 10 [Composition of 100 ml of eye drops] Neostigmine methyl sulfate 0.005 g Chlorpheniramine maleate 0.02 g Sodium flavin adenine dinucleotide 0.05 g L-potassium L-aspartate 1.0 g Boric acid 1.8 g Borax 0.05 g polysorbate 80 0.2 g hydroxypropyl methylcellulose 0.2 g l-menthol 0.01 g d-borneol 0.01 g benzalkonium chloride 0.01 g hydrochloric acid qs sodium hydroxide qs sterile purified water qs 100 ml Formulated aseptically by a conventional method, filled in a container, and added to eye drops (pH = 5.8, viscosity 4.6 mPa ·
s) was obtained.

Example 11 [Composition of 100 ml of eye drops] Dipotassium glycyrrhizinate 0.10 g Chlorpheniramine maleate 0.02 g Sodium sulfamethoxazole 4.00 g Polysorbate 80 0.2 g Hydroxypropyl methylcellulose 0.2 g l- Menthol 0.01 g d-borneol 0.01 g benzalkonium chloride 0.01 g hydrochloric acid qs sodium hydroxide qs Sterile purified water qs 100 ml Aseptically prepared using the above ingredients in a conventional manner and filled into containers. Eye drops (pH = 8.5, viscosity 4.6mPa.
s) was obtained.

Example 12 Composition of 100 ml of eye drops Neostigmine methyl sulfate 0.005 g Allantoin 0.100 g Boric acid 1.800 g Borax 0.050 g Polysorbate 80 0.200 g l-Menthol 0.010 g Hydroxypropyl methylcellulose 0.180 g Benzalkonium chloride 0.01 g Hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs 100 ml Aseptically prepared using the above ingredients in a conventional manner, filled into a container, and filled with eye drops (pH = 6.3, viscosity 3.8mPa ・
s) was obtained.

Example 13 Composition of 100 ml of eye drops Neostigmine methyl sulfate 0.005 g Allantoin 0.100 g Boric acid 1.800 g Borax 0.050 g Polysorbate 80 0.200 g l-Menthol 0.030 g Hydroxypropyl methylcellulose 0.200 g Benzalkonium chloride 0.01 g Hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs 100 ml Aseptically prepared using the above ingredients in a conventional manner, filled into a container, and filled with eye drops (pH = 6.3, viscosity 4.6mPa ・
s) was obtained.

Example 14 [Composition of 100 ml of eye drops] Neostigmine methyl sulfate 0.005 g Allantoin 0.100 g Boric acid 1.800 g Borax 0.050 g Polysorbate 80 0.200 g l-Menthol 0.050 g Hydroxypropyl methylcellulose 0.200 g Benzalkonium chloride 0.01 g Hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs 100 ml Aseptically prepared using the above ingredients in a conventional manner, filled into a container, and filled with eye drops (pH = 6.3, viscosity 4.6mPa ・
s) was obtained.

Example 15 Composition of 100 ml of eye drops Neostigmine methyl sulfate 0.005 g Allantoin 0.100 g Boric acid 1.800 g Borax 0.050 g Polysorbate 80 0.200 g l-Menthol 0.050 g Hydroxypropyl methylcellulose 0.250 g Benzalkonium chloride 0.010 g Hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs Total 100 ml The above ingredients are aseptically prepared by a conventional method, filled into a container, and filled with eye drops (pH = 6.3, viscosity 6.1mPa ・
s) was obtained.

Example 16 [Composition of 100 ml of eye drops] Neostigmine methyl sulfate 0.005 g Allantoin 0.100 g Boric acid 1.800 g Borax 0.050 g Polysorbate 80 0.200 g l-Menthol 0.050 g Hydroxypropyl methylcellulose 0.350 g Benzalkonium chloride 0.01 g Hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs 100 ml Aseptically prepared using the above ingredients in a conventional manner, filled into a container, and filled with eye drops (pH = 6.3, viscosity 10.2mPa
-S) was obtained.

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

Test Examples [Test Method] Eye drops prepared by blending a cooling component (such as l-menthol) and a thickening agent (such as hydroxypropylmethylcellulose) at various concentrations shown in Tables 1 to 3 were prepared. Eye drops were applied to the panelists who used and worked on the personal computer for 2 hours continuously,
The degree of refreshing feeling and refreshing feeling after minutes, the presence or absence of irritation (pain) felt during instillation, whether or not tired eyes were eliminated by instillation, and the degree of discomfort (discomfort) due to the fluffiness of eye drops were tested.

Table 1 shows the results. In the numerical values in the table, the degree of refreshing sensation immediately after instillation and 5 minutes after instillation, the degree of relieving tired eyes, and the degree of discomfort (discomfort) due to the stickiness of the ophthalmic solution are from "1" to "1" depending on each panelist. "3"
Are evaluated, and the average value of seven panelists is shown. The presence / absence of irritation (pain) at the time of instillation indicates the percentage (%) of panelists evaluated as having no irritation (pain).

[0071]

[Table 1]

[0072]

[Table 2]

[0073]

[Table 3]

As a result, the eye drops of Reference Examples 1 to 5 did not maintain a refreshing feeling after 5 minutes and had no effect of eliminating eyestrain. The ophthalmic solution of Reference Example 4 retains a refreshing sensation, but has an uncomfortable sensation due to flecks and is irritating. Furthermore, it was difficult to filter with a 0.2 μm membrane filter, which had a problem in production.

On the other hand, Examples 17 to 29 of the present invention
It can be seen that the ophthalmic solution maintains a cool feeling even 5 minutes after the instillation. It is also effective in eliminating fatigued eyes. Furthermore, it was shown to be a safe and comprehensively excellent eye drop because of no irritation (pain).

The effect of eliminating fatigue eyes depends on the sustaining effect of the cooling component, and it was confirmed that Examples 19 to 21 (containing 0.05% of l-menthol) had a high effect.

Further, according to the present invention, it was shown that the stimulus at the time of instillation was reduced. As shown in Reference Example 2 (Table 1), an ophthalmic solution containing 0.05% of l-menthol gives a strong irritating sensation at the time of instillation and gives discomfort to the user. In the eye drops adjusted to the viscosity range of
The feeling of irritation during instillation is reduced or alleviated. And
This effect of reducing or alleviating the irritation is the same in eye drops containing a cooling component other than l-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 when a polyoxyethylene polyoxypropylene block copolymer (poloxamer 407) was contained, the effect of eliminating fatigue eyes became higher.

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Claims (4)

[Claims] 1. An ophthalmic solution 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 ophthalmic preparation according to claim 1, wherein the cooling component is an essential oil component or an essential oil. 3. The thickening agent is selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hyaluronic acid and salts thereof, dextran, cyclodextrin, polyoxyethylene polyoxypropylene block copolymer. The eye drop according to claim 1, which is at least one kind. 4. An ophthalmic solution containing a cooling component,
A method for maintaining a refreshing feeling by containing a thickening agent and making the absolute viscosity at a temperature of 20 ° C. 3 to 15 mPa · s.