Ophthalmic solution for nonionic silicone hydrogel contact lens

Abstract

To provide an ophthalmic solution for a nonionic SHCL capable of suppressing adhesion of a corneal epithelial cell to the surface of the nonionic SHCL, in particular an ophthalmic solution instillable during wearing of the nonionic SHCL and capable of suppressing the adhesion of the corneal epithelial cell to the surface of the nonionic SHCL.SOLUTION: An ophthalmic solution for a nonionic silicone hydrogel contact lens is prepared by using (A) at least one selected from the group consisting of chlorpheniramine and a salt thereof and (B) menthol in combination, and setting the formulation ratio of the ingredient (B) at 0.001 w / v% or more.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the attachment of corneal cells to the surface of a non-ionic silicone hydrogel contact lens. Eye drops for non-ionic silicone hydrogel contact lenses capable of suppressing adhesion Regarding. [Background technology]

[0002] In recent years, the number of contact lens (CL) wearers has increased, especially soft contact lenses. The number of people wearing soft contact lenses (SCL) is increasing. In general, when wearing soft contact lenses, This reduces the amount of oxygen supplied from the atmosphere, resulting in inhibition of corneal epithelial cell division and corneal thickening. It has been pointed out that this may lead to a decrease in oxygen permeability. In recent years, development of contact lenses has progressed.

[0003] Silicone hydrogel contact lenses have high oxygen permeability under such circumstances. Silicone hydrogels are soft contact lenses that have been developed in recent years. Gel contact lenses are made by blending silicone with hydrogel, which is different from conventional gel lenses. It achieves oxygen permeability several times higher than that of hydrogel contact lenses. Therefore, it is suitable for soft contact lenses. It can improve the lens's weak point, lack of oxygen supply, and prevent the harmful effects on the cornea caused by lack of oxygen. There are high hopes that this will be able to significantly reduce the impact.

[0004] In general, eye drops applied to the eyes of soft contact lens wearers are Depending on the type of contact lens, safety and other factors must be taken into consideration when designing. In particular, soft contact lenses have different ionic and water content depending on the material. Since the level of blood flow varies widely, the eye drops applied to the eyes of soft contact lens wearers are It is customary to design a formulation depending on the properties of the soft contact lenses to which it will be applied. In the past, ingredients such as chlorpheniramine and its salts, as well as menthol, have been used to provide anti-allergic effects and a cooling sensation. These ingredients are used in eye drops for the purpose of providing The effect on silicone hydrogel contact lenses has not been determined. Furthermore, the combined use of chlorpheniramine and / or its salts with a specific amount or more of menthol However, the effects on the ocular tissues of silicone hydrogel contact lens wearers are The current situation is that there are no reports that could be used to infer anything. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2005-162747 A [Patent Document 2] JP 2005-309420 A [Patent Document 3] JP 2005-330276 A [Patent Document 4] JP 2006-39529 A [Patent Document 5] JP 2008-24701 A Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have been conducting various studies on various soft contact lenses, Unexpectedly, non-ionic silicone hydrogel contact lenses ( The lens surface of non-ionic SHCL (hereafter abbreviated as SHCL) has a significantly high adhesion to corneal epithelial cells. This is a completely new finding. When contact lenses are worn, corneal cells adhere to the lenses on the cornea, and as the lenses move, When the cells are peeled off from the eye tissue, they can be used to prevent damage to the corneal surface or to prevent the formation of corneal folds. This can cause pain and ultimately affect the quality of life of contact lens wearers. Furthermore, SHCL is more effective than other soft contact lenses. Considering that, compared to other types of hearing aids, they are often worn continuously for a relatively long period of time, The adhesion of corneal epithelial cells to non-ionic SHCL caused by continued use of SHCL may lead to serious eye diseases or ocular mucosa. It may also be a factor in causing membrane symptoms.

[0007] Therefore, we developed a non-ionic SHCL eye drop that can suppress adhesion of corneal epithelial cells to non-ionic SHCL. In particular, it is possible to instill the non-ionic SHCL when wearing the eye and to apply the non-ionic SHCL surface to the cornea. There is a need to develop eye drops that can suppress epithelial cell adhesion. [Means for solving the problem]

[0008] As a result of intensive research to solve the above problems, the present inventors have found that chlorpheniramine and and / or its salt and a specific amount of menthol, the non-ionic surfactant of the corneal epithelium is Based on this finding, the present invention provides the following: It was finally completed through further improvements.

[0009] That is, the present invention provides the following nonionic eye drops for SHCL. Item 1. (A) At least one selected from the group consisting of chlorpheniramine and its salts and (B) menthol, and the blending ratio of the (B) component is 0.001 w / v% or more. , non-ionic silicone hydrogel contact lens eye drops. Item 2. The nonionic surfactant according to Item 1, which contains chlorpheniramine maleate as component (A). Eye drops for use with hydrophilic silicone hydrogel contact lenses. Item 3. Non-ionic silicone hydrogel contact lenses with a water content of 35% or less Item 3. The eye drop for nonionic silicone hydrogel contact lenses according to Item 1 or 2. . Item 4. The nonionic surfactant according to any one of Items 1 to 3, further comprising a surfactant (C). Licone hydrogel eye drops for contact lenses. Item 5. Any of Items 1 to 4, in which the blending ratio of component (A) is 0.01 w / v% or more. An eye drop for use in a nonionic silicone hydrogel contact lens as described above. Item 6. The nonionic silicone composition according to Item 4, which contains a nonionic surfactant as component (C). Eye drops for hydrogel contact lenses. Item 7. Nonionic surfactants such as polysorbate 80 and polyoxyethylene copolymers Castor oil 60 and polyoxyethylene-polyoxypropylene block copolymer Item 7. The nonionic silicone hydrophilic composition according to item 6, comprising at least one selected from the group consisting of Rogel eye drops for contact lenses.

[0010] The present invention also provides a nonionic silicone hydrogel contact lens, The present invention provides a method for inhibiting adhesion of corneal epithelial cells to Item 8. (A) At least one selected from the group consisting of chlorpheniramine and its salts and (B) menthol, and the blending ratio of the (B) component is 0.001 w / v% or more. Non-ionic silicone hydrogel contact lens eye drops and non-ionic silicone A non-ionic silicone characterized by being brought into contact with a hydrogel contact lens. A method for inhibiting adhesion of corneal epithelial cells to hydrogel contact lenses. Item 9. The adhesion inhibitor according to Item 8, which contains chlorpheniramine maleate as component (A). method. Item 10. Non-ionic silicone hydrogel contact lenses with a water content of 35% or less Item 10. The adhesion suppression method according to Item 8 or 9, Item 11. Non-ionic silicone hydrogel contact lens eye drops are further developed in the (C) field. Item 11. The method for suppressing adhesion according to any one of Items 8 to 10, further comprising a surfactant. Item 12. (A) in eye drops for nonionic silicone hydrogel contact lenses Item 12. The adhesion inhibitor according to any one of Items 8 to 11, wherein the blending ratio of the component is 0.01 w / v% or more. Control method. Item 13. The adhesion suppression method according to Item 11, further comprising a nonionic surfactant as component (C). . Item 14. Nonionic surfactants such as polysorbate 80 and polyoxyethylene hardener Castor oil 60, and polyoxyethylene-polyoxypropylene block copolymer Item 14. The adhesion suppression method according to item 13, comprising at least one selected from the group consisting of:

[0011] The present invention also relates to a nonionic silicone hydrogel contact lens for use in an eye drop, as described below. The present invention provides a method for imparting an effect of inhibiting adhesion of corneal epithelial cells to a lens. Item 15. Nonionic silicone hydrogel contact lens eye drops containing (A) chloroform (B) menthol, together with at least one member selected from the group consisting of carbamazepine and a salt thereof; A nonionic silica gel composition comprising 0.001 w / v% or more of silica gel. Cone Hydrogel Contact Lens Eye Drops with Non-Ionic Silicone Hydrogel Cone A method for imparting an effect of inhibiting adhesion of corneal epithelial cells to a tact lens. Item 16. The composition according to item 15, containing chlorpheniramine maleate as component (A). method. Item 17. Non-ionic silicone hydrogel contact lenses with a water content of 35% or less Item 17. The method of claim 15 or 16, Item 18. A nonionic silicone hydrogel contact lens eye drop further comprising (C) Item 18. The method for applying the composition according to any one of items 15 to 17, further comprising blending a surfactant. Item 19. (A) in eye drops for nonionic silicone hydrogel contact lenses Item 19. The composition according to any one of items 15 to 18, wherein the blending ratio of the component is 0.01 w / v% or more. method. Item 20. The method of applying according to Item 18, further comprising the step of comprising a nonionic surfactant as component (C). Item 21. Nonionic surfactants such as polysorbate 80 and polyoxyethylene hardener Castor oil 60, and polyoxyethylene-polyoxypropylene block copolymer Item 21. The method of applying according to item 20, comprising at least one selected from the group consisting of:

[0012] Furthermore, the present invention also provides the following uses. Item 22. (A) At least one selected from the group consisting of chlorpheniramine and its salts , and 0.001 w / v% or more of (B) menthol, a nonionic silicone hydrogel. Use for the manufacture of eye drops for contact lenses. Item 23. (A) At least one selected from the group consisting of chlorpheniramine and its salts , and 0.001 w / v% or more of (B) menthol, a nonionic silicone hydrogel. Preparation of eye drops for inhibiting adhesion of corneal epithelial cells to contact lenses For use. Item 24. (A) Any of items 22 or 23 containing chlorpheniramine maleate as an ingredient Use of any of the above. Item 25. Non-ionic silicone hydrogel contact lenses with a water content of 35% or less 25. The use according to any one of items 22 to 24, wherein Item 26. The surfactant (C) is used in combination with the component (A) and the component (B). 26. The use according to any one of items 22 to 25. Item 27. Items 22 to 26, in which the (A) component is used at a blending ratio of 0.01 w / v% or more. 2. The use according to any one of the preceding claims. Item 28. The use according to Item 26, comprising a nonionic surfactant as component (C). Item 29. Nonionic surfactants, such as polysorbate 80 and polyoxyethylene hardener Castor oil 60, and polyoxyethylene-polyoxypropylene block copolymer Item 29. The use according to item 28, comprising at least one selected from the group consisting of: Effect of the Invention

[0013] According to the eye drop for non-ionic SHCL of the present invention, corneal epithelial cells are attached to the non-ionic SHCL. This effectively prevents damage to the corneal surface caused by the use of non-ionic SHCL and the associated It can improve the pain associated with

[0014] In addition, it is known that it is difficult to notice damage to the cornea when wearing SCLs. Repeated long-term use of on-type SHCLs may lead to serious conditions. In contrast, the nonionic SHCL eye drops of the present invention have the following properties: This has improved the safety of non-ionic SHCL for long-term continuous use. do. [Brief description of the drawings]

[0015] [Figure 1] FIG. 2 is a diagram showing the results of evaluation of adhesiveness of corneal epithelial cells to various soft contact lenses in Reference Test Example 1. [Diagram 2] FIG. 2 shows the results of evaluating the inhibitory effect of test solutions (Example 1 and Comparative Examples 1-2) on corneal epithelial cell adhesion to nonionic SHCL in Test Example 1. [Diagram 3] FIG. 1 shows the results of evaluating the inhibitory effect of test solutions (Examples 2-5, Comparative Examples 3-5) on corneal epithelial cell adhesion to nonionic SHCL in Test Example 2. [Figure 4] FIG. 13 shows the results of evaluating the inhibitory effect of test solutions (Example 6, Comparative Examples 6-7) on corneal epithelial cell adhesion to nonionic SHCL in Test Example 3. [Diagram 5] FIG. 13 is a graph showing the results of evaluating the effect of test solutions (Example 7, Comparative Example 8) on inhibiting adhesion of corneal epithelial cells to nonionic SHCL in Test Example 4. [Figure 6] FIG. 13 shows the results of evaluating the effect of test solutions (Examples 8-10, Comparative Examples 9-10) on inhibiting adhesion of corneal epithelial cells to nonionic SHCL in Test Example 5. [Figure 7] FIG. 13 is a graph showing the results of evaluating the effect of test solutions (Examples 11-12, Comparative Example 11) on inhibiting adhesion of corneal epithelial cells to nonionic SHCL in Test Example 6. [Figure 8] FIG. 13 is a graph showing the results of evaluating the inhibitory effect of test solutions (Comparative Examples 12-13) on corneal epithelial cell adhesion to nonionic SHCL in Reference Test Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] (I) Non-ionic SHCL eye drops The nonionic SHCL eye drops of the present invention are selected from the group consisting of chlorpheniramine and its salts. It contains at least one selected from the group consisting of chloro, chloro, chlorophenyl ... Lupheniramine and its salts are known compounds as antihistamines and can be synthesized by known methods. They can be synthesized or are commercially available.

[0017] Among the above-mentioned components (A) used in the present invention, the salt of chlorpheniramine is medicinally and medicinally effective. There are no particular limitations as long as it is physically (pharmaceutical) or physiologically acceptable. Specifically, organic acid salts such as maleates and fumarates; inorganic acid salts such as hydrochlorides and sulfates; and metal salts. Among these salts, preferred are organic acid salts, and more preferred are These salts of chlorpheniramine can be used alone or as a single agent. Any combination of two or more of them may be used.

[0018] Chlorpheniramine and its salts may be in the form of a hydrate, and may further include d- and l-isomers. The amino acid sequence may be either dl or dl-isomer.

[0019] The nonionic SHCL eye drop of the present invention contains, as the component (A), chlorpheniramine and Among these salts, one kind may be selected and used alone, or two or more kinds may be used arbitrarily. As the component (A), a salt of chlorpheniramine is preferable. More preferably, the organic acid salt of chlorpheniramine is used. Particularly preferably, the organic acid salt of chlorpheniramine is used. Maleate salt (chlorpheniramine maleate) is an example.

[0020] In the nonionic SHCL eye drop of the present invention, the blending ratio of the above-mentioned (A) component is as follows: The amount is appropriately determined depending on the type of ingredient, the type of other ingredients, the purpose of the eye drop, etc. The total amount of the component (A) is 0.005 w / v% or more based on the total amount of the eye drop. From the viewpoint of more effectively suppressing adhesion of corneal epithelial cells to non-ionic SHCL, Preferably, the total amount of the component (A) is 0.01 w / v% or more, more preferably 0.01 to 0.1 Examples of the concentration include w / v %, and particularly preferably 0.01 to 0.03 w / v %.

[0021] Furthermore, the nonionic SHCL eye drop of the present invention contains, in addition to the above component (A), menthol (hereinafter (sometimes simply referred to as component (B)) at a blending ratio of 0.001 w / v% or more By using menthol in a specific ratio in this way in combination with the above component (A), It becomes possible to effectively inhibit adhesion of corneal epithelial cells to ionic SHCL.

[0022] The menthol used as the component (B) may be any of the d-, l- or dl-forms. However, the inhibitory effect of non-ionic SHCL on the adhesion of corneal epithelial cells is more pronounced. From this viewpoint, the isomer is preferably used. In addition, the component (B) may contain menthol. Examples of such essential oils include peppermint oil and cool mint oil. , spearmint oil, peppermint oil, etc.

[0023] The nonionic SHCL eye drop of the present invention contains, as the component (B), one of the above-mentioned menthols. You can use one of them alone or two or more of them in any combination. May be used.

[0024] In the nonionic SHCL eye drops of the present invention, the blending ratio of the above-mentioned component (B) is the total amount of the eye drops. The total amount of the (B) component may be set to 0.001 w / v% or more. However, the inhibitory effect of non-ionic SHCL on the adhesion of corneal epithelial cells was more pronounced. From this viewpoint, the blending ratio of the component (B) is preferably 0.001 to 0.02 w / v %, and more preferably 0.001 to 0.02 w / v %. A preferred concentration is 0.001 to 0.01 w / v %. In the case of using essential oils containing menthol, the blending ratio of the essential oil shall be The menthol content is set so as to satisfy the above blending ratio.

[0025] In the nonionic SHCL eye drop of the present invention, the ratio of the above component (B) to the above component (A) is There are no particular limitations on the amount of the nonionic SH From the viewpoint of making the adhesion inhibitory effect of corneal epithelial cells against CL more pronounced, The total amount of menthol in the above-mentioned (B) component is 1 to 1,000 parts by weight per 100 parts by weight of the total amount of the (A) component. parts by weight, preferably 2 to 200 parts by weight, and more preferably 3 to 100 parts by weight. It is desirable to do so.

[0026] The nonionic SHCL eye drop of the present invention further contains a surfactant in addition to the above-mentioned components (A) and (B). (hereinafter, simply referred to as component (C)). By including an active agent, the adhesion inhibitory effect of corneal epithelial cells to non-ionic SHCL was enhanced. The nonionic SHCL eye drops of the present invention can be used more effectively. Surfactants must be medicinally, pharmacologically (pharmaceutical) or physiologically acceptable. The surfactant is not particularly limited, and may be a nonionic surfactant, an amphoteric surfactant, or an anionic surfactant. or a cationic surfactant.

[0027] Specific examples of the nonionic surfactant used as component (C) include monolaurate, POE(20) sorbitan phosphate (Polysorbate 20), POE(20) sorbitan monopalmitate (Polysorbate 40), POE(20) sorbitan monostearate (Polysorbate 60), POE(20) Sorbitan Tristearate (Polysorbate 65), POE(20) Monooleate Rubitan (polysorbate 80), etc. POE sorbitan fatty acid esters; Poloxamer 407, Poloxamer 235, Poloxamer 188, Poloxamer 403, Poloxamer 237, Poloxamer POE·POP block copolymers such as 124; POE(60) hydrogenated castor oil (polyoxyethylene hydrogenated POE hydrogenated castor oils such as castor oil 60; POE alkyl ethers such as POE (9) lauryl ether POE(20)POP(4) cetyl ether and other POE-POP alkyl ethers; POE(10) nonyl phenyl Examples of the POE alkyl phenyl ethers include POE alkyl phenyl ethers such as phenyl ether. In the compounds shown, POE stands for polyoxyethylene, POP stands for polyoxypropylene, and the The number indicates the number of moles added. In addition, the amphoteric surfactant used as the component (C) is Specific examples of the component (C) include alkyldiaminoethylglycine. Specific examples of cationic surfactants used as the surfactant include benzalkonium chloride, Benzethonium chloride and the like are examples. In addition, the anionic surfactants used as component (C) above are Specific examples of surfactants include alkylbenzene sulfonates, alkyl sulfates, poly Oxyethylene alkyl sulfate, aliphatic α-sulfomethyl ester, α-olefin sulfonate Examples include carboxylic acids.

[0028] In the nonionic SHCL eye drop of the present invention, the above surfactant may be used alone. It is also possible to use two or more of them in combination.

[0029] Among these (C) components, the non-ionic SHC component is the one that is highly safe for the eye mucosa. From the viewpoint of further improving the effect of inhibiting adhesion of corneal epithelial cells to L, More preferably, POE sorbitan fatty acid esters, POE hardeners, etc. Mash oils, POE-POP block copolymers; particularly preferred are polysorbate 80, polyoxyethylene Diethylene hydrogenated castor oil 60, POE-POP block copolymer; more preferably polysorbate POE-POP block copolymer and POE-80 are used.

[0030] When the nonionic SHCL eye drop of the present invention contains the above-mentioned component (C), the blending ratio of the component (C) is The amount of the component (C) and the amount of other components to be added may be determined appropriately depending on the type of the component (C), the type and amount of other components to be added, the purpose of the eye drop, etc. As an example of the blending ratio of the (C) component, the (C) component can be blended in an amount of 100:1 to 100:1 based on the total amount of the eye drop. The total amount of the component is 0.001 to 1.0 w / v%, preferably 0.005 to 0.5 w / v%, and more preferably Or, for example, 0.01 to 0.1 w / v %.

[0031] In the nonionic SHCL eye drop of the present invention, the ratio of the above component (C) to the above component (B) is The ratio is not particularly limited as long as it satisfies the above-mentioned blending ratio, but non-ionic From the viewpoint of making the inhibitory effect of corneal epithelial cells on adhesion to resistant SHCL more pronounced, The total amount of the component (C) is 2 to 10,000 parts by weight per part by weight of the total amount of menthol of the component (B). 0 parts by weight, preferably 5 to 50,000 parts by weight, and more preferably 5 to 10,000 parts by weight. It is desirable to meet the ratio.

[0032] The non-ionic SHCL eye drop of the present invention may further contain a buffer in addition to the above-mentioned components. The buffering agent that can be incorporated in the nonionic SHCL eye drop of the present invention is a buffering agent having medicinal and pharmacological properties. There are no particular limitations on the buffering agent, so long as it is pharmacy- or physiologically acceptable. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer. , epsilon-aminocaproic acid, aspartic acid, and aspartate salts. These buffers may be used in combination. Preferred buffers are borate buffer, Particularly preferred buffers are borate buffers, carbonate buffers and citrate buffers. The borate buffer is an alkali borate. Examples of phosphate buffers include phosphate salts, such as alkaline earth metal salts, and borates. phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of phosphate buffers include alkali metal citrate and alkaline earth metal citrate. In addition, borate or phosphate hydrates can be used as borate or phosphate buffers. More specific examples include boric acid or a salt thereof (sodium borate, tetraborate, etc.). potassium borate, potassium metaborate, ammonium borate, borax, etc.), phosphoric acid or Salts of (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, phosphorus Trisodium Phosphate, Dipotassium Phosphate, Monobasic Calcium Phosphate, Dibasic Calcium Phosphate etc.), carbonic acid or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, carbon potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.), citric acid or and its salts (sodium citrate, potassium citrate, calcium citrate, citric acid dihydrate) sodium citrate, disodium citrate, etc.), acetic acid or its salts (ammonium acetate, acetic acid potassium, calcium acetate, sodium acetate, etc.), aspartic acid or its salts (aspartic acid Aspartate, sodium aspartate, magnesium aspartate, potassium aspartate, etc. These buffers may be used alone or in any combination of two or more. They may also be used in combination.

[0033] When a buffer is added to the nonionic SHCL eye drop of the present invention, the mixing ratio of the buffer is The amount of the solution varies depending on the type of buffer used, the types and amounts of other ingredients, and the intended use of the eye drop. For example, the total amount of the buffering agent in relation to the total amount of the eye drop may be The amount is 0.01 to 10 w / v%, preferably 0.1 to 5 w / v%, and more preferably 0.5 to 2 w / v%. Examples of percentages are given below.

[0034] The pH of the non-ionic SHCL eye drops of the present invention is based on medicinal, pharmacological (pharmaceutical) and The amount of the nonionic surfactant of the present invention is not particularly limited as long as it is within a physiologically acceptable range. The pH of the ophthalmic solution for SHCL is, for example, 4.0 to 9.5, preferably 5.0 to 8.5, more preferably 5.0 to 8.5. A preferable range is 5.5 to 8.0, and a more preferable range is 6.0 to 7.5. By adjusting the pH of the nonionic SHCL eye drop of the present invention to the above range, Effectively maintains the adhesion inhibitory effect of corneal epithelial cells against CL and reduces irritation to the ocular mucosa. In one embodiment, the non-ionic SHCL of the present invention can be used with reduced dosage and with high safety. When the eye drop for use has a pH of, for example, 5.5 to 6.5, the above component (C) (preferably a non- By incorporating a nonionic surfactant, the adhesion of corneal epithelial cells to nonionic SHCL was improved. This makes it possible to achieve a more effective adhesion suppression effect.

[0035] In addition, the osmotic pressure of the nonionic SHCL eye drops of the present invention is within the range acceptable to the living body. As an example of the osmotic pressure ratio of the nonionic SHCL eye drop of the present invention, , preferably 0.7 to 5.0, more preferably 0.9 to 3.0, and particularly preferably 1.0 to The range where the osmotic pressure is 2.0 is an example. The osmotic pressure can be adjusted by using inorganic salts, polyhydric alcohols, and sugar alcohols. The osmolarity ratio can be determined by any method known in the art, using, for example, sugars, etc. Based on the revised Japanese Pharmacopoeia, the osmotic pressure of the sample is compared to the osmotic pressure of 0.9 w / v% sodium chloride solution. The osmotic pressure is measured as a ratio with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio is sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C and 40-50°C. After drying for 10 minutes, cool in a desiccator (silica gel), and weigh out 0.900 g of the mixture. Dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for measuring osmolality (0.9 w / v % sodium chloride aqueous solution) is used.

[0036] The nonionic SHCL eye drop of the present invention may contain, in addition to the above-mentioned components, The composition may contain a suitable amount of various pharmacologically active ingredients or physiologically active ingredients in combination. There are no particular limitations, and examples thereof include the OTC drug manufacturing (import) approval standards 2000 edition (Pharmaceutical Affairs and Research Institute) Examples of active ingredients in ophthalmic drugs listed in the Ophthalmic Drugs Guidelines (supervised by the Ophthalmic Drugs Research Association) are listed below. The components used in the present invention include the following: Antihistamines: for example, iproheptin, diphenhydramine, etc. Decongestants: Tetrahydrozoline, naphazoline, epinephrine, ephedrine, methine Luephedrine etc. Bactericides: e.g., acrinol, cetylpyridinium, benzalkonium, benzethonium Um, chlorhexidine, etc. Vitamins: Flavin adenine dinucleotide sodium, cyanocobalamin, acetate Retinol, retinol palmitate, pyridoxine hydrochloride, panthenol, potassium pantothenate Calcium, tocopherol acetate, etc. Amino acids: Potassium aspartate, magnesium aspartate, aminoethyls Sulfonic acid, etc. Anti-inflammatory agents: for example, glycyrrhizic acid, pranoprofen, salicylic acid Methyl acetate, glycol salicylate, allantoin, azulene, azulene sulfonic acid, guar Iazulene, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme, licorice, etc. . Astringents: For example, zinc oxide, zinc lactate, zinc sulfate, etc. Others: e.g., ketotifen fumarate, sodium cromoglycate, chondroitin Sodium sulfate, sulfamethoxazole, indomethacin, ibuprofen, ibuprofen Fenpiconol, Bufexamac, Butyl Flufenamate, Bendazac, Piroxicam Examples of such compounds include methicillin, ketoprofen, felbinac, safflower root, horse chestnut, and salts thereof.

[0037] In addition, the nonionic SHCL eye drop of the present invention may contain the following components as long as the effects of the present invention are not impaired: Depending on the purpose and form, various additives are appropriately selected according to the usual method, and one or more types are added. They may be used in combination in appropriate amounts. Examples of additives include those listed in 005 (edited by the Japan Pharmaceutical Additives Association). The following additives are included: Carrier: For example, an aqueous carrier such as water or aqueous ethanol. Thickeners: For example, carboxyvinyl polymers, hydroxyethyl cellulose, Dipropyl methylcellulose, methylcellulose, alginic acid, polyvinyl alcohol ( Completely or partially saponified), polyvinylpyrrolidone, macrogol, chondroitin sulfate Sodium etc. Sugars: for example, glucose, cyclodextrin, etc. Sugar alcohols: For example, xylitol, sorbitol, mannitol, etc. These are It may be in the d-, l- or dl-form. Preservatives, disinfectants or antibacterial agents: e.g., alkyldiaminoethylglycine hydrochloride, benzoic acid Sodium, ethanol, benzalkonium chloride, benzethonium chloride, chlorogluconate Hexidine, Chlorobutanol, Sorbic Acid, Potassium Sorbate, Sodium Dehydroacetate Sodium, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propranolol propyl, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzoyl diethyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glokill (product name manufactured by Rhodia), etc. pH adjusters: e.g., hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaprylic acid Protic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, water Magnesium oxide, sodium bicarbonate, sodium carbonate, borax, triethanolamine amine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, Gluconolactone, ammonium acetate, etc. Isotonicity agents: e.g., sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride Calcium, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, carbonated water Sodium chloride, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, Sodium Dihydrogen Phosphate, Potassium Dihydrogen Phosphate, Glycerin, Propylene Glycol etc. Stabilizers: Dibutylhydroxytoluene, trometamol, sodium formaldehyde Disulfoxylate (Rongalite), Tocopherol, Sodium Metabisulfite, Monoester Monostearate, ethanolamine, aluminum monostearate, glycerin monostearate, etc. Fragrances or fresheners: anethole, eugenol, camphor, geraniol, cineole , borneol, limonene, ryuno, etc. These are either d-, ​​l- or dl-isomers. Also, essential oils (fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc.) ) may also be used.

[0038] The nonionic SHCL eye drop of the present invention is, for example, an aqueous carrier such as purified water or physiological saline, The above components (A) and (B), and if necessary the above component (C) and other blended components are mixed to obtain the desired concentrations. It is added to the mixture and prepared in a conventional manner.

[0039] Regarding the type of nonionic SHCL to which the nonionic SHCL eye drops of the present invention are applied, There is no particular limitation regarding the type of the nonionic SH. All nonionic SH that are currently or will be commercially available in the future are usable. The term "non-ionic" as used herein means, as generally understood by those skilled in the art, a non-ionic liquid. In accordance with the FDA standards, the content of ionic components in the material is less than 1 mol%. The water content of the non-ionic SHCL to be used is not particularly limited. For example, it may be 90% or less. Preferably, the ratio is 60% or less, more preferably 50% or less, and particularly preferably 35% or less. In addition, since SHCL contains hydrogel material, it must be at least 0% water. Non-ionic SHCL with a water content of 35% or less has particularly strong adhesiveness to corneal epithelial cells. The nonionic ophthalmic solution for SHCL of the present invention has the following effect on corneal epithelial cells: The adhesion inhibitory effect of corneal epithelial cells is also effective against non-ionic SHCL, which has strong adhesive properties. In view of the above-mentioned effects of the present invention, the preferred embodiments of the nonionic ophthalmic solution for SHCL of the present invention are as follows: One suitable application is non-ionic SHCL with a moisture content of 35% or less.

[0040] The moisture content of SHCL here refers to the proportion of water in SHCL, and is calculated using the following formula: It can be seen. Moisture content (%) = (weight of absorbed water / weight of SHCL in hydrated state) x 100 Such moisture content may be measured by gravimetric methods as described in ISO 18369-4:2006.

[0041] The eye drops for non-ionic SHCL are applied directly to the eye with the non-ionic SHCL attached. In addition to the above, eye drops that are applied to the eye prior to application of the non-ionic SHCL are also included.

[0042] Conventionally, hard contact lenses made of polymethyl methacrylate (PMMA) have been used. The lens may adhere to the cornea, causing corneal epithelial damage (staining between 3 o'clock and 9 o'clock). It is known that people who wear SCLs are prone to dry eyes. For example, in patients with dry eye, the cornea is easily damaged by the lens, causing corneal staining. As shown in the test examples described below, the inventors' research has revealed that Nonionic SHCL has been shown to significantly adhere corneal epithelial cells, and SHCL is usually These non-ionic SHCLs are generally harder than non-silicone SCLs. Considering the characteristics, the use of non-ionic SHCLs does not cause the above-mentioned corneal epithelial damage. In contrast, the nonionic SHCL eye drops of the present invention can be used to treat corneal ulcers. The adhesion of membrane epithelial cells to non-ionic SHCL can be effectively suppressed, so the use of non-ionic SHCL Therefore, the non-ionic surfactant of the present invention can prevent corneal epithelial damage caused by the corneal epithelium. The ionic SHCL eye drops are used as a preventive agent for corneal epithelial disorders caused by the use of non-ionic SHCL. It can be used for people with dry eye symptoms (e.g., dry eye patients) ) is preferably used.

[0043] In addition, corneal epithelial cells also have a barrier function against allergens, Corneal epithelial damage caused by the use of non-ionic SHCL reduces the barrier function of the cornea. Therefore, there is a risk that eye allergies and the like may be easily developed or aggravated. The non-ionic SHCL eye drops are for people who use non-ionic SHCL and suffer from allergic diseases and other conditions. An eye disease preventive agent for preventing various eye diseases by increasing resistance to them (e.g., allergies) The present invention is preferably used as a preventive agent for diseases.

[0044] In addition, the nonionic SHCL eye drop of the present invention has an antihistamine effect based on the above component (A). Since the compound can also exert its effect, it is also useful as an agent for preventing or alleviating allergic symptoms. The non-ionic SHCL eye drops can also provide a cooling sensation to the eyes based on the above component (B). Therefore, it can also be used to provide a comfortable wearing experience when using non-ionic SHCLs.

[0045] (II) Method for inhibiting adhesion of corneal epithelial cells to non-ionic SHCL, Method for imparting inhibitory effect on adhesion of corneal epithelial cells and use thereof for the manufacture of eye drops As described above, in the non-ionic SHCL eye drop, the above-mentioned component (A) and a predetermined amount of component (B) are present together. By using non-ionic SHCL, we were able to inhibit the adhesion of corneal epithelial cells to non-ionic SHCL. do.

[0046] Therefore, from another aspect, the present invention provides: (A) a compound from the group consisting of chlorpheniramine and its salts; and (B) menthol, and the concentration of the (B) component is 0. Contacting non-ionic SHCL with eye drops containing 0.01 w / v% or more of non-ionic SHCL The present invention provides a method for inhibiting adhesion of corneal epithelial cells to non-ionic SHCL, the method comprising the steps of: The non-ionic SHCL eye drops further comprise: (A) a chlorpheniramine or salt thereof selected from the group consisting of chlorpheniramine and salts thereof; (B) menthol is blended at a concentration of 0.001 w / v% or more together with at least one of the above-mentioned ingredients. The present invention relates to an eye drop for non-ionic SHCL, and a method for adhering corneal epithelial cells to non-ionic SHCL. The present invention provides a method for imparting a sticking suppression effect.

[0047] From another viewpoint, the present invention provides a compound according to the present invention comprising: (A) a compound selected from the group consisting of chlorpheniramine and its salts; At least one selected from the group consisting of (B) menthol at 0.001 w / v% or more, and The present invention further provides a use of the present invention for the manufacture of an eye drop for a hydrophilic silicone hydrogel contact lens. (A) at least one selected from the group consisting of chlorpheniramine and its salts, and 0.001 w / v% or more of (B) menthol, To manufacture eye drops that impart an inhibitory effect on adhesion of corneal epithelial cells to tact lenses Provide for the use of.

[0048] In these methods and uses, the types of components (A) and (B) used, their nonionic The proportion of ingredients in SHCL eye drops, the types and concentrations of other ingredients, and the composition of non-ionic SHCL eye drops Regarding pH, formulation form of non-ionic SHCL eye drops, and type of non-ionic SHCL to be applied, etc. The details are the same as those of "(I) Nonionic SHCL eye drops" above. EXAMPLES

[0049] The present invention will be described in detail below based on test examples and examples. The present invention is not limited to the above.

[0050] Reference test example 1: Evaluation of corneal epithelial cell adhesion to various SCLs The following experiments were carried out using the five types of soft contact lenses shown in Table 1. The adhesion of corneal epithelial cells to the surface of the tact lens was evaluated. All of the tact lenses are commercially available.

[0051] [Table 1]

[0052] Specifically, the evaluation was carried out by the following method. Growth medium (DMEM medium containing 10% fetal bovine serum) Each soft contact lens was placed in a 24-well microplate containing 900 μL of Each well was immersed in a 100-well plate with the convex side facing up. A cell suspension (1 × 10 5 cells / ml) 100 μL of each was seeded and incubated at 37°C, 5% CO 2 After 48 hours of incubation under the conditions, soft contact The number of viable cells attached to the lenses was counted. As a control, neither lens was used. The cells were cultured on the bottom surface of the microplate without immersion, and the number of viable cells in each well was counted ( (Control group). The number of viable cells was measured using a Cell Counting Kit (Dojindo Chemical Industries, Ltd.). The total number of live cells in the control wells was calculated using each software. The percentage of viable cells adhering to the contact lens surface (the number of viable cells relative to the control group) The percentage of each was calculated.

[0053] The results are shown in Figure 1. As is clear from Figure 1, Lens A, which is a non-ionic SHCL, and B are ionic silicone hydrogel contact lenses, and C is a non-silicone hydrogel contact lens. Compared with lenses D and E, which are cone hydrogel contact lenses, there was no significant corneal The adhesion of the cells to soft contact lenses was also confirmed. When the condition was observed under a microscope, almost no cell adhesion was observed in lenses C, D, and E. However, it was confirmed that corneal epithelial cells were attached to the entire surface of lenses A and B. These results suggest that non-ionic SHCL is superior to other types of lenses in terms of corneal epithelial cell adhesion. It was confirmed that the corneal surface is significantly affected by non-ionic SHCL. It became clear that this could be achieved.

[0054] Test Example 1: Inhibition of adhesion of corneal epithelial cells to non-ionic SHCL Using the test solutions shown in Table 2 (Example 1 and Comparative Examples 1-2), the angle of nonionic SHCL was measured. The inhibitory effect on membrane epithelial cell adhesion was evaluated by the following method.

[0055] [Table 2]

[0056] Lens A (non-ionic SHCL) shown in Table 1 was soaked in the test solution shown in Table 2 (Example 1 and Comparative Example 1). -2) Each piece was immersed in 10 ml of the test solution and left to stand at 34°C for 24 hours. After lightly washing the lens A with saline, wipe off the moisture and place it in a growth medium (10% fetal bovine serum). Place the plate in a 24-well plate containing 900 μL of DMEM medium containing fetal serum, with the convex side facing up. Each well was filled with rabbit corneal epithelial cell line (ECL) prepared using a growth medium. SIRC (ATCC number: CCL-60) cell suspension (1 × 10 5 100μL of 100 cells / ml was seeded on each well. 7°C, 5% CO 2After culturing for 48 hours under these conditions, the number of viable cells attached to the lenses was counted ( As a control, a lens that was not immersed in any of the test solutions was used. A suspension of rabbit corneal epithelial cell line was seeded and cultured under the same conditions as above using the tube A. The number of viable cells adhering to the lens A was counted (control group). The rabbit corneal epithelial cells were then cultured in a growth medium (DMEM medium containing 10% fetal bovine serum) without being seeded. ) Prepare wells containing only 1000 μL of the medium and incubate at 37°C, 5% CO 2 Leave it for 48 hours under the conditions The number of viable cells was counted using a Cell Counting Kit (Dojindo Co., Ltd.). The cell adhesion inhibition rate (%) was calculated according to the following formula. It was revealed that even when treated with the test solution, almost no inhibitory effect on cell adhesion was observed.

[0057]

number

[0058] Based on the cell adhesion inhibition rates calculated in each Example and Comparative Example, the cell adhesion inhibition rate of Comparative Example 1 was calculated as The relative cell adhesion inhibition rate was calculated based on the value of 100. The results are shown in Figure 2. As can be seen, the non-ionic SHCL treated with the test solution of Example 1 exhibited a significantly high inhibition of epithelial cell adhesion. It was found that the cell adhesion inhibitory effect observed by the test solution of Example 1 was obtained. The results are far superior to those obtained when treated with the test solutions of Comparative Examples 1 and 2. be.

[0059] Test Example 2: Corneal epithelial cell adhesion inhibition test to non-ionic SHCL Using the test solutions shown in Table 3 (Examples 2-5, Comparative Examples 3-5), the activity against non-ionic SHCL was The inhibitory effect on adhesion of corneal epithelial cells was evaluated by the following method.

[0060] [Table 3]

[0061] Lens A (non-ionic SHCL) shown in Table 1 was immersed in 10 ml of each test solution shown in Table 3. The lenses were then immersed in the test solution and left to stand at 34°C for 24 hours. After washing lightly with , wipe off the moisture and place in a growth medium (DMEM medium containing 10% fetal bovine serum). Immerse each lens with the convex side facing up into a 24-well plate containing 970 μL of Each well was filled with rabbit corneal epithelial cell line SIRC (ATCC number: Cell suspension (1 x 10) of CCL-60 5 30μL of 1000 cells / ml was seeded on each well and incubated at 37℃, 5% CO 2 Under conditions After culturing for 5 days, the number of viable cells attached to the lens was counted (sample group). As a control, borate buffer solution (boric acid 0.5 w / v%, borax appropriate amount) was used instead of each test solution. The lens A was immersed in the above solution (pH 7.5, remaining part was purified water) and then subjected to rabbit A cell suspension of a corneal epithelial cell line was seeded and cultured, and the number of viable cells that adhered to lens A was counted. In addition, a blank was prepared by seeding rabbit corneal epithelial cells on a 3D microscope. Wells containing only 1000 μL of growth medium (DMEM medium containing 10% fetal bovine serum) The incubation was performed at 37°C and 5% CO 2 The blank group was left standing for 48 hours under the same conditions. The number of cells was measured using a Cell Counting Kit (Dojindo Laboratories, Ltd.) in the same manner as in Test Example 1 above. The cell adhesion inhibition rate (%) was calculated according to the formula shown below. Based on the cell adhesion inhibition rate, the cell adhesion inhibition rate of Comparative Example 3 is set to 100. The relative ratio was calculated. The results are shown in FIG. 3. As is clear from FIG. 3, the test solution of Example 2-5 The combination of chlorpheniramine maleate and menthol has a synergistic effect on the production of high-quality sebum. The cell adhesion inhibition rate was observed. In addition, the test solution of Comparative Example 4 did not contain menthol. It was revealed that the condition worsened compared to Comparative Example 3. In order to effectively suppress the adsorption of menthol to carboxylic SHCL, a certain amount of menthol is required. Furthermore, it was also revealed that the test solution of Example 5 had an effect of inhibiting adhesion of corneal epithelial cells. Since this was more pronounced, we further added a nonionic surfactant (polysorbate 80) to By combining this product, the effect of inhibiting adhesion of corneal epithelial cells to non-ionic SHCL was further enhanced. It also became clear that the piece would be performed in a similar way.

[0062] Test Example 3: Corneal epithelial cell adhesion inhibition test to non-ionic SHCL The test solutions shown in Table 4 (Example 6, Comparative Examples 6-7) were used to measure the corneal response of non-ionic SHCL. The effect of inhibiting epithelial cell adhesion was evaluated by the following method.

[0063] [Table 4]

[0064] Lens A (non-ionic SHCL) shown in Table 1 was immersed in 5 ml of each test solution shown in Table 4. The lenses were then placed in a 34°C bath for 24 hours. Lenses A were then removed from each test solution and soaked in saline. After washing lightly, wipe off the moisture and immerse in growth medium (DMEM medium containing 10% fetal bovine serum) for 9 h. The lenses were immersed one by one in a 24-well plate containing 50 μL of solution, with the convex side facing up. Each well was filled with rabbit corneal epithelial cell line SIRC (ATCC number: CC Cell suspension (1 x 10) in L-60 5 50μL of 1000 cells / ml were seeded on each well and incubated at 37℃, 5% CO 2 Under conditions After culturing for two days, the number of viable cells attached to the lenses was counted (sample group). As a control, borate buffer solution (boric acid 0.5 w / v%, borax appropriate amount, Lens A was immersed in purified water (pH 7.5) and then subjected to rabbit horn immersion under the same conditions as above. A cell suspension of the membrane epithelial cell line was seeded and cultured, and the number of viable cells attached to lens A was counted. In addition, rabbit corneal epithelial cells were grown without seeding as a blank. The wells were then filled with 1000 μL of growth medium (DMEM medium containing 10% fetal bovine serum). Prepared at 37℃, 5% CO 2 The cells were allowed to stand for 48 hours under the same conditions (blank group). The measurement was performed using a Cell Counting Kit (Dojindo Laboratories, Ltd.) in the same manner as in Test Example 1 above. The cell adhesion inhibition rate (%) was calculated according to the following formula.

[0065] Based on the cell adhesion inhibition rates calculated in each Example and Comparative Example, the cell adhesion inhibition rate of Comparative Example 7 was calculated as follows: The relative cell adhesion inhibition rate was calculated based on the value of 100. The results are shown in Figure 4. As shown above, the test solution of Example 6 exhibited a significantly higher cell adhesion inhibitory effect than the comparative example. From the above results, it was found that the 0.01% chlorpheniramine maleate formulation was sufficient for corneal ointment. It was revealed that an effect of inhibiting epithelial cell adhesion was obtained.

[0066] Test Example 4: Corneal epithelial cell adhesion inhibition test to non-ionic SHCL Test Example 2 shows that chlorpheniramine maleate and menthol have a synergistic effect on corneal cell adhesion. It became clear that a certain amount of menthol was required to achieve the anti-adhesive effect. Therefore, the following experiment was conducted to investigate the effective dose.

[0067] Specifically, the test liquids shown in Table 5 (Example 7, Comparative Example 8) were used to test the non-ionic SHCL. The inhibitory effect on adhesion of corneal epithelial cells was evaluated in the same manner as in Test Example 3 above.

[0068] [Table 5]

[0069] Based on the cell adhesion inhibition rates calculated in each Example and Comparative Example, the cell adhesion inhibition rate of Comparative Example 8 was calculated as follows: The relative cell adhesion inhibition rate was calculated based on the value of 100. The results are shown in FIG. 5. Thus, the ratio of menthol to be mixed with chlorpheniramine maleate is 0.001%. It was revealed that a significant inhibitory effect on corneal epithelial cell adhesion was achieved even with

[0070] Test Example 5: Corneal epithelial cell adhesion inhibition test to non-ionic SHCL Using the test solutions shown in Table 6 (Examples 8-10, Comparative Examples 9-10), The inhibitory effect on adhesion of corneal epithelial cells was evaluated by the following method.

[0071] [Table 6]

[0072] Lens B (non-ionic SHCL) shown in Table 1 was immersed in 8 ml of each test solution shown in Table 6. The lenses were then placed in a 34°C bath for 24 hours. After washing lightly, wipe off the moisture and immerse in growth medium (DMEM medium containing 10% fetal bovine serum) for 9 h. The lenses were immersed one by one in a 24-well plate containing 50 μL of solution, with the convex side facing up. Each well was filled with rabbit corneal epithelial cell line SIRC (ATCC number: CC Cell suspension (1 x 10) in L-60 5 50μL of 1000 cells / ml were seeded on each well and incubated at 37℃, 5% CO 2 Under conditions After culturing for 3 days, the number of viable cells attached to the lenses was counted (sample group). As a control, borate buffer solution (boric acid 0.8 w / v%, borax appropriate amount, Lens B was immersed in purified water (pH 5.5) and then subjected to rabbit horn immersion under the same conditions as above. A cell suspension of the membrane epithelial cell line was seeded and cultured, and the number of viable cells attached to lens B was counted. In addition, rabbit corneal epithelial cells were grown without seeding as a blank. The wells were then filled with 1000 μL of growth medium (DMEM medium containing 10% fetal bovine serum). Prepared at 37℃, 5% CO 2 The blank group was left standing under the same conditions for the same time as the sample group. The number of viable cells was measured using a Cell Counting Kit (Dojindo Laboratories, Ltd.) and the same method as described above. The cell adhesion inhibition rate (%) was calculated according to the same calculation formula as in Example 1.

[0073] Based on the cell adhesion inhibition rates calculated in each Example and Comparative Example, the cell adhesion inhibition rate of Comparative Example 9 was calculated as follows: The relative cell adhesion inhibition rate was calculated based on the value of 100. The results are shown in FIG. 6. Thus, even when the eye drop of the present invention is adjusted to a low pH of about pH 5.5 to 6.5, , a combination of chlorpheniramine maleate and 0.001 w / v% or more of menthol It was confirmed that a synergistic effect was achieved by the combination of these two agents to inhibit corneal cell adhesion. The test solution of Example 10 showed a more pronounced effect of inhibiting adhesion of corneal epithelial cells. Therefore, even if the pH of the eye drops is low, the nonionic surfactant (polysorbate 80) By further combining these, the adhesion of corneal epithelial cells to non-ionic SHCL was improved. It was confirmed that the inhibitory effect was further enhanced.

[0074] Test Example 6: Corneal epithelial cell adhesion inhibition test to non-ionic SHCL Using the test solutions shown in Table 7 (Examples 11-12, Comparative Example 11), the following was performed: The inhibitory effect on adhesion of corneal epithelial cells was evaluated by the following method.

[0075] [Table 7]

[0076] Lens B (non-ionic SHCL) shown in Table 1 was immersed in 8 ml of each test solution shown in Table 7. The lenses were then placed in a 34°C bath for 24 hours. After washing lightly, wipe off the moisture and immerse in growth medium (DMEM medium containing 10% fetal bovine serum) for 9 h. The lenses were immersed one by one in a 24-well plate containing 50 μL of solution, with the convex side facing up. Each well was filled with rabbit corneal epithelial cell line SIRC (ATCC number: CC Cell suspension (1 x 10) in L-60 5 50μL of 1000 cells / ml were seeded on each well and incubated at 37℃, 5% CO 2 Under conditions After culturing for 3 days, the number of viable cells attached to the lenses was counted (sample group). As a control, borate buffer solution (boric acid 0.8 w / v%, borax appropriate amount, Lens B was immersed in purified water (pH 6.0) and then subjected to rabbit horn immersion under the same conditions as above. A cell suspension of the membrane epithelial cell line was seeded and cultured, and the number of viable cells attached to lens B was counted. In addition, rabbit corneal epithelial cells were grown without seeding as a blank. The wells were then filled with 1000 μL of growth medium (DMEM medium containing 10% fetal bovine serum). Prepared at 37℃, 5% CO 2 The blank group was left standing under the same conditions for the same time as the sample group. The number of viable cells was measured using a Cell Counting Kit (Dojindo Laboratories, Ltd.) and the same method as described above. The cell adhesion inhibition rate (%) was calculated according to the same calculation formula as in Example 1.

[0077] Based on the cell adhesion inhibition rates calculated in each Example and Comparative Example, the cell adhesion inhibition rate of Comparative Example 11 was calculated. The relative ratio of the cell adhesion inhibition rate was calculated with the value of 100. The results are shown in FIG. 7. Thus, in this test example, as in the previous test examples, The combination of 0.001 w / v% or more menthol with lamin significantly increased corneal cell proliferation. It was confirmed that the cell adhesion inhibitory effect was obtained, and this effect was confirmed by the non-ionic surfactant (poloxamer). It was confirmed that the effect was further enhanced by further combining with Summer 407) Ta.

[0078] Reference test example 2: Corneal epithelial cell adhesion inhibition test to non-ionic SHCL To see if other terpenoids could produce similar effects, we carried out the following experiment. I did.

[0079] Specifically, the test liquids shown in Table 8 (Comparative Examples 12 and 13) were used to test the non-ionic SHCL. The inhibitory effect on adhesion of corneal epithelial cells was evaluated in the same manner as in Test Example 3 above.

[0080] [Table 8]

[0081] Based on the cell adhesion inhibition rate calculated for each comparative example, the cell adhesion inhibition rate of Comparative Example 12 was set to 100. The relative ratio of cell adhesion inhibition rate was calculated when the cell adhesion inhibition rate was 100%. The results are shown in FIG. 8. As is clear from FIG. The test solution of Comparative Example 13, which contains geraniol, is the same as that of Comparative Example 14, which does not contain geraniol. It was found that the condition worsened when 12 test solutions were used, and geraniol was effective. In other words, the results show that the effect of non-ionic SHCL is not significant. The adhesion inhibitory effect of corneal epithelial cells was measured by chlorpheniramine and / or its salts at 0.001 w / This is a unique effect that can only be achieved by combining it with menthol (v% or more). It became clear that this could not be achieved by replacing enthol with other terpenoids.

[0082] Formulation examples Non-ionic SHCL eye drops (Examples 13-22) are prepared according to the formulations shown in Table 9.

[0083] [Table 9]

Claims

[Claim 1] The invention described in the specification.

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