JP2018188486A - Eye drops for nonionic silicone hydrogel contact lenses - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide eye drops for nonionic SHCL that can inhibit the adhesion of corneal epithelial cells to a nonionic SHCL surface, particularly, can be applied at the time of wearing a nonionic SHCL, and can inhibit the adhesion of the corneal epithelial cells to the nonionic SHCL surface.SOLUTION: The eye drops 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 together, and by setting the compounding ratio of the component (B) to 0.001 w/v% or more.SELECTED DRAWING: None

Description

  The present invention relates to an eye drop for a nonionic silicone hydrogel contact lens capable of suppressing adhesion of corneal cells to the surface of the nonionic silicone hydrogel contact lens.

  In recent years, the number of wearers of contact lenses (CL) has increased, and in particular, the number of wearers of soft contact lenses (SCL) has increased. In general, it has been pointed out that when a soft contact lens is worn, the amount of oxygen supplied from the atmosphere decreases, which may result in suppression of corneal epithelial cell division and thickening of the cornea. Therefore, development of soft contact lenses having higher oxygen permeability has been advanced.

  Under such circumstances, silicone hydrogel contact lenses have been developed in recent years as soft contact lenses having high oxygen permeability. Silicone hydrogel contact lenses achieve oxygen permeability several times that of conventional hydrogel contact lenses by adding silicone to the hydrogel. Therefore, it is highly expected that the oxygen supply shortage, which is a weak point of the soft contact lens, can be improved and the adverse effects on the cornea due to the oxygen shortage can be greatly suppressed.

  In general, it is indispensable to design eye drops to be applied to the eyes of a soft contact lens wearer, taking into account the safety and other effects according to the type of soft contact lens. In particular, soft contact lenses vary in the presence or absence of ionicity and the level of moisture content depending on the material, so eye drops applied to the eyes of soft contact lens wearers depend on the nature of the applied soft contact lens. It is customary to perform formulation design. Conventionally, components such as chlorpheniramine and its salts and menthol have been used in eye drops for the purpose of imparting an antiallergic effect and a refreshing sensation (see Patent Literature 1-5), and these components are silicone hydrogels. The effect on contact lenses has not been clarified. Furthermore, there is currently no definitive report on the effect of the combined use of chlorpheniramine and / or a salt thereof and a menthol of a specific amount or more on the eye tissue of a silicone hydrogel contact lens wearer.

JP 2005-162747 A JP 2005-309420 A Japanese Patent Laying-Open No. 2005-330276 JP 2006-39529 A JP 2008-24701 A

  The present inventors have conducted various studies on various soft contact lenses and have not anticipated them at all. A lens of a nonionic silicone hydrogel contact lens (hereinafter abbreviated as nonionic SHCL). The surface obtained a completely new finding that the adhesion of corneal epithelial cells was remarkably high. Such a contact lens with high adhesion of corneal epithelial cells is obtained from the eye tissue when the contact lens is worn, when the corneal cell adheres to the lens on the cornea and the lens moves or when the lens is removed. The cells may be peeled off, resulting in damage to the corneal surface and pain associated therewith, and as a result, the quality of life (QOL) of the contact lens user is significantly reduced. Furthermore, considering that SHCL is often continuously worn over a relatively long period of time compared to other soft contact lenses, adhesion of corneal epithelial cells to nonionic SHCL caused by long-term continuous wear Can contribute to serious eye disease or ocular mucosal symptoms.

  Therefore, non-ionic SHCL eye drops that can suppress the adhesion of corneal epithelial cells to non-ionic SHCL, especially eye drops when wearing non-ionic SHCL, and corneal epithelial cell adhesion to non-ionic SHCL surface There is a need to develop eye drops that can be controlled.

  As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention used chlorpheniramine and / or a salt thereof and a specific amount of menthol to adhere corneal epithelial cells to nonionic SHCL. Has been found to be significantly suppressed. The present invention has been completed by making further improvements based on such findings.

That is, the present invention provides the following eye drops for nonionic SHCL.
Item 1. (A) at least one selected from the group consisting of chlorpheniramine and a salt thereof and (B) menthol, and the blending ratio of the component (B) is 0.001 w / v% or more, Eye drops for ionic silicone hydrogel contact lenses.
Item 2. Item 2. An ophthalmic solution for nonionic silicone hydrogel contact lenses according to Item 1, comprising chlorpheniramine maleate as component (A).
Item 3. Item 3. The eye drop for a nonionic silicone hydrogel contact lens according to Item 1 or 2, wherein the water content of the nonionic silicone hydrogel contact lens is 35% or less.
Item 4. Item 4. The eye drop for a nonionic silicone hydrogel contact lens according to any one of Items 1 to 3, further comprising (C) a surfactant.
Item 5. Item 5. The eye drop for a nonionic silicone hydrogel contact lens according to any one of Items 1 to 4, wherein the blending ratio of the component (A) is 0.01 w / v% or more.
Item 6. Item 5. An ophthalmic solution for nonionic silicone hydrogel contact lenses according to Item 4, comprising a nonionic surfactant as component (C).
Item 7. Item 7. The nonionic surfactant according to Item 6, comprising at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene-polyoxypropylene block copolymer as the nonionic surfactant. Eye drops for silicone hydrogel contact lenses.

Moreover, this invention provides the adhesion suppression method of the corneal epithelial cell with respect to a nonionic silicone hydrogel contact lens hung up below.
Item 8. (A) a non-ion containing at least one selected from the group consisting of chlorpheniramine and a salt thereof and (B) menthol, wherein the blending ratio of the component (B) is 0.001 w / v% or more A method for suppressing adhesion of corneal epithelial cells to a nonionic silicone hydrogel contact lens, comprising contacting an eye drop for a nonionic silicone hydrogel contact lens with a nonionic silicone hydrogel contact lens.
Item 9. Item 9. The adhesion suppression method according to Item 8, comprising chlorpheniramine maleate as the component (A).
Item 10. Item 10. The adhesion suppression method according to Item 8 or 9, wherein the water content of the nonionic silicone hydrogel contact lens is 35% or less.
Item 11. Item 11. The adhesion suppression method according to any one of Items 8 to 10, wherein the eye drop for a nonionic silicone hydrogel contact lens further comprises (C) a surfactant.
Item 12. Item 12. The adhesion suppression method according to any one of Items 8 to 11, wherein a blending ratio of the component (A) in the eye drop for a nonionic silicone hydrogel contact lens is 0.01 w / v% or more.
Item 13. Item 12. The adhesion suppression method according to Item 11, comprising a nonionic surfactant as the component (C).
Item 14. Item 14. The adhesion suppression method according to Item 13, comprising at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene-polyoxypropylene block copolymer as a nonionic surfactant. .

Moreover, this invention provides the method of providing the adhesion | attachment inhibitory effect of the corneal epithelial cell with respect to a nonionic silicone hydrogel contact lens to the eyedrops hung up below.
Item 15. In addition to at least one selected from the group consisting of (A) chlorpheniramine and a salt thereof, (B) menthol in a blending ratio of 0.001 w / v% or more in a nonionic silicone hydrogel contact lens ophthalmic solution A method for imparting an effect of inhibiting adhesion of corneal epithelial cells to a nonionic silicone hydrogel contact lens to an eye drop for a nonionic silicone hydrogel contact lens, comprising:
Item 16. Item 16. The application method according to Item 15, comprising chlorpheniramine maleate as the component (A).
Item 17. Item 17. The application method according to Item 15 or 16, wherein the water content of the nonionic silicone hydrogel contact lens is 35% or less.
Item 18. Item 18. The application method according to any one of Items 15 to 17, wherein (C) a surfactant is further added to the ophthalmic solution for nonionic silicone hydrogel contact lenses.
Item 19. Item 19. The application method according to any one of Items 15 to 18, wherein a blending ratio of the component (A) in the eye drop for a nonionic silicone hydrogel contact lens is 0.01 w / v% or more.
Item 20. Item 19. The application method according to Item 18, comprising a nonionic surfactant as component (C).
Item 21. Item 21. The application method according to Item 20, comprising at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene-polyoxypropylene block copolymer as the nonionic surfactant.

Furthermore, the present invention also provides the uses listed below.
Item 22. (A) For the production of eye drops for nonionic silicone hydrogel contact lenses of at least one selected from the group consisting of chlorpheniramine and salts thereof, and 0.001 w / v% or more of (B) menthol Use of.
Item 23. (A) Suppression of adhesion of corneal epithelial cells to nonionic silicone hydrogel contact lenses of at least one selected from the group consisting of chlorpheniramine and salts thereof, and 0.001 w / v% or more of (B) menthol Use for the production of eye drops to impart an effect.
Item 24. Item 24. The use according to any one of Items 22 and 23, which comprises chlorpheniramine maleate as the component (A).
Item 25. Item 25. The use according to any one of Items 22 to 24, wherein the water content of the nonionic silicone hydrogel contact lens is 35% or less.
Item 26. Item 26. The use according to any one of Items 22 to 25, wherein (C) a surfactant is used in combination with the component (A) and the component (B).
Item 27. Item 27. The use according to any one of Items 22 to 26, wherein the blending ratio of the component (A) is 0.01 w / v% or more.
Item 28. Item 27. The use according to Item 26, which comprises a nonionic surfactant as a component.
Item 29. Item 29. The use according to Item 28, wherein the nonionic surfactant includes at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene-polyoxypropylene block copolymer.

  According to the eye drop for nonionic SHCL of the present invention, it is possible to effectively suppress adhesion of corneal epithelial cells to nonionic SHCL. Can improve pain.

  In addition, since it is known that the cornea is difficult to recognize even when a failure occurs during SCL wearing, if the long-term continuous wearing of nonionic SHCL is repeated, it may be left until it becomes severe. On the other hand, according to the eye drop for nonionic SHCL of the present invention, such adverse effects can be improved, and it becomes possible to wear nonionic SHCL continuously for a long period of time with high safety.

In the reference test example 1, it is a figure which shows the result of having evaluated the adhesiveness of the corneal epithelial cell of various soft contact lenses. In Test Example 1, it is a figure which shows the result of having evaluated the corneal epithelial cell adhesion inhibitory effect with respect to nonionic SHCL of a test liquid (Example 1 and Comparative Example 1-2). In Test Example 2, it is a figure which shows the result of having evaluated the corneal epithelial cell adhesion inhibitory effect with respect to nonionic SHCL of a test liquid (Example 2-5, Comparative Example 3-5). In Test Example 3, it is a figure which shows the result of having evaluated the corneal epithelial cell adhesion inhibitory effect with respect to nonionic SHCL of a test liquid (Example 6, comparative example 6-7). In Test example 4, it is a figure which shows the result of having evaluated the corneal epithelial cell adhesion inhibitory effect with respect to nonionic SHCL of a test liquid (Example 7, comparative example 8). In Test Example 5, it is a figure which shows the result of having evaluated the corneal epithelial cell adhesion inhibitory effect with respect to nonionic SHCL of a test liquid (Example 8-10, Comparative Example 9-10). In Test Example 6, it is a figure which shows the result of having evaluated the corneal epithelial cell adhesion inhibitory effect with respect to nonionic SHCL of a test liquid (Example 11-12, Comparative Example 11). In the reference test example 2, it is a figure which shows the result of having evaluated the corneal epithelial cell adhesion inhibitory effect with respect to nonionic SHCL of a test liquid (comparative examples 12-13).

(I) Eye drops for nonionic SHCL The eye drops for nonionic SHCL of the present invention are at least one selected from the group consisting of chlorpheniramine and a salt thereof (hereinafter simply referred to as component (A)). Is also included. Chlorpheniramine and salts thereof are known compounds as antihistamines, and may be synthesized by a known method or obtained as a commercial product.

  Among the components (A) used in the present invention, the salt of chlorpheniramine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate; and various salts such as metal salts. Among these salts, organic acid salts are preferable, and maleates are more preferable. These chlorpheniramine salts may be used alone or in any combination of two or more.

  Further, chlorpheniramine and a salt thereof may be in the form of a hydrate, and may be any of d-form, l-form, and dl-form.

  In the nonionic SHCL eyedrops of the present invention, as the component (A), one kind of chlorpheniramine and a salt thereof may be selected and used alone, or two or more kinds thereof may be used. Any combination of these may be used. The component (A) is preferably a salt of chlorpheniramine, more preferably an organic acid salt of chlorpheniramine, particularly preferably a maleate of chlorpheniramine (chlorpheniramine maleate).

  In the nonionic SHCL eyedrops of the present invention, the blending ratio of the component (A) is appropriately set according to the type of the component (A), the types of other blended components, the use of the eyedrops, etc. However, as an example, the total amount of the component (A) is 0.005 w / v% or more with respect to the total amount of the eye drop. From the viewpoint of more effectively suppressing the adhesion of corneal epithelial cells to nonionic SHCL, the total amount of the component (A) is preferably 0.01 w / v% or more, more preferably 0.01 to 0.1 w. / v%, particularly preferably 0.01 to 0.03 w / v%.

  In addition to the above component (A), the nonionic SHCL ophthalmic solution of the present invention contains a menthol (hereinafter sometimes simply referred to as the component (B)) of 0.001 w / v% or more. Contains. Thus, by using menthol in a predetermined blending ratio together with the component (A), it becomes possible to effectively suppress adhesion of corneal epithelial cells to nonionic SHCL.

  The menthol used as the component (B) may be any of d-form, l-form, and dl-form, but the viewpoint of making the corneal epithelial cell adhesion inhibitory effect on nonionic SHCL even more remarkable Therefore, l-form is preferably used. Moreover, you may use the essential oil containing a menthol as said (B) component. Examples of such essential oils include mint oil, cool mint oil, spearmint oil, peppermint oil and the like.

  In the eye drop for nonionic SHCL of the present invention, as the component (B), one type may be selected from the above menthols, or two or more types may be arbitrarily selected. May be used in combination.

  In the nonionic SHCL eye drop of the present invention, the blending ratio of the component (B) is set so that the total amount of the component (B) is 0.001 w / v% or more with respect to the total amount of the eye drop. However, from the viewpoint of making the adhesion suppressing effect of corneal epithelial cells to nonionic SHCL even more remarkable, the blending ratio of the component (B) is preferably 0.001 to 0.02 w / The concentration is v%, more preferably 0.001 to 0.01 w / v%. In addition, when using the essential oil containing menthol as said (B) component, the mixture ratio of the said essential oil is set so that the menthol content in the essential oil mix | blended may satisfy | fill the said mixture ratio.

  In the ophthalmic solution for nonionic SHCL of the present invention, the ratio of the component (B) to the component (A) is not particularly limited as long as the above-described blending ratio is satisfied, but the cornea for the nonionic SHCL From the viewpoint of making the adhesion inhibitory effect of epithelial cells even more remarkable, the total amount of the menthol of the component (B) is 1 to 1000 parts by weight, preferably 2 to 200 parts by weight per 100 parts by weight of the total amount of the component (A). Part, more preferably 3 to 100 parts by weight.

  In addition to the above components (A) and (B), the nonionic SHCL eyedrops of the present invention further contain a surfactant (hereinafter sometimes simply referred to as component (C)). Also good. Thus, by including a surfactant, it becomes possible to more effectively exert the adhesion suppressing effect of corneal epithelial cells on nonionic SHCL. The surfactant that can be incorporated into the nonionic SHCL eye drops of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and is nonionic. Any of a surfactant, an amphoteric surfactant, an anionic surfactant, and a cationic surfactant may be used.

  Specific examples of the nonionic surfactant used as the component (C) include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), and monostearin. POE sorbitan fatty acid esters such as acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); poloxamer 407, poloxamer 235 POE / POP block copolymers such as Poloxamer 188, Poloxamer 403, Poloxamer 237 and Poloxamer 124; POE hydrogenated castor oil such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE (9) lauryl POE alkyl ethers such as ether; POE (20) POP (4) POE-POP alkyl ethers such as cetyl ether; POE (10) POE alkylphenyl ethers such as alkenyl phenyl ether. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added. Specific examples of the amphoteric surfactant used as the component (C) include alkyldiaminoethylglycine. Specific examples of the cationic surfactant used as the component (C) include benzalkonium chloride and benzethonium chloride. Specific examples of the anionic surfactant used as the component (C) include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, aliphatic α-sulfomethyl ester, α Examples include olefin sulfonic acid.

  In the eye drop for nonionic SHCL of the present invention, the surfactant may be used alone or in combination of two or more.

  Among these components (C), a nonionic surfactant is preferable from the viewpoint of providing high safety to the ocular mucosa and further improving the adhesion inhibitory effect of corneal epithelial cells against nonionic SHCL; More preferably POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE-POP block copolymers; particularly preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60, POE-POP block copolymer; more preferably polysorbate 80 and POE- POP block copolymers are used.

  When the component (C) is blended with the nonionic SHCL eyedrops of the present invention, the blending ratio of the component (C) is the type of the component (C), the type and amount of other blended components, It can set suitably according to the use etc. of eye drops. As an example of the blending ratio of the component (C), the total amount of the component (C) is 0.001 to 1.0 w / v%, preferably 0.005 to 0.5 w with respect to the total amount of the eye drop. / v%, more preferably 0.01 to 0.1 w / v%.

  In the ophthalmic solution for nonionic SHCL of the present invention, the ratio of the component (C) to the component (B) is not particularly limited as long as the above-described blending ratio is satisfied, but the cornea for the nonionic SHCL From the viewpoint of making the adhesion inhibitory effect of epithelial cells even more remarkable, the total amount of component (C) is 2 to 100,000 parts by weight, preferably 5 to 50,000 parts by weight per 1 part by weight of the total amount of menthol as component (B). Part, more preferably 5 to 10,000 parts by weight.

  The eye drops for nonionic SHCL of the present invention may further contain a buffering agent in addition to the above components. The buffer that can be blended in the nonionic SHCL eye drop of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartic acid, aspartate and the like. These buffering agents may be used in combination. Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer and citrate buffer. Particularly preferred buffering agents are borate buffer, citrate buffer or phosphate buffer. Examples of the borate buffer include borates such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the citrate buffer include alkali metal citrate and alkaline earth metal citrate. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. As more specific examples, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.), phosphoric acid or a salt thereof (disodium hydrogen phosphate, dihydrogen phosphate) Sodium, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate), carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, Calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.), citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.), acetic acid or a salt thereof (ammonium acetate) , Potassium acetate, calcium acetate, sodium acetate, etc.) And aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.). These buffering agents may be used alone or in any combination of two or more.

  When a buffering agent is blended in the nonionic SHCL eyedrops of the present invention, the blending ratio of the buffering agent depends on the type of buffering agent used, the type and amount of other blending components, the use of the eyedrops, etc. Depending on the total amount of the eye drops, for example, the total amount of the buffer is 0.01 to 10 w / v%, preferably 0.1 to 5 w / v%. More preferably, the ratio of 0.5 to 2 w / v% is exemplified.

  The pH of the nonionic SHCL eyedrops of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. As an example of the pH of the nonionic SHCL eye drop of the present invention, 4.0 to 9.5, preferably 5.0 to 8.5, more preferably 5.5 to 8.0, and still more preferably 6. The range which becomes 0-7.5 is mentioned. By adjusting the ophthalmic solution for nonionic SHCL of the present invention so as to be in such a pH range, the effect of suppressing adhesion of corneal epithelial cells to nonionic SHCL can be effectively maintained, and irritation to the ocular mucosa can be reduced. Safety can be provided. In one embodiment, when the nonionic SHCL eyedrop of the present invention has a pH of 5.5 to 6.5, for example, the above component (C) (preferably a nonionic surfactant) is added. This makes it possible to more effectively exert the adhesion suppressing effect of corneal epithelial cells on nonionic SHCL.

  Further, the osmotic pressure of the nonionic SHCL eye drop of the present invention is not particularly limited as long as it is within a range acceptable for a living body. As an example of the osmotic pressure ratio of the nonionic SHCL eye drop of the present invention, it is preferably 0.7 to 5.0, more preferably 0.9 to 3.0, and particularly preferably 1.0 to 2.0. A range is mentioned. The osmotic pressure can be adjusted by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, saccharides and the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 0.9w / v% sodium chloride aqueous solution based on the 15th revised Japanese Pharmacopoeia. The osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia (freezing point depression method) Measure with reference to. The standard solution for measuring the osmotic pressure ratio was sodium chloride (Japanese Pharmacopoeia standard reagent) dried at 500-650 ° C for 40-50 minutes, and then allowed to cool in a desiccator (silica gel). Dissolve in water to prepare exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

The eye drops for nonionic SHCL of the present invention may contain an appropriate amount of various pharmacologically active components and physiologically active components in addition to the above components, as long as the effects of the present invention are not hindered. Such an ingredient is not particularly limited, and examples thereof include an active ingredient in an ophthalmic drug described in the over-the-counter drug manufacturing (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee). Specifically, the following components are listed as components used in ophthalmic drugs.
Antihistamines: for example, iproheptin, diphenhydramine and the like.
Decongestant: Tetrahydrozoline, naphazoline, epinephrine, ephedrine, methylephedrine, etc.
Bactericides: for example, acrinol, cetylpyridinium, benzalkonium, benzethonium, chlorhexidine and the like.
Vitamins: flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate, etc.
Amino acids: potassium aspartate, magnesium aspartate, aminoethylsulfonic acid and the like.
Anti-inflammatory agents: for example, glycyrrhetinic acid, glycyrrhizic acid, pranoprofen, methyl salicylate, glycol salicylate, allantoin, azulene, azulenesulfonic acid, guaiazulene, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme, licorice, etc.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Other: for example, ketotifen fumarate, sodium cromoglycate, sodium chondroitin sulfate, sulfamethoxazole, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl fenfenamic acid, bendazac, piroxicam, ketoprofen, felbinac, purple root, tochinoki, And salts thereof.

In addition, the non-ionic SHCL eyedrops of the present invention can be appropriately selected from various additives according to conventional methods, depending on the use and form, as long as the effects of the invention are not impaired. An appropriate amount may be added in combination. Examples of such additives include various additives described in Pharmaceutical Additives Encyclopedia 2005 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Carrier: An aqueous carrier such as water or hydrous ethanol.
Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate and the like.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glowyl (manufactured by Rhodia) Name) etc.
pH adjuster: for example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, boro Sand, triethanolamine, 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.
Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.
Fragrance or refreshing agent: anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, ryuuno, etc. These may be either d-form, l-form or dl-form, and may be blended as essential oils (fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc.).

  Non-ionic SHCL eye drops of the present invention, for example, in the aqueous carrier such as purified water, physiological saline, etc., the components (A) and (B), if necessary, the component (C) and other blends Ingredients are added to the desired concentration and prepared according to conventional methods.

  In the eye drops for nonionic SHCL of the present invention, the type of nonionic SHCL to be applied is not particularly limited, and all nonionic SHCL currently marketed or marketed in the future are targeted for application. it can. Here, the term “nonionic” means that the content of ionic components in the material is less than 1 mol% in accordance with US FDA standards, as is generally understood by those skilled in the art. Further, the moisture content of the nonionic SHCL to be applied is not particularly limited, and examples thereof include 90% or less, preferably 60% or less, more preferably 50% or less, and particularly preferably 35% or less. Since SHCL contains a hydrogel material, it contains at least more than 0% moisture. Nonionic SHCL having a water content of 35% or less tends to have strong adhesion to corneal epithelial cells. According to the ophthalmic solution for nonionic SHCL of the present invention, the effect of suppressing the adhesion of corneal epithelial cells can be effectively exhibited even for nonionic SHCL having strong adhesion to corneal epithelial cells. In view of the effect of the present invention, an example of a suitable application target of the eye drop for nonionic SHCL of the present invention is nonionic SHCL having a water content of 35% or less.

Here, the moisture content of SHCL indicates the ratio of water in SHCL, and is specifically determined by the following calculation formula.
Moisture content (%) = (weight of hydrated water / weight of hydrated SHCL) x 100
Such moisture content can be measured by a gravimetric method according to the description of ISO18369-4: 2006.

  The usage forms of the non-ionic SHCL eye drops include a form in which the eye drops are directly applied to the eye wearing the non-ionic SHCL, and a form in which the eye drops are put on before the non-ionic SHCL is worn.

  Conventionally, it is known that wearing a hard contact lens made of polymethylmethacrylate (PMMA) material easily causes corneal epithelial disorder (3 o'clock to 9 o'clock staining) due to fixation of the lens to the cornea. . In addition, it is known that even when wearing SCL, a person who has symptoms such as dry eyes (for example, a dry eye patient) tends to damage the cornea due to the lens and tends to cause corneal staining. As shown in the test examples to be described later, the present inventors' research has confirmed that nonionic SHCL significantly adheres to corneal epithelial cells, and that SHCL is generally harder than normal non-silicone SCL. Yes. In view of the characteristics of such nonionic SHCL, it is apparent that the above-described corneal epithelial disorder is easily caused even by wearing nonionic SHCL. On the other hand, according to the ophthalmic solution for nonionic SHCL of the present invention, it is possible to effectively suppress adhesion of corneal epithelial cells to nonionic SHCL, so that corneal epithelial disorder caused by wearing nonionic SHCL Can be prevented. Therefore, the eye drop for nonionic SHCL of the present invention can be used as a preventive agent for corneal epithelial disorder caused by wearing nonionic SHCL, and particularly for those having symptoms of dry eyes (for example, dry eye For patients).

  In addition, since the corneal epithelial cells also have a barrier function against allergens, the corneal epithelial disorder caused by the nonionic SHCL wearing as described above reduces the barrier function and causes or worsens allergic diseases of the eye. There is a fear to make it easier. Therefore, the eye drop for nonionic SHCL of the present invention is an ophthalmic disease preventive agent (for example, for a person who uses nonionic SHCL to increase and prevent various eye diseases including allergic diseases) It is preferably used as a prophylactic agent for allergic diseases).

  In addition, the non-ionic SHCL eye drop of the present invention can also exhibit an antihistamine action based on the above component (A), and is therefore useful as a preventive or alleviating agent for allergic symptoms. Furthermore, the eye drop for nonionic SHCL of the present invention can impart a refreshing feeling to the eye based on the above component (B), so it is used for the purpose of giving a comfortable feeling when wearing nonionic SHCL. You can also

(II) Method for inhibiting adhesion of corneal epithelial cells to nonionic SHCL, method for imparting adhesion inhibiting effect of corneal epithelial cells to nonionic SHCL, and use for production of eye drops As described above, nonionic SHCL By allowing the component (A) and a predetermined amount of the component (B) to coexist in the ophthalmic solution for use, adhesion of corneal epithelial cells to nonionic SHCL can be suppressed.

  Accordingly, the present invention, from yet another point of view, contains (A) at least one selected from the group consisting of chlorpheniramine and a salt thereof, and (B) menthol, and the concentration of the component (B) Provided is a method for suppressing adhesion of corneal epithelial cells to nonionic SHCL, which comprises bringing a nonionic SHCL eye drop of 0.001 w / v% or more into contact with nonionic SHCL. Furthermore, (B) menthol is blended at a concentration of 0.001 w / v% or more with at least one selected from the group consisting of (A) chlorpheniramine and a salt thereof in the nonionic SHCL eyedrops. The present invention provides a method for imparting an adhesion-suppressing effect of corneal epithelial cells to nonionic SHCL to a nonionic SHCL eyedrop.

  Further, the present invention provides a nonionic silicone of (B) menthol of at least one selected from the group consisting of (A) chlorpheniramine and a salt thereof, and 0.001 w / v% or more from another viewpoint. The use for the manufacture of eye drops for hydrogel contact lenses is provided. Further, (A) at least one selected from the group consisting of chlorpheniramine and a salt thereof, and 0.001 w / v% or more of (B) menthol, a corneal epithelial cell for a nonionic silicone hydrogel contact lens The use for the manufacture of eye drops for imparting the adhesion-suppressing effect is provided.

  In these methods and uses, the types of components (A) and (B) to be used, the blending ratio in these nonionic SHCL eyedrops, the types and concentrations of other components, and nonionic SHCL eyedrops The pH, the formulation form of the nonionic SHCL eyedrops, the type of nonionic SHCL to be applied, and the like are the same as in the above “(I) Nonionic SHCL eyedrops”.

  Hereinafter, the present invention will be described in detail based on test examples, examples, and the like, but the present invention is not limited thereto.

Reference Test Example 1: Evaluation of Adhesion of Corneal Epithelial Cells of Various SCLs The following experiment was conducted using five types of soft contact lenses shown in Table 1, and the adhesion of corneal epithelial cells on the soft contact lens surface was evaluated. The soft contact lenses used in this test are all commercially available products.

Specifically, it was evaluated by the following method. Each soft contact lens was immersed in a 24-well microplate containing 900 μL of a growth medium (10% fetal bovine serum-containing DMEM medium) with the convex surface facing upward. In each well, 100 μL of a cell suspension (1 × 10 ⁵ cell / ml) of a rabbit corneal epithelial cell line SIRC (ATCC number: CCL-60) prepared using a growth medium was seeded at 37 ° C., 5 ° C. After culturing for 48 hours under% CO ₂ conditions, the number of viable cells adhered to the soft contact lens was counted. As a control, cells were cultured on the bottom of the microplate without immersing any lens, and the number of viable cells in the wells was counted (control group). In addition, Cell Counting Kit (Dojindo Laboratories) was used for the measurement of the number of viable cells. The ratio of the number of viable cells adhering to the surface of each soft contact lens (ratio of the number of viable cells to the control group;%) was calculated with respect to the total number of viable cells contained in the wells of the control group.

  The obtained results are shown in FIG. As is clear from FIG. 1, the lenses A and B, which are nonionic SHCL, are compared with the lens C, which is an ionic silicone hydrogel contact lens, and the lens D, or E, which is a nonsilicone hydrogel contact lens. It was confirmed that there was remarkable corneal epithelial cell adhesion. In addition, when the adhesion state of the cells to the soft contact lens was observed with a microscope, cell adhesion was hardly confirmed in the lenses C, D, and E, but corneal epithelial cells were present on the entire surfaces of the lenses A and B. It was confirmed that they were adhered. From the above results, it was confirmed that nonionic SHCL has significantly higher adhesion of corneal epithelial cells than other types of lenses, and wearing nonionic SHCL has adverse effects such as damage to the corneal surface. It became clear that it could be given.

Test Example 1: Adhesion Inhibition Test of Corneal Epithelial Cells to Nonionic SHCL Using the test solutions shown in Table 2 (Example 1 and Comparative Example 1-2), the effect of inhibiting corneal epithelial cell adhesion to nonionic SHCL Was evaluated by the following method.

Lens A (nonionic SHCL) shown in Table 1 was immersed one by one in 10 ml of the test solution (Example 1 and Comparative Example 1-2) shown in Table 2, and allowed to stand at 34 ° C. for 24 hours. The lens A taken out from each test solution is gently washed with physiological saline, then wiped off, and the convex surface is placed on a 24-well plate containing 900 μL of a growth medium (DMEM medium containing 10% fetal bovine serum). It was immersed one by one. In each well, 100 μL of a cell suspension (1 × 10 ⁵ cell / ml) of a rabbit corneal epithelial cell line SIRC (ATCC number: CCL-60) prepared using a growth medium was seeded at 37 ° C., 5 ° C. After culturing for 48 hours under% CO ₂ conditions, the number of viable cells adhered to the lens was counted (sample group). In addition, as a control, using a lens A that was not soaked in any of the test solutions, a cell suspension of a rabbit corneal epithelial cell line was seeded and cultured under the same conditions as described above, and adhered to the lens A. The number of viable cells was counted (control group). Furthermore, as a blank, a well containing only 1000 μL of growth medium (DMEM medium containing 10% fetal bovine serum) without seeding rabbit corneal epithelial cells was prepared, and the well was allowed to stand still at 37 ° C. and 5% CO ₂ for 48 hours. (Blank group). In addition, the cell adhesion suppression rate (%) was computed according to the following formula using Cell Counting Kit (Dojindo Laboratories) for the measurement of the number of living cells. As a result, it was revealed that even when treated with the test solution of Comparative Example 1, almost no cell adhesion inhibitory effect was observed.

  Based on the cell adhesion inhibition rate calculated in each Example and Comparative Example, the relative ratio of the cell adhesion inhibition rate when the cell adhesion inhibition rate of Comparative Example 1 was set to 100 was determined. The results are shown in FIG. As is clear from FIG. 2, it was found that the nonionic SHCL treated with the test solution of Example 1 can obtain a remarkably high epithelial cell adhesion inhibitory effect. The cell adhesion inhibitory effect observed with the test solution of Example 1 is remarkably superior to the case of being treated with the test solution of Comparative Example 1 or 2.

Test Example 2: Inhibition test of adhesion of corneal epithelial cells to nonionic SHCL Adhesion of corneal epithelial cells to nonionic SHCL using the test solutions shown in Table 3 (Example 2-5, Comparative Example 3-5) The inhibitory effect was evaluated by the following method.

Lens A (nonionic SHCL) shown in Table 1 was immersed one by one in 10 ml of each test solution shown in Table 3, and allowed to stand at 34 ° C. for 24 hours. The lens A taken out from each test solution is gently washed with physiological saline, wiped off the water, and the convex surface of the lens is placed on a 24-well plate containing 970 μL of a growth medium (DMEM medium containing 10% fetal bovine serum). Soaked one by one. Each well was seeded with 30 μL of a cell suspension (1 × 10 ⁵ cell / ml) of a rabbit corneal epithelial cell line SIRC (ATCC number: CCL-60) prepared using a growth medium at 37 ° C., 5 ° C. After culturing for 5 days under% CO ₂ conditions, the number of viable cells attached to the lens was counted (sample group). In addition, as a control, instead of each test solution, the above-mentioned lens A was used, which was immersed in a borate buffer solution (boric acid 0.5 w / v%, borax appropriate amount, remaining purified water; pH 7.5). A cell suspension of a rabbit corneal epithelial cell line was seeded under the same conditions as above and cultured, and the number of viable cells adhered to the lens A was counted (control group). Furthermore, as a blank, a well containing only 1000 μL of growth medium (DMEM medium containing 10% fetal bovine serum) without seeding rabbit corneal epithelial cells was prepared, and the well was allowed to stand still at 37 ° C. and 5% CO ₂ for 48 hours. (Blank group). For the measurement of the number of viable cells, the Cell Adhesion Inhibition Rate (%) was calculated according to the same calculation formula as in Test Example 1 using Cell Counting Kit (Dojindo Laboratories). Based on the cell adhesion inhibition rate calculated in each Example and Comparative Example, the relative ratio of the cell adhesion inhibition rate when the cell adhesion inhibition rate of Comparative Example 3 was set to 100 was determined. The results are shown in FIG. As is clear from FIG. 3, in the test solution of Example 2-5, a high cell adhesion inhibition rate was recognized synergistically by the combination of chlorpheniramine maleate and menthol. Moreover, since it became clear that the test solution of Comparative Example 4 was worse than Comparative Example 3 in which menthol was not blended, the adsorption of corneal epithelial cells to nonionic SHCL was effectively suppressed. It was also revealed that the menthol blending ratio is more than a specific amount. Furthermore, in the test solution of Example 5, the effect of suppressing the adhesion of corneal epithelial cells was more prominent. Therefore, by further adding a nonionic surfactant (polysorbate 80), the cornea against nonionic SHCL. It was also revealed that the effect of suppressing the adhesion of epithelial cells was further enhanced.

Test Example 3: Adhesion Inhibition Test of Corneal Epithelial Cells to Nonionic SHCL Using the test solutions shown in Table 4 (Example 6, Comparative Example 6-7), the effect of inhibiting corneal epithelial cell adhesion to nonionic SHCL Was evaluated by the following method.

Lens A (nonionic SHCL) shown in Table 1 was immersed one by one in 5 ml of each test solution shown in Table 4 and allowed to stand at 34 ° C. for 24 hours. The lens A taken out from each test solution is gently washed with physiological saline, wiped off the water, and the convex surface of the lens is placed on a 24-well plate containing 950 μL of a growth medium (DMEM medium containing 10% fetal bovine serum). Soaked one by one. Each well is seeded with 50 μL of a cell suspension (1 × 10 ⁵ cell / ml) of a rabbit corneal epithelial cell line SIRC (ATCC number: CCL-60) prepared using a growth medium at 37 ° C., 5 ° C. After culturing for 2 days under% CO ₂ conditions, the number of viable cells adhered to the lens was counted (sample group). In addition, as a control, instead of each test solution, the above-mentioned lens A was used, which was immersed in a borate buffer solution (boric acid 0.5 w / v%, borax appropriate amount, remaining purified water; pH 7.5). A cell suspension of a rabbit corneal epithelial cell line was seeded under the same conditions as above and cultured, and the number of viable cells adhered to the lens A was counted (control group). Furthermore, as a blank, a well containing only 1000 μL of growth medium (DMEM medium containing 10% fetal bovine serum) without seeding rabbit corneal epithelial cells was prepared, and the well was allowed to stand still at 37 ° C. and 5% CO ₂ for 48 hours. (Blank group). For the measurement of the number of viable cells, the Cell Adhesion Inhibition Rate (%) was calculated according to the same calculation formula as in Test Example 1 using Cell Counting Kit (Dojindo Laboratories).

  Based on the cell adhesion inhibition rate calculated in each Example and Comparative Example, the relative ratio of the cell adhesion inhibition rate when the cell adhesion inhibition rate of Comparative Example 7 was set to 100 was determined. The results are shown in FIG. As is clear from FIG. 4, the test solution of Example 6 also showed a significantly higher cell adhesion inhibitory effect than the comparative example. From the above results, it has been clarified that a sufficient corneal epithelial cell adhesion inhibitory effect can be obtained even when the blending ratio of chlorpheniramine maleate is 0.01%.

Test Example 4: Inhibition of adhesion of corneal epithelial cells to nonionic SHCL From Test Example 2, in order to obtain a synergistic corneal cell adhesion inhibitory effect of chlorpheniramine maleate and menthol, a menthol of a specific amount or more is required. Since it became clear that it was necessary, the following experiment was conducted in order to investigate the effective amount.

  Specifically, using the test solutions shown in Table 5 (Example 7, Comparative Example 8), the adhesion inhibitory effect of corneal epithelial cells on nonionic SHCL was evaluated by the same method as in Test Example 3 above.

  Based on the cell adhesion inhibition rate calculated in each Example and Comparative Example, the relative ratio of the cell adhesion inhibition rate when the cell adhesion inhibition rate of Comparative Example 8 was set to 100 was determined. The results are shown in FIG. As is clear from FIG. 5, it was revealed that a remarkable corneal epithelial cell adhesion inhibitory effect was obtained even when the proportion of menthol blended with chlorpheniramine maleate was 0.001%.

Test Example 5: Adhesion inhibition test of corneal epithelial cells to nonionic SHCL Adhesion of corneal epithelial cells to nonionic SHCL using the test solutions shown in Table 6 (Example 8-10, Comparative Example 9-10) The inhibitory effect was evaluated by the following method.

Lens B (nonionic SHCL) shown in Table 1 was immersed one by one in 8 ml of each test solution shown in Table 6, and allowed to stand at 34 ° C. for 24 hours. The lens B taken out from each test solution is gently washed with physiological saline, then wiped off, and the convex surface of the lens is placed on a 24-well plate containing 950 μL of growth medium (DMEM medium containing 10% fetal bovine serum). Soaked one by one. Each well is seeded with 50 μL of a cell suspension (1 × 10 ⁵ cell / ml) of a rabbit corneal epithelial cell line SIRC (ATCC number: CCL-60) prepared using a growth medium at 37 ° C., 5 ° C. After culturing under% CO ₂ conditions for 3 days, the number of viable cells adhered to the lens was counted (sample group). In addition, as a control, instead of each test solution, using the lens B immersed in a borate buffer solution (boric acid 0.8 w / v%, appropriate amount of borax, remaining purified water; pH 5.5), the above-mentioned Under the same conditions as above, a cell suspension of a rabbit corneal epithelial cell line was seeded and cultured, and the number of viable cells adhered to the lens B was counted (control group). Furthermore, as a blank, a well was prepared by adding only 1000 μL of a growth medium (DMEM medium containing 10% fetal bovine serum) without seeding rabbit corneal epithelial cells, and the sample group was obtained under conditions of 37 ° C. and 5% CO _2. It left still for the same time (blank group). For the measurement of the number of viable cells, the Cell Adhesion Inhibition Rate (%) was calculated according to the same calculation formula as in Test Example 1 using Cell Counting Kit (Dojindo Laboratories).

  Based on the cell adhesion inhibition rate calculated in each Example and Comparative Example, the relative ratio of the cell adhesion inhibition rate when the cell adhesion inhibition rate of Comparative Example 9 was set to 100 was determined. The results are shown in FIG. As is apparent from FIG. 6, even when the eye drop of the present invention is lowered to a pH of about 5.5 to 6.5, chlorpheniramine maleate and 0.001 w / v% or more of menthol It was confirmed that a high corneal cell adhesion inhibitory effect can be obtained synergistically by the combination. Furthermore, in the test solution of Example 10, since the adhesion inhibitory effect of corneal epithelial cells was more remarkably observed, a nonionic surfactant (polysorbate 80) was added even when the pH of the eye drop was low. Furthermore, it was confirmed that the effect of suppressing the adhesion of corneal epithelial cells to nonionic SHCL was further enhanced by combining them.

Test Example 6: Inhibition test of adhesion of corneal epithelial cells to nonionic SHCL Using the test solutions shown in Table 7 (Examples 11-12 and Comparative Example 11), the effect of inhibiting the adhesion of corneal epithelial cells to nonionic SHCL Was evaluated by the following method.

Lens B (nonionic SHCL) shown in Table 1 was immersed one by one in 8 ml of each test solution shown in Table 7, and allowed to stand at 34 ° C. for 24 hours. The lens B taken out from each test solution is gently washed with physiological saline, then wiped off, and the convex surface of the lens is placed on a 24-well plate containing 950 μL of growth medium (DMEM medium containing 10% fetal bovine serum). Soaked one by one. Each well is seeded with 50 μL of a cell suspension (1 × 10 ⁵ cell / ml) of a rabbit corneal epithelial cell line SIRC (ATCC number: CCL-60) prepared using a growth medium at 37 ° C., 5 ° C. After culturing under% CO ₂ conditions for 3 days, the number of viable cells adhered to the lens was counted (sample group). In addition, as a control, instead of each test solution, using the lens B that had been dipped using a borate buffer solution (boric acid 0.8 w / v%, appropriate amount of borax, remaining purified water; pH 6.0), the above-mentioned Under the same conditions as above, a cell suspension of a rabbit corneal epithelial cell line was seeded and cultured, and the number of viable cells adhered to the lens B was counted (control group). Furthermore, as a blank, a well was prepared by adding only 1000 μL of a growth medium (DMEM medium containing 10% fetal bovine serum) without seeding rabbit corneal epithelial cells, and the sample group was obtained under conditions of 37 ° C. and 5% CO _2. It left still for the same time (blank group). For the measurement of the number of viable cells, the Cell Adhesion Inhibition Rate (%) was calculated according to the same calculation formula as in Test Example 1 using Cell Counting Kit (Dojindo Laboratories).

  Based on the cell adhesion inhibition rate calculated in each Example and Comparative Example, the relative ratio of the cell adhesion inhibition rate when the cell adhesion inhibition rate of Comparative Example 11 was taken as 100 was determined. The results are shown in FIG. As is clear from FIG. 7, in this test example as well, the corneal cell adhesion inhibitory effect is remarkably high by the combination of chlorpheniramine maleate and 0.001 w / v% or more of menthol as in the previous test examples. It was confirmed that the effect was further enhanced by further combining and blending a nonionic surfactant (poloxamer 407).

Reference Test Example 2: Corneal Epithelial Cell Adhesion Inhibition Test to Nonionic SHCL The following experiment was conducted to confirm whether the same effect could be obtained with other terpenoids.

  Specifically, using the test solutions shown in Table 8 (Comparative Examples 12 and 13), the adhesion inhibitory effect of corneal epithelial cells on nonionic SHCL was evaluated by the same method as in Test Example 3.

  Based on the cell adhesion inhibition rate calculated in each comparative example, the relative ratio of the cell adhesion inhibition rate when the cell adhesion inhibition rate of Comparative Example 12 was taken as 100 was determined. The results are shown in FIG. As is clear from FIG. 8, it can be seen that the test solution of Comparative Example 13 containing geraniol is worse than the test solution of Comparative Example 12 not containing geraniol, and that geraniol has an effective effect. It became clear that it could not be obtained. That is, from this result, the adhesion inhibitory effect of corneal epithelial cells against nonionic SHCL is a unique effect that is first achieved by using chlorpheniramine and / or a salt thereof in an amount of 0.001 w / v% or more of menthol. It was clear that this was not possible by replacing menthol with other terpenoids.

Formulation Example A nonionic SHCL eye drop (Examples 13-22) is prepared according to the formulation described in Table 9.

Claims (1)

(A) it contains at least one selected from the group consisting of chlorpheniramine and a salt thereof, and (B) menthol, and the blending ratio of the component (B) is 0.001 w / v% or more. An eye drop for a nonionic silicone hydrogel contact lens.

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