JP5616621B2 - Eye drops for silicone hydrogel contact lenses - Google Patents

Description

  The present invention relates to an eye drop for a silicone hydrogel contact lens capable of improving the permeability of neostigmine and / or a salt thereof to a silicone hydrogel contact lens. The present invention also provides a method for improving the permeability of neostigmine and / or a salt thereof to a silicone hydrogel contact lens, and an effect of improving the permeability of neostigmine and / or a salt thereof to a silicone hydrogel contact lens. The present invention relates to a method of applying to eye drops. Moreover, this invention relates to the agent for improving the permeability | transmittance of neostigmine and / or its salt to a silicone hydrogel contact lens. Furthermore, the present invention relates to a method for screening a permeability enhancing substance that improves the permeability of neostigmine and / or a salt thereof to a silicone hydrogel contact lens. The present invention further relates to a method for suppressing lipid adsorption to a nonionic silicone hydrogel contact lens, a method for suppressing accumulation of pollen protein on an ionic silicone hydrogel contact lens, and the like.

  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 SCL is worn, the amount of oxygen supplied from the atmosphere decreases, which may result in suppression of corneal epithelial cell division and corneal thickening. Therefore, development of SCL having higher oxygen permeability has been advanced.

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

  In addition, SCL is generally larger than a hard contact lens, and the cornea surface is almost entirely covered during wearing. And during SCL wearing, there is almost no inflow and outflow of tears between the SCL and the corneal surface (that is, tear exchange by pump action), and tear exchange under SCL is the tear fluid via SCL. It is known that it depends on transmission (see Non-Patent Document 1-2). As described above, most of the tear fluid exchange under SCL is performed by permeation of tear fluid through SCL, so the eye drops applied to the eyes of the SCL wearer are the pharmacological components to be mixed into SCL. It is required to sufficiently increase the permeability.

  Therefore, for eye drops applied to the eyes of SCL wearers, depending on the type of SCL, not only the impact on safety, but also the permeability of pharmacologically active ingredients to SCL is fully considered. It is essential to design. In particular, since the presence or absence of ionicity and the water content of SCL vary depending on the material, it is important that eye drops applied to the eyes of SCL wearers should be formulated according to the nature of the applied SCL. .

  In recent years, it has been pointed out that silicone hydrogel contact lenses are more likely to be contaminated with lipids derived from tear film, cosmetics and the like as compared with conventional hydrogel contact lenses (Non-patent Document 3). Such lipid contamination induces cloudiness of the lens, causing discomfort to the wearer and harming the quality of life (QOL). Further, such contamination of the contact lens may adversely affect the vision correction power that the lens should originally have. Furthermore, in recent years, it has also been pointed out that such lipid contamination of contact lenses affects the occurrence of corneal epithelial disorder called corneal staining.

  By the way, hay fever is an allergic symptom caused by pollen protein contained in pollen becoming an antigen and contacting mucous membranes and the like. In recent years, the number of patients with hay fever is increasing, which is becoming a major social problem. In the field of ophthalmology, there is a strong demand for the development of eye drops useful for the prevention of hay fever and suppression of deterioration.

  On the other hand, neostigmine and / or a salt thereof is used in eye drops for the purpose of imparting an effect of improving the focus adjustment function of the pupil (see Patent Document 1). And it is known that such an action of neostigmine and / or a salt thereof is exerted when neostigmine and / or a salt thereof passes through the cornea and directly acts on the ciliary muscle existing in the back of the cornea. Yes. However, the effect of applying neostigmine and / or a salt thereof to the eye wearing a silicone hydrogel contact lens has not been clarified so far. Moreover, the present situation is that even when neostigmine and / or a salt thereof and a surfactant are used in combination and applied to a silicone hydrogel contact lens, it cannot be estimated.

Journal of Japanese Contact Lens Society, Vol. 39, 111-115, 1997 Japanese Journal of Contact Lenses, Vol. 44, 34-37, 2002 Hiroshi Shiotani, New Ophthalmology, Vol.25, No.7, 907-912, 2008

JP 2006-232822 A

  The present inventors have conducted various studies on the effects of applying neostigmine and / or a salt thereof to various SCLs. (Sometimes abbreviated as SHCL), we obtained a completely new finding that the amount of neostigmine and / or a salt thereof transmitted through the lens is significantly smaller than other SCLs. Neostigmine and / or its salt must act on the ciliary muscles in the back of the cornea in order to exert its effects. However, if the amount of lens penetration is extremely small, it is difficult for the eyes wearing SHCL. On the other hand, even if an eye drop containing neostigmine and / or a salt thereof is applied, a sufficient amount may not be supplied to the cornea and a satisfactory effect may not be obtained.

  Therefore, when instilled while wearing SHCL, the permeability of neostigmine and / or its salt to SHCL has been improved, and the development of eye drops for SHCL that can increase the amount of neostigmine and / or its salt that reaches the cornea has been developed. It has been demanded.

  As a result of intensive studies to solve the above problems, the present inventors have significantly increased the permeation amount of neostigmine and / or salt thereof to SHCL when a surfactant is used in combination with neostigmine and / or salt thereof. I found out that I can do it. Furthermore, the present inventors proceeded with studies, and when combined with a surfactant in addition to neostigmine and / or its salt, lipid adsorption to nonionic SHCL can be remarkably suppressed, and ionic SHCL can be suppressed. It was found that the accumulation of pollen protein can also be effectively 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 SHCL.
Item 1. An eye drop for a silicone hydrogel contact lens, comprising (A) at least one selected from the group consisting of neostigmine and a salt thereof, and (B) a surfactant.
Item 2. Item 5. An eye drop for a silicone hydrogel contact lens according to Item 1, comprising neostigmine methylsulfate as the component (A).
Item 3. Item 3. The silicone hydrogel contact lens according to Item 1 or 2, comprising as component (B) at least one selected from the group consisting of a nonionic surfactant, a cationic surfactant, and an amphoteric surfactant. Eye drops.
Item 4. Item 4. The eye drop for a silicone hydrogel contact lens according to any one of Items 1 to 3, further comprising (C) a buffer.
Item 5. Item 5. The eye drop for a silicone hydrogel contact lens according to any one of Items 1 to 4, wherein the blending ratio of the component (A) is 0.0005 to 0.1 w / v%.
Item 6. Item 6. The eye drop for a silicone hydrogel contact lens according to any one of Items 1 to 5, wherein the blending ratio of the component (B) is 0.001 to 1.0 w / v%.
Item 7. Item 7. The silicone hydrogel contact lens eye drop according to any one of Items 1 to 6, wherein the silicone hydrogel contact lens is nonionic.
Item 8. Item 7. The silicone hydrogel contact lens eye drop according to any one of Items 1 to 6, wherein the silicone hydrogel contact lens is ionic.

In addition, the present invention provides a method for improving the permeability of neostigmine and / or its salt to SHCL, and the method for imparting an eye drop with the effect of improving the permeability of neostigmine and / or its salt to SHCL as described below. To do.
Item 9. (A) At least one selected from the group consisting of neostigmine and a salt thereof and (B) a surfactant are used in combination, and the permeability of the component (A) to the silicone hydrogel contact lens is improved. How to improve.
Item 10. (A) A silicone hydrogel contact lens comprising (B) a surfactant in an eye drop for a silicone hydrogel contact lens containing at least one selected from the group consisting of neostigmine and a salt thereof. A method for imparting an action to improve the permeability of the component (A) to the eye drop.

Moreover, this invention provides the permeability improvement agent of neostigmine and / or its salt with respect to SHCL hung up below.
Item 11. (B) An agent for improving at least one permeability selected from the group consisting of (N) neostigmine and a salt thereof into a silicone hydrogel contact lens, which contains a surfactant.

Furthermore, this invention provides the screening method of the permeability | transmittance improvement substance hung up below.
Item 12. A screening method for a permeability-improving substance that improves the permeability of at least one neostigmine selected from the group consisting of neostigmine and a salt thereof for a silicone hydrogel contact lens,
(a) preparing a control solution containing neostigmines and a test solution containing neostigmines and a test substance as test solutions,
(b) Each of the above test solutions is brought into contact with only one side of the silicone hydrogel contact lens for a predetermined time, and the amount of neostigmine exuded from the other side of the lens not contacted with the above test solution is measured. The step of determining the permeation amount of neostigmines of each test solution, and
(c) a step of selecting a test solution having a permeation amount of neostigmine measured in the step (b) larger than that of a control solution, and selecting a test substance contained in the test solution as the permeability improving substance,
A screening method comprising:

Moreover, this invention provides the method of suppressing adsorption | suction of the lipid to nonionic SHCL hung up below.
Item 13. An eye drop for a silicone hydrogel contact lens containing (A) at least one selected from the group consisting of neostigmine and a salt thereof and (B) a surfactant is brought into contact with a nonionic silicone hydrogel contact lens. A method for inhibiting the adsorption of lipids to a nonionic silicone hydrogel contact lens.

Moreover, this invention provides the method of providing the effect | action which suppresses the adsorption | suction of the lipid to nonionic SHCL to the eyedrops for SHCL hung up below.
Item 14. A nonionic silicone hydro, characterized in that the eye drop for a silicone hydrogel contact lens contains (A) at least one selected from the group consisting of neostigmine and a salt thereof, and (B) a surfactant. A method for imparting an action of suppressing the adsorption of lipid to a gel contact lens to the eye drop.

Moreover, this invention provides the method of suppressing accumulation | storage of pollen protein to ionic SHCL hung up below.
Item 15. Contacting an eye drop for a silicone hydrogel contact lens containing (A) at least one selected from the group consisting of neostigmine and a salt thereof and (B) a surfactant with an ionic silicone hydrogel contact lens. A method for suppressing the accumulation of pollen protein in an ionic silicone hydrogel contact lens.

Furthermore, this invention provides the method of providing the effect | action which suppresses accumulation | storage of the pollen protein to ionic SHCL to the eye drop for SHCL shown below.
Item 16. An ionic silicone hydrogel comprising: (A) at least one selected from the group consisting of neostigmine and a salt thereof and (B) a surfactant in an eye drop for a silicone hydrogel contact lens A method of imparting to the eye drop an action of suppressing accumulation of pollen protein in a contact lens.

  According to the ophthalmic preparation for SHCL of the present invention, the permeability of neostigmine and / or a salt thereof to SHCL can be remarkably improved. Therefore, even when instilled during SHCL wearing, the cornea of neostigmine and / or a salt thereof As a result, it is possible to effectively improve the focus adjustment function of the eyes.

  Furthermore, the screening method of the present invention makes it possible to obtain a permeability-improving substance that can improve the permeability of neostigmine and / or its salt to SHCL, so that the permeability of neostigmine and / or its salt to SHCL is improved. It is improved, and it is useful for the development of eye drops for SHCL that can effectively improve the focus adjustment function even when used while wearing SHCL.

  In addition, it has been clarified by the present inventors that nonionic SHCL has a specific problem that lipids are easily adsorbed, but according to the eye drop for SHCL of the present invention, such nonionic SHCL It can remarkably suppress lipid adsorption to SHCL. Therefore, according to the ophthalmic solution for SHCL of the present invention, non-ionic SHCL lipid stains can be prevented, non-ionic SHCL cloudiness can be prevented, and non-ionic SHCL original vision correction power can be maintained. In addition, corneal epithelial disorders such as corneal staining caused by lipid adsorption to nonionic SHCL can be effectively prevented, and nonionic SHCL can be used comfortably and safely.

  Furthermore, studies by the present inventors have revealed that ionic SHCL has a unique problem that pollen proteins are remarkably easily adsorbed. In general, proteins are thought to be difficult to adsorb to SHCL, and this finding is completely unexpected. And generally, when wearing contact lenses, the eyes are likely to dry, and as a result, the cleaning action by tears is reduced, and foreign substances such as pollen are likely to stay in the eyes, which increases the risk of developing hay fever. It is considered. Moreover, if a large amount of pollen protein is adsorbed and accumulated on the contact lens, it will significantly increase the risk of developing hay fever and may contribute to allergic symptoms. Furthermore, if the pollen protein adsorbed on the contact lens is insufficiently removed, the wearing feeling of the contact lens is impaired, causing discomfort and shortening the use period. However, according to the ophthalmic solution for SHCL of the present invention, even when pollen protein and ionic SHCL come into contact with each other during wearing of ionic SHCL, it promotes removal of pollen protein from ionic SHCL and prevents reattachment. In this way, accumulation of pollen protein in ionic SHCL can be suppressed. Therefore, according to the eye drop for SHCL of the present invention, the risk of developing allergic symptoms can be reduced for users of hay fever or the pollinosis reserve army, and ionic SHCL can be kept clean.

In the reference test example 1, it is a figure which shows the result of having evaluated the permeability | transmittance to the SCL of methyl sulfate neostigmine. In Experiment 1, it is a figure which shows the result of having evaluated the permeability | transmittance to the SHCL of the methyl sulfate neostigmine of eye drops (Example 1-3 and Comparative Example 1). In Experiment 2, it is a figure which shows the result of having evaluated the permeability | transmittance to the SHCL of the methyl sulfate neostigmine of eye drops (Example 4 and Comparative Example 1). In the reference test example 2, it is a figure which shows the result of having evaluated the permeability | transmittance to the SHCL of the pyridoxine hydrochloride of eyedrops (reference example 1-2). In the reference test example 3, it is a figure which shows the result of having evaluated the adsorption | suction characteristic of the lipid in various soft contact lenses. In Test Example 3, it is a figure which shows the result of having evaluated the influence which acts on adsorption | suction of the lipid to nonionic SHCL about a test liquid (Example 5 and Comparative Example 2-4). In the reference test example 4, it is a figure which shows the result of having evaluated the adsorptivity of the pollen protein to various soft contact lenses. In Test example 4, it is a figure which shows the result of having evaluated the effect which the test liquid (Example 6 and Comparative Example 5-6) removes the pollen protein adsorbed to ionic SHCL.

(I) SHCL eye drops The SHCL eye drops of the present invention contain at least one selected from the group consisting of neostigmine and a salt thereof (hereinafter also referred to as component (A)). Neostigmine is a compound also called N-(-3-dimethylcarbamoyloxyphenyl) -N, N, N-trimethylammonium. Neostigmine and its salt are known compounds as an eye focus control function improving agent, and may be synthesized by a known method or obtained as a commercial product.

  Among the components (A) used in the present invention, neostigmine salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples thereof include methyl sulfate (methyl sulfate neostigmine), bromide salt (neostigmine bromide) and the like. Among these salts, methyl sulfate is preferable. These neostigmine salts may be used alone or in any combination of two or more.

  In the eye drop for SHCL of the present invention, as component (A), one kind of neostigmine and a salt thereof may be selected and used alone, or two or more kinds may be arbitrarily combined. May be used. From the viewpoint of more effectively exerting the effect of improving the SHCL permeability by the surfactant, the component (A) used in the present invention is preferably a neostigmine salt, more preferably neostigmine methylsulfate. The component (A) exemplified here is also suitable from the viewpoint of further enhancing the lipid adsorption inhibiting action on nonionic SHCL or further enhancing the pollen protein accumulation inhibiting effect on ionic SHCL.

  In the eye drop for SHCL of the present invention, the blending ratio of the component (A) is appropriately set according to the type of the component (A), the type of the other blended components, etc. The total amount of the component (A) is 0.0005 to 0.1 w / v%, preferably 0.001 to 0.05 w / v%, more preferably 0.005 to 0.01 w / v%. Is exemplified.

  Furthermore, the eye drop for SHCL of the present invention contains a surfactant (hereinafter also referred to as component (B)) in addition to the component (A). By adding a surfactant in this way, it is possible to improve the permeability of neostigmine and / or its salt to SHCL, and to remarkably suppress lipid adsorption to nonionic SHCL. Furthermore, it becomes possible to effectively suppress the accumulation of pollen protein in ionic SHCL.

  The surfactant used as the component (B) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and is a nonionic surfactant or amphoteric. Examples include surfactants, anionic surfactants, and cationic surfactants.

  Specific examples of the nonionic surfactant that can be blended as the component (B) 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.

  Further, as the amphoteric surfactant that can be blended as the component (B) (that is, a surfactant having both a cationic site and an anionic site in the molecule), specifically, an alkyldiamino Examples thereof include ethyl glycine and its salt (alkyldiaminoethyl glycine hydrochloride).

  Specific examples of the cationic surfactant that can be blended as the component (B) include quaternary ammonium salt type cationic surfactants such as benzalkonium chloride and benzethonium chloride; chlorhexidine salts Examples include amine salt-type cationic surfactants such as chlorhexidine gluconate and chlorhexidine hydrochloride, and polyhexamethylene biguanide salts (such as polyhexamethylene biguanide hydrochloride).

  Specific examples of the anionic surfactant that can be blended as the component (B) include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, α Examples include olefin sulfonic acid.

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

  Among the above components (B), from the viewpoint that the effect of improving the permeability of neostigmine and / or its salt to SHCL is greatly enhanced, preferably a nonionic surfactant, a cationic surfactant, an amphoteric interface More preferably, nonionic surfactant, cationic surfactant; more preferably, POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE / POP block copolymers, quaternary ammonium salt type positive Ionic surfactants; more preferably POE sorbitan fatty acid esters, POE hydrogenated castor oils, quaternary ammonium salt type cationic surfactants; particularly preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60, benzil chloride Luconium is exemplified. The component (B) exemplified here is also suitable from the viewpoint of further enhancing the lipid adsorption inhibiting effect on nonionic SHCL or further enhancing the pollen protein accumulation inhibiting effect on ionic SHCL.

  In the eye drop for SHCL of the present invention, the blending ratio of the component (B) is appropriately set according to the type of the component (B), the type of other blending components, etc., as an example, The total amount of the component (B) is 0.001-1 w / v%, preferably 0.005-0.5 w / v%, more preferably 0.01-0.3 w / v%. Is done.

  In the eye drop for 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 neostigmine and / or a salt thereof to SHCL From the viewpoint of more effectively improving the permeability of the component (A), the total amount of the component (B) is 10 to 20000 parts by weight, preferably 50 to 10000 parts by weight, more preferably, per 100 parts by weight of the total amount of the component (A). It is desirable to satisfy the ratio of 100 to 6000 parts by weight. In addition, by satisfying the above ratio, it becomes possible to more effectively suppress lipid adsorption to nonionic SHCL, or it is possible to more effectively suppress the accumulation of pollen protein in ionic SHCL.

  The eye drop for SHCL of the present invention may further contain a buffering agent in addition to the components (A) and (B). The buffer that can be incorporated into the eye drops for SHCL 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, tris buffer, epsilon-aminocaproic acid, aspartic acid, aspartate and the like. These buffering agents may be used in combination. Preferred buffering agents are borate buffering agents, phosphate buffering agents, carbonate buffering agents, and citrate buffering agents, and more preferred buffering agents are boric acid buffering agents and phosphate buffering agents, and particularly preferred buffering agents. Is a borate buffer. Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, 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 a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid, etc.) Calcium acetate, sodium dihydrogen citrate, disodium citrate, etc.); with acetate buffer Acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); as a Tris buffer, tris (hydroxymethyl) aminomethane or a salt thereof (hydrochloride, acetate, sulfonate, etc.); Examples include 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 SHCL eyedrops of the present invention, the blending ratio of the buffering agent varies depending on the type of buffering agent used, the type and amount of other blending components, the use of the eyedrops, etc. However, for example, the total amount of the buffer is 0.01 to 10 w / v%, preferably 0.1 to 5 w / v%, more preferably, with respect to the total amount of the eye drops. A ratio of 0.5 to 2 w / v% is exemplified.

  The eye drop for SHCL of the present invention may further contain an isotonic agent. The isotonic agent that can be incorporated into the SHCL eye drops of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such isotonic agents include, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, acetic acid Examples include potassium, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol and the like. Among these isotonic agents, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, and propylene glycol are preferable from the viewpoint of more reliably achieving the effects of the present invention. These isotonic agents may be used alone or in any combination of two or more.

  When an isotonic agent is blended in the SHCL eyedrops of the present invention, the blending ratio of the isotonic agent differs depending on the type of tonicity agent used and cannot be uniformly defined. For example, the ratio by which the total amount of the tonicity agent is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v% is exemplified.

  The pH of the eye drops for SHCL of the present invention is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As an example of the pH of the eye drops for SHCL of the present invention, 4.0 to 9.5, preferably 5.0 to 8.5, more preferably 5.5 to 8.0, still more preferably 6.0 to The range which becomes 8.0 is mentioned.

  Further, the osmotic pressure of the eye drop for SHCL 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 eye drops for SHCL of the present invention, a range of preferably 0.7 to 5.0, more preferably 0.9 to 3.0, and particularly preferably 1.0 to 2.0 is mentioned. It is done. 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 drop for 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, examples of the components used in the SHCL eyedrops of the present invention include the following components.
Antihistamines: for example, iproheptin, diphenhydramine, chlorpheniramine maleate and the like.
Decongestant: Tetrahydrozoline, naphazoline, epinephrine, ephedrine, methylephedrine, etc.
Bactericides: for example, acrinol, cetylpyridinium, etc.
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, sodium hyaluronate, sulfamethoxazole, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl flufenamate, bendazac, piroxicam, ketoprofen, felbinac, purple root , Horse chestnuts, and salts thereof.

In addition, in the eye drops for SHCL of the present invention, various additives are appropriately selected according to conventional methods according to the use and form as long as they do not impair the effects of the invention, and one or more of them are selected. An appropriate amount may be contained 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), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate, sodium hyaluronate 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 antibacterials: for example, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate Oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds, glowkill (trade name, manufactured by Rhodia), 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.
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.
Perfume or refreshing agent: menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, ryuno and the like. These may be either d-form, l-form or dl-form, and are formulated as essential oils (mint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc.) May be.

  The eye drop for SHCL of the present invention, for example, in the aqueous carrier such as purified water, physiological saline, etc., so that the above components (A) and (B), and other compounding components as required, at a desired concentration It is added and prepared according to a conventional method.

  In the eye drop for SHCL of the present invention, the type of SHCL to be applied is not particularly limited, and all SHCL currently marketed or marketed in the future can be applied. Among these, nonionic SHCL tends to be less permeable to neostigmine and / or a salt thereof than ionic SHCL. According to the eye drop for SHCL of the present invention, the permeability of neostigmine and / or a salt thereof can be effectively improved even for SHCL having such a low permeability. In view of such an effect of the present invention, non-ionic SHCL is an example of a suitable application target of the eye drop for SHCL of the present invention. In addition, a specific problem that nonionic SHCL is very easy to adsorb lipid has been clarified, and according to the eye drop for SHCL of the present invention, lipid adsorption to this nonionic SHCL is effectively suppressed. be able to. Also from this point, nonionic SHCL can be mentioned as an example of a suitable application object. From another viewpoint, ionic SHCL has a unique problem that it easily adsorbs a large amount of pollen protein. According to the SHCL eyedrop of the present invention, the accumulation of pollen protein in ionic SHCL is effective. Can be suppressed. In view of the effects of the present invention, ionic SHCL may be mentioned as an example of a suitable application target of the eye drop for SHCL of the present invention. Non-ionic here means that the ionic component content in the contact lens material is less than 1 mol% in accordance with US FDA (Food and Drug Administration) standards, as normally understood by those skilled in the art. The property means that the content of ionic components in the contact lens material is 1 mol% or more in accordance with US FDA standards. Further, the moisture content of SHCL to be applied is not particularly limited, and examples thereof include 90% or less, preferably 60% or less, and more preferably 50% or less. Since SHCL contains a hydrogel material, it contains at least more than 0% moisture.

  Moreover, in nonionic SHCL, there exists a tendency for the permeability | transmittance of neostigmine and / or its salt to become low as a moisture content becomes low. According to the eye drop for SHCL of the present invention, the permeability of neostigmine and / or a salt thereof can be effectively improved even for SHCL having such a low permeability. In view of the effect of improving the lens permeability of the present invention, an example of a suitable application target of the eye drop for SHCL of the present invention is nonionic SHCL having a low moisture content of 50% 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.

  In addition, compared to non-silicone hydrogel contact lenses, which are generally soft, SHCL, which is a hard material, tends to cause deterioration of the feeling of use due to lens deformation and reduced wettability due to the adsorption of foreign substances, and tends to cause ocular mucosal damage. It is in. According to the eyedrops for SHCL of the present invention, it is possible to effectively suppress the adsorption and accumulation of lipids and pollen proteins to the hard material SHCL that easily causes a deterioration in feeling of use and ocular mucosal damage. It is also possible to effectively prevent deterioration of the feeling of use and ocular mucosal damage. In view of the effects of the present invention, SHCL having a relatively high hardness can be cited as a suitable application target of the eye drop for SHCL of the present invention. Preferably, the hardness of SHCL to be applied is 3 g or more, preferably 4 g or more, more preferably 6 g or more, and still more preferably 8 g or more when measured by the following measuring method using a texture analyzer. Further, the upper limit value of the hardness of the SHCL to be applied is not particularly limited, but is preferably 15 g or less, more preferably 12 g or less.

  The hardness of the contact lens can be specifically measured as follows using a texture analyzer (product name: TA.XT.plus TEXTURE ANALYSER (manufactured by Stable Micro Systems Limited)).

  First, remove the contact lens to be measured from the package, wipe off excess water, rinse with physiological saline (0.9% sodium chloride solution), and then raise the convex surface on the bottom of the plastic petri dish filled with physiological saline. Arrange so that Next, the contact lens is adjusted to be directly below the probe of the measuring instrument, and measurement is performed under the following measurement conditions.

[Measurement condition]
Instrument settings:
Test mode Compression measurement Probe type φ10mm cylinder probe
Target Mode Distance
Distance 2.5mm
Triger Type Auto
Triger Force 0.1g
Test Speed 1.0mm / sec
Measure the stress when crushing the lens 2.5mm (2.5 seconds) after the probe starts to push down the lens apex, and record the maximum value as hardness.

  The eye drop for SHCL of the present invention can be applied directly to the eye wearing the SHCL.

  Since the eye drop for SHCL of the present invention can increase the amount of neostigmine and / or its salt reaching the cornea, it is effective in improving the focus adjustment function of the eye, and as an agent for improving eye fatigue (fatigue eyes), In particular, an agent for improving eye fatigue induced by wearing contact lenses (for example, when using contact lenses with overcorrected power, or when using a near-sight work on a PC for a long time while wearing contact lenses) It is useful as an agent for improving eye fatigue.

  In addition, it is said that the cutting of the trigeminal nerve distributed in the cornea reduces the amount of acetylcholine, which is a neurotransmitter, and thereby reduces the rate of cell division of corneal epithelial cells. Neostigmine, a type of cholinesterase inhibitor, inhibits cholinesterase activity and increases the acetylcholine concentration at the nerve terminal, thereby suppressing the decrease in corneal epithelial cell division rate and maintaining corneal epithelial cell homeostasis . Since the eye drop for SHCL of the present invention can increase the amount of neostigmine and / or its salt reaching the cornea, it can be advantageously used for maintaining homeostasis of such corneal epithelial cells.

  Furthermore, the ophthalmic solution for SHCL of the present invention can effectively prevent corneal epithelial disorders such as corneal staining caused by lipid adsorption to nonionic SHCL. It can be used as a preventive agent. In addition, since the eye drop for SHCL of the present invention can be easily used during ionic SHCL wearing, it can effectively suppress the adsorption and accumulation of pollen protein during ionic SHCL wearing, and ionic SHCL wearing It is possible to wear ionic SHCL comfortably while preventing discomfort inside. Therefore, the pollen protein adsorbed on the contact lens is prevented from being kept in contact with the eye for a long time, and it is also effective in preventing allergy and preventing deterioration due to pollen. Therefore, it is also suitable for application to ionic SHCL users of hay fever or hay fever reserve.

(II) A method for improving the permeability of neostigmine and / or its salt to SHCL, and a method for imparting to eye drops the effect of improving the permeability of neostigmine and / or its salt to SHCL As described above, to SHCL The permeability of the component (A) can be improved by the component (B).

  Therefore, the present invention, from yet another viewpoint, uses (A) at least one selected from the group consisting of neostigmine and a salt thereof and (B) a surfactant in combination. Provided is a method for improving the permeability of component (A). Further, the present invention provides an SHCL eye drop containing at least one selected from the group consisting of (A) neostigmine and a salt thereof, and (B) a surfactant, There is also provided a method of imparting an action to improve the permeability of the component (A).

  In the method, the types and blending ratios of the components (A) and (B) to be used, the types and blending ratios of other components, the types of SHCL to be applied to the eye drops for SHCL, etc. (I) SHCL eye drops ”.

(III) Agent for improving permeability of neostigmine and / or salt thereof to SHCL As described above, the permeability of the component (A) to SHCL can be improved by the component (B).

  Therefore, the present invention improves the permeability of at least one selected from the group consisting of (A) neostigmine and a salt thereof into SHCL, which contains (B) a surfactant as an active ingredient, from another viewpoint. An agent is provided.

  In the agent, the type of component (B) that is an active ingredient, the target SHCL, the type of component (A) that is subject to permeability to SHCL, etc., the above ((I) SHCL eye drops) It is the same.

(IV) A screening method for a substance that improves the permeability of neostigmine and / or a salt thereof to SHCL Further , as described above, the present inventor has proposed that the component (A) has a significantly low permeability to SHCL. Knowledge has been obtained. Therefore, the present invention further provides a method for screening a permeability improving substance for improving the permeability of at least one kind of neostigmine selected from the group consisting of neostigmine and a salt thereof against SHCL. Specifically, this screening method is a method including the following steps (a) to (c).
(a) preparing a control solution containing at least one kind of neostigmines selected from the group consisting of neostigmine and a salt thereof, and a test solution containing neostigmines and a test substance as test solutions,
(b) Each of the above test solutions is brought into contact with only one side of the silicone hydrogel contact lens for a predetermined time, and the amount of neostigmine exuded from the other side of the lens not contacted with the above test solution is measured. The step of determining the permeation amount of neostigmines of each test solution, and
(c) A step of selecting a test solution having a permeation amount of neostigmine measured in the step (b) larger than that of the control solution, and selecting a test substance contained in the test solution as the permeability improving substance.

  In the present screening method, the test substance is a candidate substance for the permeability improving substance to be used for screening. Moreover, it is desirable that the candidate substance is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable so that the candidate substance can be incorporated into the eye drops for SHCL.

In the step (a), the test solution is, for example, 0.0005 to 0.1 w / v% of at least one neostigmine selected from the group consisting of neostigmine and a salt thereof in an aqueous carrier such as water or a buffer. It is prepared by adding so that a test substance may be added in an appropriate amount. Here, it is desirable to dilute the test substance in stages and prepare a test solution containing a plurality of concentrations of the test substance. The control solution containing neostigmines preferably has the same composition as the test solution except that the test substance is not added. Using the test solution and the control solution thus prepared as test solutions, they are subjected to the next step (b).

  The step (b) can be performed using an apparatus or the like that has two compartments (cells) capable of containing a solution and these two compartments are separated via SHCL. As such an apparatus, for example, a membrane permeation experiment apparatus manufactured by Beadrex can be used. Specifically, the test solution (control solution or test solution) is filled in one compartment of the device, and the other compartment is not filled with anything, or preferably a solution containing no neostigmines (hereinafter referred to as “nostigmines”). Filled with a blank solution), etc., and after a predetermined time (for example, about 4 to 24 hours), moves to the other compartment (the blank solution when filled with a blank solution) via SHCL. Quantify the amount of neostigmine. The amount of neostigmine thus determined is the permeation amount of neostigmine determined in the step (b). In addition, as for the said blank solution, it is desirable that the osmotic pressure is equivalent to the test solution (control solution or test solution) with which it is filled.

  Further, in the step (c) relating to the selection of the permeability enhancing substance, in order to select a permeability enhancing substance having a strong effect of improving the permeability of neostigmines to SHCL, the neostigmines required in the step (b) A test solution having a larger amount of permeation than the control solution may be selected.

  The permeability-improving substance obtained by this screening method can be incorporated into SHCL eye drops containing neostigmine and / or its salt for the purpose of improving the permeability of neostigmine and / or its salt to SHCL. .

(V) Method for inhibiting lipid adsorption to nonionic SHCL, and method for imparting action to inhibit lipid adsorption to nonionic SHCL As described above, by using the components (A) and (B) together It is possible to suppress the adsorption of lipids to nonionic SHCL.

  Therefore, the present invention provides a non-ionic SHCL eye drop containing at least one selected from the group consisting of (A) neostigmine and a salt thereof, and (B) a surfactant, from another viewpoint. Provided is a method for suppressing adsorption of lipids to nonionic SHCL, which is characterized by contacting with SHCL. Furthermore, the ophthalmic solution for SHCL is formulated with (A) at least one selected from the group consisting of neostigmine and a salt thereof, and (B) a surfactant. Provided is a method for imparting an action of suppressing the adsorption of lipid to the eye drop.

  In this method, the types and blending ratios of components (A) and (B), the types and blending ratios of other ingredients to be blended, the SHCL eye drop formulation, the types of nonionic SHCL to be applied, etc. Is the same as “(I) SHCL eye drops”.

(VI) A method for suppressing the accumulation of pollen protein in ionic SHCL, and a method for imparting an eye drop with an action of suppressing the accumulation of pollen protein in ionic SHCL As described above, (A) and (B In combination with ingredients, even if the ionic SHCL wearing eye is exposed to pollen, it can promote the removal of pollen protein from the ionic SHCL to prevent reattachment, and the accumulation of pollen protein in the ionic SHCL It becomes possible to suppress.

  Therefore, the present invention, from yet another viewpoint, an ophthalmic solution for SHCL containing (A) at least one selected from the group consisting of neostigmine and a salt thereof and (B) a surfactant, Provided is a method for suppressing the accumulation of pollen protein in ionic SHCL, which is characterized by contacting. Furthermore, pollen protein to ionic SHCL, characterized in that at least one selected from the group consisting of (A) neostigmine and a salt thereof and (B) a surfactant are added to the eye drops for SHCL. A method for imparting the eye drop with an action of suppressing the accumulation of the above is provided.

  In the method, the types and blending ratios of the components (A) and (B) to be used, the types and blending ratios of other components, the types of ionic SHCL to be applied, etc. It is the same as “eye drops for SHCL”.

EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.
Reference Test Example 1: Comparative Evaluation of SCL Permeability of Methylsulfate Neostigmine Using SCL shown in Table 1, the lens permeability of methylsulfate neostigmine was evaluated.

  Measurement of SCL permeability evaluation of neostigmine methyl sulfate was carried out according to the following method using a membrane permeation experiment apparatus (manufactured by Beadrex). Each soft contact lens shown in Table 1 was set in a membrane permeation experiment apparatus. One cell I had 5 ml of physiological saline (0.9 w / v% sodium chloride) and the other cell II had 0.1 w / v. 5 ml of a solution containing% neostigmine methylsulfate (boric acid 0.5 w / v%, borax appropriate amount, sodium chloride 0.7 w / v%; pH 7.5) was charged. Then, 1 ml of the physiological saline solution was collected 4 hours later, and the concentration of neostigmine methyl sulfate was measured by HPLC according to a conventional method, and the amount of neostigmine methyl sulfate transferred to cell I was calculated. From the thus calculated amount of neostigmine methyl sulfate transferred to cell I, the lens transmittance of neostigmine methyl sulfate was calculated according to the following equation.

  The results are shown in FIG. As is clear from FIG. 1, it was found that the lenses A and B, which are silicone hydrogel contact lenses, have significantly poorer lens permeability of neostigmine methyl sulfate than the lens C, which is a hydrogel contact lens.

Test Example 1: Lens permeation test of neostigmine methylsulfate 1:
Using the eye drops shown in Table 2 (Examples 1-3 and Comparative Example 1), the SHCL permeability of neostigmine methylsulfate was evaluated.

  The measurement of SHCL permeability evaluation of neostigmine methylsulfate was performed according to the following method using a membrane permeation experiment apparatus (manufactured by Beadrex). The lens A (SHCL) shown in Table 1 is set in a membrane permeation experiment apparatus. One cell I contains 5 mL of physiological saline (0.9 w / v% sodium chloride), and the other cell II shows Table 2. Each eye drop was accurately filled with 5 mL. Incidentally, the osmotic pressures of the respective eye drops were arranged to be substantially the same. Subsequently, 1 mL of the physiological saline solution was collected 24 hours later, and the concentration of neostigmine methyl sulfate was measured by HPLC according to a conventional method, and the amount of neostigmine methyl sulfate transferred to Cell I was calculated. From the thus calculated amount of neostigmine methylsulfate transferred to cell I, the lens transmittance (%) of neostigmine methylsulfate was calculated in the same manner as in Reference Test Example 1.

  The results are shown in FIG. As is clear from FIG. 2, it was found that in the eye drop of Example 1-3, the lens transmittance of neostigmine was significantly increased as compared with the eye drop of Comparative Example 1. That is, it has been clarified that the use of neostigmine methyl sulfate and a nonionic surfactant (polysorbate 80 or polyoxyethylene hydrogenated castor oil 60) improves the permeability of neostigmine methyl sulfate to SHCL.

Test Example 2: Mole sulfate neostigmine lens transmission test 2:
Using the eye drops shown in Table 3 (Example 4 and Comparative Example 1), the SHCL permeability of neostigmine methyl sulfate was evaluated in the same manner as in Test Example 1 above.

  The results are shown in FIG. As can be seen from FIG. 3, the ophthalmic solution of Example 4 showed a significantly higher value of neostigmine lens transmittance than the ophthalmic solution of Comparative Example 1. That is, from this result, it was confirmed that the permeability of methylsulphate neostigmine to SHCL is improved by using neostigmine methylsulfate and a cationic surfactant (benzalkonium chloride) in combination.

Reference Test Example 2: Lens Permeability Test of Pyridoxine Hydrochloride Pyridoxine hydrochloride is known to exhibit the action of promoting metabolism of corneal cells and relieving eye fatigue. Therefore, even when pyridoxine hydrochloride is added to the eye drops for SHCL, it is required to design the formulation so that pyridoxine hydrochloride can penetrate the SHCL and reach the cornea, as in the case of adding neostigmine and / or a salt thereof. . Therefore, the following tests were conducted to evaluate the permeability of pyridoxine hydrochloride to SHCL.

  Specifically, using the eye drops shown in Table 4 (Reference Example 1-2), a test was performed in the same manner as in Test Example 1 above, and the SHCL permeability of pyridoxine hydrochloride was evaluated.

  The results are shown in FIG. From these results, it was confirmed that pyridoxine hydrochloride has low SHCL permeability like neostigmine and / or its salt, but SHCL permeability is not improved even when a surfactant (polysorbate 80) is used in combination.

Comprehensive Consideration Regarding Lens Permeability Test From the above results, eye drops containing neostigmine and / or a salt thereof and a surfactant are effective in applying an effective amount of neostigmine and / or a salt thereof to the cornea even when applied to an eye wearing SHCL. It was confirmed that a pharmacological effect based on neostigmine and / or a salt thereof can be effectively exhibited. Moreover, it was also confirmed that the improvement in SHCL permeability of the active ingredient by the combined use with such a surfactant is a unique effect recognized by selecting neostigmine and / or a salt thereof as the active ingredient.

Reference Test Example 3: Evaluation of Lipid Adsorption of Various SCLs The following experiments were conducted using the various soft contact lenses shown in Table 5 to evaluate the lipid adsorption properties of the soft contact lenses. The soft contact lenses used in this test are all commercially available products.

First, a chloroform solution and methanol containing fluorescently labeled lipid (N- (fluorescein-5-thiocarbamoyl) -1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt; manufactured by invitrogen) at a concentration of 1 mg / mL A physiological saline solution (0.9 w / v% sodium chloride) was added to 500 μL of a mixed solution prepared by mixing 1 and 4 at a volume ratio of 1: 4 to prepare a total amount of 20 mL as a fluorescent lipid solution. Each soft contact lens was immersed in physiological saline for overnight or longer and pre-tested. The sample group was obtained by immersing each soft contact lens in 1 mL of a fluorescent lipid solution in a 24-well microplate and shaking at 34 ° C. for 24 hours. Moreover, each soft contact lens was immersed one by one in physiological saline as a blank group, and the same shaking treatment as the sample group was performed. After 24 hours, each soft contact lens was transferred to a plate containing 1 mL of fresh physiological saline, and the fluorescence intensity of each well was measured using a fluorescence plate reader (Thermo Fisher Scientific Inc.) (excitation wavelength: 485 nm, (Fluorescence wavelength: 538 nm). A value obtained by subtracting the fluorescence intensity of the blank group from the fluorescence intensity of the sample group was calculated as an index of the amount of adsorbed lipid.

  The results are shown in FIG. As is clear from FIG. 5, the lipid adsorption amount of nonionic SHCL (lenses I and II) is significantly larger than that of ionic SHCL (lenses III) and conventional hydrogel lenses (lenses IV to VI). It was confirmed that the problem of lipid contamination was serious.

Test Example 3: Nonionic SHCL lipid adsorption inhibition evaluation Using the nonionic SHCL (Lens I) in which significant lipid adsorption was observed in Reference Test Example 3 above, using each test solution shown in Table 6 below, The effect of nonionic SHCL on lipid adsorption was investigated.

  First, a 1 mg / mL chloroform solution of methanol (N- (fluorescein-5-thiocarbamoyl) -1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt; manufactured by invitrogen) and methanol is used 1: Saline solution (0.9 w / v% sodium chloride) was added to 500 μL of the mixed solution mixed at a volume ratio of 4, and a total volume of 20 mL was prepared as a fluorescent lipid solution. The lens I was immersed in physiological saline for overnight or longer and pre-test treatment was performed. Next, 500 μL of each test solution (Example 5 and Comparative Example 2-4) and 1500 μL of a fluorescent lipid solution are placed in each well of a 24-well microplate, and each lens I that has undergone pre-test treatment is placed therein. It was immersed and shaken at 34 ° C. for 24 hours (sample group). In addition, a well containing 500 μL of each test solution (Example 5 and Comparative Example 2-4) and 1500 μL of physiological saline was prepared as a blank group, and each lens I that had undergone pre-test treatment was placed therein. The immersion treatment was performed in the same manner (blank group). After 24 hours, each lens I that had been shaken was transferred to a plate containing 1 mL of new physiological saline, and the fluorescence intensity of each well was measured using a fluorescence plate reader (Thermo Fisher Scientific Inc.) ( Excitation wavelength: 485 nm, fluorescence wavelength: 538 nm). The value obtained by subtracting the fluorescence intensity of the blank group from the fluorescence intensity of each sample group is obtained as an index of the amount of adsorbed lipid, and the amount of adsorbed lipid of each test solution when the amount of adsorbed lipid of the control (Comparative Example 2) is 100%. The relative value (%) was calculated.

  The result is shown in FIG. As shown in FIG. 6, it is clear that by using a combination of neostigmine methylsulfate and a surfactant, it is possible to synergistically suppress lipid adsorption to nonionic SHCL, compared to the case where each is used alone. It was.

Reference Test Example 4: Evaluation of Pollen Protein Adsorption Characteristics to SCL Four kinds of soft contact lenses shown in Table 7 were used in the test to evaluate the pollen protein adsorption characteristics to the soft contact lenses.

  First, the lenses used for the test were immersed one by one in 4 mL of physiological saline and stored overnight at room temperature (lens pretreatment).

  Pollen protein antigen (Cedar Pollen Extract-Ja, manufactured by LSL, Inc., property: freeze-dried powder (Cedar Pollen crude extract Mountain ceder, extracted from pollen of Juniperus Asheii)) dissolved in physiological saline 5 mg / 30 mL pollen protein solution was prepared. In each hole of the 24-well plate, 1.0 mL of pollen protein solution was put, and after wiping off excess moisture from the pretreated lens, it was immersed and shaken at 34 ° C. and 120 rpm for 18 hours. Next, take out the lens, quickly soak (about 1 second) in 100 mL of physiological saline, rinse the excess liquid, and then lightly drain the water using the edge of a beaker, then put the pollen protein into each hole of the 24-well plate. It was immersed in 1 mL of separation liquid (aqueous solution containing 1% sodium carbonate and 1% SDS). The mixture was shaken at 34 ° C. and 120 rpm for 3 hours to separate the pollen protein adsorbed on the lens into the pollen protein separation solution.

  Using a micro BCA assay kit (Thermo SCIENTIFIC, Pierce # 23235), the amount of pollen protein in the pollen protein separation solution was quantified as an albumin equivalent value to determine the amount of pollen protein adsorbed to the lens.

  The hardness of each soft contact lens is a value measured using a texture analyzer (product name: TA.XT.plus TEXTURE ANALYSER (manufactured by Stable Micro Systems Limited)) as described above.

  The results are shown in FIG. As shown in FIG. 7, when the lens 1 that is ionic SHCL is used, the lens 3 and the lens 4 that are non-silicon soft contact lenses and the lens 2 that is non-ionic SHCL are remarkably different. High pollen protein adsorption was observed. From this result, pollen protein tends to adsorb very large amount to ionic SHCL among soft contact lenses, and ionic SHCL has a unique problem that it is very easy to adsorb pollen protein. Was confirmed.

Test Example 4: Evaluation of inhibition of pollen protein accumulation with respect to ionic SHCL The following test was performed using the lens 1 (ionic SHCL) in which significant adsorption of pollen protein was confirmed in Reference Test Example 4 above.

  First, the lenses 1 were immersed one by one in 5 mL of physiological saline and stored at room temperature for 5 hours (lens pretreatment). Pollen protein antigen (CEL Pollen Extract-Ja, manufactured by LSL Co., Ltd.) Properties: Lyophilized powder (Cedar Pollen crude extract Mountain ceder, extracted from pollen of Juniperus Asheii) in physiological saline, A 5 mg / 50 mL pollen protein solution was prepared. 1.0 mL of the pollen protein solution was put into each hole of the 24-well plate, the excess moisture of the pretreated lens was wiped off and immersed, and shaken at 34 ° C. and 400 rpm for 24 hours.

  The lens 1 immersed in the pollen protein solution is taken out, quickly immersed in 100 mL of physiological saline (about 1 second), rinsed with excess liquid, wiped off moisture, and placed in a 24-well plate. Each sample was immersed in 1.0 mL of a test solution (Example 6, Comparative Example 5-6, and control) and shaken at 34 ° C. and 400 rpm for 18 hours. After that, take out the lens 1, soak it quickly (about 1 second) in 100 mL of physiological saline, rinse the excess liquid, and then use a beaker's edge to lightly drain the water and place it in a 24-well plate. It was immersed in 0.5 mL of the liquid for use (aqueous solution containing 1% sodium carbonate and 1% SDS). The mixture was shaken at 34 ° C. and 400 rpm for 3 hours to separate the pollen protein adsorbed on the lens into the pollen protein separation solution.

  Moreover, in order to calculate the amount of pollen protein adsorption more accurately by subtracting the influence of each test solution, as a blank group, except that the step of treating with the pollen protein solution was changed to treatment with physiological saline, In the same manner as described above, a sample treated with each test solution and treated with a pollen protein separating solution was prepared.

  Using a micro BCA assay kit (Thermo SCIENTIFIC, Pierce # 23235), the amount of pollen protein present in the pollen protein separation solution was quantified as an albumin equivalent, and the amount of pollen protein detached from lens 1 (pollen) Protein adsorption amount) was determined. In calculating the amount of pollen protein adsorbed, the amount of pollen protein adsorbed was determined by subtracting the absorbance of the blank group from the absorbance of each sample and calculating it as an albumin equivalent value. Next, according to the following formula, the rate of improvement in pollen protein adsorption (%) from the ratio of the amount of pollen protein adsorbed when using the test solution of each Example or Comparative Example to the amount of pollen protein adsorbed when using the control test solution Was calculated.

  The results are shown in FIG. As a result, when neostigmine methylsulfate and a surfactant are used in combination, a very high pollen protein adsorption improvement rate is achieved, and the amount of pollen protein adsorbed on ionic SHCL can be effectively reduced and accumulated. It became clear that it can suppress (Example 6).

Formulation Examples With the formulation described in Table 9, eye drops for SHCL (Examples 7-21) are prepared.

Claims (13)

An eye drop for a silicone hydrogel contact lens, comprising (A) at least one selected from the group consisting of neostigmine and a salt thereof, and (B) a surfactant. The eye drop for a silicone hydrogel contact lens according to claim 1, wherein the blending ratio of the component (A) is 0.0005 to 0.1 w / v%. The eye drop for a silicone hydrogel contact lens according to claim 1 or 2, wherein the blending ratio of the component (B) is 0.001 to 1 w / v%. The eye drop for a silicone hydrogel contact lens according to any one of claims 1 to 3, wherein the total amount of the component (B) per 100 parts by weight of the total amount of the component (A) is 10 to 20000 parts by weight. The eye drop for a silicone hydrogel contact lens according to any one of claims 1 to 4, further comprising (C) a buffer. The eye drop for a silicone hydrogel contact lens according to any one of claims 1 to 5 , having a pH of 4 to 9.5. (A) A fatigue eye improving agent comprising at least one selected from the group consisting of neostigmine and a salt thereof, and (B) a surfactant, and comprising an eye drop applied to a silicone hydrogel contact lens. (A) Constancy of corneal epithelial cells comprising at least one selected from the group consisting of neostigmine and a salt thereof, and (B) a surfactant, and comprising an eye drop applied to a silicone hydrogel contact lens. Agent for maintenance or prevention of disability. (A) Prevention or improvement of allergic symptoms comprising at least one selected from the group consisting of neostigmine and a salt thereof, and (B) a surfactant, and an eye drop applied to a silicone hydrogel contact lens. Agent. For improving the permeability of at least one selected from the group consisting of (A) neostigmine and a salt thereof into a silicone hydrogel contact lens containing (B) a surfactant as an active ingredient for eye drops Agent. A lipid adsorption inhibitor for a nonionic silicone hydrogel contact lens, comprising (A) at least one selected from the group consisting of neostigmine and a salt thereof, and (B) a surfactant, for eye drops. Pollen protein accumulation inhibitor for ionic silicone hydrogel contact lenses, comprising (A) at least one selected from the group consisting of neostigmine and a salt thereof, and (B) a surfactant, for eye drops . A screening method for a permeability-improving substance that improves the permeability of at least one neostigmine selected from the group consisting of neostigmine and a salt thereof for a silicone hydrogel contact lens,
(A) a step of preparing a control solution containing neostigmines and a test solution containing neostigmines and a test substance, respectively, as test solutions;
(B) Each of the test solutions is brought into contact with only one side surface of the silicone hydrogel contact lens for a predetermined time, and the amount of neostigmines exuded from the other side surface of the lens not contacting the test solution is measured. The step of determining the permeation amount of neostigmines in each test solution, and (c) the test solution having a permeation amount of neostigmines measured in the step (b) above that of the control solution is selected and included in the test solution A test substance to be selected as the permeability improving substance,
A screening method comprising:

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