JP5725786B2 - Nonionic silicone hydrogel contact lens ophthalmic composition - Google Patents

Description

  The present invention relates to an ophthalmic composition for a nonionic silicone hydrogel contact lens that can suppress the adhesion of corneal cells to the surface of the nonionic silicone hydrogel contact lens. The present invention also relates to a method for suppressing adhesion of corneal cells to the surface of a nonionic silicone hydrogel contact lens. Furthermore, the present invention improves the permeability of pemirolast and / or its salt to nonionic silicone hydrogel contact lenses, and improves the permeability of pemirolast and / or its salts to nonionic silicone hydrogel contact lenses. The present invention relates to a method for screening a permeability improving substance to be made.

  Furthermore, this invention relates to the ophthalmic composition for nonionic silicone hydrogel contact lenses by which the friction increasing effect | action with respect to the nonionic silicone hydrogel contact lens surface was reduced. The present invention also relates to a method for reducing friction on the surface of a 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 blending silicone with 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 an ophthalmic composition to be applied to a soft contact lens with sufficient consideration of safety and other effects. In particular, since soft contact lenses vary in the presence or absence of ionicity and the level of moisture content depending on the material, it is important to design a formulation according to the properties of the applied soft contact lens.

  In addition, SCL is generally larger than hard contact lenses, and during wearing, the corneal surface is almost entirely covered, and a part of the conjunctiva around the cornea is also covered. And while wearing SCL, there is almost no inflow and outflow of tears between SCL and the eye surface (that is, tear exchange by pump action), and tear exchange under SCL is permeation of tears through SCL. It is known that it depends on (see Non-Patent Document 1-2). In this way, most of the tear fluid exchange under SCL is performed by permeation of tear fluid through SCL, so in the case of eye drops applied to the eyes of SCL wearers, the efficacy of the eye drops is fully demonstrated In order to achieve this, it is required to increase the permeability of pharmacological components to SCL.

  Furthermore, it has recently been reported that the surface of a silicone hydrogel contact lens has significant irregularities that are not found on the surface of a normal hydrogel contact lens (Non-Patent Document 3). Such prominent irregularities are not only easy to attach biological substances and dirt, but also cause increased friction compared to those with a smooth surface, especially in sensitive eye tissues. It is also possible to cause discomfort such as a feeling of foreign matter and dryness.

  On the other hand, pemirolast and a salt thereof are used for topical application compositions such as eye drops, mucosa application compositions and the like for the purpose of imparting an antiallergic effect (see Patent Document 1). However, until now, there has been no report on the influence of pemirolast and / or a salt thereof and a silicone hydrogel contact lens on each other. In addition, the prior art discloses the effects of applying pemirolast and / or its salt to surfactants, vitamin B6s, terpenoids, and / or glycyrrhizic acids to silicone hydrogel contact lenses, At present, the influence on the eye tissue of the gel contact lens wearer cannot be inferred.

JP 2003-55224 A

Journal of Japanese Contact Lens Society, Vol. 39, 111-115, 1997 Japanese Journal of Contact Lenses, Vol. 44, 34-37, 2002 Akemi Hariya et al., 51st Annual Meeting of the Japanese Contact Lens Society Program Abstracts, 110 pages

  The present inventors have conducted various studies on various types of SCL, and the lens surface of a nonionic silicone hydrogel contact lens (hereinafter abbreviated as nonionic SHCL) was not expected at all. We obtained a completely new finding that the adhesion of corneal epithelial cells is remarkably high. Such a contact lens with high adhesion of corneal epithelial cells is obtained from the eye tissue every time the lens moves on the cornea due to adhesion of the corneal cells to the lens during wearing of the contact lens, 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 silicone hydrogel contact lenses are often worn continuously over a relatively long period of time compared to other soft contact lenses, the nonionic nature of corneal epithelial cells produced by prolonged wear Adhesion to SHCL can also contribute to serious eye disease or ocular mucosal symptoms. Therefore, development of an ophthalmic composition for nonionic SHCL that can suppress adhesion of corneal epithelial cells to nonionic SHCL is required.

  Further, the present inventors have obtained a completely new finding that when non-ionic SHCL is brought into contact with surfactants, vitamin B6s, terpenoids, and / or glycyrrhizic acids, the friction on the lens surface is increased. It was. Such large friction not only can cause discomfort (such as a foreign body or dry feeling) and tired eyes when wearing nonionic SHCL, but it also rubs the mucous membrane on the back of the eyelid and the nonionic SHCL surface. There is also the risk of causing epithelial damage to the keratoconjunctiva during contact or whenever nonionic SHCL moves on the surface of the eyeball. Therefore, development of an ophthalmic composition for nonionic SHCL that can reduce the increase in friction on the surface of nonionic SHCL caused by contact with surfactants, vitamin B6, terpenoids, and / or glycyrrhizic acids is also required. It has been.

  As a result of diligent studies to solve the above problems, the present inventors have found that corneal epithelial cells into nonionic SHCL when pemirolast and / or a salt thereof are used alone or surfactants are used alone. In addition to the fact that the adhesion of Pmirolast and / or its salts and surfactants is used in combination, it is quite unexpected that It was found that adhesion of corneal epithelial cells to ionic SHCL can be remarkably suppressed.

  In addition, as a result of further investigations, the present inventors have been able to remarkably increase the permeation amount of pemirolast and / or its salt to nonionic SHCL when used in combination with surfactants. I also found.

  In addition, the inventors have found that the increased friction of non-ionic SHCL surfaces upon contact with surfactants, vitamin B6s, terpenoids, and / or glycyrrhizic acids, together with these components, pemirolast and / or Or it discovered that it could suppress by using the salt. It has also been found that the effect of suppressing the increase in friction can be further enhanced by further combining pranoprofen and chlorpheniramine.

  The present invention has been completed by making further improvements based on such findings.

That is, the present invention provides the following ophthalmic compositions for nonionic SHCL.
Item 1-1. (A) contains at least one selected from the group consisting of pemirolast and salts thereof, and (B) at least one selected from the group consisting of surfactants, vitamin B6s, terpenoids, and glycyrrhizic acids An ophthalmic composition for a nonionic silicone hydrogel contact lens.
Item 1-2. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-1, further comprising (C) at least one selected from the group consisting of pranoprofens and chlorpheniramines.
Item 1-3. Item 11. The nonion according to Item 1-1 or 1-2, which contains at least one selected from the group consisting of nonionic surfactants, cationic surfactants and amphoteric surfactants as surfactants Composition for water-soluble silicone hydrogel contact lenses.
Item 1-4. Item 4. An ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-3, which contains a nonionic surfactant as a surfactant.
Item 1-5. Item 1- containing at least one selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene / polyoxypropylene block copolymers as surfactants The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of 1 to 1-4.
Item 1-6. Item 5. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-5, comprising at least one selected from the group consisting of pyridoxine and a salt thereof as vitamin B6.
Item 1-7. Item 7. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-6, which contains at least one selected from the group consisting of menthol and camphor as terpenoids.
Item 1-8. Item 8. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-7, which contains at least one selected from the group consisting of glycyrrhizic acid and a salt thereof as glycyrrhizic acids.
Item 1-9. Item (B) is any one of Items 1-1 to 1-8, comprising at least one selected from the group consisting of a nonionic surfactant, pyridoxine hydrochloride, menthol, and dipotassium glycyrrhizinate. An ophthalmic composition for nonionic silicone hydrogel contact lenses.
Item 1-10. Item 10. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-9, which contains pemirolast potassium as the component (A).
Item 1-11. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-2 to 1-10, comprising at least one selected from the group consisting of pranoprofen and a salt thereof as pranoprofen object.
Item 1-12. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-2 to 1-11, comprising at least one selected from the group consisting of chlorpheniramine and a salt thereof as chlorpheniramines object.
Item 1-13. Item 11. The nonionic silicone hydrogel contact lens according to any one of Items 1-2 to 1-12, which comprises at least one selected from the group consisting of pranoprofen and chlorpheniramine maleate as the component (C). Ophthalmic composition.
Item 1-14. Item 1-1 to 1-13, wherein the blending ratio of component (A) is 0.005 to 1.0 w / v%
The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of the above.
Item 1-15. Item 1-1 to 1-14, wherein the blending ratio of component (B) is 0.00001 to 10 w / v%
The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of the above.
Item 1-16. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-2 to 1-15, wherein the blending ratio of component (C) is 0.0006 to 0.5 w / v%.
Item 1-17. The nonionic silicone hydrogel contact according to any one of Items 1-1 to 1-16, which contains (B) component in a ratio of 0.001 to 200,000 parts by weight in total per 100 parts by weight of component (A) Ophthalmic composition for lenses.
Item 1-18. The nonionic silicone hydrogel contact lens according to any one of Items 1-2 to 1-17, which contains (C) component in a ratio of 0.1 to 10,000 parts by weight per 100 parts by weight of total amount of (A) component Ophthalmic composition.
Item 1-19. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-18, further comprising a buffer.
Item 1-20. Item 20. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-19, which contains a borate buffer as the buffer.
Item 1-21. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-20, further comprising an isotonic agent.
Item 1-22. Item 22. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-21, containing glycerin or propylene glycol as an isotonic agent.
Item 1-23. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-22, which is an eye drop.

The present invention also provides a method for suppressing adhesion of corneal epithelial cells to nonionic SHCL described below.
Item 2. A nonionic silicone hydrogel contact lens ophthalmic composition containing (A) at least one selected from the group consisting of pemirolast and a salt thereof, and (B) a surfactant; and a nonionic silicone hydrogel A method for suppressing adhesion of corneal epithelial cells to a nonionic silicone hydrogel contact lens, comprising contacting the contact lens.

The present invention also provides a method for imparting an ophthalmic composition with an adhesion inhibitory action of corneal epithelial cells on nonionic SHCL listed below.
Item 3. The ophthalmic composition for a nonionic silicone hydrogel contact lens comprises (A) at least one selected from the group consisting of pemirolast and a salt thereof, and (B) a surfactant. A method for providing an ophthalmic composition with an inhibitory effect on adhesion of corneal epithelial cells to a nonionic silicone hydrogel contact lens.

The present invention also provides the uses listed below.
Item 4-1. (A) Use of at least one selected from the group consisting of pemirolast and a salt thereof, and (B) a surfactant for the production of an ophthalmic composition for a nonionic silicone hydrogel contact lens.
Item 4-2. A nonionic silicone hydrogel contact lens for suppressing adhesion of corneal epithelial cells to nonionic SHCL of (A) at least one selected from the group consisting of pemirolast and salts thereof and (B) surfactants Use for the manufacture of an ophthalmic composition.

Moreover, this invention provides the permeability improvement method of the pemirolast and / or its salt with respect to the nonionic silicone hydrogel contact lens hung up below.
Item 5. (A) Component (A) to a nonionic silicone hydrogel contact lens, characterized by using at least one selected from the group consisting of pemirolast and a salt thereof and (B) a surfactant To improve the permeability of the water.

Moreover, this invention provides the method of providing the ophthalmic composition with the permeability | transmittance improvement effect | action of the pemirolast and / or its salt with respect to the nonionic silicone hydrogel contact lens hung up below.
Item 6. (A) A nonionic silicone hydrogel contact lens ophthalmic composition containing at least one selected from the group consisting of pemirolast and a salt thereof, (B) a surfactant is blended, A method for imparting an effect to the ophthalmic composition to improve the permeability of the component (A) to a nonionic silicone hydrogel contact lens.

Moreover, this invention provides the agent for improving the permeability | transmittance of the pemirolast and / or its salt with respect to the nonionic silicone hydrogel contact lens hung up below.
Item 7. (B) Agent for improving at least one permeability selected from the group consisting of (A) pemirolast and a salt thereof into a nonionic silicone hydrogel contact lens, containing surfactants as an active ingredient .

Moreover, this invention provides the method of reducing the friction of the nonionic silicone hydrogel contact lens hung up below.
Item 8. (B) A combination of at least one selected from the group consisting of surfactants, vitamin B6s, terpenoids, and glycyrrhizic acids and (A) at least one selected from the group consisting of pemirolast and its salts A method for reducing friction of a nonionic silicone hydrogel contact lens, which is increased by contacting the component (B).

Moreover, this invention provides the method of providing the friction reduction effect | action of the nonionic silicone hydrogel contact lens hung up below to an ophthalmic composition.
Item 9. (B) An ophthalmic composition for a nonionic silicone hydrogel contact lens containing at least one selected from the group consisting of surfactants, vitamin B6s, terpenoids, and glycyrrhizic acids, (A) pemirolast and The action of reducing friction of the nonionic silicone hydrogel contact lens, which is increased by contacting with the component (B), is characterized by comprising at least one selected from the group consisting of the salts. A method of applying to an ophthalmic composition.

Moreover, this invention provides the agent for reducing the friction of the nonionic silicone hydrogel contact lens hung up below.
Item 10. (A) containing at least one selected from the group consisting of pemirolast and salts thereof, (B) at least one selected from the group consisting of surfactants, vitamin B6s, terpenoids, and glycyrrhizic acids An agent for reducing friction of a nonionic silicone hydrogel contact lens that is increased by contact.

Further, the present invention provides a method for screening a substance for improving permeability described below.
Item 11. A method for screening a permeability-improving substance for improving the permeability of at least one kind of pemirolast selected from the group consisting of pemirolast and a salt thereof for a nonionic silicone hydrogel contact lens,
(a) preparing a control solution containing pemirolasts and a test solution containing pemirolasts and a test substance as test solutions,
(b) Each of the test solutions is brought into contact with only one side of the nonionic silicone hydrogel contact lens for a predetermined time, and the amount of the pemirolasts exuded from the other side of the lens not contacted with the test solution is measured. Measuring the permeation amount of pemirolast in each test solution by measuring, and
(c) a step of selecting a test solution in which the permeation amount of pemirolast measured in the step (b) is larger than that of the control solution, and selecting a test substance contained in the test solution as the permeability improving substance,
A screening method comprising:

  According to the ophthalmic composition for nonionic SHCL of the present invention, it is possible to effectively suppress adhesion of corneal epithelial cells to nonionic SHCL. Can improve accompanying 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 ophthalmic composition for nonionic SHCL of the present invention, such adverse effects can be improved, and nonionic SHCL can be continuously worn for a long period of time with high safety.

  In addition, SCL has a very large lens size, and during wearing, not only the cornea but also part of the conjunctiva is covered, so an ophthalmic composition (eye drops) applied to the eyes of SCL wearers In order to fully exert its medicinal effect, it is desirable to increase the permeability of the pharmacological component to SCL. On the other hand, as shown in Reference Test Example 2 to be described later, as a result of the study by the present inventors, nonionic SHCL has significantly less permeation of pemirolast and / or a salt thereof than other SCLs. It has been made clear. Therefore, even if a conventional eye drop containing pemirolast and / or a salt thereof is applied to an eye wearing nonionic SHCL, there is a possibility that the desired effect cannot be obtained. On the other hand, according to the ophthalmic composition for nonionic SHCL of the present invention, the permeability of pemirolast and / or a salt thereof to nonionic SHCL can be remarkably improved. Even when instilled, it is possible to increase the amount of pemirolast and / or its salt reaching the keratoconjunctiva under nonionic SHCL, thereby effectively exerting an antiallergic effect.

  Furthermore, according to the present invention, by using pemirolast and / or a salt thereof together with surfactants, vitamin B6s, terpenoids, and / or glycyrrhizic acids, the surfactants and the like are contained. It is possible to provide an ophthalmic composition for nonionic SHCL in which the increase in friction of the nonionic SHCL surface caused by them is remarkably suppressed. Therefore, the ophthalmic composition for nonionic SHCL of the present invention can improve the wearing feeling of nonionic SHCL, can effectively prevent the occurrence of epithelial damage in the keratoconjunctiva, and is comfortable and safe. The use of non-ionic SHCL is realized.

  Furthermore, since the screening method of the present invention makes it possible to obtain a permeation-improving substance that can improve the permeability of pemirolast and / or its salt to nonionic SHCL, pemirolast to nonionic SHCL and / or It is useful for the development of ophthalmic compositions for non-ionic SHCL with improved salt permeability.

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 the reference test example 2, it is a figure which shows the result of having evaluated the permeability | transmittance to various soft contact lenses of pemirolast potassium. In Test Example 2, it is a figure which shows the result of having evaluated the permeability | transmittance to the nonionic SHCL of the pemirolast potassium in a test liquid (Example 2-3 and Comparative Example 3). In the reference test example 3, it is a figure which shows the result of having evaluated the permeability | transmittance to the non-silicone hydrogel contact lens of the pemirolast potassium in a test liquid (Example 2-3 and the comparative example 3). In the reference test example 4, it is a figure which shows the result of having evaluated the friction (The logarithmic attenuation factor measured by a rigid pendulum physical property test) of a nonionic silicone hydrogel contact lens. In Test Example 3, it is a figure which shows the result of having evaluated the influence which a test liquid (Example 4-5 and Comparative Example 4-7) exerts on the friction of nonionic SHCL. In Test Example 4, it is a figure which shows the result of having evaluated the influence which a test liquid (Example 6 and Comparative Example 8) exerts on the friction of nonionic SHCL. In Test Example 4, it is a figure which shows the result of having evaluated the influence which a test liquid (Example 7 and Comparative Example 9) exerts on the friction of nonionic SHCL. In Test Example 5, it is a figure which shows the result of having evaluated the influence which a test liquid (Example 8-9 and Comparative Example 10-11) exerts on the friction of nonionic SHCL. In Test Example 6, it is a figure which shows the result of having evaluated the influence which a test liquid (Example 10-12) exerts on the friction of nonionic SHCL.

1. Nonionic SHCL Ophthalmic Composition The nonionic SHCL ophthalmic composition of the present invention is at least one selected from the group consisting of pemirolast and a salt thereof (hereinafter sometimes simply referred to as component (A)). Containing. Pemirolast is a known compound, also called 9-methyl-3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one, synthesized by a known method. It can also be obtained as a commercial product.

  Further, the salt of pemirolast is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, but specifically, a salt with an organic base ( For example, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [for example, ammonium salts; alkali metals (sodium, potassium, etc.), Alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc.]. Among these salts, preferred are salts with inorganic bases, more preferred are alkali metal salts, still more preferred are potassium salts and / or sodium salts, and particularly preferred are potassium salts. These pemirolast salts may be used alone or in any combination of two or more.

  In the ophthalmic composition for nonionic SHCL of the present invention, as component (A), one of these pemirolasts and salts thereof may be selected and used alone, or two or more of them May be used in any combination. Among these, from the viewpoint of more effectively suppressing adhesion of corneal epithelial cells to nonionic SHCL, the component (A) is preferably a salt of pemirolast, more preferably an alkali metal salt of pemirolast, more preferably Pemirolast potassium salt and / or sodium salt, particularly preferably pemirolast potassium salt (pemirolast potassium). The component (A) exemplified here is also suitable from the viewpoint that the nonionic SHCL permeability improving effect by the surfactants can be obtained more effectively, and nonion caused by the component (B) described later. This is also preferable from the viewpoint that the increase in friction on the surface of the conductive SHCL can be more effectively suppressed.

  In the ophthalmic composition for nonionic SHCL of the present invention, the blending ratio of the component (A) is appropriately set according to the type of the component (A), the formulation form of the ophthalmic composition, etc. The total amount of the non-ionic SHCL ophthalmic composition is 0.005 to 1.0 w / v%, preferably 0.01 to 0.5 w / v%, more preferably 0.02 to 0.2 w / v%. Is exemplified.

  The ophthalmic composition for nonionic SHCL of the present invention has at least one selected from the group consisting of surfactants, vitamin B6s, terpenoids, and glycyrrhizic acids in addition to the component (A) (hereinafter referred to as “the component (A)”). (Simply referred to as component (B)). Nonionic SHCL surface caused by component (B) by using surfactants, vitamin B6, terpenoids, and / or glycyrrhizic acids as component (B) and combining with component (A) above It is possible to suppress an increase in friction. In addition, when surfactants are used as the component (B) and combined with the component (A), it becomes possible to suppress adhesion of corneal epithelial cells to nonionic SHCL, and further, nonionic The permeability of the component (A) to SHCL can also be improved.

  Among the components (B), the surfactants are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Nonionic surfactants, amphoteric interfaces Any of an active agent, an anionic surfactant, and a cationic surfactant may be sufficient.

  Specific examples of the nonionic surfactant that can be incorporated into the ophthalmic composition for nonionic SHCL of the present invention include POE (20) sorbitan monolaurate (polysorbate 20), POE monopalmitate POE (20) sorbitan ( POE sorbitan fatty acid esters such as polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE / POP block copolymers such as poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 403, poloxamer 237, poloxamer 124; POE cured castor oils such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl such as POE (20) POP (4) cetyl ether Ether compounds; POE (10) POE alkylphenyl ethers such as nonylphenyl 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 that can be incorporated into the ophthalmic composition for nonionic SHCL of the present invention include alkyldiaminoethylglycine. Specific examples of the cationic surfactant that can be blended in the nonionic SHCL ophthalmic composition of the present invention include benzalkonium chloride and benzethonium chloride. Specific examples of the anionic surfactant that can be blended in the ophthalmic composition for nonionic SHCL of the present invention include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, and aliphatic α. -Sulfomethyl ester, α-olefin sulfonic acid and the like are exemplified. In the ophthalmic composition for nonionic SHCL of the present invention, these surfactants may be used alone or in combination of two or more.

  Among the above surfactants, from the viewpoint of further enhancing the effect of suppressing the adhesion of corneal epithelial cells to nonionic SHCL, preferably, a nonionic surfactant, an amphoteric surfactant, a cationic surfactant; More preferably nonionic surfactants; more preferably POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE / POP block copolymers; even more preferably POE sorbitan fatty acid ester, POE hydrogenated castor oil; particularly preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60 is exemplified. The surfactants exemplified here are also preferred from the viewpoint of further increasing the permeability of the component (A) to nonionic SHCL. Further, the surfactants exemplified here are also preferable from the viewpoint of more effectively exerting the friction reducing effect of nonionic SHCL by pemirolast and / or a salt thereof.

  Specific examples of vitamin B6 among the component (B) include pyridoxine, pyridoxal, pyridoxamine, and salts thereof.

  The salt of pyridoxine, pyridoxal, and pyridoxamine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, an organic acid salt [for example, Monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.), Oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salt (eg hydrochloride, sulfuric acid) Salt, nitrate, hydrobromide, phosphate, etc.). Among these salts, preferred are inorganic acid salts, more preferred are hydrochlorides and phosphates, and particularly preferred are hydrochlorides. These pyridoxine, pyridoxal, and pyridoxamine salts may be used alone or in any combination of two or more.

  In the present invention, as vitamin B6, one kind may be used alone from pyridoxine, pyridoxal, pyridoxamine, and salts thereof, or two or more kinds may be used in any combination.

  Of these vitamin B6s, pyridoxine and its salts, more preferably pyridoxine and its inorganic acid salts, from the viewpoint of more effectively exerting the friction reducing effect of nonionic SHCL by pemirolast and / or its salts More preferred are pyridoxine hydrochloride and pyridoxine phosphate, and particularly preferred is pyridoxine hydrochloride (pyridoxine hydrochloride).

  Among the components (B), terpenoids are known compounds that have a structure having isoprene units as constituent units and are widely used as cooling agents. Specific examples of terpenoids include menthol, menthone, camphor, borneol, geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, and derivatives thereof. These compounds may be d-form, l-form or dl-form. In the present invention, an essential oil containing the above compound may be used as the terpenoids. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil and the like. These terpenoids may be used alone or in any combination of two or more.

  Among these terpenoids, menthol, menthone, camphor, borneol, geraniol are preferable from the viewpoint of more effectively exerting the friction reducing effect of nonionic SHCL by pemirolast and / or a salt thereof. Examples of the essential oil containing mint include cool mint oil, peppermint oil, mint oil, camphor oil, and rose oil. More preferred are menthol and camphor, more preferred is menthol, and particularly preferred is l-menthol. Examples of essential oils containing these include cool mint oil, peppermint oil, peppermint oil, camphor oil and the like.

  Specific examples of the glycyrrhizic acids among the component (B) include glycyrrhizic acid and salts thereof.

  Glycyrrhizic acid is also known as 20β-carboxy-11-oxo-30-noroleana-12-en-3β-yl-2-O-β-D-glucopyranuronosyl-α-D-glucopyranoside uronic acid A compound. Glycyrrhizic acid and salts thereof are known compounds as anti-inflammatory agents or antiallergic agents, and may be synthesized by a known method or obtained as a commercial product.

  The salt of glycyrrhizic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include salts with organic bases (for example, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, and picoline), inorganic bases, and the like. [For example, ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc.] and the like. Among these salts, preferred are salts with inorganic bases, more preferred are salts with alkali metals such as sodium and potassium; ammonium salts and the like. More specifically, examples include salts with alkali metals such as disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, and tripotassium glycyrrhizinate; ammonium salts such as monoammonium glycyrrhizinate. Among these, Preferably the alkali metal salt of glycyrrhizic acid, More preferably, dipotassium glycyrrhizinate is mentioned. These glycyrrhizic acid salts may be used alone or in any combination of two or more.

  In the present invention, as glycyrrhizic acids, one kind of glycyrrhizic acid and salts thereof may be used alone, or two or more kinds may be used in any combination.

  Among these glycyrrhizic acids, from the viewpoint of more effectively exerting the friction reducing effect of nonionic SHCL by pemirolast and / or its salt, it is preferably a salt of glycyrrhizic acid, more preferably an inorganic base of glycyrrhizic acid. Salts, more preferably alkali metal salts of glycyrrhizic acid, particularly preferably dipotassium glycyrrhizinate.

  In the present invention, when providing an ophthalmic composition for nonionic SHCL that can suppress adhesion of corneal epithelial cells to nonionic SHCL, surfactants may be used alone as component (B), or Along with surfactants, at least one of vitamin B6s, terpenoids, and glycyrrhizic acids may be used in combination.

  In the present invention, when providing an ophthalmic composition for nonionic SHCL that can suppress the increase in friction on the surface of nonionic SHCL, as the component (B), surfactants, vitamin B6s, terpenoids, and glycyrrhizin One kind of acids may be used alone, or two or more kinds may be used in combination. Among these components (B), surfactants, vitamin B6, and terpenoids are preferable, and surface activity is more preferable from the viewpoint that the effect of suppressing the increase in friction by the component (A) can be obtained more effectively. Drugs and vitamin B6 are exemplified.

In the ophthalmic composition for nonionic SHCL of the present invention, the blending ratio of the component (B) depends on the type of the component (A), the type of the component (B), the formulation form of the ophthalmic composition, etc. As an example, the total amount of the nonionic SHCL ophthalmic composition is 0.00001 to 10 w / v%, preferably 0.0001 to 1 w / v%, more preferably 0.001 with respect to the total amount of the component (B). ˜0.5 w / v% is exemplified. More specifically, the following ranges are exemplified as the blending ratio of each component (B) with respect to the total amount of the nonionic SHCL ophthalmic composition.
When component (B) is a surfactant: These are the total amount, usually 0.001 to 10 w / v%, preferably 0.01 to 1 w / v%, more preferably 0.05 to 0.5 w / v%;
When the component (B) is vitamin B6: These are total amounts, usually 0.001 to 1.0 w / v%, preferably 0.005 to 0.5 w / v%, more preferably 0.01 to 0.2 w / v%;
When component (B) is a terpenoid: These are the total amount, usually from 0.00001 to 0.5 w / v%, preferably from 0.0001 to 0.15 w / v%, more preferably from 0.001 to 0.05 w / v% (as terpenoids) In the case of using an essential oil containing terpenoid, the terpenoid content in the blended essential oil is set so as to satisfy the above blending ratio);
When component (B) is glycyrrhizic acid: These are total amounts, usually 0.0005 to 1.25 w / v%, preferably 0.005 to 1.0 w / v%, more preferably 0.05 to 0.3 w / v%.

In the ophthalmic composition for nonionic SHCL of the present invention, the ratio of the component (B) to the component (A) is not particularly limited, but suppresses the adhesion of corneal epithelial cells to the nonionic SHCL. From the viewpoint of further enhancing the effect of, or from the viewpoint of more effectively suppressing the increase in friction of the nonionic SHCL surface caused by the component (B), per 100 parts by weight of the total amount of the component (A), Examples include a range in which the total amount of component (B) is 0.001 to 200,000 parts by weight, preferably 0.005 to 50,000 parts by weight, more preferably 0.05 to 5000 parts by weight, and even more preferably 0.5 to 2500 parts by weight. Such a ratio is also suitable from the viewpoint of further increasing the permeability of the component (A) to nonionic SHCL. More specifically, the following ranges are exemplified as the ratio of the component (B) per 100 parts by weight of the total amount of the component (A).
When component (B) is a surfactant: These are the total amount, usually 0.5 to 50000 parts by weight, preferably 5 to 5000 parts by weight, more preferably 25 to 2500 parts by weight;
When component (B) is vitamin B6: These are total amounts, usually 0.5 to 5000 parts by weight, preferably 2.5 to 2500 parts by weight, more preferably 5 to 1000 parts by weight;
When component (B) is a terpenoid: These are total amounts, usually 0.005 to 2500 parts by weight, preferably 0.05 to 750 parts by weight, more preferably 0.5 to 250 parts by weight; Is used such that the ratio of terpenoids in the blended essential oil satisfies the above range);
When component (B) is glycyrrhizic acid: these are the total amount, usually 0.25-6250 parts by weight, preferably 2.5-5000 parts by weight, more preferably 25-1500 parts by weight.

  The ophthalmic composition for nonionic SHCL of the present invention comprises at least one selected from the group consisting of pranoprofen and chlorpheniramine in addition to the components (A) and (B) (hereinafter simply referred to as ( C) may also be included. By including the component (C) in this way, the increase in friction on the surface of the nonionic SHCL caused by the component (B) is more effectively suppressed in combination with the action of the component (A). Can do.

  Among the components (C), specific examples of pranoprofen include pranoprofen and salts thereof.

  Planoprofen is a known compound also called α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid, which may be synthesized by a known method and obtained as a commercial product. You can also

  The salt of pranoprofen is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmacologically) or physiologically acceptable. Specifically, a salt with an inorganic base [for example, sodium Salts, potassium salts, calcium salts, magnesium salts, aluminum salts, etc.] and salts with organic bases [eg salts with methylamine, triethylamine, diethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.] Etc. These pranoprofen salts may be used alone or in any combination of two or more.

  In the present invention, as pranoprofen, one kind selected from pranoprofen and a salt thereof may be used alone, or two or more kinds may be used in any combination. Good.

  Among the planoprofens, pranoprofen is preferably used from the viewpoint of more effectively suppressing the increase in friction on the nonionic SHCL surface caused by the component (B).

  Among the components (C), specific examples of chlorpheniramines include chlorpheniramine and salts thereof.

  Chlorpheniramine is a known compound also called 3- (4-chlorophenyl) -N, N-dimethyl-3-pyridin-2-yl-propylamine.

  The salt of chlorpheniramine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Specific examples thereof include maleate and fumarate. Organic acid salts; inorganic acid salts such as hydrochlorides and sulfates; and various salts such as metal salts. Among these salts, an organic acid salt is preferable, and a maleic acid salt (chlorpheniramine maleate) is 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 present invention, as chlorpheniramines, one kind of chlorpheniramine and a salt thereof may be used alone, or two or more kinds may be used in any combination.

  Among chlorpheniramines, from the viewpoint of more effectively suppressing the increase in friction on the surface of the nonionic SHCL caused by the component (B), a salt of chlorpheniramine is preferable, and chlorpheniramine maleate is more preferable. Lamin.

  In the present invention, the component (C) may be used alone or in combination of two or more from pranoprofen and chlorpheniramine. Preferably, pranoprofen is used as the component (C).

In the ophthalmic composition for nonionic SHCL of the present invention, the blending ratio of the component (C) is the type of the components (A) and (B), the type of the component (C), and the formulation form of the ophthalmic composition. However, as an example, the total amount of the component (C) is 0.0006 to 0.5 w / v%, preferably 0.001 to 0.2 w / v, based on the total amount of the nonionic SHCL ophthalmic composition. %, More preferably 0.006 to 0.1 w / v%. More specifically, the following ranges are exemplified as the blending ratio of each component (C) with respect to the total amount of the ophthalmic composition for nonionic SHCL.
When component (C) is pranoprofen: These are total amounts, usually 0.005 to 0.5 w / v%, preferably 0.01 to 0.2 w / v%, more preferably 0.025 to 0.1 w / v%;
When component (C) is chlorpheniramine: These are total amounts, usually 0.0006 to 0.15 w / v%, preferably 0.001 to 0.1 w / v%, more preferably 0.006 to 0.05 w / v%.

In the ophthalmic composition for nonionic SHCL of the present invention, the ratio of the component (C) to the component (A) is not particularly limited, but the nonionic SHCL caused by the component (B) From the viewpoint of more effectively suppressing the increase in surface friction, the total amount of the component (C) is 0.1 to 10,000 parts by weight, preferably 0.3 to 2500 parts by weight per 100 parts by weight of the total amount of the component (A). More preferably, the range is 0.5 to 1000 parts by weight, and more preferably 3 to 500 parts by weight. More specifically, the following ranges are exemplified as the ratio of the component (C) per 100 parts by weight of the total amount of the component (A).
When component (C) is pranoprofen: These are the total amount, usually 2.5 to 2500 parts by weight, preferably 5 to 1000 parts by weight, more preferably 12.5 to 500 parts by weight;
When component (C) is chlorpheniramine: These are the total amount, usually 0.3 to 750 parts by weight, preferably 0.5 to 500 parts by weight, more preferably 3 to 250 parts by weight.

  The ophthalmic composition for nonionic SHCL of the present invention may further contain a buffer in addition to the components (A) and (B). The buffer that can be incorporated into the ophthalmic composition for nonionic 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, 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, and more preferred are borate buffer and phosphate buffer, and particularly preferred buffer. 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 Examples thereof include acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.). Among these, the non-ionic SHCL further enhances the inhibitory effect of corneal epithelial cell adhesion, or further enhances the permeability of the component (A) to the nonionic SHCL, or is caused by the component (B). From the viewpoint of more effectively suppressing the increase in friction on the surface of the conductive SHCL, a boric acid buffer, particularly a combination of boric acid and borax is preferred. These buffering agents may be used alone or in any combination of two or more.

  When a buffering agent is blended in the ophthalmic composition for nonionic SHCL 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, and is uniform. Although it cannot be defined, 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 nonionic SHCL ophthalmic composition A ratio of 0.5 to 2 w / v% is exemplified.

  The ophthalmic composition for nonionic SHCL of the present invention may further contain an isotonic agent. The isotonic agent that can be incorporated into the ophthalmic composition for nonionic SHCL 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, glycerin and propylene glycol are preferable. These isotonic agents may be used alone or in any combination of two or more.

  When an isotonic agent is added to the nonionic SHCL ophthalmic composition of the present invention, the mixing ratio of the tonicity agent varies depending on the type of tonicity agent to be used, etc. However, for example, the total amount of the tonicity agent is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably the total amount of the nonionic SHCL ophthalmic composition A ratio of 0.1 to 3 w / v% is exemplified.

  The pH of the ophthalmic composition for nonionic SHCL 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 ophthalmic composition for nonionic SHCL of the present invention, a range of 4.0 to 9.5, preferably 5.0 to 9.0, and more preferably 5.5 to 8.5 is given. It is done.

  Further, the osmotic pressure of the ophthalmic composition for nonionic 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 ophthalmic composition for nonionic SHCL of the present invention, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, particularly preferably 0.7 to 2.0. The range becomes. 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 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 15th revised Japanese pharmacopoeia. Measure with reference to the descent method. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then released in a desiccator (silica gel). Cool and accurately measure 0.900 g and dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

The ophthalmic composition 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, ketotifen fumarate, etc.
Decongestant: For example, tetrahydrozoline, naphazoline, epinephrine, ephedrine, methylephedrine and the like.
Bactericides: for example, cetylpyridinium, benzalkonium, benzethonium, chlorhexidine, polyhexamethylene biguanide and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, panthenol, calcium pantothenate, tocopherol acetate and the like.
Amino acids: For example, potassium aspartate, magnesium aspartate, aminoethylsulfonic acid and the like.
Anti-inflammatory agents: for example, allantoin, azulene, azulenesulfonic acid, guaiazulene, ε-aminocaproic acid, berberine, lysozyme, licorice, etc.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Other: For example, sodium cromoglycate, sodium chondroitin sulfate, sodium hyaluronate, sulfamethoxazole, and salts thereof.

In addition, in the ophthalmic composition for nonionic SHCL of the present invention, various additives are appropriately selected according to a conventional method according to the use and form as long as the effects of the invention are not impaired. Or you may make it contain in an appropriate amount using together or more. Examples of these additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (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 and the like.
Sugars: For example, cyclodextrins and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Antiseptics, bactericides or antibacterials: for example, dibutylhydroxytoluene, butylhydroxyanisole, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, sorbine Potassium acid, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc. ), Glow Kill (trade name, manufactured by Rhodia).
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.
Stabilizers: for example, dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate and the like.
Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and the like.

  The ophthalmic composition for nonionic SHCL of the present invention is prepared by adding a desired amount of the above components (A) and (B) and, if necessary, other compounding components to a desired concentration. .

  The dosage form of the nonionic SHCL ophthalmic composition of the present invention is not particularly limited as long as it can be used in the ophthalmic field, and examples thereof include liquids and ointments. Among these, liquid is preferable. Of the liquids, aqueous liquids are preferred. When the non-ionic SHCL ophthalmic composition of the present invention is made into an aqueous liquid, pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable water may be used as an aqueous carrier. Specific examples include distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like. These definitions are based on the 1st 5th Japanese Pharmacopoeia. Here, the aqueous liquid means a liquid form containing water, and usually 1% by weight or more, preferably 5% by weight or more, more preferably 20% by weight of water in the nonionic SHCL ophthalmic composition. It means that containing at least 50% by weight, more preferably at least 50% by weight.

  In addition, the ophthalmic composition for nonionic SHCL of the present invention is an eye drop that can be instilled while wearing nonionic SHCL (an eye drop for nonionic SHCL), an eye wash that can be washed while wearing nonionic SHCL ( Nonionic SHCL eyewash), nonionic SHCL mounting solution, nonionic SHCL care agent (nonionic SHCL disinfectant, nonionic SHCL preservative, nonionic SHCL cleaner, nonionic (Including cleaning preservatives for SHCL). In the case of an eye drop for nonionic SHCL, it may be applied directly to the eye wearing nonionic SHCL, or may be applied to the eye before wearing nonionic SHCL.

  Among these, the non-ionic SHCL eye drops or the non-ionic SHCL mounting solution, in particular, the non-ionic SHCL eye drops are in contact with or just before the non-ionic SHCL is in contact with the eyeball surface (for example, This is a pharmaceutical form that is strongly required to suppress the adhesion of corneal epithelial cells to nonionic SHCL (until about 10 minutes before the wearing action to be contacted). In addition, eye drops are preferable because they are generally more frequently used per day than other ophthalmic compositions, and thus can more effectively obtain the corneal epithelial cell adhesion inhibitory effect of the present invention. Furthermore, in the case of eye drops, the increase in friction of the nonionic SHCL surface caused by the blended components and the accompanying deterioration in wearing feeling may greatly impair patient compliance. Therefore, in the case of eye drops, it can be said that the formulation is required to eliminate as much as possible the factors that cause such deterioration in wearing feeling in order to comply with proper dosing instructions. In view of the above viewpoints, eye drops or mounting liquids, in particular eye drops, are suitable as the pharmaceutical form of the ionic SHCL ophthalmic composition of the present invention. In the ophthalmic composition for nonionic SHCL of the present invention, the permeability of the component (A) to nonionic SHCL is remarkably enhanced. In view of such an effect of the present invention, a non-ionic SHCL eye drop may be mentioned as a suitable formulation form.

  In the ophthalmic composition for nonionic SHCL of the present invention, the type of nonionic SHCL to be applied is not particularly limited, and all nonionic SHCL that are currently marketed or marketed in the future are applicable. Can be. In addition, nonionicity here means that the ionic component content rate in a contact lens material is less than 1 mol% according to the US FDA (US Food and Drug Administration) standard so that those skilled in the art usually understand. . 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, and more preferably 50% or less. Since SHCL contains a hydrogel material, it contains at least more than 0% moisture. Regarding the adhesion of corneal epithelial cells, nonionic SHCL having a water content of 35% or less tends to have particularly strong adhesion to corneal epithelial cells. According to the ophthalmic composition for nonionic SHCL of the present invention, the effect of suppressing adhesion of corneal epithelial cells can be effectively exhibited even for nonionic SHCL having strong adhesion to corneal epithelial cells. In view of the effects of the present invention, an example of a suitable application target of the ophthalmic composition for nonionic SHCL of the present invention is nonionic SHCL having a moisture 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.

  Since the ophthalmic composition for nonionic SHCL of the present invention can also exert an antiallergic action based on the above component (A), it is also useful as an allergy symptom reducing agent. In particular, the ophthalmic composition for nonionic SHCL of the present invention increases the amount of the component (A) transmitted through the lens and increases the amount reaching the keratoconjunctiva. Can be obtained.

  Conventionally, it has been known that wearing a hard contact lens made of polymethyl methacrylate (PMMA) material tends to cause corneal epithelial disorder (3 o'clock to 9 o'clock staining) due to adhesion of the lens to the cornea. ing. 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. Nonionic SHCL, on the other hand, has the property of remarkably adhering to corneal epithelial cells, and moreover it is generally harder than normal non-silicone SCL as an inherent property of silicone hydrogel contact lenses, thus causing physical damage to corneal epithelium. It tends to be easy. 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 composition for nonionic SHCL of the present invention, it is possible to effectively suppress adhesion of corneal epithelial cells to nonionic SHCL, so that the corneal epithelium caused by wearing nonionic SHCL Disability can be prevented. Therefore, the ophthalmic composition 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 For eye patients).

  In addition, since corneal epithelial cells also have a barrier function against allergens, corneal epithelial disorders caused by wearing nonionic SHCL as described above decrease the barrier function and cause allergic symptoms of the eye. There is a fear to make it easier. In contrast, according to the ophthalmic composition for nonionic SHCL of the present invention, corneal epithelial cells are maintained in a normal state by suppressing adhesion of corneal epithelial cells to nonionic SHCL. It is possible to maintain the barrier function of cells. Therefore, the ophthalmic composition for nonionic SHCL of the present invention is an ophthalmic disease preventive agent for a person who uses nonionic SHCL to enhance and prevent various eye diseases including allergic symptoms ( For example, it is suitably used as a prophylactic agent for allergic symptoms.

  Furthermore, since the ophthalmic composition for nonionic SHCL of the present invention can reduce friction on the surface of nonionic SHCL, it can be used for reducing friction of nonionic SHCL. In addition, since the epithelial cells of the eyeball also have a barrier function against allergens, epithelial disorders caused by cell detachment that can occur due to friction on the surface of nonionic SHCL reduce the barrier function and cause allergic diseases of the eye, etc. There is a fear of facilitating onset or exacerbation. Therefore, also from this viewpoint, the ophthalmic composition for nonionic SHCL of the present invention is used by a person who uses nonionic SHCL to prevent and enhance resistance to various eye diseases including allergic diseases. It can be used as a preventive agent for eye diseases (for example, a prophylactic agent for allergic diseases).

2. Method for inhibiting adhesion of corneal epithelial cells to nonionic SHCL, method for imparting adhesion inhibiting action of corneal epithelial cells to nonionic SHCL, and use for producing an ophthalmic composition for nonionic SHCL As described above, pemirolast In combination with the surfactant and surfactants, adhesion of corneal epithelial cells to nonionic SHCL can be suppressed.

  Accordingly, the present invention provides a nonionic ophthalmic composition for non-ionic SHCL comprising, from another viewpoint, at least one selected from the group consisting of (A) pemirolast and a salt thereof, and (B) a surfactant. And a nonionic SHCL, and a method for suppressing adhesion of corneal epithelial cells to the nonionic SHCL. Further, the nonionic SHCL ophthalmic composition comprises (A) at least one selected from the group consisting of pemirolast and a salt thereof, and (B) a surfactant. Provided is a method for imparting an adhesion suppressing action of corneal epithelial cells to nonionic SHCL to an ophthalmic composition for ionic SHCL.

  In another aspect, the present invention provides a nonionic SHCL ophthalmic composition comprising (A) at least one selected from the group consisting of pemirolast and a salt thereof, and (B) a surfactant. Provide use for. The present invention also relates to (A) at least one selected from the group consisting of pemirolast and a salt thereof, and (B) a nonionic ion for suppressing the adhesion of corneal epithelial cells to nonionic SHCL. Use for the manufacture of an ophthalmic composition for sexual SHCL is provided.

  In these methods and uses, the types and blending ratios of pemirolasts and surfactants, the types and blending ratios of other ingredients, the formulation form of the ophthalmic composition for nonionic SHCL, and the nonionic SHCL to be applied The type and the like are the same as in “1. Ophthalmic composition for nonionic SHCL”.

3. Method for improving the permeability of pemirolast and / or its salt to nonionic SHCL, and method for imparting the effect of improving the permeability of pemirolast and / or its salt to nonionic SHCL As described above, nonionic The permeability of pemirolasts to SHCL can be improved by surfactants.

  Therefore, the present invention is further characterized in that, from another viewpoint, (A) at least one selected from the group consisting of pemirolast and a salt thereof and (B) a surfactant are used in combination. Provided is a method for improving the permeability of the component (A) to SHCL. Further, the present invention is characterized in that (B) a surfactant is blended with the ophthalmic composition for nonionic SHCL containing at least one selected from the group consisting of (A) pemirolast and a salt thereof. Also provided is a method for imparting the ophthalmic composition with an effect of improving the permeability of the component (A) to nonionic SHCL.

  In this method, the types and proportions of pemirolasts and surfactants, the types and proportions of other ingredients, the formulation form of the ophthalmic composition for nonionic SHCL, the types of nonionic SHCL to be applied, etc. Is the same as “1. Ophthalmic composition for nonionic SHCL”.

4). Agent for improving permeability of pemirolast and / or salt thereof to nonionic SHCL As described above, the permeability of pemirolasts to nonionic SHCL can be improved by surfactants.

  Therefore, the present invention, from yet another viewpoint, contains at least one selected from the group consisting of (A) pemirolast and its salt into nonionic SHCL, containing (B) a surfactant as an active ingredient. An agent for improving permeability is provided.

  In the agent, the type of component (B) that is an active ingredient, the nonionic SHCL to be applied, the type of component (A) that is the target of permeability to nonionic SHCL, the blending ratio thereof, etc. And “1. Ophthalmic composition for nonionic SHCL”.

5. A method for reducing friction of nonionic SHCL; and a method for imparting an action to reduce the friction of nonionic SHCL to an ophthalmic composition As described above, by combining the component (A) and the component (B) The increase in friction on the surface of the nonionic SHCL caused by contact with the component (B) can be reduced.

  Accordingly, the present invention, from yet another viewpoint, comprises (B) at least one selected from the group consisting of surfactants, vitamin B6s, terpenoids, and glycyrrhizic acids, and (A) pemirolast and salts thereof. There is provided a method for reducing friction of nonionic SHCL, which is increased by contacting the component (B), using at least one selected from the group consisting of the above.

  The present invention also relates to (A) pemirolast, a nonionic SHCL ophthalmic composition containing at least one selected from the group consisting of (B) surfactants, vitamin B6s, terpenoids, and glycyrrhizic acids. And at least one selected from the group consisting of the salts thereof, and the composition for reducing friction of nonionic SHCL which is increased by contacting with the component (B), It also provides a method of granting.

  In this method, the types and proportions of components (A) and (B), the types and proportions of other components, the formulation form of the ophthalmic composition for nonionic SHCL, the types of nonionic SHCL to be applied And the like are the same as those in “1. Ophthalmic composition for nonionic SHCL”.

6). Agent for reducing friction of nonionic SHCL As described above, the increase in friction on the surface of nonionic SHCL caused by contacting the component (B) can be suppressed by the component (A). .

  Accordingly, the present invention, from yet another viewpoint, comprises (B) a surfactant, vitamin B6, terpenoid, and glycyrrhizin containing at least one selected from the group consisting of (A) pemirolast and a salt thereof. An agent for reducing friction of nonionic SHCL that is increased by contacting at least one selected from the group consisting of acids is provided.

  In the agent, the type of component (A) that is an active ingredient, the nonionic SHCL to be applied, the type of component (B) that causes increased friction of nonionic SHCL, the blending ratio thereof, etc. 1. Same as “Nonionic SHCL Ophthalmic Composition”.

7). A screening method for substances that improve the permeability of pemirolast and / or its salt to nonionic SHCL. Further , as described above, the inventors of the present invention have remarkably high permeability to nonionic SHCL. New knowledge that it is low is obtained. Accordingly, the present invention further provides a method for screening a substance for improving permeability that improves the permeability of at least one kind of pemirolast selected from the group consisting of pemirolast and its salt against nonionic SHCL. Specifically, this screening method is a method including the following steps (a) to (c).
(a) preparing a control solution containing at least one pemirolast selected from the group consisting of pemirolast and a salt thereof, and a test solution containing the pemirolast and a test substance, respectively, as a test solution;
(b) Each of the test solutions is brought into contact with only one side of the nonionic SHCL for a predetermined time, and the amount of pemirolast exuded from the other side of the nonionic SHCL that is not in contact with the test solution is measured. A process for determining the permeation amount of pemirolast in each test solution, and
(c) A step of selecting a test solution in which the permeation amount of the pemirolast measured in the step (b) is 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 (pharmaceutically) or physiologically acceptable so that it can be incorporated into the nonionic SHCL ophthalmic composition.

  In the step (a), the test solution is, for example, 0.05 to 0.5 w / v% of at least one pemirolast selected from the group consisting of pemirolast 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. Moreover, it is desirable that the control solution containing pemirolast 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 by nonionic 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 nothing is filled in the other compartment, or a solution containing preferably no pemirolast (hereinafter referred to as “pemirolast”). The other compartment (the blank solution when filled with the blank solution) is passed through a nonionic SHCL after a predetermined time (for example, about 4 to 48 hours) has passed. Quantify the amount of pemirolast transferred to the side. The amount of pemirolast thus determined is the permeation amount of pemirolast 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.

  In addition, in the step (c) related 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 pemirolasts to nonionic SHCL, it is required in the step (b). A test solution having a larger permeation amount of pemirolast than the control solution may be selected.

  The permeability improving substance obtained by this screening method is an ophthalmic composition for nonionic SHCL containing pemirolast and / or a salt thereof for the purpose of improving the permeability of pemirolast and / or a salt thereof to nonionic SHCL. Can be blended into the product.

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

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. Each well is seeded with 100 μL of a cell suspension (1 × 10 ⁵ cells / 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 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 that are nonionic SHCL are compared with the lens C that is an ionic silicone hydrogel contact lens and the lens D or E that 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: Inhibition test of corneal epithelial cell adhesion to nonionic SHCL:
Using the test solution shown in Table 2, the adhesion inhibitory effect of corneal epithelial cells on nonionic SHCL was evaluated.

Lens A (nonionic SHCL) shown in Table 1 was immersed one by one in 3 ml of each 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. Each well is seeded with 100 μL of a cell suspension (1 × 10 ⁵ cells / 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 48 hours under% CO ₂ conditions, the number of viable cells adhered to the lens was counted (sample group). In addition, as a control, a lens A, which was subjected to the same operation with the control test solution shown in Table 2, was seeded with a cell suspension of a rabbit corneal epithelial cell line under the same conditions as described above, and cultured. The number of viable cells adhering to 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.

  The obtained results are shown in FIG. As is clear from FIG. 2, it was confirmed that when pemirolast potassium was used alone, it not only suppressed cell adhesion but also tended to tend to adhere cells by warping (Comparative Example 1). . It was also revealed that the surfactant polysorbate 80 itself has almost no cell adhesion inhibitory effect (Comparative Example 2). On the other hand, it was completely unexpected that it was found that when pemirolast potassium and polysorbate 80 were used in combination, the cell adhesion inhibition rate against nonionic SHCL was significantly increased synergistically (Examples). 1).

Reference Test Example 2: Comparative evaluation of SCL permeability of pemirolast:
Using three types of soft contact lenses shown in Table 3, the lens permeability of pemirolast was evaluated. All soft contact lenses used in this test are also commercially available.

  Measurement of the SCL permeability evaluation of pemirolast was performed according to the following method using a membrane permeation experiment apparatus (manufactured by Beadrex). Each soft contact lens shown in Table 3 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% pemirolast potassium (boric acid 0.5 w / v%, appropriate amount of borax, glycerin 2.0 w / v%; pH 8.0) was charged. 24 hours after the start of the test, 1 ml of the physiological saline solution was collected, the concentration of pemirolast was measured by the HPLC method according to a conventional method, and the amount of pemirolast transferred to cell I was calculated.

  The results are shown in FIG. As is apparent from FIG. 3, it was found that the lens 3 that is nonionic SHCL has a significantly poor permeability of pemirolast compared to the lenses 1 and 2 that are hydrogel contact lenses.

Test Example 2: Pemirolast lens transmission test 1:
Using the test solutions shown in Table 4 (Comparative Example 3 and Example 2-3), the SHCL permeability of pemirolast was evaluated.

  Measurement of nonionic SHCL permeability evaluation of pemirolast was performed according to the following method using a membrane permeation experiment apparatus (manufactured by Beadrex). The lens 3 (nonionic SHCL) shown in Table 3 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 contains a table. Each test solution shown in 4 (Comparative Example 3 and Example 2-3) was accurately filled with 5 mL. In addition, the osmotic pressure of each test solution was arranged to be almost the same. Subsequently, 1 mL of the physiological saline solution was collected 24 hours later, and the concentration of pemirolast was quantified by HPLC according to a conventional method. From the result of the quantification, the lens transmission amount of pemirolast was determined, and the transmission amount of each example when the transmission amount of Comparative Example 3 was 100% was calculated as the pemirolast transmittance (%).

  The results are shown in FIG. As apparent from FIG. 4, it was found that the lens transmittance of pemirolast was significantly increased in the test solutions of Examples 2 and 3 as compared with the test solution of Comparative Example 3. That is, by using pemirolast and a surfactant (polysorbate 80 or polyoxyethylene hydrogenated castor oil 60) in combination, the permeability of pemirolast to nonionic SHCL is significantly improved, and instilled during nonionic SHCL wearing. It was also revealed that it is possible to provide an ophthalmic composition for nonionic SHCL that has a medicinal effect closer to that expected from the original amount of pemirolast.

Reference Test Example 3: Pemirolast lens transmission test 2:
Using the lens 1 (non-silicone hydrogel contact lens) shown in Table 3, the same experiment as in Test Example 2 was performed, and the lens permeability of pemirolast was evaluated. Experiments were conducted using the test solutions shown in Table 4 (Comparative Example 3 and Example 2-3).

  The result is shown in FIG. As is clear from FIG. 5, in the case of a conventional hydrogel lens, it is clear that the use of a surfactant in combination does not show any effect of improving the permeability, or the permeability may be deteriorated. It became.

  From the above results, it is clear that the effect of improving the lens permeability of pemirolast, which is recognized by the combined use of pemirolast and a surfactant, is an effect that is specifically observed when the target lens is nonionic SHCL. It was.

Reference Test Example 4: Evaluation of friction on nonionic SHCL surface:
Rigid pendulum physical property tester RPT-, which is known to evaluate various surface property changes such as adhesiveness, viscoelasticity, drying property, etc. in terms of increase / decrease of friction in order to measure physical properties of nonionic SHCL surface Using 3000 W (manufactured by A & D Co., Ltd.), the frictional force of each nonionic SHCL surface was evaluated. The nonionic SHCL used in the test is two types of nonionic SHCL shown in Table 5, both of which are commercially available products.

  What immersed these nonionic SHCL in the physiological saline overnight was used as a test sample. The measurement conditions were a temperature of 25 ° C., a relative humidity of 60%, a pendulum weight of 200 g, a sensor diameter of 4 mm, and each nonionic property with a logarithmic decay rate 5 minutes after the start of measurement. The friction on the SHCL surface was evaluated.

  The result is shown in FIG. The logarithmic decay rate measured here indicates the magnitude of the friction on the lens surface, and the higher the logarithmic decay rate, the greater the friction. As shown in FIG. 6, nonionic SHCL was found to have a high logarithmic decay rate and very high friction.

Test Example 3: Evaluation of reduction effect on friction of nonionic SHCL surface (1):
Using the lens I used in Reference Test Example 4 as nonionic SHCL, the friction reduction effect on the lens surface was evaluated by the following method.

  First, each test solution (Comparative Example 4-7 and Example 4-5) shown in Table 6 was prepared. The surface of the nonionic SHCL (Lens I) was thoroughly rinsed with physiological saline, and then immersed in 10 ml of each test solution one by one, and allowed to stand for 7 days. Thereafter, the lens surface was lightly wiped, and the logarithmic decay rate was measured every 10 seconds for a total of 3 minutes under the conditions of a pendulum weight of 200 g and a sensor diameter of 4 mm under conditions of a temperature of 25 ° C. and a relative humidity of 60%.

  The result is shown in FIG. As shown in FIG. 7, the logarithmic decay rate increases and the friction increases due to the addition of a nonionic surfactant (polysorbate 80, polyoxyethylene hydrogenated castor oil 60) as compared with the control (Comparative Example 4). Was observed (Comparative Examples 6 and 7). On the other hand, in the test solutions of Examples 4 and 5 in which pemirolast potassium was blended with a nonionic surfactant, the logarithmic decay rate decreased, and the friction could be reduced to the same extent as the control. This is a completely unexpected result considering that when pemirolast potassium was used alone, the friction reducing effect on nonionic SHCL was hardly observed (Comparative Example 5).

Test Example 4: Evaluation of reduction effect on friction of nonionic SHCL surface (2):
For each test solution shown in Table 7 below (Comparative Examples 8-9 and Examples 6-7), the same method as in Test Example 3 except that the immersion time in the test solution was changed from 7 days to 18 hours. The friction reducing effect on nonionic SHCL was evaluated.

  The results are shown in FIGS. As shown in FIG. 8 (comparison between Comparative Example 8 and Example 6), the same results as in Test Example 3 were also observed when the blending ratio and ratio of pemirolast potassium and polysorbate 80 were varied. It was. Further, as shown in FIG. 9 (comparison between Comparative Example 9 and Example 7), vitamin B6s (pyridoxine hydrochloride) increase the friction on the surface of the nonionic SHCL as well as the surfactants. It was recognized that the increase can be effectively suppressed by the combined use with last potassium.

Test Example 5: Evaluation of reduction effect on friction of nonionic SHCL surface (3):
For each of the test solutions shown in Table 8 below (Comparative Examples 10-11 and Examples 8-9), the test solution volume was changed from 10 ml to 6 ml in the same manner as in Test Example 4 above, with respect to nonionic SHCL. The friction reduction effect was evaluated.

  The result is shown in FIG. As shown in FIG. 10, dipotassium glycyrrhizinate and menthol also increased the friction on the surface of nonionic SHCL, similar to surfactants and vitamin B6, but using these in combination with pemirolast potassium It became clear that the increase in friction can be suppressed. Among them, a higher friction increase was observed when menthol was used, but the combined use with pemirolast potassium was able to effectively suppress the increase in friction of nonionic SHCL caused by menthol.

Test Example 6: Evaluation of reduction effect on friction of nonionic SHCL surface (4):
About each test liquid (Examples 10-12) shown in following Table 9, the friction reduction effect with respect to nonionic SHCL was evaluated by the method similar to the said test example 4. FIG.

The results are shown in FIG. As shown in FIG. 11, it was recognized that the friction reducing effect on the nonionic SHCL surface was further enhanced by combining polysorbate 80 and pemirolast potassium with chlorpheniramine maleate or pranoprofen.
Formulation Example A nonionic SHCL eye drop (Examples 13-20) is prepared according to the formulation described in Table 10.

Claims (9)

(A) at least one selected from the group consisting of pemirolast and a salt thereof, and (B) at least one selected from the group consisting of a nonionic surfactant, pyridoxine hydrochloride, menthol, and dipotassium glycyrrhizinate. An ophthalmic composition for nonionic silicone hydrogel contact lenses, comprising:   The ophthalmic composition for nonionic silicone hydrogel contact lenses according to claim 1, which contains (B) component in a ratio of 0.001 to 200000 parts by weight in total per 100 parts by weight of component (A).   The ophthalmic composition for a nonionic silicone hydrogel contact lens according to claim 1 or 2, further comprising (C) at least one selected from the group consisting of pranoprofen, chlorpheniramine, and salts thereof. object. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to claim 3 , comprising (C) component at a ratio of 0.1 to 10,000 parts by weight per 100 parts by weight of total amount of (A) component. Ophthalmic composition
(A) at least one selected from the group consisting of pemirolast and salts thereof;
(B) Inhibiting the adhesion of corneal epithelial cells to a nonionic silicone hydrogel contact lens in the ophthalmic composition, comprising containing at least one selected from the group consisting of nonionic surfactants How to grant. Ophthalmic composition
(A) at least one selected from the group consisting of pemirolast and salts thereof;
(B) Permeability of component (A) to nonionic silicone hydrogel contact lenses in the ophthalmic composition, comprising containing at least one selected from the group consisting of nonionic surfactants A method of imparting an action of improving the quality. Ophthalmic composition
(A) at least one selected from the group consisting of pemirolast and salts thereof;
(B) a nonionic silicone hydrogel containing the nonionic surfactant, pyridoxine hydrochloride, menthol, and at least one selected from the group consisting of dipotassium glycyrrhizinate in the ophthalmic composition A method for imparting an effect of reducing friction of contact lenses. (A) at least one selected from the group consisting of pemirolast and salts thereof;
(B) A friction reducing agent for a nonionic silicone hydrogel contact lens, comprising at least one selected from the group consisting of a nonionic surfactant, pyridoxine hydrochloride, menthol, and dipotassium glycyrrhizinate. (A) at least one selected from the group consisting of pemirolast and salts thereof;
(B) An ophthalmic composition applied to a nonionic silicone hydrogel contact lens, comprising at least one selected from the group consisting of a nonionic surfactant, pyridoxine hydrochloride, menthol, and dipotassium glycyrrhizinate. An allergic symptom relief agent consisting of

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