JP5616620B2 - 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. Further, the present invention improves the permeability of tranilast and / or its salt to nonionic silicone hydrogel contact lenses, and improves the permeability of tranilast 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. The present invention further relates to a method for reducing friction of nonionic silicone hydrogel contact lenses that is increased by tranilast and / or its salts.

  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.

  Soft contact lenses are 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. During the wearing of the soft contact lens, there is almost no inflow or outflow of tear fluid between the soft contact lens and the eye surface (that is, tear fluid exchange by the pump action), and tear fluid exchange under the soft contact lens is a soft contact. It is known that it depends on tear permeation through the lens (see Non-Patent Document 1-2). In this way, most of the tear fluid exchange under the soft contact lens is performed by the permeation of tear fluid through the soft contact lens. Therefore, in the case of an eye drop applied to the eye of the wearer of the soft contact lens, the eye drop In order to sufficiently exhibit the medicinal effect of the drug, it is required to increase the permeability of the pharmacological component to the soft contact lens.

  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, tranilast and / or a salt thereof has been used for internal use or eye drops for the purpose of imparting an antiallergic effect. However, until now, it has not been known at all about the influence of tranilast and / or its salt on nonionic silicone hydrogel contact lenses. In addition, from the prior art, the effect of applying tranilast and / or a salt thereof and other components to a nonionic silicone hydrogel contact lens cannot be estimated at all.

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 soft contact lenses, and have not anticipated at all that they may be abbreviated as nonionic silicone hydrogel contact lenses (hereinafter referred to as nonionic SHCL). The lens surface of) obtained a completely new finding that the adhesion of corneal epithelial cells was remarkably high. Such a contact lens with high adhesion of corneal epithelial cells is obtained from the eye tissue 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 SHCL is often continuously worn over a relatively long period of time compared to other soft contact lenses, adhesion of corneal epithelial cells to nonionic SHCL caused by long-term continuous wear Can contribute to serious eye disease or ocular mucosal symptoms. Therefore, development of an ophthalmic composition for nonionic SHCL that can suppress adhesion of corneal epithelial cells to nonionic SHCL is required.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors applied tranilast and / or a salt thereof to nonionic SHCL, thereby significantly increasing the adhesion of corneal epithelial cells to nonionic SHCL. It was found that it can be suppressed. Further, as a result of further investigation by the present inventors, tranilast and / or a salt thereof has a very low permeability to nonionic SHCL, and the permeability is an interface with tranilast and / or a salt thereof. It has been found that significant improvements can be made by using a combination of activators. Furthermore, the inventors have increased friction on the surface of nonionic SHCL caused by contact of tranilast and / or its salt by using a combination of surfactant and / or terpenoid with tranilast and / or its salt. It has also been found that can be effectively suppressed. The present invention has been completed by making further improvements based on such findings.

Specifically, the present invention provides the following ophthalmic compositions for nonionic silicone hydrogel contact lenses.
Item 1-1. An ophthalmic composition for a nonionic silicone hydrogel contact lens, comprising at least one selected from the group consisting of tranilast and a salt thereof.
Item 1-2. Item 10. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-1, wherein the blending ratio of at least one selected from the group consisting of tranilast and a salt thereof is 0.005 to 5 w / v%.
Item 1-3. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-1 or 1-2, further comprising a surfactant.
Item 1-4. Item 4. The nonionic silicone hydrogel according to Item 1-3, which contains at least one selected from the group consisting of a nonionic surfactant, a cationic surfactant, and an amphoteric surfactant as a surfactant. An ophthalmic composition for contact lenses.
Item 1-5. Item 5. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-3 or 1-4, wherein the blending ratio of the surfactant is 0.001 to 1 w / v%.
Item 1-6. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-5, further comprising a terpenoid.
Item 1-7. Item 7. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-6, comprising menthol as a terpenoid.
Item 1-8. Item 8. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-6 or 1-7, wherein the blending ratio of terpenoid is 0.0001 to 0.2 w / v%.
Item 1-9. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-8, further comprising a solubilizing agent.
Item 1-10. Item 10. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-9, which contains at least one selected from the group consisting of polyvinylpyrrolidone and monoethanolamine as a solubilizing agent.
Item 1-11. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-10, further comprising a buffer.
Item 1-12. Item 10. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to Item 1-11, which contains a borate buffer as a buffer.
Item 1-13. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of Items 1-1 to 1-12, which is an eye drop.

The present invention also provides a method for suppressing adhesion of corneal epithelial cells to the nonionic silicone hydrogel contact lens described below.
Item 2. A nonionic silicone hydrogel contact lens ophthalmic composition containing at least one selected from the group consisting of tranilast and a salt thereof is contacted with a nonionic silicone hydrogel contact lens. A method for suppressing adhesion of corneal epithelial cells to an ionic silicone hydrogel contact lens.

Moreover, this invention provides the method of providing the adhesion | attachment inhibitory effect of the corneal epithelial cell with respect to the nonionic silicone hydrogel contact lens hung up below to an ophthalmic composition.
Item 3. An ophthalmic composition for nonionic silicone hydrogel contact lenses, comprising at least one selected from the group consisting of tranilast and a salt thereof in an ophthalmic composition for nonionic silicone hydrogel contact lenses. A method for imparting an adhesion suppressing action of corneal epithelial cells to a nonionic silicone hydrogel contact lens.

The present invention also provides a method for improving the permeability of tranilast and / or a salt thereof to the nonionic silicone hydrogel contact lens described below.
Item 4. A nonionic silicone hydrogel contact lens selected from the group consisting of tranilast and a salt thereof, wherein a surfactant is used in combination with at least one selected from the group consisting of tranilast and a salt thereof. A method for improving at least one permeability.

In addition, the present invention provides a method for imparting to the ophthalmic composition the tranilast and / or salt permeation-improving action thereof for the nonionic silicone hydrogel contact lenses listed below.
Item 5. A nonionic silicone hydrogel contact comprising a surfactant in an ophthalmic composition for nonionic silicone hydrogel contact lenses containing at least one selected from the group consisting of tranilast and a salt thereof. A method for imparting to the ophthalmic composition an effect of improving at least one permeability selected from the group consisting of tranilast to a lens and a salt thereof.

Moreover, this invention provides the agent for improving the permeability | transmittance of tranilast and / or its salt with respect to the nonionic silicone hydrogel contact lens hung up below.
Item 6. An agent for improving permeability of at least one selected from the group consisting of tranilast and a salt thereof into a nonionic silicone hydrogel contact lens, comprising a surfactant.

The present invention also provides a method for reducing friction of nonionic silicone hydrogel contact lenses that is increased by tranilast and / or salts thereof listed below.
Item 7. Selected from the group consisting of tranilast and its salts, characterized by using at least one selected from the group consisting of tranilast and its salts and at least one selected from the group consisting of surfactants and terpenoids A method for reducing friction of a non-ionic silicone hydrogel contact lens that is increased by contacting at least one of the above.

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 8. Formulating at least one selected from the group consisting of a surfactant and a terpenoid into an ophthalmic composition for a nonionic silicone hydrogel contact lens containing at least one selected from the group consisting of tranilast and a salt thereof. A method for imparting to the ophthalmic composition an action for reducing friction of a nonionic silicone hydrogel contact lens that is increased by contacting at least one selected from the group consisting of tranilast and a salt thereof, .

Moreover, this invention provides the agent for reducing the friction of the nonionic silicone hydrogel contact lens increased by contacting the tranilast and / or its salt which are hung up below.
Item 9. A nonionic silicone hydrogel contact lens that is increased by contacting at least one selected from the group consisting of tranilast and a salt thereof, comprising at least one selected from the group consisting of a surfactant and a terpenoid Agent for reducing friction.

The present invention also provides a screening method for substances that improve the permeability of tranilast and / or its salts to the nonionic silicone hydrogel contact lenses listed below.
Item 10. A screening method for a permeability-improving substance that improves the permeability of at least one tranilast selected from the group consisting of tranilast and a salt thereof for a nonionic silicone hydrogel contact lens,
(a) preparing a control solution containing at least one tranilast selected from the group consisting of tranilast and a salt thereof, and a test solution containing tranilast 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 exuded from the other side of the nonionic silicone hydrogel contact lens that is not in contact with the test solution. Determining the amount of tranilast permeated in each test solution by measuring the amount of tranilast obtained, and
(c) screening comprising a step of selecting a test solution having a permeant amount of tranilast measured in the step (b) higher than that of a control solution and selecting a test substance contained in the test solution as the permeability improving substance. Method.

  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, the study by the present inventors has revealed that non-ionic SHCL has a remarkably small amount of tranilast and / or a salt thereof transmitted through the lens compared to other SCLs. Therefore, even if an eye drop containing tranilast and / or a salt thereof is applied to the eye wearing nonionic SHCL, there is a possibility that the desired effect cannot be obtained. On the other hand, according to the present invention, by using a surfactant together with tranilast and / or its salt, the permeability of tranilast and / or its salt to nonionic SHCL can be remarkably improved. Therefore, even when instilled while wearing nonionic SHCL, the amount of tranilast and / or its salt reaching the keratoconjunctiva under nonionic SHCL can be increased, and the antiallergic effect is effectively exhibited in the keratoconjunctiva. It is possible to provide an ophthalmic composition for nonionic SHCL that can be produced.

  Furthermore, the present inventors evaluated the friction of the surface of various soft contact lenses, and confirmed that the silicone hydrogel contact lens has significantly larger friction than the normal hydrogel contact lens. Furthermore, it has also been found that the friction is further increased when tranilast and / or a salt thereof is applied to nonionic SHCL. Such an increase in friction can cause discomfort (foreign material feeling, dry feeling, etc.), eye fatigue, and the like when the silicone hydrogel contact lens is worn. Furthermore, a contact lens with high friction may cause epithelial damage to the keratoconjunctiva when the mucous membrane on the back side of the eyelid and the contact lens surface rub against each other or whenever the contact lens moves on the eyeball surface. On the other hand, according to the present invention, by using a surfactant and / or a terpenoid together with tranilast and / or a salt thereof, the tranilast and / or a salt thereof is contained while containing the tranilast and / or a salt thereof. It is possible to provide an ophthalmic composition for nonionic SHCL in which the increase in friction of the nonionic SHCL surface caused by salt is remarkably suppressed.

In the reference test example 1, it is a figure which shows the result of having evaluated the corneal epithelial cell adhesiveness 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). 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 tranilast. 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 the test liquid (Example 4-5, Reference Example 2, and Comparative Example 2-4) exerts on the friction of nonionic SHCL.

1. Nonionic SHCL Ophthalmic Composition The nonionic SHCL ophthalmic composition of the present invention contains at least one selected from the group consisting of tranilast and a salt thereof. Thus, by using tranilast and / or a salt thereof, it becomes possible to suppress adhesion of corneal epithelial cells to nonionic SHCL.

  Tranilast is a known compound also referred to as N- (3,4-dimethoxycinnamoyl) anthranilic acid, which may be synthesized by a known method or obtained as a commercial product.

  The salt of tranilast is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and specifically, a salt with an organic base (for example, methylamine, Salts with organic amines such as triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals ( Calcium, magnesium, etc.), salts with metals such as aluminum, etc.]. These tranilast salts may be used alone or in any combination of two or more.

  In the ophthalmic composition for nonionic SHCL of the present invention, one of these tranilasts and salts thereof may be selected and used alone, or two or more of them may be used in any combination. May be. Among these, tranilast is preferably used from the viewpoint of more effectively suppressing adhesion of corneal epithelial cells to nonionic SHCL. Tranilast is also suitable from the viewpoint that the nonionic SHCL permeability improving effect by the surfactant is more effectively exhibited, and the friction reducing effect of the nonionic SHCL by the surfactant and / or the terpenoid is further improved. It is also suitable from the viewpoint of effective performance.

  In the ophthalmic composition for nonionic SHCL of the present invention, the mixing ratio of tranilast and / or a salt thereof is appropriately set according to the type of tranilast and / or a salt thereof, the formulation form of the ophthalmic composition, and the like. However, as an example, the total amount of tranilast and / or a salt thereof is 0.005 to 5 w / v%, preferably 0.01 to 1 w / v%, more preferably, with respect to the total amount of the ophthalmic composition for nonionic SHCL. Is exemplified by 0.02 to 0.6 w / v%.

  Moreover, it is preferable that the ophthalmic composition for nonionic SHCL of the present invention further contains a surfactant. By including a surfactant in this way, the permeability of tranilast and / or its salt to nonionic SHCL can be increased, and further the friction of nonionic SHCL caused by tranilast and / or its salt is increased. Can also be reduced.

  The surfactant used in 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. Any of an ionic surfactant, an amphoteric surfactant, an anionic surfactant, and a cationic surfactant may be used.

  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 these surfactants, nonionic surfactants, amphoteric surfactants, and cationic surfactants are preferable from the viewpoint of further increasing the nonionic SHCL permeability of tranilast and / or a salt thereof. More preferably nonionic surfactants; more preferably POE sorbitan fatty acid esters and POE hydrogenated castor oil; particularly preferably polysorbate 80 and polyoxyethylene hydrogenated castor oil 60. The surfactants exemplified here are also suitable from the viewpoint of more effectively exerting the effect of suppressing the increase in friction of nonionic SHCL caused by tranilast and / or a salt thereof.

  When a surfactant is blended with the nonionic SHCL ophthalmic composition of the present invention, the blending ratio of the surfactant is appropriately set according to the type of the surfactant, the formulation form of the ophthalmic composition, and the like. However, as an example, the total amount of the surfactant is 0.001 to 1 w / v%, preferably 0.005 to 1 w / v%, more preferably 0 to the total amount of the nonionic SHCL ophthalmic composition. .01 to 0.5 w / v% is exemplified.

  In the ophthalmic composition for nonionic SHCL of the present invention, the ratio of the surfactant to tranilast and / or a salt thereof is not particularly limited, but the nonionic SHCL of tranilast and / or a salt thereof is not particularly limited. From the viewpoint of further increasing the permeability, the total amount of the surfactant is 0.5 to 10000 parts by weight, preferably 0.8 to 4000 parts by weight, more preferably 100 parts by weight of the total amount of tranilast and / or a salt thereof. The range which becomes 1.6-2000 weight part is illustrated. Such a ratio is also suitable from the viewpoint of more effectively exerting the effect of suppressing the increase in friction of nonionic SHCL caused by tranilast and / or a salt thereof.

  The ophthalmic composition for nonionic SHCL of the present invention preferably contains a terpenoid. Thus, by containing a terpenoid, in particular by containing a combination of a terpenoid and a surfactant, it is possible to effectively suppress an increase in friction of nonionic SHCL caused by tranilast and / or a salt thereof. It becomes possible.

  The terpenoid used in the nonionic SHCL ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such 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 a terpenoid. 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 and geraniol are preferable from the viewpoint of further enhancing the effect of suppressing the increase in friction of nonionic SHCL caused by tranilast and / or a salt thereof. Examples of the essential oil to be contained include cool mint oil, peppermint oil, mint oil, camphor oil, and rose oil. 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.

  When the terpenoid is added to the ophthalmic composition for nonionic SHCL of the present invention, the mixing ratio of the terpenoid is not particularly limited, but the effect of suppressing the increase in friction of nonionic SHCL caused by tranilast and / or a salt thereof is not limited. From the viewpoint of further increasing the amount of terpenoids, the total amount of terpenoids is 0.0001 to 0.2 w / v%, preferably 0.0005 to 0.1 w / v%, based on the total amount of the nonionic SHCL ophthalmic composition, Preferably 0.001-0.07 w / v% is mentioned. In particular, when menthol is used as a terpenoid, there is no particular limitation, but generally, menthol is 0.0001 to 0.1 w / v% in total, preferably with respect to the total amount of ophthalmic composition for nonionic SHCL, preferably Examples are 0.0005 to 0.07 w / v%, more preferably 0.001 to 0.05 w / v%. In addition, when using the essential oil containing a terpenoid, it sets so that the terpenoid content in the essential oil mix | blended may satisfy | fill the said mixture ratio.

  In the ophthalmic composition for nonionic SHCL of the present invention, the ratio of terpenoid to tranilast and / or its salt is not particularly limited, but nonionic SHCL caused by tranilast and / or its salt From the viewpoint of further enhancing the effect of suppressing the increase in friction, the total amount of terpenoids per 100 parts by weight of tranilast and / or its salt is 0.01 to 1000 parts by weight, preferably 0.08 to 400 parts by weight, More preferably, the range which becomes 0.1-280 weight part is illustrated. In particular, when menthol is used as the terpenoid, there is no particular limitation, but generally, menthol is 0.01 to 1000 parts by weight, preferably 0.08 to 100 parts by weight per 100 parts by weight of tranilast and / or its salt. The range which becomes 280 weight part, More preferably, 0.1-200 weight part is illustrated. In addition, when using the essential oil containing a terpenoid, it sets so that the terpenoid content in the essential oil mix | blended may satisfy | fill the said ratio.

  Moreover, it is preferable that the ophthalmic composition for nonionic SHCL of the present invention further contains a solubilizing agent.

  The solubilizing agent used in the ophthalmic composition for nonionic SHCL of the present invention may be any component having an action of assisting in dissolving tranilast and / or a salt thereof in an aqueous solution, such as polyvinylpyrrolidone, Examples include trometamol, monoethanolamine, diethanolamine, triethanolamine, propylene glycol, and caffeine. These solubilizers may be used alone or in any combination of two or more.

  Among these solubilizers, polyvinyl pyrrolidone and monoethanolamine, and more preferably polyvinyl pyrrolidone are preferably used from the viewpoint of more effectively suppressing adhesion of corneal epithelial cells to nonionic SHCL. The molecular weight of polyvinylpyrrolidone is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, but in general, the K value by the Fikencher method is 15 to 100, preferably 20 to 99, more preferably about 22 to 98 can be used. Polyvinylpyrrolidone is also suitable from the viewpoint of more effectively exerting the nonionic SHCL permeability improving effect by the surfactant, and further exerting the friction reducing effect by the surfactant and / or the terpenoid. From this point of view, it is preferable.

  The ophthalmic composition for nonionic SHCL of the present invention may further contain a buffer in addition to the above components. 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, tris 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 Acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); as a Tris buffer, tris (hydroxymethyl) aminomethane or a salt thereof (hydrochloride, acetate, sulfonate, etc.); Examples include aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.). These buffering agents may be used alone or in any combination of two or more. Among these, from the viewpoint of further enhancing the effect of suppressing the adhesion of corneal epithelial cells to nonionic SHCL, from the viewpoint of further enhancing the nonionic SHCL permeability improving effect by the surfactant, or surfactant and / or terpenoid From the standpoint of further enhancing the friction reducing effect of the boric acid, a boric acid buffer, particularly a combination of boric acid and borax is preferred.

  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 uniformly 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 2.5 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. These isotonic agents may be used alone or in any combination of two or more. Among these, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, and propylene glycol are preferable from the viewpoint of more effectively achieving the effects of the present invention, and sodium chloride, And potassium chloride.

  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 5.5 to 9.0, and more preferably 6.5 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 hydrochloride, chlorpheniramine maleate, ketotifen fumarate, pemirolast potassium and the like.
Decongestant: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.
Fungicide: For example, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biguanide hydrochloride, and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, 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, dipotassium glycyrrhizinate, pranoprofen, allantoin, azulene, sodium azulenesulfonate, guaiazulene, ε-aminocaproic acid, berberine chloride, berberine sulfate, lysozyme chloride, 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, sodium sulfamethoxazole and the like.

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 each component.

  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.

  The ophthalmic composition for nonionic SHCL of the present invention is not limited in its form and use as long as it is used in the ophthalmic field and used to come into contact with nonionic SHCL. For example, eye drops for nonionic SHCL (eye drops that can be used while wearing nonionic SHCL), eye drops for nonionic SHCL (eyewash that can be used while wearing nonionic SHCL), nonionic Nonionic SHCL care solution (nonionic SHCL disinfectant, nonionic SHCL preserving solution, nonionic SHCL cleaning solution, nonionic SHCL cleaning preservative solution, etc.) and the like. 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, It is used within 10 minutes before the wearing action to be contacted), and is a pharmaceutical form in which the action of suppressing the adhesion of corneal epithelial cells to nonionic SHCL is strongly desired. In the case of eye drops, the increase in friction on the surface of nonionic SHCL caused by contact with tranilast and / or its salt 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, as a suitable example of the ophthalmic composition for nonionic SHCL of the present invention, an eyedrop for nonionic SHCL and a nonionic SHCL mounting solution can be mentioned, and a particularly preferable example is non- Mention may be made of eye drops for ionic SHCL. Further, when the ophthalmic composition for nonionic SHCL of the present invention contains a surfactant together with tranilast, the permeability of tranilast and / or a salt thereof to nonionic SHCL is remarkably enhanced, It is particularly suitable as an eye drop for sexual SHCL.

  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 exhibit an antiallergic action based on tranilast and / or a salt thereof, it is also useful as an allergy symptom reducing agent. In particular, when the nonionic SHCL ophthalmic composition of the present invention contains a surfactant together with tranilast and / or a salt thereof, the amount of tranilast and / or the salt thereof permeated through the lens is increased and reaches the keratoconjunctiva. Since the amount increases, a sufficient medicinal effect can be obtained even while wearing nonionic SHCL.

  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.

2. Method for inhibiting adhesion of corneal epithelial cells to nonionic SHCL, and method for imparting adhesion inhibiting action of corneal epithelial cells to nonionic SHCL As described above, by using tranilast and / or a salt thereof, nonionic SHCL Adhesion of corneal epithelial cells to can be suppressed.

  Therefore, the present invention is characterized in that the nonionic SHCL ophthalmic composition containing at least one selected from the group consisting of tranilast and a salt thereof is brought into contact with the nonionic SHCL from another viewpoint. And a method for suppressing adhesion of corneal epithelial cells to nonionic SHCL. Furthermore, at least one selected from the group consisting of tranilast and a salt thereof is added to the ophthalmic composition for nonionic SHCL, and the ophthalmic composition for nonionic SHCL against nonionic SHCL, Provided is a method for imparting an adhesion inhibitory action on corneal epithelial cells.

  In these methods, the type and ratio of tranilast and / or its salt, the type and ratio of other ingredients, the formulation form of the ophthalmic composition for nonionic SHCL, the type of nonionic SHCL to be applied, etc. Is the same as “1. Ophthalmic composition for nonionic SHCL”.

3. Method for improving the permeability of tranilast and / or its salt to nonionic SHCL, and method for imparting the action of improving the permeability of tranilast and / or its salt to nonionic SHCL As described above, nonionic The permeability of tranilast and / or its salt to SHCL can be improved by a surfactant.

  Therefore, the present invention, from yet another aspect, uses at least one selected from the group consisting of tranilast and a salt thereof and a surfactant in combination, and tranilast to nonionic SHCL, and its Provided is a method for improving the permeability of at least one selected from the group consisting of salts. In addition, the present invention provides a nonionic SHCL comprising a surfactant in a nonionic SHCL ophthalmic composition containing at least one selected from the group consisting of tranilast and a salt thereof. There is also provided a method of imparting to the ophthalmic composition an effect of improving permeability of at least one selected from the group consisting of tranilast and its salt.

  In this method, tranilast and / or its salt type and blending ratio, surfactant type and blending ratio, other blending component types and blending ratio, nonionic SHCL ophthalmic composition formulation, application target The kind of the nonionic SHCL is the same as that of the above-mentioned “1. Ophthalmic composition for nonionic SHCL”.

4). Agent for improving the permeability of tranilast and / or its salt to nonionic SHCL As described above, the permeability of tranilast and / or its salt to nonionic SHCL can be improved by a surfactant. it can.

  Therefore, the present invention, from yet another viewpoint, improves the permeability of at least one selected from the group consisting of tranilast and its salt into nonionic SHCL, which contains a surfactant as an active ingredient. Provide the agent.

  In the agent, the type of surfactant, the nonionic SHCL to be applied, the type of tranilast and / or its salt to be permeable to the nonionic SHCL, the blending ratio thereof, etc. 1. Same as “Nonionic SHCL Ophthalmic Composition”.

5. Nonionic SHCL friction reducing method; and nonionic SHCL friction reducing method for providing ophthalmic composition with friction reducing action As described above, a combination of tranilast and / or a salt thereof, a surfactant and / or a terpenoid By doing so, the friction of the non-ionic SHCL surface that is increased by tranilast and / or its salts can be reduced. Accordingly, the present invention is characterized in that, from another viewpoint, at least one selected from the group consisting of tranilast and a salt thereof and at least one selected from the group consisting of a surfactant and a terpenoid are used in combination. And a method for reducing friction of nonionic SHCL that is increased by contacting at least one selected from the group consisting of tranilast and a salt thereof.

  Moreover, this invention mix | blends at least 1 sort (s) selected from the group which consists of surfactant and a terpenoid with the ophthalmic composition for nonionic SHCL containing at least 1 sort (s) selected from the group which consists of tranilast and its salt. Also provided is a method for imparting to the ophthalmic composition an action of reducing friction of nonionic SHCL which is increased by contacting at least one selected from the group consisting of tranilast and a salt thereof. To do.

  In the friction reduction method and the application method, the type of nonionic SHCL to be applied, the type of tranilast and / or a salt thereof, the type of surfactant, the type of terpenoid, the blending ratio thereof, nonionic Regarding the types and proportions of the other ingredients to be blended in the SHCL ophthalmic composition, the method for bringing the nonionic SHCL ophthalmic composition into contact with the nonionic SHCL, etc., see “1. Nonionic SHCL ophthalmology”. The same as “composition”.

6). Agents for reducing friction of nonionic SHCL As described above, surfactants and / or terpenoids increase the friction of nonionic silicone hydrogel contact lenses caused by contact with tranilast and / or its salts. Can be suppressed.

  Therefore, the present invention, from yet another point of view, contacts at least one selected from the group consisting of tranilast and a salt thereof containing at least one selected from the group consisting of a surfactant and a terpenoid as an active ingredient. An agent for reducing friction of a nonionic silicone hydrogel contact lens, which is increased by the treatment.

  In the agent, the types of surfactants and terpenoids, the nonionic SHCL to be applied, the type of tranilast and / or its salt that causes increased friction of the nonionic SHCL, the blending ratio thereof, etc. .. Non-ionic SHCL ophthalmic composition ".

7). A screening method for a substance that improves the permeability of tranilast and / or a salt thereof to nonionic SHCL Further , as described above, the present inventors have made tranilast and / or a salt thereof permeable to nonionic SHCL. New findings have been obtained that it is significantly lower. Therefore, the present invention further provides a method for screening a substance for improving permeability that improves the permeability of at least one kind of tranilast selected from the group consisting of tranilast against nonionic SHCL and a salt thereof. Specifically, this screening method is a method including the following steps (a) to (c).
(a) preparing a control solution containing at least one tranilast selected from the group consisting of tranilast and a salt thereof, and a test solution containing tranilast and a test substance as test solutions,
(b) Each of the above test solutions is brought into contact with only one side of the nonionic SHCL for a predetermined time, and the amount of tranilast exuded from the other side of the nonionic SHCL that is not in contact with the test solution is measured. A step of determining the permeation amount of tranilasts of each test solution, and
(c) A step of selecting a test solution having a permeation amount of tranilast measured in the step (b) larger than that of a control solution and selecting a test substance contained in the test solution as the permeability improving substance.

  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 0.05 to 1.0 w / v% of at least one tranilast selected from the group consisting of tranilast 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 tranilasts 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 preferably a solution containing no tranilast (hereinafter referred to as tranilast). 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 tranilast transferred to the side. The amount of tranilast determined in this manner is the amount of tranilast permeated obtained 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) relating to the selection of the above-described permeability enhancing substance, in order to select a permeability enhancing substance having a strong effect of improving the permeability of tranilasts to nonionic SHCL, it is required in the step (b). It is sufficient to select a test solution in which the amount of tranilast permeated is larger than that of the control solution.

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

  EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

Reference Test Example 1: Evaluation of Adhesion of Corneal Epithelial Cells of Various Soft Contact Lenses The following experiment was performed 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 one by one in a 24-well microplate containing 900 μL of growth medium (DMEM medium containing 10% fetal bovine serum) so that the convex surface was on the top. Each well was seeded with 100 μL of a cell suspension (1 × 10 ⁵ cell / mL) of a rabbit corneal epithelial cell line SIRC (ATCC number: CCL-60) prepared using a growth medium, and the culture was performed 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 (made by 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 solutions shown in Table 2 (Example 1 and Comparative Example 1), the adhesion inhibitory effect of corneal epithelial cells on nonionic SHCL was evaluated.

Lens B (nonionic SHCL) shown in Table 1 was immersed one by one in 3 mL of each test solution shown in Table 2, and shaken for 24 hours at 34 ° C. The lens B taken out from each test solution is thoroughly washed with physiological saline, wiped off the moisture, 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). One by one. Each well was seeded with 100 μL of a cell suspension (1 × 10 ⁵ cell / mL) of a rabbit corneal epithelial cell line SIRC (ATCC number: CCL-60) prepared using a growth medium, and the culture was performed at 37 ° C., 5 ° C. After culturing for 48 hours under% CO ₂ conditions, the number of viable cells attached to the lens was counted. Furthermore, as a blank, a well containing only 1000 μL of growth medium (DMEM medium containing 10% fetal bovine serum) without seeding rabbit corneal epithelial cells was prepared, and the well was allowed to stand still at 37 ° C. and 5% CO ₂ for 48 hours. (Blank group). For counting the number of viable cells, Cell Counting Kit (manufactured by Dojindo Laboratories) was used, and absorbance at a wavelength of 450 nm was measured. The A450 value measured for each test solution was corrected with the A450 value of the blank group, and the ratio of the number of adherent cells in Example 1 when the number of adherent cells in Comparative Example 1 was 100% was defined as the cell adhesion rate (%). Calculated.

  The obtained results are shown in FIG. As is clear from FIG. 2, it was revealed that the adhesion of corneal cells to nonionic SHCL can be remarkably suppressed by using tranilast.

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

  Measurement of the SCL permeability evaluation of tranilast 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 0.5 w / v. 5 mL of a solution containing 1.% tranilast (1.30 w / v% boric acid, 0.75 w / v% borax, 3.00 w / v% polyvinylpyrrolidone; pH 7.5) was charged. After 24 hours from the start of the test, 1 mL of the physiological saline solution was collected, the concentration of tranilast was measured by the HPLC method according to a conventional method, and the amount of tranilast transferred to cell I was calculated.

  The results are shown in FIG. As is clear from FIG. 3, the lens 3 that is nonionic SHCL was found to have significantly worse tranilast lens permeability than the lenses 1 and 2 that are hydrogel contact lenses.

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

  The measurement of nonionic SHCL permeability evaluation of tranilast 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 (Reference Example 1 and Example 2-3) was accurately filled with 5 mL. Subsequently, 1 mL of the physiological saline solution was collected after 24 hours, and the concentration of tranilast was quantified by HPLC according to a conventional method. From the quantified result, the amount of tranilast transmitted through the lens (μg) was determined. The ratio of the lens transmission amount of the tranilast of Examples 2 and 3 when the lens transmission amount of the tranilast of reference example 1 was 100% was calculated as the tranilast transmittance (%).

  The results are shown in Table 5. As apparent from Table 5, it was found that the lens transmittance of tranilast was significantly increased in the test solutions of Examples 2 and 3 as compared with the test solution of Reference Example 1. That is, by using tranilast and a surfactant (polysorbate 80 or polyoxyethylene hydrogenated castor oil 60) in combination, the permeability of tranilast to nonionic SHCL is remarkably improved, and instilled during use of nonionic SHCL. 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 tranilast.

Reference test example 3: Tranilast lens transmission test 2:
Lenses 1 and 2 (hydrogel contact lenses) shown in Table 3 and ionic silicone hydrogel contact lenses (material classification: silicone hydrogel contact lenses, USAN: Balafilcon A, properties: ionic, moisture content: 36.0%, BC: 8.6, DIA: 14.0 mm; lens 4), and the same experiment as in Test Example 2 was performed to evaluate the lens permeability of tranilast. Experiments were conducted using the test solutions shown in Table 4 (Reference Example 1 and Example 2) as the test solution. The ratio of the lens transmission amount of the tranilast of Example 2 when the lens transmission amount of the tranilast of Reference Example 1 was 100% was calculated as the tranilast transmittance (%).

  The results are shown in Table 6. As is clear from Table 6, in the case of a conventional hydrogel contact lens, when a surfactant is used in combination with tranilast (Example 2), the effect of improving the permeability of tranilast is better than that of tranilast alone (Reference Example 1). It was revealed that there was a case where the permeability was not recognized at all or the permeability was deteriorated. Further, in the case of an ionic silicone hydrogel contact lens, even when a surfactant is used in combination with tranilast (Example 2), almost no improvement in permeability is observed compared to tranilast alone (Reference Example 1). Was confirmed.

  From the above results, it is clear that the significant improvement in the lens permeability of tranilast observed by the combined use of tranilast and surfactant is an effect that is specifically observed when the target lens is nonionic SHCL. became.

Reference test example 4: Evaluation of friction on nonionic SHCL surface In order to measure the physical properties of nonionic SHCL surface, various surface property changes such as tackiness, viscoelasticity, and drying property are evaluated in terms of frictional increase / decrease The friction force of each nonionic SHCL surface was evaluated using a rigid pendulum physical property tester RPT-3000W (manufactured by A & D). The nonionic SHCL used for the test is two types of nonionic SHCL shown in Table 7.

  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. 4, nonionic SHCL was found to have a high logarithmic decay rate and very high friction.

Test Example 3: Evaluation of reducing effect on friction of nonionic SHCL surface Using lens I shown in Table 7 as nonionic SHCL, the friction reducing effect on the lens surface was evaluated.

  First, each test solution (Example 4-5, Reference Example 2, and Comparative Example 2-4) shown in Table 8 was prepared. After thoroughly rinsing the nonionic SHCL surface with physiological saline, two pieces of nonionic SHCL were immersed in 20 mL of each test solution and allowed to stand overnight at room temperature. The next day, the water on the surface of the nonionic SHCL was wiped off lightly, and the logarithmic decay rate was measured every 10 seconds for 3 minutes under the conditions of a temperature of 25 ° C. and a relative humidity of 60% under a pendulum weight of 200 g and a sensor diameter of 4 mm.

  The result is shown in FIG. As shown in FIG. 5, it was found that when the tranilast was blended (Reference Example 2), the friction on the nonionic SHCL surface was further increased. Further, when only polysorbate 80 is used (Comparative Example 3), the friction on the surface of nonionic SHCL is increased, and when polysorbate 80 and l-menthol are combined (Comparative Example 4), the friction is further increased. It became clear that. On the other hand, unexpectedly, when tranilast and polysorbate 80 were combined in combination (Example 4), the friction on the nonionic SHCL surface deteriorated by tranilast was suppressed, and further, tranilast and polysorbate 80 and l- In the case where menthol was blended in combination (Example 5), it was revealed that the friction was remarkably suppressed to almost the same level as the control (Comparative Example 2) while containing tranilast.

Formulation Example In the formulation shown in Table 9, non-ionic SHCL eye drops (Example 6-12), non-ionic SHCL mounting solution (Example 13), non-ionic SHCL mounting solution and eye drops (Example 14) ) And a non-ionic SHCL eyewash (Example 15).

Claims (10)

An ophthalmic composition for a nonionic silicone hydrogel contact lens, comprising at least one selected from the group consisting of tranilast and a salt thereof. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to claim 1, comprising at least one selected from the group consisting of tranilast and a salt thereof in a total amount of 0.005 to 5 w / v%. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to claim 1 or 2, further comprising a surfactant. The ophthalmic composition for a nonionic silicone hydrogel contact lens according to any one of claims 1 to 3, further comprising a terpenoid. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of claims 1 to 4 , having a pH of 4.0 to 9.5. The ophthalmic composition for nonionic silicone hydrogel contact lenses according to any one of claims 1 to 5 , which is an eye drop. By containing at least one selected from the group consisting of tranilast and its salt, the ophthalmic composition for nonionic silicone hydrogel contact lenses has an inhibitory effect on corneal epithelial cell adhesion to the nonionic silicone hydrogel contact lenses. How to grant. An ophthalmic composition for nonionic silicone hydrogel contact lenses by blending at least one selected from the group consisting of tranilast and salts thereof and at least one selected from the group consisting of surfactants and terpenoids And a method for imparting a friction reducing action to a nonionic silicone hydrogel contact lens. By blending at least one selected from the group consisting of tranilast and a salt thereof with a surfactant , the ophthalmic composition for a nonionic silicone hydrogel contact lens is added to a nonionic silicone hydrogel contact lens. A method for imparting a tranilast permeability enhancing effect. An allergic symptom alleviating agent comprising an ophthalmic composition applied to a nonionic silicone hydrogel contact lens, containing at least one selected from the group consisting of tranilast and a salt thereof.

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