JP2020111603A - Ophthalmic composition for silicone hydrogel contact lens - Google Patents

Abstract

To provide an ophthalmic composition for a silicone hydrogel contact lens that can suppress the adsorption of lipids to the surface of a non-ionic silicone hydrogel contact lens or that can suppress the adsorption of pollen protein to an ionic silicone hydrogel contact lens.SOLUTION: The ophthalmic composition for a silicone hydrogel contact lens is prepared by the combination of (A) at least one selected from the group consisting of a polyhexanide and salts thereof, and (B) at least one selected from the group consisting of chlorpheniramine, chromoglycic acid, pranoprofen, glycyrrhizic acid, neostigmine and salts thereof.SELECTED DRAWING: None

Description

The present invention relates to ophthalmic compositions for silicone hydrogel contact lenses. More specifically, an ophthalmology for silicone hydrogel contact lenses capable of suppressing lipid adsorption on nonionic silicone hydrogel contact lenses or suppressing accumulation of pollen proteins on ionic silicone hydrogel contact lenses. It relates to a composition. The present invention also relates to a method for suppressing lipid adsorption on a nonionic silicone hydrogel contact lens. The present invention also relates to a method for suppressing the accumulation of pollen proteins on ionic silicone hydrogel contact lenses.

In recent years, the number of wearers of contact lenses (hereinafter sometimes referred to as CL) is increasing, and especially, the number of wearers of soft contact lenses (hereinafter sometimes referred to as SCL) is also increasing. 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 corneal thickening. Therefore, development of soft contact lenses having higher oxygen permeability has been promoted.

Silicone hydrogel contact lenses (hereinafter sometimes referred to as SHCL) have been recently developed as soft contact lenses having high oxygen permeability under such a background. Silicone hydrogel contact lenses achieve several times the oxygen permeability of conventional hydrogel contact lenses by blending silicone with hydrogel. Therefore, it is highly expected that the weak point of oxygen supply, which is a weak point of the soft contact lens, can be improved, and the adverse effect on the cornea due to the oxygen shortage can be significantly suppressed.

On the other hand, it has been pointed out that silicone hydrogel contact lenses are more likely to be stained with lipids derived from the tear film, cosmetics, etc. as compared with conventional hydrogel contact lenses (Non-Patent Document 1). Such lipid stains cause clouding of the lens and the like to make the wearer uncomfortable and impair QOL (Quality of Life). In addition, such contamination of the contact lens may adversely affect the visual correction power that the lens should originally have. Furthermore, it has been recently pointed out that such lipid stains on contact lenses influence the occurrence of corneal epithelial disorders called corneal staining.

Therefore, it is indispensable to design an ophthalmic composition used for a contact lens in consideration of safety and the like, depending on the type of the contact lens. In particular, since soft contact lenses are made of various materials, it is important to design the formulation of the ophthalmic composition used for soft contact lenses according to the characteristics of the target soft contact lens.

In addition, pollinosis is an allergic symptom caused by the pollen protein contained in pollen acting as an antigen and contacting mucous membranes and the like. In recent years, the number of patients with hay fever is increasing, which is becoming a major social problem. In the field of ophthalmology, there is also a strong demand for the development of ophthalmic compositions useful for preventing pollen allergy and for suppressing the deterioration.

On the other hand, conventionally, polyhexanide and its salt have been known to have a disinfecting action and are used in ophthalmic compositions (see Patent Document 1). In addition, chlorpheniramine, cromoglycic acid, pranoprofen, glycyrrhizic acid, neostigmine and salts thereof are also known to have useful effects such as antiallergic action, anti-inflammatory action, and eye focus control function improving action. Used in things. However, the effects of these components on the dirt of silicone hydrogel contact lenses have not been clarified. Furthermore, it is the present situation that the effect of the combination of specific components among these on the silicone hydrogel contact lens cannot be inferred at all.

Special table 2001-501605 gazette

Hiroshi Shiotani, New Ophthalmology Vol.25, No.7, 907-912, 2008

The present inventors conducted various studies on the lipid adsorption properties of various soft contact lenses, and found that nonionic silicone hydrogel contact lenses (hereinafter sometimes referred to as nonionic SHCL) were soft contact lenses. Among them, it was confirmed that the lipid was remarkably easily adsorbed. Such remarkable lipid stains may cause clouding of the lens and impair the QOL (Quality of Life) of the wearer, and may also adversely affect the vision correction power of the lens. Furthermore, such lipid stains may induce corneal epithelial disorders such as corneal staining. Therefore, by suppressing the adsorption of lipids to nonionic SHCL, it prevents clouding of the lens and improves the feeling of wearing, and it also maintains the original visual correction power of the lens and prevents the occurrence of corneal epithelial disorders. Therefore, it is required to develop means that enable comfortable and safe use of SHCL.

Furthermore, the present inventors have conducted various studies on the adsorption properties of pollen proteins on various soft contact lenses, and found that ionic silicone hydrogel contact lenses (hereinafter sometimes referred to as ionic SHCL) have pollen. We have obtained a completely new finding that proteins are significantly adsorbed. Generally, proteins are considered to be difficult to adsorb to SHCL, and such findings are completely unexpected. And, in general, when wearing contact lenses, the eyes tend to dry easily, and as a result, the cleaning action by tear fluid is reduced, and foreign matter such as pollen easily accumulates in the eyes, which increases the risk of developing pollinosis. It is considered. Moreover, if a large amount of pollen protein is adsorbed and accumulated on the contact lens, the risk of developing pollinosis is significantly increased, which may be one of the causes of inducing or aggravating allergic symptoms. Further, if the pollen protein adsorbed on the contact lens is insufficiently removed, the wearing feeling of the contact lens is impaired, discomfort or cloudiness of the contact lens is induced, and the use period is shortened. Therefore, it is required to develop means capable of suppressing the accumulation of pollen protein in ionic SHCL.

Then, one of the objectives of this invention is to provide the ophthalmic composition for SHCL which can suppress the lipid adsorption to nonionic SHCL. Another object of the present invention is to provide an ophthalmic composition for SHCL, which can suppress the accumulation of pollen proteins in ionic SHCL, or can wash pollen proteins adsorbed in ionic SHCL. It is to be.

The present inventors, as a result of extensive studies to solve the above problems, (A) polyhexanide, and at least one selected from the group consisting of salts thereof, (B) chlorpheniramine, cromoglycic acid, pranopron It has been found that the combined use of at least one selected from the group consisting of phen, glycyrrhizinic acid, neostigmine and salts thereof synergistically suppresses lipid adsorption to nonionic SHCL. Further, the present inventors have found that the combined use of the above components makes it possible to suppress the accumulation of pollen proteins in the ionic SHCL and effectively wash the pollen proteins adsorbed on the ionic SHCL. The present invention has been completed by further improving based on such knowledge.

［式(1)中、R₁及びR₂は、同一又は異なって、下記一般式(2)に示される基又はアミノ基であり、ｎは１〜５００の整数を示す。］

項1-3.式(1)中、R₁はアミノ基であり、且つR₂は一般式(2)に示される基である、項1-2に記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-4．(A)成分として、ポリヘキサニドの塩酸塩を含む、項1-1〜1-3のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-5．(A)成分を総量で0.000005〜0.002w/v％含有する、項1-1〜1-4のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-6．(B)成分として、マレイン酸クロルフェニラミン、クロモグリク酸ナトリウム、プラノプロフェン、グリチルリチン酸二カリウム及びメチル硫酸ネオスチグミンからなる群より選択される少なくとも１種を含む、項1-1〜1-5のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-7．(B)成分を総量で0.0005〜3.5w/v％含有する、項1-1〜1-6のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-8． 更に、緩衝剤を含有する、項1-1〜1-7のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-9． 緩衝剤としてホウ酸緩衝剤を含む、項1-8に記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-10． 緩衝剤を総量で0.01〜10w/v％含有する、項1-8又は1-9に記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-11． 更に、等張化剤を含有する、項1-1〜1-10のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-12． 等張化剤として、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、グリセリン、及びプロピレングリコールからなる群より選択される少なくとも１種を含む、項1-11に記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-13． 等張化剤を総量で0.01〜10w/v％含有する、項1-11又は1-12に記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-14． 更に、界面活性剤を含有する、項1-1〜1-13のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-15． 界面活性剤として非イオン性界面活性剤を含む、項1-14に記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-16． 界面活性剤を総量で0.01〜10w/v％含有する、項1-14又は1-15に記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-17． 点眼剤である、項1-1〜1-16のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-18． 非イオン性シリコーンハイドロゲルコンタクトレンズ用である、項1-1〜1-17のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。
項1-19． イオン性シリコーンハイドロゲルコンタクトレンズ用である、項1-1〜1-17のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用眼科組成物。 That is, the present invention provides the following ophthalmic compositions for SHCL.
Item 1-1. (A) polyhexanide, and at least one selected from the group consisting of salts thereof, (B) at least selected from the group consisting of chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine and salts thereof. An ophthalmic composition for a silicone hydrogel contact lens, which comprises one or more kinds.
Item 1-2. As the component (A), at least one selected from the group consisting of the compound represented by the following general formula (1) and salts thereof, for the silicone hydrogel contact lens according to Item 1-1: Ophthalmic composition.

[In the formula (1), R ₁ and R ₂ are the same or different and each is a group represented by the following general formula (2) or an amino group, and n represents an integer of 1 to 500. ]

Item 1-3. In the formula (1), R ₁ is an amino group, and R ₂ is a group represented by the general formula (2), the ophthalmic composition for a silicone hydrogel contact lens according to Item 1-2. Stuff.
Item 1-4. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-3, which comprises, as the component (A), a hydrochloride of polyhexanide.
Item 1-5. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-4, which contains the component (A) in a total amount of 0.000005 to 0.002 w/v %.
Item 1-6. As the component (B), at least one selected from the group consisting of chlorpheniramine maleate, sodium cromoglycate, pranoprofen, dipotassium glycyrrhizinate, and neostigmine methylsulfate is contained, and the items 1-1 to 1-5 An ophthalmic composition for silicone hydrogel contact lenses according to any one of claims.
Item 1-7. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-6, which contains the component (B) in a total amount of 0.0005 to 3.5 w/v %.
Item 1-8. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-7, which further contains a buffering agent.
Item 1-9. Item 9. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-8, which contains a borate buffer as a buffer.
Item 1-10. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-8 or 1-9, which contains a buffering agent in a total amount of 0.01 to 10 w/v %.
Item 1-11. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-10, which further contains a tonicity agent.
Item 1-12. Ophthalmology for silicone hydrogel contact lenses according to Item 1-11, comprising at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, and propylene glycol as an isotonicity agent. Composition.
Item 1-13. Item 11. The ophthalmic composition for silicone hydrogel contact lens according to Item 1-11 or 1-12, which contains 0.01 to 10 w/v% in total in terms of tonicity agent.
Item 1-14. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-13, which further contains a surfactant.
Item 1-15. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-14, which comprises a nonionic surfactant as a surfactant.
Item 1-16. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-14 or 1-15, which contains 0.01 to 10 w/v% of a total amount of a surfactant.
Item 1-17. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-16, which is an eye drop.
Item 1-18. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-17, which is for nonionic silicone hydrogel contact lenses.
Item 1-19. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-17, which is for ionic silicone hydrogel contact lenses.

The present invention also provides a method for suppressing the adsorption of lipids on the following nonionic silicone hydrogel contact lenses.
Item 2. (A) polyhexanide, and at least one selected from the group consisting of salts thereof, and (B) at least selected from the group consisting of chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine and salts thereof. Suppressing lipid adsorption on a nonionic silicone hydrogel contact lens, characterized by contacting a nonionic silicone hydrogel contact lens with an ophthalmic composition for silicone hydrogel contact lenses containing one how to.

Further, the present invention provides a method for imparting a lipid adsorption inhibitory effect to nonionic SHCL to the SHCL ophthalmic composition listed below.
Item 3. Ophthalmic composition for silicone hydrogel contact lens, (A) polyhexanide, and at least one selected from the group consisting of salts thereof, (B) chlorpheniramine, cromoglic acid, pranoprofen, glycyrrhizic acid, neostigmine and An effect of suppressing adsorption of lipids to a nonionic silicone hydrogel contact lens in an ophthalmic composition for silicone hydrogel contact lens, which is characterized by blending with at least one selected from the group consisting of these salts How to give.

The present invention also provides the following methods for suppressing the accumulation of pollen proteins in ionic SHCL.
Item 4. (A) polyhexanide, and at least one selected from the group consisting of salts thereof, and (B) at least selected from the group consisting of chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine and salts thereof. A method for suppressing the accumulation of pollen proteins on an ionic silicone hydrogel contact lens, which comprises contacting an ophthalmic composition for silicone hydrogel contact lens containing 1 type with an ionic silicone hydrogel contact lens. ..

The present invention also provides the following methods for imparting an action of suppressing the accumulation of pollen proteins to ionic SHCL to an ophthalmic composition for SHCL.
Item 5. In the ophthalmic composition for silicone hydrogel contact lens, (A) polyhexanide, and at least one selected from the group consisting of salts thereof, (B) chlorpheniramine, cromoglic acid, pranoprofen, glycyrrhizic acid, neostigmine and A method for imparting to the ophthalmic composition an action of suppressing the accumulation of pollen proteins in an ionic silicone hydrogel contact lens, which comprises blending with at least one selected from the group consisting of these salts.

INDUSTRIAL APPLICABILITY The SHCL ophthalmic composition of the present invention can significantly suppress lipid adsorption on nonionic SHCL. Therefore, according to the ophthalmic composition for SHCL of the present invention, the lipid stain of the nonionic SHCL is prevented, the cloudiness of the nonionic SHCL is prevented, and the feeling of use of the nonionic SHCL is kept good, and Non-ionic SHCL can maintain the original visual correction power, and effectively prevent corneal epithelial disorders such as corneal staining caused by adsorption of lipid stains on SHCL, making it non-ionic comfortably and safely. It becomes possible to use SHCL.

Furthermore, according to the ophthalmic composition for SHCL of the present invention, even if the pollen protein and the ionic SHCL come into contact during the wearing of the ionic SHCL, the removal of the pollen protein from the ionic SHCL is promoted and the re-adhesion is also prevented. By doing so, the accumulation of pollen protein in ionic SHCL can be suppressed. Therefore, it is possible to reduce the risk of developing allergic symptoms for users of hay fever or a hay fever reserve army. Furthermore, according to the ophthalmic composition for SHCL of the present invention, the ionic SHCL can be kept clean during or before wearing the ionic SHCL, and the feeling of use of the ionic SHCL can be kept good.

Thus, the ophthalmic composition for SHCL of the present invention can solve the problems of concern when wearing nonionic and ionic SHCL all at once, and thus ensure high safety and comfort in the use of SHCL. You can

It is a figure which shows the result of having evaluated the adsorption|suction characteristic of the lipid in various soft contact lenses in the reference test example 1. In test example 1, it is a figure which shows the result of having evaluated the influence which the test liquid (Examples 1-1 to 1-5 and comparative examples 1-1 to 1-6) has on the adsorption of lipid to SHCL. It is a figure which shows the result of having evaluated the influence which the test liquid (Examples 1-6 to 1-11 and Comparative Examples 1-7 to 1-12) has on the adsorption of lipid to SHCL in Test Example 1. In Test Example 1, it is a diagram showing the results of evaluating the effects of the test liquids (Examples 1-12 to 1-16 and Comparative Examples 1-13 to 1-18) on the adsorption of lipids onto SHCL. In reference test example 2, it is a figure which shows the result of having evaluated the adsorbability of pollen protein to various soft contact lenses. In Test example 2, it is a figure which shows the result of having evaluated the effect which the test liquid (Examples 2-1 to 2-2, comparative examples 2-1 to 2-3) removes the pollen protein adsorbed to ionic SHCL. ..

1. Ophthalmic Composition for SHCL The ophthalmic composition for SHCL of the present invention contains at least one selected from the group consisting of polyhexanide and a salt thereof (hereinafter sometimes referred to as component (A) or PHMB).

The polyhexanide used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The compound shown in (1) is exemplified.

In the general formula (1), R ₁ and R ₂ are the same or different and each represents a group or an amino group represented by the following general formula (2). Preferably R ₁ is an amino group, and R ₂ is a group or amino group represented by the general formula (2), more preferably R ₁ is an amino group, R ₂ is represented by the general formula (2) It is a group that is

Moreover, in general formula (1), n shows the integer of 1-500. The integer is preferably 2 to 200, more preferably 4 to 100, and particularly preferably 8 to 20.

The salt of polyhexanide is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of the salt of polyhexanide include inorganic acid salts such as hydrochloric acid, hydrogen bromide, sulfuric acid and boric acid; organic acid salts such as acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid and citric acid. It is illustrated. Among these polyhexanide salts, inorganic acid salts are preferable, and hydrochloride salts are more preferable. These polyhexanide salts may be used alone or in any combination of two or more.

In the ophthalmic composition for SHCL of the present invention, as the component (A), one of polyhexanide and a salt thereof may be used alone, or two or more thereof may be used in any combination. May be. Among the components (A), from the viewpoint of further enhancing the lipid adsorption inhibitory action on nonionic SHCL, or further enhancing the accumulation inhibitory action on pollen protein ionic SHCL, preferably polyhexanide or an inorganic acid salt thereof, Preferred is polyhexanide or a hydrochloride thereof, and particularly preferred is a hydrochloride of polyhexanide.

In the ophthalmic composition for SHCL of the present invention, the mixing ratio of the component (A) is appropriately set according to the type of the component (A), the type of the component (B) used in combination, the formulation form of the ophthalmic composition for the SHCL, etc. However, as an example, with respect to the total amount of the ophthalmic composition for SHCL, the total amount of the component (A) is 0.000005 to 0.002 w/v%, preferably 0.00001 to 0.001 w/v%, and more preferably 0.00005 to 0.0003w. /v% is exemplified.

The mixing ratio of the component (A) is preferable from the viewpoint of further enhancing the lipid adsorption inhibitory action on nonionic SHCL and further enhancing the pollen protein accumulation inhibiting action on ionic SHCL.

The ophthalmic composition for SHCL of the present invention, in addition to the component (A), at least one selected from the group consisting of chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine and salts thereof (hereinafter , (B) may be referred to as the component). Thus, by using the components (A) and (B) together, it is possible to effectively suppress the adsorption of lipids on nonionic SHCL, and also effectively suppress the accumulation of pollen proteins on ionic SHCL. It is possible to

Further, of the component (B), cromoglycic acid is 5,5′-[(2-hydroxy-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-benzopyran-2- It is a known compound also referred to as "carboxylic acid", which may be synthesized by a known method or may be obtained as a commercial product.

The salt of cromoglycic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and is, for example, an alkali metal such as sodium salt or potassium salt. And salts of alkaline earth metals such as calcium salts and magnesium salts. Among these salts, the alkali metal salt is preferable, and the sodium salt is more preferable. These salts of cromoglycic acid may be used alone or in any combination of two or more.

Also, cromoglic acid and its salts can be used in the form of hydrates.

Among cromoglic acid and its salts, from the viewpoint of further enhancing the lipid adsorption inhibitory effect on nonionic SHCL, or from the viewpoint of further enhancing the accumulation inhibitory effect on pollen protein ionic SHCL, preferably a salt of cromoglic acid, more preferably Is an alkali metal salt of cromoglycic acid, particularly preferably sodium cromoglycate.

Further, among the component (B), chlorpheniramine is a known compound also called 3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine. Alternatively, it may be synthesized by a known method or may be obtained as a commercial product.

The salt of chlorpheniramine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and examples thereof include organic acid salts such as maleic acid salts and fumaric acid salts. Inorganic salts such as hydrochlorides and sulfates; 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.

In addition, chlorpheniramine and its salts may be in the form of hydrate, and may be in any of d-form, l-form and dl-form.

Among chlorpheniramine and its salts, from the viewpoint of further enhancing the lipid adsorption inhibitory effect on nonionic SHCL, or from the viewpoint of further enhancing the accumulation inhibitory effect on pollen protein ionic SHCL, preferably a salt of chlorpheniramine, More preferred is an organic acid salt of maleic acid, and particularly preferred is chlorpheniramine maleate.

In addition, of the component (B), pranoprofen is a known compound also called α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid, and can be prepared by a known method. It may be synthesized or obtained as a commercial product.

The salt of pranoprofen is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, but, for example, a salt with an alkali metal such as sodium salt or potassium salt. Salts with alkaline earth metals such as calcium salts and magnesium salts; salts with metals such as aluminum salts; methylamine salts, triethylamine salts, diethylamine salts, triethanolamine salts, morpholine salts, piperazine salts, pyrrolidine salts, tripyridine Examples thereof include salts and salts with organic bases such as picoline salts. These pranoprofen salts may be used alone or in any combination of two or more.

Moreover, pranoprofen and its salt can also be used in the form of a hydrate.

Among pranoprofen and its salts, from the viewpoint of further enhancing the lipid adsorption inhibitory action on nonionic SHCL or further enhancing the accumulation inhibitory action on pollen protein to ionic SHCL, preferably pranoprofen is mentioned. ..

Glycyrrhizic acid is 20β-carboxy-11-oxo-30-noroleana-12-en-3β-yl=(β-D-glucopyranosyluronic acid)-(1→2)-α-D-glucopyranosideuronic acid It is a known compound also referred to as, and may be synthesized or extracted by a known method, or may be 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, and examples thereof include alkali metal salts such as sodium salt and potassium salt. And salts; ammonium salts and the like. More specifically, examples thereof include salts with alkali metals such as disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, and tripotassium glycyrrhizinate; ammonium salts such as monoammonium glycyrrhizinate. Among these, an alkali metal salt of glycyrrhizinate is preferable, and dipotassium glycyrrhizinate is more preferable. These glycyrrhizinic acid salts may be used alone or in any combination of two or more.

Among glycyrrhizinic acid and its salts, from the viewpoint of further enhancing the lipid adsorption inhibitory effect on nonionic SHCL, or from the viewpoint of further enhancing the accumulation inhibitory effect on pollen protein ionic SHCL, a salt of glycyrrhizic acid is more preferred. Is an alkali metal salt of glycyrrhizinate, particularly preferably dipotassium glycyrrhizinate.

Further, of the component (B), neostigmine is a known compound also called N-(-3-dimethylcarbamoyloxyphenyl)-N,N,N-trimethylammonium, and can be synthesized by a known method. It is often available as a commercial product.

The salt of neostigmine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and includes, for example, methylsulfate (neostigmine methylsulfate), bromide salt (bromination). Neostigmine) and the like. Among the salts of neostigmine, methylsulfate is preferable. These neostigmine salts may be used alone or in any combination of two or more.

Among neostigmine and its salts, from the viewpoint of further enhancing the lipid adsorption inhibitory effect on nonionic SHCL, or further enhancing the accumulation inhibitory effect on pollen protein ionic SHCL, preferably neostigmine salt, more preferably methyl. Neostigmine sulfate is mentioned.

In the ophthalmic composition for SHCL of the present invention, the component (B) may be used alone from chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine and salts thereof. Also, two or more kinds may be used in any combination. Suitable examples of the component (B) used in the present invention include chlorpheniramine maleate, sodium cromoglycate, pranoprofen, dipotassium glycyrrhizinate and neostigmine methylsulfate.

Among components (B) used in the present invention, from the viewpoint of further enhancing the lipid adsorption inhibitory effect on nonionic SHCL, chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, and these Salt; more preferably, pranoprofen is exemplified.

Further, from the viewpoint of further increasing the effect of suppressing the accumulation of pollen proteins in the ionic SHCL, the component (B) is preferably glycyrrhizic acid, neostigmine and salts thereof; more preferably neostigmine and salts thereof. ..

In particular, among components (B), glycyrrhizinic acid, neostigmine and salts thereof are excellent in both the action of inhibiting lipid adsorption to nonionic SHCL and the action of inhibiting pollen protein accumulation in ionic SHCL. Is preferred.

In the ophthalmic composition for SHCL of the present invention, the mixing ratio of the component (B) is appropriately set according to the type of the component (B), the type of the component (A) used in combination, and the like. The total amount of the component (B) is 0.0005 to 3.5 w/v%, preferably 0.001 to 2.5%, relative to the total amount of the composition. More specifically, the following range is exemplified as the mixing ratio of the component (B).
When the component (B) is chlorpheniramine and/or a salt thereof: the total amount thereof is usually 0.001 to 0.1 w/v%, preferably 0.006 to 0.03 w/v%, more preferably 0.01 to 0.03 w/v%. ;
When the component (B) is cromoglycic acid and/or a salt thereof: the total amount thereof is usually 0.05 to 3 w/v%, preferably 0.1 to 2 w/v%, more preferably 0.5 to 1 w/v%;
In the case where the component (B) is pranoprofen and/or a salt thereof, the total amount thereof is usually 0.001 to 0.2 w/v%, preferably 0.01 to 0.1 w/v%, more preferably 0.01 to 0.05 w/v%. ;
When the component (B) is glycyrrhizic acid and/or its salt: These are the total amount, usually 0.001 to 0.5 w/v%, preferably 0.005 to 0.3 w/v%, more preferably 0.05 to 0.25 w/v%;
In the case where the component (B) is neostigmine and/or a salt thereof, the total amount thereof is usually 0.0005 to 0.01 w/v%, preferably 0.0007 to 0.007 w/v%, more preferably 0.001 to 0.005 w/v%.

The blending ratio of the component (B) is preferable from the viewpoint of further increasing the lipid adsorption inhibiting action on nonionic SHCL and further enhancing the pollen protein accumulation inhibiting action on ionic SHCL.

Further, in the ophthalmic composition for SHCL of the present invention, the ratio of the component (B) to the component (A) is not particularly limited, but further enhances the lipid adsorption inhibitory effect on the nonionic SHCL, or From the viewpoint of further increasing the effect of suppressing the adsorption of pollen proteins to ionic SHCL, the total amount of the above (B) component is 1 to 100,000 parts by weight, preferably 1 to 50,000 parts by weight, per 1 part by weight of the (A) component. The range is as follows. More specifically, the following range is exemplified as the ratio of the component (B) per 1 part by weight of the total amount of the component (A):
When the component (B) is chlorpheniramine and/or its salt: usually 10 to 2000 parts by weight, preferably 20 to 1000 parts by weight, more preferably 30 to 600 parts by weight;
When the component (B) is cromoglycic acid and/or its salt: These are in total amount, usually 500 to 100,000 parts by weight, preferably 1000 to 50,000 parts by weight, more preferably 1500 to 20,000 parts by weight;
When the component (B) is pranoprofen and/or a salt thereof, the total amount thereof is usually 10 to 5000 parts by weight, preferably 20 to 2000 parts by weight, more preferably 30 to 1000 parts by weight;
When the component (B) is glycyrrhizic acid and/or a salt thereof: the total amount thereof is usually 50 to 20000 parts by weight, preferably 100 to 10000 parts by weight, more preferably 150 to 5000 parts by weight;
When the component (B) is neostigmine and/or a salt thereof: The total amount thereof is usually 1 to 500 parts by weight, preferably 2 to 200 parts by weight, more preferably 3 to 100 parts by weight.

The ophthalmic composition for SHCL of the present invention preferably further contains a cooling agent. The cooling agent that can be added to the ophthalmic composition for SHCL of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such a refreshing agent include menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and leucon. These may be d-form, l-form or dl-form, and may be an essential oil containing them. Examples of such essential oils include peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil and the like. Among these cooling agents, from the viewpoint of more reliably exerting the effect of the present invention, menthol, camphor, geraniol, borneol, bergamot oil, eucalyptus oil are mentioned, and more preferably menthol, camphor, geraniol. , Borneol, especially preferred are menthol and camphor, and even more preferred is menthol. These cooling agents may be used alone or in any combination of two or more.

When blending a refreshing agent in the ophthalmic composition for SHCL of the present invention, the blending ratio of the refreshing agent varies depending on the type of the refreshing agent to be used, etc., and cannot be specified uniformly, for example, , The total amount of the cooling agent is 0.0001 to 1 w/v%, preferably 0.001 to 0.1 w/v%, more preferably 0.002 to 0.03 w/v%, particularly preferably 0.1. The ratio of 005 to 0.02 w/v% is exemplified.

The ophthalmic composition for SHCL of the present invention preferably further contains a tonicity agent. The isotonicity agent that can be incorporated into the ophthalmic composition for SHCL of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such a tonicity agent 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 thereof include potassium, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin and propylene glycol. Among these tonicity agents, from the viewpoint of more reliably exhibiting the effect of the present invention, glycerin, propylene glycol, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride are preferable, and more preferably. Examples thereof include sodium chloride and glycerin, and particularly preferable is sodium chloride. These tonicity agents may be used alone or in any combination of two or more.

When a tonicity agent is added to the ophthalmic composition for SHCL of the present invention, the mixing ratio of the tonicity agent varies depending on the type of the tonicity agent to be used and cannot be uniformly specified. However, for example, the ratio of the tonicity agent is 0.01 to 10 w/v% in total, preferably 0.05 to 5 w/v%, more preferably 0.1 to 3 w/v%. ..

The ophthalmic composition for SHCL of the present invention preferably further contains a buffer. The buffering agent that can be added to the ophthalmic composition for SHCL of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartic acid, aspartate and the like. These buffer agents may be used in combination. Preferred buffers are borate buffers, phosphate buffers, carbonate buffers, and citrate buffers, more preferred buffers are borate buffers and phosphate buffers, particularly preferred buffers. Is a borate buffer. Examples of the borate buffer include boric acid or borate 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 carbonic acid or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citric acid buffer include citric acid, alkali metal citrate salts, and alkaline earth metal citrate salts. Further, a borate or a hydrate of a phosphate may be used as the borate buffer or the phosphate buffer. As a more specific example, boric acid or a salt thereof as a boric acid buffer (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphoric acid or a phosphoric acid buffer thereof as a phosphoric acid buffer Salts (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 hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citric acid buffer, citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid). Calcium acid, sodium dihydrogen citrate, disodium citrate, etc.; acetic acid as a buffer, 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.) and the like. Among these buffering agents, the borate buffering agent is expected to exert the effects of the present invention more reliably, and thus is preferably used in the ophthalmic composition for SHCL of the present invention. These buffers may be used alone or in any combination of two or more.

When a buffering agent is added to the ophthalmic composition for SHCL of the present invention, the mixing ratio of the buffering agent depends on the type of the buffering agent used, the type and amount of other compounding ingredients, the formulation form of the ophthalmic composition, etc. The amount of the buffering agent is 0.01 to 10 w/v%, preferably 0.1 to 5 w/% with respect to the total amount of the ophthalmic composition for SHCL, although it cannot be uniformly defined. An example is v%, more preferably 0.5 to 2 w/v%.

The ophthalmic composition for SHCL of the present invention may further contain a surfactant. The surfactant that can be incorporated into the ophthalmic composition for SHCL of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and a nonionic surfactant. It may be any of an agent, an amphoteric surfactant, an anionic surfactant and a cationic surfactant.

Specific examples of the nonionic surfactant that can be incorporated into the ophthalmic composition for SHCL of the present invention include POE (20) sorbitan monolaurate (polysorbate 20) and POE (20) sorbitan monopalmitate (polysorbate 40). POE sorbitan fatty acid esters such as POE (20) sorbitan monostearate (polysorbate 60), POE (20) sorbitan tristearate (polysorbate 65), POE (20) sorbitan monooleate (polysorbate 80); Poloxamer 407, POE/POP block copolymers such as Poloxamer 235, Poloxamer 188, Poloxamer 403, Poloxamer 237, and Poloxamer 124; POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60) and other POE hydrogenated castor oils; POE (9 ) POE alkyl ethers such as lauryl ether; POE-POP alkyl ethers such as POE(20)POP(4) cetyl ether; POE alkylphenyl ethers such as POE(10) 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 added to the ophthalmic composition for SHCL of the present invention include alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride). Specific examples of the cationic surfactant that can be incorporated in the SHCL ophthalmic composition of the present invention include benzalkonium chloride and benzethonium chloride. Further, as the anionic surfactant that can be blended in the SHCL ophthalmic composition of the present invention, specifically, alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, aliphatic α-sulfomethyl Examples thereof include esters and α-olefin sulfonic acids.

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

Among the above-mentioned surfactants, preferably nonionic surfactants; more preferably POE sorbitan fatty acid esters, POE hydrogenated castor oils, or POE/POP block copolymers; more preferably POE sorbitan fatty acid esters, POE Hydrogenated castor oils; particularly preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60, poloxamer 407 are used.

When blending a surfactant in the ophthalmic composition for SHCL of the present invention, the blending ratio of the surfactant is such that the type of the surfactant, the type and amount of other blending components, and the ophthalmic composition for the SHCL. It can be appropriately set depending on the formulation form and the like. As an example of the mixing ratio of the surfactant, the total amount of the surfactant is 0.001 to 1.0 w/v%, preferably 0.005 to 0.7 w/ with respect to the total amount of the ophthalmic composition for SHCL. v%, and more preferably 0.01 to 0.5 w/v%.

The pH of the ophthalmic composition for SHCL of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. An example of the pH of the ophthalmic composition for SHCL of the present invention is in the range of 4.0 to 9.5, preferably 5.0 to 9.0, and more preferably 5.5 to 8.5.

Further, the osmotic pressure of the ophthalmic composition for SHCL of the present invention is not particularly limited as long as it is within the range that is acceptable for the living body. As an example of the osmotic pressure ratio of the ophthalmic composition for SHCL of the present invention, a range of preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and particularly preferably 0.7 to 2.0. Can be mentioned. The osmotic pressure can be adjusted by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a saccharide, or 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, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia (freezing point). (Descent method) The standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) was dried with 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, measure exactly 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution).

The ophthalmic composition for SHCL of the present invention may contain a suitable amount of various pharmacologically active ingredients or physiologically active ingredients in combination with the above-mentioned ingredients, as long as the effects of the present invention are not impaired. Such ingredients are not particularly limited, and examples thereof include active ingredients in ophthalmic drugs described in the OTC drug manufacturing (import) approval standard 2000 version (supervised by the Pharmaceutical Affairs Review and Study Group). Specifically, the components used in the ophthalmic drug include the following components.
Antihistamines: For example, iproheptin, diphenhydramine hydrochloride, ketotifen fumarate, pemirolast potassium, etc.
Decongestants: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride and the like.
Bactericide: For example, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate and the like.
Amino acids: For example, potassium aspartate, magnesium aspartate, aminoethylsulfonic acid and the like.
Anti-inflammatory agent: For example, allantoin, azulene, sodium azulenesulfonate, guaiazulene, ε-aminocaproic acid, berberine chloride, berberine sulfate, lysozyme chloride and the like.
Astringent: for example, zinc white, zinc lactate, zinc sulfate and the like.
Others: For example, sodium chondroitin sulfate, sulfamethoxazole, sulfamethoxazole sodium and the like.

Further, in the SHCL ophthalmic composition of the present invention, as long as the effect of the invention is not impaired, depending on the use and form thereof, according to a conventional method, various additives are appropriately selected, and one or more kinds May be used in combination and contained in an appropriate amount. Examples of such additives include various additives described in Encyclopedia of Pharmaceutical Additives 2007 (edited by Japan Pharmaceutical Additives Association). The following additives are listed as typical components.
Carrier: For example, an aqueous carrier such as water or hydrous ethanol.
Thickener: For example, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, alginic acid, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol and the like.
Sugars: For example, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Preservative, bactericide or antibacterial agent: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, glowkill (trade name of Rhodia), etc.
pH adjuster: For example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydrogen carbonate, 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 (Rongalit), 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 SHCL of the present invention is prepared by adding desired amounts of the above-mentioned components (A) and (B) and, if necessary, other compounding ingredients so as to have a desired concentration.

The formulation of the ophthalmic composition for SHCL of the present invention is not particularly limited as long as it can be used in the field of ophthalmology, and examples thereof include liquids and ointments. Of these, liquid is preferable. Among the liquids, an aqueous liquid is preferable. When the SHCL ophthalmic composition of the present invention is formed into an aqueous liquid, pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable water may be used as an aqueous carrier. Specifically, distilled water, ordinary water, purified water, sterile purified water, water for injection, distilled water for injection and the like are exemplified. These definitions are based on the 15th revised 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 or more of water in the ophthalmic composition for SHCL. , More preferably 50% by weight or more.

The formulation of the ophthalmic composition for SHCL of the present invention is not limited as long as it is used in the field of ophthalmology and used so as to come into contact with SHCL. For example, eye drops for SHCL (eye drops that can be used while wearing SHCL), eye washes for SHCL (eye drops that can be used while wearing SHCL), SHCL mounting solutions, SHCL care solutions (SHCL disinfectant, SHCL) Storage solution, SHCL cleaning solution, SHCL cleaning storage solution, etc.) and the like.

Among these, the eye drops for SHCL are formulations that are frequently used per day, and it is possible to effectively suppress lipid adsorption on SHCL. In view of such lipid adsorption inhibitory action, an eye drop for SHCL is exemplified as an example of a suitable formulation form of the ophthalmic composition for SHCL.

Further, eye drops for SHCL, eye drops for SHCL, and cleaners for SHCL, particularly eye drops for SHCL, are formulation forms that strongly require an action of suppressing the accumulation of pollen proteins in ionic SHCL. From this point of view, suitable examples of the ophthalmic composition for SHCL of the present invention include eye drops for SHCL, eye washes for SHCL, and cleaners for SHCL, particularly preferably eye drops for SHCL.

The method of using the ophthalmic composition for SHCL of the present invention is not particularly limited as long as it is a known method having a step of bringing the ophthalmic composition for SHCL into contact with SHCL. For example, in the case of an eye drop for SHCL, an appropriate amount of the eye drop may be instilled before or during wearing of SHCL, and it is particularly preferable to instill with SHCL attached. Also, in the case of an eye wash for SHCL, an appropriate amount of the eye wash may be used for eye wash before or during wearing of SHCL, and it is particularly preferable to wash the eye with the SHCL attached. If the ophthalmic composition for SHCL of the present invention is an eye drop for SHCL or an eye wash for SHCL, it can be used for the purpose of eye drop or eye wash even when not wearing, as well as when wearing SHCL. it can. Further, in the case of the SHCL mounting solution, it is used by contacting SHCL with an appropriate amount of the mounting solution when the SHCL is mounted. Furthermore, in the case of a SHCL care liquid, it is used by immersing SHCL in an appropriate amount of the care liquid, or by contacting the care liquid with SHCL and rubbing and washing.

In the ophthalmic composition for SHCL of the present invention, the type of SHCL to be applied is not particularly limited, regardless of whether it is ionic or nonionic, all SHCLs currently marketed or to be marketed in the future. Can be applied. ADVANTAGE OF THE INVENTION According to the ophthalmic composition for SHCL of this invention, adsorption of a lipid with respect to nonionic SHCL can be suppressed, when nonionic SHCL is applied. Moreover, when ionic SHCL is applied, the accumulation of pollen proteins in ionic SHCL can be suppressed. In addition, the ionic here means that the content of the ionic component in the contact lens material is 1 mol% or more according to the US FDA (US Food and Drug Administration) standards, and the nonionic is the US FDA ( According to the US Food and Drug Administration standard, it means that the content of ionic components in the contact lens material is less than 1 mol%.

Further, in the ophthalmic composition for SHCL of the present invention, the water content of SHCL to be applied is not particularly limited, and examples thereof include 90% or less, preferably 60% or less, and more preferably 50% or less. Since SHCL contains a hydrogel material, it contains at least more than 0% water.

Here, the water content of SHCL indicates the proportion 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 a water content can be measured by a gravimetric method according to the description of ISO18369-4:2006.

SHCL, which is harder than non-silicone hydrogel contact lenses, which is generally softer, tends to cause a deterioration in usability due to lens deformation and wettability deterioration due to the adsorption of foreign matter, and tends to cause ocular mucosal damage. It is in. According to the ophthalmic composition for SHCL of the present invention, it is possible to effectively suppress the accumulation of lipids and pollen proteins in SHCL, which is a hard material that easily causes usability deterioration and ocular mucosal damage, and thus the lens of It is also possible to prevent deformation and deterioration and effectively prevent deterioration of the feeling of use and ocular mucous membrane damage. In view of such effects of the present invention, SHCL having a relatively high hardness is mentioned as a suitable application target of the ophthalmic composition for SHCL of the present invention. Preferably, the SHCL to be applied has a hardness of 3 g or more, preferably 4 g or more, more preferably 6 g or more, still more preferably 8 g or more when measured by the following measurement method using a texture analyzer. The upper limit of the hardness of SHCL to be applied is not particularly limited, but it is preferably 15 g or less, more preferably 12 g or less.

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

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

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

INDUSTRIAL APPLICABILITY The ophthalmic composition for SHCL of the present invention can exhibit unique physiological activity based on the above components (A) and (B), and can be used for various purposes. For example, based on the component (A), it may be used for antiseptic, sterilization, and disinfection applications, and based on the component (B), it may be used for applications such as anti-allergy, anti-inflammatory, and improvement of eye focus control function. You can also

Further, the ophthalmic composition for SHCL of the present invention can effectively prevent corneal epithelial disorders such as corneal staining caused by lipid adsorption to nonionic SHCL, and therefore, a preventive agent for corneal epithelial disorders. Can also be used as

Furthermore, the ophthalmic composition for SHCL of the present invention promotes the removal of pollen protein from ionic SHCL and can prevent re-attachment, so that the accumulation of pollen protein in ionic SHCL can be effectively suppressed. Therefore, the pollen protein adsorbed on the contact lens is prevented from being kept in contact with the eye for a long time, and it is also effective in preventing allergy and deterioration of pollen. Therefore, it is suitable for application to ionic SHCL users of hay fever or reserve hay fever.

2. Method for suppressing lipid adsorption to nonionic SHCL, and method for imparting action to suppress lipid adsorption to nonionic SHCL As described above, by using the above components (A) and (B) together, a nonionic Adsorption of lipids on the SHCL can be suppressed.

Therefore, the present invention, from still another aspect, (A) polyhexanide, and at least one selected from the group consisting of salts thereof, (B) chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine. And an ophthalmic composition for SHCL containing at least one selected from the group consisting of these salts, and contacting the nonionic SHCL, suppressing the adsorption of lipids to the nonionic SHCL Provide a way to do. Furthermore, in the ophthalmic composition for SHCL, (A) polyhexanide, and at least one selected from the group consisting of salts thereof, (B) chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine and these. The present invention provides a method for imparting an action of suppressing lipid adsorption to nonionic SHCL to an ophthalmic composition for SHCL, which is characterized by blending with at least one selected from the group consisting of salts of

In these methods, (A) and (B) types and mixing ratios of components, types and mixing ratios of other components to be mixed, formulation forms of ophthalmic compositions for SHCL, types of nonionic SHCL to be applied Etc. are the same as the above-mentioned "1. SHCL ophthalmic composition".

3. Method for suppressing the accumulation of pollen protein in ionic SHCL, and method for imparting an effect of suppressing the accumulation of pollen protein in ionic SHCL Also, as described above, the above (A) and (B) components are used in combination. Even if the eye wearing ionic SHCL is exposed to pollen, it can promote the removal of pollen protein from ionic SHCL and prevent re-attachment, so it is possible to suppress the accumulation of pollen protein in ionic SHCL become. Therefore, the present invention, from still another aspect, (A) polyhexanide, and at least one selected from the group consisting of salts thereof, (B) chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine. And an ophthalmic composition for SHCL containing at least one selected from the group consisting of these salts, characterized by contacting with ionic SHCL, a method for suppressing adsorption of pollen protein to ionic SHCL I will provide a. Furthermore, in the ophthalmic composition for SHCL, (A) polyhexanide, and at least one selected from the group consisting of salts thereof, (B) chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine and these. The present invention provides a method for imparting to the ophthalmic composition an action of suppressing the accumulation of pollen protein in ionic SHCL, which is characterized by being mixed with at least one selected from the group consisting of the salts of

In these methods, (A) and (B) types and mixing ratios of components, types and mixing ratios of other components to be mixed, formulation forms of ophthalmic compositions for SHCL, types of ionic SHCL to be applied, etc. Is the same as the above "1. SHCL ophthalmic composition".

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

Reference Test Example 1: Evaluation of Lipid Adsorption of Various SCLs The following experiments were carried out using various soft contact lenses shown in Table 1 to evaluate the lipid adsorption of soft contact lenses. The soft contact lenses used in this test are all commercially available products.

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

The results are shown in Figure 1. As is clear from FIG. 1, the lipid adsorption amount of nonionic SHCL (lenses A and B) is significantly higher than that of ionic SHCL (lens C) and conventional hydrogel lenses (lenses D to F). It was confirmed that the problem of lipid stain was serious.

Test Example 1: Evaluation of SHCL Lipid Adsorption Inhibition Using the nonionic SHCL (lens A) in which remarkable lipid adsorption was observed in Reference Test Example 1 above, each test solution shown in Tables 2 to 7 below (Example 1-1) was used. ~ 1-16 and Comparative Examples 1-1 to 1-18), the effect of nonionic SHCL on lipid adsorption was examined.

First, a 1 mg/ml chloroform solution of fluorescently labeled lipid (N-(fluorescein-5-thiocarbamoyl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt; manufactured by Invitrogen) and methanol were mixed with 1: To 500 μL of the mixed solution mixed at a volume ratio of 4, physiological saline (0.9 w/v% sodium chloride) was added to make a total volume of 20 ml, to prepare a fluorescent lipid solution. Lens A was immersed in physiological saline for one night or more to perform a test pretreatment. Then, 200 μL of each test solution (Examples 1-1 to 1-11 and Comparative Examples 1-1 to 1-12) and 1000 μL of fluorescent lipid solution were placed in each well of a 24-well microplate to prepare wells, The lenses A which had been subjected to the test pretreatment were immersed in each one and shaken at 34° C. for 24 hours (sample group). Further, as a blank group, 200 μL of each test solution (Examples 1-1 to 1-11 and Comparative Examples 1-1 to 1-12) and a well containing 1000 μL of physiological saline were prepared, and a well was prepared before the test. The treated lenses A were immersed one by one and similarly shaken (blank group). After 24 hours, each lens A after shaking treatment was transferred to a plate containing 1 ml of fresh physiological saline, and the fluorescence intensity of each well was measured using a fluorescence plate reader (manufactured by Thermo Fisher Scientific Inc.) ( Excitation wavelength: 485 nm, fluorescence wavelength: 538 nm). The value obtained by subtracting the fluorescence intensity of the blank group from the fluorescence intensity of each sample group was obtained as an index for the amount of adsorbed lipid, and the adsorbed lipid amount of the test solution (control test solution) consisting of sodium chloride, borate buffer and purified water was 100. The relative value (%) of the amount of adsorbed lipid of each test solution when calculated as% was calculated. Specifically, for the test solutions of Examples 1-1 to 1-5 and Comparative Examples 1-2 to 1-6, Comparative Example 1-1 was a control test solution, Examples 1-6 to 1-11 and Comparative Examples For the test solutions of Examples 1-8 to 1-12, Comparative Example 1-7 was used as a control test solution, and the relative value (%) of the adsorbed lipid amount of each test solution was determined.

In addition, in the case of using Examples 1-12 to 1-16 and Comparative Examples 1-13 to 1-18 as the test solution, 600 μL of each test solution and 600 μL of the fluorescent lipid solution were prepared as a sample group to prepare a well. A well containing 600 μL of each test solution and 600 μL of physiological saline was prepared as a blank group, and the test was conducted in the same manner as above. Relative value (%) of the amount of adsorbed lipid of each test solution, for the test solutions of Examples 1-12 to 1-16 and Comparative Examples 1-14 to 1-18, Comparative Example 1-13 was used as a control test solution, It was determined in the same manner as above.

The obtained results are shown in FIGS. As shown in FIGS. 2 to 4, when PHMB, chlorpheniramine maleate, sodium cromoglycate, pranoprofen, dipotassium glycyrrhizinate, or neostigmine methylsulfate is used alone, the effective lipid adsorption inhibitory effect is I was not able to admit. On the other hand, quite unexpectedly, when used in combination with PHMB, chlorpheniramine maleate, sodium cromoglycate, pranoprofen, dipotassium glycyrrhizinate, or neostigmine methylsulfate (Examples 1-1 to 1). -16) showed that lipid adsorption on nonionic SHCL could be suppressed synergistically.

In addition, the test liquids of Examples 1-1 to 1-16 were prepared as eye drops and instilled while wearing the nonionic SHCL. As a result, the feeling of use of the nonionic SHCL was kept good.

Reference Test Example 2: Evaluation of Pollen Protein Adsorption Property on Soft Contact Lens Four kinds of soft contact lenses shown in Table 8 were used in the test to evaluate the adsorption property of pollen protein on the soft contact lens.

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

Pollen protein antigen ( CEdar Co., Ltd. Cedar Pollen Extract-Ja, properties: lyophilized powder (cedar pollen crude extract mountain ceder , extracted from Juniperus Asheii pollen)) is dissolved in physiological saline. , 5 mg/30 mL pollen protein solution was prepared. The pollen protein solution (1.0 mL) was put into each hole of a 24-well plate, the excess water of the pretreated lens was wiped off, the plate was immersed, and the plate was shaken at 34° C. and 120 rpm for 18 hours. Then, take out the lens, immerse it in 100 mL of physiological saline quickly (about 1 second) to rinse out excess liquid, then gently drain the water using the beaker edge, and put the pollen protein in each hole of the 24-well plate. It was immersed in 1 mL of a separation liquid (aqueous solution containing 1% sodium carbonate and 1% SDS). By shaking at 34° C. and 120 rpm for 3 hours, the pollen protein adsorbed on the lens was separated in the pollen protein separating liquid.

Using a micro BCA assay kit (Thermo SCIENTIFIC, Pierce #23235), the amount of pollen protein in the pollen protein separation liquid was quantified as an albumin conversion value, and the amount of pollen protein adsorbed on the lens was determined.

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

Results are shown in FIG. As shown in FIG. 5, when the lens 1 which is ionic SHCL is used, it is remarkably compared with the lenses 3 and 4 which are non-silicon soft contact lenses and the lens 2 which is nonionic SHCL. High adsorption of pollen proteins was observed. From these results, pollen proteins tend to be adsorbed to ionic SHCL in an extremely large amount even among soft contact lenses, and ionic SHCL has a unique problem that pollen proteins are very easily adsorbed. Was confirmed.

Test Example 2: Evaluation of Suppression of Pollen Protein Accumulation to Ionic SHCL The following test was carried out using Lens 1 (ionic SHCL) in which the remarkable adsorption of pollen protein was confirmed in Reference Test Example 2 above.

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

Take out the lens 1 soaked in the pollen protein solution, quickly (about 1 second) soak it in 100 mL of physiological saline to rinse excess liquid, wipe off the water, and put it in a 24-well plate. The test solutions (Examples 2-1 to 2-2 and Comparative Examples 2-1 to 2-4) were immersed in 1.0 mL each and shaken at 34° C. and 400 rpm for 18 hours. After that, the lens 1 is taken out, it is immersed in 100 mL of physiological saline quickly (about 1 second) to rinse excess liquid, then the water of the beaker is used to lightly remove water, and the pollen protein separated in a 24-well plate is separated. It was immersed in 0.5 mL of a working solution (aqueous solution containing 1% sodium carbonate and 1% SDS). By shaking at 400 rpm for 3 hours at 34°C, the pollen protein adsorbed on the lens was separated in the pollen protein separation liquid.

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

Using a micro BCA assay kit (Thermo SCIENTIFIC, Pierce #23235), the amount of pollen protein present in the pollen protein separation liquid was quantified as an albumin conversion value, and the amount of pollen protein detached from lens 1 (pollen The protein adsorption amount) was determined. In calculating the amount of pollen protein adsorbed, the amount of pollen protein adsorbed was calculated by subtracting the absorbance of the blank group from the absorbance of each sample and calculating the albumin conversion value. Then, according to the following formula, relative to the pollen protein adsorption amount when using the test solution of Comparative Example 2-4, from the ratio of the pollen protein adsorption amount when using the test solution of each Comparative Example and Example, pollen protein adsorption The improvement rate (%) was calculated.

Results are shown in FIG. From these results, PHMB, dipotassium glycyrrhizinate, or neostigmine methylsulfate did not improve pollen protein accumulation when used alone (Comparative Examples 2-1 to 2-3). On the other hand, quite unexpectedly, when PHMB was used in combination with dipotassium glycyrrhizinate or neostigmine methylsulfate (Examples 2-1 and 2-2), the improvement rate of pollen protein adsorption was synergistic. It was clarified that the amount of pollen protein adsorbed on ionic SHCL could be effectively reduced and the accumulation could be suppressed.

Formulation example According to the formulation shown in Table 10, SHCL eye drops (Example 3-7), SHCL wearing solution (Example 8), SHCL wearing and eye drops (Example 9), SHCL eye wash (Example 10) ), and SHCL washes (Examples 11-12) are prepared.

Claims (1)

(A) polyhexanide, and at least one selected from the group consisting of salts thereof, and (B) at least selected from the group consisting of chlorpheniramine, cromoglicic acid, pranoprofen, glycyrrhizic acid, neostigmine and salts thereof. An ophthalmic composition for a silicone hydrogel contact lens, which comprises 1 type.

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