JP2017014283A - Ophthalmic compositions for silicone hydrogel contact lenses - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide silicone hydrogel contact lens ophthalmic compositions that can inhibit the adsorption of chlorobutanol to silicone hydrogel contact lenses.SOLUTION: An ophthalmic composition for silicone hydrogel contact lenses is prepared by using (A) chlorobutanol in combination with (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropyl methylcellulose, and salts thereof.SELECTED DRAWING: None

Description

  The present invention suppresses the adsorption of chlorobutanol to the silicone hydrogel contact lens even when it is applied to a silicone hydrogel contact lens while containing chlorobutanol. The present invention relates to an ophthalmic composition for a silicone hydrogel contact lens that can be used safely by facilitating elution by elution treatment with a saline solution or the like. The present invention also relates to a method for suppressing adsorption of chlorobutanol to a silicone hydrogel contact lens. Furthermore, the present invention relates to a method for suppressing bacterial adhesion to a silicone hydrogel contact lens.

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

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

  In general, it is important that an ophthalmic composition used for a contact lens is designed in consideration of safety and other effects depending on the type of contact lens. In particular, soft contact lenses vary in the presence or absence of ionicity and the level of moisture content depending on the material, so ophthalmic compositions for soft contact lenses should be formulated according to the characteristics of the applied soft contact lens. Is essential.

  On the other hand, chlorobutanol has been used in ophthalmic compositions as a preservative. It is also known that chlorobutanol has a problem that it is very easily adsorbed to conventional soft contact lenses (Patent Document 1).

  However, until now, the effect of chlorobutanol on silicone hydrogel contact lenses has not been elucidated at all. In addition, when chlorobutanol and other specific components are used in combination, there is currently no appreciable effect on the silicone hydrogel contact lens.

International Publication No. 05/025539 Pamphlet

  Chlorobutanol is a component that is desired to be used for preserving ophthalmic compositions, but the present inventor has conducted various studies on the influence of chlorobutanol on various soft contact lenses. The present inventors have obtained a new finding that butanol is very easily adsorbed to a silicone hydrogel contact lens (hereinafter sometimes referred to as SHCL) as compared with a conventional hydrogel lens. The amount of chlorobutanol adsorbed on SHCL is an amount that cannot be compared with that of conventional hydrogel contact lenses. Further, as a result of further investigation, the present inventor has found that a large amount of chlorobutanol still remains even when the SHCL after adsorption of chlorobutanol is subjected to an elution treatment with physiological saline. This means that a large amount of adsorbed chlorobutanol remains in the SHCL without being washed away by tears or the like. If the preservative component remains and accumulates in the lens in this way, there is a concern about the adverse effect of the component remaining on the lens, as well as the possibility of causing SHCL discoloration, light transmittance reduction, deformation, etc. is there.

  Therefore, there is a demand for development of means that can suppress adsorption of chlorobutanol to SHCL, facilitate elution by elution treatment with physiological saline or the like, and reduce the residual amount of chlorobutanol on SHCL.

  As a result of intensive studies to solve the above problems, the present inventors have surprisingly found (A) chlorobutanol, (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof. When used in combination with at least one selected from the group, adsorption of chlorobutanol to SHCL can be suppressed, and even if chlorobutanol is once adsorbed to SHCL, it can be easily eluted by elution treatment with physiological saline or the like. I found out.

  Furthermore, the present inventor combined (A) chlorobutanol with (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof to SHCL. By effectively using at least one selected from the group consisting of vitamin B6s, tetrahydrozolines, and allantoins, the effect of inhibiting bacterial adhesion to SHCL can be effectively suppressed. It has also been found that further improvement is possible. The present invention has been completed by further studies based on this finding.

That is, this invention provides the ophthalmic composition for SHCL of the aspect hung up below.
Item 1-1. An ophthalmic composition for a silicone hydrogel contact lens, comprising (A) chlorobutanol and (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof .
Item 1-2. Item 1. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-1, wherein the blending ratio of component (A) is 0.01 to 5 w / v%.
Item 1-3. Item (B) The silicone hydrogel contact lens according to Item 1-1 or 1-2, which contains at least one selected from the group consisting of sodium hyaluronate, sodium chondroitin sulfate, alginic acid, and hydroxypropylmethylcellulose. Ophthalmic composition.
Item 1-4. Item 4. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-3, wherein the blending ratio of component (B) is 0.0001 to 5 w / v%.
Item 1-5. The ophthalmology for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-4, further comprising (C) at least one selected from the group consisting of vitamin B6s, tetrahydrozolines, and allantoins Composition.
Item 1-6. Item 5. The ophthalmic composition for a silicone hydrogel contact lens according to any one of Items 1-1 to 1-5, wherein the blending ratio of the component is 0.0001 to 1 w / v%.
Item 1-7. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-6, further comprising a buffer.
Item 1-8. Item 8. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-7, comprising a buffering agent in a total amount of 0.01 to 10 w / v%.
Item 1-9. Item 10. The ophthalmic composition for silicone hydrogel contact lens according to any one of Items 1-1 to 1-8, further comprising an isotonic agent.
Item 1-10. Item 10. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-9, which contains an isotonic 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 is an eye drop.

Moreover, this invention provides the method of suppressing adsorption | suction of chlorobutanol to SHCL hung up below.
Item 2. A silicone hydrogel contact comprising (A) chlorobutanol and (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof. A method for suppressing adsorption of the component (A) to a lens.

In addition, the present invention provides a method for imparting an ophthalmic composition with the action of suppressing adsorption of chlorobutanol to SHCL described below.
Item 3. (A) At least one selected from the group consisting of (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof is added to the ophthalmic composition for silicone hydrogel contact lenses containing chlorobutanol. A method for imparting an action to the ophthalmic composition to suppress the adsorption of the component (A) to the silicone hydrogel contact lens.

Moreover, this invention provides the agent for suppressing adsorption | suction of chlorobutanol to SHCL hung up below.
Item 4. An agent for suppressing adsorption of chlorobutanol to a silicone hydrogel contact lens, comprising at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof.

Moreover, this invention provides the method of suppressing adhesion of the bacteria to SHCL hung up below.
Item 5-1. A silicone hydrogel contact comprising (A) chlorobutanol and (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof. A method for suppressing the adhesion of bacteria to the lens.
Item 5-2. Furthermore, (C) at least one selected from the group consisting of vitamin B6s, tetrahydrozolines, and allantoins is used in combination, wherein the bacteria to the silicone hydrogel contact lens according to Item 5-1. A method for suppressing adhesion.

Moreover, this invention provides the method of providing the effect | action which suppresses adhesion of the bacterium to SHCL mentioned below to an ophthalmic composition.
Item 6-1. In the ophthalmic composition, (A) chlorobutanol is blended with (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof. And a method for imparting an action to inhibit adhesion of bacteria to a silicone hydrogel contact lens to the ophthalmic composition.
Item 6-2. Furthermore, (C) at least one selected from the group consisting of vitamin B6s, tetrahydrozolines, and allantoins is added, characterized in that the bacteria to the silicone hydrogel contact lens according to Item 6-1 A method of imparting an action of suppressing adhesion to the ophthalmic composition.

Furthermore, the present invention also provides the uses listed below.
Item 7-1. (A) chlorobutanol, and (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof for the production of an ophthalmic composition for silicone hydrogel contact lenses Use of seeds.
Item 7-2. At least one selected from the group consisting of (A) chlorobutanol, (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof for the production of an ophthalmic composition for silicone hydrogel contact lenses And (C) at least one use selected from the group consisting of vitamin B6s, tetrahydrozolines, and allantoins.
Item 7-3. The use according to Item 7-1 or Item 7-2, wherein the ophthalmic composition for a silicone hydrogel contact lens is the ophthalmic composition according to any one of Items 1-1 to 1-11.
Item 7-4. (B) at least selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof for the production of an agent for suppressing adsorption of chlorobutanol to a silicone hydrogel contact lens One use.
Item 7-5. A group consisting of (A) chlorobutanol and (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof for the manufacture of an agent for inhibiting bacterial adhesion to silicone hydrogel contact lenses At least one use selected from.
Item 7-6. From the group consisting of (A) chlorobutanol, (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof for the manufacture of an agent for inhibiting bacterial adhesion to silicone hydrogel contact lenses And at least one selected from the group consisting of (C) vitamin B6s, tetrahydrozolines, and allantoins.

  The ophthalmic composition for SHCL of the present invention can suppress the adsorption of chlorobutanol to SHCL, and even if chlorobutanol is once adsorbed to SHCL, the chlorobutanol can be easily washed away with tears or SHCL washing solution. It is possible to reduce the residual amount of chlorobutanol in SHCL. Therefore, according to the ophthalmic composition for SHCL of the present invention, chlorobutanol can be prevented from remaining and accumulating in SHCL while containing chlorobutanol, and can be applied to SHCL comfortably and safely. become.

  Furthermore, although SHCL has a great merit that it can supply a sufficient amount of oxygen to the cornea, it also has the disadvantage that conjunctival bacteria tend to adhere (MDP Willcox et al., Bacterial interactions with contact lenses; effects of lens material, lens wear and microbial physiology, Biomaterials 22 (2001), 3235-3247). Many conjunctival resident bacteria are non-pathogenic, but if excessive adhesion or proliferation occurs, a biofilm is formed on the surface of SHCL by extracellular substances secreted from the attached / proliferated bacteria, causing pathogenicity. There is a danger of becoming a hotbed of microorganisms. Furthermore, since SHCL has a high oxygen permeability, it may be worn continuously for up to 1 month, so it can be said that it tends to promote bacterial adhesion during wearing, which is one of the risk factors for bacterial infections. It is also pointed out. On the other hand, according to the ophthalmic composition for SHCL of the present invention, since bacterial adhesion to SHCL can be suppressed, the growth of pathogenic microorganisms can be suppressed, and bacterial infection can be achieved even after prolonged SHCL wearing. The risk of this can be reduced and SHCL can be used safely.

In the reference test example 1, it is a figure which shows the result of having evaluated the adsorption | suction characteristic of chlorobutanol to various soft contact lenses. In the reference test example 1, it is a figure which shows the result of having evaluated the chlorobutanol residual amount after performing the elution process with the physiological saline with respect to the various soft contact lenses which chlorobutanol adsorb | sucked. In Experiment 1, it is a figure which shows the result of having evaluated the adsorption amount of the chlorobutanol to SHCL at the time of using various test liquids (Example 1-4 and Comparative Example 1). In Test Example 1, it is a figure which shows the result of having evaluated the residual amount of chlorobutanol after performing the elution process with physiological saline about SHCL made to contact with various test liquids (Example 1-4 and Comparative Example 1). . In Test Example 2, it is a figure which shows the result of having evaluated the bacterial adhesion inhibitory effect to SHCL of various test liquids (Example 5-6 and Comparative Example 2-3). In Test Example 3, it is a figure which shows the result of having evaluated the bacterial adhesion inhibitory effect to SHCL of various test liquids (Example 7-9 and Comparative Example 4). In Test Example 4, it is a figure which shows the result of having evaluated the bacterial adhesion inhibitory effect to SHCL of various test liquids (Example 10-11 and Comparative Example 5).

1. The ophthalmic composition for SHCL The ophthalmic composition for SHCL of the present invention contains chlorobutanol (hereinafter also referred to as component (A)).

  Chlorobutanol is a known compound also called 1,1,1, -trichloro-2-methyl-2-propanol, and may be synthesized by a known method or obtained as a commercial product.

  In the ophthalmic composition for SHCL of the present invention, the blending ratio of the component (A) is appropriately set according to the formulation form of the ophthalmic composition for SHCL, but as an example, the total amount of the ophthalmic composition for SHCL On the other hand, the total amount of component (A) is 0.01 to 5 w / v%, preferably 0.05 to 1 w / v%, more preferably 0.05 to 0.5 w / v%.

  In addition to the component (A), the ophthalmic composition for SHCL of the present invention is at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof (hereinafter simply referred to as ( B) may be described as component). By containing the component (B) in this way, the adsorption of the component (A) to the SHCL is suppressed, and the component (A) adsorbed to the SHCL is easily eluted by an elution treatment with physiological saline or the like. It becomes possible to do. Further, by containing the component (B) in addition to the component (A), bacterial adhesion to SHCL can be effectively suppressed.

  Among the components (B), hyaluronic acid is a polymer composed of the basic structure (repeat unit) of GlcUA-GlcNAc in which glucuronic acid (GlcUA) and N-acetylglucosamine (GlcNAc) are combined. It is a known high molecular compound as a kind of glycosaminoglycan that exhibits a moisturizing action.

  The salt of hyaluronic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As the salt of hyaluronic acid, specifically, a salt with an organic base (for example, a salt with an organic amine such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), an inorganic base And various salts such as ammonium salts (for example, salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), metals such as aluminum, etc.). Among these salts, preferred are salts with inorganic bases, more preferred are alkali metal salts, still more preferred are sodium salts and potassium salts, and particularly preferred are sodium salts. These hyaluronic acid salts may be used alone or in any combination of two or more.

The hyaluronic acid and salts thereof used in the present invention are not particularly limited in terms of their origin, and for example, they may be obtained from chicken crowns, may be derived from microorganisms, It may be a synthetic product. The viscosity average molecular weight of hyaluronic acid and salts thereof used in the present invention is not particularly limited, but is, for example, 10 million to 5 million, preferably 10 thousand to 4 million, more preferably 10,000 to 3 million. More preferable examples include those in the range of 100,000 to 2.5 million, particularly preferably in the range of 500,000 to 2,000,000. Here, the viscosity average molecular weight can be determined by a known measuring method. Specifically, hyaluronic acid or a salt thereof (dried product) is dissolved in a 0.2 M sodium chloride solution, and the intrinsic viscosity (η) at 30 ± 0 ° C. is obtained with an Ubbelohde viscometer, and the Laurent equation (η (intrinsic viscosity) = 3.6 × 10 ⁻⁴ M ^0.78 where M is the viscosity average molecular weight). The intrinsic viscosity (η) is measured according to the 15th revision Japanese Pharmacopoeia General Test Method Viscosity Measurement Method Method 1: Capillary Viscometer Method.

  Among hyaluronic acid and its salts, the action of suppressing the adsorption of component (A) on SHCL is further enhanced, and the component (A) adsorbed on SHCL is made easier to elute, and the residual amount of chlorobutanol in SHCL is further increased. From the viewpoint of reducing or further suppressing the adhesion of bacteria to SHCL, preferably a salt of hyaluronic acid, more preferably a salt of hyaluronic acid with an inorganic base, more preferably an alkali metal salt of hyaluronic acid, Even more preferred are sodium and potassium salts of hyaluronic acid, and particularly preferred is the sodium salt of hyaluronic acid (sodium hyaluronate).

  In addition, of the components (B), chondroitin sulfate has a structure in which sulfate is bound to a sugar chain that repeats the two sugars of D-glucuronic acid and N-acetyl-D-galactosamine. It is a known high molecular compound as a kind of glycosaminoglycan to be exhibited.

  Further, the chondroitin sulfate salt is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. The thing of the same form as the salt which can be taken is illustrated. Among the salt forms, preferred are salts with inorganic bases, more preferred are alkali metal salts, still more preferred are sodium salts and potassium salts, and most preferred are sodium salts. These chondroitin sulfate salts may be used alone or in any combination of two or more.

  The chondroitin sulfate and salt thereof used in the present invention are not particularly limited in their origin, and are obtained from animals such as mammals and fish cartilage (for example, salmon and shark cartilage). Or may be obtained from microorganisms or may be a synthetic product. Although it does not restrict | limit especially as a viscosity average molecular weight of the chondroitin sulfate and its salt used for this invention, For example, it is 1010,000-100,000, Preferably it is 50,000-70,000, More preferably, it is 10,000- Those in the range of 50,000 can be used. Here, the viscosity average molecular weight is determined according to the fifteenth revised Japanese Pharmacopoeia General Test Method Viscosity Measurement Method First Method: Intrinsic Viscosity η according to Capillary Viscometer Method (Measurement Condition: Solution 0.2M Sodium Chloride Solution, Temperature 25.0 ± 0 ° C., Ubbelohde viscometer) and the obtained intrinsic viscosity η is calculated from the following formula I.

Formula I: [η] = 5.8 × 10 ⁻⁴ M ^0.74 (where M is the viscosity average molecular weight)
Among chondroitin sulfate and its salts, the action of suppressing the adsorption of component (A) to SHCL is further enhanced, and the component (A) adsorbed to SHCL is made easier to elute, and the residual amount of chlorobutanol in SHCL is further increased. From the viewpoint of reducing or further suppressing the adhesion of bacteria to SHCL, preferably a salt of chondroitin sulfate, more preferably a salt of chondroitin sulfate with an inorganic base, more preferably an alkali metal salt of chondroitin sulfate, Even more preferably, sodium salt and potassium salt of chondroitin sulfate, particularly preferably sodium salt of chondroitin sulfate (sodium chondroitin sulfate).

  Among the components (B), alginic acid is a linear polymer in which β-D-mannuronic acid and α-L-guluronic acid are linked by 1,4-glycosidic acid, and a homopolymer fraction of mannuronic acid (MM fraction). ), A homopolymer fraction of guluronic acid (GG fraction), and a fraction in which mannuronic acid and guluronic acid are randomly arranged (MG fraction) are arbitrarily linked. Further, the mannuronic acid / guluronic acid ratio (M / G ratio; molar ratio) in alginic acid is not particularly limited, but is generally 4.0 or less, preferably 3.0 or less, more preferably 2.5 or less, Particularly preferred is 2.0 or less. The lower limit of the M / G ratio is not particularly limited, but is generally 0.1 or more, preferably 0.4 or more, and more preferably 1.0 or more. The M / G ratio is a value calculated by fractionating alginic acid in block units and quantifying each, specifically, A. Haug et al., Carbohyd. Res. 32 (1974), It is measured according to the method described in p.217-225.

  The salt of alginic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. The thing of the same form as the salt to obtain is illustrated. Among the salt forms, preferred are salts with inorganic bases, more preferred are alkali metal salts, still more preferred are sodium salts and potassium salts, and most preferred are sodium salts. These alginic acid salts may be used alone or in any combination of two or more.

  In the present invention, alginic acid and a salt thereof may be either natural products or synthetic products. The molecular weight of alginic acid used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. One having about 10,000 to 1,500,000, preferably 50,000 to 1,000,000, and more preferably about 7,000 to 500,000 can be used.

  Among alginic acid and its salts, the action to suppress the adsorption of the (A) component on SHCL is further enhanced, and the (A) component adsorbed on SHCL is easily eluted to further reduce the residual amount of chlorobutanol in SHCL. Or alginic acid and its alkali metal salt, more preferably alginic acid and its sodium salt and potassium salt, and still more preferably alginic acid and its sodium salt (from the viewpoint of reducing the adhesion of bacteria to SHCL) Sodium alginate), particularly preferably alginic acid.

  Of the component (B), hydroxypropylmethylcellulose is a cellulose ether in which a methoxy group and a hydroxypropoxy group are introduced into the hydroxy group of cellulose.

  The hydroxypropyl methylcellulose used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Further, the content of methoxy group and hydroxypropoxy group in hydroxypropylmethylcellulose is not particularly limited. For example, the molecule (100% by weight) contains 19 to 31.5% by weight of methoxy group and 4% of hydroxypropoxy group. What has -12 weight% is illustrated. Specific examples of hydroxypropylmethylcellulose used in the present invention include hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 1828, and the like.

  Further, the salt of hydroxypropylmethylcellulose is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, the above-mentioned hyaluronic acid Of the same form as the salt that can be taken. Among the salt forms, preferred are salts with inorganic bases, more preferred are alkali metal salts, still more preferred are sodium salts and potassium salts, and most preferred are sodium salts. These hydroxypropylmethylcellulose salts may be used alone or in any combination of two or more.

  The molecular weight of hydroxypropylmethylcellulose and its salt varies depending on the type and degree of substitution of the substituent, but is usually from 10,000 to 1,500,000, preferably from 50,000 to 1,300,000, more preferably from a weight average molecular weight. About 10,000 to 1,000,000 can be used.

  Among hydroxypropylmethylcellulose and its salts, the action to suppress the adsorption of the (A) component to SHCL is further enhanced, and the (A) component adsorbed to SHCL is easily eluted, thereby reducing the residual amount of chlorobutanol in SHCL. From the viewpoint of further reducing or further suppressing the adhesion of bacteria to SHCL, hydroxypropylmethylcellulose is preferably used.

  In the ophthalmic composition for SHCL of the present invention, as the component (B), one of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof may be used alone, or 2 More than one species may be used in any combination. Preferable examples of the component (B) used in the present invention include sodium hyaluronate, sodium chondroitin sulfate, alginic acid, and hydroxypropyl methylcellulose.

  Among the components (B) used in the present invention, the action of suppressing the adsorption of the component (A) on the SHCL is further enhanced, and the component (A) adsorbed on the SHCL is easily eluted, and the chlorobutanol in the SHCL From the viewpoint of further reducing the residual amount of hyaluronic acid, chondroitin sulfate, and salts thereof, more preferably, alkali metal salts of hyaluronic acid and alkali metal salts of chondroitin sulfate, particularly preferably sodium hyaluronate and chondroitin sulfate Sodium is exemplified. Further, from the viewpoint of further suppressing the adhesion of bacteria to SHCL, preferably chondroitin sulfate, hydroxypropylmethylcellulose, and salts thereof, more preferably, alkali metal salt of chondroitin sulfate and hydroxypropylmethylcellulose, particularly preferably chondroitin. Examples are sodium sulfate and hydroxypropylmethylcellulose.

In the ophthalmic composition for SHCL of the present invention, the blending ratio of the component (B) is appropriately set according to the type of the component (B), the type of the component (A) to be used together, etc. With respect to the total amount of the composition, the total amount of component (B) is 0.0001 to 5 w / v%, preferably 0.005 to 1 w / v%. More specifically, the following ranges are exemplified as the blending ratio of each component (B) with respect to the total amount of the ophthalmic composition for SHCL.
When component (B) is hyaluronic acid and / or a salt thereof: these are generally in a total amount of 0.001 to 5 w / v%, preferably 0.005 to 1 w / v%, more preferably 0.05 to 0.3 w / v%;
When the component (B) is chondroitin sulfate and / or a salt thereof: These are generally in a total amount of 0.005 to 5 w / v%, preferably 0.02 to 2 w / v%, more preferably 0.05 to 1 w / v%;
When the component (B) is alginic acid and / or a salt thereof: these are generally in a total amount of 0.0001 to 1 w / v%, preferably 0.001 to 0.5 w / v%, more preferably 0.005 to 0.2 w / v%;
When component (B) is hydroxypropylmethylcellulose and / or a salt thereof: These are generally in a total amount of 0.005 to 5 w / v%, preferably 0.02 to 2 w / v%, more preferably 0.05 to 1 w / v%.

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 it further acts to suppress the adsorption of the component (A) to the SHCL. From the viewpoint of enhancing and facilitating the elution of the component (A) adsorbed on SHCL and further reducing the residual amount of chlorobutanol in SHCL, or from the viewpoint of further suppressing the adhesion of bacteria to SHCL (A The range in which the total amount of the component (B) is 0.1 to 20000 parts by weight, preferably 10 to 1000 parts by weight per 100 parts by weight of the total component). More specifically, the following ranges are exemplified as the ratio of each component (B) per 100 parts by weight of the total amount of component (A):
When the component (B) is hyaluronic acid and / or a salt thereof: These are total amounts, usually 0.1 to 4000 parts by weight, preferably 1 to 2000 parts by weight, more preferably 10 to 500 parts by weight;
When component (B) is chondroitin sulfate and / or a salt thereof: These are total amounts, usually 1 to 4000 parts by weight, preferably 2 to 2000 parts by weight, more preferably 50 to 1000 parts by weight;
When component (B) is alginic acid and / or a salt thereof: these are the total amount, usually 0.1 to 20000 parts by weight, preferably 1 to 5000 parts by weight, more preferably 10 to 500 parts by weight;
When the component (B) is hydroxypropylmethylcellulose and / or a salt thereof: these are generally 1 to 4000 parts by weight, preferably 2 to 2000 parts by weight, more preferably 50 to 1000 parts by weight.

  The ophthalmic composition for SHCL of the present invention is at least one selected from the group consisting of (C) vitamin B6s, tetrahydrozolines, and allantoins in addition to the components (A) and (B) (below) In some cases, it may be simply expressed as component (C). Thus, by containing (C) component, the adhesion of bacteria to SHCL can be more effectively suppressed.

  Among the components (C), vitamin B6 is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, pyridoxine, pyridoxal, pyridoxamine , And their salts.

  Among the vitamin B6 compounds used in the present invention, the salt form is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, Organic acid salts [for example, monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylates (fumarate, maleate, succinate) , Malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salt (For example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.). Among these salts, preferred are inorganic acid salts, more preferred are hydrochlorides and phosphates, and particularly preferred are hydrochlorides. These pyridoxine, pyridoxal, and pyridoxamine salts may be used alone or in any combination of two or more.

  These vitamin B6s may be used alone or in any combination of two or more. Among these vitamin B6s, from the viewpoint of more effectively suppressing bacterial adhesion to SHCL, preferably pyridoxine and its salt, more preferably pyridoxine and its inorganic acid salt, more preferably pyridoxine hydrochloride and Pyridoxine phosphate, particularly preferably pyridoxine hydrochloride (pyridoxine hydrochloride) is mentioned.

  Among the components (C), the tetrahydrozolines are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and specific examples include tetrahydrozolines and salts thereof. It is done.

  Among the tetrahydrozolines used in the present invention, the salt form is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, The same form as the salt which the said vitamin B6 class can take is illustrated. Among these salts, preferred are inorganic acid salts, more preferred are hydrochlorides and nitrates, and particularly preferred are hydrochlorides. These tetrahydrozoline salts may be used alone or in any combination of two or more.

  These tetrahydrozolines may be used alone or in any combination of two or more. Among these tetrahydrozolines, from the viewpoint of more effectively suppressing bacterial adhesion to SHCL, preferably tetrahydrozoline and its salt, more preferably tetrahydrozoline and its inorganic acid salt, more preferably tetrahydrozoline hydrochloride and tetrahydrozoline. Nitrate, particularly preferably tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride) is mentioned.

  Among the components (C), allantoins are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Specifically, allantoin, its derivatives, and These salts are mentioned.

  Among allantoins used in the present invention, allantoin derivatives, and allantoin and salts thereof are particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples include allantoindihydroxyaluminum, allantoinchlorohydroxyaluminum, allantoinglycylretin, allantoinacetyl-DL-methionine, allantoin DL-pantothenyl alcohol, allantoin polygalacturonic acid, and the like.

  These allantoins may be used alone or in any combination of two or more of allantoin, derivatives thereof, and salts thereof. Among these allantoins, allantoin, allantoindihydroxyaluminum, and allantoinchlorohydroxyaluminum, more preferably allantoin, and allantoindihydroxyaluminum, particularly preferably, from the viewpoint of more effectively suppressing bacterial adhesion to SHCL. Is allantoin.

  In the ophthalmic composition for SHCL of the present invention, as the component (C), one of vitamin B6s, tetrahydrozolines, and allantoins may be used alone, or two or more of them may be arbitrarily combined. May be used. Preferable examples of the component (C) used in the present invention include allantoin, pyridoxine hydrochloride (pyridoxine hydrochloride), and tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride).

When the component (C) is blended in the SHCL ophthalmic composition of the present invention, for the blending ratio of the component (C), the type of the component (C), the type of the component (A) and the component (B) to be used in combination, etc. As an example, the total amount of component (C) is 0.0001 to 1.0 w / v%, preferably 0.01 to 0.5 w / v%, based on the total amount of the ophthalmic composition for SHCL. The More specifically, the following ranges are exemplified as the blending ratio of each component (C) with respect to the total amount of the ophthalmic composition for SHCL.
When component (C) is vitamin B6: These are total amounts, usually 0.001 to 1.0 w / v%, preferably 0.005 to 0.5 w / v%, more preferably 0.01 to 0.2 w / v%;
When component (C) is a tetrahydrozoline: These are total amounts, usually 0.0001 to 0.15 w / v%, more preferably 0.005 to 0.1 w / v%, particularly preferably 0.01 to 0.07 w / v%;
When component (C) is allantoin: These are total amounts, usually 0.001 to 1.0 w / v%, preferably 0.01 to 0.7 w / v%, more preferably 0.05 to 0.5 w / v%.

In addition, when the component (C) is added to the ophthalmic composition for SHCL of the present invention, the ratio of the component (C) to the component (A) is not particularly limited, but more bacteria adhere to the SHCL. From the viewpoint of more effectively suppressing, the range in which the total amount of the component (C) is 0.1 to 20000 parts by weight, preferably 10 to 1000 parts by weight per 100 parts by weight of the total amount of the component (A) is exemplified. More specifically, the following ranges are exemplified as the ratio of each component (C) per 100 parts by weight of the total amount of component (A):
When component (C) is vitamin B6: These are the total amount, usually 0.1 to 4000 parts by weight, preferably 1 to 2000 parts by weight, more preferably 10 to 500 parts by weight;
When component (C) is a tetrahydrozoline: These are the total amount, usually 0.1 to 20000 parts by weight, preferably 1 to 5000 parts by weight, more preferably 10 to 500 parts by weight;
When component (C) is allantoin: These are total amounts, usually 1 to 4000 parts by weight, preferably 2 to 2000 parts by weight, more preferably 50 to 1000 parts by weight.

  The ophthalmic composition for SHCL of the present invention may further contain a buffer. The buffer 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. 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 or citrates such as 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.). Among these buffering agents, boric acid buffering agents are preferably used in the ophthalmic composition for SHCL of the present invention because they are expected to exhibit the effects of the present invention more reliably. These buffering agents may be used alone or in any combination of two or more.

  When a buffering agent is blended with the ophthalmic composition for SHCL of the present invention, the blending ratio of the buffering agent depends on the type of buffering agent used, the type and amount of other blending components, the formulation form of the ophthalmic composition, etc. Depending on the total amount of the ophthalmic composition for SHCL, for example, the total amount of the buffer is 0.01 to 10 w / v%, preferably 0.1 to 5 w / Examples are v%, more preferably 0.5 to 2 w / v%.

  The ophthalmic composition for SHCL of the present invention may further contain an isotonic agent. The isotonic 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 isotonic agents include, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, acetic acid Examples include potassium, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol and the like. Among these isotonic agents, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, and propylene glycol are preferable from the viewpoint of achieving the effect of the present invention more surely, and more preferably. Sodium chloride or glycerin is mentioned, Especially preferably, sodium chloride is mentioned. These isotonic agents may be used alone or in any combination of two or more.

  When an isotonic agent is blended in the ophthalmic composition for SHCL of the present invention, the blending ratio of the tonicity agent varies depending on the type of tonicity agent used and cannot be defined uniformly. However, for example, the proportion of the tonicity agent is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v% in the total amount. .

  The ophthalmic composition for SHCL of the present invention may further contain a surfactant. The surfactant that can be blended in 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 is a nonionic surfactant. Any of an agent, 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 SHCL of the present invention include monolauric acid POE (20) sorbitan (polysorbate 20) and monopalmitic acid POE (20) sorbitan (polysorbate 40). POE sorbitan fatty acid esters such as 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 235, poloxamer 188, poloxamer 403, poloxamer 237, poloxamer 124; POE cured castor oil such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE (9 ) POE alkyl ethers such as lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether 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 blended in the ophthalmic composition for SHCL of the present invention include alkyldiaminoethylglycine. Specific examples of the cationic surfactant that can be incorporated into the ophthalmic composition for SHCL of the present invention include benzalkonium chloride and benzethonium chloride. Specific examples of the anionic surfactant that can be incorporated into the ophthalmic composition for SHCL of the present invention include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, and aliphatic α-sulfomethyl. Examples include esters and α-olefin sulfonic acids.

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

  Among the above surfactants, nonionic surfactants are preferably used; more preferably, POE sorbitan fatty acid esters, POE hydrogenated castor oil, or POE / POP block copolymers are used.

  When a surfactant is blended in the ophthalmic composition for SHCL of the present invention, the blending ratio of the surfactant is the type of the surfactant, the type and amount of other blended components, the ophthalmic composition for SHCL. It can set suitably according to a formulation form etc. As an example of the blending 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 / relative to the total amount of the ophthalmic composition for SHCL. An example is v%, 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 (pharmaceutical) or physiologically acceptable range. An example of the pH of the ophthalmic composition for SHCL of the present invention is 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 a range acceptable for a 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, particularly preferably 0.7 to 2.0. Can be mentioned. The osmotic pressure can be adjusted by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, saccharides and the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 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 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 nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, phenylephrine hydrochloride.
Eye muscle modifier: for example, neostigmine methyl sulfate.
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, sodium pantothenate, tocopherol acetate, etc.
Amino acids: For example, potassium aspartate, magnesium aspartate, magnesium and potassium aspartate (a mixture of equal amounts), aminoethylsulfonic acid and the like.
Inorganic salts: For example, potassium chloride, calcium chloride, sodium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate 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, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, glucose, alkylpolyaminoethylglycine and the like.

In addition, in the ophthalmic composition for SHCL of the present invention, various additives are appropriately selected according to a conventional method according to its use and form as long as they do not impair the effects of the invention, and one or more of them are selected. May be used in an appropriate amount. 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.
Thickener: For example, carboxyvinyl polymer, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol (completely or partially saponified product), polyvinyl pyrrolidone, 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.
Preservatives, bactericides or antibacterials: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate , 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), etc. .
pH adjuster: for example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, boro Sand, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, ammonium acetate etc.
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), ethylenediaminetetraacetic acid Disodium acetate, disodium ethylenediaminetetraacetate dihydrate, etc.
Perfume or refreshing agent: for example, menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, ryuno and the like. These may be either d-form, l-form or dl-form, and are formulated as essential oils (mint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc.) May be.

  The ophthalmic composition for SHCL of the present invention is prepared by adding a desired amount of the above-mentioned components (A) and (B) and, if necessary, the component (C) or other compounding components to a desired concentration. Is done.

  The ophthalmic composition for SHCL 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 ophthalmic composition for SHCL of the present invention is made into an aqueous liquid, pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable water may be used as an aqueous carrier. Specifically, distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection and the like are exemplified. 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 or more of water in the ophthalmic composition for SHCL. More preferably, it means one containing 50% by weight or more.

  The ophthalmic composition for SHCL of the present invention is not limited in its formulation form as long as it is used in the ophthalmic field and is 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 drops for SHCL (eye wash that can be used while wearing SHCL), SHCL wearing liquid, SHCL care liquid (SHCL disinfectant, SHCL Storage solution, SHCL cleaning solution, SHCL cleaning storage solution, etc.). Among these, eye drops for SHCL are generally more frequently used per day than other ophthalmic compositions, easily adsorb and accumulate chlorobutanol on SHCL, and suppress adsorption of chlorobutanol on SHCL. This is a highly desired formulation. Furthermore, the eye drops for SHCL are also preferable from the viewpoint that they can be easily used to suppress bacterial adhesion even when SHCL is continuously worn for a long period of time. In view of such a point of view, a preferred example of the ophthalmic composition for SHCL of the present invention is an eye drop for SHCL.

  The method for 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 SHCL eye drops, an appropriate amount of the eye drops may be instilled before or during the wearing of SHCL. Further, in the case of an eye wash for SHCL, an appropriate amount of the eye wash may be used for eye washing before or during wearing of SHCL. In addition, when 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 drops or eye wash even when not wearing SHCL. it can. Moreover, in the case of SHCL mounting liquid, it is used by contacting SHCL with an appropriate amount of the mounting liquid when SHCL is mounted. Furthermore, in the case of an SHCL care solution, it is used by immersing SHCL in an appropriate amount of the care solution, or by bringing SHCL into contact with the care solution and scrubbing.

  In the ophthalmic composition for SHCL of the present invention, the type of SHCL to be applied is not particularly limited, and any SHCL that is currently marketed or will be marketed in the future regardless of whether it is ionic or nonionic. Can be applied. Here, ionic refers to the FDA (US Food and Drug Administration) standard, and the ionic component content in the contact lens material is 1 mol% or more. Nonionic refers to the US FDA standard. The ionic component content in the contact lens material is less than 1 mol%. Among them, ionic SHCL tends to easily adsorb a large amount of chlorobutanol. According to the ophthalmic composition for SHCL of the present invention, adsorption of chlorobutanol can be effectively suppressed even for ionic SHCL that easily adsorbs chlorobutanol. In view of the effects of the present invention, ionic SHCL can be mentioned as an example of a suitable application target of the ophthalmic composition for SHCL of the present invention.

  In the ophthalmic composition for SHCL of the present invention, the moisture content of the 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.

  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.

  According to the ophthalmic composition for SHCL of the present invention, adsorption of chlorobutanol to SHCL can be effectively suppressed, and chlorobutanol adsorbed to SHCL can be easily eluted by elution treatment with physiological saline or the like. Thus, the residual amount of chlorobutanol in SHCL can be significantly reduced. Therefore, according to the ophthalmic composition for SHCL of the present invention, various adverse effects caused by adsorption / accumulation of chlorobutanol (for example, corneal epithelial disorder which can be induced by long-term accumulation of chlorobutanol in SHCL, , Corneal epithelial damage that can be induced by deformation of SHCL caused by adsorbed chlorobutanol and the like.

  Moreover, since it has been found that SHCL easily adheres to bacteria and can be continuously worn for a long period of time, it may be used in a form of use in which adhesion of bacteria is easily promoted during wearing. On the other hand, according to the present invention, since bacterial adhesion to SHCL can be effectively suppressed, it can also be used as a preventive or alleviating agent for bacterial infections of the ocular mucosa.

  In another aspect, the present invention provides (A) chlorobutanol and (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and these for the production of an ophthalmic composition for silicone hydrogel contact lenses. At least one use selected from the group consisting of:

  Further, the present invention provides an ophthalmic composition for a silicone hydrogel contact lens, comprising (A) chlorobutanol, (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropyl methylcellulose, and salts thereof. There is also provided at least one selected and (C) at least one use selected from the group consisting of vitamin B6s, tetrahydrozolines, and allantoins.

2. A method for inhibiting adsorption of chlorobutanol to SHCL, a method for imparting an action of inhibiting adsorption of chlorobutanol to SHCL, and an agent for inhibiting adsorption of chlorobutanol to SHCL. By using the component (B) together with the component A), it becomes possible to suppress the adsorption of the component (A) to the SHCL. Therefore, the present invention, from yet another viewpoint, comprises (A) chlorobutanol and (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof. Provided is a method for suppressing adsorption of the component (A) to SHCL, which is used in combination. Furthermore, (A) at least one selected from the group consisting of (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof is added to the ophthalmic composition for SHCL containing chlorobutanol. A method for imparting an action of suppressing the adsorption of the component (A) to SHCL is provided to the ophthalmic composition. The present invention also provides an agent for suppressing adsorption of chlorobutanol to SHCL, comprising at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof. Also provide.

  In these methods and agents, the types and mixing ratios of components (A) and (B), the types and mixing ratios of other components to be mixed, the dosage form of the ophthalmic composition for SHCL, the types of SHCL to be applied, etc. Is the same as “1. Ophthalmic composition for SHCL”.

  In another aspect, the present invention provides (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and an agent for producing an agent for suppressing adsorption of chlorobutanol to a silicone hydrogel contact lens. There is provided at least one use selected from the group consisting of these salts.

3. A method for inhibiting bacterial adhesion to SHCL, a method for imparting action to inhibit bacterial adhesion to SHCL, and , as described above, by using both (A) component and (B) component, It becomes possible to suppress the adhesion of bacteria. Furthermore, by using the (C) component together with the (A) component and the (B) component, it is possible to further suppress bacterial adhesion to SHCL. Therefore, the present invention, from yet another viewpoint, comprises (A) chlorobutanol and (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof. Provided is a method for suppressing bacterial adhesion to SHCL, which is used in combination. Further, the present invention provides (A) chlorobutanol, (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof, and (C) vitamin B6s. There is also provided a method for inhibiting bacterial adhesion to SHCL, which comprises using at least one selected from the group consisting of tetrahydrozolines and allantoins.

  From another viewpoint, in the ophthalmic composition, the present invention provides at least one selected from the group consisting of (A) chlorobutanol and (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof. Provided is a method for imparting to the ophthalmic composition an action of suppressing adhesion of bacteria to a silicone hydrogel contact lens, which comprises blending a seed. Furthermore, the present invention provides an ophthalmic composition comprising: (A) chlorobutanol; (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof; ) The ophthalmic composition has the effect of suppressing the adhesion of bacteria to the silicone hydrogel contact lens, characterized by comprising at least one selected from the group consisting of vitamin B6s, tetrahydrozolines, and allantoins Provide a method of granting.

  In these methods, the types and proportions of the components (A), (B) and (C), the types and proportions of the other components to be blended, the formulation form of the ophthalmic composition for SHCL, the SHCL to be applied The type and the like are the same as in “1. SHCL ophthalmic composition”.

  In another aspect, the present invention provides (A) chlorobutanol, as well as (B) hyaluronic acid, chondroitin sulfate, alginic acid, for the production of an agent for suppressing bacterial adhesion to silicone hydrogel contact lenses. There is provided at least one use selected from the group consisting of hydroxypropylmethylcellulose, and salts thereof.

  Furthermore, the present invention provides (A) chlorobutanol, (B) hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and these for the production of an agent for inhibiting bacterial adhesion to silicone hydrogel contact lenses. And at least one selected from the group consisting of (C) vitamin B6s, tetrahydrozolines, and allantoins.

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: Adsorption amount and residual amount of chlorobutanol on various SCLs Using five kinds of soft contact lenses shown in Table 1, the adsorption amount of chlorobutanol on soft contact lenses and elution with physiological saline The residual amount of chlorobutanol after the treatment was evaluated.

  First, each soft contact lens was washed with physiological saline, and the liquid was wiped clean. Next, as a sample group, each soft contact lens was immersed in 10 mL of a chlorobutanol-containing test solution (Comparative Example 1) shown in Table 2 and shaken for 24 hours under conditions of 120 rpm and 34 ° C. In addition, as a blank group, the test solution was shaken under the same conditions as the sample group without immersing any soft contact lens. Subsequently, chlorobutanol contained in the test solution of the sample group and the blank group was quantified by HPLC according to a conventional method, and the difference was defined as the amount of chlorobutanol adsorbed on the soft contact lens (chlorobutanol adsorption amount). Next, each soft contact lens of the sample group after the shaking treatment is gently washed with physiological saline, and then each soft contact lens is immersed in 10 mL of physiological saline and shaken for 24 hours under conditions of 120 rpm and 34 ° C. went. Chlorobutanol contained in physiological saline after shaking treatment was quantified by HPLC according to a conventional method, and the amount of chlorobutanol eluted from the soft contact lens (soft contact lens adsorbed with chlorobutanol) into the physiological saline (chlorobutanol) Elution amount) was determined. Then, by subtracting the chlorobutanol elution amount from the chlorobutanol adsorption amount on the soft contact lens, the amount of chlorobutanol remaining on the soft contact lens after treatment with physiological saline (the residual amount of chlorobutanol) was calculated. .

  As a result, the chlorobutanol adsorption amount of each soft contact lens is shown in FIG. 1, and the chlorobutanol residual amount in each soft contact lens after elution treatment with physiological saline is shown in FIG. As is clear from this result, compared to conventional hydrogel lenses (lenses A and B), SHCL (lenses C to E) remarkably easily adsorbs chlorobutanol (FIG. 1), and in physiological saline. Even after the elution treatment, it was confirmed that there was a specific problem that chlorobutanol was not sufficiently eluted and remained in a large amount in SHCL (FIG. 2). Above all, this problem was remarkable in ionic SHCL (lens C).

Test Example 1: Chlorobutanol Adsorption and Residual Inhibition Test on SHCL Using the lens C (SHCL) in which remarkable adsorption and residual chlorobutanol was confirmed in Reference Test Example 1 above, test solutions shown in Table 3 (Examples) 1-4 and Comparative Example 1) were used to determine the amount of chlorobutanol adsorbed on SHCL and the amount of chlorobutanol remaining on SHCL after elution with physiological saline by the same test as in Reference Test Example 1 above. It was.

  As a result, the results of measuring the amount of chlorobutanol adsorbed on SHCL when each test solution is used are shown in FIG. 3, and when each test solution is used, the SHCL after elution treatment with physiological saline is shown. The result of measuring the residual amount of chlorobutanol in is shown in FIG. As is clear from this result, in the test solution (Example 1-4) containing hydroxypropylmethylcellulose, alginic acid, sodium chondroitin sulfate, or sodium hyaluronate together with chlorobutanol, the test solution containing chlorobutanol alone (Comparative Example) Compared to 1), the amount of chlorobutanol adsorbed on SHCL was suppressed (Fig. 3), and the residual amount of chlorobutanol was remarkably reduced after elution treatment with physiological saline (Fig. 4). did. In particular, when chondroitin sulfate sodium or sodium hyaluronate is used (Example 3-4), the residual amount after elution treatment with physiological saline can be significantly reduced, and chlorobutanol on SHCL can be reduced. It was confirmed that the residue after adsorption and elution treatment can be effectively suppressed, and an extremely safe ophthalmic composition for SHCL can be obtained while containing chlorobutanol.

Test Example 2: Test for evaluating bacterial adhesion to SHCL (1)
The adhesion of Staphylococcus aureus (ATCC No. 6538) to various soft contact lenses was evaluated using the test solutions shown in the following table (Example 5-6 and Comparative Example 2-3). The lens is SHCL, Lens F (nonionic SHCL, main constituent monomer: N, N-dimethylacrylamide, pyrrolidone compound, silicon-containing methacrylate compound, silicon-containing acrylate compound (USAN: Asmofilcon A), water content 40% BC8.60, DIA14.0), and the lens B of Reference Test Example 1 was used as a non-silicone hydrogel contact lens (non-SHCL).

First, each lens was immersed in 5 mL of sterile physiological saline for 4 hours or more (lens pretreatment). Next, 1 mL of each test solution (Examples 5-6 and Comparative Example 2-3) was placed in a 24-well multiplate, and pretreated SHCLs were placed one by one. Further, non-silicone hydrogel contact lenses were similarly treated with the test solution according to Comparative Example 2. Lightly absorb the moisture on the surface of each lens with a non-woven fabric after overnight treatment, and then add a 6-well multiplate containing 5 mL of 10 ^7-8 CFU / mL S. aureus bacterial solution (suspended in physiological saline) And stored at room temperature for 30 minutes. After 30 minutes, each lens was transferred to a 6-well plate containing 5 mL of physiological saline with tweezers and shaken for 1 minute. Next, each lens is transferred to a Spitz tube containing 5 mL of new physiological saline, subjected to ultrasonic waves (38 kHz) for 3 minutes, and then stirred for 1 minute in a test tube mixer to remove bacteria attached to each lens. The adherent bacteria solution was used.

  The obtained adherent bacterial solution was diluted to an appropriate concentration and seeded on a soy bean / casein / digest / agar medium (SCDLP agar medium). After culturing overnight at 33 ° C., the number of colonies observed was counted, and the number of bacteria attached to each lens (viable cell count) was determined by correcting with the dilution factor.

  The results are shown in FIG. 5 below. As shown in FIG. 5, it is recognized that SHCL is remarkably easier to attach S. aureus than non-silicone hydrogel lenses (Comparative Example 2), and the number of adherent bacteria is slightly reduced by the addition of chlorobutanol. Was observed (Comparative Example 3). On the other hand, unexpectedly, it was recognized that the number of bacteria attached to SHCL can be significantly reduced by applying hydroxypropylmethylcellulose in combination with this chlorobutanol (Example 5). Furthermore, it became clear that the number of adherent bacteria can be reduced more remarkably by combining allantoin with chlorobutanol and hydroxypropylmethylcellulose (Example 6).

Test Example 3: Evaluation test for bacterial adhesion to SHCL (2)
For the test solutions shown in the following table (Examples 7-9 and Comparative Example 4), the type of SHCL used was substantially the same as Test Example 2 except that the lens D of Reference Test Example 1 was changed. The adhesion of Staphylococcus aureus (ATCC No. 6538) to SHCL was evaluated.

  The results are shown in FIG. 6 below. As shown in FIG. 6, even when the type of SHCL was changed, the same bacterial adhesion inhibitory effect as in Test Example 2 was confirmed by the combination of chlorobutanol and hydroxypropylmethylcellulose (Example 7). In addition, it was also clarified that even when pyridoxine hydrochloride or tetrahydrozoline hydrochloride is further combined with chlorobutanol and hydroxypropylmethylcellulose, a more remarkable effect of suppressing bacterial adhesion is exhibited (Examples 8 and 9). .

Test Example 4: Evaluation test for bacterial adhesion to SHCL (3)
For the test solutions (Examples 10-11 and Comparative Example 5) shown in the following table, Staphylococcus aureus (SHCL) with the lens F of Test Example 2 was used as SHCL in substantially the same manner as Test Example 2. The adhesion of ATCC No. 6538) was evaluated.

The results are shown in FIG. 7 below. As shown in FIG. 7, even when sodium chondroitin sulfate was used in place of hydroxypropylmethylcellulose, it was confirmed that the same bacterial adhesion inhibitory effect as in the previous test examples was exhibited (Examples). 10-11).
Formulation Example With the formulation described in Table 7, SHCL eye drops (Examples 12-24) and SHCL disinfectant (Examples 25-27) are prepared.

Claims (1)

  An ophthalmic composition for a silicone hydrogel contact lens, comprising (A) chlorobutanol and (B) at least one selected from the group consisting of hyaluronic acid, chondroitin sulfate, alginic acid, hydroxypropylmethylcellulose, and salts thereof .

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