JP2020128437A - Ophthalmic composition for silicone hydrogel contact lenses - Google Patents

Abstract

To provide ophthalmic compositions for silicone hydrogel contact lenses that can reduce the friction on the surface of a silicone hydrogel contact lens to improve a wearing feel thereof, effectively prevent generation of keratoconjunctival epithelial disorders, and allows the comfortable and safety use of silicone hydrogel contact lens.SOLUTION: An ophthalmic composition for silicone hydrogel contact lenses is prepared by combining dibutylhydroxytoluene and/or butylhydroxyanisol.SELECTED DRAWING: None

Description

The present invention relates to an ophthalmic composition for a silicone hydrogel contact lens, which can reduce friction on the surface of the silicone hydrogel contact lens, improve the feeling of wearing, and effectively prevent epithelial damage in the keratoconjunctiva. The invention also relates to a method of reducing the friction on the surface of a silicone hydrogel contact lens. Furthermore, the present invention relates to a method for suppressing cell detachment when removing a silicone hydrogel contact lens from the surface of the eyeball.

In recent years, the number of wearers of contact lenses (CL) has increased, and especially 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 corneal thickening. Therefore, development of soft contact lenses having higher oxygen permeability has been promoted.

Under such circumstances, silicone hydrogel contact lenses have been recently developed as soft contact lenses having high oxygen permeability. Silicone hydrogel contact lenses achieve several times the oxygen permeability of conventional hydrogel contact lenses by blending hydrogel with silicone. Therefore, it is greatly expected that the shortage 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 shortage of oxygen can be significantly suppressed.

On the other hand, it has been recently reported that the surface of a silicone hydrogel contact lens has remarkable irregularities that cannot be seen on the surface of a normal hydrogel contact lens (see Non-Patent Document 1). It is expected that such remarkable unevenness not only makes it easier for substances of biological origin and dirt to adhere to those that have a smooth surface, but also causes an increase in friction, especially in sensitive eye tissues. It is fully conceivable that an unpleasant sensation such as a feeling of foreign matter or a feeling of dryness will be caused. Furthermore, it is feared that a contact lens having remarkable unevenness has a risk of rubbing against the ocular mucosa during wearing and causing epithelial damage to the keratoconjunctiva.

Dibutylhydroxytoluene and/or butylhydroxyanisole are well known as antioxidants and are widely used as additives to be added to foods and pharmaceuticals (see Patent Documents 1 and 2). However, up to now, nothing has been known about the effect of dibutylhydroxytoluene and/or butylhydroxyanisole on silicone hydrogel contact lenses. Furthermore, from the prior art, it is the present situation that the effect of applying dibutylhydroxytoluene and/or butylhydroxyanisole and other components to silicone hydrogel contact lenses in combination cannot be inferred at all.

Japanese Patent No. 3021312 JP, 2007-99697, A

Akemi Haritani et al., Proc. of the 51st Annual Meeting of the Contact Lens Society of Japan Program, 110 pages

The present inventors conducted various studies on the physical properties of various soft contact lenses, and found that a silicone hydrogel contact lens (hereinafter sometimes simply referred to as “SHCL”) is better than a conventional hydrogel contact lens. It was confirmed that the friction on the lens surface was extremely large. It is considered that this large frictional force is partly due to the existence of remarkable irregularities on the surface that have already been reported, but such a large frictional force causes discomfort (such as feeling of foreign matter or dryness) when wearing SHCL. It may cause eye fatigue. Further, a contact lens having large friction may cause epithelial damage to the keratoconjunctiva when the mucous membrane on the back side of the eyelid rubs against the surface of the contact lens or whenever the contact lens moves on the surface of the eyeball. Therefore, the friction of the surface of the silicone hydrogel contact lens is reduced, the wearing feeling is improved, the occurrence of epithelial damage in the corneal conjunctiva can be effectively prevented, and the silicone hydrogel contact lens can be used comfortably and safely. It is required to develop a means to

As a result of intensive studies to solve the above problems, the present inventors have found that the friction of SHCL can be greatly reduced by applying dibutylhydroxytoluene and/or butylhydroxyanisole to SHCL. The friction of this SHCL can be further reduced by applying dibutylhydroxytoluene and/or butylhydroxyanisole in combination with pranoprofen and/or its salts. Further, the present inventors have further studied and found that the use of dibutylhydroxytoluene and/or butylhydroxyanisole can effectively suppress cell detachment that occurs when SHCL is removed from the eyeball surface. The present invention has been completed by further improving based on such knowledge.

That is, the present invention provides the following ophthalmic compositions for silicone hydrogel contact lenses.
Item 1-1. An ophthalmic composition for a silicone hydrogel contact lens, containing at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole.
Item 1-2. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-1, which contains dibutylhydroxytoluene.
Item 1-3. Item 1. For a silicone hydrogel contact lens according to Item 1-1 or 1-2, containing at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole in a total amount of 0.00005 to 0.05 w/v %. Ophthalmic composition.
Item 1-4. Furthermore, the ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-3, containing at least one selected from the group consisting of pranoprofen and salts thereof.
Item 1-5. Item 10. The ophthalmic composition for silicone hydrogel contact lens according to Item 1-4, containing at least one selected from the group consisting of pranoprofen and salts thereof in a total amount of 0.001 to 0.3 w/v%.
Item 1-6. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-5, which further contains a surfactant.
Item 1-7. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-6, which contains a nonionic surfactant as a surfactant.
Item 1-8. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-6 or 1-7, which contains a total amount of the surfactant of 0.001 to 1.0 w/v %.
Item 1-9. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-8, which further contains a buffering agent.
Item 1-10. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-9, which contains a borate buffer as a buffer.
Item 1-11. Item 11. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-9 or 1-10, which contains 0.01 to 10 w/v% in total.
Item 1-12. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-11, which further contains a tonicity agent.
Item 1-13. Ophthalmology for silicone hydrogel contact lenses according to Item 1-12, comprising at least one selected from the group consisting of glycerin, propylene glycol, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride as an isotonicity agent. Composition.
Item 1-14. The ophthalmic composition for silicone hydrogel contact lenses according to Item 1-12 or 1-13, which contains 0.01 to 10 w/v% of the isotonic agent in total.
Item 1-15. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-14, which is an eye drop.
Item 1-16. The ophthalmic composition for a silicone hydrogel contact lens according to any one of Items 1-1 to 1-15, which is used for reducing the friction of the silicone hydrogel contact lens.
Item 1-17. The ophthalmic composition for silicone hydrogel contact lenses according to any one of Items 1-1 to 1-15, which is used for suppressing cell detachment that occurs when removing the silicone hydrogel contact lens from the surface of the eyeball.

Further, the present invention provides the following methods for reducing friction of silicone hydrogel contact lenses.
Item 2-1. A method for reducing friction of a silicone hydrogel contact lens, which comprises contacting at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole with a silicone hydrogel contact lens.
Item 2-2. Item 2. The method according to Item 2-1, wherein the ophthalmic composition for silicone hydrogel contact lens according to any one of Items 1-1 to 1-17 is contacted with the silicone hydrogel contact lens.

Furthermore, the present invention provides a method for imparting the friction-reducing action of silicone hydrogel contact lenses listed below to an ophthalmic composition.
Item 3. At least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole is added to the ophthalmic composition for silicone hydrogel contact lenses, which has the effect of reducing friction of the silicone hydrogel contact lenses. A method of applying to an ophthalmic composition.

Furthermore, the present invention provides a method for suppressing cell detachment from the surface of the eye due to removal of the silicone hydrogel contact lens listed below.
Item 4-1. A cell from the surface of the eye along with removal of the silicone hydrogel contact lens, characterized in that at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole is brought into contact with the silicone hydrogel contact lens. A method of suppressing peeling.
Item 4-2. Item 4. The method according to Item 4-1, wherein the silicone hydrogel contact lens ophthalmic composition according to any one of Items 1-1 to 1-17 is contacted with the silicone hydrogel contact lens.

Further, the present invention provides a method for imparting to the ophthalmic composition an action of suppressing cell detachment from the surface of the eyeball due to removal of the silicone hydrogel contact lens listed below.
Item 5. At least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole is added to an ophthalmic composition for a silicone hydrogel contact lens, from the surface of the eye along with the removal of the silicone hydrogel contact lens. A method for imparting to the ophthalmic composition the effect of suppressing cell detachment.

Furthermore, the present invention also provides the uses listed below.
Item 6-1. Use of at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole for the manufacture of an ophthalmic composition for silicone hydrogel contact lenses.
Item 6-2. At least one selected from the group consisting of (A) dibutylhydroxytoluene and butylhydroxyanisole, and (B) selected from the group consisting of pranoprofen and salts thereof, for producing an ophthalmic composition for silicone hydrogel contact lenses At least one use.
Item 6-3. The use according to Item 6-1 or Item 6-2, wherein the ophthalmic composition for silicone hydrogel contact lens is the ophthalmic composition according to any one of Items 1-1 to 1-17.
Item 6-4. Use of at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole for the preparation of an agent for reducing the friction of silicone hydrogel contact lenses.
Item 6-5. From at least one selected from the group consisting of (A) dibutylhydroxytoluene and butylhydroxyanisole and (B) pranoprofen and its salts for the preparation of agents for reducing the friction of silicone hydrogel contact lenses Use of at least one selected from the group consisting of:
Item 6-6. Use of at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole for the preparation of an agent for suppressing cell detachment from the ocular surface associated with the removal of a silicone hydrogel contact lens.
Item 6-7. At least one selected from the group consisting of (A) dibutylhydroxytoluene and butylhydroxyanisole for the production of an agent for suppressing cell detachment from the ocular surface due to removal of a silicone hydrogel contact lens, and ( B) Use of at least one selected from the group consisting of pranoprofen and salts thereof.

According to the ophthalmic composition for SHCL of the present invention, the friction on the SHCL surface can be greatly reduced. Therefore, by the ophthalmic composition for SHCL of the present invention, it is possible to improve the feeling of wearing SHCL, and it is possible to effectively prevent the possibility of epithelial lesion occurrence in the keratoconjunctiva, and to use SHCL comfortably and safely. Will be realized.

Moreover, according to the ophthalmic composition for SHCL of the present invention, the risk of cell detachment that occurs when SHCL is removed from the ocular surface can be greatly reduced. Therefore, according to the ophthalmic composition for SHCL of the present invention, it becomes possible to safely remove SHCL without damaging the epithelial cells on the surface of the eye.

In reference test example 1, it is a figure which shows the result of having evaluated the friction (logarithmic attenuation factor measured by the rigid body pendulum physical property test) of various soft contact lenses. In Test Example 1, it is a diagram showing the results of evaluating the friction reducing effect of the test liquids (Example 1-2 and Comparative Example 1-2) on SHCL (lens A). FIG. 6 is a diagram showing the results of evaluation of the friction reducing effect of test liquids (Example 1-2 and Comparative Example 1) on SHCL (lens C) in Test Example 1. FIG. 6 is a diagram showing the results of evaluating the friction reducing effect of the test liquids (Example 1 and Comparative Example 1) on the hydrogel lens (lens D) in Test Example 1. FIG. 6 is a diagram showing the results of evaluating the friction reducing effect of the test liquids (Example 3 and Comparative Example 3) on SHCL (lens A) in Test Example 2. FIG. 7 is a diagram showing the results of evaluation of the effect of the test solutions (Example 5 and Comparative Example 5) in Test Example 3 on suppressing cell detachment associated with SHCL removal.

1. SHCL Ophthalmic Composition The SHCL ophthalmic composition of the present invention comprises at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole (hereinafter, simply referred to as “dibutylhydroxytoluenes”). contains. By using such dibutyl hydroxytoluenes, it becomes possible to reduce the friction on the SHCL surface, and it is possible to suppress cell detachment that occurs when the SHCL is removed from the ocular surface.

Dibutylhydroxytoluene (chemical name 2,6-di-tert-butyl-4-methylphenol; sometimes abbreviated as BHT) and butylhydroxyanisole (chemical name 2-tert-butyl-4-methoxyphenol and 3- (tert-butyl-4-methoxyphenol; sometimes abbreviated as BHA) is a compound in which the benzene ring of hydroxytoluene or hydroxyanisole is substituted with a t-butyl group, and is known as an antioxidant. Dibutylhydroxytoluene and butylhydroxyanisole may be synthesized by known methods or may be commercially available.

In the ophthalmic composition for SHCL of the present invention, either one of dibutylhydroxytoluene and butylhydroxyanisole may be used alone as dibutylhydroxytoluene, or these may be used in combination. Among them, dibutylhydroxytoluene can greatly reduce the friction of SHCL, and can effectively suppress cell detachment that occurs when SHCL is removed from the surface of the eyeball. From this viewpoint, dibutylhydroxytoluene can be particularly preferably used in the present invention.

In the SHCL ophthalmic composition of the present invention, the mixing ratio of the dibutylhydroxytoluenes may be appropriately set depending on the type of the dibutylhydroxytoluenes, the formulation form of the SHCL ophthalmic composition, and the like. From the viewpoint of effectively reducing friction, and also from the viewpoint of effectively suppressing cell detachment when removing SHCL from the ocular surface, for example, relative to the total amount of the SHCL ophthalmic composition, dibutyl hydroxy. The total amount of toluenes is 0.00005 to 0.05 w/v%, preferably 0.0001 to 0.03 w/v%, more preferably 0.0005 to 0.01 w/v%, and particularly preferably 0.001. ˜0.005 w/v% is exemplified.

Further, the ophthalmic composition for SHCL of the present invention is, in addition to the above dibutylhydroxytoluenes, at least one selected from the group consisting of pranoprofen and salts thereof (hereinafter, simply referred to as “pranoprofen”). There is also). Thus, by using the above-mentioned dibutyl hydroxytoluenes in combination with pranoprofens, it becomes possible to enhance the effect of reducing friction on the SHCL surface.

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

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

In the ophthalmic composition for SHCL of the present invention, as pranoprofen, from pranoprofen and salts thereof, one kind may be selected and used alone, and two or more kinds may be optionally used. You may use it in combination. Among these, pranoprofen is preferable from the viewpoint of further enhancing the friction reducing effect of the SHCL surface by the above dibutylhydroxytoluenes.

When blending pranoprofens into the SHCL ophthalmic composition of the present invention, the blending ratio thereof is appropriately set according to the type of the dibutylhydroxytoluenes, the formulation form of the SHCL ophthalmic composition, and the like. For example, the total amount of pranoprofens relative to the total amount of the ophthalmic composition for SHCL is 0.001 to 0.3 w/v%, preferably 0.005 to 0.2 w/v%, and more preferably 0.00. The ratio of 01 to 0.1 w/v% is exemplified.

When blending pranoprofens in the ophthalmic composition for SHCL of the present invention, the ratio of the pranoprofens to the dibutylhydroxytoluenes is not particularly limited, but the SHCL surface by the dibutylhydroxytoluenes is not particularly limited. From the viewpoint of effectively enhancing the friction reducing effect of, for example, the total amount of pranoprofens is 20 to 40,000 parts by weight, preferably 100 to 20,000 parts by weight, and more preferably 100 parts by weight per 100 parts by weight of the total amount of the dibutylhydroxytoluenes. Is in the range of 200 to 10,000 parts by weight.

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(20)POP(4) cetyl ether and other POE-POP alkyl ethers; POE(10) nonylphenyl ether and other POE alkylphenyl ethers. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added. Specific examples of the amphoteric surfactant that can be incorporated into the ophthalmic composition for SHCL of the present invention include alkyldiaminoethylglycine and the like. 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. 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 surfactants may be used alone or in combination of two or more.

Among the above 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 or POE. Hydrogenated castor oils; particularly preferably POE sorbitan fatty acid esters are used. Among the POE sorbitan fatty acid esters, polysorbate 80 is particularly preferable.

When blending a surfactant in the SHCL ophthalmic composition of the present invention, the blending ratio of the surfactant, the type of the surfactant, the type and amount of other compounding ingredients, the SHCL ophthalmic composition It can be appropriately set according to the formulation form and the like. 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/ with respect to the total amount of the ophthalmic composition for SHCL. v%, more preferably 0.01 to 0.5 w/v%, particularly preferably 0.1 to 0.5 w/v% is exemplified.

The ophthalmic composition for SHCL of the present invention may further contain 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, tris buffer, epsilon-aminocaproic acid, aspartic acid, aspartic acid salt 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, alkaline earth metal citrate, and the like. Further, a borate or a hydrate of 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 buffer, acetic acid or salts thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); Tris buffer, tris (hydroxymethyl) Examples thereof include aminomethane or a salt thereof (hydrochloride, acetate, sulfonate, etc.); aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.). Among these buffers, the borate buffer is expected to exert the effects of the present invention more reliably, and is therefore 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 buffering agent used, the type and amount of other compounding ingredients, the formulation form of the ophthalmic composition, etc. Depending on the amount, the total amount of the buffer is 0.01 to 10 w/v%, preferably 0.1 to 5 w/, relative to the total amount of the ophthalmic composition for SHCL. 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 tonicity agent. The isotonicity 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 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 exerting the effect of the present invention, preferably glycerin, propylene glycol, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride, and more preferably Glycerin and sodium chloride are included. 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 isotonicity agent in the total amount of 0.01 to 10 w/v%, preferably 0.05 to 5 w/v%, more preferably 0.1 to 3 w/v% is exemplified. ..

The pH of the 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 a 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) is dried in a desiccator (silica gel) after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes. 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, chlorpheniramine maleate, ketotifen fumarate, pemirolast potassium and the like.
Decongestants: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, etc.
Bactericide: For example, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biguanide hydrochloride and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate and the like.
Amino acids: For example, potassium aspartate, magnesium aspartate, aminoethylsulfonic acid and the like.
Anti-inflammatory: dipotassium glycyrrhizinate, allantoin, azulene, sodium azulene sulfonate, guaiazulene, ε-aminocaproic acid, berberine chloride, berberine sulfate, lysozyme chloride, licorice and the like.
Astringent: for example, zinc white, zinc lactate, zinc sulfate and the like.
Others: For example, sodium cromoglycate, sodium chondroitin sulfate, sodium hyaluronate, sulfamethoxazole, sodium sulfamethoxazole and the like.

Further, in the ophthalmic composition for SHCL of the present invention, as long as the effect of the invention is not impaired, depending on the application and form thereof, according to a conventional method, various additives are appropriately selected, and one or more kinds thereof are selected. You may use together and may contain 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.
Thickeners: for example, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, alginic acid, polyvinyl alcohol (completely or partially saponified product), polyvinyl pyrrolidone, 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.
Preservatives, fungicides or antibacterial agents: 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, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), glowkill (product of Rhodia) Name) 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.
Stabilizer: For example, 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.
Fragrance or refreshing agent: For example, menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, rheumatoid and the like. These may be d-form, l-form or dl-form, and are blended as essential oils (mint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc.) You may.

The ophthalmic composition for SHCL of the present invention is prepared by adding a desired amount of the above dibutylhydroxytoluenes and, if necessary, other compounding ingredients so as to have a desired concentration.

The dosage form 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 liquid form and ointment form. Of these, liquid is preferable. Among the liquids, an aqueous liquid is preferable. When the SHCL ophthalmic composition of the present invention is made into an aqueous liquid, pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable water may be used as an aqueous carrier. Specifically, distilled water, ordinary water, purified water, sterilized purified water, water for injection, distilled water for injection and the like are exemplified. These definitions are based on the Japanese Pharmacopoeia Fifth Amendment. 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 wash for SHCL (eye drops that can be used while wearing SHCL), SHCL mounting solution, SHCL care solution (SHCL disinfectant, SHCL Storage solution, SHCL cleaning solution, SHCL cleaning storage solution, etc.) and the like. Among these, eye drops for SHCL or SHCL mounting solution, especially eye drops for SHCL, when SHCL is in contact with the eyeball surface or immediately before contact (for example, within 10 minutes before the wearing action that causes contact). ), and is a formulation form in which it is strongly desired to exert the friction reducing action of SHCL. In particular, eye drops have an advantage that they can be used immediately on the spot when discomfort or eye fatigue is felt while wearing SHCL. In addition, since eye drops are generally used more frequently per day than other ophthalmic compositions, there is also an advantage that the friction reducing effect of the SHCL ophthalmic composition of the present invention can be more effectively obtained. Furthermore, from the viewpoint of enabling safe removal of SHCL, it is convenient to use an eye drop formulation that can be used immediately before removing SHCL (for example, within 10 minutes before the action of removing SHCL). Peeling can be suppressed more effectively. From this point of view, as a suitable example of the ophthalmic composition for SHCL of the present invention, an eye drop for SHCL and a SHCL mounting solution can be mentioned, and a particularly preferable example is an eye drop 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 eye drops for SHCL, before using SHCL (for example, immediately before wearing 10 minutes before wearing, etc.) or during wearing (for example, including just before putting on and taking off 10 minutes before wearing, etc.), apply an appropriate amount of the eye drop. You can instill it. Further, also in the case of an eyewash for SHCL, an appropriate amount of the eyewash may be used for eyewash before the SHCL is attached (immediately before attachment, etc.) or during the wearing (immediately before desorption, etc.). 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 SHCL, as well as when wearing SHCL. it can. Further, in the case of the SHCL mounting solution, it is used by contacting an appropriate amount of the SHCL and the mounting solution when mounting the SHCL. Further, in the case of an 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.

In the ophthalmic composition for SHCL of the present invention, the type of SHCL to be applied is not particularly limited, and regardless of whether it is ionic or nonionic, all SHCL that is currently marketed or that is marketed in the future. Can be applied. It should be noted that 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) standard, 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, the water content of SHCL to be applied is not particularly limited, but generally, as the water content becomes lower, friction on the surface of SHCL increases, and cell detachment tends to occur when SHCL is removed. According to the ophthalmic composition for SHCL of the present invention, even with SHCL in which friction is likely to increase and cell detachment is easily caused, friction can be effectively reduced and cell detachment can be effectively suppressed. From this viewpoint, as an example of the water content of SHCL to be applied, specifically, 90% or less, preferably 60% or less, and more preferably 50% or less can be mentioned. 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 calculated by the following calculation formula.

Moisture content (%) = (weight of water containing water / weight of SHCL containing water) x 100
Such a water content can be measured by a gravimetric method according to the description of ISO18369-4:2006.

INDUSTRIAL APPLICABILITY The ophthalmic composition for SHCL of the present invention can reduce friction on the surface of SHCL, and thus can be used for reducing friction of SHCL. Furthermore, since the ophthalmic composition for SHCL of the present invention can suppress cell detachment that occurs when SHCL is detached from the ocular surface, it can also be used as a SHCL remover solution (for inhibiting cell detachment during SHCL detachment). In addition, since the epithelial cells of the eye also have a barrier function against allergens, the above-mentioned friction of the SHCL surface, or epithelial damage caused by cell detachment caused by the removal of SHCL, reduces its barrier function, There is a fear that it may easily cause or worsen eye allergic diseases. Therefore, the ophthalmic composition for SHCL of the present invention, a person who uses SHCL, an eye disease preventive agent for increasing and preventing resistance to various eye diseases including allergic diseases (for example, prevention of allergic diseases It can be preferably used as an agent). Further, when the SHCL ophthalmic composition of the present invention contains pranoprofen and/or a salt thereof, it can also exert an antiallergic action based on these components, and thus is useful as a relieving agent for allergic symptoms. is there.

The invention also provides, from another aspect, the use of at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole for the production of an ophthalmic composition for silicone hydrogel contact lenses.

Furthermore, the present invention provides at least one selected from the group consisting of (A) dibutylhydroxytoluene and butylhydroxyanisole for the production of an ophthalmic composition for silicone hydrogel contact lenses, and (B) pranoprofen and Also provided is at least one use selected from the group consisting of the salts.

2. Method of reducing friction of SHCL; and method of imparting action of reducing friction of SHCL to an ophthalmic composition As described above, dibutylhydroxytoluene and butylhydroxyanisole can reduce friction of SHCL surface. Therefore, in still another aspect, the present invention is a method for reducing friction of SHCL, which comprises contacting SHCL with at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole. I will provide a.

Specifically, the friction reducing method may be carried out by directly contacting dibutylhydroxytoluenes with SHCL or by contacting the above-mentioned ophthalmic composition for SHCL containing dibutylhydroxytoluenes with SHCL.

Further, the present invention is characterized in that at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole is added to an ophthalmic composition for SHCL, which has the action of reducing the friction of SHCL. It also provides a method of giving to.

In addition, in the above friction reduction method and the above application method, the type of SHCL to be applied, the method of bringing dibutylhydroxytoluenes into contact with SHCL, and the like are also the same as those in the above "1. SHCL ophthalmic composition".

The invention further provides the use of at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole, for the preparation of an agent for reducing the friction of silicone hydrogel contact lenses.

3. Method for suppressing cell detachment associated with SHCL removal; and method for imparting action to cell detachment associated with SHCL removal to an ophthalmic composition As described above, dibutylhydroxytoluene and butylhydroxyanisole are applied from the surface of the eye. Cell detachment that occurs when SHCL is removed can be suppressed. Therefore, in still another aspect, the present invention is characterized in that at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole is brought into contact with SHCL, and the ocular surface accompanying removal of the SHCL is characterized. A method for suppressing cell detachment from above is provided.

The cell exfoliation suppressing method may be specifically carried out by directly contacting dibutylhydroxytoluenes with SHCL or by contacting the above ophthalmic composition for SHCL containing dibutylhydroxytoluenes with SHCL. ..

Further, the present invention is characterized in that at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole is added to an ophthalmic composition for SHCL, and cell detachment from the ocular surface accompanying removal of SHCL is characterized. There is also provided a method for imparting an action of suppressing the above to the ophthalmic composition.

In addition, in the cell exfoliation suppression method and the application method described above, the type of SHCL to be applied, the method of contacting dibutylhydroxytoluenes with SHCL, and the like are the same as in the above-mentioned “1. SHCL ophthalmic composition”. ..

Furthermore, the present invention is, from another aspect, at least selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole for the production of an agent for suppressing cell detachment from the ocular surface associated with the removal of SHCL. One use is also provided.

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

Reference Test Example 1: SCL surface friction evaluation
In order to measure the physical properties of the SCL surface, a rigid pendulum physical property tester RPT-3000W (( The frictional force of each SCL surface was evaluated by using A&D Co., Ltd.). The SCL used in the test is specifically the six lenses shown in Table 1 below.

What immersed these SCL in physiological saline overnight was used as a test sample. The measurement was performed under the conditions of a temperature of 25° C. and a relative humidity of 60%, a pendulum weight of 200 g, and a sensor diameter of 4 mm, and a comparison was made between each SCL using a logarithmic decay rate 5 minutes after the start of measurement.

The result is shown in FIG. The logarithmic decrement measured here indicates the magnitude of the friction on the lens surface, and the higher the logarithmic decrement, the greater the friction. As is clear from FIG. 1, it was confirmed that SHCL (lenses A to C) had a significantly higher logarithmic decrement than the non-silicone hydrogel lenses (lenses D to F) and had very large friction.

Test Example 1: Evaluation of reduction effect on SCL surface friction
With regard to SHCL, two kinds of lenses A and C used in the above reference test example 1 are used, and as the non-silicone hydrogel lens, the lens D used in the above reference test example 1 is used. The evaluation was performed by the method.

First, each test liquid shown in Table 2 (Comparative Example 1-2 and Example 1-2) was prepared. After thoroughly rinsing the surface of the SHCL (lenses A and C) with physiological saline, two sheets were immersed in 20 ml of each test solution and left to stand overnight. Separately, also for the non-silicone hydrogel lens (lens D), after thoroughly rinsing the surface with physiological saline, dip two each in 20 ml of each test solution (Comparative Example 1 and Example 1), Let stand overnight. The next day, water on the lens surface was wiped off lightly, and the logarithmic decay rate was measured every 10 seconds for a total of 3 minutes under the conditions of a pendulum weight of 200 g and a sensor diameter of 4 mm under the conditions of 25° C. and relative humidity of 60%.

The results are shown in FIGS. As shown in FIGS. 2 and 3, in both cases of lenses A and C in SHCL, the logarithmic decrement was significantly reduced by the blending of dibutylhydroxytoluene (Example 1) as compared with the control (Comparative Example 1). Was found, and it became clear that the friction was greatly reduced. Further, although pranoprofen itself was observed to have little or no effect on friction as compared with the control (Comparative Example 1) (Comparative Example 2), it was quite unexpected. It was found that when used in combination with dibutylhydroxytoluene (Example 2), the friction reducing effect was further improved.

On the other hand, as shown in FIG. 4, in the conventional hydrogel lens (non-silicone hydrogel lens), the above friction reducing effect was not observed at all.

From the above results, the effect of reducing the friction of the SCL surface by dibutylhydroxytoluene alone or the combined use of dibutylhydroxytoluene and pranoprofen is an effect that is specifically observed when the target SCL is SHCL. It became clear.

Test Example 2: Evaluation of reduction effect on SCL surface friction:
The lens A used in Reference Test Example 1 was used as the SHCL, and the SHCL friction reducing effect was evaluated by the following method.

First, the surface of SHCL (lens A) was thoroughly rinsed with physiological saline and then immersed in physiological saline overnight to pretreat the lens.

Next, each test solution shown in Table 3 (Example 3-4 and Comparative Example 3-4) was prepared, and each pretreated lens was immersed in 10 ml of each test solution one by one and allowed to stand for 3 days. I put it. After 3 days, the water on the lens surface was lightly wiped off, and the logarithmic decay rate was measured every 10 seconds for 3 minutes under the conditions of 25° C. and 60% relative humidity under the conditions of a pendulum weight of 200 g and a sensor diameter of 4 mm.

The result of comparison between Example 3 and Comparative Example 3 is shown in FIG. As shown in FIG. 5, in lens A, a decrease in the logarithmic decrement was observed by using the test liquid (Example 3) containing dibutylhydroxytoluene, as compared with the control (Comparative Example 3). It became clear that the friction was reduced. Further, from the results of Example 4 and Comparative Example 4, it was confirmed that the logarithmic decay rate was similarly reduced even when the nonionic surfactant was changed from polysorbate 80 to polyoxyethylene hydrogenated castor oil. It was

Test Example 3: Evaluation of cell detachment suppression effect
The lens A used in Reference Test Example 1 above was used as SHCL, and the effect of suppressing cell detachment due to removal of SHCL from the surface of the eyeball was evaluated by the following method.

First, each test liquid shown in Table 4 (Comparative Example 5 and Example 5) was prepared. The lens A was hollowed out with a trepan (perforator) having a diameter of 6 mm, and immersed in 2 ml of each test solution (Comparative Example 5 and Example 5) for 24 hours. The next day, excess muscle and conjunctival tissue were removed from pig eyes (obtained from Dard Co., Ltd.) to prepare eyes covered only with the sclera and cornea, which were washed with physiological saline for 5 to 10 minutes. The eyeball thus obtained was carefully wiped off excess water with a non-woven fabric. Then, the SHCL that had been soaked for 24 hours was taken out from each test solution, and excess water was carefully wiped off with a non-woven fabric. Separately, the lens A immediately after opening, which was not dipped in any test solution, was used for the test as an untreated lens group. Next, the above-mentioned eyeball was set on a test stand so that the corneal surface faced up, and one eyeball (that is, one cornea) had an untreated lens, a lens treated with the test solution of Comparative Example 5, and the one of Example 5. A total of 3 lenses of test liquid treatment lenses were mounted. The test environment was adjusted so that the temperature was 25 to 27° C. and the relative humidity was 62 to 68%.

After 10 minutes, the end of the SHCL on the eyeball was gently pinched with round tweezers (ring tweezers) and slowly and carefully peeled off. The peeled SHCL was washed once with physiological saline and immersed in a 4% by volume paraformaldehyde solution to fix the cells attached to the SHCL. Then, the cells were stained with Meyer's hematoxylin solution, and the number of stained cells (the number of corneal cells attached to and detached from SHCL) was counted under a microscope. The number of cells counted was classified according to the evaluation criteria in Table 5, and the degree of cell detachment associated with SHCL removal was evaluated by a score.

Results are shown in FIG. As shown in FIG. 6, the test liquid of Comparative Example 5 had almost no effect of suppressing cell detachment. On the other hand, when treated with the test solution of Example 5 containing dibutylhydroxytoluene, it was revealed that the number of cells attached to and detached from SHCL when the SHCL was removed from the eyeball surface could be significantly reduced.

Formulation Example With the formulation shown in Table 6, SHCL eye drops (Examples 6-10) are prepared.

Claims (1)

An ophthalmic composition for a silicone hydrogel contact lens, containing at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole.

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