JP2011219445A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ophthalmic composition capable of inhibiting the adhesion of Acanthamoeba castellanii to cornea.SOLUTION: This ophthalmic composition capable of inhibiting the adhesion of the Acanthamoeba castellanii to the cornea can be prepared by using (A) glutathione and (B) a biguanide-based bactericide simultaneously.

Description

  The present invention relates to an ophthalmic composition that can suppress adhesion of Acanthamoeba to the cornea. The present invention also relates to a method for suppressing adhesion of an Acanthamoeba to the cornea. Furthermore, the present invention relates to a method for improving glutathione stability and a method for suppressing lipid adsorption to contact lenses.

Acanthamoeba corneal infection (Ameba keratitis) is a corneal infection caused by Acanthamoeba (for example, Acanthamoeba castellanii , Acanthamoeba polyphaga, etc.) infecting the cornea, and is an intractable corneal disease that leaves strong turbidity in the cornea. Most people with Acanthamoeba corneal infection have experienced contact lens wear, and the use of contact lenses with Acanthamoeba has been found to be the main cause of infection.

  Conventionally, there are no specific medicines and antifungal agents have been used for the treatment of Acanthamoeba corneal infection, but in some cases, further treatment for scraping the infected corneal surface is required. In addition, the cure of Acanthamoeba corneal infection may take a long period of several months, and if it is not cured, corneal transplantation may be forced. As described above, once an Acanthamoeba corneal infection is affected, it is difficult to cure the Acanthamoeba corneal infection. Therefore, it is considered important to prevent Acanthamoeba corneal infection.

  So far, contact lens solution compositions containing predetermined amounts of proteolytic enzymes, anionic surfactants, non-reducing polyhydric alcohols, boric acid buffering agents, and water-soluble polymer compounds have been effective in disinfecting Acanthamoeba. Has been reported (see, for example, Patent Document 1). It has also been reported that polylysine is effective for disinfecting Acanthamoeba against contact lenses other than highly hydrous / ionic hydrous soft contact lenses (Group 4 lenses) (see Patent Document 2). However, the techniques described in Patent Documents 1 and 2 are performed only for the purpose of disinfecting Acanthamoeba, and do not suppress the adhesion of Acanthamoeba to the cornea. Even if disinfection is performed on contact lenses with acanthamoeba, if the disinfection effect is not sufficiently obtained due to insufficient disinfection, for example, the acanthamoeba adhering to the contact lens comes into contact with the cornea, and amoeba keratitis May cause. In particular, since the multi-purpose solution for contact lenses is a preparation that directly contacts the cornea via the contact lens, the type and concentration of the bactericidal agent to be blended is limited to a range that does not adversely affect the cornea. Therefore, in order to prevent Acanthamoeba corneal infection more effectively, it is important to suppress the adhesion of Acanthamoeba to the cornea in addition to disinfection of Acanthamoeba.

  Under such background of the prior art, development of an ophthalmic composition capable of suppressing adhesion of Acanthamoeba to the cornea has been eagerly desired.

  On the other hand, glutathione is composed of an oligopeptide in which glutamic acid, cysteine and glycine are linked by peptide bonds from the N-terminal side, and has a thiol group as an electron donor, and reduced glutathione. A form of oxidized glutathione in which two molecules are linked by a disulfide bond is known. Glutathione exists mainly as a reduced form in vivo. Conventionally, glutathione has been used in various ophthalmic applications. For example, reduced glutathione is used for the prevention and treatment of early senile cataract, corneal ulcer, corneal epithelial detachment, keratitis, etc., and oxidized glutathione is used during ophthalmic surgery such as cataract, vitreous, and glaucoma. It is used for internal and extraocular cleaning and eye perfusion.

  In addition, biguanide fungicides such as polyhexanide and salts thereof are known to have a disinfecting action and are used in ophthalmic compositions (see Patent Document 3).

  However, regarding glutathione, no influence on the adhesion of Acanthamoeba to the cornea has been clarified. In addition, when glutathione and a biguanide fungicide are used in combination, the effect on the adhesion of the amoeba to the cornea cannot be inferred.

JP 2003-57610 A JP 2002-143277 A JP 2001-501605 A

  An object of the present invention is to provide an ophthalmic composition capable of suppressing adhesion of Acanthamoeba to the cornea.

  As a result of intensive studies to solve the above problems, the present inventors have surprisingly found that an ophthalmic composition using a biguanide fungicide such as polyhexanide and / or a salt thereof together with glutathione is applied to the cornea. It was found that the adhesion of Acanthamoeba can be effectively suppressed. Furthermore, as a result of investigations by the present inventors, surprisingly, a monomer having at least one biguanide residue, a polymer composed of the monomer, and / or a biguanide fungicide which is a salt form thereof, It has been found that the stability of glutathione can be improved by using it in combination with glutathione. Furthermore, the present inventors have a specific problem that nonionic silicone hydrogel contact lenses (hereinafter sometimes referred to as nonionic SHCL) easily adsorb lipids, but glutathione and biguanide series It has also been found that by using a fungicide in combination, the adsorption of lipids to nonionic SHCL can be suppressed. The present invention has been completed by further studies based on this finding.

That is, this invention provides the ophthalmic composition of the aspect hung up below.
Item 1-1. An ophthalmic composition comprising (A) glutathione and (B) a biguanide fungicide.
Item 1-2. Item 5. The ophthalmic composition according to Item 1-1, which contains oxidized glutathione as the component (A).
Item 1-3. The ophthalmic composition according to Item 1-1 or 1-2, wherein the content ratio of the component (A) is 0.0001 to 2 w / v%.
Item 1-4. Item 4. The ophthalmic composition according to any one of Items 1-1 to 1-3, which comprises at least one selected from the group consisting of polyhexanide and a salt thereof as component (B).
Item 1-5. Item 5. The ophthalmic composition according to any one of Items 1-1 to 1-4, comprising as component (B) at least one selected from the group consisting of a compound represented by the following general formula (1) and a salt thereof.

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

Item 1-6. Item 5. The ophthalmic composition according to Item 1-5, wherein in Formula (1), R ₁ is an amino group, and R ₂ is a group represented by Formula (2).
Item 1-7. Item 7. The ophthalmic composition according to any one of Items 1-1 to 1-6, comprising polyhexanide hydrochloride as the component (B).
Item 1-8. The ophthalmic composition according to any one of Items 1-1 to 1-7, wherein the content of component (B) is 0.000005 to 0.002 w / v%.
Item 1-9. Item 9. The ophthalmic composition according to any one of Items 1-1 to 1-8, which has a pH of 4.0 to 9.5.
Item 1-10. Item 10. The ophthalmic composition according to any one of Items 1-1 to 1-9, which is an ophthalmic composition for contact lenses.
Item 1-11. The ophthalmic composition according to any one of Items 1-1 to 1-10, which is a contact lens care agent.
Item 1-12. The ophthalmic composition according to any one of Items 1-1 to 1-11, which is an ophthalmic composition for soft contact lenses.
Item 1-13. The ophthalmic composition according to any one of Items 1-1 to 1-12, which is an agent for soft contact lens care.
Item 1-14. Item 14. The ophthalmic composition according to any one of Items 1-1 to 1-13, which is an ophthalmic composition for nonionic silicone hydrogel contact lenses.
Item 1-15. Item 15. The ophthalmic composition according to any one of Items 1-1 to 1-14, which is a nonionic silicone hydrogel contact lens care agent.

The present invention also provides a method for suppressing adhesion of Acanthamoeba to the cornea as described below.
Item 2. (A) Glutathione and (B) Biguanide fungicide are used together, The method of suppressing the adhesion | attachment of the acanthamoeba to a cornea characterized by the above-mentioned.

The present invention also provides a method for imparting an ophthalmic composition with the action of suppressing the adhesion of Acanthamoeba to the cornea as described below.
Item 3. A method for imparting an action of suppressing the adhesion of Acanthamoeba to the cornea to the ophthalmic composition, which comprises blending (A) glutathione and (B) a biguanide fungicide in the ophthalmic composition.

The present invention also provides a method for improving the stability of glutathione listed below.
Item 4. A method for improving the stability of glutathione, which comprises using (A) glutathione and (B) a biguanide fungicide in combination.

In addition, the present invention provides a method for imparting an action for improving the stability of glutathione listed below to an ophthalmic composition.
Item 5. (A) A method of imparting an action of improving the stability of glutathione to the composition, which comprises blending a biguanide fungicide with a composition containing glutathione.

Moreover, this invention provides the suppression method of the lipid adsorption | suction to the nonionic SHCL hung up below.
Item 6. A method for suppressing the adsorption of lipids to nonionic SHCL, comprising contacting an ophthalmic composition containing (A) glutathione and (B) a biguanide fungicide with nonionic SHCL.

The present invention also provides a method for imparting an ophthalmic composition with the action of suppressing lipid adsorption to the nonionic SHCL listed below.
Item 7. A method for imparting to an ophthalmic composition an action of suppressing adsorption of lipids to nonionic SHCL, which comprises blending (A) glutathione and (B) a biguanide fungicide in the ophthalmic composition.

  According to the ophthalmic composition of the present invention, since the adhesion of Acanthamoeba to the cornea can be suppressed, Acanthamoeba corneal infection can be prevented. Contact lenses are also said to be the source of Acanthamoeba corneal infection. According to the ophthalmic composition of the present invention, even if the disinfection is insufficient and the contact lens with the acanthamoeba still attached is worn, the adhesion of the acanthamoeba to the cornea can be suppressed. Can reduce the risk of Acanthamoeba corneal infection.

  Furthermore, according to the ophthalmic composition of the present invention, glutathione can be stably maintained, so that even when stored for a long period of time, other effects of the present invention are effectively exhibited without impairing the desired activity of glutathione. Can be made. Further, according to the ophthalmic composition of the present invention, since glutathione can be stabilized regardless of whether it is oxidized or reduced, there is an advantage in that various formulation designs are possible.

  In addition, non-ionic SHCL has a unique problem that lipids are easily adsorbed by studies by the present inventors. Lipid adsorption can cause problems such as cloudiness and reduced vision correction. However, according to the ophthalmic composition of the present invention, lipid adsorption to such nonionic SHCL can be remarkably suppressed. Therefore, according to the ophthalmic composition of the present invention, non-ionic SHCL lipid stains can be prevented, non-ionic SHCL cloudiness and the like can be maintained, and the non-ionic SHCL original vision correction power can be maintained. In addition, corneal epithelial disorders such as corneal staining caused by lipid adsorption to nonionic SHCL can be effectively prevented, and nonionic SHCL can be used comfortably and safely.

In Test Example 3, it is a figure which shows the result of having evaluated the stability of the reduced glutathione contained in a test liquid (Example 3-7, Comparative Example 4-5). In the reference test example 1, it is a figure which shows the result of having evaluated the adsorption | suction characteristic of the lipid in various soft contact lenses. In Test Example 4, it is a figure which shows the result of having evaluated the influence which acts on adsorption | suction of the lipid to nonionic SHCL about a test liquid (Example 8-9 and Comparative Example 6-9).

1. Ophthalmic Composition The ophthalmic composition of the present invention contains glutathione (hereinafter sometimes simply referred to as component (A)).

  Glutathione is a known compound composed of an oligopeptide in which glutamic acid, cysteine and glycine are bound by a peptide bond. The glutathione used in the present invention may be synthesized by a known method or may be obtained as a commercial product.

  There are two forms of glutathione: reduced glutathione (GSH) having a thiol group as an electron donor and oxidized glutathione (GSSG) in which two molecules of reduced glutathione are linked by a disulfide bond. When simply described as “glutathione” in the present specification, it means both reduced glutathione and oxidized glutathione. In the present invention, any one of oxidized glutathione and reduced glutathione may be used alone or in combination. From the viewpoint of further enhancing the action of suppressing the adhesion of Acanthamoeba to the cornea, preferably oxidized glutathione is used.

  In the ophthalmic composition of the present invention, the content ratio of the component (A) is appropriately set according to the type of the component (A), the type of the component (B) to be used together, the formulation form of the ophthalmic composition, etc. As an example, the total amount of the component (A) is 0.0001 to 2 w / v%, preferably 0.0005 to 1 w / v%, more preferably 0.001 to 0.2 w / v with respect to the total amount of the ophthalmic composition. Examples are v%, particularly preferably 0.001 to 0.02 w / v%.

  The content ratio of the component (A) is preferable from the viewpoint of further enhancing the action of suppressing the adhesion of Acanthamoeba to the cornea, and further improving the stability of glutathione or suppressing the adsorption of lipid to nonionic SHCL. It is also suitable from the viewpoint of further enhancement.

  The ophthalmic composition of the present invention contains a biguanide fungicide in addition to the component (A). The biguanide fungicide is a monomer having at least one biguanide group [—NHC (═NH) NHC (═NH) NH—], a polymer composed of the monomer, and a fungicide known as a salt form thereof. It can be produced by a known method or can be obtained as a commercial product.

  The biguanide fungicide used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, and is selected from the group consisting of, for example, polyhexanide and salts thereof. At least one (hereinafter also referred to as component (B)). Polyhexanide is sometimes referred to as polyhexamethylene biguanide or PHMB. Thus, by using the components (A) and (B) in combination, it is possible to remarkably suppress the adhesion of the Acanthamoeba to the cornea. Further, the combined use of the components (A) and (B) makes it possible to improve the stability of the component (A) and to effectively suppress the adsorption of lipids to nonionic SHCL.

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

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

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

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

  In the ophthalmic composition of the present invention, as the component (B), one kind of biguanide fungicide may be used alone, or two or more kinds may be used in any combination. . Among the components (B), from the viewpoint of further enhancing the action of inhibiting the adhesion of Acanthamoeba to the cornea, preferably polyhexanide and / or a salt thereof, more preferably polyhexanide represented by the general formula (1) or an inorganic acid salt thereof, Particularly preferred is polyhexanide represented by the general formula (1) or a hydrochloride thereof, and particularly preferred is a polyhexanide hydrochloride represented by the general formula (1). The component (B) exemplified here is also preferable from the viewpoint of further enhancing the stability of glutathione or further enhancing the lipid adsorption inhibiting action on nonionic SHCL.

  In the ophthalmic composition of the present invention, the content 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, the formulation form of the ophthalmic composition, etc. As an example, the total amount of the component (B) is 0.000005 to 0.002 w / v%, preferably 0.00001 to 0.001 w / v%, more preferably 0.00005 to 0.001 w / v% with respect to the total amount of the ophthalmic composition. The

  The content ratio of the component (B) is suitable from the viewpoint of further enhancing the action of suppressing the adhesion of Acanthamoeba to the cornea, and further improving the stability of glutathione or suppressing the adsorption of lipid to nonionic SHCL. It is also suitable from the viewpoint of further enhancement.

  Further, in the ophthalmic composition of the present invention, the ratio of the component (B) to the component (A) is not particularly limited, but from the viewpoint of further enhancing the action of suppressing the adhesion of Acanthamoeba to the cornea ( The total amount of the component (B) is 0.00001 to 1 part by weight, preferably 0.0001 to 0.2 parts by weight, more preferably 0.0005 to 0.1 parts by weight, and particularly preferably 0.001 to 0.06 parts by weight per 1 part by weight of the total amount of the component (A). This range is exemplified. The ratios exemplified here are also suitable from the viewpoint of further enhancing the stability of glutathione or further enhancing the lipid adsorption inhibiting action on nonionic SHCL.

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

  When a buffering agent is blended in the ophthalmic composition of the present invention, the content of the buffering agent depends on the type of buffering agent used, the type and content of other blending components, the formulation form of the ophthalmic composition, etc. However, for example, the total amount of the buffer is 0.01 to 10 w / v%, preferably 0.1 to 5 w / v%, based on the total amount of the ophthalmic composition. More preferably, the ratio is 0.2 to 2 w / v%.

  The ophthalmic composition of the present invention may further contain a surfactant. The surfactant that can be blended in the ophthalmic composition 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 amphoteric surfactant, an anionic surfactant, and a cationic surfactant may be used.

  Specific examples of the nonionic surfactant that can be blended in the ophthalmic composition of the present invention include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), mono POE sorbitan fatty acid esters such as stearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); poloxamer 407, poloxamer 235 POE / POP block copolymers such as Poloxamer 188, Poloxamer 403, Poloxamer 237 and Poloxamer 124; POE hydrogenated castor oil such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE (9) lauryl POE alkyl ethers such as ether; POE (20) POP (4) POE-POP alkyl ethers such as cetyl ether; POE (1 0) 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 of the present invention include alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride). Specific examples of the cationic surfactant that can be blended in the ophthalmic composition of the present invention include benzalkonium chloride and benzethonium chloride. Examples of the anionic surfactant that can be blended in the ophthalmic composition of the present invention include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, aliphatic α-sulfomethyl ester, Examples include α-olefin sulfonic acid.

  In the ophthalmic composition of the present invention, the above 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 oil, or POE / POP block copolymers; more preferably polysorbate 80, polyoxyethylene cured Castor oil 60 and Poloxamer 407 are used.

  When a surfactant is blended in the ophthalmic composition of the present invention, the content of the surfactant is, for example, the type of the surfactant, the type and content of other blended components, the formulation form of the ophthalmic composition, etc. It can be set appropriately according to. As an example of the content 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 / v% based on the total amount of the ophthalmic composition. More preferably, 0.01 to 0.5 w / v% is exemplified.

  The ophthalmic composition of the present invention may further contain an isotonic agent. The isotonic agent that can be incorporated into the ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such 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, preferably, glycerin, propylene glycol, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride are mentioned, more preferably sodium chloride or glycerin is mentioned, and sodium chloride is particularly preferred. Can be mentioned. These isotonic agents may be used alone or in any combination of two or more.

  When a tonicity agent is added to the ophthalmic composition of the present invention, the content of the tonicity agent varies depending on the type of tonicity agent used and cannot be uniformly defined. For example, the ratio by which 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 total is exemplified.

  The pH of the ophthalmic composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. As an example of the pH of the ophthalmic composition of the present invention, 4.0-9.5, preferably 5.0-9.0, more preferably 6.2-8.5, particularly preferably 6.5-8. The range becomes.

  Further, the osmotic pressure of the ophthalmic composition of the present invention is not particularly limited as long as it is within a range acceptable for a living body. An example of the osmotic pressure ratio of the ophthalmic composition of the present invention is preferably in the range of 0.3 to 5.0, more preferably 0.4 to 3.0, and particularly preferably 0.5 to 1.5. . 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 of the present invention may contain an appropriate amount of a combination of various pharmacologically active ingredients and physiologically active ingredients in addition to the above ingredients, as long as the effects of the present invention are not hindered. Such an ingredient is not particularly limited, and examples thereof include an active ingredient in an ophthalmic drug described in the over-the-counter drug manufacturing (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee). Specifically, the following components are listed as components used in ophthalmic drugs.
Antihistamines: for example, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, pemirolast potassium and the like.
Decongestant: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.
Bactericides: for example, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate and the like.
Amino acids: For example, potassium aspartate, magnesium aspartate 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.
Other: For example, sodium cromoglycate, sodium chondroitin sulfate, sodium hyaluronate, sulfamethoxazole, sodium sulfamethoxazole and the like.

In addition, in the ophthalmic composition of the present invention, various additives are appropriately selected according to a conventional method according to the use and the form of the preparation, as long as the effects of the invention are not impaired. An appropriate amount may be contained in combination. 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.
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 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, Glow Kill (trade name, manufactured by Rhodia) and the like.
pH adjuster: for example, hydrochloric acid, boric acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, borax, 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 and the like.
Stabilizers: for example, dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate and the like.

  The ophthalmic composition of the present invention is prepared by adding a desired amount of the above components (A) and (B) and, if necessary, other blending components so as to have a desired content ratio.

  The ophthalmic composition of the present invention is not particularly limited as long as it can be used in the ophthalmic field, and examples thereof include liquid forms and ointments. Among these, liquid is preferable. Of the liquids, aqueous liquids are preferred. When the 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. Examples thereof include distilled water, ordinary water, purified water, sterilized purified water, water for injection, and distilled water for injection. These definitions are based on the 15th revision 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, Preferably, it means one containing 50% by weight or more.

  If the ophthalmic composition of this invention is used in the ophthalmic field | area, it will not restrict | limit about the formulation form. For example, eye drops (including eye drops for contact lenses), eye wash (including eye drops for contact lenses), contact lens mounting liquid, contact lens care liquids (contact lens disinfecting liquid, contact lens preserving liquid, contact lens cleaning liquid) Contact lens cleaning / preserving solution, contact lens disinfecting / cleaning / preserving solution (multipurpose solution), and the like. In particular, Acanthamoeba corneal infection is most affected among contact lens wearers, and the contact lens wearer is strongly required to suppress the adhesion of Acanthamoeba to the cornea. Therefore, as a suitable formulation form of the ophthalmic composition of the present invention, eye drops for contact lenses (eye drops that can be used while wearing contact lenses), eye wash for contact lenses (eye drops that can be used while wearing contact lenses) Agent), contact lens mounting liquid, contact lens care ophthalmic composition and the like. Among them, the contact lens care agent is capable of exerting the effects of the present invention more remarkably because it comes into contact with the cornea in a state where the preparation is attached to the front and back of the contact lens. Particularly preferred. In particular, a contact lens disinfecting / cleaning / preserving solution (multipurpose solution) is a preparation that directly contacts the cornea via a contact lens because the contact lens is disinfected, cleaned, and stored in one solution. Therefore, the type and concentration of the disinfectant to be blended must be limited to a range that does not impair the safety, and in order to obtain a sufficient disinfecting power, it is important to observe the disinfecting time, rubbing and other usage methods. ing. However, in reality, the usage method may not be observed, and as a result, sufficient disinfecting power may not be obtained. Therefore, contact lens disinfecting / cleaning / preserving solution is very important to prevent Acanthamoeba keratitis by suppressing adhesion of Acanthamoeba, and is particularly suitable as a preparation form of the ophthalmic composition of the present invention.

  In the present invention, the contact lens includes any of a soft contact lens, a hard contact lens, and an oxygen permeable hard contact lens. Soft contact lenses include both ionic and non-ionic, and include both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses (soft contact lenses that are not silicone hydrogel lenses). Acanthamoeba corneal infection often affects soft contact lens wearers among contact lens wearers, and there is a strong demand for soft contact lens wearers to suppress the adhesion of Acanthamoeba to the cornea. Therefore, the ophthalmic composition for soft contact lenses (that is, the ophthalmic composition for contact lenses in which the application target lens is a soft contact lens) is preferable as the formulation form of the ophthalmic composition of the present invention.

  In addition, when the ophthalmic composition of the present invention is made into a pharmaceutical contact lens ophthalmic composition, the water content of the soft contact lens to be applied is not particularly limited, and is, for example, 90% or less, preferably 60%. Hereinafter, 50% or less is more preferable. The water content exemplified here is also suitable from the viewpoint of lipid adsorption inhibiting action. Note that the soft contact lens contains at least more than 0% moisture.

  Here, the moisture content of the soft contact lens indicates the ratio of water in the soft contact lens, and is specifically obtained by the following calculation formula.

Moisture content (%) = (weight of water contained / weight of soft contact lens in water content) x 100
Such moisture content can be measured by a gravimetric method according to the description of ISO18369-4: 2006.

  In addition, when the ophthalmic composition of the present invention is made into a formulation of an ophthalmic composition for soft contact lenses, the application of the soft contact lens to be applied to nonionic SHCL has an effect of suppressing lipid adsorption to the nonionic SHCL. It is also possible to make it. In view of the effects of the present invention, as a preferred embodiment of the ophthalmic composition of the present invention, an ophthalmic composition for nonionic SHCL (that is, an ophthalmic composition for soft contact lenses in which the application target lens is nonionic SHCL). ) Is exemplified. Here, nonionic SHCL means that the ionic component content in the silicone hydrogel contact lens material is less than 1 mol% in accordance with US FDA (US Food and Drug Administration) standards.

  Among soft contact lenses, a silicone hydrogel contact lens made of a hard material is liable to cause deterioration of the feeling of use due to deformation of the lens due to adsorption of foreign matter and a decrease in wettability, and to cause ocular mucosal damage. According to the ophthalmic composition of the present invention, it is possible to effectively suppress lipid accumulation in the nonionic SHCL, which is a hard material that easily causes a deterioration in the feeling of use and ocular mucosal damage. By preventing deterioration, it is possible to effectively prevent deterioration of the feeling of use and ocular mucosal damage. Even in view of the effects of the present invention, a preferred embodiment of the ophthalmic composition of the present invention is a nonionic SHCL ophthalmic composition. Preferably, the hardness of the nonionic SHCL to be applied is 3 g or more when measured by the following measurement method using a texture analyzer. Further, the upper limit value of the hardness of the SHCL to be applied is not particularly limited, but is preferably 15 g or less, more preferably 12 g or less.

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

  First, remove the nonionic SHCL to be measured from the package, wipe off excess water, rinse with physiological saline (0.9% sodium chloride aqueous solution), and then convex on the bottom of the plastic petri dish filled with physiological saline. Is placed so that is at the top. Next, the nonionic SHCL is adjusted to be directly under the probe of the measuring instrument, and measurement is performed under the following measurement conditions.

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

  Since the ophthalmic composition of the present invention can exert the action of suppressing the adhesion of Acanthamoeba to the cornea, it can be used for the prevention of Acanthamoeba corneal infection.

  The ophthalmic composition of the present invention can be used for the prevention and treatment of early senile cataract, corneal ulcer, corneal epithelial detachment, keratitis, etc. based on the action of the component (A).

  In addition, when the ophthalmic composition of the present invention is formulated into a nonionic SHCL composition, corneal epithelial disorders such as corneal staining caused by lipid adsorption to the nonionic SHCL are caused. Since it can prevent effectively, it can also be used as a preventive agent of corneal epithelial disorder.

2. Method for suppressing adhesion of Acanthamoeba to cornea, and method for imparting an action to suppress adhesion of Acanthamoeba to cornea to ophthalmic composition As described above, combined use of the above components (A) and (B) Can suppress adhesion of Acanthamoeba to the cornea.

  Accordingly, the present invention provides a method for suppressing the adhesion of Acanthamoeba to the cornea, characterized by using (A) glutathione and (B) a biguanide fungicide in combination from another viewpoint. Further, the present invention provides the ophthalmic composition with an action of suppressing the adhesion of Acanthamoeba to the cornea, characterized in that (A) glutathione and (B) biguanide fungicide are blended in the ophthalmic composition. A method of granting is also provided.

  In these methods, the types and content ratios of the components (A) and (B) to be used, the types and content ratios of other components, the formulation form of the ophthalmic composition, etc. are described in “1. Ophthalmic composition”. Is the same.

3. A method for improving the stability of glutathione, and a method for imparting an action to improve the stability of glutathione to the composition As described above, by using the components (A) and (B) in combination, in the ophthalmic composition, The stability of glutathione can be improved.

  Therefore, the present invention provides a method for improving the stability of glutathione, characterized in that (A) glutathione and (B) a biguanide fungicide are used in combination. In addition, the present invention provides a method for imparting an action of improving the stability of glutathione to the composition, characterized by comprising (B) a biguanide fungicide in a composition containing (A) glutathione. Also provide.

  In these methods, the types and content ratios of the components (A) and (B) to be used, the types and content ratios of the other components, the formulation form of the composition, etc. are described in “1. Ophthalmic composition”. It is the same.

4). Method for inhibiting lipid adsorption to nonionic SHCL, and method for imparting an action of inhibiting lipid adsorption to nonionic SHCL to an ophthalmic composition As described above, the components (A) and (B) are used in combination. Thus, the adsorption of lipid to nonionic SHCL can be suppressed.

  Therefore, the present invention, from yet another point of view, is characterized by contacting an ophthalmic composition containing (A) glutathione and (B) a biguanide fungicide with a nonionic SHCL. A method for suppressing the adsorption of lipids to SHCL is provided. Further, the ophthalmic composition is provided with an action of suppressing the adsorption of lipids to nonionic SHCL, characterized by comprising (A) glutathione and (B) a biguanide fungicide in the ophthalmic composition. Provide a way to do it.

  In these methods, the types and proportions of components (A) and (B), the types and proportions of other components to be blended, the formulation form of ophthalmic compositions, the types of nonionic SHCL to be applied, etc. Is the same as “1. Ophthalmic composition”.

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

Test Example 1 Acanthamoeba Adhesion Inhibition Test to the Cornea The adhesion inhibitory effect of Acanthamoeba to the cornea was evaluated. Acanthamoeba is known to secrete protease when adhering to the cornea (Claude Anger et al., Eye & Contact Lens, 34 (5): 247-253, 2008). As an index of the adhesion amount of Acanthamoeba, the amount of protease secreted from Acanthamoeba was measured.

The specific test method is as follows. HCE-T cells (Riken Cell Bank, RCB1384), a human corneal epithelial cell, are seeded in a 24-well cell culture plate (Corning) at a cell count of 6 × 10 ⁴ cells / well and 5% FCS (fetal bovine serum) For 72 hours (37 ° C., 5% CO ₂ , relative humidity 90%) in DMEM / F-12 medium (GIBCO). On the day of the test, after confirming that the HCE-T cells were confluent, as a pretreatment, the culture supernatant was treated with serum-free DMEM / F-12 medium containing 0.4% BSA (bovine serum albumin) (Sigma Aldrich). And incubated for 1 hour (37 ° C., 5% CO ₂ , 90% relative humidity).

Separately, in DMEM / F-12 medium, Acanthamoeba castellanii (ATCC30868) of 1.25 × 10 ⁵ cells / ml and polyhexanide hydrochloride and / or oxidized glutathione so that the final concentration is as shown in Table 1. Were mixed and incubated at room temperature for 30 minutes to prepare a test solution (pH 7.4 to 7.6). The medium in each well of the 24-well cell culture plate containing HCE-T cells prepared above was replaced with 0.5 ml of the above test solution, and cultured for 24 hours at 37 ° C., 5% CO ₂ , and 90% relative humidity. . After the culture, the protease secreted from Acanthamoeba was quantified in the test solution. For the measurement of protease, Fluorescent Protease Assay Kit (Thermo Scientific) was used. The measurement method is to mix the sample (test medium after culture) and the substrate FITC-casein (supplied with the kit above) 50 μl at a time and incubate at room temperature for 60 minutes under light-shielded conditions. It was measured. The fluorescence was measured using a fluorescence spectrophotometer (Fluoroskan Ascent CF) at a measurement wavelength of excitation 485 nm / fluorescence 538 nm. The activity of the protease secreted from Acanthamoeba in the test sample is determined by referring to the amount of fluorescence of the substrate degradation product at each concentration of TPCK-Trypsin (supplied with the above kit), which is a standard protease. Calculated as (ng / ml). As a control, a TPCK-Trypsin equivalent protease concentration was calculated by conducting a test under the same conditions as described above except that a DMEM / F-12 medium in which neither polyhexanide hydrochloride nor oxidized glutathione was mixed was used.

  The adhesion inhibition rate of Acanthamoeba was calculated according to the following formula.

  The obtained results are shown in Table 1. From this result, the combined use of oxidized glutathione and polyhexanide hydrochloride synergistically suppresses the adhesion of acanthamoeba to the cornea compared to the use of oxidized glutathione alone or polyhexanide hydrochloride alone. It has been clarified that the effect of suppressing the adhesion of Acanthamoeba to the cornea is excellent.

Test Example 2 Stability Evaluation Test of Oxidized Glutathione In order to evaluate the stability of oxidized glutathione, the following tests were performed using the test solutions shown in Table 2 (Example 2 and Comparative Example 3).

  Test solutions shown in Table 2 were prepared, and each test solution was filled in 5 mL in a 10 mL headspace vial and stored under light-shielding conditions at 70 ° C. for 7 days.

  Before and after storage, the concentration of oxidized glutathione contained in the test solution was measured by HPLC, and the stability improvement rate of oxidized glutathione was calculated according to the following formula.

  The obtained results are also shown in Table 2. In the test solution (Example 2) in which oxidized glutathione and polyhexanide hydrochloride are used in combination, the decomposition of oxidized glutathione is suppressed as compared with the case of containing oxidized glutathione alone (Comparative Example 3). It was confirmed that glutathione was stably maintained.

Test Example 3 Stability Evaluation Test of Reduced Glutathione In order to evaluate the stability of reduced glutathione, the following tests were conducted using the test solutions shown in Table 3 (Example 3-7, Comparative Example 4-5). went.

  Test solutions shown in Table 3 were prepared, and each test solution was filled in 5 mL in a 10 mL headspace vial and stored under light-shielding conditions at 70 ° C. for 24 hours.

  Before and after storage, the concentration of reduced glutathione contained in the test solution was measured by HPLC, and the residual ratio of reduced glutathione was calculated according to the following formula.

  The obtained results are shown in FIG. In the test solution containing the reduced glutathione alone (Comparative Example 4-5), it was observed that the reduced glutathione was significantly degraded. On the other hand, in the test solution (Example 3-7) in which reduced glutathione and polyhexanide hydrochloride were used in combination, it was confirmed that the decomposition of reduced glutathione was suppressed and the reduced glutathione was stably held. It was. From the above results, it was revealed that the combined use of reduced glutathione and polyhexanide can improve the stability of reduced glutathione regardless of pH.

Reference Test Example 1: Evaluation of lipid adsorption property of various SCLs The following experiments were conducted using various soft contact lenses shown in Table 4 to evaluate the lipid adsorption property of the soft contact lenses. The soft contact lenses used in this test are all commercially available products.

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

  The results are shown in FIG. As is apparent from FIG. 2, the lipid adsorption amount of nonionic SHCL (lenses A and B) is compared with that of ionic silicone hydrogel contact lens (lens C) and conventional hydrogel lenses (lenses D to F). As a result, it was confirmed that the problem of lipid contamination was serious.

Test Example 4: Nonionic SHCL Lipid Adsorption Inhibition Evaluation Using the nonionic SHCL (Lens A) in which significant lipid adsorption was observed in Reference Test Example 1 above, each test solution shown in Table 5 below (Example 8- 9 and Comparative Examples 6-9) were used to examine the effect of nonionic SHCL on lipid adsorption.

  First, a 1 mg / ml chloroform solution of methanol (N- (fluorescein-5-thiocarbamoyl) -1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt; manufactured by invitrogen) and methanol is used 1: A physiological saline solution (0.9 w / v% sodium chloride) was added to 500 μL of the mixed solution mixed at a volume ratio of 4, and a total volume of 20 ml was prepared as a fluorescent lipid solution. Lens A was immersed in physiological saline for one night or longer and pre-test treatment was performed. Next, a well in which 200 μL of each test solution (Examples 8-9 and Comparative Example 6-9) and 1000 μL of a fluorescent lipid solution were placed in each well of a 24-well microplate was prepared, and the test pretreatment was completed therein. Each lens A was immersed one by one and shaken at 34 ° C. for 24 hours (sample group). In addition, a well containing 200 μL of each test solution (Examples 8-9 and Comparative Examples 6-9) and 1000 μL of physiological saline was prepared as a blank group, and a lens A that had undergone pre-test treatment was placed therein. The pieces were soaked one by one and similarly subjected to a shaking treatment (blank group). After 24 hours, each lens A after the shaking treatment was transferred to a plate containing 1 ml of new physiological saline, and the fluorescence intensity of each well was measured using a fluorescence plate reader (Thermo Fisher Scientific Inc.) ( Excitation wavelength: 485 nm, fluorescence wavelength: 538 nm). The value obtained by subtracting the fluorescence intensity of the blank group from the fluorescence intensity of each sample group is obtained as an index of the amount of adsorbed lipid, and the amount of adsorbed lipid of each test solution when the amount of adsorbed lipid of the test solution of Comparative Example 6 is 100%. The relative value (%) was calculated.

  The obtained results are shown in FIG. From this result, it became clear that the combined use of oxidized or reduced glutathione and polyhexanide hydrochloride provides an excellent lipid adsorption suppression effect.

Formulation Example A contact lens disinfecting / cleaning / preserving solution (multipurpose solution) (Examples 10-15) is prepared according to the formulation shown in Table 6.

Claims (9)

  An ophthalmic composition comprising (A) glutathione and (B) a biguanide fungicide.   The ophthalmic composition according to claim 1, which contains oxidized glutathione as the component (A).   The ophthalmic composition according to claim 1 or 2, comprising as component (B) at least one selected from the group consisting of polyhexanide and salts thereof. The ophthalmic composition according to any one of claims 1 to 3, comprising as component (B) at least one selected from the group consisting of a compound represented by the following general formula (1) and a salt thereof.

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

The ophthalmic composition according to claim 4, wherein in formula (1), R ₁ is an amino group, and R ₂ is a group represented by general formula (2).   The ophthalmic composition according to any one of claims 1 to 5, wherein the content ratio of the component (A) is 0.0001 to 2 w / v%.   The ophthalmic composition according to any one of claims 1 to 6, wherein the content of component (B) is 0.000005 to 0.002 w / v%.   The ophthalmic composition according to any one of claims 1 to 7, which is an ophthalmic composition for contact lenses.   The ophthalmic composition according to any one of claims 1 to 8, which is a contact lens care agent.

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