WO2023140275A1 - Antifungal eye drop - Google Patents
Antifungal eye drop Download PDFInfo
- Publication number
- WO2023140275A1 WO2023140275A1 PCT/JP2023/001285 JP2023001285W WO2023140275A1 WO 2023140275 A1 WO2023140275 A1 WO 2023140275A1 JP 2023001285 W JP2023001285 W JP 2023001285W WO 2023140275 A1 WO2023140275 A1 WO 2023140275A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polyoxyethylene
- hydrogenated castor
- castor oil
- ophthalmic solution
- polyoxypropylene glycol
- Prior art date
Links
- 239000003889 eye drop Substances 0.000 title claims abstract description 101
- 230000000843 anti-fungal effect Effects 0.000 title abstract description 10
- 229940121375 antifungal agent Drugs 0.000 title abstract description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 96
- -1 polyoxyethylene Polymers 0.000 claims abstract description 68
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 58
- YTAOBBFIOAEMLL-REQDGWNSSA-N Luliconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@H](CS\1)SC/1=C(\C#N)N1C=NC=C1 YTAOBBFIOAEMLL-REQDGWNSSA-N 0.000 claims abstract description 54
- 229960000570 luliconazole Drugs 0.000 claims abstract description 54
- 239000004359 castor oil Substances 0.000 claims abstract description 48
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 235000019438 castor oil Nutrition 0.000 claims abstract description 45
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 45
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims abstract description 44
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims abstract description 42
- 235000019445 benzyl alcohol Nutrition 0.000 claims abstract description 14
- 229940012356 eye drops Drugs 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 46
- 239000002997 ophthalmic solution Substances 0.000 claims description 39
- 229940054534 ophthalmic solution Drugs 0.000 claims description 39
- 229920001451 polypropylene glycol Polymers 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 8
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- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 239000002562 thickening agent Substances 0.000 claims description 4
- 239000002826 coolant Substances 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
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- 235000010384 tocopherol Nutrition 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Definitions
- the present invention relates to eye drops containing luliconazole as an active ingredient.
- Luliconazole has excellent antifungal activity in the field of dermatology, and is marketed as a therapeutic agent for tinea pedis (trade name Lulicon) and a therapeutic agent for tinea unguium (trade name Luconac). Luliconazole is known to exhibit excellent antifungal activity against a wide range of fungi such as Aspergillus, Fusarium, Candida, Scitalidium and Malassezia in addition to Trichophyton (mainly Trichophyton) (see, for example, Patent Documents 1 to 5).
- Lulicon Liquid 1% which is a liquid preparation containing luliconazole as an active ingredient, consists of medium-chain fatty acid triglycerides and Macrogol 400 (solubilizer), methyl ethyl ketone (solubilizer), phosphoric acid (pH adjuster), and absolute ethanol (solvent), and does not contain water.
- Luconac Topical Nail Solution 5% Another liquid formulation containing luliconazole as an active ingredient, Luconac Topical Nail Solution 5%, consists of N-methyl-2-pyrrolidone, benzyl alcohol, diisopropyl adipate, lactic acid, povidone and absolute ethanol. Therefore, no drug containing water has been developed so far as a liquid formulation containing luliconazole as an active ingredient.
- Mycoses in the field of ophthalmology are caused by various fungi, and it is necessary to identify the causative bacterium in order to select an appropriate therapeutic agent. However, if it is possible to prescribe drugs that are effective against a wide range of fungi without identifying the causative bacterium, rapid treatment will be possible, and its social significance is great.
- an object of the present invention is to find an appropriate combination of surfactants for formulating luliconazole, which has low water solubility, as a water-based formulation, including aqueous eye drops.
- the present inventors have made intensive studies to overcome the above problems, and as a result, have found that a combination of benzyl alcohol and a specific surfactant can dissolve luliconazole and form a desired ophthalmic formulation, thus completing the present invention. That is, the present invention [1] eye drops containing 1) luliconazole, 2) benzyl alcohol, and 3) one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil; [2] The ophthalmic solution according to [1], wherein the content of luliconazole is 0.03 to 0.8 w/v% of the total ophthalmic solution.
- the content of luliconazole is 0.05 to 0.5 w/v% of the entire eye drop
- the content of benzyl alcohol is 2.0 to 5.2 w/v% of the entire eye drop
- the content of polyoxyethylene polyoxypropylene glycol is 2.0 to 20 w/v% of the entire eye drop
- the content of polyoxyethylene hydrogenated castor oil is 1.0 to 20 w/v% of the entire eye drop.
- ophthalmic solution according to [7] 3) The ophthalmic solution according to any one of [1] to [6], which contains polyoxyethylene polyoxypropylene glycol as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, wherein the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (200) polyoxypropylene glycol (70); [8] 3) The ophthalmic solution according to any one of [1] to [7], which contains polyoxyethylene hydrogenated castor oil as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60; [9] The ophthalmic solution according to any one of [1] to [8], wherein the ophthalmic solution is an aqueous ophthalmic solution; [10] The ophthalmic solution according to any one of [1] to [9], further comprising one or more additives selected from thickeners
- the ophthalmic solution according to any one of [1] to [10], which is a therapeutic agent for mycoses in the field of ophthalmology [12] The method for producing an eye drop according to any one of [1] to [11], characterized by adding one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil diluted with purified water to a solution obtained by dissolving luliconazole in benzyl alcohol, and further diluting with purified water.
- the present invention it is possible to provide a water-based antifungal ophthalmic solution, particularly an aqueous ophthalmic solution, containing luliconazole as an active ingredient.
- the ophthalmic solution of the present invention is a water-based agent (e.g., aqueous eyedrops)
- the active ingredient easily repels water and inhibits the absorption of other eyedrops as in oily eyedrops
- the eye drops of the present invention have the effect of enabling efficient delivery of luliconazole, which is an active ingredient, to the affected area, and enabling luliconazole to be used in combination with other eye drops.
- INDUSTRIAL APPLICABILITY According to the present invention, there is provided a water-based formulation such as an eye drop containing luliconazole, which has low water solubility, as an active ingredient. Such formulations are visually clear, water-based formulations.
- preparation of an ophthalmic formulation containing luliconazole as an active ingredient has not even been attempted due to the difficulty of overcoming the low water solubility of luliconazole.
- the above-mentioned effects of the present invention can be said to be remarkable effects that even a person skilled in the art could not have predicted from the prior art.
- the ophthalmic solution of the present invention is an antifungal agent containing luliconazole as an active ingredient, and is characterized by containing benzyl alcohol and one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil as ingredients that increase the water solubility of luliconazole. Ingredients used in the eye drops of the present invention are further described below.
- Luliconazole which is the active ingredient in the eye drops of the present invention, is a chemical compound represented by the following structural formula, represented by the chemical name (R)-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile, and is almost insoluble in water. Its production method and antifungal properties are already known.
- the content of luliconazole in the eye drops of the present invention is not limited, but the content may be 0.01 to 1 mass-to-volume percent concentration (hereinafter referred to as w/v%), preferably 0.03 to 0.8 w/v%, more preferably 0.05 to 0.5 w/v%, relative to the entire eye drop.
- w/v% mass-to-volume percent concentration
- the range specified by the symbol "-" also includes the two numerical values described at both ends of the symbol "-”.
- the present invention provides a water-based antifungal eye drop containing luliconazole as an active ingredient by containing 2) benzyl alcohol, and 3) one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil as ingredients for enhancing the water solubility of luliconazole. It is believed that the above component 3) acts synergistically with 2) benzyl alcohol to increase the water solubility of luliconazole.
- the contents of the above components 2) and 3) are not limited as long as they are amounts that enhance the water solubility of luliconazole, and may be adjusted according to the blending amount of luliconazole. More specifically, it is as follows. 2) Benzyl Alcohol
- the content of benzyl alcohol in the eye drops of the present invention is not limited, but the content may be in the range of 1.0 to 10 w/v%, preferably 1.5 to 7.0 w/v%, more preferably 2.0 to 5.2 w/v%, relative to the entire eye drop.
- the ratio of the content of benzyl alcohol to the content of luliconazole is not limited as long as it is a ratio at which luliconazole dissolves. Such a ratio may be, for example, 10-fold to 40-fold.
- the amount of polyoxyethylene-polyoxypropylene glycol to be added is not limited, but the content is 0.5% relative to the entire eye drop. It may be 1 to 30 w/v%, preferably 1.0 to 25 w/v%, more preferably 2.0 to 20 w/v%.
- the total amount of polyoxyethylene-polyoxypropylene glycols added can be within the ranges described above.
- the amount of polyoxyethylene hydrogenated castor oil added is not limited.
- the added amount can be in the range of 1.0 to 20 w/v%.
- the total amount of polyoxyethylene hydrogenated castor oils to be added may fall within the ranges described above.
- at least one polyoxyethylene polyoxypropylene glycol and at least one polyoxyethylene hydrogenated castor oil may be used in combination.
- the amounts of at least one polyoxyethylene polyoxypropylene glycol and at least one polyoxyethylene hydrogenated castor oil to be added may be within the range of the addition amount of the polyoxyethylene polyoxypropylene glycol and the addition amount of the polyoxyethylene hydrogenated castor oil, respectively.
- the ratio of the content of one or two types selected from 3) polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil to the content of luliconazole is not limited as long as luliconazole is dissolved. Such a ratio may be, for example, 10-fold to 60-fold.
- polyoxyethylene polyoxypropylene glycol there are various types of polyoxyethylene polyoxypropylene glycol depending on the degree of polymerization, and polyoxyethylene (105) polyoxypropylene (5) glycol (the value in parentheses represents the average degree of polymerization; the same shall apply hereinafter), polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, and polyoxy Ethylene (200) polyoxypropylene (70) glycol is exemplified.
- the polyoxyethylene-polyoxypropylene glycol used in the eye drops of the present invention is not limited by the degree of polymerization, and any of the above polyoxyethylene-polyoxypropylene glycols may be used.
- Polyoxyethylene hydrogenated castor oil has various types depending on the degree of polymerization.
- the polyoxyethylene hydrogenated castor oil used in the eye drops of the present invention is not limited by the degree of polymerization, and any of the above polyoxyethylene hydrogenated castor oils may be used.
- polyoxyethylene hydrogenated castor oil 60 sold under the trade name HCO-60 is preferred in the eye drops of the present invention.
- the eye drop of the present invention has a luliconazole content of 0.05 to 0.5 w/v%, a benzyl alcohol content of 2.0 to 5.2 w/v% of the entire eye drop, and a polyoxyethylene polyoxypropylene glycol content of 2.0 to 20 w/v% of the entire eye drop, or a polyoxyethylene hydrogenated castor oil content of 1.0 to 20 w/v% of the entire eye drop.
- luliconazole is preferred because it dissolves more stably.
- ophthalmic solution of the present invention it is preferable to use one or two selected from 3) polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil at a content of about 0.3 to about 4 times the content of 2) benzyl alcohol from the viewpoint of more reliably dissolving luliconazole.
- Eye drops are broadly classified into aqueous eye drops, oily eye drops, and suspension eye drops.
- the eye drops of the present invention are classified into water-based eye drops, such as aqueous eye drops.
- the ophthalmic solution of the present invention contains water, and preferably contains 40 w/v% or more of water, more preferably 60 w/v% or more of water, and even more preferably 70 w/v% or more of water.
- An eye drop containing 40 w/v % or more of water with respect to the entire eye drop is referred to as an aqueous eye drop in the present invention.
- the type of water to be blended in the eye drops of the present invention is not limited, and may be water used in ordinary eye drops.
- Examples of water to be incorporated in the eye drops of the present invention include distilled water, ordinary water, purified water, sterilized purified water, water for injection, and distilled water for injection.
- the eye drops of the present invention can contain additives commonly used for eye drops as long as they do not impair the effects of the present invention.
- the additives may be used singly or in combination of two or more in any ratio.
- Additives include thickeners, sugars, antioxidants, preservatives, solubilizers, pH adjusters, tonicity agents, cooling agents, buffers, stabilizers and the like.
- polyoxyethylene polyoxypropylene glycol or polyoxyethylene hydrogenated castor oil is used as a surfactant, and other surfactants may be used together within a range that does not impair the effects of the present invention.
- Other surfactants include povidone K30, macrogol 4000, polyoxyl stearate 40, polysorbate 80, and polyethylene glycol monostearate (10E.0.). These surfactants, like polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, are nonionic surfactants.
- Thickening agents include carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, alginic acid, polyvinyl alcohol, polyvinylpyrrolidone, macrogol, and the like.
- “Sugars” include glucose, cyclodextrin, xylitol, sorbitol, mannitol, and the like.
- Antioxidants include dibutylhydroxytoluene, butylhydroxyanisole, hydroquinone, propyl gallate, sodium hydrogen sulfite, and the like.
- Preservatives include alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine gluconate hydrochloride, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, etc. are mentioned.
- the ophthalmic solution of the present invention it is preferable to use three components, chlorobutanol, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate, or two components, chlorobutanol and benzalkonium chloride, in combination for the purpose of achieving effective preservative efficacy and improving storage stability.
- the three components of chlorobutanol, ethyl parahydroxybenzoate and propyl parahydroxybenzoate are used together, their contents are preferably 0.25% by mass, 0.013w/v% and 0.007w/v%, respectively, based on the total eye drop.
- Solubilizers include alcohols such as ethanol, polysorbates, poloxamines, alkyldiaminoethylglycine, alkyl quaternary ammonium salts, polyethylene glycol, epsilon aminocaproic acid and propylene glycol.
- Ethanol is particularly preferred in the present invention, and the amount of ethanol to be used may be appropriately selected within the range that can be used for eye drops, but 2.0 to 5.0 volume-to-volume percent concentration (v/v%) is particularly preferable.
- pH adjusters include hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, boric acid, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate (sodium hydrogen phosphate), sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, borax, triethanolamine, monoethanolamine, and the like.
- type of "pH adjuster” in the eye drops of the present invention is not particularly limited, it is preferable to adjust the pH of the eye drops in the range of 5.0 to 7.0 in order to maintain good storage stability of the active ingredient.
- isotonizing agents include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate (sodium hydrogen phosphate), sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, boric acid, glycerin, propylene glycol, and the like.
- Refreshing agents include d-camphor, dl-camphor, geraniol, d-borneol, l-menthol, rhubarb, fennel oil, peppermint water, peppermint oil, bergamot oil, eucalyptus oil, and the like. Peppermint oil and l-menthol are preferred in the present invention.
- Buffers include citrate buffers, acetate buffers, carbonate buffers, borate buffers, phosphate buffers, tartrate buffers, amino acids, and the like.
- Stabilizers include epsilon aminocaproic acid, dibutylhydroxytoluene, trometamol, tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, tetrasodium edetate, sodium edetate, boric acid, and the like.
- Boric acid is preferably used in the eye drops of the present invention.
- the content of boric acid is preferably 0.25 to 1.0 w/v%, particularly preferably 0.35 to 0.7 w/v%, relative to the total eye drop.
- the method of using the ophthalmic solution of the present invention is not limited as long as the intended effect is achieved.
- the eye drops of the present invention can be used by, for example, 1 to 3 drops per time, 2 to 6 times per day, and in an amount of about 30 to about 200 ⁇ L per time, but not limited thereto, and can be used in any dosage and administration.
- the frequency and amount of administration of the eye drops of the present invention may be adjusted in consideration of the age, body weight, condition, therapeutic purpose, and the like of the subject to be administered.
- the ophthalmic solution of the present invention may be used by spraying, or may be applied to the affected area.
- the eye drops of the present invention may also be used as an eye wash, an injection, or the like. When the eye drop of the present invention is used as an eye wash, an eye wash cup or the like may be used.
- the eye drops of the present invention are effective for the prevention and treatment of eye diseases caused by fungi such as Fusarium, Aspergillus, and Candida, and can improve symptoms such as bloodshot eyes, itchy eyes, blurred vision due to mucus, watery eyes, and a rumbling foreign body sensation.
- the eye drops of the present invention can be used to treat fungal eye diseases such as fungal endophthalmitis (endogenous fungal endophthalmitis) and keratomycosis.
- the eye drops of the present invention can be produced by a known method for producing eye drops. For example, it can be produced by dissolving luliconazole in benzyl alcohol, adding the surfactant and other additives of the present invention diluted or not diluted with distilled or purified water, adding distilled or purified water for dilution, adjusting the osmotic pressure and pH to a predetermined level, and filling a container. A sterilization step can also be included in the manufacturing process if desired.
- the shape and material of the container are not limited, and those used for ordinary eye drops may be used.
- As the container an eye drop container having an injection hole for easily dripping the eye drops is preferable.
- the material of the container is not limited, synthetic resins such as polyethylene resin, polypropylene resin, and polyethylene terephthalate resin are preferable from the viewpoint of usability, airtightness, durability, and the like.
- Example 1 0.1 g of luliconazole was dissolved in 2.6 g of benzyl alcohol at room temperature and diluted with 4 ml of ethanol. Separately, an aqueous solution was prepared by dissolving 2.5 g of Unilube 70DP-950B in 12.5 ml of purified water, and this solution was added to the diluted solution at room temperature and mixed, then purified water was added to bring the total liquid volume to 100 ml. After adjustment, it was allowed to stand at room temperature for 30 minutes, and its properties were visually observed. Table 1 shows the results.
- Examples 2 to 9 According to the formulation shown in Table 1, eye drops of Examples 2 to 9 of the present invention were prepared in the same manner as in Example 1, and their properties were visually observed. Table 1 shows the results.
- Comparative Examples 1 to 3 According to the formulation shown in Table 2, Comparative Examples 1 to 3, which are formulations without the surfactant of the present invention, were prepared in the same manner as in Example 1, and their properties were visually observed. Table 2 shows the results.
- Comparative Examples 4 to 12 which are formulations using surfactants other than the surfactant of the present invention and commonly used in eye drops formulations, were prepared in the same manner as in Example 1, and their properties were visually observed. Table 3 shows the results. As a result of visual observation of the eye drops according to each of the examples and comparative examples, when insoluble matter of luliconazole was not visible and the eye drops were not cloudy, they were rated as "clear”. In addition, when an insoluble portion of luliconazole was visually observed, it was described as "insoluble”, or the properties of the entire ophthalmic solution were described as "separated into two layers".
- the percentage concentration of each component in Tables 1 to 3 indicates the mass-to-volume percent concentration (w/v%) of each component with respect to the entire eye drop, except for ethanol, and ethanol indicates the volume-to-volume percent concentration (v/v%).
- various surfactants described as trade names correspond to the following general names.
- Unilube 70DP-950B polyoxyethylene (200) polyoxypropylene glycol (70) HCO-60: Polyoxyethylene hydrogenated castor oil 60
- PVP K30 Povidone K30 (Daiichi Kogyo Seiyaku Co., Ltd.)
- PEG4000 Macrogol 4000 (manufactured by Tokyo Chemical Industry Co., Ltd.)
- MYS-40MV Polyoxyl stearate 40 (manufactured by Nikko Chemicals)
- TO-10V Polysorbate 80 (manufactured by Nikko Chemicals)
- MYS-10V Polyethylene glycol monostearate (10E.0.) (manufactured by Nikko Chemicals)
- the formulation of the eye drops of the present invention is an eye drop formulation capable of dissolving luliconazole.
- an eye drop formulation capable of dissolving luliconazole cannot be prepared without using the two surfactants used in the eye drop formulation of the present invention.
- the nonionic surfactants used in the eye drops cannot be substituted, and that the two surfactants used in the prescription of the eye drops of the present invention are components having special and remarkable effects in solving the problems of the present invention.
- the present invention can provide an antifungal eye drop containing luliconazole as an active ingredient, particularly an aqueous eye drop.
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Abstract
The present invention addresses the problem of providing an antifungal eye drop, particularly, an aqueous eye drop, the eye drop containing luliconazole as an active ingredient. The problem is solved by the eye drop which contains: 1) luliconazole; 2) benzyl alcohol; and 3) one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil.
Description
本発明は、ルリコナゾールを有効成分とする点眼剤に関する。
The present invention relates to eye drops containing luliconazole as an active ingredient.
ルリコナゾールは皮膚科分野において優れた抗真菌活性を有し、足白癬治療剤（商品名ルリコン）および爪白癬治療剤（商品名ルコナック）が販売されている。ルリコナゾールは、白癬菌（主にトリコフィトン属）以外にもアスペルギルス属、フサリウム属、カンジダ属、スキタリジウム属、マラセチア属などの幅広い真菌に対しても優れた抗真菌活性を示すことが知られている（例えば、特許文献１～５を参照）。しかしながら、皮膚科分野における製剤化の際には、ルリコナゾールの難水溶性や良好な結晶性などの物理化学的性質によって、溶媒、特に水を含む溶媒への可溶化や製剤中での結晶析出が製剤製造上の大きな課題となっており、これら課題を克服するため、各種界面活性剤などの添加剤が検討されている（例えば、特許文献６～１５を参照）。
Luliconazole has excellent antifungal activity in the field of dermatology, and is marketed as a therapeutic agent for tinea pedis (trade name Lulicon) and a therapeutic agent for tinea unguium (trade name Luconac). Luliconazole is known to exhibit excellent antifungal activity against a wide range of fungi such as Aspergillus, Fusarium, Candida, Scitalidium and Malassezia in addition to Trichophyton (mainly Trichophyton) (see, for example, Patent Documents 1 to 5). However, when formulating in the field of dermatology, due to the physicochemical properties of luliconazole such as poor water solubility and good crystallinity, solubilization in solvents, particularly solvents containing water, and precipitation of crystals in the formulation have become major issues in formulation manufacturing. In order to overcome these issues, additives such as various surfactants have been investigated (see, for example, Patent Documents 6 to 15).
上記のように、ルリコナゾールは幅広い真菌に対して優れた抗真菌活性を有することから、主にフサリウム属を原因菌とした真菌症が問題となっている眼科分野においても有用な治療剤になると考えられてきたが、ルリコナゾールの難水溶性が原因で水性点眼剤のような水を基剤とした製剤は検討されておらず、また知られてもいなかった。
なお、ルリコナゾールを有効成分として含む液剤であるルリコン液１％は、中鎖脂肪酸トリグリセリドおよびマクロゴール４００（溶解剤）、メチルエチルケトン（溶解補助剤）、リン酸（ｐH調整剤）、ならびに無水エタノール（溶剤）からなり、水は含有されていない。また、ルリコナゾールを有効成分として含む他の液剤であるルコナック爪外用液５％は、Ｎ－メチル－２－ピロリドン、ベンジルアルコール、アジピン酸ジイソプロピル、乳酸、ポビドン及び無水エタノールからなる。
したがって、ルリコナゾールを有効成分として含む液剤として、水を含む医薬品は、これまで開発されていない。 As described above, since luliconazole has excellent antifungal activity against a wide range of fungi, it has been considered to be a useful therapeutic agent in the field of ophthalmology, where mycoses caused mainly by fungi of the genus Fusarium are a problem.
Lulicon Liquid 1%, which is a liquid preparation containing luliconazole as an active ingredient, consists of medium-chain fatty acid triglycerides and Macrogol 400 (solubilizer), methyl ethyl ketone (solubilizer), phosphoric acid (pH adjuster), and absolute ethanol (solvent), and does not contain water. Another liquid formulation containing luliconazole as an active ingredient, Luconac Topical Nail Solution 5%, consists of N-methyl-2-pyrrolidone, benzyl alcohol, diisopropyl adipate, lactic acid, povidone and absolute ethanol.
Therefore, no drug containing water has been developed so far as a liquid formulation containing luliconazole as an active ingredient.
なお、ルリコナゾールを有効成分として含む液剤であるルリコン液１％は、中鎖脂肪酸トリグリセリドおよびマクロゴール４００（溶解剤）、メチルエチルケトン（溶解補助剤）、リン酸（ｐH調整剤）、ならびに無水エタノール（溶剤）からなり、水は含有されていない。また、ルリコナゾールを有効成分として含む他の液剤であるルコナック爪外用液５％は、Ｎ－メチル－２－ピロリドン、ベンジルアルコール、アジピン酸ジイソプロピル、乳酸、ポビドン及び無水エタノールからなる。
したがって、ルリコナゾールを有効成分として含む液剤として、水を含む医薬品は、これまで開発されていない。 As described above, since luliconazole has excellent antifungal activity against a wide range of fungi, it has been considered to be a useful therapeutic agent in the field of ophthalmology, where mycoses caused mainly by fungi of the genus Fusarium are a problem.
Lulicon Liquid 1%, which is a liquid preparation containing luliconazole as an active ingredient, consists of medium-chain fatty acid triglycerides and Macrogol 400 (solubilizer), methyl ethyl ketone (solubilizer), phosphoric acid (pH adjuster), and absolute ethanol (solvent), and does not contain water. Another liquid formulation containing luliconazole as an active ingredient, Luconac Topical Nail Solution 5%, consists of N-methyl-2-pyrrolidone, benzyl alcohol, diisopropyl adipate, lactic acid, povidone and absolute ethanol.
Therefore, no drug containing water has been developed so far as a liquid formulation containing luliconazole as an active ingredient.
眼科分野の真菌症は、様々な真菌が原因であり、適切な治療薬の選択にあたっては原因菌の特定が必要であるが、原因菌を特定せずに幅広い真菌に対して有効な薬剤を処方できれば迅速な治療が可能になり、その社会的意義は大きい。本発明は、幅広い真菌に対して優れた抗真菌活性を有するルリコナゾールを眼科分野の真菌症治療剤へと適用拡大するため、水溶解度の低いルリコナゾールを、水性点眼剤を包含する、水を基剤とした製剤として製剤化すべく、適切な界面活性剤の組み合わせを見出すことを課題とする。
Mycoses in the field of ophthalmology are caused by various fungi, and it is necessary to identify the causative bacterium in order to select an appropriate therapeutic agent. However, if it is possible to prescribe drugs that are effective against a wide range of fungi without identifying the causative bacterium, rapid treatment will be possible, and its social significance is great. In order to expand the application of luliconazole, which has excellent antifungal activity against a wide range of fungi, to therapeutic agents for mycoses in the field of ophthalmology, an object of the present invention is to find an appropriate combination of surfactants for formulating luliconazole, which has low water solubility, as a water-based formulation, including aqueous eye drops.
本発明者らは上記課題を克服すべく鋭意検討を重ねた結果、ベンジルアルコールと特定の界面活性剤との組み合わせがルリコナゾールを溶解し、所望の点眼剤処方になりうることを見出し、本発明を完成させた。すなわち、本発明は、
［１］１）ルリコナゾールと、２）ベンジルアルコールと、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種とを含有する、点眼剤、
［２］ルリコナゾールの含有量が、点眼剤全体に対して０．０３～０．８ｗ／ｖ％である、［１］に記載の点眼剤、
［３］ベンジルアルコールの含有量が、点眼剤全体に対して１．５～７．０ｗ／ｖ％である、［１］または［２］に記載の点眼剤、
［４］３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレンポリオキシプロピレングリコールを含み、ポリオキシエチレンポリオキシプロピレングリコールの含有量が、点眼剤全体に対して１．０～２５ｗ／ｖ％である、［１］乃至［３］いずれかに記載の点眼剤、
［５］３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレン硬化ヒマシ油を含み、ポリオキシエチレン硬化ヒマシ油の含有量が、点眼剤全体に対して０．５～２５ｗ／ｖ％である、［１］乃至［４］いずれかに記載の点眼剤、
［６］ルリコナゾールの含有量が点眼剤全体に対して０．０５～０．５ｗ／ｖ％であり、ベンジルアルコールの含有量が点眼剤全体に対して２．０～５．２ｗ／ｖ％であり、かつポリオキシエチレンポリオキシプロピレングリコールの含有量が点眼剤全体に対して２．０～２０ｗ／ｖ％であるか、またはポリオキシエチレン硬化ヒマシ油の含有量が、点眼剤全体に対して１．０～２０ｗ／ｖ％である、［１］に記載の点眼剤、
［７］３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレンポリオキシプロピレングリコールを含み、ポリオキシエチレンポリオキシプロピレングリコールが、ポリオキシエチレン（２００）ポリオキシプロピレングリコール（７０）である、［１］乃至［６］いずれかに記載の点眼剤、
［８］３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレン硬化ヒマシ油を含み、ポリオキシエチレン硬化ヒマシ油が、ポリオキシエチレン硬化ヒマシ油６０である、［１］乃至［７］いずれかに記載の点眼剤、
［９］点眼剤が水性点眼剤である、［１］乃至［８］いずれかに記載の点眼剤、
［１０］増粘剤、糖類、抗酸化剤、防腐剤、溶解補助剤、ｐＨ調節剤、等張化剤、清涼化剤、緩衝剤および安定化剤から選択される１種または２種以上の添加物をさらに含有する［１］乃至［９］いずれかに記載の点眼剤、
［１１］眼科分野の真菌症治療剤である［１］乃至［１０］いずれかに記載の点眼剤、
［１２］ルリコナゾールをベンジルアルコールに溶解して得られる溶液に、精製水で希釈した、ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種を添加し、さらに精製水で希釈することを特徴とする、［１］乃至［１１］いずれかに記載の点眼剤の製造方法、に関する。 The present inventors have made intensive studies to overcome the above problems, and as a result, have found that a combination of benzyl alcohol and a specific surfactant can dissolve luliconazole and form a desired ophthalmic formulation, thus completing the present invention. That is, the present invention
[1] eye drops containing 1) luliconazole, 2) benzyl alcohol, and 3) one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil;
[2] The ophthalmic solution according to [1], wherein the content of luliconazole is 0.03 to 0.8 w/v% of the total ophthalmic solution.
[3] The ophthalmic solution according to [1] or [2], wherein the content of benzyl alcohol is 1.5 to 7.0 w/v% relative to the total ophthalmic solution;
[4] 3) The eye drop according to any one of [1] to [3], which contains polyoxyethylene polyoxypropylene glycol as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, and the content of polyoxyethylene polyoxypropylene glycol is 1.0 to 25 w/v% of the total eye drop.
[5] 3) The ophthalmic solution according to any one of [1] to [4], which contains polyoxyethylene hydrogenated castor oil as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, and the content of polyoxyethylene hydrogenated castor oil is 0.5 to 25 w/v% of the total ophthalmic solution.
[6] The content of luliconazole is 0.05 to 0.5 w/v% of the entire eye drop, the content of benzyl alcohol is 2.0 to 5.2 w/v% of the entire eye drop, and the content of polyoxyethylene polyoxypropylene glycol is 2.0 to 20 w/v% of the entire eye drop, or the content of polyoxyethylene hydrogenated castor oil is 1.0 to 20 w/v% of the entire eye drop. ophthalmic solution according to
[7] 3) The ophthalmic solution according to any one of [1] to [6], which contains polyoxyethylene polyoxypropylene glycol as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, wherein the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (200) polyoxypropylene glycol (70);
[8] 3) The ophthalmic solution according to any one of [1] to [7], which contains polyoxyethylene hydrogenated castor oil as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60;
[9] The ophthalmic solution according to any one of [1] to [8], wherein the ophthalmic solution is an aqueous ophthalmic solution;
[10] The ophthalmic solution according to any one of [1] to [9], further comprising one or more additives selected from thickeners, saccharides, antioxidants, preservatives, solubilizers, pH adjusters, tonicity agents, cooling agents, buffers and stabilizers.
[11] The ophthalmic solution according to any one of [1] to [10], which is a therapeutic agent for mycoses in the field of ophthalmology,
[12] The method for producing an eye drop according to any one of [1] to [11], characterized by adding one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil diluted with purified water to a solution obtained by dissolving luliconazole in benzyl alcohol, and further diluting with purified water.
［１］１）ルリコナゾールと、２）ベンジルアルコールと、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種とを含有する、点眼剤、
［２］ルリコナゾールの含有量が、点眼剤全体に対して０．０３～０．８ｗ／ｖ％である、［１］に記載の点眼剤、
［３］ベンジルアルコールの含有量が、点眼剤全体に対して１．５～７．０ｗ／ｖ％である、［１］または［２］に記載の点眼剤、
［４］３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレンポリオキシプロピレングリコールを含み、ポリオキシエチレンポリオキシプロピレングリコールの含有量が、点眼剤全体に対して１．０～２５ｗ／ｖ％である、［１］乃至［３］いずれかに記載の点眼剤、
［５］３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレン硬化ヒマシ油を含み、ポリオキシエチレン硬化ヒマシ油の含有量が、点眼剤全体に対して０．５～２５ｗ／ｖ％である、［１］乃至［４］いずれかに記載の点眼剤、
［６］ルリコナゾールの含有量が点眼剤全体に対して０．０５～０．５ｗ／ｖ％であり、ベンジルアルコールの含有量が点眼剤全体に対して２．０～５．２ｗ／ｖ％であり、かつポリオキシエチレンポリオキシプロピレングリコールの含有量が点眼剤全体に対して２．０～２０ｗ／ｖ％であるか、またはポリオキシエチレン硬化ヒマシ油の含有量が、点眼剤全体に対して１．０～２０ｗ／ｖ％である、［１］に記載の点眼剤、
［７］３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレンポリオキシプロピレングリコールを含み、ポリオキシエチレンポリオキシプロピレングリコールが、ポリオキシエチレン（２００）ポリオキシプロピレングリコール（７０）である、［１］乃至［６］いずれかに記載の点眼剤、
［８］３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレン硬化ヒマシ油を含み、ポリオキシエチレン硬化ヒマシ油が、ポリオキシエチレン硬化ヒマシ油６０である、［１］乃至［７］いずれかに記載の点眼剤、
［９］点眼剤が水性点眼剤である、［１］乃至［８］いずれかに記載の点眼剤、
［１０］増粘剤、糖類、抗酸化剤、防腐剤、溶解補助剤、ｐＨ調節剤、等張化剤、清涼化剤、緩衝剤および安定化剤から選択される１種または２種以上の添加物をさらに含有する［１］乃至［９］いずれかに記載の点眼剤、
［１１］眼科分野の真菌症治療剤である［１］乃至［１０］いずれかに記載の点眼剤、
［１２］ルリコナゾールをベンジルアルコールに溶解して得られる溶液に、精製水で希釈した、ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種を添加し、さらに精製水で希釈することを特徴とする、［１］乃至［１１］いずれかに記載の点眼剤の製造方法、に関する。 The present inventors have made intensive studies to overcome the above problems, and as a result, have found that a combination of benzyl alcohol and a specific surfactant can dissolve luliconazole and form a desired ophthalmic formulation, thus completing the present invention. That is, the present invention
[1] eye drops containing 1) luliconazole, 2) benzyl alcohol, and 3) one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil;
[2] The ophthalmic solution according to [1], wherein the content of luliconazole is 0.03 to 0.8 w/v% of the total ophthalmic solution.
[3] The ophthalmic solution according to [1] or [2], wherein the content of benzyl alcohol is 1.5 to 7.0 w/v% relative to the total ophthalmic solution;
[4] 3) The eye drop according to any one of [1] to [3], which contains polyoxyethylene polyoxypropylene glycol as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, and the content of polyoxyethylene polyoxypropylene glycol is 1.0 to 25 w/v% of the total eye drop.
[5] 3) The ophthalmic solution according to any one of [1] to [4], which contains polyoxyethylene hydrogenated castor oil as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, and the content of polyoxyethylene hydrogenated castor oil is 0.5 to 25 w/v% of the total ophthalmic solution.
[6] The content of luliconazole is 0.05 to 0.5 w/v% of the entire eye drop, the content of benzyl alcohol is 2.0 to 5.2 w/v% of the entire eye drop, and the content of polyoxyethylene polyoxypropylene glycol is 2.0 to 20 w/v% of the entire eye drop, or the content of polyoxyethylene hydrogenated castor oil is 1.0 to 20 w/v% of the entire eye drop. ophthalmic solution according to
[7] 3) The ophthalmic solution according to any one of [1] to [6], which contains polyoxyethylene polyoxypropylene glycol as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, wherein the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (200) polyoxypropylene glycol (70);
[8] 3) The ophthalmic solution according to any one of [1] to [7], which contains polyoxyethylene hydrogenated castor oil as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60;
[9] The ophthalmic solution according to any one of [1] to [8], wherein the ophthalmic solution is an aqueous ophthalmic solution;
[10] The ophthalmic solution according to any one of [1] to [9], further comprising one or more additives selected from thickeners, saccharides, antioxidants, preservatives, solubilizers, pH adjusters, tonicity agents, cooling agents, buffers and stabilizers.
[11] The ophthalmic solution according to any one of [1] to [10], which is a therapeutic agent for mycoses in the field of ophthalmology,
[12] The method for producing an eye drop according to any one of [1] to [11], characterized by adding one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil diluted with purified water to a solution obtained by dissolving luliconazole in benzyl alcohol, and further diluting with purified water.
本発明によれば、ルリコナゾールを有効成分とし、水を基剤とした抗真菌薬の点眼剤、特に水性点眼剤を提供することができる。本発明の点眼剤は、水を基剤とした剤（例えば水性点眼剤）であるため、油性点眼剤のように有効成分が水をはじきやすく、他の点眼薬の吸収を阻害してしまうという欠点がないばかりでなく、懸濁性点眼剤のように水に溶けにくく吸収されにくいといった欠点がない。そのため本発明の点眼剤は、有効成分であるルリコナゾールの患部への送達を効率的に行うことを可能とするとともに、ルリコナゾールを他の点眼剤と併用することを可能にするといった効果を奏する。
本発明によれば、水溶解度が低いルリコナゾールを有効成分として含む、水を基剤とした点眼剤等の製剤が提供される。かかる製剤は、目視にて澄明な、水を基剤とした製剤である。
従来技術においては、ルリコナゾールを有効成分として含む眼科用製剤の調製は、ルリコナゾールの水難溶性を克服することが困難であるため、試みられることさえなかった。かかる背景に鑑みれば、本発明が奏する上記の効果は、従来技術からは当業者といえども予測しえない顕著な効果であるといえる。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a water-based antifungal ophthalmic solution, particularly an aqueous ophthalmic solution, containing luliconazole as an active ingredient. Since the ophthalmic solution of the present invention is a water-based agent (e.g., aqueous eyedrops), it does not have the drawback that the active ingredient easily repels water and inhibits the absorption of other eyedrops as in oily eyedrops, and it does not have the drawback that it is difficult to dissolve in water and is difficult to be absorbed as in suspension eyedrops. Therefore, the eye drops of the present invention have the effect of enabling efficient delivery of luliconazole, which is an active ingredient, to the affected area, and enabling luliconazole to be used in combination with other eye drops.
INDUSTRIAL APPLICABILITY According to the present invention, there is provided a water-based formulation such as an eye drop containing luliconazole, which has low water solubility, as an active ingredient. Such formulations are visually clear, water-based formulations.
In the prior art, preparation of an ophthalmic formulation containing luliconazole as an active ingredient has not even been attempted due to the difficulty of overcoming the low water solubility of luliconazole. In view of this background, the above-mentioned effects of the present invention can be said to be remarkable effects that even a person skilled in the art could not have predicted from the prior art.
本発明によれば、水溶解度が低いルリコナゾールを有効成分として含む、水を基剤とした点眼剤等の製剤が提供される。かかる製剤は、目視にて澄明な、水を基剤とした製剤である。
従来技術においては、ルリコナゾールを有効成分として含む眼科用製剤の調製は、ルリコナゾールの水難溶性を克服することが困難であるため、試みられることさえなかった。かかる背景に鑑みれば、本発明が奏する上記の効果は、従来技術からは当業者といえども予測しえない顕著な効果であるといえる。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a water-based antifungal ophthalmic solution, particularly an aqueous ophthalmic solution, containing luliconazole as an active ingredient. Since the ophthalmic solution of the present invention is a water-based agent (e.g., aqueous eyedrops), it does not have the drawback that the active ingredient easily repels water and inhibits the absorption of other eyedrops as in oily eyedrops, and it does not have the drawback that it is difficult to dissolve in water and is difficult to be absorbed as in suspension eyedrops. Therefore, the eye drops of the present invention have the effect of enabling efficient delivery of luliconazole, which is an active ingredient, to the affected area, and enabling luliconazole to be used in combination with other eye drops.
INDUSTRIAL APPLICABILITY According to the present invention, there is provided a water-based formulation such as an eye drop containing luliconazole, which has low water solubility, as an active ingredient. Such formulations are visually clear, water-based formulations.
In the prior art, preparation of an ophthalmic formulation containing luliconazole as an active ingredient has not even been attempted due to the difficulty of overcoming the low water solubility of luliconazole. In view of this background, the above-mentioned effects of the present invention can be said to be remarkable effects that even a person skilled in the art could not have predicted from the prior art.
［本発明の点眼剤において用いられる成分］
本発明の点眼剤は、ルリコナゾールを有効成分とする抗真菌薬であって、ベンジルアルコールと、ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種とを、ルリコナゾールの水溶性を高める成分として含有することを特徴とする。
本発明の点眼剤において用いられる成分について、以下にさらに説明する。
●１．１）ルリコナゾール
本発明の点眼剤における有効成分であるルリコナゾールは、下記構造式で表される、化学名（Ｒ）－（－）－（Ｅ）－［４－（２，４－ジクロロフェニル）－１，３－ジチオラン－２－イリデン］－１－イミダゾリルアセトニトリルで表される水にほとんど溶解しない化合物であり、その製法と抗真菌特性は既に知られている。
本発明の点眼剤におけるルリコナゾールの含有量は限定されないところ、該含有量としては、点眼剤全体に対して０．０１～１質量対容量パーセント濃度（以下、ｗ／ｖ％と表記する。）であってよく、好ましくは０．０３～０．８ｗ／ｖ％、更に好ましくは０．０５～０．５ｗ／ｖ％の範囲の含有量であることができる。なお、本明細書において、記号「～」により特定される範囲には、記号「～」の両端に記載される２つの数値も包含される。
●２．１）ルリコナゾールの水溶性を高める成分
本発明は、ルリコナゾールの水溶性を高める成分として
２）ベンジルアルコール、及び
３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種
を含有することにより、ルリコナゾールを有効成分として含み、水を基剤とした抗真菌薬の点眼剤を提供する。上記３）の成分は、２）ベンジルアルコールと相乗的に作用して、ルリコナゾールの水溶性を高めると考えられる。
上記２）および３）の成分の含有量は、ルリコナゾールの水溶性を高める量であれば限定されず、また、ルリコナゾールの配合量に応じて調整してよい。より具体的には以下のとおりである。
２）ベンジルアルコール
本発明の点眼剤におけるベンジルアルコールの含有量は限定されないところ、該含有量は、点眼剤全体に対して１．０～１０ｗ／ｖ％であり、好ましくは１．５～７．０ｗ／ｖ％、更に好ましくは２．０～５．２ｗ／ｖ％の範囲の含有量であることができる。
本発明の点眼剤において、ベンジルアルコールの含有量のルリコナゾールの含有量に対する割合は、ルリコナゾールが溶解する割合であれば限定されない。かかる割合は、例えば１０倍～４０倍であってよい。
３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種
本発明の点眼剤において、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種として、ポリオキシエチレンポリオキシプロピレングリコールが用いられる場合、該ポリオキシエチレンポリオキシプロピレングリコールの添加量（本発明の点眼剤が調製された際に含有される量）は限定されないところ、該含添加量は、点眼剤全体に対して０．１～３０ｗ／ｖ％であってよく、好ましくは１．０～２５ｗ／ｖ％、更に好ましくは２．０～２０ｗ／ｖ％の範囲の添加量であることができる。また、本発明の点眼剤において、２種以上のポリオキシエチレンポリオキシプロピレングリコールが用いられる場合、ポリオキシエチレンポリオキシプロピレングリコールの総添加量は、上記各範囲の添加量であることができる。
本発明の点眼剤において、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種として、ポリオキシエチレン硬化ヒマシ油が用いられる場合、該ポリオキシエチレン硬化ヒマシ油の添加量（本発明の点眼剤が調製された際に含有される量）は限定されないところ、該添加量は、点眼剤全体に対して０．１～３０ｗ／ｖ％であってよく、好ましくは０．５～２５ｗ／ｖ％、更に好ましくは１．０～２０ｗ／ｖ％の範囲の添加量であることができる。また、本発明の点眼剤において、２種以上のポリオキシエチレン硬化ヒマシ油が用いられる場合、ポリオキシエチレン硬化ヒマシ油の総添加量は、上記各範囲の添加量であることができる。
本発明の点眼剤においては、少なくとも１種のポリオキシエチレンポリオキシプロピレングリコールおよび少なくとも１種のポリオキシエチレン硬化ヒマシ油を併用してよい。この場合、少なくとも１種のポリオキシエチレンポリオキシプロピレングリコールおよび少なくとも１種のポリオキシエチレン硬化ヒマシ油の添加量は、それぞれ、上述したポリオキシエチレンポリオキシプロピレングリコールの添加量の範囲の添加量、およびポリオキシエチレン硬化ヒマシ油の添加量の範囲の添加量、であってよい。
本発明の点眼剤において、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種の含有量のルリコナゾールの含有量に対する割合は、ルリコナゾールが溶解する割合であれば限定されない。かかる割合は、例えば１０倍～６０倍であってよい。
なお、ポリオキシエチレンポリオキシプロピレングリコールは、その重合度によって様々な種類があるところ、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール（かっこ内は平均重合度を表す。以下において同様）、ポリオキシエチレン（１２０）ポリオキシプロピレン（４０）グリコール、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール、およびポリオキシエチレン（２００）ポリオキシプロピレン（７０）グリコールが例示される。本発明の点眼剤において用いられるポリオキシエチレンポリオキシプロピレングリコールは、重合度により限定されず、上記いずれのポリオキシエチレンポリオキシプロピレングリコールを用いてもよい。ポリオキシエチレンポリオキシプロピレングリコールとして、例えば商品名ユニルーブ７０ＤＰ－９５０Ｂとして販売されているポリオキシエチレン（２００）ポリオキシプロピレングリコール（７０）は、本発明の点眼剤において好ましい。
また、ポリオキシエチレン硬化ヒマシ油は、その重合度によって様々な種類があるところ、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０、およびポリオキシエチレン硬化ヒマシ油１００が例示される。本発明の点眼剤において用いられるポリオキシエチレン硬化ヒマシ油は、重合度により限定されず、上記いずれのポリオキシエチレン硬化ヒマシ油を用いてもよい。ポリオキシエチレン硬化ヒマシ油として、商品名ＨＣＯ－６０として販売されているポリオキシエチレン硬化ヒマシ油６０は、本発明の点眼剤において好ましい。ルリコナゾールの含有量が点眼剤全体に対して０．０５～０．５ｗ／ｖ％であり、ベンジルアルコールの含有量が点眼剤全体に対して２．０～５．２ｗ／ｖ％であり、かつポリオキシエチレンポリオキシプロピレングリコールの含有量が点眼剤全体に対して２．０～２０ｗ／ｖ％であるか、またはポリオキシエチレン硬化ヒマシ油の含有量が、点眼剤全体に対して１．０～２０ｗ／ｖ％である本発明の点眼剤は、ルリコナゾールが一層安定して溶解するため好ましい。
本発明の点眼剤において、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種を、２）ベンジルアルコールの含有量に対して、約０．３倍～約４倍の含有量で用いることは、ルリコナゾールを一層確実に溶解させる観点から好ましい。 [Ingredients used in the eye drops of the present invention]
The ophthalmic solution of the present invention is an antifungal agent containing luliconazole as an active ingredient, and is characterized by containing benzyl alcohol and one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil as ingredients that increase the water solubility of luliconazole.
Ingredients used in the eye drops of the present invention are further described below.
1.1) Luliconazole Luliconazole, which is the active ingredient in the eye drops of the present invention, is a chemical compound represented by the following structural formula, represented by the chemical name (R)-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile, and is almost insoluble in water. Its production method and antifungal properties are already known.
The content of luliconazole in the eye drops of the present invention is not limited, but the content may be 0.01 to 1 mass-to-volume percent concentration (hereinafter referred to as w/v%), preferably 0.03 to 0.8 w/v%, more preferably 0.05 to 0.5 w/v%, relative to the entire eye drop. In this specification, the range specified by the symbol "-" also includes the two numerical values described at both ends of the symbol "-".
2.1) Ingredients for enhancing the water solubility of luliconazole The present invention provides a water-based antifungal eye drop containing luliconazole as an active ingredient by containing 2) benzyl alcohol, and 3) one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil as ingredients for enhancing the water solubility of luliconazole. It is believed that the above component 3) acts synergistically with 2) benzyl alcohol to increase the water solubility of luliconazole.
The contents of the above components 2) and 3) are not limited as long as they are amounts that enhance the water solubility of luliconazole, and may be adjusted according to the blending amount of luliconazole. More specifically, it is as follows.
2) Benzyl Alcohol The content of benzyl alcohol in the eye drops of the present invention is not limited, but the content may be in the range of 1.0 to 10 w/v%, preferably 1.5 to 7.0 w/v%, more preferably 2.0 to 5.2 w/v%, relative to the entire eye drop.
In the ophthalmic solution of the present invention, the ratio of the content of benzyl alcohol to the content of luliconazole is not limited as long as it is a ratio at which luliconazole dissolves. Such a ratio may be, for example, 10-fold to 40-fold.
3) One or two selected from polyoxyethylene-polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil In the eye drops of the present invention, when polyoxyethylene-polyoxypropylene glycol is used as one or two selected from 3) polyoxyethylene-polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, the amount of polyoxyethylene-polyoxypropylene glycol to be added (the amount contained when the eye drops of the present invention are prepared) is not limited, but the content is 0.5% relative to the entire eye drop. It may be 1 to 30 w/v%, preferably 1.0 to 25 w/v%, more preferably 2.0 to 20 w/v%. Moreover, when two or more kinds of polyoxyethylene-polyoxypropylene glycols are used in the eye drops of the present invention, the total amount of polyoxyethylene-polyoxypropylene glycols added can be within the ranges described above.
In the eye drops of the present invention, when polyoxyethylene hydrogenated castor oil is used as one or two selected from 3) polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, the amount of polyoxyethylene hydrogenated castor oil added (the amount contained when the eye drops of the present invention are prepared) is not limited. Preferably, the added amount can be in the range of 1.0 to 20 w/v%. Moreover, when two or more types of polyoxyethylene hydrogenated castor oils are used in the eye drops of the present invention, the total amount of polyoxyethylene hydrogenated castor oils to be added may fall within the ranges described above.
In the eye drops of the present invention, at least one polyoxyethylene polyoxypropylene glycol and at least one polyoxyethylene hydrogenated castor oil may be used in combination. In this case, the amounts of at least one polyoxyethylene polyoxypropylene glycol and at least one polyoxyethylene hydrogenated castor oil to be added may be within the range of the addition amount of the polyoxyethylene polyoxypropylene glycol and the addition amount of the polyoxyethylene hydrogenated castor oil, respectively.
In the ophthalmic solution of the present invention, the ratio of the content of one or two types selected from 3) polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil to the content of luliconazole is not limited as long as luliconazole is dissolved. Such a ratio may be, for example, 10-fold to 60-fold.
There are various types of polyoxyethylene polyoxypropylene glycol depending on the degree of polymerization, and polyoxyethylene (105) polyoxypropylene (5) glycol (the value in parentheses represents the average degree of polymerization; the same shall apply hereinafter), polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, and polyoxy Ethylene (200) polyoxypropylene (70) glycol is exemplified. The polyoxyethylene-polyoxypropylene glycol used in the eye drops of the present invention is not limited by the degree of polymerization, and any of the above polyoxyethylene-polyoxypropylene glycols may be used. Polyoxyethylene (200) polyoxypropylene glycol (70) sold as polyoxyethylene polyoxypropylene glycol, eg, under the trade name Unilube 70DP-950B, is preferred in the eye drops of the present invention.
Polyoxyethylene hydrogenated castor oil has various types depending on the degree of polymerization. The polyoxyethylene hydrogenated castor oil used in the eye drops of the present invention is not limited by the degree of polymerization, and any of the above polyoxyethylene hydrogenated castor oils may be used. As a polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60 sold under the trade name HCO-60 is preferred in the eye drops of the present invention. The eye drop of the present invention has a luliconazole content of 0.05 to 0.5 w/v%, a benzyl alcohol content of 2.0 to 5.2 w/v% of the entire eye drop, and a polyoxyethylene polyoxypropylene glycol content of 2.0 to 20 w/v% of the entire eye drop, or a polyoxyethylene hydrogenated castor oil content of 1.0 to 20 w/v% of the entire eye drop. , luliconazole is preferred because it dissolves more stably.
In the ophthalmic solution of the present invention, it is preferable to use one or two selected from 3) polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil at a content of about 0.3 to about 4 times the content of 2) benzyl alcohol from the viewpoint of more reliably dissolving luliconazole.
本発明の点眼剤は、ルリコナゾールを有効成分とする抗真菌薬であって、ベンジルアルコールと、ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種とを、ルリコナゾールの水溶性を高める成分として含有することを特徴とする。
本発明の点眼剤において用いられる成分について、以下にさらに説明する。
●１．１）ルリコナゾール
本発明の点眼剤における有効成分であるルリコナゾールは、下記構造式で表される、化学名（Ｒ）－（－）－（Ｅ）－［４－（２，４－ジクロロフェニル）－１，３－ジチオラン－２－イリデン］－１－イミダゾリルアセトニトリルで表される水にほとんど溶解しない化合物であり、その製法と抗真菌特性は既に知られている。
本発明の点眼剤におけるルリコナゾールの含有量は限定されないところ、該含有量としては、点眼剤全体に対して０．０１～１質量対容量パーセント濃度（以下、ｗ／ｖ％と表記する。）であってよく、好ましくは０．０３～０．８ｗ／ｖ％、更に好ましくは０．０５～０．５ｗ／ｖ％の範囲の含有量であることができる。なお、本明細書において、記号「～」により特定される範囲には、記号「～」の両端に記載される２つの数値も包含される。
●２．１）ルリコナゾールの水溶性を高める成分
本発明は、ルリコナゾールの水溶性を高める成分として
２）ベンジルアルコール、及び
３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種
を含有することにより、ルリコナゾールを有効成分として含み、水を基剤とした抗真菌薬の点眼剤を提供する。上記３）の成分は、２）ベンジルアルコールと相乗的に作用して、ルリコナゾールの水溶性を高めると考えられる。
上記２）および３）の成分の含有量は、ルリコナゾールの水溶性を高める量であれば限定されず、また、ルリコナゾールの配合量に応じて調整してよい。より具体的には以下のとおりである。
２）ベンジルアルコール
本発明の点眼剤におけるベンジルアルコールの含有量は限定されないところ、該含有量は、点眼剤全体に対して１．０～１０ｗ／ｖ％であり、好ましくは１．５～７．０ｗ／ｖ％、更に好ましくは２．０～５．２ｗ／ｖ％の範囲の含有量であることができる。
本発明の点眼剤において、ベンジルアルコールの含有量のルリコナゾールの含有量に対する割合は、ルリコナゾールが溶解する割合であれば限定されない。かかる割合は、例えば１０倍～４０倍であってよい。
３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種
本発明の点眼剤において、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種として、ポリオキシエチレンポリオキシプロピレングリコールが用いられる場合、該ポリオキシエチレンポリオキシプロピレングリコールの添加量（本発明の点眼剤が調製された際に含有される量）は限定されないところ、該含添加量は、点眼剤全体に対して０．１～３０ｗ／ｖ％であってよく、好ましくは１．０～２５ｗ／ｖ％、更に好ましくは２．０～２０ｗ／ｖ％の範囲の添加量であることができる。また、本発明の点眼剤において、２種以上のポリオキシエチレンポリオキシプロピレングリコールが用いられる場合、ポリオキシエチレンポリオキシプロピレングリコールの総添加量は、上記各範囲の添加量であることができる。
本発明の点眼剤において、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種として、ポリオキシエチレン硬化ヒマシ油が用いられる場合、該ポリオキシエチレン硬化ヒマシ油の添加量（本発明の点眼剤が調製された際に含有される量）は限定されないところ、該添加量は、点眼剤全体に対して０．１～３０ｗ／ｖ％であってよく、好ましくは０．５～２５ｗ／ｖ％、更に好ましくは１．０～２０ｗ／ｖ％の範囲の添加量であることができる。また、本発明の点眼剤において、２種以上のポリオキシエチレン硬化ヒマシ油が用いられる場合、ポリオキシエチレン硬化ヒマシ油の総添加量は、上記各範囲の添加量であることができる。
本発明の点眼剤においては、少なくとも１種のポリオキシエチレンポリオキシプロピレングリコールおよび少なくとも１種のポリオキシエチレン硬化ヒマシ油を併用してよい。この場合、少なくとも１種のポリオキシエチレンポリオキシプロピレングリコールおよび少なくとも１種のポリオキシエチレン硬化ヒマシ油の添加量は、それぞれ、上述したポリオキシエチレンポリオキシプロピレングリコールの添加量の範囲の添加量、およびポリオキシエチレン硬化ヒマシ油の添加量の範囲の添加量、であってよい。
本発明の点眼剤において、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種の含有量のルリコナゾールの含有量に対する割合は、ルリコナゾールが溶解する割合であれば限定されない。かかる割合は、例えば１０倍～６０倍であってよい。
なお、ポリオキシエチレンポリオキシプロピレングリコールは、その重合度によって様々な種類があるところ、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール（かっこ内は平均重合度を表す。以下において同様）、ポリオキシエチレン（１２０）ポリオキシプロピレン（４０）グリコール、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール、およびポリオキシエチレン（２００）ポリオキシプロピレン（７０）グリコールが例示される。本発明の点眼剤において用いられるポリオキシエチレンポリオキシプロピレングリコールは、重合度により限定されず、上記いずれのポリオキシエチレンポリオキシプロピレングリコールを用いてもよい。ポリオキシエチレンポリオキシプロピレングリコールとして、例えば商品名ユニルーブ７０ＤＰ－９５０Ｂとして販売されているポリオキシエチレン（２００）ポリオキシプロピレングリコール（７０）は、本発明の点眼剤において好ましい。
また、ポリオキシエチレン硬化ヒマシ油は、その重合度によって様々な種類があるところ、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０、およびポリオキシエチレン硬化ヒマシ油１００が例示される。本発明の点眼剤において用いられるポリオキシエチレン硬化ヒマシ油は、重合度により限定されず、上記いずれのポリオキシエチレン硬化ヒマシ油を用いてもよい。ポリオキシエチレン硬化ヒマシ油として、商品名ＨＣＯ－６０として販売されているポリオキシエチレン硬化ヒマシ油６０は、本発明の点眼剤において好ましい。ルリコナゾールの含有量が点眼剤全体に対して０．０５～０．５ｗ／ｖ％であり、ベンジルアルコールの含有量が点眼剤全体に対して２．０～５．２ｗ／ｖ％であり、かつポリオキシエチレンポリオキシプロピレングリコールの含有量が点眼剤全体に対して２．０～２０ｗ／ｖ％であるか、またはポリオキシエチレン硬化ヒマシ油の含有量が、点眼剤全体に対して１．０～２０ｗ／ｖ％である本発明の点眼剤は、ルリコナゾールが一層安定して溶解するため好ましい。
本発明の点眼剤において、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種を、２）ベンジルアルコールの含有量に対して、約０．３倍～約４倍の含有量で用いることは、ルリコナゾールを一層確実に溶解させる観点から好ましい。 [Ingredients used in the eye drops of the present invention]
The ophthalmic solution of the present invention is an antifungal agent containing luliconazole as an active ingredient, and is characterized by containing benzyl alcohol and one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil as ingredients that increase the water solubility of luliconazole.
Ingredients used in the eye drops of the present invention are further described below.
1.1) Luliconazole Luliconazole, which is the active ingredient in the eye drops of the present invention, is a chemical compound represented by the following structural formula, represented by the chemical name (R)-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile, and is almost insoluble in water. Its production method and antifungal properties are already known.
The content of luliconazole in the eye drops of the present invention is not limited, but the content may be 0.01 to 1 mass-to-volume percent concentration (hereinafter referred to as w/v%), preferably 0.03 to 0.8 w/v%, more preferably 0.05 to 0.5 w/v%, relative to the entire eye drop. In this specification, the range specified by the symbol "-" also includes the two numerical values described at both ends of the symbol "-".
2.1) Ingredients for enhancing the water solubility of luliconazole The present invention provides a water-based antifungal eye drop containing luliconazole as an active ingredient by containing 2) benzyl alcohol, and 3) one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil as ingredients for enhancing the water solubility of luliconazole. It is believed that the above component 3) acts synergistically with 2) benzyl alcohol to increase the water solubility of luliconazole.
The contents of the above components 2) and 3) are not limited as long as they are amounts that enhance the water solubility of luliconazole, and may be adjusted according to the blending amount of luliconazole. More specifically, it is as follows.
2) Benzyl Alcohol The content of benzyl alcohol in the eye drops of the present invention is not limited, but the content may be in the range of 1.0 to 10 w/v%, preferably 1.5 to 7.0 w/v%, more preferably 2.0 to 5.2 w/v%, relative to the entire eye drop.
In the ophthalmic solution of the present invention, the ratio of the content of benzyl alcohol to the content of luliconazole is not limited as long as it is a ratio at which luliconazole dissolves. Such a ratio may be, for example, 10-fold to 40-fold.
3) One or two selected from polyoxyethylene-polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil In the eye drops of the present invention, when polyoxyethylene-polyoxypropylene glycol is used as one or two selected from 3) polyoxyethylene-polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, the amount of polyoxyethylene-polyoxypropylene glycol to be added (the amount contained when the eye drops of the present invention are prepared) is not limited, but the content is 0.5% relative to the entire eye drop. It may be 1 to 30 w/v%, preferably 1.0 to 25 w/v%, more preferably 2.0 to 20 w/v%. Moreover, when two or more kinds of polyoxyethylene-polyoxypropylene glycols are used in the eye drops of the present invention, the total amount of polyoxyethylene-polyoxypropylene glycols added can be within the ranges described above.
In the eye drops of the present invention, when polyoxyethylene hydrogenated castor oil is used as one or two selected from 3) polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, the amount of polyoxyethylene hydrogenated castor oil added (the amount contained when the eye drops of the present invention are prepared) is not limited. Preferably, the added amount can be in the range of 1.0 to 20 w/v%. Moreover, when two or more types of polyoxyethylene hydrogenated castor oils are used in the eye drops of the present invention, the total amount of polyoxyethylene hydrogenated castor oils to be added may fall within the ranges described above.
In the eye drops of the present invention, at least one polyoxyethylene polyoxypropylene glycol and at least one polyoxyethylene hydrogenated castor oil may be used in combination. In this case, the amounts of at least one polyoxyethylene polyoxypropylene glycol and at least one polyoxyethylene hydrogenated castor oil to be added may be within the range of the addition amount of the polyoxyethylene polyoxypropylene glycol and the addition amount of the polyoxyethylene hydrogenated castor oil, respectively.
In the ophthalmic solution of the present invention, the ratio of the content of one or two types selected from 3) polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil to the content of luliconazole is not limited as long as luliconazole is dissolved. Such a ratio may be, for example, 10-fold to 60-fold.
There are various types of polyoxyethylene polyoxypropylene glycol depending on the degree of polymerization, and polyoxyethylene (105) polyoxypropylene (5) glycol (the value in parentheses represents the average degree of polymerization; the same shall apply hereinafter), polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, and polyoxy Ethylene (200) polyoxypropylene (70) glycol is exemplified. The polyoxyethylene-polyoxypropylene glycol used in the eye drops of the present invention is not limited by the degree of polymerization, and any of the above polyoxyethylene-polyoxypropylene glycols may be used. Polyoxyethylene (200) polyoxypropylene glycol (70) sold as polyoxyethylene polyoxypropylene glycol, eg, under the trade name Unilube 70DP-950B, is preferred in the eye drops of the present invention.
Polyoxyethylene hydrogenated castor oil has various types depending on the degree of polymerization. The polyoxyethylene hydrogenated castor oil used in the eye drops of the present invention is not limited by the degree of polymerization, and any of the above polyoxyethylene hydrogenated castor oils may be used. As a polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60 sold under the trade name HCO-60 is preferred in the eye drops of the present invention. The eye drop of the present invention has a luliconazole content of 0.05 to 0.5 w/v%, a benzyl alcohol content of 2.0 to 5.2 w/v% of the entire eye drop, and a polyoxyethylene polyoxypropylene glycol content of 2.0 to 20 w/v% of the entire eye drop, or a polyoxyethylene hydrogenated castor oil content of 1.0 to 20 w/v% of the entire eye drop. , luliconazole is preferred because it dissolves more stably.
In the ophthalmic solution of the present invention, it is preferable to use one or two selected from 3) polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil at a content of about 0.3 to about 4 times the content of 2) benzyl alcohol from the viewpoint of more reliably dissolving luliconazole.
［その他の成分］
点眼剤は、大きく水性点眼剤、油性点眼剤、懸濁性点眼剤に分類されるが、本発明の点眼剤は、水を基剤とした点眼剤、例えば水性点眼剤に分類される。
本発明の点眼剤は、水を含むものであり、点眼剤全体に対して、好ましくは水を４０ｗ／ｖ％以上含み、より好ましくは水を６０ｗ／ｖ％以上含み、一層より好ましくは水を７０ｗ／ｖ％以上含む。点眼剤全体に対して、水を４０ｗ／ｖ％以上含む点眼剤を、本発明においては水性点眼剤と称する。
本発明の点眼剤に配合される水の種類は限定されず、通常の点眼剤に用いられるものであってよい。本発明の点眼剤に配合される水として、蒸留水、常水、精製水、滅菌精製水、注射用水、および注射用蒸留水等が例示されるところ、これらの種類の水は、第十八改正日本薬局方に定義されるとおりのものである。
また、本発明の点眼剤は、本発明の効果を損なわない範囲で、点眼剤に通常用いられる添加物を含有することができる。添加物は、１種または２種以上を任意の割合で併用してもよい。添加物としては、増粘剤、糖類、抗酸化剤、防腐剤、溶解補助剤、ｐＨ調節剤、等張化剤、清涼化剤、緩衝剤、安定化剤等が挙げられる。
また、本発明においては、界面活性剤として、ポリオキシエチレンポリオキシプロピレングリコールまたはポリオキシエチレン硬化ヒマシ油が用いられるところ、本発明の効果を損なわない範囲で、他の界面活性剤を併せて用いてよい。他の界面活性剤として、ポビドン Ｋ３０、マクロゴール４０００、ステアリン酸ポリオキシル４０、ポリソルベート８０、およびモノステアリン酸ポリエチレングリコール（１０Ｅ．０．）等が例示される。これらの界面活性剤は、ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油と同様に、非イオン界面活性剤である。 [Other ingredients]
Eye drops are broadly classified into aqueous eye drops, oily eye drops, and suspension eye drops. The eye drops of the present invention are classified into water-based eye drops, such as aqueous eye drops.
The ophthalmic solution of the present invention contains water, and preferably contains 40 w/v% or more of water, more preferably 60 w/v% or more of water, and even more preferably 70 w/v% or more of water. An eye drop containing 40 w/v % or more of water with respect to the entire eye drop is referred to as an aqueous eye drop in the present invention.
The type of water to be blended in the eye drops of the present invention is not limited, and may be water used in ordinary eye drops. Examples of water to be incorporated in the eye drops of the present invention include distilled water, ordinary water, purified water, sterilized purified water, water for injection, and distilled water for injection.
In addition, the eye drops of the present invention can contain additives commonly used for eye drops as long as they do not impair the effects of the present invention. The additives may be used singly or in combination of two or more in any ratio. Additives include thickeners, sugars, antioxidants, preservatives, solubilizers, pH adjusters, tonicity agents, cooling agents, buffers, stabilizers and the like.
In addition, in the present invention, polyoxyethylene polyoxypropylene glycol or polyoxyethylene hydrogenated castor oil is used as a surfactant, and other surfactants may be used together within a range that does not impair the effects of the present invention. Other surfactants include povidone K30, macrogol 4000, polyoxyl stearate 40, polysorbate 80, and polyethylene glycol monostearate (10E.0.). These surfactants, like polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, are nonionic surfactants.
点眼剤は、大きく水性点眼剤、油性点眼剤、懸濁性点眼剤に分類されるが、本発明の点眼剤は、水を基剤とした点眼剤、例えば水性点眼剤に分類される。
本発明の点眼剤は、水を含むものであり、点眼剤全体に対して、好ましくは水を４０ｗ／ｖ％以上含み、より好ましくは水を６０ｗ／ｖ％以上含み、一層より好ましくは水を７０ｗ／ｖ％以上含む。点眼剤全体に対して、水を４０ｗ／ｖ％以上含む点眼剤を、本発明においては水性点眼剤と称する。
本発明の点眼剤に配合される水の種類は限定されず、通常の点眼剤に用いられるものであってよい。本発明の点眼剤に配合される水として、蒸留水、常水、精製水、滅菌精製水、注射用水、および注射用蒸留水等が例示されるところ、これらの種類の水は、第十八改正日本薬局方に定義されるとおりのものである。
また、本発明の点眼剤は、本発明の効果を損なわない範囲で、点眼剤に通常用いられる添加物を含有することができる。添加物は、１種または２種以上を任意の割合で併用してもよい。添加物としては、増粘剤、糖類、抗酸化剤、防腐剤、溶解補助剤、ｐＨ調節剤、等張化剤、清涼化剤、緩衝剤、安定化剤等が挙げられる。
また、本発明においては、界面活性剤として、ポリオキシエチレンポリオキシプロピレングリコールまたはポリオキシエチレン硬化ヒマシ油が用いられるところ、本発明の効果を損なわない範囲で、他の界面活性剤を併せて用いてよい。他の界面活性剤として、ポビドン Ｋ３０、マクロゴール４０００、ステアリン酸ポリオキシル４０、ポリソルベート８０、およびモノステアリン酸ポリエチレングリコール（１０Ｅ．０．）等が例示される。これらの界面活性剤は、ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油と同様に、非イオン界面活性剤である。 [Other ingredients]
Eye drops are broadly classified into aqueous eye drops, oily eye drops, and suspension eye drops. The eye drops of the present invention are classified into water-based eye drops, such as aqueous eye drops.
The ophthalmic solution of the present invention contains water, and preferably contains 40 w/v% or more of water, more preferably 60 w/v% or more of water, and even more preferably 70 w/v% or more of water. An eye drop containing 40 w/v % or more of water with respect to the entire eye drop is referred to as an aqueous eye drop in the present invention.
The type of water to be blended in the eye drops of the present invention is not limited, and may be water used in ordinary eye drops. Examples of water to be incorporated in the eye drops of the present invention include distilled water, ordinary water, purified water, sterilized purified water, water for injection, and distilled water for injection.
In addition, the eye drops of the present invention can contain additives commonly used for eye drops as long as they do not impair the effects of the present invention. The additives may be used singly or in combination of two or more in any ratio. Additives include thickeners, sugars, antioxidants, preservatives, solubilizers, pH adjusters, tonicity agents, cooling agents, buffers, stabilizers and the like.
In addition, in the present invention, polyoxyethylene polyoxypropylene glycol or polyoxyethylene hydrogenated castor oil is used as a surfactant, and other surfactants may be used together within a range that does not impair the effects of the present invention. Other surfactants include povidone K30, macrogol 4000, polyoxyl stearate 40, polysorbate 80, and polyethylene glycol monostearate (10E.0.). These surfactants, like polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, are nonionic surfactants.
「増粘剤」としては、カルボキシビニルポリマー、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、カルボキシメチルセルロース、アルギン酸、ポリビニルアルコール、ポリビニルピロリドン、マクロゴール等が挙げられる。
"Thickening agents" include carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, alginic acid, polyvinyl alcohol, polyvinylpyrrolidone, macrogol, and the like.
「糖類」としては、グルコース、シクロデキストリン、キシリトール、ソルビトール、マンニトール等が挙げられる。
"Sugars" include glucose, cyclodextrin, xylitol, sorbitol, mannitol, and the like.
「抗酸化剤」としては、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、ヒドロキノン、没食子酸プロピル、亜硫酸水素ナトリウム等が挙げられる。
"Antioxidants" include dibutylhydroxytoluene, butylhydroxyanisole, hydroquinone, propyl gallate, sodium hydrogen sulfite, and the like.
「防腐剤」としては、塩酸アルキルジアミノエチルグリシン、安息香酸ナトリウム、エタノール、ベンザルコニウム塩化物、塩化ベンゼトニウム、塩化セチルピリジニウム、塩酸グルコン酸クロルヘキシジン、クロロブタノール、ソルビン酸、ソルビン酸カリウム、デヒドロ酢酸ナトリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、硫酸オキシキノリン、フェネチルアルコール、ベンジルアルコール等が挙げられる。本発明の点眼剤においては、有効な保存効力を達成するためおよび保存安定性の向上を目的として、クロロブタノール、パラオキシ安息香酸エチルおよびパラオキシ安息香酸プロピルの３成分を併用するか、またはクロロブタノールおよびベンザルコニウム塩化物の２成分を併用することが好ましい。クロロブタノール、パラオキシ安息香酸エチルおよびパラオキシ安息香酸プロピルの３成分を併用する場合、それらの含有量は点眼剤全体に対して、それぞれ０．２５質量％、０．０１３ｗ／ｖ％および０．００７ｗ／ｖ％が好ましく、クロロブタノールおよびベンザルコニウム塩化物の２成分を併用する場合、それらの含有量は点眼剤全体に対してそれぞれ０．２５ｗ／ｖ％および０．０１ｗ／ｖ％が好ましい。
"Preservatives" include alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine gluconate hydrochloride, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, etc. are mentioned. In the ophthalmic solution of the present invention, it is preferable to use three components, chlorobutanol, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate, or two components, chlorobutanol and benzalkonium chloride, in combination for the purpose of achieving effective preservative efficacy and improving storage stability. When the three components of chlorobutanol, ethyl parahydroxybenzoate and propyl parahydroxybenzoate are used together, their contents are preferably 0.25% by mass, 0.013w/v% and 0.007w/v%, respectively, based on the total eye drop.
「溶解補助剤」としては、エタノールなどのアルコール類、ポリソルベート類、ポロキサミン、アルキルジアミノエチルグリシン、アルキル４級アンモニウム塩、ポリエチレングリコール、イプシロンアミノカプロン酸およびプロピレングリコール等が挙げられる。本発明においてはエタノールが特に好ましく、エタノールの使用量は点眼剤に使用可能な範囲で適宜選択すればよいが、２．０～５．０容量対容量パーセント濃度（ｖ／ｖ％）が特に好ましい。
"Solubilizers" include alcohols such as ethanol, polysorbates, poloxamines, alkyldiaminoethylglycine, alkyl quaternary ammonium salts, polyethylene glycol, epsilon aminocaproic acid and propylene glycol. Ethanol is particularly preferred in the present invention, and the amount of ethanol to be used may be appropriately selected within the range that can be used for eye drops, but 2.0 to 5.0 volume-to-volume percent concentration (v/v%) is particularly preferable.
「ｐＨ調節剤」としては、塩酸、リン酸、酢酸、酒石酸、ホウ酸、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム、炭酸ナトリウム、リン酸水素二ナトリウム（リン酸水素ナトリウム）、リン酸二水素ナトリウム水和物、リン酸二水素カリウム、ホウ砂、トリエタノールアミン、モノエタノールアミン等が挙げられる。本発明の点眼剤における「ｐＨ調節剤」の種類は特に限定されないが、有効成分の保存安定性を良好に保つためには、点眼剤のｐＨを５．０から７．０の範囲に調整することが好ましい。
"pH adjusters" include hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, boric acid, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate (sodium hydrogen phosphate), sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, borax, triethanolamine, monoethanolamine, and the like. Although the type of "pH adjuster" in the eye drops of the present invention is not particularly limited, it is preferable to adjust the pH of the eye drops in the range of 5.0 to 7.0 in order to maintain good storage stability of the active ingredient.
「等張化剤」としては、亜硫酸水素ナトリウム、亜硫酸ナトリウム、塩化カリウム、塩化カルシウム、塩化ナトリウム、塩化マグネシウム、酢酸カリウム、酢酸ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、チオ硫酸ナトリウム、硫酸マグネシウム、リン酸水素二ナトリウム（リン酸水素ナトリウム）、リン酸二水素ナトリウム水和物、リン酸二水素カリウム、ホウ酸、グリセリン、プロピレングリコール等が挙げられる。
Examples of "isotonizing agents" include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate (sodium hydrogen phosphate), sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, boric acid, glycerin, propylene glycol, and the like.
「清涼化剤」としては、ｄ－カンフル、ｄｌ－カンフル、ゲラニオール、ｄ－ボルネオール、ｌ－メントール、リュウノウ、ウイキョウ油、ハッカ水、ハッカ油、ベルガモット油、ユーカリ油等が挙げられる。本発明においてはハッカ油およびｌ－メントールが好ましい。
"Refreshing agents" include d-camphor, dl-camphor, geraniol, d-borneol, l-menthol, rhubarb, fennel oil, peppermint water, peppermint oil, bergamot oil, eucalyptus oil, and the like. Peppermint oil and l-menthol are preferred in the present invention.
「緩衝剤」としては、クエン酸緩衝剤、酢酸緩衝剤、炭酸緩衝剤、ホウ酸緩衝剤、リン酸緩衝剤、酒石酸塩緩衝剤、アミノ酸等が挙げられる。
"Buffers" include citrate buffers, acetate buffers, carbonate buffers, borate buffers, phosphate buffers, tartrate buffers, amino acids, and the like.
「安定化剤」としては、イプシロンアミノカプロン酸、ジブチルヒドロキシトルエン、トロメタモール、トコフェロール、ピロ亜硫酸ナトリウム、モノエタノールアミン、モノステアリン酸アルミニウム、エデト酸四ナトリウム、エデト酸ナトリウム、ホウ酸等が挙げられる。本発明の点眼剤においては、ホウ酸を用いることが好ましい。ホウ酸の含有量は、点眼剤全体に対して０．２５～１．０ｗ／ｖ％が好ましく、０．３５～０．７ｗ／ｖ％が特に好ましい。
"Stabilizers" include epsilon aminocaproic acid, dibutylhydroxytoluene, trometamol, tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, tetrasodium edetate, sodium edetate, boric acid, and the like. Boric acid is preferably used in the eye drops of the present invention. The content of boric acid is preferably 0.25 to 1.0 w/v%, particularly preferably 0.35 to 0.7 w/v%, relative to the total eye drop.
［本発明の点眼剤の使用方法・用途］
本発明の点眼剤の使用方法は、所期の効果を奏するものであれば限定されない。本発明の点眼剤は、例えば、１回１～３滴、１日あたり２～６回、１回あたり約３０～約２００μＬの量の範囲で点眼して使用することができるが、これに限定されず、任意の用法・用量で使用することができる。本発明の点眼剤を投与する頻度および量は、投与対象の年齢、体重、状態、および治療目的等を考慮して調整してよい。
本発明の点眼剤は、噴霧して用いてよいし、患部に塗布して用いてもよい。
本発明の点眼剤はまた、洗眼剤、または注射剤等として用いてよい。本発明の点眼剤を洗眼剤として用いる場合には、洗眼カップ等を用いてよい。 [Usage and application of eye drops of the present invention]
The method of using the ophthalmic solution of the present invention is not limited as long as the intended effect is achieved. The eye drops of the present invention can be used by, for example, 1 to 3 drops per time, 2 to 6 times per day, and in an amount of about 30 to about 200 μL per time, but not limited thereto, and can be used in any dosage and administration. The frequency and amount of administration of the eye drops of the present invention may be adjusted in consideration of the age, body weight, condition, therapeutic purpose, and the like of the subject to be administered.
The ophthalmic solution of the present invention may be used by spraying, or may be applied to the affected area.
The eye drops of the present invention may also be used as an eye wash, an injection, or the like. When the eye drop of the present invention is used as an eye wash, an eye wash cup or the like may be used.
本発明の点眼剤の使用方法は、所期の効果を奏するものであれば限定されない。本発明の点眼剤は、例えば、１回１～３滴、１日あたり２～６回、１回あたり約３０～約２００μＬの量の範囲で点眼して使用することができるが、これに限定されず、任意の用法・用量で使用することができる。本発明の点眼剤を投与する頻度および量は、投与対象の年齢、体重、状態、および治療目的等を考慮して調整してよい。
本発明の点眼剤は、噴霧して用いてよいし、患部に塗布して用いてもよい。
本発明の点眼剤はまた、洗眼剤、または注射剤等として用いてよい。本発明の点眼剤を洗眼剤として用いる場合には、洗眼カップ等を用いてよい。 [Usage and application of eye drops of the present invention]
The method of using the ophthalmic solution of the present invention is not limited as long as the intended effect is achieved. The eye drops of the present invention can be used by, for example, 1 to 3 drops per time, 2 to 6 times per day, and in an amount of about 30 to about 200 μL per time, but not limited thereto, and can be used in any dosage and administration. The frequency and amount of administration of the eye drops of the present invention may be adjusted in consideration of the age, body weight, condition, therapeutic purpose, and the like of the subject to be administered.
The ophthalmic solution of the present invention may be used by spraying, or may be applied to the affected area.
The eye drops of the present invention may also be used as an eye wash, an injection, or the like. When the eye drop of the present invention is used as an eye wash, an eye wash cup or the like may be used.
本発明の点眼剤は、真菌、例えば、フサリウム属、アスペルギルス属、カンジダ属などを原因菌とする眼疾患の予防・治療に有効であり、目の充血、目のかゆみ、目やにによる目のかすみ、なみだ目、ゴロゴロとした異物感等の症状を改善させることができる。本発明の点眼剤は、真菌性眼内炎（内因性真菌性眼内炎）および角膜真菌症といった真菌性の眼疾患の処置に用いえる。
The eye drops of the present invention are effective for the prevention and treatment of eye diseases caused by fungi such as Fusarium, Aspergillus, and Candida, and can improve symptoms such as bloodshot eyes, itchy eyes, blurred vision due to mucus, watery eyes, and a rumbling foreign body sensation. The eye drops of the present invention can be used to treat fungal eye diseases such as fungal endophthalmitis (endogenous fungal endophthalmitis) and keratomycosis.
［本発明の点眼剤の製造方法］
本発明の点眼剤は、点眼剤の製造方法として公知の方法により製造できる。例えば、ルリコナゾールをベンジルアルコールに溶解し、本発明の界面活性剤や他の添加物を蒸留水もしくは精製水で希釈または希釈せずして加えた後、蒸留水または精製水を加えて希釈し、所定の浸透圧およびｐＨに調整し、容器に充填することにより製造できる。また、必要に応じて滅菌処理工程を製造工程中に入れることもできる。
前記容器の形状や材質は限定されず、通常の点眼剤に用いられるものを用いてよい。容器として、点眼剤の滴下を容易に行うための注液孔を備えた点眼容器は好ましい。該容器の材質は限定されないところ、使用のしやすさや気密性および耐久性等の観点から、ポリエチレン樹脂、ポリプロピレン樹脂、およびポリエチレンテレフタレート樹脂等の合成樹脂は好ましい。 [Method for producing eye drops of the present invention]
The eye drops of the present invention can be produced by a known method for producing eye drops. For example, it can be produced by dissolving luliconazole in benzyl alcohol, adding the surfactant and other additives of the present invention diluted or not diluted with distilled or purified water, adding distilled or purified water for dilution, adjusting the osmotic pressure and pH to a predetermined level, and filling a container. A sterilization step can also be included in the manufacturing process if desired.
The shape and material of the container are not limited, and those used for ordinary eye drops may be used. As the container, an eye drop container having an injection hole for easily dripping the eye drops is preferable. Although the material of the container is not limited, synthetic resins such as polyethylene resin, polypropylene resin, and polyethylene terephthalate resin are preferable from the viewpoint of usability, airtightness, durability, and the like.
本発明の点眼剤は、点眼剤の製造方法として公知の方法により製造できる。例えば、ルリコナゾールをベンジルアルコールに溶解し、本発明の界面活性剤や他の添加物を蒸留水もしくは精製水で希釈または希釈せずして加えた後、蒸留水または精製水を加えて希釈し、所定の浸透圧およびｐＨに調整し、容器に充填することにより製造できる。また、必要に応じて滅菌処理工程を製造工程中に入れることもできる。
前記容器の形状や材質は限定されず、通常の点眼剤に用いられるものを用いてよい。容器として、点眼剤の滴下を容易に行うための注液孔を備えた点眼容器は好ましい。該容器の材質は限定されないところ、使用のしやすさや気密性および耐久性等の観点から、ポリエチレン樹脂、ポリプロピレン樹脂、およびポリエチレンテレフタレート樹脂等の合成樹脂は好ましい。 [Method for producing eye drops of the present invention]
The eye drops of the present invention can be produced by a known method for producing eye drops. For example, it can be produced by dissolving luliconazole in benzyl alcohol, adding the surfactant and other additives of the present invention diluted or not diluted with distilled or purified water, adding distilled or purified water for dilution, adjusting the osmotic pressure and pH to a predetermined level, and filling a container. A sterilization step can also be included in the manufacturing process if desired.
The shape and material of the container are not limited, and those used for ordinary eye drops may be used. As the container, an eye drop container having an injection hole for easily dripping the eye drops is preferable. Although the material of the container is not limited, synthetic resins such as polyethylene resin, polypropylene resin, and polyethylene terephthalate resin are preferable from the viewpoint of usability, airtightness, durability, and the like.
以下に、実施例を挙げて、本発明について、更に詳細に説明するが、本発明はかかる実施例に限定されるものではない。
The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.
＜実施例１＞
ルリコナゾール０．１ｇをベンジルアルコール２．６ｇに室温で溶解し、エタノール４ｍｌを加えて希釈した。別途、ユニルーブ７０ＤＰ－９５０Ｂ２．５ｇを精製水１２．５ｍｌに溶解した水溶液を調製し、これを前記の希釈液に室温で加えて混合した後、精製水を加えて全体の液量を１００ｍｌとして実施例１の点眼剤を調製した。調整後、室温で３０分間静置し、その性状を目視で観察した。結果を表１に示す。 <Example 1>
0.1 g of luliconazole was dissolved in 2.6 g of benzyl alcohol at room temperature and diluted with 4 ml of ethanol. Separately, an aqueous solution was prepared by dissolving 2.5 g of Unilube 70DP-950B in 12.5 ml of purified water, and this solution was added to the diluted solution at room temperature and mixed, then purified water was added to bring the total liquid volume to 100 ml. After adjustment, it was allowed to stand at room temperature for 30 minutes, and its properties were visually observed. Table 1 shows the results.
ルリコナゾール０．１ｇをベンジルアルコール２．６ｇに室温で溶解し、エタノール４ｍｌを加えて希釈した。別途、ユニルーブ７０ＤＰ－９５０Ｂ２．５ｇを精製水１２．５ｍｌに溶解した水溶液を調製し、これを前記の希釈液に室温で加えて混合した後、精製水を加えて全体の液量を１００ｍｌとして実施例１の点眼剤を調製した。調整後、室温で３０分間静置し、その性状を目視で観察した。結果を表１に示す。 <Example 1>
0.1 g of luliconazole was dissolved in 2.6 g of benzyl alcohol at room temperature and diluted with 4 ml of ethanol. Separately, an aqueous solution was prepared by dissolving 2.5 g of Unilube 70DP-950B in 12.5 ml of purified water, and this solution was added to the diluted solution at room temperature and mixed, then purified water was added to bring the total liquid volume to 100 ml. After adjustment, it was allowed to stand at room temperature for 30 minutes, and its properties were visually observed. Table 1 shows the results.
＜実施例２～９＞
表１に示す処方に従って、実施例１と同様にして本発明の点眼剤である実施例２～９を調製し、その性状を目視で観察した。結果を表１に示す。 <Examples 2 to 9>
According to the formulation shown in Table 1, eye drops of Examples 2 to 9 of the present invention were prepared in the same manner as in Example 1, and their properties were visually observed. Table 1 shows the results.
表１に示す処方に従って、実施例１と同様にして本発明の点眼剤である実施例２～９を調製し、その性状を目視で観察した。結果を表１に示す。 <Examples 2 to 9>
According to the formulation shown in Table 1, eye drops of Examples 2 to 9 of the present invention were prepared in the same manner as in Example 1, and their properties were visually observed. Table 1 shows the results.
＜比較例１～３＞
表２に示す処方に従って、実施例１と同様にして本発明の界面活性剤を使用しない処方である比較例１～３を調製し、その性状を目視で観察した。結果を表２に示す。 <Comparative Examples 1 to 3>
According to the formulation shown in Table 2, Comparative Examples 1 to 3, which are formulations without the surfactant of the present invention, were prepared in the same manner as in Example 1, and their properties were visually observed. Table 2 shows the results.
表２に示す処方に従って、実施例１と同様にして本発明の界面活性剤を使用しない処方である比較例１～３を調製し、その性状を目視で観察した。結果を表２に示す。 <Comparative Examples 1 to 3>
According to the formulation shown in Table 2, Comparative Examples 1 to 3, which are formulations without the surfactant of the present invention, were prepared in the same manner as in Example 1, and their properties were visually observed. Table 2 shows the results.
＜比較例４～１２＞
表３に示す処方に従って、実施例１と同様にして本発明の界面活性剤以外で通常の点眼剤処方に用いられる界面活性剤を使用した処方である比較例４～１２を調製し、その性状を目視で観察した。結果を表３に示す。
なお、各実施例及び比較例による点眼剤の目視による観察した結果は、ルリコナゾールの不溶分が視認できず、点眼剤に濁りがない場合には「澄明」とした。また、ルリコナゾールの不溶分が視認された場合には、「不溶」と記載するか、または点眼剤全体の性状を「二層に分離」の表現により記載した。 <Comparative Examples 4 to 12>
According to the formulations shown in Table 3, Comparative Examples 4 to 12, which are formulations using surfactants other than the surfactant of the present invention and commonly used in eye drops formulations, were prepared in the same manner as in Example 1, and their properties were visually observed. Table 3 shows the results.
As a result of visual observation of the eye drops according to each of the examples and comparative examples, when insoluble matter of luliconazole was not visible and the eye drops were not cloudy, they were rated as "clear". In addition, when an insoluble portion of luliconazole was visually observed, it was described as "insoluble", or the properties of the entire ophthalmic solution were described as "separated into two layers".
表３に示す処方に従って、実施例１と同様にして本発明の界面活性剤以外で通常の点眼剤処方に用いられる界面活性剤を使用した処方である比較例４～１２を調製し、その性状を目視で観察した。結果を表３に示す。
なお、各実施例及び比較例による点眼剤の目視による観察した結果は、ルリコナゾールの不溶分が視認できず、点眼剤に濁りがない場合には「澄明」とした。また、ルリコナゾールの不溶分が視認された場合には、「不溶」と記載するか、または点眼剤全体の性状を「二層に分離」の表現により記載した。 <Comparative Examples 4 to 12>
According to the formulations shown in Table 3, Comparative Examples 4 to 12, which are formulations using surfactants other than the surfactant of the present invention and commonly used in eye drops formulations, were prepared in the same manner as in Example 1, and their properties were visually observed. Table 3 shows the results.
As a result of visual observation of the eye drops according to each of the examples and comparative examples, when insoluble matter of luliconazole was not visible and the eye drops were not cloudy, they were rated as "clear". In addition, when an insoluble portion of luliconazole was visually observed, it was described as "insoluble", or the properties of the entire ophthalmic solution were described as "separated into two layers".
なお、表１～３中の各種成分のパーセント濃度は、エタノール以外は点眼剤全体に対する各種成分の質量対容量パーセント濃度（ｗ／ｖ％）を示し、エタノールは容量対容量パーセント濃度（ｖ／ｖ％）を示す。また、商品名で記載した各種界面活性剤は以下の一般名に対応する。
The percentage concentration of each component in Tables 1 to 3 indicates the mass-to-volume percent concentration (w/v%) of each component with respect to the entire eye drop, except for ethanol, and ethanol indicates the volume-to-volume percent concentration (v/v%). In addition, various surfactants described as trade names correspond to the following general names.
ユニルーブ７０ＤＰ－９５０Ｂ： ポリオキシエチレン（２００）ポリオキシプロピレングリコール（７０）
ＨＣＯ－６０： ポリオキシエチレン硬化ヒマシ油６０
ＰＶＰ Ｋ３０： ポビドン Ｋ３０（第一工業製薬社製）
ＰＥＧ４０００： マクロゴール４０００（東京化成工業製）
ＭＹＳ－４０ＭＶ： ステアリン酸ポリオキシル４０（日光ケミカルズ製）
ＴＯ－１０Ｖ： ポリソルベート８０（日光ケミカルズ製）
ＭＹＳ－１０Ｖ： モノステアリン酸ポリエチレングリコール（１０Ｅ．０．）（日光ケミカルズ製） Unilube 70DP-950B: polyoxyethylene (200) polyoxypropylene glycol (70)
HCO-60: Polyoxyethylene hydrogenated castor oil 60
PVP K30: Povidone K30 (Daiichi Kogyo Seiyaku Co., Ltd.)
PEG4000: Macrogol 4000 (manufactured by Tokyo Chemical Industry Co., Ltd.)
MYS-40MV: Polyoxyl stearate 40 (manufactured by Nikko Chemicals)
TO-10V: Polysorbate 80 (manufactured by Nikko Chemicals)
MYS-10V: Polyethylene glycol monostearate (10E.0.) (manufactured by Nikko Chemicals)
ＨＣＯ－６０： ポリオキシエチレン硬化ヒマシ油６０
ＰＶＰ Ｋ３０： ポビドン Ｋ３０（第一工業製薬社製）
ＰＥＧ４０００： マクロゴール４０００（東京化成工業製）
ＭＹＳ－４０ＭＶ： ステアリン酸ポリオキシル４０（日光ケミカルズ製）
ＴＯ－１０Ｖ： ポリソルベート８０（日光ケミカルズ製）
ＭＹＳ－１０Ｖ： モノステアリン酸ポリエチレングリコール（１０Ｅ．０．）（日光ケミカルズ製） Unilube 70DP-950B: polyoxyethylene (200) polyoxypropylene glycol (70)
HCO-60: Polyoxyethylene hydrogenated castor oil 60
PVP K30: Povidone K30 (Daiichi Kogyo Seiyaku Co., Ltd.)
PEG4000: Macrogol 4000 (manufactured by Tokyo Chemical Industry Co., Ltd.)
MYS-40MV: Polyoxyl stearate 40 (manufactured by Nikko Chemicals)
TO-10V: Polysorbate 80 (manufactured by Nikko Chemicals)
MYS-10V: Polyethylene glycol monostearate (10E.0.) (manufactured by Nikko Chemicals)
表１の結果から、本願発明の点眼剤にかかる処方はルリコナゾールを溶解可能な点眼剤処方であることがわかる。また、表２の結果から、本発明の点眼剤にかかる処方で用いた２種の界面活性剤を使用ない場合、ルリコナゾールを溶解可能な点眼剤処方は調製できないことがわかる。さらに、表３の結果から、点眼剤に使用する他の非イオン界面活性剤への代替はできず、本発明の点眼剤にかかる処方で用いた２種の界面活性剤が、本発明の課題解決において特別で顕著な効果を有する成分であることがわかる。
From the results in Table 1, it can be seen that the formulation of the eye drops of the present invention is an eye drop formulation capable of dissolving luliconazole. Moreover, from the results in Table 2, it can be seen that an eye drop formulation capable of dissolving luliconazole cannot be prepared without using the two surfactants used in the eye drop formulation of the present invention. Furthermore, from the results in Table 3, it can be seen that the nonionic surfactants used in the eye drops cannot be substituted, and that the two surfactants used in the prescription of the eye drops of the present invention are components having special and remarkable effects in solving the problems of the present invention.
本発明は、ルリコナゾールを有効成分とする抗真菌薬の点眼剤、特に水性点眼剤を提供することができる。
The present invention can provide an antifungal eye drop containing luliconazole as an active ingredient, particularly an aqueous eye drop.
Claims (12)
- １）ルリコナゾールと、２）ベンジルアルコールと、３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種とを含有する、点眼剤。 An ophthalmic solution containing 1) luliconazole, 2) benzyl alcohol, and 3) one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil.
- ルリコナゾールの含有量が、点眼剤全体に対して０．０３～０．８ｗ／ｖ％である、請求項１に記載の点眼剤。 The ophthalmic solution according to claim 1, wherein the content of luliconazole is 0.03 to 0.8 w/v% relative to the total ophthalmic solution.
- ベンジルアルコールの含有量が、点眼剤全体に対して１．５～７．０ｗ／ｖ％である、請求項１または２に記載の点眼剤。 The ophthalmic solution according to claim 1 or 2, wherein the content of benzyl alcohol is 1.5 to 7.0 w/v% with respect to the whole ophthalmic solution.
- ３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレンポリオキシプロピレングリコールを含み、ポリオキシエチレンポリオキシプロピレングリコールの含有量が、点眼剤全体に対して１．０～２５ｗ／ｖ％である、請求項１乃至３いずれか１項に記載の点眼剤。 3) The eye drop according to any one of claims 1 to 3, which contains polyoxyethylene polyoxypropylene glycol as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, and the content of polyoxyethylene polyoxypropylene glycol is 1.0 to 25 w/v% with respect to the entire eye drop.
- ３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレン硬化ヒマシ油を含み、ポリオキシエチレン硬化ヒマシ油の含有量が、点眼剤全体に対して０．５～２５ｗ／ｖ％である、請求項１乃至４いずれか１項に記載の点眼剤。 3) The ophthalmic solution according to any one of claims 1 to 4, which contains polyoxyethylene hydrogenated castor oil as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, and the content of polyoxyethylene hydrogenated castor oil is 0.5 to 25 w/v% with respect to the entire eye drop.
- ルリコナゾールの含有量が点眼剤全体に対して０．０５～０．５ｗ／ｖ％であり、ベンジルアルコールの含有量が点眼剤全体に対して２．０～５．２ｗ／ｖ％であり、かつポリオキシエチレンポリオキシプロピレングリコールの含有量が点眼剤全体に対して２．０～２０ｗ／ｖ％であるか、またはポリオキシエチレン硬化ヒマシ油の含有量が、点眼剤全体に対して１．０～２０ｗ／ｖ％である、請求項１に記載の点眼剤。 Claim 1, wherein the content of luliconazole is 0.05-0.5 w/v% of the entire eye drop, the content of benzyl alcohol is 2.0-5.2 w/v% of the entire eye drop, and the content of polyoxyethylene polyoxypropylene glycol is 2.0-20 w/v% of the entire eye drop, or the content of polyoxyethylene hydrogenated castor oil is 1.0-20 w/v% of the entire eye drop. Eye drops as described.
- ３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレンポリオキシプロピレングリコールを含み、ポリオキシエチレンポリオキシプロピレングリコールが、ポリオキシエチレン（２００）ポリオキシプロピレングリコール（７０）である、請求項１乃至６いずれか１項に記載の点眼剤。 3) The ophthalmic solution according to any one of claims 1 to 6, which contains polyoxyethylene polyoxypropylene glycol as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, and the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (200) polyoxypropylene glycol (70).
- ３）ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種としてポリオキシエチレン硬化ヒマシ油を含み、ポリオキシエチレン硬化ヒマシ油が、ポリオキシエチレン硬化ヒマシ油６０である、請求項１乃至７いずれか１項に記載の点眼剤。 3) The ophthalmic solution according to any one of claims 1 to 7, which contains polyoxyethylene hydrogenated castor oil as one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil, and the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60.
- 点眼剤が水性点眼剤である、請求項１乃至８いずれか１項に記載の点眼剤。 The ophthalmic solution according to any one of claims 1 to 8, which is an aqueous ophthalmic solution.
- 増粘剤、糖類、抗酸化剤、防腐剤、溶解補助剤、ｐＨ調節剤、等張化剤、清涼化剤、緩衝剤および安定化剤から選択される１種または２種以上の添加物をさらに含有する請求項１乃至９いずれか１項に記載の点眼剤。 The ophthalmic solution according to any one of claims 1 to 9, further comprising one or more additives selected from thickeners, saccharides, antioxidants, preservatives, solubilizers, pH adjusters, tonicity agents, cooling agents, buffers and stabilizers.
- 眼科分野の真菌症治療剤である請求項１乃至１０いずれか１項に記載の点眼剤。 The ophthalmic solution according to any one of claims 1 to 10, which is a therapeutic agent for mycoses in the field of ophthalmology.
- ルリコナゾールをベンジルアルコールに溶解して得られる溶液に、精製水で希釈した、ポリオキシエチレンポリオキシプロピレングリコールおよびポリオキシエチレン硬化ヒマシ油から選択される１種または２種を添加し、さらに精製水で希釈することを特徴とする、請求項１乃至１１いずれか１項に記載の点眼剤の製造方法。 The method for producing the ophthalmic solution according to any one of claims 1 to 11, characterized by adding one or two selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil diluted with purified water to a solution obtained by dissolving luliconazole in benzyl alcohol, and further diluting with purified water.
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| JP2014152135A (en) * | 2013-02-08 | 2014-08-25 | Pola Pharma Inc | Pharmaceutical compositions |
| WO2019070221A1 (en) * | 2017-10-03 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Topical pharmaceutical compositions of luliconazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2014152135A (en) * | 2013-02-08 | 2014-08-25 | Pola Pharma Inc | Pharmaceutical compositions |
| WO2019070221A1 (en) * | 2017-10-03 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Topical pharmaceutical compositions of luliconazole |
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| DAISUKE TODOKORO, TAKASHI SUZUKI, SHUN TAMURA, KOICHI MAKIMURA, HIDEYO YAMAGUCHI, HIDEO AKIYAMA: "GK-05-4 Antifungal activity of luliconazole against Fusarium isolated from keratitis", FOURSOME 2018 TOKYO PROGRAM AND LECTURE ABSTRACTS; 55TH JAPANESE SOCIETY FOR EYE INFECTIOUS DISEASES: JULY 14TH (SAT) - 15TH (SUN), 2018, JAPANESE SOCIETY OF OCULAR INFECTIOUS DISEASES, JP, 14 July 2018 (2018-07-14), JP, pages 68, XP009548017 * |
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