JP6635974B2 - Epinastine-containing ophthalmic solution - Google Patents
Epinastine-containing ophthalmic solution Download PDFInfo
- Publication number
- JP6635974B2 JP6635974B2 JP2017085128A JP2017085128A JP6635974B2 JP 6635974 B2 JP6635974 B2 JP 6635974B2 JP 2017085128 A JP2017085128 A JP 2017085128A JP 2017085128 A JP2017085128 A JP 2017085128A JP 6635974 B2 JP6635974 B2 JP 6635974B2
- Authority
- JP
- Japan
- Prior art keywords
- ophthalmic solution
- salt
- acid
- epinastine
- preservative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000002997 ophthalmic solution Substances 0.000 title claims description 63
- 229940054534 ophthalmic solution Drugs 0.000 title claims description 62
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims description 55
- 229960003449 epinastine Drugs 0.000 title claims description 40
- 230000002335 preservative effect Effects 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 62
- 239000003755 preservative agent Substances 0.000 claims description 44
- 239000000872 buffer Substances 0.000 claims description 10
- 239000003002 pH adjusting agent Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 5
- 239000006172 buffering agent Substances 0.000 claims description 3
- 239000007951 isotonicity adjuster Substances 0.000 claims description 3
- 230000003204 osmotic effect Effects 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000012929 tonicity agent Substances 0.000 description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
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- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
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- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
- 229960004504 chlorhexidine hydrochloride Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002526 disodium citrate Substances 0.000 description 1
- 235000019262 disodium citrate Nutrition 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000008378 epithelial damage Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
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- 230000002538 fungal effect Effects 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 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 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
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- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229940111695 potassium tartrate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 description 1
- 235000019250 sodium sorbate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- HLWRUJAIJJEZDL-UHFFFAOYSA-M sodium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC([O-])=O HLWRUJAIJJEZDL-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、０．０７５％（ｗ／ｖ）超の濃度のエピナスチン又はその塩を含有する点眼液であって、実質的に防腐剤および防腐作用を有する成分を含有しないことを特徴とする、点眼液（以下、「本発明の点眼液」ともいう）に関する。 The present invention relates to an ophthalmic solution containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v), which is substantially free of a preservative and a component having a preservative action. The present invention relates to an ophthalmic solution (hereinafter, also referred to as “the ophthalmic solution of the present invention”).
点眼液は、繰り返しの使用に伴う菌類等の繁殖を防止するため、一定以上の防腐対策が要求される。そのため、点眼液には通常、防腐剤が配合されている。防腐剤として例えば、ベンザルコニウム塩化物は水溶性であり、化学的に安定で、他の防腐剤と比較しても防腐効力が高いので、汎用的に点眼液に使用される。しかし、ベンザルコニウム塩化物には細胞障害性があり、曝露量が増えると角膜上皮障害を引き起こす可能性が増大する。そのため、特にベンザルコニウム塩化物に過敏な反応を示す患者や重度の角膜上皮障害を有する患者には使用することができない。 Ophthalmic solutions are required to have a certain level of preservative measures in order to prevent the propagation of fungi and the like due to repeated use. For this reason, preservatives are usually added to eye drops. As a preservative, for example, benzalkonium chloride is water-soluble, chemically stable, and has a high preservative effect as compared with other preservatives. However, benzalkonium chloride is cytotoxic and increasing exposure increases the potential for causing corneal epithelial damage. Therefore, it cannot be used especially for patients who have a hypersensitivity reaction to benzalkonium chloride or patients with severe corneal epithelial disorder.
現在、日本で上市されているアレジオン（登録商標）点眼液０．０５％は、エピナスチン塩酸塩を有効成分とする点眼液であり、ベンザルコニウム塩化物のような防腐剤を添加しない代わりに、防腐作用を有する別の成分（ホウ酸、エデト酸（ＥＤＴＡ））が添加されている（非特許文献１）。つまりエピナスチン又はその塩を含有する点眼液を繰り返し使用するためには、ベンザルコニウム塩化物のような防腐剤を必ずしも含有しなくてもよいが、それに代わる別の防腐作用を有する成分で、防腐効力を担保する必要があることは認識されている。一方で、防腐剤および防腐作用を有する成分のいずれも添加されていない、エピナスチン又はその塩を含有する点眼液は一切知られていない。 Currently, 0.05% of Alesion (registered trademark) ophthalmic solution marketed in Japan is an ophthalmic solution containing epinastine hydrochloride as an active ingredient, and instead of not adding a preservative such as benzalkonium chloride, Another component having antiseptic action (boric acid, edetic acid (EDTA)) is added (Non-Patent Document 1). In other words, in order to repeatedly use an ophthalmic solution containing epinastine or a salt thereof, it is not always necessary to contain a preservative such as benzalkonium chloride, but another component having an antiseptic action instead of the preservative may be used. It is recognized that efficacy needs to be guaranteed. On the other hand, there is no known ophthalmic solution containing epinastine or a salt thereof to which neither a preservative nor a component having a preservative action is added.
なお、上市されている点眼液において、防腐剤および防腐作用を有する成分のいずれも添加されていない点眼液は知られているが、それらはユニットドーズ型（１回使い切りタイプ）のものまたは防腐剤フリー容器（防腐効果を発揮するための特別な構造を有する容器）に保存されているものであり、有効成分自身が防腐作用を発揮するような点眼液は知られていない。つまり、エピナスチン又はその塩自身が防腐作用を有することは一切知られていない。 In addition, in the marketed ophthalmic solution, an ophthalmic solution to which neither a preservative nor a component having an antiseptic action is added is known, but these are unit dose type (single use type) or preservative. It is stored in a free container (a container having a special structure for exhibiting an antiseptic effect), and there is no known ophthalmic solution in which the active ingredient itself exerts an antiseptic effect. That is, it is not known at all that epinastine or a salt thereof itself has a preservative action.
したがって、実質的に防腐剤および防腐作用を有する成分を含有しない、エピナスチン又はその塩を含有する点眼液を提供することは興味深い課題である。 Therefore, it is an interesting subject to provide an ophthalmic solution containing epinastine or a salt thereof, which is substantially free of a preservative and a component having a preservative action.
本発明者らは、防腐剤および防腐作用を有する成分のいずれも添加されていない、またはそれらの量が減量されたエピナスチン又はその塩を含有する点眼液を見出すために鋭意研究を行ったところ、点眼液中のエピナスチン又はその塩の濃度を０．０７５％（ｗ／ｖ）超とすることにより、実質的に防腐剤または防腐作用を有する成分を含有することなく、十分な防腐効果が得られることを見出し、本発明に至った。具体的に、本発明は以下を提供する。
（１）０．０７５％（ｗ／ｖ）超の濃度のエピナスチン又はその塩を含有する点眼液であって、実質的に防腐剤および防腐作用を有する成分を含有しない、点眼液。
（２）０．１％〜５．０％（ｗ／ｖ）の濃度のエピナスチン又はその塩を含有する、（１）に記載の点眼液。
（３）エピナスチン又はその塩が、エピナスチン塩酸塩である、（１）または（２）に記載の点眼液。
（４）防腐剤および防腐作用を有する成分が、塩化ベンザルコニウム、クロルヘキシジン又はその塩、ホウ酸、ホウ砂、およびエデト酸又はその塩からなる群から選択される少なくとも一つの成分である、（１）に記載の点眼液。
（５）有効成分として０．０７５％（ｗ／ｖ）超の濃度のエピナスチン又はその塩のみを含有し、添加物として緩衝剤、等張化剤、およびｐＨ調節剤のみを含有する、点眼液。
（６）０．１％〜５．０％（ｗ／ｖ）の濃度のエピナスチン又はその塩を含有する、（５）に記載の点眼液。
（７）エピナスチン又はその塩が、エピナスチン塩酸塩である、（５）または（６）に記載の点眼液。
（８）緩衝剤がリン酸又はその塩である（５）〜（７）のいずれか１記載の点眼液。
（９）等張化剤がイオン性等張化剤である（５）〜（８）のいずれか１記載の点眼液。
（１０）マルチドーズ型点眼液である、（１）〜（９）のいずれか１記載の点眼液。
（１１）実質的に防腐剤および防腐作用を有する成分を含有せず、エピナスチン又はその塩を０．０７５％（ｗ／ｖ）超の濃度で配合することで、エピナスチン又はその塩を含有する点眼液に防腐効力を付与する方法。
（１２）実質的に防腐剤および防腐作用を有する成分を含有せず、エピナスチン又はその塩を０．０７５％（ｗ／ｖ）超の濃度で配合することで、エピナスチン又はその塩を含有する点眼液の防腐効力を維持する方法。
なお、前記（１）から（１２）の各構成は、任意に２以上を選択して組み合わせることができる。
さらに、本発明は以下も提供する。
（１３）治療が必要な患者に、治療上の有効量の（１）〜（１０）のいずれか１記載の点眼液を投与することを特徴とする、アレルギー性結膜炎を治療および／または予防する方法。
（１４）アレルギー性結膜炎の治療および／または予防に使用する、（１）〜（１０）のいずれか１記載の点眼液。
The present inventors have conducted intensive studies to find an ophthalmic solution containing epinastine or a salt thereof to which neither a preservative nor a component having a preservative action is added, or the amount of which is reduced, When the concentration of epinastine or a salt thereof in the ophthalmic solution is more than 0.075% (w / v), a sufficient preservative effect can be obtained without substantially containing a preservative or a component having a preservative action. This led to the present invention. Specifically, the present invention provides the following.
(1) An ophthalmic solution containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v), which does not substantially contain a preservative and a component having an antiseptic action.
(2) The ophthalmic solution according to (1), which contains epinastine or a salt thereof at a concentration of 0.1% to 5.0% (w / v).
(3) The ophthalmic solution according to (1) or (2), wherein the epinastine or a salt thereof is epinastine hydrochloride.
(4) the preservative and the component having a preservative action are at least one component selected from the group consisting of benzalkonium chloride, chlorhexidine or a salt thereof, boric acid, borax, and edetic acid or a salt thereof; The ophthalmic solution according to 1).
(5) An ophthalmic solution containing only epinastine or a salt thereof at a concentration of more than 0.075% (w / v) as an active ingredient, and containing only a buffer, an isotonic agent, and a pH adjuster as additives. .
(6) The ophthalmic solution according to (5), which contains epinastine or a salt thereof at a concentration of 0.1% to 5.0% (w / v).
(7) The ophthalmic solution according to (5) or (6), wherein the epinastine or a salt thereof is epinastine hydrochloride.
(8) The ophthalmic solution according to any one of (5) to (7), wherein the buffer is phosphoric acid or a salt thereof.
(9) The ophthalmic solution according to any one of (5) to (8), wherein the tonicity agent is an ionic tonicity agent.
(10) The ophthalmic solution according to any one of (1) to (9), which is a multi-dose type ophthalmic solution.
(11) Ophthalmic solution containing epinastine or a salt thereof by containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v) without substantially containing a preservative and a component having a preservative action A method of imparting a preservative effect to a liquid.
(12) Ophthalmic solution containing epinastine or a salt thereof by blending epinastine or a salt thereof at a concentration of more than 0.075% (w / v) without substantially containing a preservative and a component having a preservative action A method for maintaining the preservative efficacy of a liquid.
In addition, each of the above-described configurations (1) to (12) can be arbitrarily selected from two or more and combined.
Further, the present invention also provides the following.
(13) treating and / or preventing allergic conjunctivitis, which comprises administering a therapeutically effective amount of the ophthalmic solution according to any one of (1) to (10) to a patient in need of treatment. Method.
(14) The ophthalmic solution according to any one of (1) to (10), which is used for treatment and / or prevention of allergic conjunctivitis.
本発明は、防腐剤および防腐作用を有する成分のいずれも添加しなくても防腐効果を有する、エピナスチン又はその塩を含有する点眼液を得ることができる。 According to the present invention, an ophthalmic solution containing epinastine or a salt thereof having an antiseptic effect can be obtained without adding any of a preservative and a component having an antiseptic effect.
以下に、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明において、「エピナスチン」とは、化学名（±）−３−Ａｍｉｎｏ−９，１３ｂ−ｄｉｈｙｄｒｏ−１Ｈ−ｄｉｂｅｎｚ［ｃ，ｆ］ｉｍｉｄａｚｏ［１，５−ａ］ａｚｅｐｉｎｅで表される化合物であり、また下記式：
本発明の点眼液において、含有されるエピナスチンは塩であってもよく、医薬として許容される塩であれば特に制限はない。塩としては例えば、無機酸との塩、有機酸との塩等が挙げられる。
無機酸との塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。
有機酸との塩としては、酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、アラニン、乳酸、馬尿酸、１，２−エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、没食子酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、硫酸ラウリル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸等との塩が挙げられる。
エピナスチンの塩としては、一塩酸塩（エピナスチン塩酸塩）が特に好ましい。
In the ophthalmic solution of the present invention, the contained epinastine may be a salt, and there is no particular limitation as long as it is a pharmaceutically acceptable salt. Examples of the salt include a salt with an inorganic acid and a salt with an organic acid.
Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
As salts with organic acids, acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Salts with toluene sulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid and the like can be mentioned.
As the salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferred.
本発明において、含有されるエピナスチン又はその塩は、水和物又は溶媒和物の形態をとってもよい。 In the present invention, the contained epinastine or a salt thereof may be in the form of a hydrate or a solvate.
本発明において、エピナスチン又はその塩の含有量は、０．０７５％（ｗ／ｖ）超であれば十分であるが、０．０８５％（ｗ／ｖ）以上、または０．１％（ｗ／ｖ）以上とすることもでき、その上限は眼科製剤として許容される濃度であればよく、例えば５％（ｗ／ｖ）である。エピナスチン又はその塩の含有量としては、０．１〜５．０％（ｗ／ｖ）が好ましく、０．１〜３．０％（ｗ／ｖ）がより好ましく、０．１〜１．０％（ｗ／ｖ）がさらに好ましい。特に好ましくは、０．１〜０．５％（ｗ／ｖ）、０．１〜０．３％（ｗ／ｖ）であるが、０．１％（ｗ／ｖ）、０．２％（ｗ／ｖ）、０．３％（ｗ／ｖ）、０．４％（ｗ／ｖ）、０．５％（ｗ／ｖ）もさらにより好ましい。
なお、本発明においてエピナスチンの塩が含有される場合、これらの値はエピナスチンの塩の含有量である。「％（ｗ／ｖ）」は、本発明の点眼液１００ｍＬ中に含まれる対象成分（ここでは、エピナスチン又はその塩）の質量（ｇ）を意味する。以下、特に断りがない限り同様とする。
In the present invention, the content of epinastine or a salt thereof is sufficient if it exceeds 0.075% (w / v), but is 0.085% (w / v) or more, or 0.1% (w / v). v) or more, and the upper limit may be any concentration acceptable for ophthalmic preparations, for example, 5% (w / v). The content of epinastine or a salt thereof is preferably 0.1 to 5.0% (w / v), more preferably 0.1 to 3.0% (w / v), and 0.1 to 1.0%. % (W / v) is more preferred. Particularly preferred are 0.1 to 0.5% (w / v) and 0.1 to 0.3% (w / v), but 0.1% (w / v) and 0.2% (w / v). w / v), 0.3% (w / v), 0.4% (w / v), 0.5% (w / v) are even more preferred.
In the present invention, when a salt of epinastine is contained, these values are the contents of the salt of epinastine. “% (W / v)” means the mass (g) of the target component (here, epinastine or a salt thereof) contained in 100 mL of the ophthalmic solution of the present invention. The same applies hereinafter unless otherwise specified.
本発明において、防腐剤としては例えば、塩化ベンザルコニウム、臭化ベンザルコニウム、塩化ベンゼトニウム、クロルヘキシジン又はその塩、ソルビン酸又はその塩、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、クロロブタノール等が挙げられる。
クロルヘキシジン又はその塩としては、クロルヘキシジングルコン酸塩、クロルヘキシジン塩酸、クロルヘキシジン酢酸等が挙げられる。
ソルビン酸又はその塩としては、ソルビン酸ナトリウム、ソルビン酸カリウム等が挙げられる。
In the present invention, examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or a salt thereof, sorbic acid or a salt thereof, methyl paraoxybenzoate, methyl paraoxybenzoate, propyl paraoxybenzoate and chlorobutanol. Can be
Examples of chlorhexidine or a salt thereof include chlorhexidine gluconate, chlorhexidine hydrochloride, and chlorhexidine acetic acid.
Examples of sorbic acid or a salt thereof include sodium sorbate and potassium sorbate.
本発明において、防腐作用を有する成分としては例えば、ホウ酸、ホウ砂、エデト酸又はその塩等が挙げられる。
エデト酸又はその塩としては、エデト酸一ナトリウム、エデト酸二ナトリウム、エデト酸四ナトリウム等が挙げられる。
In the present invention, examples of the component having an antiseptic effect include boric acid, borax, edetic acid, and salts thereof.
Examples of the edetic acid or a salt thereof include monosodium edetate, disodium edetate, tetrasodium edetate, and the like.
本発明において、「防腐剤および防腐作用を有する成分を含有しない」とは、点眼液に該「防腐剤および防腐作用を有する成分」を一切含有しない、または該「防腐剤および防腐作用を有する成分」が単独で第１７改正日本薬局方に記載の保存効力試験法に適合しない程度に含まれる、ことを指す。上記の「単独で第１７改正日本薬局方に記載の保存効力試験法に適合しない程度」とは、例えばＥＤＴＡであれば０．０１％（ｗ／ｖ）または０．０２％（ｗ／ｖ）程度であってもよいが、これはＥＤＴＡのもつ防腐作用ではなく安定化作用を得るために点眼液に含まれる。また、例えばホウ酸であれば０．０１％（ｗ／ｖ）または０．０２％（ｗ／ｖ）程度であってもよいが、これはホウ酸のもつ防腐作用ではなく緩衝作用を得るために点眼液に含まれる。本発明において「実質的に」とは本質が変わらなければよく、従って本発明において、「実質的に防腐剤および防腐作用を有する成分を含有しない」とは、該「防腐剤および防腐作用を有する成分」を一切含有しない、または防腐効果を意図しない場合において該「防腐剤および防腐作用を有する成分」が単独で第１７改正日本薬局方に記載の保存効力試験法に適合しない程度に含まれる、ことを指す。 In the present invention, "containing no preservative and preservative component" means that the ophthalmic solution does not contain any of the "preservative and preservative component", or the "preservative and preservative component" "Alone is included to such an extent that it does not conform to the preservative efficacy test method described in the 17th revised Japanese Pharmacopoeia. The above-mentioned “to the extent that it alone does not conform to the preservative efficacy test method described in the 17th revised Japanese Pharmacopoeia” means, for example, 0.01% (w / v) or 0.02% (w / v) of EDTA. It may be included in the ophthalmic solution in order to obtain a stabilizing effect, not a preservative effect of EDTA. Further, for example, in the case of boric acid, the concentration may be about 0.01% (w / v) or 0.02% (w / v). Contained in eye drops. In the present invention, “substantially” does not need to change its essence. Therefore, in the present invention, “contains substantially no preservative and preservative component” means the “preservative and preservative In the case where it does not contain any `` components '' or does not intend to have a preservative effect, the `` preservatives and components having a preservative effect '' are included alone to the extent that they do not conform to the preservative efficacy test method described in the 17th revised Japanese Pharmacopoeia, Refers to
本発明において、マルチドーズ型点眼液とは、マルチドーズ型容器に入れられた点眼液を指す。マルチドーズ型容器とは、複数回使用することを目的にキャップ等の開閉を自由に行えるようにした容器であり、開封後一定期間に渡って使用することができ、持ち運びも容易である。本発明において、容器本体の大きさや形状に特に制限はなく、ユニットドーズ型容器（１回使い切りタイプ）であってもよいが、点眼液に防腐効果が付与されているためマルチドーズ型容器がより好ましい。逆流防止機能等の防腐効果を発揮するための特別な構造を有する容器、例えばＰＦＭＤ（Ｐｒｅｓｅｒｖａｔｉｖｅ Ｆｒｅｅ Ｍｕｌｔｉ Ｄｏｓｅ）容器は含まれない。なお、容器の素材に特に制限はなく、一般に汎用される容器、例えば、ポリエチレン（ＰＥ）製、ポリプロピレン（ＰＰ）製、ポリエチレンテレフタレート（ＰＥＴ）製等の容器を用いることができる。 In the present invention, the multidose-type ophthalmic solution refers to an ophthalmic solution placed in a multidose-type container. A multidose container is a container that can be freely opened and closed with a cap or the like for the purpose of being used a plurality of times, and can be used for a certain period of time after being opened, and is easy to carry. In the present invention, the size and shape of the container body are not particularly limited, and may be a unit dose type container (single use type). However, since the ophthalmic solution has an antiseptic effect, a multidose type container is more preferable. preferable. A container having a special structure for exhibiting a preservative effect such as a backflow prevention function, for example, a PFMD (Preservative Free Multi Dose) container is not included. The material of the container is not particularly limited, and generally used containers such as containers made of polyethylene (PE), polypropylene (PP), and polyethylene terephthalate (PET) can be used.
本発明において、点眼液は、構成成分が全て溶解または一部懸濁していてもよいが、構成成分が全て溶解している液状がより好ましい。 In the present invention, the ophthalmic solution may have all of the components dissolved or partially suspended, but is more preferably a liquid in which all of the components are dissolved.
本発明において、点眼液に緩衝剤を配合する場合の緩衝剤は、医薬品の添加物として使用可能な緩衝剤を適宜配合することができるが、例えば、リン酸又はその塩、クエン酸又はその塩、酢酸又はその塩、炭酸又はその塩、酒石酸又はその塩、ε−アミノカプロン酸、トロメタモール等が挙げられ、これらの水和物又は溶媒和物であってもよい。
リン酸又はその塩としては、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられ、これらの水和物であってもよい。
クエン酸又はその塩としては、クエン酸ナトリウム、クエン酸二ナトリウム等が挙げられ、これらの水和物であってもよい。
酢酸又はその塩としては、酢酸ナトリウム、酢酸カリウム等が挙げられ、これらの水和物であってもよい。
炭酸又はその塩としては、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、これらの水和物であってもよい。
酒石酸又はその塩としては、酒石酸ナトリウム、酒石酸カリウム等が挙げられ、これらの水和物であってもよい。
本発明において、点眼液に緩衝剤を配合する場合の緩衝剤は、リン酸又はその塩がより好ましく、リン酸二水素ナトリウム、リン酸水素二ナトリウムまたはこれらの水和物が特に好ましい。また緩衝剤を２以上一緒に用いてもよい。
本発明において、点眼液に緩衝剤を配合する場合の緩衝剤の含有量は、緩衝剤の種類などにより適宜調整することができるが、０．００１〜１０％（ｗ／ｖ）が好ましく、０．０１〜５％（ｗ／ｖ）がより好ましく、０．１〜３％（ｗ／ｖ）がさらに好ましく、０．２〜１．５％（ｗ／ｖ）が最も好ましい。
In the present invention, when a buffering agent is added to the ophthalmic solution, a buffering agent that can be used as a pharmaceutical additive can be appropriately added, for example, phosphoric acid or a salt thereof, citric acid or a salt thereof. Acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol, and the like, and a hydrate or a solvate thereof may be used.
Examples of phosphoric acid or a salt thereof include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the like. There may be.
Examples of citric acid or a salt thereof include sodium citrate, disodium citrate and the like, and hydrates thereof may be used.
Examples of acetic acid or a salt thereof include sodium acetate, potassium acetate and the like, and hydrates thereof may be used.
Examples of the carbonic acid or a salt thereof include sodium carbonate, sodium hydrogencarbonate and the like, and hydrates thereof may be used.
Examples of tartaric acid or a salt thereof include sodium tartrate and potassium tartrate, and hydrates thereof.
In the present invention, when a buffer is added to the ophthalmic solution, the buffer is more preferably phosphoric acid or a salt thereof, and particularly preferably sodium dihydrogen phosphate, disodium hydrogen phosphate or a hydrate thereof. Also, two or more buffers may be used together.
In the present invention, the content of the buffer when the buffer is added to the ophthalmic solution can be appropriately adjusted depending on the type of the buffer, and is preferably 0.001 to 10% (w / v), 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is further preferable, and 0.2 to 1.5% (w / v) is most preferable.
本発明において、点眼液に等張化剤を配合する場合の等張化剤は、医薬品の添加物として使用可能な等張化剤を適宜配合することができるが、例えば、イオン性等張化剤や非イオン性等張化剤等が挙げられる。
イオン性等張化剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等が挙げられる。
非イオン性等張化剤としては、グリセリン、プロピレングリコール、ポリエチレングリコール、ソルビトール、マンニトール、トレハロース、マルトース、スクロース等が挙げられる。
本発明において、点眼液に等張化剤を配合する場合の等張化剤は、イオン性等張化剤がより好ましく、塩化ナトリウムが特に好ましい。また等張化剤を２以上一緒に用いてもよい。
本発明において、点眼液に等張化剤を配合する場合の等張化剤の含有量は、等張化剤の種類などにより適宜調整することができるが、０．００１〜１０％（ｗ／ｖ）が好ましく、０．０１〜５％（ｗ／ｖ）がより好ましく、０．１〜１％（ｗ／ｖ）がさらに好ましく、０．２〜０．５％（ｗ／ｖ）が最も好ましい。
本発明において、点眼液の浸透圧比は眼科製剤に許容される範囲内にあればよく、例えば０．５〜２．０であり、０．７〜１．６が好ましく、０．８〜１．４がより好ましく、０．９〜１．２がさらに好ましい。
In the present invention, when the tonicity agent is blended with the ophthalmic solution, the tonicity agent which can be used as an additive for pharmaceuticals can be appropriately blended with an isotonicity agent. Agents and nonionic tonicity agents.
Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
Examples of the nonionic tonicity agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose and the like.
In the present invention, when a tonicity agent is added to the ophthalmic solution, the tonicity agent is more preferably an ionic tonicity agent, and particularly preferably sodium chloride. Two or more tonicity agents may be used together.
In the present invention, the content of the tonicity agent in the case where the tonicity agent is blended with the ophthalmic solution can be appropriately adjusted depending on the type of the tonicity agent, but is preferably 0.001 to 10% (w / v) is preferable, 0.01 to 5% (w / v) is more preferable, 0.1 to 1% (w / v) is further preferable, and 0.2 to 0.5% (w / v) is most preferable. preferable.
In the present invention, the osmotic pressure ratio of the ophthalmic solution may be within the range acceptable for ophthalmic preparations, for example, 0.5 to 2.0, preferably 0.7 to 1.6, and more preferably 0.8 to 1. 4, more preferably 0.9 to 1.2.
本発明において、点眼液にｐＨ調節剤を配合する場合のｐＨ調節剤は、医薬品の添加物として使用可能なｐＨ調節剤を適宜配合することができるが、例えば、酸又は塩基であり、酸としては例えば、塩酸、リン酸、クエン酸、酢酸等、塩基としては例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。
本発明において、点眼液のｐＨは眼科製剤に許容される範囲内にあればよく、４．０〜８．０の範囲内が好ましく、６．０〜８．０がより好ましく、６．５〜７．５がさらに好ましい。特に好ましいｐＨは、６．７〜７．３であるが、６．７、６．８、６．９、７．０、７．１、７．２、７．３もさらにより好ましい。
In the present invention, when a pH adjuster is added to the ophthalmic solution, a pH adjuster that can be used as an additive for pharmaceuticals can be appropriately added, for example, an acid or a base. For example, hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like, and as the base, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like can be mentioned.
In the present invention, the pH of the ophthalmic solution may be within the range acceptable for ophthalmic preparations, preferably in the range of 4.0 to 8.0, more preferably 6.0 to 8.0, and more preferably 6.5 to 8.0. 7.5 is more preferred. Particularly preferred pH is 6.7 to 7.3, but 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 are even more preferred.
本発明において、上記緩衝剤、等張化剤、およびｐＨ調節剤以外にも必要に応じて眼科製剤に許容される添加物（防腐剤および防腐作用を有する成分を除く）を１以上加えることができ、その添加物としては例えば、可溶化剤、安定化剤、抗酸化剤、粘稠化剤等を加えることができる。また、特に断りのない限り、エピナスチン又はその塩以外の点眼液に用いられる有効成分を含んでいてもよい。
可溶化剤としては、例えばポリオキシエチレン硬化ヒマシ油、ポビドン、ポリソルベート８０等、安定化剤としては、例えばポビドン、ポリソルベート８０等、抗酸化剤としては、ジブチルヒドロキシトルエン、亜硫酸ナトリウム等、粘稠化剤としては、例えば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等が挙げられる。これらの添加物は眼科製剤に許容される範囲内で加えることができ、例えばそれぞれ２％以下で加えることができ、または０．２％以下、０．０２％以下、０．００２％以下の範囲であっても加えることができる。
In the present invention, one or more additives (excluding preservatives and components having an antiseptic action) acceptable for ophthalmic preparations may be added, if necessary, in addition to the above-mentioned buffer, tonicity agent and pH adjuster. For example, solubilizers, stabilizers, antioxidants, thickeners and the like can be added as additives. Further, unless otherwise specified, it may contain an active ingredient used in eye drops other than epinastine or a salt thereof.
Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, povidone, polysorbate 80, and the like. Examples of the stabilizer include povidone, polysorbate 80, and the like. Examples of the antioxidant include dibutylhydroxytoluene and sodium sulfite. Examples of the agent include a carboxyvinyl polymer and hydroxyethyl cellulose. These additives can be added within the range acceptable for ophthalmic preparations, for example, each can be added at 2% or less, or at 0.2% or less, 0.02% or less, 0.002% or less. Can be added.
本発明の点眼液は、アレルギー性結膜炎の治療剤として有用である。 The ophthalmic solution of the present invention is useful as a therapeutic agent for allergic conjunctivitis.
本発明の点眼液を投与する場合、所望の薬効を奏するのに十分であれば用法用量に特に制限はないが、１回１滴、１日１〜１０回、好ましくは１日２〜６回、より好ましくは１日２〜４回、さらに好ましくは１日２回、１日４回に分けて点眼することができる。また、本発明の点眼液は、コンタクトレンズ装用時においても使用することができる。 When the ophthalmic solution of the present invention is administered, the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, but one drop at a time, 1 to 10 times a day, preferably 2 to 6 times a day. More preferably, the composition can be instilled 2 to 4 times a day, more preferably 2 times a day, and 4 times a day. The ophthalmic solution of the present invention can also be used when wearing a contact lens.
以下に、製剤例および防腐効力試験の結果を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 Hereinafter, the formulation examples and the results of the preservative efficacy test are shown, but these are for better understanding of the present invention, and do not limit the scope of the present invention.
［製剤例］
以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は製剤１ｍＬ中の含量である。
[Formulation example]
The representative preparation examples of the present invention are shown below. In addition, in the following preparation examples, the compounding amount of each component is the content in 1 mL of the preparation.
製剤例１
マルチドーズ型容器（１ｍＬ）中
エピナスチン塩酸塩 １ｍｇ
リン酸二水素ナトリウム ３ｍｇ
塩化ナトリウム ５ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
Formulation Example 1
Epinastine hydrochloride 1mg in multidose type container (1mL)
Sodium dihydrogen phosphate 3mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs
製剤例２
マルチドーズ型容器（１ｍＬ）中
エピナスチン塩酸塩 ３ｍｇ
リン酸二水素ナトリウム ３ｍｇ
リン酸水素二ナトリウム １２ｍｇ
塩化ナトリウム ４ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
Formulation Example 2
Epinastine hydrochloride 3mg in multidose type container (1mL)
Sodium dihydrogen phosphate 3mg
12mg disodium hydrogen phosphate
Sodium chloride 4mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs
防腐効力試験（１）
本試験は、第１７改正日本薬局方に記載の保存効力試験法に準じて実施した。
１．被験製剤の調製
エピナスチン（５０ｍｇ）、リン酸二水素ナトリウム（２５ｍｇ）、リン酸水素二ナトリウム水和物（１２２ｍｇ）、塩化ナトリウム（４０ｍｇ）を水に溶解し濾過滅菌を行い、ｐＨ調節剤と水を加えて全量を１０ｍＬとすることにより、実施例１の製剤を調製した。
Preservative efficacy test (1)
This test was performed according to the preservative efficacy test method described in the 17th revised Japanese Pharmacopoeia.
1. Preparation of test preparation Epinastine (50 mg), sodium dihydrogen phosphate (25 mg), disodium hydrogen phosphate hydrate (122 mg), and sodium chloride (40 mg) were dissolved in water, sterilized by filtration, and a pH adjuster and water Was added to make the total amount 10 mL, thereby preparing the preparation of Example 1.
実施例１
１ｍＬ中
エピナスチン塩酸塩 ５ｍｇ
リン酸二水素ナトリウム ２．５ｍｇ
リン酸水素二ナトリウム水和物 １２．２ｍｇ
塩化ナトリウム ４ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ６．７
Example 1
Epinastine hydrochloride 5mg in 1mL
2.5mg sodium dihydrogen phosphate
12.2 mg disodium hydrogen phosphate hydrate
Sodium chloride 4mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.7
実施例１の調製方法と同様の方法にて、実施例２〜４および比較例１〜２の製剤を調製した。 The preparations of Examples 2 to 4 and Comparative Examples 1 and 2 were prepared in the same manner as the preparation method of Example 1.
実施例２
１ｍＬ中
エピナスチン塩酸塩 ５０ｍｇ
リン酸二水素ナトリウム ２．５ｍｇ
リン酸水素二ナトリウム水和物 １２．２ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ６．７
Example 2
Epinastine hydrochloride 50mg in 1mL
2.5mg sodium dihydrogen phosphate
12.2 mg disodium hydrogen phosphate hydrate
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.7
実施例３
１ｍＬ中
エピナスチン塩酸塩 １ｍｇ
リン酸二水素ナトリウム ２．５ｍｇ
リン酸水素二ナトリウム水和物 １２．２ｍｇ
塩化ナトリウム ４．７ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ６．７
Example 3
Epinastine hydrochloride 1mg in 1mL
2.5mg sodium dihydrogen phosphate
12.2 mg disodium hydrogen phosphate hydrate
4.7 mg of sodium chloride
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.7
実施例４
１ｍＬ中
エピナスチン塩酸塩 ２ｍｇ
リン酸二水素ナトリウム ２．５ｍｇ
リン酸水素二ナトリウム水和物 １２．２ｍｇ
塩化ナトリウム ４．５ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ６．７
Example 4
Epinastine hydrochloride 2mg in 1mL
2.5mg sodium dihydrogen phosphate
12.2 mg disodium hydrogen phosphate hydrate
4.5mg sodium chloride
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.7
比較例１
１ｍＬ中
エピナスチン塩酸塩 ０．５ｍｇ
リン酸二水素ナトリウム ２．５ｍｇ
リン酸水素二ナトリウム水和物 １２．２ｍｇ
塩化ナトリウム ５ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ６．７
Comparative Example 1
Epinastine hydrochloride 0.5mg in 1mL
2.5mg sodium dihydrogen phosphate
12.2 mg disodium hydrogen phosphate hydrate
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.7
比較例２
１ｍＬ中
エピナスチン塩酸塩 ０．７５ｍｇ
リン酸二水素ナトリウム ２．５ｍｇ
リン酸水素二ナトリウム水和物 １２．２ｍｇ
塩化ナトリウム ４．７ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ６．７
Comparative Example 2
Epinastine hydrochloride 0.75mg in 1mL
2.5mg sodium dihydrogen phosphate
12.2 mg disodium hydrogen phosphate hydrate
4.7 mg of sodium chloride
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.7
２．試験方法
接種菌として以下の菌株を使用した。
細菌：
大腸菌，Escherichia Coli ATCC 8739（E.coliともいう）
緑膿菌，Pseudomonas aeruginosa ATCC 9027（P.aeruginosaともいう）
黄色ブドウ球菌，Staphylococcus aureus ATCC 6538（S.aureusともいう）
酵母菌およびカビ類：
カンジダ，Candida albicans ATCC 10231（C.albicansともいう）
クロコウジカビ，Aspergillus brasiliensis ATCC16404（A.brasiliensisともいう）
2. Test method The following strains were used as the inoculum.
Bacteria:
Escherichia coli, Escherichia Coli ATCC 8739 (also called E. coli)
Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 9027 (also called P. aeruginosa)
Staphylococcus aureus ATCC 6538 (also called S. aureus)
Yeasts and molds:
Candida albicans ATCC 10231 (also called C. albicans)
Aspergillus brasiliensis ATCC16404 (also called A. brasiliensis)
各製剤からなる試験試料中の菌液濃度が１０５〜１０６個／ｍＬ（５菌種共）となるように、接種菌液を試験試料に接種した。具体的には、１０７〜１０８ｃｆｕ／ｍＬとなるように接種菌液を調製し、この接種菌液を１０５〜１０６ｃｆｕ／ｍＬとなるように、実施例１〜４及び比較例１〜２の製剤からなる試験試料に各接種菌液を接種し、均一に混合し試料とした。これらの試料を遮光下２０〜２５℃に保存し、各サンプリングポイント（７日後、１４日後、又は２８日後）において、各試料からマイクロピペットで１ｍＬを採取し、生菌数を測定した。各サンプリングポイントでは、試料溶液の蓋を空けてサンプリングを実施し、蓋を閉める操作を行った。 The test sample was inoculated with the inoculated bacterial solution so that the concentration of the bacterial solution in the test sample composed of each preparation was 10 5 to 10 6 cells / mL (all five bacterial species). Specifically, an inoculum was prepared so as to have a concentration of 10 7 to 10 8 cfu / mL, and Examples 1 to 4 and Comparative Examples were prepared such that the inoculum was adjusted to be 10 5 to 10 6 cfu / mL. A test sample comprising the preparations of Nos. 1 and 2 was inoculated with each inoculum, and mixed uniformly to obtain a sample. These samples were stored at 20 to 25 ° C. in the absence of light, and at each sampling point (after 7, 14, or 28 days), 1 mL of each sample was collected with a micropipette, and the viable cell count was measured. At each sampling point, sampling was performed by opening the lid of the sample solution and closing the lid.
３．試験結果及び考察
試験結果を表１および表２に示す。表１および表２の試験結果は、生菌数を測定したときの菌数（Ａ）に対する接種時の菌数（Ｂ）の比（Ｂ／Ａ）の常用対数値で示しており、たとえば、値が「１」の場合には、検査時の生菌数が接種菌数の１０％に減少したことを示している。
試験の合否判定について、細菌種（E.coli、P.aeruginosa、S.aureus）に対しては、播種７日後に１．０以上、かつ１４日後または２８日後に３．０以上であること、および真菌種（C.albicans、A.brasiliensis）に対しては、播種７日後と比較して播種１４日後または２８日後の数値が減少していないこと、をいずれも満たす時に適合とした。
3. Test results and discussion Table 1 and Table 2 show the test results. The test results in Tables 1 and 2 are shown as common logarithmic values of the ratio (B / A) of the number of bacteria at inoculation (B) to the number of bacteria (A) when the number of viable bacteria was measured. When the value is "1", it indicates that the number of viable bacteria at the time of the test has been reduced to 10% of the number of inoculated bacteria.
Regarding the pass / fail judgment of the test, the bacterial species (E. coli, P. aeruginosa, S. aureus) should be 1.0 or more after 7 days from seeding and 3.0 or more after 14 or 28 days. For fungal species (C. albicans, A. brasiliensis), it was determined that the condition was satisfied when none of the values at 14 days or 28 days after sowing was smaller than that at 7 days after sowing.
表１および表２に示されるように、エピナスチン又はその塩を含有する実施例１〜４の製剤は、防腐剤および防腐作用を有する成分を含有しないにもかかわらず、いずれの菌に対しても十分な防腐効果を示した。これに対して、比較例１および比較例２の製剤は、十分な防腐効果を有さないことが示された。これにより、０．０７５％（ｗ／ｖ）超の濃度のエピナスチンまたはその塩を含有する本発明の点眼液は、防腐剤および防腐作用を有する成分を含有しなくても、マルチドーズ型点眼液として、繰り返し容器を開閉して使用可能であることが示唆された。 As shown in Tables 1 and 2, the preparations of Examples 1 to 4 containing epinastine or a salt thereof did not contain a preservative and a component having a preservative action, but did not inhibit any bacteria. It showed a sufficient preservative effect. On the other hand, it was shown that the preparations of Comparative Examples 1 and 2 did not have a sufficient preservative effect. Thus, the ophthalmic solution of the present invention containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v) can be used as a multi-dose type ophthalmic solution without containing a preservative and a component having a preservative action. It was suggested that the container could be used by repeatedly opening and closing the container.
本発明は、０．０７５％（ｗ／ｖ）超の濃度のエピナスチン又はその塩を含有する点眼液であって、実質的に防腐剤および防腐作用を有する成分を含有しない、点眼液を提供する。 The present invention provides an ophthalmic solution containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v), which is substantially free of a preservative and a component having a preservative action. .
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