JP2022173166A - Epinastine-containing eye drops - Google Patents
Epinastine-containing eye drops Download PDFInfo
- Publication number
- JP2022173166A JP2022173166A JP2022142452A JP2022142452A JP2022173166A JP 2022173166 A JP2022173166 A JP 2022173166A JP 2022142452 A JP2022142452 A JP 2022142452A JP 2022142452 A JP2022142452 A JP 2022142452A JP 2022173166 A JP2022173166 A JP 2022173166A
- Authority
- JP
- Japan
- Prior art keywords
- epinastine
- acid
- salt
- antiseptic
- ophthalmic solution
- 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.)
- Pending
Links
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 229960003449 epinastine Drugs 0.000 title claims abstract description 40
- 239000003889 eye drop Substances 0.000 title claims abstract description 19
- 229940012356 eye drops Drugs 0.000 title abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 60
- 230000002421 anti-septic effect Effects 0.000 claims abstract description 51
- 239000004615 ingredient Substances 0.000 claims abstract description 15
- 239000002997 ophthalmic solution Substances 0.000 claims description 45
- 229940054534 ophthalmic solution Drugs 0.000 claims description 42
- 239000003755 preservative agent Substances 0.000 claims description 23
- 230000002335 preservative effect Effects 0.000 claims description 14
- 229960002548 epinastine hydrochloride Drugs 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 10
- 239000006172 buffering agent Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000012929 tonicity agent Substances 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 6
- 229940064004 antiseptic throat preparations Drugs 0.000 abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
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- 229910000403 monosodium phosphate Inorganic materials 0.000 description 11
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 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
- 230000003139 buffering effect Effects 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
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- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
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- 239000004359 castor oil Substances 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
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- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003247 decreasing 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
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- 239000000174 gluconic acid Substances 0.000 description 1
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- 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
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- 230000009610 hypersensitivity Effects 0.000 description 1
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- 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 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
- 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
- 230000003204 osmotic effect Effects 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
- 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
- 230000002265 prevention Effects 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
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 is an ophthalmic solution containing epinastine or a salt thereof at a concentration greater than 0.075% (w/v), which is substantially free of preservatives and ingredients having preservative action. The present invention relates to eye drops (hereinafter also referred to as "eye drops 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。 Eye drops require a certain level of antiseptic measures in order to prevent the growth of fungi and the like that accompany repeated use. Therefore, eye drops are usually formulated with preservatives. As an antiseptic, benzalkonium chloride, for example, is water-soluble, chemically stable, and has a high antiseptic effect compared to other antiseptics, so that it is generally used in ophthalmic solutions. However, benzalkonium chloride is cytotoxic, and increased exposure increases the potential for corneal epithelial damage. Therefore, it cannot be used particularly in patients who show hypersensitivity to benzalkonium chloride or patients with severe corneal epithelial disorders.
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。 Alesion (registered trademark) ophthalmic solution 0.05% currently on the market in Japan is an ophthalmic solution containing epinastine hydrochloride as an active ingredient, and instead of adding preservatives such as benzalkonium chloride, Another component with antiseptic action (boric acid, edetic acid (EDTA)) is added (Non-Patent Document 1). In other words, for repeated use of eye drops containing epinastine or a salt thereof, it is not necessary to contain a preservative such as benzalkonium chloride, but another component having a preservative action may be used instead. It is recognized that there is a need to ensure efficacy. On the other hand, no ophthalmic solution containing epinastine or a salt thereof to which neither an antiseptic nor an ingredient having an antiseptic action is added is known.
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 the eye drops on the market, eye drops containing neither preservatives nor components with preservative action are known. It is stored in a free container (container with a special structure for exerting antiseptic effect), and no ophthalmic solution is known in which the active ingredient itself exerts an antiseptic effect. That is, it is not known at all that epinastine or its salt itself has an antiseptic 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 problem to provide an ophthalmic solution containing epinastine or a salt thereof which is substantially free of preservatives and ingredients with antiseptic 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 conducted intensive research to find an ophthalmic solution containing epinastine or a salt thereof to which neither an antiseptic nor an ingredient having an antiseptic action is added, or the amount thereof is reduced. By setting the concentration of epinastine or its salt in the ophthalmic solution to more than 0.075% (w/v), a sufficient antiseptic effect can be obtained without substantially containing an antiseptic or a component having an antiseptic action. This discovery led to the present invention. Specifically, the present invention provides the following.
(1) An ophthalmic solution containing more than 0.075% (w/v) of epinastine or a salt thereof, which is substantially free of preservatives and ingredients having antiseptic action.
(2) The ophthalmic solution according to (1), containing 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 its salt is epinastine hydrochloride.
(4) The antiseptic and antiseptic component is at least one component selected from the group consisting of benzalkonium chloride, chlorhexidine or its salts, boric acid, borax, and edetic acid or its salts, ( 1) The ophthalmic solution described in 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 buffering agent, a tonicity agent, and a pH adjusting agent as additives. .
(6) The ophthalmic solution according to (5), containing 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 its salt is epinastine hydrochloride.
(8) The ophthalmic solution according to any one of (5) to (7), wherein the buffering agent 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 ophthalmic solution.
(11) Eye drops containing epinastine or a salt thereof by formulating epinastine or a salt thereof at a concentration exceeding 0.075% (w/v) without substantially containing an antiseptic or an ingredient having an antiseptic action A method of imparting an antiseptic effect to a liquid.
(12) Eye drops containing epinastine or a salt thereof by formulating epinastine or a salt thereof at a concentration exceeding 0.075% (w/v) without substantially containing preservatives and ingredients having antiseptic action A method of preserving the antiseptic efficacy of a liquid.
Two or more of the configurations (1) to (12) can be arbitrarily selected and combined.
Furthermore, the present invention also provides the following.
(13) Treating and/or preventing allergic conjunctivitis, characterized by 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 treating and/or preventing 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。 INDUSTRIAL APPLICABILITY According to the present invention, an ophthalmic solution containing epinastine or a salt thereof having an antiseptic effect can be obtained without adding any antiseptic or an ingredient having an antiseptic effect.
以下に、本発明について詳細に説明する。 The present invention will be described in detail below.
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。
Epinastine to be contained in the ophthalmic solution of the present invention may be a salt, and there is no particular limitation as long as it is a pharmaceutically acceptable salt. Salts include, for example, salts with inorganic acids, salts with organic acids, and the like.
Salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, and 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 toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic 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 hydrate or 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 a concentration acceptable as an ophthalmic preparation, 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 0.1-0.5% (w/v), 0.1-0.3% (w/v), but 0.1% (w/v), 0.2% ( w/v), 0.3% (w/v), 0.4% (w/v), 0.5% (w/v) are even more preferred.
In addition, when the salt of epinastine is contained in this invention, these values are the content 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 shall apply 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 antiseptics include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or its salts, sorbic acid or its salts, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like. be done.
Chlorhexidine or salts thereof include chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine acetic acid and the like.
Sorbic acid or salts thereof include sodium sorbate, potassium sorbate and the like.
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, the antiseptic component includes, for example, boric acid, borax, edetic acid and salts thereof.
Examples of edetic acid or salts 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, "does not contain antiseptic agent or component with antiseptic action" means that the ophthalmic solution does not contain the "preservative and component with antiseptic action" at all, or the "preservative and component with antiseptic action" " alone is included to the extent that it does not comply with the preservative efficacy test method described in the 17th revision of the Japanese Pharmacopoeia. The above-mentioned "extent of not conforming to the preservative efficacy test method described in the 17th revision of the Japanese Pharmacopoeia alone" is, for example, 0.01% (w/v) or 0.02% (w/v) in the case of EDTA. To some extent, it is included in eye drops to obtain a stabilizing effect rather than the antiseptic effect of EDTA. Also, for example, boric acid may be about 0.01% (w/v) or 0.02% (w/v), but this is to obtain a buffering effect rather than a preservative effect of boric acid. included in ophthalmic solutions. In the present invention, "substantially" does not have to change its essence, therefore, in the present invention, "substantially free of preservatives and components having antiseptic action" means "having preservatives and antiseptic action". does not contain "components" at all, or when the antiseptic effect is not intended, the "preservatives and components with antiseptic action" alone are included to the extent that they do not comply with the preservative efficacy test method described in the 17th revision of the Japanese Pharmacopoeia. point 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, a multi-dose eye drop refers to an eye drop contained in a multi-dose container. A multi-dose type container is a container whose cap or the like can be freely opened and closed for the purpose of multiple uses, and can be used for a certain period of time after opening and is easy to carry. In the present invention, there are no particular restrictions on the size and shape of the container body, and a unit dose type container (single use type) may be used. preferable. A container having a special structure for exhibiting antiseptic effects such as a backflow prevention function, such as a PFMD (Preservative Free Multi Dose) container, is not included. The material of the container is not particularly limited, and commonly used containers such as polyethylene (PE), polypropylene (PP), and polyethylene terephthalate (PET) containers 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 its constituents dissolved or partially suspended, but is more preferably liquid in which all of its constituents 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 buffer is added to the ophthalmic solution, a buffer that can be used as a pharmaceutical additive can be appropriately added. , acetic acid or salts thereof, carbonic acid or salts thereof, tartaric acid or salts thereof, ε-aminocaproic acid, trometamol and the like, and hydrates or solvates thereof may also be used.
Examples of phosphoric acid or salts thereof include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc., and hydrates thereof. There may be.
Examples of citric acid or salts thereof include sodium citrate, disodium citrate and the like, and hydrates thereof may also be used.
Acetic acid or salts thereof include sodium acetate, potassium acetate and the like, and hydrates thereof may be used.
Examples of carbonic acid or salts thereof include sodium carbonate, sodium hydrogen carbonate and the like, and hydrates thereof may also be used.
Examples of tartaric acid or salts thereof include sodium tartrate and potassium tartrate, and hydrates thereof may also be used.
In the present invention, phosphoric acid or a salt thereof is more preferable, and sodium dihydrogen phosphate, disodium hydrogen phosphate, or hydrates thereof are particularly preferable as the buffer when blending the ophthalmic solution with a buffer. Also, two or more buffering agents may be used together.
In the present invention, the content of the buffering agent when blending the buffering agent in the ophthalmic solution can be appropriately adjusted depending on the type of the buffering agent. 0.01-5% (w/v) is more preferred, 0.1-3% (w/v) is more preferred, and 0.2-1.5% (w/v) is most preferred.
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 an isotonizing agent is added to the ophthalmic solution, an isotonizing agent that can be used as a pharmaceutical additive can be appropriately added. agents, nonionic tonicity agents, and the like.
Ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
Nonionic tonicity agents include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose and the like.
In the present invention, when an isotonizing agent is added to the ophthalmic solution, the isotonizing agent is more preferably an ionic isotonizing agent, and particularly preferably sodium chloride. Also, two or more tonicity agents may be used together.
In the present invention, the content of the tonicity agent when the tonicity agent is blended in the ophthalmic solution can be appropriately adjusted depending on the type of the tonicity agent, and is 0.001 to 10% (w/ v) is preferred, 0.01-5% (w/v) is more preferred, 0.1-1% (w/v) is more preferred, and 0.2-0.5% (w/v) is most preferred. preferable.
In the present invention, the osmotic pressure ratio of the ophthalmic solution may be within the range allowed for ophthalmic preparations, such as 0.5 to 2.0, preferably 0.7 to 1.6, and 0.8 to 1.0. 4 is more preferred, and 0.9 to 1.2 is even more preferred.
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 adjusting agent is added to the ophthalmic solution, the pH adjusting agent that can be used as an additive for pharmaceuticals can be appropriately added. Examples include hydrochloric acid, phosphoric acid, citric acid, and acetic acid, and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, and the like.
In the present invention, the pH of the ophthalmic solution may be within the range allowed for ophthalmic preparations, preferably 4.0 to 8.0, more preferably 6.0 to 8.0, and 6.5 to 8.0. 7.5 is more preferred. A particularly preferred pH is between 6.7 and 7.3, but even more preferred is 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3.
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 ingredients having antiseptic action) acceptable for ophthalmic preparations may be added as necessary in addition to the above-described buffering agent, tonicity agent, and pH adjusting agent. Additives such as solubilizers, stabilizers, antioxidants, thickeners and the like can be added. In addition, unless otherwise specified, it may contain active ingredients other than epinastine or salts thereof, which are used in ophthalmic solutions.
Examples of solubilizers include polyoxyethylene hydrogenated castor oil, povidone, and polysorbate 80. Examples of stabilizers include povidone and polysorbate 80. Examples of antioxidants include dibutylhydroxytoluene, sodium sulfite, and the like. Examples of the agent include carboxyvinyl polymer, hydroxyethyl cellulose and the like. These additives can be added within the range allowed for ophthalmic formulations, for example, each can be added at 2% or less, or in the range of 0.2% or less, 0.02% or less, 0.002% or less. can also 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, there are no particular restrictions on the dosage and administration as long as it is sufficient to exhibit the desired efficacy. , more preferably 2 to 4 times a day, more preferably 2 times a day, 4 times a day. The ophthalmic solution of the present invention can also be used when wearing contact lenses.
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。 Formulation examples and antiseptic efficacy test results are shown below, 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]
Representative formulation examples of the present invention are shown below. In addition, in the following formulation examples, the amount of each component is the content in 1 mL of the formulation.
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
1 mg of epinastine hydrochloride in a multi-dose container (1 mL)
Sodium dihydrogen phosphate 3 mg
5 mg of sodium chloride
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount
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 3 mg in a multi-dose container (1 mL)
Sodium dihydrogen phosphate 3 mg
Disodium hydrogen phosphate 12mg
4 mg of sodium chloride
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount
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。
Antiseptic efficacy test (1)
This test was conducted according to the preservative efficacy test method described in the Japanese Pharmacopoeia 17th Edition.
1. Preparation of test formulation Epinastine (50 mg), sodium dihydrogen phosphate (25 mg), disodium hydrogen phosphate hydrate (122 mg), and sodium chloride (40 mg) were dissolved in water and sterilized by filtration. The formulation of Example 1 was prepared by adding to a total volume of 10 mL.
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 5 mg in 1 mL
Sodium dihydrogen phosphate 2.5 mg
Disodium hydrogen phosphate hydrate 12.2 mg
4 mg of sodium chloride
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount 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。 Preparations of Examples 2-4 and Comparative Examples 1-2 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 50 mg in 1 mL
Sodium dihydrogen phosphate 2.5 mg
Disodium hydrogen phosphate hydrate 12.2 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount 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 1 mg in 1 mL
Sodium dihydrogen phosphate 2.5 mg
Disodium hydrogen phosphate hydrate 12.2 mg
4.7 mg sodium chloride
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount 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 2 mg in 1 mL
Sodium dihydrogen phosphate 2.5 mg
Disodium hydrogen phosphate hydrate 12.2 mg
4.5 mg sodium chloride
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount 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 0.5 mg in 1 mL
Sodium dihydrogen phosphate 2.5 mg
Disodium hydrogen phosphate hydrate 12.2 mg
5 mg of sodium chloride
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount 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 0.75 mg in 1 mL
Sodium dihydrogen phosphate 2.5 mg
Disodium hydrogen phosphate hydrate 12.2 mg
4.7 mg sodium chloride
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount 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 inoculum.
Bacteria:
Escherichia coli ATCC 8739 (also known as E.coli)
Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 9027 (also known as P.aeruginosa)
Staphylococcus aureus, Staphylococcus aureus ATCC 6538 (also known as S. aureus)
Yeasts and molds:
Candida, Candida albicans ATCC 10231 (also known as C.albicans)
Aspergillus brasiliensis ATCC16404 (also known as 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 inoculum 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 (for all 5 strains). Specifically, an inoculum solution was prepared so as to have 10 7 to 10 8 cfu/mL, and this inoculum solution was adjusted to 10 5 to 10 6 cfu/mL in Examples 1 to 4 and Comparative Examples. A test sample consisting of formulations 1 and 2 was inoculated with each inoculum solution and uniformly mixed to obtain a sample. These samples were stored at 20 to 25° C. under light shielding, and at each sampling point (7 days, 14 days, or 28 days), 1 mL was collected from each sample with a micropipette and the viable cell count was measured. At each sampling point, sampling was performed with the lid of the sample solution opened, and then the lid was closed.
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 Test results are shown in Tables 1 and 2. The test results in Tables 1 and 2 are shown in common logarithmic values of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when measuring the number of viable bacteria. A value of "1" indicates that the number of viable bacteria at the time of inspection decreased to 10% of the number of inoculated bacteria.
Regarding the pass/fail judgment of the test, for bacterial species (E.coli, P.aeruginosa, S.aureus), 1.0 or more 7 days after seeding, and 3.0 or more 14 days or 28 days after seeding, and for fungal species (C.albicans, A.brasiliensis), the values were not reduced 14 days or 28 days after seeding compared to 7 days after seeding.
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 formulations of Examples 1 to 4 containing epinastine or a salt thereof did not contain any preservatives or ingredients with antiseptic action, and were not effective against any bacteria. It showed sufficient antiseptic effect. In contrast, the preparations of Comparative Examples 1 and 2 were shown not to have a sufficient antiseptic effect. As a result, the eye drops of the present invention containing more than 0.075% (w/v) of epinastine or a salt thereof can be multi-dose eye drops without containing preservatives and ingredients having antiseptic action. As a result, it was suggested that the container can be opened and closed repeatedly.
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 greater than 0.075% (w/v), which is substantially free of preservatives and ingredients with preservative action. .
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| JP2003514021A (en) * | 1999-11-12 | 2003-04-15 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Solution containing epinastine |
| JP2015521182A (en) * | 2012-05-15 | 2015-07-27 | エフ．ホルツァー ゲゼルシャフト ミット ベシュレンクテル ハフツング | Use of ophthalmic vehicle systems, ophthalmic kits and ophthalmic compositions for drugs |
| WO2015125921A1 (en) * | 2014-02-20 | 2015-08-27 | わかもと製薬株式会社 | Medical aqueous composition having preservative effectiveness |
| JP2018070500A (en) * | 2016-10-28 | 2018-05-10 | 参天製薬株式会社 | Epinastine-containing eye drops |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003514021A (en) * | 1999-11-12 | 2003-04-15 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Solution containing epinastine |
| JP2015521182A (en) * | 2012-05-15 | 2015-07-27 | エフ．ホルツァー ゲゼルシャフト ミット ベシュレンクテル ハフツング | Use of ophthalmic vehicle systems, ophthalmic kits and ophthalmic compositions for drugs |
| WO2015125921A1 (en) * | 2014-02-20 | 2015-08-27 | わかもと製薬株式会社 | Medical aqueous composition having preservative effectiveness |
| JP2018070500A (en) * | 2016-10-28 | 2018-05-10 | 参天製薬株式会社 | Epinastine-containing eye drops |
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| Title |
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| アレルギー・免疫, vol. 23, no. 2, JPN6016047825, January 2016 (2016-01-01), pages 124 - 130, ISSN: 0005145386 * |
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