JP4725699B2 - Ophthalmic composition and preservative for blending ophthalmic composition - Google Patents

Description

（ここで、Ｒ＝Ｃ ₈ 〜Ｃ ₂₄ 飽和または不飽和炭化水素であり；Ｘ＝ＨまたはＣＨ ₃ であり；Ｙ＝Ｈ、（ＣＨ ₂ ） ₄ ＮＨ ₂ 、または（ＣＨ ₂ ） ₃ ＮＨＣ（ＮＨ ₂ ）＝Ｎ ⁺ Ｈ ₂ であり；そしてＭ ⁺ ＝Ｈまたは薬学的に受容可能な塩である）
および
【化６】

（ここで、Ｒ ¹ ＝Ｃ ₈ 〜Ｃ ₂₄ 飽和または不飽和炭化水素であり；そしてＭ ⁺ は上記の定義通りである。）
[２]．（Ｂ）成分がホウ酸である[１]記載の点眼剤または洗眼剤である眼科用組成物。
[３]．ドライアイ治療剤、角結膜損傷治療剤、又は抗アレルギー用治療剤であることを特徴とする[１]又は[２]記載の点眼剤または洗眼剤である眼科用組成物。
[４]．眼科用組成物に配合する眼科用組成物配合用防腐剤であって、
上記眼科用組成物が、塩化ベンザルコニウム、塩化ベンゼトニウム、ソルビン酸、ソルビン酸塩、パラオキシ安息香酸エステル、グルコン酸クロルヘキシジン、チロメサール、フェニルエチルアルコール及び塩酸アルキルジアミノエチルグリシンから選ばれる刺激性防腐剤が無配合であり、かつｐＨが５〜７．５である点眼剤または洗眼剤であり（但し、上記眼科用組成物が、イオン交換樹脂を含有するもの、下記式（Ｉ）又は（ＩＩ）で表されるアニオン界面活性剤を含有するもの、脂肪酸／アミノ酸セッケンであって、Ｃ ₈ 〜Ｃ ₂₄ 脂肪酸から誘導される脂肪酸成分、ならびにリジンおよびアルギニンからなる群から選択されるアミノ酸成分を有する、脂肪酸／アミノ酸セッケンを含有するものを除く。）。
【化７】

（ここで、Ｒ＝Ｃ ₈ 〜Ｃ ₂₄ 飽和または不飽和炭化水素であり；Ｘ＝ＨまたはＣＨ ₃ であり；Ｙ＝Ｈ、（ＣＨ ₂ ） ₄ ＮＨ ₂ 、または（ＣＨ ₂ ） ₃ ＮＨＣ（ＮＨ ₂ ）＝Ｎ ⁺ Ｈ ₂ であり；そしてＭ ⁺ ＝Ｈまたは薬学的に受容可能な塩である）
および
【化８】

（ここで、Ｒ ¹ ＝Ｃ ₈ 〜Ｃ ₂₄ 飽和または不飽和炭化水素であり；そしてＭ ⁺ は上記の定義通りである。）、
上記眼科用組成物配合用防腐剤が、（Ａ）トロメタモールと、（Ｂ）ホウ酸、リン酸、酢酸、マレイン酸、フタル酸及びε−アミノカプロン酸から選ばれる１種または２種以上とを含有し、上記（Ａ）成分と（Ｂ）成分とを、（Ａ）／（Ｂ）＝１／５〜５／１（質量比）の範囲で含有し、上記眼科用組成物中に（Ａ）トロメタモールが１．０〜５．０重量／質量％となるように配合することを特徴とする眼科用組成物配合用防腐剤。
【０００８】
【発明の実施の形態】
本発明の眼科製剤用防腐組成物は、防腐有効成分として、（Ａ）トロメタモールを含有するものである。トロメタモールの含有量は、組成物全量に対して０．０５〜５ｇ／１００ｍｌ（以下、ｗ／ｖ％と記載）配合する。好ましくは０．５〜５ｗ／ｖ％、より好ましくは０．８〜５ｗ／ｖ％、更に好ましくは１〜５ｗ／ｖ％である。この範囲で本発明の目的とする（Ｂ）成分との併用による防腐力向上効果が得られ、しかも眼刺激がない組成物を得ることができる。
【０００９】
本発明の（Ｂ）成分は、ホウ酸、リン酸、酢酸、マレイン酸、フタル酸、ε−アミノカプロン酸から選ばれる１種または２種以上である。好ましくは、ホウ酸、リン酸、ε−アミノカプロン酸、特に好ましくはホウ酸を使用する。
（Ｂ）成分の含有量は、（Ａ）成分との含有比で決定され、その比は、下記（Ａ）成分の量による。
・（Ａ）が０．５〜５．０ｗ／ｖ％、０．８〜５．０ｗ／ｖ％、１．０〜５．０ｗ／ｖ％のときは、（Ａ）／（Ｂ）＝１／５〜５／１（質量比）の範囲とする。
・（Ａ）が０．０５〜５．０ｗ／ｖ％未満のときは、（Ａ）／（Ｂ）＝１／５０〜５０／１かつ、（Ａ）／（Ｂ）≧３／1または（Ａ）／（Ｂ）≦３／２（共に質量比）の範囲とする。
前記範囲で、（Ａ）（Ｂ）を併用した優れた防腐組成物が得られる。
【００１０】
また、本発明の（Ｂ）成分はトロメタモールの防腐効力を向上させる効果を有する他、中〜弱酸領域で設定した眼科用組成物のｐＨ安定性を維持する効果を有する。すなわち、眼科用組成物は、通常ｐＨ５〜８の間で調整されるが、ｐＨ５〜７．５、好ましくは５．０〜７．０、特に好ましくは５．５〜７．０の中〜弱酸性領域で特に刺激がない良好な使用感が得られる。しかし、一般に使用されるトロメタモール−塩酸緩衝液のみで眼科用剤を上記の中〜弱酸性領域で調整した場合、長期保存でｐＨが低下し、安定性に問題がある。
【００１１】
ｐＨ安定性に対するトロメタモールの組成物中の含有量としては、好ましくは０．１〜５ｗ／ｖ％、より好ましくは０．５〜５ｗ／ｖ％、特に好ましくは１〜５ｗ／ｖ％の範囲である。この範囲で、眼科用組成物とした場合のｐＨ安定性が良好で、しかも眼刺激がない眼科用組成物が得られる。
【００１２】
本発明の眼科製剤用防腐組成物は、前記成分の他、エデト酸及び／またはその塩を含有することが、さらに防腐効果を向上させるため、好ましい。エデト酸塩としては、ナトリウム塩、カリウム塩などが好ましく使用される。
エデト酸及び／またはその塩の含有量は、組成物中、０．００５〜０．５ｗ／ｖ％、より好ましくは０．０１〜０．２ｗ／ｖ％であることが好ましい。
【００１３】
また、本発明は、メントール、カンフル、ボルネオールなどのテルペノイド化合物を配合すると、さらに高い防腐効果が得られて好ましい。テルペノイド化合物は、組成物中に０．０００１〜１ｗ／ｖ％の範囲で含有され、より好ましくは０．０００５〜０．２ｗ／ｖ％、更に好ましくは、０．００１〜０．１ｗ／ｖ％の範囲である。
【００１４】
本発明の眼科製剤用防腐組成物は、その他の眼科製剤に使用される各種成分を添加して、眼科用組成物として使用する。
本発明の眼科用組成物のｐＨは、上述したように、ｐＨ５〜７．５、好ましくは５．０〜７．０、特に５．５〜７．０であることが好ましく、（Ｂ）成分の量で調整できない場合は、他のｐＨ調整剤を使用して調整することもできる。使用するｐＨ調整剤としては、塩酸、硫酸、水酸化ナトリウム、エタノールアミンなどが好ましく使用できる。
【００１５】
本発明の眼科用組成物には、前記防腐組成物の他、眼科用組成物に配合する各種成分を、本発明の効果を損なわない範囲で配合することができる。それらの成分としては、各種薬物、安定化剤、清涼化剤、滞留性向上剤、溶解補助剤、色素、等張化剤などがあげられる。
【００１６】
薬物としては、アミノ酸（但しε−アミノカプロン酸を除く；例として、アスパラギン酸、アミノエチルスルホン酸、グルタミン酸、コンドロイチン硫酸、ヒアルロン酸などとそれらの塩）を配合することが好ましい。アミノ酸は、ダメージを受けた眼粘膜の改善効果を有する。
【００１７】
その他の薬物として、充血除去剤（塩酸ナファゾリン、塩酸テトラヒドロゾリン、塩酸フェニレフリン等）、消炎・収斂剤（メチル硫酸ネオスチグミン、アラントイン、塩化ベルベリン、硫酸亜鉛、塩化リゾチーム等）、抗ヒスタミン剤（塩酸ジフェンヒドラミン、塩酸イソチペンジル、マレイン酸クロルフェニラミン等）、水溶性ビタミン類（活性型ビタミンＢ2、ビタミンＢ6、ビタミンＢ12）、脂溶性ビタミン類(ビタミンＡ類（例えば酢酸レチノール、パルミチン酸レチノール）、ビタミンＥ類（酢酸トコフェロール（例えば、酢酸ｄ−α−トコフェロール）、サルファ剤、殺菌剤（イオウ、イソプロピルメチルフェノール、ヒノキチオール等）、局所麻酔剤（リドカイン、塩酸リドカイン、塩酸プロカイン、塩酸ジブカイン等）を適宜配合することができる。これらは１種単独で又は２種以上を適宜組み合わせて使用することができる。
薬物の中には刺激を有する成分も存在するが、本発明のトロメタモールはそのような薬物による眼刺激性を緩和する効果をも有する。
【００１８】
ドライアイやコンタクトレンズ着用による水分低下による眼粘膜のトラブル改善を目的にする場合は、前記薬物中、特に、脂溶性ビタミン類、コンドロイチン硫酸ナトリウム、ヒアルロン酸ナトリウムを配合すると好ましい。
【００１９】
本発明の眼科用組成物における上記薬物の含有量は、特に制限されるものではないが、通常、組成物全量に対して、０．００１〜１０ｗ／ｖ％、好ましくは０．００３〜５ｗ／ｖ％、より好ましくは０．００５〜４ｗ／ｖ％であると好適である。また、トロメタモールに対する含有割合は、トロメタモール：薬物（質量比）＝５０００：１〜１：２０、好ましくは１０００：１〜１：１０、より好ましくは５００：１〜１：８であると、薬物による眼刺激が緩和されて好適である。
【００２０】
溶解補助剤としては、例えば、プロピレングリコール、グリセリン等の多価アルコール、エタノール、ポリオキシエチレン（ｐ＝６０）硬化ヒマシ油などのポリオキシエチレン高級脂肪酸エステル、ポリオキシエチレン（ｐ＝２０）ソルビタンモノオレエートなどのポリオキシエチレンソルビタン高級脂肪酸エステルなどのノニオン界面活性剤、が挙げられる。ノニオン界面活性剤は、刺激性が懸念されることから、好ましくは多価アルコールを用いる。
等張化剤としては、例えば、塩化ナトリウム、塩化カリウム等が挙げられる。
【００２１】
安定化剤としては、例えば、シクロデキストリン、亜硫酸塩、ジブチルヒドロキシトルエン等が挙げられる。特にジブチルヒドロキシトルエンはトロメタモールの防腐効力を高めるので好ましい。安定化剤は、通常、０．００１〜０．１ｗ／ｖ％配合すると好適であり、より好ましくは０．００１〜０．０１ｗ／ｖ％の範囲である。
【００２２】
薬物の眼粘膜への滞留性向上剤としては、例えば、ポリビニルピロリドン、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリビニルアルコール、ヒアルロン酸ナトリウム、コンドロイチン硫酸ナトリウム、カルボキシビニルポリマー等が挙げられる。好ましい滞留性向上剤は、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、ヒアルロン酸ナトリウムである。これらの配合量は、組成物中、０．００１〜２０ｗ／ｖ％、より好ましくは０．０１〜１０ｗ／ｖ％であることが好ましい。
本発明の眼科用組成物の好ましい粘度は、２０℃における粘度１〜２００ｍＰａ・ｓ、好ましくは １〜５０ｍＰａ・ｓである。
清涼化剤としては、例えば、メントール、カンフル、ボルネオール、ゲラニオール、クロロブタノール、エタノール等が挙げられる。
【００２３】
本発明の眼科用組成物は、トロメタモールと特定の弱酸物質を組み合わせて防腐力を付与するものであり、組成物中に、従来から使用される塩化ベンザルコニウムなどの刺激性防腐剤を必要としない。したがって、刺激性防腐剤は含有しないことが好ましい。配合する場合でも配合量は０．０００５ｗ／ｖ％以下とし、好ましくは０．０００１ｗ／ｖ％以下とする。本発明でいう「刺激性防腐剤」とは、従来から使用された防腐剤で眼粘膜に刺激を与えるものを指し、塩化ベンザルコニウム、塩化ベンゼトニウム、ソルビン酸またはその塩、パラオキシ安息香酸エステル（メチルパラベン、エチルパラベン、プロピルパラベン）、グルコン酸クロルヘキシジン、チロメサール、フェニルエチルアルコール、塩酸アルキルジアミノエチルグリシンンがあげられる。
【００２４】
本発明の好ましい態様を、以下にまとめる。
〔１〕（Ａ）トロメタモール１．０〜５．０重量／質量％、（Ｂ）ホウ酸、リン酸、酢酸、マレイン酸、フタル酸及びε−アミノカプロン酸から選ばれる１種または２種以上を、（Ａ）／（Ｂ）＝１／５〜５／１（質量比）の範囲で含有し、上記（Ａ）成分及び（Ｂ）成分により防腐力を有し、塩化ベンザルコニウム、塩化ベンゼトニウム、ソルビン酸、ソルビン酸塩、パラオキシ安息香酸エステル、グルコン酸クロルヘキシジン、チロメサール、フェニルエチルアルコール及び塩酸アルキルジアミノエチルグリシンから選ばれる刺激性防腐剤が無配合であり、ｐＨが５〜７．５の点眼剤または洗眼剤である眼科用組成物（但し、イオン交換樹脂を含有するもの、下記式（Ｉ）又は（ＩＩ）で表されるアニオン界面活性剤を含有するもの、脂肪酸／アミノ酸セッケンであって、Ｃ ₈ 〜Ｃ ₂₄ 脂肪酸から誘導される脂肪酸成分、ならびにリジンおよびアルギニンからなる群から選択されるアミノ酸成分を有する、脂肪酸／アミノ酸セッケンを含有するものを除く。）。
【化９】

（ここで、Ｒ＝Ｃ ₈ 〜Ｃ ₂₄ 飽和または不飽和炭化水素であり；Ｘ＝ＨまたはＣＨ ₃ であり；Ｙ＝Ｈ、（ＣＨ ₂ ） ₄ ＮＨ ₂ 、または（ＣＨ ₂ ） ₃ ＮＨＣ（ＮＨ ₂ ）＝Ｎ ⁺ Ｈ ₂ であり；そしてＭ ⁺ ＝Ｈまたは薬学的に受容可能な塩である）
および
【化１０】

（ここで、Ｒ ¹ ＝Ｃ ₈ 〜Ｃ ₂₄ 飽和または不飽和炭化水素であり；そしてＭ ⁺ は上記の定義通りである。）
〔２〕（Ｂ）成分がホウ酸である〔２〕記載の点眼剤または洗眼剤である眼科用組成物。
〔３〕アミノ酸（ε−アミノカプロン酸を除く）を含有する、〔１〕又は〔２〕記載の点眼剤または洗眼剤である眼科用組成物。
〔４〕ドライアイ治療剤であることを特徴とする、〔１〕〜〔３〕のいずれかに記載の点眼剤または洗眼剤である眼科用組成物。
〔５〕角結膜損傷治療剤であることを特徴とする、〔１〕〜〔３〕のいずれかに記載の点眼剤または洗眼剤である眼科用組成物。
〔６〕抗アレルギー用治療剤であることを特徴とする、〔１〕〜〔３〕のいずれかに記載の点眼剤または洗眼剤である眼科用組成物。
〔７〕コンタクトレンズ用、特にソフトコンタクトレンズ用点眼剤である、〔１〕〜〔３〕のいずれかに記載の眼科用組成物。
〔８〕眼科用組成物に配合する眼科用組成物配合用防腐剤であって、
上記眼科用組成物が、塩化ベンザルコニウム、塩化ベンゼトニウム、ソルビン酸、ソルビン酸塩、パラオキシ安息香酸エステル、グルコン酸クロルヘキシジン、チロメサール、フェニルエチルアルコール及び塩酸アルキルジアミノエチルグリシンから選ばれる刺激性防腐剤が無配合であり、かつｐＨが５〜７．５である点眼剤または洗眼剤であり、
上記眼科用組成物配合用防腐剤が、（Ａ）トロメタモールと、（Ｂ）ホウ酸、リン酸、酢酸、マレイン酸、フタル酸及びε−アミノカプロン酸から選ばれる１種または２種以上とを含有し、上記（Ａ）成分と（Ｂ）成分とを、（Ａ）／（Ｂ）＝１／５〜５／１（質量比）の範囲で含有し、上記眼科用組成物中に（Ａ）トロメタモールが０．５〜５．０重量／質量％となるように配合することを特徴とする眼科用組成物配合用防腐剤。
〔９〕メント−ル、カンフル、ボルネオールなどのテルペノイド化合物を含有することを特徴とする〔８〕記載の眼科用組成物配合用防腐剤。
【００２５】
【発明の効果】
本発明によれば、刺激性防腐剤が低含量好ましくは含有しないため、ダメージを受けた眼に対しても安全で、刺激がなく、しかも安定性に優れた眼科用組成物が得られる。したがって、本発明の眼科用組成物は、ドライアイなどの角結膜に損傷を有する患者用の点眼剤等として、好ましく使用できる。
【００２６】
【実施例】
以下、本発明をさらに実施例をあげて説明する。表１に示す眼科用組成物を調製し、防腐力試験と、眼刺激感の有無を評価した。
【００２７】
＜試験１＞ 防腐効力試験
表１に示す組成に対して、第１４改正日本薬局方・参考情報の保存効力試験法を参考にし、一部変更を加えて実施した。被検菌株は以下に示す細菌及び真菌の５種を用い各実施例及び比較例の試料１ｍＬあたり１０⁵〜１０⁶個になるように加え、２５℃に静置し、７日後に菌を接種した溶液１ｍＬのそれぞれを培養した後、生菌数を測定し、接種菌数に対する生存率を算出した。
【００２８】

【００２９】
７日後の生存率が細菌では接種菌数の０．１％以下、真菌では接種菌数の同レベルもしくはそれ以下となる場合に○、一つの菌種でも満たさないものは×とした。
【００３０】
なお、培養は細菌に対してはＳＣＤＬＰ寒天培地（Ｓｏｙｂｅａｎ Ｃａｓｅｉｎ Ｄｉｇｅｓｔ Ａｇａｒ ｗｉｔｈ Ｌｅｒｃｔｈｉｎ ＆ Ｐｏｌｙｓｏｒｂａｔｅ８０）（日本製薬（株）製）、真菌にはＧＰＬＰ寒天培地（Ｇｌｕｃｏｓｅ Ｐｅｐｔｏｎｅ Ａｇａｒ ｗｉｔｈ Ｌｅｒｃｔｈｉｎ ＆ Ｐｏｌｙｓｏｒｂａｔｅ８０）（日本製薬（株）製）の各種培地を使用した。
【００３１】
＜試験２＞ 眼刺激試験
男女各３名（計６名）のドライアイに悩むＯＡ機器操作者をパネラーとし、点眼したときの眼刺激性を下記評価基準に基づいて評価した。合計が０〜２点を○、３〜５点を△、６点以上を×とした。
【００３２】
＜評価基準＞
２：眼刺激性を感じた
１：やや眼刺激性を感じた
０：眼刺激は感じなかった
【００３３】
【表１】

【００３４】
表１の結果から明らかなように、トロメタモールに弱酸を併用した実施例１〜６は、弱酸を併用しない比較例１に対し、防腐力が向上し(試験１)、眼刺激性も良好であった(試験２)
また、実施例１〜６では、ｐＨ安定性を維持する効果を有しており５０℃１ヵ月保存においてもｐＨがほとんど変化しない安定性を示した。
【００３５】
表２に示した眼科用組成物についても同様の評価を行い、いずれも良好な評価結果を得た。
【００３６】
【表２】

【００３７】
【表３】

【００３８】
表４に示した眼科用組成物についても同様の評価を行い、いずれも良好な評価結果を得た。
【００３９】
【表４】

【００４０】
本発明の各実施例の眼科用剤を、ソフトコンタクトレンズ装用のため眼の不快な症状（乾き、痛み）を訴えるパネラー５名に１日４回、７日間点眼し評価したところ、刺激なく良好な使用感で、しかも４名が実効感を感じた。[0001]
[Industrial application fields]
The present invention has a low content of preservatives such as benzalkonium chloride and sorbic acid, and preferably does not contain it, and is also irritating to eyes having troubles such as dry eye, corneal damage, allergic symptoms, various damage due to contact lens wearing, etc. The present invention relates to an ophthalmic composition (such as an eye drop, an eye wash, a contact lens wearing agent, etc.) that is safe and has excellent antiseptic power and good stability, and an antiseptic composition used in such an ophthalmic composition.
[0002]
[Prior art]
Ophthalmic compositions are required to prevent spoilage of formulations derived from secondary contamination, and for that purpose, cationic surfactants such as benzalkonium chloride and paraoxybenzoates such as methylparaben are usually used. Contains various preservatives such as acid esters. However, these preservatives have the property of irritating the mucous membranes. In some cases, chlorobutanol with local anesthetic action is added to relieve eye irritation or masking of irritation by adding a cooling agent. And designed the formulation.
However, with the recent increase in VDT work and contact lens wearers due to the popularization of OA devices, the number of dry eye patients has increased rapidly, and the number of people with allergies such as hay fever has increased, and the keratoconjunctiva has been damaged. The number of patients with eye problems is increasing rapidly. These patients are clearly damaged in the keratoconjunctiva compared with healthy individuals and may not be able to relieve irritation even when coping therapy with stimulants or masking. Furthermore, when the preservative comes into contact with damaged cells, the symptoms may be difficult to improve or worsen.
[0003]
As an ophthalmic composition that does not contain a preservative (preservative-free), it can be considered to be an ophthalmic preparation that can be used once. However, such a preparation has low versatility in terms of cost. .
Therefore, an ophthalmic composition that can withstand secondary contamination without containing a conventional preservative (such as benzalkonium chloride) has been desired.
Trometamol is used in pharmaceutical preparations as a TRIS-hydrochloric acid buffer, and is a well-known component as a buffering agent in ophthalmic preparations (Japanese Patent Publication No. 8-508049, Japanese Patent Laid-Open No. 10-203960). The present inventors have found that trometamol itself has a good antiseptic power, and have already filed a patent application in Japanese Patent Application No. 2001-121619 for blending it into an ophthalmic composition as an antiseptic active ingredient.
The present invention has been further studied to improve the antiseptic power of trometamol.
[0004]
[Patent Document 1]
Special table flat 8-508049
[Patent Document 2]
JP-A-10-203960
[Patent Document 3]
Japanese Patent Application 2001-121619
[0005]
[Problems to be solved by the invention]
The present invention provides an antiseptic composition for ophthalmic preparations that has no eye irritation and can be safely applied to eyes having troubles such as dry eye, eye strain, corneal damage, antiallergy, and contact lens wear. In addition, the present invention provides an ophthalmic composition having excellent antiseptic power even without containing a preservative that irritates the ocular mucosa such as benzalkonium chloride.
[0006]
[Means for Solving the Invention]
As a result of the study, the inventors have used trometamol at a certain concentration or higher and a compound selected from boric acid, phosphoric acid, acetic acid, carbonic acid, maleic acid, phthalic acid, and ε-aminocaproic acid in a specific ratio, It has been found that the antiseptic effect of an ophthalmic composition containing trometamol can be improved, and the present invention has been completed.
[0007]
That is, the present invention provides an ophthalmic composition which is the following eye drop or eye wash, and an antiseptic for blending an ophthalmic composition to be added to the eye drop or eye wash.
[1]. (A) trometamol 1.0 to 5.0 wt / mass%, (B) one or more selected from boric acid, phosphoric acid, acetic acid, maleic acid, phthalic acid and ε-aminocaproic acid, (A ) / (B) = 1/5 to 5/1 (mass ratio), and has antiseptic properties due to the components (A) and (B), benzalkonium chloride, benzethonium chloride, sorbic acid Eye drops or eyewashes containing no irritating preservatives selected from sorbate, sorbate, paraoxybenzoate, chlorhexidine gluconate, thimerosal, phenylethyl alcohol and alkyldiaminoethylglycine hydrochloride, and having a pH of 5 to 7.5 a is an ophthalmic composition (although agents, those containing an ion exchange resin, those containing anionic surfactant represented by the following formula (I) or (II), fatty acid / A amino acid soap, a fatty acid component derived from C ₈ -C ₂₄ fatty acids, as well as having an amino acid component selected from the group consisting of lysine and arginine, except those containing fatty acid / amino acid soap.).
[Chemical formula 5]

(Where R = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; X = H or CH ₃ ; Y = H, (CH ₂ ) ₄ NH ₂ , or (CH ₂ ) ₃ NHC (NH ₂ ) = N ⁺ H ₂ ; and M ⁺ = H or a pharmaceutically acceptable salt)
And

(Where R ¹ = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; and M ⁺ is as defined above.)
[2]. (B) The ophthalmic composition which is an eye drop or eye wash according to [1], wherein the component is boric acid.
[3]. The ophthalmic composition as an eye drop or eye wash according to [1] or [2], which is a dry eye therapeutic agent, a keratoconjunctival injury therapeutic agent, or an antiallergic therapeutic agent.
[4]. A preservative for ophthalmic composition blended in an ophthalmic composition,
The ophthalmic composition is an irritating preservative selected from benzalkonium chloride, benzethonium chloride, sorbic acid, sorbate, p-hydroxybenzoate, chlorhexidine gluconate, tyromesal, phenylethyl alcohol, and alkyldiaminoethylglycine hydrochloride. It is an ophthalmic solution or an eyewash that is not compounded and has a pH of 5 to 7.5 ( provided that the ophthalmic composition contains an ion exchange resin, represented by the following formula (I) or (II)) Fatty acids containing anionic surfactants, fatty acid / amino acid soaps, fatty acid components derived from C _{8 to} C ₂₄ fatty acids, and amino acid components selected from the group consisting of lysine and arginine / Excluding those containing amino acid soap) .
[Chemical 7]

(Where R = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; X = H or CH ₃ ; Y = H, (CH ₂ ) ₄ NH ₂ , or (CH ₂ ) ₃ NHC (NH ₂ ) = N ⁺ H ₂ ; and M ⁺ = H or a pharmaceutically acceptable salt)
And [Chemical Formula 8]

Where R ¹ = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; and M ⁺ is as defined above.
The preservative for blending the ophthalmic composition contains (A) trometamol and (B) one or more selected from boric acid, phosphoric acid, acetic acid, maleic acid, phthalic acid and ε-aminocaproic acid The component (A) and the component (B) are contained in the range of (A) / (B) = 1/5 to 5/1 (mass ratio), and the ophthalmic composition contains the component (A). An antiseptic for blending an ophthalmic composition, which is blended so that trometamol is 1.0 to 5.0% by weight / mass%.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
The antiseptic composition for ophthalmic preparations of the present invention contains (A) trometamol as an antiseptic active ingredient. The content of trometamol is blended in an amount of 0.05 to 5 g / 100 ml (hereinafter referred to as w / v%) based on the total amount of the composition. Preferably it is 0.5-5 w / v%, More preferably, it is 0.8-5 w / v%, More preferably, it is 1-5 w / v%. Within this range, the effect of improving the antiseptic power by the combined use with the component (B) which is the object of the present invention can be obtained and a composition free from eye irritation can be obtained.
[0009]
The component (B) of the present invention is one or more selected from boric acid, phosphoric acid, acetic acid, maleic acid, phthalic acid, and ε-aminocaproic acid. Preferably, boric acid, phosphoric acid, ε-aminocaproic acid, particularly preferably boric acid is used.
The content of the component (B) is determined by the content ratio with the component (A), and the ratio depends on the amount of the following component (A).
When (A) is 0.5 to 5.0 w / v%, 0.8 to 5.0 w / v%, 1.0 to 5.0 w / v%, (A) / (B) = 1 / 5 to 5/1 (mass ratio).
When (A) is less than 0.05 to 5.0 w / v%, (A) / (B) = 1/50 to 50/1 and (A) / (B) ≧ 3/1 or ( A) / (B) ≦ 3/2 (both mass ratio).
In the said range, the outstanding antiseptic composition which used (A) (B) together is obtained.
[0010]
In addition, the component (B) of the present invention has the effect of improving the antiseptic efficacy of trometamol, and also has the effect of maintaining the pH stability of the ophthalmic composition set in the medium to weak acid region. That is, the ophthalmic composition is usually adjusted to a pH of 5 to 8, but a pH of 5 to 7.5, preferably 5.0 to 7.0, particularly preferably 5.5 to 7.0. A good feeling of use with no particular irritation can be obtained in the acidic region. However, when the ophthalmic preparation is adjusted in the above-mentioned medium to weakly acidic region with only the commonly used trometamol-hydrochloric acid buffer, the pH is lowered during long-term storage, and there is a problem in stability.
[0011]
As content in the composition of trometamol with respect to pH stability, Preferably it is 0.1-5 w / v%, More preferably, it is 0.5-5 w / v%, Most preferably, it is the range of 1-5 w / v%. is there. Within this range, an ophthalmic composition having good pH stability and no eye irritation when obtained as an ophthalmic composition can be obtained.
[0012]
The antiseptic composition for ophthalmic preparations of the present invention preferably contains edetic acid and / or a salt thereof in addition to the above components, since the antiseptic effect is further improved. As the edetate, sodium salt, potassium salt and the like are preferably used.
The content of edetic acid and / or a salt thereof is preferably 0.005 to 0.5 w / v%, more preferably 0.01 to 0.2 w / v% in the composition.
[0013]
In the present invention, when a terpenoid compound such as menthol, camphor, or borneol is blended, a higher antiseptic effect is obtained, which is preferable. The terpenoid compound is contained in the composition in the range of 0.0001 to 1 w / v%, more preferably 0.0005 to 0.2 w / v%, still more preferably 0.001 to 0.1 w / v%. Range.
[0014]
The antiseptic composition for ophthalmic preparations of the present invention is used as an ophthalmic composition by adding various components used in other ophthalmic preparations.
As described above, the ophthalmic composition of the present invention has a pH of 5 to 7.5, preferably 5.0 to 7.0, particularly preferably 5.5 to 7.0, and component (B). If the amount cannot be adjusted, other pH adjusting agents can be used. As the pH adjuster to be used, hydrochloric acid, sulfuric acid, sodium hydroxide, ethanolamine and the like can be preferably used.
[0015]
In the ophthalmic composition of the present invention, in addition to the antiseptic composition, various components blended in the ophthalmic composition can be blended within a range that does not impair the effects of the present invention. Examples of these components include various drugs, stabilizers, cooling agents, retention improvers, solubilizers, dyes, and isotonic agents.
[0016]
As the drug, it is preferable to blend amino acids (except ε-aminocaproic acid; as an example, aspartic acid, aminoethylsulfonic acid, glutamic acid, chondroitin sulfate, hyaluronic acid, and salts thereof). Amino acids have the effect of improving damaged ocular mucosa.
[0017]
Other drugs include decongestants (such as naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride), anti-inflammatory / astringent agents (neostigmine methyl sulfate, allantoin, berberine chloride, zinc sulfate, lysozyme chloride, etc.), antihistamines (diphenhydramine hydrochloride, istipendil hydrochloride, Chlorpheniramine maleate), water-soluble vitamins (active vitamin B2, vitamin B6, vitamin B12), fat-soluble vitamins (vitamin A (eg, retinol acetate, retinol palmitate), vitamin E (tocopherol acetate ( For example, acetic acid d-α-tocopherol), sulfa drugs, bactericides (sulfur, isopropylmethylphenol, hinokitiol, etc.), local anesthetics (lidocaine, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, etc.) These can be used singly or in appropriate combination of two or more.
Some drugs have irritation components, but trometamol of the present invention also has an effect of relieving eye irritation caused by such drugs.
[0018]
For the purpose of improving troubles in the ocular mucosa due to water loss due to dry eye or wearing contact lenses, it is preferable to add fat-soluble vitamins, sodium chondroitin sulfate, sodium hyaluronate, among the drugs.
[0019]
The content of the drug in the ophthalmic composition of the present invention is not particularly limited, but is usually 0.001 to 10 w / v%, preferably 0.003 to 5 w / v based on the total amount of the composition. It is suitable that it is v%, more preferably 0.005 to 4 w / v%. The content ratio with respect to trometamol is trometamol: drug (mass ratio) = 5000: 1 to 1:20, preferably 1000: 1 to 1:10, more preferably 500: 1 to 1: 8, depending on the drug. Eye irritation is alleviated, which is preferable.
[0020]
Examples of solubilizing agents include polyhydric alcohols such as propylene glycol and glycerin, ethanol, polyoxyethylene higher fatty acid esters such as polyoxyethylene (p = 60) hydrogenated castor oil, and polyoxyethylene (p = 20) sorbitan mono Nonionic surfactants such as polyoxyethylene sorbitan higher fatty acid esters such as oleate. As the nonionic surfactant, polyhydric alcohol is preferably used because of concern about irritation.
Examples of the isotonic agent include sodium chloride and potassium chloride.
[0021]
Examples of the stabilizer include cyclodextrin, sulfite, dibutylhydroxytoluene and the like. In particular, dibutylhydroxytoluene is preferable because it increases the antiseptic effect of trometamol. In general, the stabilizer is suitably blended in an amount of 0.001 to 0.1 w / v%, and more preferably in the range of 0.001 to 0.01 w / v%.
[0022]
Examples of the agent for improving the retention of a drug in the ocular mucosa include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, and carboxyvinyl polymer. Preferred retention improvers are hydroxypropyl methylcellulose, polyvinyl alcohol, and sodium hyaluronate. It is preferable that these compounding quantities are 0.001-20 w / v% in a composition, More preferably, it is 0.01-10 w / v%.
The preferred viscosity of the ophthalmic composition of the present invention is 1 to 200 mPa · s, preferably 1 to 50 mPa · s at 20 ° C.
Examples of the refreshing agent include menthol, camphor, borneol, geraniol, chlorobutanol, ethanol and the like.
[0023]
The ophthalmic composition of the present invention is a combination of trometamol and a specific weak acid substance that imparts antiseptic power and requires a conventionally used stimulating preservative such as benzalkonium chloride. do not do. Therefore, it is preferable not to contain an irritating preservative. Even when blended, the blending amount is 0.0005 w / v% or less, preferably 0.0001 w / v% or less. The term “irritating preservative” as used in the present invention refers to a conventionally used antiseptic that irritate the ocular mucosa. Benzalkonium chloride, benzethonium chloride, sorbic acid or a salt thereof, paraoxybenzoic acid ester ( Methylparaben, ethylparaben, propylparaben), chlorhexidine gluconate, thimerosal, phenylethyl alcohol, and alkyldiaminoethylglycine hydrochloride.
[0024]
Preferred embodiments of the present invention are summarized below.
[1] (A) trometamol 1.0 to 5.0 wt / mass%, (B) one or more selected from boric acid, phosphoric acid, acetic acid, maleic acid, phthalic acid and ε-aminocaproic acid , (A) / (B) = 1/5 to 5/1 (mass ratio), and has antiseptic power due to the above components (A) and (B), benzalkonium chloride, benzethonium chloride Ophthalmic solution containing no irritating preservative selected from sorbic acid, sorbic acid salt, paraoxybenzoic acid ester, chlorhexidine gluconate, tyromesal, phenylethyl alcohol and alkyldiaminoethylglycine hydrochloride, and having a pH of 5 to 7.5 is a agent or eyewash ophthalmic composition (however, those containing ion-exchange resin, those containing anionic surfactant represented by the following formula (I) or (II), fat An acid / amino acid soap, a fatty acid component derived from C ₈ -C ₂₄ fatty acids, as well as having an amino acid component selected from the group consisting of lysine and arginine, except those containing fatty acid / amino acid soap.).
[Chemical 9]

(Where R = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; X = H or CH ₃ ; Y = H, (CH ₂ ) ₄ NH ₂ , or (CH ₂ ) ₃ NHC (NH ₂ ) = N ⁺ H ₂ ; and M ⁺ = H or a pharmaceutically acceptable salt)
And

(Where R ¹ = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; and M ⁺ is as defined above.)
[2] The ophthalmic composition which is the eye drop or eye wash according to [2], wherein the component (B) is boric acid.
[3] An ophthalmic composition which is an eye drop or eye wash according to [1] or [2], which contains an amino acid (excluding ε-aminocaproic acid) .
[4] The ophthalmic composition as the eye drop or eye wash according to any one of [1] to [3] , which is a dry eye treatment .
[5] The ophthalmic composition as the eye drop or eye wash according to any one of [1] to [3] , which is a therapeutic agent for keratoconjunctival damage .
[6] The ophthalmic composition as the eye drop or eye wash according to any one of [1] to [3] , which is an antiallergic therapeutic agent .
[7] The ophthalmic composition according to any one of [1] to [3], which is an eye drop for contact lenses, particularly soft contact lenses.
[8] A preservative for blending an ophthalmic composition to be blended with an ophthalmic composition,
The ophthalmic composition is an irritating preservative selected from benzalkonium chloride, benzethonium chloride, sorbic acid, sorbate, p-hydroxybenzoate, chlorhexidine gluconate, tyromesal, phenylethyl alcohol, and alkyldiaminoethylglycine hydrochloride. It is an eye drop or an eye wash having no formulation and a pH of 5 to 7.5,
The preservative for blending the ophthalmic composition contains (A) trometamol and (B) one or more selected from boric acid, phosphoric acid, acetic acid, maleic acid, phthalic acid and ε-aminocaproic acid The component (A) and the component (B) are contained in the range of (A) / (B) = 1/5 to 5/1 (mass ratio), and the ophthalmic composition contains the component (A). An antiseptic for blending an ophthalmic composition, which is formulated so that trometamol is 0.5 to 5.0% by weight / mass%.
[9] The preservative for blending ophthalmic compositions according to [8], comprising a terpenoid compound such as menthol, camphor, borneol and the like .
[0025]
【The invention's effect】
According to the present invention, since an irritating preservative is preferably contained in a low content, an ophthalmic composition that is safe for a damaged eye, is not irritating, and has excellent stability can be obtained. Therefore, the ophthalmic composition of the present invention can be preferably used as an eye drop for a patient having damage to the keratoconjunctiva such as dry eye.
[0026]
【Example】
Hereinafter, the present invention will be further described by way of examples. The ophthalmic compositions shown in Table 1 were prepared, and the antiseptic test and the presence or absence of eye irritation were evaluated.
[0027]
<Test 1> Preservative efficacy test The composition shown in Table 1 was subjected to the preservation efficacy test method of the 14th revised Japanese Pharmacopoeia / Reference Information with some changes. The test strains are 5 kinds of bacteria and fungi shown below, added to 10 ⁵ to 10 ⁶ per 1 mL of each Example and Comparative Example, left at 25 ° C., and inoculated with bacteria 7 days later. After culturing each 1 mL of the solution, the number of viable bacteria was measured, and the survival rate relative to the number of inoculated bacteria was calculated.
[0028]

[0029]
In the case where the survival rate after 7 days was 0.1% or less of the number of inoculated bacteria in bacteria, and in the case of fungi the same or less than the number of inoculated bacteria, ○, and those that did not satisfy even one bacterial type were marked as x.
[0030]
In addition, culture is SCDLP agar medium (manufactured by Nippon Pharmaceutical Co., Ltd.) for bacteria, and GPLP agar medium (Glucose Peptone Agar with 80%) for fungi. Various media manufactured by Kogyo Co., Ltd. were used.
[0031]
<Test 2> Eye irritation test The OA equipment operator who suffered from dry eyes of 3 men and women (6 people in total) was used as a panel, and eye irritation when instilled was evaluated based on the following evaluation criteria. A total of 0 to 2 points was evaluated as ◯, 3 to 5 points as Δ, and 6 or more points as ×.
[0032]
<Evaluation criteria>
2: Felt eye irritation 1: Felt eye irritation 0: No eye irritation [0033]
[Table 1]

[0034]
As is clear from the results in Table 1, Examples 1 to 6 in which a weak acid is used in combination with trometamol have improved antiseptic power (Test 1) and good eye irritation compared to Comparative Example 1 in which a weak acid is not used in combination. (Test 2)
Moreover, in Examples 1-6, it had the effect which maintains pH stability, and showed the stability which pH hardly changes even if it preserve | saves at 50 degreeC for 1 month.
[0035]
The same evaluation was performed on the ophthalmic compositions shown in Table 2, and good evaluation results were obtained in all cases.
[0036]
[Table 2]

[0037]
[Table 3]

[0038]
The same evaluation was performed on the ophthalmic compositions shown in Table 4, and good evaluation results were obtained in all cases.
[0039]
[Table 4]

[0040]
The ophthalmic preparations of each example of the present invention were evaluated by instilling and evaluating 4 panelists a day for 7 days to 5 panelists complaining of eye discomfort (dryness, pain) because of wearing soft contact lenses. The four people felt a sense of effectiveness.

Claims (4)

(A) trometamol 1.0 to 5.0 wt / mass%, (B) one or more selected from boric acid, phosphoric acid, acetic acid, maleic acid, phthalic acid and ε-aminocaproic acid, (A ) / (B) = 1/5 to 5/1 (mass ratio), and has antiseptic properties due to the components (A) and (B), benzalkonium chloride, benzethonium chloride, sorbic acid Eye drops or eyewashes containing no irritating preservatives selected from sorbate, sorbate, paraoxybenzoate, chlorhexidine gluconate, thimerosal, phenylethyl alcohol and alkyldiaminoethylglycine hydrochloride, and having a pH of 5 to 7.5 a is an ophthalmic composition (although agents, those containing an ion exchange resin, those containing anionic surfactant represented by the following formula (I) or (II), fatty acid / A amino acid soap, a fatty acid component derived from C ₈ -C ₂₄ fatty acids, as well as having an amino acid component selected from the group consisting of lysine and arginine, except those containing fatty acid / amino acid soap.).

(Where R = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; X = H or CH ₃ ; Y = H, (CH ₂ ) ₄ NH ₂ , or (CH ₂ ) ₃ NHC (NH ₂ ) = N ⁺ H ₂ ; and M ⁺ = H or a pharmaceutically acceptable salt)
and

(Where R ¹ = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; and M ⁺ is as defined above.)   The ophthalmic composition as the eye drop or eye wash according to claim 1, wherein the component (B) is boric acid.   The ophthalmic composition as an eye drop or eye wash according to claim 1 or 2, which is a dry eye therapeutic agent, a keratoconjunctival injury therapeutic agent, or an antiallergic therapeutic agent. A preservative for ophthalmic composition blended in an ophthalmic composition,
The ophthalmic composition is an irritating preservative selected from benzalkonium chloride, benzethonium chloride, sorbic acid, sorbate, paraoxybenzoic acid ester, chlorhexidine gluconate, tyromesal, phenylethyl alcohol, and alkyldiaminoethylglycine hydrochloride. It is an ophthalmic solution or an eyewash that is not compounded and has a pH of 5 to 7.5 ( provided that the ophthalmic composition contains an ion exchange resin, represented by the following formula (I) or (II)) Fatty acids containing anionic surfactants, fatty acid / amino acid soaps, fatty acid components derived from C _{8 to} C ₂₄ fatty acids, and amino acid components selected from the group consisting of lysine and arginine / Excluding those containing amino acid soap) .

(Where R = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; X = H or CH ₃ ; Y = H, (CH ₂ ) ₄ NH ₂ , or (CH ₂ ) ₃ NHC (NH ₂ ) = N ⁺ H ₂ ; and M ⁺ = H or a pharmaceutically acceptable salt)
and

Where R ¹ = C ₈ -C ₂₄ saturated or unsaturated hydrocarbon; and M ⁺ is as defined above.
The preservative for blending the ophthalmic composition contains (A) trometamol and (B) one or more selected from boric acid, phosphoric acid, acetic acid, maleic acid, phthalic acid and ε-aminocaproic acid The component (A) and the component (B) are contained in the range of (A) / (B) = 1/5 to 5/1 (mass ratio), and the ophthalmic composition contains the component (A). An antiseptic for blending an ophthalmic composition, which is blended so that trometamol is 1.0 to 5.0% by weight / mass%.