JP2021513515A - 脂質ベースの眼科用エマルジョン - Google Patents
脂質ベースの眼科用エマルジョン Download PDFInfo
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- JP2021513515A JP2021513515A JP2020541669A JP2020541669A JP2021513515A JP 2021513515 A JP2021513515 A JP 2021513515A JP 2020541669 A JP2020541669 A JP 2020541669A JP 2020541669 A JP2020541669 A JP 2020541669A JP 2021513515 A JP2021513515 A JP 2021513515A
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- emulsion
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- ophthalmic
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Abstract
Description
本出願は、35USC§119(e)の下で、参照によってその全体が援用される2018年2月21日に出願された米国仮特許出願第62/633359号の利益を主張する。
水相を形成する水と、
油相を形成する油と、
10〜18のHLB値を有する親水性界面活性剤と、
1〜6のHLB値を有する疎水性界面活性剤と、
荷電リン脂質と、
ボラートと、
粘膜付着性ガラクトマンナンポリマーと、
保存料と
を含む眼科用エマルジョンに関し、
粘膜付着性ガラクトマンナンポリマーは、少なくとも約0.1w/v%であるが0.5w/v%以下である濃度でエマルジョン中に存在し、
保存料は実質的に塩化ベンザルコニウムを含まず、且つ
眼科用エマルジョンは、対照エマルジョンよりも少なくとも10%高い、乾燥に対する水和保護を有し、ここで、眼科用エマルジョンで使用されるものと同じガラクトマンナンポリマーを0.05w/v%含有することを除いて、対照エマルジョンは眼科用エマルジョンと同じ組成を有する。
水相を形成する水と、
油相を形成する油と、
10〜18のHLB値を有する親水性界面活性剤と、
1〜6のHLB値を有する疎水性界面活性剤と、
荷電リン脂質と、
ボラートと、
粘膜付着性ガラクトマンナンポリマーと、
保存料と
を含む眼科用エマルジョンに関し、
粘膜付着性ガラクトマンナンポリマーは、少なくとも約0.1w/v%であるが0.5w/v%以下である濃度でエマルジョン中に存在し、
保存料は実質的に塩化ベンザルコニウムを含まず、且つ
眼科用エマルジョンは、対照エマルジョンよりも少なくとも10%高い、乾燥に対する水和保護を有し、ここで、眼科用エマルジョンで使用されるものと同じガラクトマンナンポリマーを0.05w/v%含有することを除いて、対照エマルジョンは眼科用エマルジョンと同じ組成を有する。
本発明のエマルジョン製剤は、水相中のHPグアー、ホウ酸、プロピレングリコール(粘滑薬)、エデト酸二ナトリウム、ソルビトール及びポリクアッド(polyquad)(保存料)と、油相中の鉱油、アニオン性リン脂質(ジミリストイルホスファチジルグリセロール)並びにトリステアリン酸ソルビタン及びポリオキシル40ステアラート(乳化剤)とを包含した。本発明のエマルジョン(HPグアーエマルジョンと示される)及び比較エマルジョン(SYSBエマルジョンと示される)は同じ一般組成を有するが、液滴サイズに関して異なり、そして表1に示されるようにHPグアーの濃度が異なる。
細胞の水和及び表面保持アッセイ
コラーゲンIV被覆48ウェルプレートにおいて、カルシウムを含有し、ヒト角膜成長サプリメントが補充されたEpiLife(登録商標)培地中で約48時間、単層FTT(14−3−3)ヒト角膜上皮(HCE)細胞をコンフルエンスまで成長させた。次に、細胞を150μLの試験製剤(HPグアーエマルジョン、SYSB又は媒体)と共に37℃で30分間インキュベートした。乾燥に対する細胞の水和保護を測定するために、試験製剤を静かに除去し、細胞を37℃及び相対湿度45%で30分間乾燥させた。乾燥後の水和保持を測定するために、試験製剤を静かに除去し、細胞を培地(カルシウムを含むEpiLife(登録商標)培地)で3回洗浄してから、上記のように乾燥させた。
伸長レオメーターHAAKE CaBER1(Thermo Scientific)を使用して、各試験製剤のポリマーフィラメント破断時間(PFBUT)を特徴付けした。試験製剤をレオメーターの2つのプレート間に装着させた。上部プレートを、上まぶたと下まぶたの間の平均距離である8.00mmの距離まで引き延ばした。高精度レーザーマイクロメーターを使用して、細くなっているフィラメントの直径を時間の関数として測定した。2つのプレート間で製剤が破断するのにかかる時間をPFBUTとして記録した。
細胞の水和保持及び水和保護:
HPグアーエマルジョンは、SYSB比較製剤と比較して、乾燥後に著しく大きい水和保護を実証した。試験製剤で前処理した培養HCE細胞における乾燥後の細胞生存率%(平均±SD)は、本発明のHPグアーエマルジョンでは39.5±14.6(サンプルサイズ、n=33)であり、SYSB比較製剤では7.1±10.0(サンプルサイズ、n=63)であった(図1)。乾燥培地対照(任意のHPグアーエマルジョンを含まないがHPグアーエマルジョンと同じ配合)で前処理した培養HCE細胞における乾燥後の細胞生存率%(平均±SD)は、−0.1±0.9(サンプルサイズ、n=38)であった。
本発明のHPグアーエマルジョンは、SYSB比較製剤と比較して、弾性フィラメント強度の著しい増大を示した(p<0.05)。せん断速度10-1sにおけるPFBUT(平均±SD)は、本発明のHPグアーエマルジョンでは0.031±0.008sであり、SYSB比較製剤では0.016±0.005sであった(図3)。せん断速度10-1sにおけるPFBUT(平均±SD)は、培地対照(任意のHPグアーエマルジョンを含まないがHPグアーエマルジョンと同じ配合)では0.017±0.001sであった。
Claims (16)
- 水相を形成する水と、
油相を形成する油と、
10〜18のHLB値を有する親水性界面活性剤と、
1〜6のHLB値を有する疎水性界面活性剤と、
荷電リン脂質と、
ボラートと、
粘膜付着性ガラクトマンナンポリマーと、
保存料と
を含む眼科用エマルジョンであって、
前記粘膜付着性ガラクトマンナンポリマーが、少なくとも約0.1w/v%であるが0.5w/v%以下である濃度で前記エマルジョン中に存在し、
前記保存料が実質的に塩化ベンザルコニウムを含まず、且つ
前記眼科用エマルジョンが、対照エマルジョンよりも少なくとも10%高い、乾燥に対する水和保護を有し、ここで、前記眼科用エマルジョンで使用されるものと同じガラクトマンナンポリマーを0.05w/v%含有することを除いて、前記対照エマルジョンが前記眼科用エマルジョンと同じ組成を有する、
眼科用エマルジョン。 - 前記油が、鉱油、パラフィン油及びペトロラタムから選択される炭化水素である、請求項1に記載のエマルジョン。
- 前記油が前記エマルジョンの少なくとも0.1w/v%であり、且つ3w/v%以下である、請求項1に記載のエマルジョン。
- 前記親水性界面活性剤が、少なくとも0.08w/v%であり、且つ約0.8w/v%以下である量で前記エマルジョン中に存在する、請求項3に記載のエマルジョン。
- 前記親水性界面活性剤がポリオキシエチレン−40−ステアラートである、請求項4に記載のエマルジョン。
- 前記疎水性界面活性剤が少なくとも約0.01w/v%であり、且つ2.0w/v%以下である、請求項4に記載のエマルジョン。
- 前記疎水性界面活性剤がトリステアリン酸ソルビタンである、請求項6に記載のエマルジョン。
- 前記粘膜付着性ガラクトマンナンポリマーが、グアー及びヒドロキシプロピルグアーからなる群から選択される、請求項1に記載のエマルジョン。
- 前記粘膜付着性ガラクトマンナンポリマーが、少なくとも約0.12w/v%であるが0.4w/v%以下である濃度で前記エマルジョン中に存在する、請求項8に記載のエマルジョン。
- 前記荷電リン脂質が、ジミリストイルホスファチジルグリセロールという名前のアニオン性リン脂質である、請求項8に記載のエマルジョン。
- 前記リン脂質が、約0.13〜0.3重量パーセントの濃度で前記エマルジョン中に存在する、請求項10に記載のエマルジョン。
- ボラート/ポリオール緩衝系をさらに含む、請求項1に記載のエマルジョン。
- 前記保存料が高分子第4級アンモニウム化合物である、請求項12に記載のエマルジョン。
- i.前記油相が前記水相内で液滴状であり、前記液滴が、約700nm以下であるが少なくとも10nmであるD90直径を有し、
ii.前記エマルジョンを個人の眼の中に滴下注入したときに、前記ボラート及びガラクトマンナンポリマーが協同的に作用してゲルを形成する、
請求項1に記載のエマルジョン。 - 前記油相が前記水相内で液滴状であり、前記液滴が、約500nm以下であるが少なくとも30nmであるD90直径を有する、請求項14に記載のエマルジョン。
- 前記油相が前記水相内で液滴状であり、前記液滴が、約300nm以下であるが少なくとも50nmであるD90直径を有する、請求項15に記載のエマルジョン。
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KR20200123408A (ko) | 2020-10-29 |
AU2019224830B2 (en) | 2024-05-30 |
WO2019162882A1 (en) | 2019-08-29 |
US10925892B2 (en) | 2021-02-23 |
CN111670028A (zh) | 2020-09-15 |
RU2020130800A (ru) | 2022-03-22 |
CA3086977A1 (en) | 2019-08-29 |
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