JP6142419B2 - 塩感受性エマルジョン系を用いたヒト涙液膜への効率的脂質送達 - Google Patents
塩感受性エマルジョン系を用いたヒト涙液膜への効率的脂質送達 Download PDFInfo
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- JP6142419B2 JP6142419B2 JP2014546154A JP2014546154A JP6142419B2 JP 6142419 B2 JP6142419 B2 JP 6142419B2 JP 2014546154 A JP2014546154 A JP 2014546154A JP 2014546154 A JP2014546154 A JP 2014546154A JP 6142419 B2 JP6142419 B2 JP 6142419B2
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Description
本出願は、2011年12月7日に出願された米国仮出願第61/568,089号、および2012年4月17日に出願された同第61/625,401号の利益を主張し、その開示は参照によりその全体を本明細書に援用される。
[2] 粘滑剤
[3] 粘滑剤および等張化剤
[4] 安定化オキシクロロ錯体(Purite)。分析値によって添加。
[5] Pemulen TR−2NF(カルボマーコポリマーA型、Ph Eurに対して試験した)。第2の乳化剤。
[6] 親油性ビヒクル
[7] pH標的7.3
[8] 親水性ビヒクル
1) 人工涙液として有用な組成物であって、ヒマシ油を含む無塩エマルジョンであり、具体的にオリーブ油を除外し、かつポリソルベート、カルボキシメチルセルロース、およびグリセリンからなる群から選択される少なくとも1つの活性薬剤を含有する、組成物。
2) 該混合物は、約0.1重量/重量%〜0.5重量/重量%のヒマシ油を含む、項1の組成物。
3) ヒマシ油は、エマルジョン中の唯一の油である、項1〜2の組成物。
4) ヒマシ油は、水相中で乳化される、項1〜3の組成物。
5) ヒマシ油は、約0.25重量/重量%で存在する、項4の組成物。
6) 第1の乳化剤および第2の乳化剤を更に含む、項4〜5の組成物。
7) 組成物は、防腐剤を含有する、項1〜6の組成物。
8) 防腐剤は、PURITEおよび塩化ベンザルコニウム(benzalkoniuim chloride)からなる群から選択される、項7の組成物。
11. 防腐剤は、PURITEであり、約0.01重量/体積%の濃度で存在する、項8の組成物。
12. ドライアイの治療における使用のためのエマルジョンであって、無塩であり、かつヒマシ油、ポリソルベート80、カルボキシメチルセルロース、およびグリセリンを含む、エマルジョン。
13. エマルジョンは、乳化剤ペムリン(pemulin)も含有する、項12の組成物。
14. エリトリトールおよびレボカルニチンを更に含む、項12〜13のエマルジョン。
15. 表1に示す通りのドライアイを治療するためのエマルジョン。
16. 項1〜15の組成物またはエマルジョンのうちのいずれか1つの投与を含む、ドライアイを治療する方法。
17.ドライアイまたは乾性角結膜炎の治療のための組成物であって、約0.5重量/重量%のポリソルベート80、約0.5重量/重量%のカルボキシメチルセルロース、約1.0重量/重量%のグリセリン、約0.6重量/重量%のホウ酸、約0.1重量/重量%のペムリン(pemulin)、約0.25重量/重量%のヒマシ油、約0.25重量/重量%のエリトリトール、約0.25重量/重量%のレボカルニチン、pHを約7.3に調整するための水酸化ナトリウム、および水を含む、組成物。
18.0.01%のPurite(登録商標)を更に含む、請求項17の組成物。
19.組成物は、ドライアイを罹患する眼に局所的に適用される、請求項17の組成物。
20.組成物は、ドライアイの兆候を緩和するために眼に局所的に適用される、請求項17の組成物。
21.組成物は、ドライアイ症候群を予防するために眼に局所的に適用される、請求項17の組成物。
脂質をヒト涙液膜へ送達して、マイボーム腺の機能不全および他の原因によってしばしば不十分である天然の脂質層を補充および強化することは、ドライアイの兆しおよび兆候の治療における広く認められている戦略である。これは理論的には、低湿度、または他の内的/外的要因が涙液膜蒸発を増加させる場合に特に有益である。涙液膜からの過度の水損失は、塩含有量の増加を引き起こし、また眼表面の細胞に対する高浸透圧ストレスを引き起こす。
1)製品を震盪する必要がない−ボトル内での優れた安定性および均質性
2)塩誘発性の粘度減少、およびより効率的な脂質放出を可能にするエマルジョン構造の不安定化に起因する、眼の上での脂質の効率的送達、
3)総脂質含有量を低下させることによる向上された認容性
4)天然脂質層の効率的安定化および補充、ならびに
5)より高い涙液塩含有量を有する患者における有益な脂質の潜在的により多くの送達、いわゆる「高性能な」ビヒクルが挙げられるが、これらに限定されない。
これは、NGE UDの安全性、有効性、および許容可能性を市販されているOPTIVE(商標)感受性の防腐剤を含まない潤滑性点眼薬単位投薬(「OPTIVE UD」)に対して、NGE UDの安全性、有効性、および許容可能性を次世代エマルジョン複数回投薬(「NGE MD」)(表1のものと同一の製剤であるが、Purite(登録商標)を含む)に対して、またNGE MDの安全性、有効性、および許容可能性をOPTIVE(商標)潤滑性点眼薬複数回投薬(「OPTIVE MD」)に対して比較するように設計された、多角的な研究者盲検、無作為化、活性制御された4アーム並行群間研究であった。
約300名の対象が本研究に参加するように計画した。合計315名の対象が参加した。
診断/ドライアイ疾患の兆しおよび兆候を有する対象
18以上かつ65以下のベースライン(1日目)OSDIスコア(0〜100スケールに基づく)を有する、18歳以上の男性または女性の対象が、参加に適格であった。対象は、平均してベースラインの前に少なくとも3ヶ月間、少なくとも1日2回、ドライアイ用の局所用目薬を使用していなければならなかった。RESTASIS(登録商標)シクロスポリン点眼用エマルジョンの日常的使用があれば、6ヶ月以上使用していなければならなかった。ベースライン時に少なくとも片方の目において10秒以下の3回の連続した涙液層破壊時間(TBUT)試験が必要とされた。修正された国立眼学研究所(National Eye Institute)(NEI)グリッドを用いて、全対象は、ベースライン時に少なくとも片方の眼において、ドライアイに関連する角膜の5つの区域のうちの少なくとも1つ、または結膜の6つの区域のうちの少なくとも1つにおいて、少なくともグレード1の染色を有している必要があった。
重要な対象除外基準は、ベースライン時にいずれかの眼においてシルマー試験(麻酔有)2mm以下、ベースライン時にいずれかの眼の5つの角膜区域または6つの結膜区域のいずれかにおける角膜または結膜染色スコア5(修正されたNEIグリッド)、ドライアイ症状または視覚に影響を及した可能性のある全身投薬の使用、但し、その投薬が、研究参加の前に少なくとも3ヶ月間、同一容量で使用されており、投薬量が研究のコースの間に変化すると予想されない場合を除く、ベースライン前12ヶ月以内の角膜感受性に影響を及ぼした可能性のある前眼部手術または外傷(例えば、白内障手術、レーザー角膜切削形成術[LASIK]、レーザー屈折矯正角膜切除術、または角膜縁または角膜切開に関与する任意の手術)の履歴、ならびに任意の局所用点眼薬(例えば、局所用点眼用ステロイド、緑内障点眼薬、Restasis(登録商標)以外の任意の局所用シクロスポリン製品)の現行使用、および/またはベースラインの前2週間以内の使用、および/または研究期間中の使用の可能性が含まれた。ベースライン前の3ヶ月未満にRestasis(登録商標)の日常的使用を中断した対象は、研究から除外した。
有効性:第1-OSDI質問表スコア
包括解析(ITT)集団は、全ての無作為化された対象で構成され、無作為化された治療に基づく有効性データの分析のために使用された。安全性集団は、全ての治療された対象で構成され、実際に受けた治療に基づく全ての安全性データの分析のために使用された。パープロトコル(PP)集団は、データベースロック前に決定した際に、主要なプロトコル違反を有さない無作為化された対象で構成された。
・第1の有効性エンドポイントは満たされた。30日目において、ITT集団内でOSDIスコアにおける平均変化(95%信頼区間[−5.42,2.51])において、NGE UD群とOPTIVE UD群との間で、統計的有意差は観察されなかった。NGE UD製剤は、OSDIスコアにおけるベースラインからの変化によって測定した際、乾燥の兆候の重篤度の低減においてOPTIVE UD製剤に対して非劣性であった。
・任意の因果関係の少なくとも1つの治療中に発現した有害事象(TEAE)が、NGE UD群、OPTIVE UD群、NGE MD群、およびOPTIVE MD群のそれぞれ11.4%、15.5%、13.7%、および10.7%の対象に報告された。
有効性:本研究の結果は、NGE UD製剤は、軽度から重度のドライアイを罹患する患者における乾燥の兆候の重篤度の低減において、OPTIVE UD製剤に対して非劣性であることを実証する。
Claims (15)
- 0.25質量/質量%のヒマシ油と、
少なくとも1つの活性薬剤と、
を含有する、無塩エマルジョンである、人工涙液として有用な組成物であって、
前記活性薬剤は、ポリソルベート、カルボキシメチルセルロース、およびグリセリンからなる群から選択され、且つ
前記ヒマシ油は、前記エマルジョン中の唯一の油である、前記組成物。 - 前記ヒマシ油は、水相中に乳化されている、請求項1に記載の組成物。
- 第1の乳化剤および第2の乳化剤を更に含む、請求項1に記載の組成物。
- 前記組成物は、防腐剤を含有する、請求項1に記載の組成物。
- 前記防腐剤は、オキシクロロ錯体および塩化ベンザルコニウム(benzalkoniuim chloride)からなる群から選択される、請求項4に記載の組成物。
- 前記防腐剤は、オキシクロロ錯体であり、0.01質量/質量%の濃度で存在する、請求項5に記載の組成物。
- ドライアイの治療における使用のためのエマルジョンであって、無塩であり、かつ0.25質量/質量%のヒマシ油及び活性薬剤を含み、
前記活性薬剤が、ポリソルベート80、カルボキシメチルセルロース、およびグリセリンであり、且つ
前記ヒマシ油が前記エマルジョン中の唯一の油である、前記エマルジョン。 - 前記エマルジョンは、カルボマーコポリマーも含有する、請求項7に記載のエマルジョン。
- エリトリトールおよびレボカルニチンを更に含む、請求項8に記載のエマルジョン。
- 0.25質量/質量%のヒマシ油と、
少なくとも1つの活性薬剤と、
を含む、ドライアイを治療するためのエマルジョンであって、
前記活性薬剤は、ポリソルベート、カルボキシメチルセルロース、およびグリセリンからなる群から選択され、且つ
前記ヒマシ油は、前記エマルジョン中の唯一の油である、前記エマルジョン。 - 0.25質量/質量%のヒマシ油と、
少なくとも1つの活性薬剤と、
を含む、ドライアイを治療するための医薬組成物であって、
前記活性薬剤は、ポリソルベート、カルボキシメチルセルロース、およびグリセリンからなる群から選択され、且つ
前記ヒマシ油は、前記医薬組成物中の唯一の油である、前記組成物。 - 防腐剤を含まない、請求項11に記載の医薬組成物。
- 少なくとも1日1回適用されるように用いられる、請求項11に記載の医薬組成物。
- ドライアイ症候群の兆候を緩和する、請求項12に記載の医薬組成物。
- ドライアイ症候群を治療および予防する、請求項12に記載の医薬組成物。
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US201161568089P | 2011-12-07 | 2011-12-07 | |
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US61/625,401 | 2012-04-17 | ||
PCT/US2012/068615 WO2013086449A1 (en) | 2011-12-07 | 2012-12-07 | Efficient lipid delivery to human tear film using a salt-sensitive emulsion system |
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