JP2014088450A - 安定な正のゼータ電位を有する眼科用水中油型乳剤 - Google Patents
安定な正のゼータ電位を有する眼科用水中油型乳剤 Download PDFInfo
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- JP2014088450A JP2014088450A JP2014029816A JP2014029816A JP2014088450A JP 2014088450 A JP2014088450 A JP 2014088450A JP 2014029816 A JP2014029816 A JP 2014029816A JP 2014029816 A JP2014029816 A JP 2014029816A JP 2014088450 A JP2014088450 A JP 2014088450A
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- ophthalmic
- oil
- zeta potential
- water emulsion
- emulsion according
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Abstract
【解決手段】界面膜で覆われた油のコアを有するコロイド粒子を含み、少なくとも1種類のカチオン性物質及び少なくとも1種類の非イオン性界面活性剤を含み、正のゼータ電位を有し、ゼータ電位安定性試験Aの条件を満たす眼科用水中油型乳剤。前記乳剤の製造方法。レンズ、眼科用パッチ、インプラント、インサートからなる群から選択される本発明の眼科用水中油型乳剤の送達手段。
【選択図】なし
Description
ゼータ電位は、懸濁液中に含まれる全ての粒子が示す物理的性質の尺度である。ゼータ電位を用いて、種々の環境下における懸濁液の挙動の予測、懸濁液及び乳剤の処方の最適化、及び長期安定性の予測を行うことができる。
粒子の表面に電荷が存在することによる重要な帰結は、粒子と印加された電場とが相互作用することである。これらの効果を総称して界面動電効果という。印加された電場の影響下にある液体中に分散した粒子の運動が誘起される場合、特に電気泳動という。電解質を横断するように電場が印加されると、電解質中に分散した荷電粒子は、反対の電荷を有する電極に引き付けられる。粒子に作用する粘性力は、この運動を妨げようとする。これらの拮抗する作用の間で平衡が成立すると、粒子は一定の速度で運動するようになる。この速度は、電場の強さ又は電位勾配、媒質の誘電定数、媒質の粘度及びゼータ電位に依存する。単位電場中での粒子の速度を、その粒子の電気液動移動度という。ゼータ電位は、ヘンリーの式によって電気泳動移動度と関連付けられる。
試験Aは、熱ストレス下で乳剤のゼータ電位の安定性を測定するものである。
CTAB:臭化ヘキサデシルトリメチルアンモニウム、臭化テトラデシルトリメチルアンモニウム及び臭化ドデシルトリメチルアンモニウムの混合物
MCT:TCM(商品名)(フランス製油業協会)
BAK:塩化ベンザルコニウム
BEC:塩化ベンゼトニウム
BCB:臭化ベンジルジメチルドデシルアンモニウム
OA:オレイルアミン(Sigma社、米国)
SA:ステアリルアミン(Sigma社、米国)
CsA:シクロスポリンA
クレモフォア:クレモフォアEL(BASF社、フランス)
ルトロール:ルトロールF68(BASF社、フランス)
オキシポール(Gattefosse社、フランス)
モンターヌ 20(SEPPIC社、フランス)
オキシポール(Gattefosse社、サンプリースト、フランス)
モンターヌ 20(SEPPIC社、フランス)
リポイドE80(リポイド社、ドイツ)
方法:
方法:
オートクレーブ殺菌した乳剤の80℃における安定性(液滴サイズ、ゼータ電位)を14日間モニターした。
方法:
オートクレーブ殺菌した乳剤の80℃における安定性(ゼータ電位)を15日間モニターした。
方法:
方法:
方法:
方法:
方法:
剤(ただし、Z06EM046は参考例)
方法及び結果:
方法及び結果:
用途に適していないカチオン性乳剤
方法及び結果:
参考例1に記載の方法により調製を行った。
方法:
上述のとおり。
安定でないカチオン性乳剤(但し、Z01EM086は参考例)
方法及び結果:
参考例1に記載の方法により調製を行った。オートクレーブ殺菌した乳剤の80℃にお
ける安定性(液滴サイズ、ゼータ電位)をT=0、7、15日目にモニターした。
本実験の目的は、カチオン性乳剤(Z01EM134、Z06EM048、Z06EM
050及びZ06EM053。組成については上記実施例を参照)を、白ウサギの右眼に
、1日に複数回、28日間連続眼球局所投与した後における眼球への許容性を決定するこ
とである。
1グループあたり10羽(オス5羽、メス5羽)のニュージーランド産白ウサギを使用した。処置(50μl眼球局所投与)を1日4回、28日間連続して行った。全身への許容性(体重、食餌及び水の摂取量、全身の外見、臨床的症状、血液学的所見及び血液生化学的所見)、眼球への許容性(検眼鏡による観察、スリットランプ試験及び眼球組織学的所見)、及び検視(全巨視的検視、主要臓器の重量)の検討を行った。体重及び臓器重量、食餌及び水の摂取量データ、及び血液学的パラメータ及び生化学パラメータについては、統計的解析(多変量分散分析−最小有意差検定)も併せて行った。
全体的挙動、食餌の摂取量及び水の摂取量、体重、臓器重量は、処置により影響を受けなかった。検視においても、処置に起因する顕著な所見は見出されなかった。検眼鏡による観察、及び眼や付属器官の顕微鏡検査からも副作用は見出されなかった。眼球の反応は、本実験に用いた全ての動物について、結膜がわずかに赤くなっていることのみであったが、これは、眼科製品を複数回点眼したウサギに共通して見られる現象である。
Claims (30)
- 眼科用水中油型乳剤であって、界面膜で覆われた油のコアを有するコロイド粒子を含み、0.001〜0.1%w/wの少なくとも1種類のカチオン性物質及び0.01%w/w以上1%w/w未満の少なくとも1種類の非イオン性界面活性剤を含み、正のデータ電位を有し、リン脂質を含まず、
前記カチオン性物質は、C10〜C24の第一級アルキルアミン、第三級脂肪族アミン、第四級アンモニウム化合物、カチオン性脂質、アミノアルコール、ビグアニド塩、カチオン性ポリマー、及びこれらの2種類以上の混合物からなる群より選択され、
前記非イオン性界面活性剤は、ポリソルベート、ポリオキシエチレンヒマシ油誘導体、ソルビタンエステル、ステアリン酸ポリオキシル及びこれらの2種類以上の混合物からなる群より選択されるものを含む、眼科用水中油型乳剤。 - 前記カチオン性物質を、0.002〜0.05%w/w含む請求項1記載の眼科用水中油型乳剤。
- 前記カチオン性物質を、0.003〜0.03%w/w含む請求項2記載の眼科用水中油型乳剤。
- 前記油の濃度が、0.5〜7%w/wである請求項1〜3のいずれか1項記載の眼科用水中油型乳剤。
- 前記油の濃度が、0.5〜5%w/wである請求項4記載の眼科用水中油型乳剤。
- 前記油の濃度が、1〜3%w/wである請求項5記載の眼科用水中油型乳剤。
- カチオン性物質/油の重量比が、0.0025〜0.06である請求項1〜6のいずれか1項記載の眼科用水中油型乳剤。
- カチオン性物質/油の重量比が、0.005〜0.04である請求項7記載の眼科用水中油型乳剤。
- 前記非イオン性界面活性剤の濃度が0.01〜0.6%w/wの範囲内に含まれる請求項1〜8のいずれか1項記載の眼科用水中油型乳剤。
- 前記ビグアニド塩が、クロロヘキシジン及びその塩、ポリアミノプロピルビグアニド、フェンホルミン、アルキルビグアニド、又はこれらの2種類以上の混合物からなる群より選択される請求項1〜9のいずれか1項記載の眼科用水中油型乳剤。
- 前記第四級アンモニウム化合物が、ハロゲン化ベンザルコニウム、ハロゲン化ラウラルコニウム、セトリミド、ハロゲン化ヘキサデシルトリメチルアンモニウム、ハロゲン化テトラデシルトリメチルアンモニウム、ハロゲン化ドデシルトリメチルアンモニウム、ハロゲン化セトリモニウム、ハロゲン化ベンゼトニウム、ハロゲン化ベヘナルコニウム、ハロゲン化セタルコニウム、ハロゲン化セテチルジモニウム、ハロゲン化セチルピリジニウム、ハロゲン化ベンゾドデシニウム、ハロゲン化クロラリルメテナミン、ハロゲン化ミリスタルコニウム、ハロゲン化ステアラルコニウム、又はこれらの2種類以上の混合物からなる群より選択され、ハロゲン化物は好ましくは塩化物又は臭化物である請求項1〜9のいずれか1項記載の眼科用水中油型乳剤。
- 前記カチオン性物質が、塩化ベンザルコニウム、塩化ラウラルコニウム、臭化ベンゾドデシニウム、塩化ベンゼセニウム、臭化ヘキサデシルトリメチルアンモニウム、臭化テトラデシルトリメチルアンモニウム、臭化ドデシルトリメチルアンモニウム又はこれらの2種類以上の混合物からなる群より選択される請求項1〜9のいずれか1項記載の眼科用水中油型乳剤。
- 前記カチオン性物質が、キトサン、1,2‐ジオレオイル‐3‐トリメチルアンモニウムプロパン、カチオン性グリコスフィンゴ脂質若しくはカチオン性コレステロール誘導体、又はこれらの2種類以上の混合物からなる群より選択される請求項1〜9のいずれか1項記載の眼科用水中油型乳剤。
- 前記コロイド粒子が、100nm〜1μmの平均粒径を有する請求項1〜13のいずれか1項記載の眼科用水中油型乳剤。
- 前記コロイド粒子が、100〜300nmの平均粒径を有する請求項14記載の眼科用水中油型乳剤。
- 前記コロイド粒子が、100〜250nmの平均粒径を有する請求項15記載の眼科用水中油型乳剤。
- 薬理活性物質を含む請求項1〜16のいずれか1項記載の眼科用水中油型乳剤。
- 前記活性物質が、抗生物質(テトラサイクリン、クロルテトラサイクリン、バシトラシン、ネオマイシン、ポリミキシン、グラミシジン、セファレキシン、オキシテトラサイクリン、クロラムフェニコール、カナマイシン、リファンピシン、トブラマイシン、ゲンタマイシン、シプロフロキサシン、アミノグリコシド、エリスロマイシン及びペニシリン、キノロン、セフタジジム、バンコマイシン、イミペネム等)、アンフォテリシンB及びミコナゾール等の抗真菌剤、スルホンアミド、スルファジアジン、スルファセタミド、スルファメチゾール及びスルフィソキサゾール、ニトロフラゾン、及びプロピオン酸ナトリウム等の抗菌剤、イドクスウリジン、トリフルオロチミジン、アシクロビル、ガンシクロビル、シドフォビル、及びインターフェロン等の抗ウィルス剤、ニトロフラゾン及びプロピオン酸ナトリウム等の抗菌物質、ヨウ素製剤トリクロサン、クロロヘキシジン等の非抗生、感染防止性の抗細菌剤又は抗菌剤、クロモグリク酸ナトリウム、アンタゾリン、メタピリリン、クロロフェニラミン、セチリジン、ピリラミン、及びプロフェンピリダミン等の抗アレルギー剤、サリドマイド等の抗増殖剤、合成糖質コルチコイド及び鉱質コルチコイド、より一般的にはコレステロール代謝に由来するホルモン誘導体(プロゲステロン、エストロゲン、テストステロン、DHEA及びそれらの誘導体等のアンドロゲンホルモン)、ヒドロコルチゾン、酢酸ヒドロコルチゾン、デキサメタゾン、デキサメタゾン21−リン酸塩、フルオロシノレン、メドリソン、酢酸プレドニソロン、ルオロメタロン、トリアムシノロン及びトリアムシノレンアセトニド並びにそれらの誘導体等の抗炎症剤、サリチル酸塩、インドメタシン、イブプロフェン、ジクロフェナク、フルビプロフェン、及びピロキシカム等の非ステロイド性抗炎症剤、及びロフェコキシブ、ジクロフェナク、ニメスリド、ネパフェナク等のCOX2阻害剤、カルムスチン、シスプラチン、マイトマイシン、及びフルオロウラシル等の抗腫瘍薬、ワクチン、免疫増強剤等の免疫薬、インスリン、カルシトニン、副甲状腺ホルモン及びペプチド並びにバソプレッシン視床下部放出因子、マレイン酸チモロール、レボブノール塩酸塩及びベタキソロール塩酸塩、チモロール塩基、ベタキソロール、アテノロール、エピネフリン、ジピバリル、オキソノロール、アセタゾールアミド塩基及びメタゾールアミド等のβアドレナリン遮断薬、サイトカイン、インターロイキン及び成長因子(上皮細胞成長因子、線維芽細胞成長因子、血小板由来成長因子、形質転換成長因子β、毛様体神経成長因子、グリア誘導神経栄養因子、NGF、EPO、PlGF等の成長因子)、抗体又は抗体断片、オリゴアプタマー、アプタマー及び遺伝子断片(オリゴヌクレオチド、プラスミド、リボザイム、短鎖干渉RNA、核酸断片、ペプチド、アンチセンス配列)、シクロスポリン、シロリムス、及びタクロリムス等の免疫抑制剤、エンドキサン、タモキシフェン等の免疫調整剤、抗トロンビン剤及びrtPA、ウロキナーゼ、プラスミン、一酸化窒素供与体等の血管拡張剤、ルテイン、ビタミン等の酸化防止剤及び/又はそれらの誘導体及び/又はそれらの光学的に許容される塩からなる群より選択される請求項17記載の眼科用水中油型乳剤。
- 前記活性物質が、シクロスポリン、シロリムス及びタクロリムスからなる群より選択される免疫抑制剤である請求項18記載の眼科用水中油型乳剤。
- 前記活性物質が、シクロスポリンAである請求項19記載の眼科用水中油型乳剤。
- ゼータ電位安定性試験Aの条件に適合し、
前記ゼータ電位安定性試験Aは、前記眼科用水中油型乳剤を調整後すぐに測定したゼータ電位をZ0、5〜10mlの前記眼科用水中油型乳剤を有効量10mlのガラス容器(タイプI)に入れ、窒素雰囲気下でバグリングは行わずに密封し、80℃で15時間保存した後測定したゼータ電位をZ15hとし、Z15hとZ0との差をδAとしたとき、δAが10mV未満のとき、ゼータ電位安定性試験Aに適合したとする、請求項1〜20のいずれか1項記載の眼科用水中油型乳剤。 - ゼータ電位安定性試験Bの条件に適合し、
前記ゼータ電位安定性試験Bは、前記眼科用水中油型乳剤を調整後すぐに測定したゼータ電位をZ0、5〜10mlの前記眼科用水中油型乳剤を有効量10mlのガラス容器(タイプI)に入れ、窒素雰囲気下でバグリングは行わずに密封し、80℃で48時間保存した後測定したゼータ電位をZ2とし、Z2とZ0との差をδBとしたとき、δBが10mV未満のとき、ゼータ電位安定性試験Bに適合したとする、請求項21記載の眼科用乳剤。 - ゼータ電位安定性試験Cの条件に適合し、
前記ゼータ電位安定性試験Cは、前記眼科用水中油型乳剤を調整後すぐに測定したゼータ電位をZ0、5〜10mlの前記眼科用水中油型乳剤を有効量10mlのガラス容器(タイプI)に入れ、窒素雰囲気下でバグリングは行わずに密封し、80℃で7日間保存した後測定したゼータ電位をZ7とし、Z7とZ0との差をδCとしたとき、δCが10mV未満のとき、ゼータ電位安定性試験Cに適合したとする、請求項22記載の眼科用乳剤。 - ゼータ電位安定性試験Dの条件に適合し、
前記ゼータ電位安定性試験Dは、前記眼科用水中油型乳剤を調整後すぐに測定したゼータ電位をZ0、5〜10mlの前記眼科用水中油型乳剤を有効量10mlのガラス容器(タイプI)に入れ、窒素雰囲気下でバグリングは行わずに密封し、80℃で14日間保存した後測定したゼータ電位をZ14とし、Z14とZ0との差をδDとしたとき、δDが10mV未満のとき、ゼータ電位安定性試験Dに適合したとする、請求項23記載の眼科用乳剤。 - 請求項1〜24のいずれか1項記載の眼科用水中油型乳剤の製造方法であって、水相と油相とを混合して得られる粗乳剤をせん断混合後高圧ホモゲナイズする工程を有する方法。
- ドライアイ症状の治療のための眼科用製剤の調製への請求項1〜24のいずれか1項記載の眼科用水中油型乳剤の使用。
- 緑内障、角膜炎、ブドウ膜炎、眼球内炎症等の眼性炎症疾患、ドライアイ症候群、眼性感染症、眼性アレルギー、眼球感染症、ガン性増殖、角膜からの新生血管増殖、網膜浮腫、黄斑浮腫、糖尿病性網膜症、未熟児網膜症、網膜変性症(黄斑変性症、網膜ジストロフィー)、グリア細胞の増殖に関連する網膜症等の眼の症状の治療用製剤の調製への請求項17〜20のいずれか1項記載の眼科用水中油型乳剤の使用。
- 請求項1〜24のいずれか1項記載の眼科用水中油型乳剤を含み、必要に応じて眼科的に許容される担体と組み合わせ、点眼剤、眼用軟膏又は眼用ゲルの形態を有する眼科用製剤。
- 前記眼科的に許容される担体中に、薬理的に有効量の有効成分を含む請求項28記載の眼科用製剤。
- レンズ、眼科用パッチ、インプラント、インサートからなる群から選択され、請求項1〜24のいずれか1項記載の乳剤を含む送達手段。
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