TWI478730B - 眼科乳劑 - Google Patents
眼科乳劑 Download PDFInfo
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- TWI478730B TWI478730B TW099139702A TW99139702A TWI478730B TW I478730 B TWI478730 B TW I478730B TW 099139702 A TW099139702 A TW 099139702A TW 99139702 A TW99139702 A TW 99139702A TW I478730 B TWI478730 B TW I478730B
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- Taiwan
- Prior art keywords
- emulsion
- oil
- present
- amount
- phospholipid
- Prior art date
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- 239000000839 emulsion Substances 0.000 title claims description 128
- 239000003921 oil Substances 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 51
- 239000004094 surface-active agent Substances 0.000 claims description 44
- 239000012071 phase Substances 0.000 claims description 29
- 150000003904 phospholipids Chemical class 0.000 claims description 28
- 230000002209 hydrophobic effect Effects 0.000 claims description 22
- -1 hydroxypropyl Chemical group 0.000 claims description 20
- 229920000642 polymer Polymers 0.000 claims description 17
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- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 10
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- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical group CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 claims description 3
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- OMDQUFIYNPYJFM-XKDAHURESA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[[(2r,3s,4r,5s,6r)-4,5,6-trihydroxy-3-[(2s,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]methoxy]oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@H](O)[C@H](O)O1 OMDQUFIYNPYJFM-XKDAHURESA-N 0.000 claims 3
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Description
本申請案係申明美國臨時申請案系列號61/266,207，於2009年12月3日提申，之優先權。
本發明係相關於一種眼科乳劑。更特別的是，本發明係相關於一種具有獨特成分組合之眼科乳劑，可幫助乳劑中小油滴的穩定，並幫助該乳劑之醫藥傳送能力。
目前已有各種形式之眼科組成物，如水溶液、水性懸浮液與其他形式。有時眼科組成物亦會配製成乳劑形式。眼科乳劑一般使用於希望包含二或多種成分，相較於單一組成物呈不互溶，因而在組成物中形成二個分離相之情況下。此類乳劑可允許單一組成物提供二相之優點(如傳送特性上之優點)。例如，乳劑可在水相中形成油滴，其中該油滴可使用作為活性成分如醫療試劑(如藥物)之載體，或作為賦形劑，其具有較低之水中溶解度及/或穩定度。
乳劑之範例包括美國專利號：4,914,088；5,278,151；5,294,607；5,371,108與5,578,586。這些專利每一者皆在此併入本案以作為參考資料。
特別希望乳劑中之一相可實質上均勻地分散於另一相中。此種分散可明顯地影響乳化劑傳送治療成分之能力。此外，此種分散通常為乳化劑本身穩定度之指標。
乳劑之各分離相很難均勻地分散於組成物中，由於每一相皆傾向於與本身結合，而非另一相。因此，維持某一相(即分散相)在另一相(即連續相)中之分佈，是相當複雜的。此外，通常很難在乳劑中包含其他成分，由於許多成分會抑制分散相在連續相中之分散及/或均勻分佈。
本發明乳劑為含有油滴分散於水中之二相。油滴尺寸一般小於1000nm，但一般大於10nm。要達成此種油滴尺寸是相當困難的，由於一般熱力學因素或其他不穩定因素，並需要一或多種賦形劑以提供乳劑之穩定性，並預防油滴結合。乳劑之去乳化作用需要在動力學上受阻礙，尤其是在惡化條件下如於高室溫下儲存該乳劑時(如夏季倉庫，尤其是在熱帶或中央大陸或地中海型氣候下，或在配製過程中置於加熱與冷卻循環條件下所遭遇之溫度循環)。此外，在水相中之高離子強度存在會導致去乳化。
當小油滴尺寸難以於簡單乳劑中維持時，油滴尺寸之維持便變得相當複雜，當額外成分需包含於乳劑中時(請見Surface properties and emulsification activity of galactomannans,
Food Hydrocolloids,Volume 8,Issue 2,May 1994,Pages 155-173 Nissim Garti,Dov Reichman)。就眼科乳劑而言，要整合黏膜黏附材料尤其是黏膜黏附型聚合物至乳劑中，而不產生不希望之乳劑油滴尺寸不穩定是相當困難的。希望可提供一種可維持小油滴之乳劑，特別希望能在黏膜黏附型聚合物存在下維持小油滴。
因此，目前需要一種方法，其可製造含黏膜黏附型聚合物之穩定乳劑。此外，特別希望是水性乳劑，具有剪切稀薄特性，可有效提供潤滑性，並可保護角膜(乾眼症病患)。此外，目前亦需要一種方法，可製造含有微細分散油滴之乳劑，其可以抗菌劑保存，以及一種製造穩定保存乳劑之方法。
本發明之一目的為提供一種可製造具小平均滴液之穩定乳劑，在黏膜黏附型聚合物存在下。
本發明之另一目的為提供一種乳劑，其可避免相分離，尤其是可避免在儲存於標準溫度與加熱/冷卻循環條件下之相分離。
本發明係相關於一種眼科乳劑，其包括下列成分：形成水相之水；形成油相之油；親水性界面活性劑；疏水性界面活性劑；帶電荷之磷脂質；硼酸鹽；以及黏膜黏附型聚合物(如半乳甘露醣聚合物)。該油相在水相中為油滴狀，且該油滴具有平均直徑不大於約1500奈米(nm)，一般不大於約1000nm，更常見為不大於約500nm。這些油滴一般具有平均直徑至少2nm，更常見為至少10nm，尤常見為至少100nm。當乳劑滴入個體眼中時，該硼酸鹽與半乳甘露醣聚合物會共同作用形成凝膠。
本發明係描述一種眼科水包油乳劑，其中該乳劑具有相對小的平均油滴尺寸。該乳劑一般為水性，且包括大量之水。該乳劑亦包括陰離子性磷脂質、親水性界面活性劑(高HLB)，以及疏水性界面活性劑(低HLB)。此外，該乳劑一般包括一或多種黏膜黏附型成分(如半乳甘露醣聚合物)，以幫助維持乳劑於眼角膜表面，及/或幫助傳送一或多種親脂性化合物至角膜表面。本發明乳劑最希望用於乾眼症之治療。然而，不受限制地，乳劑亦可用於藥物傳送、維生素傳送、植物性藥物傳送、隱形眼鏡保濕與隱形眼鏡潤滑。
除非另有特別指出，所有乳劑成分或百分比皆為重量體積百分比(w/v%)。
乳劑中的油類係完全分散於連續水相或水性相中，呈實質上各自獨立且分開之小油滴形式。應瞭解到，各項獨立且分開表示在任一時間點，該油滴皆為獨立且分開。然而，乳劑中的油滴可隨著時間結合與分開，以維持平均油滴尺寸或直徑。本發明乳劑中之油滴一般具有平均直徑不大於1500奈米(nm)，更一般為不大於約1000nm，尤佳不大於約600nm。這些油滴一般亦具有平均直徑至少2nm，更佳為至少10nm，尤佳為至少100nm。
可使用顆粒或液滴尺寸分析儀測定乳劑中的液滴尺寸。例如，Microtrac S3500粒徑分析儀(軟體版本10.3.1)為三雷射粒徑分析儀，可用於測量乳劑中之油滴尺寸。此特別的顆粒分析儀會測量由流動流中顆粒(如液滴)所繞射(散射)出的雷射光。散射光的強度與方向係由二光學偵測器偵測。繞射路徑由軟體進行運算分析，產生液滴尺寸之體積分佈。使用對應於90%較小體積分佈之液滴尺寸。
本發明乳劑為水包油乳劑。該油可為各種礦物油、蔬菜油與合成物質，及/或動物與蔬菜油脂，或油類之任一組合。該油可溶於各種有機溶劑中如醚類，但並不溶於水中。該油相可包含，若希望為液體烴類，如礦物油、石蠟油、石油或烴類油。尤佳為礦物油。亦可使用矽油。油相可額外地包括蠟烴，如石蠟、氫化蓖麻油、Synchrowax HRC、Carnabau、蜂蠟、經修飾蜂蠟、微結晶蠟，以及聚乙烯蠟。油類一般為至少0.01w/v%，更特別地是至少為0.1w/v%，尤其是0.8w/v%乳劑。該油類一般不大於約20w/v%，更佳不大於約5w/v%，尤其是不大於約3，甚至1.5w/v%乳劑。
本發明乳劑一般會加入二或多種界面活性劑，其作為乳劑乳化過程中之乳化劑輔助物。一般而言，這些界面活性劑為非離子性。乳劑中之乳化界面活性劑濃度通常選自於0.1至10%w/v之範圍中，在許多案例中為0.5至5%w/v。較佳選自於至少一乳化劑/界面活性劑為親水性，且具有HLB值至少8，通常為至少10(如10至18)。更佳選自於至少一乳化劑/界面活性劑為疏水性，且具有HLB值低於8，尤其是1至6。藉由使用適當比例之兩種界面活性劑/乳化劑，可更容易獲得可促進乳劑形成之加權平均HLB值。就本發明之大部分乳劑而言，所選擇之平均HLB值為約6至12，大部分為7至11。
舉例而言，示範用界面活性劑與礦物油之HLB值如下：疏水性界面活性劑(2.1)、親水性界面活性劑(16.9)，以及礦物油(10.5)。示範性乳劑中所使用之疏水性界面活性劑與親水性界面活性劑之濃度分別為0.38%與0.29%，以這些計算為基礎
29/.67=0.43，以及.38/.67=0.57
疏水性界面活性劑與親水性界面活性劑間之比例等於1.32，其可用於選擇二界面活性劑之濃度比例。示範性乳劑中所使用之疏水性界面活性劑與親水性界面活性劑之濃度分別為0.38%與0.29%，以這些計算為基礎。
乳劑中之親水性界面活性劑存在量一般至少約0.01w/v%，更佳至少約0.08w/v%，尤佳為至少約0.14w/v%。乳劑中之親水性界面活性劑之存在量一般不大於約1.5w/v%，更佳不大於約0.8w/v%，尤佳不大於約0.44w/v%。
該親水性界面活性劑可為脂肪酸、酯類、醚類、酸類或其任一組合。該親水性界面活性劑可為離子性或非離子性，但較佳為非離子性。許多適用之界面活性劑/乳化劑為非離子性酯類或醚類乳化劑，包含聚氧基烯基片段，尤其是聚氧基乙烯片段，通常含有約2至80個，尤其是5至60個氧基乙烯單元，及/或含有聚羥基化合物如甘油或山梨糖醇，或其他多羥基糖醇(alditol)，作為親水性片段。該親水性片段包含聚氧基丙烯。乳化劑額外地包含一疏水性烷基、烯基或芳烷基片段，一般包含約8至50個碳原子，尤其是10至30個碳原子。親水性界面活性劑/乳化劑之範例包括鯨蠟硬脂醇聚醚-10至鯨蠟硬脂醇聚醚-25、鯨蠟硬脂醇聚醚10-25(ceteth-10-25)、硬脂醇聚醚-10-25，以及PEG-15-25硬脂酸酯或二硬脂酸酯。其他適當範例包括C10-C20脂肪酸單、二或三甘油酯。其他範例包括聚乙烯氧化物之C18-C22脂肪醇醚類(8至12EO)。尤佳之親水性界面活性劑為聚氧化乙烯-40-硬脂酸酯，其商標名為MYRJ-52，商業上得自Nikko Chemicals。
乳劑中之疏水性界面活性劑一般存在量為至少約0.01w/v%，更佳為至少約0.11w/v%，尤佳為至少約0.16w/v%。乳劑中之疏水性界面活性劑一般存在量為不大於約10.0w/v%，更佳不大於約2.0w/v%，尤佳不大於約0.62w/v%。
疏水性界面活性劑可為脂肪酸、酯類、醚類、酸類或其任一組合。疏水性界面活性劑可為離子性或非離子性，但較佳為非離子性。疏水性界面活性劑一般包括疏水性片段。疏水性片段可為直鏈或支鏈，通常為飽和，雖然亦可為不飽和，且可選擇性地經氟化。疏水性片段可包含鏈長度之混合物，如衍生自動物脂、豬油、棕櫚油、葵花籽油或大豆油者。此類非離子性界面活性劑亦可衍生自聚羥基化合物，如甘油或山梨糖醇或其他羥基糖醇(alditols)。疏水性界面活性劑之範例包括，但不受限於，脂肪酸山梨糖醇酯如單油酸山梨糖醇酯、單硬脂酸山梨糖醇酯、單月桂酸山梨糖醇酯、單棕櫚酸山梨糖醇酯、單異硬脂酸山梨糖醇酯、三油酸山梨糖醇酯、三硬脂酸山梨糖醇酯、倍半油酸山梨糖醇酯、倍半硬脂酸山梨糖醇酯，其組合物或其類似物。一尤佳之疏水性界面活性劑為三硬脂酸山梨糖醇酯，商標名為SPAN-65，商業上購自Croda Worldwide。
本發明使用之半乳甘露醣一般衍生自瓜爾膠、刺槐豆膠，以塔拉膠。使用於此，術語“半乳甘露醣”，係指一多醣類，衍生自上述含有甘露醣或半乳醣片段或二者基團作為主要結構成分之天然膠或類似天然或合成膠。本發明較佳之半乳甘露醣係由直鏈(1-4)-β-D-吡喃甘露醣苷單元，與α-D-吡喃半乳醣苷單元以(1-6)橋聯聯結組成。較佳之半乳甘露醣，其D-半乳醣比D-甘露醣之比例可變化，一般自約1：2至1：4。最佳為具有D-半乳醣：D-甘露醣比例為約1：2之半乳甘露醣。此外，其他多醣類之化學修飾變異物亦包括於“半乳甘露醣”定義中。例如，羥基乙基、羥基丙基與羧基甲基羥基丙基取代基，可用於組成本發明之半乳甘露醣。半乳甘露醣之非離子性變異物，如含有烷氧基與烷基(C1-C6)基團者為尤佳，當希望為軟凝膠時(如羥基丙基取代基)。最佳為非順式羥基位置上之取代基。本發明半乳甘露醣之非離子性取代基範例為羥基丙基瓜爾膠，具有莫耳取代約0.4。陰離子性取代亦可組成半乳甘露醣。尤佳為陰離子性取代基，若希望為強反應性凝膠時。本發明配方中之半乳甘露醣濃度一般為至少約0.005w/v%，更佳為至少約0.01w/v%，尤佳為至少約0.03w/v%，但一般不大於約5w/v%，更佳為不大於約1.0w/v%，尤佳為不大於約0.3w/v%，特佳為不大於約0.08w/v%。本發明之較佳半乳甘露醣為瓜爾膠與羥基丙基瓜爾膠。
該乳劑可包含額外的聚合物成分及/或黏性試劑。範例包括，但不受限於，羧基甲基纖維素、羥基丙基甲基纖維素、羥基乙基纖維素、羧基乙烯基聚合物、黃原膠、透明質酸，其任一組合或類似物。
本發明乳劑包括至少一磷脂質，用於幫助維持乳劑穩定性，且用於降低油滴尺寸。已知複合磷脂質可於其分子結構之一端包含極性基團，且於另一端包含非極性基團。關於磷脂質的討論請見Lehninger,Biochemistry,2 ed.,Worth Publishers,New York,pp. 279-306，在此併入本案以作為參考資料。
許多複合磷脂質為技術上已知。不同處在於尺寸、形狀以及極性端基團之電荷。磷酸甘油脂為一化合物，其中甘油上之主要羥基經磷酸酯化，而其他兩個羥基則被脂肪酸酯化。因此，此系列之原始化合物為甘油之磷酸酯。此化合物具有不對稱碳原子，因此術語磷酸甘油酯包括其空間異構物。所有磷酸甘油酯皆於pH7時，在磷酸基上具有負電荷，且此基團之pKa
範圍為1至2。磷脂醯肌醇、磷脂醯甘油包括二磷脂醯甘油(一般名稱為心磷脂(cardiolipins))與磷脂醯醣類之頭部基團不具電荷，所有皆為極性，由於其高羥基含量。由於磷酸基的負電荷，且頭部基團不帶電荷，這些材料每一者的淨電荷皆為負電，且這些材料皆落於本發明範疇中。適當之磷脂質為在使用條件下帶有淨正電或淨負電。較佳材料為帶有淨負電荷者，由於負電材料會與眼球表面之負電相排斥，因而允許在施加至眼部時維持相對厚之水層。最佳之磷脂質為陰離子性磷脂質，名為二肉荳蔻醯基磷脂醯甘油酯(DMPG)，其為一種多元醇，帶有淨負電荷。磷脂酸甘油酯或磷脂酸肌醇酯為其他範例。適當之磷脂質添加物係如上述美國專利號4,914,088所揭示，在此併入本案以作為參考資料。
大部分磷脂質為水不溶性。然而，用於施加至眼部，希望磷脂質可均勻地完全分佈於水性介質中。就少數在可用濃度範圍內具溶解度，而使用作為治療組成物之磷脂質而言，磷脂質之生理食鹽水單純水性溶液便可滿足。就實質上為水不溶性之磷脂質而言，可使用乳劑形式之水性組成物。乳劑可提供一種治療組成物，其中含有磷脂質成分之相係均勻分佈於整個水性載劑中。
治療組成物中之磷脂質濃度可在廣範圍中變化。含有複合磷脂質量低至0.01%重之治療組成物，可提供某些幫助。當治療組成物為乳劑形式，含有高濃度磷脂質之組成物可能會將乳劑分為水相與磷脂質相。磷脂質在載劑中之臨床實際濃度範圍由約0.05變化至7.0 w/v%磷脂質重，較佳為0.1至5.0w/v%。應注意到水性組成物中最佳之磷脂質濃度會依據情況而不同。
其他添加物可存在於包含中性脂質之磷脂質治療組成物中，如一或多種三酸甘油酯、膽固醇酯、天然蠟與膽固醇；較高分子量之異戊間二烯；穩定劑；防腐劑；pH調整劑，以提供組成物pH值較佳介於約6至8間，更佳介於約7.0至7.4之間；濃度足以形成等張組成物之鹽類；藥物等。
如上所述，本發明乳劑可包括硼酸鹽或硼酸鹽/多元醇緩衝系統。使用於此，術語“硼酸鹽”包括硼酸、硼酸之鹽類、其他醫藥上可接受之硼酸鹽，以及其組合。下列硼酸鹽為尤佳：硼酸、硼酸鈉、硼酸鉀、硼酸鈣、硼酸鎂、硼酸錳，以及其他此類硼酸鹽。
使用於此，術語“多元醇”包括兩相鄰碳原子間具有至少一羥基，互相不呈反式構形。多元醇可為直鏈或環狀、經取代或未經取代，或其混合物，只要所得複合物為水溶性，且為醫藥上可接受。此類化合物之範例包括：醣類、糖醇、糖酸，與糖醛酸。較佳之多元醇為醣類、糖醇與糖酸，包括但不侷限於：甘露醣醇、甘油、木糖醇與山梨糖醇。尤佳之多元醇為甘露糖醇與山梨糖醇；最佳為山梨糖醇。
使用硼酸鹽-多元醇複合物於眼科組成物中，係描述於美國專利號6,503,497(Chowhan)，在此併入本案以作為參考資料。本發明乳劑較佳含有一或多種硼酸鹽，濃度為至少約0.01%w/v，更佳為至少約0.3%w/v，尤佳為至少約0.8%w/v，但一般不大於約5.0%w/v，較佳為不大於約2.0%w/v，更佳為不大於約1.2%w/v，一般希望該一或多種硼酸鹽之量足以允許硼酸鹽/多元醇複合物產生，若希望的話，可在乳劑施加至眼部時，幫助半乳甘露醣聚合物形成凝膠。
本發明組成物一般包括防腐劑。可使用之防腐劑包括，但不受限於，過氧化氫、含氯防腐劑如氯化芐烷銨或其他。然而，依據一較佳觀點，本發明之眼科組成物實質上不含任何含氯防腐劑，尤其是實質上不含氯化芐烷銨。眼科組成物中所包含之最佳防腐劑為聚合性四級銨化合物。
使用於此，術語“實質上不含”係指一眼科組成物成分，該眼科溶液中完全避免該特定成分，或僅包含微量之該特定成分。
本發明使用於組成物中之聚合性四級銨化合物，為具有抗菌作用且為眼科可接受者。此類較佳化合物係描述於美國專利號3,931,319；4,027,020；4,407,791；4,525,346；4,836,986；5,037,647與5,300,287；以及PCT申請案WO 91/09523(Dziabo et al.)。最佳之聚合性銨類化合物為聚季銨1，另一已知名稱為POLYQUAD.RTM.，或ONAMERM.RTM.，具有數目平均分子量2,000至30,000。較佳為，該數目平均分子量介於3,000至14,000之間。
使用於本發明組成物中之聚合性四級銨化合物一般量大於約0.00001w/v%，更佳大於約0.0003w/v%，尤佳大於約0.0007w/v%眼科組成物。此外，使用於本發明組成物中之聚合性四級銨化合物一般量小於約3w/v%，更佳小於約0.003w/v%，尤佳小於約0.0015w/v%眼科組成物。
本發明乳劑可包括多種眼用治療試劑。可使用於本發明中之眼科醫療試劑包括：抗青光眼劑、抗血管生成劑、抗感染劑、抗發炎劑；生長因子；免疫抑製劑和抗過敏劑。抗青光眼劑包括β-阻斷劑，如倍他洛爾(betaxolol)與左倍他洛爾(levobetaxolol)；碳酸酐酶抑製劑，如派立明(brinzolamide)和多佐胺(dorzolamide)，前列腺素，如曲伏前列素(travoprost)，比馬前列素(bimatoprost)和拉坦前列素(latanoprost)；血清素(seretonergics)；蕈毒素(muscarinics)；多巴胺受體協同劑。抗血管生成劑包括阿耐可他醋酸鹽(anecortave acetate)(RETAANETM
,AlconTM
Laboratories,Inc. of Fort Worth,Tex.)，以及受體酪胺酸激酶抑制劑(RTKi)。抗發炎劑包括非固醇類與固醇類抗發炎劑，如曲安奈德錒(triamcinolone actinide)、素普芬(suprofen)、雙氯芬酸(diclofenac)、痛力克(ketorolac)、奈帕芬胺(nepafenac)、瑞米所隆(rimexolone)和四氫皮質醇(tetrahydrocortisol)。生長因子包括EGF或VEGF。抗過敏劑包括奧洛他定(olopatadine)和依匹斯汀(epinastine)。該眼科藥物可為醫藥上可接受鹽類形式存在。
本發明特別可用於傳送醫療試劑，其可緩解乾眼症之症狀。範例包括，但不受限於，固醇類及/或非固醇類抗發炎劑；選擇性PDE IV抑制劑，如西洛司特(cilomilast)、環孢黴素(cyclosporins)，其組合物或類似物。本發明乳劑亦可用於其他領域，如傳送冷卻試劑；傳送抗氧化劑(omega-3與omega-6脂肪酸)，與其他眼科用途之生物活性物質。例如，營養物如維生素A(視醇)、維生素D(骨化醇)、維生素B、生育酚、維生素K(奎寧)、β-胡蘿蔔素(前-維生素-A)，及其組合。
一般而言，當使用時，治療試劑之量可依據所使用之試劑而變化。因此，該治療試劑之濃度可為至少約0.005w/v%，更佳為至少約0.01w/v%，尤佳為至少約0.1w/v%，但一般不大於約10w/v%，更佳為不大於約4.0w/v%，尤佳為不大於約2.0w/v%。
本發明乳劑可選擇性地包含一或多種額外賦形劑，及/或一或多種額外活性成分。可使用於眼科乳劑中之賦形劑包括，但不侷限於，黏漿藥(demulcents)、張力劑、防腐劑、鉗合劑、緩衝劑與界面活性劑。其他賦形劑包含溶解劑、穩定劑、舒緩增強劑(comfort-enhancing agents)、聚合物、潤膚劑、pH-調整劑，及/或潤滑劑。
該乳劑一般為水性，因此包括大量之水，一般經純化。乳劑一般包括水濃度為至少約50w/v%，更佳為至少約85w/v%，尤佳為至少約93w/v%，但一般不大於約99.99w/v%，更佳不大於約99.0w/v%，尤佳不大於約0.3w/v%，特佳不大於約98w/v%。
本發明乳劑可使用各種合併與混合流程，以及此領域者已知之技術形成。然而，依據一較佳實施例，各成分係依據特定流程混合與合併。在此流程中，形成多種混合物，這些混合物係合併形成乳劑。第一混合物係於高溫下混合該油類與界面活性劑，以形成一油相混合物而形成。第二混合物藉由於高溫下混陰離子性磷脂質至水中，以形成一水相混合物而形成。之後，於高溫下混合該油相混合物與水相混合物，之後將油相混合物與水相混合物均質化，形成初始乳劑。第三混合物，藉由將半乳甘露醣聚合物與水混合，並調整pH值至所需值，以形成半乳甘露醣聚合物漿液而形成。之後混合半乳甘露醣聚合物漿液與初始乳劑，以形成聚合物強化乳劑。第四混合物藉由混合下列物質之組合，以形成一鹽類溶液：硼酸鹽、多元醇、防腐劑與任一其他成分而形成。之後混合該鹽類溶液與強化乳劑，之後加入足夠量(Q.S)之水，並調整pH值。
該乳劑可使用作為眼科潤滑劑、藥物傳送載劑或類似物。然而，已發現特別希望用於乾眼症之治療。因此，被診斷患有或已患有乾眼症之病患，可將該乳劑散佈於個體眼中，以減輕乾眼症之症狀。一般而言，該乳劑係置於眼藥滴入器中提供，使個體可規律地或依需要滴入一、二或多滴眼藥至一眼或二眼中。在滴入時，該乳劑一般會在眼角膜表面形成凝膠，而維持更明顯的治療效果，因而幫助液體傳送至眼球表面。
較佳為，本發明水包油乳劑之穩定可幫助潤滑及/或液體傳送(如液體治療試劑)至眼球表面。這些液體可幫助眼淚薄膜之穩定，及/或可提供其他眼部治療優點。此外，該黏膜黏附型聚合物可幫助乳劑在眼中之殘留時間，使得乳劑可更有效。
上表1為本發明之一示範乳劑之配方。應瞭解到表I中所示之重量/體積百分比可變異為這些重量/體積百分比之±10%、±20%、±30%、±90%，或更多，這些變化異可特別用於產生本發明成分之一範圍。例如，重量/體積百分比10%，變藝量為±20%，代表該成分具有重量/體積百分比範圍為8至12w/v%。
上表2為本發明之一示範乳劑之配方。應瞭解到表II中所示之重量/體積百分比可變異為這些重量/體積百分比±10%、±20%、±30%、±90%，或更多，這些變異可特別用於產生本發明成分之一範圍。例如，重量/體積百分比10%，變異量為±20%，代表該成分具有重量/體積百分比範圍為8至12w/v%。
申請人特別將所有引用之參考文獻完整加入。此外，當提及一劑量、濃度或其他值或參數呈某一範圍、一較佳範圍、或較佳值之上限或下限時，應瞭解為特定揭示所有範圍皆形成自任一上限範圍或較佳值，與下限範圍或較佳值之配對，不論該範圍是否有單獨揭示。當引用某範圍之數值時，除非另有指出，該範圍係包括其端點，以及該範圍中之所有整數與分數。當定義一範圍時，本發明範疇不應被限制於引用之特定數值。
本發明之其他實施例可由此技術領域者，依據本發明所揭示內容而更臻清楚並可實施。應瞭解到本說明書與範例僅用於示範，本發明之真正範疇與精神係依據下列申請專利範圍及其等效範圍為準。
Claims (21)
- 一種眼科乳劑，該乳劑包含：形成水相之水；形成油相之油；親水性界面活性劑，其具有HLB值至少8；疏水性界面活性劑，其具有HLB值低於8；帶電荷之磷脂質；硼酸鹽；以及黏膜黏附型半乳甘露醣聚合物；其中：i.該油相在水相中為油滴狀，且該油滴具有平均直徑不大於1000nm，但至少為10nm，其中該平均直徑是對應於90%累積過小體積分佈(cumulative undersize distribution by volume)，其係使用一Microtrac S3500粒徑分析儀(軟體版本10.3.1)來測量；以及ii.當乳劑滴入個體眼中時，該硼酸鹽與半乳甘露醣聚合物係共同作用形成凝膠。
- 如申請專利範圍第1項之乳劑，其中該油為一烴類，選自於礦物油、石蠟油與石油。
- 如申請專利範圍第1項之乳劑，其中該油為至少0.1w/v%，且不大於3w/v%乳劑。
- 如申請專利範圍第1項之乳劑，其中該油為至少0.8w/v%，且不大於1.5w/v%乳劑。
- 如申請專利範圍第3項之乳劑，其中該親水性界面活性 劑在乳劑中之存在量為至少0.08w/v%，且在乳劑中之存在量為不大於0.8w/v%。
- 如申請專利範圍第3項之乳劑，其中該親水性界面活性劑在乳劑中之存在量為至少0.14w/v%，且在乳劑中之存在量為不大於0.44w/v%。
- 如申請專利範圍第5項之乳劑，其中該親水性界面活性劑為聚氧基乙烯-40-硬脂酸酯。
- 如申請專利範圍第5項之乳劑，其中該疏水性界面活性劑在乳劑中之存在量為至少0.01w/v%，且在乳劑中之存在量為不大於2.0w/v%。
- 如申請專利範圍第5項之乳劑，其中該疏水性界面活性劑在乳劑中之存在量為至少0.16w/v%，且在乳劑中之存在量為不大於0.62w/v%。
- 如申請專利範圍第8項之乳劑，其中該疏水性界面活性劑為山梨醇三硬脂酸酯。
- 如申請專利範圍第1項之乳劑，其中該黏膜黏附型半乳甘露醣聚合物係選自於由瓜爾膠(guar)與羥基丙基瓜爾膠組成之族群。
- 如申請專利範圍第11項之乳劑，其中該黏膜黏附型半乳甘露醣聚合物在乳劑中之存在濃度為至少0.01w/v%，但不大於1.0w/v%。
- 如申請專利範圍第11項之乳劑，其中該黏膜黏附型半乳甘露醣聚合物在乳劑中之存在濃度為至少0.01w/v%，但不大於0.08w/v%。
- 如申請專利範圍第11項之乳劑，其中該帶電荷之磷脂質為陰離子性磷脂質，名為二肉荳蔻醯基磷脂醯甘油酯。
- 如申請專利範圍第14項之乳劑，其中該磷脂質在乳劑中之濃度為0.05至7.0wt%。
- 如申請專利範圍第1項之乳劑，其更包含一硼酸鹽/多醇緩衝系統。
- 如申請專利範圍第16項之乳劑，其更包含一作為抗菌防腐劑之聚合性四級銨鹽化合物。
- 如申請專利範圍第1至17項中任一項之眼科乳劑，其中該油相在水相中為油滴狀，且該油滴具有平均直徑不大於500nm，但至少為100nm，其中該平均直徑是對應於90%累積過小體積分佈，其係使用一Microtrac S3500粒徑分析儀(軟體版本10.3.1)來測量。
- 如申請專利範圍第1項之乳劑，其中該乳劑係用於一包含將其滴入哺乳動物眼中之方法。
- 如申請專利範圍第19項之乳劑，其中該哺乳動物為人類，以及該乳劑係由眼科用滴液器滴入。
- 一種形成如申請專利範圍第1至20項中任一項之乳劑之方法，包含形成第一混合物，其係藉由於高溫下混合該油類與界面活性劑，以形成一油相混合物；形成第二混合物，其係藉由於高溫下混合該陰離子性磷脂質至純化水中，以形成一水相混合物；於高溫下混合該油相混合物與水相混合物，之後將 油相混合物與水相混合物均質化，形成初始乳劑；以及形成第三混合物，其係藉由將半乳甘露醣聚合物與水混合，並調整pH值至所需，以形成半乳甘露醣聚合物漿液；以及混合該半乳甘露醣聚合物漿液與初始乳劑，以形成聚合物強化乳劑；以及形成第四混合物，其係藉由混合下列物質之任一組合，以形成一鹽類溶液：硼酸鹽、多元醇、防腐劑與任一其他成分；以及混合該鹽類溶液與該強化乳劑，之後加入足夠量(Q.S)之水，並調整pH值。
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| TWI658828B (zh) * | 2014-10-31 | 2019-05-11 | 中國醫藥大學 | 用於舒緩及減輕近視之醫藥組合物及其製備方法與用途 |
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| EP3758686A4 (en) * | 2018-02-26 | 2021-12-22 | R.P. Scherer Technologies, LLC | PHARMACEUTICAL DOSAGE FORM FOR AN EMULSION OF SIMETHICON AND LOPERAMIDE |
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| CN114533672B (zh) * | 2022-03-03 | 2023-12-26 | 南京臣功制药股份有限公司 | 一种维生素k1纳米乳剂及其制备方法 |
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