TWI552772B - 包含11-去氧-前列腺素化合物之醫藥組成物及使該化合物安定化之方法 - Google Patents
包含11-去氧-前列腺素化合物之醫藥組成物及使該化合物安定化之方法 Download PDFInfo
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- TWI552772B TWI552772B TW103122235A TW103122235A TWI552772B TW I552772 B TWI552772 B TW I552772B TW 103122235 A TW103122235 A TW 103122235A TW 103122235 A TW103122235 A TW 103122235A TW I552772 B TWI552772 B TW I552772B
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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Description
本發明係有關包含特定11-去氧-前列腺素化合物之醫藥組成物、使該具有治療效果之11-去氧-前列腺素化合物安定化之方法及包含該11-去氧-前列腺素化合物作為活性成分之軟明膠膠囊劑。
前列腺素具有下式所示之前列腺素烷酸結構式:
有許多前列腺素表現多種治療效力。
11-去氧-前列腺素化合物,例如11-去氧-15-酮基-16,16-二氟前列腺素E1:
可用於改善中樞神經系統官能障礙以及周邊循環官能障礙(WO2006/093348與WO2006/080549,該等引用參考案併入本文以資參考)。
本發明之目的在於提供包含呈安定型之特定11-去氧-前列腺素化合物之醫藥組成物。本發明之另一目的在於提供使該特定11-去氧-前列腺素化合物安定化之方法。本發明之進一步目的在於提供軟明膠膠囊。
於本發明之第一態樣中,係提供包含下式(I)所示之11-去氧-前列腺素化合物與脂肪酸酯之醫藥組成物:
式中L與N為氫、羥基、鹵素、低鏈烷基、羥基(低鏈)烷基、低鏈烷醯氧基或酮基,其中該五員環視需要可具有至少一個雙鍵;A為-CH3、-CH2OH、-COCH2OH、-COOH或其官能衍生物;R1為飽和或不飽和二價低鏈或中鏈脂族烴,其係未經取代或被鹵素、低鏈烷基、羥基、酮基、芳基或雜環基取代,且該脂族烴中之至少一個碳原子視需要可被氧、氮或硫取代;及
R0為飽和或不飽和低鏈或中鏈脂族烴殘基,其係未經取代或被鹵素、酮基、羥基、低鏈烷基、低鏈烷氧基、低鏈烷醯氧基、環(低鏈)烷基、環(低鏈)烷氧基、芳基、芳氧基、雜環基或雜環-氧基取代;低鏈烷氧基;低鏈烷醯氧基;環(低鏈)烷基;環(低鏈)烷氧基;芳基;芳氧基;雜環基;雜環-氧基;且該脂族烴中之至少一個碳原子視需要可被氧、氮或硫取代。
於本申請案之第二態樣中,係提供使如上文界定之11-去氧-前列腺素化合物安定化之方法,該方法包括使該11-去氧-前列腺素化合物與脂肪酸酯混合。
於本申請案之第三態樣中,係提供一種軟明膠膠囊劑,該膠囊劑包含:由作為增塑劑之多元醇及/或糖醇構成之軟明膠膠囊殼,及由上文界定之11-去氧-前列腺素化合物與醫藥上可接受之載劑構成之醫藥組成物;其中係將該組成物裝入該明膠膠囊殼中。
於本發明中使用之更佳之11-去氧-前列腺素化合物係如下式(II)所示:
式中B為單鍵、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或
-CH2-C≡C-;Z為
式中R4與R5為氫、羥基、鹵素、低鏈烷基、低鏈烷氧基或羥基(低鏈)烷基,其中R4與R5不同時為羥基及低鏈烷氧基;Ra為飽和或不飽和低鏈或中鏈脂族烴殘基,其係未經取代或被鹵素、酮基、羥基、低鏈烷基、低鏈烷氧基、低鏈烷醯氧基、環(低鏈)烷基、環(低鏈)烷氧基、芳基、芳氧基、雜環基或雜環-氧基取代;低鏈烷氧基;低鏈烷醯氧基;環(低鏈)烷基;環(低鏈)烷氧基;芳基;芳氧基;雜環基;雜環-氧基;且該脂族烴中之至少一個碳原子視需要可被氧、氮或硫取代;及L、N、A與R1與上文之界定相同。
上述化合物中,特佳之11-去氧-前列腺素化合物組群係如下式(III)所示:
式中X1與X2為氫、低鏈烷基、或鹵素;
R2為單鍵或低鏈伸烷基;R3為低鏈烷基、低鏈烷氧基、低鏈烷醯氧基、環(低鏈)烷基、環(低鏈)烷氧基、芳基、芳氧基、雜環基或雜環-氧基;且該脂族烴中之至少一個碳原子視需要可被氧、氮或硫取代;及L、A、B、R1與Z與上文之界定相同。
上式中,R1與Ra界定中之"不飽和"一詞代表含有孤立的、分隔的或連續的出現於主鏈及/或側鏈碳原子間的一或多個雙鍵及/或參鍵之脂族烴。根據一般命名法,兩個連續位置間之不飽和鍵係以該二位置之較低數字表示;兩個遠端位置間之不飽和鍵係以該二位置表示。
"低鏈或中鏈脂族烴"一詞係指具有1至14個碳原子(就側鏈而言,較佳為1至3個碳原子)之直鏈或分支鏈烴基;就R1而言,較佳為1至10個,尤佳為6至10個碳原子;就Ra而言,較佳為1至10個,尤佳為1至8個碳原子。
"鹵素"一詞涵蓋氟、氯、溴與碘。
除非另行指明,否則整個說明書中之"低鏈"一詞係指包括具有1至6個碳原子之基團。
"低鏈烷基"一詞係指含有1至6個碳原子之直鏈或分支鏈飽和烴基,包括,例如,甲基、乙基、丙基、異丙基、
丁基、異丁基、第二丁基、第三丁基、戊基與己基。
"低鏈烷氧基"一詞係指低鏈烷基-O-所示基團,其中低鏈烷基如上文所界定。
"羥基(低鏈)烷基"一詞係指被至少一個羥基取代之如上文界定之低鏈烷基,例如羥甲基、1-羥乙基、2-羥乙基與1-甲基-1-羥乙基。
"低鏈烷醯氧基"一詞係指式RCO-O-所示之基團,其中RCO-係如上文界定之低鏈烷基基團氧化形成之醯基基團,例如乙醯基。
"環(低鏈)烷基"一詞係指如上文界定之低鏈烷基基團環化形成之環狀基團,含有三或多個碳原子,包括,例如,環丙基、環丁基、環戊基與環己基。
"環(低鏈)烷氧基"一詞係指環(低鏈)烷基-O-所示基團,其中環(低鏈)烷基如上文所界定。
"芳基"一詞可包括未經取代或經取代之芳族烴環(較佳為單環基團),例如,苯基、萘基、甲苯基與二甲苯基。取代基之實例為鹵原子與經鹵素取代之低鏈烷基,其中鹵原子及低鏈烷基如上文所界定。
"芳氧基"一詞係指式ArO-所示之基團,其中Ar為如上文界定之芳基。
"雜環基"一詞可包括單-至三-環,較佳為5至14員,更佳為5至10員之單環雜環基,其視需要可具有經取代之碳原子及1至4個,較佳為1至3個選自氮原子、氧原子與硫原子之1或2種雜原子。該雜環基之實例包括呋喃基、
噻吩基、吡咯基、唑基、異唑基、噻唑基、異噻唑基、咪唑基、吡唑基、呋呫基、吡喃基、吡啶基、嗒基、嘧啶基、吡基、2-吡咯啉基、吡咯啶基、2-咪唑啉基、咪唑啶基、2-吡唑啉基、吡唑啶基、N-哌啶基、哌基、N-嗎啉基、吲哚基、苯并噻吩基、喹啉基、異喹啉基、嘌呤基、喹唑啉基、咔唑基、吖啶基、啡啶基、苯并咪唑基、苯并咪唑啉基、苯并噻唑基、啡噻基;此情形下之取代基實例包括鹵素、及經鹵素取代之低鏈烷基,其中鹵原子與低鏈烷基均如上述。
"雜環-氧基"一詞意指式HcO-所示之基團,其中Hc為如上述之雜環基。
A之"官能衍生物"一詞包括鹽類(較佳為醫藥上可接受之鹽類)、醚類、酯類及醯胺類。
適當之"醫藥上可接受之鹽類"包括習用之無毒鹽類,例如與無機鹼之鹽如鹼金屬鹽(例如鈉鹽與鉀鹽)、鹼土金屬鹽(例如鈣鹽與鎂鹽)、銨鹽;或與有機鹼之鹽例如胺鹽(例如甲胺鹽、二甲胺鹽、環己胺鹽、苄胺鹽、哌啶鹽、伸乙二胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、參(羥基甲胺基)乙烷鹽、單甲基-單乙醇胺鹽、普魯卡因(procaine)鹽及咖啡鹼鹽)、鹼性胺基酸鹽(例如精胺酸鹽與離胺酸鹽)、四烷銨鹽等。彼等鹽類可利用習知方法製備,例如以對應酸與鹼或利用鹽交換法予以製備。
醚類之實例包括烷基醚類,例如,低鏈烷基醚類例如甲基醚、乙基醚、丙基醚、異丙基醚、丁基醚、異丁基醚、
第二丁基醚、第三丁基醚、戊基醚與1-環丙基乙基醚;及中鏈或高鏈烷基醚類例如辛基醚、二乙基己基醚、月桂基醚與鯨蠟基醚;不飽和醚類例如油烯基醚與亞油基醚;低鏈烯基醚類例如乙烯基醚、烯丙基醚;低鏈炔基醚類例如乙炔基醚與丙炔基醚;羥基(低鏈)烷基醚類例如羥乙基醚與羥基異丙基醚;低鏈烷氧基(低鏈)烷基醚類例如甲氧甲基醚與1-甲氧乙基醚;視需要經取代之芳基醚類例如苯基醚、對甲苯磺醯基醚、第二丁基醚、第三丁基苯基醚、柳基醚、3,4-di-甲氧苯基醚與苯甲磺醯基苯基醚;及芳基(低鏈)烷基醚類例如苄基醚、三苯甲基醚與二苯甲基醚。
酯類之實例包括脂族酯類,例如,低鏈烷基酯類例如甲酯、乙酯、丙酯、異丙酯、丁酯、異丁酯、第二丁酯、第三丁酯、戊酯與1-環丙基乙酯;低鏈烯基酯類例如乙烯酯與烯丙酯;低鏈炔基酯類例如乙炔酯與丙炔酯;羥基(低鏈)烷基酯例如羥基乙酯;低鏈烷氧基(低鏈)烷基酯類例如甲氧甲酯與1-甲氧乙酯;及視需要經取代之芳基酯類,例如,苯酯、對甲苯磺醯酯、第三丁基苯酯、柳基酯、3,4-二-甲氧苯酯與苯甲磺醯基苯酯;及芳基(低鏈)烷基酯例如苄基酯、三苯甲酯與二苯甲酯。
A之醯胺意指式-CONR'R"所示之基團,式中R'與R"各為氫原子、低鏈烷基、芳基、烷基-或芳基-磺醯基、低鏈烯基與低鏈炔基,舉例而言,包括低鏈烷醯胺類例如甲醯胺、乙醯胺、二甲醯胺與二乙醯胺;芳醯胺類例如醯基苯胺與醯基甲苯胺;及烷基-或芳基-磺醯基醯胺類例如甲
磺醯基醯胺、乙磺醯基-醯胺與甲苯磺醯基醯胺。
L之較佳實例包括羥基與酮基,其提供5員環結構,尤其是PGF或PGE類型的5員環結構。
A之較佳實例為-COOH、其醫藥上可接受之鹽、酯及其醯胺。
B之較佳實例為-CH2-CH2-,其提供所謂13,14-二氫類型化合物結構。
X1與X2之較佳實例為氫,或者彼等至少一者為鹵素,更佳為,二者均為鹵素,尤其是氟,而提供所謂16,16-二氟類型化合物結構。
較佳之R1為含有1至10個碳原子,較佳為6至8個碳原子,之烴;再者,該脂族烴中至少一個碳原子視需要可被氧、氮或硫取代。
R1之實例包括,例如,下述基團:-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-O-CH2-、-CH2-CH=CH-CH2-O-CH2-、-CH2-C≡C-CH2-O-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-、與-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
較佳之Ra為含有1至10個碳原子,更佳為1至8個碳原子,尤其是5至7個碳原子,之烴。Ra之烴中可另外具有一或兩個含一個碳原子之側鏈。
較佳之R2為單鍵。
較佳之R3為低鏈烷基,更佳為,具有4至6個碳原子之烷基。R3之低鏈烷基中可另外具有一或兩個含一個碳原子之側鏈。
本發明化合物之典型實例為11-去氧-13,14-二氫-16,16-二氟-PGE或PGF化合物、11-去氧-13,14-二氫-15-酮基-16,16-二氟-PGE或PGF化合物、2-去羧基-2-(2-羧乙基)-11-去氧-13,14-二氫-15-酮基-16,16-二氟-PGE或PGF化合物、或11-去氧-13,14-二氫-15-酮基-16,16-二氟-20-乙基-PGE或PGF化合物及其衍生物或類似物。
該等化合物之較佳實例可包括11-去氧-13,14-二氫-15-酮基-16,16-二氟-PGE1、11-去氧-13,14-二氫-16,16-二氟-PGE1、11-去氧-13,14-二氫-15-酮基-16,16-二氟-PGE1異丙
酯、2-去羧基-2-(2-羧乙基)-11-去氧-13,14-二氫-15-酮基-16,16-二氟-PGE1異丙酯、2-去羧基-2-(2-羧乙基)-11-去氧-13,14-二氫-15-酮基-16,16-二氟-PGE1、11-去氧-13,14-二氫-15-酮基-16,16-二氟-20-甲基-PGE1異丙酯、11-去氧-13,14-二氫-15-酮基-16,16-二氟-20-甲基-PGE1、11-去氧-13,14-二氫-15-酮基-16,16-二氟-20-乙基-PGE1、11-去氧-13,14-二氫-15-酮基-16,16-二氟-PGE1甲酯、11-去氧-13,14-二氫-15-酮基-16,16-二氟-20-乙基-PGE1異丙酯或11-去氧-13,14-二氫-15-酮基-16,16-二氟-20-乙基-PGF1 α異丙酯。
於本發明中,具式(I)之11-去氧-前列腺素化合物涵蓋式(I)之任何異構物包括各個互變異構型異構物、其混合物、或光學異構物、其混合物、消旋混合物、與其他立體異構物。
於本發明中使用之若干化合物可利用揭示於WO2006/080549與WO2006/093348及其中引用之參考文獻中之方法製備(彼等引用文獻併入本文以資參考)。
本發明之醫藥組成物包含上述11-去氧-前列腺素化合物與脂肪酸酯。
於本發明中使用之脂肪酸酯類之實例包括以脂肪酸與醇製得之脂肪酸酯類,例如,可具分支鏈之飽和或不飽和甘油酯類。構成脂肪酸酯類之較佳脂肪酸包括具有至少6個碳原子,較佳為6至24個碳原子之中或高鏈脂肪酸,例如己酸(C6)、辛酸(C8)、癸酸(C10)、月桂酸(C12)、肉荳蔻酸(C14)、棕櫚酸(C16)、棕櫚油酸(C16)、硬脂酸(C18)、油
酸(C18)、亞麻油酸(C18)、次亞麻油酸(C18)、蓖麻油酸(C18)與花生酸(C20)。構成該脂肪酸酯之較佳醇類可包含C1-6單元醇及多元醇類例如甘油、聚乙二醇與丙二醇。
較佳之脂肪酸酯類包括可具分支鏈之飽和或不飽和脂肪酸之甘油酯、甘油脂肪酸酯與丙二醇脂肪酸酯。二或多種甘油酯類可呈混合物使用。
甘油酯類混合物之實例為辛酸甘油三酯與癸酸甘油三酯之混合物、植物油例如蓖麻油、玉米油、橄欖油、芝麻油、油菜油、沙拉油、棉籽油、山茶油、花生油、棕櫚油與葵花油。
衍生自脂肪酸與單元醇之脂肪酸酯亦適合使用。該脂肪酸酯較佳為C8-20脂肪酸與C2-3單元醇之酯,例如肉荳蔻酸異丙酯、棕櫚酸異丙酯、亞麻油酸乙酯與油酸乙酯。
本發明組成物可利用溶解或分散上述11-去氧-前列腺素化合物於脂肪酸酯中而製備。當11-去氧-前列腺素化合物難以直接溶解於脂肪酸酯中時,可將彼等各自溶於二者分別可溶解之溶劑中,然後混合該等溶液。
該組成物中脂肪酸酯之量,相較於11-去氧-前列腺素化合物之量,並未受限制,只要11-去氧-前列腺素化合物於組成物中安定即可。一般而言,對每一重量份之11-去氧-前列腺素化合物而言,脂肪酸酯之量可為1至5,000,000,較佳為5至1,000,000及最佳為10至500,000重量份。
本發明之醫藥組成物可進一步包含對該式(I)化合物
之安定性不會有不利作用之生理上可接受之添加劑。可於本發明中使用之添加劑包括,惟不限於,賦形劑、稀釋劑、填充劑、溶劑、潤滑劑、輔助劑、黏合劑、崩解劑、塗覆劑、膠囊化劑、軟膏基底、栓劑基底、氣溶膠、乳化劑、分散劑、懸浮液、黏度增加劑、等張劑、緩衝劑、止痛劑、防腐劑、抗氧化劑、矯正劑、調味劑、著色劑、及功能劑例如環糊精、可生物降解之聚合物。該等添加劑可選自製藥領域任何一般教科書中敘述者。本發明組成物可進一步包含一或多個製藥上之其他活性成分。
根據本發明,組成物之劑型並無特別限制,較佳為適用於經口投與之形式。更佳為,本發明組成物係呈膠囊之形式,例如硬膠囊或軟膠囊。
業界已知,衍生自玉米澱粉之糖醇溶液與甘油可用作製造軟明膠膠囊之增塑劑。亦已知,當衍生自玉米澱粉之糖醇溶液與甘油直接與本申請案之11-去氧-前列腺素化合物摻合時,會損害該化合物之安定性,因此,此項技藝預期於併入本發明之11-去氧-前列腺素化合物作為活性成分製造軟明膠膠囊時,糖醇類或多元醇類不可作為增塑劑使用。本發明人驚奇地發現,當包含11-去氧-前列腺素化合物與脂肪酸酯之組成物裝入以明膠與作為增塑劑之糖醇或多元醇製造之軟明膠膠囊殼中時,該軟明膠膠囊殼不會使本發明11-去氧-前列腺素化合物之安定性下降。
根據本發明,裝填於軟明膠膠囊殼中之組成物可將上述11-去氧-前列腺素化合物溶解或分散於室溫下為液體之
醫藥上可接受之載劑中而製得。當11-去氧-前列腺素化合物難以直接溶解於該載劑中時,可將彼等各自溶於二者分別可溶解之溶劑中,然後混合該等溶液。
醫藥上可接受之載劑可為任何使用於製造藥劑者,只要彼等不會使活性成分(11-去氧-前列腺素化合物)之安定性下降即可。
欲裝填於軟明膠膠囊殼中之組成物之較佳具體實例為包含11-去氧-前列腺素化合物與脂肪酸酯之組成物。
該組成物中載劑之量,相較於11-去氧-前列腺素化合物之量,並未受限制,只要11-去氧-前列腺素化合物於最終調配物中安定即可。一般而言,對每一重量份之11-去氧-前列腺素化合物而言,載劑之量可為1至5,000,000,較佳為5至1,000,000及最佳為10至500,000重量份。
根據本發明,欲裝填於該軟明膠膠囊中之醫藥組成物可進一步包含脂肪酸酯以外之油溶劑,例如礦油、液態石蠟、與生育酚。
於本發明中使用之多元醇為具有二或三個羥基基團之醇類。多元醇之較佳實例可包括甘油、聚乙二醇與丙二醇。
於本發明中使用之糖醇增塑劑係利用醣醛基之氫還原反應而製得之醇;其實例包含山梨糖醇、甘露糖醇、麥芽糖醇、乳糖醇、益壽糖醇(palatinit)、木糖醇與赤藻糖醇;及衍生自玉米澱粉之糖醇溶液,亦即山梨糖醇、山梨糖醇酐、甘露糖醇與氫化澱粉水解物之混合物,氫化麥芽糖澱粉糖漿,亦即麥芽糖醇、山梨糖醇與寡醣醇之混合物。
較佳之糖醇類可包括山梨糖醇、山梨糖醇酐、麥芽糖醇、衍生自玉米澱粉之糖醇溶液及氫化麥芽糖澱粉糖漿。尤其是,較佳為使用衍生自玉米澱粉及市售商品名稱為"Anidrisorb"或"Polysorb"之糖醇溶液。
根據本發明,用於製備軟明膠膠囊殼之糖醇之量並未特別限制,只要所得膠囊之物理性質未下降即可。一般而言,每100重量份明膠,糖醇增塑劑之量為20至60重量份,較佳為30至50重量份。
包含11-去氧-前列腺素化合物作為活性成分之軟明膠膠囊劑可經由將11-去氧-前列腺素化合物與醫藥上可接受之載劑構成之組成物裝填至由明膠及增塑劑、多元醇及/或糖醇所製成之軟明膠膠囊殼中而製得。如此製得之軟明膠膠囊劑可長期保持該11-去氧-前列腺素化合物之安定性。軟明膠膠囊殼之製造及裝填組成物至該殼中可根據習知方法進行。
茲利用下述實例更詳細地說明本發明,惟彼等實例僅供說明用途,而不宜對本發明範圍構成侷限。
化合物1:11-去氧-13,14-二氫-15-酮基-16,16-二氟PGE1
將化合物1溶於下文表1所示載劑中,得到250μg/g溶液。接著,將該溶液置於硬玻璃容器中,於55℃加熱。利用HPLC測定該溶液中化合物1之精確量(第0天)。保持容器於55℃ 10天,其後,利用HPLC測定該溶液中化合
物1之精確量(第10天)。
以下述方法測定化合物含量。將約0.2g試樣與精確之2mL內標準溶液混合,然後與表1所示溶解劑混合至得到5mL試樣溶液。精確稱量約5mg對照標準化合物1,添加乙腈至得到精確50mL溶液。精確吸取1ml該溶液,添加精確4mL內標準溶液,接著添加該溶解劑至得到10mL對照溶液。
添加螢光標記劑至各別溶液中,攪拌,於室溫靜置30分鐘以上。接著,添加2%乙酸之乙腈溶液至該溶液中,攪拌,於室溫反應30分鐘,得到試樣溶液及標準溶液。然後,將理論上得到3.6ng化合物1之各別溶液量裝載於管柱上,於下述條件下進行分析:
管柱:裝填供HPLC用之經十八基矽烷處理之矽膠(5μm)於5mm×25cm之不鏽鋼管柱
移動相:乙腈(HPLC等級)與過氯酸鹽緩衝液之混合物
溫度:35℃
檢測器:螢光分光光度計
結果示於表1。
1)以理論量(250μg/g)計之百分比
2)Miglyol 812N,構成脂肪酸:己酸(C6)NMT 2.0%、辛酸(C8)50.0至80.0%、癸酸(C10)20.0至50.0%、月桂酸(C12 NMT)3.0%、與肉荳蔻酸(C14)NMT 1.0%(NF/EP)。
3)Inwitor 742,甘油單酯總量為44至55%
4)Rikemal PO-100V,丙二醇單油酸酯,Riken Vitamin Co.,Ltd.
根據實施例1敘述之相同方法,測定化合物1於多種載劑中之安定性。
結果示於表2。
1)以理論量(250μg/g)計之百分比
根據實施例1與比較例1之結果,藉由使化合物1與脂肪酸酯例如甘油酯混合,可顯著增進其安定性。對照之下,化合物1於多元醇例如甘油、糖、糖醇、聚乙二醇、聚山梨糖醇酯80、與脂肪酸中之安定性低。
化合物1:使用11-去氧-13,14-二氫-15-酮基-16,16-二氟PGE1。
於適量水中添加60重量份衍生自玉米澱粉之糖醇溶液,攪拌並加熱。接著,於其內添加100重量份明膠,得到明膠溶液。使化合物1溶於中鏈脂肪酸甘油三酯(USP/NF等級)中,得到含120μg/g化合物1之液態混合物。將該
明膠溶液及該液態混合物裝載於軟膠囊成形及裝填機器中,得到含有該液態混合物之膠囊,乾燥,得到具適當硬度之軟明膠膠囊劑。
將製劑例中製得之軟明膠膠囊劑於40℃保持6個月或於55℃保持一個月。其後,以純水使20個膠囊膨脹,並於其中添加10mL乙酸乙酯(HPLC等級)。將膠囊切開,取得其內所含液體。每100μg理論量化合物1添加1mL內標準溶液於該液體,並添加乙酸乙酯(HPLC等級),俾使化合物1之理論濃度為10μg/mL,而得到試樣溶液。
另一方面,精確稱量約0.025g標準化合物1,添加乙酸乙酯(HPLC等級)至得到精確100mL溶液。量取2mL該溶液,於其內添加精確5mL內標準溶液,並添加乙酸乙酯(HPLC等級),俾使總量為50mL,而得到標準化合物1溶液。
添加螢光標記劑至試樣溶液及標準溶液中,攪拌並於室溫反應。
將理論上得到3.6ng化合物1之各別溶液量裝載於管柱上,於下述條件下進行分析:
管柱:裝填供HPLC用之經十八基矽烷處理之矽膠(5μm)於5mm×25cm之不鏽鋼管柱
移動相:乙腈(HPLC等級):甲醇(HPLC等級):乙酸銨(0.05mol/L)
溫度:35℃
檢測器:螢光分光光度計
使用一點校正曲線測定試樣溶液中化合物1之量。結果示於下文表3與4:
糖醇溶液/多元醇與化合物1直接摻和時會降低化合物1之安定性,但是作為增塑劑使用時,則不影響其安定性。
Claims (18)
- 一種軟明膠膠囊劑,其包括:含有作為增塑劑之多元醇及/或糖醇之軟明膠膠囊殼,及含有下式(III)所示之11-去氧-前列腺素化合物與醫藥上可接受之載劑之醫藥組成物,其中,係將該醫藥組成物裝入該明膠膠囊殼中者:
- 如申請專利範圍第1項之膠囊劑,其中,L為酮基。
- 如申請專利範圍第1項之膠囊劑,其中,A為-COOH。
- 如申請專利範圍第1項之膠囊劑,其中,X1及X2皆為鹵素。
- 如申請專利範圍第1項之膠囊劑,其中,該鹵素為氟。
- 如申請專利範圍第1項之膠囊劑,其中,R1為含有6至8個碳原子之脂族烴。
- 如申請專利範圍第6項之膠囊劑,其中,R1係選自下述者所成群組:-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-O-CH2-、-CH2-CH=CH-CH2-O-CH2-、-CH2-C≡C-CH2-O-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-、 -CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-、與-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
- 如申請專利範圍第7項之膠囊劑,其中,R1為-CH2-CH2-CH2-CH2-CH2-CH2-。
- 如申請專利範圍第1項之膠囊劑,其中,該脂肪酸酯係具6至24個碳原子之脂肪酸與甘油之酯。
- 如申請專利範圍第9項之膠囊劑,其中,該脂肪酸酯係具6至20個碳原子之脂肪酸與甘油之酯。
- 如申請專利範圍第9項之膠囊劑,其中,該脂肪酸酯係二或多種脂肪酸酯之混合物。
- 如申請專利範圍第1項之膠囊劑,其中,該脂肪酸酯係具6至24個碳原子之脂肪酸與丙二醇之酯。
- 如申請專利範圍第1項之膠囊劑,其中,該脂肪酸酯係具6至24個碳原子之脂肪酸與C1-6單元醇之酯。
- 如申請專利範圍第13項之膠囊劑,其中,該脂肪酸酯係棕櫚酸異丙酯。
- 如申請專利範圍第1項之膠囊劑,其中,該脂肪酸酯係與脂肪酸酯以外之油載劑混合。
- 如申請專利範圍第15項之膠囊劑,其中,該油載劑係礦油。
- 如申請專利範圍第1項之膠囊劑,其中,該增塑劑係糖醇。
- 如申請專利範圍第17項之膠囊劑,其中,該糖醇係衍生自玉米澱粉之糖醇溶液。
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RU2648474C2 (ru) * | 2011-08-05 | 2018-03-26 | Сукампо Аг | Способ лечения шизофрении |
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US10716544B2 (en) | 2015-10-08 | 2020-07-21 | Zmk Medical Technologies Inc. | System for 3D multi-parametric ultrasound imaging |
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US4310543A (en) | 1980-10-09 | 1982-01-12 | Hoffmann-La Roche Inc. | Prostaglandin compositions |
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