CN1901885A - 包含低水溶性药物和环氧乙烷-环氧丙烷嵌段共聚物的熔混分散体 - Google Patents
包含低水溶性药物和环氧乙烷-环氧丙烷嵌段共聚物的熔混分散体 Download PDFInfo
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- CN1901885A CN1901885A CNA2004800401389A CN200480040138A CN1901885A CN 1901885 A CN1901885 A CN 1901885A CN A2004800401389 A CNA2004800401389 A CN A2004800401389A CN 200480040138 A CN200480040138 A CN 200480040138A CN 1901885 A CN1901885 A CN 1901885A
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- Prior art keywords
- beneficial agent
- oxirane
- scope
- carrier
- expoxy propane
- Prior art date
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Abstract
本发明涉及用于提高低水溶性有益剂溶出度和生物利用度的组合物和方法。
Description
发明领域
本发明涉及提高低水溶性有益剂的溶出度和生物利用度的组合物和方法。
发明背景
提高低水溶性有益剂的溶出度和生物利用度在本领域中意义重大。此类化合物包括所有可归为美国食品和药品管理局(FDA)划分的2类化合物,FDA颁布一套概括生物药物分类系统(BCS)的指南。BCS是根据其水溶性和肠渗透性将药用物质分类的科学框架。当与药品的溶出度结合时,BCS考虑决定IR固体口服剂型中药物吸收速率和程度的三个主要因素:溶出度、溶解度和肠渗透性。按照BCS,药用物质分类如下:1类:高溶解度-高渗透性;2类:低溶解度-高渗透性;3类:高溶解度-低渗透性;和4类:低溶解度-低渗透性。在2类药物中,溶解分子在胃肠道的溶出度/增溶作用和腔转运是吸收的限制步骤,因此提高溶出速率是重要的目的。
可通过很多方法提高溶出速率,包括将有益剂的粒度减至几微米或更小数量级以增加表面积。
过去,使用机械方法例如球磨、空气射流磨和高压匀化减少粒度。但是,这些方法的局限性在于有益剂的晶体结构保持不变。而且,这些方法费时,并需要大量能量而收率相对低。
相反,本发明包括涉及其中有益剂颗粒均匀分布在整个固体基质载体中的固体分散体的组合物和方法。固体分散体提供的能力将有益剂粒度减至近分子水平,降低有益剂熔点和减少有益剂结晶度,因而提高低水溶性有益剂的溶出度和生物利用度。
发明概述
本发明描述制备用于释放低水溶性有益剂的固体分散体的方法,该方法包括将有益剂与聚合物载体熔化,将得到的混合物匀化,和将混合物冷却。
描述制备用于释放给患者低水溶性有益剂的固体分散体的方法,这些方法包括将有益剂与聚合物载体熔化,将得到的混合物匀化,将混合物冷却,和给予患者分散的有益剂。
附图简述
图1是频率百分比对纯黄体酮粒度的图。
图2是频率百分比对本发明组合物粒度的图。
图3是纯黄体酮、本发明组合物和自乳化制剂的DSC图。
图4是显示纯黄体酮、本发明组合物和自乳化制剂溶出曲线的曲线图。
图5是从本发明组合物中沉淀黄体酮的粒度对聚合物载体粘度的图。
图6是本发明组合物随时间释放药物百分比的曲线图。
详述
本发明描述制备用于释放低水溶性有益剂的固体分散体的方法,该方法包括将有益剂与聚合物载体熔化,将得到的混合物匀化和将混合物冷却。
通过将混合物加热至高于聚合物载体熔点,但低于有益剂或聚合物载体降解温度的温度,实现有益剂与聚合物载体的熔化。大多数载体在约-40℃至约60℃熔化。将有益剂和聚合物载体混合物加热至高温不会发生有害作用,条件是该温度低于有益剂或聚合物载体降解的温度。另外,有益剂无须熔化,因为它会在熔化载体中溶解。优选,将混合物加热至约60℃至约150℃。更优选约135℃。
用常规方法实现匀化。
用常规方法实现冷却。优选,将混合物快速冷却。
用于本发明的有益剂包括已知对人或动物有效并且具有低水溶性的所有化合物。此类化合物包括所有那些可归类为美国食品和药品管理局(FDA)提出的生物药物分类系统(BCS)下的2类化合物。可用本领域技术人员熟知的常规实验确定以下药物所属BCS类别。
可通过本发明渗透系统释放的有益剂示例包括乙二磺酸丙氯拉嗪、硫酸亚铁、氨基己酸、氯化钾、盐酸美卡拉明、盐酸普鲁卡因胺、硫酸苯丙胺、盐酸苄非他明、硫酸异丙肾上腺素、盐酸去氧麻黄碱、盐酸芬美曲嗪、氯贝胆碱、偏氯化胆碱(metacholine chloride)、盐酸毛果芸香碱、硫酸阿托品、甲溴东茛菪碱(methascopolamine bromide)、异丙碘铵、曲地氯铵、盐酸苯乙双胍、盐酸哌甲酯、盐酸氧烯洛尔、酒石酸美托洛尔、盐酸西咪替丁、地芬尼多、盐酸美克洛嗪、马来酸丙氯拉嗪、酚苄明、马来酸硫乙拉嗪、anisindone、二苯茚酮、丁四硝酯、地高辛、异氟磷、利血平、乙酰唑胺、醋甲唑胺、苄氟噻嗪、氯磺丙脲、妥拉磺脲、氯地孕酮、非那二醇、别嘌醇、阿司匹林铝、甲氨蝶呤、醋磺胺异嗯唑、红霉素、黄体酮、estrogenic progrestational、皮质类固醇、氢化可的松、醋酸氢化皮质酮、醋酸可的松、曲安西龙、甲睾酮、17β-雌二醇、炔雌醇、炔雌醇3-甲醚、泼尼松龙、醋酸17-羟孕酮、19-去甲黄体酮、炔诺孕酮、orethindone、norethiderone、黄体酮、诺孕酮(norgestrone)、异炔诺酮、阿司匹林、吲哚美辛、萘普生、非诺洛芬、舒林酸、双氯芬酸、吲哚洛芬、硝酸甘油、普萘洛尔、美托洛尔(metroprolol)、丙戊酸钠、丙戊酸、紫杉烷类例如紫杉醇、喜树碱类例如9-氨基喜树碱、氧烯洛尔、噻吗洛尔、阿替洛尔、阿普洛尔、西咪替丁、可乐定、丙咪嗪、左旋多巴、chloropropmazine、利血平(resperine)、甲基多巴、二羟基苯丙氨酸、盐酸α-甲基多巴新戊酰氧基乙基酯、茶碱、葡糖酸钙乳酸亚铁、酮洛芬、布洛芬、头孢氨苄、haloperiodol、佐美酸、长春胺、安定、酚苄明、硝苯地平、地尔硫、维拉帕米、赖诺普利、卡托普利、雷米普利、福辛普利、贝那普利、赖苯普利、西拉普利、西拉普利拉、培哚普利、佐芬普利、依那普利、地拉普利(indalapril)、喹那普利(qumapril)等。在配药技术领域中已知的其它有益剂见以下文献:Pharmaceutical Sciences,Remington,第14版,1979,Mack Publishing Co.出版,Easton,Pa.;The Beneficial agent,TheNurse,The Patient,Including Current Beneficial agent Handbook,1976,Falconer等,Saunder Company,Philadelphia,Pa.;Medical Chemistry,第3版,第1和2卷,Burger,Wiley-Interscience出版,New York;和Physician′s Desk Reference,第55版,1998,Medical Economics Co.,NewJersey出版。有益剂可以是各种形式,例如分子原形、分子络合物、药理上可接受的盐,例如盐酸盐、氢溴酸盐、硫酸盐、月桂酸盐、棕榈酸盐、磷酸盐、亚硝酸盐、硝酸盐、硼酸盐、乙酸盐、马来酸盐、酒石酸盐、油酸盐、水杨酸盐等。对于酸性有益剂,可使用金属、胺或有机阳离子的盐,例如季铵盐。可使用有益剂的衍生物,例如碱、酯、醚和酰胺。
例如小于50μg/ml的低水溶性有益剂可用于本发明。有益剂包括黄体酮、醋酸甲地孕酮、托吡酯、萘普生、氟比洛芬、酮洛芬、地昔帕明、双氯芬酸、伊曲康唑、吡罗昔康、卡马西平、苯妥英、维拉帕米、硫酸茚地那韦、拉米夫定、司他夫定、甲磺酸奈非那韦、拉米夫定和齐多夫定的组合、甲磺酸沙奎那韦、利托那韦、齐多夫定、去羟肌苷、奈韦拉平、更昔洛韦、扎西他滨、盐酸fluoexetine、盐酸舍曲林、盐酸帕罗西汀、盐酸安非他酮、盐酸奈法唑酮、米氮平、auroix、盐酸米安色林、扎那米韦、奥氮平、利培酮、富马酸喹硫平、盐酸丁螺环酮、阿普唑仑、劳拉西泮、leotan、氯氮二钾、氯氮平、舒必利、氨磺必利、盐酸哌甲酯和匹莫林。
优选,有益剂包括黄体酮、醋酸甲地孕酮、托吡酯、萘普生、氟比洛芬、酮洛芬、地昔帕明、双氯芬酸、伊曲康唑、吡罗昔康、卡马西平、苯妥英和维拉帕米。更优选,此类化合物包括黄体酮、醋酸甲地孕酮、托吡酯和萘普生。最优选,有益剂是黄体酮。
在一个方法实施方案中,存在的有益剂占组合物约0.0001%至约95%重量。优选,存在的有益剂占组合物约1%至约20%重量。
在一个方法实施方案中,载体与有益剂的比例为约10至约1。
在一个方法实施方案中,载体与有益剂的比例为约10至约5。
载体是环氧丙烷和环氧乙烷的嵌段共聚物,该嵌段共聚物衍生自环氧乙烷和环氧丙烷与乙二胺、聚乙二醇或聚环氧乙烷的加成。
在一个方法实施方案中,环氧丙烷和环氧乙烷的嵌段共聚物为式HO-(环氧乙烷)x-(环氧丙烷)y-(环氧乙烷)x′-H。优选,x的范围为约2至约150,y的范围为约20至约70,且x′的范围为约2至约150。BASFCorporation,New Jersey,USA出售环氧丙烷和环氧乙烷的嵌段共聚物,商品名为PLURONIC。PLURONIC嵌段共聚物是美国和英国药典中收载的药用赋形剂。
其中需要相对低的有益剂浓度,即其中载体与有益剂的比例为约10至约1,优选,x的范围为约20至约150,y的范围为约20至约70,且x′的范围为约20至约150。
其中需要相对高的有益剂浓度,即其中载体与有益剂的比例为约10至约5,优选,x的范围为约2至约80,y的范围为约20至约70,且x′的范围为约2至约80。
在一个方法实施方案中,x为约41,y为约16,且x′为约41。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF38。
在一个方法实施方案中,x为约79,y为约28,且x′为约79。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF68。
在一个方法实施方案中,x为约64,y为约37,且x′为约64。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF87。
在一个方法实施方案中,x为约26,y为约39,且x′为约26。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICP85。
在一个方法实施方案中,x为约141,y为约44,且x′为约141。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF108。
在一个方法实施方案中,x为约101,y为约56,且x′为约101。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF127。
BASF Corporation,New Jersey,USA出售由环氧乙烷和环氧丙烷与乙二胺加成衍生的嵌段共聚物,商品名为TETRONIC。可选择该分子的各种疏水和亲水部分,得到宽范围的功能特性,满足具体载体的需要,一旦用于本发明公开,需要特性的选择完全在本领域技术人员技能范围内。
在一个方法实施方案中,所存在的载体占组合物约5%至约95%重量。优选,所存在的载体占组合物约20%至约60%重量。
在一个方法实施方案中,混合物还包含赋形剂。优选,赋形剂是以下赋形剂中的至少一种:硬脂酸、癸酸或三癸精、三月桂精、三肉豆蔻精、三棕榈精、三硬脂精、氢化椰子甘油酯、甘油单硬脂酸酯、甘油二十二烷酸酯、甘油棕榈酰硬脂酸酯、月桂酸、棕榈酸、二十二烷酸或棕榈酸十六烷基酯。优选,赋形剂是硬脂酸。优选,所存在的赋形剂占组合物约1%至约50%重量。更优选,所存在的赋形剂占组合物约1%至约30%重量。
在本发明的另一个实施方案中,描述制备用于释放给患者低水溶性有益剂的固体分散体的方法,该方法包括将有益剂与聚合物载体熔化;将得到的混合物匀化;将混合物冷却;和给予患者分散的有益剂。
通常,可通过任何已知方法给予患者的有益剂剂量为约0.01至约1.0mmol/kg体重(以及剂量范围和其中具体剂量的所有组合和亚组合)。给予的有效剂量和具体的给药模式取决于此类因素例如年龄、体重和所治疗的病症以及具体使用的有益剂,这对本领域技术人员而言显而易见。通常,开始时给药剂量水平低,然后增加直至达到需要的诊断结果。
本发明方法通常可用于含有益剂制剂的市售明胶胶囊。本发明尤其适用于即释明胶封囊液体,按照本发明,可将常规制备和销售的有益剂制剂转变为控释剂型。
通过将混合物加热至高于聚合物载体熔点,但低于有益剂或聚合物载体降解温度的温度,实现有益剂与聚合物载体的熔化。大多数载体在约-40℃至约60℃熔化。将有益剂和聚合物载体混合物加热至高温不会发生有害作用,条件是该温度低于有益剂或聚合物载体降解的温度。另外,无须将有益剂熔化,因为它会在熔化载体中溶解。优选,将混合物加热至约60℃至约150℃。更优选加热至约135℃。
用常规方法实现匀化。
用常规方法实现冷却。优选,将混合物快速冷却。
用于本发明的有益剂包括已知对人或动物有效并且具有低水溶性的所有化合物。此类化合物包括所有那些可归类为美国食品和药品管理局(FDA)提出的生物药物分类系统(BCS)下的2类化合物,可用本领域技术人员熟知常规实验确定以下药物所属BCS类别。
可通过本发明渗透系统释放的示例性有益剂包括乙二磺酸丙氯拉嗪、硫酸亚铁、氨基己酸、氯化钾、盐酸美卡拉明、盐酸普鲁卡因胺、硫酸苯丙胺、盐酸苄非他明、硫酸异丙肾上腺素、盐酸去氧麻黄碱、盐酸芬美曲嗪、氯贝胆碱、偏氯化胆碱、盐酸毛果芸香碱、硫酸阿托品、甲溴东莨菪碱、异丙碘铵、曲地氯铵、盐酸苯乙双胍、盐酸哌甲酯、盐酸氧烯洛尔、酒石酸美托洛尔、盐酸西咪替丁、地芬尼多、盐酸美克洛嗪、马来酸丙氯拉嗪、酚苄明、马来酸硫乙拉嗪、anisindone、二苯茚酮、丁四硝酯、地高辛、异氟磷、利血平、乙酰唑胺、醋甲唑胺、苄氟噻嗪、氯磺丙脲、妥拉磺脲、氯地孕酮、非那二醇、别嘌醇、阿司匹林铝、甲氨蝶呤、醋磺胺异嗯唑、红霉素、黄体酮、estrogenic progrestational、皮质类固醇、氢化可的松、醋酸氢化皮质酮、醋酸可的松、曲安西龙、甲睾酮、17β-雌二醇、炔雌醇、炔雌醇3-甲醚、泼尼松龙、醋酸17-羟孕酮、19-去甲黄体酮、炔诺孕酮、orethindone、norethiderone、黄体酮、诺孕酮(norgestrone)、异炔诺酮、阿司匹林、吲哚美辛、萘普生、非诺洛芬、舒林酸、双氯芬酸、吲哚洛芬、硝酸甘油、普萘洛尔、美托洛尔(metroprolol)、丙戊酸钠、丙戊酸、紫杉烷类例如紫杉醇、喜树碱类例如9-氨基喜树碱、氧烯洛尔、噻吗洛尔、阿替洛尔、阿普洛尔、西咪替丁、可乐定、丙咪嗪、左旋多巴、chloropropmazine、利血平(resperine)、甲基多巴、二羟基苯丙氨酸、盐酸α-甲基多巴新戊酰氧基乙基酯、茶碱、葡糖酸钙乳酸亚铁、酮洛芬、布洛芬、头孢氨苄、haloperiodol、佐美酸、长春胺、安定、酚苄明、硝苯地平、地尔硫、维拉帕米、赖诺普利、卡托普利、雷米普利、福辛普利、贝那普利、赖苯普利、西拉普利、西拉普利拉、培哚普利、佐芬普利、依那普利、地拉普利、喹那普利等。在配药技术领域中已知的其它有益剂见以下文献:Pharmaceutical Sciences,Remington,第14版,1979,Mack Publishing Co.出版,Easton,Pa.;TheBeneficial agent,The Nurse,The Patient,Including Current Beneficialagent Handbook,1976,Falconer等,Saunder Company,Philadelphia,Pa.出版;Medical Chemistry,第3版,第1和2卷,Burger,Wiley-Interscience出版,New York;和Physician′s Desk Reference,第55版,1998,MedicalEconomics Co.,New Jersey出版。有益剂可以是各种形式,例如分子原形、分子络合物、药理上可接受的盐,例如盐酸盐、氢溴酸盐、硫酸盐、月桂酸盐、棕榈酸盐、磷酸盐、亚硝酸盐、硝酸盐、硼酸盐、乙酸盐、马来酸盐、酒石酸盐、油酸盐、水杨酸盐等。对于酸性有益剂,可使用金属、胺或有机阳离子的盐,例如季铵盐。可使用有益剂的衍生物,例如碱、酯、醚和酰胺。
例如小于50μg/ml的低水溶性有益剂可用于本发明。有益剂包括黄体酮、醋酸甲地孕酮、托吡酯、萘普生、氟比洛芬、酮洛芬、地昔帕明、双氯芬酸、伊曲康唑、吡罗昔康、卡马西平、苯妥英、维拉帕米、硫酸茚地那韦、拉米夫定、司他夫定、甲磺酸奈非那韦、拉米夫定和齐多夫定的组合、甲磺酸沙奎那韦、利托那韦、齐多夫定、去羟肌苷、奈韦拉平、更昔洛韦、扎西他滨、盐酸fluoexetine、盐酸舍曲林、盐酸帕罗西汀、盐酸安非他酮、盐酸奈法唑酮、米氮平、auroix、盐酸米安色林、扎那米韦、奥氮平、利培酮、富马酸喹硫平、盐酸丁螺环酮、阿普唑仑、劳拉西泮、leotan、氯氮二钾、氯氮平、舒必利、氨磺必利、盐酸哌甲酯和匹莫林。
优选,有益剂包括黄体酮、醋酸甲地孕酮、托吡酯、萘普生、氟比洛芬、酮洛芬、地昔帕明、双氯芬酸、伊曲康唑、吡罗昔康、卡马西平、苯妥英和维拉帕米。更优选,此类化合物包括黄体酮、醋酸甲地孕酮、托吡酯和萘普生。最优选,有益剂是黄体酮。
在一个方法实施方案中,存在的有益剂占组合物约0.0001%至约95%重量。优选,存在的有益剂占组合物约1%至约20%重量。
在一个方法实施方案中,载体与有益剂的比例为约10至约1。
在一个方法实施方案中,载体与有益剂的比例为约10至约5。
载体是环氧丙烷和环氧乙烷的嵌段共聚物,该嵌段共聚物衍生自环氧乙烷和环氧丙烷与乙二胺、聚乙二醇或聚环氧乙烷的加成。
在一个方法实施方案中,环氧丙烷和环氧乙烷的嵌段共聚物为式HO-(环氧乙烷)x-(环氧丙烷)y-(环氧乙烷)x′-H。优选,x的范围为约2至约150,y的范围为约20至约70,且x′的范围为约2至约150。BASFCorporation,New Jersey,USA出售环氧丙烷和环氧乙烷的嵌段共聚物,商品名为PLURONIC。PLURONIC嵌段共聚物是美国和英国药典中收载的药用赋形剂。
其中需要相对低的有益剂浓度,即其中载体与有益剂的比例为约10至约1,优选,x的范围为约20至约150,y的范围为约20至约70,且x′的范围为约20至约150。
其中需要相对高的有益剂浓度,即其中载体与有益剂的比例为约1O至约5,优选,x的范围为约2至约80,y的范围为约20至约70,且x′的范围为约2至约80。
在一个方法实施方案中,x为约41,y为约16,且x′为约41。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF38。
在一个方法实施方案中,x为约79,y为约28,且x′为约79。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF68。
在一个方法实施方案中,x为约64,y为约37,且x′为约64。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF87。
在一个方法实施方案中,x为约26,y为约39,且x′为约26。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICP85。
在一个方法实施方案中,x为约141,y为约44,且x′为约141。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF108。
在一个方法实施方案中,x为约101,y为约56,且x′为约101。这种环氧丙烷和环氧乙烷的嵌段共聚物有售,商品名为PLURONICF127。
BASF Corporation,New Jersey,USA出售由环氧乙烷和环氧丙烷与乙二胺加成衍生的嵌段共聚物,商品名为TETRONIC。可选择该分子的各种疏水和亲水部分,得到宽范围的功能特性,满足具体载体的需要,一旦用于本发明公开,需要特性的选择完全在本领域技术人员技能范围内。
在一个方法实施方案中,所存在的载体占组合物约5%至约95%重量。优选,所存在的载体占组合物约20%至约60%重量。
在一个方法实施方案中,混合物还包含赋形剂。优选,赋形剂是以下赋形剂中的至少一种:硬脂酸、癸酸或三癸精、三月桂精、三肉豆蔻精、三棕榈精、三硬脂精、氢化椰子甘油酯、甘油单硬脂酸酯、甘油二十二烷酸酯、甘油棕榈酰硬脂酸酯、月桂酸、棕榈酸、二十二烷酸或棕榈酸十六烷基酯。优选,赋形剂是硬脂酸。优选,所存在的赋形剂占组合物约1%至约50%重量。更优选,所存在的赋形剂占组合物约1%至约30%重量。
至于有益剂释放系统,采用使有益剂更容易通过患者的胃肠膜并进入血液吸收的有益剂液体制剂获得了优良结果,例如,如美国专利号6,596,314、6,419,952和6,174,547中所述,在L-OROSTM HARDCAPTM有益剂释放系统中,将有益剂层和渗透引擎装入由控制速度的半渗透膜包围的硬胶囊中。前述每篇文件公开内容通过引用整体结合到本文中。简而言之,由惰性物质组成的隔离层将渗透引擎与有益剂层分开,防止有益剂层与渗透引擎反应。由激光在渗透引擎相对端的膜上钻释放孔,为有益剂提供出口。
因此,在本发明的还另一个实施方案中,有益剂释放系统描述为包括具有孔并包围渗透引擎层、隔离层和有益剂层的胶囊,其中有益剂层包含通过使有益剂与熔化载体混合分散在聚合物载体中的有益剂。
本发明通过以下实施例进一步描述。
实施例
实施例1
黄体酮是自然产生的低水溶性类固醇(在人工肠液(″AIF″)中,在37℃下,12μg/ml)。黄体酮通常用于避孕(制剂,例如PROGESTASERT或THERAPIX),还处方用于预防自然流产或早产。其化学名是孕-4-烯-3,20-二酮。它的实验式为C21H30O2,分子量为314.5。黄体酮的熔点是127-131℃。
将需要比例例如10∶1或10∶5的PLURONIC共聚物和黄体酮加入聚合物混合器的筒体(30cc或10cc)中。用油加热器(30cc聚合物混合器)或电加热器(10cc聚合物混合器)将混合物的温度升至135℃。混合物熔化,在108rpm(30cc聚合物混合器)或56rpm(10cc聚合物混合器)下搅拌15min。将得到的均匀热熔化溶液迅速用油(30cc聚合物混合器)或冷却水(10cc聚合物混合器)冷却,得到固体分散体。
实施例2
将需要比例的PLURONIC共聚物、黄体酮和赋形剂加入聚合物混合器的筒体(30cc或10cc)中。用油加热器(30cc聚合物混合器)或电加热器(10cc聚合物混合器)将混合物的温度升至135℃。混合物熔化,在108rpm(30cc聚合物混合器)或56rpm(10cc聚合物混合器)下搅拌15min。将得到的均匀热熔化溶液迅速用油(30cc聚合物混合器)或冷却水(10cc聚合物混合器)冷却,得到固体分散体。
实施例3
将含-4mg黄体酮的下述样品加入15mlAIF中,然后在37℃水浴中振动。用Horiba LA-910激光散射粒度分析仪测量黄体酮沉淀的粒度。
如图1所示,纯黄体酮的平均粒度为72.4μm。图2显示按照实施例1方法制备的PLURONIC F108共聚物/黄体酮(10∶5)熔混制剂中黄体酮沉淀的粒度。有益剂的粒度由其纯品形式的72.4μm减至按照实施例1方法制备混合物的1.5um。
实施例4
将下述样品与AIF混合,在37℃水浴中振动6h。用真空滤器使混合物通过0.45μm硝酸纤维素膜过滤。用去离子水将颗粒洗涤几次,除去Pluronic。使样品在30℃干燥箱中干燥过夜。用TA仪2920进行差示扫描量热法测量。用干燥5级氮气作吹扫气体。将样品在铝密封样品盘中封囊。将热程序应用于所有在20℃下平衡的样品。使样品按10℃/分钟升温至150℃。
如图3所示,显示了包括以下样品的差示扫描量热法(DSC)结果:a)纯黄体酮,b)按实施例1方法制备的PLURONIC共聚物F108/黄体酮(10∶1),c)按实施例2方法制备的PLURONIC共聚物F108/黄体酮(progestrone)/硬脂酸(10∶1∶2.5),d)按实施例1方法制备的具有x=2、y=30和x′=2的PLURONIC共聚物F108/黄体酮/L61液体PLURONIC共聚物(10∶1∶2.5),和e)自乳化制剂(SEF)CREMOPHOR EL牌聚乙氧基化蓖麻油/癸酸(“CA”)/黄体酮(5∶5∶1)。样品a、b、d和e在~130℃下具有对应于黄体酮熔点的尖锐吸热峰,表明PLURONIC共聚物和SEF未改变黄体酮的结晶性。
相反,样品c仅在56.4℃出现一个峰。这种结晶黄体酮峰完全不存在表明硬脂酸存在会降低黄体酮的熔点和结晶性。
实施例5
用USPII系统进行溶出度研究。将相当于30mg黄体酮的下述样品加入900mlAIF(pH=6.8)。将溶出介质的温度保持在37℃。用在线UV,在249nm处测量黄体酮浓度。
图4表示以下样品的溶出曲线:a)按实施例1方法制备的PLURONIC共聚物F108/黄体酮(10∶1);b)自乳化制剂(SEF)EL/CA/黄体酮(5∶5∶1);c)PLURONIC共聚物F108/黄体酮(20∶1)的干燥(即未熔化)混合物;和d)纯黄体酮。样品a具有最佳溶出度。
实施例6
按实施例1和2制备样品。图5表示各种熔混制剂中的黄体酮沉淀粒度对使用PLURONIC共聚物粘度的曲线。对于10∶1和10∶5的有益剂载量系统,存在使粒度最小化的最佳粘度。
低粘度在高温下促使有益剂在聚合物中分散,它可帮助减少聚合物基质中的有益剂粒度。但是,在冷却过程中,结晶生长速度在较低粘度系统中可较高。低有益剂载量系统的最佳载体是PLURONIC共聚物F68。由于与PLURONIC共聚物分子相比,黄体酮分子小的多,增加有益剂载量可降低熔化混合物的粘度,较高有益剂载量系统的最佳制剂移向具有较高粘度的PLURONIC共聚物。较高有益剂载量系统的最佳载体是PLURONIC共聚物F108。
实施例7
按实施例1和2制备样品。
按美国专利号6,596,314、6,419,952和6,174,547中所述,制备L-OROSTMHARDCAPTM有益剂释放系统,用于以控制方式在延长时间内分配黄体酮。
先将具有渗透引擎层(350mg)和隔离层的双层片装入具有隔离面的羟丙基甲基纤维素(″HPMC″)″0″号胶囊(用9.5mg SURELEASE乙基纤维素水分散液包底衣),所述渗透引擎层含63.67%重量POLYOX303聚环氧乙烷、30%重量NaCl、5%重量HPMC E5羟丙基甲基纤维素、1%重量氧化铁红、0.25%重量硬脂酸镁和0.08%重量丁基化羟基甲苯(″BHT″),和所述隔离层含100mg KOLLIDON SR聚乙酸乙烯酯和聚乙烯吡咯烷酮以及共混的少量得自BASF Corporation的十二烷基硫酸钠和胶体二氧化硅缓释赋形剂。
然后,用含90%重量醋酸纤维素398-10和10%重量PLURONIC共聚物F68的100mg半渗透膜涂覆胶囊组合。通过模块钻直径为0.0625英寸的孔。
将PLURONIC共聚物和黄体酮(10∶5重量)加入聚合物混合器的筒体(10cc)中。用电加热器将混合物的温度升至135℃。混合物熔化,在56rpm下搅拌15min。用1ml注射器将得到的均匀热熔化溶液迅速通过孔注入模块,将该热熔化制剂冷却,其在环境条件下固化。将平均546mg溶混制剂注入模块,该模块含182mg黄体酮。
在37℃下,在AIF(pH=6.8)中测量黄体酮的体外释放速率。通过UV光谱,在245nm处分析样品。图6表示黄体酮在~20h内的零级释放曲线。
该文件中引用或描述的各专利、专利申请和出版物内容,通过引用整体结合到本文中。
每个列举的范围包括范围的所有组合和亚组合,以及其中包含的具体数字。
根据前述说明书,除本文中所述的那些外,对本领域技术人员来讲本发明的各种修改是显而易见的。此类修改将落入权利要求书的范围内。
Claims (65)
1.一种制备固体分散体的方法,所述分散体用于释放低水溶性有益剂,所述方法包括:
将所述有益剂与聚合物载体熔化;
将得到的混合物匀化;和
冷却该混合物。
2.权利要求1的方法,其中将所述混合物加热至高于所述聚合物载体的熔点,但低于所述有益剂或聚合物载体降解温度的温度。
3.权利要求1的方法,其中将所述混合物加热至约60℃至约150℃。
4.权利要求1的方法,其中将所述混合物快速冷却。
5.权利要求1的方法,其中所述有益剂选自至少一种II类药物。
6.权利要求1的方法,其中所述有益剂选自至少一种以下药物:黄体酮、醋酸甲地孕酮、托吡酯、萘普生、氟比洛芬、酮洛芬、地昔帕明、双氯芬酸、伊曲康唑、吡罗昔康、卡马西平、苯妥英和维拉帕米。
7.权利要求1的方法,其中所述有益剂选自至少一种以下药物:黄体酮、醋酸甲地孕酮、托吡酯和萘普生。
8.权利要求1的方法,其中所述有益剂是黄体酮。
9.权利要求1的方法,其中所述有益剂存在的量占组合物约0.0001%至约95%重量。
10.权利要求1的方法,其中所述有益剂存在的量占组合物约1%至约20%重量。
11.权利要求1的方法,其中所述载体与有益剂的比例为约10至约1。
12.权利要求1的方法,其中所述载体与有益剂的比例为约10至约5。
13.权利要求1的方法,其中所述载体是环氧丙烷和环氧乙烷的嵌段共聚物,所述嵌段共聚物衍生自环氧乙烷和环氧丙烷与乙二胺、聚乙二醇或聚环氧乙烷的加成。
14.权利要求13的方法,其中所述共聚物具有式HO-(环氧乙烷)x-(环氧丙烷)y-(环氧乙烷)x′-H。
15.权利要求14的方法,其中x的范围为约2至约150,y的范围为约20至约70,且x′的范围为约2至约150。
16.权利要求14的方法,其中x的范围为约20至约150,y的范围为约20至约70,且x′的范围为约20至约150。
17.权利要求14的方法,其中x的范围为约2至约80,y的范围为约20至约70,且x′的范围为约2至约80。
18.权利要求14的方法,其中x为约41,y为约16,且x′为约41。
19.权利要求14的方法,其中x为约79,y为约28,且x′为约79。
20.权利要求11的方法,其中所述载体是环氧丙烷和环氧乙烷的嵌段共聚物,所述共聚物具有式HO-(环氧乙烷)x-(环氧丙烷)y-(环氧乙烷)x′-H,和其中x为约79,y为约28,且x′为约79。
21.权利要求14的方法,其中x为约64,y为约37,且x′为约64。
22.权利要求14的方法,其中x为约26,y为约39,且x′为约26。
23.权利要求14的方法,其中x为约141,y为约44,且x′为约141。
24.权利要求12的方法,其中所述载体是环氧丙烷和环氧乙烷的嵌段共聚物,所述共聚物具有式HO-(环氧乙烷)x-(环氧丙烷)y-(环氧乙烷)x′-H,和其中x为约141,y为约44,且x′为约141。
25.权利要求14的方法,其中x为约101,y为约56,且x′为约101。
26.权利要求1的方法,其中所述载体存在的量占组合物约5%至约95%重量。
27.权利要求1的方法,其中所述载体存在的量占组合物约20%至约60%重量。
28.权利要求1的方法,其中所述混合物还包含赋形剂。
29.权利要求28的方法,其中所述赋形剂为至少一种以下赋形剂:硬脂酸、癸酸或三癸精、三月桂精、三肉豆蔻精、三棕榈精、三硬脂精、氢化椰子甘油酯、甘油单硬脂酸酯、甘油二十二烷酸酯、甘油棕榈酰硬脂酸酯、月桂酸、棕榈酸、二十二烷酸或棕榈酸十六烷基酯。
30.权利要求28的方法,其中所述赋形剂是硬脂酸。
31.权利要求28的方法,其中所述赋形剂存在的量占组合物约1%至约50%重量。
32.权利要求28的方法,其中所述赋形剂存在的量占组合物约1%至约30%重量。
33.一种制备固体分散体的方法,所述分散体用于将低水溶性有益剂释放给患者,所述方法包括:
将所述有益剂与聚合物载体熔化;
将得到的混合物匀化;
冷却该混合物;和
将所述分散的有益剂给予所述患者。
34.权利要求33的方法,其中将所述混合物加热至高于所述聚合物载体熔点,但低于所述有益剂或聚合物载体降解温度的温度。
35.权利要求33的方法,其中将所述混合物加热至约60℃至约150℃。
36.权利要求33的方法,其中将所述混合物快速冷却。
37.权利要求33的方法,其中所述有益剂选自至少一种II类药物。
38.权利要求33的方法,其中所述有益剂选自至少一种以下药物:黄体酮、醋酸甲地孕酮、托吡酯、萘普生、氟比洛芬、酮洛芬、地昔帕明、双氯芬酸、伊曲康唑、吡罗昔康、卡马西平、苯妥英和维拉帕米。
39.权利要求33的方法,其中所述有益剂选自至少一种以下药物:黄体酮、醋酸甲地孕酮、托吡酯和萘普生。
40.权利要求33的方法,其中所述有益剂是黄体酮。
41.权利要求33的方法,其中所述有益剂存在的量占组合物约0.0001%至约95%重量。
42.权利要求33的方法,其中所述有益剂存在的量占组合物约1%至约20%重量。
43.权利要求33的方法,其中所述载体与有益剂的比例为约10至约1。
44.权利要求33的方法,其中所述载体与有益剂的比例为约10至约5。
45.权利要求33的方法,其中所述载体是环氧丙烷和环氧乙烷的嵌段共聚物,所述嵌段共聚物衍生自环氧乙烷和环氧丙烷与乙二胺、聚乙二醇或聚环氧乙烷的加成。
46.权利要求45的方法,其中所述共聚物具有式HO-(环氧乙烷)x-(环氧丙烷)y-(环氧乙烷)x′-H。
47.权利要求46的方法,其中x的范围为约2至约150,y的范围为约20至约70,且x′的范围为约2至约150。
48.权利要求46的方法,其中x的范围为约20至约150,y的范围为约20至约70,且x′的范围为约20至约150。
49.权利要求46的方法,其中x的范围为约2至约80,y的范围为约20至约70,且x′的范围为约2至约80。
50.权利要求46的方法,其中x为约41,y为约16,且x′为约41。
51.权利要求46的方法,其中x为约79,y为约28,且x′为约79。
52.权利要求43的方法,其中所述载体是环氧丙烷和环氧乙烷的嵌段共聚物,所述共聚物具有式HO-(环氧乙烷)x-(环氧丙烷)y-(环氧乙烷)x′-H,和其中x为约79,y为约28,且x′为约79。
53.权利要求46的方法,其中x为约64,y为约37,且x′为约64。
54.权利要求46的方法,其中x为约26,y为约39,且x′为约26。
55.权利要求46的方法,其中x为约141,y为约44,且x′为约141。
56.权利要求44的方法,其中所述载体是环氧丙烷和环氧乙烷的嵌段共聚物,所述共聚物具有式HO-(环氧乙烷)x-(环氧丙烷)y-(环氧乙烷)x′-H,和其中x为约141,y为约44,且x′为约141。
57.权利要求46的方法,其中x为约101,y为约56,且x′为约101。
58.权利要求33的方法,其中所述载体存在的量占组合物约5%至约95%重量。
59.权利要求33的方法,其中所述载体存在的量占组合物约20%至约60%重量。
60.权利要求33的方法,其中所述混合物还包含赋形剂。
61.权利要求60的方法,其中所述赋形剂为至少一种以下赋形剂:硬脂酸、癸酸或三癸精、三月桂精、三肉豆蔻精、三棕榈精、三硬脂精、氢化椰子甘油酯、甘油单硬脂酸酯、甘油二十二烷酸酯、甘油棕榈酰硬脂酸酯、月桂酸、棕榈酸、二十二烷酸或棕榈酸十六烷基酯。
62.权利要求60的方法,其中所述赋形剂是硬脂酸。
63.权利要求60的方法,其中所述赋形剂存在的量占组合物约1%至约50%重量。
64.权利要求60的方法,其中所述赋形剂存在的量占组合物约1%至约30%重量。
65.一种有益剂释放系统,所述系统包含:
具有孔并包围渗透引擎层、隔离层和有益剂层的胶囊,其中所述有益剂层包含通过使该有益剂与熔化载体混合分散在聚合物载体中的有益剂。
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US (1) | US20050106242A1 (zh) |
EP (1) | EP1682092A2 (zh) |
JP (1) | JP2007511518A (zh) |
KR (1) | KR20060123279A (zh) |
CN (1) | CN1901885A (zh) |
AU (1) | AU2004291080A1 (zh) |
CA (1) | CA2545919A1 (zh) |
IL (1) | IL175600A0 (zh) |
MX (1) | MXPA06005461A (zh) |
NO (1) | NO20062699L (zh) |
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CN107198677A (zh) * | 2017-05-25 | 2017-09-26 | 长春金赛药业股份有限公司 | 黄体酮混悬型长效注射剂及其制备方法和黄体酮混悬注射粉针 |
CN110494178A (zh) * | 2017-04-04 | 2019-11-22 | 株式会社界优维 | 用于减轻或治疗外科手术后切口部位疼痛的器具 |
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WO2008027557A2 (en) * | 2006-08-31 | 2008-03-06 | Spherics, Inc. | Topiramate compositions and methods of enhancing its bioavailability |
JP5489719B2 (ja) * | 2006-11-17 | 2014-05-14 | スパーナス ファーマシューティカルズ インコーポレイテッド | トピラマートの徐放性配合物 |
CA2658521C (en) * | 2006-12-04 | 2015-06-09 | Supernus Pharmaceuticals, Inc. | Enhanced immediate release formulations of topiramate |
EP1972336A1 (en) * | 2007-03-19 | 2008-09-24 | LEK Pharmaceuticals D.D. | Hot-melt micropellets |
KR100958138B1 (ko) * | 2008-01-10 | 2010-05-18 | 박성순 | 안정성이 우수한 초산메게스트롤 약학 조성물 및 그제조방법 |
GB2497023A (en) * | 2010-08-11 | 2013-05-29 | Conocophillips Co | Delayed gelling agents |
WO2013037396A1 (en) * | 2011-09-12 | 2013-03-21 | Bioneer A/S | Solution of polymer in api for a solid dosage form |
US8652527B1 (en) | 2013-03-13 | 2014-02-18 | Upsher-Smith Laboratories, Inc | Extended-release topiramate capsules |
US9101545B2 (en) | 2013-03-15 | 2015-08-11 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
WO2018089832A1 (en) * | 2016-11-10 | 2018-05-17 | University Of Washington | Drug-polymer particles with sustained release properties |
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US3862311A (en) * | 1971-04-12 | 1975-01-21 | Ciba Geigy Corp | Novel method of enhancing progestational endometrial proliferation with progesterone |
US5082655A (en) * | 1984-07-23 | 1992-01-21 | Zetachron, Inc. | Pharmaceutical composition for drugs subject to supercooling |
EP0179583A1 (en) * | 1984-10-04 | 1986-04-30 | Merck & Co. Inc. | A system for enhancing the water dissolution rate and solubility of poorly soluble drugs |
FR2722984B1 (fr) * | 1994-07-26 | 1996-10-18 | Effik Lab | Procede de preparation de formes pharmaceutiques seches et les compositions pharmaceutiques ainsi realisees |
IE80467B1 (en) * | 1995-07-03 | 1998-07-29 | Elan Corp Plc | Controlled release formulations for poorly soluble drugs |
ATE232087T1 (de) * | 1997-10-27 | 2003-02-15 | Merck Patent Gmbh | Feste lösungen und dispersionen von eines schlecht wasserlöslichen wirkstoffes |
IE980115A1 (en) * | 1998-02-16 | 2000-02-09 | Biovail Internat Ltd | Solubilizing delivery systems and method of manufacture |
CN1272785A (zh) * | 1998-06-11 | 2000-11-08 | Em工业股份有限公司 | 微渗透药物控释系统 |
CA2423336C (en) * | 2000-09-20 | 2011-03-08 | Rtp Pharma Inc. | Stabilised fibrate microparticles |
US7217431B2 (en) * | 2001-07-06 | 2007-05-15 | Lifecycle Pharma A/S | Controlled agglomeration |
WO2003011254A1 (en) * | 2001-07-31 | 2003-02-13 | Capricorn Pharma Inc. | Amorphous drug beads |
SE0200895D0 (sv) * | 2002-03-22 | 2002-03-22 | Astrazeneca Ab | New pharmaceutical composition |
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CN110494178A (zh) * | 2017-04-04 | 2019-11-22 | 株式会社界优维 | 用于减轻或治疗外科手术后切口部位疼痛的器具 |
CN107198677A (zh) * | 2017-05-25 | 2017-09-26 | 长春金赛药业股份有限公司 | 黄体酮混悬型长效注射剂及其制备方法和黄体酮混悬注射粉针 |
CN107198677B (zh) * | 2017-05-25 | 2021-07-09 | 长春金赛药业有限责任公司 | 黄体酮混悬型长效注射剂及其制备方法和黄体酮混悬注射粉针 |
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JP2007511518A (ja) | 2007-05-10 |
EP1682092A2 (en) | 2006-07-26 |
WO2005048990A3 (en) | 2005-10-13 |
IL175600A0 (en) | 2006-09-05 |
ZA200604832B (en) | 2007-12-27 |
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