CN112004520A - 包括具有触发脉冲药物释放的胃内滞留筏形成系统的调节释放药物粉末组合物 - Google Patents
包括具有触发脉冲药物释放的胃内滞留筏形成系统的调节释放药物粉末组合物 Download PDFInfo
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Abstract
本发明提供一种可口服施用的药物粉末组合物,其形成具有至少两个触发脉冲的胃内滞留筏。所述组合物至少包含(a)至少一种具有立即释放脉冲释放形式的药物;(b)至少一种具有延迟触发释放形式的药物;(c)至少一种无毒气体发生剂;以及(d)筏系统,其中在口服摄取后,所述组合物提供自组装的胃内滞留筏,所述自组装的胃内滞留筏中包埋(a)和(b)中的所述至少一种药物以及由所述无毒气体发生剂原位产生的气体,由此提供漂浮的胃内滞留筏,所述漂浮的胃内滞留筏具有双脉冲系统,所述双脉冲系统中至少第二脉冲是触发脉冲,并且所述漂浮的胃内滞留筏将所述至少一种药物保持在胃中至少约3小时,前提是所述组合物不包括γ‑羟基丁酸酯和其盐、水合物、互变异构体或溶剂化物,或它们的络合物。
Description
背景技术
一些药物分子从小肠的上部表现出部位特异性吸收。这些分子在GI道的上部(胃、十二指肠和空肠)吸收较快、较大,而在GI道的下部(回肠、结肠和直肠)吸收较慢、较小。对于此类分子,由于不完全吸收,传统的长效液体剂型可能显示出较低的生物利用度,因为剂型可能在完成药物释放之前和吸收之前转移。WO2016087952A1涉及一种胃内滞留缓释悬浮液组合物,其中据报道所述组合物的特征在于,在储存至少七天后体外溶出释放曲线没有实质变化。其中讨论的缓释(ER)悬浮液包含渗透剂。悬浮基中产生的高渗状态影响活性成分从缓释包衣核心中的浸出到悬浮基中。据报道,这种高渗状态使药物从ER组分中的浸出最小化,因此在组合物的整个保质期内提供了基本上相似的活性成分的体外缓释。
在文献中已经描述了基于筏的胃内滞留药物递送系统。某些筏系统是漂浮的,其包含聚合物和气体发生剂,被设计成将筏系统从胃中延迟清除。现有技术中讨论的不同筏形成方法包括:基于溶胀的筏形成、基于温度依赖型胶凝的筏形成、基于pH依赖型胶凝剂的筏形成、基于离子交联的筏形成[Pawar Ashish Yashwantrao等人,《筏形成系统:胃内滞留的新颖方法》(A Raft forming system:A Novel approach for gastro-retention),Int.J.Pure App.Biosci.3(4):2015(178-192)。]然而,筏形成已被应用于药物输送领域,但成功率有限,特别是当应用于在GI道的上部表现出部位特异性吸收和具有以下中的至少一种的药物分子时,成功率有限:GI道和肝脏中的饱和初过代谢,消除半衰期非常短(<3小时),用于以长效液体的形式治疗生物节律后疾病。
本领域需要开发一种递送在GI道的上部表现出部位特异性吸收和具有以下中的至少一种的药物分子的技术:GI道和肝脏中的饱和初过代谢,消除半衰期非常短(<3小时),用于以长效粉末和/或悬浮液的粉末形式治疗生物节律后疾病。
发明内容
本发明提供一种组合物,所述组合物可以产生两种药物释放脉冲,给药后立即产生的第一脉冲和第一脉冲后2至6小时的第二脉冲,同时将剂型在GI道的上部保留更长的时间段。
在一个方面,提供一种可口服施用的药物粉末组合物,所述组合物形成具有至少两个触发脉冲的胃内滞留筏。一种组合物,包括:(a)至少一种具有第一脉冲的药物;(b)至少一种具有延迟触发释放形式的药物;以及(c)筏系统,其中在口服摄取后,所述组合物提供自组装的胃内滞留筏,所述自组装的胃内滞留筏中包埋(a)和(b)中的所述至少一种药物以及由无毒气体发生剂原位产生的气体,由此提供漂浮的胃内滞留筏,所述漂浮的胃内滞留筏具有双脉冲系统,所述双脉冲系统中至少第二脉冲是触发脉冲,并且所述漂浮的胃内滞留筏将所述至少一种药物保持在胃中至少约3小时,前提是所述组合物不包括γ-羟基丁酸酯和其盐、水合物、互变异构体或溶剂化物,或它们的络合物。
在某些实施例中,组合物包括至少一种具有第一脉冲的药物和至少一种具有pH S形延迟触发系统的药物。这种触发系统包括(a)至少一种药物和/或药物-离子交换树脂络合物;用反向肠溶包衣进行包衣的有机酸;任选的气体发生剂;任选的膨胀剂;以及(b)包括至少一种在(a)的颗粒上的pH非依赖性的、水不溶性的、水可渗透的扩散阻挡包衣聚合物(例如,甲基丙烯酸铵共聚物A型(例如,RL)和甲基丙烯酸铵共聚物B型(例如,RS))的包衣,其中所述包衣在(a)的有机酸存在的情况下溶解,由此在酸存在的情况下摄取后,形成包括(a)的药物的pH S形延迟触发的筏。
在某些实施例中,组合物包括至少一种具有第一脉冲的药物和至少一种具有腐蚀延迟触发系统的药物。这种触发系统包括:至少一种腐蚀阻挡形成聚合物;任选的气体发生剂;至少一种药物和/或药物-离子交换树脂络合物;以及任选的膨胀剂,由此在胃酸存在的情况下,形成包括药物的腐蚀延迟触发系统的筏。
在某些实施例中,组合物包括至少一种具有第一脉冲的药物和至少一种具有pH溶胀延迟触发系统的药物。这种触发系统包括:(i)颗粒剂,所述颗粒剂包括至少一种pH改性剂、用至少一种肠溶聚合物包衣的至少一种溶胀剂,(ii)任选地进一步用反向肠溶包衣(例如,EPO)进行包衣的步骤(i)的颗粒剂,由此在胃酸存在的情况下,形成包括(i)的药物的pH溶胀延迟触发系统的筏。
在某些实施例中,组合物至少一种具有第一脉冲的药物和至少一种具有溶胀延迟触发系统的药物。所述触发系统包括:(i)颗粒剂,所述颗粒剂包括至少一种药物和/或药物-离子交换络合物、至少一种胶凝剂、至少一种溶胀增强剂、在胃酸存在的情况下产生气体的任选的气体发生剂、任选地膨胀剂,以及(ii)至少一种在(i)的颗粒剂上的水可渗透的扩散阻挡包衣,由此在胃酸存在的情况下,形成包括(i)的药物的溶胀延迟触发系统的筏。
在某些实施例中,提供具有至少一种第一脉冲的药物和至少一种触发脉冲释放的药物的胃内滞留筏形成组合物用于治疗患者的用途。在某些实施例中,所述组合物包含用于治疗变应性鼻炎、类风湿性关节炎和相关病症、哮喘、癌症、心血管疾病、炎性疾病和溃疡中的一种或多种的一种或多种药物。
通过以下对本发明的详细描述,本发明的这些和其他优点将显而易见。
附图说明
图1A和图1B提供人类胃肠系统的示意图。图1A提供包括胃、十二指肠、空肠的消化系统的概图。图1B提供胃的放大示意图,说明从食管进入胃和从胃通过幽门瓣离开进入十二指肠。在胃内,在给药后的不同时间说明筏在胃液上的漂浮,包括“漂浮”以及药物释放后何时“下沉”以通过幽门瓣清除。
图2提供说明性缓释格隆溴铵脉冲释放粉末悬浮液(POS)的溶出曲线。在6小时的测试时段内,相对于时间绘制了累积释放百分比(%)。
图3提供说明性缓释异丙嗪脉冲释放粉末悬浮液(POS)的溶出曲线。在6小时的测试时段内,相对于时间绘制了累积释放百分比(%)。
图4提供说明性缓释普萘洛尔脉冲释放粉末悬浮液(POS)的溶出曲线。在8小时的测试时段内,相对于时间绘制了累积释放百分比(%)。
图5提供说明性缓释缬沙坦脉冲释放粉末悬浮液(POS)的溶出曲线。在8小时的测试时段内,相对于时间绘制了累积释放百分比(%)。
图6提供说明性缓释曲马多脉冲释放粉末悬浮液(POS)的溶出曲线。在8小时的测试时段内,相对于时间绘制了累积释放百分比(%)。
具体实施方式
如本文提供的胃内滞留(GR)脉冲释放(PR)组合物可以是粉末,其在给药后为至少一个选定生物活性部分提供至少两个脉冲释放。组合物可以在给药时用水重构以形成可以被填充到胶囊中的悬浮液或糊剂或布丁。
如本文所用,术语“生物活性部分”或“生物有用部分”可以包括“活性药物成分”或“API”、营养品、维生素或其他期望部分。如本文所用,API是意图用于制造药物产品的任何物质或物质混合物,并且在用于药物生产时成为药物产品中的活性成分。因此,API可以是例如一种或多种小分子药物、癌症治疗剂或生物制剂(例如激素、酶、肽、多肽、抗体、抗体片段、单结构域抗体等)。小分子药物的分子量通常低于约900道尔顿,并且可以是游离碱或酸性药物或其药学上可接受的盐、溶剂化物或水合物。在某些实施例中,生物有用部分在颗粒或颗粒剂中。在某些实施例中,此类颗粒或颗粒剂可以包含一种或多种药物-离子交换树脂络合物。在某些实施例中,此类颗粒或颗粒剂包含赋形剂。在某些实施例中,此类生物活性部分(和/或包含其的络合物、颗粒或颗粒剂)可以是未包衣的,或用调节释放包衣进行包衣。除非另有说明,否则在本说明书中使用术语“药物”时,另一个生物活性部分可以被取代。还将理解,除非另有说明,否则可以使用多于一种药物。在某些实施例中,本文提供的组合物不包括γ-羟基丁酸酯、其盐、水合物、互变异构体或溶剂合物或其络合物。在某些实施例中,基于最终剂型的总重量,生物活性部分为约0.1w%至90wt%,更优选地约1wt%至75wt%,或约15wt%至60wt%。在某些实施例中,组合物可以包括0.1mg至15g的活性药物。
“药物-离子交换树脂络合物”是指通过将至少一种药物加载到离子交换树脂上而得到的产物。例如在通过引用并入本文的WO 2007/109104和US 2007/0215511A1中描述了用于制备此类络合物的方法。在某些实施例中,这描述了在将活性药物和离子交换树脂在水性介质中混合在一起以促进药物的盐与离子交换树脂的“离子”之间的“交换”和络合物形成时发生的络合。除非另有说明,否则药物-离子交换树脂络合物可以未包衣或包衣。在某些实施例中,药物-离子交换树脂络合物可以具有与相同的离子交换树脂络合的两种或更多种不同药物。在某些实施例中,药物-交换树脂络合物不包含γ-羟基丁酸酯、其盐、水合物、互变异构体或溶剂合物或其络合物。
在某些实施例中,本文提供的GR PR组合物在组合物给药后约三小时内产生药物释放的第一脉冲,并且在第一脉冲后约2小时至约6小时产生药物的至少第二脉冲。
如本文所用,术语“胃内滞留”或“GR”是指给药后(例如,通过口服摄取)至少一部分给药的组合物在胃中保留的时间长于从胃中正常排空时间,即至少约2小时且至多约24小时、至少约3小时至至多约24小时、约4小时至约16小时、约5小时至约12小时、或约6小时至约8个小时。
在本文的实施例中描述了用于评估胃内滞留期的合适测定的实例,包括在不含酶的模拟胃液(SGF)中漂浮的发生和持续时间以及在SGF中的完整性/弹性的测定的实例。另外,可以在人体中进行γ-闪烁显像研究,以实际观察剂型在胃中的保留情况(及上GIT)以及其在胃中的停留时间。参见例如SS Davis等人,《消化道和胰腺药物剂型穿过小肠的转运》(Alimentary tract and pancreas Transit of pharmaceutical dosage formsthrough the small intestine),Gut,1986,27,886-892。
如本文所用,“脉冲”是指药物释放系统,其中以滞后时间完全且快速的药物释放的方式释放预定量的药物。
如本文所用,“粉末悬浮液”或“POS”是指被配制为粉末的组合物,其被设计成在患者口服摄取之前悬浮在悬浮基中。
在某些实施例中,胃内滞留脉冲释放(GRPR)POS特别适合与生物活性部分一起使用:(i)在GI道上部表现出部位特定吸收,并在GI道和肝脏中表现出饱和代谢;(ii)在GI道上部表现出部位特定吸收,且消除半衰期非常短(<3小时),和/或(iii)在小肠上部表现出部位特定吸收,并且用于跟随生物节律治疗疾病。然而,本文描述了可用于本发明的其他合适的生物活性部分和/或基于以下描述而对于本领域技术人员将是显而易见的。
如前段以及整个说明书中所用,用于吸收的“GI道上部”包括胃、十二指肠和空肠。
通常,在胃的pH条件下(在pH 4下)具有溶解性或稳定性问题的API不适合本文描述的组合物。然而,某些未络合的药物可以药物-离子交换树脂络合物或颗粒剂、颗粒或本文描述的其他形式设计,以解决这些溶解性或稳定性问题。
本文描述的触发释放机构可以与多种筏形成系统和/或新颖的浮动IPN形成系统结合使用,所述系统在标题为“包括浮动互穿聚合物网络形成系统的药物组合物”的美国临时专利申请中详细描述,所述美国临时专利申请将与之同时提交并通过引用全文并入本文。在下文更详细地描述此类筏系统。
从GR POS脉冲释放(PR)部分
在某些实施例中,本文提供的组合物被设计为具有至少两个脉冲:第一脉冲和至少第二脉冲,所述第二脉冲是触发脉冲。任选地,组合物可以提供附加脉冲释放。合适地,基于呈游离形式的活性部分的重量(即,不包括任何盐或络合物的重量)计,第一脉冲中的活性部分(例如,一种或多种药物)的量与第二脉冲中的活性部分(例如,一种或多种药物)的量的比可以为2:98至85:15。在某些实施例中,所述比可以为约1:10至约10:1、或约1:1、约1:20、约2:1、约1:4、约4:1。可以容易地选择它们之间的值。
在某些实施例中,本文提供的组合物可具有三个或更多个脉冲。在此类实施例中,通常第一脉冲是瞬时的,且至少一个其他脉冲是如本文描述的触发释放脉冲。在某些实施例中,组合物提供相同药物的至少两个脉冲。在其他实施例中,组合物提供两种或更多种药物,其可以包括与至少第一脉冲或至少第二脉冲中。在此类情况下,相对于相同药物的第一脉冲的定时而确定至少第二脉冲的定时。
如在本发明的组合物中一样,第一脉冲可以基本上即刻在给药后。在某些实施例中,本文提供的组合物提供具有对应于总剂量的约10%至约80%的第一脉冲的药物,其被配制成游离药物、药物-离子交换树脂络合物和/或其混合物。如本文描述,组合物被设计为在给药后约3小时内、或给药后约2小时内或给药后约1小时内(例如,约10分钟至60分钟)提供第一脉冲。
本文提供的组合物提供至少第二脉冲,其使用触发机制。在某些实施例中,本文提供的组合物向药物提供至少第二脉冲,其对应于总剂量的约20%至约90%被配制为触发原理。使用不同的触发机制来在第一脉冲后约2小时至约6小时释放API的第二脉冲。可以通过使用游离药物、药物-离子交换树脂络合物和/或其混合物来获得第二脉冲。
合适的触发机制包括(a)pH作为触发:S型释放系统、(b)侵蚀作为触发、(c)pH加溶胀作为触发以产生第二脉冲、(d)溶胀作为触发、这些系统的组合、和/或这些系统中的一个或多个与诸如本文标识的其他触发系统的组合。在下文更详细地描述此类系统。
应注意,对于“第一脉冲”,可以以适合于在少于约3小时内释放且在某些实施例中在少于约2小时内或少于约1小时内释放的任何形式提供生物活性部分。在某些实施例中,部分(例如,药物)以游离碱或酸API或其药学上可接受的盐的形式递送。在某些实施例中,所述部分处于药物-离子交换络合物中,而没有调节释放包衣。在某些实施例中,在没有调节释放包衣的情况下,用于第一脉冲的部分是颗粒、颗粒剂或分层到球形上。
另外,本文提供的组合物包含至少第二脉冲形式的至少一个生物活性部分。以下段落描述组合物中的至少第二种脉冲形式的合适触发脉冲释放。
如本文提供,“气体发生剂”是指在与胃液接触时产生无毒气体的试剂。合适的气体发生剂包括但不限于碱金属或碱土金属的碳酸盐或碳酸氢盐,例如碳酸钾或碳酸氢钾、碳酸钠或碳酸氢钠、碳酸钙、甘氨酸碳酸钠、碳酸镁和碳酸铝;以及亚硫酸盐,诸如亚硫酸钠、亚硫酸氢钠和偏亚硫酸氢钠。这些盐可以单独使用或与酸源组合用作气体发生剂对。本文提供的最终组合物包括气体发生剂。气体发生剂可以存在于触发脉冲系统、筏形成组合物中的一个或多个中,或者与组合物中的一种或多种其他组分混合。通常,一旦气体困在GR筏中,只要保持筏的完整性,浮力就会继续。因此,用于3小时(hr)漂浮的相同浓度的气体也适用于更长的时间段,例如12小时漂浮。在某些实施例中,气体发生剂以GR筏的总重量的约1%w/w至约25%w/w的浓度范围存在。合适地,气体发生剂提供快速发生(少于约15分钟)和至少或大于约3小时漂浮。可使用合适的测定,诸如本文描述的测定法,例如在500ml不含酶的模拟胃液中,和/或本领域已知的其他测定,来在体外评估漂浮。
合适地,GR筏提供了生物有用部分(例如,药物),其在胃中的保留时间长于所述部分在直接施用的情况下将具有的时间。在某些实施例中,这导致“胃肠道”包括胃、十二指肠和/或空肠的生物利用度、吸收度和/或活性增加。
溶胀作为触发
在某些实施例中,一种组合物包含至少一种生物活性部分和(i)选自水凝胶形成聚合物的至少一种胶凝剂;(ii)选自以下超级崩解剂的非限制性列表的至少一种溶胀增强剂;(iii)至少一种水可渗透的扩散阻挡包衣;(iv)任选地气体发生剂;(v)任选地膨胀剂,例如微晶纤维素(MCC),包括例如硅化MCC、甘露醇等。
包括至少一种生物活性部分(例如,API或药物-离子交换树脂络合物或其混合物)、胶凝剂和溶胀增强剂的颗粒剂用扩散阻挡层包衣。不受任何理论的束缚,据信在与水性介质接触时,它是不饱和的;溶胀增强剂会导致快速吸水。胶凝剂开始形成水凝胶并溶胀,并开始推动包衣。优化了核心赋形剂的相对比例和包衣厚度,使得由于2小时和6小时之前的溶胀而完全去除包衣。通过调整溶胀增强剂与胶凝剂的相对比例且通过改进包衣厚度来改进第二脉冲的发生。一旦去除了包衣,那么较高比例的溶胀增强剂和较低比例的胶凝剂可确保快速释放药物。
一种或多种胶凝剂选自在水性介质中形成水凝胶的亲水性聚合物的非限制性列表:卡波姆、瓜尔胶、黄原胶、阿拉伯胶、黄蓍胶、纤维素聚合物及其衍生物(诸如羟丙基甲基纤维素(HPMC))、羟丙基纤维素、甲基纤维素和羟乙基纤维素(HEC)、羧甲基乙基纤维素、羟乙基甲基羧甲基纤维素、羟乙基甲基纤维素、羧甲基纤维素、甲基羟乙基纤维素、甲基羟丙基纤维素或其任何混合物)、多糖及其衍生物、聚环氧烷、聚乙二醇、壳聚糖、聚(乙烯醇)、黄原胶、马来酸酐共聚物、淀粉基聚合物、交联聚丙烯酸和其组合。
一种或多种至少一种溶胀增强剂,例如超级崩解剂,选自超级崩解剂的非限制性列表:交聚维酮、SSG、交联羧甲基纤维素钠。溶胀增强剂促进大量水性流体的快速吸收。
覆盖颗粒剂的至少一种水可渗透的扩散阻挡包衣,包括API、胶凝剂和溶胀增强剂。在某些实施例中,阻挡包衣使包衣的颗粒剂增加约5%w/w至约80%w/w。
扩散阻挡包衣包含形成扩散阻挡层的至少一种聚合物体系。合适的阻挡包衣包括但不限于水不溶性的释放改性剂或水溶性释放改性剂或其组合。可以使用的水不溶性的释放改性剂包括聚合物水不溶性的释放改性剂或非聚合物水不溶性的释放改性剂或其组合。合适的聚合物水不溶性的释放改性剂包括但不限于纤维素聚合物及其衍生物、聚丙烯酸和聚甲基丙烯酸聚合物及其衍生物、马来酸共聚物及其衍生物、聚乙烯基衍生物;等或其任何组合。在一个实施例中,合适的聚合物水不溶性的释放改性剂包括但不限于聚乙酸乙烯酯、聚氯乙烯、聚碳酸乙烯酯、乙基纤维素、硝化纤维素、偏二氯乙烯-丙烯腈共聚物、丙烯腈-苯乙烯共聚物、乙烯乙酸乙烯酯、乙酸纤维素、邻苯二甲酸乙酸纤维素、乙酸丁酸纤维素、乙烯基吡咯烷酮的共聚物、包括聚乙酸乙烯酯、羟丙基甲基纤维素邻苯二甲酸酯的聚合物的共混物、甲基丙烯酸共聚物,诸如L100/S100/L100-55等或其混合物;甲基丙烯酸酯共聚物,诸如E100/EPO、RL100/RL30D/RLPO、RS100/RS30D/RSPO等及其混合物。合适的非聚合物水不溶性的释放改性剂包括但不限于脂肪、油、蜡、脂肪酸、脂肪酸酯、甘油酯、长链一元醇及其酯、磷脂、萜烯或其组合。这些类别中的每一个中的合适的释放改性剂已在上文列出。
在一个实施例中,阻挡包衣是pH非依赖性的、水不溶性的、水可渗透的阻挡包衣,其任选地包含一种或多种增塑剂,并且任选地被固化。任选地,包衣包括以百分比范围使用的增塑剂,或增塑剂的混合物结合起来占包衣层的按重量计约2至约50%,更优选地包衣药物-离子交换树脂络合物上包衣层的按重量计约2.5%至约20%。优选地,基于包衣络合物,占包衣层的按重量计约5%至约10%的增塑剂提供最期望的性能。合适的增塑剂是水溶性和水不溶性的。合适的增塑剂的实例包括例如癸二酸二丁酯、丙二醇、聚乙二醇、聚乙烯醇、柠檬酸三乙酯、柠檬酸乙酰基三乙酯、柠檬酸乙酰基三丁酯、柠檬酸三丁酯、三醋精和Soluphor P及其混合物。其他增塑剂描述于2003年5月29日的专利申请公开号US 2003/0099711A1,第4页(0041)中,其公开内容通过引用并入本文。
在某些实施例中,pH非依赖性阻挡包衣系统包含聚乙酸乙烯酯聚合物,其在某些实施例中以水性包衣分散体形式施加。聚乙酸乙烯酯在室温下不溶于水,并且可以以基本上纯的形式或以共混物形式使用。商业共混物主要包含聚乙酸乙烯酯聚合物、稳定剂和少量表面活性剂,诸如十二烷基硫酸钠。更具体地,期望的水基包衣溶液是SR30D(BASF Corporation),其组成为约27%的聚乙酸乙烯酯、约2.7%的聚乙烯吡咯烷酮(PVP)、约0.3%的月桂基硫酸钠(固体含量为30%w/w)。在一个实施例中,如果使用基本上纯的PVA形式,那么可以将其溶解在合适的非水溶剂中以提供用于药物离子交换树脂络合物的包衣溶液。SR-30D水性分散体可固化约1至约24小时。在替代性实施例中,包衣在高温例如约50℃至约65℃,优选约60℃下固化约4至约16小时,优选约5小时。在阻挡包衣包括聚乙酸乙烯酯的情况下,聚乙酸乙烯酯以最终阻挡包衣层的约70%至约90%w/w、至少约75%、至少约80%、最终阻挡包衣层的约85%w/w的量存在。当阻挡包衣也包括PVP作为稳定剂组分时(例如,如TMSR30D中存在),最终阻挡包衣层通常包含约5至约10%w/w的聚乙烯基吡咯烷酮。
颗粒剂还包含一种或多种气体发生剂。气体发生剂在与胃液接触时产生无毒气体,并且选自非限制性列表:包括碱金属或碱土金属的碳酸盐或碳酸氢盐,诸如碳酸钾或碳酸氢钾、碳酸钠或碳酸氢钠、碳酸钙、甘氨酸钠碳酸盐、碳酸镁和碳酸铝;以及亚硫酸盐,诸如亚硫酸钠、亚硫酸氢钠和偏亚硫酸氢钠。这些盐可以单独使用或与酸源组合用作气体发生剂对。
颗粒剂还包括选自非限制性列表的一种或多种膨胀剂:微晶纤维素、硅化MCC、磷酸二钙脱水。
渗透作为触发
在某些实施例中,本发明的组合物包含至少一中生物活性部分;(i)如本文定义的至少一种胶凝剂;(ii)非限制性渗透剂列表中的至少一种渗透剂;(iii)至少一种水可渗透的扩散阻挡包衣;(iv)任选的气体发生剂;(v)任选地膨胀剂。
包括至少一种生物活性部分(例如,至少一种药物-离子交换树脂络合物)、胶凝剂和渗透剂的颗粒剂用扩散阻挡层包衣。不受任何理论的束缚,据信在与水性介质接触时,它是不饱和的;渗透剂促进快速吸水。胶凝剂开始形成水凝胶并溶胀,并开始推动包衣。优化了核心赋形剂的相对比例以及包衣厚度,使得由于2小时和6小时之前的溶胀而完全去除包衣。通过修改渗透剂与胶凝剂的相对比例且通过修改包衣厚度来修改第二脉冲的发生。一旦去除了包衣,那么较高比例的溶胀增强剂和较低比例的胶凝剂可确保快速释放药物。
渗透剂促进快速吸收大量的水性流体。渗透剂或药学上可接受的惰性水溶性化合物的合适实例选自包括以下各项的群组:碳水化合物,诸如木糖醇、甘露醇、山梨糖醇、阿拉伯糖、核糖、木糖、葡萄糖、果糖、甘露糖、半乳糖、蔗糖、麦芽糖、乳糖、右旋糖和棉子糖;无机酸的水溶性盐,诸如氯化镁、硫酸镁、硫酸钾、氯化锂、氯化钠、氯化钾、磷酸氢锂、磷酸氢钠、磷酸氢钾、磷酸二氢锂、磷酸二氢钠、磷酸二氢钾和磷酸氢三钠;有机酸的水溶性盐,诸如乙酸钠、乙酸钾、琥珀酸镁、苯甲酸钠、柠檬酸钠和抗坏血酸钠;水溶性氨基酸,诸如甘氨酸、亮氨酸、丙氨酸、蛋氨酸;尿素或其衍生物;丙二醇;甘油;聚环氧乙烷;黄原胶;羟丙基甲基纤维素;或其混合物。
任选地,颗粒剂还包括一种或多种膨胀剂,或者称为“填充剂”,诸如整个说明书中描述。
在以下说明性实施例中,以反映触发系统的w/w的百分比来提供组分。
pH作为触发:S型释放系统:
此脉冲触发系统包括至少一种生物活性部分(例如API、药物-离子交换树脂络合物或其混合物)加:(i)反向肠溶包衣有机酸;(ii)任选的气体发生剂;(iii)任选地膨胀剂;(iii)至少一种pH非依赖性的、水不溶性的、水可渗透的扩散阻挡包衣聚合物,例如甲基丙烯酸铵共聚物A型(例如Eudragit RL)和甲基丙烯酸铵盐共聚物B型(例如Eudragit RS)。在某些实施例中,此脉冲触发系统包括呈药物-离子交换树脂络合物形式的至少一种生物活性部分(此脉冲触发系统的约60%w/w、10%w/w至80%w/w),加:(i)反向肠溶包衣有机酸(约8%w/w、3%w/w至25%w/w);(ii)任选的气体发生剂(约5%w/w、0至10%w/w);(iii)任选地膨胀剂(约5%、0至30%w/w);(iii)至少一种pH非依赖性的、水不溶性的、水可渗透的扩散阻挡包衣聚合物,例如,甲基丙烯酸铵盐共聚物B型(约20%、10%w/w至60%w/w)。通常,在用稀释剂制粒后,有机酸用反向肠溶聚合物(例如,EPO)包衣。将这些颗粒剂与API(且任选地与气体发生剂和膨胀剂)进一步混合并制粒。这些颗粒剂用pH非依赖性的、水不溶性的、水可渗透的扩散阻挡包衣聚合物(例如,RS/RL或共混物)包衣。不受理论的束缚,据信在与胃液接触时,进入包衣颗粒的酸性介质会影响微环境的pH。这增加反向肠溶包衣在有机酸颗粒剂上的渗透性,从而允许释放有机酸。基于有机酸的pKa且基于微环境pH,有机酸会解离。离解酸与阻挡包衣中存在的甲基丙烯酸铵盐共聚物A型、甲基丙烯酸铵盐共聚物B型或两者(Eudragit RS/RL/两者)反应,并增加包衣的渗透性,从而导致S形药物释放,产生第二脉冲。
一种或多种有机酸选自非限制性列表:琥珀酸、苹果酸、富马酸、柠檬酸、酒石酸等及其混合物。
反向肠溶包衣是pH依赖性的,并且被设计成在大于约pH 4或大于约4.5的pH下不增溶或溶胀。一种合适的反向肠溶聚合物是丙烯酸酯聚合物或共聚物。特别合适的反向肠溶包衣包括可以以水性分散体形式施用的那些聚合物。一种合适的水性分散体基于甲基丙烯酸甲酯和甲基丙烯酸二乙氨基乙基酯共聚物。此反向肠溶包衣的一个实例是Smartseal 30D,它是固体浓度约为30%的水性聚合物分散体。它包含甲基丙烯酸甲酯和甲基丙烯酸二乙氨基乙基酯共聚物,并用约0.6%的聚乙二醇十六硬脂基醚和0.8%的十二烷基硫酸钠稳定化。其他反向肠溶聚合物包括例如E 100(Evonik)、EPO(Evonik)、甲基丙烯酸甲酯、甲基丙烯酸羟乙酯、以及基于甲基丙烯酸甲酯、甲基丙烯酸2-羟乙酯和4-乙烯基吡啶的无规三元共聚物。EPO是1:2:1的聚(甲基丙烯酸丁酯-共-(2-二甲基氨基乙基)甲基丙烯酸酯-共-甲基丙烯酸甲酯)(CAS号:24938-16-7),即,基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物。商业化EPO Ready Mix由碱性丁基化甲基丙烯酸酯共聚物、十二烷基硫酸钠、硬脂酸和滑石粉组成。然而,在其他配方中,其他表面活性剂(包括其他阴离子表面活性剂)也可以代替月桂基硫酸钠。除阴离子表面活性剂月桂基硫酸钠以外的合适表面活性剂的实例是技术人员已知的。类似地,除硬脂酸以外的润滑剂和除滑石粉以外的助流剂是本领域已知的并且可以选择。还描述了并且可以如例如US 2006/062844(2006);US2005/0136114、US 7294347中描述而制备其他反向肠溶聚合物,其公开内容通过引用并入本文。当存在时,这些包衣的重量百分比按加入的重量计以加入的重量的约5%至约60%、或约5%至约20%、或约8%至约12%的量提供。在某些实施例中,至少一种反向肠溶聚合物选自Eudragit EPO、Smartseal 30D及其用途。
诸如本文所定义的至少一种pH非依赖性的、水不溶性的、水可渗透的扩散阻挡包衣聚合物(例如,Eudragit RS)覆盖了包括生物活性部分、包衣酸、任选地膨胀剂和气体发生剂的颗粒剂。
任选地,颗粒剂还包括一种或多种膨胀剂。
侵蚀作为触发
在某些实施例中,本发明的组合物包括至少一个触发侵蚀系统。此系统包括:(i)至少一种生物活性部分(例如,API、药物-离子交换树脂络合物或其混合物);(ii)选自非限制性列表的形成腐蚀阻挡层的至少一种聚合物:HPMC、HEC、其他纤维素醚、瓜耳胶;(iii)任选的气体发生剂;(iv)任选地,膨胀剂。合适地,活性部分和赋形剂用易蚀阻挡层包衣。在某些实施例中,腐蚀触发系统包括(i)至少一种生物活性部分(例如,API、药物-离子交换树脂络合物或其混合物);(约60%w/w、5%w/w至80%w/w)(ii)选自非限制性列表的形成腐蚀阻挡层的至少一种聚合物:HPMC、HEC、其他纤维素醚、瓜耳胶;(约15%、5%w/w至20%w/w)(iii)任选的气体发生剂(约7%、0至15%w/w);(iv)任选地,膨胀剂(约15%w/w、0至75%w/w)。合适地,活性部分和赋形剂用易蚀阻挡层包衣。
不受理论的束缚,据信在与水性介质接触时;包衣开始腐蚀。可以通过调整聚合物的溶解度、粘度、膜厚来调整包衣侵蚀的速率。可以通过使用具有不同溶解度和溶解速率的聚合物来定制包衣侵蚀的速率,例如,当使用纤维素醚时,与具有较长链长(如羟丙基纤维素)取代基的那些相比,具有较小链长(如乙基、羟基乙基纤维素HEC)取代基的那些具有更大的溶解度和更快的溶解速率。包衣聚合物的粘度在调整包衣侵蚀速率方面起着重要作用。与低粘度聚合物(如HPMC K100LV)相比,高粘度聚合物(如HPMC K100M)表现出较慢的腐蚀速率。包衣水平越高,腐蚀越慢。因此,为了减缓侵蚀速率,选择缓慢溶解(例如HPC、HPMC)的具有较高包衣水平(>20%w/w)的粘性聚合物(粘度>4000cps)。
pH加溶胀作为触发
在某些实施例中,本发明的组合物包括至少包含以下的颗粒剂:(i)至少一种生物活性部分(例如,药物、药物-离子交换树脂络合物或其混合物)、(ii)至少一种pH改性剂;(iii)任选地,溶胀剂。所述颗粒剂用至少一种肠溶聚合物包衣,且所述包衣的颗粒剂任选地还用反向肠溶聚合物包衣。在某些实施例中,本发明的组合物包括至少包含以下的颗粒剂:(i)至少一种生物活性部分(例如,药物、药物离子交换树脂络合物或其混合物),(约40%、10%w/w至75%w/w)、(ii)至少一种pH改性剂(约20%、5%w/w至50%w/w);(iii)任选地,溶胀剂(约10%w/w,5%w/w至-25%w/w)。所述颗粒剂用至少一种肠溶聚合物包衣,并且所述包衣的颗粒剂任选地还用反向肠溶聚合物包衣。
不受理论的束缚,据信由pH改性剂产生的碱性微环境pH导致肠溶性聚合物的溶解。溶胀进一步导致外包衣喷发,其也溶解在周围的酸性pH中。可以使用各种方法来在2到6个小时之间修改第二触发脉冲的发生,包括例如肠溶包衣的水平、反向肠溶包衣的水平、f溶胀剂和pH改性剂使人能够调整时间API释放的第二脉冲。
多种肠溶包衣是已知的和/或可商购的。此类肠溶包衣是pH依赖性的,同时被设计成在约1至约3.5至约4的pH下稳定,所述pH存在于胃酸中以溶解于较高的小肠(例如约7至约9)中。可以选择某些pH依赖性(肠溶性)聚合物,包括例如EUDRAGIT聚合物家族的成员,例如L、S和E,以及可商购的其他聚合物。
本文提供的组合物可以包含第一脉冲释放系统、一个或多个前述触发脉冲释放系统的组合和/或第一脉冲释放和这些触发脉冲系统中的一个或多个与另一脉冲释放系统的组合。此类脉冲释放系统与其他合适的组分一起掺入本文提供的组合物中。
胃内滞留筏脉冲释放的组分
除了本发明的组合物中的至少两个脉冲药物释放系统外,所述组合物还包含一种或多种胃内滞留筏形成系统,以及其他组分。此类筏形成系统被设计成在气体存在的情况下在体内(原位)形成并截留一个或多个脉冲,其中至少一个是触发脉冲系统。任选地,第一(或立即释放)脉冲由组合物提供但不截留在筏中。可以选择多种筏形成系统。
基于离子交联的筏形成系统
在某些实施例中,选择基于离子交联的筏形成系统。此系统包括:至少一种阴离子聚合物,其量为约2%w/w至约75%w/w、或约2%w/w至约50%w/w、或约5%w/w至约40%w/w、或约10%w/w至约30%w/w、或约10%w/w至约75%w/w、或约15%w/w至约65%w/w w、或约20%w/w至约55%w/w、或约25%w/w至约45%w/w。一种或多种阴离子聚合物可以选自以下非限制性列表:海藻酸钠、卡拉胶I、果胶、吉兰糖胶、藻酸、卡拉胶k、羧甲基纤维素钠和/或黄原胶;选自以下二价和三价金属盐的非限制性列表的至少一种交联剂:钙盐,如碳酸钙、氯化钙、葡萄糖酸钙;镁盐、亚铁盐、铁盐、铝盐和/或锌盐;至少一种气体发生剂,如碳酸氢钠、碳酸氢铵、碳酸钙、碳酸钠、其在与酸和/或亚硫酸盐反应时产生二氧化碳气体;以及任选地泡腾剂对。
不受理论的束缚,据信在与酸性介质接触时,阴离子聚合物与交联剂发生交联。在与胃酸反应后,由气体发生剂产生的气体(例如,二氧化碳)被截留在交联聚合物中,从而导致其漂浮。任选地,使用泡腾剂对以释放二氧化碳气体。
可以选择多种阴离子聚合物,包括例如一种或多种:果胶、藻酸、结冷胶、卡拉胶和黄原胶和/或其组合。果胶是多糖的家族,其中聚合物主链主要包括α-(1-4)-D半乳糖醛酸残基。游离钙离子交联半乳糖醛酸链,并且可以包括于制剂中以诱导果胶交联。有利地,果胶是水溶性的,因此在制剂中有机溶剂不是必需的。海藻酸是由β-D-甘露糖醛酸和通过1,4-糖苷键连接的α-L-葡糖醛酸残基组成的线性嵌段共聚物多糖。藻酸盐的水溶液通过协同过程与二价和三价金属离子交联,所述协作过程涉及藻酸盐链的α-L-葡糖醛酸嵌段中的连续的葡糖醛酸残基。结冷胶(可作为GelriteTM或KelcogelTM商购)是具有一个α-L-鼠李糖、一个β-D-葡糖醛酸和两个β-D-葡糖醛酸残基的四糖重复单元的阴离子脱乙酰化的胞外多糖。卡拉胶是直链硫酸化多糖的家族。卡拉胶共有三种主要变种,其硫酸化程度不同。Kappa-卡拉胶每二糖具一个硫酸根,Iota-卡拉胶有两个,而λ-卡拉胶有三个。Iota卡拉胶通过二价阳离子交联,而Kappa卡拉胶通过单价阳离子交联。黄原胶是由五糖重复单元组成的阴离子多糖,其包括摩尔比为2:2:1的葡萄糖、甘露糖和葡萄糖醛酸。
基于溶胀的筏形成系统
在某些实施例中,本文提供的组合物包括基于溶胀的筏形成系统。此系统包括:(i)选自非限制性列表的至少一种溶胀剂:pH依赖性溶胀剂(例如,聚(丙烯酸)(PAA)(例如,971P)、其他卡波姆、壳聚糖),pH非依赖性溶胀剂(例如,polyox、HPMC、其他纤维素醚);(ii)任选地至少一种气体发生剂;(iii)任选地一种或多种pH改性剂;(iv)任选的泡腾剂对。例如,一种溶胀筏系统包括:(i)至少一种溶胀剂(占筏的约30%、10%w/w至75%w/w);(ii)至少一种气体发生剂;碳酸氢钾(约10%、5%w/w至约30%w/w)(iii)任选地一种或多种pH改性剂;碳酸氢钠(约10%w/w、5%w/w至约30%w/w)。例如,另一种溶胀筏系统包括:(i)至少一种溶胀剂(占筏的约30%w/w、10%w/w至约75%w/w)(例如约30%Polyox);(ii)至少一种气体发生剂(5%w/w至30%w/w、或约10%,例如碳酸氢钾)。
可以使用各种pH依赖性聚合物,其导致系统中原位胶凝的形成。各种聚合物,诸如PAA(卡波姆)或其衍生物、聚乙烯醇缩醛二乙基氨基乙酸酯(AEA)、聚(甲基丙烯酸)(PMA)与聚乙二醇(PEG)的混合物)随pH改变而从溶胶变为凝胶。在弱酸性(阴离子)基团的情况下,水凝胶的溶胀随着外部pH的增加而增加,但在聚合物包含弱碱性(阳离子)基团的情况下,水凝胶的溶胀减小。聚(甲基丙烯酸)(PMA)与聚(乙二醇)(PEG)的混合物也已用作pH敏感系统以实现胶凝。pH敏感聚合物本质上可以是中性或离子性的。阴离子网络包含带负电荷的部分,阳离子网络包含带正电荷的部分,而中性网络包含正和负电荷的部分。在包含羧酸或磺酸基团的阴离子聚合物网络的情况下,当外部溶胀介质的pH升高至高于所述可电离部分的pKa时,发生电离。
Carbopol是一种粘膜粘附性聚合物,其不仅可以提高配方的机械强度,而且还可以增加与眼组织的表面相互作用,从而增加接触时间。当pH升高至高于其约5.5的pKa时,Carbopol在水溶液中显示出从固体到凝胶的转变。因此,为了易于给药,在卡波普相变之前需要酸性pH。壳聚糖是由葡糖胺和N-乙酰基葡糖胺的共聚物组成的阳离子多糖,它们是通过几丁质脱乙酰化而获得的天然聚合物。它无毒、生物相容、可生物降解的多糖、具有生物粘附且具抗菌作用。壳聚糖水溶液在pH超过6.2时会形成水合凝胶,类似于沉淀物。
基于温度依赖性胶凝的筏形成系统
在某些实施例中,组合物包括温度依赖性胶凝的筏形成系统。此系统可以包括(i)任选地至少一种胶凝剂,其在37℃下胶凝,但在室温下保持溶解(例如,占筏形成系统的约25%w/w至约80%w/w、30%w/w至约75%w/w、或约40%w/w至约65%w/w、或约45%w/w至约55%w/w)。合适的胶凝剂的实例可以选自以下非限制性列表:木葡聚糖、泊洛沙姆188、泊洛沙姆407和其组合。所述系统还包含(ii)至少一种气体发生剂(例如,占筏形成系统的约10%w/w至约40%w/w、或约15%w/w至约35%w/w、或约20%w/w至约30%w/w),并且另外包含任选的泡腾剂对。例如,一种基于温度依赖性胶凝的筏形成系统包括泊洛沙姆407(占筏形成系统的约50%、25%w/w至80%w/w、碳酸氢钠(约25%、10%w/w至40%w/w)。在另一实例中,基于温度依赖性胶凝的筏形成系统包括泊洛沙姆188(占筏形成系统的40%,205-80%w/w)、碳酸氢钠(约25%、10%w/w至-40%w/w)。
木葡聚糖是由(1-4)-β-D葡聚糖主链组成的多糖,其具有被(1-2)-βD半乳糖醛糖部分取代的(1-6)-α-D木糖分支。当木葡聚糖被β-半乳糖苷酶部分降解时,所得产物通过杆状链的侧向堆叠而表现出热可逆胶凝。溶胶-凝胶转变温度随半乳糖消除的度而变化。在升温至体温时会形成热可逆胶凝。它在口服给药中的潜在应用利用了拟议中的缓慢胶凝时间(数分钟),这种胶凝时间允许在口服冷木葡聚糖溶液后在胃中原位胶凝。
基于交联的半乳甘露聚糖的筏形成系统
在某些实施例中,组合物包括至少一种基于交联的半乳甘露聚糖的筏形成系统。此系统通常包括:(i)至少一种半乳甘露聚糖多糖,其占可以从以下非限制性列表选择的筏形成系统的量为约30%w/w至约80%w/w、或约30%w/w至约60%w/w、或约35%w/w至约55%w/w:瓜尔豆胶、葫芦巴胶、刺槐豆胶;(ii)至少一种交联剂,其占可以从以下非限制性列表选择的筏形成系统的量为约5%w/w至约20%w/w、或约5%w/w至约15%w/w、或约10%w/w:硼砂、戊二醛、二价金属盐、三价金属盐;(iii)任选地至少一种气体发生剂,其量为约2%w/w至约20%w/w、或约2%w/w至约15%w/w、或约2%w/w至约10%w/w、或约5%w/w至约20%w/w、或约10%w/w至约20%w/w;(iv)任选地,可以加入pH改性剂以促进半乳甘露聚糖交联。在某些实施例中,基于交联的半乳甘露聚糖的筏形成系统包括瓜耳胶(约50%w/w、30%w/w至80%w/w)、硼砂(约10%、6%w/w至16%w/w)、磷酸氢钙脱水(约5%、2%w/w至20%w/w)。在某些实施例中,基于交联的半乳甘露聚糖的筏形成系统包括胡芦巴胶(约50%、30%w/w至80%w/w)、硼砂(约10%、6%w/w至16%w/w)、葡甲胺(约5%、2%w/w至20%w/w)。
半乳甘露聚糖是由具有半乳糖侧基的甘露糖主链组成的多糖(更具体地说,是(1-4)-连β-D-甘露吡喃糖主链,其分支点的6位与α-D-半乳糖相连,即1-6连α-D-吡喃半乳糖)。按增加的甘露糖与半乳糖之比的顺序,合适的半乳甘露聚糖的实例包括:胡芦巴胶、甘露糖:半乳糖~1:1;瓜耳胶、甘露糖:半乳糖~2:1;塔拉胶、甘露糖:半乳糖~3:1;刺槐豆胶或角豆胶、甘露糖:半乳糖~4:1。这些不是对半乳甘露聚糖的限制,其是有用的,并且可以从多种来源获得,包括下文标识的来源。
豆科物种的半乳甘露聚糖
表2:非豆科植物的半乳甘露聚糖
与半乳甘露聚糖一起使用的合适的交联剂可以选自以下非限制性列表:硼砂、戊二醛、硼酸、有机钛酸酯、其他有机金属交联剂,包括Zr、Al、Cr或其组合。
基于液晶的筏形成系统。
在某些实施例中,组合物包括至少一种基于液晶的筏形成系统。这种系统通常包括:(i)至少一种液晶形成物质,其占筏形成系统的量为约30%w/w至约80%w/w、或约35%w/w至约70%w/w、或约40%w/w到约60%w/w或约50%w/w、(ii)至少一种气体发生剂,其量为约10%w/w至约25%w/w、或约15%%w/w至约25%w/w、或约10%w/w至约20%w/w、或约15%w/w)和iii)任选地稀释剂。液晶形成物质的实例包括甘油单油酸酯(GMO,2,3-二羟丙基油酸酯)。其他合适的液晶形成物质可以包括例如植物三醇(PT 3,7,11,15-四甲基-1,2,3-十六烷三醇)和其他脂质,诸如单亚麻酸、单亚麻油、磷脂酰乙醇胺、油酰基乙醇酰胺、磷脂、聚乙二醇化的磷脂、D-α-聚乙二醇、甘油酸烷基酯和糖脂;甘油甘油酯(OG,2,3-二羟基丙酸十八烷基-9-烯基酯)和植酸甘油酯(PG,2,3-二羟基丙酸3,7,11,15-四甲基-十六烷基酯)。在某些实施例中,基于液晶的筏形成系统包括D-α-聚乙二醇(TPGS)(占筏形成系统的约50%w/w、30%w/w至约80%w/w)、碳酸氢钠(约15%、10%w/w至25%w/w)。在某些实施例中,基于液晶的筏形成系统包括GMO(约50%w/w、30%w/w至80%w/w)、碳酸氢钠(约15%w/w、10%w/w至25%w/w)、微晶纤维素(MCC)(约15%、10%w/w至约25%w/w)。
在某些实施例中,本发明的组合物可以包括多于一种筏形成系统。
生物活性/有用部分
本文提供的组合物可用于递送至少一种生物活性部分。不管它们以何种形式掺入组合物中,选择以包括于组合物中的选定生物学上有用的部分或它们的颗粒、颗粒剂、络合物等的平均尺寸小于约500微米,优选地小于约425微米。然而,可以根据递送的总重量(剂量)和/或通过调整气体发生剂的量来选择具有较大尺寸的部分(颗粒、颗粒剂、络合物等)。
可以选择多种药物用于本发明的组合物中。特别合适的药物包括在GI道上部表现出部位特定吸收,并在GI道和肝脏中表现出饱和代谢的药物、在GI道上部表现出部位特定吸收且消除半衰期非常短(<3小时)的药物,和/或在GI道上部表现出部位特定吸收并且用于跟随生物节律治疗疾病的药物。
可能受益于脉冲释放的病症或失调的实例包括但不限于变应性鼻炎、抗炎性失调(例如类风湿性关节炎和相关疼痛性关节失调)、哮喘治疗、化学疗法(抗肿瘤剂)、心血管疗法和/或溃疡治疗。
适合于胃内滞留脉冲释放(GRPR)粉末、POS和悬浮液的药物的实例包括选自以下各项的至少一种药物:右美沙芬、安非他命、盐酸吗啡、盐酸曲马多、巴氯芬、格隆溴铵、普瑞巴林、盐酸去氧肾上腺素、盐酸维拉沙嗪、盐酸马新多、孟鲁司特钠、盐酸雷卡地平、氧氟沙星、左氧氟沙星、瑞巴派特、醋丁洛尔、盐酸乙酰胺、醋氯芬酸、马来酸苯乙那嗪、乙砜钠、盐酸阿考达唑、盐酸阿达色林、盐酸沙丁胺醇、阿仑膦酸钠、阿仑膦酸、氢溴酸阿仑特莫、盐酸氯丙胺、盐酸阿芬太尼、盐酸阿洛司琼、盐酸阿普洛尔、盐酸吡罗诺辛、阿司他丁钠、酒石酸丹参、盐酸金刚烷胺、盐酸阿美达林、安非那克钠、阿氟沙星、氨磷汀、阿米卡星、盐酸阿米洛利、盐酸氨氯林、氨基苯甲酸钾、氨基苯甲酸钠、盐酸阿米普利糖、盐酸阿米喹、氨氯地平、氨巴比妥钠、氨二喹、盐酸氨二喹、阿莫西林、硫酸苯丙胺、两性霉素、两性霉素B、氨苄西林、安非昔康、硫酸氨苄嗪、盐酸阿扑吗啡、盐酸阿普拉卡定、盐酸阿普林定、无心钠、嘌呤酸、阿司匹林、阿朴西林、阿替洛尔、阿托伐他汀、阿扎那司他盐酸盐、富马酸阿扎洛沙、马来酸氮杂酸酯、硫唑嘌呤钠、阿奇霉素、阿佐洛林、氮丙啶、阿佐塞米、偶氮霉素、天青烯钠、盐酸巴卡西林、杆菌肽、巴氯芬、巴洛沙星、硫酸巴胺、盐酸苯氨茶碱、巴米地平、盐酸巴那普利、马来酸贝特拉平、盐酸贝那普嗪、盐酸贝那普利、贝那普利拉、甲磺酸苯达洛尔、贝尼地平、贝诺沙芬、盐酸苯甲酸酯、苄索氯铵、盐酸苄西米特、溴苯苄铵、盐酸苯并吡啶、盐酸苯甲他明、盐酸苯乙胺、盐酸贝普地尔、盐酸倍他洛尔、盐酸贝伐洛尔、苯扎贝特、盐酸比拉米可、盐酸比西发定、盐酸双氯地尔、盐酸比萘莫尔、盐酸联苯胺、比索洛尔、硫代硫酸钠、硫酸博来霉素、盐酸溴芬太尼、马来酸溴苯那敏、盐酸丁克利嗪、布地奈德、叔丁哌苯、丁双胍、盐酸布洛尔、盐酸布比卡因、盐酸丁丙诺啡、盐酸安非他酮、盐酸丁螺环酮、丁巴比妥、盐酸丁那莫尔、丁酸四钠、盐酸布洛嗪、布托啡诺、盐酸丁氧胺、盐酸布替替林、坎地沙坦、念珠菌素、卡托普利、卡巴斯匹林钙、羧苄青霉素钾、卡贝索龙钠、卡比多巴、卡比多巴-左旋多巴、马来酸卡宾沙明、盐酸卡比芬、盐酸卡布特罗、马来酸卡那嗪、卡洛芬、盐酸卡替洛尔、盐酸卡比星、卡鲁莫南钠、卡维地洛、盐酸卡伏曲林、头孢克洛、头孢羟氨苄、头孢曼多、头孢泊乐、头孢他嗪、头孢扎氟钠、头孢唑林、头孢哌酮、头孢卡培萘酯、戊酸头孢达肟酯、头孢地尼、头孢托仑酯、头孢吡肟、看守人、头孢替考、头孢克肟、头孢普列南、盐酸头孢诺肟、头孢噻唑、头孢氨苄、头孢地嗪、头孢尼西钠、头孢哌酮钠、头孢酰胺、头孢塞利、头孢噻肟钠、头孢替坦、头孢替安、头孢西丁、头孢唑仑、头孢吡唑、头孢吡胺、头孢匹罗、头孢泊肟酯、头孢普利、头孢罗定、头孢磺啶、头孢他啶、头孢特仑、头孢替丁、头孢唑肟钠、头孢曲松、头孢呋辛、头孢乙腈钠、头孢氨苄、脑白蛋白、西他本钠、头孢氯铵、盐酸西他洛尔、西替利嗪、噻吩酚、盐酸头孢曲酯、盐酸氯二酚、葡萄糖酸氯己定、盐酸氯普鲁卡因、马来酸氯苯那敏、盐酸西拉多巴、西司他丁钠、盐酸锡南色林、马来酸桂哌酯、环丙沙星、克拉维酸钾、马来酸克仑他唑、溴化溴化铵、克林沙星、盐酸氯米帕明、可乐定、盐酸氯哌酮、盐酸氯雷普林、西沙西林、可待因、盐酸考来替波尔、盐酸环吩嗪、环磷酰胺、环铂、盐酸达泊西汀、达格列酮钠、盐酸地昔帕明、右旋溴苯那敏、右氯苯那敏、盐酸右克莫尔、盐酸右芬氟拉明、右旋苯丙胺、右美沙芬、盐酸右啡烷、右旋甲状腺素钠、右维拉帕米、盐酸二醋洛尔、环乙氨磺酸双胺氧卡因、二酰胺、盐酸二苯西平、双氯芬酸钠、双氯西林、盐酸地氟沙星、盐酸双氟萘、盐酸地利伐洛尔、盐酸地尔硫卓、盐酸二甲芬、盐酸二噁胺、盐酸二噁唑醇、盐酸二甲双胍、双丙戊酸钠、马来酸地佐西平、盐酸度洛西汀、麻黄碱、肾上腺素、依普罗沙坦、氢溴雌醇、乙酸乙酯、乙炔酸、盐酸乙胺丁醇、依托度酸、非洛地平、非诺贝特、非诺洛芬、氟比洛芬、氟伐他汀、氟伐他汀钠、磷卡那钠、速尿、加本丁、甘草丁酸钠、格隆溴铵、氢溴酸阿托品、盐酸肼苯哒嗪、氢可酮酒石酸氢盐、盐酸氢吗啡酮、氢溴酸苯丙胺、盐酸羟嗪、布洛芬、盐酸丙咪嗪、盐酸吲哚普利、消炎痛钠、吲哚洛芬、烟酸、盐酸异丙肾上腺素、酮洛芬、酮咯酸、盐酸拉贝洛尔、拉莫三嗪、盐酸来酰亚胺、左氧氟沙星、酒石酸左啡烷、盐酸洛苏拉嗪、甲氯芬酸钠、盐酸盐酸美达西泮、甲芬那酸、盐酸甲氟喹、盐酸美金刚、盐酸哌替啶、二甲双胍、甲氧西林钠、甲氨蝶呤、盐酸哌醋甲酯、孟鲁司特钠、吗啡、硫酸吗啡、纳多洛尔、萘夫西林钠、盐酸萘丁胺、盐酸尼卡地平、硝苯地平、去甲肾上腺素酒石酸氢盐、氧氟沙星、盐酸普萘洛尔、盐酸奥昔布宁、羟考酮、盐酸羟吗啡酮、盐酸罂粟碱、盐酸优降宁、帕罗西汀、培美多拉克、青霉素G钾、青霉素G钠、青霉素V钾、盐酸吩甲嗪、盐酸苯氧苄明、盐酸芬特明、盐酸去氧肾上腺素、苯丙醇胺盐酸盐、哌拉西林钠、马来酸哌酰胺、匹伐他汀、盐酸哌唑嗪、普瑞巴林、盐酸异丙嗪、盐酸普罗帕酮、盐酸普萘洛尔、盐酸伪麻黄碱、地氯雷他定/硫酸伪麻黄碱、雷米普利、盐酸雷马西米、盐酸瑞芬太尼、罗匹尼罗、罗苏伐他汀、盐酸他西明、盐酸他克林、盐酸他尼西林、盐酸他普仑、盐酸坦美曲林、N去甲基他莫昔芬盐酸盐、富马酸坦帕明、盐酸坦洛新、盐酸丹胺、替米沙坦、盐酸替洛蒽醌、盐酸替鲁地平、盐酸替马沙星、盐酸噻帕米尔、盐酸噻乙酰胺、盐酸替哌啶酮、盐酸替萘洛尔、盐酸噻哌地尔、盐酸喹喹酰胺、盐酸曲马多、盐酸曲唑啉、盐酸曲唑酮、盐酸曲唑酮、盐酸三苯甲胺、盐酸曲芬太尼、盐酸三氟拉嗪、丙戊酸钠、丙戊酸、缬沙坦伐地那非、文拉法辛、盐酸维拉多林、盐酸维拉帕米、盐酸维洛拉平、盐酸维拉沙嗪、佐芬普利钙、盐酸佐拉明、盐酸唑拉西泮。其他合适药物对于本领域技术人员将是显而易见的。
可以在至少一种药物-离子交换树脂络合物中使用一种或多种药物。通常,这涉及用来自离子交换树脂的抗衡离子交换化合物(例如,药物或矿物质)的酸或碱盐。但是,某些药物的两性离子或非盐形式可能与离子交换树脂络合物形成络合物。此类络合物可能包含一种或多种药物。在某些实施例中,可以在单一组合物中使用具有不同药物的两种或更多种药物-离子交换树脂络合物。在某些实施例中,可以在单一组合物中使用呈不同释放形式(例如速释、调节释放)的两种或更多种药物-离子交换树脂络合物,包括不同的调节释放包衣。
将药物与离子交换树脂络合的方法是本领域已知的。例如,在通过引用并入本文的美国专利8,062,667、US 8287848、US 8,202,542中描述了用于制备此类络合物的合适方法和合适的离子交换树脂的实例。适于药物用途的离子交换树脂通常是水不溶性的,并且包括优选地具有药理学惰性的有机和/或无机基质,所述有机和/或无机基质包含离子性的或能够在适当的pH条件下被离子化以便准许和与之络合的药物(其他部分)进行离子交换的官能团。有机基质可以是合成的(例如,丙烯酸、甲基丙烯酸、磺化的苯乙烯、磺化的二乙烯基苯的聚合物或共聚物)或部分合成的(例如,改性的纤维素和右旋糖酐)。无机基质优选地包括通过加入离子基团而改性的硅胶。共价键合的离子基团可以是强酸性的(例如,磺酸、磷酸)、弱酸性的(例如,羧酸)、强碱性的(例如,伯胺)、弱碱性的(例如,季铵)或酸性与碱性基团的组合。通常,适合于离子交换色谱以及适合于诸如水去离子等应用的离子交换剂类型适用于控释药物制剂。此类离子交换剂由H.F.Walton于Chromatography(E.Heftmann,编辑),van Nostrand Reinhold公司,纽约(1975年)在《离子交换原理》(Principles of Ion Exchange)(第312至343页)和《离子交换色谱技术和应用》(Techniques and Applications of Ion-Exchange Chromatography)(第344至361页)中描述。可用于本发明的离子交换树脂的交换容量为约6毫当量(meq)/克,优选为地约5.5meq/克或更低。对于液体剂型,离子交换颗粒的尺寸通常为约5微米至约750微米,优选地颗粒尺寸介于约40微米至约250微米的范围内,尽管对于固体剂型,也可使用最大约1,000微米的颗粒,例如片剂、丸剂、粉末(包括悬浮用粉末)和胶囊剂。基本上低于下限的粒度通常在加工的所有步骤中都难以处理。通常,未包衣药物-离子交换树脂颗粒倾向于在此范围的较低端,而包衣药物-离子交换树脂颗粒倾向于在此范围的较高端。然而,未包衣和包衣药物离子交换树脂颗粒都可以设计在此尺寸范围内。
配方中最常用有机树脂是交联的聚苯乙烯和聚甲基丙烯酸酯聚合物。离子交换树脂大致分为两大类,即阳离子交换树脂和阴离子交换树脂。阳离子交换树脂包含与聚合物和活性阳离子相连的阴离子。阳离子交换树脂是通过苯乙烯与二乙烯基苯的共聚反应制备的,并且将磺酸基(-SO3H)引入大多数苯环中。之所以称其为强酸阳离子树脂,是因为它们的化学行为类似于强酸的化学行为。这些树脂以磺酸基团(-SO3H)的酸(R-SO3H)和盐(RSO3Na)两者的形式高度离子化。氢和钠形式的强酸树脂高度解离,且可交换的Na+和H+易于在整个pH范围内交换。因此,强酸树脂的交换能力与溶液pH无关。例如,聚苯乙烯磺酸钠USP(Amberlite IRP 69)。弱酸性阳离子交换树脂;这些树脂的行为类似于弱离解的弱有机酸。在弱酸树脂中,可电离基团是羧酸(COOH),与在强酸树脂中使用的磺酸基团(SO3H)相反。溶液pH强烈影响弱酸树脂的解离度。因此,树脂容量部分取决于溶液pH。典型的弱酸树脂在pH低于6.0时容量有限。
可以通过首先将苯乙烯-二乙烯基苯共聚物的苯环氯甲基化以连接CH2Cl基团,并接着使它们与诸如三乙胺等叔胺反应来制备阴离子交换树脂。强碱型阴离子交换树脂被高度离子化,且交换容量不受pH的影响。在某些实施例中,强碱性阴离子交换剂包含连接到苯乙烯和二乙烯基苯共聚物的季铵基团。强碱阴离子交换树脂的一个实例是消胆胺。DuoliteAP143/1083是由陶氏化学公司(Dow Chemical Company)提供的消胆胺USP。弱碱性阴离子交换树脂在pH高于7时表现出最小的类型交换容量。弱碱性阴离子交换剂的一个实例包含与苯乙烯和二乙烯基苯连接的聚烷基胺基。
无机离子交换剂包括沸石,其是微孔铝硅酸盐矿物。沸石具有多孔结构,其可以容纳各种阳离子,诸如Na+、K+、Ca2+、Mg2+等。这些阳离子保持较松散,并且可以易于在接触溶液中交换。一些更常见的矿物沸石是方沸石、菱沸石、斜发沸石、片沸石、钠沸石、钙十字沸石和辉沸石。沸石的矿物配方的一个实例是:Na2Al2Si3O10·2H2O,钠沸石的配方。
选定离子交换树脂可以由制造商或购买者进一步处理,以使药物使用的安全性或组合物的性能最大化。树脂中存在的杂质可通过在络合之前或络合期间或之后的任何制备阶段掺入普通螯合剂、抗氧化剂、乙二胺四乙酸二钠、诸如亚硫酸氢钠等防腐剂来消除或中和。在用制粒剂和任选的调节释放包衣进一步处理离子交换树脂之前,可以去除这些杂质以及与它们结合的螯合剂。
选定药物或药物组合与离子交换树脂的结合可以使用本领域已知的方法来完成。如本领域中已知,可以例如以分批或柱工艺进行结合。通常,通过过滤收集由此形成的药物-离子交换树脂络合物,并且用适当的溶剂洗涤以去除任何未结合的药物或副产物。络合物可以在流化床干燥器或其他合适干燥器中的托盘中在室温或升高的温度下风干。
在一个实例中,可以通过将药物溶解在去离子水中,在搅拌下加入离子交换树脂USP并继续搅拌来制备药物-离子交换树脂络合物。再继续搅拌15分钟至20小时,更优选地30分钟至10小时,更优选地1小时至5小时。在一个实施例中,可以使用本领域已知的方法来制备药物-离子交换树脂络合物,诸如但不限于共混、制浆、捏合、研磨、筛分、填充、压缩、冻干、喷雾干燥、流体床干燥或离心制粒。如本领域中已知,可以例如以分批或柱工艺进行药物-树脂结合。在一个说明性实施例中,药物-离子交换树脂络合物通过分批工艺制备。在一个实施例中,通过将药物和离子交换树脂的水性浆料搅拌约0.5小时至约12小时,随后过滤并干燥形成的药物-离子交换树脂络合物,来制备药物-树脂络合物。络合物(也称为树脂酸盐)中的药物:离子交换树脂的重量比可以为1:0.1至1:100,更优选地为1:1至1:10。可以负载到树脂上的药物的量通常为药物-离子交换树脂颗粒的重量的按重量计约1%至约75%。在一个实施例中,可以采用药物-离子交换树脂颗粒的按重量计约10%至约40%,更期望地按重量计约15%至约30%的负载量。可以有利地采用药物-离子交换树脂颗粒的按重量计约25%的典型负载量。
任选地,可以将药物-离子交换树脂络合物与聚合物制粒,以制备制剂和/或进一步加工(例如,包衣)。这种聚合物可以任选地为络合物中的药物提供调节释放特性。合适地,制粒剂不在药物-离子交换树脂络合物上形成单独的包衣层,而是与其形成基质。合适的聚合物体系的实例包括例如聚乙酸乙烯酯聚合物或包含聚乙酸乙烯酯的聚合物的混合物(例如,SR 30D)、乙酸纤维素、乙基纤维素聚合物(例如,AQUACOATTMECD-30或SURELEASETM)、基于丙烯酸的聚合物或共聚物(例如,以丙烯酸树脂的EUDRAGIT系列为代表)、邻苯二甲酸纤维素或此类水不溶性的聚合物或聚合物体系的任一组合。一种可以提供释放延缓特性的合适聚合物体系是本文所述的聚乙酸乙烯酯聚合物或EUDRAGIT系列的丙烯酸聚合物。EUDRAGIT系列的合适的丙烯酸聚合物的实例可以包括例如包括丙烯酸乙酯和甲基丙烯酸甲酯的共聚物(例如,EUDRAGIT NE-30D)或EUDRAGIT RS、RL30D、RL100或NE,它们是很大程度上pH非依赖性聚合物;尽管不太理想,但是可以选择EUDRAGIT聚合物系列的某些pH依赖性成员,例如L、S和E聚合物。不提供任何显著的延迟延缓特性的聚合物和/或聚合物体系的实例包括例如在美国专利号4,221,778和公开的美国专利申请公开号US2003/009971A1中描述的浸渍剂,所述美国专利和所述公开的美国专利申请公开的公开内容通过引用并入本文。合适的浸渍剂的具体实例包括丙二醇、聚乙二醇、聚乙烯醇、聚乙烯吡咯烷酮(例如,K30)甘露醇、甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素和山梨糖醇。制粒剂的量通常为未包衣药物-离子交换树脂颗粒的按重量计约3%至约30%或更多。更优选地制粒剂(如果使用的话)为未包衣药物-离子交换树脂颗粒的按重量计约5%至约20%,且最优选地约10%至约15%。这些制粒剂可以在药物-离子交换树脂络合物的形成期间在已发生大量络合物形成的初期、中期或之后加入。在更优选的实施例中,在形成药物-离子交换树脂络合物之后加入阻滞剂。在将药物-离子交换树脂络合物颗粒与制粒剂混合后,将混合物干燥并适当研磨。在一些情况下,可以在将络合物完全干燥之前进行研磨,接着再次进行进一步的干燥,随后进行研磨以获得所需的大小或其他所需的特性。
药学上可接受的赋形剂
本发明的组合物可以是例如粉末、粉末悬浮液(POS)、胶囊粉末或悬浮液。相应地选择组合物的赋形剂。悬浮液和/或ER POS中的赋形剂可以包括悬浮剂和/或增稠剂、润湿剂和/或防腐剂。赋形剂将在后续部分中进行讨论。
本文提供的定时、脉冲释放组合物通常以悬浮液的形式从与悬浮液基质优选地水性悬浮液基质混合的粉末给予。如本文所用,水性悬浮液是指其中悬浮液的液体组分的至少约50%v/v、优选大于约60%w/v、大于约80%w/w、至少约90%至多100%为水的悬浮液。悬浮基还可以包含包括粘合剂、稀释剂、流涎剂、表面活性剂、调味剂、甜味剂、着色剂、酸味剂、增粘剂、助流剂、螯合剂、润滑剂、增溶剂、稳定剂、助悬剂、防腐剂、共溶剂、防结块剂、缓冲剂等,或其任何组合。合适的粘合剂的实例包括但不限于淀粉、预胶凝淀粉、聚乙烯吡咯烷酮、共聚维酮、纤维素衍生物,诸如羟丙基甲基纤维素、羟丙基纤维素和羧甲基纤维素及其盐。合适的稀释剂的实例包括但不限于淀粉、微晶纤维素、乳糖、木糖醇、甘露醇、麦芽糖、多元醇、果糖、瓜耳胶、山梨糖醇、氢氧化镁、磷酸二钙、共加工的甘露醇和硅酸钙等,或其任何组合。润滑剂的实例包括但不限于硬脂酸镁、硬脂酸钙、硬脂酸、滑石粉和硬脂富马酸钠。合适的助流剂包括但不限于胶体二氧化硅、硅胶、沉淀二氧化硅,或其组合。合适的流涎剂包括但不限于微粉化的聚乙二醇、氯化钠或沉淀的微粉化的二氧化硅。增溶剂的实例包括但不限于鲸蜡硬脂醇、胆固醇、二乙醇胺、油酸乙酯、乙二醇棕榈硬脂酸酯、甘油、单硬脂酸甘油酯、肉豆蔻酸异丙酯、卵磷脂、中链甘油酯、单乙醇胺、油酸、丙二醇、聚氧乙烯烷基醚、聚氧乙烯蓖麻油糖苷、聚氧乙烯脱水山梨糖醇脂肪酸酯、聚乙烯脱水山梨糖醇脂肪酸酯、聚氧乙烯硬脂酸酯、褐藻酸丙二醇酯、脱水山梨糖醇脂肪酸酯、硬脂酸、葵花籽油、三乙醇胺,或其组合。酸味剂包括但不限于富马酸钠和/或柠檬酸。本发明的组合物还可以包括稳定剂,诸如但不限于上文在药物-树脂络合物下描述的稳定剂。上文已经讨论了可以采用的合适的螯合剂。合适的增粘剂包括但不限于共加工的微晶纤维素,诸如但不限于AvicelRC591、Avicel CL-611、D-山梨醇溶液;聚环氧烷,诸如但不限于聚环氧乙烷;纤维素醚,诸如但不限于羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、微晶纤维素;胶,诸如但不限于阿拉伯胶藻酸盐、琼脂、藻酸钠瓜耳胶、刺槐豆、角叉菜胶、塔拉、阿拉伯胶、黄蓍胶、果胶、黄原胶、结冷胶、麦芽糖糊精、半乳甘露聚糖、石脐素、昆布多糖、小核菌葡聚糖、阿拉伯胶、菊粉、梧桐胶、崴兰(whelan);多元醇,例如但不限于二丙二醇、聚丙二醇、丙二醇、聚乙二醇(PEG)、山梨糖醇和甘油;卡波姆、淀粉和淀粉基聚合物,诸如但不限于预胶凝淀粉、丙烯酸和甲基丙烯酸聚合物及其酯、马来酸酐聚合物;聚马来酸;聚(丙烯酰胺);聚(烯烃醇);聚(N-乙烯基内酰胺);聚氧乙烯化糖;聚噁唑啉;聚乙烯胺;聚乙酸乙烯酯;多亚胺;聚乙烯吡咯烷酮、乙烯基吡咯烷酮/乙酸乙烯酯共聚物和聚乙酸乙烯酯、聚乙酸乙烯酯和聚乙烯吡咯烷酮的混合物、甲壳质、环糊精、明胶、壳聚糖等,或其任何混合物。合适的表面活性剂包括但不限于阴离子、非离子、阳离子和两性离子表面活性剂或其混合物。组合物中采用的非离子表面活性剂可以包括但不限于乙氧基化脂肪酸酯、乙氧基化脂肪酸醚、乙氧基化脱水山梨糖醇醚、乙氧基化烷基酚、甘油酯、甘油糖酯、聚氧乙烯甘油单月桂酸酯、聚氧乙烯甘油单硬脂酸酯、聚氧乙烯-20-鲸蜡醇硬脂酸酯、聚氧乙烯-25-鲸蜡醇硬脂酸酯、聚氧乙烯(25)-单硬脂酸氧丙烯、聚氧乙烯-20-脱水山梨糖醇单棕榈酸酯、聚氧乙烯-16-叔辛基苯酚、聚氧乙烯-20-鲸蜡基醚、聚乙二醇(1000)单鲸蜡基醚、乙氧基化蓖麻油、聚氧乙烯山梨醇-羊毛脂衍生物、聚氧乙烯(25)丙二醇硬脂酸酯、聚氧乙烯山梨醇酯、聚氧乙烯-20-山梨糖醇单棕榈酸酯、聚氧乙烯-16-叔辛基苯酚、聚氧乙烯-20-鲸蜡基醚、十一碳烯酸甘油酯和聚山梨酯60、capmul(中链甘油酯)、peceol(甘油单油酸酯)、月桂酸甘油酯和甘油基辛酸酯(Capmul MCM)、PEG脱水山梨糖醇脂肪酸酯,如PEG-20脱水山梨糖醇单月桂酸酯(Tween 20)、PEG-20脱水山梨糖醇单硬脂酸酯(Tween 60)、PEG-20脱水山梨糖醇单油酸酯(Tween 80),脱水山梨糖醇脂肪酸酯,如脱水山梨醇单月桂酸酯(Span 20)、硬脂酸甘油酯(Cithrol GMS)等,及其混合物。合适的阳离子表面活性剂包括但不限于季铵化合物、烷基酰胺基胺和季酯化合物、二硬脂基二甲基氯化铵、二肉豆蔻基二甲基氯化铵、二软脂基二甲基氯化铵等及其混合物。合适的阴离子表面活性剂包括但不限于脂肪醇硫酸盐、α-烯烃磺酸盐、磺基琥珀酸盐、磷酸酯、羧酸盐、肌氨酸盐、烷基苯磺酸盐、烷基磺酸盐、烯烃磺酸盐、烷基醚磺酸盐、甘油醚磺酸盐、a-甲基酯磺酸盐、磺酸脂肪酸、烷基硫酸盐、脂肪醇醚硫酸盐、甘油醚硫酸盐、混合羟基醚硫酸盐、单酸甘油酯(醚)硫酸盐、脂肪酸酰胺(醚)硫酸盐、磺基琥珀酸酯、磺基琥珀酸酯、磺基甘油三酸酯、酰胺皂、醚羧酸、羟乙磺酸盐、肌氨酸盐、牛磺酸、烷基寡糖苷硫酸盐、烷基(醚)磷酸盐等,及其混合物。所采用的合适的两性离子表面活性剂包括但不限于N-烷基-N,N-二甲基甘氨酸铵,例如椰油烷基二甲基甘氨酸铵,N-酰基氨基丙基-N,N-二甲基甘氨酸铵、椰油酰基氨乙基羟乙基羧甲基甘氨酸铵等,及其混合物。另外,本发明的组合物还可以包括防腐剂,诸如但不限于对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和苯甲酸钠。可以使用的合适的共溶剂,包括但不限于乙醇和多元醇,诸如但不限于甘油、丙二醇、低分子量聚乙二醇,及其混合物。可以任选地并入的其他防结块剂包括但不限于胶体二氧化硅、磷酸三钙、粉末状纤维素、三硅酸镁、淀粉,及其混合物。合适的甜味剂包括但不限于阿斯巴甜、甜菊提取物、甘草、糖精、糖精钠、乙酰磺胺酸、三氯蔗糖、甘草酸二钾、半乳糖、果糖、高果糖玉米糖浆、右旋糖、蔗糖、糖、麦芽糖、部分水解的淀粉、玉米糖浆固体、山梨糖醇、木糖醇、甘露醇等,或其混合物。组合物可以包括一种或多种天然和/或人工调味剂,诸如但不限于薄荷调味剂、橙子调味剂、柠檬调味剂、草莓香料、香草调味剂、覆盆子香料、樱桃调味剂、什锦水果调味剂、magnasweet 135、酸橙调味剂、葡萄调味剂、trusil art 511815和水果提取物等。合适的着色剂包括但不限于颜料和染料,诸如FD&C红、FD&C黄、FD&C绿和FD&C蓝等,或其组合。
一种组合物,所述组合物形成具有至少两个触发脉冲的胃内滞留筏,所述组合物包括:(a)至少一种具有立即释放脉冲释放形式的生物活性部分;(b)至少一种具有延迟触发释放形式的生物活性部分;以及(c)筏系统,其中在口服摄取后,所述组合物提供自组装的胃内滞留筏,所述自组装的胃内滞留筏中包埋(a)和(b)中的至少一种生物活性部分以及由无毒气体发生剂原位产生的气体,由此提供漂浮的胃内滞留筏,所述漂浮的胃内滞留筏具有双脉冲系统,所述双脉冲系统中至少第二脉冲是触发脉冲,并且所述漂浮的胃内滞留筏将至少一种生物活性部分保持在胃中至少约3小时,前提是所述组合物不包括γ-羟基丁酸酯和其盐、水合物、互变异构体或溶剂化物,或它们的络合物。
在某些实施例中,组合物包括pH S形延迟触发系统,所述pH S形延迟触发系统包括颗粒,所述颗粒包括:(a)至少一种药物或药物-离子交换树脂络合物;用反向肠溶包衣进行包衣的有机酸;任选的气体发生剂;任选的膨胀剂;以及(b)在(a)的颗粒上的甲基丙烯酸铵共聚物A型(例如,Eudragit RL)和甲基丙烯酸铵共聚物B型(例如,Eudragit RS)或两种包衣,其中所述包衣在(a)的有机酸存在的情况下溶解,由此在酸存在的情况下摄取后,形成包括(a)的药物的pH S形延迟触发的筏。在某些实施例中,这种脉冲触发系统包括至少一种具有药物-离子交换树脂络合物形式的生物活性部分(这种脉冲触发系统的约60%w/w、10%w/w至80%w/w),以及:(i)反向肠溶包衣的有机酸;(约8%,3至25%w/w)(ii)任选的气体发生剂(约5%,0至10%w/w);(iii)任选地,膨胀剂(约5%,0至30%w/w);(iv)至少一种pH非依赖性的、水不溶性的、水可渗透的扩散阻挡包衣聚合物(例如,甲基丙烯酸铵共聚物B型),约20%,10至60%w/w),基于触发系统的重量。
在某些实施例中,这种脉冲触发系统包括至少一种生物活性部分(约触发系统的10%,5%w/w至40%w/w),以及(i)反向肠溶包衣的有机酸;(约3%w/w,1%w/w至10%w/w),(ii)任选的气体发生剂(约2%,0至6%w/w),(iii)任选地膨胀剂(约10%,5%w/w至25%w/w),(iv)触发系统的至少一种pH非依赖性的、水不溶性的、水可渗透的扩散阻挡包衣聚合物(例如,甲基丙烯酸铵共聚物B型),约10%,4%w/w至40%w/w。
在某些实施例中,所述组合物包括腐蚀延迟触发系统,所述腐蚀延迟触发系统包括:至少一种腐蚀阻挡形成聚合物;任选的气体发生剂;至少一种药物或药物-离子交换树脂络合物;以及任选的膨胀剂,由此在胃酸存在的情况下,形成包括药物的腐蚀延迟触发系统的筏。在某些实施例中,所述腐蚀触发系统包括:(i)至少一种生物活性部分(例如,API、药物-离子交换树脂络合物,或其混合物);(约60%,5%w/-80%w/w),(ii)选自非限制性列表的至少一种腐蚀阻挡形成聚合物:HPMC、HEC、其他纤维素醚、瓜耳胶;(约15%,5%w/w至20%w/w),(iii)任选的气体发生剂(约7%w/s,0至15%w/w);(iv)任选地,触发系统的膨胀剂(约15%w/w,0至75%w/w)。合适地,活性部分和赋形剂用易蚀的阻挡层包衣。
在某些实施例中,组合物具有pH溶胀延迟触发系统,所述pH溶胀延迟触发系统包括:(i)颗粒剂,所述颗粒剂包括至少一种药物或药物-离子交换树脂络合物;至少一种pH改性剂;至少一种溶胀剂;任选地,用至少一种肠溶聚合物包衣的气体发生剂;(ii)(i)的颗粒剂上的反向肠溶包衣,由此在胃酸存在的情况下,形成包括(i)的药物的pH溶胀延迟触发系统的筏。在某些实施例中,本发明的组合物包括至少包含以下的颗粒剂:(i)至少一种生物活性部分(例如,药物、药物-离子交换树脂络合物,或其混合物),(约40%w/w,10%w/w至-75%w/w),(ii)至少一种pH改性剂(约20%w/w,5%w/w至50%w/w);(iii)任选地,触发系统的溶胀剂(约10%w/w,5%w/w至25%w/w)。颗粒剂用至少一种肠溶聚合物包衣,并且包衣颗粒剂进一步用反向肠溶聚合物包衣。
在某些实施例中,组合物具有溶胀延迟触发系统,所述溶胀延迟触发系统包括:(i)颗粒剂,所述颗粒剂包括至少一种药物或药物-离子交换络合物、至少一种胶凝剂、至少一种溶胀增强剂、在胃酸存在的情况下产生气体的任选的气体发生剂、任选地膨胀剂,以及(ii)至少一种在(i)的颗粒剂上的水可渗透的扩散阻挡包衣,由此在胃酸存在的情况下,形成包括(i)的药物的溶胀延迟触发系统的筏。在某些实施例中,本发明的组合物包括至少包含以下的颗粒剂:(i)至少一种生物活性部分(药物-离子交换树脂络合物,触发剂的约20%w/w,10%w/w至50%w/w),(ii)至少一种胶凝剂HPMCK4M,(约6%w/w,3%w/w至15%w/w);(iii)至少一种溶胀增强剂(约20%,10%w/w至50%w/w),(iv)膨胀剂,MCC(约20%w/w,10%w/w至50%w/w)。颗粒剂用触发系统的至少一种扩散阻挡PVA(约15%,10%w/w至40%w/w)包衣。
在某些实施例中,组合物具有渗透延迟触发系统,所述渗透延迟触发系统包括:(i)颗粒剂,所述颗粒剂包括至少一种药物-离子交换树脂络合物;至少一种胶凝剂;至少一种渗透剂;在胃酸存在的情况下产生气体的任选的气体发生剂;任选的膨胀剂;以及(ii)至少一种在(in)的所述颗粒剂上的水可渗透的扩散阻挡包衣,由此在胃酸存在的情况下,形成包括(i)的所述药物的所述渗透延迟触发系统的筏。在某些实施例中,本发明的组合物包括至少包含以下的颗粒剂:(i)至少一种生物活性部分(药物-离子交换树脂络合物,触发剂的约20%w/w,10%w/w至50%w/w),(ii)至少一种胶凝剂HPMCK4M,(约8%w/w,3%w/w至15%w/w);(iii)至少一种渗透剂(约20%,10%w/w至50%w/w),(iv)触发系统中的膨胀剂,MCC(约20%w/w,10%w/w至50%w/w)。颗粒剂用至少一种扩散阻挡PVA(约15%w/w,10%w/w至40%w/w)包衣。
在某些实施例中,组合物具有两种或更多种不同的延迟触发脉冲释放。
在某些实施例中,组合物包括两种或更多种不同的药物。
在某些实施例中,筏包括两种或更多种不同的药物。
在某些实施例中,筏包括具有多于两种不同释放形式的相同药物。
在某些实施例中,如例如使用实例中描述并通过引用并入本文的测定方法在体外测量,形成的筏最初的宽度为至少约15mm。
在某些实施例中,组合物包括两种或更多种不同的筏系统。
在某些实施例中,筏形成系统包括至少一种可交联的多糖、至少一种交联剂和至少一种气体发生剂,所述气体发生剂与胃酸反应以形成气体。在某些实施例中,可交联的多糖是选自的瓜尔豆胶、胡芦巴胶或刺槐豆胶的半乳甘露聚糖,且所述至少一种交联剂选自硼砂、戊二醛和/或锆。在某些实施例中,筏包括胶凝剂,其中胶凝剂在室温下是液体,且在体温下胶凝,并且选自木葡聚糖或泊洛沙姆。在某些实施例中,筏包括立方相形成脂质。
用途
合适地,本发明的组合物包含具有释放触发脉冲的GR筏形成系统,所述GR筏形成系统在酸(例如,胃酸(stomach acid)或胃酸(gastric acid))存在的情况下在体内形成。在某些实施例中,组合物为受试者提供定时的一种或多种药物的脉冲释放,其中第一脉冲小于约3小时,第二脉冲是触发脉冲,以及任选地或更多的其他脉冲。
不希望受理论的束缚,据信与酸反应后,组合物中的气体发生剂(和/或泡腾剂对)形成无毒气体,所述气体使得包含生物活性部分的GR筏保留在胃中至少2小时,优选地约3小时至4小时。据信此滞留时间是由GR筏超过幽门瓣的大小至少两个小时引起的。因此,据信在此时间长度内,组合物形成宽度至少约15mm,或更通常至少约20mm的GR筏。
本发明的组合物非常适合用于治疗患有各种病状、病症和/或疾病的受试者。在某些实施例中,组合物提供增加的胃递送和/或组合物中活性部分的增加的生物利用度。本发明的组合物非常适合用于治疗患有多种病状、病症和/或疾病,变应性鼻炎、类风湿性关节炎和相关病症、哮喘、癌症、心血管疾病、炎性疾病和溃疡中的一种或多种的受试者。在某些实施例中,组合物为受试者提供GR筏中的一种或多种药物的调节释放,所述调节释放曲线为至少2小时,更优选地为至少3小时至4小时。
词语“包括(comprise)”、“包括(comprises)”和“包括(comprising)”以及“包含(contain)”、“包含(containing)”和“包含(contains)”应被包括性地而非排他性地解释。词语“consist(组成)”、“consisting(组成)”和其变型应被排他性地而非包括性地解释。
如本文参考本文所提供的数值所使用的,术语“约”可以指示高达10%的可变性。
实例
虽然已经参考示例性实施例描述了本发明,但是本领域技术人员将理解,在不脱离本发明的范围的情况下,可以进行各种改变并且可以用等同物代替其元件。在以下非限制性示例性说明中提供了本发明的细节,包括其目的和优点。
实例1.溶胀作为触发
表1:悬浮液(POS)的格隆溴铵GRPR悬浮液的组成
I.药物-离子交换树脂络合物的制备
将称重量的格隆溴铵HBr溶解在1000ml水中。在搅拌下将称重量的树脂加入到药物溶液中,并继续搅拌4小时。通过过滤分离药物-树脂络合物,并在60℃下干燥。使药物-树脂络合物通过#60号筛网。
II.PR载体组合物的制备
将称重量的第二脉冲的药物-离子交换树脂络合物与称重量的MCC、HPMCK4M、交联聚维酮、碳酸钙混合15分钟,并使用10%w/v的PVP K30溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。在搅拌下将三醋精加入纯净水中,并继续搅拌以得到澄清溶液。在搅拌下将三醋精溶液逐渐加入到SR30D分散体中,并继续搅拌1小时。通过#40号筛来筛分包衣分散体。干燥的颗粒剂使用制备的分散体包衣,并在整个包衣过程中继续搅拌。在流化床包衣机中进行包衣,并将包衣络合物在60℃下干燥。使包衣络合物通过#40号筛网。
III.GR载体组合物的制备
将称重量的第一脉冲的药物-离子交换树脂络合物与称重量的iota卡拉胶、kappa卡拉胶、柠檬酸钾、碳酸钙混合15分钟,并使用10%w/v的共聚维酮溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。
IV.将步骤II的颗粒剂和步骤III的颗粒剂与称重并过筛(#40)量的HPMC K100LV、香蕉调味剂、滑石粉、苯甲酸钠、甘露醇和三氯蔗糖混合15分钟。对于4.8mg格隆溴铵HBr相当剂量,在给药时应使用2gm纯净水重构160mg的POS。
体外测试
I.漂浮的发生和持续时间
将相当于4.8mg格隆溴铵HBr剂量的悬浮液加入500ml不含酶的SGF中。筏漂浮所需的时间和漂浮的持续时间预计为:
漂浮的发生(分钟) | ≤20 |
漂浮的持续时间(小时) | 12 |
II.筏的弹性
将相当于4.8mg格隆溴铵HBr剂量的悬浮液加入500ml不含酶的SGF,0.1N HCl溶液。接着使用设置在37℃和75rpm的机械振荡器进行搅拌。预计的观察结果:筏在12小时的时间段内保持完整性
III.体外释放研究
使用设置在50rpm和37℃的II型USP设备并将500ml不含酶的SGF用作介质来执行溶出研究。预计的释放在图2中予以说明。
实例2.溶胀加渗透作为触发
表2:异丙嗪GRPR POS的组成
I.药物-离子交换树脂络合物的制备
将称重量的异丙嗪HCl溶解在1000ml水中。在搅拌下将称重量的树脂加入到药物溶液中,并继续搅拌4小时。通过过滤分离药物-树脂络合物,并在60℃下干燥。使药物-树脂络合物通过#60号筛网。
II.PR载体组合物的制备
将称重量的第二脉冲的药物-离子交换树脂络合物与称重量的MCC、HPMCK4M、甘露醇、碳酸钙混合15分钟,并使用10%w/v的PVP K30溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。在搅拌下将三醋精加入纯净水中,并继续搅拌以得到澄清溶液。在搅拌下将三醋精溶液逐渐加入到SR30D分散体中,并继续搅拌1小时。通过#40号筛来筛分包衣分散体。干燥的颗粒剂使用制备的分散体包衣,并在整个包衣过程中继续搅拌。在流化床包衣机中进行包衣,并将包衣络合物在60℃下干燥。使包衣络合物通过#40号筛网。
III.GR载体组合物的制备
将称重量的第一脉冲的药物-离子交换树脂络合物与称重量的iota卡拉胶、kappa卡拉胶、柠檬酸钾、碳酸钙混合15分钟,并使用10%w/v的共聚维酮溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。
IV.将步骤II的颗粒剂和步骤III的颗粒剂与称重并过筛(#40)量的HPMC K100LV、香蕉调味剂、滑石粉、苯甲酸钠、甘露醇和三氯蔗糖混合15分钟。对于25mg异丙嗪HCl相当剂量,在给药时应使用2gm纯净水重构318mg的POS。
体外测试
I.漂浮的发生和持续时间
将相当于25mg异丙嗪HCl的重构悬浮液加入500ml不含酶的SGF中。预计筏漂浮所需的时间和漂浮的持续时间。
漂浮的发生(分钟) | ≤20 |
漂浮的持续时间(小时) | 12 |
II.筏的弹性
将相当于25mg异丙嗪HCl剂量的重构悬浮液加入500ml不含酶的SGF,0.1N HCl溶液。接着使用设置在37℃和75rpm的机械振荡器进行搅拌。预计的观察结果:筏在12小时的时间段内保持完整性。
III.体外释放研究
使用设置在50rpm和37℃的II型USP设备并将500ml不含酶的SGF用作介质,使用相当于25mg异丙嗪HCl剂量的重构悬浮液来执行溶出研究。预计的溶出曲线在图3中提供。
实施例3.pH作为触发,用于产生第二脉冲的S形释放系统
表3:GRPR POS的组成
I.药物-离子交换树脂络合物的制备
将称重量的普萘洛尔HCl溶解在1000ml水中。在搅拌下将称重量的树脂加入到药物溶液中,并继续搅拌4小时。通过过滤分离药物-树脂络合物,并在60℃下干燥。使药物-树脂络合物通过#60号筛网。
II.PR载体组合物的制备
混合称重量的富马酸和20gm MCC,并使用包含2gm共聚维酮的水溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。颗粒剂使用用三醋精增塑的Eudragit EPO包衣。使包衣颗粒剂通过#40号筛网。将这些颗粒剂与称重量的第二脉冲的药物-离子交换树脂络合物和碳酸钙混合15分钟,并使用10%w/v的共聚维酮溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。颗粒剂使用用三醋精增塑的Eudragit RS包衣。在流化床包衣机中进行包衣,并将包衣络合物在60℃下干燥。使包衣颗粒剂通过#40号筛网。
III.GR载体组合物的制备
将称重量的卡拉胶iota、果胶、结冷胶、碳酸氢钠、碳酸钙混合15分钟,并使用10%w/v的共聚维酮溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。
IV.将步骤I的称重量的药物-离子交换树脂络合物、步骤II的PR颗粒剂和步骤III的颗粒剂与称重并过筛(#40)量的HPMC K100LV、香蕉调味剂、滑石粉、苯甲酸钠、甘露醇和三氯蔗糖混合15分钟。对于80mg普萘洛尔HCl,在给药时应使用5gm纯净水重构708mg的POS。
体外测试
I.漂浮的发生和持续时间
将相当于80mg普萘洛尔HCl的重构悬浮液加入500ml不含酶的SGF中。筏漂浮所需的时间和漂浮的持续时间预计为:
漂浮的发生(分钟) | ≤20 |
漂浮的持续时间(小时) | 12 |
II.筏的弹性
将相当于80mg普萘洛尔HCl剂量的重构悬浮液加入500ml不含酶的SGF,0.1N HCl溶液。接着使用设置在37℃和75rpm的机械振荡器进行搅拌。预计的观察结果:筏在12小时的时间段内保持完整性。
III.体外释放研究
使用设置在50rpm和37℃的II型USP设备并将500ml不含酶的SGF用作介质,使用相当于25mg异丙嗪HCl剂量的重构悬浮液来执行溶出研究。预计的溶出曲线在图4中提供。
实例4.侵蚀作为触发
表4:GRPR粉末悬浮液(POS)的组成
I.药物-离子交换树脂络合物的制备
将称重量的普瑞巴林溶解在1000ml水中。在搅拌下将称重量的树脂加入到药物溶液中,并继续搅拌4小时。通过过滤分离药物-树脂络合物,并在60℃下干燥。使药物-树脂络合物通过#60号筛网。
II.PR载体组合物的制备
将称重量的第二脉冲的药物-离子交换树脂络合物与称重量的MCC、HPMC K4M、碳酸钙混合15分钟,并使用10%w/v的PVP K30溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。干燥的颗粒剂使用用PEG 400增塑的HPMC K100LV在流化床处理机中包衣。包衣颗粒剂在60℃下干燥。包衣颗粒剂通过#30号筛网。
III.GR载体组合物的制备
将称重量的卡拉胶iota、果胶、碳酸氢钠、碳酸钙和HPMC K100LV混合15分钟并制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。
IV.将称重量的第一脉冲的药物-离子交换树脂络合物、步骤II的颗粒剂和步骤III的颗粒剂与称重并过筛(#40)量的HPMC K100LV、香蕉调味剂、滑石粉、苯甲酸钠、甘露醇和三氯蔗糖混合15分钟。对于300mg普瑞巴林相当剂量,在给药时应使用30gm纯净水重构3870mg的POS。
体外测试
I.漂浮的发生和持续时间
将相当于300mg普瑞巴林的重构悬浮液加入500ml不含酶的SGF中。筏漂浮所需的时间和漂浮的持续时间预计如下:
漂浮的发生(分钟) | ≤15 |
漂浮的持续时间(小时) | 12 |
II.筏的弹性
将相当于300mg普瑞巴林的重构悬浮液加入500ml不含酶的SGF,0.1N HCl溶液。接着使用设置在37℃和75rpm的机械振荡器进行搅拌。预计的观察结果:筏在12小时的时间段内保持完整性。
实施例5.pH作为触发,用于产生第二脉冲的S形释放系统
I.熔融颗粒剂的制备
表5:
成分 | Gm |
缬沙坦 | 100 |
PEG 8000 | 50 |
泊洛沙姆407 | 50 |
微晶纤维素 | 100 |
将称重量的PEG 8000和泊洛沙姆407一起熔融。在混合下将称重量的缬沙坦加入到熔融物料中,并继续混合5分钟。在混合下加入称重量的微晶纤维素。在连续混合下将整个物料冷却至环境温度。使冷却的物料通过#20号筛网。
表6:GRPR PCS的组成
II.PR载体组合物的制备
混合称重量的富马酸和20gm MCC,并使用包含2gm共聚维酮的水溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。颗粒剂使用用三醋精增塑的Eudragit EPO包衣。使包衣颗粒剂通过#40号筛网。将这些颗粒剂与称重量的第二脉冲的缬沙坦熔融颗粒剂、MCC和碳酸钙混合15分钟,并使用10%w/v的共聚维酮溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。颗粒剂使用用三醋精增塑的RS包衣。在流化床包衣机中进行包衣,并将包衣络合物在60℃下干燥。使包衣颗粒剂通过#40号筛网。
III.GR载体组合物的制备
将称重量的卡拉胶iota、果胶、结冷胶、碳酸氢钠、碳酸钙混合15分钟,并使用10%w/v的共聚维酮溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。
IV.将称重量的第一脉冲的熔融颗粒剂、步骤II的PR颗粒剂和步骤III的颗粒剂与称重并过筛(#40)量的HPMC K100LV、香蕉调味剂、滑石粉、苯甲酸钠、甘露醇和三氯蔗糖混合15分钟。对于80mg缬沙坦,在给药时应使用3gm纯净水重构674mg的POS。
体外测试
I.漂浮的发生和持续时间
将相当于80mg缬沙坦的重构悬浮液加入500ml不含酶的SGF中。预计筏漂浮所需的时间和漂浮的持续时间。
漂浮的发生(分钟) | ≤20 |
漂浮的持续时间(小时) | 12 |
II.筏的弹性
将相当于80mg缬沙坦的重构悬浮液加入500ml不含酶的SGF,0.1N HCl溶液。接着使用设置在37℃和75rpm的机械振荡器进行搅拌。预计的观察结果:筏在12小时的时间段内保持完整性。
III.体外释放研究
使用设置在50rpm和37℃的II型USP设备并将500ml不含酶的SGF用作介质,使用相当于80mg缬沙坦的重构悬浮液来执行溶出研究。预计的溶出曲线在图5中提供。
实施例6.pH作为触发,用于产生第二脉冲的S形释放系统
表7:GRPR PCS的组成
I.药物颗粒剂的制备
将称重量的普萘洛尔HCl与MCC混合,并使用10%w/v的共聚维酮溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。
II.PR载体组合物的制备
混合称重量的琥珀酸和20gm MCC,并使用包含2gm共聚维酮的水溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。颗粒剂使用用三醋精增塑的Eudragit EPO包衣。使包衣颗粒剂通过#40号筛网。将这些颗粒剂与称重量的第二脉冲的药物-离子交换树脂络合物和碳酸钙混合15分钟,并使用10%w/v的共聚维酮溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。颗粒剂使用用三醋精增塑的Eudragit RS包衣。在流化床包衣机中进行包衣,并将包衣络合物在60℃下干燥。使包衣颗粒剂通过#40号筛网。
III.GR载体组合物的制备
将称重量的卡拉胶iota、果胶、结冷胶、碳酸氢钠、碳酸钙混合15分钟,并使用10%w/v的共聚维酮溶液制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。
IV.将步骤I的称重量的药物颗粒剂、步骤II的PR颗粒剂和步骤III的颗粒剂与称重并过筛(#40)量的HPMC K100LV、香蕉调味剂、滑石粉、苯甲酸钠、甘露醇和三氯蔗糖混合15分钟。对于80mg普萘洛尔HCl,在给药时应使用5gm纯净水重构454mg的POS。
体外测试
I.漂浮的发生和持续时间
将相当于80mg普萘洛尔HCl的重构悬浮液加入500ml不含酶的SGF中。筏漂浮所需的时间和漂浮的持续时间预计为:
漂浮的发生(分钟) | ≤10 |
漂浮的持续时间(小时) | 12 |
II.筏的弹性
将相当于80mg普萘洛尔HCl剂量的重构悬浮液加入500ml不含酶的SGF,0.1N HCl溶液。接着使用设置在37℃和75rpm的机械振荡器进行搅拌。预计的观察结果:筏在12小时的时间段内保持完整性
实例7:pH加溶胀作为触发
表8:GRPR POS的组成
I.第一脉冲中的盐酸曲马多颗粒剂
将称重量的盐酸曲马多与MCC混合15分钟,并使用10%w/v的共聚维酮水溶液制粒。湿颗粒剂在60℃下干燥。使干燥的颗粒通过#40号筛网。
II.PR载体组合物的制备
将称重量的第二脉冲中的盐酸曲马多与称重量的二水磷酸二钙混合,并使用PVP溶液制粒。湿颗粒剂被干燥,并通过#60号筛网。颗粒剂使用用三醋精增塑的EudragitL100-55包衣。包衣颗粒剂进一步用由TEC增塑的Eudragit EPO包衣。使包衣颗粒剂通过#40号筛网。
III.GR载体组合物的制备
将称重量的卡拉胶iota、果胶、结冷胶、碳酸氢钠、碳酸钙和HPMC K4M混合15分钟并制粒。湿颗粒剂在60℃下干燥,并通过#40号筛网。
IV.将步骤I的颗粒剂、步骤III的包衣颗粒剂和步骤IV的颗粒剂与称重并过筛(#40)量的HPMC K100LV、香蕉调味剂、滑石粉、苯甲酸钠、甘露醇和三氯蔗糖混合15分钟。
对于100mg盐酸曲马多,在给药时应使用3gm纯净水重构415mg的POS。
体外测试
I.漂浮的发生和持续时间
将相当于100mg盐酸曲马多的重构悬浮液加入500ml不含酶的SGF中。筏漂浮所需的时间和漂浮的持续时间预计如下。
漂浮的发生(分钟) | ≤5 |
漂浮的持续时间(小时) | 12 |
II.筏的弹性
将相当于100mg盐酸曲马多的重构悬浮液加入500ml不含酶的SGF,0.1N HCl溶液。接着使用设置在37℃和75rpm的机械振荡器进行搅拌。预计的观察结果:筏在12小时的时间段内保持完整性。
体外释放研究
使用设置在50rpm和37℃的II型USP设备并将500ml不含酶的SGF用作介质来执行溶出研究。加入相当于100mg盐酸曲马多的重构悬浮液。采样点:1、2、3、4、6、8、10、12小时。预计的溶出曲线在图6中提供。
本说明书中列出的所有专利、专利出版物和其他出版物均通过引用并入本文。2017年12月18日提交的美国专利申请第62/607,141号通过引用并入。虽然已经参考特别优选的实施例描述了本发明,但是应理解,可以在不脱离本发明的精神的情况下进行修改。此类修改意图落入所附权利要求的范围内。
Claims (19)
1.一种可口服施用的药物粉末组合物,所述组合物形成具有至少两个触发脉冲的胃内滞留筏,所述组合物包括:
(a)至少一种具有第一脉冲释放形式的药物,所述具有第一脉冲释放形式的药物在少于约3小时内释放;
(b)至少一种具有触发释放形式的药物;
(c)至少一种无毒气体发生剂;
(d)筏系统,并且
其中在口服摄取后,所述组合物提供自组装的胃内滞留筏,所述自组装的胃内滞留筏中包埋(a)和(b)中的所述至少一种药物以及由所述无毒气体发生剂原位产生的气体,由此提供漂浮的胃内滞留筏,所述漂浮的胃内滞留筏具有双脉冲系统,所述双脉冲系统中至少第二脉冲是触发脉冲,并且所述漂浮的胃内滞留筏将所述至少一种药物保持在胃中至少约3小时,前提是所述组合物不包括γ-羟基丁酸酯和其盐、水合物、互变异构体或溶剂化物,或它们的络合物。
2.根据权利要求1所述的可口服施用的粉末组合物,其中所述组合物包括pH S形延迟触发系统,所述pH S形延迟触发系统包括颗粒,所述颗粒包括:
(a)至少一种药物、药物-离子交换树脂络合物,或其混合物;用反向肠溶包衣进行包衣的有机酸;任选的气体发生剂;任选的膨胀剂;以及
(b)至少一种在(a)的颗粒上的pH非依赖性的、水不溶性的、水可渗透的扩散阻挡包衣聚合物,其中所述包衣在(a)的所述有机酸存在的情况下溶解,由此在酸存在的情况下摄取后,形成包括(a)的所述药物的pH S形延迟触发的筏。
3.根据权利要求1所述的可口服施用的粉末组合物,其中所述组合物包括腐蚀延迟触发系统,所述腐蚀延迟触发系统包括:至少一种腐蚀阻挡形成聚合物;任选的气体发生剂;至少一种药物、药物-离子交换树脂络合物,或其混合物;以及任选的膨胀剂,由此在胃酸存在的情况下,形成包括所述药物的所述腐蚀延迟触发系统的筏。
4.根据权利要求1所述的可口服施用的粉末组合物,其中所述组合物具有pH溶胀延迟触发系统,包括:(i)颗粒剂,所述颗粒剂包括至少一种药物、药物-离子交换络合物,或其混合物;至少一种pH改性剂;至少一种溶胀剂;用至少一种肠溶聚合物包衣的任选的气体发生剂;(ii)任选地,(i)的所述颗粒剂上的反向肠溶聚合物包衣,由此在胃酸存在的情况下,形成包括(i)的所述药物的所述pH溶胀延迟触发系统的筏。
5.根据权利要求1所述的可口服施用的粉末组合物,其中所述组合物具有溶胀延迟触发系统,包括:(i)颗粒剂,所述颗粒剂包括至少一种药物或任何药物盐或药物-离子交换络合物;至少一种胶凝剂;至少一种溶胀增强剂;在胃酸存在的情况下产生气体的任选的气体发生剂;任选地,膨胀剂;以及(ii)至少一种在(i)的所述颗粒剂上的水可渗透的扩散阻挡包衣,由此在胃酸存在的情况下,形成包括(i)的所述药物的所述溶胀延迟触发系统的筏。
6.根据权利要求1所述的可口服施用的粉末组合物,其中所述组合物具有渗透延迟触发系统,包括:(i)颗粒剂,所述颗粒剂包括至少一种药物或任何药物盐或药物-离子交换树脂络合物;至少一种胶凝剂;至少一种渗透剂;在胃酸存在的情况下产生气体的任选的气体发生剂;任选的膨胀剂;以及(ii)至少一种在(in)的所述颗粒剂上的水可渗透的扩散阻挡包衣,由此在胃酸存在的情况下,形成包括(i)的所述药物的所述渗透延迟触发系统的筏。
7.根据权利要求1至6中任一项所述的可口服施用的粉末组合物,其中所述筏具有两种或更多种不同的延迟触发脉冲释放。
8.根据权利要求1至7中任一项所述的可口服施用的粉末组合物,其中所述组合物包括两种或更多种不同药物。
9.根据权利要求1至7中任一项所述的可口服施用的粉末组合物,其中所述筏包括两种或更多种不同药物。
10.根据权利要求1至9中任一项所述的可口服施用的粉末组合物,其中所述筏包括具有多于两种不同释放形式的相同药物。
11.根据任一权利要求1所述的可口服施用的粉末组合物,其中形成的所述筏的大小最初为至少15mm。
12.根据权利要求1至11中任一项所述的可口服施用的粉末组合物,其中所述组合物包括两种或更多种不同筏系统。
13.根据权利要求1至11中任一项所述的可口服施用的粉末组合物,其中所述筏形成系统包括至少一种可交联的多糖、至少一种交联剂和至少一种气体发生剂,所述气体发生剂与胃酸反应以形成气体。
14.根据权利要求1所述的可口服施用的药物组合物,其中所述可交联的多糖是选自的瓜尔豆胶、胡芦巴胶或刺槐豆胶的半乳甘露聚糖,且所述至少一种交联剂选自硼砂、戊二醛和/或锆。
15.根据权利要求1至12中任一项所述的可口服施用的药物组合物,其中所述筏包括所述胶凝剂,其中所述胶凝剂在室温下是液体,且在体温下胶凝,并且选自木葡聚糖或泊洛沙姆。
16.根据权利要求1至12中任一项所述的可口服施用的药物组合物,其中所述筏是包括立方相形成脂质的液晶筏。
17.根据权利要求1至16中任一项所述的可口服施用的药物组合物,其中所述气体发生剂选自碱金属或碱土金属的碳酸盐或碳酸氢盐、亚硫酸盐或其组合,或它们与形成气体发生剂对的酸源的组合。
18.根据权利要求17所述的可口服施用的药物组合物,其中所述碱金属或碱土金属的碳酸盐或碳酸氢盐选自碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠、碳酸钙、甘氨酸碳酸钠、碳酸镁或碳酸铝。
19.根据权利要求1至18中任一项所述的可口服施用的药物组合物,其中所述药物可用于治疗变应性鼻炎、类风湿性关节炎和相关病症、哮喘、癌症、心血管疾病、炎性疾病和溃疡中的一种或多种。
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US11839597B2 (en) | 2016-07-22 | 2023-12-12 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
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CN114569584A (zh) * | 2022-05-06 | 2022-06-03 | 山东华铂凯盛生物科技有限公司 | 一种盐酸达泊西汀口腔速溶膜及其制备方法 |
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US11337919B2 (en) | 2022-05-24 |
EP3740189A1 (en) | 2020-11-25 |
AU2018388577B2 (en) | 2024-06-06 |
IL275444A (en) | 2020-08-31 |
US20220241189A1 (en) | 2022-08-04 |
JP2021506984A (ja) | 2021-02-22 |
WO2019126218A1 (en) | 2019-06-27 |
JP2024009904A (ja) | 2024-01-23 |
AU2018388577A1 (en) | 2020-07-09 |
US20210015745A1 (en) | 2021-01-21 |
CA3086153A1 (en) | 2019-06-27 |
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