CN105263480A - 肠溶包衣的多微粒控释薄荷油组合物和相关方法 - Google Patents
肠溶包衣的多微粒控释薄荷油组合物和相关方法 Download PDFInfo
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- CN105263480A CN105263480A CN201380052353.XA CN201380052353A CN105263480A CN 105263480 A CN105263480 A CN 105263480A CN 201380052353 A CN201380052353 A CN 201380052353A CN 105263480 A CN105263480 A CN 105263480A
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Abstract
一种由多个单独的核形成的多微粒组合物,单独的核包括含有分散在微晶纤维素基凝胶中的薄荷油的疏水相和含有水凝胶的亲水相。肠溶包衣位于单独的核上方。多微粒组合物可以用于治疗胃肠疾病。
Description
相关申请的交叉引用
本申请是于2012年2月7日提交的美国申请第13/367,747号的部分继续申请,其要求于2011年5月16日提交的美国临时申请第61/486,523号以及于2011年2月11日提交的美国临时申请第61/441,716号的优先权。本申请也要求于2013年4月23日提交的美国临时申请第61/815,073号以及于2013年9月20日提交的美国临时申请第61/880,294号的优先权。所有这些在先申请通过引用结合于此作为参考。
技术领域
本发明涉及肠溶包衣的多微粒组合物,并且更具体地,涉及含有薄荷油的肠溶包衣的多微粒组合物。
背景技术
薄荷油用于解决胃肠问题,因为它能抑制胃肠道中的平滑肌收缩。然而,不幸的是,如果薄荷油在胃中释放,则它将被很快地吸收并且会使胃感到不舒服。为了克服这个问题,其他人已经开发了肠溶包衣的薄荷油制剂,该肠溶包衣的薄荷油制剂允许薄荷油在被释放之前进入肠道。
在传统的肠溶包衣的薄荷油制剂中,薄荷油装入肠溶的空心胶囊内。肠溶包衣防止胶囊在胃中溶解,但允许胶囊在肠道内溶解并释放薄荷油。
诸如这些的单单位肠溶包衣的薄荷油胶囊具有多种缺陷。首先,实际上被摄入胶囊的人的肠道所吸收的薄荷油的剂量是不可预知的。原因之一是,当胶囊溶解后,它将全部薄荷油迅速地倾释到肠道的相同区域内,由于薄荷油水溶性不大使得这成为问题。对于这的另一原因是在胃肠道中的食物会影响吸收的薄荷油的量。
与单单位肠溶包衣的薄荷油胶囊相关的第二个缺陷是薄荷油的起效是不可靠的。延迟起效的主要因素是胶囊在胃中耗费的时间量,其范围超过几个小时并且取决于胃中的食物的量。为了获得可靠的起效,人们应当空腹摄入胶囊。但是由于一些胃肠疾病在饭后发作,人们往往想马上治疗这种发作。因此,对于治疗通过食物引发的严重的胃肠发作,这种单单位肠溶包衣胶囊是不理想的。
与单单元肠溶包衣的薄荷油胶囊相关的第三个缺陷是,事实上薄荷油是挥发性的。如果将胶囊在远超过室温的条件下运输或储存较长的时间,薄荷油可以蒸发并渗透胶囊。
我们认为,可以通过开发含薄荷油的肠溶包衣的多微粒组合物来解决这些问题,但是发现由于薄荷油非常容易挥发而难以实现。如果将含有薄荷油的多微粒核在远超过室温的条件下加热或储存较长的时间,薄荷油的挥发性组分离开核并且渗透肠溶包衣。这使得难以加工核,特别是当在升高的温度下固化核上的肠溶包衣时。
在美国专利公布第2012/0207842号中,我们描述了制备肠溶包衣的多微粒L-薄荷醇的组合物。为了防止当加工核时L-薄荷醇升华,我们采取低温加工技术。在该申请中描述的L-薄荷醇的多微粒组合物提供了我们所希望的释放曲线,并且对一些应用行之有效,但是其对于所有的应用而言不是最佳的。
我们已经确定了对避免与单单元肠溶包衣胶囊相关的缺陷并且能够使用传统的室温加工技术制造的薄荷油组合物的需要。
发明内容
一种体现了这些原理的多微粒组合物包括多个单独的肠溶包衣的核,肠溶包衣的核包括含有分散在微晶纤维素基凝胶中的薄荷油的疏水相和含有水凝胶的亲水相。微晶纤维素用作用于控制薄荷油释放的聚合物,从而防止剂量倾释并且当加工核时使薄荷油稳定。
在本发明的另一组合物方面中,多微粒组合物包括多个单独的肠溶包衣的核,肠溶包衣的核含有约15%w/w至约40%w/w的薄荷油、约35%w/w至约75%w/w的微晶纤维素和约2%w/w至约15%w/w的甲基纤维素,其中,所述%w/w是相对于肠溶包衣的核的%w/w。
在一些情况下,因为蛋白质次级包衣层进一步提高了薄荷油的稳定性,因此包括覆盖单独的核并且将单独的核与它们相应的肠溶包衣分隔开的连续的蛋白质次级包衣层是有利的。连续的蛋白质次级包衣适于防止薄荷油与肠溶包衣混合。
一些优选的蛋白质次级包衣具有以下属性:次级包衣可以包括粘附至核的明胶膜和/或次级包衣可以包括干的蛋白质凝胶。
肠溶包衣可以具有比薄荷油的标准沸点更高的玻璃化转变温度。
在一个具体的实施例中,肠溶包衣的核在放置于0.1N的HCl溶液中的约2小时内释放不超过约20%的薄荷油,以及随后,在放置于基本上中性的pH环境中的约8小时内释放不少于约85%的薄荷油。
优选地,肠溶包衣的核是直径不大于3毫米的球形。
在本发明的第一方法的方面中,制造多微粒组合物的方法包括将薄荷油、微晶纤维素、形成水凝胶的聚合物和水混合以形成湿团块,湿团块包括含有分散在由微晶纤维素形成的凝胶中的薄荷油的疏水相和含有羟丙基甲基纤维素和水的亲水相;挤出湿团块以形成挤出物;将挤出物分成单独的湿核;从湿核中的亲水相去除水以形成干核;以及对干核应用肠溶包衣。
该方法可以进一步包括在应用肠溶包衣之前,用液体蛋白质材料对干核进行包衣和干燥该液体蛋白质材料以形成次级包衣的核。液体蛋白质材料包括明胶。液态蛋白质类材料的具体实例是含有至少约50%的明胶的溶液。
可以通过将液体蛋白质材料喷涂到干核上来用液体蛋白质材料对干核进行包衣。
一旦制成,肠溶包衣的核优选是球形并且直径不超过3mm。
优选地,在基本上不去除薄荷油的情况下实现从湿核中的亲水相去除水。
在本发明的第二方法的方面中,治疗受试者胃肠疾病的方法,包括向受试者施用多微粒组合物,该多微粒组合物包括多个单独的肠溶包衣的核,该肠溶包衣的核包括含有分散在微晶纤维素基凝胶中的薄荷油的疏水相和含有甲基纤维素基基凝胶的亲水相。优选地,实施肠内施用。如果期望,在施用之前,可以将多微粒组合物与酸性载体混合。
通过参考附图以及优选实施例的详细描述可以更好地理解本发明的这些和其他方面、实施例和优势。
附图说明
图1是示出根据本发明的实施例的在40摄氏度和75%相对湿度下储存4周的多微粒组合物的加速稳定性试验的结果的图;以及
图2是示出根据本发明的实施例的组合物在40摄氏度和75%相对湿度下储存之后的多微粒组合物的两阶段溶出度测试的结果的图。
具体实施方式
在发明内容和优选实施例的详细描述中,参考本发明的特定特征(包括方法步骤)。应当理解,在说明书中本发明的公开包括这些特定特征的所有可能的组合,即使这些组合并没有在一起明确公开。例如,其中,在本发明的特定方面或实施例的上下文中公开特定特征,在可能的范围内,特征可以与本发明的其他特定方面和实施例组合和/或在本发明的其他特定方面和实施例的上下文中并且在本发明中使用。
术语“包括”在本文中用于表示可以任选地存在的其他成分,步骤等。当本文参考包括两个或多个限定的步骤的方法时,这些步骤可以以任何顺序或同时进行(除非上下文中排除那种可能性),并且该方法可以包括在任何限定的步骤之前、两个限定的步骤之间或所有限定的步骤之后(除了上下文中排除那种可能性)实施的一个或多个步骤。
在本部分中,将参考本发明的优选实施例更加充分地描述本发明。然而,本发明可以体现为许多不同的形式并且不应被解释为限于本文阐述的实施例。相反,提供这些实施例使得本发明将对本领域普通技术人员传达本发明的优选实施例。
由于薄荷油是如此易挥发的,很难制造含有薄荷油的剂型。用于制造药物剂型的传统的加工方法涉及加热,这种传统的智慧暗示本领域普通技术人员当使用挥发性成分时应当避免加热。我们发现,由于这种和其他原因,制造稳定的多微粒的含有薄荷油的组合物是很困难的。
微晶纤维素,或“MCC”,是一种被广泛地用作固体口服剂型中的崩解剂的药物赋形剂。MCC促进片剂在水性环境中的分解以提高药物释放。它通过借助片剂的孔吸湿,弱化片剂并使其崩解来实现这一点。由于MCC被用作崩解剂,其导致固体口服剂型中的活性成分比活性成分的其他方式更快地释放。
我们发现,MCC也用作薄荷油的释放控制聚合物并且开发的多微粒肠溶包衣的薄荷油组合物将MCC用作核中的释放控制聚合物。MCC将薄荷油逐渐释放进肠道内,而不是在肠道的小区域中快速倾释全部剂量。因此,我们的多微粒薄荷油组合物中的MCC实施与崩解剂相反的功能,并且克服了由传统的单单元肠溶包衣胶囊持有的剂量倾释的缺陷。
首先描述了本发明的多微粒组合物的方面。多微粒组合物适于将薄荷油携带到肠道内,并且包括多个微粒,微粒优选地是球形形状和尺寸适合穿过处于松弛状态的幽门括约肌。每个微粒的直径优选在约0.1mm至约3mm的范围内,约1mm至约2.5mm的范围内或小于约1.4mm。这种直径的微粒是有利的,因为它们可以适合穿过幽门括约肌,并且不像单单元胶囊那样长时间地留在胃中,从而提供更可靠的起效。
多微粒组合物包括多个单独的含有薄荷油的核,每个核都是肠溶包衣的。肠溶包衣允许单独的核穿过胃而不会释放大量的薄荷油。在肠内的pH值中,肠溶包衣溶解,暴露出核并且允许薄荷油释放。
该核包含主要的活性成分薄荷油,但也可以含有其他的次要活性成分,诸如一种或多种其他的诸如萜烯、萜类化合物和/或精油的萜烯基物质。可以用作次要活性成分的萜烯类物质包括但不限于L-薄荷醇、葛缕子油、橙油、姜油、姜黄油、姜黄素油和茴香油等。
可选地,次要活性成分可以是帮助从胃肠疾病症状的各种措施来缓解胃肠疾病症状的非萜烯基物质。非萜烯基次要活性成分的实例包括但不限于多酚类,诸如绿茶提取物和芦荟粉末、质子泵抑制剂、消炎药以及免疫抑制剂等。
诸如薄荷油、葛缕子油、橙油、茴香油等的精油在室温下是液体。它们通常作为液体配制在胶囊中,在胶囊上方具有肠溶包衣。我们发现,精油可以与纤维素填充剂和粘合剂进行混合,以制造面团或湿团块,但是通过将这些材料简单地混合在一起形成的面团不产生用于次级包衣和进一步加工的具有期望的强度的核。通过向湿团块加入水,我们生产出含有薄荷油的核,该核足够强健以用于随后的加工。
该核也可以含有一种或多种抗氧化剂,抗氧化剂可以保持薄荷油和其他活性成分(如果使用)的纯度。因为薄荷油可以氧化以形成不希望的衍生物,因此这是有用的。可以使用的抗氧化剂的实例包括但不限于生育酚(维生素E)、BHT(丁基羟基甲苯)、BHA(丁基化羟基苯甲醚)和抗坏血酸。
在核中,薄荷油与MCC和形成聚合物粘合剂的水凝胶结合在一起,聚合物粘合剂诸如纤维素基、淀粉基和/或聚维酮基粘合剂。应该理解的是,“纤维素基”、“淀粉基”粘合剂和“聚维酮基”粘合剂包括纤维素、淀粉和聚维酮的衍生物。当与水混合时,粘合剂溶胀以形成水凝胶基质。与此相反,MCC和薄荷油是疏水性的。纤维素基粘合剂的实例包括甲基纤维素基聚合物,例如,甲基纤维素基聚合物包括甲基纤维素和羟丙基甲基纤维素。特别优选在组合物中使用甲基纤维素。
当在加工期间向核加入水,这些材料分成疏水相和亲水相。疏水相含有分散在微晶纤维素基凝胶中的薄荷油并且亲水相含有水凝胶。因此,薄荷油分散在整个疏水相中,而疏水相与亲水相接触。
将薄荷油分散到MCC中的一种优势是它允许多余的水从核去除而不也去除大量薄荷油。常规的干燥技术将导致核中的薄荷油与水一起蒸发。因此,通过使核包括含有分散到微晶纤维素基凝胶中的薄荷油的疏水相,以及含有甲基纤维素基聚合物的亲水相,可以在不存在大量损失薄荷油的风险下加工核。
该核也可以包括药学上可接受的填充剂、稳定剂、粘合剂、表面活性剂、加工助剂和/或崩解剂。仅以实例的方式,提供用于实施这些功能的合适的材料。
优选的填充剂包括纤维素填充材料,诸如微晶纤维素、磷酸氢钙和/或其他药学上可接受的填充剂。
优选的粘合剂包括纤维素的水溶性聚合物,诸如甲基纤维素、淀粉、羟丙基纤维素、明胶、聚乙烯吡咯烷酮、聚乙二醇和/或其他药学上可接受的粘合剂。
在一些情况下,包括作为增溶剂的表面活性剂可能是有利的。如果使用的话,优选的增溶剂包括但不限于聚山梨醇酯80和/或十二烷基硫酸钠。有利地,当使用聚山梨酸酯80时,它也可增强萜烯基活性成分到血浆中的吸收。
合适的加工助剂包括药学上可接受的加工助剂以用于帮助增加加工期间的核材料的流动性。优选的加工助剂包括但不限于胶态二氧化硅、滑石、硬脂酸镁、硬脂和/或其他药学上可接受的加工助剂。
优选的崩解剂包括但不限于交联羧甲纤维素钠、聚乙烯吡咯烷酮(交聚维酮)淀粉羟乙酸钠和/或其他药学上可接受的加工助剂。
在一个特别优选的多微粒组合物的实施例中,核包含约15%w/w至约40%w/w的薄荷油、约35%w/w至约75%w/w的微晶纤维素和约2%w/w至约15%w/w的甲基纤维素,其中%w/w是相对于肠溶包衣的核的%w/w。
因为常常希望能够以非冷藏车运输产品并且将它们存储很长的时间,我们优选地当将我们的含有薄荷油的多微粒组合物存储于40摄氏度和75%的相对湿度时,在1天至30天之间以及甚至更长的时间内是稳定的。如果将多微粒组合物分布于位于气候区IV中的区域,这将也是有益的。
然而,当开发含有萜烯基活性成分的多微粒组合物时,我们发现挥发性成分有时透过我们用于将核与它们的包衣材料分离的传统的次级包衣材料。正因为如此,如果温度升高(25℃-50℃)或该组合物储存了较长的一段时间,活性成分会来与肠溶包衣接触。这多少会减小肠溶性包衣的有效性和位于核中的活性成分的量。
我们通过开发新的次级包衣材料来解决这一问题,该新的次级包衣材料可以应用于完成的核并且防止核中的挥发性活性成分离开核和在升高的温度下渗透该肠溶包衣。次级包衣包括沿着每个核的外表面应用的蛋白质材料以形成基本上连续的薄膜,该薄膜在核和在次级包衣之后应用的肠溶包衣之间形成阻挡。
可以用于次级包衣中的蛋白质材料的实例包括蛋白质,诸如但不限于酪蛋白、乳清蛋白、大豆蛋白以及各种类型的明胶(A型、B型或明胶的衍生物)或具有蛋白样结构的蛋白质材料。用于形成次级包衣的特别优选的材料是含有分散在溶剂中的至少约50%的蛋白质材料的溶液。优选地,溶剂是但不一定是水。特别优选的蛋白质材料是A型明胶。
优选地以液体形式将蛋白质次级包衣应用于核以及随后对核进行干燥。当干燥时,次级包衣粘附至核。液体形式的蛋白质次级包衣材料的实例包括熔体和凝胶。当干燥时,次级包衣在核上方形成连续的膜并且提供核和肠溶包衣之间的阻挡。
明胶典型地在约35摄氏度熔化,其低于约37℃的正常人体体温。考虑到这些,人们可能期望,如果将包括明胶次级包衣的多微粒组合物加热至高于35摄氏度,次级包衣将熔化并从核释放活性成分。然而,我们观察到,即使当被加热超过35摄氏度,明胶次级包衣的多微粒组合物不从核释放萜烯基活性成分。这是特别出乎意料的结果,它提供了许多益处。
因为即使当被加热超过蛋白质材料的熔点,蛋白质次级包衣防止挥发性薄荷油从核中释放,所以通过应用蛋白质次级包衣,人们未必需要避免在加工过程中加热次级包衣。当应用肠溶包衣时,其中的一种情景是有利的。肠溶包衣聚合物具有通常超过35摄氏度的玻璃化转变温度(Tg)。当被应用于核之后,肠溶包衣的微粒被优选地加热至超过Tg,从而使得肠溶包衣聚合物可以固化,从而实现核的最佳的肠溶保护(entericprotection)。因此,在核和肠溶包衣之间使用蛋白质次级包衣允许实现最佳肠溶保护而不会从核释放薄荷油。
次级包衣可以以含明胶的次级包衣溶液应用到核。溶剂可以是在其中明胶是可溶的任何溶剂,诸如水。在优选的实施例中,次级包衣溶液包括约5%至约30%w/w的明胶和约70%至约95%的溶剂。当允许在核周围干燥次级包衣溶液时,溶剂蒸发,留下粘附至核的薄明胶膜,并且形成核和肠溶包衣之间的阻挡。明胶膜次级包衣优选为肠溶包衣的微粒的约3.5%w/w至约35%w/w。令人惊奇的是,在我们的实验中,在约15摄氏度至约25摄氏度下干燥含薄荷油和水的核,随着水被从流化床干燥去除,不会导致薄荷油的显著损失。
在每个核上方应用肠溶包衣,或者如果使用次级包衣在次级包衣上方应用肠溶包衣。在优选的实施例中,肠溶包衣为肠溶包衣的微粒的约2%w/w至约35%w/w。优选的肠溶包衣材料是甲基丙烯酸基材料,诸如甲基丙烯酸基共聚物。这些材料可以与诸如用于形成肠溶包衣溶液的增塑剂的其他材料结合。在典型的实施例中,肠溶包衣溶液包含约5%w/w至约35%w/w的水,并且肠溶包衣的干的多微粒包含0.5%w/w至约5%w/w的增塑剂、约0.05%w/w至约5%w/w的抗粘剂和约2%w/w至约35%w/w的甲基丙烯酸共聚物。仅通过实例的方式,合适的增塑剂是柠檬酸三乙酯以及合适的抗粘剂是(艾默生资源公司,诺里斯敦,PA)。肠溶包衣优选为肠溶包衣的微粒的约3.5%w/w至约35%w/w。
肠溶包衣的微粒可以涂覆有饰面层。例如,饰面层用于克服一些肠溶包衣材料的粘膜粘着性能,粘膜粘着性能使得在加工、储存或通过管分配期间多微粒粘在一起以用于肠内给药。饰面层优选为纤维素衍生物,诸如HPMC(羟丙基甲基纤维素)、HPC(羟丙基纤维素)、CMC(羧甲基纤维素)或其他药学上可接受的饰面层材料。当使用时,饰面层优选为成品多微粒的约1%w/w至约10%w/w。
因为HPMC不具有粘膜粘附性,因此HPMC是特别优选的饰面层材料。因此,它防止了多微粒粘到胃壁以及胃中的食物。这允许多微粒快速到达肠,使得起效比单单元胶囊更可靠。
可以改变薄荷油在体内的释放曲线以治疗不同的疾病。薄荷油可以用于治疗多种胃肠疾病,诸如肠道易激综合征、炎症性肠病、胃轻瘫和功能性消化不良,但是最好在胃肠道中的特定点释放活性成分以最佳地治疗每种疾病。
为了治疗与肠道易激综合征相关的胃肠疾病,配制多微粒组合物以使释放到胃和结肠的薄荷油的量最小,从而使大部分的薄荷油被释放到小肠中。优选地,20%或20%以下的薄荷油被释放到胃内,并且20%或20%以下的薄荷油被释放到结肠内。此外,在诸如IBS的多种情况下,在多微粒通过幽门括约肌进入小肠内之后,薄荷油优选地在约4小时至约8小时的过程中逐渐释放以便在小肠中局部地传递活性成分。这种释放曲线通过稳定消化系统和减轻与诸如肠道易激综合症的疾病相关的症状而治疗胃肠疾病。
为了治疗诸如功能性消化不良(分类为胃十二指肠疾病)的胃肠疾病,配置多微粒组合物,从而使得当多微粒通过胃和幽门之后,薄荷油在约0小时至约2小时的过程中快速地释放以将薄荷油局部地传递至小肠的十二指肠部分以帮助稳定消化系统和/或减轻与功能性消化不良相关的症状。优选地,20%或20%以下的薄荷油被释放到胃内,并且20%或20%以下的薄荷油被释放到小肠的空肠和回肠段(其沿着十二指肠)以及结肠内。
为了治疗诸如炎症性肠病的胃肠疾病(包括溃疡性结肠炎或克罗恩病),配置多微粒组合物,从而使得在多微粒通过胃和小肠之后,薄荷油在约4小时至约6小时的过程中快速地释放以将薄荷油局部地传递至结肠以减弱炎症反应和/或减轻与炎症性肠病相关的症状。优选地,30%或30%以下的薄荷油在胃和小肠中释放,并且大于70%的薄荷油在多微粒达到结肠的pH值后的最初2小时中释放。
在特别优选的实施例中,多微粒组合物的肠溶包衣的核在放置于0.1N的HCl溶液中的约2小时内释放不超过约20%的薄荷油,并且随后在放置于基本上中性的pH环境中的约8小时内释放不少于约85%的薄荷油。
应当理解的是,其中,本公开内容涉及治疗胃肠道病症,即,术语“治疗”、“处理”或词“治疗”的任何其他变型包括胃肠疾病的预防。
该核制剂允许人们实现合适的释放曲线,这是因为MCC充当薄荷油的释放控制聚合物。本领域技术人员将认识到可以通过包括实际上用作崩解剂的崩解剂或其他传统的释放控制聚合物来调整薄荷油从核的释放速率,
含有薄荷油的多微粒组合物的日剂量为约20mg至约1200mg的薄荷油,分成每天2或3剂。每种剂型可以含有10mg至140mg之间的薄荷油,更优选地,约90mg至110mg的薄荷油。
当需要治疗胃肠道的急性炎症时,多微粒组合物的剂量可以零星地施用或可以作为用于治疗诸如肠道易激综合征、功能性消化不良、胃轻瘫或炎症性肠病的GI疾病的长期治疗方案的一部分施用。治疗受试者可以是人或动物。
可以将肠溶包衣的多微粒制备成合适的药物或医疗食品剂型,诸如胶囊、片剂或小药囊(sachet),或与酸性食物载体混合并且通过饲管直接给药。典型的剂型含有约400mg的微粒,但是取决于期望的剂量,可以调整这种量。酸性食物载体包括柑橘类果汁和食物,诸如,例如,苹果酱和苹果汁。
多微粒组合物优选配制成向人或动物受试者肠内施用,诸如口服或通过饲管,以确保受试者在摄入后的几小时的过程中接受有效量的薄荷油。饲管可以帮助具有失弛缓症、吞咽困难或不允许他们用水口服地施用胶囊的其他疾病的受试者。可选地,可以将多微粒撒在苹果酱上以用于不能吞咽较大尺寸的胶囊的患者。
现在描述制备多微粒组合物的优选方法。通常通过对核材料进行湿法造粒而将核材料制成湿团块、挤出湿团块以形成挤出物、将将挤出物剪切为多个核块以及使核块球化来制备核。然后在诸如流化床干燥器的干燥器中干燥球化的核块以除去水。如果期望,然后筛分干的球化的核以分离不同尺寸的核。
如果期望,然后用蛋白质次级包衣材料对干的球化的核进行包衣。对核应用次级包衣材料的一种方法是制备次级包衣溶液和将次级包衣溶液喷到核上。存在实现此目的的各种常规方法,但是优选的方法是底喷流化床包衣或流化床包衣(顶喷或底喷)。随后使次级包衣溶液在核上方干燥,从而留下涂覆有薄的连续的蛋白质膜的每个核。如果期望,然后筛分次级包衣的核以将核分离成不同的尺寸。
然后将肠溶包衣应用于次级包衣的核或者如果没有使用次级包衣则将肠溶包衣直接地应用于核。应用肠溶包衣的一种方法是将它喷到次级包衣的核上。存在实现此目的的各种常规方法,但是优选的方法是底喷流化床包衣或流化床包衣。随后干燥肠溶包衣的微粒。在肠溶包衣期间,优选地在约20摄氏度至约50摄氏度的环境中加热核以在肠溶包衣材料的Tg之上固化肠溶包衣材料。
如果期望,可以在肠溶包衣的微粒上方应用饰面层。应用饰面层的一种方法是将它喷到肠溶包衣的核上。存在实现此目的的各种常规方法,但优选的方法是底喷流化床包衣或流化床包衣。
一种制备多微粒组合物的更特别的方法涉及将薄荷油、微晶纤维素、形成水凝胶的聚合物和水混合以形成湿团块。湿团块包括含有分散在由微晶纤维素形成的凝胶中的薄荷油的疏水相和含有水凝胶和水的亲水相。然后将湿团块挤出以形成挤出物以及将挤出物分成单独的湿核。从湿核中的亲水相去除水以形成干核。然后对干核应用肠溶包衣。
本发明的另一方法方面是治疗胃肠疾病的方法。该方法包括向受试者施用多微粒组合物,多微粒组合物包括多个单独的核以及位于单独的核上方的肠溶性包衣,多个单独的核包括含有分散在微晶纤维素基凝胶中的薄荷油的疏水相和含有甲基纤维素的亲水相。
可以通过使用常规的口服剂型(诸如片剂、囊片、胶囊或小药囊等)来肠内地施用多微粒组合物。
用于施用(口服或通过管)该多微粒组合物的另一种肠内方法是将多微粒组合物加入到食物中。在这种情况下,多微粒组合物与诸如苹果汁的酸性食物载体或防止活性成分的过早释放的其他酸性载体混合,然后由受试者摄取。
实例
本部分提供了本发明的多微粒组合物和方法的方面的具体实例。提供这些实例以示出本发明的特定优选方面和实施例,但是本范明的范围并不限于这些实例的教导。
实例1:微粒组合物的制备
使用市售的商品名为102(FMCCorp.,Philadelphia,PA)的微晶纤维素(MCC)、市售的商品名为15LV(DowChemicalCo.,Midland,MI)的甲基纤维素、蒸馏薄荷油以及USP纯化水来制备核。
将33.25kg的MCC、1.75kg的甲基纤维素和15kg的薄荷油与水混合以形成湿团块。在高剪切造粒机中对湿团块进行造粒。然后挤出和球化造粒的湿团块。随后在流化床干燥器中干燥球化的微粒以形成未包衣的核。干燥温度为约16摄氏度。
然后用37kg的含有约15%的酸性骨明胶和85%的USP水的次级包衣组合物对未包衣的核进行底喷流化床包衣并且干燥。
用31kg的20%w/w的肠溶包衣悬浮液对次级包衣的核进行底喷流化床包衣,肠溶包衣悬浮液含有30DP、柠檬酸三乙酯(USP)和纯化水(USP)。30DP的干固体重量为约5.4kg。柠檬酸三乙酯的干固体重量为约0.28kg。的干固体重量为约0.5kg,然后在约40摄氏度下干燥肠溶包衣的核。
然后用26kg的含有约10%w/w的羟丙基甲基纤维素和90%的水(USP)的饰面溶液对肠溶包衣的核进行底喷流化床包衣并且在约40摄氏度下干燥。
实例2:实例1的多微粒组合物的稳定性测试
随后对实例1中描述的多微粒组合物进行测试以确保当在升高的温度下存储较长的时间时明胶次级包衣防止薄荷油蒸发并离开核。
在第一组实验中,我们制备含有多微粒组合物的胶囊,并且将胶囊在40摄氏度和75%的相对湿度下存储四周。每周,我们测量挑选的胶囊中薄荷油的量。图1将本研究的结果示出为作为时间的函数的每个胶囊的L-薄荷醇的毫克数的图。结果表明,在四周的时间段期间,胶囊中L-薄荷醇的量或多或少地保持恒定并且保持在约34mg。这表明,明胶次级包衣保持核的完整性。
在第二组实验中,我们模拟胃肠环境并且测量多微粒组合物的溶出曲线以确保肠溶包衣发挥作用,并且几乎所有的薄荷油在约8.5小时内从核释放。这是传统的两阶段溶出研究,其中,将样品放置在酸性介质(0.1NHCl)中持续约2小时,以及随后将样品放置在中性介质(pH=6.8)中持续剩余的时间。
该实验的结果在图2中示出为相对于时间的薄荷油的释放%(报告为L-薄荷醇的量)。在酸性介质中2小时之后,每个测试样品仅释放约10%或更少的薄荷油,这表明肠溶包衣是完整的并且工作正常。在在中性介质中的接下来的6.5小时内,薄荷油逐渐从核释放。
除非另限定,否则本文中使用的所有的技术和科技术语旨在与本领域中通常理解的术语(与本发明相关以及在本发明申请时的术语)具有相同的意思。尽管在本发明的实践或测试中可以使用与本文描述的那些类似或等效的各种方法和材料,但是描述了合适的方法和材料。本领域技术人员应当理解,使用和描述的方法和材料是实例,并且并不只是适合用于本发明的唯一的方法和材料。
说明书公开了本发明的典型的优选的实施例,并且尽管采用的具体的术语,但是术语仅用于描述的目的而不用于限制的目的。已经详细地描述了本发明,但是显而易见地,在如上述的说明书和权利要求书中所描述的本发明的精神和范围内,可以对本发明做出各种修改和变化。
Claims (26)
1.一种多微粒组合物,包括:
多个单独的肠溶包衣的核,所述核包括含有分散在微晶纤维素基凝胶中的薄荷油的疏水相和含有水凝胶的亲水相。
2.根据权利要求1所述的多微粒组合物,还包括:连续的蛋白质次级包衣层,覆盖单独的所述核并且将单独的所述核与单独的所述核的相应的肠溶包衣分隔开。
3.根据权利要求2所述的多微粒组合物,其中,所述连续的蛋白质次级包衣包括粘附至所述核的明胶膜。
4.根据权利要求2所述的多微粒组合物,其中,所述连续的蛋白质次级包衣包括干的蛋白质凝胶。
5.根据权利要求2所述的多微粒组合物,其中,所述连续的蛋白质次级包衣适合于防止所述薄荷油与所述肠溶包衣混合。
6.根据权利要求2所述的多微粒组合物,其中,所述肠溶包衣的玻璃化转变温度高于所述薄荷油的标准沸点。
7.根据权利要求1所述的多微粒组合物,其中,所述肠溶包衣的核在放置于0.1NHCl溶液中的约2小时内释放不超过约20%的所述薄荷油,并且随后在放置于基本中性的pH环境中的约8小时内释放不少于约85%的所述薄荷油。
8.根据权利要求1所述的多微粒组合物,其中,所述肠溶包衣的核是球形的并且直径不超过3mm。
9.一种多微粒组合物,包括:
多个单独的肠溶包衣的核,含有约15%w/w至约40%w/w的薄荷油、约35%w/w至约75%w/w的微晶纤维素和约2%w/w至约15%w/w的甲基纤维素,其中,所述%w/w是相对于所述肠溶包衣的核的%w/w。
10.根据权利要求9所述的多微粒组合物,还包括:连续的蛋白质次级包衣层,覆盖所述核并且将所述核与所述核的相应的肠溶包衣分隔开。
11.根据权利要求10所述的多微粒组合物,其中,所述连续的蛋白质次级包衣包括粘附至所述核的明胶膜。
12.根据权利要求10所述的多微粒组合物,其中,所述连续的蛋白质次级包衣包括干的蛋白质凝胶。
13.根据权利要求10所述的多微粒组合物,其中,所述连续的蛋白质次级包衣适合于防止所述薄荷油与所述肠溶包衣混合。
14.根据权利要求10所述的多微粒组合物,其中,所述肠溶包衣的玻璃化转变温度高于所述薄荷油的标准沸点。
15.根据权利要求10所述的多微粒组合物,其中,所述肠溶包衣的核在放置于0.1NHCl溶液中的约2小时内释放不超过约20%的所述薄荷油,并且随后在放置于基本中性的pH环境中的约8小时内释放不少于约85%的所述薄荷油。
16.根据权利要求9所述的多微粒组合物,其中,所述肠溶包衣的核是球形的并且直径不超过3mm。
17.一种制备多微粒组合物的方法,所述方法包括:
将薄荷油、微晶纤维素、形成水凝胶的聚合物和水混合以形成湿团块,所述湿团块包括含有分散在微晶纤维素凝胶中的所述薄荷油的疏水相和含有所述形成水凝胶的聚合物和水的亲水相;
挤出所述湿团块以形成挤出物;
将所述挤出物分成单独的湿核;
从所述湿核中的所述亲水相去除水以形成干核;以及
对所述干核应用肠溶包衣。
18.根据权利要求17所述的方法,还包括:在应用所述肠溶包衣之前,用液体蛋白质材料对所述干核进行包衣并且干燥所述液体蛋白质材料以形成次级包衣的核。
19.根据权利要求18所述的方法,其中,所述液体蛋白质材料包括明胶。
20.根据权利要求18所述的方法,其中,所述液体蛋白质材料是含有至少约50%明胶的溶液。
21.根据权利要求18所述的方法,其中,用所述液体蛋白质材料对所述干核进行包衣包括将所述液体蛋白质材料喷到所述干核上。
22.根据权利要求17所述的方法,其中,肠溶包衣的所述核是球形的并且直径不超过3mm。
23.根据权利要求17所述的方法,其中,在基本上不去除所述薄荷油的情况下,实现从所述湿核中的所述亲水相去除所述水以形成所述干核。
24.一种治疗受试者中胃肠疾病的方法,所述方法包括:
对所述受试者施用多微粒组合物,所述多微粒组合物包括多个单独的肠溶包衣的核,所述核包括含有分散在微晶纤维素基凝胶中的薄荷油的疏水相和含有水凝胶的亲水相。
25.根据权利要求24所述的方法,其中,肠内地实施所述施用。
26.根据权利要求24所述的方法,其中,在施用之前,将所述多微粒组合物与酸性载体混合。
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