CN112261936A - 硅酸制剂及其用途 - Google Patents
硅酸制剂及其用途 Download PDFInfo
- Publication number
- CN112261936A CN112261936A CN201980038837.6A CN201980038837A CN112261936A CN 112261936 A CN112261936 A CN 112261936A CN 201980038837 A CN201980038837 A CN 201980038837A CN 112261936 A CN112261936 A CN 112261936A
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- Prior art keywords
- capsule
- cellulose
- silicic acid
- acid
- formulation
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 title claims abstract description 93
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 29
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Abstract
胶囊包括胶囊壳并填充有包含稳定化硅酸的酸性液体制剂,其中该胶囊壳包含多糖和/或多糖衍生物。可以用季铵化合物来实现稳定化。胶囊可以是胶囊包胶囊产品的一部分,其中外胶囊还包含组合物,例如油。该胶囊可以用作饮食补充剂或药物。
Description
技术领域
本发明涉及包含稳定化硅酸的硅补充剂,并且涉及其作为药物或食品补充剂的用途。本发明还涉及用作药物的包含稳定化硅酸的剂型。
背景技术
矿物硅以原硅酸(Orthosilicic acid,OSA)的形式存在于饮品和水中。OSA在稀释浓度即<10-3M时是化学稳定的(Iler 1979)。在较高的浓度下,OSA发生缩聚反应,从而导致低聚物和聚合物的形成。在人体中的吸收研究表明,只有OSA是可生物利用的,而它的缩聚形式没有被吸收(Jugdaohsingh et al.2000)。OSA的有限的稳定性及其快速转化为高度pH依赖性的非生物可利用的物种,对于最适营养是个难题,此外,也由于其他矿物质和营养物可引发缩聚反应。
可以通过稳定剂来稳定原硅酸,稳定剂合适地选自季铵化合物和氨基酸、氨基酸的来源或其组合。一种已知的稳定剂是胆碱化合物。在实践中,观察到一些低聚反应。然而,这种低聚反应不能将原硅酸转化为二氧化硅,而是转化为低聚物,该低聚物可以在胃肠道中转化(特别是通过水解)为原硅酸。原硅酸及其低聚物(以可从胃肠道中吸收到血液循环中的形式或可以转化为可从胃肠道中吸收到血液循环中的形式)在下文中称为稳定化硅酸。
本申请人已经发明了稳定化硅酸的液体和固体制剂,并已开发成可商购的产品。EP0743922中公开了液体制剂,EP1551763中公开了通过挤出滚圆技术制备的固体版本。这些产品已在各种临床测试中进行了测试,其中在骨骼、软骨、头发、指甲和皮肤上均发现了有益的结果。已经发现在口服摄入稳定化硅酸之后,所摄取的硅化合物主要被发现是血液和尿液中的原硅酸。
在开发有效产品时,消费者的依从性几乎与直接生物利用度一样重要。如果消费者不按预期的频率服用产品,则无法达到体内的治疗有效浓度,因此不会对骨骼、软骨、指甲、皮肤和头发产生有益的影响。在这方面,通过季铵化合物(例如胆碱)来稳定原硅酸在技术上很麻烦。实际上,这种化合物给液体制剂带来难闻的气味和非常苦涩的鱼腥味,这使得消费者难以吞咽。固体制剂没有上述缺点,但是其中的有效硅浓度低。挤出滚圆法导致许多粒料被包装到胶囊中。胶囊总体上包含大量的载体材料,例如微晶纤维素。结果,临床有效剂量所需的胶囊尺寸非常大。这种大胶囊不是优选的。
因此,期望创造稳定化硅酸的另一种制剂,该制剂在饮食上和/或药学上是有效的(并且其中任何低聚物均被转化为可吸收形式的原硅酸),并导致良好的顾客或患者依从性。然而,这并不简单,因为稳定化OSA是一种技术困难的产品。首先,考虑到季铵化合物例如胆碱的存在,OSA是高度吸湿的。其次,形成用于液体和固体制剂的基础的浓缩的稳定化OSA的液体形式是酸性的,pH值大约为1,以防止缩聚。
发明内容
因此,本发明的目的是提供稳定化硅酸的又一种制剂,该制剂导致通过粘液吸收(可选地在胃肠道中部分水解之后),并且还有效地获得了高的顾客或患者依从性。
本发明的另一个目的是提供制备这种制剂的方法。
本发明的又一个目的是提供预防、抑制和治疗与骨质流失和软骨退变有关的疾病、头发和指甲质量的流失以及皮肤老化疾病的方法以及用于该方法的制剂,该方法在临床上是有效的并且有利于获得良好的依从性。
本发明的另一个目的是提供用于药物的稳定化硅酸制剂,更特别地是用于预防、抑制和治疗骨质流失、软骨退变、头发和指甲质量的流失以及皮肤老化疾病的药物。
根据第一个方面,本发明提供了胶囊,该胶囊包括胶囊壳并填充有酸性液体制剂,该酸性液体制剂包含稳定化硅酸,其中该胶囊壳包含多糖或多糖衍生物。
根据第二个方面,本发明提供了制备根据前述权利要求中任一项所述的胶囊的方法,包括步骤:
-制备稳定化硅酸的酸性液体制剂;
-用该液体制剂填充胶囊壳,以及
-密该封胶囊壳以得到所述胶囊。
根据第三个方面,本发明提供了用于药物的本发明的为硅补充剂的胶囊,更特别地用于预防、抑制和治疗骨质流失、软骨退变、头发和指甲质量的流失以及皮肤老化疾病的药物。
根据另一个方面,本发明涉及本发明的硅补充剂在预防、抑制和治疗骨质流失、软骨退变、头发和指甲质量的流失以及皮肤老化疾病中的用途和/或作为食品补充剂的用途。
又根据另一方面,本发明涉及胶囊产品,该胶囊产品包含至少一个存在于第二外胶囊内的第一内胶囊,其中本发明的胶囊作为第一胶囊存在,并且其中外胶囊进一步包含饮食上和/或药学上可接受的组合物。
根据另一方面,本发明涉及稳定化硅酸的酸性液体制剂,其还包含选自无定形二氧化硅、磷酸和/或其盐和甘油三酯的流变添加剂。
在导出本发明的实验中令人惊讶地发现,稳定化硅酸在包含多糖或多糖衍生物的胶囊壳的胶囊中证明是稳定的。这是非常令人惊讶的,因为这种胶囊与包含水的液体制剂组合时通常是不稳定的,参见Chiwele et al(2000)。实际上,胶囊被设计为使其在酸性水溶液环境(例如胃)中打开。
在一个优选的实施方式中,液体制剂的pH在0至2.5、更优选0.5至2.0、例如0.8至1.3的范围内。实验数据出乎意料地显示出,这种液体制剂在包含多糖或多糖衍生物的胶囊壳的胶囊中具有高稳定性,而发现相同制剂在明胶胶囊中会泄漏。在所述范围之上和之下,液体制剂都具有更高的缩聚风险。
在另一个优选的实施方式中,液体制剂的稳定化硅酸包含季铵化合物作为稳定剂。用胆碱化合物如氯化胆碱已观察到特别好的结果。然而,不排除其他胆碱化合物的存在,例如醋酸胆碱和酒石酸胆碱、氢氧化胆碱。季铵化合物是带电荷的,其被认为对硅酸的稳定性具有积极影响。此外,根据本发明,使用带电荷的化合物可以很好地有助于观察到的胶囊的稳定性。优选地,稳定剂以液体制剂的至少15wt%的量存在。本文中稳定剂的量是基于不含抗衡离子的季铵离子(因此是胆碱而不是氯化胆碱)来定义的。
在另一个优选的实施方式中,特别适合与使用季铵化合物作为稳定剂进行组合,稳定化硅酸包含水。令人惊讶地,发现在制剂和胶囊壳之间没有发生明显的水迁移。如果水从胶囊壳迁移到稳定化原硅酸制剂中,则胶囊将变脆。正如持续3个月和9个月的实验中所观察到的那样,这不会发生。如果水迁移到胶囊壳,胶囊壳将开始分解,这不会发生,如在实验中观察到的。在一个优选的实施方式中,水以对应于制剂的至多30wt%的量存在于稳定化硅酸中。在一个更优选的实施方式中,水以至多20wt%的水、例如至多15wt%的水的量存在于液体制剂中。
优选地,在本发明中,稳定化硅酸基本上包含原硅酸的低聚物和/或单体。低聚物是例如每分子包含少于1000个单体、优选少于100个单体的低聚物。更优选地,低聚物是在本文中硅原子的至少80%并且优选至少90%经由硅-氧-硅桥键合至至多3个其他硅原子的低聚物。在本文中术语“基本上”合适地是指至少95wt%,优选至少98wt%,更优选至少99wt%。
在另一个实施方式中,制剂的粘度在0.08.103mPas至2.0.103mPas的范围内。低于所述最小值80mPas的粘度倾向于导致胶囊的泄漏,而高于所述最大值的粘度则导致胶囊的不正确填充。在本文中粘度是用布氏粘度计(Brookfield viscometer)和25℃的恒温水浴测量的。
在本文的一个实施方式中,粘度是通过添加流变添加剂来改进的。该添加剂是合适地以固体形式添加到制剂中,然后在其中溶解或在其中细分散的化合物。在本文中,细分散体是特别地具有至多1微米的平均粒径的分散体。这种细分散体也称为胶体溶液或胶体悬浮液。在该实施方式中,添加剂以多达10wt%、例如3wt%-6wt%的量合适地添加。添加剂合适地选自以下组:羟丙基甲基纤维素(Hydroxylpropyl methylcellulose,HPMC)和其他纤维素衍生物、二氧化硅颗粒(更优选地无定形二氧化硅颗粒)、磷酸及其盐、甘油三酯、黄原胶和其他树胶、硬脂酸盐(例如硬脂酸铝和硬脂酸镁)。
合适的无定形二氧化硅制品是,例如气相二氧化硅颗粒。更优选地,二氧化硅颗粒具有亲水性表面而不是被处理以使表面疏水。磷酸或其盐可以作为次磷酸盐、例如磷酸二氢钙这种盐很好地添加,然后其与制剂中存在的酸反应为磷酸。磷酸可以作为正磷酸存在,但是不排除发生聚合。甘油三酯合适地为脂肪酸的甘油三酯。更优选地,甘油三酯是链长在6至14个碳原子范围内的脂肪酸的甘油三酯,其也被称为中链甘油三酯。在制备稳定化硅酸之后,将流变添加剂合适地添加到制剂中。除了流变添加剂之外,液体制剂还可以包含稀释剂。
在另一个实施方式中,液体制剂可以包含稀释剂。已经发现有利的是,使用这种稀释剂不会导致液体制剂的pH值变化很大。稀释剂合适地选自以下组:甘油、聚乙二醇、聚丙二醇。因此,它们不会破坏液体制剂的稳定性。液体制剂中一种或多种稀释剂的重量含量可以高达80wt%。然而,优选的是稀释剂以至多为20wt%的量存在。更优选地,酸性液体制剂包含至多10wt%的量的稀释剂或甚至不含稀释剂。如果稀释剂的量小于20wt%,并且特别是小于10wt%,或者如果液体制剂不含稀释剂,则液体制剂优选包含如上所述的流变添加剂。用未稀释的液体制剂填充胶囊的优点在于,其提供最大程度上减小尺寸,而稳定化硅酸的稳定性却不会降低。
胶囊壳的多糖或多糖衍生物材料优选选自以下组:纤维素、纤维素衍生物(包括烷基纤维素、羧烷基纤维素、羟烷基纤维素、羟烷基烷基纤维素、羧烷基-烷基纤维素及其衍生物)、淀粉、改性淀粉(例如淀粉醚和氧化淀粉、羧甲基淀粉、羟烷基化淀粉和琥珀酸淀粉)、支链淀粉、葡聚糖和/或其组合。
更优选的可选的衍生多糖材料选自以下组:羟烷基纤维素和羟烷基烷基纤维素。烷基为C1-C4烷基中的一个或多个,更优选为直链烷基。最优选地,可选的衍生多糖选自以下组:羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素和羟丙基甲基纤维素、羟丁基甲基纤维素、羟乙基纤维素醚、羟丙基纤维素醚、羟乙基甲基纤维素醚、羟乙基乙基纤维素醚、羟丙基甲基纤维素醚及其衍生物,以及它们的混合物。使用羟丙基甲基纤维素(HPMC)或衍生物已获得良好的结果。纤维素单元的取代基上的羟基基团的存在可以有助于液体制剂的稳定性。
不排除使用替代纤维素及其衍生物。实例包括:甲基纤维素、乙基纤维素、醋酸邻苯二甲酸纤维素、羧甲基纤维素钠、甲基纤维素醚以及其混合物,以及与如上所述的任何羟烷基纤维素或羟烷基烷基纤维素的混合物。
多糖衍生物更优选为酸改性的纤维素、烷基纤维素、羟烷基纤维素或羟烷基烷基纤维素,其中酸改性优选产生邻苯二甲酸酯、琥珀酸酯、乙酸酯、马来酸酯、偏苯三酸酯中的一种或多种。因此,酸改性导致在纤维素的羟基基团和所施加的酸之间形成酯。羟烷基纤维素或羟烷基烷基纤维素的酸改性是优选的。术语“烷基”在本文中定义为C1-C4烷基。这种纤维素的具体实例已在上文中指出。
如本领域中已知的,胶囊通常包括多于一个部件。通常,使用两件式胶囊,通常称为胶囊的主体和盖。术语“胶囊壳”实际上是指胶囊件的外壳,例如胶囊主体的外壳。然后,胶囊主体将填充有酸性液体制剂。填充之后,将通常包含壳的胶囊盖组装到盖上。这之后,使胶囊主体和胶囊盖彼此密封。然而,本发明不限于常规的胶囊制造和组装技术,并且例如也可以应用于包含用于填充的孔的单件式胶囊,该单件式胶囊随后在不首先组装胶囊的第二部件的情况下被密封。本发明方法中胶囊的填充可以以已知方式的进行。优选地,填充在20℃至40℃的温度范围内、例如在室温下进行,并且最优选地,不进行制剂的加热步骤和/或制剂的冷却步骤。具有胶囊壳的胶囊更特别地是所谓的硬胶囊。
胶囊壳优选包含按重量计最终胶囊壳的90%至99%的量的多糖或多糖衍生物材料(和/或如上所述的优选实例)。胶囊壳还可以包含本领域已知的胶凝剂,例如选自以下组的胶凝剂:海藻酸及其盐(例如钠盐、钾盐和钙盐)、琼脂、角叉菜胶、槐树豆胶和结冷胶。发现胶凝剂的选择不是关键的。胶囊壳通常包含肠溶聚合物和成膜剂。HPMC和/或其衍生物可以是肠溶聚合物和成膜剂。肠溶聚合物是,例如包含酸性基团的聚合物。然后,HPMC衍生物、例如酸改性的羟烷基纤维素被应用。酸的实例包括马来酸(酸酐)、琥珀酸、乙酸、邻苯二甲酸、偏苯三酸。优选的衍生物是羟丙基甲基纤维素乙酸琥珀酸酯,或者羟丙基甲基纤维素邻苯二甲酸酯被认为是非常合适的选择,以及其他酸改性的HPMC衍生物。优选地,任何酸性基团为羧酸基团。成膜剂例如选自HPMC、甲基纤维素、结冷胶、角叉菜胶及其混合物,并且优选至少包括HPMC。通常,当成膜剂是HPMC或甲基纤维素时,肠溶聚合物与成膜剂的比例在1.5至3.5的范围内,例如2.0至2.5。
可选地,对胶囊壳进行包衣以改变其溶解特性,例如通过肠溶包衣使胶囊对胃酸具有抗性。通常使用的包衣剂是:阴离子聚甲基丙烯酸酯(甲基丙烯酸与甲基丙烯酸甲酯或丙烯酸乙酯的共聚物)、纤维素基聚合物(例如邻苯二甲酸乙酸纤维素)或聚乙烯基衍生物(例如邻苯二甲酸聚乙酸乙烯酯)。
又在另一个的实施方式中,通过应用多糖的溶液(例如羟丙基甲基纤维素的醇溶液)来密封胶囊壳。
又在另一个的实施方式中,胶囊壳的尺寸至多为尺寸0。更优选地,胶囊壳的尺寸至多为1。发明人认为,在不希望受其约束的情况下,胶囊中稳定化原硅酸的稳定性随着胶囊尺寸的增加而降低。尺寸为01型或更小的(例如2-5型)胶囊非常合适。
被填充的胶囊合适地包装在初级包装中,该初级包装保护胶囊不受潮。优选的包装材料是铝/铝(ALU/ALU)泡罩(blister)或带封、或带有磁感应铝密封件和干燥剂袋的高密度聚乙烯瓶(High density polyethylene bottle,HDPE)。在这种情况下(如以下所讨论的,存在内胶囊和外胶囊),所指尺寸为内胶囊的尺寸。在该实施例中,内胶囊的尺寸最合适地至多为1。外胶囊可以根据需要具有任何尺寸。
根据本发明的一个优选实施方式,本发明的胶囊以内胶囊的形式存在于外胶囊内,该外胶囊还包含饮食上和/或药学上可接受的组合物。饮食上和/或药学上可接受的组合物(存在于外胶囊内)合适地为液体,但是在替代实施方式中为固体,例如粉末或挤出颗粒。不排除存在分散体、乳液、乳膏、凝胶或其他所谓的半固体制剂作为饮食上和/或药学上可接受的组合物。如本文所用,术语“饮食上和/或药学上可接受的组合物”是指符合本领域技术人员已知的、指定用于特定应用的标准的组合物或制剂。此外,该组合物应与内胶囊相容,以防止内胶囊泄漏和/或提前打开。在所述组合物为液体或包含液体的实施方式中,其中所述组合物优选包含疏水性液体,例如油。在所述组合物为固体或包含固体的实施方式中,固体合适地包含本领域技术人员本身已知的饮食上或药学上可接受的赋形剂。在一个更优选的实施方式中,所述组合物是基本上或完全无水的,其中术语“基本上”在本文中是指至多5wt%,更优选至多2wt%。在本发明的优选实施方式中,包含在第一胶囊中的酸性液体制剂包含至多20wt%、并且更优选至多10wt%的量的稀释剂,并且优选不含稀释剂。
包括在第二外胶囊内的第一内胶囊的这种胶囊产品的形成被认为提供了非常有利的选择。第一,第二外胶囊以及其中的饮食上和/或药学上可接受的组合物为稳定化硅酸提供了额外的封装,使其更不易失去水分。这对于存储持续时间是有益的。第二,使用更少要求的初级包装变得可行。
其次,可以选择第二外胶囊以达到预定的剂量释放,例如缓释胶囊。以这种方式,可以实现稳定化硅酸不在胃中释放,而仅在肠甚至结肠中释放。这被认为增强了吸收。在本文中,内胶囊和/或外胶囊,并且尤其是内胶囊可以设有肠溶包衣。
第三,可以将稳定化硅酸与其他饮食的药物成分结合。一种合适的饮食成分是,例如油,比如omega-3油和/或鱼油。后者的油通常包含多不饱和脂肪酸作为相关营养物。在人类生理中涉及的三种类型的多不饱和脂肪酸为α-亚油酸、二十碳五烯酸和二十二碳六烯酸。作为辅助药物,可以使用抗骨质疏松症、骨量减少的试剂,例如阿仑膦酸盐、唑来膦酸、利塞膦酸盐、伊班膦酸盐、雷洛昔芬、狄诺塞麦,还可以选择维生素,例如维生素E、维生素K。将理解的是,更多的组合治疗是可行的。此外,另外的成分可以例如选自:多糖、氨基酸、肽、维生素和矿物质或其他治疗活性化合物,包括抗氧化剂和刺激结缔组织成分合成的化合物。
为了完整起见,观察到外胶囊可以是软胶囊或硬胶囊,并且可以基于一种或多种合适的胶囊材料,例如明胶、多糖和多糖衍生物,例如淀粉、改性淀粉、纤维素和其衍生物。外胶囊的尺寸通常比内胶囊的尺寸大至少一个尺寸,但是也可以大两个或更多个尺寸。每个外胶囊的内胶囊的数量可以是一个或多于一个,这取决于内胶囊和外胶囊的相对尺寸。每个外胶囊的内胶囊的数量为例如1-10,并且更优选为1-5。
该胶囊可以应用为药剂和食疗剂,即食品补充剂。其主要意在供人类使用,尽管不排除供动物使用。仅通过打开胶囊就可以从胶囊中释放稳定化硅酸被认为是有益的。因此,该胶囊也非常适合于消化受限的患者,消化受限不能完全从活性成分(即稳定化硅酸)中去除任何固体载体。此外,认为有利的是,液体制剂保持其预定形式,直到其从胶囊中释放出来为止。当患者将液体制剂的液滴与饮料混合或用水稀释液滴时,由于pH值的变化和伴随的缩聚反应,OSA(和/或其低聚物)的量有减少的风险。
作为药物,具体适应症包括骨质流失、软骨退变、头发和指甲质量的流失以及皮肤老化和疾病。该药物被认为特别适合于抑制这些适应症,同时还观察到通过保持足够的硅浓度来起到预防作用。在本文中,治疗被理解为至少部分地支持骨骼、软骨、头发和指甲质量的再生。具体疾病包括骨量减少、骨质疏松、骨关节炎、风湿病学和皮肤病学领域的疾病。
最优选以每天5mg-20mg硅、优选每天10mg硅的剂量给予药剂或食疗剂,优选持续至少6个月,更优选持续至少12个月。
尽管本发明的制剂高度适合于任何类型的患者组,但是特别地期望儿童和青少年(至多20岁,最优选地在10-16岁的年龄组中)以及至少50岁的老年人(例如年龄至少65岁的老年人)的患者组具有益处。初步调查证实,这些组的依从性有所提高。
根据另一个优选的方面,本发明提供了稳定化硅酸的酸性液体制剂,其还包含选自以下组的流变添加剂:无定形二氧化硅、磷酸和甘油三酯。优选地,流变添加剂以液体制剂的至多10wt%的量添加。
更优选地,流变添加剂为无定形二氧化硅,例如气相二氧化硅。这种气相二氧化硅包括平均粒径为约100纳米的一级粒子。这些一级粒子可以相互粘附到聚集体上。聚集体可以结合成团聚物,其中聚集体之间的键不如聚集体内的一级粒子之间的键强。因此,气相二氧化硅容易分散并且也可以溶解在酸性液体制剂中。已经观察到,通过这种流变添加剂可以有效地调节酸性液体制剂的粘度。此外,观察到流变添加剂对稳定化硅酸的稳定性没有负面影响。
更优选地,本文的稳定化硅酸包含用于稳定化的季铵化合物,例如胆碱。此外,稳定化硅酸可以包含水。在一个最优选的实施方式中,本方面的酸性液体制剂包含2.5vol%-4.0vol%的硅、45wt%-60wt%的胆碱化合物和15wt%-30wt%的水,以及2%-8%的气相二氧化硅。胆碱化合物的量在本文中基于不含抗衡离子的胆碱离子。优选的抗衡离子是胆碱,但是可以代替氯或优选地除氯之外还存在其他抗衡离子。硅的量是通过原子吸收光谱法(Atomic Absorption Spectrometry,AAS)测量的元素硅。
可以看出,即使在前面没有明确讨论的情况下,关于一个方面讨论的优选实施方式也以对应的方式适用于本发明的另一个方面。
此外,观察到术语“稳定化硅酸”是指硅酸的一种形式,该硅酸被稳定化以抵抗聚合(也称为缩聚)成二氧化硅(即完全缩聚化的)。因此,硅酸为单体形式和/或为低聚形式,特别地由于胃肠道中存在的酸性条件,使得低聚物水解为单体在胃肠道中发生。不排除在本文中稳定化硅酸为所谓的胶体形式。一种实现稳定的已知方法在于使用稳定剂化合物,例如基于季铵化合物,并且最优选为胆碱。
术语“多糖”是本领域众所周知的。其被定义为具有六个或更多个重复单元的糖类化合物。这定义为(由USPTO)通过糖苷键相互连接的糖基。典型的多糖是纤维素、淀粉、糖原、几丁质。
术语“多糖衍生物”定义为其中至少部分重复单元被至少一种改性剂化学改性的多糖。典型的改性剂是烷基链和取代的烷基链,例如羟烷基和羧烷基。本文中的烷基优选为低级烷基,例如甲基、乙基、丙基、丁基。术语“纤维素衍生物”以相应的方式用作纤维素的替代版本。
如本申请中所指的,术语HPMC或另一种单独的纤维素的“衍生物”是指改性的HPMC,例如通过用有机酸改性以改善加工性能。这种衍生物还可以为盐形式或为共轭碱形式。
附图说明
参考附图,将进一步阐明本发明的这些方面和其他方面,其中:
图1图示示出了HPMC胶囊的溶解,该HPMC胶囊填充有胆碱-稳定化原硅酸和甘油的液体混合物。
具体实施方式
实施例
制备实施例1
用无水盐酸处理氯化胆碱。将四氯化硅(IV)添加到形成的胆碱溶液中(SiCl4与氯化胆碱的比率:1摩尔:1至5摩尔)。通过在-10℃至-30℃的温度范围内冷却的同时添加水(冰/冰水)来水解所得溶液。通过添加氢氧化钠并保持温度低于0℃来中和溶液。最终pH在1-1.5之间。用商购自Stratos的pH A分析仪(型号MS A405,Knick)来测量pH,该pH分析仪装配有具有Ag/AgCl2参比体系的Memosens pH电极和液态KCl电解质。用活性炭纯化后,通过过滤将沉淀物与活性炭一起除去。通过在真空下蒸馏来降低水浓度,直到获得含有按体积计2.5%-4%的硅和按重量计65%-80%的氯化胆碱和按重量计15%-30%的水的制剂。通过过滤除去蒸馏过程中形成的沉淀。使用移液管用含有浓缩的稳定化(原)硅酸的液体制剂来填充硬HPMC胶囊。可以使用非常小的HPMC胶囊(3型)来容纳190mg液体制剂。使用HPMC(Pharmacoat 603)的乙醇溶液密封被填充的胶囊。
制备实施例2
用无水盐酸处理氯化胆碱。将四氯化硅(IV)添加到形成的胆碱溶液中(SiCl4与氯化胆碱的比率:1摩尔:1至5摩尔)。通过在-10℃至-30℃的温度范围内冷却的同时添加水(冰/冰水)来水解所得溶液。通过添加氢氧化钠并保持温度低于0℃来中和溶液。最终pH在1-1.5之间,如使用上面定义的pH传感器测得的。用活性炭纯化后,通过过滤将沉淀物与活性炭一起除去。通过在真空下蒸馏来降低水浓度,直到获得含有按体积计2.5%-4%的硅和按重量计65%-80%的氯化胆碱和按重量计15%-30%的水的制剂。通过过滤除去蒸馏过程中形成的沉淀。向含有浓缩的稳定化(原)硅酸的液体制剂中添加5%的二氧化硅以将粘度从56mPas增加到93mPas。将获得的混合物封装到硬HPMC胶囊中。可以使用非常小的HPMC胶囊(3型)来容纳195mg制剂。使用HPMC(Pharmacoat603)的乙醇溶液密封被填充的胶囊。
制备实施例3
用无水盐酸处理氯化胆碱。将四氯化硅(IV)添加到形成的胆碱溶液中(SiCl4与氯化胆碱的比率:1摩尔:1至5摩尔)。通过在-10℃至-30℃的温度范围内冷却的同时添加水(冰/冰水)来水解所得溶液。通过添加氢氧化钠并保持温度低于0℃来中和溶液。最终pH在1-1.5之间。用活性炭纯化后,通过过滤将沉淀物与活性炭一起除去。通过在真空下蒸馏来降低水浓度,直到获得含有按体积计2.5%-4%的硅和按重量计65%-80%的氯化胆碱和按重量计15%-30%的水的制剂。通过过滤除去蒸馏过程中形成的沉淀。用甘油稀释液体稳定化原硅酸制剂,并使用标准方法将所得混合物封装到硬HPMC胶囊中。用至多0.66g液体混合物来填充HPMC胶囊(最大尺寸为0型)。使用HPMC(Pharmacoat 603)的乙醇溶液密封被填充的胶囊。
制备实施例4
用无水盐酸处理氯化胆碱。将四氯化硅(IV)添加到形成的胆碱溶液中(SiCl4与氯化胆碱的比率:1摩尔:1至5摩尔)。通过在-10℃至-30℃的温度范围内冷却的同时添加水(冰/冰水)来水解所得溶液。通过添加氢氧化钠并保持温度低于0℃来中和溶液。最终pH在1-1.5之间,如使用上面定义的pH传感器测得的。用活性炭纯化后,通过过滤将沉淀物与活性炭一起除去。通过在真空下蒸馏来降低水浓度,直到获得含有按体积计2.5%-4%的硅和按重量计65%-80%的氯化胆碱和按重量计15%-30%的水的制剂。通过过滤除去蒸馏过程中形成的沉淀。向含有浓缩的稳定化(原)硅酸的液体制剂中添加5%的二氧化硅以将粘度从56mPas增加到93mPas。将所得混合物封装到3型硬HPMC胶囊中,其包含195mg制剂。使用HPMC(Pharmacoat 603)的乙醇溶液密封被填充的胶囊。使用双工位封装设备,将密封的3型、含有浓缩的稳定化(原)硅酸的胶囊放入OO型HPMC主体中,该主体中已填充有400mg纯化鱼油(甘油三酯形式48%EPA和21%DHA),随后用OO型盖封闭被填充的外部主体。使用HPMC(Pharmacoat 603)的乙醇溶液密封所得的“胶囊包胶囊(capsule-in-capsules)”。
表征实施例1
将根据实施例3制备的填充有稳定化硅酸制剂的胶囊进行崩解测试。使用由Capsugel提供的细长的O型HPMC胶囊。崩解测试是在不同的水浓度下进行的,并根据标准Pharma Tests DTC-70和DIST-3来执行。其中,首先将胶囊在溶解系统中孵育24小时,随后在崩解系统中孵育12小时(总共36小时)。孵育后胶囊是完好无损的,即未观察到崩解迹象。结果示于表1。
表1.根据制备实施例3制备的填充有稳定化硅酸和甘油的混合物的HPMC胶囊的孵育时间。
表征实施例2
对根据实施例1填充的胶囊进行化学分析。将该胶囊包装在具有磁感应铝密封件和干燥剂袋的HDPE瓶中,并在室温下储存12个月。使用ETAAS和比色法对胶囊进行测试,并目测确定脆性。ETAAS是一种也称为电热原子吸收光谱法的测量技术。其用于测量元素硅的量(分析误差为10%)。比色实验是根据钼蓝法进行的。该方法专用于原硅酸(单体),即该测试测量原硅酸形式的硅的量(分析误差为10%)。
结果提供在表2和表3中。从其中可知,元素硅和硅酸的浓度均保持稳定。同样,如稳定的原硅酸浓度所证明的,储存在高相对湿度的铝/铝泡罩中的胶囊在12个月后未显示出聚合迹象(表3)。
表2.包装在带有磁感应密封件的HDPE瓶中的填充有胆碱-稳定化原硅酸的3型HPMC胶囊的化学稳定性。
表3.包装在ALU/ALU泡罩中的填充有胆碱-稳定化原硅酸的3型HPMC胶囊的化学稳定性。
表征实施例3
将根据制备实施例2制备的2000个胶囊在真空下(在200mbar的压力下)、室温下保持2小时。没有发现任何一个胶囊泄漏,并且胶囊重量没有变化(<0.03%)。将胶囊储存在alu/alu密封袋中,并在1个月后重复进行泄漏测试。储存的2000个胶囊中,没有任何一个泄漏,并且胶囊重量没有变化(<0.03%)。
表征实施例4
将根据制备实施例3制备的被填充的胶囊溶解在缓冲溶液中,该缓冲溶液是生理盐溶液。结果如图1所示。这些结果显示出,稳定化原硅酸在溶解介质中非常迅速且完全地从胶囊中释放出来而没有缩聚。
表征实施例5
将按照制备实施例3制备的胶囊在不同温度和不同相对湿度下孵育。使用ETAAS和比色法对胶囊进行测试,并目测确定脆性。ETAAS是一种也称为电热原子吸收光谱法的测量技术。其用于测量元素硅的量(分析误差为10%)。比色实验是根据钼蓝法进行的。该方法专用于原硅酸(单体),即该测试测量原硅酸形式的硅的量(分析误差为10%)。
结果在表4和表5中示出。从这些表中可以清楚地看出,胶囊的物理完整性和胆碱-稳定化硅酸的稳定性都很好。胶囊壳既不会变脆,也没有观察到稳定化硅酸的缩聚。
表4.根据制备实施例3制备的填充有胆碱-稳定化原硅酸和甘油的液体混合物的1型HPMC胶囊的化学和物理稳定性。
表5.根据制备实施例3制备的填充有胆碱-稳定化原硅酸和甘油的液体混合物的1型HPMC胶囊的化学和物理稳定性。
表征实施例6
将表征实施例5中指定的组合物A和组合物B在TA XT Plus纹理分析仪上进行压缩测试(10%分析误差)。结果在表6和表7中示出。
表6.对组合物A进行的压缩测试
表7.对组合物B进行的压缩测试
表征实施例7
重复表征实施例5中进行的测试,但是现在将制剂封装在更大的胶囊中,即O型而不是1型。此外,测试在更长的时间内进行,即是9个月而不是3个月。
表8.O型HPMC胶囊的长期化学和物理稳定性,该O型HPMC胶囊填充有胆碱-稳定化原硅酸和甘油的液体混合物。
表9.O型HPMC胶囊的长期化学和物理稳定性,该O型HPMC胶囊填充有胆碱-稳定化原硅酸和甘油的液体混合物。
比较实施例
使用根据实施例3中指定的方案制备的液体稳定化原硅酸与甘油的混合物来直接填充软明胶胶囊和硬明胶胶囊。胶囊在室温下储存在包装容器(HDPE瓶)中。将软明胶胶囊储存1周,然后评估该胶囊的状态。将硬明胶胶囊储存3个月,然后评估该胶囊的状态。
结果示于表1和表2。结果表明,水分别在明胶壳、稳定化硅酸混合物和包装容器中的空气之间迁移,从而导致胶囊变形和泄漏。使用特定的初级包装材料不能解决该稳定性问题。
表10.含多元醇混合物的填充有ch-OSA的软明胶胶囊的稳定性。对于每种组合物,将4粒胶囊在室温下且在具有受控温度和相对湿度(25℃,60%RH)的稳定柜中储存1周。1周后目视检查胶囊。
表11.含多元醇混合物的填充有ch-OSA的硬明胶胶囊的稳定性。对于每种组合物,将5粒胶囊在室温下在敞开的皮氏培养皿中或包装在HDPE瓶中储存3个月。3个月后目视检查胶囊。
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Claims (18)
1.胶囊,所述胶囊包含胶囊壳并填充有酸性液体制剂,所述酸性液体制剂包含稳定化硅酸,其中所述胶囊壳包含多糖和/或多糖衍生物。
2.根据权利要求1所述的胶囊,其特征在于,所述稳定化硅酸基本上包含硅酸的单体和/或低聚物,优选为原硅酸和/或其低聚物。
3.根据权利要求1或2所述的胶囊,其特征在于,所述液体制剂的pH在0至2.5、优选0.5至2.0、例如0.8至1.3的范围内。
4.根据前述权利要求中任一项所述的胶囊,其特征在于,所述硅酸用季铵化合物、例如胆碱化合物稳定化,其中所述季铵化合物优选以所述液体制剂的至少20wt%的浓度存在。
5.根据前述权利要求中任一项所述的胶囊,其特征在于,所述制剂包含至多30wt%的量的水,优选地至多20wt%的水,更优选地至多15wt%的水。
6.根据前述权利要求中任一项所述的胶囊,其特征在于,所述制剂的粘度在0.08.103mPas至2.0.103mPas的范围内。
7.根据权利要求6所述的胶囊,其特征在于,所述制剂还包含流变添加剂,所述流变添加剂优选选自以下组:无定形二氧化硅,例如气相二氧化硅、磷酸和/或其盐和甘油三酯。
8.根据前述权利要求中任一项、特别是权利要求7所述的胶囊,其特征在于,所述液体制剂含有至多20wt%、以及更优选至多10wt%的量的稀释剂或不含稀释剂。
9.根据前述权利要求中任一项所述的胶囊,其特征在于,所述多糖和/或多糖衍生物选自以下组:纤维素、纤维素衍生物、淀粉、改性淀粉、支链淀粉和葡聚糖及其混合物,并且优选选自以下组:纤维素和纤维素衍生物,例如烷基纤维素、烷基烷基纤维素、羧烷基纤维素、羟烷基纤维素、羟烷基烷基纤维素。
10.根据权利要求9所述的胶囊,其特征在于,所述纤维素和/或纤维素衍生物选自以下组:羟烷基纤维素、羟烷基烷基纤维素或衍生物,其中烷基为C1-C4烷基中的一个或多个,并且优选选自羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素和羟丙基甲基纤维素及其衍生物。
11.胶囊产品,所述胶囊产品包含至少一个存在于外胶囊内的内胶囊,其中,根据前述权利要求中任一项所述的胶囊作为所述内胶囊存在,并且其中,所述外胶囊还包含药学上或饮食上可接受的组合物。
12.根据权利要求11所述的胶囊产品,其特征在于,所述药学上和/或饮食上可接受的组合物为液体疏水制剂,并且例如包含油。
13.制备根据前述权利要求1-10中任一项所述的胶囊的方法,包括步骤:
制备稳定化硅酸的酸性液体制剂;
用所述液体制剂填充胶囊壳,以及
密封所述胶囊壳以得到所述胶囊。
14.硅食品补充剂,所述硅食品补充剂包含根据前述权利要求1-10中任一项所述的胶囊或根据权利要求11-12中所述的胶囊产品,以及其作为硅的来源的用途。
15.用于药物的根据权利要求1-10中任一项所述的胶囊或根据权利要求11-12中任一项所述的胶囊产品。
16.用于预防、抑制或治疗骨质流失、软骨退变、头发和指甲质量的流失以及皮肤老化疾病的根据权利要求15所述的胶囊或胶囊产品。
17.根据权利要求11-12或15-16所述的胶囊产品,其特征在于,所述饮食上和/或药学上可接受的组合物包含饮食上和/或药学上有效的成分。
18.酸性液体制剂,所述酸性液体制剂包含稳定化硅酸和流变添加剂,所述流变添加剂选自:无定形二氧化硅、磷酸和/或其盐和甘油三酯,特别地选自无定形二氧化硅,例如气相二氧化硅。
Applications Claiming Priority (3)
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EP18166152.1A EP3549578A1 (en) | 2018-04-06 | 2018-04-06 | Silicic acid formulation and use thereof |
EP18166152.1 | 2018-04-06 | ||
PCT/EP2019/058802 WO2019193200A1 (en) | 2018-04-06 | 2019-04-08 | Silicic acid formulation and use thereof |
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US (1) | US20210023125A1 (zh) |
EP (1) | EP3549578A1 (zh) |
JP (1) | JP7315654B2 (zh) |
KR (1) | KR20200141480A (zh) |
CN (1) | CN112261936A (zh) |
BR (1) | BR112020020470A2 (zh) |
CA (1) | CA3096534A1 (zh) |
EA (1) | EA202092418A1 (zh) |
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WO (1) | WO2019193200A1 (zh) |
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EP3632449A1 (en) | 2018-10-05 | 2020-04-08 | Bio Minerals N.V. | Silicic acids for use in the treatment of periodontitis |
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BR112014032948A2 (pt) * | 2012-07-02 | 2017-06-27 | Dsm Ip Assets Bv | cápsulas contendo timoquinona |
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- 2018-04-06 EP EP18166152.1A patent/EP3549578A1/en active Pending
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2019
- 2019-04-08 EA EA202092418A patent/EA202092418A1/ru unknown
- 2019-04-08 KR KR1020207032136A patent/KR20200141480A/ko not_active Application Discontinuation
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IL277892A (en) | 2020-11-30 |
WO2019193200A1 (en) | 2019-10-10 |
EA202092418A1 (ru) | 2021-03-10 |
JP2021523219A (ja) | 2021-09-02 |
CA3096534A1 (en) | 2019-10-10 |
US20210023125A1 (en) | 2021-01-28 |
BR112020020470A2 (pt) | 2021-03-23 |
KR20200141480A (ko) | 2020-12-18 |
JP7315654B2 (ja) | 2023-07-26 |
IL277892B1 (en) | 2024-06-01 |
EP3549578A1 (en) | 2019-10-09 |
AU2019247705A1 (en) | 2020-11-12 |
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