CN118593436A - 包含共加工的微晶纤维素和经表面反应碳酸钙的高性能赋形剂 - Google Patents
包含共加工的微晶纤维素和经表面反应碳酸钙的高性能赋形剂 Download PDFInfo
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- CN118593436A CN118593436A CN202410524616.2A CN202410524616A CN118593436A CN 118593436 A CN118593436 A CN 118593436A CN 202410524616 A CN202410524616 A CN 202410524616A CN 118593436 A CN118593436 A CN 118593436A
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- excipient
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- calcium carbonate
- nutritional
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Abstract
本发明涉及颗粒状药物或营养赋形剂,制备该颗粒状药物或营养赋形剂的方法,包含该颗粒状药物或营养赋形剂的药物或营养组合物以及制造药物或营养组合物的方法。
Description
本申请是基于申请日为2019年9月17日、申请号为201980060710.4、发明名称为“包含共加工的微晶纤维素和经表面反应碳酸钙的高性能赋形剂”的中国专利申请的分案申请。
技术领域
本发明涉及颗粒状药物或营养赋形剂,制备该颗粒状药物或营养赋形剂的方法,包含该颗粒状药物或营养赋形剂的药物或营养组合物以及制造药物或营养组合物的方法。
背景技术
微晶纤维素是药物和营养行业中最常用的赋形剂。作为直接压实填料和粘合剂,它具有出色的可压实性和粘合性能。但是,这种赋形剂的流动性能通常有限,因此进一步限制了流动性差的活性物质的稀释潜力和配制。因而通常有必要通过添加其他材料来调适性能,以用于改善特定需求。
用于药物或营养应用的赋形剂是本领域众所周知的。例如,US 4,744,987涉及用作药物赋形剂的物质组合物,其包含共加工的微晶纤维素和碳酸钙的经干燥的颗粒状附聚物,两种组分以约75:25至35:65的微晶纤维素:碳酸钙的重量比存在,并且彼此紧密缔合。所使用的碳酸钙优选是沉淀材料。
US2015/0283082A1涉及包含官能化的天然和/或合成碳酸钙、至少一种活性成分和至少一种崩解剂的快速崩解剂型,其中所述官能化的天然或合成碳酸钙是天然或合成碳酸钙与二氧化碳和一种或多种酸的反应产物,其中该二氧化碳通过酸处理就地形成和/或由外部来源供应,并且其中片剂在小于3分钟或3分钟内崩解。该至少一种崩解剂可选自改性纤维素胶、不溶性交联聚乙烯吡咯烷酮、乙醇酸淀粉、微晶纤维素、烷基纤维素酯、羟基烷基纤维素酯、羧烷基纤维素酯、藻酸盐、微晶纤维素及其多晶型、离子交换树脂、树胶、甲壳质、壳聚糖、粘土、结冷胶、交联泼拉克林共聚物、琼脂、明胶、糊精、丙烯酸聚合物、羧基甲基纤维素钠/钙、羟丙基甲基纤维素邻苯二甲酸酯、虫胶或其混合物,并且可存在的量为约0.3%重量-约10%重量,基于该官能化的天然或合成碳酸钙的重量计。
US 8,632,819B2涉及可用作可再压实的药物赋形剂的共加工的组合物,其包含碳酸钙粒子和微晶纤维素粒子,其中微晶纤维素:碳酸钙的重量比为大于75:25至可高达85:15。该碳酸钙是沉淀碳酸钙或研磨石灰石。
US 6,232,351B1涉及直接压片试剂,其包含共加工的以下物质的经干燥的颗粒:a.植物;b.微晶纤维素;和c.碳酸钙,其中这三种组分彼此紧密缔合。该碳酸钙是沉淀材料、开采的材料或收获的材料如牡蛎壳。
US 5,747,067涉及包含共加工的微晶纤维素和颗粒状USP碳酸钙的颗粒状药物片剂赋形剂组合物,其中碳酸钙的平均粒子尺寸为7-22μm,碳酸钙与微晶纤维素的重量比在70:30到90:10的范围内。该碳酸钙是研磨石灰石或沉淀碳酸钙。
然而,一直都需要提供高流动性能和高堆积密度的适用于药物和营养应用的赋形剂。除此之外,期望提供下述这样的赋形剂:该赋形剂具有快速崩解时间,较少的硬度依赖性以及较少的润滑剂敏感性,以及在遍及最终组合物中的改善的药物分布。此外,期望该赋形剂具有比微晶纤维素更高的压实性,并且因而允许对差压实性的活性物质进行压片并且减少或消除其他赋形剂的使用。
发明内容
因此,本发明的目的可被视为提供适用于药物和营养应用的赋形剂。本申请的另一个目的在于提供下述这样的赋形剂:该赋形剂具有高流动性和高堆积密度以及加快的崩解时间和较少的硬度依赖性。本申请的又一个目的在于提供下述这样的赋形剂:该赋形剂提供较少的润滑剂敏感性,以及在遍及最终组合物中的改善的药物分布。本申请的再一个目的在于提供下述这样的赋形剂:该赋形剂具有比微晶纤维素更高的压实性,并且因而允许对差压实性的活性物质进行压片并且减少或消除其他赋形剂的使用。
前述目的以及其他目的通过如在独立权利要求中在本文中定义的主题来解决。本发明的有利实施方案在本文中并且也在从属权利要求中定义。
根据本发明的一个方面,提供了一种颗粒状药物或营养赋形剂。该赋形剂包含a)微晶纤维素,和b)经表面反应碳酸钙,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50。
根据一种实施方案,该经表面反应碳酸钙具有:i)体积中值粒子尺寸d50为0.5-50μm,更优选1-40μm,甚至更优选1.2-30μm并且最优选1.5-15μm,和/或ii)使用氮气和根据ISO9277:2010的BET法测量的BET比表面积为5-200m2/g,优选15-150m2/g,更优选40-100m2/g,和/或iii)由汞孔隙率测定法测量结果计算的0.1-2.3cm3/g、更优选0.2-2.0cm3/g、尤其优选0.4-1.8cm3/g且最优选0.6-1.6cm3/g的粒子内侵入式比孔容。
根据另一种实施方案,i)该天然研磨碳酸钙选自大理石、白垩、石灰石及其混合物,或ii)该沉淀碳酸钙选自具有文石、球霰石或方解石晶型的沉淀碳酸钙及其混合物。
根据另一种实施方案,该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、柠檬酸、草酸、酸式盐、醋酸、甲酸及其混合物,优选地,该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、草酸、由选自Li+、Na+和/或K+的阳离子至少部分中和的H2PO4 -、由选自Li+、Na+、K+、Mg2+和/或Ca2+的阳离子至少部分中和的HPO4 2-、及其混合物,更优选地,该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、草酸或其混合物,并且最优选地,该至少一种H3O+离子供体是磷酸。
根据一种实施方案,该微晶纤维素具有i)松散堆积密度为0.20-0.52g/ml,更优选0.26-0.36g/ml,和/或ii)重量中值粒子尺寸d50为10-1000μm、优选15-500μm、最优选20-200μm。
根据另一种实施方案,该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至75:25,优选99:1至80:20并且最优选98:2至90:10。
根据又一种实施方案,该赋形剂包含共加工的微晶纤维素和经表面反应碳酸钙,其中该经表面反应碳酸钙与该微晶纤维素紧密缔合(association)。
根据一种实施方案,该赋形剂具有松散堆积密度为0.25-0.90g/ml,更优选为0.25-0.65g/ml。
根据另一方面,提供了一种用于制备如本文定义的颗粒状药物或营养赋形剂的方法。该方法包括以下步骤:
a)将微晶纤维素和经表面反应碳酸钙混合,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
b)共加工步骤a)中获得的混合物,从而获得该颗粒状药物或营养赋形剂。
根据该方法的一种实施方案,共加工步骤b)通过干法或湿法加工、优选高剪切混合、喷雾干燥、研磨或其混合来进行。
根据该方法的另一种实施方案,混合步骤a)在水性介质中进行以形成包含该微晶纤维素和该经表面反应碳酸钙的水性浆料。
根据再一个方面,提供了包含如本文定义的颗粒状药物或营养赋形剂和任选的至少一种活性成分的药物或营养组合物,优选地,该至少一种活性成分选自药物或营养活性成分、非活性药物或营养前体、生物活性成分、非活性生物前体及其混合物。
根据一种实施方案,该药物或营养组合物还包含至少一种辅助剂,该辅助剂选自天然或合成香味剂、天然或合成调味剂、天然或合成着色剂、天然或合成甜味剂、润滑剂、崩解剂、助流剂及其混合物。
根据再一个方面,提供了一种用于制造如本文所定义的药物或营养组合物的方法。该方法包括以下步骤:
a)提供如本文定义的颗粒状药物或营养赋形剂,
b)使该颗粒状药物或营养赋形剂经历干法制粒、湿法制粒、熔融制粒或直接压制,优选直接压制,从而获得该组合物。
根据一种实施方案,该方法还包括步骤c):使步骤b)之前的颗粒状药物或营养赋形剂或步骤b)中获得的组合物与至少一种活性成分和/或至少一种辅助剂接触,优选地,该至少一种活性成分选自药物或营养活性成分、非活性药物或营养前体、生物活性成分、非活性生物前体及其混合物,该辅助剂选自天然或合成香味剂、天然或合成调味剂、天然或合成着色剂、天然或合成甜味剂、润滑剂、崩解剂、助流剂及其混合物。
应理解,出于本发明的目的,以下术语具有以下含义:
术语“赋形剂”是指与药物或营养活性成分一起配制的非活性物质/成分。该赋形剂被有意添加到组合物中,以使活性成分能够以合适的形式施用于使用者并充当活性成分的载体。应理解,该赋形剂没有药用性能。
术语“药物”赋形剂是指适合于将药物活性成分配制成药物组合物如药物剂型的赋形剂。
术语“营养(nutraceutical)”赋形剂是指适合于将营养活性成分配制成营养组合物如营养剂型的赋形剂。
在本发明含义中的“天然研磨碳酸钙”(GCC)为自天然来源(例如石灰石、大理石或白垩)获得的碳酸钙,并且其通过湿式和/或干式处理如研磨、筛选和/或分级(例如借助于旋风器或分级器)进行加工。
在本发明含义中的“沉淀碳酸钙”(PCC)为合成的物质,通过在水性、半干燥或潮湿环境中在二氧化碳与石灰反应之后沉淀或通过钙和碳酸根离子源在水中沉淀而获得。PCC可以是球霰石、方解石或文石晶型。PCC被描述于例如以下文献中:EP 2 447 213A1、EP 2524898A1、EP 2 371 766A1、EP 1 712 597A1、EP 1 712 523A1或WO 2013/142473A1。
在本申请含义中的术语“经表面反应(surface-reacted)”将被用来指示材料已经经历了包括在利用H3O+离子供体处理时(例如,通过使用水溶性游离酸和/或酸式盐)在水性环境中部分溶解所述材料的过程,之后是可在不存在或存在另外的结晶添加剂的情况下发生的结晶过程。
在本发明上下文中的“H3O+离子供体”是酸和/或酸式盐,即包含酸性氢的盐。
如本文中所使用的术语“酸”是指在由和Lowry定义的含义中的酸(例如,H2SO4、HSO4 -)。
当在本说明书和权利要求书中使用术语“包括或包含(comprising)”时,并不排除其它未具体指出的具有主要或次要功能重要性的要素。出于本发明的目的,术语“由……构成(consisting of)”被认为是术语“包括或包含(comprising of)”的优选实施方案。如果在下文中定义一个组集(group)包括至少一定数目的实施方案,则这也被理解为公开了一个组集,其优选仅由这些实施方案构成。
无论何处使用术语“包括或包含(including)”或者“具有(having)”,这些术语被认为等同于上述的“包括或包含(comprising)”。
在谈论单数名词时使用不定冠词或定冠词如“a”、“an”或“the”的情况下,这包括了该名词的复数,除非一些情况下另外具体指出。
诸如“可获得(obtainable)”或“可定义(definable)”及“获得(的)(obtained)”或“定义(的)(defined)”的术语可互换使用。这例如意味着,除非上下文另外明确指出,否则术语“获得(的)”并不意味着指示例如一种实施方案必须通过例如术语“获得(的)”之后的步骤序列来获得,虽然术语“获得(的)”或“定义(的)”总是包括此类限制性理解作为优选实施方案。
在下文中,将更详细地阐述本发明赋形剂的细节和优选实施方案。应理解,这些技术细节和实施方案也适用于所有本发明的产品和方法。
颗粒状药用或营养赋形剂
该颗粒状药物或营养赋形剂包含a)微晶纤维素,和b)经表面反应碳酸钙,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50。
因此,本发明的一个要求是:该颗粒状药物或营养赋形剂包含微晶纤维素。
微晶纤维素优选通过以下方式制备:将由纤维质植物材料以浆料形式获得的纤维素利用稀无机酸溶液进行部分解聚。水解后,将由此获得的水解纤维素通过过滤进行纯化,并将水性浆料喷雾干燥以获得干燥的微晶纤维素。另外可选地,可以在沸腾温度下用盐酸对纤维素进行水解处理,以除去无定形部分并形成结晶纤维素的聚集体。可通过过滤收集聚集体,用水和氨水洗涤,并通过剧烈的机械手段例如搅拌机将其分解成小片段。
该微晶纤维素的来源和性质并不被认为是关键的。因此,该微晶纤维素可以是已知适合于药物或营养应用的任何微晶纤维素。
例如,该微晶纤维素可以是来自传统微晶纤维素制造工艺的湿饼,即还未干燥的材料。该微晶纤维素也可以是已被干燥的传统微晶纤维素。
该微晶纤维素的重量中值粒子尺寸d50优选为10-1000μm,更优选15-500μm并且最优选20-200μm。
额外地或另外可选地,该微晶纤维素具有的松散堆积密度为0.20-0.52g/ml,更优选为0.26-0.36g/ml。
例如,该微晶纤维素具有的松散堆积密度为0.20-0.52g/ml并且更优选为0.26-0.36g/ml,或者重量中值粒子尺寸d50为10-1000μm,优选15-500μm并且最优选20-200μm。
另外可选地,该微晶纤维素具有的松散堆积密度为0.20-0.52g/ml并且更优选为0.26-0.36g/ml,并且重量中值粒子尺寸d50为10-1000μm,优选15-500μm并且最优选20-200μm。
本发明的另一要求是:该赋形剂包含经表面反应碳酸钙。
应理解,该经表面反应碳酸钙是天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应。
在一种优选实施方案中,该经表面反应碳酸钙通过包括以下步骤的方法获得:(a)提供天然或沉淀碳酸钙的悬浮液,(b)向步骤(a)的该悬浮液中添加至少一种在20℃下具有0或更低的pKa值、或在20℃下具有0至2.5的pKa值的酸,以及(c)在步骤(b)之前、期间或之后利用二氧化碳处理步骤(a)的该悬浮液。根据另一种实施方案,该经表面反应碳酸钙通过包括以下步骤的方法获得:(A)提供天然或沉淀碳酸钙,(B)提供至少一种水溶性酸,(C)提供气态CO2,(D)使步骤(A)的所述天然或沉淀碳酸钙与步骤(B)的该至少一种酸并且与步骤(C)的CO2接触,其特征在于:(i)步骤(B)的该至少一种酸在20℃下具有大于2.5且小于或等于7的与其第一可用氢的电离相关的pKa,并且在此第一可用氢失去时形成能够形成水溶性钙盐的相应阴离子,并且(ii)在使该至少一种酸与天然或沉淀碳酸钙接触之后,另外提供至少一种水溶性盐,其在含氢盐的情况下在20℃下具有大于7的与该第一可用氢的电离相关的pKa,且其盐阴离子能够形成水不溶性钙盐。
“天然研磨碳酸钙”(GCC)优选选自含碳酸钙的矿物,所述矿物选自大理石、白垩、石灰石及其混合物。天然研磨碳酸钙可包含另外的天然存在的成分如碳酸镁、铝硅酸盐等。
通常,天然研磨碳酸钙的研磨可以是干式或湿式研磨步骤并且可例如在使得粉碎主要由使用辅助体冲击产生的条件下,用任何传统研磨装置进行,也即在以下的一种或多种中进行:球磨机、棒磨机、振动研磨机、轧碎机、离心冲击研磨机、立式珠磨机、磨碎机、销棒粉碎机、锤磨机、粉磨机、撕碎机、去块机、切割机(knife cutter)或本领域技术人员已知的其他此类设备。在含碳酸钙的矿物材料包含湿式研磨的含碳酸钙的矿物材料的情况下,研磨步骤可在使得发生自体研磨的条件下和/或通过水平球磨和/或本领域技术人员已知的其他此类方法来进行。由此获得的经湿式加工的研磨的天然碳酸钙可通过众所周知的方法,例如通过絮凝、过滤或强制蒸发(在干燥之前)来洗涤并脱水。后续干燥步骤(必要时)可在单一步骤(例如喷雾干燥)中进行,或者在至少两个步骤中进行。还常见地,这种矿物材料进行选矿步骤(例如浮选、漂白或磁性分离步骤)以去除杂质。
在本发明含义中的“沉淀碳酸钙”(PCC)为合成材料,通常通过在水性环境中在二氧化碳与氢氧化钙反应之后沉淀或通过将钙离子和碳酸根离子(例如,CaCl2及Na2CO3)从溶液中沉淀出来而获得。生产PCC的其他可能方式为石灰纯碱法,或者Solvay法,其中PCC为氨生产的副产物。沉淀碳酸钙以三种初级晶型存在:方解石、文石和球霰石,且对于这些晶型中的每一晶型而言存在许多不同的多晶型物(晶体惯态)。方解石具有三角结构,该三角结构具有典型的晶体惯态如偏三角面体的(S-PCC)、斜方六面体的(R-PCC)、六角形棱柱的、轴面的、胶体的(C-PCC)、立方的及棱柱的(P-PCC)。文石为正斜方晶结构,该正斜方晶结构具有成对六角形棱晶的典型晶体惯态,以及细长棱柱的、弯曲叶片状的、陡锥状、凿尖晶体、分叉树及珊瑚或蠕虫状的形式的多种分类。球霰石属于六方晶系。所获得的PCC浆料可机械脱水和干燥。
根据本发明的一种实施方案,该沉淀碳酸钙是下述这样的沉淀碳酸钙:其优选包含文石、球霰石或方解石矿物晶型,或其混合物。
沉淀碳酸钙可在用二氧化碳和至少一种H3O+离子供体处理之前通过与用于研磨如上所述的天然碳酸钙的相同方式进行研磨。
根据本发明的一种实施方案,天然研磨碳酸钙或沉淀碳酸钙为粒子的形式,所述粒子具有0.05-10.0μm、优选0.2-5.0μm并且最优选0.4-3.0μm的重量中值粒子尺寸d50。根据本发明的另一种实施方案,天然研磨碳酸钙或沉淀碳酸钙为粒子的形式,所述粒子具有0.15-30μm、优选0.6-15μm、更优选1.2-10μm、最优选1.5-4μm并且尤其是1.6μm的顶切粒子尺寸d98。
该天然研磨碳酸钙和/或沉淀碳酸钙可干燥使用或悬浮在水中。优选地,相应的浆料具有基于所述浆料的重量计在1%重量-90%重量、更优选3%重量-60%重量、甚至更优选5%重量-40%重量并且最优选10%重量-25%重量范围内的天然研磨碳酸钙和/或沉淀碳酸钙的含量。
用于制备经表面反应碳酸钙的该一种或多种H3O+离子供体可为在制备条件下产生H3O+离子的任何强酸、中强酸或弱酸或其混合物。根据本发明,该至少一种H3O+离子供体也可以是在制备条件下产生H3O+离子的酸式盐。
根据一种实施方案,该至少一种H3O+离子供体为在20℃下具有0或更小的pKa的强酸。
根据另一种实施方案,该至少一种H3O+离子供体为在20℃下pKa值为0-2.5的中强酸。如果在20℃下的pKa为0或更小,则该酸优选选自硫酸,盐酸或者其混合物。如果在20℃下的pKa为0-2.5,则H3O+离子供体优选选自H2SO3、H3PO4、草酸或其混合物。该至少一种H3O+离子供体也可以是酸式盐,例如HSO4 -或H2PO4 -(其为通过相应阳离子如Li+、Na+或K+至少部分中和的),或者HPO4 2-(其为通过相应阳离子如Li+、Na+、K+、Mg2+或Ca2+至少部分中和的)。该至少一种H3O+离子供体也可以是一种或多种酸和一种或多种酸式盐的混合物。
根据又另一种实施方案,该至少一种H3O+离子供体为弱酸,其具有在20℃下测量时为大于2.5且小于或等于7的pKa值(与第一可用氢的电离相关),并且具有能够形成水溶性钙盐的相应阴离子。之后,额外提供至少一种水溶性盐,其在含氢盐的情况下具有在20℃下测量时为大于7的pKa(与第一可用氢的电离相关)并且其盐阴离子能够形成水不溶性钙盐。根据更优选的实施方案,该弱酸具有在20℃下大于2.5至5的pKa值,并且更优选地,该弱酸选自醋酸、甲酸、丙酸及其混合物。所述水溶性盐的示例性阳离子选自钾、钠、锂及其混合物。在一种更优选的实施方案中,该阳离子为钠或钾。所述水溶性盐的示例性阴离子选自磷酸根、磷酸二氢根、磷酸单氢根、草酸根、硅酸根、其混合物及其水合物。在一种更优选的实施方案中,所述阴离子选自磷酸根、磷酸二氢根、磷酸单氢根、其混合物及其水合物。在一种最优选的实施方案中,所述阴离子选自磷酸二氢根、磷酸单氢根、其混合物及其水合物。可逐滴或在一个步骤中进行水溶性盐的添加。在逐滴添加的情况下,该添加优选在10分钟的时间周期内发生。更优选地,在一个步骤中添加所述盐。
根据本发明的一种实施方案,该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、柠檬酸、草酸、醋酸、甲酸及其混合物。优选地,该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、草酸、H2PO4 -(其为通过相应阳离子如Li+、Na+或K+至少部分中和的),HPO4 2-(其为通过相应阳离子如Li+、Na+、K+、Mg2+或Ca2+至少部分中和的),及其混合物,更优选地,该至少一种酸选自盐酸、硫酸、亚硫酸、磷酸、草酸或其混合物,并且最优选地,该至少一种H3O+离子供体是磷酸。
该一种或多种H3O+离子供体可作为浓缩溶液或更稀释的溶液被添加至该悬浮液中。优选地,该H3O+离子供体与该天然或沉淀碳酸钙的摩尔比为0.01至4,更优选0.02至2,甚至更优选0.05至1并且最优选0.1至0.58。
作为另外可选方案,也可在悬浮该天然或沉淀碳酸钙之前将该H3O+离子供体添加至水中。
在下一个步骤中,利用二氧化碳处理天然研磨碳酸钙或沉淀碳酸钙。如果诸如硫酸或盐酸的强酸被用于天然研磨碳酸钙或沉淀碳酸钙的H3O+离子供体处理,则二氧化碳自动形成。另外可选地或者额外地,二氧化碳可从外部来源供应。
H3O+离子供体处理和利用二氧化碳的处理可同时进行,当使用强酸或中强酸时情况就是如此。也可首先进行H3O+离子供体处理,例如利用在20℃下具有0-2.5范围内的pKa的中强酸来进行,其中二氧化碳原位形成,并且因此,二氧化碳处理将自动地与H3O+离子供体处理同时进行,接着进行利用从外部来源供应的二氧化碳的额外处理。
优选地,悬浮液中气态二氧化碳的浓度就体积而言使得比率(悬浮液体积):(气态CO2的体积)为1:0.05至1:20,甚至更优选为1:0.05至1:5。
在一种优选实施方案中,H3O+离子供体处理步骤和/或二氧化碳处理步骤重复至少一次,更优选多次。根据一种实施方案,在至少约5分钟、典型地约5-约30分钟的时间周期内添加该至少一种H3O+离子供体。另外可选地,在约30分钟、优选约45分钟并且有时约1小时或更长的时间周期内添加该至少一种H3O+离子供体。
在H3O+离子供体处理及二氧化碳处理之后,在20℃下测量的水性悬浮液的pH值自然地达到大于6.0、优选大于6.5、更优选大于7.0、甚至更优选大于7.5的值,由此将表面反应的天然或沉淀碳酸钙制备为具有大于6.0、优选大于6.5、更优选大于7.0、甚至更优选大于7.5的pH的水性悬浮液。
应理解,H3O+离子供体处理以及利用二氧化碳的处理可以在宽温度范围内进行。优选地,H3O+离子供体处理以及利用二氧化碳的处理可在室温或升高的温度下进行。例如,如果H3O+离子供体处理以及利用二氧化碳的处理在升高的温度下进行,则该处理优选在30-90℃、更优选40-80℃并且最优选50-80℃如60-80℃的范围内。
关于经表面反应的天然碳酸钙的制备的进一步细节公开在以下文献中:WO 00/39222A1,WO 2004/083316A1,WO 2005/121257A2,WO 2009/074492A1,EP 2264108A1,EP2264109A1和US 2004/0020410A1,这些参考文献的内容在此被包括在本申请中。
类似地,获得经表面反应的沉淀碳酸钙。正如可从WO 2009/074492A1详细获取的,经表面反应的沉淀碳酸钙通过如下方式获得:使沉淀碳酸钙与H3O+离子并且与溶解于水性介质中且能够形成水不溶性钙盐的阴离子在水性介质中接触,以形成经表面反应的沉淀碳酸钙的浆料,其中所述经表面反应的沉淀碳酸钙包含在沉淀碳酸钙的至少一部分的表面上形成的所述阴离子的不溶性的、至少部分结晶的钙盐。
所述溶解的钙离子对应于相对于沉淀碳酸钙被H3O+离子溶解而自然生成的溶解钙离子来说过量的溶解的钙离子,其中所述H3O+离子仅以该阴离子的抗衡离子的形式提供,也即经由添加酸或非钙酸式盐的形式的阴离子,并且不存在任何另外的钙离子或钙离子生成来源。
所述过量的溶解的钙离子优选通过添加可溶中性或酸式钙盐而提供,或通过添加原位产生可溶中性或酸式钙盐的酸或中性或酸式非钙盐而提供。
所述H3O+离子可通过添加酸或所述阴离子的酸式盐而提供,或通过添加同时用于提供所有或部分的所述过量的溶解的钙离子的酸或酸式盐而提供。
在制备经表面反应的天然研磨碳酸钙或沉淀碳酸钙的一种进一步优选的实施方案中,使天然研磨碳酸钙或沉淀碳酸钙在至少一种选自以下的化合物的存在下与该酸和/或二氧化碳反应:硅酸盐、二氧化硅、氢氧化铝、碱土铝酸盐如铝酸钠或铝酸钾、氧化镁或其混合物。优选地,该至少一种硅酸盐选自硅酸铝、硅酸钙或碱土金属硅酸盐。这些组分可在添加该酸和/或二氧化碳之前被添加至包含天然研磨碳酸钙或沉淀碳酸钙的水性悬浮液中。
另外可选地,硅酸盐和/或二氧化硅和/或氢氧化铝和/或碱土铝酸盐和/或氧化镁组分可在天然或沉淀碳酸钙与酸和二氧化碳已经开始反应时添加至天然或沉淀碳酸钙的水性悬浮液中。关于在至少一种硅酸盐和/或二氧化硅和/或氢氧化铝和/或碱土铝酸盐组分存在下制备经表面反应的天然或沉淀碳酸钙的其他细节被公开于WO 2004/083316A1中,该参考文献的内容在此被包含在本申请中。
可使经表面反应碳酸钙保持悬浮液状态,任选地通过分散剂使其进一步稳定化。可使用本领域技术人员已知的传统分散剂。优选的分散剂包括聚丙烯酸和/或羧甲基纤维素。
另外可选地,可干燥上述水性悬浮液,由此获得呈粒料或粉末形式的固体(也即干燥的或含有不呈流体形式的很少的水)经表面反应的天然研磨碳酸钙或沉淀碳酸钙。
该经表面反应碳酸钙可具有不同的粒子形状,例如玫瑰、高尔夫球和/或大脑的形状。
根据一种实施方案,该经表面反应碳酸钙具有使用氮气和BET方法测量的5m2/g至200m2/g、优选15m2/g至150m2/g并且最优选40m2/g至100m2/g的比表面积。在本发明含义中的BET比表面积被定义为粒子的表面积除以粒子的质量。如本文中所使用,该比表面积使用BET等温线通过吸附测量(ISO 9277:2010)且以m2/g具体指定。
额外地或另外可选地,该经表面反应碳酸钙具有0.5-50μm、优选1-40μm、更优选1.2-30μm且最优选1.5至15μm的体积中值粒子尺寸d50。
此外可优选地,该经表面反应碳酸钙粒子具有2-150μm、优选4-100μm、更优选6-80μm、又更优选8-60μm且最优选8-30μm的体积顶切粒子尺寸d98。
在本申请通篇中,值dx表示下述这样的直径:相对于该直径,x%的粒子具有小于dx的直径。这意味着d98值是指下述这样的粒子尺寸:其中所有粒子的98%小于该粒子尺寸。d98值也被称作“顶切(top cut)”。dx值可以用体积或重量百分数给出。d50(重量)值因而是重量中值粒子尺寸,也即所有颗粒的50%重量小于该粒子尺寸,并且d50(体积)值是体积中值粒子尺寸,也即所有颗粒的50%体积小于该粒子尺寸。
本文中的经表面反应碳酸钙的“粒子尺寸”被描述为基于体积的粒子尺寸分布。使用Malvern Mastersizer 2000激光衍射系统评价体积中值颗粒直径d50。使用MalvernMastersizer 2000激光衍射系统测量的d50或d98值指示出的直径值为:分别50%或98%体积的粒子具有小于这个值的直径。通过测量获得的原始数据使用米氏理论、以粒子折射率1.57以及吸收系数0.005进行分析。
在本申请的通篇中,重量中值颗粒直径通过沉降法测量,所述沉降法是在重力场中的沉降行为的分析。使用Micromeritics Instrument Corporation的SedigraphTM 5120进行测量。方法及仪器为本领域技术人员所知且通常用于确定填料和颜料的颗粒尺寸。在0.1%重量Na4P2O7的水溶液中进行测量。使用高速搅拌器及超声分散样品。
方法及仪器为本领域技术人员所知且通常用于确定填料和颜料的颗粒尺寸。
该赋形剂在最终组合物中主要用作填料和/或粘合剂。它还能够缔合和运输活性成分。该缔合优选是吸附即加载到赋形剂的表面上和/或内部。应理解,可以通过本领域技术人员众所周知的不同方法来实现利用至少一种活性成分对赋形剂的加载。
优选地,该经表面反应碳酸钙具有由汞孔隙率测定法测量结果计算的粒子内孔隙率为5%体积至50%体积,优选20%体积至50%体积,尤其是30%体积至50%体积。
因此,以每单位粒子体积的孔体积确定的粒子内孔隙率优选为20%体积至99%体积,更优选30%体积至80%体积,甚至更优选40%体积至70%体积并且最优选50%体积至65%体积,由汞孔隙率测定法测量结果计算。
优选地,该经表面反应碳酸钙具有由汞孔隙率测定法测量结果计算的0.1-2.3cm3/g、更优选0.2-2.0cm3/g、尤其优选0.4-1.8cm3/g且最优选0.6-1.6cm3/g的粒子内侵入式比孔容。
该经表面反应碳酸钙的粒子内孔尺寸优选为0.004-1.6μm,更优选0.005-1.3μm,特别优选0.006-1.15μm并且最优选0.007-1.0μm,例如0.004-0.16μm,由汞孔隙率测定法测量结果确定。
根据一种示例性的实施方案,该经表面反应碳酸钙具有体积中值粒子尺寸d50为0.5-50μm,更优选1-40μm,甚至更优选1.2-30μm并且最优选1.5-15μm;和/或使用氮气和根据ISO 9277:2010的BET法测量的BET比表面积为5-200m2/g,优选15-150m2/g,更优选40-100m2/g;和/或由汞孔隙率测定法测量结果计算的0.1-2.3cm3/g、更优选0.2-2.0cm3/g、尤其优选0.4-1.8cm3/g且最优选0.6-1.6cm3/g的粒子内侵入式比孔容。
例如,该经表面反应碳酸钙具有体积中值粒子尺寸d50为0.5-50μm,更优选1-40μm,甚至更优选1.2-30μm并且最优选1.5-15μm,以及使用氮气和根据ISO 9277:2010的BET法测量的BET比表面积为5-200m2/g,优选15-150m2/g,更优选40-100m2/g;以及由汞孔隙率测定法测量结果计算的0.1-2.3cm3/g、更优选0.2-2.0cm3/g、尤其优选0.4-1.8cm3/g且最优选0.6-1.6cm3/g的粒子内侵入式比孔容。
根据本发明的一种实施方案,该经表面反应碳酸钙包含至少一种酸的阴离子的水不溶性的、至少部分结晶的钙盐,其形成于该天然研磨碳酸钙或沉淀碳酸钙的表面上。根据一种实施方案,该至少一种酸的阴离子的水不溶性的、至少部分结晶的盐至少部分地、优选完全地覆盖该天然研磨碳酸钙或沉淀碳酸钙的表面。取决于所使用的至少一种酸,该阴离子可以是硫酸根、亚硫酸根、磷酸根、柠檬酸根、草酸根、乙酸根、甲酸根和/或氯离子。
例如,磷酸、H2PO4 -或HPO4 2-作为H3O+离子供体的使用可导致羟磷灰石的形成。因此,在一种优选的实施方案中,该至少一种水不溶性钙盐是羟磷灰石。
根据一种实施方案,该至少一种水不溶性钙盐是羟磷灰石,其中该经表面反应碳酸钙提供的羟磷灰石对方解石、文石和/或球霰石(优选对方解石)的比例以重量计为在1:99至99:1的范围内。优选地,该经表面反应碳酸钙提供的羟磷灰石对方解石、文石和/或球霰石(优选对方解石)的比例以重量计为在1:9至9:1、优选1:7至8:1、更优选1:5至7:1且最优选1:4至7:1的范围内。
以类似的方式,其他H3O+离子供体的使用可导致在该经表面反应碳酸钙的表面的至少一部分上形成非碳酸钙的相应水不溶性钙盐。在一种实施方案中,该至少一种水不溶性钙盐因而选自磷酸八钙、羟磷灰石、氯磷灰石、氟磷灰石、碳酸磷灰石及其混合物,其中该经表面反应碳酸钙显示出该至少一种水不溶性钙盐对方解石、文石和/或球霰石(优选对方解石)的比例以重量计在1:99至99:1、优选1:9至9:1、更优选1:7至8:1、又更优选1:5至7:1且最优选1:4至7:1的范围内。
为了实现本发明的优点,要求该微晶纤维素(MCC)与该经表面反应碳酸钙(SRCC)的重量比为99.9:0.1至50:50。优选地,该微晶纤维素(MCC)与该经表面反应碳酸钙(SRCC)的重量比为99.9:0.1至75:25,优选地为99:1至80:20,并且最优选为98:2至90:10。
应理解,本发明赋形剂的微晶纤维素与经表面反应碳酸钙彼此紧密缔合。因此,该微晶纤维素和该经表面反应碳酸钙优选进行共加工。
也就是说,该赋形剂包含共加工的微晶纤维素和经表面反应碳酸钙,因为该经表面反应碳酸钙与该微晶纤维素紧密缔合。优选地,该赋形剂通过包括以下步骤的方法获得:
a)将微晶纤维素和经表面反应碳酸钙混合,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
b)共加工步骤a)中获得的混合物,从而获得该颗粒状药物或营养赋形剂。
优选地,步骤b)中的共加工通过干法或湿法加工、优选高剪切混合、喷雾干燥、研磨或其混合来进行。
在本申请含义中的术语“颗粒(状)(particulate)”是指由多个粒子(particle)组成的材料。所述多个粒子可例如通过其粒子尺寸分布来定义。表述“颗粒(状)”可包括粒料、粉末、颗粒(grains)、片剂或碎屑(crumbles)。
优选地,该赋形剂具有的松散堆积密度为0.25-0.90g/ml,更优选为0.25-0.65g/ml。
根据另一个方面,本发明涉及制备颗粒状药物或营养赋形剂的方法。该方法包括以下步骤:
a)将微晶纤维素和经表面反应碳酸钙混合,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
b)共加工步骤a)中获得的混合物,从而获得该颗粒状药物或营养赋形剂。
关于赋形剂、经表面反应碳酸钙、微晶纤维素的定义及其优选实施方案,可参考以上在讨论本发明的颗粒状药物或营养赋形剂的技术细节时所提供的陈述。
在一种实施方案中,用于制备颗粒状药物或营养赋形剂的方法由以下步骤构成:
a)将微晶纤维素和经表面反应碳酸钙混合,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
b)共加工步骤a)中获得的混合物,从而获得该颗粒状药物或营养赋形剂。
微晶纤维素与经表面反应碳酸钙混合的步骤a)优选在混合条件下进行,以实现混合微晶纤维素和经表面反应碳酸钙的均匀混合物。该均匀混合物优选使得该经表面反应碳酸钙均匀地分布在该微晶纤维素内。本领域技术人员将根据其工艺设备来调适这些混合条件(例如混合托盘的配置和混合速度)。
在一种实施方案中,混合步骤a)可通过将微晶纤维素和经表面反应碳酸钙以干燥状态混合来进行。
优选地,混合步骤a)在水性介质中进行,以形成包含该微晶纤维素和该经表面反应碳酸钙的水性浆料。这种实施方案是有利的,因为其特别导致获得微晶纤维素与经表面反应碳酸钙的均匀混合物。
所形成的水性浆料优选具有5-80%重量的固体含量,基于该水性浆料的总重量计。根据一种优选的实施方案,该水性浆料的固体含量为8-70%重量,更优选8-60%重量并且最优选10-40%重量,基于该水性浆料的总重量计。
术语“水性”浆料是指下述这样的体系:在该体系中液相包含水,优选由水构成。但是,所述术语并不排除水性浆料的液相包含少量的至少一种与水混溶的有机溶剂,所述有机溶剂选自甲醇、乙醇、丙酮、乙腈、四氢呋喃及其混合物。如果该水性浆料包含至少一种与水混溶的有机溶剂,则该水性浆料的液相以0.1-40.0%重量、优选0.1-30.0%重量、更优选0.1-20.0%重量并且最优选0.1-10.0%重量的量包含该至少一种与水混溶的有机溶剂,基于该水性浆料的液相的总重量计。例如,该水性浆料的液相由水构成。
在一种优选的实施方案中,该水性浆料由水、该微晶纤维素和该经表面反应碳酸钙构成。
应理解,在进行方法步骤a)之前,可以通过轻微研磨(或研磨)将该经表面反应碳酸钙预活化。也就是说,可以使预活化的经表面反应碳酸钙进行方法步骤a),即在方法步骤a)中与该微晶纤维素混合。
根据本方法的步骤b),步骤a)中获得的混合物进行共加工,从而获得该颗粒状药物或营养赋形剂。
应理解,术语“共加工(co-processing)”或“共加工的(co-processed)”是指一种使得在所得赋形剂中该经表面反应碳酸钙与该微晶纤维素紧密缔合的方法或工艺步骤。
例如,共加工步骤b)可以通过干法或湿法进行。特别地,优选通过高剪切混合、喷雾干燥、研磨或其混合来进行共加工步骤b)。
应理解,步骤b)中使用的方法优选取决于步骤a)中获得的混合物是该经表面反应碳酸钙与该微晶纤维素的干燥混合物还是水性浆料。
例如,如果在步骤a)中获得该经表面反应碳酸钙与该微晶纤维素的干燥混合物,则优选通过干法进行共加工步骤b)。在一种实施方案中,共加工步骤b)通过高剪切混合和/或研磨,优选通过高剪切混合或研磨,例如通过高剪切混合来进行。
高剪切混合和研磨在本领域中是众所周知的,并且本领域技术人员将根据其工艺设备来调适混合或研磨条件(例如混合托盘的配置和混合速度)。混合速度可以例如为1000-3000rpm。例如,可以使用德国Somakon Verfahrenstechnik UG的混合物。
在一种实施方案中,可以将该经表面反应碳酸钙轻微研磨(或研磨),然后与该微晶纤维素混合并且共加工,这通过使混合物进行高剪切混合来进行。
如果在步骤a)中获得该经表面反应碳酸钙与该微晶纤维素的水性浆料,则优选通过喷雾干燥或研磨、优选喷雾干燥来进行共加工步骤b)。
优选地,步骤a)中获得的混合物为水性浆料的形式,并且共加工步骤b)通过喷雾干燥进行。
喷雾干燥在本领域中是众所周知的,并且本领域技术人员将根据其工艺设备来调适相应的条件(例如喷雾压力、入口和出口温度以及泵)。
在一种优选的实施方案中,该颗粒状药物或营养赋形剂通过包括以下步骤的方法制备:
a)将微晶纤维素和经表面反应碳酸钙混合,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
b)共加工步骤a)中获得的混合物,从而获得该颗粒状药物或营养赋形剂。
根据另一个方面,提供了该颗粒状药物或营养赋形剂用于制造药物或营养组合物的用途。
关于该颗粒状药物或营养赋形剂的定义及其优选实施方案,可参考以上在讨论本发明的颗粒状药物或营养赋形剂的技术细节时所提供的陈述。
应理解,该颗粒状药物或营养赋形剂提供了优异的流动性性能。
因此,在另一方面中,本发明涉及共加工的微晶纤维素和经表面反应碳酸钙用于改善赋形剂的流动性性能的用途。
额外地或另外可选地,该颗粒状药物或营养赋形剂与单独的微晶纤维素相比表现出较高的堆积密度的特征。
因此,在另一方面中,提供了共加工的微晶纤维素和经表面反应碳酸钙用于提高赋形剂的松散堆积密度的用途。例如,该赋形剂具有的松散堆积密度为0.25-0.90g/ml,更优选为0.25-0.65g/ml。
药物或营养组合物
本发明在另一方面中涉及药物或营养组合物,其包含该颗粒状药物或营养赋形剂和任选的至少一种活性成分。
关于该颗粒状药物或营养赋形剂的定义及其优选实施方案,可参考以上在讨论本发明的颗粒状药物或营养赋形剂的技术细节时所提供的陈述。
应理解,在被制造为药物或营养组合物之前,该药物或营养赋形剂可首先用该至少一种活性成分加载或与之混合。在这种实施方案中,本发明因而涉及包含该颗粒状药物或营养赋形剂和至少一种活性成分的药物或营养组合物。
另外可选地,可首先将该药物或营养赋形剂制造为药物或营养组合物。在这种实施方案中,本发明因而涉及一种药物或营养组合物,其由该颗粒状药物或营养赋形剂和用于制备该组合物的任选的辅助剂构成,即不含活性成分。随后,由该颗粒状药物或营养赋形剂和任选的辅助剂构成的药物或营养组合物可进一步用活性成分加载。在这种实施方案中,本发明涉及一种药物或营养组合物,其包含该颗粒状药物或营养赋形剂和至少一种活性成分和任选的一种或多种辅助剂。
该赋形剂是递送活性成分的优良试剂,该活性成分被加载到该赋形剂上或与之混合。因此,通常,任何试剂均适合于由本发明的赋形剂运输。例如,活性成分例如是从以下组中选择的那些:药物或营养活性成分,非活性药物或营养前体,生物活性成分,非活性生物前体及其混合物。根据一种实施方案,至少一种活性成分与赋形剂缔合。
在本发明的含义中,术语“活性成分”是指在有机体中具有特定效果且在人类、动物、微生物和/或植物中引起特定反应的物质。
应理解,该活性成分可为手性化合物。因而,活性成分涵盖(R)-对映异构体、(S)-对映异构体及其混合物,例如外消旋混合物。
额外地或另外可选地,该成分可为异构化合物。因而,该活性成分涵盖(Z)-异构体、(E)-异构体及其混合物。
在本发明的上下文中,活性成分还涵盖将在随后的阶段被活化的非活性药物、营养和生物前体。
这类非活性前体的活化是本领域技术人员已知的并且常见地用在例如胃和/或胃肠途径中的活化,例如酸性活化,胰蛋白酶裂解,糜蛋白酶裂解或胃蛋白酶原裂解。
在本领域技术人员的理解范围内,所提及的活化方法仅具有说明性特性,且不旨在具有限制性特性。
该药物活性成分或其药物非活性前体优选选自合成来源、半合成来源、天然来源及其组合的药物活性成分或药物非活性前体。
因而,药物活性成分涉及合成来源、半合成来源、天然来源及其组合的药物活性成分。另外,该药物活性成分的药物非活性前体涉及合成来源、半合成来源、天然来源及其组合的药物非活性前体并且将在随后阶段中被活化成相应的药物活性成分。
应注意,该药物活性成分或其药物非活性前体可为本领域技术人员已知的任何此类化合物。
药物活性成分因而包括当施用于人和/或动物时提供预防和/或治疗性能的任何化合物。实例包括但不限于药物活性剂、治疗活性剂、兽用活性剂和生长调节剂。
该药物活性成分或其药物非活性前体可为抗炎剂。这种试剂可包括但不限于非类固醇抗炎剂或NSAID,例如丙酸衍生物;乙酸衍生物;芬那酸衍生物;联苯羧酸衍生物;和昔康(oxicams)。所有这些NSAID被充分描述于Sunshine等人的美国专利第4,985,459号中,关于这些NSAID的描述,其全文通过引用并入本文中。可用的NSAID的实例包括乙酰水杨酸、布洛芬(ibuprofen)、萘普生(naproxen)、苯洛芬(benoxaprofen)、氟比洛芬(flurbiprofen)、非诺洛芬(fenoprofen)、芬布芬(fenbufen)、酮洛芬(ketoprofen)、吲哚洛芬(indoprofen)、吡洛芬(pirprofen)、卡洛芬(carprofen)、奥沙普嗪(oxaprozin)、普拉洛芬(pranoprofen)、微洛芬(microprofen)、硫洛芬(tioxaprofen)、舒洛芬(suprofen)、阿明洛芬(alminoprofen)、噻洛芬酸(tiaprofenic acid)、氟洛芬(fluprofen)、布氯酸(bucloxic acid)及其混合物。
同样可用的是类固醇抗炎药如氢化可的松等,以及COX-2抑制剂如美洛昔康(meloxicam)、塞来昔布(celecoxib)、罗非考昔(rofecoxib)、伐地考昔(valdecoxib)、艾托考昔(etoricoxib)或其混合物。可使用任何上述抗炎剂的混合物。
可用作药物活性成分或其药物非活性前体的其他材料包括常见已知的口腔和咽喉产品。这些产品包括但不限于上呼吸道试剂如苯肾上腺素、苯海拉明、右美沙芬(dextromethorphan)、溴己新和氯苯吡胺(chiorpheniramine);胃肠试剂如法莫替丁(famotidine)、洛哌丁胺(loperamide)和聚二甲基硅油;抗真菌剂如硝酸咪康唑(miconazole nitrate);抗生素和镇痛剂如酮洛芬和氟比洛芬(fluribuprofen)。
该药物活性成分或其药物非活性前体也可选自焦亚硫酸钠、丁基羟基甲苯、丁基化羟基苯甲醚。
该药物活性成分或其药物非活性前体也可选自麻黄碱(ephedrine)、镁加铝(magaldrate)、假麻黄碱(pseudoephedrine)、西地那非(sildenafil)、利多卡因(xylocaine)、苯扎氯铵(benzalconiumchloride)、咖啡因(caffeine)、去养肾上腺素(phenylephrine)、安非拉酮(amfepramone)、奥利司他(orlistat)、对乙酰氨基酚(acetaminophen)、阿司匹林(aspirin)、格列酮(glitazones)、二甲双胍(metformin)、氯丙嗪(chlorpromazine)、乘晕宁(dimenhydrinat)、多潘立酮(domperidone)、美克洛嗪(meclozine)、甲氧氯普胺(metoclopramide)、奥丹西隆(odansetron)、泼尼松龙(prednisolone)、普鲁米近(promethazine)、阿伐斯汀(acrivastine)、西替利嗪(cetirizine)、桂利嗪(cinnarizine)、氯马斯汀(clemastine)、赛克利嗪(cyclizine)、地氯雷他定(desloratadine)、右氯苯那敏(dexchlorpheniramine)、茶苯海明(dimenhydrinate)、依巴司汀(ebastine)、非索非那定(fexofenadine)、布洛芬(ibuprofen)、左沃普洛辛(levolevoproricin)、氯雷他定(loratadine)、美克洛嗪(meclozine)、咪唑斯汀(mizolastine)、普鲁米近(promethazine)、咪康唑(miconazole)、二乙酸氯己定(chlorhexidine diacetate)、氟化物、十肽KSL(decapeptide KSL)、氟化铝、氨基螯合钙(aminochelated calcium)、氟化铵、氟硅酸铵、单氟磷酸铵、氟化钙、葡萄糖酸钙、甘油磷酸钙、乳酸钙、单氟磷酸钙、碳酸钙、尿素、氯化十六烷基吡啶氯己定、二葡萄糖酸氯己定(chlorhexidine digluconate)、氯化氯己定(chlorhexidine chloride)、氯己定二乙酸酯(chlorhexidine diacetate)、CPP酪蛋白磷酸肽(CPP caseine phosphopeptide)、赫克特丁(hexetedine)、十八碳烯基氟化铵(octadecentyl ammoniumfluoride)、氟硅酸钾、氯化钾、单氟磷酸钾、碳酸氢钠、碳酸钠、氟化钠、氟硅酸钠、单氟磷酸钠、三聚磷酸钠、氟化亚锡、硬脂酰三羟乙基丙二胺二氢氟化物、氯化锶、焦磷酸四钾、焦磷酸四钠、正磷酸三钾、正磷酸三钠、藻酸、氢氧化铝、碳酸氢钠、西地那非(sildenafil)、他达拉非(tadalafil)、伐地那非(vardenafil)、育亨宾(yohimbine)、西咪替丁(cimetidine)、尼沙替丁(nizatidine)、雷尼替丁(ranitidine)、乙酰水杨酸、氯吡格雷(clopidogrel)、乙酰半胱氨酸、溴己新(bromhexine)、可待因(codeine)、右美沙芬(dextromethorphan)、苯海拉明(diphenhydramine)、诺斯卡品(noscapine)、苯丙醇胺(phenylpropanolamine)、维生素D、辛伐他汀(simvastatin)、吡沙可啶(bisacodyl)、乳糖醇(lactitol)、乳果糖(lactulose)、氧化镁、匹克硫酸钠、番泻叶苷(senna glycosides)、苯佐卡因(benzocaine)、利多卡因(lidocaine)、四卡因(tetracaine)、阿莫曲坦(almotriptan)、依来曲坦(eletriptan)、那拉曲坦(naratriptan)、利扎曲坦(rizatriptan)、舒马曲坦(sumatriptan)、佐米曲坦(zolmitriptan)、钙、铬、铜、碘、镁、锰、钼、磷、硒、锌、氯胺、氢过氧化物、甲硝唑、曲安奈德(triamcinolonacetonide)、苯索氯铵(benzethonium chl.)、十六基吡啶氯(cetyl pyrid.chl.)、氯己定、氟化物、利多卡因、双性霉素(amphotericin)、咪康唑(miconazole)、制霉菌素(nystatin)、鱼油、银杏(ginkgo biloba)、人参、姜、紫松果菊(purple coneflower)、锯棕榈(saw palmetto)、西替利嗪(cetirizine)、左旋西替利嗪(levocetirizine)、氯雷他定(loratadine)、双氯芬酸(diclofenac)、氟比洛芬(flurbiprofen)、阿伐斯丁假麻黄碱(acrivastine pseudoephedrine)、氯雷他定假麻黄碱(loratadine pseudoephedrine)、葡糖胺、透明质酸、十肽KSL-W、十肽KSL、白藜芦醇(resveratrol)、迷索前列醇(misoprostol)、安非他酮(bupropion)、盐酸恩丹西酮(ondansetron HCl)、埃索美拉唑(esomeprazole)、兰索拉唑(lansoprazole)、奥美拉唑(omeprazole)、泮托拉唑(pantoprazole)、雷贝拉唑(rabeprazole)、细菌等、洛哌丁胺(loperamide)、聚二甲基础硅油(simethicone)、乙酰水杨酸等、硫糖铝(sucralfate)、克霉唑(clotrimazole)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、特比萘芬(terbinafine)、别嘌呤醇(allopurinol)、丙磺舒(probenecid)、阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、烟酸(nicotinic acid)、普伐他汀(pravastatin)、罗素他汀(rosuvastatin)、辛伐他汀(simvastatin)、匹鲁卡品(pilocarpine)、萘普生(naproxen)、阿仑膦酸盐(alendronate)、依替膦酸盐(etidronate)、雷诺昔酚(raloxifene)、利塞膦酸盐(risedronate)、苯并二氮卓类(benzodiazepines)、戒酒硫(disulphiram)、纳曲酮(naltrexone)、丁丙诺啡(buprenorphine)、可待因(codeine)、右旋丙氧吩(dextropropoxyphene)、芬太尼(fentanyl)、氢吗啡酮(hydromorphone)、凯托米酮(ketobemidone)、酮洛芬(ketoprofen)、美沙酮(methadone)、吗啡(morphine)、萘普生(naproxen)、尼可吗啡(nicomorphine)、羟考酮(oxycodone)、哌替啶(pethidine)、曲马多(tramadol)、阿莫西林(amoxicillin)、氨苄青霉素(ampicillin)、阿奇霉素(azithromycin)、环丙沙星(ciprofloxacin)、克拉霉素(clarithromycin)、强力霉素(doxycyclin)、红霉素(erythromycin)、夫西地酸(fusidic acid)、赖甲环素(lymecycline)、甲硝唑(metronidazole)、莫西沙星(moxifloxacin)、氧氟沙星(ofloxacin)、土霉素(oxytetracycline)、苯氧基甲基青霉素 (phenoxymethylpenicillin)、利福霉素(rifamycins)、罗红霉素(roxithromycin)、磺胺噻唑(sulphamethizole)、四环素(tetracycline)、甲氧苄啶(trimethoprim)、万古霉素(vancomycin)、阿卡波糖(acarbose)、格列本脲(glibenclamide)、格列齐特(gliclazide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、胰岛素(insulin)、瑞格列奈(repaglinide)、甲苯磺丁脲(tolbutamide)、奥司他韦(oseltamivir)、阿昔洛韦(aciclovir)、泛昔洛韦(famciclovir)、喷昔洛韦(penciclovir)、缬更昔洛韦(valganciclovir)、氨氯地平(amlopidine)、地尔硫卓(diltiazem)、非洛地平(felodipine)、硝苯地平(nifedipine)、维拉帕米(verapamil)、非那雄胺(finasteride)、米诺地尔(minoxidil)、丁丙诺啡(buphrenorphin)、氯压定(clonidine)、美沙酮(methadone)、纳曲酮(naltrexone)、钙拮抗剂(calcium antagonists)、氯压定(clonidine)、麦角胺(ergotamine)、β-阻断剂(β-blockers)、醋氯芬酸(aceclofenac)、塞内昔布(celecoxib)、右布洛芬(dexiprofen)、依托度酸(etodolac)、吲哚美辛(indometacin)、酮洛芬(ketoprofen)、酮咯酸(ketorolac)、氯诺昔康(lornoxicam)、美洛昔康(meloxicam)、萘丁美酮(nabumetone)、厄罗昔康(oiroxicam)、帕瑞考昔(parecoxib)、保泰松(phenylbutazone)、吡罗昔康(piroxicam)、噻洛芬酸(tiaprofenic acid)、托芬那酸(tolfenamic acid)、阿立哌唑(aripiprazole)、氯丙嗪(chlorpromazine)、氯丙硫葸(chlorprothixene)、氯氮平(clozapine)、氟哌噻吨(flupentixol)、氟非那嗪(fluphenazine)、氟哌啶醇(haloperidol)、碳酸锂、柠檬酸锂、美哌隆(melperone)、五氟利多(penfluridol)、哌氰嗪(periciazine)、奋乃静(perphenazine)、哌迷清(pimozide)、匹泮哌隆(pipamperone)、丙氯拉嗪(prochlorperazine)、利培酮(risperidone)、硫醚嗪(thioridizin)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、伏立康唑(voriconazole)、苯二氮卓(benzodiazepines)、氢新(hydroxine)、甲丙胺酯(meprobamate)、啡噻嗪(phenothiazine)、氨基乙酸铝(aluminiumaminoacetate)、艾美拉唑(esomeprazole)、法莫替丁(famotidine)、氧化镁、尼扎替丁(nizatide)、奥美拉唑(omeprazole)、泮托拉唑(pantoprazole)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、甲硝唑(metronidazole)、苯丙胺(amphetamine)、阿替洛尔(atenolol)、富马酸比索洛尔(bisoprolol fumarate)、美托洛尔(metoprolol)、美托洛尔(metropolol)、吲哚洛尔(pindolol)、普萘洛尔(propranolol)、金诺芬(auranofin)和苄达酸(bendazac)。
可用的药物活性成分或其药物非活性前体的其他实例可包括选自以下治疗剂的活性成分:镇痛剂、麻醉剂、退热剂、抗过敏药、抗心律失常剂、食欲抑制剂、抗真菌剂、抗炎剂、支气管扩张剂、心血管药物、冠状动脉扩张剂、脑扩张剂、外周血管扩张剂、抗感染剂、精神药物、抗躁狂剂、兴奋剂、抗组胺药、轻泻剂、减充血剂、胃肠镇静剂、性功能障碍剂、消毒剂、抗腹泻剂、抗心绞痛剂、血管扩张剂、抗高血压剂、血管收缩剂、偏头痛治疗剂、抗生素、镇静剂、抗精神病剂、抗肿瘤药物、抗凝血剂、抗血栓剂、催眠剂、镇静剂、止吐剂、抗恶心剂、抗惊厥剂、神经肌肉剂、高血糖剂和低血糖剂、甲状腺剂和抗甲状腺剂、利尿剂、抗痉挛剂、子宫松弛剂、抗肥胖剂、厌食剂、解痉剂、合成代谢剂、促红细胞生成剂、抗哮喘剂、祛痰剂、咳嗽抑制剂、黏液溶解剂、抗尿毒症剂、牙科赋形剂、口气清新剂、抗酸剂、抗利尿剂、抗胀气剂、β阻断剂、牙齿增白剂、酶、辅酶、蛋白质、能量增强剂、纤维、益生菌、益生元、NSAID、止咳剂、碱充血剂、抗组胺药、祛痰剂、止泻剂、氢拮抗剂、质子泵抑制剂、通用非选择性CNS抑制剂、通用非选择性CNS兴奋剂、选择性CNS功能改良药物、抗帕金森病药、麻醉镇痛药、镇痛剂、精神药理学药和性功能障碍剂。
可用的药物活性成分或其药物非活性前体的实例也可包括:酪蛋白糖基巨肽(CGMP)、三氯生(Triclosan)、氯化十六烷基吡啶溴化度米芬(Domiphen bromide)、季铵盐、锌组分、血根碱、氟化物、阿来西定(Alexidine)、欧克尼定(Octonidine)、EDTA、阿司匹林、对乙酰氨基酚、布洛芬、酮洛芬、二氟尼柳(diflunisal)、非诺洛芬钙、萘普生、托美丁钠、吲哚美辛、苯佐那酯(Benzonatate)、乙二磺酸卡拉美芬(Caramiphen edisylate)、薄荷醇、氢溴酸右美沙芬、盐酸可可碱、盐酸氯苯达诺(Chlophendianol Hydrochloride)、盐酸假麻黄碱、苯肾上腺素(Phenylephrine)、苯丙醇胺、硫酸假麻黄碱、马来酸溴苯那敏(Brompheniramine maleate)、马来酸氯苯那敏(Chlorpheniramine maleate)、马来酸卡比沙明(Carbinoxamine maleate)、富马酸氯马斯汀(Clemastine fumarate)、马来酸地氯苯那敏(Dexchlorpheniramine maleate)、盐酸苯海拉明(Dephenhydraminehydrochloride)、盐酸二苯胺、马来酸哌吡庚啶(Azatadine maleate)、柠檬酸苯海拉明(Diphenhydramine citrate)、琥珀酸多西拉敏(Doxylamine succinate)、盐酸异丙嗪(Promethazine hydrochloride)、马来酸吡拉明(Pyrilamine maleate)、柠檬酸三苯胺(Tripellenamine citrate)、盐酸曲普利啶(Triprolidine hydrochloride)、阿昔伐他汀(Acrivastine)、氯雷他定(Loratadine)、溴苯那敏(Brompheniramine)、德溴非明(Dexbrompheniamine)、愈创甘油醚(Guaifenesin)、吐根(Ipecac)、碘化钾、水合萜品(Terpin hydrate)、洛哌丁胺(Loperamide)、法莫替丁(Famotidine)、雷尼替丁(Ranitidine)、奥美拉唑(Omeprazole)、兰索拉唑(Lansoprazole)、脂族醇、巴比妥酸盐(Barbiturate)、咖啡因(caffeine)、马钱子碱(strychnine)、木防己苦毒素(Picrotoxin)、戊四氮、苯基乙内酰脲、苯巴比妥(Phenobarbital)、普里米酮(Primidone)、卡马西平(Carbamazapine)、乙琥胺、甲琥胺、苯琥胺(Phensuximide)、三甲双酮(Trimethadione)、地西泮(Diazepam)、苯并二氮卓(Benzodiazepine)、苯乙酰脲、苯丁酰脲、乙酰唑胺、苏太明(Sulthiame)、溴化物、左旋多巴(Levodopa)、金刚胺(Amantadine)、吗啡碱(Morphine)、海洛因(Heroin)、氢吗啡酮(Hydromorphone)、美托酮(Metopon)、羟吗啡酮(Oxymorphone)、左吗喃(Levophanol)、可待因(Codeine)、氢可酮(Hydrocodone)、羟考酮(Xycodone)、纳洛芬(Nalorphine)、纳洛酮(Naloxone)、纳曲酮(Naltrexone)、水杨酸盐、苯基丁氮酮(Phenylbutazone)、吲哚美辛(Indomethacin)、非那西汀(Phenacetin)、氯丙嗪(Chlorpromazine)、左美丙嗪(Methotrimeprazine)、氟哌啶醇(Haloperidol)、氯氮平(Clozapine)、利血平(Reserpine)、丙咪嗪(Imipramine)、反苯环丙胺(Tranylcypromine)、苯乙肼(Phenelzine)、锂、柠檬酸西地那非(Sildenafil citrate)、他达拉非(Tadalafil)和伐地那非CL(Vardenafil CL)。例如,丁香酚可被用作麻醉剂。
可用的药物活性成分或其药物非活性前体的实例可包括选自以下的活性成分:ACE抑制剂、抗心绞痛药、抗心律失常剂、抗哮喘剂、抗胆固醇血剂、镇痛剂、麻醉剂、抗惊厥剂、抗抑郁剂、抗糖尿病剂、抗腹泻制剂、解毒剂、抗组胺药、抗高血压药、抗炎剂、抗脂质剂、抗躁剂、止恶心药、抗中风剂、抗甲状腺制剂、抗肿瘤药物、抗病毒剂、痤疮药物、生物碱、氨基酸制剂、止咳剂、抗尿毒症剂、抗病毒药物、合成代谢制剂、全身和非全身抗感染剂、抗肿瘤药、抗帕金森病剂、抗风湿病剂、食欲刺激剂、生物学反应调节剂、血液改良剂、骨骼代谢调节剂、心血管剂、中枢神经系统刺激剂、胆碱酯酶抑制剂、避孕药、碱充血剂、膳食补充剂、多巴胺受体促效剂、子宫内膜异位处理剂、酶、勃起功能障碍疗法(例如目前以ViagraTM出售的柠檬酸西地那非(sildenafil citrate)、生育剂、胃肠道药、顺势疗法治疗物、激素、高钙血症处理剂和低钙血症处理剂、免疫调节剂、免疫抑制剂、偏头痛制剂、动晕症治疗剂、肌肉松弛剂、肥胖管理剂、骨质疏松症制剂、催产剂、副交感神经阻断药、副交感神经药、前列腺素、精神治疗剂、呼吸道剂、镇静剂、戒烟助剂(例如溴麦角环肽)、交感神经剂、震颤制剂、泌尿道药、血管扩张剂、轻泻剂、抗酸剂、离子交换树脂、退烧药、食欲抑制剂、祛痰剂、抗焦虑剂、抗溃疡剂、抗炎物质、冠状动脉扩张剂、脑扩张剂、外周血管扩张剂、精神药物、兴奋剂、抗高血压药物、血管收缩剂、偏头痛治疗剂、抗生素、安神剂、抗精神病药、抗肿瘤药物、抗凝血剂、抗血栓药物、安眠药、止吐药、抗恶心药、抗惊厥剂、神经肌肉药、高血糖剂和低血糖剂、甲状腺和抗甲状腺制剂、利尿剂、抗痉挛药、子宫松弛剂、抗肥胖药物、促红血球生成药、抗哮喘剂、止咳剂、黏液溶解剂、DNA和遗传修饰药以及其组合。
预期可用的药物活性成分或其药物非活性前体的实例也可包括抗酸剂、H2-拮抗剂和镇痛剂。例如,可单独使用碳酸钙成分或与氢氧化镁和/或氢氧化铝组合来制备抗酸剂。此外,抗酸剂可与H2-拮抗剂组合使用。
镇痛剂包括布洛芬、阿司匹林、对乙酰氨基酚及其可任选地包括咖啡因的组合。
其他可用的药物活性成分或其药物非活性前体可包括止泻剂,例如ImmodiumTMAD、抗组胺药、止咳剂、碱充血剂、维生素和口气清新剂。也预期在本文中使用的是抗焦虑剂,例如XanaxTM;抗精神病药,例如ClozarilTM和HaldolTM;非类固醇抗炎剂(NSAID),例如布洛芬、萘普生钠、VoltarenTM和LodineTM;抗组胺药,例如ClaritinTM、HismanalTM、RelafenTM和TavistTM;止吐药,例如KytrilTM和CesametTM;支气管扩张剂,例如BentolinTM、ProventilTM;抗抑郁药,例如ProzacTM、ZoloftTM和PaxilTM;抗偏头痛剂,例如ImigraTM;ACE抑制剂,例如VasotecTM、CapotenTM和ZestrilTM;抗阿尔茨海默病药,例如NicergolineTM;以及CaH拮抗剂,例如ProcardiaTM、AdalatTM和CalanTM。
预期用于本发明中的普遍的H2-拮抗剂包括西咪替丁、盐酸雷尼替丁、法莫替丁、尼沙替丁(nizatidine)、乙溴替丁(ebrotidine)、咪芬替丁(mifentidine)、罗沙替丁(roxatidine)、匹沙替丁(pisatidine)和乙酸罗沙替丁(aceroxatidine)。
活性抗酸成分可包括但不限于以下物质:氢氧化铝、氨基乙酸二羟基铝、氨基乙酸、磷酸铝、碳酸二羟铝钠、碳酸氢盐、铝酸铋、碳酸铋、碱式碳酸铋、碱式没食子酸铋、次硝酸铋、次水杨酸铋(bismuth subsilysilate)、磷酸钙、柠檬酸根离子(酸或盐)、氨基乙酸、水合硫酸镁铝、镁加铝、硅酸镁铝、碳酸镁、甘氨酸镁、氢氧化镁、氧化镁、三硅酸镁、乳固体、磷酸氢二或二氢铝钙、磷酸三钙、碳酸氢钾、酒石酸钠、碳酸氢钠、硅酸镁铝、酒石酸和盐。
在一些实施方案中,该药物活性成分或其药物非活性前体可选自镇痛剂/麻醉剂,例如薄荷醇、苯酚、己基间苯二酚、苯佐卡因、盐酸达克罗宁、苯甲醇、水杨醇及其组合。在一些实施方案中,该药物活性成分或其药物非活性前体可选自缓和剂,例如滑榆树皮(slippery elm bark)、果胶、明胶及其组合。在一些实施方案中,该药物活性成分或其药物非活性前体可选自防腐败剂(antiseptic)成分,例如氯化十六烷基吡啶溴化杜米芬(domiphen bromide)、地喹氯铵(dequalinium chloride)、丁香酚及其组合。
在一些实施方案中,该药物活性成分或其药物非活性前体可选自止咳成分,例如盐酸氯苯达诺、可待因、磷酸可待因、硫酸可待因、右美沙芬、氢溴酸右美沙芬、柠檬酸苯海拉明和盐酸苯海拉明及其组合。
在一些实施方案中,该药物活性成分或其药物非活性前体可选自咽喉舒缓剂,例如蜂蜜、蜂胶、芦荟(aloe vera)、丙三醇、薄荷醇及其组合。在其他实施方案中,该药物活性成分或其药物非活性前体可选自咳嗽抑制剂。这种咳嗽抑制剂可分成两组:改变痰的质地或产量的那些,例如黏液溶解剂和祛痰药;以及抑制咳嗽反射的那些,例如可待因(麻醉性咳嗽抑制剂)、抗组胺、右美沙芬和异丙肾上腺素(非麻醉性咳嗽抑制剂)。
在其他实施方案中,该药物活性成分或其药物非活性前体可选自以下的止咳剂:可待因、右美沙芬、右羟吗喃、苯海拉明、氢可酮、诺斯卡品、羟考酮、喷托维林及其组合。在一些实施方案中,该药物活性成分或其药物非活性前体可选自抗组胺药,例如阿伐斯汀、阿扎他定、溴苯那敏、氯非尼拉敏、氯马斯汀、赛庚啶、右溴苯那敏、茶苯海明、苯海拉明、苯吡拉明、安泰乐、美克利嗪、苯茚胺、苯托沙敏、普鲁米近、比拉明、曲吡那明、曲普利定及其组合。在一些实施方案中,该药物活性成分或其药物非活性前体可选自非镇静抗组胺药,例如阿司咪唑、西替利嗪、依巴斯汀、非索非那定、氯雷他定、特非那定及其组合。
该营养活性成分或其营养非活性前体优选选自合成来源、半合成来源、天然来源及其组合的营养活性成分或营养非活性前体。
因而,营养活性成分涉及合成来源、半合成来源、天然来源及其组合的营养活性成分。另外,该营养活性成分的营养非活性前体涉及合成来源、半合成来源、天然来源及其组合的营养非活性前体并且将在随后阶段中被活化成相应的营养活性成分。
应注意,该营养活性成分或其营养非活性前体可为本领域技术人员已知的任何此类化合物。
营养活性成分优选包括当施用于人和/或动物时提供预防和/或治疗性能的任何化合物。应理解,营养活性成分可以具有与药物活性成分相同的效果并且可涵盖相同的化合物。但是,膳食补充剂和食品添加剂典型地被认为是营养活性成分。营养活性成分的实例包括但不限于维生素、矿物质、植物化学物质、益生菌、益生元和其他物质如姜黄素、白藜芦醇和异黄酮。
例如,可使用维生素A、维生素B1、维生素B6、维生素B12、维生素B2、维生素B6、维生素D、维生素E(即生育酚)、维生素K、硫胺素、核黄素、生物素、叶酸、烟酸、泛酸、Q10、α硫辛酸、二氢硫辛酸、姜黄素、叶黄素、β-隐黄质、番茄红素、叶黄素、玉米黄素、虾青素、β-胡萝卜素、胡萝卜素、混合类胡萝卜素、多酚、类黄酮、钠、钾、钙、镁、硫、氯、胆碱;和/或植物化学成分,例如类胡萝卜素、叶绿素、叶绿酸、纤维、类黄酮、花青素、矢车菊色素(cyaniding)、花翠素、锦葵色素、天竺葵色素、芍药色素、矮牵牛花素、黄烷醇、儿茶素、表儿茶素、表没食子儿茶素、表没食子儿茶素没食子酸酯、茶黄素、茶红素、原花青素、黄酮醇、槲皮素、堪非醇、杨梅素、异鼠李素、黄碱醇橙皮素(flavononeshesperetin)、柚皮素、圣草酚、桔皮素、黄酮类、芹黄素、木犀草素、木脂素、植物雌激素、白藜芦醇、异黄酮、大豆黄素、染料木黄酮、黄豆黄素、大豆异黄酮及其组合。可用作活性成分的营养剂的实例阐述于美国专利申请公开第2003/0157213Al号、第2003/0206993号和第2003/0099741Al号中,出于所有目的,通过引用将其全文并入本文中。
在一种实施方案中,可使用矿物质,优选痕量矿物质,例如锰、锌、铜、氟、钼、碘、钴、铬、硒、磷及其组合。
应理解,该药物或营养组合物优选以0.1-99%重量、更优选0.2-60%重量并且最优选0.2-50%重量的量包含该至少一种活性成分,基于该组合物的总重量计。
本发明的药物或营养组合物可进一步包含至少一种辅助剂,该辅助剂选自天然或合成香味剂、天然或合成调味剂、天然或合成着色剂、天然或合成甜味剂、润滑剂、崩解剂、助流剂及其混合物。
适合的天然或合成香味剂包括人类或其他动物通常在极低浓度下通过嗅觉感知的一种或多种挥发性化合物。
适合的天然或合成调味剂包括但不限于薄荷如胡椒薄荷,薄荷醇,香草,肉桂,各种水果调味剂(单独或混合的),精油如麝香草酚,桉树脑,薄荷醇和水杨酸甲酯,烯丙基吡嗪,甲氧基吡嗪,2-异丁基-3-甲氧基吡嗪,乙酰基-L-吡嗪,2-乙酰氧基吡嗪,醛,醇,酯,酮,吡嗪,酚醛树脂,萜类及其混合物。
该调味剂通常以将根据个人口味而改变的量利用,且可例如以最终组合物的重量的约0.5%-约4%的范围内利用。
适合的天然或合成着色剂包括但不限于二氧化钛、黄酮染料、异喹啉染料、多烯着色剂、吡喃着色剂、萘醌染料、醌和蒽醌染料、苯并吡喃染料、苯并吡喃酮染料以及靛类染料和吲哚着色剂。其实例为焦糖着色、胭脂树红、叶绿酸、胭脂虫红、甜菜苷、姜黄、番红花、红辣椒、番茄红素、露兜树和蝶豆花。
适合的天然或合成甜味剂包括但不限于木糖、核糖、葡萄糖、甘露糖、半乳糖、果糖、右旋糖、蔗糖、糖、麦芽糖、部分水解淀粉或玉米糖浆固体,以及糖醇如山梨糖醇、木糖醇、甘露糖醇及其混合物;水溶性人造甜味剂如可溶性糖精盐(即糖精钠或钙盐)、环己基氨基磺酸盐、丁磺胺-K等,以及游离酸形式的糖精和基于阿斯巴甜的甜味剂如L-天冬氨酸-苯丙氨酸甲酯、或
一般而言,甜味剂的量将随针对特定片剂组成而选择的甜味剂的期望量而变化。
为了促进药物或营养组合物的快速崩解,可以使用崩解剂。此类崩解剂及其作用机理是本领域技术人员已知的。
如果存在崩解剂的话,则根据本发明的药物或营养组合物优选包含选自以下的崩解剂:改性纤维素胶、不溶性交联聚乙烯吡咯烷酮、乙醇酸淀粉、微晶纤维素、预胶凝化淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、N-乙烯基-2-吡咯烷酮的均聚物、烷基纤维素酯、羟基烷基纤维素酯、羧烷基纤维素酯、藻酸盐、离子交换树脂、树胶、甲壳质、壳聚糖、粘土、结冷胶、交联泼拉克林共聚物、琼脂、明胶、糊精、丙烯酸聚合物、羧基甲基纤维素钠/钙、羟丙基甲基纤维素邻苯二甲酸酯、虫胶或其混合物。
合适的润滑剂包括但不限于滑石、二氧化硅、脂肪如植物硬脂、硬脂酸镁、硬脂基富马酸钠或硬脂酸。
合适的助流剂包括但不限于滑石、气相法二氧化硅或碳酸镁。
应理解,该至少一种辅助剂优选以0.1-20%重量、更优选0.2-7%重量的量存在于该药物或营养组合物中,基于该组合物的总重量计。
在一种实施方案中,该药物或营养组合物包含以下物质,优选由以下物质构成:该颗粒状药物或营养赋形剂、活性成分和作为该至少一种辅助剂的润滑剂。
根据另一方面,提供了一种用于制造药物或营养组合物的方法。该方法包括以下步骤:
a)提供颗粒状药物或营养赋形剂,
b)使该颗粒状药物或营养赋形剂经历干法制粒、湿法制粒、熔融制粒或直接压制,优选直接压制,从而获得该组合物。
关于该颗粒状药物或营养赋形剂的定义及其优选实施方案,可参考以上在讨论本发明的颗粒状药物或营养赋形剂的技术细节时所提供的陈述。
在一种实施方案中,该方法还包括步骤c):使步骤b)之前的颗粒状药物或营养赋形剂或步骤b)中获得的组合物与至少一种活性成分接触。优选地,该方法还包括步骤c):使步骤b)之前的颗粒状药物或营养赋形剂与至少一种活性成分接触。
应理解,该至少一种活性成分选自药物或营养活性成分、非活性药物或营养前体、生物活性成分、非活性生物前体及其混合物,和/或该辅助剂选自天然或合成香味剂、天然或合成调味剂、天然或合成着色剂、天然或合成甜味剂、润滑剂、崩解剂、助流剂及其混合物。
应理解,该药物或营养“组合物”特别地是指以特定构造和剂量包含赋形剂和活性成分的固体药物或营养药品产品。这样的组合物是众所周知的,并且通常用于药物或营养应用,例如是片剂(tablet)。该组合物(优选片剂)可以是本领域中已知的任何形状和尺寸。
考虑到前述内容,可以通过本领域技术人员已知的导致获得片剂的形状的任何技术来形成该药物或营养组合物。
根据步骤b),该颗粒状药物或营养赋形剂因而进行干法制粒、湿法制粒、熔融制粒或直接压制,从而获得该组合物。
在一种实施方案中,使该颗粒状药物或营养赋形剂经历干法制粒以形成组合物。在这种情况下,该颗粒状药物或营养赋形剂的粒子在干燥条件下在高压下被压实/制粒。用于干法制粒的方法和设备在本领域中是众所周知的,并且本领域技术人员将相应地调适干法制粒的条件。例如,干法制粒可通过摇摆式制粒机或辊式压实机进行。
在一种替代实施方案中,使该颗粒状药物或营养赋形剂进行湿法制粒,例如通过高剪切混合或流化床制粒来进行,以形成组合物。在这种情况下,该组合物通过如下方式形成:将制粒液体添加到受到叶轮螺杆或空气的影响的颗粒状药物或营养赋形剂床上。导致该系统与赋形剂的润湿一起的搅拌导致其聚集。用于湿法制粒的方法和设备在本领域中是众所周知的,并且本领域技术人员将相应地调适湿法制粒的条件。
在一个替代的实施方案中,使该颗粒状药物或营养赋形剂经历熔融制粒以形成组合物。在这种情况下,该组合物通过如下方式形成:将该颗粒状药物或营养赋形剂与在相对较低的温度(约40-80℃)下熔融或软化的粘合剂合并,以实现赋形剂的附聚。用于熔体制粒的方法和设备在本领域中是众所周知的,并且本领域技术人员将相应地调适熔体制粒条件。
如果使该颗粒状药物或营养赋形剂经历干法制粒、湿法制粒或熔融制粒以形成组合物,则应理解,该微晶纤维素(MCC)与该经表面反应碳酸钙(SRCC)的重量比可为99.9:0.1至10:90,优选99.9:0.1至25:75。
在一种实施方案中,使该颗粒状药物或营养赋形剂经历直接压制以形成组合物。在这种情况下,通过直接压制该颗粒状药物或营养赋形剂来形成组合物,该颗粒状药物或营养赋形剂通常预先加载或混合有至少一种活性成分。用于直接压制的方法和设备在本领域中是众所周知的,并且本领域技术人员将相应地调适直接压制条件。
优选地,该组合物通过直接压制形成。
在一种实施方案中,用于制造药物或营养组合物的方法包括以下步骤:
a)提供通过包括以下步骤的方法制备的颗粒状药物或营养赋形剂,
i)将微晶纤维素和经表面反应碳酸钙混合,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
ii)通过喷雾干燥来共加工步骤a)中获得的混合物,从而获得该颗粒状药物或营养赋形剂,并且
b)使该颗粒状药物或营养赋形剂经历直接压制,从而获得该组合物。
在一种实施方案中,用于制造药物或营养组合物的方法包括以下步骤:
a)提供通过包括以下步骤的方法制备的颗粒状药物或营养赋形剂,
i)将微晶纤维素和经表面反应碳酸钙混合,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
ii)通过喷雾干燥来共加工步骤a)中获得的混合物,从而获得该颗粒状药物或营养赋形剂,并且
b)使该颗粒状药物或营养赋形剂经历直接压制,从而获得该组合物。
c)使步骤b)之前的颗粒状药物或营养赋形剂与至少一种活性成分接触。
附图说明
图1显示了随主压制力[kN]变化的赋形剂的片剂硬度[N]。
图2显示了随主压制力[kN]变化的共加工的配混物的片剂拉伸强度[MPa]。
图3显示了对于样品4以及MCC与SRCC的简单共混物来说,随主压制力[kN]变化的片剂硬度[N]的对比。
图4显示了对于样品4以及比例为90:10的MCC与SRCC的简单共混物来说,随主压制力[kN]变化的片剂拉伸强度[MPa]的对比。
图5显示了对于样品1至4来说,随片剂硬度[N]变化的崩解时间[秒]。
图6显示了对于样品4以及比例为90:10的MCC与SRCC的简单共混物来说,随片剂硬度[N]变化的崩解时间[秒]的对比。
图7显示了随主压制力[kN]变化的赋形剂的片剂硬度[N]。SRCC(粗体)与GCC(虚线)进行对比。样品编号1是指没有SRCC或GCC的MCC。
图8显示了随主压制力[kN]变化的赋形剂的片剂拉伸强度[MPa]。SRCC(粗体)与GCC(虚线)进行对比。
图9显示了随片剂硬度[N]变化的崩解时间[秒]。SRCC(粗体)与GCC(虚线)进行对比。样品编号1是指没有SRCC或GCC的MCC。
图10显示了随主压制力[kN]变化的赋形剂的片剂硬度[N]。
图11显示了随主压制力[kN]变化的赋形剂的片剂拉伸强度[MPa]。
图12显示了随片剂硬度[N]变化的崩解时间[秒]。
图13显示了静止角β的计算,该静止角为斜面侧边相对于水平线的角度。
具体实施方式
以下的实施例和测试将说明本发明,但并非意味着以任何方式限制本发明。
实施例
测量方法
在下文中将描述在实施例中实施的测量方法。
粒子尺寸分布
使用Malvern Mastersizer 3000Laser Diffraction System(MalvernInstruments Plc.,英国)评价体积确定中值粒子尺寸d50(体积)和体积确定顶切粒子尺寸d98(体积)。d50(体积)或d98(体积)值指示出的直径值为:分别50%或98%体积的粒子具有小于这个值的直径。使用米氏(Mie)理论分析通过测量结果获得的原始数据,其中粒子折射率为1.57并且吸收系数为0.005。方法及仪器为本领域技术人员所知并且通常用于确定填料和颜料的粒子尺寸分布。样品在干燥条件下没有任何预先处理来测量。
重量确定中值粒子尺寸d50(重量)通过沉降法测量,所述沉降法是在重力场中的沉降行为的分析。使用美国Micromeritics Instrument Corporation的SedigraphTM 5120进行测量。方法及仪器为本领域技术人员所知且通常用于确定填料和颜料的颗粒尺寸。在0.1%重量Na4P2O7的水溶液中进行测量。使用高速搅拌器及超声分散样品。
比表面积(SSA)
通过将样品在250℃下加热30分钟的时间周期进行调理之后,通过使用氮气根据ISO 9277:2010经由BET方法测量比表面积。在这种测量之前,样品在布氏漏斗内过滤,用去离子水冲洗并且在110℃下在烘箱中干燥至少12小时。
粒子内侵入式比孔容(以cm3/g表示)
使用Micromeritics Autopore V 9620汞孔率计,使用汞侵入孔隙率测定法测量结果测量比孔容,所述汞孔率计具有最大施加汞压为414MPa(60 000psi),等效于0.004μm(~nm)的拉普拉斯喉径。在每个压力步骤使用的平衡时间是20秒。将样品材料密封在5cm3室的粉末透度计中用于分析。使用软件Pore-Comp(Gane,P.A.C.,Kettle,J.P.,Matthews,G.P.和Ridgway,C.J.,“Void Space Structure of Compressible Polymer Spheres andConsolidated Calcium Carbonate Paper-Coating Formulations”,Industrial andEngineering Chemistry Research,35(5),1996年,第1753-1764页),针对汞压缩、透度计膨胀和样品材料压缩来校正数据。
在累积侵入数据中见到的总孔体积可被分成两个区域,其中从214μm降至约1-4μm的侵入数据显示具有强烈贡献的任何附聚结构之间的样品的粗填充。在这些直径之下的是粒子自身的精细粒子间填充。如果它们也具有粒子内孔,则此区域显现双峰,并且通过获取由汞侵入比峰转折点更细(即比双峰拐点更细)的孔的比孔容,定义比粒子内孔体积。这三个区域的总和给出了粉末的总全部孔体积,但强烈地取决于原始样品压实/在分布的粗孔末端处的粉末的沉降。
通过获取累积侵入曲线的第一导数,揭示了基于等效拉普拉斯直径的孔尺寸分布,其必然包括孔屏蔽。微分曲线清楚地显示了粗附聚孔结构区域、粒子间孔区域和粒子内孔区域(如果存在的话)。已知粒子内孔直径范围,则可以从总孔体积中减去剩余粒子间和附聚体间孔体积,以给出在每单位质量孔体积(比孔容)方面的单独的内部孔的希望的孔体积。当然,相同的减法原理也适用于分离任何感兴趣的其他孔尺寸区域。
堆积密度
通过粉末漏斗将100±0.5g的相应材料小心地填充入250mL量筒中,并将体积读数精确至1mL。松散堆积密度根据下式计算:
松散堆积密度[g/mL]=堆积体积[mL]/称重的样品[g]
并记录结果精确至0.01g/mL。
振实密度
经由粉末漏斗,将100±0.5g的相应材料小心地填充至250mL量筒中。
该带刻度的筒连接至配备有能够产生振实的沉降设备的支撑物上。该筒固定于该支撑物中并且在1250次振实之后读取体积。随后进行由1250次振实构成的第二振实步骤并且读取体积值。当该第二振实体积值与该第一振实体积值相差不超过2mL时,就是振实体积。当该值相差超过2mL时,重复1250次振实的振实步骤直到在随后的步骤中观测到不超过2mL的差值为止。
Hausner比率
Hausner比率是与粉末材料的流动性相关的数,其如下计算:
Hausner比率=(振实密度)/(堆积密度)
压缩指数
如下计算压缩指数:
压缩指数(%)=(振实密度-堆积密度)/振实密度×100静止角
在流动性测试仪中测量静止角。装备有10mm喷嘴的料斗填充有大约150mL的相应材料。在排空料斗之后,借助激光束测量粒料斜面并且计算静止角。静止角β为图13中所示计算的斜面侧边相对于水平线的角度。
SEM
扫描电镜
通过过滤悬浮液并使其在110℃下的干燥箱中干燥来制备用于SEM研究的样品。在拍摄照片之前,将样品用20nm金溅射。
1、颜料材料
微晶纤维素
使用来自爱尔兰FMC BioPolymer的微晶纤维素PH 102。
经表面反应碳酸钙
SRCC
经表面反应碳酸钙(SRCC)(d50(体积)=6.6μm,d98=13.7μm,SSA=59.9m2/g)。粒子内侵入式比孔容为0.939cm3/g(对于0.004-0.51μm的孔径范围来说)。
SRCC通过在混合容器中制备350升的研磨碳酸钙的水性悬浮液而获得,这通过如下方式实现:调节来自Orgon的Omya SAS的研磨石灰石碳酸钙(具有通过沉降法确定的1.3μm的重量基中值粒子尺寸d50(重量))的固体含量以使得获得基于该水性悬浮液的总重量计为10%重量的固体含量。
在以6.2m/s的速度混合该浆料的同时,在70℃的温度下在20分钟的周期内向所述悬浮液中加入11.2kg的磷酸,所述磷酸为包含30%重量磷酸的水溶液的形式。在加入该酸之后,将浆料再搅拌5分钟,然后将其从容器中移出并使用喷射干燥器干燥。
研磨碳酸钙(GCC)
研磨碳酸钙(GCC)是来自法国Orgon的研磨石灰石,其d50(重量)=3μm,d98=12μm,并且SSA=2.6m2/g。
2、制备赋形剂的共加工实验
A、喷雾干燥
使用具有以下设置的压力喷嘴,在Mobile Minor的Niro喷雾干燥机上进行喷雾干燥试验:
·入口温度:240℃
·出口温度:95℃
·喷雾压力:55%
·泵转速:22.3ml/min
·喷嘴孔:1mm
将微晶纤维素(MCC)和经表面反应碳酸钙(SRCC)以不同比例的混合物制成的水性浆料用于喷雾干燥实验,从而制备了赋形剂。该水性浆料显示的固体含量为15%重量,基于浆料的总重量计。
表1显示了已用于制备赋形剂的微晶纤维素(MCC)与经表面反应碳酸钙(SRCC)的比例:
表1:MCC与SRCC的比例
表2列出了获得的共加工的赋形剂的密度和可压缩性值。
表2:密度和可压缩性值
共加工的配混物的压片(tabletting)测验(样品1至4)
在Turbula混合机(Willy A.Bachofen,Turbula T10B)中,将所获得的赋形剂(样品1-4)与0.5%重量的润滑剂(硬脂酸镁,Ligamed MF-2-V,Cas#557-04-0,Peter Greven)进一步混合5分钟。混合物进一步用于在使用EU1”工具、10mm填充凸轮、8个标准凸圆形10mm冲头以及15000片/小时的压片速度的Fette 1200i中来制备片剂。调节填充深度以获得2kN一直到20kN的压制力并且片剂重量固定在175mg。
图1显示了随主压制力[kN]变化的赋形剂的片剂硬度[N]。图2显示了随主压制力[kN]变化的共加工的配混物的片剂拉伸强度[MPa]。图3显示了对于样品4以及比例为90:10的MCC与SRCC的简单共混物来说,随主压制力[kN]变化的片剂硬度[N]的对比。图4显示了对于样品4以及比例为90:10的MCC与SRCC的简单共混物来说,随主压制力[kN]变化的片剂拉伸强度[MPa]的对比。
崩解测验
使用Pharmatron的DisiTest 50自动片剂崩解测试仪进行崩解测试。
为了进行测试,将烧杯装入720ml蒸馏水。将水加热到37.0℃,然后将6个片剂放在坚固的篮子中。
该设备自动检测并记录崩解时间。另外,还目视监测崩解时间。
图5显示了对于样品1至4来说,随片剂硬度[N]变化的崩解时间[秒]。图6显示了对于样品4以及比例为90:10的MCC与SRCC的简单共混物来说,随片剂硬度[N]变化的崩解时间[秒]的对比。
SRCC与GCC的对比
使用具有以下设置的压力喷嘴,在Mobile Minor的Niro喷雾干燥机上进行SRCC和GCC的喷雾干燥试验:
·入口温度:240℃
·出口温度:95℃
·喷雾压力:55%
·泵转速:22.3ml/min
·喷嘴孔:1mm
将微晶纤维素(MCC)和经表面反应碳酸钙(SRCC)或研磨碳酸钙(GCC)以不同比例的混合物制成的水性浆料用于喷雾干燥实验,从而制备了赋形剂。该水性浆料显示的固体含量为15%重量,基于浆料的总重量计。
表3和表4显示了已用于制备赋形剂的微晶纤维素(MCC)与经表面反应碳酸钙(SRCC)或研磨碳酸钙(GCC)的比例:
表3:MCC与SRCC的比例
表4:MCC与GCC的比例
表5和表6中列出了表3和表4中给出的所获得的共加工的赋形剂的密度和可压缩性值。
表5:表3中给出的共加工的赋形剂的密度和可压缩性值
表6:表4中给出的共加工的赋形剂的密度和可压缩性值
在Turbula混合机(Willy A.Bachofen,Turbula T10B)中,将表5和表6中列出的所获得的赋形剂与0.5%重量的润滑剂(硬脂酸镁,Ligamed MF-2-V,Cas#557-04-0,PeterGreven)进一步混合5分钟。混合物进一步用于在使用EU1”工具、10mm填充凸轮、8个标准凸圆形10mm冲头以及15000片/小时的压片速度的Fette 1200i中来制备片剂。调节填充深度以获得2kN一直到20kN的压制力并且片剂重量固定在175mg。
图7显示了随主压制力[kN]变化的赋形剂的片剂硬度[N]。图8显示了随主压制力[kN]变化的赋形剂的片剂拉伸强度[MPa]。
使用Pharmatron的DisiTest 50自动片剂崩解测试仪进行崩解测试。
为了进行测试,将烧杯装入720ml蒸馏水。将水加热到37.0℃,然后将6个片剂放在坚固的篮子中。
该设备自动检测并记录崩解时间。另外,还目视监测崩解时间。
图9显示了对于表5和表6给出的赋形剂来说,随片剂硬度[N]变化的崩解时间[秒]。
不同加工条件的对比
进行各试验,其中样品编号3已通过如上所述的喷雾干燥制备(参见“SRCC与GCC的对比”)。样品编号3C通过干燥共加工(即在高剪切混合机中)来制备,其中在Somakon混合机中制备了4kg的包含5%SRCC和95%MCC的共混物。在环境温度下以1000rpm的速度进行共混10分钟。样品编号3D通过预先温和研磨SRCC然后进行干燥共加工(即在高剪切混合机中)来制备,其中SRCC在销棒粉碎机中研磨至d50为4.5μm,然后与MCC混合(以针对样品编号3C所述相同的方式)。
表7显示了已用于制备赋形剂的微晶纤维素(MCC)与经表面反应碳酸钙(SRCC)的比例:
表7:MCC与SRCC的比例
表8列出了表7中给出的所获得的共加工的赋形剂的密度和可压缩性值。
表8:表7中给出的共加工的赋形剂的密度和可压缩性值
图10显示了随主压制力[kN]变化的赋形剂的片剂硬度[N]的对比。图11显示了随主压制力[kN]变化的赋形剂的片剂拉伸强度[MPa]的对比。
使用Pharmatron的DisiTest 50自动片剂崩解测试仪进行崩解测试。
为了进行测试,将烧杯装入720ml蒸馏水。将水加热到37.0℃,然后将6个片剂放在坚固的篮子中。
该设备自动检测并记录崩解时间。另外,还目视监测崩解时间。
图12显示了对于表8给出的样品来说,随片剂硬度[N]变化的崩解时间[秒]。
本发明还涉及以下项目:
项目1、颗粒状药物或营养赋形剂,该赋形剂包含
a)微晶纤维素,和
b)经表面反应碳酸钙,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,
其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50。
项目2、根据项目1的颗粒状药物或营养赋形剂,其中该经表面反应碳酸钙具有:
i)体积中值粒子尺寸d50为0.5-50μm,更优选1-40μm,甚至更优选1.2-30μm并且最优选1.5-15μm,和/或
ii)使用氮气和根据ISO 9277:2010的BET法测量的BET比表面积为5-200m2/g,优选15-150m2/g,更优选40-100m2/g,和/或
iii)由汞孔隙率测定法测量结果计算的0.1-2.3cm3/g、更优选0.2-2.0cm3/g、尤其优选0.4-1.8cm3/g且最优选0.6-1.6cm3/g的粒子内侵入式比孔容。
项目3、根据项目1或2的颗粒状药物或营养赋形剂,其中
i)该天然研磨碳酸钙选自大理石、白垩、石灰石及其混合物,或
ii)该沉淀碳酸钙选自具有文石、球霰石或方解石晶型的沉淀碳酸钙及其混合物。
项目4、根据前述项目中任一项的颗粒状药物或营养赋形剂,其中该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、柠檬酸、草酸、酸式盐、醋酸、甲酸及其混合物,优选地,该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、草酸、由选自Li+、Na+和/或K+的阳离子至少部分中和的H2PO4 -、由选自Li+、Na+、K+、Mg2+和/或Ca2+的阳离子至少部分中和的HPO4 2-、及其混合物,更优选地,该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、草酸或其混合物,并且最优选地,该至少一种H3O+离子供体是磷酸。
项目5、根据前述项目中任一项的颗粒状药物或营养赋形剂,其中该微晶纤维素具有
i)松散堆积密度为0.20-0.52g/ml,更优选0.26-0.36g/ml,和/或
ii)重量中值粒子尺寸d50为10-1000μm、优选15-500μm、最优选20-200μm。
项目6、根据前述项目中任一项的颗粒状药物或营养赋形剂,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至75:25,优选99:1至80:20并且最优选98:2至90:10。
项目7、根据前述项目中任一项的颗粒状药物或营养赋形剂,其中该赋形剂包含共加工的微晶纤维素和经表面反应碳酸钙,其中该经表面反应碳酸钙与该微晶纤维素紧密缔合。
项目8、根据前述项目中任一项的颗粒状药物或营养赋形剂,其中该赋形剂具有松散堆积密度为0.25-0.90g/ml,更优选为0.25-0.65g/ml。
项目9、制备根据项目1-8中任一项的颗粒状药物或营养赋形剂的方法,该方法包括以下步骤:
a)将微晶纤维素和经表面反应碳酸钙混合,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
b)共加工步骤a)中获得的混合物,从而获得该颗粒状药物或营养赋形剂。
项目10、根据项目9的方法,其中共加工步骤b)通过干法或湿法加工、优选高剪切混合、喷雾干燥、研磨或其混合来进行。
项目11、根据项目9或10的方法,其中混合步骤a)在水性介质中进行以形成包含该微晶纤维素和该经表面反应碳酸钙的水性浆料。
项目12、包含根据项目1-8中任一项的颗粒状药物或营养赋形剂和任选的至少一种活性成分的药物或营养组合物,优选地,该至少一种活性成分选自药物或营养活性成分、非活性药物或营养前体、生物活性成分、非活性生物前体及其混合物。
项目13、根据项目12的药物或营养组合物,其中该药物或营养组合物还包含至少一种辅助剂,该辅助剂选自天然或合成香味剂、天然或合成调味剂、天然或合成着色剂、天然或合成甜味剂、润滑剂、崩解剂、助流剂及其混合物。
项目14、制造根据项目12或13的药物或营养组合物的方法,该方法包括以下步骤:
a)提供根据项目1-8中任一项的颗粒状药物或营养赋形剂,
b)使该颗粒状药物或营养赋形剂经历干法制粒、湿法制粒、熔融制粒或直接压制,优选直接压制,从而获得该组合物。
项目15、根据项目14的方法,其中该方法还包括步骤c):使步骤b)之前的颗粒状药物或营养赋形剂或步骤b)中获得的组合物与至少一种活性成分和/或至少一种辅助剂接触,优选地,该至少一种活性成分选自药物或营养活性成分、非活性药物或营养前体、生物活性成分、非活性生物前体及其混合物,该辅助剂选自天然或合成香味剂、天然或合成调味剂、天然或合成着色剂、天然或合成甜味剂、润滑剂、崩解剂、助流剂及其混合物。
Claims (34)
1.颗粒状药物赋形剂或颗粒状营养赋形剂,该赋形剂包含
a)微晶纤维素,和
b)经表面反应碳酸钙,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该经表面反应碳酸钙具有:
i)体积中值粒子尺寸d50为0.5-50μm,和/或
ii)使用氮气和根据ISO 9277:2010的BET法测量的BET比表面积为5-200m2/g,和/或
iii)由汞孔隙率测定法测量结果计算的0.1-2.3cm3/g的粒子内侵入式比孔容,并且
其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
其中该赋形剂包含共加工的微晶纤维素和经表面反应碳酸钙,其中该经表面反应碳酸钙与该微晶纤维素紧密缔合。
2.根据权利要求1的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该经表面反应碳酸钙具有:
i)体积中值粒子尺寸d50为1-40μm。
3.根据权利要求2的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该经表面反应碳酸钙具有:
i)体积中值粒子尺寸d50为1.2-30μm。
4.根据权利要求2的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该经表面反应碳酸钙具有:
i)体积中值粒子尺寸d50为1.5-15μm。
5.根据权利要求1的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该经表面反应碳酸钙具有:
ii)使用氮气和根据ISO 9277:2010的BET法测量的BET比表面积为15-150m2/g。
6.根据权利要求5的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该经表面反应碳酸钙具有:
ii)使用氮气和根据ISO 9277:2010的BET法测量的BET比表面积为40-100m2/g。
7.根据权利要求1的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该经表面反应碳酸钙具有:
iii)由汞孔隙率测定法测量结果计算的0.2-2.0cm3/g的粒子内侵入式比孔容。
8.根据权利要求7的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该经表面反应碳酸钙具有:
iii)由汞孔隙率测定法测量结果计算的0.4-1.8cm3/g的粒子内侵入式比孔容。
9.根据权利要求7的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该经表面反应碳酸钙具有:
iii)由汞孔隙率测定法测量结果计算的0.6-1.6cm3/g的粒子内侵入式比孔容。
10.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中
i)该天然研磨碳酸钙选自大理石、白垩、石灰石及其混合物,或
ii)该沉淀碳酸钙选自具有文石、球霰石或方解石晶型的沉淀碳酸钙及其混合物。
11.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、柠檬酸、草酸、酸式盐、醋酸、甲酸及其混合物。
12.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、草酸、由选自Li+、Na+和/或K+的阳离子至少部分中和的H2PO4 -、由选自Li+、Na+、K+、Mg2+和/或Ca2+的阳离子至少部分中和的HPO4 2-、及其混合物。
13.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该至少一种H3O+离子供体选自盐酸、硫酸、亚硫酸、磷酸、草酸或其混合物。
14.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该至少一种H3O+离子供体是磷酸。
15.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该微晶纤维素具有
i)松散堆积密度为0.20-0.52g/ml,和/或
ii)重量中值粒子尺寸d50为10-1000μm。
16.根据权利要求15的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该微晶纤维素具有
i)松散堆积密度为0.26-0.36g/ml。
17.根据权利要求15的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该微晶纤维素具有
ii)重量中值粒子尺寸d50为15-500μm。
18.根据权利要求15的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该微晶纤维素具有
ii)重量中值粒子尺寸d50为20-200μm。
19.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至75:25。
20.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99:1至80:20。
21.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该微晶纤维素与该经表面反应碳酸钙的重量比为98:2至90:10。
22.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该赋形剂具有松散堆积密度为0.25-0.90g/ml。
23.根据权利要求1-9中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,其中该赋形剂具有松散堆积密度为0.25-0.65g/ml。
24.制备根据权利要求1-23中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂的方法,该方法包括以下步骤:
a)将微晶纤维素和经表面反应碳酸钙混合,其中该经表面反应碳酸钙为天然研磨碳酸钙或沉淀碳酸钙与二氧化碳和一种或多种H3O+离子供体的反应产物,其中该二氧化碳通过H3O+离子供体处理就地形成和/或由外部来源供应,其中该微晶纤维素与该经表面反应碳酸钙的重量比为99.9:0.1至50:50,并且
b)共加工步骤a)中获得的混合物,从而获得该颗粒状药物赋形剂或颗粒状营养赋形剂。
25.根据权利要求24的方法,其中共加工步骤b)通过干法或湿法加工来进行。
26.根据权利要求24的方法,其中共加工步骤b)通过高剪切混合、喷雾干燥、研磨或其混合来进行。
27.根据权利要求24-26中任一项的方法,其中混合步骤a)在水性介质中进行以形成包含该微晶纤维素和该经表面反应碳酸钙的水性浆料。
28.包含根据权利要求1-23中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂和任选的至少一种活性成分的药物或营养组合物。
29.根据权利要求28的药物或营养组合物,其中该至少一种活性成分选自药物或营养活性成分、非活性药物或营养前体、生物活性成分、非活性生物前体及其混合物。
30.根据权利要求28或29的药物或营养组合物,其中该药物或营养组合物还包含至少一种辅助剂,该辅助剂选自天然或合成香味剂、天然或合成调味剂、天然或合成着色剂、天然或合成甜味剂、润滑剂、崩解剂、助流剂及其混合物。
31.制造根据权利要求28-30中任一项的药物或营养组合物的方法,该方法包括以下步骤:
a)提供根据权利要求1-23中任一项的颗粒状药物赋形剂或颗粒状营养赋形剂,
b)使该颗粒状药物赋形剂或颗粒状营养赋形剂经历干法制粒、湿法制粒、熔融制粒或直接压制,从而获得该组合物。
32.根据权利要求31的方法,其中在步骤b)中,使该颗粒状药物赋形剂或颗粒状营养赋形剂经历直接压制,从而获得该组合物。
33.根据权利要求31或32的方法,其中该方法还包括步骤c):使步骤b)之前的颗粒状药物赋形剂或颗粒状营养赋形剂或步骤b)中获得的组合物与至少一种活性成分和/或至少一种辅助剂接触。
34.根据权利要求33的方法,其中该至少一种活性成分选自药物或营养活性成分、非活性药物或营养前体、生物活性成分、非活性生物前体及其混合物,和/或该至少一种辅助剂选自天然或合成香味剂、天然或合成调味剂、天然或合成着色剂、天然或合成甜味剂、润滑剂、崩解剂、助流剂及其混合物。
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