CN112022821A - 药物组合物 - Google Patents
药物组合物 Download PDFInfo
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- CN112022821A CN112022821A CN202010986012.1A CN202010986012A CN112022821A CN 112022821 A CN112022821 A CN 112022821A CN 202010986012 A CN202010986012 A CN 202010986012A CN 112022821 A CN112022821 A CN 112022821A
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Abstract
包含高载量羟基氧化铁的口服给药的药物组合物,尤其是以将直接吞咽或能够在口腔中崩解的经口传递系统给药。
Description
本申请为一项发明专利申请的分案申请,其母案的申请日为2008年11月13日、申请号为200880116176.6、发明名称为“药物组合物”。
技术领域
本发明涉及包含高载量羟基氧化铁(iron oxy-hydroxide)的药物组合物,其以适于口服给药的形式,特别适于作为完整吞咽的剂型(例如薄膜包衣)或作为能够快速崩解的剂型的经口传递系统给药,还涉及其制备方法。
背景技术
在患有慢性肾功能不全的患者中,由于肾小球滤过率的降低导致出现血清磷酸盐水平病理性增加。随其发生的继发性甲状旁腺功能亢进被认为是肾性骨病发生的原因之一。常规地通过以下方法维持平衡状态下磷酸盐的平衡:透析,或者口服给药磷酸盐吸附剂,其抑制食品磷酸盐在胃肠道的再吸收,或者将上述两种方法合用,但是在现有的技术水平下,这是不够有效的、不经济的,或者具有副作用。
近来,已描述了基于羟基氧化铁的新型且有效的磷酸盐吸附剂,尤其是含有β-羟基氧化铁,其通过如糖类和/或腐殖酸的稳定剂来稳定(EP 0 868 125)。这些吸附剂显示超强的吸附水溶液中磷酸盐的能力,例如吸附无机磷酸盐和与结合至食物的磷酸盐(EP 0868 125),并且在高磷酸酯酶血症的治疗中已显示是有效的口服磷酸盐结合剂(Neophrol.Dial.Transplant 14,863,1999)。
为了达到最大疗效,同时维持良好的患者依从性,期望这类吸附剂能以高剂量给药。但是,具有高铁载量的磷酸盐吸附剂仍是不可得到的。诸多因素如通常给药的容易度、难以接受的味道以及贮藏和稳定性问题,都限制了目前可用的磷酸盐结合剂的施用性。
WO 2006/000547公开了基于磷酸盐吸附剂的硫酸亚铁制备的方法,该吸附剂可用于预防和治疗高磷酸盐状态。描述的是羟基氧化铁组合物,其形成含有选自腐殖酸和糖类的稳定剂的硫酸铁和/或硝酸铁进行制备,并且其具有的铁的含量最高为20.3~22.3重量%。这些组合物通过旋转蒸发获得。未公开特定口服制剂如片剂。这说明了铁组合物可用于与常规辅料和辅剂一起制成片剂或其它口服制剂。这意味着由羟基氧化铁组合物得到的片剂可能具有最高20%(w/w)的铁含量,其对应于32%(w/w)的羟基氧化铁。
EP 1 757 299描述了铁(III)糖类络合物,以及其在经口或非经口治疗患有慢性炎性肠病的患者的铁缺乏症中的应用。在文件中,可参考含有100mg铁(III)的薄膜衣片。该片剂中铁的含量为16重量%,对应于25.6%w/w羟基氧化铁。该制剂用于治疗铁缺乏症,即用于释放铁(III),与本发明中定义的磷酸盐吸附剂相反。未描述干燥过程。
WO 92/01458公开了氧化铁化合物,尤其是铁氧化物、铁氢氧化物和羟基氧化铁,其被制成用作磷酸盐吸附剂的治疗性剂型。未公开特定的口服制剂,并且未提及特定的铁载量。此外,未具体公开辅料和制造方法,但是可参考"可接受的方法和辅料"。认为每一种口服剂量可含有50mg~约500mg或更多的氧化铁化合物。根据现有技术水平,含有500mg氧化铁化合物的片剂将是巨大的尺寸,以至于患者不能吞咽,为了达到期望的磷酸盐吸附度这样的片剂是必需的。此文件未公开如何获得高铁载量的任何信息。
US 5,514,281公开了多核羟基氧化铁,其结合至载体如皂化的二乙烯基乙烯尿素乙酸乙烯酯共聚物、Lewatit硅石、玻璃以及用葡聚糖改性的有机多孔载体。担载铁(III)的载体的最大铁载量报道为29.3干重%。该产物由干燥的载体制成,所述载体可膨大,并且该产物此后不能被干燥,这是由于从透析液除去了磷酸盐根本不能发挥作用。US5,51 4,281中未描述口服给药的干燥/片剂剂型的实施例。描述吸附剂的实施例全都表明可体外使用,并且用于其产物的载体没有可适用于医学用途的。口服制剂的制备仅被描述为"压制成用于...的粉体"。开发这些产品以释放铁。
对于广泛的药物,口服剂型如片剂明显是优选的传递形式。这是由于患者的接受度和依从性高(因为它们提供准确的剂量并且易于给药)以及在制造期间和制造后的有利的特征,如它们通常显示令人满意的物理和化学稳定性,方便包装、运输和给药,并提供制造速度和成本的优势。
但是,口服剂型需要仔细设计的崩解特征,以达到合并药物的预期的生物利用度,即溶出必须在吸收之前,在直接释放的情况中,片剂应在吞咽后快速崩解以促进药物溶出。而且,由于潜在的胃肠刺激(由局部高浓度所引起)和/或患者依从性(其限制大小和形状以达到易于吞咽),普通的片剂制剂的药物载量通常受限。
这些限制已阻止了羟基氧化铁作为高载量磷酸盐结合剂的有效经口传递系统的开发。
申请人现已发现羟基氧化铁(下文也称为活性剂),尤其是含β-羟基氧化铁的羟基氧化铁,尤其是还含有如EP 0 868 125 B1中所述可用作稳定剂的糖类和/或腐殖酸的羟基氧化铁,可被成功地制成高载量的经口传递系统的形式(下文也称为药物组合物或本发明的组合物),优选作为完整吞咽的剂型(例如薄膜包衣)或作为能够快速崩解的剂型(在口腔中或在之前在少量液体中)。因此,本发明的药物组合物实现到高载量和适合的崩解特性,同时维持最小的尺寸,因而能够克服当前已知制剂的缺点。
本发明组合物具有低的铁释放率,为2.5%w/w以下,这对于磷酸盐吸附剂是必要的。与之相反,用于治疗铁缺乏症的组合物具有高的铁释放率,因此完全不同于本发明的组合物。
此外,已发现本发明的药物组合物可优选通过常规地模塑或制片方法得到,更优选直接压片法,在一种或多种辅料存在下实现,例如其中粘合剂和/或填充剂和/或崩解剂的作用。
还发现如果以能够在口腔中崩解的剂型给药,与活性剂相关的任何不良味道能够使用适当的掩味剂、甜味剂和/或增味剂进行消除。
此外,发现如果它们包含基本量的流动粉体,可以得到具有特别高的羟基氧化铁载量的良好的片剂制剂,所述流动粉体已通过喷雾干燥成分的水悬浊液制备。
发明内容
本发明的目的在于,提供包含羟基氧化铁的药物组合物,其以适于口服给药的形式,尤其是具有高载量的经口传递系统,优选为完整吞咽的剂型(例如薄膜包衣)或能够快速崩解(在口腔中或在吞咽之前在少量的液体中)的剂型。
在优选的实施方式中,含羟基氧化铁的药物组合物包含一种或多种糖类和/或腐殖酸,优选糖类如单-、二-或多糖,优选蔗糖(蔗糖)、淀粉、琼脂糖、葡聚糖、糊精、纤维素和它们各自的衍生物。如EP 0 868 125 B1所述,那些糖类和/或腐殖酸可作为稳定剂起作用。除此之外,糖类和/或腐殖酸可作为粘合剂和/或填充剂和/或崩解剂起作用。
在再另一个实施方式中,本发明的组合物包含一种或多种掩味剂和/或着色剂,如调味剂、甜味剂、增味剂、着色剂等。
依据片剂的预期使用,即它是用于完整吞咽还是快速崩解(在口腔中或在吞下之前在少量的液体中),如咀嚼片,如果需要可添加通常的辅料如超级崩解剂、助流剂、润滑剂、抗氧化剂、助压剂等。如果需要,片剂可用通常的薄膜成形剂包衣。
在另一个实施方案中,本发明的药物组合物是适于口服给药的任何剂型,并且尤其包括片剂和丸剂,以完整吞咽的形式(例如薄膜包衣)或能够快速崩解的形式(在吞咽后在口腔中或在吞咽之前在少量的液体中),包括可咀嚼形式、干粉、颗粒、包含它们的胶囊或囊剂、薄片剂(wafers)、膜剂、锭剂等。
本发明的另一个目的在于,提供制成根据本发明的经口传递系统的方法,尤其是以下经口传递系统:完整吞咽的剂型(例如薄膜包衣)或能够快速崩解的剂型(在口腔中或在吞咽之前在少量的液体中),其包含高载量的羟基氧化铁,通过常规模塑或制片法,优选直接压片法的方法。
因此,在第一方式中,本发明涉及包含作为活性剂的高载量羟基氧化铁的药物组合物,其以适于口服给药的形式,显示期望的崩解特征。
特别地,本发明涉及具有高载量活性剂的可口服给药的药物组合物,其是完整吞咽的剂型(例如薄膜包衣)或能够快速崩解的剂型(在口腔中或在吞咽之前在少量的液体中)。
如上文所示,如本文所使用的术语"活性剂"包括羟基氧化铁(III)。羟基氧化铁(III)或羟基铁(III)氧化物通常是指FeO(OH)或Fe2O3 xH2O。根据本发明所使用的这类羟基氧化铁通常经在铁(III)-盐水溶液中的水解并沉淀形成(参见,例如,LexikonChemie,10,Auflage,1997;U.Schwertmann,R.M.Cornell"Iron Oxides in theLaboratory",VCH Verlagsgesellschaft mbH,1991,Seiten 95-100)。因此如本文所使用的术语"羟基氧化铁"包括,尤其是α、β、γ和δFeOOH及其混合物。优选地,羟基氧化铁包含βFeOOH任选与其它羟基氧化铁混合。
根据本发明所使用的羟基氧化铁优选,如EP 0868125 B1中所述,通过在铁(III)-盐水溶液中添加碱,随后干燥来制备。
优选地,使用通过稳定剂稳定的羟基氧化铁。
语句"羟基氧化铁,其通过稳定剂稳定"优选包括与稳定剂一起的羟基氧化铁,所述稳定剂尤其包括糖类和腐殖酸。如EP 0868125 B1所述,这类稳定剂通常不作为络合物与羟基氧化铁结合,这表明例如水溶性稳定剂可通过用水洗涤稳定化的羟基氧化铁而除去。如EP 0868125 B1进一步描述的,提供稳定剂以使羟基氧化铁稳定而不被老化,由此保持其磷酸盐吸附能力。这表明与未稳定化的羟基氧化铁相比,稳定化的羟基氧化铁通常具有较高的磷酸盐吸附能力(如EP 0868125 B1所测定的)。根据本发明,优选的"羟基氧化铁,其通过稳定剂稳定"如EP 0868125 B1所述,包含用至少一种糖类和/或腐殖酸稳定化的β羟基氧化铁。
通常,由于其化学性质,根据本发明所使用和给药的羟基氧化铁基本不被人体所吸收,即它们基本上是非-生物可吸收的。
因此,如本文所使用的术语"稳定剂"优选包括至少一种糖类和/或腐殖酸,尤其是如EP 0868125 B1所述。在一个实施方式中,至少一种糖类是可溶性的,并包括至少一种单-、二-或多糖,如琼脂糖、葡聚糖、糊精、葡聚糖衍生物、纤维素和纤维素衍生物、蔗糖(蔗糖)、麦芽糖或乳糖,优选蔗糖(蔗糖)、糊精或淀粉。
如本文所使用术语"淀粉"包括任何通常使用的淀粉产品(如马铃薯淀粉、玉米淀粉、米淀粉、木薯淀粉),其为天然的、预糊化的、降解的、改性的和衍生化形式,优选适于直接压片法,和它们的混合物。
优选的产品包括天然淀粉和预糊化淀粉,如具有(天然:预胶化)比例为10:1~0.5:1范围,优选3:1~0.5:1范围,更优选2:1~1:1范围的混合物。天然和预糊化淀粉混合物的使用特别产生在制造高铁载量的片剂中的优势,这是由于其允许制备稳定化的预混合物,其可以直接或与非常少量的其它辅料压制成适宜的片剂。
在一个特定的实施方案中,选择的稳定剂可以以1.0~50%(w/w),优选5.0~30%(w/w)的量存在。
如果不另外指出,本说明书所有的重量%(w/w)都相对于药物组合物的总重量表示。
如本文所使用的术语"高载量"是指羟基氧化铁以10~80%(w/w),更优选30~65%(w/w)的量存在。
羟基氧化铁的含量以大约1.6x铁含量计算。
因此,上文提及的值对应的铁含量为6~50%w/w,更优选19~41%(w/w)。
在本发明的优选实施方式中,甚至实现更高的铁载量,即超过50%(w/w)~90%(w/w)的羟基氧化铁,优选56%-65%(w/w),对应于31~56%(w/w),优选35%~41%(w/w)的铁。
否则,羟基氧化铁优选以>300mg/剂型,更优选300~2000mg/剂型的量存在。应当理解,活性剂的量取决于预期的给药途径,即完整吞咽的薄膜包衣(例如薄膜包衣)片中存在的量优选是350~850mg,而能够快速崩解(在口腔中或在吞咽之前在少量的液体中)的口服剂型中存在的量优选是700~1700mg。
除活性剂外,常规的药物组合物通常含有许多额外的无活性成分,已知为辅料和/或添加剂。特别地,当需要完成的期望的治疗、营养或化学作用的活性剂的量非常小时,惰性稀释剂、填充剂、粘合剂、辅料和崩解剂、润滑剂、助流剂和甜味剂、掩味剂、着色剂等的存在通常是关键的,以确保使口服剂型达到准确和有效的活性剂给药的实用性和方便性。
与此相反,关于含有高载量活性剂的经口给药的药物组合物,如本发明所述,这类额外的无活性成分是最少的,这是由于经口给药的药物组合物的大小对于达到良好的患者依从性是关键特征。
如上文所示,糖类如单-、二-或多糖,优选蔗糖(蔗糖)、淀粉、琼脂糖、葡聚糖、糊精、纤维素及其各自的衍生物,更优选蔗糖(蔗糖)、糊精或淀粉,除其对羟基氧化铁的稳定作用外,可在本发明的药物组合物中作为粘合剂和/或填充剂和/或崩解剂起作用。
因此,优选的本发明的组合物可包含上述特定的量的羟基氧化铁,选择的稳定剂的量为1.0~50%(w/w),优选5.0~30%(w/w),选择的辅料不同于稳定剂,其量为1.0~50%(w/w),优选5.0~30%(w/w),各自相对于组合物的总重量表示。
在另一个实施方案中,本发明的组合物包含一种或多种掩味剂和着色添加剂,如调味剂、甜味剂、增味剂、着色剂等,其通常用于口服剂型。
掩味剂,如增味剂、调味剂和/或天然的或非天然的甜味剂,包括浓烈的甜味剂,掺入口服剂型如咀嚼剂型中,以得到更令人愉快的味道或掩盖令人不愉快的味道。
典型的甜味剂包括但不限于,糖,其是葡萄糖、蔗糖、果糖、乳糖、糖果、糖粉,或者是多元醇,其是山梨醇(例如Neosorb)、木糖醇、麦芽糖醇、麦芽糖和聚葡萄糖,或者其混合物。典型的浓烈甜味剂可包括但不限于,天冬甜素、三氯半乳蔗糖、阿糖精K和/或糖精衍生物,或者其混合物。另外的适宜的甜味剂或增味剂包括苷类如新橙皮苷二氢查耳酮(新橙皮苷DC或NHDC)、甘草甜、谷氨酸等。后者可以非常小的量使用,因此在下文中也可称为增味剂。以上所有物质都适于单独使用,或作为与其它甜味剂和/或调味剂的混合物使用。这些物质确保甜味的长期逗留,并掩盖任何不期望的余味。优选的甜味剂和/或增味剂包括苷类如新橙皮苷二氢查耳酮。
在一个实施方式中,选择的甜味剂可以0.01~2.5%(w/w),优选0.1~1.5%(w/w),最优选0.2~1.0%(w/w)的量存在,其相对于组合物的总重量。
选择的增味剂以0.1~50ppm,优选1~10ppm,最优选1~5ppm的量存在,其相对于组合物的总重量。
典型的调味剂包括适于药物应用的任何天然的和非天然的调味剂,如衍生自香料、水果或果汁、蔬菜或蔬菜汁等的调味剂,例如基于以下的风味:可可、焦糖、香草、苹果、杏、浆果(例如黑莓、红醋栗、黑茶藨子、草莓、覆盆子、woodberry等)、薄荷、意大利节日糕点(panettone)、蜂蜜、坚果、麦芽、可乐类饮料、马鞭草(马鞭草属植物),或者其任意组合,如焦糖/香草、水果/乳酪(例如草莓/乳酪)等。
在一个实施方式中,选择的调味剂可以以0.01~10%(w/w),优选0.1~5%(w/w),最优选0.1~1%(w/w)的量存在,相对于组合物的总重量。
因此,本发明的另一个组合物可包含上述特定的量的羟基氧化铁,选择的稳定剂的量为1.0~50%(w/w),优选5.0~30%(w/w),选择的辅料不同于稳定剂,其量为1.0~50%(w/w),优选5.0~30%(w/w),并且选择的增味剂,其以0.1~50ppm,优选1~10ppm,最优选1~5ppm的量存在,和/或选择的调味剂,其以0.01~10%(w/w),优选0.1~5%(w/w),最优选0.1~1%(w/w)的量存在,各自相对于组合物的总重量。
在另一个实施方式中,辅料如超级崩解剂、助流剂、润滑剂、抗氧化剂等如果需要可添加到本发明的组合物中,取决于片剂的预期用法,即它是完整吞咽还是快速崩解(在口腔中或在吞咽之前在少量的液体中)。
因此,在特别的实施方式中,本发明的组合物可进一步包含超级崩解剂。
如本文所使用的术语"超级崩解剂"是指一组本领域技术人员公知的崩解剂,其可以常规崩解剂的部分量使用以获得在给药后促进剂型崩解或"崩溃"的相同作用。适当的实例包括但不限于交联聚乙烯吡咯烷酮(市售名为CL和XL),尤其是改性淀粉,尤其是羟基乙酸淀粉钠(市售商品名为和),淀粉1500,改性纤维素,尤其是交联羧甲基纤维素钠(交联羧甲基纤维素钠,市售商品名为Ac-Di-Sol),LHPC(低取代羟丙纤维素)和在根据本发明的片剂中使用的优选的实例包括交联聚乙烯吡咯烷酮和改性淀粉,尤其是羟基乙酸淀粉钠。
根据本发明,片剂中的超级崩解剂将以0.1~10%(w/w),优选0.5~8%(w/w),更优选2.5~6%(w/w)的量存在,相对于组合物的总重量。超级崩解剂可以是单个超级崩解剂或超级崩解剂的组合,或者可以与一种或多种普通的崩解剂组合使用,所述普通崩解剂例如有淀粉、甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、羟丙纤维素、微晶纤维素、胶态二氧化硅、交联羧甲基纤维素钠、预糊化淀粉、粘土、纤维素、粉状纤维素、预糊化淀粉、藻酸钠、藻酸、瓜尔胶、硅酸镁铝、波尔阿克里林钾盐等。
因此,本发明的另一个组合物可包含上述特定的量的羟基氧化铁,选择的稳定剂的量为1.0~50%(w/w),优选5.0~30%(w/w),选择的辅料不同于稳定剂,其量为1.0~50%(w/w),优选5.0~30%(w/w),所述辅料包含超级崩解剂,其量为0.1~10%,优选0.5~8%(w/w),更优选2.5~6%(w/w),并且选择的增味剂的量为0.1~50ppm(w/w),优选1~10ppm(w/w),更优选1~5ppm(w/w),和/或选择的调味剂的量为0.01~10%(w/w),优选0.1~5%(w/w),更优选0.1~1%(w/w),所有重量范围都相对于组合物的总重量。
在再另一个实施方案中,本发明的组合物可进一步包含助流剂和/或润滑剂。
如本文所使用的术语"助流剂"和/或"润滑剂"是指一组通过达到适宜的流动性、可压性等用于使片剂易于制造的添加剂。适宜的助流剂的实例包括但不限于氧化镁、硬脂酸镁、硬脂酸钙、硬脂酸、甘油二十二烷酸酯、硬脂酸甘油酯、棕榈酰硬脂酸甘油酯、氢化蓖麻油、I型氢化植物油、苯甲酸钠、十二烷基硫酸钠、硬脂基富马酸钠、聚乙二醇、滑石、硬脂酸锌、硅石衍生物如胶态硅石(例如)、热解硅石、水合硅铝酸钠、胶态二氧化硅和矿物油及轻质矿物油。
优选的助流剂包括氧化镁、硬脂酸镁、滑石、胶态硅石。
在一个实施方式中,选择的助流剂可以0.01~10%(w/w),优选0.1~5%(w/w),最优选1~2%(w/w)的量存在,相对于组合物的总重量。
特别用于能够在口腔中快速崩解的口服剂型的其它添加剂可包括唾液分泌剂(能够刺激唾液产生的化合物)以易于吞咽。这些化合物通常是药学上可接受的酸,例如枸橼酸、苹果酸、酒石酸或化合物和必须注意,通过使用这类酸性化合物例如枸橼酸,铁的释放不会增加,因此这些物质的量须适当选择。在一个实施方案中,选择的酸可以0.01~10%(w/w),优选0.1~5%(w/w),最优选2~5%(w/w)的量存在,相对于组合物的总重量。
如上文所提及的,药物组合物是适于口服给药的形式,以便选择性除去无机磷酸盐,尤其适于以完整吞咽的薄膜包衣剂型或能崩解的剂型(在口腔中或在吞咽之前在少量的液体中)的经口传递系统给药。
因此,本发明的药物组合物包括适于口服给药的任何剂型,尤其是可包括片剂和丸剂,其为完整吞咽的形式(例如薄膜包衣)或能够快速崩解的形式(在吞咽后在口腔中或在吞咽之前在少量的液体中),包括咀嚼形式、干粉、颗粒、含有这些颗粒的胶囊或囊剂、薄片剂、锭剂等。如果需要,完整吞咽的形式可以为薄膜包衣。
优选的剂型包括片剂和丸剂,其为完整吞咽的形式(例如薄膜包衣)或咀嚼形式、颗粒和包含这些颗粒的胶囊或囊剂及锭剂。
对于经口给药的剂型,如果需要薄膜包衣,则这些剂型是完整吞咽的,并且崩解发生在胃中,由此用于吸收磷酸盐的活性剂释放以减少其全身吸收。
如本文所使用的术语"薄膜包衣"与药学上可接受的辅料的混合物相关,所述辅料通常适用于压制片剂、粒料(beads)、颗粒或压制成片剂的活性成分颗粒。或者,其也可与活性剂组合、混合或添加到活性剂中。应当理解,选择的包衣必须与活性剂相容。还应当理解,本领域技术人员将知道如何进行包衣以通过选择制成包衣的辅料、其类型和/或其厚度实现在胃中崩解。
在优选的实施方式中,薄膜包衣施用于药物组合物,其在压制形式中包含羟基氧化铁和至少一种辅料。
根据本发明的用于薄膜包衣的适宜聚合物在pH约1.2~约5是可溶的,例如羟丙基甲基纤维素(HPMC)单独和/或与羟丙纤维素(HPC)、羧甲基纤维素、甲基纤维素、乙基纤维素的组合,丙烯酸树脂和聚乙烯吡咯烷酮及明胶或其它市售可得的薄膜包衣制品如(Crompton&Knowles Corp.,Mahwah,NJ.)或(Colorcon,WestPoint Pa.)。
本发明优选的薄膜包衣包含市售的薄膜-包衣产品,其设计为含有水溶性的成膜的树脂、羟丙基甲基纤维素和聚乙二醇(或其它适宜的增塑剂如丙二醇或甘油)及任选含有二氧化钛(或其它着色剂或遮光剂)的水性薄膜包衣。这类产品是市售可得的,商品名为White(Colorcon,West Point,Pa.)。
包衣用的适宜的共混物可包含0~约20%w/w二氧化钛或着色剂,约5~约95%w/w羟丙基甲基纤维素,和0~约25%w/w聚乙二醇。最优选的实施方式包含10.5%非水添加剂,其中7.5%是相对于包衣的总重量。
该包衣用共混物可进一步包含上文所定义的调味剂、掩味剂和唾液分泌剂,其为少量的,如基于包衣用共混物的总重量为0.1~1.0%(w/w),优选0.1~0.4%。优选的调味剂和/或掩味剂可选自上文定义的试剂。优选的量通过平衡下述的两个目的而容易确定:添加的量足以掩盖片剂核的味道并提供截然不同的特征性的令人愉快的味道的目的,和使片剂不太像糖果制品的目的。期望的调味和/或掩味剂的强度可根据片剂的类型和预期的受者及调味和/或掩味剂的特性而变化。
片剂上沉积的包衣的量通常为约1.0%~约6.0%重量增加,优选2.0%~4.0%重量增加,这表明相对于未包衣片剂的重量,包衣引起片剂的重量增加。
对于口服给药,快速崩解剂型,崩解在给药时立即发生,以使其在口腔中快速释放活性剂或形成含有活性剂的小颗粒。适宜的崩解速率为1秒~3分钟。优选的崩解时间通常少于30秒,其根据标准的欧洲药典检测法测定。
因此,在一个实施方式中,制剂是由如直接压片和干法制粒的标准制片技术制得的片剂,其包含羟基氧化铁、稳定剂、辅料(不同于稳定剂),特别包括一种或多种甜味剂、增味剂、调味剂、超级崩解剂、助流剂、抗氧化剂等。必须避免湿法处理技术。这是由于以下事实:当使用有机溶剂通常为异丙醇时,溶剂在干燥后仍残留在颗粒中,这与产品技术要求不相容。当使用水作为湿法制粒的溶剂时,增加铁从产品的释放,这对于本发明的磷酸盐吸附剂组合物在任何情况下都应避免。挤出技术可引起以下问题:当使用高载量铁时,可形成小的硬球,其不适于本发明,这是由于它们几乎不显示任何磷酸盐的吸附性质。
在干法制粒中,粉体成分通常在被压实之前(也称为预压)混合,以得到硬的坯料,然后在添加其它成分和最后压制之前将其研磨和过筛。
优选地,本发明的组合物通过直接压片法制得,此方法被认为是最简单且最经济的制备片剂的方法。
在本发明的优选实施方式中,本发明的组合物通过混合大多数成分(超过50%,优选超过70%,更优选超过90%至多100%的成分总重量)制得,例如表1中所列的那些成分,以水悬浊液的形式(干物质的量例如为1~50%(w/w),优选10~40%(w/w),更优选20~30%(w/w)),对所述悬浊液在暴露于热气体如空气或优选氮、温度为135℃~200℃的常规条件下进行已知的喷雾干燥处理,以得到流动性粉体,其任选随后与额外的成分(例如表2中所示)混合,随后在一定范围的压制力如10~20kN下直接压片,得到片剂。
优选地,所述悬浊液含有3~9%(w/w)的铁,更优选4~8%(w/w),最优选6%(w/w)。
必须注意,喷雾干燥柱的直径和高度是足够大的。而且,温度必须选择在辅料和其它成分既不熔化也不焦糖化的范围内。这两种处理不产生干粉,而产生固体熔化物,这不适于本发明。
优选地,制片之前,流动性粉体首先使用干法压制来压实,以便减少细粉(粉尘)的量并使粒径均匀。由此,获得的片剂的硬度达到25~400N。压制力在以下范围内调整:由压制的混合物得到的片剂的硬度,对于咀嚼片是50~100N,对于包衣片或吞咽片是100~200N。如果使用此范围,得到的片剂的崩解时间在欧洲药典要求的规范之内。
已惊奇地发现,特别地,由于这种方法,可减少得到具有适宜性质的片剂所需要的辅料的量,所述适宜性质例如为关于片剂强度、崩解行为等方面。由此可生产药物组合物,特别是具有高载量羟基氧化铁的片剂形式。
应当理解,成分的准确量将决定片剂的大小和厚度。能够快速崩解(在口腔中,即咀嚼片,或者在吞咽之前的少量液体中)的片剂可具有任何几何形状,如圆形、方形、三角形等。通常,它们是圆形的,并优选具有的直径为15~30mm,最优选20mm,且高度为2~8mm,优选4~6mm。用于完整吞咽的薄膜包衣片剂通常为长方形形式,例如长约19mm,宽约10mm,且高约8mm。这些实例仅仅是举例说明,并不意味着限制。本领域技术人员将知道根据总成分的重量选择适当的形式。压制应当充分以在剂量给药期间保持成分聚集,同时使得在口腔中易于崩解。通常使用10~20kN。
在另一个实施方式中,药物组合物是适于在口腔中崩解或在少量的水中快速溶出的颗粒形式。此颗粒可以通过高剪切制粒法,或者优选流化床制粒或(干燥)混合处理制备。如上文所指出,使用溶剂的湿法技术必须避免。颗粒可填充在胶囊或囊剂中,以贮存和施用于口腔。
在另一个实施方式中,作为喷雾干燥的替代方法,药物组合物可以薄片剂形式提供。薄片剂可通过压制粉体、冻干团块或蒸发悬浊液、乳液或凝胶形成。或者,混合的干燥物质可在压片机器中或辊之间变平或被压制,以形成粉体例如形成小片,其可被切割成可放入口腔中的适宜尺寸。在一个实施方式中,薄片剂通过将活性剂、溶剂、粘合剂或其它添加剂混悬在溶剂如水中形成。将预设量的悬浊液置于塑料模具的孔中,并在孔中冻干以除去水并形成薄片剂。
如上文所提及的,本发明的组合物适用于已知的基本上非-生物吸附羟基氧化铁的适应症,尤其适用于选择性除去无机磷酸盐如治疗高磷酸酯酶血症。
因此,在另一方面中,本发明提供用于治疗高磷酸酯酶血症的本发明组合物。
在另一方面中,本发明提供一种用于治疗高磷酸酯酶血症的方法,包含对需要此的患者给药本发明的组合物。
在另一方面中,本发明提供本发明组合物在制备用于治疗高磷酸酯酶血症的药物中的应用。
本发明组合物的效用可在标准临床试验中观察到。
所给药的羟基氧化铁和组合物的准确的量取决于几个因素,例如疾病的严重度、所期望的治疗持续时间等。
本发明通过以下具体的非限制实施例更详细地说明:
实施例
直接压片法使用标准压片机在10~20kN的压制力下进行。喷雾干燥处理在135~200℃的温度下进行。
片剂检测方法:
片剂硬度和崩解时间根据标准欧洲药典检验法测定。
实施例1:制备稳定化羟基氧化铁预混合物
稳定化羟基氧化铁预混合物通过将一定量/比例的羟基氧化铁悬浊液(根据EP 0868 125 B1制备)与表1的辅料混合而制备。此悬浊液在135~200℃进行喷雾干燥,得到流动性粉体形式的预混合物。此预混合物进行直接压制得到片剂,其中的组合物显示于表1中。
表1:
1)稳定剂
2)填充剂/崩解剂
3)稳定剂/粘合剂/填充剂/崩解剂
4)超级崩解剂
5)干燥后预混合物中不再存在水,除约干重的约5%(其它成分的总量)残余部分外
实施例2:制备片剂
干燥混合物通过将根据表2的各成分混合而制备,并进行直接压片得到片剂。
表2:
实施例3:片剂的薄膜包衣
根据实施例2得到的片剂,但是仅具有50%的量,被压制为长方形形式,随后通过混合根据下表的成分进行薄膜包衣(重量增加为2~5%):
表3:
实施例4:颗粒
使用高剪切制粒机,以异丙醇作为制粒液体,通过添加根据下表的成分,将根据实施例1e得到的粉体进行湿法制粒:
表4:
实施例5:制备用于填充囊剂或条带包囊剂(stickpacks)的最终可立即分散的颗粒:
干燥混合物通过混合根据下表的成分制备,随后进行填充入囊剂或条带包囊剂中:
表5:
成分 | mg |
颗粒(Ex.4,由不同的基质得到的变体) | 3797.5 |
天冬甜素 | 15 |
香料* | 70 |
枸橼酸 | 155 |
*"令人爽快的香料"如可乐类饮料、马鞭草、黑莓
实施例6:制备用于填充囊剂或条带包囊剂的最终可立即分散的颗粒:
干燥混合物通过混合根据下表的成分而制备,随后进行填充入囊剂或条带包囊剂中:
实施例7:制备流动性粉体
将9.6kg FeOOH(对应于6.0kg Fe)和表7a中所示的一定量的辅料和辅剂一起在水中混悬。将100kg的悬浊液进行喷雾干燥。得到的粉体的铁载量显示于表7b中。
表7a:
1)马铃薯淀粉
2)预糊化淀粉,由Roquette得到
表8:
1)干燥失重,根据卤素水分分析仪测定(恒重;质量的变化不超过1mg/180秒)。
实施例8:将得到的流动性粉体制片
将实施例7a)~g)中得到的产物与表9a中所示的成分混合,并将得到的混合物制成片剂。得到片剂的Fe含量、pH 3时Fe释放以及磷酸盐吸附在表9b中给出。
根据欧洲药典2.9.3章,使用如此章节中所述的标准溶出仪器和参数,测定Fe释放。试验介质为水,使用盐酸调节pH 3。2h后取样品,并通过滴定法分析铁含量。
磷酸盐吸附如WO 2006/000547中所述测定,通过将得到的片剂溶解于确定量的特定浓度的磷酸盐溶液中,调节pH至3,于37℃反应2小时,离心、倾析并通过离子色谱法或光度测定法测定磷酸盐含量。
表9a:
表9b:
Claims (25)
1.包含高载量羟基氧化铁的药物组合物,其为适于口服给药的形式。
2.包含高载量羟基氧化铁的药物组合物,其为适于口服给药的形式,作为用于完整吞咽的薄膜包衣剂型或作为能够在口腔中崩解的剂型。
3.根据权利要求1或2的组合物,其中所述组合物含有至少一种糖类和/或腐殖酸。
4.根据权利要求3的组合物,其中所述糖类选自单-、二-或多糖,如琼脂糖、葡聚糖、糊精、葡聚糖衍生物、纤维素和纤维素衍生物、蔗糖、麦芽糖及乳糖,优选蔗糖、糊精和淀粉。
5.根据前述权利要求任一项的组合物,其中所述羟基氧化铁含有β羟基氧化铁。
6.根据前述权利要求任一项的组合物,其中羟基氧化铁以10~80%(w/w),优选30~65%(w/w)的量存在,其以相对于所述组合物的总重量表示。
7.根据前述权利要求任一项的组合物,其中所述糖类和/或腐殖酸以1~50%(w/w),优选5~30%(w/w)的总量存在,其以相对于所述组合物的总重量表示。
8.根据前述权利要求任一项的组合物,其进一步包含一种或多种调味剂、甜味剂、增味剂和/或着色剂。
9.根据权利要求8的组合物,其中所述甜味剂是天然的或非天然的甜味剂,选自糖、多元醇、天冬甜素、三氯半乳蔗糖、阿糖精K和/或糖精,并且所述增味剂选自苷类,如新橙皮苷二氢查耳酮、甘草甜、谷氨酸。
10.根据权利要求8或9的组合物,其中所述甜味剂以0.01~2.5%(w/w)的量存在,并且所述增味剂以0.1~10ppm的量存在,各自以相对于所述组合物的总重量表示。
11.根据权利要求8的组合物,其中所述调味剂以0.01~10%(w/w),优选0.1~5%(w/w),最优选0.1~1%(w/w)的量存在,其以相对于与组合物的总重量表示。
12.根据前述权利要求任一项的组合物,其进一步包含一种或多种辅料,如超级崩解剂、助流剂、抗氧化剂。
13.根据权利要求12的组合物,其中所述超级崩解剂选自交联聚乙烯吡咯烷酮、改性淀粉和改性纤维素。
14.根据权利要求12或13的组合物,其中所述超级崩解剂以0.1~10%(w/w),优选0.5~8%(w/w),更优选2.5~6%(w/w)的量存在,其以相对于组合物的总重量表示。
15.根据权利要求12的组合物,其中所述助流剂选自硬脂酸镁、硅石衍生物如胶态硅石、热解硅石、水合硅铝酸钠、胶态二氧化硅、滑石及它们的混合物,优选硬脂酸镁、胶态硅石或滑石。
16.根据权利要求12或15的组合物,其中所述助流剂以0.01~10%(w/w),优选0.1~5%(w/w)的量存在,其以相对于组合物的总重量表示。
17.根据前述权利要求任一项的组合物,包含:10~80%(w/w)的羟基氧化铁,总量1.0~50%(w/w)的至少一种糖类和/或腐殖酸,总量1.0~50%(w/w)的任选一种或多种辅料,总量0.1~10ppm的一种或多种增味剂,和/或总量0.01~10%(w/w)一种或多种调味剂,各自以相对于组合物的总重量表示。
18.根据权利要求17的组合物,其包含总量0.1~10重量%(w/w)的一种或多种超级崩解剂。
19.根据前述权利要求任一项的组合物,其为完整吞咽的形式或能够快速崩解的形式,如可咀嚼片剂或丸剂、干粉、颗粒、包含这些颗粒的胶囊或囊剂、薄片剂或锭剂。
20.前述权利要求任一项的组合物在制造用于治疗高磷酸酯酶血症的药物中的应用。
21.前述权利要求任一项的组合物在制造用于治疗患有慢性肾功能不全患者的药物中的应用。
22.一种制备为片剂形式的前述权利要求任一项组合物的方法,其通过直接压片法或干法制粒。
23.一种制备为片剂形式的前述权利要求任一项组合物的方法,其中制备水悬浊液,其基于最终组合物总重量,包含至少90%(w/w)的成分,然后使其进行喷雾干燥以获得流动性粉体,其任选与剩余的成分混合,随后被压制以得到片剂。
24.通过权利要求23的方法得到的片剂。
25.一种片剂,其包含:40~65%(w/w)的羟基氧化铁,5~30%(w/w)的蔗糖,以及5~30%(w/w)的淀粉,其以相对于不包括任选存在的片剂包衣重量的片剂组合物的总重量表示。
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