CN110051642A - 包含包封于硬胶囊中的多单元球状片剂(must)的复合制剂及其制备方法 - Google Patents
包含包封于硬胶囊中的多单元球状片剂(must)的复合制剂及其制备方法 Download PDFInfo
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- CN110051642A CN110051642A CN201910062530.1A CN201910062530A CN110051642A CN 110051642 A CN110051642 A CN 110051642A CN 201910062530 A CN201910062530 A CN 201910062530A CN 110051642 A CN110051642 A CN 110051642A
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Abstract
本申请涉及包含包封于硬胶囊中的多单元球状片剂(MUST)的复合制剂及其制备方法。本发明的硬胶囊复合制剂能够有效地将MUST填充于有限的胶囊空间中,这允许将高剂量的不同药物活性成分填充于具有相对小尺寸的胶囊中,从而提高了生产率并使其易于给药于患者。此外,胶囊具有良好的溶解速率,因为胶囊中包含的药物活性成分是彼此分离的;因此,各种成分的溶解速率不太彼此受到影响。这或许也可能最大化药物活性成分的治疗效果,因为复合制剂具有良好的稳定性。
Description
本申请是申请日为2013年4月12日的题为“包含包封于硬胶囊中的多单元球状片剂(MUST)的复合制剂及其制备方法”的中国专利申请第201380019865.6号的分案申请。
技术领域
本发明涉及含有多单元(多单位,multi-unit)球状(类球状,spheroidal)片剂(MUST)的硬胶囊复合制剂及其制备方法。
背景技术
在医药领域中的进步已经提高了生命质量,并增加了人的预期寿命。然而,对于单种药物活性成分在治疗患有医学病症的患者中的功效还有一定限制。因此,通常为了协同效应会同时或按序给药具有不同作用机理(模式)的多种药物。
然而,两种或多种独立药物单元(单位,unit)的联合给药或许会降低患者服药的顺应性,从而对经受连续药物治疗的患者造成极大的不便。此外,患者不得不一次服用这种多个药物单元,并一直随身将其携带。这也会给患者在其日常生活带来极大的不便。
为了调整这些问题,人们已经提出将许多药物封装于单个包中的方法。例如,Torrent Pharmaceuticals Ltd.(印度)已经发布了一种复合制剂“CVpill”,一种用于治疗心血管疾病的含胶囊和片剂的单个试剂盒。CVpill由含10mg粉末形式的阿托伐他汀,粉末形式的雷米普利和75mg肠衣涂层阿司匹林片剂的胶囊和含有50mg美托洛尔的缓释片剂构成。随身胶囊和片剂必须每天一次同时给药。但这种包含简单试剂盒的组合包装产品几乎不能改善患者服药的顺应性,然而,这在复合制剂中或许是所企求的。因此,对于开发特定活性成分的“组合药物或复合制剂”的研究的需求不断增长。
正如本文中所用的术语“复合制剂”是指两种的组合或多种不同活性成分或药物在单一单元剂量如片剂或胶囊中的组合。然而,对于特定活性成分的复合制剂的开发由于以下原因有时是非常困难的。
首先,对于复合制剂所使用的特定活性成分的组合应该易于进行。而且,含有活性成分和药用赋形剂的组合物对于其给药应该具有合适的尺寸和重量。然而,并不总是很容易地开发出符合这种要求的复合制剂。如果要使用的药物含量过量或不足,则这将很难将组合物的重量调节至合适的水平。此外,意想不到的问题可能会偶发于处理由药物的药代动力学和药物特性所致的各种条件的过程中。
其次,在制备复合制剂中活性成分之间的化学相互作用可能降低药物的稳定性。尤其是,如果其稳定性或许由于其组合时的化学相互作用而降低时,则更加难以开发具有对药物组合的足够物理化学稳定性的固定组合剂量形式。
当制备片剂的复合制剂时,双层或三层制片机能够用于分离活性成分。此外,不仅这种方法需要特殊的设备,而且机械上也不可能完全分离每层中的主要成分,因为不希望的反应可能发生于这些层的界面上。
对于胶囊剂(胶囊,capsule),常规硬胶囊会填充粉末、颗粒或丸粒形式的药物。而且,只有单一活性成分通过单个填充步骤填充到硬胶囊中。此外,粉末、颗粒或丸粒形式的药物具有的密度比片剂的密度低,因为前者并不经受高压压制步骤。因此,填充到胶囊中的粉末、颗粒或丸粒形式的药物量存在限制。为了在单个硬胶囊中填充高剂量的一种活性成分或多于一种活性成分,胶囊的尺寸必须增大,才能容纳这样大量的药物。然而,如果胶囊的尺寸为了容纳大量的药物变得过大,则可能会导致难以吞咽,吞咽困难。具体而言,具有No.00(8.5mm胶囊帽直径和23.3mm胶囊长度)和No.0(7.6mm胶囊帽直径和21.7mm胶囊长度)的大尺寸的胶囊可能会导致老人或小孩将其吞咽的困难。这也可能由于其大尺寸而将其携带不便。
因此,本发明的发明人努力解决了复合制剂的缺点,并已经开发出一种含有每种主成分少量,例如,1至3个片剂的硬胶囊。然而,硬胶囊的初始溶解速率(15分钟内)由于所述硬胶囊的崩解时间的延迟而减缓,并观察到各个溶解测试结果之间的偏差增加。因此,如果含有需要快速吸收速率的药物,例如,1~2h的最大药物浓度时间(T最大),则可能很难从复合制剂预期单一剂量形式的相同生物等效性。因此,仍需要开发一种具有良好生产率和稳定性而不具有初始溶解速率延迟的制剂。
发明内容
因此,本发明的一个目的是提供一种具有在15分钟内初始溶解速率无延迟,并由于每一溶解速率变化小表现出的良好体内吸收率,以及良好的生产率和稳定性的复合制剂。
本发明的另一目的是提供用于制备复合制剂的方法。
按照本发明的一个目的,提供了一种包含两种或更多种药物活性成分的硬胶囊复合制剂,其中每一药物活性成分包含于多单元球状片剂(MUST)中并且每种药物活性成分的多个MUST封装于硬胶囊中。
按照本发明的另一个目的,提供了一种用于制备硬胶囊复合制剂的方法,其包括以下步骤:(1)制备包含药物活性成分的MUST;和(2)将多个MUST包封于硬胶囊中而使硬胶囊复合制剂包含两种或更多种药物活性成分。
根据本发明包含多单元球状片剂(MUST)的硬胶囊复合制剂能够有效地将MUST填充于有限空间的胶囊中,这允许在具有相对较小尺寸的胶囊中填充高剂量的不同药物活性成分,从而提高生产率并使其易于给药于患者。胶囊具有良好溶解速率,是因为包含于胶囊中的药物活性成分彼此是分离的;因此,这些成分的溶解速率彼此影响不大。这也可以最大化药物活性成分的疗效,因为复合制剂具有良好的稳定性。
附图说明
图1显示了根据本发明一个实施方式的硬胶囊复合制剂的示意图。
图2显示了填充于硬胶囊复合制剂中的多单元球状片剂(MUST)的示意图。
图3和图4分别是根据测试实施例1显示孟鲁司特和左西替利嗪溶解速率(溶解率,dissolution rate)的曲线图。
图5是根据测试实施例2显示氨溴索溶解速率的曲线图。
图6和7分别是根据测试实施例3显示孟鲁司特和左西替利嗪血浆水平的曲线图。
具体实施方式
以下对本发明的实施方式进行详细说明。
本发明提供了一种包含多单元球状片剂(MUST)的硬胶囊复合制剂。图1中显示了根据本发明的硬胶囊复合制剂的示意图。
正如本文所用的术语“复合制剂”是指在单一单位剂量中两种或更多种不同活性成分或药物的组合。本发明的复合制剂包括胶囊,和多个多单元小型片剂,其包含任一药物活性成分,具有包封于胶囊中的类球形形状。
在本发明的复合制剂中,胶囊可以是制药工业中使用的任何常规胶囊,优选硬胶囊。硬胶囊由胶囊体和帽(cap)构成,如此而使内容物填充于胶囊体的内部空间,而胶囊帽用于封闭胶囊体之用。实际上给药于患者的最终胶囊产品,以其盖封闭,具有带有半球形端部的圆柱形体的形状,而内容物充填于胶囊体的内部空间中。在一般情况下,传统胶囊的内部空间一般经常填充粉末、颗粒或丸粒,然而,相反本发明复合制剂的内部空间特征在于填充微型片剂。微型片剂的尺寸较小,而因此多个微型片剂,例如,4个或更多,能够填充于本发明复合制剂的内部空间中。
具有各种尺寸编号的胶囊根据胶囊的尺寸进行使用,但具有大尺寸如00号(8.5mm胶囊帽直径和23.3mm胶囊长度)的胶囊可能导致老人或小孩对其吞咽的困难。由于其大尺寸它也可能不便携带。
因此,本发明的复合制剂胶囊的尺寸优选是硬胶囊0号或更小,例如,硬胶囊0号(7.6mm胶囊帽直径和21.7mm胶囊长度),硬胶囊1号(6.9mm胶囊帽直径和19.1mm胶囊长度),硬胶囊2号(6.4mm胶囊帽直径和17.6mm胶囊长度),硬胶囊3号(5.8mm胶囊帽直径和15.7mm胶囊长度)或硬胶囊4号(5.3mm胶囊帽直径和14.2mm胶囊长度),而更优选硬胶囊1号或更小。
在本发明的复合制剂中,MUST可以包含药物活性成分和药用添加剂。
MUST能够通过将药物活性成分和药用添加剂的混合物或颗粒经历采用压片机的压制步骤进行制备。在这种情况下,片剂的硬度通过压制压力的大小决定。
片剂能够制备成圆形、矩形或椭圆形的形式,然而,圆形形式是优选的,因为它允许更容易包装于硬胶囊的内部空间中。具体而言,当圆形片剂的直径类似于圆形片剂的厚度时,其具有球形形状,这改善了片剂的可流动性,并也通过形成所需的包装排布而最小化胶囊中形成的空隙。
因此,要填充于胶囊中的片剂优选以圆形的形式,更优选微型球状片剂(MUST)。包含于本发明复合制剂中的多单元球状片剂如图2中所示。
为了制备球形形式的圆形片剂,每一MUST的圆形片剂直径与其厚度的比率需要处于1:0.7至1:1.3,优选1:0.8至1:1.2的范围内。根据本发明具有1:0.7至1:1.3范围内的圆形片剂直径与其厚度比率的MUST能够完全填充硬胶囊的内部空间,而不形成任何空隙,因此,用量更大的药物组合物甚至能够填充于更小的胶囊中。
另外,当MUST的圆柱高度与总厚度之比处于特定范围内时,MUST的压片特性得以改善,而此能够改善压片工艺过程中的速度。
具体而言,圆柱高度等于片剂的总长度减去两个半球形端部(顶部和底部)合并的长度,如图2所示。如果总厚度中圆柱高度的比率过高,则片剂会形成矩形形状,这可能使片剂的流动性变差,并由此在包装工艺过程期间招致麻烦。如果总厚度中圆柱高度的比率过低时,片剂会倾向于在压片工艺过程中破碎。因此,根据本发明的MUST的厚度与圆柱高度之比范围为1:0.3至1:0.9,优选1:0.5至1:0.8。
此外,MUST是具有小尺寸的微型片剂,而由此胶囊的内部空间包含至少4个或更多个微型片剂,优选4至40个MUST/每种药物活性成分。
因此,在根据本发明的复合制剂的MUST的直径小于硬胶囊主体的内径,并且优选小于或等于硬胶囊内径的1/2。
如果MUST直径过大(例如,大于硬胶囊主体内径的1/2),则就很难将这些片剂充填到胶囊的内部空间中,而同时充填到胶囊内部空间的片剂总数会减少,从而抑制溶解速率的提高或溶解速率的标准偏差的降低。片剂即使在充填之后,也不允许形成所需的填塞排布设计结构,而由此导致胶囊内形成空隙。另一方面,当MUST直径过小(例如,小于1mm),单个片剂中填充的量受限,并且片剂的物理性质也可能在压片工艺过程期间很大程度上受到环境变量影响。
因此,根据本发明的MUST具有范围为1至4mm,优选范围为1.5至3mm的直径。如果片剂的直径处于范围内,则所期望的填塞排布设计就能够实现,这允许最大化胶囊内要填充的内容物,而这也由于具有多个片剂而产生溶解速率的改善。
相比于用颗粒或丸粒填充的常规硬胶囊,本发明的复合制剂具有良好的充填率。
胶囊的填充率能够通过胶囊体的体积内填充到胶囊内的原料的重量进行计算。例如,当150mg组合物填充到2号胶囊(体积:0.37mL)中时,填充率为约0.41g/mL。一般而言,如果填充颗粒或丸粒材料,则由于填充材料浓度低或丸粒中存在空隙而很难达到0.6g/mL或更大的填充率。与此相反,根据本发明的复合制剂具有0.6g/mL至1.0mg/mL的填充率,而因此具有0.6mg/mL或更大的填充率,这使之有可能降低硬胶囊的尺寸,使其易于给药于患者。
另外,根据本发明的复合制剂相比于传统填充具有直径为5mm或更大的典型片剂的常规胶囊具有显著更低的孔隙率(空空间率)(the rate of empty space)。由于填充率和孔隙率值之间存在反比关系,则本发明的MUST能够以最佳水平填充到胶囊的内部空间中。
根据本发明的一个方面,提供了一种包含多个直径小于或等于硬胶囊体内径的1/2而范围为1mm至4mm的MUST的硬胶囊复合制剂。在这些制剂中,MUST的直径可以处于1.5mm至3mm的范围内。
根据本发明另一个方面,提供了一种包含多个厚度与圆柱高度比率范围为1:0.7至1:1.3而其直径范围为1mm至4mm的MUST的硬胶囊复合制剂。在这些制剂中,MUST的厚度/圆柱高度比率可以处于1:0.8至1:1.2的范围内,而其直径可以处于1.5mm至3mm的范围内。
根据本发明的另一方面,提供了一种包含多个直径小于或等于硬胶囊体内径的1/2的MUST而MUST的厚度与圆柱体高度之比处于1:0.8至1:1.2范围内的硬胶囊复合制剂。
任何两种或更多种本领域中已知的药物都能够用作本发明的MUST的活性成分。本发明中使用的药物可以选自相同或不同的药物组。可采用的药物的实例包括解热剂、镇痛剂、消炎剂和肌肉松弛剂如反胺苯环醇、萘普生、布洛芬、右旋布洛芬、阿司匹林、对乙酰氨基酚、吲哚美辛、双氯芬酸钠、醋氯芬酸、酮洛芬、异丙安替比林、非那西汀、氟比洛芬、保泰松、依托度酸、塞来昔布、依托昔布、乙哌立松、及其药用盐;抗溃疡药如奥美拉唑、埃索美拉唑、泮托拉唑、西米替丁、法莫替丁、雷尼替丁、尼扎替丁、罗沙替丁、及其药用盐;心血管药或血管扩张药如氯沙坦、伊贝沙坦(ibesartan)、坎地沙坦、替米沙坦、缬沙坦、硝苯地平、氨氯地平、维拉帕米、卡托普利、盐酸地尔硫、普萘洛尔、氧烯洛尔、硝酸甘油、依那普利、及其药用盐;抗糖尿病药、如二甲双胍、格列美脲、西他列汀、罗格列酮、吡格列酮、及其药用盐;抗高血脂剂如辛伐他汀、瑞舒伐他汀、阿托伐他汀、及其药用盐;抗生素如氨苄青霉素、羟氨苄青霉素、头孢氨苄、头孢呋辛、头孢地尼、头孢羟氨苄、头孢丙烯、头孢泊肟、头孢妥仑、头孢克洛、头孢克肟、头孢拉定、氯碳头孢、头孢布烯、头孢曲秦、头孢卡品、红霉素、四环素类、喹诺酮类、及其药用盐;止咳药或抗哮喘药如孟鲁司特、茶碱、氨茶碱、磷酸可待因、盐酸甲基麻黄素、右旋甲吗喃、那可汀、舒喘灵、氨溴索、左羟丙哌嗪、盐酸克伦特罗、特布他林、及其药用盐、止吐剂或GIT调节剂如恩丹西酮、甲氧氯普胺、多潘立酮、马来酸曲美布汀、西沙必利、左旋舒必利、及其药用盐;抗阳痿药物如西地那非、伐地那非、他达拉非、乌地那非、及其药用盐;以及抗痴呆药如多奈哌齐、加兰他敏、利凡斯的明、乙酰左旋肉碱、美金刚、扎利罗登、及其药用盐。
除此之外,抗BPH药物如坦索罗辛;抗偏头痛药如佐米曲坦和利扎曲坦;精神兴奋剂;抗微生物剂;抗组胺剂如西替利嗪、左西替利嗪和氯雷他定;抗糖尿病药;抗变态反应药;避孕药;补充维生素;抗凝血剂如氯吡格雷;肌肉松弛剂;大脑代谢增强剂;利尿剂如托拉塞米和呋塞米;抗癫痫剂如加巴喷丁、普瑞巴林、丙戊酸、托吡酯、卡马西平、拉莫三嗪,奥卡西平;和抗帕金森氏病药如司来吉兰;抗精神病药物如利培酮、齐拉西酮、喹硫平、奥氮平、氯氮平和帕潘立酮、及其药用盐,也可以用于本发明中。此外,生物制剂如口服疫苗可以用于本发明中。
优选活性成分可以选自由左西替利嗪、孟鲁司特、氨溴索、左羟丙哌嗪、氯沙坦、艾伯沙坦、氨氯地平、瑞舒伐他汀、阿托伐他汀、阿司匹林、氯吡格雷、醋氯芬酸、乙哌立松、埃索美拉唑、萘普生、及其药用盐组成的组中。
在本发明的复合制剂中,MUST可以进一步包含选自由药用稀释剂、崩解剂、粘合剂、稳定剂、润滑剂、着色剂、及其混合物组成的组中的药用添加剂。
稀释剂可以选自由微晶纤维素、乳糖、甘露糖醇、磷酸二氢钙、淀粉、低取代羟丙基纤维素、及其混合物组成的组。稀释剂的用量基于片剂总重量可为约1wt%至99wt%,优选约5wt%至90wt%。
崩解剂可以是任何在液体环境安全溶胀的物质,其选自由交聚维酮、羟基乙酸淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素、淀粉、藻酸盐、或其钠盐、或其混合物组成的组。在本发明的一个优选实施方式中,崩解剂选自由低取代羟丙基纤维素、交聚维酮、羟基乙酸淀粉钠、交联羧甲基纤维素钠、及其混合物组成的组。崩解剂的用量基于片剂总重量可以为约1wt%至30wt%,优选约2wt%至15wt%。
粘合剂可以选自由羟丙基纤维素、羟丙基甲基纤维素、聚乙烯基吡咯烷酮、共聚维酮、聚乙二醇、轻质无水硅酸、合成硅酸铝、硅酸盐衍生物如硅酸钙或偏硅酸铝酸镁、磷酸盐如磷酸氢钙、碳酸盐如碳酸钙、及其混合物组成的组,而所采用的粘合剂的量基于片剂总重量可以为约1wt%至30wt%,优选约2wt%至15wt%。
稳定剂可以是抗氧化剂、酸化剂、或碱化剂。
抗氧化剂的具体实例包括丁基羟基甲苯(BHT)、丁基羟基苯甲醚(BHA)、抗坏血酸、棕榈酸抗坏血酸酯、乙二胺四乙酸(EDTA)、焦亚硫酸钠、及其混合物;特别是丁基羟基甲苯是优选的。酸化剂的具体例子包括有机酸如富马酸、柠檬酸、酒石酸、琥珀酸、乳酸、苹果酸、甲苯磺酸、草酸、抗坏血酸、谷氨酸、藻酸、马来酸、己二酸等;无机酸如盐酸、硫酸、硝酸、磷酸、乙酸、硼酸等、及其混合物,优选富马酸、柠檬酸、酒石酸和磷酸。碱化剂的实例包括精氨酸、赖氨酸、组氨酸、葡甲胺、硅酸铝镁、偏硅酸铝镁、或碱性矿物质、如NaHCO3、CaCO3、MgCO3、KH2PO4、K2HPO3、和磷酸三钙等,优选NaHCO3、CaCO3、MgCO3或其混合物。
稳定剂能够根据药物活性成分的性质进行选择,而所采用的稳定剂的用量基于所选择的药物活性成分的总量可以为0.01wt%至10wt%。
润滑剂可以选自由硬脂酸、金属硬脂酸盐如硬脂酸钙和硬脂酸镁、滑石粉、胶体二氧化硅、脂肪酸蔗糖酯、氢化植物油、高熔点蜡、甘油脂肪酸酯、甘油二山嵛酸酯(glyceroldibehenate)及其混合物组成的组,而所采用的润滑剂的用量基于片剂总重量可以处于约0.02wt%至5wt%,优选约0.3wt%至3wt%的范围内。
着色剂可以选自由红色氧化铁颜料、黄色氧化铁颜料、二氧化钛、蓝色1号、蓝色2号、及其混合物组成的组,而所采用的着色剂的用量基于片剂总重量可以处于约0.001wt%至2wt%,优选约0.01wt%至1.5wt%的范围内。
本发明的复合制剂包含多个MUST,而由此具有非常快速的溶解速度而没有经历初始溶解速率降低。通常,传统的硬胶囊制剂需要胶囊的崩解时间,因此由于初始溶解速率减缓(15min内)而存在溶解测试结果的偏差增加的缺点。因此,如果复合制剂包含的药物需要快速吸收速率,例如,1至2h的最大药物浓度的时间(T最大),可能很难期望复合制剂单剂量形式的相同生物等效性。然而,本发明的复合制剂包含多个具有小尺寸而能够迅速同时崩解的片剂,而因此不存在初始溶解速率的延迟。
因此,本发明的复合制剂的一种或多种活性成分是立即释放药物,一种或多种活性成分具有给药5min内30%或更高的体外初始溶解速率,和给药10min内80%或更高的体外初始溶解速率(参照图3至图5)。
另外,本发明的复合制剂完全分隔开每种活性成分,当长期储存时确保改善的溶解速率和良好的稳定性。这种有利的效果能够进一步通过对MUST涂层而增强。因此,本发明的MUST可以用聚合物膜涂覆层涂覆而使之物理性防止两种或更多种活性成分之间的任何可能的相互作用。
任何可以形成薄膜涂层的传统聚合物都可以用于本发明的膜涂覆层(膜包衣层,film coating layer)中。具体的例子包括水溶性聚合物如聚乙烯醇、羟乙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、及其混合物;水不溶性聚合物如邻苯二甲酸羟丙甲纤维素酯(HPMCP)、聚醋酸乙烯酯(例如,SR30D)、水不溶性聚甲基丙烯酸酯共聚物[如,聚(丙烯酸乙酯-甲基丙烯酸甲酯)共聚物(例如,NE30D)、聚(丙烯酸乙酯-甲基丙烯酸甲酯-三甲基氨基乙基甲基丙烯酸酯氯化物)共聚物(例如,RSPO)等]、乙基纤维素、纤维素酯、纤维素醚、纤维素丙烯酸酯、纤维素二丙烯酸酯、纤维素三丙烯酸酯、醋酸纤维素、纤维素二乙酸酯、纤维素三乙酸酯、及其混合物,但不限于此。
这种聚合物的使用不仅起到将活性成分彼此分离之用,而且起到容许在同一胶囊中形成具有不同溶解速率(例如,即时/缓释或立即的/肠衣的)的MUST。在这种情况下,MUST涂覆聚合物,然后能够按照药物设计者预想的所需比率充填以便调节同一种药物组之间或不同的药物组之间的溶解速率。这种有利的效果通过采用多个微型片剂片作为本发明中的MUST而使之成为可能。
聚合物的量可以经过调节而按照有效的模式提供具有合适的尺寸和溶解速率的片剂,这基于片剂总重量优选为约1wt%至50wt%,更优选约1wt%至20wt%。每个片剂完全分开,并形成独立剂量形式,防止了这些片剂之间的任何相互作用。另外,在根据本发明制备的活性成分的稳定性的分析中,通过分析单一药物的传统方法代替为此的任何特殊方法,就足以分析胶囊中包含的每个片剂的稳定性。
此外,本发明提供了一种用于制备硬胶囊复合制剂的方法,其包括如下步骤:(1)制备包含药物活性成分的MUST;和(2)将多个MUST包封于硬胶囊中而使硬胶囊复合制剂包含两种或更多种药物活性成分。本方法还可以进一步包括在上述方法的步骤(1)期间用聚合物膜涂覆MUST的附加步骤。
在下文中,本发明通过以下实施例更具体地进行描述,但这些都只是用于说明目的而提供,而本发明并不限于此。
实施例1:复合制剂I的制备
-左西替利嗪层-
-孟鲁司特层-
含左西替利嗪(levocetirizine)的片剂层如下述进行制备。将左西替利嗪二盐酸盐、(BASF)、微晶纤维素、柠檬酸、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,而随后将所得的混合物使用具有模头直径2.0mm的压片机压制成片剂,而得到10个MUST,其中每片剂具有8.3mg的重量,约2.0mm的厚度,和1.3mm的圆柱高度。
另外,涂层溶液通过将Y-1-7000溶解于蒸馏水中而制备,并将涂层溶液涂施于以上制得的含左西替利嗪的MUST上。这样得到的10个MUST的总重量为85mg,而其中的左西替利嗪总重量为5mg。
同时,含孟鲁司特(montelukast)的片剂层如下制备。将孟鲁司特钠、D-甘露醇、微晶纤维素、轻质无水硅酸、羟丙基纤维素、羟基乙酸淀粉钠和硬脂酸镁进行筛分并混合,而随后将所得的混合物使用具有模头直径2.0mm的压片机压制成片剂,而获得20个MUST,其中每片剂具有8.3mg的重量,厚度约2.0mm,和1.3mm的圆柱高度。
另外,涂层溶液通过将羟丙甲纤维素、羟丙基纤维素、二氧化钛、红色氧化铁、和黄色氧化铁溶解于蒸馏水中而制备,并将涂层溶液涂施于以上制备的含孟鲁司特的MUST上。这样获得的20个MUST的总重量为170mg,而其中的孟鲁司特的总重量为10mg。
这两种以上制备的不同MUST,10个含左西替利嗪的MUST和20个含孟鲁司特的MUST,填充于用主要用明胶制成的1号硬胶囊的胶囊体中而产生含有10mg孟鲁司特和5mg左西替利嗪的硬胶囊制剂。
实施例2:复合制剂II的制备
-氨溴索层-
-左羟丙哌嗪层-
含氨溴索(ambroxol)的片剂层如下进行制备。将氨溴索盐酸盐、乳糖水合物和预胶化淀粉一起混合,添加通过将聚维酮K-30溶解于蒸馏水中制备的粘合溶液,而混合物进行湿法制粒。向其中加入轻质无水硅酸和硬脂酸镁,并使用具有模头直径2.0mm的压片机将混合物压制成片剂,而获得10个MUST,其中每个片剂具有7.8mg的重量而厚度约2.0mm,并且圆柱高度为1.3mm。这样得到的10个MUST的总重量为78mg,而其中的氨溴索盐酸盐的总重量为30mg。
同时,含左羟丙哌嗪(levodropropizine)的片剂层如下制备。将左羟丙哌嗪、乳糖水合物、微晶纤维素、羟基乙酸淀粉钠和硬脂酸镁进行筛分并混合,而随后将所得的混合物使用具有模头直径2.0mm的压片机压制成片剂,而获得20个MUST,其中每片剂具有8.0mg的重量,厚度约2.0mm,和1.4mm的圆柱高度。20个由此获得的MUST的总重量为160mg,而其中的左羟丙哌嗪的总重量为60mg。
以上制备的这两种不同MUST,10个含氨溴索盐酸盐的MUST和20个含左羟丙哌嗪的MUST,填充于用主要用明胶制成的1号硬胶囊的胶囊体中而产生含有30mg氨溴索盐酸盐和60mg左羟丙哌嗪的硬胶囊制剂。
实施例3:复合制剂III的制备
-氯沙坦层-
-氨氯地平层-
含氯沙坦(losartan)的片剂层如下进行制备。将氯沙坦钾、(BASF)、共聚维酮、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁一起混合,而随后将混合物使用具有模头直径2.0mm的压片机压制成片剂,而获得12个MUST,其中每个片剂具有8.3mg的重量而厚度约2.0mm,并且圆柱高度为1.2mm。
另外,涂层溶液通过将Y-1-7000溶解于蒸馏水中而制备,并将涂层溶液涂施于以上制得的含氯沙坦的MUST上。这样得到的12个MUST的总重量为102mg,而其中的氯沙坦总重量为50mg。
同时,含氨氯地平的片剂层如下制备。将氨氯地平右旋樟脑磺酸(氨氯地平坎西雷特,Amlodipine camsylate)、甘露醇、微晶纤维素、羟基乙酸淀粉钠、羟丙基纤维素和硬脂酸镁进行筛分并混合,而随后将所得的混合物使用具有模头直径2.0mm的压片机压制成片剂,而获得12个MUST,其中每片剂具有8.3mg的重量,厚度约2.0mm,和1.3mm的圆柱高度。
另外,涂层溶液通过将Y-1-7000溶解于蒸馏水中而制备,并将涂层溶液涂施于以上制备的含氨氯地平的MUST上。这样获得的12个MUSTs的总重量为102mg,而其中的氨氯地平的总重量为10mg。
这两种以上制备的不同MUSTs,12个含氯沙坦的MUST和12个含氨氯地平的MUST,填充于用主要用明胶制成的2号硬胶囊的胶囊体中而产生含有50mg氯沙坦和10mg氨氯地平的硬胶囊制剂。
实施例4:复合制剂IV的制备
-瑞舒伐他汀层-
-阿司匹林层-
含瑞舒伐他汀(rosuvastatin)的片剂层如下进行制备。将舒伐他汀钙、乳糖水合物、微晶纤维素、交联聚维酮和硬脂酸镁一起混合,而随后将混合物使用具有模头直径2.0mm的压片机压制成片剂,而获得10个MUST,其中每个片剂具有8.3mg的重量,厚度约2.0mm,和1.3mm的圆柱高度。
另外,涂层溶液通过将Y-1-7000溶解于蒸馏水中而制备,并将涂层溶液涂施于以上制得的含瑞舒伐他汀的MUST上。这样得到的10个MUST的总重量为86mg,而其中的瑞舒伐他汀总重量为10mg。
同时,含阿司匹林的片剂层如下制备。将阿司匹林、微晶纤维素、预胶化淀粉和轻质无水硅酸进行混合。向所得到的混合物中加入硬脂酸作为润滑剂,而随后将所得的混合物使用具有模头直径2.0mm的压片机压制成片剂,而获得20个MUST,其中每片剂具有7.05mg的重量,厚度约2.0mm,和1.2mm的圆柱高度。
另外,涂层溶液通过将邻苯二甲酸羟丙甲纤维素酯、二氧化钛和乙酰化单甘油酯溶解于乙醇和丙酮的混合溶剂中而制备,并将涂层溶液涂施于以上制备的含阿司匹林的MUST上。这样获得的20个MUST的总重量为160mg,而其中的阿司匹林的总重量为100mg。
以上制备的这两种不同MUST,10个含瑞舒伐他汀的MUST和20个含阿司匹林的MUST,填充于用主要用明胶制成的1号硬胶囊的胶囊体中而产生含有10mg瑞舒伐他汀和100mg阿司匹林的硬胶囊制剂。
实施例5:复合制剂V的制备
-氯吡格雷层-
-阿司匹林层-
含氯吡格雷(clopidogrel)的片剂层如下进行制备。将氯吡格雷硫酸氢盐、D-甘露醇、低取代羟丙基纤维素和脂肪酸的蔗糖酯进行筛分并一起混合,而随后将混合物使用具有模头直径2.0mm的压片机压制成片剂,而获得20个MUST,其中每个片剂具有8.0mg的重量,厚度约2.0mm,和1.3mm的圆柱高度。
另外,涂层溶液通过将32K-14834溶解于蒸馏水中而制备,而涂层溶液涂施于以上制得的含氯吡格雷的MUST上。这样得到的20个MUST的总重量为164mg,而其中的氯吡格雷总重量为75mg。
同时,含阿司匹林的层如下制备。将阿司匹林、微晶纤维素、预胶化淀粉和轻质无水硅酸进行混合。向所得到的混合物中加入硬脂酸作为润滑剂,而随后将所得的混合物使用具有模头直径2.0mm的压片机压制成片剂,而获得20个MUST,其中每片剂具有7.05mg的重量,厚度约2.0mm,和1.2mm的圆柱高度。
另外,涂层溶液通过将邻苯二甲酸羟丙甲纤维素酯、二氧化钛和乙酰化单甘油酯溶解于乙醇和丙酮的混合溶剂中而制备,并将涂层溶液涂施于以上制备的含阿司匹林的MUST上。这样获得的20个MUST的总重量为160mg,而其中的阿司匹林的总重量为100mg。
以上制备的这两种不同MUST,20个含氯吡格雷的MUST和20个含阿司匹林的MUST,填充于用主要用明胶制成的1号硬胶囊的胶囊体中而产生含有75mg氯吡格雷和100mg阿司匹林的硬胶囊制剂。
对照实施例(比较实施例)1:复合制剂VI的制备
-左西替利嗪层-
-孟鲁司特层-
含左西替利嗪的片剂层如下述进行制备。将左西替利嗪二盐酸盐、(BASF)、微晶纤维素、柠檬酸、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,而随后将所得的混合物使用具有模头直径5.0mm的压片机压制成片剂。然后,通过将Y-1-7000溶解于蒸馏水中而制备的涂层溶液涂施于片剂上而生成左西替利嗪片剂。这样得到的片剂总重量为85mg,而其中的左西替利嗪总重量为5mg。
同时,含孟鲁司特的片剂层如下制备。将孟鲁司特钠、D-甘露醇、微晶纤维素、轻质无水硅酸、羟丙基纤维素、羟基乙酸淀粉钠和硬脂酸镁进行筛分并混合,而随后将所得的混合物使用具有模头直径5.0mm的压片机压制成片剂,而获得两个片剂。另外,涂层溶液通过将羟丙甲纤维素,羟丙基纤维素,二氧化钛,红色氧化铁和黄色氧化铁溶解于蒸馏水中而制备,而将涂层溶液涂施于以上片剂上而生成孟鲁司特片剂。这样获得的片剂的总重量为170mg,而其中的孟鲁司特的总重量为10mg。
以上制备的这两种不同片剂,1个左西替利嗪片剂和2个孟鲁司特片剂,填充于用主要用明胶制成的1号硬胶囊的胶囊体中而产生含有5mg左西替利嗪和10mg孟鲁司特的硬胶囊制剂。
对照实施例2:复合制剂VII的制备
-氨溴索层-
-左羟丙哌嗪层-
含氨溴索的片剂层如下述进行制备。将氨溴索盐酸盐、乳糖水合物和预胶化淀粉混合,添加通过将聚维酮K-30溶于蒸馏水中制备的粘合溶液,而随后将所得的混合物湿法造粒。向其中加入轻质无水硅酸和硬脂酸镁,并将混合物使用具有模头直径5.0mm的压片机压制成片剂。由此得到的片剂总重量为78mg,而其中的氨溴索盐酸盐总重量为30mg。
同时,含左羟丙哌嗪的片剂层如下制备。将左羟丙哌嗪、乳糖水合物、微晶纤维素、羟基乙酸淀粉钠和硬脂酸镁进行筛分并混合,而随后将所得的混合物使用具有模头直径5.0mm的压片机压制成片剂,而获得两个片剂。这样获得的片剂的总重量为160mg,而其中的左羟丙哌嗪的总重量为60mg。
这两种以上制备的不同片剂,1个氨溴索片剂和2个左羟丙哌嗪片剂,填充于用主要用明胶制成的1号硬胶囊的胶囊体中而产生含有30mg氨溴索盐酸盐和60mg左羟丙哌嗪的硬胶囊制剂。
测试实施例1:孟鲁司特和左西替利嗪的溶解测试
含有实施例1和对照实施例1中制备的孟鲁司特和左西替利嗪的复合制剂,和分别用作孟鲁司特和左西替利嗪参考药物的片剂(MSD,10mg)和片剂(韩国-UCB Co.,5mg),在以下条件下使用用于每种药物的6个测试容器进行药物溶解测试。其结果示于表1,以及图3和如图4中。
<测试条件>
-溶解介质:
对于孟鲁司特=0.5%月桂基硫酸钠(SLS)溶液,900mL
对于左西替利嗪=蒸馏水,900mL
-溶解测试系统:平桨,75rpm
-温度:37℃
<分析条件-同时测定孟鲁司特和左西替利嗪>
-柱子:填充5μm十八烷基硅烷基硅胶的不锈钢柱子用于液相色谱(Inertsil C8,4.6×150mm,5μm)
-流动相:0.025M磷酸二氢钾(pH 6.6),乙腈(40:60,v/v)
-检测器:紫外分光光度计(225nm)
-流速:1.0mL/min
-注样体积:10μL
-柱温:45℃
[表1]
如表1和图3和图4中所示,实施例1中制备的包含MUST的复合制剂相比于对照实施例1含有传统片剂的制剂表现出高得多的初始溶解速率(10分钟内),甚至类似于参照药物,片剂(孟鲁司特)和片剂(左西替利嗪)。
此外,实施例1的孟鲁司特和左西替利嗪的溶解测试结果比对照实施例1的溶解测试的结果表现出显著较低的标准偏差值,而因此由本发明的复合制剂能够预期身体吸收速率变化更小。因此,这也能够预期对于本发明包含MUST的硬胶囊复合制剂将会更易于与其参考药物和是生物等效的。
测试实施例2:氨溴索的溶解测试
含有实施例2和对照实施例2中制备的含氨溴索和左羟丙哌嗪的复合制剂,和用作氨溴索参考药物的片剂(Boehringer Ingelheim,30mg),在以下条件下使用用于每种药物的6个测试容器进行药物溶解测试。其结果示于表2,以及图5中。
<测试条件>
-溶解介质:pH 1.2人工胃液,900mL
-溶解测试系统:平桨,50rpm
-温度:37℃
<分析条件-氨溴索>
-柱子:填充5μm十八烷基硅烷基硅胶的不锈钢柱子用于液相色谱(Waters ODS-2,4.6mm×50mm,5μm)
-流动相:0.05M磷酸二氢钾(使用磷酸调节至pH 3.0),甲醇(88:12,v/v)
-检测器:紫外分光光度计(254nm)
-流速:1.0mL/min
-注样体积:10μL
-柱温:30℃
[表2]
如表2和图5所示,实施例2中制备的含有MUST的复合制剂呈现比对照实施例2填充传统片剂的制剂高得多的初始溶解速率(10分钟内)和小得多的标准偏差变化值。
因此,这可以预期,如果氨溴索,其初始溶解速率被认为临界于其给定的0.25~1小时的T最大,以本发明含有MUST的硬胶囊复合制剂的形式制备,则对于本发明的复合制剂将会更易于与其参照药物,片剂,是生物等效性,并也预期体内吸收速率变化更小。
测试实施例3:孟鲁司特和左西替利嗪的吸收测试
实施例1制备的含有孟鲁司特和左西替利嗪的复合制剂,和分别作为孟鲁司特和左西替利嗪的参考药物的片剂10mg和片剂5mg,口服给药于测试动物而在下述条件下进行生物利用度测试。
测试动物是健康的,雄性,20个月大的比格犬,体重12±2kg,而每个测试组分配5只狗。这些狗放置于笼子里,让其自由使用商业狗饲料(每天400克),然后实验前禁食一段14小时的时间。将狗分为两组:第1组(实施例1)和第2组(片剂+片剂)。各狗口服给药相应的制剂,并强制给予40mg水。血液样品(2mL)采用具有抗凝血剂(1,000IU/mL,肝素5μL)的管子在口服给药之后0(初始)、0.25、0.5、1、2、3、4、8、10、24和48h时从头静脉采集。所有血液样品离心(12000rpm,2分钟,Eppendorf)至血浆,并在-20℃下盛装于冰箱中以通过以下条件之下的LC-MS对每一样品进行后续分析:
柱子:Halo C18(2.1×50mm,2.7μm)
流动相:甲醇,10mM甲酸铵(85:15,v/v)
注入量:10μL
检测:Turbo离子喷雾离子化模式(正电)
Cmax和Tmax获自血浆浓度相对于时间曲线,而给药后从0至24h的AUC使用曲线根据梯型定则进行计算。结果如表3、图6和图7所示。
[表3]
如表3、以及图6和图7中所示,实施例1的复合制剂具有比同时服用两种单一制剂参照片剂同等或更好的生物利用度。
根据实施例1的复合制剂导致孟鲁司特和左西替利嗪与其参照药物,片剂和片剂,具有类似的AUC和C最大值,并显示出T最大值没有延迟,而是微小的T最大值。
Claims (11)
1.一种包含两种或更多种药物活性成分的硬胶囊复合制剂,其中,每种药物活性成分包含于具有范围为1mm至4mm的直径的多单元球状片剂(MUST)中并且每种药物活性成分的4至40个所述MUST包封于所述硬胶囊中,并且
其中,每个MUST具有范围为1:0.7至1:1.3的直径与厚度的比和范围为1:0.3至1:0.9的厚度与圆柱高度的比,
其中,每种药物活性成分选自由以下各项所组成的组中:左西替利嗪、孟鲁司特、左羟丙哌嗪、氯沙坦、伊贝沙坦、瑞舒伐他汀、阿托伐他汀、氯吡格雷、醋氯芬酸、乙哌立松、埃索美拉唑、萘普生以及它们的药用盐。
2.根据权利要求1所述的硬胶囊复合制剂,其中,每个MUST的直径小于或等于所述硬胶囊内径的1/2。
3.根据权利要求1所述的硬胶囊复合制剂,其中,所述厚度与圆柱高度的比的范围为1:0.5至1:0.8。
4.根据权利要求1所述的硬胶囊复合制剂,其中,所述硬胶囊是硬胶囊0号、硬胶囊1号、硬胶囊2号、硬胶囊3号或硬胶囊4号。
5.根据权利要求1所述的硬胶囊复合制剂,其中,每个MUST包含药用添加剂。
6.根据权利要求5所述的硬胶囊复合制剂,其中,所述药用添加剂选自由药用的稀释剂、崩解剂、粘合剂、稳定剂、润滑剂、着色剂、以及它们的混合物组成的组中。
7.根据权利要求1所述的硬胶囊复合制剂,其中,每个MUST涂覆有聚合物膜涂覆层。
8.根据权利要求1所述的硬胶囊复合制剂,其中,一种或多种所述药物活性成分是立即释放的。
9.根据权利要求8所述的硬胶囊复合制剂,其中,一种或多种所述药物活性成分具有从给药起5分钟内30%或更高的体外初始溶解速率和从给药起10分钟内80%或更高的体外初始溶解速率。
10.一种用于制备根据权利要求1所述的硬胶囊复合制剂的方法,所述方法包括:
(1)制备包含药物活性成分的具有范围为1mm至4mm的直径的MUST,其中,每个MUST具有范围为1:0.7至1:1.3的直径与厚度的比,和范围为1:0.3至1:0.9的厚度与圆柱高度的比;以及
(2)将4至40个所述MUST包封于所述硬胶囊中而使所述硬胶囊复合制剂包含两种或更多种药物活性成分,
其中,每种药物活性成分选自由以下各项所组成的组中:左西替利嗪、孟鲁司特、左羟丙哌嗪、氯沙坦、伊贝沙坦、瑞舒伐他汀、阿托伐他汀、氯吡格雷、醋氯芬酸、乙哌立松、埃索美拉唑、萘普生以及它们的药用盐。
11.根据权利要求10所述的方法,所述方法进一步包括在步骤(1)期间用聚合物膜涂覆每个MUST。
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2014
- 2014-10-08 PH PH12014502271A patent/PH12014502271A1/en unknown
- 2014-10-09 CL CL2014002717A patent/CL2014002717A1/es unknown
- 2014-11-10 CO CO14247711A patent/CO7131367A2/es unknown
- 2014-11-12 ZA ZA2014/08285A patent/ZA201408285B/en unknown
-
2015
- 2015-06-16 HK HK15105701.2A patent/HK1204959A1/zh unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1462098A1 (en) * | 2003-03-03 | 2004-09-29 | SPRL Franpharma | Stabilised pharmaceutical composition comprising a non-steroidal anti-inflammatory agent and a prostaglandin |
WO2007078110A1 (en) * | 2006-01-03 | 2007-07-12 | Neomedics Co., Ltd. | Pharmaceutical formulation containing amlodipine and aspirin |
Also Published As
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BR112014024964A2 (pt) | 2017-06-20 |
EP2836207B1 (en) | 2020-02-19 |
PH12014502271B1 (en) | 2014-12-10 |
BR112014024964A8 (pt) | 2021-06-15 |
BR112014024964B1 (pt) | 2022-03-15 |
SG11201406298RA (en) | 2014-11-27 |
JP6129295B2 (ja) | 2017-05-17 |
CN104220050A (zh) | 2014-12-17 |
PT2836207T (pt) | 2020-03-26 |
PH12014502271A1 (en) | 2014-12-10 |
UA116102C2 (uk) | 2018-02-12 |
MY171703A (en) | 2019-10-23 |
MX2014012144A (es) | 2014-12-05 |
KR101378973B1 (ko) | 2014-03-28 |
TWI544936B (zh) | 2016-08-11 |
HK1204959A1 (zh) | 2015-12-11 |
WO2013154390A1 (en) | 2013-10-17 |
TW201345568A (zh) | 2013-11-16 |
MX354328B (es) | 2018-02-27 |
CN110051642B (zh) | 2021-12-31 |
CL2014002717A1 (es) | 2015-01-09 |
JP2015517998A (ja) | 2015-06-25 |
PE20142035A1 (es) | 2014-12-24 |
EP2836207A4 (en) | 2015-08-19 |
EP2836207A1 (en) | 2015-02-18 |
ES2778864T3 (es) | 2020-08-12 |
US20150098992A1 (en) | 2015-04-09 |
ZA201408285B (en) | 2016-09-28 |
RU2014145557A (ru) | 2016-06-10 |
PL2836207T3 (pl) | 2020-07-27 |
CO7131367A2 (es) | 2014-12-01 |
KR20130115864A (ko) | 2013-10-22 |
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