CN102119027A - 含有药物活性剂的包衣颗粒 - Google Patents
含有药物活性剂的包衣颗粒 Download PDFInfo
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- CN102119027A CN102119027A CN2009801316719A CN200980131671A CN102119027A CN 102119027 A CN102119027 A CN 102119027A CN 2009801316719 A CN2009801316719 A CN 2009801316719A CN 200980131671 A CN200980131671 A CN 200980131671A CN 102119027 A CN102119027 A CN 102119027A
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Abstract
本发明涉及含有药物活性剂的颗粒的片剂,其中所述颗粒包覆有(a)含有调释聚合物的第一薄膜层及(b)含有(i)第一聚合物和(ii)第二聚合物的第二薄膜层,其中所述第一聚合物是丙烯酸乙酯和甲基丙烯酸甲酯的聚合物,其中所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的聚合物。
Description
背景技术
压制片剂(如胶囊形片剂)是已知可用于递送药物活性剂的性价比、消费者友好性和便利性最好的剂型之一。压制片剂通常涉及多个工序以便将药物活性剂掺入该剂型中,因为仅某些材料可用于压制。材料必须具有恰当的压制特性如流动和可压制性,以维持在压片机上的可操作性,保持形状和外形而不破损,并在适当的时间范围内在胃肠道中溶解。为了实现这些特性,常常必须利用高剪切技术、辊压技术(chilsonation)或流化床技术将共混物或粉末状材料造粒,以增加尺寸和保持可流动的颗粒形状。直接压制方法和湿法造粒方法是本领域公知的,在例如Lachman等人,The Theorv and Practice of Industrial Pharmacy,第11章(1986年第3版)中有详细描述。
压制片剂已被用于以调释方式递送药物活性剂。一种制备这类片剂的方法是用调释聚合物包覆含有药物活性剂的颗粒。但是,这些聚合物往往具有这样的缺点,即在压制时在与片剂内周围片剂基质材料接触下会破裂。破裂或裂开的包衣可导致药物活性剂不再保持预定的调释特性。一种克服这个问题的方法是在包衣中使用高含量的增塑剂。但是,增塑剂也会损及聚合物的调释特性和/或导致片剂的一些部分粘附在片剂加工工具的表面上。当片剂的一些部分粘附时,会出现几个问题,包括各个片剂之间重量变动和浮凸标记被脱除。另一种克服这些问题的方法是向包衣添加高拉伸强度的聚合物,如乙酸纤维素。但是,这个方法的缺点可包括要使用溶剂来施加包衣和/或该聚合物具有不利地改变包衣的释放特性的影响。
本发明提供包覆有两个薄膜层且适宜于压制成片剂的含药物活性剂的颗粒。
发明内容
在一个方面,本发明涉及包含含有药物活性剂的颗粒的片剂,其中所述颗粒包覆有(a)含有调释聚合物的第一薄膜层及(b)含有(i)第一聚合物和(ii)第二聚合物的第二薄膜层,其中所述第一聚合物是丙烯酸乙酯和甲基丙烯酸甲酯的聚合物,且其中所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的聚合物。
在另一个方面,本发明涉及含有药物活性剂的颗粒,其中所述颗粒包覆有(a)含有调释聚合物的第一薄膜层及(b)含有(i)第一聚合物和(ii)第二聚合物的第二薄膜层,其中所述第一聚合物是丙烯酸乙酯和甲基丙烯酸甲酯的聚合物,且其中所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的聚合物。
通过本发明的详细描述和权利要求书,本发明的其他特征和优点将变得显而易见。
具体实施方式
据信,本领域技术人员可以在此处描述的基础上,充分利用本发明。下面的具体实施例可理解为仅为示例性的,并且无论如何都不会以任何方式限制本公开内容的其余部分。
除非另有规定,本文使用的所有技术和科学术语,具有本发明所属技术领域公知的相同含义。此外,本文提及的所有出版物、专利申请、专利和其他参考文献一并以参照方式纳入。本文所用的所有百分比均按重量计,除非另外指明。
颗粒
本发明涉及含有药物活性剂(例如一种或多种药物活性剂)的颗粒。在一个实施例中,所述颗粒包覆有(a)含有调释聚合物的第一薄膜层及(b)含有(i)第一聚合物和(ii)第二聚合物的第二薄膜层,其中所述第一聚合物是丙烯酸乙酯和甲基丙烯酸甲酯的聚合物,且其中所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的聚合物。
第一薄膜层
第一薄膜层含有调释聚合物。本文所用的“调释”应适用于药物活性剂在溶解介质(如胃肠液)中的被改变的释放或溶解。调释的类型包括(i)延释和(ii)迟释。通常,配制调释片剂来使得药物活性剂在摄取后在长时间内可以利用,这因而使得与常规片剂中相同药物活性剂的给药相比,给药频率减少。调释片剂还使得能使用其中一种药物活性剂的持续时间可与另一药物活性剂的持续时间不同的药物活性剂组合。
所谓“延释”是指在施用后,药物活性剂以基本上连续的、受调节的方式从片剂释放出来,且药物活性剂从片剂完全释放(例如耗竭)的时间比同样药物活性剂的速释片剂长。延释的类型包括控制释放、持续释放和延长释放,且可为零级释放或一级释放。
所谓“迟释”是指在施用后,至少一段时间药物活性剂不从片剂释放,例如药物活性剂的释放不是在口服给药后立即发生。迟释是可包括脉冲式释放和pH依赖性释放,如肠溶释放。
固体剂型可采用以多种方式展示调释特性形式的聚合物;包括片剂包衣、片剂湿法造粒、在片剂基质中的直接压片和颗粒包衣。用于颗粒包衣的调释聚合物的例子包括但不限于乙基纤维素、乙酸纤维素、羟丙基纤维素、羟丙甲纤维素、聚醋酸乙烯酯、聚乙烯醇和聚甲基丙烯酸聚合物,如以三甲基氨甲基丙烯酸乙酯(trimethyl-ammonioethylmethacrylate)为官能团的甲基丙烯酸/丙烯酸共聚物(可获自Evonik Corporation(Theodore,Alabama,USA),商品名为Eudragit RSTM和Eudragit RLTM)。
合适的颗粒调释包衣的例子在美国专利4,173,626、4,863,742、4,980,170、4,984,240、5,286,497、5,912,013、6,270,805和6,322,819中有描述。
也可采用市售的调释药物活性剂。例如,用调释聚合物通过凝聚法包封的对乙酰氨基酚颗粒可用于本发明。这种凝聚法包封的对乙酰氨基酚例如可从Eurand America,Inc.(Vidalia,Ohio,USA)或Circa Inc.(Dayton,Ohio,USA)市售获得。
在一个实施例中,调释聚合物是pH依赖性的成膜聚合物,如肠溶性聚合物。pH依赖性的成膜聚合物的例子包括但不限于肠溶纤维素衍生物,例如羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯和乙酸纤维素邻苯二甲酸酯;天然树脂,如紫胶和玉米醇溶蛋白;肠溶乙酸酯衍生物,例如聚乙酸乙烯邻苯二甲酸酯、乙酸纤维素邻苯二甲酸酯和乙醛二甲基纤维素乙酸酯;及肠溶丙烯酸衍生物,如基于聚甲基丙烯酸的聚合物,如聚(甲基丙烯酸,甲基丙烯酸甲酯)1∶2(其可以商品名EUDRAGIT STM市售获得)和聚(甲基丙烯酸,甲基丙烯酸甲酯)1∶1(其可以商品名EUDRAGIT LTM市售获得),以及它们的混合物。
第一薄膜层可含有增塑剂,其数量占第一包衣的约0.01重量%至约40重量%,如占第一包衣的约1重量%至约20重量%。适用于第一包衣的增塑剂的例子包括甘油、聚乙二醇、丙二醇、癸二酸二丁酯、柠檬酸三乙酯、甘油三乙酸酯、柠檬酸三丁酯、植物油如蓖麻油、表面活性剂如聚山梨醇酯-80、十二烷基硫酸钠和二辛基硫化琥珀酸钠以及聚碳水化合物。在一个实施例中,第一薄膜层还含有色素和/或遮光剂。
在一个实施例中,第一薄膜层的平均厚度为约1微米至约20微米,例如约2微米至约15微米或者约4至约9微米。基于向其添加第二包衣之前的包衣颗粒的总重量,第一薄膜层的存在量可为约5%至约60%,例如约25%至约60%。
在一个实施例中,第一薄膜层占添加第二薄膜层后的颗粒的总重量的约10重量%至约60重量%,如占该颗粒的总重量的约15重量%至约45重量%。
第二薄膜层
第二薄膜层含有(i)第一聚合物和(ii)第二聚合物,其中所述第一聚合物是丙烯酸乙酯和甲基丙烯酸甲酯的聚合物,且其中所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的聚合物。
第一聚合物的例子包括但不限于丙烯酸乙酯、甲基丙烯酸甲酯共聚物2∶1(可以商品名Eudragit NE-30DTM和Eudragit NE-40DTM市售获得)。
第二聚合物的例子包括但不限于丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸7∶3∶1(可以商品名Eudragit FS-30DTM市售获得)。
在一个实施例中,第一聚合物与第二聚合物的重量比为约1∶3至约3∶1,如约1.5∶1至约2.5∶1。
在一个实施例中,第二薄膜层包含约25重量%至约75重量的第一聚合物和约75重量%至约25重量%的第二聚合物,如约60重量%至约75重量%的第一聚合物和约25重量%至约40重量%的第二加合物。
在一个实施例中,第二薄膜层占包含第一和第二包衣层的颗粒的总重量的约20重量%至约50重量%,如约25重量%至约45重量%。
第二包衣层可含有另外的材料,例如防粘剂或表面活性剂。合适的防粘剂可包括但不限于滑石粉和硬脂酸镁。合适的表面活性剂的例子包括来自合成和天然来源的离子型和非离子型材料,包括但不限于卵磷脂、甘油酯、糖酯、聚山梨醇酯、脂肪酸的单甘油酯和二甘油酯、丙二醇酯、蔗糖脂肪酸酯、脱水山梨糖醇脂肪酸酯的聚氧乙烯衍生物和西甲硅油。有用的聚山梨醇酯的例子包括失水山梨醇三油酸酯、失水山梨醇单棕榈酸酯、失水山梨醇单月桂酸酯、丙二醇单月桂酸酯、甘油单硬脂酸酯、二甘油单硬脂酸酯和甘油乳酰棕榈酸酯。乳酸衍生物包括但不限于硬脂酰乳酸钙和硬脂酰乳酸钙。在一个实施例中,当第二包衣层中存在表面活性剂时,基于第二包衣层的总重量,表面活性剂的存在量为约0.5重量%至约10重量%。在一个实施例中,硬脂酸镁的用量占第二包衣的约2重量%至约20重量%。
在一个实施例中,包衣芯材上的第二包衣层的平均厚度为约1至约20微米,例如约2至约15微米或约4微米至约9微米。
含有药物活性剂的颗粒的制备
在一个实施例中,药物活性剂颗粒直接包覆以第一薄膜层,且为晶体的形式。在另一个实施例中,首先是将药物活性剂层积在基材的顶部上并干燥,其中层积时使用或不使用粘合剂。接着是随后将包衣的第一层和第二层施加到经层积的颗粒。适用于进行层积的基材包括但不限于糖和糖醇(如但不限于一水右旋糖、蔗糖、乳糖、乳糖醇、山梨糖醇、甘露糖醇、麦芽糖醇、木糖醇、non pareil bead和赤藓糖醇)、淀粉(如改性淀粉)和纤维素(如微晶纤维素)。合适的粘合剂包括但不限于羟丙甲纤维素、羟丙基纤维素、淀粉、改性淀粉和聚乙烯吡咯烷酮。在一个实施例中,粘合剂掺入在经层积的颗粒中的量占经层积的颗粒的约0.1重量%至约10重量%。
药物活性剂层积可通过流化床层积来实现,其中活性剂被悬浮或溶解于合适的溶剂如醇、水、丙二醇、甘油、丙酮、异丙醇和甲醇中,随后被喷雾到惰性层上。合适的流化床层积技术包括底部喷雾层积,切向喷雾层积和顶部喷雾层积;其中在层积过程中对空气流动、空气温度、喷雾速度和喷雾雾化进行调节以优化颗粒大小。在一个实施例中,将较低剂量的药物活性剂层积到较高剂量的药物活性剂上。在一个实施例中,将粘合剂放置到包衣悬浮液中以有利于粘合到惰性层。在一个实施例中,将粘合剂与惰性材料一起放置并共混到流化的粉末中。在一个实施例中,较低剂量的药物活性剂是洛哌丁胺、去氧肾上腺素、伪麻黄碱、苯海拉明或氯苯那敏,较高剂量的药物活性剂是对乙酰氨基酚或布洛芬。惰性材料与药物活性剂的合适比例包括但不限于约50∶50至约99.5∶0.5。
在一个实施例中,将药物活性剂颗粒与另一材料如粘合剂一起造粒。这可通过包括但不限于以下方法实现:湿法造粒、高剪切造粒、辊压造粒和流化床造粒。合适的粘合剂包括以下所列的那些粘合剂。在另一个实施例中,先将一种以上的药物活性剂一起进行共造粒,然后再添加调释包衣。在一个造粒实施例中,将药物活性剂与填料和粘合剂进行混合,用水、醇或它们的组合进行湿润,干燥并任选通过筛子进行筛分。在一个实施例中,将粘合剂先制备成溶液再添加到药物活性剂。
含有药物活性剂的颗粒的包覆
施加到药物活性剂颗粒的包衣可利用流化床包覆法进行层积,其中每个层在含水(水基)系统或有机溶剂系统中制备并相续喷雾到流化床中流化的颗粒上,直到达到所需的包衣水平。在含水系统中,这些聚合物通常制备成分散液。
在一个实施例中,在造粒或层积步骤后,包衣颗粒的平均颗粒大小为约150微米至约320微米,例如约220至约300微米。在一个实施例中,在添加第一薄膜包衣层后,包衣颗粒的平均颗粒大小为约200至约425微米,例如约250至约375微米。在一个实施例中,在添加第二薄膜包衣层后,包衣药物活性剂颗粒的平均颗粒大小为约300微米至约600微米,例如约350微米至约525微米。
颗粒的使用
在一个实施例中,将包衣颗粒包括在压制片剂中(例如供口服摄取)。在一个实施例中,在摄取时,片剂适于在摄取2小时内释放出包衣颗粒当中所含的药物活性剂的约20至约50重量%(如约25至约40重量%),在摄取4小时内释放出药物活性剂的约40至约70重量%(如约50至约65重量%),在摄取6小时内释放出药物活性剂的约65至约90重量%(如约70至约80重量%)。在另一个实施例中,包衣颗粒可与片剂基质当中的另外的第二药物活性剂进行组合。在一个实施例中,第一药物活性剂的释放速度与片剂基质中的第二药物活性剂的释放速度基本上匹配。在另一个实施例中,对颗粒中的第一药物活性剂的释放速度加以控制,使得第一药物活性剂的释放速度与片剂基质中的第二速释药物活性剂的临床持续时间匹配。在一个实施例中,第一药物活性剂是去氧肾上腺素,而速释但持续时间至少12小时的第二药物活性剂是西替利嗪。在一个实施例中,第一药物活性剂是去氧肾上腺素,而速释但持续时间至少4小时的第二药物活性剂是布洛芬。在一个实施例中,第一药物活性剂是去氧肾上腺素,而速释但持续时间至少6小时的第二药物活性剂是萘普生。
本文所用的“基本上包覆”应意指小于约20重量%、例如小于约15重量%或小于约1重量%的颗粒表面积被暴露(例如不被所需的包衣覆盖)。
片剂的制备
在本发明的一个实施例中,将包衣颗粒与含有药物可接受的载体的粉末(在本文中也定义为片剂基质)进行混合。在一个实施例中,粉末的平均颗粒大小为约50微米至约500微米,如在50微米至300微米之间。在这个大小范围的颗粒尤其适用于直接压片工艺。
在实施例中,将粉末的各组分共混在一起,例如作为干粉,并送料进设备的冲模腔中,该设备施加压力以形成片剂。可使用任何合适的压实设备,包括但不限于常规的单冲式或旋转式压片机。在一个实施例中,可通过用旋转式压片机(例如,诸如Fette America Inc.(Rockaway,N.J.)或Manesty Machines LTD(Liverpool,UK)市售的那些)进行压实来形成片剂。通常,将计量体积的粉末充填进旋转式压片机的冲模腔中,其中粉末是从送料器重力式送料或者机械式送料,并且冲模腔作为“模具台”的一部分从填充位置旋转至压实位置。在压实位置,粉末在上冲头和下冲头之间被压实,然后所得的片剂通过下冲头从冲模腔被推出,接着通过静止的“引离棒(take-off bar)”引导至注射斜槽。有利地,当使用直接压片工艺时,其可最小化或消除可能对溶解有负面影响的水溶性、非糖类聚合物粘合剂,如聚乙烯吡咯烷酮、海藻酸盐、羟丙基纤维素和羟丙基甲基纤维素、羟乙基纤维素。
在另一个实施例中,可通过在美国专利申请公开说明书No.20040156902中所描述的压制方法和设备来制备片剂。具体地讲,可用单个设备中的包括填充区、插入区、压制区、弹出区和清除区的旋转压制模块来制备片剂,该单个设备具有双排冲模构造。然后可借助真空对压制模块的冲模进行填充,每个冲模之中或附近设置有过滤器。压制模块的清除区包括任选的粉末回收系统,以从过滤器回收多余的粉末并将粉末送回冲模。
在另一个实施例中,片剂基质可通过湿法造粒方法制备,其中将赋形剂与湿粘合剂溶液或分散液(例如水煮淀粉糊或聚乙烯吡咯烷酮溶液)进行混合并造粒。适用于湿法造粒的设备包括低剪切混合机(如行星混合机)、高剪切混合机和流化床(包括旋转流化床)。然后可将所得的颗粒状材料干燥,并任选与另外的成分(例如赋形剂如润滑剂、着色剂等)进行干混。最终的干共混物则适于通过前面段落中描述的方法进行压制。直接压片和湿法造粒的工艺方法是本领域已知的。在一个实施例中,片剂基质包括湿法造粒,其被配制成具有调释特性。在一个实施例中,将较低剂量的药物活性剂包覆以本发明的包衣,并与较高剂量的药物活性剂的控释片剂基质进行混合,然后压成片剂。
在一个实施例中,通过公布的美国专利No.6,767,200(将该专利的公开内容以引用方式并入本文中)中所描述的压制方法和设备来制备片剂。具体地讲,可用具有双排冲模构造的单个设备中的包括填充区、压制区、弹出区的旋转压制模块来制备片剂,如本文图6所示。优选借助真空对压制模块的冲模进行填充,每个冲模之中或附近带有过滤器。
在本发明的一个实施例中,片剂可以是从基本上不含水溶性聚合物粘结剂和水合聚合物的粉末制成的直接压制片剂。本文所用的“基本上不含”是指小于5重量%,如小于1重量%,如小于0.1重量%,如完全不含(例如0重量%)。该组合物对于保持速释溶出特性(profile)、使加工和材料成本减至最低以及使片剂的物理和化学稳定性最佳是有利的。在一个实施例中,片剂的密度大于约0.9g/cc。
该片剂可具有多种不同形状中的其中一种。例如,片剂可成形为多面体,如立方体、棱椎、棱柱等;或者可具有带一些非平坦表面的空间外形的几何形状,如圆锥体、截头圆锥体、圆柱体、球体、圆环体等。在某些实施例中,片剂具有一个或多个主表面。例如,片剂表面通常具有通过与压制机器中的上冲头表面和下冲头表面接触而形成的相对的上表面和下表面。在这类实施例中,片剂表面通常还包括位于上表面和下表面之间的“腹带”,其通过与压制机器中的冲模壁接触而形成。片剂还可以是多层片剂。
或者,如果相同组成的片剂要用于剂型中,则压制模块可装配有多头压制模具。例如,可将四头模具用于在一个冲模内制备四片片剂。片剂可具有单层或多层。
在某些实施例中,可用本文所述的发明制备多层片剂(例如可制备双层或三层片剂)。在一个实施例中,将片剂冲模填充以粉末的第一部分,并任选将粉末床压制第一次,然后加入粉末的第二部分并将片剂压制,然后将片剂从冲模放出。在一个实施例中,粉末的第二部分具有与粉末的第一部分相同的共混物组成。在另一个实施例中,粉末的第二部分具有与粉末的第一部分不同的组成。在一个实施例中,粉末的第一部分含有药物活性剂,粉末的第二部分含有另一不同的药物活性剂。在一个实施例中,第一部分是为了即释,第二部分是为了调释。在一个实施例中,第一部分含有第一和第二药物活性剂的速释剂量,而第二部分含有一部分的包覆有本发明包衣的第一药物活性剂并含有含第二药物活性剂的调释片剂基质。
本发明的包衣组合物的一个好处可通过按照美国药典(USP)第29号所述的指导进行的含量均匀度分析来证明。具体地讲,可如下确定特定药物活性剂的含量均匀度:从一个批次当中随机抽取10个片剂,并测量药物活性剂的浓度,以确定样品是否具有6重量%,即小于约5重量%或小于约3重量%或小于2重量%或小于约1重量%的总体相对标准偏差(RSD)。这将表明在压片过程中片剂材料损失或粘附于片剂冲压机表面的情况将极少乃至没有。
本发明的包衣组合物的另一个好处可通过对在溶解中的各个容器进行标准偏差分析来证明。具体地讲,可如下确定特定药物活性剂的标准偏差:测量药物活性剂在溶解容器中的浓度,并用6个容器的平均值进行比较。在一个实施例中,在任何单个时间点,6个容器的标准偏差小于6重量%或小于5重量%。这将表明在压片过程中包衣层的破裂程度均匀,因为释放速度将是均匀的,这进一步表明第二层起到执行保护功能的作用。
粉末
如上面所论述的,通过压制含有可药用载体的粉末来制造片剂。载体可含有一种或多种适用于配制片剂的赋形剂。合适的赋形剂的例子包括但不限于:填充剂、吸附剂、粘结剂、崩解剂、润滑剂、助流剂、调节释放的赋形剂、甜味剂、超级崩解剂、风味剂和芳香剂、抗氧化剂、质构增强剂以及它们的混合物。
合适的填料包括但不限于水溶性可压制碳水化合物,如糖(例如右旋糖、蔗糖、麦芽糖和乳糖)、淀粉(例如玉米淀粉)、糖醇(例如甘露糖醇、山梨糖醇、麦芽糖醇、赤藓糖醇和木糖醇)、淀粉水解物(例如糊精和麦芽糊精)和水不溶性塑性变形材料(例如微晶纤维素或其他纤维素衍生物)以及它们的混合物。
合适的吸附剂(例如吸附液态药物组合物)包括但不限于水不溶性吸附剂,如磷酸二钙、磷酸三钙、硅酸化微晶纤维素(例如,如以商品名PROSOLV(PenWest Pharmaceuticals,Patterson,NY)配销的)、偏硅酸铝镁(例如,如以商品名NEUSILINTM(Fuji Chemical Industries(USA)Inc.,Robbinsville,NJ)配销的)、黏土、二氧化硅、膨润土、沸石、硅酸镁、水滑石、veegum以及它们的混合物。
合适的粘合剂包括但不限于干粘合剂如聚乙烯吡咯烷酮和羟丙基甲基纤维素;湿粘合剂如水溶性聚合物,包括亲水胶体如阿拉伯胶、海藻酸盐、琼胶、瓜尔豆胶、刺槐豆胶、卡拉胶、羧甲基纤维素、他拉胶、阿拉伯树胶、黄蓍胶、果胶、黄原胶、结冷胶、明胶、麦芽糊精、半乳甘露聚糖、石耳素、海带多糖、小核菌葡聚糖、菊粉、威兰胶(whelan)、鼠李胶(rhamsan)、菌胶团(zooglan)、甲兰胶(methylan)、几丁质、环糊精、壳聚糖、聚乙烯吡咯烷酮、纤维素、蔗糖和淀粉;以及它们的混合物。
合适的崩解剂包括但不限于:羟基乙酸淀粉钠、交联聚乙烯吡咯烷酮、交联羧甲基纤维素、淀粉类、微晶纤维素,以及它们的混合物。
合适的润滑剂包括但不限于:长链脂肪酸以及它们的盐(例如硬脂酸镁和硬脂酸)、滑石、甘油酯、蜡,以及它们的混合物。
合适的助流剂包括但不限于胶态二氧化硅。
合适的调节释放的赋形剂包括但不限于:溶胀性可溶蚀亲水性材料、不溶性可食用材料、pH依赖性聚合物,以及它们的混合物。
供用作调释赋形剂的合适的可溶胀易蚀亲水性材料包括但不限于水可溶胀纤维素衍生物、聚亚烷基二醇、热塑性聚环氧烷、丙烯酸聚合物、亲水胶体、黏土、胶化淀粉、溶胀交联聚合物以及它们的混合物。合适的水可溶胀纤维素衍生物的例子包括但不限于羧甲基纤维素钠、交联羟丙基纤维素、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羟基异丙基纤维素、羟丁基纤维素、羟苯基纤维素、羟乙基纤维素(HEC)、羟戊基纤维素、羟丙基乙基纤维素、羟丙基丁基纤维素和羟丙基乙基纤维素以及它们的混合物。合适的聚亚烷基二醇的例子包括但不限于聚乙二醇。合适的热塑性聚环氧烷的例子包括但不限于聚环氧乙烷。合适的丙烯酸聚合物的例子包括但不限于甲基丙烯酸钾二乙烯基苯共聚物、聚甲基丙烯酸甲酯、高分子量交联丙烯酸均聚物和共聚物(可获自Noveon Chemicals,商品名为CARBOPOLTM(例如当分散在碱性溶液中,采用布氏RVT型粘度计,用7号转子在25℃下测试时,具有大于50,000厘泊的粘度))。合适的亲水胶体的例子包括但不限于:海藻酸盐、琼脂、瓜耳胶、刺槐豆胶、κ卡拉胶、ι卡拉胶、塔拉胶、阿拉伯树胶、黄蓍胶、果胶、黄原胶、结冷胶、麦芽糊精、半乳甘露聚糖、石耳素、昆布多糖、小核菌葡聚糖、阿拉伯树胶、菊粉、果胶、明胶、威兰胶、鼠李胶、菌胶团、甲兰胶、几丁质、环糊精、壳聚糖,以及它们的混合物。合适的黏土的例子包括但不限于绿土如膨润土、高岭土和合成锂皂石(laponite);三硅酸镁;硅酸镁铝;以及它们的混合物。合适的胶化淀粉的例子包括但不限于:酸水解淀粉、溶胀淀粉(例如羟基乙酸淀粉钠及其衍生物),以及它们的混合物。合适的溶胀交联聚合物的例子包括但不限于:交联聚乙烯吡咯烷酮、交联琼脂和交联羧甲基纤维素钠,以及它们的混合物。
供用作调释赋形剂的合适的不溶性可食材料包括但不限于水不溶性聚合物和低熔点疏水材料、它们的共聚物、以及它们的混合物。合适的水不溶性聚合物的例子包括但不限于:乙基纤维素、聚乙烯醇、聚乙酸乙烯酯、聚己酸内酯、乙酸纤维素及其衍生物、丙烯酸酯、甲基丙烯酸酯、丙烯酸共聚物、它们的共聚物,以及它们的混合物。合适的低熔点疏水性材料包括但不限于:脂肪、脂肪酸酯、磷脂、蜡,以及它们的混合物。合适的脂肪的例子包括但不限于:氢化植物油(例如可可脂、氢化棕榈仁油、氢化棉籽油、氢化向日葵油和氢化大豆油)、游离脂肪酸和它们的盐,以及它们的混合物。合适的脂肪酸酯的例子包括但不限于:蔗糖脂肪酸酯、甘油一酯、甘油二酯和甘油三酯、甘油基二十二烷酸酯、甘油基棕榈酰硬脂酸酯、甘油基单硬脂酸酯、甘油基三硬脂酸酯、甘油基三月桂酸酯、甘油基肉豆蔻酸酯、GlycoWax-932、月桂酰聚乙二醇-32甘油酯和硬脂酰聚乙二醇-32甘油酯,以及它们的混合物。合适的磷脂的例子包括磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酸,以及它们的混合物。合适的蜡的例子包括但不限于巴西棕榈蜡、鲸蜡、蜂蜡、小烛树蜡、紫胶蜡、微晶蜡和石蜡;含脂肪的混合物如巧克力,以及它们的混合物。
供用作调释赋形剂的合适的pH依赖性聚合物包括但不限于肠溶纤维素衍生物,如羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸酯琥珀酸酯、乙酸纤维素邻苯二甲酸酯;天然树脂,如紫胶和玉米醇溶蛋白;肠溶乙酸酯衍生物,例如聚乙酸乙烯邻苯二甲酸酯、乙酸纤维素邻苯二甲酸酯、乙醛二甲基纤维素乙酸酯;及肠溶丙烯酸衍生物,如基于聚甲基丙烯酸的聚合物,如聚(甲基丙烯酸,甲基丙烯酸甲酯)1∶2(其可以商品名EUDRAGIT STM市售获得)和聚(甲基丙烯酸,甲基丙烯酸甲酯)1∶1(其可以商品名EUDRAGIT LTM市售获得),以及它们的混合物。
合适的甜味剂的例子包括但不限于合成或天然糖类、三氯半乳蔗糖、糖精、糖精钠、天冬甜素、安赛蜜K或安赛蜜、安赛蜜钾、非洲甜果素、甘草素、二氢查耳酮、阿力甜、奇异果素、应乐果甜蛋白、甜菊糖以及它们的混合物。
超级崩解剂的例子包括但不限于:交联羧甲基纤维素钠、羟基乙酸淀粉钠和交联聚维酮(交联聚乙烯吡咯烷酮)。在一个实施例中,片剂含有最多约5重量%的这种超崩解剂。
合适的香料和芳香剂的例子包括但不限于:精油,包括含有醇、酯、醛和内酯的混合物的切花、叶子、果皮或打浆全果的蒸馏物、溶剂萃取物或冷榨出物;香精,包括精油的稀释溶液,或者经共混以匹配水果(例如草莓、树莓和黑加仑)的天然香料的合成化学品的混合物;酿造酒和蒸馏酒(例如法国白兰地酒、威士忌酒、朗姆酒、杜松子酒、雪利酒、波尔多红葡萄酒和葡萄酒)的人造和天然香料;烟草、咖啡、茶叶、可可和薄荷;果汁,包括从洗擦过的水果如柠檬、橙和莱母酸橙榨出的果汁;薄荷;姜;肉桂;可可;香草;甘草;薄荷醇;桉树;大茴香;坚果(例如花生、椰子、榛子、栗子、胡桃和可乐果);杏仁;葡萄干;和粉末、面粉或植物材料部分,包括烟草植物部分(例如烟草属(Nicotiana),其数量不显著导致治疗性尼古丁的水平),以及它们的混合物。
抗氧化剂的例子包括但不限于:生育酚、抗坏血酸、焦亚硫酸钠、丁基羟基甲苯、丁基化羟基苯甲醚、依地酸和依地酸盐,以及它们的混合物。防腐剂的例子包括但不限于:柠檬酸、酒石酸、乳酸、苹果酸、乙酸、苯甲酸和山梨酸,以及它们的混合物。
质构增强剂的例子包括但不限于果胶、聚环氧乙烷和卡拉胶以及它们的混合物。在一个实施例中,质构增强剂的用量为约0.1重量%至约10重量%。
药物活性剂
本发明的片剂包含至少一种药物活性剂。“药物活性剂”是指经美国食品与药物管理局(U.S.Food and Drug Administration)、欧洲药品管理局(European Medicines Agency)或它们的任何后继实体许可或批准的用于口服以治疗病症或疾病的物质(如化合物)。合适的药物活性剂包括但不限于镇痛剂、抗炎剂、抗组胺药、抗生素(如抗菌剂、抗病毒剂和抗真菌剂)、抗抑郁药、抗糖尿病剂、解痉药、食欲抑制剂、支气管扩张剂、心血管治疗药(如他汀类药物)、中枢神经系统治疗药、镇咳剂、减充血剂、利尿剂、祛痰剂、胃肠治疗剂、麻醉剂、黏液溶解剂、肌肉松弛剂、骨质疏松治疗剂、兴奋剂、尼古丁以及镇静剂。
合适的胃肠处理剂的例子包括但不限于:抗酸剂,如含铝的药物活性剂(例如碳酸铝、氢氧化铝、碳酸二羟铝钠和磷酸铝)、含碳酸氢盐的药物活性剂、含铋的药物活性剂(例如铝酸铋、碳酸铋、次碳酸铋、次没食子酸铋和次硝酸铋)、含钙的药物活性剂(例如碳酸钙)、甘氨酸、含镁的药物活性剂(例如镁铝水合物、硅酸镁铝、碳酸镁、甘氨酸镁、氢氧化镁、氧化镁和三硅酸镁)、含磷酸盐的药物活性剂(例如磷酸铝和磷酸钙)、含钾的药物活性剂(例如碳酸氢钾)、含钠的药物活性剂(例如碳酸氢钠)和硅酸盐;轻泻剂如软便剂(例如多库酯)和刺激性轻泻剂(例如比沙可啶);H2受体拮抗剂,如法莫替丁、雷尼替丁、西咪替丁和尼扎替丁;质子泵抑制剂如奥美拉唑和兰索拉唑;胃肠细胞保护剂,如硫糖铝和米索前列醇;胃肠促动力药如普卢卡必利;幽门螺旋杆菌的抗生素,如克拉霉素、阿莫西林、四环素和甲硝唑;止泻药,如次水杨酸铋、高岭土、苯乙哌啶和洛哌丁胺;格隆溴胺;止痛剂,如美沙胺;止吐剂如昂丹司琼、赛克利嗪、苯海拉明、茶苯海明、氯苯甲嗪、异丙嗪和羟嗪;益生细菌,包括但不限于乳酸杆菌;乳糖酶;消旋卡多曲;和排气药物如聚二甲基硅氧烷(例如二甲硅油和西甲硅油,包括美国专利4,906,478、5,275,822和6,103,260中公开的那些);它们的异构体;以及它们的可药用盐和前药(例如酯)。
合适的镇痛剂、抗炎剂以及解热剂的例子包括(但不限于)非甾体类抗炎药(NSAID),例如丙酸衍生物(如布洛芬、萘普生、酮洛芬、氟比洛芬、芬布芬、非诺洛芬、吲哚洛芬、氟洛芬、吡洛芬、卡洛芬、噁丙嗪、普拉洛芬以及舒洛芬)和COX抑制剂,例如塞来考昔;对乙酰氨基酚;乙酰水杨酸;乙酸衍生物,例如消炎痛、双氯芬酸、舒林酸以及托美丁;芬那酸衍生物,例如甲芬那酸、甲氯芬那酸以及氟芬那酸;联苯甲酸衍生物,例如二氟苯水杨酸和氟苯乙酰水杨酸;以及昔康类,例如吡罗昔康、舒多昔康、伊索昔康以及美洛昔康;它们的异构体;以及它们的可药用盐和前药。
抗组胺药和减充血剂的例子包括(但不限于)溴苯那敏、氯环嗪、右溴苯那敏、溴己新、苯茚胺、非尼拉敏、美吡拉敏、松齐拉敏、pripolidine、麻黄碱、去氧肾上腺素、伪麻黄碱、去甲麻黄碱、扑尔敏、右美沙芬、苯海拉明、多西拉敏、阿司咪唑、特非那丁、非索非那丁、萘甲唑林、羟甲唑啉、孟鲁斯特、丙己君、苯丙烯啶、克立马丁、阿伐斯汀、普鲁米近、奥索马嗪、美喹他嗪、安其敏、溴己新、酮替芬、特非那丁、依巴斯汀、苯咪唑嗪、赛洛唑啉、氯雷他定、脱羧氯雷他定以及西替利嗪;它们的异构体;以及它们的可药用盐和酯。
止咳剂和祛痰剂的例子包括但不限于:苯海拉明、右美沙芬、诺斯卡品、氯苯达诺、薄荷醇、苯佐那酯、乙基吗啡、可待因、乙酰半胱氨酸、羧甲半胱胺酸、氨溴索、莨菪类生物碱、索布瑞醇、愈疮木酚和愈创甘油醚;它们的异构体;以及它们的可药用盐和前药。
肌肉松弛剂的例子包括但不限于环苯扎林和氯唑沙宗、美他沙酮、奥芬那君、美索巴莫;它们的异构体;以及它们的可药用盐和前药。
兴奋剂的例子包括但不限于咖啡因。
镇静剂的例子包括(但不限于)安眠药,例如抗组胺药(如苯海拉明)、右佐匹克隆以及佐沛眠;它们的异构体;以及它们的可药用盐和前药。
食欲抑制剂的例子包括但不限于苯丙醇胺、芬特明和二乙基卡西酮;它们的异构体;以及它们的可药用盐和前药。
麻醉剂(如用于治疗咽喉痛)的例子包括(但不限于)达克罗宁、苯佐卡因以及果胶;它们的异构体;以及它们的可药用盐和前药。
合适的他汀类药物的例子包括但不限于阿托伐他汀、罗苏伐他汀、氟伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀和普伐他汀;它们的异构体;以及它们的可药用盐和前药。
在一个实施例中,片剂中所包含的药物活性剂选自去氧肾上腺素、右美沙芬、伪麻黄碱、对乙酰氨基酚、布洛芬、酮洛芬、洛哌丁胺、法莫替丁、碳酸钙、西甲硅油和薄荷醇;它们的异构体;以及它们的可药用盐和前药。
在一个实施例中,药物活性剂选自去氧肾上腺素、右美沙芬、伪麻黄碱、氯苯那敏、美索巴莫、氯苯达诺、抗坏血酸、薄荷醇、果胶、达克罗宁和苯唑卡因;它们的异构体;以及它们的可药用盐和前药。
如上所述,本发明的药物活性剂还可以可药用盐的形式存在,例如酸式/阴离子盐或碱式/阳离子盐。可药用酸式/阴离子盐包括(但不限于)乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、依地酸钙、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、依托酸盐、乙磺酸酯、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、对羟乙酰氨基苯胂酸盐、己基间苯二酚盐、海巴明、氢溴酸盐、盐酸盐、羟萘酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘液酸盐、萘磺酸盐、硝酸盐、双羟萘酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、硫酸盐、鞣酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐以及三乙基碘。可药用的碱式/阳离子盐包括(但不限于)铝、苄星、钙、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、锂、镁、葡甲胺、钾、普鲁卡因、钠和锌。
如上所述,本发明的药物活性剂还可以药物活性剂的前药形式存在。通常,此类前药将为药物活性剂的官能衍生物,该官能衍生物在体内易于转化成所需的药物活性剂。选择和制备合适的前药衍生物的常规方法在(例如)以下文献中有所描述:“Design of Prodrugs”,ed.H.Bundgaard,Elsevier,1985(前药设计,H.Bundgaard编辑,Elsevier,1985年)。除了盐外,本发明还提供所述化合物的酯、酰胺以及其他受保护的或衍生的形式。
如果根据本发明的药物活性剂具有至少一个手性中心,则它们可作为对映异构体存在。如果药物活性剂具有两个或更多个手性中心,则它们另外还可作为非对应异构体存在。应当理解,所有这些异构体以及它们的混合物均涵盖在本发明的范围内。此外,药物活性剂的某些晶体形式可作为多晶型物存在,并且此类多晶型物同样旨在包括在本发明的范围内。另外,某些药物活性剂可以与水形成溶剂化物(如水合物)或与普通有机溶剂形成溶剂化物,并且这些溶剂化物也旨在包括在本发明的范围内。
在一个实施例中,药物活性剂或试剂以治疗有效量存在于片剂中,治疗有效量为口服后能产生所需治疗响应的量,可容易由本领域的技术人员确定。在确定该量时,如本领域所知,必须考虑所施用的具体药物活性剂、药物活性剂的生物利用率特性、给药方案、患者的年龄和体重以及其他因素。
药物活性剂可以各种形式存在。例如,药物活性剂可在包覆前以分子水平分散(例如熔化)在细粒(granule)中,或者可为颗粒(particle)的形式,颗粒进而可进行包覆。第二药物活性剂可存在于包衣颗粒中,或者在片剂基质中未进行包覆。如果药物活性剂为颗粒的形式,颗粒在进行包覆、造粒或层积之前通常具有约1至约1000微米的平均颗粒大小。在一个实施例中,这种颗粒在进行包覆、沉积或造粒之前为具有约1至约300微米的平均颗粒大小的晶体。在另一个实施例中,颗粒具有约50至约2000微米、如约50至约1000微米、如约100至约800微米的平均颗粒大小。
如果没有包覆有本发明的调释包衣的第二药物活性剂具有令人不快的味道,则第二药物活性剂可用本领域知道的掩味包衣进行包覆。合适的掩味包衣的例子在美国专利No.4,851,226、美国专利No.5,075,114以及美国专利No.5,489,436中有所描述。也可采用可商购获得的经掩味处理的药物活性剂。例如,通过凝聚法用乙基纤维素或其他聚合物包封的对乙酰氨基酚颗粒可用于本发明。凝聚包封的对乙酰氨基酚可从Eurand America,Inc.(Vandalia,Ohio)或Circa Inc.(Dayton,Ohio)商购获得。
药物活性剂在添加调释包衣之前可以纯晶体形式存在或者以颗粒状形式存在。可以使用造粒技术来改善药物活性剂的流动特性或粒度,使其更适于压制或进行后续的包衣。适用于造粒的粘合剂包括(但不限于)淀粉、聚乙烯基吡咯烷酮、聚甲基丙烯酸酯、羟丙基甲基纤维素和羟丙基纤维素。包含药物活性剂的颗粒可用本领域已知的任何造粒方法通过将药物活性剂与合适的基质颗粒共同成粒而制备。这种造粒方法的例子包括但不限于高剪切湿法造粒和流化床造粒,如旋转流化床造粒,有关细节公开于“The Theory and Practice of Industrial Pharmacy,第3版”,第11章,Lachman,Leon等人,1986。
在一个实施例中,在添加本发明的第一包衣之前,可将一种或多种药物活性剂或者一部分药物活性剂结合到离子交换树脂。
在一个实施例中,药物活性剂在与流体如水、胃酸、肠液等接触时能够溶解。在另一个实施例中,对药物活性剂的溶解特性进行调节:当用USP溶解装置1(篮式)和USP装置2(桨式)在适当的介质(包括但不限于水、pH 5.8磷酸盐缓冲液和pH 7.2磷酸盐缓冲液)中以50-150rpm进行分析时,所述调节例如为控制、维持、延长、延迟、拖延、延缓等。
片剂包衣
在一个实施例中,本发明方法还包括对片剂进行包覆(如用外包衣进行包覆)。在一个实施例中,该方法还包括给片剂包覆底包衣,然后再给片剂施加外包衣。
底包衣
在一个实施例中,片剂含有一个或多个底包衣层。在一个实施例中,底包衣层基本上覆盖片剂的表面。底包衣的使用为本领域所熟知的,并且在(例如)美国专利No.3,185,626中有所公开,将该专利以引用的方式并入本文。合适的底包衣的例子在美国专利No.4,683,256、No.4,543,370、No.4,643,894、No.4,828,841、No.4,725,441、No.4,802,924、No.5,630,871和No.6,274,162中有所公开,将所有这些专利以引用方式并入本文中。合适的底包衣可包含以下成分中的一种或多种:纤维素醚如羟丙基甲基纤维素、羟丙基纤维素和羟乙基纤维素;聚碳水化合物如黄原胶、淀粉和麦芽糊精;增塑剂,包括例如甘油、聚乙二醇、丙二醇、癸二酸二丁酯、柠檬酸三乙酯,植物油如蓖麻油,表面活性剂如聚山梨醇酯-80、十二烷基硫酸钠和二辛基硫化琥珀酸钠;聚碳水化合物;色素;和遮光剂。
在一个实施例中,基于底包衣的总重量,底包衣包含约2重量%至约8重量%(如约4重量%至约6重量%)的水溶性纤维素醚和约0.1重量%至约1重量%的蓖麻油,这在美国专利No.5,658,589中详细公开,该专利以引用方式并入本文。在另一个实施例中,基于底包衣的总重量,底包衣包含约20重量%至约50重量%(如约25重量%至约40重量%)的HPMC;约45重量%至约75重量%(如约50重量%至约70重量%)的麦芽糖糊精;和约1重量%至约10重量%(如约5重量%至约10重量%)的PEG 400。
基于片剂的干重,底包衣的存在量通常为约0重量%至约5重量%。基于片剂和任选的底包衣的干重,干燥的浸涂层的存在量通常为约1.5重量%至约10重量%。在一个实施例中,片剂基本上无底包衣。
外包衣
所谓外包衣是指包衣片的外表面上的包衣。在一个实施例中,外包衣基本上覆盖片剂的表面(例如覆盖90重量%)。
干燥的浸涂层的平均厚度通常为约40至约400微米。然而,本领域技术人员将无需过多实验就会容易地认识到,浸涂包衣厚度可以变化,以提供更光滑、更容易吞咽的片剂,或者实现所需的溶出特性。此外,视基材的形状而定,浸膜包衣的厚度可在基材上的不同位置变化。例如,基材边缘或拐角处的包衣厚度可比基材主表面的中央处的包衣厚度小50重量%至70重量%。该差异可例如通过使用较厚的底包衣或者使用能导致在基材上的增重较高的浸渍组合物来减至最低。
在其中需要更厚的浸涂包衣的实施例中,可将有效量的增重提升剂(例如西甲硅油、聚山梨醇酯80和它们的混合物)加到含有成膜剂和任选的增稠剂(如亲水胶体)的成膜组合物。增重增强剂的用量要足以提升当干燥时基材上的包覆液体的增重例如达至少约10重量%、达至少约20重量%或达至少约30重量%。增重提升百分数是基于以下两个总重量之差测定的:用包含增重加强剂的包衣组合物涂覆的基材的总重量,和在相似处理条件下用不包含有效量的增重加强剂的包衣组合物涂覆的等同基材的总重量。
在一个实施例中,该方法还包括在片剂的不涂覆外包衣的部分的底包衣中产生一个或多个开口,以在包衣片剂的表面上使片剂暴露,如美国专利申请No.2005/0152970中所述。
在一个实施例中,该方法还包括在外包衣中产生一个或多个开口以暴露片剂,但开口没有穿透底包衣,这在美国专利申请No.2005/0152970中有公开。由于明胶不适宜于激光钻孔,因此在具有这种明胶包衣的片剂中有必要先暴露底包衣再用激光钻开口。
在一个实施例中,外包衣仅覆盖片剂的一部分,如仅覆盖包衣片的一半。片剂的另一半可含有另一类型的外包衣例如明胶,或者专门暴露底包衣或片剂。
在其中需要药物活性剂的调释的某些实施例中,可任选用已知的调释包衣包覆药物活性剂或压制片剂。这有利地提供对药物活性剂从片剂的释放进行调节的附加手段(例如除了颗粒上的调释包衣之外)。在一个实施例中,包衣含有pH依赖性成膜加合物,如肠溶聚合物。在一个实施例中,外包衣是调释包衣,而片剂中的活性剂包衣颗粒具有不同的调释,使得可显示可变的释放速度;包括片剂包衣所显示的脉冲式释放和包覆的药物活性剂所显示的一级释放。在另一个实施例中,将外调释包衣放在片剂上,以便以调释方式从片剂释放第二包覆的药物活性剂颗粒,而以另一调释方式释放第一颗粒包覆药物活性剂。
本文所用的“基本上包覆”应意指小于约20重量%、例如小于约15重量%或小于约1.0重量%的片剂表面积被暴露,例如不被所需的包衣覆盖。
在一个实施例中,片剂包衣含有热塑性水溶性成膜聚合物,如羟丙基甲基纤维素化合物。这种化合物的一个例子是“HPMC 291”,其是取代度为约1.9、羟丙基摩尔取代度为0.23,且基于化合物的总重量含有约29重量%至约30重量%的甲氧基基团和约7重量%至约12重量%的羟丙基基团的纤维素醚。HPMC 2910可从Dow Chemical公司市售获得,商品名为METHOCEL ETM。METHOCEL E5TM是适用于本发明的一种类别的HPMC-2910,其通过Ubbelohde粘度计在2重量%水溶液中在20C下测得的粘度为约4至6厘泊(4至6毫帕斯卡-秒)。类似地,METHOCEL E6TM是适用于本发明的另一种类别的HPMC-2910,其通过Ubbelohde粘度计在2重量%水溶液中在20C下测得的粘度为约5至7厘泊(5至7毫帕斯卡-秒)。METHOCEL E15TM是适用于本发明的另一种类别的HPMC-2910,其通过Ubbelohde粘度计在2重量%水溶液中在20C下测得的粘度为约15000厘泊(15毫帕斯卡-秒)。本文所用的术语“取代度”意指附接到脱水葡萄糖环上的取代基的平均数目,而术语“羟丙基摩尔取代”意指每摩尔脱水葡萄糖的羟丙基摩尔数。
在一个实施例中,包衣含有聚乙烯醇和聚乙二醇的共聚物。一种供用作片剂包衣的合适的聚乙烯醇和聚乙二醇共聚物可以商品名KOLLICOAT IRTM从BASF公司市售获得。
在一个实施例中,包衣含有改性淀粉。如本文所用,用于片剂包衣的“改性淀粉”包括已通过交联进行改性,化学改性(用于改善稳定性或优化性能)或物理改性(用于改善溶解特性或优化性能)的淀粉。化学改性淀粉的例子是本领域所熟知的,通常包括那些已通过化学处理以导致其某些羟基被酯基或醚基替代的淀粉。当相邻淀粉分子上的两个羟基基团发生化学连接时,会在改性淀粉中出现如本文所用的交联。本文所用的术语“预胶凝淀粉”或“速溶淀粉”指已经预先湿润然后干燥以提高其冷水溶解度的改性淀粉。
供用于片剂包衣的合适的改性淀粉可从几个供应商市售获得,例如A.e.Staley Manufacturing公司和National Starch & Chemical公司。一种合适的成膜改性淀粉包括预糊化的糯玉米衍生淀粉(它们可以商品名PURITY GUMTM和FILMSETTM从National Starch & Chemical公司市售获得)以及它们的混合物。基于淀粉的总重量,这种糯玉米淀粉通常含有约0重量%至约18重量%的直链淀粉和约100重量%至约88重量%的支链淀粉。
其他适用于片剂包衣的成膜改性淀粉包括羟丙基化淀粉,其中该淀粉的羟基基团中的一些已经用羟丙基基团醚化,通常是通过用环氧丙烷处理来醚化。具有成膜性质的合适的羟丙基淀粉的一个例子可以商品名PURE-COTE B790TM从Grain Processing公司市售获得。
在一个实施例中,片剂包衣含有木薯糊精。供作为成膜剂用作片剂包衣的合适的木薯糊精包括但不限于可以商品名CRYSTAL GUMTM或K-4484TM获自National Starch & Chemical公司的那些木薯糊精,以及它们的衍生物,如可以商品名PURITY GUM 40TM获自National Starch and Chemical的木薯衍生的改性食品级淀粉,以及它们的共聚物和混合物。
在一个实施例中,片剂包衣含有增稠剂。这类增稠剂的例子包括但不限于:亲水胶体(在本文中也称为胶凝聚合物)、粘土、胶凝淀粉和可结晶碳水化合物,以及它们的混合物。
适于用作片剂包衣的亲水胶体(本文又称凝胶聚合物)的例子包括海藻酸盐、琼脂、瓜尔胶、刺槐豆胶、卡拉胶、塔拉胶、阿拉伯树胶、黄蓍胶、果胶、黄原胶、结冷胶、麦芽糊精、半乳甘露聚糖、石耳素、昆布多糖、小核菌葡聚糖、阿拉伯树胶、菊粉、果胶、威兰胶、鼠李胶、菌胶团、甲兰胶、几丁质、环糊精、壳聚糖。合适的黏土的例子包括绿土如膨润土、高岭土和合成锂皂石(laponite);三硅酸镁;硅酸镁铝;以及它们的混合物。合适的胶凝淀粉的例子包括酸水解淀粉以及它们的混合物。另外的合适增稠亲水胶体包括低水分的聚合物溶液,如明胶和其他亲水胶体的水分含量最多约30重量%的混合物,例如那些用于制备“gummi”糖果形式的混合物。另外的合适增稠剂包括但不限于可结晶碳水化合物。
在本发明的一个实施例中,片剂包衣含有明胶。明胶是天然的热胶凝聚合物。它是白蛋白类衍生蛋白质的无味无色混合物,通常可溶于温水中。通常使用两种类型的明胶-A型和B型。A型明胶是经酸处理的原材料的衍生物。B型明胶是经碱处理的原材料的衍生物。明胶的含水量以及其Bloom强度、组成和初始明胶加工条件决定其在液体和固体之间的转变温度。Bloom是明胶凝胶的强度的标准量度,与分子量大致相关。Bloom定义为将半英寸直径的塑料柱塞移动进入已在10C下保持17小时的6.67重量%明胶凝胶中4mm所需的重量,以克为单位。在一个优选的实施例中,可流动材料是含有20重量% 275 Bloom猪皮明胶、20重量% 250 Bloom骨明胶和60重量%水的水溶液。
片剂的用途
在一个实施例中,本发明描述了治疗疾病的方法,该方法包括口服给予上述片剂,其中该片剂包含一定量的对治疗该疾病有效的药物活性剂。此类疾病的例子包括(但不限于)疼痛(例如头痛、偏头痛、咽喉痛、绞痛、背痛和肌痛)、发烧、炎症、上呼吸道疾病(例如咳嗽和充血)、感染(例如细菌和病毒感染)、抑郁症、糖尿病、肥胖症、心血管疾病(例如高胆固醇、高三甘油酯和高血压)、胃肠疾病(例如恶心、痢疾、过敏性肠综合征和气胀)、睡眠障碍、骨质疏松和尼古丁依赖。
在一个实施例中,该方法是用于治疗上呼吸道疾病,其中药物活性剂选自去氧肾上腺素、西替利嗪、氯雷他定、非索非那定、苯海拉明、右美沙芬、氯苯那敏、氯苯达诺和伪麻黄碱。
在该实施例中,“单位剂量”通常随附有给药说明,该说明指导患者根据(例如)该患者的年龄或体重服用一定量的药物活性剂,该量可以是多个该单位剂量。通常,单位剂量将含有对最小的患者治疗有效的量的药物活性剂。例如,合适的单位剂量体积可包括一个片剂。
片剂可在可使外颗粒包衣裂开但不会损及内包衣所显示的调释特性的力量下进行压片。作为两个包衣的有效性的度量,片剂可在一定的压片力下进行压制并显示一定的硬度。合适的压片力为约2千牛顿至约30千牛顿(例如约5千牛顿至约20千牛顿)。在一个实施例中,包含本发明的双包衣颗粒的压制片剂具有超过约5kp/cm2、如超过6kp/cm2、如超过9kp/cm2的硬度。
硬度测试
在一个实施例中,本发明的片剂具有至少5kp/cm2的平均硬度值。硬度这个术语在本领域中用来描述直径破碎强度,该强度是按照Leiberman等人,Pharmaceutical Dosage Forms-Tablets,第2卷,第2版,Marcel Dekker Inc.,1990,第213-217页、第327-29页中所述通过Schleuniger硬度测试仪测量的。为了进行硬度测试,将单个片剂放入硬度测试仪内的钢腔室中,然后钢活塞推压该剂型直至它破裂,测量所施加的力量作为硬度测量值。通常,对来自任何一个样本的5个片剂进行测试,以提供以千克力为单位的平均硬度值。
实例
通过以下实例来举例说明本发明的具体实施例。本发明并不受限于在这些实例中所示出的具体限定。
实例1:调释包衣的压片保护包衣的制备
如下制备调释包衣:在环境条件下,将甲基丙烯酸和甲基丙烯酸酯的阴离子共聚物(Eudragit RS-POTM)、硬脂酸镁和乙酰柠檬酸三丁酯分散在丙酮/异丙醇(2∶1)中,使得最终分散液含有18重量%的包衣材料。基于最终包衣的干燥重量,包衣材料在最终薄膜中的重量%在下表A中示出:
表A:调释包衣的组成
在另一容器中,如下制备压片保护包衣:在环境条件下,将Eudragit NE30DTM(丙烯酸乙酯与甲基丙烯酸甲酯共聚物(2∶1)的30重量%含水悬浮液)、Eudragit FS30DTM(丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的30重量%含水悬浮液)、硬脂酸镁、西甲硅油和十二烷基硫酸钠分散在纯化水中,使得最终分散液含有20.5重量%的包衣材料。基于最终包衣的干燥重量,包衣材料的重量%在下表B中示出:
表B:压片保护包衣的组成
实例2:具有调释包衣和压片保护包衣的药物活性剂包衣颗粒的制备
A部分:去氧肾上腺素层积的颗粒:首先如下制备层积的去氧肾上腺素颗粒:将1440g的盐酸去氧肾上腺素和150g的Eudragit NE30DTM(500g的30重量%含水分散液,用作粘合剂)溶解于1100g的纯化水中,同时用实验室混合器在50rpm下混合。用Glatt GPCG-5/9流体床装置的顶部喷雾嵌件(spray insert),将这个混合物以40g/分钟和约35℃至约45℃产品温度喷雾到6560g的改性淀粉上。最终的层积颗粒含有17.7重量%去氧肾上腺素HCl(“PHE”)、80.5重量%改性淀粉和1.8重量%Eudragit NE30DTM。
B部分:具有两个包衣层的去氢肾上腺素包衣颗粒的制备:将2000g根据以上A部分制备的去氧肾上腺素层积颗粒在Glatt GPCG-5/9流体床装置中,用wurster嵌件在约20℃至约25℃产品温度条件和2.0巴雾化空气压力下,依次地和独立地包覆以实例1的调释包衣(喷雾速度为约30g/分钟)和实例1的压片保护包衣(喷雾速度为约30g/分钟)。
基于颗粒和两个包衣层的总干燥重量,所得的包衣PHE颗粒含有约27重量%的调释第一包衣层(来自调释包衣)和约34重量%的第二包衣层(来自压片保护包衣)。在施加第二包衣层之前,基于包覆以第一包衣层的颗粒的总干燥重量,所得的PHE包衣颗粒含有约39重量%的第一包衣层。最终的包衣颗粒在进行共混和压制之前,先在50至60℃的烘箱中固化24小时。
实例3:含有去氧肾上腺素与调释包衣和压片保护包衣的评估用片剂
的生产
将含有77.8重量%对乙酰氨基酚(“APAP”)、在下表C显示的对乙酰氨基酚颗粒手工通过30目筛。通过将实例2的B部分中制备的去氧肾上腺素包衣颗粒与对乙酰氨基酚颗粒进行混合,产生出一公斤的共混物。
表C:片剂的组分
将对乙酰氨基酚颗粒和包衣的去氧肾上腺素按表C中所示的比例在V共混机中进行组合,并翻转混合5分钟。然后将共混物从共混机卸出,并在旋转式压片机上用0.7英寸(长)*0.3英寸(宽)的2通道锥形凹面改进型胶囊形片剂加工工具以60rpm进行压制,以产生具有987mg的重量和约20千克力的硬度范围的片剂。
实例4:仅具有调释包衣的药物活性剂包衣颗粒的制备
A部分:去氧肾上腺素层积的颗粒:首先如下制备层积的去氧肾上腺素颗粒:将1440g的盐酸去氧肾上腺素和150g的Eudragit NE30DTM(500g的30重量%含水分散液,用作粘合剂)溶解于1100g的纯化水中,同时用实验室混合器在50rpm下混合。用G1att GPCG-5/9的顶部喷雾嵌件,将这个混合物以40g/分钟和约35℃至约45℃产品温度喷雾到6560g的改性淀粉上。最终的层积颗粒含有17.7重量%去氧肾上腺素HCl(“PHE”)、80.5重量%改性淀粉和1.8重量%Eudragit NE30DTM。
B部分:仅具有调释包衣层的去氧肾上腺素包衣颗粒的制备:
将2000g根据以上A部分制备的去氧肾上腺素层积颗粒在Glatt GPCG-5/9流体床装置中,用wurster嵌件在约19℃至约21℃产品温度条件和2.0巴雾化空气压力下,独立地包覆以实例1的调释包衣(喷雾速度为约16g/分钟)。基于颗粒和包衣层的总干燥重量,所得的PHE包衣颗粒含有约35.9重量%的单个包衣层。
实例5:含有去氧肾上腺素与调释包衣层的评估用片剂的生产
将含有77.8重量%对乙酰氨基酚(“APAP”)、在下表D显示的对乙酰氨基酚颗粒手工通过30目筛。通过将仅制备有1层的去氧肾上腺素包衣颗粒(实例4的B部分中)进行混合,产生出一公斤的共混物。
表D:片剂的成分
将对乙酰氨基酚颗粒和包衣的去氧肾上腺素按表D中所示的比例在V共混机中进行组合,并翻转混合5分钟。然后将共混物从共混机卸出,并在旋转式压片机上用0.7英寸(长)*0.3英寸(宽)的2通道锥形凹面改进型胶囊形片剂加工工具以60rpm进行压制,以产生具有879mg的重量和约20千克力的硬度范围的片剂。
实例6:溶解数据的分析-在不同的溶解介质中进行的去氧肾上腺素溶 解试验:
A部分:去离子水溶解介质分析:将实例3中产生的片剂放入含有900mL的37℃去离子水的USP II型装置(桨式,50rpm)中。采用Program VK8000自动采样器在1、2、3、4、5、6、7和8小时从每个容器移取10mL,并通过高压液相色谱仪(HPLC)分析所采集的样品的PHE。
B部分:溶解分析:采用以下条件分析所采集的片剂溶解样品:Waters XTerra RP18,3.5μm,4.6×50mm柱,装备有设定在274nm的UV检测器的Waters HPLC,注射体积30μL,流速2.2mL/分钟,流动相为0.2重量%甲酸,用氢氧化铵调至pH 3.7。
实例2和3中制备的去氧肾上腺素包衣颗粒按相同方式进行采样以供溶解,例外的是在分析开始时称取各个剂量的去氧肾上腺素并喷洒到每个溶解槽中。用装备有设定在274nm的UV光纤光学探头的分光光度计分析颗粒样品的去氧肾上腺素浓度。分析所有片剂和颗粒样品的去氧肾上腺素和APAP数量,与在理论浓度下制备以达到100重量%活性剂释放的标准溶液进行比较。
将仅含有单一调释包衣的实例4颗粒压制成片剂(实例5)并分析溶解情况。表E中的数据证明,实例4的颗粒可提供去氧肾上腺素的调释(第1列)。但是,当将颗粒压制成片剂时去氧肾上腺素的这个释放速度被削弱(第2列),这由即使在60分钟时也缺乏缓释特性得到证实。
表E:去氧肾上腺素片剂和颗粒在去离子水中的溶解分析
240分钟 | 45 | 81 |
300分钟 | 52 | 81 |
360分钟 | 58 | 81 |
420分钟 | 64 | 81 |
480分钟 | 68 | 82 |
如表F中所示,所得的数据还显示具有调释包衣的颗粒显示出一定的所需调释缓释速度(第3列)。在添加压片保护包衣后,这个释放速度进一步降低(即减慢)(第2列)。但是,在压制成片剂后,压制片剂中的释放速度(第1列)出乎意料地与具有单一调释包衣的颗粒的释放速度近似(例如将第1列和第3列比较),这表明出乎意料的是,第二包衣在片剂压制步骤中充当屏障以保持第一包衣所显示的所需释放速度。
表F:去氧肾上腺素片剂和颗粒在去离子水中的溶解分析
应当了解,虽然已结合本发明的具体实施方式描述了本发明,但是前述描述旨在说明而非限制由随附权利要求书所限定的本发明的范围。其他方面、优点和修改均在权利要求书范围内。
Claims (20)
1.一种包含含有药物活性剂的颗粒的片剂,其中所述颗粒包覆有:
(a)包含调释聚合物的第一薄膜层;和
(b)包含(i)第一聚合物和(ii)第二聚合物的第二薄膜层,其中所述第一聚合物是丙烯酸乙酯和甲基丙烯酸甲酯的聚合物,其中所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的聚合物;
2.根据权利要求1所述的片剂,其中所述第一聚合物是丙烯酸乙酯、甲基丙烯酸甲酯共聚物2∶1。
3.根据权利要求1所述的片剂,其中所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸7∶3∶1。
4.根据权利要求2所述的片剂,其中所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸7∶3∶1。
5.根据权利要求1所述的片剂,其中所述第一聚合物与所述第二聚合物的重量比为约1∶3至约3∶1。
6.根据权利要求1所述的片剂,其中所述第一聚合物与所述第二聚合物的重量比为约1.5∶1至约2.5∶1。
7.根据权利要求1所述的片剂,其中所述第二薄膜层包含约45重量%至约75重量%的所述第一聚合物和约20重量%至约50重量%的所述第二聚合物。
8.根据权利要求1所述的片剂,其中所述第一薄膜层占颗粒的总重量的约10重量%至约60重量%。
9.根据权利要求1所述的片剂,其中所述第二薄膜层占颗粒的总重量的约20重量%至约50重量%。
10.根据权利要求1所述的片剂,其中在摄取时,所述片剂适于在所述摄取2小时内释放约25%至约40%的所述药物活性剂,在所述摄取4小时内释放约50%至约65%的所述药物活性剂,以及在所述摄取6小时内释放约70%至约80%的所述药物活性剂。
11.一种包含药物活性剂的颗粒,其中所述颗粒包覆有:
(b)包含调释聚合物的第一薄膜层;和
(b)包含(i)第一聚合物和(ii)第二聚合物的第二薄膜层,其中所述第一聚合物是丙烯酸乙酯和甲基丙烯酸甲酯的聚合物,其中所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的聚合物。
12.根据权利要求11所述的颗粒,其中所述颗粒的颗粒大小为约200微米至约600微米。
13.根据权利要求11所述的颗粒,其中所述第一聚合物是丙烯酸乙酯、甲基丙烯酸甲酯共聚物2∶1,所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸7∶3∶1。
14.根据权利要求11所述的颗粒,其中所述第一聚合物与所述第二聚合物的重量比为约1∶3至约3∶1。
15.根据权利要求11所述的颗粒,其中在摄取时,所述片剂适于在所述摄取2小时内释放约25%至约40%的所述药物活性剂,在所述摄取4小时内释放约50%至约65%的所述药物活性剂,和在所述摄取6小时内释放约70%至约80%的所述药物活性剂。
16.一种制备片剂的方法,包括以下步骤:i)施加第一薄膜层到活性颗粒,ii)施加第二薄膜层的第一聚合物和第二聚合物的含水分散液到包含第一薄膜层的包衣颗粒上,和iii)压制多个根据权利要求10所述的颗粒以形成所述片剂。
17.根据权利要求16所述的方法,其中所述方法包括将所述多个颗粒与多个包含第二药物活性剂的第二颗粒进行共混。
18.根据权利要求16所述的方法,其中所述颗粒的颗粒大小为约200微米至约600微米。
19.根据权利要求16所述的方法,其中所述第一聚合物是丙烯酸乙酯、甲基丙烯酸甲酯共聚物2∶1,所述第二聚合物是丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸7∶3∶1。
20.根据权利要求16所述的方法,其中所述第一聚合物与所述第二聚合物的重量比为约1∶3至约3∶1。
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-
2009
- 2009-06-24 CN CN2009801316719A patent/CN102119027A/zh active Pending
- 2009-06-24 CA CA2729015A patent/CA2729015A1/en not_active Abandoned
- 2009-06-24 US US12/490,465 patent/US8282957B2/en active Active
- 2009-06-24 BR BRPI0915411A patent/BRPI0915411A2/pt not_active IP Right Cessation
- 2009-06-24 EP EP09770901A patent/EP2309999A1/en not_active Withdrawn
- 2009-06-24 RU RU2011102777/15A patent/RU2011102777A/ru not_active Application Discontinuation
- 2009-06-24 WO PCT/US2009/048367 patent/WO2009158368A1/en active Application Filing
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110251478A (zh) * | 2019-05-15 | 2019-09-20 | 浙江维康药业股份有限公司 | 一种用于微滴丸的耐高温肠溶包衣工艺 |
CN110251478B (zh) * | 2019-05-15 | 2021-06-18 | 浙江维康药业股份有限公司 | 一种用于微滴丸的耐高温肠溶包衣工艺 |
Also Published As
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US20090324716A1 (en) | 2009-12-31 |
RU2011102777A (ru) | 2012-08-10 |
EP2309999A1 (en) | 2011-04-20 |
CA2729015A1 (en) | 2009-12-30 |
WO2009158368A1 (en) | 2009-12-30 |
US8282957B2 (en) | 2012-10-09 |
BRPI0915411A2 (pt) | 2015-11-03 |
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