CN1592610A - 改良的释放剂型 - Google Patents

改良的释放剂型 Download PDF

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CN1592610A
CN1592610A CNA028233476A CN02823347A CN1592610A CN 1592610 A CN1592610 A CN 1592610A CN A028233476 A CNA028233476 A CN A028233476A CN 02823347 A CN02823347 A CN 02823347A CN 1592610 A CN1592610 A CN 1592610A
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preparation
active component
substrate
granule
described preparation
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D·-Y·李
S·-P·李
H·S·索登
M·托马斯
D·怀恩
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Johnson and Johnson Consumer Inc
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McNeil PPC Inc
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Priority claimed from US09/966,939 external-priority patent/US6837696B2/en
Priority claimed from US09/966,509 external-priority patent/US6767200B2/en
Priority claimed from US09/967,414 external-priority patent/US6742646B2/en
Priority claimed from US09/966,450 external-priority patent/US6982094B2/en
Priority claimed from US09/966,497 external-priority patent/US7122143B2/en
Application filed by McNeil PPC Inc filed Critical McNeil PPC Inc
Publication of CN1592610A publication Critical patent/CN1592610A/zh
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Abstract

在一个实施方式中,制剂含有至少一种活性组分和一种模制基质,其中模制基质含有10-100%熔点约在100℃以下的材料,该材料选自以下物质:热塑性的聚环氧烷、低熔点的疏水性材料、热塑性的聚合物、热塑性的淀粉以及上述物质的混合物,其中基质能使制剂在接触到液体介质时改良地释放活性组分。制剂还可以包括未包被的颗粒,该颗粒至少含有一种活性组分。在另外的实施方式中,制剂含有至少一种活性组分、一组颗粒和一种模制基质,其中至少一部分颗粒是包被的。包被颗粒、基质或二者同时含有至少一种活性组分,包被颗粒、基质或二者都能使制剂在接触到液体介质时改良地释放活性组分。

Description

改良的释放剂型
发明背景
发明领域
本发明涉及控释剂型如控释药用组合物。进一步说,本发明涉及控释剂型,其中一种模制基质使制剂中的至少一种活性组分在制剂接触到液体介质时控制释放。
背景信息
控释药用制剂的应用历史很长,一般用于改善药物的传输以及增强病人的适应性,特别是可以通过减少患者每日的服药次数来达到上述目的。因此,就需要调节药物释放进入患者胃肠(g.i.)液的速度(特别是对于一种优选的活性组分来说),尤其是使药物缓慢释放以使药物在体内的作用时效延长。
口服的药用活性组分到达其作用位点的快慢取决于几个因素,其中包括药物在胃肠道粘膜内的吸收速率和范围。药物要被吸收进入循环系统(血液)就必须首先在胃肠液内溶解。对于多数药物来说,扩散通过胃肠道粘膜的速度要比溶解的速度快。在这种情况下,活性组分的溶解就是药物吸收的限速步骤,控制药物溶解的速度就可以控制药物吸收进入患者循环系统的速度。
控释制剂的一个重要目的就在于使药物相对于时间分布(药物动力学分布,PK)来说达到一个期望的血药浓度。一般来说,药物的PK分布是由药物吸收进入血液的速度及药物从血液中消除的速度决定的。PK分布的类型依赖于特定的活性组分及患者的生理状况。
对于许多药物来说比较理想的PK分布是一种血药浓度在一个相当长的时间内维持在一个相对恒定水平上的分布曲线(即药物吸收的速度与药物消除的速度基本相同)。这种给药系统有助于减少服药次数,增强病人的耐药性,还可以在保持完全疗效的情况下使药物的副作用降到最低。一种能达到“零级”释放或持续释放的药物剂型有助于达到此目的。由于真正的零级释放系统是很难实现的,因此通常用近似于持续释放速度如时间的一级分布或平方根分布的系统来使药物持续(延迟、延长或滞后)释放。
另外一种比较理想的PK分布是通过一种能延迟释放的剂型来达到,其中制剂在被患者消化后药物延迟一段预先设定的时间从制剂中释放出来。延迟期(延迟时间)后可以是一个活性组分的快速释放期(“延迟爆发”)或是一个活性组分的持续(延长、延伸或滞后)释放期(“延迟后持续”)。
剂型(或药物传输系统)以一种控制(持续、延长、延伸或滞后)的速率运输药物的已知机制包括扩散、浸蚀和渗透。
一种经典的扩散控制释放系统包括一个含活性组分的“储存库”,外面包裹一层“膜”,活性组分必须透过这个膜才能被吸收进入患者的血液系统。药物释放的速度(dM/dt)与膜的面积(A)、扩散路径的长度(l)、药物穿过膜的浓度梯度(C)、药物进入膜的分配系数(K)以及扩散系数(D)有关:
dM/dt={ADK C}/l
由于上面的一项或多项参数,特别是扩散路径长度和浓度梯度一般是非恒定的,因此扩散控制系统通常以非恒定速率释放药物。一般而言,药物从扩散控制释放系统中释放的速率符合一级动力学。膜储存库型释放系统的一个缺点是其容易破损造成药物的集中释放。扩散膜必须在制剂的整个功能生涯中保持完整,不出现裂缝,这样才能避免出现过量的药物释放而引发毒性效应。一种典型的扩散膜储存库系统包括一个作为储存库的压缩片剂核和一个包裹核的作为扩散膜的外壳(或包衣)。目前这种核一外壳系统的使用由于其制造方法及合适材料的缺乏而受到限制。具有控释特性的核或外壳一般是由传统方法制备的,例如在包被盘中喷雾包被。用喷雾盘包被只能制备一层包被核的简单外壳。在包被的过程中常常出现缺损,如“撤拉”、“粘结”和“孪生双片”,其结果造成意外的孔洞,导致药物大量泄漏。可以通过喷雾包被的组合物的应用因其粘滞度而受到限制。高粘滞度的溶液很难通过喷嘴泵出或喷出。喷雾包被的方法因耗时及高成本而受到进一步的限制。为了控制活性组分的释放需要用几个小时才能喷上有效量的包被物。花费8-24小时进行包被是很常见的。
另一类常见的扩散控制释放系统含有遍布于整个不溶性多孔基质中的活性组分,活性组分必须扩散透过这种基质才能被吸收进入患者的血液循环中。在一定时间内,药物(M)在沉陷条件下(即基质表面的药物浓度远远高于在总溶液中的浓度)释放的量与基质的面积(A)、扩散系数(D)、基质的空隙率(E)和弯曲度(T)、药物在溶解介质中的浓度(Cs)、时间(t)以及制剂中的药物浓度(Cp)有关:
M=A(DE/T(2Cp-ECs)(Cs)t)1/2
在上述关系式中值得注意的是药物释放的量一般与时间的平方根成正比。假如因子如基质的空隙率和弯曲度在一种剂型中是恒定的,药物的释放量应与时间的平方根成线性关系。一种典型的扩散基质系统可以通过将活性组分与可溶性和不溶性材料的混合物一起压缩而制备,预先设计使可溶性材料在溶解到液体介质或胃肠液中时产生预期的空隙率和弯曲度。
常用的浸蚀控制释放系统含有一种“基质”,药物分布于整个基质中。基质一般含有一种能在表面膨胀的材料,并且可以一层一层地慢慢溶解,在溶解时将药物释放。该系统中药物释放的速度(dM/dt)与基质浸蚀的速度(dx/dt)、基质中的浓度分布以及系统表面积(A)有关:
dM/dt=A{dx/dt}{f(C)}
另外,一个或多个条件发生变化,如表面积,通常会导致药物以非恒定速率释放。一般来说,药物从浸蚀控制释放系统释放的速度符合一级动力学。制备这种浸蚀基质系统的典型方法是通过将活性组分与可压缩赋形剂的混合物混合后压缩而制备的,可压缩赋形剂的混合物含有可在水中膨胀及浸蚀的材料,这种材料在膨胀时可以形成一个临时的屏障,只允许少量的活性组分释放,随着表面层的持续消失药物慢慢溶解到溶液中或胃肠液中。
另外一类浸蚀控制释放系统使用通过表面浸蚀慢慢膨胀和溶解的材料来使药用活性组分延迟释放。延迟释放可用于脉动或重复作用的给药系统,在此系统中有部分药物立即释放,经过有一个预定的迟滞期,随后又有药物从系统中释放出来。在这些系统中,迟滞期的长短(T1)依赖于可浸蚀层的厚度(h)和基质浸蚀的速度(dx/dt),后者又与基质成分的膨胀速度和可溶性有关:
T1=h(dx/dt)
在一定的时间内药物从这些系统中释放的累积量一般符合下列公式:
M=(dM/dt)(t-T1)
其中dM/dt一般如上面扩散控制或浸蚀控制公式中所描述的,T1代表迟滞时间。
通过压缩扩散基质或浸蚀基质制备控释制剂的例子见美国专利5,738,874号和6,294,200号,以及WO 99/51209号中的描述。压缩制剂由于很难达到所要的几何形状及难于找到合适的制造材料而受到限制。
WO 97/49384描述了一种由治疗化合物和高分子聚环氧乙烷组成的热熔解可塑性混合物。在某些实施方式中该制剂还包括聚乙二醇。所用的高分子聚环氧乙烷的分子量在约1,000,000~10,000,000道尔顿之间。高分子聚环氧乙烷与活性组分的最小比例为80∶20。这个文献中所描述的剂型所能运送的活性组分的量是受限的。所能运送的活性组分最大量不超过组合物重量的20%。经典的热熔解系统还受到高处理温度的限制,因此不适于运送低熔点的或低热稳定性的活性组分。另外,由于在通过挤压机或喷咀时的高处理温度和高剪切力,需要经典的热熔解系统不适于运送活性组分的包被颗粒。
我们希望找到一种通用的低成本的方法制备不易出现制剂突发崩解的控释基质系统。我们还希望该方法所制备的控释基质系统具有各种各样的形状,或者为了功能的目的,如通过某种特定的几何形状达到所期望的释放模式,或者为了便于患者服用,如利于吞咽、漂亮的外观、以及易于区别等。另外我们也希望这种控释基质系统所含有的基质是透明的或半透明的,这样便于患者看到其中所含有的各种形状的颗粒。这种控释基质系统最好能以相对较小的剂型运送相对较多的活性组分。我们还希望该系统能运送低熔点的或热稳定性差的活性组分。再有就是我们希望该系统能运送活性组分的包被颗粒。
本发明的目的之一就是提供一种剂型,该剂型至少含有一种活性组分在制剂与液体介质接触时具有控释特性。本领域的技术人员通过下面的详细描述可以很容易地理解本发明的其他目的、特征及优势。
发明概述
在一个实施方式中,本发明的制剂含有一种模制基质和至少一种活性组分。基质含有10-100%的熔点小于约100℃的材料,该材料选自下列一组:热塑性的聚环氧烷、低熔点的疏水性材料、热塑性的聚合物、热塑性的淀粉以及上述物质的混合物,该基质能使活性组分在制剂接触液体介质时控制释放。
在本发明的另外一个实施方式中,制剂含有一种模制基质和至少一种约占总重量20%以上的活性组分。基质含有10-100%的熔点小于约100℃的材料,该基质能使活性组分在制剂接触液体介质时控制释放。
在另外一个实施方式中,制剂含有一组颗粒,其中至少一部分颗粒含有至少一种活性组分。
在本发明的另外一个实施方式中,至少一部分颗粒被包衣包被,该包衣能使活性组分在制剂接触液体介质时控制释放。
在另外一个实施方式中,至少一部分颗粒被包衣包被,该包衣含有能使活性组分在制剂接触液体介质时控制释放的物质。
在另外一个实施方式中,至少一部分颗粒是用含释放控制聚合物的包衣包被的,该聚合物占总重量的10-100%,选自下列一组:pH依赖的聚合物、水溶性的聚合物、不溶于水的聚合物及上述物质的共聚物、衍生物和混合物。
在另外一个实施方式中,基质至少含有一种活性组分。
在另外一个实施方式中,制剂一旦接触到液体介质,至少有一部分活性组分以持续的方式释放。
在另外一个实施方式中,制剂以基本恒定的速率释放活性组分。
在另外一个实施方式中,制剂一旦接触到液体介质,在至少一部分活性组分释放前有一个时间迟滞。
在另外一个实施方式中,一部分活性组分在迟滞期后以持续的方式释放。
在另外一个实施方式中,制剂还含有一组颗粒和一种基质,该基质含有第一批活性组分。至少有一部分颗粒含有第二批活性组分,这批活性组分与第一批相同或不同。制剂接触到液体介质时,第一批活性组分立即释放,经过一个迟滞期后第二批活性组分释放。
在另外一个实施方式中,制剂还含有一组颗粒和一种基质,该基质含有第一批活性组分。至少有一部分颗粒含有第二批活性组分,这批活性组分与第一批相同或不同。制剂接触到液体介质时,第一批活性组分立即释放,然后第二批活性组分持续释放。
在另外一个实施方式中,制剂含有至少一种活性组分、一个模制基质和分散于基质中的一组颗粒,其中至少一部分颗粒是被包被的,制剂在接触到液体介质时能够控制释放活性组分。
在另外一个实施方式中,制剂在接触到液体介质时基质能使活性组分控制释放。
在另外一个实施方式中,制剂还含有至少一种分散于基质中的未包被的活性组分。
在另外一个实施方式中,至少一部分包被颗粒至少含有一种活性组分并被包衣包被,该包衣能使活性组分在制剂接触到液体介质时控制释放。
在另外一个实施方式中,至少一部分颗粒是用含释放控制聚合物的包衣包被的,该聚合物占总重量的10-100%,选自下列一组:pH依赖的聚合物、水溶性的聚合物、不溶于水的聚合物及上述物质的共聚物、衍生物和混合物。
在另外一个实施方式中,制剂一旦接触到液体介质,就至少有一部分活性组分以持续的方式释放。
在另外一个实施方式中,制剂以基本恒定的速率释放活性组分。
在另外一个实施方式中,制剂一旦接触到液体介质,在至少一部分活性组分释放前有一个时间迟滞。
在另外一个实施方式中,一部分活性组分在迟滞期后以持续的方式释放。
在另外一个实施方式中,制剂含有相同或不同的第一批和第二批活性组分。制剂接触到液体介质时,第一批活性组分以持续的方式释放,在第二批活性组分释放前经过一个迟滞期。
在另外一个实施方式中,基质含有分散于其中的第一批活性组分和至少一部分颗粒,该颗粒含有与第一批活性组分相同或不同的第二批活性组分。制剂接触到液体介质时,第一批活性组分立即释放,经过一个迟滞期后第二批活性组分释放。
在另外一个实施方式中,基质含有分散于其中的第一批活性组分和至少一部分颗粒,该颗粒含有与第一批活性组分相同或不同的第二批活性组分。制剂接触到液体介质时,第一批活性组分立即释放,然后第二批活性组分持续释放。
在另外一个实施方式中,热可逆载体选自下列物质:聚己内酯、聚乙酸乙烯酯、聚亚烷基二醇(polyalkylene glcol)、以及上述物质的混合物。
在另外一个实施方式中,热可逆载体选自下列物质:分子量约为100-20,000道尔顿的聚乙二醇、分子量约为100,000-900,000的聚环氧乙烷、以及上述物质的混合物。
在另外一个实施方式中,热可逆载体约占基质重量的30%-70%。
在另外一个实施方式中,模制基质还可以含有一种控制释放的可模制的赋形剂,包括可膨胀可浸蚀的亲水材料、pH依赖的聚合物、不溶性的可浸蚀材料、孔洞形成物以及上述物质的混合物。
在另外一个实施方式中,控制释放的赋形剂约占模制基质重量的1%-55%。
在另外一个实施方式中,控制释放的赋形剂是虫胶。
在另外一个实施方式中,模制基质还含有控制释放的赋形剂,该赋形剂是交联羟甲基纤维素钠。
在另外一个实施方式中,制剂中还含有作为可塑剂的柠檬酸三丁酯。
附图简要描述
图1A描述的是本发明的一个实施方式中剂型的截面侧视图。
图1B描述的是本发明的另外一个实施方式中剂型的截面侧视图。
图2描述的是实施例1的剂型中活性组分的%释放率与时间(小时)的关系。
本发明的详细描述
本文所用的术语“制剂”可以指任何固体、半固体或液体组合物,该组合物含有一种特定的预定量的某种组分,如下面所定义的活性组分。适宜的制剂可以是药用药物传输系统,包括通过口服给药、口腔给药、直肠给药、局部或粘膜给药、皮下植入的药物传输系统以及其他植入给药系统;或者是运送矿物质、维生素或其他营养物质、口服安慰剂等的组合物。本发明的优选剂型是固体的,但可以含有液体或半固体成分。在一个特别优选的实施方式中,制剂通过口服给药系统将药用活性组分运送到人的胃肠道中。
本发明的制剂具有控制释放制剂中一种或多种活性组分的能力。一种或多种活性组分可以包含在基质中,也可以包含在分布于基质中的包被或未包被的颗粒内。本文所用的术语“控释”适用于能以任何方式改变活性组分释放的制剂、基质、颗粒、包衣及其一部分或组合物。控释的类型包括控制的、延长的、持续的、延伸的、延迟的、脉动的、重复作用的等。达到各种类型控释的机制包括扩散、浸蚀、通过几何学原理控制表面积和/或不渗透的屏障,以及本领域所熟知的其他机制。另外,制剂的控释特性也可以通过基质或一部分基质的设计来达到,或者通过基质的设计与制剂的其他特征相结合而达到。
本发明的第一个实施方式描述于图1A中,显示的是制剂2的截面侧视图,该制剂含有模制基质4和一组未包被的颗粒6,颗粒包含在基质4内。在这个实施方式中,基质所含有的材料占基质重量的10-100%,其熔点约在100℃以下。基质、颗粒或二者内都可以含有活性组分或组分。基质可以使制剂在接触到水、胃肠液等液体介质时控制释放活性组分。在其他实施方式中,模制基质4可以含有非颗粒形式的活性组分。
本发明的另外一个实施方式描述于图1B中,显示的是制剂102的截面侧视图,该制剂含有模制基质104,基质内含有-组颗粒,其中至少有一部分颗粒是包被颗粒106。在这个特定的实施方式中,基质所包含的材料不需要是熔点在100℃以下的。基质、包被颗粒或二者内都可以含有一种或几种活性组分。颗粒的包衣、基质或者二者都可以使制剂在接触到水、胃肠液等液体介质时控制释放活性组分。
本发明制剂中所用的一种或几种活性组分可以包含在基质中,也可以包含在颗粒(包被的或未包被的)中,或者二者都包含活性组分。本发明所用的适宜活性组分包括药物、矿物质、维生素及其他营养物质、口服护理药物、食用香料以及上述物质的混合物。适宜的药物包括镇痛药、抗炎药、治疗关节炎的药物、麻醉药、抗组胺药、镇咳药、抗生素、抗感染药、抗病毒药、抗凝血剂、抗抑郁药、治疗糖尿病药物、止吐药、排气药、抗真菌药、抗惊厥药、食欲抑制剂、支气管扩张剂、心血管药、中枢神经系统药物、中枢神经系统激动剂、减充血剂、利尿剂、祛痰药、胃肠药、治疗偏头疼药、运动疾病药物、黏液溶解剂、肌肉松弛剂、口服避孕药、骨质疏松治疗药、多聚二甲硅氧烷、呼吸系统药物、催眠药、泌尿系统药物及上述药物的组合。
适宜的口腔护理剂包括呼吸清凉剂、洁齿剂、抗微生物药物、牙齿矿物质剂、牙齿腐蚀抑制剂、局麻药、粘膜保护剂等。
适宜的食用香料包括薄荷脑、薄荷、薄荷香料、水果香料、巧克力、香草、泡泡糖添加剂、咖啡添加剂、利口酒添加剂及上述物质的组合等。
适宜的胃肠道药物包括抑酸剂如碳酸钙、氢氧化镁、氧化镁、碳酸镁、氢氧化铝、碳酸氢钠、二羟化铝碳酸钠;刺激性泻剂如比沙可啶、鼠李皮、丹蒽醌、番泻叶、酚酞、芦荟、蓖麻油、蓖麻油酸、脱氢胆酸及上述物质混合物;H2受体拮抗剂如法莫替丁、雷尼替丁、西咪替丁、尼扎替丁;质子泵抑制剂如奥美拉唑或兰索拉唑;胃肠道细胞保护剂如sucraflate和米索前列醇;胃肠道动力药如prucalopride;抗幽门杆菌抗生素如克拉霉素、阿莫西林、四环素及甲硝唑;止泻药如苯乙哌啶和洛哌丁胺;溴环扁吡酯;止吐药如奥丹西隆;止痛药如氨基水杨酸。
在本发明的一个实施方式中,活性药物可选自比沙可啶、法莫替丁、雷尼替丁、西咪替丁、prucalopride、苯乙哌啶、洛哌丁胺、乳糖酶、氨基水杨酸、铋、抑酸剂、及其药用盐、酯、异构体或上述物质的混合物。
在另外一个实施方式中,活性组分选自止痛药、抗炎药和解热药,即非甾体类抗炎药(NSAIDS),包括丙酸衍生物如布洛芬、萘普生、酮洛芬等;醋酸衍生物如吲哚美辛、二氯芬酸、舒林酸、甲苯酰吡咯乙酸等;灭酸衍生物如mefanamic acid、甲氯灭酸、Flufenamic acid等;biphenylcarbodylic acid衍生物如二氟苯水杨酸、氟苯柳等;oxicams如吡罗昔康、舒多昔康、伊索昔康、美洛昔康等。在一个特别优选的实施方式中,活性组分选自丙酸衍生物NSAID,如布洛芬、萘普生、氟布洛芬、芬布芬、非诺洛芬、吲哚洛芬、酮洛芬、氟洛芬、吡洛芬、卡洛芬、oxaprozin、普拉洛芬、舒洛芬及其药用盐、衍生物或上述物质的混合物。在本发明的一个特定实施方式中,活性组分可选自对乙酰氨基酚、乙酰水杨酸、布洛芬、甲氧奈普酸、酮洛芬、氟布洛芬、二氯芬酸、环苯扎林、美洛昔康、rofecoxib、Celecoxib、及其药用盐、酯、异构体或上述物质的混合物。
在本发明的另外一个实施方式中,活性药物可选自伪麻黄碱、苯丙醇胺、扑尔敏、右美沙芬、苯海拉明、阿司咪唑、特非那定、fexofenadine、氯雷他定、desloratadine、西替立嗪、上述物质的混合物、及其药用盐、酯、异构体或其混合物。
适宜的聚二甲硅氧烷包括而不限于二甲聚硅氧烷和二甲硅油,这些在美国专利4,906,478,5,275,822和6,103,260号中有描述。本文所用的术语“二甲硅油”是指一类较宽范围的聚二甲硅氧烷,包括而不限于二甲硅油和二甲聚硅氧烷。
活性组分或组分是以有效治疗量包含在制剂中的,其所包含的量在口服后足以达到所期望的治疗效果,并且可以被本领域的技术人员迅速地确定。在确定其剂量时,如本领域所熟知的那样要考虑服用的特定活性组分、活性组分的生物利用度、给药方案、病人的年龄和体重以及其他需考虑的因素。在本发明的一个优选实施方式中,制剂含有一种或多种活性组分,该组分的含量超过约20%,即至少占制剂重量的约25%,或至少约30%,或至少约50%。
活性组分或成分可以任何形式存在于制剂中。例如,活性组分可以在分子水平分散开来,即熔化或溶解在制剂中,或者以颗粒的形式存在,因而可以是包被的,也可以是不包被的。如果活性组分以颗粒形式存在,典型颗粒(包被或未包被)的平均粒径约为1-2000微米。在一个优选实施方式中,这些颗粒是平均粒径为约1-300微米的晶体。在另外一个优选实施方式中,这些颗粒是平均粒径为约50-2000微米的粒子或小球,较好的是约50-1000微米,最好的是100-800微米。
本发明的模制基质是通过模制而成的,尤其是通过无溶剂的模制过程。在一个优选实施方式中,基质含有可流动材料。可流动材料可以是任何可食用材料,该材料在约37℃到约250℃之间是可流动的,而在约-10℃到80℃之间是固体、半固体或凝胶状的。在一个优选实施方式中,可流动材料含10-100%的熔点在约100℃以下的热可逆载体,优选熔点在约20℃到100℃之间的;可流动材料内还可以选择地添加最高达30%的各种佐剂,如本领域熟知的可塑剂、凝胶剂、显色剂、稳定剂、防腐剂等。基质内还可以含有高达约55%的一种或多种上述释放控制赋形剂。
在本发明的一个实施方式中,基质内含有10-100%的熔点在约100℃以下的热可逆载体,这种低熔点的材料包括热塑性的聚环氧烷、低熔点的疏水性材料、热塑性的聚合物、热塑性的淀粉等。优选的低熔点材料是热塑性的聚合物、热塑性的聚环氧烷、低熔点的疏水性材料、以及上述物质的组合。
适宜制备模制基质的热可逆载体包括熔点低于110℃的热塑性材料,较好的是熔点在约20℃到约100℃之间的热塑性材料。适宜无溶剂模制的热可逆载体包括热塑性的聚亚烷基二醇、热塑性的聚环氧烷、低熔点的疏水性材料、热塑性的聚合物、热塑性的淀粉等。优选的热可逆载体包括聚乙二醇和聚环氧乙烷。适宜作为热可逆载体的热塑性聚亚烷基二醇包括分子量在约100到约20000道尔顿之间的聚乙二醇,如约100到8000道尔顿之间、或者说1000到8000道尔顿之间。适宜的热塑性聚环氧烷(polyalkalene oxide)包括分子量在约100000到900000道尔顿之间的聚环氧乙烷。适宜作为热可逆载体的低熔点疏水性材料包括脂肪、脂肪酸酯、磷脂、以及室温下为固体的蜡、含脂混合物如巧克力等。适宜的脂肪包括氢化的植物油如可可脂、氢化的棕榈仁油、氢化的棉花子油、氢化的葵花子油以及氢化的大豆油;以及游离脂肪酸及其盐。适宜的脂肪酸酯包括蔗糖脂肪酸酯、单甘油酯、甘油二酯、甘油三酯、山萮酸甘油酯,棕榈酸硬脂酸甘油酯、甘油单硬脂酸酯、甘油三硬脂酸酯、甘油三月桂酸酯、肉豆蔻酸甘油酯,GlycoWax-932,lauroyl macrogol-32 glycerides,andstearoyl macrogol-32 glycerides。适宜的磷脂包括磷脂酰胆碱、phosphotidyl serene、phosphotidyl enositol及磷脂酸。室温下为固体的适宜蜡包括巴西棕榈蜡、鲸腊、蜂蜡、小烛树蜡、虫胶蜡、微晶体蜡以及石蜡。
在一个优选实施方式中,基质所含有的低熔点热可逆载体选自聚己酸内酯、聚乙酸乙烯酯、聚亚烷基二醇以及上述物质的组合物,所占的比率约为基质重量的30%-70%之间,如约35%到50%之间。低熔点热可逆聚合物的熔点约在100℃以下。在一个这种实施方式中,基质还含有能使基质加固的聚合物如热塑性的聚环氧乙烷,其所占的重量比约在15%到25%之间。用于本发明的具有合适热塑性的聚环氧乙烷分子量约在100000到900000之间。在另外一个这种实施方式中,基质基本不含聚环氧乙烷,就是说所含有的聚环氧乙烷重量比小于1%或0.1%。
在本发明的另外一个实施方式中,基质所含有的热可逆载体不需要是熔点在100℃以下的,基质组合物可以包含任何熔点在100℃以下的材料,基质内还可以含有本领域所熟知的其他材料,如释放控制剂、各种佐剂如可塑剂、凝胶剂、显色剂、稳定剂、防腐剂等。
适于通过模塑制备模制基质或部分模制基质的释放控制可模塑赋形剂包括而不限于可膨胀可腐蚀的亲水材料、pH依赖的聚合物、不溶性的可食用材料以及孔洞形成物。
适于通过模塑制备模制基质或部分模制基质的作为释放控制赋形剂的可膨胀可腐蚀亲水材料包括水溶性的纤维素衍生物,如羧甲纤维素钠、交联的羟丙纤维素、羟丙纤维素、羟丙甲基纤维素、羟异丙基纤维素、羟丁基纤维素、羟苯纤维素、羟乙基纤维素、羟戊基纤维素、羟丙基乙基纤维素、羟丙基丁基纤维素、羟丙基乙基纤维素聚乙二醇、聚环氧乙烷、甲基丙烯酸钾二乙烯基苯共聚物、聚甲基丙烯酸甲酯、CARBOPOL(高分子量的交联丙烯酸均聚物或共聚物)等;水状胶体如藻酸盐、琼脂、瓜耳胶、洋槐豆树胶、卡帕角叉菜胶、约塔角叉菜胶、剌去实胶、阿拉伯树胶、黄蓍胶、果胶、黄原胶、胶凝糖、糊精-麦芽糖复合剂、半乳甘露聚糖、石脐素、昆布多糖、硬葡聚糖、阿拉伯树胶、菊糖、果胶、明胶、whelan、rhamsan、zooglan、methylan、几丁质、环糊精、壳聚糖、黏土、凝胶淀粉如酸解淀粉及其衍生物,以及上述物质的混合物;交联的聚乙烯吡咯烷酮、交联的琼脂、淀粉甘醇酸钠及交联羟甲基纤维素钠。
适于通过模塑制备模制基质或部分模制基质的作为释放控制赋形剂的pH依赖聚合物包括羟丙基甲基纤维素苯二甲酸酯、羟丙基甲基纤维素乙酸盐琥珀酸酯、醋酞纤维素、虫胶、肠溶性的乙酸酯衍生物如聚醋酸乙烯酯苯二甲酸酯、以及肠溶性的丙烯酸衍生物如聚甲基丙烯酸酯来源的聚合物,如聚(2-甲基丙烯酸,甲基丙烯酸甲酯)1∶2,该物质可从Rohm Pharma GmbH购买,商品名为EUDRAGITS聚合物,以及聚(2-甲基丙烯酸,甲基丙烯酸甲酯)1∶1,该物质可从Rohm Pharma GmbH购买,商品名为EUDRAGITL聚合物。
适于通过模制制备模制基质或部分模制基质的作为释放控制赋形剂的不溶性的可食用材料包括丙烯酸酯、丙烯酸共聚物、醋酸纤维素、醋酸丙酸纤维素、丙酸纤维素、醋酸丁酸纤维素、醋酞纤维素、乙醛乙酸二甲基纤维素、醋酸纤维素氨基甲酸乙酯、醋酸纤维素氨基甲酸甲酯、醋酸纤维素二乙基氨基乙酸酯、乙基纤维素、甲基丙烯酸酯、聚乙烯醇、聚乙酸乙烯酯、聚己酸内酯等;脂肪如可可脂、氢化的植物油如棕榈仁油、棉花子油、葵花子油和豆油、单甘油酯、甘油二酯、甘油三酯、磷脂、长链脂肪酸、脂肪酸酯;蜡如巴西棕榈蜡、鲸蜡、蜂蜡、小烛树蜡、虫胶、微晶体蜡以及石蜡。
适于通过模塑制备模塑基质或部分模塑基质的作为释放控制赋形剂的孔洞形成物包括水溶性的有机和无机材料。适宜的水溶性有机材料包括水溶性的聚合物,如水溶性的纤维素衍生物包括羟丙基甲基纤维素、羟丙基纤维素;水溶性的碳水化合物如糖、淀粉;水溶性的聚合物如聚乙烯吡咯烷酮、聚乙二醇;微晶体纤维素;盐如氯化钠、氯化钾等,以及上述物质的混合物。
适于通过模塑制备模制基质或部分模制基质的可塑剂包括三醋汀、乙酰化的单甘油酯、菜籽油、橄榄油、芝麻油、乙酰柠檬酸三丁酯、甘油山梨醇、草酸二乙酯、苹果酸二乙酯、富马酸二乙酯、丁二酸二丁酯、丙二酸二乙酯、邻苯二甲酸二辛酯、丁二酸二丁酯、柠檬酸三乙酯、柠檬酸三丁酯、甘油三丁酸酯、丙二醇、聚乙二醇、氢化的蓖麻油、脂肪酸、取代的甘油三酯以及甘油酯等。
基质可以有不同的形状。例如,基质可以是多角体如正方体、锥体、棱柱体等;或者是具有非平面的空间结构的几何体,如圆锥体、截断的圆锥体、圆柱体、球体、园环体等。在某些实施方式中,基质有一个或多个主要面。例如在某些特定实施方式中,基质具有与模子上下表面接触而形成的两个相对的主面。在此实施方式中,基质表面的两个主面之间还可以有一个环形带,是由模子的侧壁挤压形成的。
在本发明的一个实施方式中,基质是用热设定成型方法和设备制备的,见美国专利申请09/966,450号第57-63页的详细描述,本文已纳入作为参考。在这个实施方式中,核是通过将可流动形式的起始材料注入模腔中形成的。起始材料优选含有活性组分的,热设定材料的温度优选在其熔点温度之上但在活性组分的降解温度之下的温度。起始材料在模腔中被冷却固化成为成型的核(即具有模制形状的核)。
根据本方法,起始材料必须是可流动的。例如可以含有悬浮于熔化的基质如聚合物基质的固体颗粒。起始材料应该是完全熔化的或是浆糊的形式。起始材料可以含有溶于熔化材料中的活性组分。另外,起始材料可以通过将固体溶于溶剂中制备,该溶剂在材料成型后可以被蒸发掉。
起始材料可以含有任何期望掺入到成形产物中的可食用材料,包括活性组分、营养物质、维生素、矿物质、香料、甜料等。起始材料优选包含一种活性组分和一种热设定材料。热设定材料可以是任何可食用材料,该材料在约37-120℃之间是可流动的,在约0-35℃之间是固体。优选的热设定材料包括水溶性的聚合物如聚亚烷基二醇、聚环氧乙烷及其衍生物、蔗糖酯;脂肪类物质如可可脂、氢化植物油如棕榈仁油、棉花子油、葵花子油和大豆油;单酸甘油酯、甘油二酯及甘油三酯、磷酸酯,蜡类如巴西棕榈蜡、鲸蜡、蜂蜡、小烛树蜡、虫胶、微晶体蜡及石蜡;含脂混合物如巧克力;无定型玻璃状的糖如制作硬糖果的糖、过饱和糖溶液如用于制作软糖的糖溶液;低水分的聚合物溶液如水分含量达到约30%的凝胶和其他水状胶体混合物,例如制作粘性甜食的那些物质。在一个特别优选的实施方式中,热设定材料是一种水溶性聚合物如聚乙二醇。
在另外一个实施方式中,基质是用热循环模塑方法和设备制备,见美国专利申请09/966,497号第27-51页的详细描述,本文已纳入作为参考。在美国专利申请09/966,497号描述的热循环模塑方法和设备中,具有图3所示的通用结构的热循环模塑模具被使用。热循环模塑模具200包含一个转头202,在其周围有一组模塑单元204。热循环模塑模具包括一个储存槽206(见图4),用于包裹可流动材料并使其成为基质。另外,热循环模塑模具还含有一个温度控制系统用于快速地加热和冷却模塑单元。图55和图56就描述了这样一个温度控制系统600。
如果基质中包含颗粒,颗粒(包被或未包被)的平均粒径一般约为1-2000微米。在一个优选实施方式中,这些颗粒是平均粒径为约1-300微米的活性组分或组分的晶体。在另外一个优选实施方式中,这些颗粒是平均粒径为约50-2000微米的粒子或小球,较好的是约50-1000微米,最好的是100-800微米。
在本发明的一个特定实施方式中,颗粒是未包被的,含有本文所描述的活性组分,或者为了使制剂的外观易于区别的无活性颗粒。
在一个特定实施方式中,基质材料是透明的或半透明的。在这样的实施方式中,不论是包被的颗粒或是未包被的颗粒,不论是含活性组分的还是不含活性组分的,都可以从制剂的外面看到。
在本发明的一个特定实施方式中所使用的颗粒是包被的,颗粒如本文所描述的那样其包衣是比重为10-100%的膜形成物(以包衣的重量计),还可以选择性地添加占包衣重量最高约50%的孔洞形成物以及最高约30%的各种佐剂或赋形剂如可塑剂等。颗粒可以用本领域技术人员所熟知的常规技术包被,包括微包囊技术如凝聚法、喷雾干燥法及液化床包衣法包括正切喷雾转子包衣法和底部喷雾混悬包衣法。合适的颗粒包衣方法和材料在美国专利5,286,497、4,863,742、4,173,626、4,980,170、4,984,240、5,912,013、6,270,805和6,322,819号中有描述。在某些实施方式中,这种包被颗粒可以使其内含的活性组分控制释放。
适宜作颗粒包衣的膜形成物包括而不限于成膜水溶性聚合物、成膜蛋白、成膜不溶性聚合物以及成膜pH依赖的聚合物。在一个实施方式中,作为颗粒包衣的膜形成物选自醋酸纤维素、B型氨溶的甲基丙烯酸酯共聚物、虫胶、羟丙基甲基纤维素、聚环氧乙烷以及上述物质的组合。
适宜作颗粒包衣的成膜水溶性聚合物包括水溶性的乙烯基聚合物如聚乙烯醇;水溶性的聚碳水化合物如羟丙基淀粉、羟乙基淀粉、支链淀粉、甲乙基淀粉、羧甲基淀粉、预先制成胶状的淀粉以及成膜修饰淀粉;水膨胀纤维素衍生物如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、甲基纤维素(MC)、羟乙基甲基纤维素(HEMC)、羟丁基甲基纤维素(HBMC)、羟乙基乙基纤维素(HEEC)以及羟乙基羟丙基甲基纤维素(HEMPMC);水溶性的共聚物如2-甲基丙烯酸和甲基丙烯酸酯的共聚物、聚乙烯醇和聚乙二醇的共聚物、聚环氧乙烷和聚乙烯吡咯烷酮的共聚物;上述物质的衍生物及混合物。
适宜的成膜蛋白质可以是天然的,也可以是经化学修饰的,包括明胶、乳清蛋白、肌纤维蛋白、可凝结的蛋白如白蛋白、酪蛋白、酪蛋白盐和酪蛋白分离物、大豆蛋白和大豆蛋白分离物、玉米素;以及上述物质的聚合物、衍生物及混合物。
在颗粒包衣具有使其中的一种或多种活性组分控制释放功能的实施方式中,适宜的膜形成物选自成膜不溶性聚合物、成膜pH依赖的聚合物、及其共聚物和混合物。在这种颗粒包衣作为扩散膜的特定实施方式中,具有控制释放作用的颗粒包衣优选含有孔洞形成物的。
适用于控释颗粒包衣的成膜不溶性聚合物包括乙基纤维素、聚乙烯醇、聚乙酸乙烯酯、聚己酸内酯、醋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、以及上述物质的衍生物、共聚物和混合物。
适用于释放控制颗粒包衣的pH依赖聚合物包括肠溶性纤维素衍生物如苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、醋酞纤维素;天然树脂如虫胶和玉米素;肠溶性乙酸盐衍生物如聚醋酸乙烯酯苯二甲酸酯、醋酞纤维素、乙醛二甲基纤维素乙酸酯;以及肠溶性的丙烯酸衍生物如聚甲基丙烯酸酯来源的聚合物,如聚(2-甲基丙烯酸,甲基丙烯酸甲酯)1∶2,该物质可从Rohm Pharma GmbH购买,商品名为EUDRAGITS聚合物,以及聚(2-甲基丙烯酸,甲基丙烯酸甲酯)1∶1,该物质可从Rohm Pharma GmbH购买,商品名为EUDRAGITL聚合物。
适用于释放控制颗粒包衣的孔洞形成物包括水溶性的有机和无机材料。在一个实施方式中,孔洞形成物选自羟丙基纤维素和羟丙基甲基纤维素。适宜的水溶性有机材料包括水溶性的纤维素衍生物如羟丙基甲基纤维素和羟丙基纤维素;水溶性的碳水化合物如糖、淀粉;水溶性的聚合物如聚乙烯吡咯烷酮和聚乙二醇;不溶性的膨胀聚合物如微晶体纤维素。适宜的水溶性无机材料包括盐如氯化钠和氯化钾和/或其混合物。
适宜作颗粒包衣的佐剂或赋形剂包括可塑剂、去粘性剂、保湿剂、表面活性剂、除泡剂、显色剂、造影剂等。适宜的增塑剂包括而不限于聚乙二醇;丙二醇;甘油;山梨醇;柠檬酸三乙酯;柠檬酸三丁酯;葵二酸二丁酯;植物油如蓖麻油、菜籽油、橄榄油和芝麻油;表面活性剂如土温85、十二烷基硫酸钠和十六烷基磺基丁二酸钠;单乙酸甘油;甘油二酯;甘油三酯;天然树胶;三醋汀;乙酰柠檬酸三丁酯;草酸二乙酯;苹果酸二乙酯;富马酸二乙酯;丙二酸二乙酯;邻苯二甲酸二辛酯;丁二酸二丁酯;甘油三丁酸酯;氢化的蓖麻油;脂肪酸;取代的甘油三酯和甘油酯;和/或上述物质的混合物。在一个实施方式中,增塑剂是柠檬酸三乙酯。在某些实施方式中,外壳基本不含增塑剂,即所含的增塑剂少于约1%或0.01%。
在本发明的某些特别优选实施方式中,制剂以持续的、延伸的、延长的或滞后的方式释放其中的一种或多种活性组分,较好的是当制剂接触到液体介质时以基本恒定的速率释放活性介质。在这种实施方式中,模制基质是作为扩散基质或浸蚀基质而发挥功能的。在模制基质作为浸蚀基质的实施方式中,活性组分以持续的、延伸的、延长的或滞后的方式释放使活性组分从中扩散出来,模制基质优选含有可模塑释放控制赋形剂的,如可膨胀可浸蚀的亲水材料、pH依赖的聚合物、不溶性的可食用材料以及上述物质的组合。在模制基质作为扩散基质的实施方式中,活性组分以持续的、延伸的、延长的或滞后的方式释放使活性组分从中扩散出来,模制基质优选含有可模塑释放控制赋形剂的,如不溶性的可食用材料和孔洞形成物的混合物。另外在用无溶剂模塑过程制备基质的实施方式中,热可逆载体可以通过溶解并形成孔洞或通道使活性组分释放出来。
在本发明的某些其他优选实施方式中,制剂以持续的、延伸的、延长的或滞后的方式释放其中的至少第一批和第二批活性组分。在这种实施方式中,第一批活性组分和第二批活性组分具有不同的未修饰的释放特征,但是制剂赋予了第一批活性组分和第二批活性组分不同类型的修饰从而使二者从制剂中溶解的特征是一致的。在另外某些实施方式中,制剂赋予了第一批活性组分和第二批活性组分不同类型的修饰从而使二者从制剂中溶解的特征不一致,即在制剂接触到液体介质时第一批活性组分和第二批活性组分以不同的速率或不同的时间从制剂中释放出来。在一个特别优选的实施方式中,制剂接触到液体介质时第一批活性组分和第二批活性组分都以基本恒定的速率从制剂中释放。
在本发明的其他特定实施方式中,制剂一旦接触到液体介质,在一种或多种活性组分的至少一部分释放之前有一个时间延迟,随后延迟释放的活性组分以持续的方式释放出来。在这种实施方式中,时间延迟是由于模制基质的全部或部分溶解,随后的持续释放是由于活性组分颗粒的一层或多层包衣溶解。在这种实施方式中,模制基质优选含有释放控制赋形剂的,如pH依赖的聚合物。在此实施方式中,颗粒包衣优选含有控制释放赋形剂的,如孔洞形成物和不溶性可食用材料的混合物;可膨胀可浸蚀的亲水材料;pH依赖的聚合物;以及上述物质的混合物。
在本发明的另外一个特定实施方式中,制剂含有相同或不同的第一批活性组分和第二批活性组分,当制剂接触到液体介质时第一批活性组分持续释放,然后第二批活性组分持续释放。在这种实施方式中,第一批活性组分的持续释放是由模制基质的全部或部分控制溶解造成的,第二批活性组分的持续释放是由活性组分颗粒的一层或多层包衣溶解造成的。在此实施方式中,模制基质优选含有释放控制赋形剂的,如可膨胀可食用的亲水材料、pH依赖的聚合物、不溶性的可食用材料以及上述物质的组合物。在此实施方式中,颗粒包衣优选含有控制释放赋形剂的,如孔洞形成物和不溶性可食用材料的混合物;可膨胀可浸蚀的亲水材料;pH依赖的聚合物;以及上述物质的混合物。
在本发明的其他特别优选实施方式中,基质含有第一批活性组分,基质内的颗粒含有与第一批相同或不同的第二批活性组分,制剂一旦接触到液体介质第一批活性组分立即释放,经过一个迟滞期后,第二批活性组分延迟释放。在这种实施方式中,基质优选含有能在胃肠液中快速溶解的材料。例如立即释放的外壳部分可以含有易于溶于水的材料,如水溶性的或水膨胀性的热塑膜形成物、水溶性的或水膨胀性的增稠剂及非结晶性的碳水化合物。在这种特定的实施方式中,适宜的水溶性的或水膨胀性的热塑膜形成物可选自可膨胀的纤维素衍生物、热塑性的淀粉、聚亚烷基二醇、聚环氧乙烷、无定型的糖玻璃以及上述物质的混合物。在其他这种实施方式中,适宜的膜形成物可选自成膜水溶性的聚合物如水溶性的乙烯基聚合物、水溶性的多聚碳水化合物、水膨胀性的纤维素衍生物、水溶性的共聚物、膜形成蛋白以及上述物质的混合物。在其他这种实施方式中,适宜的增稠剂可选自凝胶聚合物或水状胶体、凝胶状淀粉、可结晶的碳水化合物以及上述物质的混合物。在其他这种实施方式中,适宜的非结晶性碳水化合物可选白多聚葡萄糖、淀粉水解物、非结晶性的糖醇、以及上述物质的混合物。在这种实施方式中,立即释放的基质优先释放延迟释放活性组分的包被颗粒,该释放是通过在30分钟、900ml水、0.1N盐酸或磷酸缓冲液、37℃用USP2型(浆板法)50-100rpm搅拌使其裂解或溶解而完成的。在这些实施方式中,时间延迟期是由含第二批活性组分的颗粒包衣提供的。优选的延迟释放颗粒包衣含有的释放控制赋形剂选自可膨胀可食用的亲水材料、pH依赖的聚合物及其混合物。
在本发明的另一个特别优选实施方式中,基质含有第一批活性组分,基质内的颗粒含有与第一批相同或不同的第二批活性组分,制剂一旦接触到液体介质第一批活性组分立即释放,然后第二批活性组分持续释放。在这种实施方式中,基质优选含有能在胃肠液中快速溶解的材料。例如立即释放的外壳部分可以含有易于溶于水的材料,如水溶性的或水膨胀性的热塑膜形成物、水溶性的或水膨胀性的增稠剂、结晶性的及非结晶性的碳水化合物。在这种特定的实施方式中,适宜的水溶性的或水膨胀性的热塑膜形成物可选自可膨胀的纤维素衍生物、热塑性的淀粉、聚亚烷基二醇、聚环氧烷、无定型的糖玻璃以及上述物质的混合物。在其他这种实施方式中,适宜的膜形成物可选自成膜水溶性的聚合物如水溶性的乙烯基聚合物、水溶性的聚碳水化合物、水膨胀性的纤维素衍生物、水溶性的共聚物、膜形成蛋白以及上述物质的混合物。在其他这种实施方式中,适宜的增稠剂可选自凝胶聚合物或水状胶体、凝胶状淀粉、可结晶的碳水化合物。在其他这种实施方式中,适宜的非结晶性碳水化合物可选自多聚葡萄糖、淀粉水解物、非结晶性的糖醇。在这种实施方式中,立即释放的基质优先释放延迟释放活性组分的包被颗粒,该释放是通过在30分钟、900ml水、0.1N盐酸或磷酸缓冲液、37℃用USP2型(浆板法)50-100rpm搅拌使其裂解或溶解而完成的。在这些实施方式中,持续释放是由含第二批活性组分的颗粒包衣提供的。优选的持续释放颗粒包衣含有的释放控制赋形剂选自孔洞形成物和不溶性可食用材料的混合物、可膨胀可食用的亲水材料、pH依赖的聚合物。
本发明的优选模制基质是按照本文所描述的方法通过将可流动材料经过一个室口注入模具腔隙内,然后使可流动材料固化而形成的。在一个制剂内含有颗粒的这种实施方式中,室口的直径大于颗粒的直径,即约1000-4000毫米,或者说约2000-3000毫米。在这种特定实施方式中,颗粒是以溶于基质材料中的可流动混悬液的形式进入模具腔隙中的。可流动的混悬液在压力下通过室口被挤入腔隙内。在一个实施方式中,模塑组件包括一个弹性体塞子型阀门,在其关闭时颗粒无法进入模具腔隙。
本方法的优点是提供了一种通用的低成本的制备本发明控释模制基质系统的过程。本发明的方法还具有如下优点:在相对较低的温度下处理从而可以使低熔点的、热稳定的活性组分及包被颗粒添加到模制基质中。本发明的方法和材料结合起来有一个优点:可以使相对较大量的活性组分掺入到模制基质中;可以制备出透明或半透明基质的具有独特优雅外观的制剂。
下面的实施例用于解释本发明,但这些实施例并不意味着以任何方式对本发明作出限制。
本发明含有模制基质的制剂是用下面表A所列的组分制备的:
表A
片剂   商品名 厂商   重量    毫克/片
异博定盐酸盐E.R.片   Verelan PM300mg胶囊 SchwarzPharma,Inc.,Gainesville,GA   17.0    77
聚乙二醇3350   Carbowax UnionCarbideCorporation,Danbury,CT   42.0    190
虫胶粉   正规漂白的虫胶 Mantrose-Haeuser Company,Atteboro,MA   10.0    45
交联羟甲基纤维素   Ac-Di-Sol FMC Corporation,Newark,DE   21.0    95
伪麻黄碱盐酸盐结晶 BASF PharmaChemikalien GmbH& Co.,Ludwigshafen/Rhein   10.0    45
将一个烧杯浸入水浴锅(Ret digi-visc;Antal-Direct,Wayne,PA)中,水温设定在70℃。将聚乙二醇(PEG)3350加入到烧杯中,用一把药刀搅拌混合直到所有的PEG熔化。将虫胶粉用#40目网状筛子过筛后加入到熔化的PEG中混合直到所有的粉末都分散开来。加入交联羟甲基纤维素钠,将所有的组分再混合2分钟。然后加入伪麻黄碱盐酸盐再混合2分钟。加入从VERELAN PM 300mg胶囊中取出的异博定盐酸E.R.丸,再混合5分钟。取410-500mg熔化的混合物加入到一个圆凹形的下位冲头和冲模单元(直径0.5000英寸)中,人工用上位的冲头使其结合以制成一个模制片剂。将模制片剂从冲模中弹出。
图2描述的是实施例1的制剂和其他制剂中活性组分%释放率与时间(小时)的关系。更具体地说,这个图中所展示的是本发明两种不同类型活性组分的溶解速率与两种商品溶解速率的比较。曲线(a)表示的是异博定盐酸从本发明的异博定盐酸片剂中持续释放的速率。曲线(b)来源于商品化的Verelan PM 300mg胶囊(含异博定盐酸)的持续释放剂型。曲线(c)表示的是伪麻黄碱盐酸盐从本发明的基质中释放出来的速率。曲线(d)来自于商品化的Sudafed片剂(含伪麻黄碱盐酸盐)的即刻释放剂型。所有的曲线都是用下面的溶解分析方法测得的:USP II型装置(桨板,50RPM),pH=7.2的磷酸缓冲液,37℃。分别检测0.5,1,2,4,8,12,16,20,24小时样品中的伪麻黄碱盐酸盐和异博定盐酸。用一个标准对比分析溶解样品中的伪麻黄碱盐酸盐和异博定盐酸,该标准是指每种化合物假定100%释放时的理论浓度。样品是用配备Waters717自动进样器和Waters486紫外检测仪的HPLC分析的,检测波长为214nm,流动相是用55%的乙腈和45%18mM的磷酸钾缓冲液制备的。在一轮约8分钟的时间内上样量为50L,泵流速为2.0mL/min。所用的柱子为Zorbax300-SCX(4.6mm×25cm)。
实施例2
本发明的制剂形式,包含模制基质,该模制基质含有上述表A中所列的组分,该制剂是用美国专利申请09/966,497号27-51页所描述的热循环模塑模具以连续的过程制备的。组分按实施例1所描述的方法制备并以流动的形式提供给热循环成型基质。
热循环成型模具具有美国专利申请09/966,497号图3和27-51页所描述的通用结构,其描述的热循环成型模具200包含一个转头202,在其周围有一组塑模单元204。热循环成型模具包括一个储存槽206(见图4),用于贮放可流动材料。另外,热循环成型模具还含有一个温度控制系统用于快速地加热和冷却塑模单元。美国专利申请09/966,497号的图55和图56就描述了这样一个温度控制系统600。
热循环成型模具具有美国专利申请09/966,497号图26A所描述的特定结构。热循环成型模具包括中心塑模组件212和上位塑模组件214,如图26C所描述,二者相配共同形成塑模腔隙。转子202旋转时,对面的中心塑模组件及上位塑模组件闭合。制备基质的可流动材料在储存槽中被加热成可流动的状态,然后被注入到形成的腔隙中。可流动材料的温度下降,使可流动材料硬化成基质。然后模塑组件打开并将基质弹出。
尽管已经用特定的实施方式对本发明作了阐述,但显然本领域的技术人员可以在本发明的范围内对本发明作各种改变和修正。

Claims (37)

1.一种含有模制基质和至少一种活性组分的制剂,其中基质含有10-100%的熔点小于约100℃的热可逆载体,该载体选自下列物质:热塑性的聚环氧烷、低熔点的疏水性材料、热塑性的聚合物、热塑性的淀粉以及上述物质的混合物,该基质能使活性组分在制剂接触液体介质时进行改良的释放。
2.一种含有模制基质和至少一种约占总重量20%以上的活性组分的制剂,其中基质含有10-100%的熔点小于约100℃的材料,该基质能使活性组分在制剂接触液体介质时进行改良的释放。
3.权利要求1或2所述的制剂,其特征在于,基质含有能提供使活性组分在制剂接触液体介质时行改良的释放的手段。
4.权利要求1所述的制剂,其特征在于,制剂包含许多颗粒,至少一部分该颗粒含有至少一种活性组分。
5.权利要求4所述的制剂,其特征在于,至少有一部分颗粒是被包衣包被的,该包衣能使活性组分在制剂接触液体介质时进行改良的释放。
6.权利要求4所述的制剂,其特征在于,至少有一部分颗粒是被包衣包被的,该包衣含有能提供使活性组分在制剂接触液体介质时进行改良的释放的手段。
7.权利要求4所述的制剂,其特征在于,至少一部分颗粒是用含能改良释放的聚合物的包衣包被的,该聚合物占总重量的10-100%,聚合物选自下列一组:pH依赖的聚合物、水溶性聚合物、不溶于水的聚合物及其共聚物、衍生物以及上述物质的混合物。
8.权利要求1所述的制剂,其特征在于,基质包含至少一种活性组分。
9.权利要求1所述的制剂,其特征在于,制剂一旦接触到液体介质,就至少有一部分活性组分以持续的方式释放。
10.权利要求9所述的制剂,其特征在于,制剂以基本恒定的速率释放活性组分。
11.权利要求1所述的制剂,其特征在于,制剂一旦接触到液体介质,在至少一部分活性组分释放前有一个时间迟滞。
12.权利要求11所述的制剂,其特征在于,一部分活性组分在迟滞期后以持续的方式释放。
13.权利要求11所述的制剂,其特征在于,制剂还包含许多颗粒,所述基质含有第一批活性组分,至少有一部分颗粒含有第二批活性组分,第二批活性组分与第一批可以相同或不同,制剂接触到液体介质时,第一批活性组分立即释放,经过一个迟滞期后第二批活性组分释放。
14.权利要求1所述的制剂,其特征在于,制剂还包含许多颗粒,所述基质含有第一批活性组分,至少有一部分颗粒含有第二批活性组分,第二批活性组分可以与第一批相同或不同,制剂接触到液体介质时,第一批活性组分立即释放,然后第二批活性组分持续释放。
15.一种含有至少一种活性组分、一种模制基质和分散于基质中的许多颗粒的制剂,其中至少一部分颗粒是被包被的,制剂在接触到液体介质时能够改良地释放活性组分。
16.权利要求15所述的制剂,其特征在于,制剂含有提供在接触到液体介质时能使活性组分进行改良的释放的手段。
17.权利要求15所述的制剂,其特征在于,在制剂接触到液体介质时基质能使活性组分进行改良的释放。
18.权利要求15所述的制剂,其特征在于,基质含有提供在接触到液体介质时能使活性组分进行改良的释放的手段。
19.权利要求15所述的制剂,其特征在于,制剂还含有至少一种分散于基质中的未包被的活性组分。
20.权利要求15所述的制剂,其特征在于,至少一部分包被颗粒含有至少一种活性组分,该颗粒被包衣包被,该包衣能使其中的活性组分在制剂接触到液体介质时进行改良的释放。
21.权利要求15所述的制剂,其特征在于,至少一部分包被颗粒含有至少一种活性组分,该颗粒被包衣包被,该包衣含有提供能使其中的活性组分在制剂接触到液体介质时进行改良的释放的手段。
22.权利要求15所述的制剂,其特征在于,至少一部分颗粒是用含释放得到改良的聚合物的包衣包被的,该聚合物占总重量的10-100%,选自下列一组:pH依赖的聚合物、水溶性的聚合物、不溶于水的聚合物及其共聚物、衍生物以及上述物质的混合物。
23.权利要求15所述的制剂,其特征在于,制剂一旦接触到液体介质,就至少有一部分活性组分以持续的方式释放。
24.权利要求23所述的制剂,其特征在于,制剂以基本恒定的速率释放活性组分。
25.权利要求15所述的制剂,其特征在于,制剂一旦接触到液体介质,在至少一部分活性组分释放前有一个时间迟滞。
26.权利要求25所述的制剂,其特征在于,一部分活性组分在迟滞期后以持续的方式释放。
27.权利要求15所述的制剂,其特征在于,制剂含有相同或不同的第一批和第二批活性组分,制剂接触到液体介质时,第一批活性组分以持续的方式释放,在第二批活性组分释放前经过一个迟滞期。
28.权利要求15所述的制剂,其特征在于,基质含有分散于其中的第一批活性组分和至少一部分颗粒,该颗粒含有与第一批活性组分相同或不同的第二批活性组分,制剂接触到液体介质时,第一批活性组分立即释放,经过一个迟滞期后第二批活性组分释放。
29.权利要求15所述的制剂,其特征在于,基质含有分散于其中的第一批活性组分和至少一部分颗粒,该颗粒含有与第一批活性组分相同或不同的第二批活性组分,制剂接触到液体介质时,第一批活性组分立即释放,然后第二批活性组分持续释放。
30.权利要求1所述的制剂,其特征在于,热可逆载体选自下列物质:聚己酸内酯、聚乙酸乙烯酯、聚亚烷基二醇、以及上述物质的混合物。
31.权利要求1所述的制剂,其特征在于,热可逆载体选自下列物质:分子量约为100-20000道尔顿的聚乙二醇、分子量为100000-900000道尔顿的聚环氧乙烷、以及上述物质的混合物。
32.权利要求1所述的制剂,其特征在于,热可逆载体约占基质重量的30%-70%。
33.权利要求1所述的制剂,其特征在于,模制基质还可以含有一种改良释放的可模制赋形剂,该赋形剂选自可溶胀可浸蚀的亲水材料、pH依赖的聚合物、不溶性的可食用的材料、孔洞形成剂以及上述物质的混合物。
34.权利要求33所述的制剂,其特征在于,改良释放的赋形剂约占模制基质重量的1%-55%。
35.权利要求33所述的制剂,其特征在于,改良释放的赋形剂是虫胶。
36.权利要求33所述的制剂,其特征在于,改良释放的赋形剂是交联羟甲基纤维素钠。
37.权利要求1所述的制剂,其特征在于,制剂中还含有作为增塑剂的柠檬酸三丁酯。
CNA028233476A 2001-09-28 2002-09-28 改良的释放剂型 Pending CN1592610A (zh)

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US09/966,939 US6837696B2 (en) 2001-09-28 2001-09-28 Apparatus for manufacturing dosage forms
US09/966,497 2001-09-28
US09/967,414 2001-09-28
US09/966,509 US6767200B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,509 2001-09-28
US09/967,414 US6742646B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,450 US6982094B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,450 2001-09-28
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US09/966,497 US7122143B2 (en) 2001-09-28 2001-09-28 Methods for manufacturing dosage forms

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BR0212951A (pt) 2004-10-26
KR20040045030A (ko) 2004-05-31
KR20040037207A (ko) 2004-05-04
EP1429737A1 (en) 2004-06-23
KR20040045033A (ko) 2004-05-31
WO2003026627A1 (en) 2003-04-03
WO2003026628A2 (en) 2003-04-03
JP2005508328A (ja) 2005-03-31
US20040018327A1 (en) 2004-01-29
WO2003026614A9 (en) 2004-02-26
EP1429745A2 (en) 2004-06-23
NZ532097A (en) 2006-02-24
AU2002330164A1 (en) 2003-04-07
US20050019407A1 (en) 2005-01-27
MXPA04002979A (es) 2005-06-20
WO2003026624A1 (en) 2003-04-03
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CA2447984A1 (en) 2003-04-03
CO5570655A2 (es) 2005-10-31
WO2003026614A1 (en) 2003-04-03
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CA2461659A1 (en) 2003-04-03
BR0212921A (pt) 2004-10-13
BR0212946A (pt) 2004-10-26
EP1429746A2 (en) 2004-06-23
CN1592611A (zh) 2005-03-09
CN1592612A (zh) 2005-03-09
CN100364515C (zh) 2008-01-30
US7972624B2 (en) 2011-07-05
CA2461656A1 (en) 2003-04-03
BR0213589A (pt) 2004-08-31
JP2005508330A (ja) 2005-03-31
NO20032363L (no) 2003-07-23
US20040213849A1 (en) 2004-10-28
ATE376826T1 (de) 2007-11-15
EP1429743A1 (en) 2004-06-23
EP1463489A1 (en) 2004-10-06
ATE404179T1 (de) 2008-08-15
CN1596100A (zh) 2005-03-16
EP1429742B1 (en) 2011-05-04
WO2003026615A2 (en) 2003-04-03
WO2003026616A1 (en) 2003-04-03
WO2003026629A2 (en) 2003-04-03
HUP0401686A3 (en) 2008-04-28
WO2003026626A3 (en) 2003-10-16
CA2461682A1 (en) 2003-04-03
MXPA04002992A (es) 2005-06-20
DE60223269T2 (de) 2008-08-21
BR0206061A (pt) 2004-01-13
US7635490B2 (en) 2009-12-22
CN1592613A (zh) 2005-03-09
BR0206086A (pt) 2003-12-23
WO2003026629A3 (en) 2004-03-04
HK1072902A1 (en) 2005-09-16
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ES2444549T3 (es) 2014-02-25
JP2005508325A (ja) 2005-03-31

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