CN1156461C - 改良的水溶性药物制剂 - Google Patents
改良的水溶性药物制剂 Download PDFInfo
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Abstract
本发明描述了一种微溶于水的结晶态药物活性剂制剂，其中活性剂被转化成它的非晶态即通常疏水性载体的固溶体形式，并在该状态下稳定。非晶态通过制剂的组分来稳定，使改良后的组合物储藏期限长。该稳定的制剂其活性剂的溶解度和生物利用度增加。活性剂溶液由其组分来稳定，防止了微溶性结晶态的活性剂从它的水溶液中重结晶和沉淀。
Description
本发明涉及通过将低水溶性的结晶态药物化合物转化为能在颗粒药物制剂中稳定的非晶态来改良其水溶性的方法和制剂。特别涉及了改良唑类杀真菌药剂的水溶性和生物利用度的方法，它是将唑类杀真菌药剂转化为非晶态，在该状态下稳定，并使之制粒以形成稳定的颗粒。还涉及通过该种方法制备的药物制剂、由此制备的固体剂型及其稳定的水溶液。
发明背景
许多结晶态药物化合物很难溶于人体中的水。广为人知的是，将结晶态化合物转化为它的非晶态，能大大改进该化合物的水溶性，从而增加它的生物利用度。
至今为止用来改进微溶性活性组分水溶性的方法包括使活性组分和经化学改良的非晶态环糊精进行络合。虽然活性组分不是从结晶态转化为非晶态的，但活性组分/环糊精的络合物也增加了微溶性组分的的溶解度。
在某些情况下，可以熔化结晶态活性剂，并使之在熔融状态下保持有限时间，然后将它冷却成非晶态固体。该方法限于特殊的活性组分，该组分能制得稳定的非晶态固体，且不会由于加热步骤而降解。
欧洲专利出版物0852140 A1揭示了一种将微溶性药物转化为水溶性较高的非晶态的方法，据记载，其中微溶于水的药物、非晶态诱发剂和非晶态稳定剂如羟丙基甲基纤维素的混合物被加热到药物变成非晶态的温度。
杀真菌剂的二氯甲烷溶液可用任何方法来溶解-诱发干燥，如先以低速率，然后以高速率喷雾干燥，从而形成活性组分的非晶态粉末。接着该粉末和赋形剂压紧干燥制粒，以用于片剂或硬明胶胶囊。
在另一种非晶态杀真菌剂的生产过程中，试剂和羟丙基甲基纤维素溶解于二氯甲烷/链烷醇溶液中。然后在流态床中将该溶液喷到球体如糖球上。然后对被喷涂的球体涂敷密封包衣，这样就可用于填充硬明胶胶囊了。
在另一种形成非晶态固体分散体的过程中，微溶性的活性剂和聚乙烯吡咯烷酮在两者都熔融的情况下混合，然后使之冷却。据记载该方法生产出的活性剂在水中溶出更快。
国际申请PCT\EP97\02507中述及，用于稳定非晶态伊曲康唑的进一步方法是通过熔融挤出伊曲康唑和水溶性聚合物的混合物。
上述方法看似在改进微溶性活性剂的溶解性方面有不同程度的成功。但是，生物利用度的重大改进也需要活性组分的所得溶液是稳定的。如果不稳定，溶解的活性剂会产生结晶和沉淀，因而降低了尚未被患者血流吸收的活性剂的生物利用度。
发明概述
根据本发明，增加微溶于水的结晶态药物活化剂如伊曲康唑的溶解性和生物利用度的方法，是熔化通常是固体的疏水性载体如硬脂酸甘油酯，在超过载体的正常熔点但低于活性剂的正常熔点或降解温度的温度下，在该固体载体中溶解微溶于水的通常是结晶态(即是一种在处理成非晶态之前，在环境温度和压力下是结晶态和微溶于水的化合物)的药物活性剂，然后使熔融产物和崩解剂以及任选的添加剂一起制粒。在第一个实施方案中，稳定剂在制粒之前加入熔化溶液。在第二个实施方案中，熔化溶液与稳定剂和崩解剂的混合物一起制粒。在第一个实施方案中，优选的制粒过程在一冷却的制粒床中进行，以快速冷却经稳定的产物。在在第二个实施方案中，制粒过程在高温下进行，并且所得颗粒在短暂的制粒过程后快速冷却。然后可以把所得颗粒研磨成适当的粒径，并填入胶囊，或与其它赋形剂掺混并处理成固体剂型。
因此本发明所得的产物包括颗粒制剂，该颗粒包括溶解于药学上可接受的通常为固体的疏水性载体熔化溶液中的非晶态药物活性剂固溶体，该活性剂在环境温度和压力下通常是结晶态和微溶于水的，该疏水性载体熔化溶液中的活性剂在高温下可溶；还包括使活性剂在其非晶形状态时保持稳定的稳定剂；崩解剂；以及可选的粘合剂，其中溶解的活性剂在所述颗粒中的固溶体形式的非晶态下是基本稳定的。
因此就得到一个完整而即时可用的颗粒制剂，其中活性剂非晶态在疏水性载体基体中，作为非晶态活性剂固溶体形式是长期稳定的，从而增加了药物活性剂在摄入和进入水介质(如胃中的水介质)时的溶解性和生物利用度，并且延长了由此制得的颗粒和产品的储藏期限。
发明详述
本发明用于增加微溶于水的通常是结晶态的药物活性剂在水介质中的溶解性的新型制剂包括：通常为固体的疏水性载体、一种或多种稳定剂、粘合剂和崩解剂。要增加通常是结晶态的活性剂的溶解性，最基本就是要将它转化成固溶体形式的非晶态，然后稳定非晶态，从而防止它恢复成结晶态。本发明的制剂实现了活性剂非晶态的稳定，并且使之保持长期稳定，在溶解性和生物利用度增加的同时延长了活性剂的储藏寿命。此外，该制剂出乎意料的益处在于由增溶的活性剂颗粒制剂制得的溶液具有稳定性。该溶液对于活性组分的固有溶解度来说其实是或可能是过饱和的，但根据本发明是稳定的，可防止产生重结晶。
因此本发明的新型颗粒制剂包括(a)微溶于水且通常为结晶态的药物活性剂的固溶体；(b)用于所述药物活性剂的通常为固体的疏水性载体，所述载体在超过所述载体熔点但低于所述药物活性剂正常熔点的温度下能够溶解所述药物活性剂；(c)稳定剂，选自聚乙二醇、糖、山梨醇、甘露醇、聚乙烯吡咯烷酮和纤维素醚如甲基纤维素、羟丙基甲基纤维素和羟丙基纤维素及相似物；(d)崩解剂，选自交联甲羧纤维素钠、羟基乙酸淀粉钠、聚乙烯聚吡咯烷酮和交联聚丙烯酸酯，其中通常微溶于水的活性剂在所述载体中的固溶体形式的非晶态下是可溶和稳定的。根据活性组分和各成分量，本发明的制粒过程也可包括粘合剂、填料或其它常规赋形剂。
更为特别的是，本发明的颗粒制剂包括以下颗粒：(a)在载体固体基体中完全为非晶态的药物活性剂固溶体，更确切地说，是非晶态药物活性剂和药学上可接受的疏水性载体的固溶体，其中药物活性剂在环境压力和温度下通常是结晶态和微溶于水的，并且其中所述的药物活性剂在所述载体熔化液中的实质上的非晶态下是可溶和稳定的；(b)稳定剂，以及(c)崩解剂。所用的词语“固溶体”是指活性剂在疏水性载体熔化溶液溶解过程和附加过程时是固体。
药物活性剂的适用载体是药物可用的疏水性载体，在环境温度下通常为固体，但在低于药物活性剂的正常熔点或降解温度下不降解地熔化。此外，载体特性是必须能在高于其本身熔点但低于活性剂熔点的温度下溶解活性剂。更确切地说，本发明载体应该有约超过60℃的熔点，并且应该在温度上升至活性剂变得可溶于载体时是稳定的。根据活性组分，载体应至少在140℃时稳定的，更优选是在温度达到250℃或甚至略微超过时也是稳定的。另外，它在加热到该温度时不能挥发或蒸发或降解。载体的准确选择一部分取决于活性剂，特别是活性剂的溶解性质。用于溶解唑类杀真菌剂如伊曲康唑的优选载体是硬脂酸甘油酯(glycerylmonostearate)，而其它各种长链单酸甘油酯、甘油二酯、甘油三酯，和蜡包括蜂蜡和微晶蜡，以及它们的混合物也可能是使用于本发明的合适载体。所用载体总量的有效范围是占颗粒制剂约3％到约55％干燥的重量百分数。在优选的实施方案中，载体是硬脂酸甘油酯，其浓度应是占制剂干重约5％到约50％，更优选约5％到约35％。
除了作为溶解活性剂的载体以外，本发明所用的载体也可为颗粒制剂提供第二个有益功能，即作为活性剂在非晶态下稳定的稳定剂和促进剂，并因此防止它在制粒过程期间或之后恢复成通常的结晶态。
本发明还使用了稳定剂，照惯例用于使活性剂在非晶态下稳定，并防止它恢复成通常的结晶态。这些原料也可作为孔的形成剂，这些颗粒制剂需要这些原料来促进水进入含有经稳定的非晶态活性剂的颗粒体内。通过提供水进入颗粒的途径，从而增加了非晶态活性剂的溶出。适用的稳定剂包括聚乙二醇、其它多元醇、糖、山梨醇、甘露醇、聚乙烯吡咯烷酮和纤维素醚如甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素和它们的混合物。也作为活性剂颗粒孔形成剂的优选稳定剂是羟丙基甲基纤维素。本发明的颗粒制剂中所含稳定剂的适宜范围占颗粒干重的约1％到约60％，优选约1％到约50％。
甘油也可用于本制剂，它可作为孔形成剂，并在某些情况下有助于活性剂的溶出，但在稳定非晶态活性剂时不一定会表现出任何实质性益处。使用时它的合适用量占本发明颗粒干重约15％到约30％。
该制剂所用的合适崩解剂是指特级崩解剂。该类崩解剂包括交联甲羧纤维素钠(交联羧甲基纤维素)、羟基乙酸淀粉钠、聚乙烯聚吡咯烷酮(交联聚乙烯吡咯烷酮)和交联聚丙烯酸酯。优选的崩解剂是交联甲羧纤维素钠，它在制剂中的含量占配料干重约1％到约25％，优选约3％到约25％。
粘合剂选自微晶纤维素、纤维素絮凝物、淀粉、糖如乳糖或蔗糖、磷酸钙、碳酸钙和高岭土。优选的粘合剂是微晶纤维素，如AvicelPH-101。粘合剂的含量占配料干重约5％到约35％，优选约5％到约20％。
适用的活性剂在环境温度下通常为结晶态且在该状态下只能微溶于水介质，熔点在50℃和200℃之间且能高达约300℃，它们能通过加热转化为非晶态，并且在冷却和重固化时易于恢复成通常不可溶的结晶态。用于本发明活性剂的术语“微溶”一般是指通常是结晶态形式的活性剂在环境温度下的水溶性很小，包括溶解性从微溶(＝1∶100到1∶1000)到不溶(大于1∶10,000)的物质。通过在制粒过程中或制粒前使疏水性载体溶液中的这些活性剂在非晶态下稳定，提供了一种稳定的制粒过程，其中活性剂在非晶态下延长稳定期限，从而使其具有理想的储藏寿命并增加了它们的溶解性和生物利用度。熔点约低于50℃的活性剂是不稳定的，至少在达到令人满意的储藏期限所需期间是不稳定的。此外，活性剂必须在它溶解于熔融稳定剂的温度下或者高于该温度时是稳定的。如果产生分解，这不仅会降低制剂中的活性含量，而且还有可能会将分解产物引入制剂。从生产角度看，温度超过约250℃会导致生产费用增加，这使得其它增溶和稳定方法要更省钱。
例如，增加活性成分溶解性的方法适用于称作唑类的杀真菌剂类别，包括酮康唑、伊曲康唑、赛泊康唑(saperconazole)、氟康唑、密康唑和相似物。所有该类活性剂在水介质中的溶解度都很低，并且能从本文所述的将之转化为非晶态、并在该状态下稳定的方法中获益。更确切地说，该方法能非常有效地用于伊曲康唑。可以改变伊曲康唑的浓度以获得形式方便的颗粒剂量。通常该浓度范围是颗粒制剂约5％到约60％。优选制剂中，该浓度范围是约20％到约35％。
含有伊曲康唑的本发明制剂显示出高的溶出速率。30分钟内有36％-86％的伊曲康唑溶解于人工胃液中。比较起来，同样条件下30分钟后结晶伊曲康唑只有1％溶出。60分钟后，经稳定的非晶态伊曲康唑的该数值增加到45％-95％，而结晶材料只有2％。不仅伊曲康唑的溶解度显著增加，而且所得溶液是稳定的，这样伊曲康唑就不会重结晶和从溶液中沉淀了。
本文所述的新型制剂在通过制剂溶出而制得的水溶液中有稳定作用。虽然能够确定对这些溶液的稳定更有影响的制剂成分，但相信该稳定过程需要整个制剂及其成分间产生可见的相互作用。因此，本发明颗粒包括20％到约35％的药物活性剂，优选为伊曲康唑；约5％到约35％的疏水性载体，优选为硬脂酸甘油酯；约3％到约25％的崩解剂，优选为交联甲羧纤维素；以及约1％到约50％的稳定剂，优选为羟丙基甲基纤维素，所有数值都以占颗粒干重的重量百分数计。
在一个特别优选的实施方式中，上面笼统描述的颗粒包括约15％到约25％的羟丙基甲基纤维素，最优选约20％；约5％到约15％的微晶纤维素作为粘合剂，最优选为约10％，示于实施例5。
在另一个特别优选的实施例中，颗粒包括约30％到35％的活性剂，优选为伊曲康唑；约5％到15％的硬脂酸甘油酯；约10％到15％的交联甲羧纤维素钠；和45％到约55％的羟丙基甲基纤维素，所有数值都以占颗粒干重计，示于实施例6和7。
根据本发明的第一种方法，经稳定的本发明颗粒制剂的制备包括以下步骤：
(a)将疏水性载体加热到载体熔化的温度或略高于活性成分在熔融载体中溶解时的温度；
(b)在熔融载体中溶解药物活性剂，以形成药物活性剂在所述载体中的熔化溶液；
(c)在熔化溶液中加入稳定有效量的稳定剂；
(d)使来自于(c)的熔融混合物和崩解剂及可选的粘合剂在约低于30℃的温度下制粒，优选低于5℃；从而形成的颗粒包括更可溶的非晶态形式的药物活性剂稳定于疏水性溶剂中的固溶体。
根据本发明的第二种方法，该制剂的制备被改良成以下步骤：
(a)将疏水性载体加热到载体熔化的温度或略高于活性剂在熔融载体中溶解时的温度；
(b)将药物活性剂溶解在熔融载体中，以形成药物活性剂在载体中的熔化溶液；
(c)使熔化溶液与稳定剂、崩解剂和可选的粘合剂组成的混合物在或高于活性剂在稳定剂中溶解的温度下制粒，以形成颗粒；并且
(d)快速冷却所得颗粒。
活性剂溶解时的温度可能在某些情况下低于活性剂的熔点。但它必须高到足以使溶液快速和完全形成。在第一个实施例中，稳定剂被直接加到载体和活性剂的熔化溶液中，然后在能使熔融原料快速冷却的条件下，使所得熔融产物与粘合剂、崩解剂和可选的其它赋形剂组成的冷混合物制粒以作为制粒过程，从而减少了会恢复成通常不可溶的结晶态的活性剂量。例如造粒机应在环境温度或约低于30℃的任何温度下合理操作，但优选在低于5℃的温度下操作。在第二个模式中，稳定剂除了可直接加到熔化溶液外，还可与崩解剂和可选的一种或多种粘合剂或其它赋形剂混合，然后熔化溶液和该混合物一起制粒。用于该实施方案的造粒机优选在或大约在活性剂在载体中溶解时的温度下操作，因此在活性剂有机会恢复成它通常的结晶态之前就在非晶态下稳定了，然后快速冷却颗粒，合适的方法是使热颗粒通过液氮出料。
本领域的技术人员可根据活性剂和载体的特性来进行估计，即使在理想条件下，也会有少量活性剂不溶于载体且因此不能转化非晶态，但相信该量相对于形成本发明主要成分的进入固溶体的大比例原料来说关系不大。小部分活性剂可能恢复成通常不溶于水的结晶态活性组分，因此降低了用于治病的活性有效成分。虽然这些量很难用已知分析技术来定量，但人们相信和期望至少有85％，90％较有利，或优选至少95％到99％或甚至100％的活性组分能在颗粒中作为在所得固溶体中非晶态固体形式存在。
本领域的技术人员知道，如果操作过程中的溶解温度过高/或高温保持过长时间，活性剂可能会部分降解，从而在颗粒中形成降解产物。
对两种操作模式的选择和/或在何种确定条件下进行其中一种操作的选择取决于多种因素。两种模式都是可行和有效的，能用伊曲康唑和硬脂酸甘油酯达到前述目的。但总的来说，优选在或约在活性剂在载体中溶解时最低的温度下进行溶解过程，并且要避免将载体和/或载体和活性剂的溶液加热到超过活性剂开始进行明显降解时的温度。使用伊曲康唑时，经稳定的溶液的溶解过程和生产过程优选在低于伊曲康唑熔点的温度下进行。
虽然优选使用高剪切造粒机来制造最终制剂，但用例如挤出造粒机、流化床造粒机、喷雾冷冻机和喷雾干燥机这样的造粒机也能得到同样好地提供稳定形成活性组分非晶态特性所需的冷却。
如果最终制粒过程的颗粒大到不合需要的程度，合适的做法是将其研磨，并过筛到可接受的、更为统一的粒径。在这种情况下，研磨过程可与有效的冷却过程一起进行，例如，防止活性组分恢复成结晶态所需的冷却量同时提供用于有效研磨的足够脆度。使用液氮或一些其它冷却方法通常都是可行的。
用本发明制得的颗粒可直接填入硬明胶胶囊来形成最终剂型。如有需要，这些颗粒中可加入润滑剂和助流剂以增加颗粒装入胶囊的流动性。另外，通过本发明第二种方法制粒的原料可从将颗粒和粘合剂以及可选的附加崩解剂进行干掺混中获益。另一方面，如果希望用压片机将颗粒压缩成药片，就需要加入润滑剂来防止与此操作有关的加工问题。两种制造方法都作为本发明的一部分。
下面的实施例用来说明制造和使用本发明的方法，但它们仅仅作为本发明的示例，而不作为限定。本领域的技术人员知道，可以对其作明显的改动，并包括在本发明的范围内。在这些实施例中，如果没有另外特别指出，所有百分数都是占颗粒制剂的重量百分数，所有温度都是摄氏度。
另外，每一制剂的溶出速率是用以100转/分运行，并含有900毫升的不含胃蛋白酶的仿胃液的USP装置2(桨式)测定的。该胃液被加热到37℃，并使用了含100毫克活性剂的颗粒样本。在30分钟和60分钟后进行测量。为确定溶解的活性剂总量，60分钟的读数后搅拌要增加到200转/分，并且在两小时后进行最终读数。该最终测定提供了通过组合，非晶态稳定效力的粗测值；100％溶解等于非晶态转化完全，并且该状态下100％稳定。
实施例1
将含11.88克丙三醇的烧杯加热到90℃和100℃之间。在热的丙三醇中加入11.88克硬脂酸甘油酯(Eastman化学公司)。搅拌该混合物直到硬脂酸甘油酯完全分散，然后升温至130℃和150℃之间，在此期间将12.50克伊曲康唑加入熔融混合物中。持续搅拌直到伊曲康唑完全溶解，得到清澈溶液。一边搅拌一边在该溶液中加入1.25克羟丙基甲基纤维素E4M(Dow化学公司)。同时将12.50克微晶纤维素(AvicelPH-101，FMC公司)和12.50克交联甲羧纤维素钠(Ac-Di-Sol，FMC公司)放入在25℃水浴中冷却的造粒机槽中。然后将熔融混合物一边加到颗粒槽中的固体一边搅混，直到整个混合物的温度达到25-30℃。溶出试验显示30分钟内有43％的伊曲康唑溶解，并且60分钟后溶解的伊曲康唑增加到51％。在同样条件下，微晶伊曲康唑的溶出速率是30分钟和60分钟时各为1％和2％。
实施例2
用实施例1的方法，将7.5克丙三醇、7.5克硬脂酸甘油酯和15.5克伊曲康唑一起熔化。伊曲康唑在144℃时加入溶液中。在该熔融混合物中加入1.5克甲基纤维素A15C。所得分散体显示出低于实施例1的可比分散体的粘度。然后将该分散体与15.5克AvicelPH-101和2.5克交联甲羧纤维素钠的混合物一起制粒。溶出试验确定30分钟内有43％的伊曲康唑溶解，并且60分钟后溶解的伊曲康唑增加到54％。
实施例3
用实施例1的方法，将11.88克丙三醇、5.94克硬脂酸甘油酯和12.5克伊曲康唑一起熔化。在该熔融混合物中加入1.25克羟丙基甲基纤维素E4M。熔融相混合良好，且流动性强。然后将该分散体与7.37克AvicelPH-101和7.37克交联甲羧纤维素钠的混合物一起制粒。该制粒过程的颗粒相对较小，并显示出特别均匀的外观。溶出试验确定30分钟内有51％的伊曲康唑溶解，并且60分钟后该数值增加到61％。
实施例4
用实施例1的方法，将11.88克丙三醇、2.97硬脂酸甘油酯和12.5克伊曲康唑一起熔化。伊曲康唑在140℃时加入。在该熔融混合物中加入1.25克羟丙基甲基纤维素E4M，它将熔融混合物进行大程度增稠，并且比实施例3所见的更快。然后将该分散体与12.5克AvicelPH-101和12.5克交联甲羧纤维素钠的混合物一起制粒。溶出试验确定30分钟内有47％的伊曲康唑溶解，并且60分钟后该数值增加到56％。
实施例5
将含180克硬脂酸甘油酯(Eastman化学公司)的不锈钢烧杯加热到100℃。当硬脂酸甘油酯熔融后，温度升至145℃，然后缓慢加入180克结晶伊曲康唑，同时保持温度在145℃和155℃间。持续搅拌直到伊曲康唑完全溶解，得到清澈溶液。一边搅拌一边在该溶液中加入120克羟丙基甲基纤维素E5(Dow化学公司)。同时将60克微晶纤维素(AvicelPH-101，FMC公司)和60克交联甲羧纤维素钠(Ac-Di-Sol，FMC公司)放入冷却到-4.2℃的高剪切造粒机槽中。然后以使颗粒温度保持低于5℃的速度将熔融混合物加到颗粒槽中的固体。造粒机刀片以312转/分和设置在1#的切碎机一起工作。一旦熔融混合物添加完毕，混合持续额外的五分钟，直到温度低于-1℃。制粒过程的完成需要95分钟。该颗粒通过粗筛被研磨，同时用液氮冷却。同样用液氮冷却的第二次研磨过程是使用装有60筛目(250微米)金属丝网筛的M5型Fitz研磨机完成的。最终颗粒适于填入硬明胶胶囊中。该颗粒在37℃仿胃液中测试溶出度，3小时后显示有86％的有效伊曲康唑溶出。60分钟后该值增加到95％。在上述同样条件下3小时后，有100％的伊曲康唑溶解。
实施例6
在加热到150-165℃的搅拌锅内放入0.25千克硬脂酸甘油酯。当硬脂酸甘油酯完全熔化后，开始缓慢加入1.5千克伊曲康唑。一旦加入完成，就对混合物进行加热和搅拌，直到所有伊曲康唑都完全溶解。同时将2.25千克羟丙基甲基纤维素E5(Dow化学公司)和0.60千克交联甲羧纤维素钠(Ac-Di-Sol，FMC公司)的干掺混物放入加热到150℃的高剪切造粒机中。在干掺混物的温度达到150℃后，造粒机主切刀以300转/分工作且左右交叉螺纹以全速工作，将硬脂酸甘油酯和伊曲康唑的熔融混合物在一分钟内从反应锅被抽到造粒机中。制粒过程进行1.5分钟后，粒化的混合物被排到液氮流中，快速冷却和固化颗粒。用装有1512-0027多孔板筛的M5型Fitz研磨机来研磨颗粒，并用液氮冷却。将研磨好的颗粒放入双筒混合机，加入0.4千克Avicel Ph-200，并进行掺混以制备用于填充硬明胶胶囊的最终制剂。使用如实施例5所述的测试条件，粉状颗粒在30分钟后有87％溶解，一小时后有94％。为进行比较，胶囊在30分钟后有84％溶出和在一小时后有98％溶出，这显示了两种溶出试验没有太大的不同。
实施例7
本实施例的颗粒用实施例6所述方法分别进行制备、研磨和干掺混，不同的是，颗粒和0.25千克微晶纤维素和0.15千克滑石一起干掺混，以有助于最终制剂的掺混和处理。颗粒和添加剂的最终掺混物包括30％伊曲康唑、5％硬脂酸甘油酯、12％交联甲羧纤维素钠、45％HPMC、5％微晶纤维素和3％滑石，以占所得掺混物的重量百分数计。溶出结果和实施例所得结果一致。
Claims (4)
1.一种固体剂型，其特征在于它包括治疗有效量的包含以下组分的颗粒：
(a)唑类杀菌剂和可用于药物的疏水性载体的固溶体，所述的疏水性载体包括硬脂酸甘油酯、单酸甘油酯、甘油二酯、甘油三酯或蜡；
(b)稳定剂，包括聚乙二醇、糖、山梨醇、甘露醇、聚乙烯吡咯烷酮，或一种或多种纤维素醚；以及
(c)崩解剂，包括交联甲羧纤维素钠、羟基乙酸淀粉钠、聚乙烯聚吡咯烷酮或交联聚丙烯酸酯；
所述的颗粒由包括以下步骤的方法制成：
(i)将所述的疏水性载体加热到所述的唑类杀菌剂在熔融的疏水性载体中溶解时的温度；
(ii)将所述的唑类杀菌剂溶解在熔融的疏水性载体中，以形成所述唑类杀菌剂在所述疏水性载体中的熔化溶液；然后
(iii)在所述熔化溶液中加入稳定有效量的所述稳定剂；并且
(iv)使来自于步骤(iii)的熔融混合物和经冷却的崩解剂和可选的粘合剂一起制粒，以形成颗粒。
2.如权利要求1所述的固体剂型，其特征在于所述的唑类杀菌剂是伊曲康唑。
3.如权利要求2所述的固体剂型，其特征在于所述的疏水性载体是硬脂酸甘油酯且占所述颗粒干重5％-35％，所述的崩解剂是交联甲羧纤维素钠且占所述颗粒干重3％-25％，以及所述的稳定剂是羟丙基甲基纤维素且占所述颗粒干重1％-50％。
4.如权利要求1所述的固体剂型，它包括硬明胶胶囊。
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-
2000
- 2000-03-20 DE DE60023465T patent/DE60023465T2/de not_active Expired - Fee Related
- 2000-03-20 CA CA002362728A patent/CA2362728C/en not_active Expired - Fee Related
- 2000-03-20 AT AT00918139T patent/ATE307808T1/de not_active IP Right Cessation
- 2000-03-20 WO PCT/US2000/007298 patent/WO2000056726A1/en active IP Right Grant
- 2000-03-20 EP EP00918139A patent/EP1163234B1/en not_active Expired - Lifetime
- 2000-03-20 CN CNB008053995A patent/CN1156461C/zh not_active Expired - Fee Related
- 2000-03-20 IL IL14514000A patent/IL145140A0/xx active IP Right Grant
- 2000-03-20 DK DK00918139T patent/DK1163234T3/da active
- 2000-03-20 BR BR0009176-6A patent/BR0009176A/pt active Pending
- 2000-03-20 US US09/528,624 patent/US6497905B1/en not_active Expired - Fee Related
- 2000-03-20 JP JP2000606587A patent/JP2003531099A/ja not_active Ceased
- 2000-03-20 ES ES00918139T patent/ES2251985T3/es not_active Expired - Lifetime
- 2000-03-20 AU AU39003/00A patent/AU3900300A/en not_active Abandoned
- 2000-05-10 TW TW089105331A patent/TWI245644B/zh not_active IP Right Cessation
-
2001
- 2001-06-21 US US09/886,493 patent/US6511681B2/en not_active Expired - Fee Related
- 2001-06-21 US US09/886,100 patent/US6379707B2/en not_active Expired - Fee Related
- 2001-08-27 IL IL145140A patent/IL145140A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US20020012706A1 (en) | 2002-01-31 |
| EP1163234B1 (en) | 2005-10-26 |
| TWI245644B (en) | 2005-12-21 |
| ATE307808T1 (de) | 2005-11-15 |
| ES2251985T3 (es) | 2006-05-16 |
| DE60023465D1 (de) | 2005-12-01 |
| EP1163234A4 (en) | 2003-05-02 |
| US6511681B2 (en) | 2003-01-28 |
| IL145140A0 (en) | 2002-06-30 |
| CA2362728A1 (en) | 2000-09-28 |
| IL145140A (en) | 2006-08-20 |
| CN1379768A (zh) | 2002-11-13 |
| JP2003531099A (ja) | 2003-10-21 |
| DK1163234T3 (da) | 2006-02-27 |
| AU3900300A (en) | 2000-10-09 |
| DE60023465T2 (de) | 2006-07-20 |
| BR0009176A (pt) | 2001-12-18 |
| US20020037324A1 (en) | 2002-03-28 |
| US6497905B1 (en) | 2002-12-24 |
| WO2000056726A1 (en) | 2000-09-28 |
| US6379707B2 (en) | 2002-04-30 |
| EP1163234A1 (en) | 2001-12-19 |
| CA2362728C (en) | 2009-06-23 |
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