CN105283203A - 用于热熔挤出的组合物以及通过使用该组合物制备热熔挤出物的方法 - Google Patents
用于热熔挤出的组合物以及通过使用该组合物制备热熔挤出物的方法 Download PDFInfo
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- CN105283203A CN105283203A CN201480030211.8A CN201480030211A CN105283203A CN 105283203 A CN105283203 A CN 105283203A CN 201480030211 A CN201480030211 A CN 201480030211A CN 105283203 A CN105283203 A CN 105283203A
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Abstract
提供了用于热熔挤出的组合物,其至少包含药物和羟基丙氧基摩尔取代为0.40以上且乙酰基与琥珀酰基的摩尔比小于1.6的醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)。还提供了用于制备热熔挤出物的方法,其至少包括以下步骤:在热熔温度下加热、熔化并挤出至少包含药物和摩尔羟基丙氧基取代为0.40以上且乙酰基与琥珀酰基的摩尔比小于1.6的醋酸羟丙甲纤维素琥珀酸酯的用于热熔挤出的组合物,所述热熔温度不低于该醋酸羟丙甲纤维素琥珀酸酯的熔融温度或者不低于该醋酸羟丙甲纤维素琥珀酸酯和该药物均熔融的温度。
Description
技术领域
本发明涉及用于热熔挤出的组合物以及通过使用该组合物制备热熔挤出物的方法。
背景技术
近些年,包括热熔挤出药物和聚合物的混合物的步骤的用于生产制剂的方法已经受到关注。
例如,由通过热熔挤出固化水溶性不良的药物和聚合物所获得的固体分散体包括处于无定形态的药物并且具有以分子形式分散在聚合物载体中的药物。此类固体分散体显著地增加了表观溶解性并且提高了生物利用度。由于热熔挤出可在无溶剂的条件下进行,因此其适用于在水中不稳定的药物。在热熔挤出中不需要回收溶剂具有安全、无环境问题、节约用于溶剂回收步骤的能源、以及改善工人的安全的优点。此外,与常规间歇式生产系统不同,热熔挤出允许连续生产,并且从每小时的生产力和能源消耗的角度也已受到关注。
用于热熔挤出的聚合物之一为通过引入总共四种取代基而获得的醋酸羟丙甲纤维素琥珀酸酯(以下也称为“HPMCAS”)。HPMCAS包含被引入纤维素骨架中用于形成醚结构的甲氧基(-OCH3)和羟基丙氧基(-OC3H6OH)两种取代基,以及用于形成酯结构的乙酰基(-COCH3)和琥珀酰基(-COC2H4COOH)两种取代基。
在第16版日本药典(JapanesePharmacopoeia16thEdition)中列出的HPMCAS的各个取代基的含量限定如下(非专利文献1)。
表1
含量(wt%) | 摩尔取代(MS)*1 | |
甲氧基 | 12.0至28.0 | 0.73至2.83 |
羟基丙氧基 | 4.0至23.0 | 0.10至1.90 |
乙酰基 | 2.0至16.0 | 0.09至2.30 |
琥珀酰基 | 4.0至28.0 | 0.08至1.78 |
*1:摩尔取代意为在纤维素的每个葡萄糖环单元上引入的各取代基的平均摩尔数。
关于包含HPMCAS的固体分散体,例如,已经提出了通过向包含HPMCAS(摩尔取代为0.16至0.35的市售AS-LF)的组合物添加水而降低HPMCAS或水溶性不良的药物的玻璃化转变温度或软化温度的方法,其中使所得的混合物随后进行热熔挤出以形成固体分散体(专利文献1)。
还提出了用于通过热熔挤出形成包含水溶性不良的药物泊沙康唑和HPMCAS(摩尔取代为0.15至0.34的市售AS-MF或AS-MG)的制剂的方法(专利文献2);以及用于通过热熔挤出形成包含水溶性不良的药物脂质抑制剂CETP(胆固醇酯转移蛋白)和HPMCAS(摩尔取代为0.15至0.34的市售AS-MF)的制剂的方法(专利文献3)。
此外,提出了用于喷雾干燥包含水溶性不良的药物和羟基丙氧基摩尔取代为0.25、琥珀酰基摩尔取代为0.02以上、乙酰基摩尔取代为0.65以上、乙酰基和琥珀酰基的总摩尔取代为0.85以上且在相对湿度(RH)为0%下的玻璃化转变温度为131℃至146℃的HPMCAS的组合物以形成固体分散体的方法(专利文献4)。另外,提出了用于喷雾干燥包含水溶性不良的药物和羟基丙氧基摩尔取代为0.21以下、甲氧基摩尔取代为1.45以下且乙酰基和琥珀酰基的总摩尔取代为1.25以上的HPMCAS的组合物以形成固体分散体的方法(专利文献5)。
现有技术文献
专利文献
专利文献1:WO2003/077827A。
专利文献2:WO2009/129300A的第JP2011-516612T号日本国家阶段公开。
专利文献3:WO2003/063832A的第2005-523895T号日本国家阶段公开。
专利文献4:WO2005/115330A的第2008-501009T号日本国家阶段公开。
专利文献5:WO2011/159626A。
非专利文献
非专利文献1:第16版日本药典增刊I中官方专著的“醋酸羟丙甲纤维素琥珀酸酯”。
发明概述
发明所解决的问题
近些年,亟需通过简单的方法来制备固体分散体,并且在热熔挤出中降低热熔温度已成为必要的。
然而,专利文献1中的方法具有以下缺点:由于水是水溶性不良的药物的不良溶剂,因此水可以增强药物的结晶度并且阻止药物被无定形化;在高温处理中由于热和湿度使水溶性不良的药物失活;以及在高湿度的条件下由于热和水的影响使药物或载体容易水解而成为失活的。
另一方面,专利文献2至5中的每种方法都具有以下缺点:通过由热熔挤出的高温而热分解HPMCAS所产生的游离酸使水溶性不良的药物失活,或者使水溶性不良的药物热分解。
尤其在专利文献4的方法中,乙酰基与琥珀酰基的高摩尔比使得在小肠中HPMCAS的溶解度降低,使药物难以迅速释放。因此,药物不能以溶解状态在小肠中停留很长时间,降低了药物的生物可吸收性。
本发明是鉴于上述情况而做出的,并提供了用于制备热熔挤出物的方法,其中比常规热熔挤出的温度更低的热熔挤出温度防止药物由于热等而失活并且还防止在小肠的上部中药物的溶解度降低,并且以此可以较通过喷雾干燥更简单地获得热熔挤出物。
解决问题的方案
为了解决上述问题,通过广泛的研究,本发明人发现,对于HPMCAS中的四种取代基,选择在特定范围内的羟基丙氧基摩尔取代基以及乙酰基与琥珀酰基的摩尔比可以:获得玻璃化转变温度(Tg)较常规HPMCAS的玻璃化转变温度更低的HPMCAS,在较低的热熔挤出温度下制备热熔挤出物,并且防止挤出物在小肠的上部中的溶解度降低从而允许药物被迅速释放到小肠中;并且完成了本发明。
根据本发明,提供了用于热熔挤出的组合物,其包含药物和羟基丙氧基摩尔取代为0.40以上且乙酰基与琥珀酰基的摩尔比小于1.6的醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)。此外,提供了用于制备热熔挤出物的方法,其包括步骤:在热熔温度下热熔挤出包含药物和羟基丙氧基摩尔取代为0.40以上且乙酰基与琥珀酰基的摩尔比小于1.6的醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)的用于热熔挤出的组合物,所述热熔温度不低于该醋酸羟丙甲纤维素琥珀酸酯的熔融温度或者不低于该醋酸羟丙甲纤维素琥珀酸酯和该药物均熔融的温度。所述醋酸羟丙甲纤维素琥珀酸酯可用于制备用于热熔挤出的组合物或热熔挤出物。
本发明的效果
根据本发明,获得了具有高的初始溶出并且使药物在小肠中迅速释放的热熔挤出物,其中药物以溶解状态在小肠中停留很长时间,在那里药物被有效吸收,并且其中在小肠的上部中药物的溶出的降低受到抑制从而增强在小肠的上部中表现出高的可吸收性的药物的生物可吸收性。此外,由于热熔融挤出可以在较常规方法的温度更低的温度下进行,可以通过较喷雾干燥等更简单的方法来制备热熔挤出物而不使药物由于热等失活。
优选实施方案的描述
下面将更详细地对本发明进行说明。
HPMCAS中羟基丙氧基的摩尔取代为0.40以上,优选0.40至1.50,更优选0.40至1.0,进一步优选0.40至0.90。当羟基丙氧基摩尔取代小于0.40时,由于醋酸羟丙甲纤维素琥珀酸酯的热分解,热熔挤出温度升高而导致水解,并且使部分酯基从纤维素骨架释放出来而形成醋酸和琥珀酸,这使药物通过与它们的相互作用而失活。
通过第16版日本药典增刊I中官方专著的“醋酸羟丙甲纤维素琥珀酸酯”中所描述的方法可以测量包含羟基丙氧基的HPMCAS中取代基的各含量。
HPMCAS的玻璃化转变温度(Tg)优选为115℃以下,更优选60℃至115℃,进一步优选70℃至100℃。当玻璃化转变温度高于115℃时,热熔挤出温度也升高,从而可能发生上述热分解。
通常以下述方式用差示扫描量热仪(DSC)测量玻璃化转变温度(Tg)。具体而言,在氮气氛中将10mg的HPMCAS从室温以10℃/分钟的升高速率加热至高达150℃;进一步地,以10℃/分钟的降低速率将其冷却至25℃;随后以10℃/分钟的升高速率再次将其加热至高达230℃,由此观察被选为玻璃化转变温度的拐点。由于样品中含有的水分影响Tg的测量值,因此在绝对干燥状态下测量玻璃化转变温度。
甲氧基的摩尔取代(其是HPMCAS中除羟基丙氧基以外的取代基之一)不受特别限制。甲氧基的摩尔取代优选为0.70至2.90,更优选1.00至2.40,进一步优选1.4至1.9。
HPMCAS中乙酰基的摩尔取代也不受特别限制。乙酰基的摩尔取代优选为0.10至2.50,更优选0.10至1.00,进一步优选0.16至0.96。
HPMCAS中琥珀酰基的摩尔取代也不受特别限制。琥珀酰基的摩尔取代优选为0.10至2.50,更优选0.10至1.00,进一步优选0.10至0.60。
发明人已经发现,当羟基丙氧基的摩尔取代如上所述升高时,HPMCAS的溶解pH值提高,使得在pH值比小肠的下部的pH值更低的小肠的上部中HPMCAS的溶解度降低。因此,从防止在小肠的上部中HPMCAS的溶解度降低的角度,乙酰基与琥珀酰基的摩尔比小于1.6,优选0.6至1.5,更优选0.8至1.5,特别优选0.8至1.3。
在20℃下含有2wt%的HPMCAS的稀氢氧化钠水溶液(0.1mol/L)的粘度优选为1.1mPa·s至20mPa·s,更优选1.5mPa·s至3.6mPa·s。当该粘度小于1.1mPa·s时,在热熔挤出过程中熔融粘度可能过低而不能接受剪切力,使得活塞或螺杆可能空转并且从出料口挤出可能变得困难。当粘度超过20mPa·s时,该粘度作为用于热熔挤出的组合物的粘度可能过高,使得过大的扭矩可能施加于活塞或螺杆,并且因此,活塞或螺杆可能不移动或为了安全可能停机。通过第16版日本药典的一般测试(GeneralTests)中的“粘度测定(ViscosityDetermination)”所描述的方法可以测量HPMCAS的粘度。
通过使用,例如,JP54-061282A中所描述的方法可以制备HPMCAS。将原料羟丙甲纤维素(另一个名称为:羟丙基甲基纤维素,以下也称为“HPMC”)溶解在冰醋酸中,并添加作为酯化试剂的醋酸酐和琥珀酸酐以及作为反应催化剂的醋酸钠以用于通过加热的反应。在反应完成后,将大量的水加入反应溶液以获得HPMCAS的沉淀。将该沉淀物用水洗涤并且随后干燥。当使用羟基丙氧基摩尔取代为0.40以上的HPMC时,所制备的HPMCAS也具有0.40以上的羟基丙氧基摩尔取代。
药物不受特别限制,只要其可口服给药。药物的实例包括用于中枢神经系统的药物,用于循环系统的药物,用于呼吸系统的药物,用于消化系统的药物,抗生素,镇咳祛痰剂,抗组胺药,镇痛解热抗炎药,利尿剂,植物神经药物,抗疟药,止泻剂,精神药物和维生素及其衍生物。
用于中枢神经系统的药物的实例包括地西泮、艾地苯醌、阿司匹林、布洛芬、对乙酰氨基酚、萘普生、吡罗昔康、双氯芬酸、吲哚美辛、舒林酸、劳拉西泮、硝西泮、苯妥英、乙酰氨基酚、乙柳酰胺、酮洛芬和利眠宁。
用于循环系统的药物的实例包括吗多明、长春西汀、普萘洛尔、甲基多巴、双嘧达莫、呋塞米、氨苯蝶啶、硝苯啶、阿替洛尔、螺内酯、美托洛尔、吲哚洛尔、卡托普利、二硝酸异山梨醇酯、单硝酸异山梨醇酯、盐酸地拉普利、盐酸甲氯芬酯、盐酸地尔硫卓、盐酸乙苯福林、洋地黄毒苷、盐酸普萘洛尔和盐酸心得舒。
用于呼吸系统的药物的实例包括氨来呫诺、右美沙芬、茶碱、伪麻黄碱、沙丁胺醇和愈创甘油醚。
用于消化系统的药物的实例包括诸如2-[[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲基亚磺酰基]苯并咪唑和5-甲氧基-2-[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基亚磺酰基]苯并咪唑的具有抗溃疡作用的苯并咪唑类药物;西米替丁;雷尼替丁;盐酸哌仑西平;胰酶制剂;比沙可啶;以及5-氨基水杨酸。
抗生素的实例包括盐酸酞氨西林、盐酸巴氨西林、头孢克洛和红霉素。
镇咳祛痰剂的实例包括盐酸诺斯卡品、柠檬酸咳必清、氢溴酸右美沙芬、柠檬酸异米尼尔和磷酸二甲啡烷。
抗组胺药的实例包括扑尔敏、盐酸苯海拉明和盐酸异丙嗪。
镇痛解热抗炎药的实例包括布洛芬、双氯芬酸钠、氟灭酸、安乃近、阿司匹林和酮洛芬。
利尿剂的实例包括咖啡因。
植物神经药物的实例包括磷酸双氢可待因、dl-盐酸甲基麻黄碱、盐酸普萘洛尔、硫酸阿托品、氯化乙酰胆碱和新斯的明。
抗疟药的实例包括二盐酸奎宁。
止泻剂的实例包括盐酸洛哌丁胺。
精神药物的实例包括氯丙嗪。
维生素及其衍生物的实例包括维生素A、维生素B1、呋喃硫胺、维生素B2、维生素B6、维生素B12、维生素C、维生素D、维生素E、维生素K、泛酸钙和氨甲环酸。
具体而言,通过将HPMCAS用作根据本发明的固体分散体中的水溶性不良的药物的载体,水溶性不良的药物可以改善溶解性。如本文所用的术语“水溶性不良的药物”意为第16版日本药典中所描述的归类为“微溶”、“极微溶”或“几乎不溶或不溶”于水的药物。术语“微溶”意为当将1g或1mL的固体形式的药物置于烧杯中,将水倒入该烧杯,并且将所得的混合物每间隔五分钟剧烈震动30秒时,在20±5℃下用30分钟溶解所需要的水的量为100mL以上但小于1000mL。术语“极微溶”意为当以相同的方式测量时,在20±5℃下用30分钟溶解所需要的水的量为1000mL以上但小于10000mL。术语“几乎不溶或不溶”意为当以相同的方式测量时,在20±5℃下用30分钟溶解所需要的水的量为10000mL以上。
在上述药物试验中,水溶性不良的药物的溶解度意为该药物在溶剂中溶解或成为可混溶的并且没有观察到未溶解的纤维等,或者即使观察到也仅是其痕量。
水溶性不良的药物的具体实例包括诸如伊曲康唑、酮康唑、氟康唑和咪康唑的唑类化合物;诸如硝苯地平、尼群地平、氨氯地平、尼卡地平、尼伐地平、非洛地平和依福地平的二氢吡啶类化合物;诸如布洛芬、酮洛芬和萘普生的丙酸类化合物;以及诸如吲哚美辛和阿西美辛的吲哚乙酸类化合物。额外的实例包括灰黄霉素、苯妥英、卡马西平和双嘧达莫。
HPMCAS与药物的重量比不受特别限。从无定形化形式的储存稳定性角度,HPMCAS与药物的重量比优选为1:0.01至1:100,更优选1:0.1至1:10,还更优选1:0.2至1:5。
此外,根据本发明,可以向组合物添加诸如增塑剂和表面活性剂的添加剂以用于在热熔挤出中改善成型性等。
增塑剂的实例包括丙酮;甲醇;乙醇;异丙醇;诸如十六烷醇和十八烷醇的高级醇;诸如甘露醇、山梨醇和甘油的多元醇;蜂蜡;柠檬酸三乙酯;诸如聚乙二醇和聚丙二醇的亚烷基二醇;三醋精;癸二酸二丁酯;单硬脂酸甘油酯;以及醋酸单甘油酯。
表面活性剂的实例包括诸如十二烷基硫酸钠的阴离子表面活性剂;诸如甘油二酯、泊洛沙姆、聚氧乙烯脱水山梨醇脂肪酸酯(Twin20、60、80)、甘油脂肪酸酯和聚丙二醇脂肪酸酯的非离子表面活性剂;以及诸如卵磷脂和牛磺胆酸钠的天然表面活性剂。
各自从储存稳定性角度,增塑剂的量相对于HPMCAS的量优选为30wt%以下,并且表面活性剂的量相对于HPMCAS的量优选为10wt%以下。
热熔挤出物可以任选地包括在本领域中以一般方式通常使用的各种添加剂,诸如赋形剂、粘合剂、崩解剂、润滑剂或防聚集剂,并且可以以诸如片剂、颗粒剂、细粒剂和胶囊的口服固体制剂的形式或口腔膜剂的形式使用。
赋形剂的实例包括诸如蔗糖、乳糖、甘露醇和葡萄糖的糖;淀粉;以及结晶纤维素。
粘合剂的实例包括聚乙烯醇、聚丙烯酸、聚乙烯吡咯烷酮、羟乙基纤维素、羟丙甲基纤维素、羟丙基纤维素、聚乙二醇、阿拉伯树胶、明胶和淀粉。
崩解剂的实例包括低取代羟丙基纤维素、羧甲基纤维素或其盐、交联羧甲基纤维素钠、羧甲基淀粉钠、交聚维酮、结晶纤维素和结晶纤维素·羧甲基纤维素钠。
润滑剂和防聚集剂的实例包括滑石、硬脂酸镁、硬脂酸钙、胶体二氧化硅、硬脂酸、蜡、氢化油、聚乙二醇和苯甲酸钠。
所获得的口服固体制剂可以被诸如甲基纤维素和羟丙甲纤维素的水溶性包被剂膜包被,或者为用诸如醋酸羟丙甲纤维素琥珀酸酯、邻苯二甲酸羟丙甲纤维素和甲基丙烯酸酯-丙烯酸酯共聚物的肠溶包被剂肠溶包被。
下面将对用于制备热熔挤出物的方法进行说明。
首先,将药物、羟基丙氧基摩尔取代为0.40以上的HPMCAS以及任选的组分混合以制备用于热熔挤出的组合物。可将制备的用于热熔挤出的组合物通过热熔挤出机挤出以获得具有诸如环形或方形、或柱状或膜状的所需形状的挤出物。
热熔挤出机不受特别限制,只要其是包含以下结构的挤出机,即,允许将HPMCA、药物等加热以熔融并且在系统中用活塞或螺杆的剪切力捏合以及允许将所得的混合物从模具挤出。从获得更均匀的挤出物的角度,所述热熔挤出机优选为双轴式挤出机。热熔挤出机的具体实例包括ToyoSeikiSeisaku-sho,Ltd.生产的Capilograph(单轴活塞式挤出机);LeistritzAG生产的Nano-16(双轴螺杆式挤出机);以及各自由ThermoFisherScientificInc.生产的MiniLab(双轴螺杆式挤出机)和PharmaLab(双轴螺杆式挤出机)。
热熔温度不受特别限制。热熔温度优选在可以使用于热熔挤出的组合物熔融且平稳地挤出、并且可以尽量避免药物和聚合物的热分解的温度范围内选择。当不制备固体分散体时,热熔温度优选等于或高于HPMCAS的熔融温度。当制备固体分散体时,热熔温度优选等于或高于HPMCAS和药物均熔融的温度。另外,当在药物的存在下HPMCAS的熔点降低时,热熔温度优选等于或高于HPMCAS和药物均熔融的温度。更具体地,热熔温度优选为50℃至250℃,更优选60℃至200℃,还更优选90℃至190℃。当热熔温度低于50℃时,组合物可能不完全熔融并且难以挤出。当热熔温度超过250℃时,HPMCAS或药物的分子量可能由于其热分解而降低,并且药物可能因为HPMCAS的取代基的水解而失活。
热熔挤出条件不受特别限制,只要在热熔挤出过程中可以挤出粘度优选为1Pa·s至100000Pa·s的用于热熔挤出的组合物。当使用单轴活塞式挤出机时,挤出速率优选为1mm/分钟至1000mm/分钟,更优选1mm/分钟至500mm/分钟。当使用双轴螺杆式挤出机时,螺杆转速优选为1rpm至1000rpm,更优选1rpm至500rpm。当挤出速率小于1mm/分钟或螺杆转速小于1rpm时,在系统中的停留时间被延长从而可能发生热分解。当挤出速率大于1000mm/分钟或螺杆转速大于1000rpm时,在捏合部分中热熔过程可能不足,使得在热熔挤出物中药物和聚合物的熔融状态可能不均匀。
挤出后的热熔挤出物在模具出料口中以及在模具出料口之后在室温(1℃至30℃)下自然冷却或通过吹入的冷气而冷却。为了最小化药物的热分解,或为了抑制无定形药物的重结晶,期望将挤出物迅速冷却至优选50℃以下,更优选室温以下(即,30℃以下)。
冷却后的热熔挤出物可以用切割机(cutter)任选地造粒为0.1mm至5mm或更小的粒料。可通过粒径控制将所述粒料进一步粉碎成颗粒或粉末。从由于其结构而较不易升高挤出温度的角度,粉碎机可以优选冲击粉碎机,诸如喷射式粉碎机(jetmill)、切碎机(knifemill)和针磨机(pinmill)。当切割机和粉碎机的内部温度变高时,HPMCAS会被热软化并且HPMCAS颗粒会彼此粘附,因此优选边通过吹入的冷气冷却边粉碎挤出物。
实施例
将基于实施例和比较例对本发明进行说明。然而,不应理解为本发明受这些实施例限制或限于这些实施例。
<HPMCAS-1的合成>
50L的捏合机中装入12kg的冰醋酸,并将6kg的羟基丙氧基摩尔取代为0.97且甲氧基摩尔取代为1.67的羟丙甲纤维素(HPMC)加入其中,并且在其中溶解。此外,将3.7kg的醋酸酐、2.0kg的琥珀酸酐以及4.8kg的醋酸钠加入其中以在85℃下反应5小时。将纯水6.7kg加入其中并且搅拌,随后再将纯水加入其中以使HPMCA以颗粒形式沉淀。将该沉淀物过滤以收集HPMCAS粗产物。将HPMCAS粗产物用纯水洗涤、干燥,随后通过10目的筛网(开口:1700μm)筛选以获得最终含水量为1.2wt%的HPMCAS-1。
通过第16版日本药典增刊I中描述的方法测量由此获得的HPMCAS-1的各取代基的含量。发现羟基丙氧基的含量为24.1wt%(1.00的摩尔取代),甲氧基的含量为16.7wt%(1.67的摩尔取代),乙酰基的含量为5.6wt%(0.40的摩尔取代)以及琥珀酰基的含量为16.4wt%(0.50的摩尔取代)。
从使药物的过饱和状态保持更长一段时间的角度,乙酰基与琥珀酰基的摩尔比优选为1.6至4.0,更优选1.8至3.8。
<HPMCAS-2至HPMCAS-7的合成>
使用取代基含量不同的原料HPMC并且适当改变醋酸酐和琥珀酸酐的量,以相同的方式制备表2中的HPMCAS-2至HPMCAS-7。
表2
<HPMCAS的玻璃化转变温度的测量>
用差示扫描量热仪(Bruker公司生产的DSC3200SA)测量了HPMCAS-1至HPMCAS-7的玻璃化转变温度(Tg)。具体而言,将在氮气氛中的10mg的每一HPMCAS从室温以10℃/分钟的升高速率加热至高达150℃,然后以10℃/分钟的降低速率冷却至25℃,并且以10℃/分钟的升高速率再次加热至230℃。因此,获得吸热和放热曲线,并且将曲线中拐点的温度(其是在第二次温度升高中测量的拐点的温度)选为玻璃化转变温度。
<实施例1至5和比较例1至2>
将HPMCAS-1至HPMCAS-7预先干燥以使得含水量经测量为小于1wt%。使用1mm的模具直径、10mm的模具高度以及50mm/分钟的挤出速率从真空挤出机(单轴活塞式熔融挤出机:ToyoSeikiSeisaku-sho,Ltd.生产的Capilograph)中的模具出料口挤出干燥的HPMCAS-1至HPMCAS-7,并且测量HPMCAS-1至HPMCAS-7的最低挤出温度。其结果在表3中示出。
表3
HPMCAS | 玻璃化转变温度(℃) | 最低挤出温度(℃) | |
实施例1 | HPMCAS-1 | 70 | 110 |
实施例2 | HPMCAS-2 | 81 | 140 |
实施例3 | HPMCAS-3 | 94 | 140 |
实施例4 | HPMCAS-4 | 101 | 140 |
实施例5 | HPMCAS-5 | 112 | 150 |
比较例1 | HPMCAS-6 | 85 | 140 |
比较例2 | HPMCAS-7 | 126 | 180 |
实施例1至5及比较例1中所使用的羟基丙氧基摩尔取代为0.40以上的HPMCAS,与比较例2中所使用的羟基丙氧基摩尔取代小于0.40的HPMCAS相比,玻璃化转变温度低且最低挤出温度也低。
从上述结果明显看出,根据本发明,用于热熔挤出的组合物可以在更低的温度下挤出从而可以获得挤出物而不使药物热分解。
<实施例6至10和比较例3至4>
使用水溶性不良的药物抗坏血酸制备热熔挤出物。抗坏血酸具有176℃的热分解温度并且是模型药物,其引起了对在热熔挤出过程中由于热分解而导致的失活的关注。
以1:0.5的HPMCAS与抗坏血酸的重量比在研钵中混合各个HPMCAS和抗坏血酸粉末以制备用于热熔挤出的组合物。
随后,在130℃或更高的温度下用具有共转双轴螺杆(5/14mm的直径、109.5mm的长度、100rpm的螺杆转速、5分钟的停留时间)的热熔挤出机(ThermoFisherScientific公司生产的HAAKEMiniLab)使上述混合粉末进行热熔挤出。以与实施例1相同的方式测量热熔挤出物的最低挤出温度。此外,用粉碎机(OsakaChemicalCo.,Ltd.生产的WonderBlenderWB-1)将由此获得的热熔挤出物在20000rpm下粉碎并且通过30目的筛网(500μm的开口)筛选。用SM色彩计算机(SugaTestInstrumentsCo.,Ltd.生产的SM-T)对由此获得的粉末和挤出之前的用于热熔挤出的组合物进行黄度指数(YI)的测量。其结果在表4中示出。
表4
在使用包含羟基丙氧基摩尔取代为0.40以上的HPMCAS的组合物的实施例6至10以及比较例3中,最低挤出温度能够与抗坏血酸的热分解温度(176℃)相比降低了26℃以上;所获得的热熔挤出物的外观没有从白色变化并且具有20以下的黄度指数(YI),其与挤出前的混合粉末的黄度指数(YI=16.8)几乎相同;并且所述抗坏血酸经过热熔挤出而未热分解并且未失活。另一方面,在使用包含HPMCAS的组合物的比较例4中,最低挤出温度为160℃,其比实施例6至10以及比较例3的最低挤出温度更高;所获得的热熔挤出物的外观从原料粉末的白色变为棕色并且具有在很大程度上超过20的黄度指数(YI);并且已证实,所述抗坏血酸经过热熔挤出而热分解并失活。
<实施例11至15和比较例5至6>
通过使用HPMCAS-1至HPMCAS-7制备膜试验片并且使其在磷酸盐缓冲液中进行溶解时间的测量。将16gHPMCAS在64g的二氯甲烷与乙醇的重量比为1:1的二氯甲烷和乙醇的混合溶剂中的溶液浇铸在玻璃板上并且在室温下干燥。所得的膜在80℃下干燥2小时,并且切成厚度为100μm、长为1cm且宽为1cm的试验片。
根据第16版日本药典中的崩解试验(辅助管)测量试验片的溶解时间。更具体地,将试验片之一置于1L的pH值为6.0的磷酸盐缓冲液中,并用日本药典崩解测试仪(ToyamaSangyoCo.,Ltd.生产的NT-400)进行该试验片被溶解至观察到没有未溶物质所需的时间的测量。该磷酸盐缓冲液具有6.0的pH值,其相当于如美国药典36中所描述的在小肠的上部至中部中的消化液的pH值。其结果在表5中示出。
表5
HPMCAS | 膜溶解时间(分钟) | |
实施例11 | HPMCAS-1 | 63.2 |
实施例12 | HPMCAS-2 | 44.4 |
实施例13 | HPMCAS-3 | 38.9 |
实施例14 | HPMCAS-4 | 36.7 |
实施例15 | HPMCAS-5 | 25.3 |
比较例5 | HPMCAS-6 | 120以上 |
比较例6 | HPMCAS-7 | 120以上 |
药物优选迅速溶解于小肠的上部中以更有效地吸收药物,并且特别优选在短于120分钟内溶解。在比较例5中,包含乙酰基与琥珀酰基的摩尔比为1.77且摩尔羟基丙氧基取代为0.84的HPMCAS的试验片需要长时间来溶解,并且甚至在120分钟之后仍存在未溶解的试验片。这被认为是归因于HPMCAS的溶解pH值由于乙酰基与琥珀酰基的高摩尔比以及增加的羟基丙氧基摩尔取代而提高,从而使在pH值为6.0(相当于在小肠的上部至中部中的具有相对低的pH的消化液的pH值)的磷酸盐缓冲液中药物的溶解度降低。在比较例6中,包含乙酰基与琥珀酰基的摩尔比大于3.5的HPMCAS的试验片表现出在磷酸盐缓冲液中溶解度降低,并且甚至在120分钟之后仍存在未溶解的试验片。这是因为亲水的琥珀酰基的摩尔取代很小而疏水的乙酰基的摩尔取代很大。
另一方面,与在比较例中制备的试验片相比,在实施例11至15中,虽然羟基丙氧基摩尔取代为0.4以上,但乙酰基与琥珀酰基的摩尔比小于1.6的试验片更迅速地溶解于pH6.0的磷酸盐缓冲液中,并且到试验片被溶解时其花费了短于53分钟的时间。
从上述结果明显看出,通过将乙酰基与琥珀酰基的摩尔比选择在特定范围内,试验片可以迅速溶解于小肠的上部。另外,羟基丙氧基摩尔取代为0.4以上的HPMCAS具有提高的溶解pH,但可以迅速溶解于小肠的上部。
<实施例16至20和比较例7至8>
将每一HPMCAS和熔点为148℃的水溶性不良的药物酮康唑以1:1的HPMCAS与酮康唑的重量比在研钵中混合以制备用于热熔挤出的组合物。
随后,在150℃下用具有共转双轴螺杆(5/14mm的直径、109.5mm的长度、100rpm的螺杆转速、5分钟的停留时间)的热熔挤出机(ThermoFisherScientificInc.生产的HAAKEMiniLab)使上述混合粉末进行热熔挤出。用粉碎机(OsakaChemicalCo.,Ltd.生产的WonderBlenderWB-1)将由此获得的热熔挤出物在20000rpm下粉碎并且通过30目的筛网(500μm的开口)筛选。使由此获得的粉末进行第16版日本药典中的溶出试验。
通过使用900mL的描述于美国药典36中的pH值为6.0的磷酸盐缓冲液并且使用日本药典溶出测试仪(ToyamaSangyoCo.,Ltd.生产的NTR-6100A)在100rpm的桨叶转速下测量从180mg粉末溶出的酮康唑的溶出率(wt%)(对应于90mg酮康唑)。在通过测量酮康唑的已知浓度的UV吸光度值而预先制作的吸光度-转换直线的基础上,由在225nm的波长和10mm的光程长度下的UV吸光度而定量测定酮康唑的溶出率。其结果在表6中示出。
表6
*1:其示出在各个溶出测试时间(分钟)下的酮康唑的溶出率。
在实施例16至20中,包含乙酰基与琥珀酰基的摩尔比少于1.6的HPMCAS的组合物甚至在90分钟后显示出50wt%的高溶出率。
另一方面,在比较例7和8中,包含羟基丙氧基摩尔取代为0.40以上且乙酰基与琥珀酰基的摩尔比为1.6以上的HPMCAS的组合物以及包含乙酰基与琥珀酰基的摩尔比大于3.5的HPMCAS的组合物甚至在试验开始后90分钟保持在27wt%以下的低溶出率。
由上述结果认为,通过将乙酰基与琥珀酰基的摩尔比选择为小于1.6,HPMCAS在具有相对较低的pH值(诸如小肠的上部的pH值)的水溶液中的溶解度得以提高从而使溶出增加。
此外,用小型台式粉碎机(OsakaChemicalCo.,Ltd.生产的WonderBlenderWB-1)将获得的热熔挤出物在20000rpm下粉碎并且通过30目的筛网(500μm的开口)筛选。对由此获得的粉末进行X射线衍射图像的测量,从而发现在X射线衍射图像中没有观察到酮康唑的结晶峰并且酮康唑的溶出率特别高。从上述事实明显看出,通过热熔融挤出获得的组合物形成具有分散在HPMCAS中的酮康唑的固体分散体,所述酮康唑处于无定形态。
Claims (5)
1.用于热熔挤出的组合物,其包含药物和羟基丙氧基摩尔取代为0.40以上且乙酰基与琥珀酰基的摩尔比小于1.6的醋酸羟丙甲纤维素琥珀酸酯。
2.根据权利要求1所述的用于热熔挤出的组合物,其中所述醋酸羟丙甲纤维素琥珀酸酯的玻璃化转变温度Tg为115℃以下。
3.根据权利要求1或2所述的用于热熔挤出的组合物,其中所述药物是水溶性不良的药物。
4.用于制备热熔挤出物的方法,其包括以下步骤:在热熔温度下热熔挤出包含药物和羟基丙氧基摩尔取代为0.40以上且乙酰基与琥珀酰基的摩尔比小于1.6的醋酸羟丙甲纤维素琥珀酸酯的用于热熔挤出的组合物,所述热熔温度不低于所述醋酸羟丙甲纤维素琥珀酸酯的熔融温度或者不低于所述醋酸羟丙甲纤维素琥珀酸酯和所述药物均熔融的温度。
5.根据权利要求4所述的用于制备热熔挤出物的方法,其中所述热熔温度为50℃至250℃。
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