CN102245171A - 缓释微粒及其制备方法 - Google Patents

缓释微粒及其制备方法 Download PDF

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CN102245171A
CN102245171A CN2009801499086A CN200980149908A CN102245171A CN 102245171 A CN102245171 A CN 102245171A CN 2009801499086 A CN2009801499086 A CN 2009801499086A CN 200980149908 A CN200980149908 A CN 200980149908A CN 102245171 A CN102245171 A CN 102245171A
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申光炫
金栽宽
全宰逸
洪德基
裵埈浩
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Abstract

本发明涉及缓释微粒，其包括：包含药理学活性组分的基质；以及缓释层，所述缓释层包含在基质上形成缓释膜的物质。本发明的缓释微粒不仅允许对药物双重释放的有效的控制，而且还可以表现出优异的溶解特性，即使当使用少量包衣物质时也是如此。

Description

缓释微粒及其制备方法
技术领域
本公开涉及包括含有药理学活性组分的基质的控释微粒及其制备方法。
背景技术
包括药物和前药在内的许多药理学活性物质被制备为允许控释(也称为缓释或持续释放)的可口服制剂。
当以控释片剂形式给药如盐酸坦洛新这样的药物时，因为其通过幽门括约肌的不均匀速率，常常出现血液水平的增加和由此导致的浓度依赖性副作用。因此已经尝试制备具有小粒径的片剂，其在口腔中迅速崩解。
例如，韩国专利第0530546号公开了用于片剂的组合物，其包含350μm或更小的含有药物的控释微粒、赋形剂和粘合剂。然而，该专利涉及不具有包含药物的基质的控释微粒。该公开的控释微粒的缺点在于难以控制药物的释放，需要大量的包衣物质以达到微粒的控释，并且需要长的包衣时间。
发明内容
技术问题
本公开涉及提供使得药物释放易于控制的控释微粒。
本公开还涉及提供制备使得药物释放易于控制的控释微粒的方法。
技术方案
在一方面，本公开提供了控释微粒，其包括：包含药理学活性组分的基质；以及控释层，所述控释层包含在基质上形成控释膜的物质。药理学活性组分可以均匀地分散或分布在基质中。
在另一方面，本公开提供了制备控释微粒的方法，其包括：制备包含药理学活性组分的基质；以及形成控释层，所述控释层包含在基质上形成控释膜的物质。
有益效果
本公开的控释微粒不仅允许有效的药物释放控制，而且还可以表现出优异的溶解特性，即使当使用少量包衣物质时也是如此。
附图说明
图1显示了实施例5和比较例1中制备的控释微粒的溶解实验结果。
具体实施方式
本公开提供了双重控释系统，其包括：包含药理学活性组分的基质；以及控释层，所述控释层包含在基质上形成控释膜的物质。基质允许活性组分的主要控释，而额外的包衣层允许活性组分的次要控释。包衣物质的量和包衣时间可以显著减少。因此，可以表现出相当的或更好的溶解特性，即使当使用更少量的包衣物质时也是如此。
在实施方案中，形成控释膜的物质可以为选自由水不溶性聚合物、胃溶性聚合物、肠溶性聚合物、水溶性聚合物和它们的混合物组成的组中的聚合物。可以根据目的适当地选择聚合物材料。
形成控释膜的物质可以为使得能够实现受控的药物释放的不依赖于pH的水不溶性聚合物。例如，水不溶性聚合物可以为选自由乙基纤维素、水不溶性纤维素醚例如Aquacoat(FMC)等、丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯三甲基铵乙基酯共聚物(例如Eudragit RS，Evonik)、聚乙酸乙烯酯、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和它们分散体(作为丙烯酸乙酯-甲基丙烯酸甲酯共聚物分散体的示例，可以使用Eudragit NE30D(Evonik))组成的组中的一种或多种。
例如，胃溶性聚合物可以为选自由聚乙烯基乙缩醛二乙基氨基乙酸酯和甲基丙烯酸甲酯-甲基丙烯酸丁酯-甲基丙烯酸二甲基氨基乙基酯共聚物(例如Eudragit E，Evonik)组成的组中的一种或多种。
形成控释膜的物质可以为用于提供肠溶解度的肠溶性聚合物。例如，肠溶性聚合物可以为选自由羟丙基甲基纤维素乙酸酯琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、羟甲基乙基纤维素邻苯二甲酸酯、羧甲基乙基纤维素、甲基丙烯酸-甲基丙烯酸甲酯共聚物(例如Eudragit L100和Eudragit S，Evonik)和甲基丙烯酸-丙烯酸乙酯共聚物(例如Eudragit L 100-55和EudragitL30D55，Evonik)组成的组中的一种或多种。
例如，水溶性聚合物可以为选自由羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮和聚乙烯醇组成的组中的一种或多种。
这些聚合物材料可以单独使用或组合使用以达到期望的控释。
在实施方案中，基于控释微粒的总重量，控释层可以占15-60重量％，更特别地，占20-40重量％。在上述范围内，可以有效控制药物释放并且可以在短时间内完成包衣。
活性组分可以均匀地分散或分布在基质中。活性组分可以是任何需要控释的治疗性或预防性活性组分，没有特别限制。
例如，活性组分可以选自由以下组成的组中：选自由醋磺己脲、胰岛素、甲苯磺丁脲、去氨加压素和格列吡嗪组成的组中的抗糖尿病药；选自由氢氯噻嗪、泊利噻嗪和氨苯蝶啶组成的组中的利尿药；选自由氨基比林、马来酸福莫特罗和茶碱组成的组中的支气管扩张药；选自由磷酸可待因、那可丁、磷酸二甲啡烷和右美沙芬组成的组中的止咳药；选自由硝酸奎尼丁、洋地黄毒苷、盐酸普罗帕酮和普鲁卡因胺组成的组中的抗心律不齐剂；选自由苯佐卡因、利多卡因和盐酸地布卡因组成的组中的局部麻醉药；选自由苯妥英、乙琥胺和扑米酮组成的组中的抗癫痫药；选自由氢化可的松、泼尼松龙、曲安西龙和倍他米松组成的组中的合成肾上腺皮质类固醇；选自由法莫替丁、盐酸雷尼替丁、西咪替丁、硫糖铝、舒必利、替普瑞酮、普劳诺托、5-氨基水杨酸、柳氮磺吡啶、奥美拉唑、泮托拉唑和兰索拉唑组成的组中的消化性溃疡药；选自由茚洛秦、艾地苯醌、盐酸硫必利、盐酸二苯美伦和高泛酸钙组成的组中的中枢神经系统药；选自由普伐他汀钠、辛伐他汀、洛伐他汀、氟伐他汀和阿托伐他汀组成的组中的抗高血脂剂；选自由邻苯二甲酰氨苄西林盐酸盐、头孢替坦和交沙霉素组成的组中的抗生素；选自由盐酸坦洛新、甲磺酸多沙唑嗪和盐酸特拉唑嗪组成的组中的良性前列腺肥大活性成分；选自由普仑司特、
Figure BPA00001388234300031
沙丁胺醇、氨溴索、布地奈德和左旋沙丁胺醇组成的组中的平喘剂；选自由莫沙必利、枸橼酸莫沙必利、伊托必利、盐酸伊托必利、西沙必利、西沙必利一水合物、酒石酸西沙必利、多潘立酮、马来酸多潘立酮、甲氧氯普胺、盐酸甲氧氯普胺、曲美布汀、马来酸曲美布汀、氯波必利、马来酸氯波必利、溴必利和左舒必利组成的组中的胃动力剂；抗抑郁药；外周循环改善剂；抗血栓剂；抗高血压药；心衰药；糖尿病并发症药；皮肤溃疡药；以及它们的组合。
在基质中，活性组分可以单独存在或者以两种或多种的组合存在。活性组分可以以任何治疗有效量存在，没有特别限制。例如，基于基质的总重量，活性组分在基质中的量可以为1-80重量％，特别是5-30重量％。
在具体实施方案中，基质可以包含赋形剂和粘合剂。
基质中包含的赋形剂没有特别限制，只要其具有适合基质形成的性质即可，并且可以根据目的适当地选择。例如，赋形剂可以选自由有机赋形剂例如纤维素衍生物和糖类、无机赋形剂例如磷酸钙、以及它们的混合物组成的组中。纤维素衍生物可以选自由微晶纤维素和低取代羟丙基纤维素组成的组中，糖类可以选自由乳糖、淀粉和预胶化淀粉组成的组中，磷酸钙可以为选自由无水磷酸氢钙、二水磷酸氢钙和磷酸三钙组成的组中的一种或多种。
基质中赋形剂的量可以根据药物的剂量和/或微粒的最终大小来适当地控制。基于基质，其存在的量可以为20-99重量％，特别是70-95重量％。在上述范围内，仅用基质即可以有效地控制药物释放。
基质中包含的粘合剂没有特别限制，只要其起用于微粒制备的粘合剂的作用即可。例如，粘合剂可以为选自水、甲基丙烯酸共聚物的水性悬浮液、乙基纤维素的水性悬浮液和聚乙酸乙烯酯的水性悬浮液中的一种或多种。
基质中粘合剂的量可以根据药物的剂量和/或微粒的最终大小来适当地控制。基于固体含量，其在基质中存在的量可以为多于0但低于30重量％，特别是多于0但低于10重量％。
在实施方案中，控释微粒的平均粒径可以为，例如300μm或更小、250μm或更小或者200μm或更小。此外，控释微粒的平均粒径可以为，例如300-100μm、300-150μm、250-100μm、250-150μm或200-100μm。通常，实现300μm或更小的微粒的控释需要大量包衣物质和长的包衣时间。然而，本公开的包括含有药理学活性组分的基质和控释层且所述控释层含有在基质上形成控释膜的物质的控释微粒即使当粒径为300μm或更小时仍允许有效的释放控制，并且即使当使用更少量的包衣物质时仍表现出相当的或更好的溶解特性。
必要时，控释微粒可以根据需要通过普通片剂制备方法或者通过增湿/干燥或加热而制备为片剂例如快速崩解片剂、混悬片剂(suspension tablet)或咀嚼片剂或者制备为胶囊剂。为此目的，还可以包括药学可接受的添加剂，其常见示例包括增塑剂、润滑剂和其他补充助剂。
本公开还提供了制备控释微粒的方法，其包括：制备包含药理学活性组分的基质；以及形成控释层，所述控释层包含在基质上形成控释膜的物质。
在实施方案中，在制备包含药理学活性组分的基质的步骤中，可以将药物、赋形剂和粘合剂混合直至该混合物变得均匀以制备基质。赋形剂和粘合剂与上述那些相同。
用于制备基质的装置没有特别限制。例如，可以使用诸如流式成粒机或高剪切混合器的装置。可以适当地控制基质的直径以使得控释微粒的最终直径可以为300μm或更小。
通过这样，药物可以均匀分布在基质中，并且可以通过粘合剂将药物和赋形剂结合在一起。结果，基质可以通过扩散和侵蚀来如期望地释放药物。
然后，在基质上形成包含形成控释膜的物质的控释层。根据目的，形成控释膜的物质可以为不同聚合物层。例如，聚合物层可以通过以下方式形成：将其中溶解有聚合物组分的溶液喷洒至基质，直至达到期望的药物释放速率所需的厚度。可以用于聚合物层的聚合物与上述相同。
实施例
现在将描述实施例和实验。以下实施例和实验仅作说明用途而不是为了限制本公开的范围。
基质的制备
实施例1
将盐酸坦洛新(3.33g)充分研磨并与微晶纤维素粉末(Vivapur PH101，496.67g)混合。然后，制备包含盐酸坦洛新的球形基质，同时用旋转式流化床装置(GPCG-1，Glatt，Germany)喷洒水(500g)。
在制备的颗粒中，仅选择粒径为150-250μm(60-100目)的那些。
实施例2
以与实施例1中相同的方式制备球形基质，不同之处在于喷洒包含Eudragit L30D-55(88.90g；固体26.67g(固体含量＝30％)，水62.23g)和水(437.77g)的分散体。仅选择粒径为150-250μm(60-100目)的颗粒。
实施例3
将盐酸坦洛新(3.33g)充分研磨并与微晶纤维素(346.67g)、磷酸氢钙(100g)和乳糖(50g)混合。然后，制备球形基质，同时喷洒包含EudragitL30D-55(88.90g；固体26.67g(固体含量＝30％)，水62.23g)和水(437.77g)的分散体。
在制备的颗粒中，仅选择粒径为150-250μm(60-100目)的那些。
控释微粒的制备
实施例4
用相同的流化床装置通过底部喷洒将乙基纤维素(ECD，206.3g；固体61.89g)的30％水性分散体以及Kollicoat IR(3.26g，重量比＝9.5∶0.5)和柠檬酸三乙酯(14.85g)的混合水性分散体(533.33g，固体含量15％)反复喷洒至实施例1中制备的含有盐酸坦洛新的基质(800g)，以包衣至10％、20％、30％和40％的重量比(基于微粒重量)。然后，通过在室温和60℃下分别硬化12小时来制备平均粒径为250μm的控释微粒。
实施例5
将ECD(190.5g，固体57.15g)以及Kollicoat IR(6.35g，重量比＝9∶1)和柠檬酸三乙酯(13.70g)的混合水性分散体(533.33g，固体含量15％)反复喷洒至实施例1中制备的含有盐酸坦洛新的基质(800g)，以包衣至10％、15％、20％和30％的重量比(基于微粒重量)。然后，通过在室温和60℃下分别硬化12小时来制备平均粒径为230μm的控释微粒。
用相同的流化床装置，通过底部喷洒使用Eudragit L30D-55(381.3g，固体114.3g)、滑石(34.2g)、柠檬酸三乙酯(11.4g)和纯化水(373g)的混合溶液将分别具有15％、20％和30％的重量比的包衣的各个控释微粒(800g)包衣至20％的重量比(基于控释微粒的重量)。由此制备了平均粒径为约250μm，具有35％、40％和50％的重量比的包衣的肠溶性控释微粒。
实施例6
用与实施例4中相同的方式制备平均粒径为230μm的控释微粒，不同之处在于喷洒ECD(680g，固体204g)以及Kollicoat IR(36g，重量比＝8.5∶1.5)和柠檬酸三乙酯(57.6g)的混合水性分散体(1984g，固体含量＝15.0％)。
实施例7
将ECD(680g，固体204g)以及Kollicoat IR(36g，重量比＝8.5∶1.5)和柠檬酸三乙酯(57.6g)的混合水性分散体(1984g，固体含量15.0％)反复喷洒至实施例2中制备的含有盐酸坦洛新的基质(800g)，以包衣至37.2％的重量比(基于微粒重量)。然后，通过在60℃下硬化12小时来制备平均粒径为250μm的控释微粒。
比较例1
将盐酸坦洛新(20g)和羟丙基甲基纤维素(20g)溶解在纯化水(76g)和甲醇(684g)的混合溶液中。将具有大约50-150μm粒径的惰性核心(球形微晶纤维素颗粒，1000g)放入旋转式流化床装置(GPCG-1，Glatt，Germany)之后，核心被该混合溶液包衣以制备盐酸坦洛新微粒。
另外，将乙基纤维素(133.25g)和羟丙基甲基纤维素(46.75g)溶解在纯化水(174.5g)和甲醇(5645.5g)的混合溶液中以制备包衣溶液。
将盐酸坦洛新微粒(1000g)放入相同的流化床装置中并用另外制备的包衣溶液包衣至18％的重量比(基于微粒)以制备控释微粒。
将制备的控释微粒(1000g)放入相同的流化床装置中并用ECD(500g)、Eudragit L30D-55(1000g)、Eudragit NE30D(166.75g)和纯化水(1666.75g)的混合溶液包衣至50％的重量比(基于微粒)以制备平均直径为约250μm的肠溶性控释微粒。
实验例：溶解实验
将实施例和比较例1中制备的各个盐酸坦洛新0.2mg微粒填充入胶囊中并根据韩国药典溶解实验2号(Korean Pharmacopeia Dissolution Test No.2)比较溶解速率。该测定在75rpm下进行，使用崩解实验溶液2号(pH 6.8，500mL)。在溶解实验开始后30分钟、1小时和4小时时取样(10mL)。加入0.5N HCl(1.0mL)然后过滤，用高效液相色谱法(HPLC)在以下条件下定量滤液。各个微粒测定6个样品。
柱：LUNA C18(4.6x 150mm，5μm)
检测器：UV 225nm
流速：以保持坦洛新停留时间为约6分钟。
进样体积：100μL
柱温度：40℃
流动相：将高氯酸(8.7mL)和氢氧化钠(3.0g)溶解在水(1900mL)中以制备氢氧化钠实验溶液。调节至pH 2.0后，加入水以使最终体积为2000mL。将乙腈(600mL)加入所得溶液(1400mL)中以用作流动相。
结果在图1中示出。可以看到实施例5的控释微粒(包衣至35％的重量比)表现出与比较例1(包衣至58％的重量比)相似的溶解曲线。因此，可以证明根据本公开的控释微粒表现出与比较例1相当的溶解特性，即使用更少量的包衣物质和更少的包衣时间也是如此。
本领域技术人员应当理解前述说明书中所公开的概念和具体实施方案可以容易地用作修改或设计用于实现本公开相同目的的其他实施方案的基础。本领域技术人员还应当理解这样的等同实施方案并不偏离所附权利要求中所述的本公开的精神和范围。

Claims (15)

1.控释微粒，其包含：
包含药理学活性组分的基质；以及
控释层，所述控释层包含在基质上形成控释膜的物质。
2.如权利要求1所述的控释微粒，其中所述形成控释膜的物质为选自由水不溶性聚合物、胃溶性聚合物、肠溶性聚合物、水溶性聚合物和它们的混合物组成的组中的聚合物。
3.如权利要求2所述的控释微粒，其中所述水不溶性聚合物为选自由乙基纤维素、纤维素醚、丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯三甲基铵乙基酯共聚物、聚乙酸乙烯酯、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和它们的分散体组成的组中的一种或多种。
4.如权利要求2所述的控释微粒，其中所述胃溶性聚合物为选自由聚乙烯基乙缩醛二乙基氨基乙酸酯和甲基丙烯酸甲酯-甲基丙烯酸丁酯-甲基丙烯酸二甲基氨基乙基酯共聚物组成的组中的一种或多种。
5.如权利要求2所述的控释微粒，其中所述肠溶性聚合物为选自由羟丙基甲基纤维素乙酸酯琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、羟甲基乙基纤维素邻苯二甲酸酯、羧甲基乙基纤维素、甲基丙烯酸-甲基丙烯酸甲酯共聚物和甲基丙烯酸-丙烯酸乙酯共聚物组成的组中的一种或多种。
6.如权利要求2所述的控释微粒，其中所述水溶性聚合物为选自由羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮和聚乙烯醇组成的组中的一种或多种。
7.如权利要求1所述的控释微粒，其中基于所述控释微粒的总重量，所述控释层占15-60重量％。
8.如权利要求1所述的控释微粒，其中所述活性组分选自由以下组成的组中：选自由醋磺己脲、胰岛素、甲苯磺丁脲、去氨加压素和格列吡嗪组成的组中的抗糖尿病药；选自由氢氯噻嗪、泊利噻嗪和氨苯蝶啶组成的组中的利尿药；选自由氨基比林、马来酸福莫特罗和茶碱组成的组中的支气管扩张药；选自由磷酸可待因、那可丁、磷酸二甲啡烷和右美沙芬组成的组中的止咳药；选自由硝酸奎尼丁、洋地黄毒苷、盐酸普罗帕酮和普鲁卡因胺组成的组中的抗心律不齐剂；选自由苯佐卡因、利多卡因和盐酸地布卡因组成的组中的局部麻醉药；选自由苯妥英、乙琥胺和扑米酮组成的组中的抗癫痫药；选自由氢化可的松、泼尼松龙、曲安西龙和倍他米松组成的组中的合成肾上腺皮质类固醇；选自由法莫替丁、盐酸雷尼替丁、西咪替丁、硫糖铝、舒必利、替普瑞酮、普劳诺托、5-氨基水杨酸、柳氮磺吡啶、奥美拉唑、泮托拉唑和兰索拉唑组成的组中的消化性溃疡药；选自由茚洛秦、艾地苯醌、盐酸硫必利、盐酸二苯美伦和高泛酸钙组成的组中的中枢神经系统药；选自由普伐他汀钠、辛伐他汀、洛伐他汀、氟伐他汀和阿托伐他汀组成的组中的抗高血脂剂；选自由邻苯二甲酰氨苄西林盐酸盐、头孢替坦和交沙霉素组成的组中的抗生素；选自由盐酸坦洛新、甲磺酸多沙唑嗪和盐酸特拉唑嗪组成的组中的良性前列腺肥大活性成分；选自由普仑司特、
Figure FPA00001388234200021
沙丁胺醇、氨溴索、布地奈德和左旋沙丁胺醇组成的组中的平喘剂；选自由莫沙必利、枸橼酸莫沙必利、伊托必利、盐酸伊托必利、西沙必利、西沙必利一水合物、酒石酸西沙必利、多潘立酮、马来酸多潘立酮、甲氧氯普胺、盐酸甲氧氯普胺、曲美布汀、马来酸曲美布汀、氯波必利、马来酸氯波必利、溴必利和左舒必利组成的组中的胃动力剂；抗抑郁药；外周循环改善剂；抗血栓剂；抗高血压药；心衰药；糖尿病并发症药；皮肤溃疡药；以及它们的组合。
9.如权利要求1所述的控释微粒，其中所述基质还包含赋形剂和粘合剂。
10.如权利要求9所述的控释微粒，其中所述赋形剂选自纤维素衍生物、糖类、磷酸钙和它们的混合物。
11.如权利要求10所述的控释微粒，其中所述纤维素衍生物选自由微晶纤维素和低取代羟丙基纤维素组成的组中，所述糖类选自由乳糖、淀粉和预胶化淀粉组成的组中，所述磷酸钙选自由无水磷酸氢钙、二水磷酸氢钙和磷酸三钙组成的组中。
12.如权利要求9所述的控释微粒，其中所述粘合剂为选自水、甲基丙烯酸共聚物的水性悬浮液、乙基纤维素的水性悬浮液和聚乙酸乙烯酯的水性悬浮液中的一种或多种。
13.如权利要求1所述的控释微粒，其中所述控释微粒的平均粒径为300μm或更小。
14.如权利要求1所述的控释微粒，其中所述控释微粒制备为片剂或胶囊剂。
15.用于制备如权利要求1至14之一所述的控释微粒的方法，其包括：
制备包含药理学活性组分的基质；以及
形成控释层，所述控释层包含在基质上形成控释膜的物质。
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