CN102781429A - 经熔体涂覆的药物剂型 - Google Patents
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- CN102781429A CN102781429A CN2011800124846A CN201180012484A CN102781429A CN 102781429 A CN102781429 A CN 102781429A CN 2011800124846 A CN2011800124846 A CN 2011800124846A CN 201180012484 A CN201180012484 A CN 201180012484A CN 102781429 A CN102781429 A CN 102781429A
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Abstract
本发明涉及不易溶于水的活性剂的制剂,其由具有含有活性剂的涂层的载体颗粒构成,其中使不易溶于水的活性剂包埋于由两亲共聚物制成的涂层中,且涂层以无溶剂熔体的形式施用。
Description
本发明涉及涂覆有含活性成分涂层的载体颗粒,其中使微水溶性活性成分包埋于由两亲共聚物构成的涂层中,所述两亲共聚物通过使乙酸乙烯酯和N-乙烯基内酰胺在聚醚存在下聚合而得到,且涂层以熔体的形式施用。本发明进一步涉及生产该经涂覆的载体颗粒和该颗粒的附聚物的方法,及其在药物给药剂型中的用途。
用含活性成分涂料涂覆颗粒通常通过喷雾施用涂料溶液而进行。
由溶液加工的缺点是有机溶剂的复杂处理,这对环境和设备施加高要求。此外,通常难以找到用于微溶性活性成分的合适有机溶剂。
WO 2005/034908公开了将包含贝特类和他汀类的组合作为活性成分的熔体或分散体在流化床造粒机中施用于载体颗粒上。活性成分组合呈活性成分在亲水性或疏水性或pH相关性可溶聚合物的固溶体或固体分散体的形式。由此所得颗粒可被压成片剂。
通过乙酸乙烯酯和N-乙烯基内酰胺在聚醚存在下自由基聚合得到的两亲共聚物如接枝聚合物是本身已知的。
WO 2007/051743公开了N-乙烯基内酰胺、乙酸乙烯酯和聚醚的水溶性或水分散性共聚物在药物、化妆品、营养、农用化学或其它工业应用中作为增溶剂的用途。其中非常一般性地说明了相应的接枝聚合物也可与活性成分以熔体加工。
WO 2009/013202公开了可将N-乙烯基内酰胺、乙酸乙烯酯和聚醚的这类接枝聚合物在挤出机中熔融并与粉末或液体活性成分混合并加工成片剂。
本发明的目的是找到一种涂覆和附聚载体颗粒的改进方法。
因此,开发了一种用含活性成分涂料涂覆载体颗粒的方法,其中使微水溶性活性成分包埋于由两亲共聚物构成的涂层中,所述两亲共聚物通过使乙酸乙烯酯和N-乙烯基内酰胺在聚醚存在下聚合而得到,其中涂层以熔体的形式施用。
熔体为无溶剂的。在本发明上下文中,“无溶剂”是指存在小于5000ppm溶剂。
此外,发现相应的经涂覆的载体颗粒。
用于包埋水溶性活性成分的合适两亲共聚物及其通过熔体挤出的加工性例如由WO 2007/051743已知。
相应共聚物通过如下组分的混合物的自由基引发聚合而得到:
i)30-80重量%N-乙烯基内酰胺,
ii)10-50重量%乙酸乙烯酯,和
iii)10-50重量%聚醚,
条件是i)、ii)和iii)之和为100重量%。
在本发明一个实施方案中,使用由如下组分得到的优选共聚物:
i)30-70重量%N-乙烯基内酰胺,
ii)15-35重量%乙酸乙烯酯,和
iii)10-35重量%聚醚。
特别优选使用的共聚物可由如下组分得到:
i)40-60重量%N-乙烯基内酰胺,
ii)15-35重量%乙酸乙烯酯,和
iii)10-30重量%聚醚。
非常特别优选使用的共聚物可由如下组分得到:
i)50-60重量%N-乙烯基内酰胺,
ii)25-35重量%乙酸乙烯酯,和
iii)10-20重量%聚醚。
就优选和特别优选的组成而言,适用组分i)、ii)和iii)之和为100重量%的条件。
有用的N-乙烯基内酰胺为N-乙烯基己内酰胺或N-乙烯基吡咯烷酮或其混合物。优选使用N-乙烯基己内酰胺。
因此,尤其优选由N-乙烯基己内酰胺、乙酸乙烯酯和聚醚形成的两亲共聚物。
所用接枝基体为聚醚。有用的聚醚优选为聚亚烷基二醇。聚亚烷基二醇可具有1000-100 000Da[道尔顿],优选1500-35 000Da,更优选1500-10 000Da的分子量。分子量由根据DIN 53240测量的OH值测定。
特别优选的聚亚烷基二醇为聚乙二醇。额外合适的还有聚丙二醇、聚四氢呋喃或由2-乙基环氧乙烷或2,3-二甲基环氧乙烷得到的聚丁二醇。
合适的聚醚还有由氧化乙烯、氧化丙烯和氧化丁烯得到的聚亚烷基二醇的无规或嵌段共聚物,例如聚乙二醇-聚丙二醇嵌段共聚物。嵌段共聚物可以为AB型或ABA型。
优选的聚亚烷基二醇还包括在一个或两个OH端基上烷基化的那些。有用的烷基包括支化或非支化C1-C22烷基,优选C1-C18烷基,例如甲基、乙基、正丁基、异丁基、戊基、己基、辛基、壬基、癸基、十二烷基、十三烷基或十八烷基。
制备根据本发明使用的共聚物的一般方法是本身已知的。该制备通过优选在溶液中、在非水有机溶剂中或在混合非水/含水溶剂中自由基引发聚合而进行。合适的制备方法例如描述于WO 2007/051743和WO2009/013202中,明确参考其关于制备方法的公开内容。
所用两亲共聚物尤其是通过使乙酸乙烯酯和N-乙烯基内酰胺在聚醚存在下聚合而得到的聚合物。
也可将其它聚合物或低分子量物质掺入涂层中。
本发明方法的特征在于将载体颗粒用熔体涂覆。熔体由微溶性活性成分、溶解聚合物和任选其它添加剂构成。熔体的冷却和凝固产生包含溶解形式的活性成分的涂层。
用熔体涂覆载体颗粒在常规流化床单元中进行。在这种情况下,将熔体喷雾于由载体颗粒构成的流化床上。
熔体有利地在实际喷雾以前已在温度可控的储蓄容器中提供。在本发明一个实施方案中,可将由聚合物、活性成分和任选其它添加剂构成的熔体借助同样温度可控的熔体泵通过喷嘴喷雾。所用喷嘴可以为单流体喷嘴(einstoffdüse)或多流体喷嘴(mehrstoffdüse)。合适的多流体喷嘴尤其是双流体喷嘴(zweistoffdüse)。
除流化床单元外,也可使用其它设备,其中载体颗粒通过罐的旋转或通过引入空气发动,例如涂覆罐、强力混合机、水平辊筒涂布机、Kugelcoater、Innojet单元。适用于施用所述配制剂的还有称为喷射流化床的(Procell技术)。
进料空气温度通常为30-200℃,优选40-120℃。产物温度一般为20-100℃,优选30-80℃。
在本发明另一实施方案中,熔体还可不经雾化而施用,例如通过倾入薄料流中。
如已描述的,熔体为无溶剂的。通常用于这类目的的溶剂,例如链烷醇如乙醇、甲醇或异丙醇,以及丙酮、乙酸乙酯、二氯甲烷、氯仿、二甲基甲酰胺和/或甲基乙基酮的总含量应小于5000ppm。链烷醇的含量应优选小于10ppm。
合适的载体颗粒特别是球形或至少近似球形的颗粒,已知为“彩色糖粒(nonpareilles)”。在本发明的一个实施方案中,彩色糖粒整体,即100重量%由药物赋形剂构成。彩色糖粒可由常规药物赋形剂,例如蔗糖、角叉菜聚糖、淀粉或微晶纤维素构成。它们可以以不同尺寸(100–2000μm)获得。粒度通常为700-1000μm。
所用载体颗粒也可以为片剂或颗粒。
通常,涂层中活性成分与两亲聚合物的重量比为1:99-80:20,优选10:90-60:40。这在载体颗粒最终固化的聚合物涂层中产生基于总质量为1-80重量%的活性成分浓度。
也可涂覆作为载体颗粒的颗粒或细粉,但是后一种情况还可产生载体颗粒的附聚。在本发明一个实施方案中,这种颗粒或粉末还可包含一种或多种活性成分。
两亲共聚物的含活性成分涂层的层厚度可以为5-1000μm,优选10-700μm。
根据本发明,术语“微水溶性”还包括基本不溶性物质且指对于20°C下的该物质在水中的溶液,每g物质需要至少30g至100g水。在基本不溶性物质的情况下,每g物质需要至少10000g水。
就本发明而言,微水溶性物质优选应理解为指生物活性物质,例如用于人类和动物的药物活性成分、化妆品或农用化学活性成分或食品增补剂或饮食活性成分。
此外,要溶解的可用微溶性物质还包括染料如无机或有机颜料。
根据本发明,可用的生物活性物质原则上包括熔点在涂料混合物的熔融条件下的分解点的所有固态活性成分。该共聚物通常可在至多260°C的温度下加工。温度下限在每种情况下取决于待熔融混合物的组成和待加工的微溶性物质。温度下限可以为30℃。
较低的温度取决于熔体的粘度,其必须足够低以喷雾。此外,喷嘴形状和直径对经由温度建立的熔体粘度而言是重要的。
所用活性药物成分为水溶性由不溶性至微溶性变化的物质。根据DAB9(Deutsches Arzneimittelbuch,German Pharmacopeia),药物活性成分的溶解性分类如下:微溶性(在30-100份溶剂中可溶);轻微可溶(在100-1000份溶剂中可溶);基本不溶性(在大于10 000份溶剂中可溶)。活性成分可来自任何指示区。
此处,实例包括苯并二氮杂类、抗高血压药、维生素、细胞抑制剂—尤其是紫杉醇、麻醉药、神经安定药、抗抑郁药、抗病毒剂如抗HIV药、抗生素、抗真菌剂、抗老年痴呆药、杀真菌剂、化疗药物、泌尿系统用药、血小板凝集抑制剂、磺酰胺类、解痉药、激素、免疫球蛋白、血清、甲状腺治疗药、精神药物、抗帕金森药和其他抗运动机能亢进药、眼科用药、神经病用制剂、钙代谢调节剂、肌肉松弛药、麻醉剂、类脂降低药、肝治疗药、冠状动脉药、心脏药、免疫治疗药、调节性肽及其抑制剂、催眠药、镇静药、妇科用药、痛风治疗药、纤维蛋白溶解药、酶制剂和运输蛋白、酶抑制剂、催吐药、血流刺激药、利尿药、诊断助剂、皮质激素类、胆碱药、胆用治疗药、平喘药、支气管扩张药、β受体阻断剂、钙拮抗剂、ACE抑制剂、抗动脉硬化药、抗炎药、抗凝血药、抗低血压药、抗低血糖药、抗高血压药、抗纤维蛋白溶解药、抗癫痫药、抗呕吐药、解毒药、抗糖尿病药、抗心律不齐药、抗贫血药、抗过敏药、驱肠虫药、止痛药、兴奋剂、醛固酮拮抗药、减肥药。
也可加工来自传统中药的微溶性活性成分。
药物配制剂中本发明增溶剂的含量取决于活性成分为20-99重量%。
当然可将其它药物常规赋形剂加入本发明配制剂,例如其它增溶剂、聚合物、染料、无机载体、崩解剂、凝胶形成剂、阻滞剂、抗氧化剂、芳香剂、增塑剂、缓冲物质。耐胃液聚合物或阻滞聚合物的掺入允许控制活性成分的释放。
结晶抑制物质如Kollidon 30的加入允许提高固熔体的稳定性。
合适的增塑剂的实例包括三醋精、柠檬酸三乙酯、单硬脂酸甘油酯、聚乙二醇或泊洛沙姆。
合适的额外增溶剂为HLB(亲水-亲脂平衡)值大于11的界面活性物质,例如用40个氧化乙烯单元乙氧基化的氢化蓖麻油(RH 40)、用35个氧化乙烯单元乙氧基化的蓖麻油(Cremophor EL)、聚山梨醇酯80、泊洛沙姆或月桂基硫酸钠。
染料如铁氧化物、二氧化钛、三苯基甲烷染料、偶氮染料、喹啉染料、靛蓝染料、类胡萝卜素以使给药剂型染色,不透明剂如二氧化钛或滑石以提高不透明度和节约染料。
除用于化妆品和药物外,根据本发明生产的配制剂还适用于食品领域中,例如用于微水溶性或水不溶性营养、助剂或添加剂如脂溶性维生素或类胡萝卜素的掺入。
根据本发明得到的配制剂在农用化学中的用途可尤其包括包含农药、除草剂、杀真菌剂或杀虫剂的配制剂,特别是用作用于喷雾或洒水的配制剂的作物保护组合物的那些配制剂。
根据本发明得到的经涂覆的载体颗粒可用作胶囊填料或用于小药囊中。
也可将丸剂或颗粒形式的经涂覆的载体颗粒压制成片剂。也可使用其它常规制片助剂如填料、粘合剂、崩解剂以及流动助剂和分离助剂。
借助本发明方法,可得到在载体颗粒上的含活性成分涂层作为包含微溶性物质的所谓固溶体。根据本发明,固溶体指其中观察不到微溶性物质的结晶组分的体系。
通过本发明方法得到的配制剂如所述以无定形形式存在,无定形形式是指生物活性物质的结晶组分小于5重量%。无定形状态优选借助DSC或XRD检测。这种无定形状态也可称为X射线无定形状态。
本发明方法允许生产具有高活性成分负载和就微溶性物质的无定形状态而言的良好稳定性的稳定配制剂。
本方法的特定特征为两亲聚合物与微溶性活性成分一起以无溶剂熔体形式使用。两亲聚合物甚至在其熔点以下熔融或溶解活性成分。涂层因此不是常规丸剂或片剂涂层,而是保持微溶性活性成分为溶解形式的涂层。形成的固溶体也可用作载体颗粒之间的粘合桥,因此用作造粒助剂。固溶体的优点是微溶性活性成分可由此更好地生物利用。活性成分可以以无定形形式或分子溶解形式存在于涂层或粘合剂层中。
由于两亲聚合物结构,聚合物显著适用作固溶体的基体。如上所述,固体溶解可借助熔体挤出方法实现。一流的可选方法为固溶体作为在固体剂型如丸剂、颗粒、粉末或片剂上的涂层形成。常规流化床体系的使用使得该方法更加有意义。此外,熔体中无溶剂对涂层的性能具有积极影响。它们是较少孔的,但较光滑且更均匀。
该加工方法的另一优点是可将微溶性活性成分的固溶体加工成多颗粒固体药物剂型。这些多颗粒药物剂型可例如填充到硬明胶胶囊中或甚至加成片剂。
实施例
所用两亲共聚物为由13重量%MW为6000的聚乙二醇、57重量%N-乙烯基己内酰胺和30重量%平均摩尔质量为44 000道尔顿的乙酸乙烯酯形成的接枝聚合物。
加工在Glatt流化床造粒机(GPCG 3.1)中进行。喷雾用直径4mm的双流体喷嘴进行。
熔体通过将涂料组分加热至70℃并将它们施用于由蔗糖(粒度为710-850μm的丸剂(筛分级分))或Granulac 200(乳糖,来自Meggle,(d50)=30μm,堆密度535g/l)构成的载体颗粒上而得到。
对于各个实施例,描述在流化床造粒机中加工的工艺参数。
使用如下仪器和条件借助XRD和DSC分析所产生的涂层的结晶度或无定形度。
XRD (X射线衍射图)
仪器:具有9位样品转换器的D 8Advance衍射仪(来自Bruker/AXS)
测量方法:θ-θ反射几何
角范围2θ:2-80°
步长:0.02°
每角步的测量时间:4.8秒
反散射狭缝:Soller狭缝
检测器:Sol-X检测器
温度:室温
发生器设置:40kV/50mA
在如下实施例中,对不同的载体颗粒提供含活性成分涂层。
实施例1:
组成 | 量 |
PEG 6000 | 400g |
共聚物 | 50g |
非诺贝特 | 100g |
蔗糖丸剂 | 1000g |
工艺参数 | 值 |
进料空气温度[℃] | 40 |
喷雾空气压力[巴] | 4.0 |
XRD分析未显示任何结晶活性成分部分。
活性成分从400mg丸剂中的释放在USP设备2中在700ml 0.1N HCl中进行。在60分钟以后,释放90%活性成分。
实施例2:
组成 | 量 |
PEG 10 000 | 1600g |
PEG 400 | 50g |
共聚物 | 200g |
桂利嗪 | 100g |
蔗糖丸剂 | 1000g |
工艺参数 | 值 |
进料空气温度[℃] | 45 |
喷雾空气压力[巴] | 4.0 |
XRD分析未显示任何结晶活性成分部分。
活性成分从0.6g丸剂中的释放在USP设备2中在700ml 0.1N HCl中进行。在60分钟以后,释放70%活性成分。
实施例3:
组成 | 量 |
Lutrol F 681) | 1400g |
共聚物 | 150g |
吡罗昔康 | 80g |
MCC丸剂 | 1000g |
1)泊洛沙姆188
工艺参数 | 值 |
进料空气温度[℃] | 42 |
喷雾空气压力[巴] | 4.5 |
XRD分析未显示任何结晶活性成分部分。
活性成分从400mg丸剂中的释放在USP设备2中在700ml 0.1N HCl中进行。在40分钟以后,释放100%活性成分。
实施例4:
组成 | 量 |
Lutrol F 68 | 800g |
Lutrol F 1272) | 1000g |
共聚物 | 200g |
桂利嗪 | 100g |
蔗糖丸剂 | 1000g |
2)泊洛沙姆407
工艺参数 | 值 |
进料空气温度[℃] | 45 |
喷雾空气压力[巴] | 5 |
XRD分析未显示任何结晶活性成分部分。
活性成分从515mg丸剂中的释放在USP设备2中在700ml 0.1N HCl中进行。在30分钟以后,释放100%活性成分。
实施例5:
组成 | 量 |
PEG 10 000 | 1600g |
Lutrol F 68 | 50g |
共聚物 | 200g |
克霉唑 | 100g |
蔗糖丸剂 | 1000g |
工艺参数 | 值 |
进料空气温度[℃] | 45 |
喷雾空气压力[巴] | 4.0 |
XRD分析未显示任何结晶活性成分部分。
活性成分从300mg丸剂中的释放在USP设备2中在700ml 0.1N HCl中进行。在30分钟以后,释放100%活性成分。
实施例6:
组成 | 量 |
PEG 6000 | 2800g |
共聚物 | 160g |
酮康唑 | 80g |
蔗糖丸剂 | 1000g |
工艺参数 | 值 |
进料空气温度[℃] | 50 |
喷雾空气压力[巴] | 4.0 |
XRD分析未显示任何结晶活性成分部分。
活性成分从420mg丸剂中的释放在USP设备2中在700ml 0.1N HCl中进行。在60分钟以后,释放100%活性成分。
实施例7:
组成 | 量 |
Lutrol F 127 | 1000g |
Lutrol F 68 | 1000g |
共聚物 | 220g |
酮康唑 | 80g |
蔗糖丸剂 | 1000g |
工艺参数 | 值 |
进料空气温度[℃] | 45 |
喷雾空气压力[巴] | 4.5 |
XRD分析未显示任何结晶活性成分部分。
活性成分从600mg丸剂中的释放在USP设备2中在700ml 0.1N HCl中进行。在60分钟以后,释放100%活性成分。
实施例8:
组成 | 量 |
Lutrol F 127 | 1000g |
Lutrol F 68 | 1000g |
共聚物 | 220g |
酮康唑 | 80g |
Granulac 200 | 1000g |
工艺参数 | 值 |
进料空气温度[℃] | 45 |
喷雾空气压力[巴] | 4.5 |
XRD分析未显示任何结晶活性成分部分。
活性成分从600mg颗粒中的释放在USP设备2中在700ml 0.1N HCl中进行。在60分钟以后,释放100%活性成分。
实施例9:
物质 | 量 |
PEG 6000 | 1000g |
共聚物 | 220g |
桂利嗪 | 80g |
Granulac 200 | 1000g |
工艺参数 | 值 |
进料空气温度[℃] | 45 |
喷雾空气压力[巴] | 4.5 |
XRD分析未显示任何结晶活性成分部分。
活性成分从400mg颗粒中的释放在USP设备2中在700ml 0.1N HCl中进行。在60分钟以后,释放85%活性成分。
Claims (18)
1.一种微水溶性活性成分的配制剂,由具有含活性成分涂层的载体颗粒构成,其中使所述微溶性活性成分包埋于由两亲共聚物构成的涂层中,且涂层以无溶剂熔体的形式施用。
2.根据权利要求1的配制剂,其中使用通过如下组分的混合物的自由基引发聚合获得的两亲共聚物:
i)30-80重量%N-乙烯基内酰胺,
ii)10-50重量%乙酸乙烯酯,和
iii)10-50重量%聚醚,
条件是i)、ii)和iii)之和为100重量%。
3.根据权利要求1和2的配制剂,其中所述共聚物由如下组分得到:
i)30-70重量%N-乙烯基内酰胺,
ii)15-35重量%乙酸乙烯酯,和
iii)10-35重量%聚醚。
4.根据权利要求1-3中任一项的配制剂,其中所述共聚物由如下组分得到:
i)40-60重量%N-乙烯基内酰胺,
ii)15-35重量%乙酸乙烯酯,和
iii)10-30重量%聚醚。
5.根据权利要求1-4中任一项的配制剂,其中所述共聚物由如下组分得到:
i)50-60重量%N-乙烯基内酰胺,
ii)25-35重量%乙酸乙烯酯,和
iii)10-20重量%聚醚。
6.根据权利要求1-5中任一项的配制剂,其中所用载体颗粒为由药物赋形剂构成的丸剂。
7.根据权利要求1-6中任一项的配制剂,其中所述载体颗粒由蔗糖、角叉菜聚糖、淀粉、乳糖或微晶纤维素构成。
8.根据权利要求1-7中任一项的配制剂,其中所述载体颗粒具有100-2000μm的粒度。
9.根据权利要求1-5中任一项的配制剂,其中所用载体为由活性成分和两亲聚合物构成的颗粒。
10.根据权利要求1-9中任一项的配制剂,其中所述涂层额外包含药物赋形剂。
11.根据权利要求1-10中任一项的配制剂,其中所述涂层包含20-99重量%两亲聚合物。
12.一种生产根据权利要求1-11中任一项的配制剂的方法,其包括通过将包含一种或多种活性成分和两亲共聚物的熔体施用于由载体颗粒构成的流化床上而生产配制剂。
13.根据权利要求12的方法,其中所述熔体通过喷雾施用。
14.根据权利要求12或13的方法,其中所述熔体在30-260℃的温度下得到。
15.根据权利要求12-14中任一项的方法,其中所述熔体是无溶剂的。
16.根据权利要求12-15中任一项的方法,其中所述熔体的溶剂含量小于5000ppm。
17.一种剂型,包含根据权利要求1-11中任一项的配制剂。
18.根据权利要求17的剂型,其呈片剂、胶囊或小药囊的形式。
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