CN102655857A - 含有基于聚醚的两亲性共聚物与亲水聚合物组合的速溶性固体药物制剂 - Google Patents
含有基于聚醚的两亲性共聚物与亲水聚合物组合的速溶性固体药物制剂 Download PDFInfo
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Abstract
本发明涉及含有在包含两亲性聚醚共聚物和至少一种亲水聚合物的聚合物基体中的低水溶性活性物质的制剂的剂型,其中低水溶性活性物质以无定形形式存在于聚合物基体中。
Description
本发明涉及包含微水溶性活性成分和两亲性共聚物与能影响配制剂稳定性和/或生物活性物质释放的亲水聚合物组合的固体药物配制剂,所述两亲性共聚物通过乙酸乙烯基酯和N-乙烯基内酰胺在聚醚的存在下聚合而得到。本发明进一步涉及用于生产这些配制剂的方法及其用途。
基于聚醚的相应共聚物用作微水溶性活性成分的增溶剂。
在均质配制剂,尤其是生物活性物质的生产中,疏水性,即微水溶性物质的增溶具有非常大的实践重要性。
增溶应理解为指通过表面活性化合物,增溶剂使微溶或不溶于特定溶剂,尤其是水中的物质增溶。这类增溶剂能将微水溶性或水不溶性物质转化成透明,至多乳白色的水溶液而不使这些物质的化学结构在该过程中经受任意变化。
在所产生的增溶物中,微水溶性或水不溶性物质以胶态溶解形式存在于形成于水溶液中的表面活性化合物的分子缔合物如疏水性域或胶束中。所得溶液为具有视觉透明至乳白色外观的稳定或亚稳单相体系。
在药物配制剂的情况下,药物的生物利用度和因此功效可通过使用增溶剂而提高。
对于增溶剂的另一理想要求是用微溶性物质形成所谓“固溶体”的能力。术语“固溶体”描述了物质以胶态分散或理想地分子分散在固体基体如聚合物基体中的一种状态。这类固溶体,例如当用于微溶性活性成分的固体药物给药剂型中时导致改善的活性成分释放。对于该类固溶体的重要要求是它们在长时间,甚至在储存过程中为稳定的,这是指活性成分不结晶出来。此外,固溶体的载量或换言之形成具有最大活性成分含量的稳定固溶体的能力也是重要的。
WO2007/051743公开了N-乙烯基内酰胺、乙酸乙烯基酯和聚醚的两亲性水溶性或水分散性共聚物在药物、化妆品、食品技术、农业化学或其他工业应用中作为增溶剂的用途。其中以非常一般性的术语描述了相应的接枝聚合物还可以与活性成分以熔体加工。
WO2009/013202公开了可将N-乙烯基内酰胺、乙酸乙烯基酯和聚醚的这种接枝聚合物在挤出机中熔融并与粉状或液体活性成分混合,其中描述了在显著低于活性成分的熔点的温度下挤出。
然而,熔融接枝聚合物与粉状或液体活性成分的混合不能总是达到令人满意的高且同时稳定的活性成分负载。特别地,活性成分的稳定X射线无定形状态的实现不总是达到令人满意的程度。
本发明的目的是找到微水溶性活性成分的改善配制剂,所述配制剂能受控释放并具有良好的生物利用度,且额外在相对高的空气湿度下就稳定而言具有改善的性能。
因此,发现了在基于两亲性共聚物与亲水聚合物组合的聚合物基体中的微水溶性活性成分的配制剂。
两亲性共聚物可以通过如下组分的混合物的自由基引发的聚合得到:
i)30-80重量%N-乙烯基内酰胺,
ii)10-50重量%乙酸乙烯基酯,和
iii)10-50重量%聚醚,
条件是i)、ii)和iii)之和等于100重量%。
在本发明的一个实施方案中,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%乙酸乙烯基酯,和
iii)10-35重量%聚醚。
特别优选使用的共聚物可以由如下组分得到:
i)40-60重量%N-乙烯基内酰胺,
ii)15-35重量%乙酸乙烯基酯,和
iii)10-30重量%聚醚。
非常特别优选使用的共聚物可以由如下组分得到:
i)50-60重量%N-乙烯基内酰胺,
ii)25-35重量%乙酸乙烯基酯,和
iii)10-20重量%聚醚。
组分i)、ii)和iii)之和等于100重量%的条件也适用于优选和特别优选的组合物。
可用的N-乙烯基内酰胺包括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。
所用接枝基质为聚醚。可用的聚醚优选为聚亚烷基二醇。聚亚烷基二醇的分子量可以为1000-100000D[道尔顿],优选1500-35000D,更优选1500-10000D。
分子量由根据DIN 53240测得的OH值进行测定。
特别优选的聚亚烷基二醇包括聚乙二醇。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也是额外合适的。
合适的聚醚还为由氧化乙烯、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。可用的烷基包括支化或未支化的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。
用于制备本发明接枝共聚物的一般方法是本身已知的。它们通过自由基引发的聚合,优选在溶液中、在非水有机溶剂中或在混合非水/含水溶剂中制备。合适的制备方法例如描述于WO2007/051743和WO2009/013202中,清楚引入其关于制备方法的公开内容。
对于受控释放,增溶共聚物与适用于影响生物活性物质释放的其他聚合物组合使用。影响释放的程度通常取决于受控释放的聚合物的浓度。
通过加入亲水聚合物,可以影响所得挤出物在释放过程中的分解速度。亲水性的增加可实现在释放中的更快地润湿且更快地分解。适用于该目的的尤其为具有低分子量(<100000道尔顿)的亲水聚合物。具有较高分子量的(>100000道尔顿)的亲水聚合物可以被认为是所得固溶体的稳定剂,因为它们提高了基体的硬度并防止活性成分由过饱和溶液结晶出来。因此可以制备稳定的过饱和固溶体,该固溶体具有特别高比例的药物。
亲水聚合物通常为水溶性的,至少在特定的pH范围内为水溶性的。就此而言,“水溶性”指在20℃下至少0.1g溶于1ml。
合适的亲水聚合物的实例包括:K值为12-90的聚乙烯基吡咯烷酮、N-乙烯基吡咯烷酮共聚物,例如与乙烯基酯如乙酸乙烯基酯或丙酸乙烯基酯的共聚物,尤其是N-乙烯基吡咯烷酮与乙酸乙烯基酯以60∶40的重量比的共聚物,聚乙烯醇,羟烷基化纤维素衍生物如羟丙基纤维素(HPC)或羟丙基甲基纤维(HPMC),羟烷基化和羧烷基化纤维素衍生物,丙烯酸-甲基丙烯酸共聚物。
就本发明而言,根据DAB 9使用术语“水不溶性”或“微溶性”。根据DAB 9(Deutsches Arzneimittelbuch[German Pharmacopeae]),物质的溶解性分类如下:低溶性(可溶于30-100份溶剂中);微溶性(可溶于100-1000份溶剂中);基本不溶(可溶于大于10000份溶剂中),每种情况下基于在20℃下1份要溶解物质。
固体配制剂可通过本身已知的方法生产。
在一个实施方案中,首先将配制剂的所有成分一起在合适溶剂中制成溶液,然后除去溶剂。这可借助所有可能类型的干燥方法,例如借助喷雾干燥、流化床干燥、使用超临界气体干燥、冷冻干燥、蒸发而进行。
在优选程序中,固体配制剂通过挤出生产。可将聚合物以粉状形式或以溶液或分散体形式供入挤出机中。
可将聚合物的分散体或溶液通过除去挤出机中熔融态的分散剂或溶剂并冷却熔体而转化成固体形式。
然后可将如此得到的熔体冷却和造粒。这在空气或保护气体下如在特氟隆或链带上进行所谓的热切割或冷却,随后将冷却的熔体挤出物造粒而进行。然而,冷却还可在聚合物在其中不具有显著溶解度的溶剂中进行。
原则上可以使用如下方法A-E:
对于本发明方法,合适的挤出机类型原则上为本领域技术人员已知的常规挤出机类型。这些通常包含外壳、具有传动的驱动单元和由挤出机轴或装配有螺杆元件的轴构成的加工单元,在这种情况下呈现出部件结构。
挤出机由多个部分构成,其各自分配给特定的加工单元。这些部分各自由作为最小的独立单元的一个或多个桶(桶段)和具有对应于工艺任务的螺杆元件的相应螺杆部分构成。
各个桶应为可加热的。此外,桶还可设计用于冷却,例如用水冷却。各个桶段优选为独立地可加热和可冷却的,使得沿着挤出方向还可建立不同的温度区域。
挤出机有利地构造为同向旋转(corotatory)的双螺杆挤出机。螺杆构造可根据产物具有不同的剪切度。螺杆构造可与特定要求相匹配,根据配制剂的组成具有常规可变的结构元件如传输元件、捏合元件、备用元件等。
合适的双螺杆挤出机可具有16-70mm的螺杆直径和25-40D的长度。
整个挤出机由温度可单独控制的桶段构成。最初两个桶可为温度控制的以更好地引入材料。自第三桶优选建立恒温,其应具体根据材料选择并尤其取决于所用活性成分的熔点和聚合物的玻璃化转变温度。然而,所得产物温度通常取决于所用螺杆元件的剪切度且在一些情况下可以比形成的桶温度高20-30℃。
熔融区下游可以为有利地在环境压力下操作的排气区。
所用圆模可具有0.5-5mm的直径。同样可使用其他模形状如缝隙式模,尤其是当需要较大的材料生产量时。
可将所得挤出物用造粒机加工为粒料,又可将这些进一步粉碎(研磨)为粉末。可将粒料或粉末装入胶囊中或使用常规压片助剂压制为片剂。就此而言还可使用其他受控释放助剂。
此外,在挤出过程中可使用水、有机溶剂、缓冲物质或增塑剂。水或挥发性醇尤其适用于该目的。该方法能够在相对低的温度下反应。溶剂或增塑剂的量通常为可挤出材料的0-30%。可将水或溶剂在标准压力下通过挤出机中的排气位置或通过施加降低的压力除去。或者,当挤出物离开挤出机且压力降至标准压力时,这些组分蒸发。在较不具挥发性组分的情况下,可相应随后将挤出物干燥。
在生产方法的特定方案中,在挤出以后直接将热塑性材料压延为片剂状压块,其构成最终的给药剂型。在该方案中,可适当地在挤出以前或期间实际上加入其他成分,例如用于调节玻璃化转变温度和熔体粘度的聚合物、崩解剂、增溶剂、增塑剂、染料、香料、增甜剂等。原则上,当首先将挤出物粉碎,然后压制为片剂时也可使用这些物质。
具有高玻璃化转变温度的水溶性聚合物如K值为17-120的聚乙烯吡咯烷酮、羟烷基纤维素或羟烷基淀粉可用于调节配制剂的玻璃化转变温度。配制剂的玻璃化转变温度过高可通过加入增塑剂而降低。用于该目的的合适增塑剂原则上为还用于药物包衣的所有增塑剂如柠檬酸三乙酯、柠檬酸三丁酯、柠檬酸乙酰三丁酯、三醋精、丙二醇、聚乙二醇400、癸二酸二丁酯、单硬脂酸甘油酯、月桂酸、鲸蜡基硬脂醇。
此外,还可额外将降低熔体粘度和因此挤出温度的表面活性剂掺入配制剂中。这些物质还可正面影响可能的结晶并产生更好的配制剂润湿和更快的溶解。合适的物质为离子和非离子表面活性剂,例如HS 15(聚乙二醇-15羟基硬脂酸酯)、80、聚氧乙基化脂肪酸衍生物如RH40(聚氧乙烯(40)氢化蓖麻油,USP)、Cremophor EL(聚氧乙烯(35)氢化蓖麻油,USP)、泊洛沙姆、多库酯钠或月桂基硫酸钠。
优选通过模将仍塑性的混合物挤出,冷却并粉碎。原则上,合适的粉碎方法为常用于此的所有已知常规技术如热切割或冷切割。
将挤出物例如用旋转刀片或用空气喷射切割,然后用空气或在保护气体下冷却。
还可将挤出物以熔体线材放在冷却带(不锈钢、特氟隆、链带)上并在固化以后将它造粒。
随后可任选将挤出物研磨。配制剂以自由流动水溶性粉末得到。优选形成20-250μm的粒度。
此外,还可通过注塑加工聚合物和活性物质的塑性混合物。
令人惊奇的是,本发明配制剂具有显著改善的稳定性,即活性成分以分子分散或无定形状态保留在配制剂中且不结晶出来。因此,释放性能不随时间而改变。
本发明配制剂具有比不含水溶性聚合物的配制剂高的活性成分生物利用度。
通过本发明方法得到的配制剂原则上可用于所有其中仅微水溶性或水不溶性物质用于含水配制剂中或在含水介质中显示出其作用的领域。
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在20℃下该物质在水中的溶液,每g物质需要至少30-100g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,要溶解的可用的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所有固态活性成分,其熔点在共聚物的挤出条件下小于分解点。该共聚物通常可以在至多260℃的温度下挤出。温度下限取决于每种情况下要挤出混合物的组成和要加工的微溶性物质。
所用药物活性成分根据已经提及的DAB 9定义为水不溶性物质或低水溶性的物质。
活性成分可源自任何指示领域。
这里实例包括苯并二氮杂抗高血压药、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。
在上述药物配制剂中,特别优选为可口服给药的配制剂的那些。
药物配制剂中本发明增溶剂的含量取决于活性成分为1-75重量%,优选5-60重量%,更优选5-50重量%。
为了生产药物给药剂型如片剂,可将挤出物与常规药物赋形剂混合。
这些为选自填料、增塑剂、增溶剂、粘合剂、硅酸盐和崩解剂和吸附剂、润滑剂、流动剂、染料、稳定剂如抗氧化剂、润湿剂、防腐剂、脱模剂、芳香剂或增甜剂,优选填料、增塑剂和增溶剂种类的物质。
加入的填料例如为无机填料如镁、铝、硅的氧化物、碳酸钛或碳酸钙、磷酸钙或磷酸镁,或有机填料如乳糖、蔗糖、山梨醇、甘露醇。
合适的增塑剂例如为三醋精、柠檬酸三乙酯、单硬脂酸甘油酯、低分子量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)值为大于11的表面活性物质,例如用40个氧化乙烯单元乙氧基化的氢化蓖麻油(RH40)、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。
所用润滑剂可以为铝、钙、镁和锡的硬脂酸盐以及硅酸镁、聚硅氧烷等。
所用流动剂例如可以为滑石或胶状二氧化硅。
合适的粘合剂例如为微晶纤维素。
崩解剂可以为交联聚乙烯吡咯烷酮或交联羧甲基淀粉钠。稳定剂可以为抗坏血酸或生育酚。
染料例如对于给药剂型着色而言,为铁氧化物、二氧化钛、三苯基甲烷染料、偶氮染料、喹啉染料、靛青染料、类胡萝卜素,对于提高透明度和节省染料而言,为遮光剂如二氧化钛或滑石。
除用于化妆品和药物中外,根据本发明生产的配制剂还适用于食品领域,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。实例包括饮料,其用类胡萝卜素着色。
根据本发明得到的配制剂在农用化学中的用途可包括包含农药、除草剂、杀真菌剂或杀虫剂的配制剂,尤其是用作喷雾或洒水用配制剂的作物保护组合物的那些配制剂。
所谓包含微溶性物质的固溶体可借助本发明方法得到。根据本发明,其中观察不到微溶性物质的结晶组分的体系称为固溶体。
当视觉评估稳定的固溶体时,很明显没有无定形组分。视觉评估可用光学显微镜,用或不用极化滤波器在40倍放大下进行。
此外,还可借助XRD(X射线衍射法)和DSC(差示扫描量热法)检测配制剂的结晶度或无定形性。
如所述,通过本发明方法得到的配制剂以无定形形式存在,这是指生物活性物质的结晶组分小于5重量%。优选借助DSC或XRD检查无定形状态。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且就微溶性物质的无定形状态而言具有良好稳定性的稳定配制剂。
本发明方法允许生产具有高活性成分负载的稳定配制剂。
令人惊奇地是,该组合具有显著降低的水分敏感性,即该配制剂可以在高空气湿度下储存而不使活性成分结晶出来。
实施例
聚合物1的制备
在搅拌设备中,将不含进料2的一部分的起始加料在N2气氛下加热至77℃。当达到77℃的内部温度时,加入进料2的一部分并部分聚合15分钟。随后,在5小时内计量加入进料1,并在2小时内计量加入进料2。一旦已计量加入所有进料,则使反应混合物再聚合3小时。在进一步聚合后,将溶液调整至50重量%的固体含量。
起始加料:25g乙酸乙烯基酯
104.0g PEG 6000
1.0g进料2
进料1:240g乙酸乙烯基酯
456g乙烯基己内酰胺
240g乙酸乙酯
进料2:10.44g过氧化新戊酸叔丁酯(75重量%,在脂族化合物混合物中)67.90g乙酸乙酯。
随后,通过喷雾方法除去溶剂以得到粉状产物。在1重量%乙醇溶液测量中测得K值为16。
用于生产以下实施例所述配制剂的双螺杆挤出机具有16mm的螺杆直径和40D的长度。整个挤出机由8个可单独控温的桶段构成。为更好地引入材料,最初两个桶的温度分别控制在20℃和70℃下。由第三个桶开始建立恒温。
使用以下设备和条件借助XRD(X射线衍射法)和DSC(差示扫描量热法)检测生产的固溶体的结晶度和无定形性:
XRD
仪器:具有9管样品转换器的D8 Advance衍射计(来自Bruker/AXS)
测量方法:θ-θ反射几何
2θ角范围:2-80°
步宽:0.02°
每角步的测量时间:4.8秒
发散狭缝:具有0.4mm插入孔的镜
防散射狭缝:Soller狭缝
探测器:Sol-X探测器
温度:室温
发生器设置:40kV/50mA
DSC
来自TA仪器的DSC Q 2000
参数:
起始重量约8.5mg
加热速率:20K/min
活性成分释放使用USP设备(桨式法)2,37℃,50rpm(BTWS 600,Pharmatest)进行。借助造粒机将挤出物线材分至3mm的长度并引入硬明胶胶囊中。所释放活性成分通过UV光谱(Lamda-2,Perkin Elmer)检测。
通过XRD和DSC分析固溶体并发现为无定形的。在pH6.8的磷酸盐缓冲物中活性成分的释放在2小时后为27%,在10小时后,释放出82%最初使用的活性成分。
实施例1
将1200g聚合物1、400gVA 64(N-乙烯基吡咯烷酮与乙酸乙烯基酯以60/40的重量比的共聚物)和400g桂利嗪(熔点122℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:140℃
·螺杆速度200rpm
·生产量:500g/小时
·模直径3mm
通过XRD和DSC检测固溶体并发现为无定形的。在0.1标称HCl中1小时以后,释放出95%活性成分。
实施例2
将1200g聚合物1、400g Kollidon VA 64和40g达那唑(熔点225℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:160℃
·螺杆速度200rpm
·生产量:500g/小时
·模直径3mm
通过XRD和DSC检测固溶体并发现为无定形的。在0.1标称HCl中1小时以后,释放出95%活性成分。
实施例3
将1200g聚合物1、500g Kollidon VA 64和400g非诺贝特(熔点81℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:100℃
·螺杆速度200rpm
·生产量:500g/小时
·模直径3mm
通过XRD和DSC检测固溶体并发现为无定形的。在0.1标称HCl中2小时以后,释放出100%活性成分。
实施例4
将1100g聚合物1、400g Kollidon VA 64、100g PEG 1500和400g伊曲康唑(熔点166℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:130℃
·螺杆速度200rpm
·生产量:500g/小时
·模直径3mm
PEG 1500的加入将挤出温度降至130℃,其对固溶体没有影响。通过XRD和DSC检测透明固溶体并发现为无定形的。在0.1标称HCl中1小时以后,释放出95%活性成分。
实施例5
将1200g聚合物1、500g Kollidon 12PF(聚乙烯基吡咯烷酮K12)和300g非诺贝特(熔点81℃)称重加入Turbula混合容器中并在T10BTurbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:90℃
·螺杆速度200rpm
·生产量:500g/小时
·模直径3mm
通过XRD和DSC检测固溶体并发现为无定形的。加入Kollidon 12PF实现了粒料在释放过程中更快的溶解。在0.1标称HCl中1小时以后,释放出100%活性成分。
实施例6
将1200g聚合物1、400g Kollidon 17PF(聚乙烯基吡咯烷酮K17)和400g克霉唑(熔点148℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:120℃
·螺杆速度200rpm
·生产量:500g/小时
·模直径3mm
通过XRD和DSC检测固溶体并发现为无定形的。加入Kollidon 17PF实现了粒料在释放过程中更快的溶解。在0.1标称HCl中1小时以后,释放出80%活性成分。
实施例7
将800g聚合物1、800g Kollidon 90(聚乙烯基吡咯烷酮K90)和400g萘普生(熔点157℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:160℃
·螺杆速度200rpm
·生产量:600g/小时
·模直径3mm
通过XRD和DSC检测固溶体并发现为无定形的。在0.1标称HCl中1小时以后,释放出89%活性成分。
实施例8
将1200g聚合物1、400gIR(PEG 6000/聚乙烯醇的接枝聚合物)、100g PEG 1500和400g伊曲康唑(熔点166℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:140℃
·螺杆速度200rpm
·生产量:800g/小时
·模直径3mm
通过XRD和DSC检测固溶体并发现为无定形的。在0.1标称HCl中1小时以后,释放出99%活性成分。
实施例9
将1000g聚合物1、600g Kollicoat IR和400g非诺贝特(熔点81℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:130℃
·螺杆速度200rpm
·生产量:1000g/小时
·模直径3mm
通过XRD和DSC检测固溶体并发现为无定形的。在0.1标称HCl中2小时以后,活性成分的释放小于20%。在改变缓冲物至pH6.8再10小时以后,总共释放出80%活性成分。
实施例10
将1200g聚合物1、400g HPMC和400g桂利嗪(熔点122℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第三桶的区域温度:160℃
·螺杆速度100rpm
·生产量:800g/小时
·模直径3mm
加入HPMC导致挤出物线材更软,其更容易造粒。通过XRD和DSC检测固溶体并发现为无定形的。在0.1标称HCl中2小时以后,活性成分的释放小于10%;在改变缓冲物至pH6.8之后,释放出100%。
实施例11
将1000g聚合物1、600g HPC和400g卡马西平(熔点192℃)称重加入Turbula混合容器中并在T10B Turbula混合机中混合10分钟。
将混合物在如下条件下挤出:
·第一桶的区域温度:20℃;第二桶:40℃
·自第3桶的区域温度:170℃
·螺杆速度200rpm
·生产量:600g/小时
·模直径3mm
通过XRD和DSC检测固溶体并发现为无定形的。在0.1标称HCl中1小时以后,释放出95%活性成分。
Claims (8)
1.一种含有在包含两亲性聚醚共聚物和至少一种亲水聚合物的聚合物基体中的微水溶性活性成分的配制剂的剂型,其中所述微水溶性活性成分以无定形形式存在于聚合物基体中。
2.根据权利要求1的剂型,其中所述聚醚共聚物通过30-80重量%N-乙烯基内酰胺、10-50重量%乙酸乙烯基酯和10-50重量%聚醚的混合物的自由基引发的聚合得到。
3.根据权利要求1或2的剂型,其包含在20℃下在水中溶解度为至少0.1g/ml的那些聚合物作为亲水聚合物。
4.根据权利要求1-3中任一项的剂型,其包含聚乙烯基吡咯烷酮、N-乙烯基吡咯烷酮共聚物,聚乙烯醇,羟烷基化纤维素衍生物,羧烷基化纤维素衍生物,丙烯酸-甲基丙烯酸共聚物,聚乙二醇,聚乙二醇与聚乙烯醇单元的接枝聚合物或该类聚合物的混合物作为亲水聚合物。
5.根据权利要求1-4中任一项的剂型,其包含聚乙烯基吡咯烷酮或N-乙烯基吡咯烷酮与乙酸乙烯基酯的共聚物作为亲水聚合物。
6.根据权利要求1-4中任一项的剂型,其包含羟丙基纤维素或羟丙基甲基纤维素作为亲水聚合物。
7.根据权利要求1-4中任一项的剂型,其包含聚醚和聚乙烯醇单元的接枝聚合物作为亲水聚合物。
8.根据权利要求1-7中任一项的剂型,其中聚醚共聚物与亲水聚合物之比为1∶99-99∶1。
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US8636929B2 (en) | 2010-05-21 | 2014-01-28 | Basf Se | Nanoporous foamed active compound-containing preparations based on pharmaceutically acceptable thermoplastically workable polymers |
US8715729B2 (en) | 2010-12-22 | 2014-05-06 | Basf Se | Rapidly disintegrating, solid coated dosage form |
US20160000720A1 (en) * | 2013-02-14 | 2016-01-07 | Aurobindo Pharma Limited | Pharmaceutical compositions comprising Tadalafil |
US20160193151A1 (en) * | 2015-01-06 | 2016-07-07 | Maria Del Pilar Noriega Escobar | Dosage form incorporating an amorphous drug solid solution |
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