CN102365082B - 生产不良水溶性物质的制剂的方法 - Google Patents
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Abstract
本发明涉及一种生产不良水溶性物质的制剂的方法,其中所述不良水溶性物质以包埋形式存在于共聚物中并且所述共聚物通过自由基引发聚合具有如下组分的混合物而得到: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,条件是组分i)、ii)和iii)的总和等于100重量%,其中不良溶性物质在共聚物中包埋在该不良溶性物质的熔点以上的温度下进行。
Description
本发明涉及一种通过将微水溶性物质包埋到通过在聚醚存在下聚合乙酸乙烯酯和N-乙烯基内酰胺得到的共聚物中而生产微水溶性物质配制剂的方法。该包埋通过挤出以及在该微水溶性物质的熔点以上的温度下进行,其中所述物质以无定形形式存在于挤出的配制剂中。
相应的共聚物适合作为微水溶性物质的增溶剂。
在均相配制剂,尤其是生物活性物质的均相配制剂的生产中,疏水性物质,即微水溶性物质的增溶具有非常大的实践重要性。
增溶应理解为指在特定溶剂,尤其是水中微溶或不溶的物质通过界面活性化合物,即增溶剂而增溶。该类增溶剂能够将微水溶性或水不溶性物质转化成透明,至多呈乳色的水溶液,而这些物质的化学结构在该过程中不发生任何变化(参见Chemie Lexikon,第9版,第5卷,第4203页,Thieme Verlag,Stuttgart,1992)。
在产生的增溶物中,微水溶性或水不溶性物质以胶体溶解形式存在于例如在水溶液中形成疏水域或胶束的表面活性化合物的分子缔合物中。所得溶液为稳定或亚稳定单相体系,具有视觉上透明至乳色的外观。
增溶剂例如可以通过使配制剂透明而改善化妆品配制剂和食品配制剂的外观。此外,在药物配制剂的情况下,通过使用增溶剂可以提高药物的生物利用率以及因此提高效力。
对增溶剂的另一所需要求是与微溶性物质形成所谓的“固溶体”的能力。术语“固溶体”描述的是其中物质以胶态分散体或理想分子分散体分布于固体基质,例如聚合物基质中的状态。该类固溶体例如在以微溶性活性成分的固体药物给药形式使用时导致活性成分的释放改善。对该类固溶体的重要要求是它们甚至在储存过程中也长时间稳定,这意味着活性成分不会结晶出来。此外,固溶体的容量,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。
在固溶体的形成中,除了增溶剂形成固溶体的基本能力外,增溶剂的吸湿性也起重要作用。由环境空气吸收太多水的增溶剂导致固溶体的潮解和活性成分的不希望结晶。在加工成给药形式的过程中太大的吸湿性也可能存在问题。
许多已知聚合物增溶剂具有的缺点是它们不形成稳定的固溶体。此外,就在含水体系中的增溶而言它们仍有改进余地。对于加工性,一些已知增溶剂由于其发粘的倾向而也具有缺点,因为它们不是充分自由流动的粉末。
DE-A 19935063公开了基于乙烯基内酰胺和乙酸乙烯酯的含聚氧化烯的接枝聚合物及其作为气体水化物抑制剂的用途。
EP-A 953347公开了含聚氧化烯的接枝聚合物作为增溶剂的用途。其中所述乙酸乙烯酯和聚氧化烯的接枝聚合物通常不为粉末,而是为粘的液体,这就应用而言是不利的。
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作为用于药物、化妆品、食品技术、农业化学和其他工业应用的增溶剂的用途。其中非常一般性地描述了对应的接枝聚合物也可以与活性成分一起在熔体中加工。
WO 2009/013202公开了N-乙烯基内酰胺,乙酸乙烯酯和聚醚的该类接枝聚合物可以在挤出机中熔融并与粉状或液体活性成分混合,其中挤出在显著低于活性成分熔点的温度下进行。
然而,熔融接枝聚合物与粉状或液体活性成分的混合不能实现令人满意地高且同时稳定的活性成分负载。具体而言,活性成分的稳定X射线无定形状态并不能总是以令人满意的程度实现。
本发明的目的是提供一种能够以改善的溶解度将微水溶性物质掺入配制剂中的改进方法。
因此,发现了一种生产微水溶性物质配制剂的方法,其中所述微溶性物质以包埋形式存在于共聚物中并且所述共聚物通过自由基引发聚合具有如下组分的混合物而得到:
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,
条件是组分i)、ii)和iii)的总和等于100重量%,该方法包括在生物活性物质的熔点以上的温度下进行包埋。
在本发明的一个实施方案中,使用由如下组分得到的优选聚合物:
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。
特别优选使用的聚合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聚合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。
对于优选和特别优选的组合物,组分i)、ii)和iii)的总和等于100重量%的条件也适用。
有用的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。有用的聚醚优选为聚亚烷基二醇。聚亚烷基二醇可以具有1000-100000Da[道尔顿],优选1500-35000Da,更优选1500-10000Da的分子量。
分子量由根据DIN 53240测量的OH值确定。
特别优选的聚亚烷基二醇包括聚乙二醇。也额外合适的是聚丙二醇、聚四氢呋喃或聚丁二醇,它们由2-乙基环氧乙烷或2,3-二甲基环氧乙烷得到。
合适的聚醚也为由氧化乙烯、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类型或ABA类型。
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未支化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。
根据本发明的一个实施方案,使用K值为10-60的共聚物。根据本发明的一个优选实施方案,使用K值为15-40的共聚物。
制备本发明接枝共聚物的一般方法本身是已知的。它们通过自由基引发聚合制备,优选在溶液中、在非水有机溶剂中或在混合非水/含水溶剂中聚合。合适的制备方法例如描述于WO 2007/051743和WO 2009/013202中,对于制备方法明确参考这些文献的公开内容。
包埋优选通过熔体挤出进行。
共聚物可以以粉状形式或以溶液或分散体形式供入挤出机中。
该聚合物的分散体或溶液可以通过在挤出机中以熔融状态除去分散剂或溶剂并冷却该熔体而转化成固体形式。
随后可以将如此得到的熔体冷却并造粒。因为该聚合物通常是水溶性的,因此不太选择通过借助水冷却而将热塑性熔体造粒的常规方法。替换方法是所谓的热切或在空气或保护气体下冷却,例如在Teflon或链带上冷却并随后对冷却的熔体挤出物造粒。
原则上可以使用下列方法A-E:
对于本发明方法,合适的挤出机类型原则上是本领域熟练技术人员已知的常规挤出机类型。这些通常包括外壳、具有传动的驱动单元和由装备有螺杆元件的挤出机轴构成的加工单元,此时呈组件式构造。
挤出机由多个各自分配给特定加工单元的区段构成。这些区段各自由一个或多个作为最小独立单元的机筒(筒段)和具有与加工任务相对应的螺杆元件的相应螺杆段构成。
各机筒应可加热。此外,机筒还可以设计用于冷却,例如用于用水冷却。各筒段优选可独立加热和冷却,从而也可以沿挤出方向产生不同的温度区。
挤出机有利地构造成同向旋转的双螺杆挤出机。螺杆构造可以根据产物具有不同剪切程度。尤其在熔融区中必须使用捏合元件。还可以使用反向捏合元件。
合适的双螺杆挤出机可以具有16-70mm的螺杆直径和25-40D的长度。
整个挤出机由其温度可以单独控制的筒段构成。为了更好地输入材料,可以对最初的两个机筒进行温度控制。由第三机筒开始优选产生恒定温度,这应对该材料进行特殊选择且尤其取决于所用活性成分的熔点和该聚合物的玻璃化转变温度。然而,所得产品温度通常取决于所用螺杆元件的剪切程度且在某些情况下可以比机筒温度高20-30°C。
在熔融区下游可以是排气区,其有利地在环境压力下操作。
所用圆形模头可以具有0.5-5mm的直径。同样可以使用其他模头形式如槽形模头,尤其当需要更大的材料通过量时。
两个同向旋转螺杆的设计应使得在由输送元件构成的输入区下游,已经在第三加热区中使用具有下游限流器的捏合段。在由输送元件构成的短减压区之后,将现已熔融的材料再次在捏合区中混合。这之后是具有下游捏合元件的输送元件区。再往后是具有下游捏合区的输送元件区。最后,由输送元件区确保材料的排出。
所得挤出物可以用造粒机加工成颗粒,后者又可进一步粉碎(研磨)成粉末。可以将颗粒或粉末填充到胶囊中或者使用常规压片助剂压制成片剂。
此外,可以在挤出过程中使用水、有机溶剂、缓冲剂物质或增塑剂。尤其将水或挥发性醇用于该目的。该方法使得可以在相对低温下进行反应。溶剂或增塑剂的量通常为可挤出材料的0-30%。水或溶剂可能已经通过挤出机中的排气点在标准压力下除去,或者通过施加减压而除去。或者,这些组分在挤出物离开挤出机并且将压力降至标准压力时蒸发。在非挥发性组分的情况下,挤出物随后可以相应地干燥。
在该生产方法的特殊方案中,直接在挤出之后将热塑性材料压延成构成最终给药形式的片剂状压制品。在该方案中,可行的是实际在挤出之前或之中加入其他成分,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,调味剂,增甜剂等。原则上还可以在首先将挤出物粉碎并随后压制成片剂时使用这些物质。
结晶抑制物质如Kollidon 30的加入提高了固溶体的稳定性。
此外,也额外可以向配制剂中掺入降低熔体粘度并因此降低挤出温度的表面活性剂。这些物质也可以正面影响可能的结晶。合适的物质例如为HS 15、80、Cremophor RH40、多库脂钠或月桂基硫酸钠。
将仍为塑性的混合物优选通过模头挤出,冷却并粉碎。合适的粉碎方法原则上是所有常用于此的已知技术,如热切或冷切。
例如用旋转刀片或空气射流切割挤出物,然后用空气冷却或在保护气体下冷却。
还可以将挤出物作为熔体线料铺在冷却的带(不锈钢,Teflon,链带)上并在固化之后造粒。
然后可以任选研磨挤出物。配制剂以自由流动的水溶性粉末得到。优选产生20-250μm的粒度。
此外,还可以通过注塑加工聚合物和活性物质的塑料混合物。
由本发明方法得到的配制剂原则上可以用于其中要将仅微水溶性或水不溶性物质用于含水配制剂或要在含水介质中显示其作用的所有领域中。
根据本发明,术语“微水溶性”也包括基本不溶性物质且指对于该物质在20°C下的水溶液而言每g至少30-100g水。在基本不溶性物质的情况下,每g至少10000g水。
在本发明上下文中,微水溶性物质优选应理解为指生物活性物质如用于人类和动物的药物活性成分,化妆品或农业化学活性成分,或食品补充剂或营养活性成分。
此外,待增溶的有用微溶性物质还包括染料如无机或有机颜料。
根据本发明,有用的生物活性物质原则上包括所有熔点在共聚物在挤出条件下的分解点以下的固体活性成分。共聚物通常可以在至多260°C的温度下挤出。温度下限由每种情况下待挤出混合物的组成和待加工的微溶性物质决定。
根据本发明的一个实施方案,在本发明方法中加入防止再结晶的试剂。
所用药物活性成分是水不溶性物质或具有低水溶性的物质。根据DAB9(Deutsches Arzneimittelbuch,German Pharmacopeia),药物活性成分的溶解性按如下分类:低溶解性(可溶于30-100份溶剂中);微溶性(可溶于100-1000份溶剂中);基本不溶性(可溶于大于10000份溶剂中)。活性成分可以来自任何适应症领域。
这里的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,***,抗精神病药,抗抑郁药,抗病毒药,例如抗HIV药物,抗生素,抗真菌药,抗痴呆药,杀真菌剂,化疗药,泌尿用药,血小板聚集抑制剂,磺酰胺类,解痉药,激素,免疫球蛋白,血清,甲状腺治疗药,精神病药物,抗帕金森药和其他抗运动机能亢进药,眼科用药,神经病药制剂,钙代谢调节剂,肌肉松弛剂,***,降脂药,肝病治疗药,冠心病药,强心药,免疫治疗药,调节肽及其抑制剂,催眠药,镇静药,妇科用药,痛风治疗药,纤维蛋白溶解药,酶制剂和转运蛋白,酶抑制剂,催吐药,血液流动刺激剂,利尿药,诊断助剂,皮质激素类,胆碱能药,胆道治疗药,抗哮喘药,支气管扩张药,β受体阻断剂,钙拮抗剂,ACE抑制剂,动脉硬化治疗药,抗炎药,抗凝血药,抗低血压药,抗低血糖药,抗高血压药,抗纤溶药,抗癫痫药,止吐药,解毒药,抗糖尿病药,抗心律失常药,抗贫血药,抗过敏药,驱虫药,镇痛药,回苏剂,醛固酮拮抗剂,减肥药。
在上述药物配制剂中,特别优选为可口服给药配制剂的那些。
本发明增溶剂在药物配制剂中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%。
进一步特别优选的实施方案涉及其中活性成分和共聚物作为固溶体存在的药物配制剂。此时,溶剂的除去和活性物质的掺入可以在一个工艺步骤中进行。共聚物与活性成分的重量比在这里优选为1:1-4:1,但可以为至多100:1,尤其是至多15:1。唯一的因素是当用于最终药物剂型中时,首先在该药物剂型中存在足够量的活性成分,其次该剂型在口服药物形式的情况下不会变得太大。
为了生产药物给药剂型,例如片剂,可以将挤出物与常规药物赋形剂混合。
这些为选自如下类别的物质:填料,增塑剂,增溶剂,粘合剂,硅酸盐以及崩解剂和吸附剂,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,香料或甜味剂,优选填料、增塑剂和增溶剂。
加入的填料例如可以是无机固体如镁、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、甘露糖醇。
合适的增塑剂例如为三醋精,柠檬酸三乙酯,甘油单硬脂酸酯,低分子量聚乙二醇或泊洛沙姆。
合适的额外增溶剂是HLB(亲水亲油平衡)值大于11的界面活性物质,例如被40个氧化乙烯单元乙氧基化的氢化蓖麻油(RH 40),被35个氧化乙烯单元乙氧基化的蓖麻油(Cremophor EL),聚山梨酸酯80,泊洛沙姆或月桂基硫酸钠。
所用润滑剂可以是铝、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态二氧化硅。
合适的粘合剂例如为微晶纤维素。
崩解剂可以是交联的聚乙烯基吡咯烷酮或交联的羧甲基淀粉钠。稳定剂可以为抗坏血酸或生育酚。
染料例如为铁氧化物、二氧化钛、三苯基甲烷染料、偶氮染料、喹啉染料、靛蓝染料、类胡萝卜素类,以对给药剂型染色,不透明剂如二氧化钛或滑石,以提高透明度和节省染料。
除了用于化妆品和药物中外,按照本发明生产的配制剂也适合用于食品领域,例如用于掺入微水溶性或水不溶性营养素、助剂或添加剂,例如脂溶性维生素或类胡萝卜素。实例包括饮料,其用类胡萝卜素染色。
按照本发明得到的配制剂在农业化学中的用途可以包括包含农药、除草剂、杀真菌剂或杀虫剂的配制剂,尤其还有用作喷雾或浇灌配制剂的作物保护组合物的那些配制剂。
借助本发明方法可以得到包含微溶性物质的所谓固溶体。按照本发明,固溶体指其中观察不到微溶性物质的结晶组分的体系。
当视觉评价稳定的固溶体时,未见无定形成分。视觉评价可以用带有或不带有偏振光滤器的光学显微镜在40倍放大倍数下进行。
此外,也可以借助XRD(X射线衍射)和DSC(差示扫描量热法)检测该配制剂的结晶度或无定形度。
由本发明方法得到的配制剂如上所述以无定形形式存在,这意味着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。该无定形状态还可以称为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在微溶性物质的无定形状态方面具有良好稳定性的稳定配制剂。
实施例
聚合物制备
在搅拌的设备中,在N2气氛下将没有来自进料2的部分的初始进料加热到77°C。当达到77°C的内部温度时,加入来自进料2的部分并部分聚合15分钟。然后在5小时内计量加入进料1并在2小时内计量加入进料2。一旦计量加入所有进料,将反应混合物再聚合3小时。在该再聚合之后,将该溶液调节至固含量为50重量%。
初始进料:25g乙酸乙酯,
104.0g PEG 6000,
1.0g进料2
进料1:240g乙酸乙烯酯
进料2:456g乙烯基己内酰胺
240g乙酸乙酯
进料3:10.44g过新戊酸叔丁酯(75重量%,在脂族混合物中)
67.90g乙酸乙酯
然后通过喷雾方法除去溶剂,得到粉状产品。在1重量%乙醇溶液中测得K值为36。
用于生产下列实施例中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个可单独控制温度的筒段形成。为了更好地输入材料,将最初两个机筒的温度分别控制为20°C和70°C。从第三机筒开始产生恒定的温度。
借助XRD和DSC使用下列设备和条件检测所生产的固溶体的结晶度和无定形度:
XRD
仪器:D 8Advance Diffractometer,具有9管样品变换器(来自Bruker/AXS)
测量方法:反射中的θ-θ几何
2θ角范围:2-80°
步进宽度:0.02°
每步进角的测量时间:4.8s
发散狭缝:具有0.4mm***孔的镜
抗散射狭缝:Soller狭缝
检测器:Sol-X检测器
温度:室温
发生器设置:40kV/50mA
DSC
来自TA Instruments的DSC Q 2000
参数:
起始重量约8.5mg
加热速率:20K/min
固溶体的制备
实施例1
将1600g聚合物和400g非诺贝特(熔点81°C)称重到Turbula混合容器中并在T10B Turbula混合器中混合10分钟。
在下列条件下挤出该混合物:
●由第三圆筒开始的区域温度:130°C
●螺杆速度:200rpm
●通过量:1000g/h
●模头直径:1mm
●模头压力:11巴
●电流消耗:2.8A
●功率消耗:0.3kW
通过XRD和DSC研究固溶体,发现其呈无定形。
实施例2
将800g聚合物和200g桂利嗪(熔点122°C)称重到Turbula混合容器中并在T10B Turbula混合器中混合10分钟。
在下列条件下挤出该混合物:
●由第三圆筒开始的区域温度:140°C
●螺杆速度:200rpm
●通过量:900g/h
●模头直径:1mm
●材料温度:148°C
●模头压力:12巴
●电流消耗:2.6A
●功率消耗:0.26kW
通过XRD和DSC研究所制备的固溶体,发现其呈无定形。
实施例3
800g聚合物和200g酮康唑(熔点146°C)称重到Turbula混合容器中并在T10B Turbula混合器中混合10分钟。
在下列条件下挤出该混合物:
●由第三圆筒开始的区域温度:150°C
●螺杆速度:200rpm
●通过量:900g/h
●模头直径:1mm
●材料温度:155°C
●模头压力:10巴
●电流消耗:2.5A
●功率消耗:0.24kW
所制备的固溶体根据XRD和DSC呈无定形。
实施例4
将800g聚合物和200g克霉唑(熔点为147°C)称重到Turbula混合容器中并在T10B Turbula混合器中混合10分钟。
在下列条件下挤出该混合物:
●由第三圆筒开始的区域温度:150°C
●螺杆速度:200rpm
●通过量:900g/h
●模头直径:1mm
●材料温度:158°C
●模头压力:13巴
●电流消耗:2.9A
●功率消耗:0.3kW
所制备的固溶体根据XRD和DSC呈无定形。
实施例5
800g聚合物和200g非洛地平(熔点145°C)称重到Turbula混合容器中并在T10B Turbula混合器中混合10分钟。
在下列条件下挤出该混合物:
●由第三圆筒开始的区域温度:150°C
●螺杆速度:200rpm
●通过量:900g/h
●模头直径:1mm
●材料温度:155°C
●模头压力:12巴
●电流消耗:2.6A
●功率消耗:0.26kW
所制备的固溶体根据XRD和DSC呈无定形。
实施例6
将1400g聚合物、400g非诺贝特(熔点81°C)和200g Povidon K30称重到Turbula混合容器中并在T10B Turbula混合器中混合10分钟。
在下列条件下挤出该混合物:
●由第三圆筒开始的区域温度:150°C
●螺杆速度:200rpm
●通过量:1000g/h
●模头直径:1mm
●模头压力:14巴
●电流消耗:3.2A
●功率消耗:0.35kW
所制备的固溶体根据XRD和DSC呈无定形。
实施例7
将760g聚合物、40g月桂基硫酸钠和200g非洛地平(熔点145°C)称重到Turbula混合容器中并在T10B Turbula混合器中混合10分钟。
在下列条件下挤出该混合物:
●由第三圆筒开始的区域温度:160°C
●螺杆速度:200rpm
●通过量:900g/h
●模头直径:1mm
●材料温度:165°C
●模头压力:10巴
●电流消耗:2.4A
●功率消耗:0.24kW
所制备的固溶体根据XRD和DSC呈无定形。
Claims (18)
1.一种生产微水溶性物质的配制剂的方法,其中所述微溶性物质以包埋形式存在于共聚物中形成固溶体,所述固溶体呈无定形,并且所述共聚物通过自由基引发聚合具有如下组分的混合物而得到:
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,
条件是组分i)、ii)和iii)的总和等于100重量%,所述方法包括在所述微溶性物质的熔点以上的温度下将所述微溶性物质包埋到所述共聚物中。
2.根据权利要求1的方法,其中使用由如下组分得到的共聚物:
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。
3.根据权利要求1的方法,其中使用将N-乙烯基吡咯烷酮或N-乙烯基己内酰胺或混合物用作组分i)而得到的共聚物。
4.根据权利要求2的方法,其中使用将N-乙烯基吡咯烷酮或N-乙烯基己内酰胺或混合物用作组分i)而得到的共聚物。
5.根据权利要求1-4中任一项的方法,其中使用将N-乙烯基己内酰胺用作i)而得到的共聚物。
6.根据权利要求1-4中任一项的方法,其中使用将聚乙二醇用作组分iii)而得到的共聚物。
7.根据权利要求5的方法,其中使用将聚乙二醇用作组分iii)而得到的共聚物。
8.根据权利要求1-4中任一项的方法,其中使用将分子量为1000-10000道尔顿的聚乙二醇用作组分iii)而得到的共聚物。
9.根据权利要求1-4中任一项的方法,其中使用K值为10-60的共聚物。
10.根据权利要求9的方法,其中使用K值为15-40的共聚物。
11.根据权利要求1-4中任一项的方法,其中所述微水溶性物质为生物活性物质。
12.根据权利要求1-4中任一项的方法,其用于生产治疗疾病用药物配制剂。
13.根据权利要求1-4中任一项的方法,其用于生产化妆品配制剂。
14.根据权利要求1-4中任一项的方法,其用于生产食品补充剂或营养试剂。
15.根据权利要求1-4中任一项的方法,其用于生产染料配制剂。
16.根据权利要求1-4中任一项的方法,其中所述微溶性物质通过熔体挤出包埋到所述共聚物中。
17.根据权利要求1-4中任一项的方法,其中所述包埋在至多260°C的温度下进行。
18.根据权利要求1-4中任一项的方法,其中加入防止再结晶的试剂。
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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 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101299994A (zh) * | 2005-11-04 | 2008-11-05 | 巴斯夫欧洲公司 | 共聚物作为微水溶性化合物的加溶剂的用途 |
WO2009013202A1 (de) * | 2007-07-26 | 2009-01-29 | Basf Se | Verfahren zur herstellung von durch pfropfpolymerisation in lösung erhaltenen copolymeren auf basis von polyethern in fester form |
EP2158922A1 (de) * | 2008-08-28 | 2010-03-03 | Basf Se | Verfahren zur Trocknung von als Solubilisatoren für in Wasser schwerlösliche Verbindungen geeigneten Copolymeren auf Basis von Polyethern |
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DE19814739A1 (de) | 1998-04-02 | 1999-10-07 | Basf Ag | Verwendung von Polyalkylenoxid-haltigen Pfropfpolymerisaten als Solubilisatoren |
DE19935063A1 (de) | 1999-07-28 | 2001-02-01 | Basf Ag | Pfropfpolymerisate als Gashydratinhibitoren |
WO2007001451A2 (en) * | 2004-11-09 | 2007-01-04 | Board Of Regents, The University Of Texas System | Stabilized hme composition with small drug particles |
DE102005026755A1 (de) * | 2005-06-09 | 2006-12-14 | Basf Ag | Herstellung von festen Lösungen schwerlöslicher Wirkstoffe durch Kurzzeitüberhitzung und schnelle Trocknung |
EP2022805A3 (en) | 2007-08-03 | 2009-02-25 | Basf Se | Copolymers based on N-vinyllactams and olefins as their use as solubilizers for slightly water-soluble compounds |
US20100280047A1 (en) | 2007-12-12 | 2010-11-04 | Basf Se | Salts of active ingredients with polymeric counter-ions |
US20110178183A1 (en) | 2008-09-25 | 2011-07-21 | Meyer-Boehm Kathrin | Use Of Polyether-Based And Vinyl Monomer-Based Copolymers As Binders For Dosing Forms Comprising Solid Active Ingredients |
WO2010040686A1 (de) | 2008-10-07 | 2010-04-15 | Basf Se | Verfahren zur herstellung oraler darreichungsformen mit kontrollierter freisetzung |
WO2010072573A1 (de) | 2008-12-23 | 2010-07-01 | Basf Se | Verwendung von copolymeren auf basis von polyethern und vinylmonomeren als stabilisierungsmittel für emulsionen |
EP2413907B1 (de) | 2009-03-31 | 2014-10-01 | Basf Se | Verfahren zur herstellung von zubereitungen von in wasser schwerlöslichen substanzen |
EP2477593A1 (de) * | 2009-09-18 | 2012-07-25 | Basf Se | Verfahren zur herstellung von zubereitungen von in wasser schwer löslichen substanzen |
EP2504033A1 (en) * | 2009-11-24 | 2012-10-03 | Basf Se | Film-like pharmaceutical dosage forms |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101299994A (zh) * | 2005-11-04 | 2008-11-05 | 巴斯夫欧洲公司 | 共聚物作为微水溶性化合物的加溶剂的用途 |
WO2009013202A1 (de) * | 2007-07-26 | 2009-01-29 | Basf Se | Verfahren zur herstellung von durch pfropfpolymerisation in lösung erhaltenen copolymeren auf basis von polyethern in fester form |
EP2158922A1 (de) * | 2008-08-28 | 2010-03-03 | Basf Se | Verfahren zur Trocknung von als Solubilisatoren für in Wasser schwerlösliche Verbindungen geeigneten Copolymeren auf Basis von Polyethern |
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