CN1499959A - 含有水溶性差的活性成分、表面活性剂和水溶性聚合物的药物组合物 - Google Patents
含有水溶性差的活性成分、表面活性剂和水溶性聚合物的药物组合物 Download PDFInfo
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- CN1499959A CN1499959A CNA028073460A CN02807346A CN1499959A CN 1499959 A CN1499959 A CN 1499959A CN A028073460 A CNA028073460 A CN A028073460A CN 02807346 A CN02807346 A CN 02807346A CN 1499959 A CN1499959 A CN 1499959A
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- water
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- polymer
- surfactant
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Abstract
本发明公开了固体组合物和含有所述固体组合物的固体或液体剂型,特别是片剂、包衣片、胶囊或栓剂或水溶液,所述固体组合物包含(a)阴离子表面活性剂和水溶性碱性聚合物的组合或(b)阳离子表面活性剂和水溶性酸性聚合物的组合和(c)至少一种水溶性差的药物活性成分。所述表面活性剂/聚合物体系可溶于水并且可使活性成分增溶,以在治疗用量得到良好的生物利用度。所述水溶液适合用于鼻、胃肠外或眼部治疗。
Description
本发明涉及基于药用载体的固体剂型,例如片剂、包衣片、胶囊或栓剂,其包含由水溶性碱性聚合物和阴离子表面活性剂或水溶性酸性聚合物和阳离子表面活性剂与水溶性差的药物活性成分组成的固体混合物;由水溶性碱性聚合物和阴离子表面活性剂或水溶性酸性聚合物和阳离子表面活性剂与水溶性差的药物活性成分组成的固体混合物;阴离子表面活性剂和水溶性碱性聚合物或水溶性酸性聚合物和阳离子表面活性剂与水溶性差的药物活性成分在水、有机溶剂或水和有机溶剂的混合物中的溶液;以及制备所述固体混合物的方法。本发明还涉及用于局部、鼻、胃肠外或眼部施用的水溶液。
药物活性成分的水溶性差以及经常与其相关联的溶解速率低对于药剂师而言是一个难题,因为很难将这种类型的活性成分配制成具有充分的生物利用度的固体(口服、经鼻和经直肠)或液体(经鼻、胃肠外)剂型或眼用剂型以获得所需的治疗效果。理论上讲,活性成分只能以溶解的形式被吸收。如果活性成分在通过胃肠道时没有被溶解,那么只有一部分活性成分可以被吸收,因此只能获得非常弱的作用或根本没有作用。如果不能将这种水溶性差的活性成分转化为能够以所需的剂量服用并且当通过胃肠道期间可形成活性成分的溶液的剂型,那么许多有价值的活性物质就不能用于治疗用途。
在Adv.Drug Del.Rev.25,103-128页(1997)中,A.J.Humberstone等人描述了包含表面活性剂、脂质、辅助表面活性剂和活性成分的微乳系统,应用此系统,可以将单独的水溶性差的活性成分通过填充至软明胶胶囊中而制成单独分装的应用形式。WO 00/48571描述了含有N-苯甲酰基星形孢菌素(staurosporine)的浓缩物,其在水中可自发分散为胶体并且含有亲水性成分和表面活性剂。通过将它们填充至软明胶胶囊中可以将其制成口服施用的剂型。该技术的缺点是:液体系统的微囊化不是标准技术。此外,使用标准设备不能将这些系统制成硬明胶胶囊或片剂。
在Pharmazie 31,11卷,784至786页(1976)中,H.O.Ammer描述了例如对-羟基烷基苯甲酸盐在包含十二烷基硫酸钠(SDS)/聚乙烯吡咯烷酮(PVP)/水的体系中的增溶实验。在两种情况下,如果加入PVP,可以观察到溶解度相比仅仅使用SDS时有所增加。这些结果显示:通过同时使用SDS和PVP可以增加所述物质在水性介质中的溶解度。但是文献中没有提及所述系统的固化形式或所述水溶液的用途。
EP-B-0296110描述了在N-甲基氨基上被取代的星形孢菌素,其作为蛋白激酶C(PKC)的选择性抑制剂是有价值的药物活性成分。
现已惊讶地发现:水溶性差的活性成分可以足量增溶于由阴离子表面活性剂/水溶性碱性聚合物或阳离子表面活性剂/水溶性酸性聚合物和水组成的系统中。通过除去水可以将这些水性系统转化为固态物质。将这些固态物质加入水中后,很快又可以得到不易于发生过饱和的光学透明并稳定的溶液或乳白色分子分散体。特别地,这些溶液和分散体在胃肠道的pH范围内也是稳定的,所以可以获得显著的生物利用度。因此所述固态物质特别适合于制备固体和液体剂型,其含有药学有效量的水溶性差的药物活性成分,并且其被改善的溶解度可以确保得到令人满意的生物利用度。此外,这些固体物质可以以一种简单的、具有相同或相似特征的方式,通过将组分溶解在有机溶剂中然后除去有机溶剂而制备。
一方面,本发明提供了一种固体组合物,其包含:
(a)阴离子表面活性剂和水溶性碱性聚合物的组合,或(b)阳离子表面活性剂和水溶性酸性聚合物的组合,和
(c)至少一种水溶性差的药物活性成分。
在本发明的上下文中,水溶性差的药物活性成分指的是活性成分在1升20℃的水中的溶解量小于100mg,优选小于50mg,更优选小于10mg,最优选小于1mg。
已知多种类型的阴离子表面活性剂。对于本发明的组合物而言,选择的是生理学可接受的表面活性剂。其它优选的表面活性剂是那些通过与水溶性聚合物相互作用可形成聚合物和表面活性剂的复合物、从而改善体系的溶解性能的表面活性剂。这种类型的表面活性剂是已知的。它们主要是含有疏水取代基的有机酸和其生理学可接受的盐,例如碱金属盐(Na或K)或碱土金属盐(Mg或Ca)。适宜的酸有例如羧酸、磺酸、亚磺酸、膦酸、亚膦酸、硫酸单酯、亚硫酸单酯、磷酸单酯或双酯和亚磷酸的单酯或双酯。优选的酸为磺酸、膦酸、硫酸单酯和磷酸单酯或双酯。特别优选的是硫酸单酯和磷酸单酯或双酯。
所述酸优选含有烃基,所述烃基含有至少6个、优选至少8个碳原子并且不超过30个、优选不超过20个碳原子。所述烃基可以被O、S、CO、-C(O)-O-和/或-C(O)-NH-间隔,和/或是未取代的或被-OH、-O-C1-C20-烷基、-NH-C(O)-C1-C20-烷基和/或-O-C(O)-C1-C20-烷基取代。所述烃基可以选自直链和支链烷基;C5-C12环烷基,优选被C1-C20烷基取代的C5-C8环烷基;被C1-C20烷基取代的C6-C10芳基以及被C5-C12环烷基或C8-C30多环烷基取代的C1-C20烷基。多环烷基可以优选地为如在天然甾体或胆汁酸中可见的稠环体系。
特别优选的阴离子表面活性剂对应于通式I和Ia,
R-X (I),
R-C(O)-NH-R1-SO3H (Ia),
其中R是6至30个碳原子的烃基,其任选被-O-、-S-、-CO-、-C(O)-O-和/或-C(O)-NH-间隔,和/或是未取代的或被-OH、-O-C1-C20-烷基、-NH-C(O)-C1-C20-烷基和/或-O-C(O)-C1-C20-烷基取代;R1表示C2-C4亚烷基,X是-SO3H或-OSO3H,以及它们的钠、钾、镁和钙盐。通式I的表面活性剂的例子有C6-C20单烷基硫酸盐如辛基硫酸盐、癸基硫酸盐、十二烷基硫酸盐、十四烷基硫酸盐、十六烷基硫酸盐和十八烷基硫酸盐。通式Ia的表面活性剂的例子有1-酰基氨基-乙烷-2-磺酸,如1-辛酰基氨基-乙烷-2-磺酸、1-癸酰基氨基-乙烷-2-磺酸、1-十二酰基氨基-乙烷-2-磺酸、1-十四酰基氨基-乙烷-2-磺酸、1-十六酰基氨基-乙烷-2-磺酸、1-十八酰基氨基-乙烷-2-磺酸、牛磺胆酸和牛磺脱氧胆酸。胆汁酸的例子有胆酸和脱氧胆酸。
阳离子表面活性剂同样普遍已知并且市售可得。它们实质上是具有长链烃基的生理可接受的鎓盐,优选铵盐。铵盐的阴离子可以得自无机或有机酸。阴离子的例子有氯离子、溴离子、碘离子、硫酸根、硫酸氢根、碳酸根、碳酸氢根、磷酸根、甲酸根、乙酸根和甲磺酸根。铵盐优选是伯胺、仲胺和叔胺的铵盐,或是含有烃基的季铵盐,所述烃基含有至少8个、优选至少10个碳原子并且不超过30个、优选不超过20个碳原子。所述烃基可以被O、S、CO、-C(O)-O-和/或-C(O)-NH-间隔,和/或是未取代的或被-OH、-O-C1-C20-烷基、-NH-C(O)-C1-C20-烷基和/或-O-C(O)-C1-C20-烷基取代。所述烃基可以选自直链和支链烷基;C5-C12环烷基,优选被C1-C20烷基取代的C5-C8环烷基;被C1-C20烷基取代的C6-C10芳基和被C5-C12环烷基或C8-C30的多环烷基取代的C1-C20烷基。所述多环烷基可以优选为稠环体系。
用于本发明的适宜的阳离子表面活性剂包括苯扎氯铵、十六烷基二甲基苄基氯化铵、十六烷基氯化铵、十六烷三甲基氯化铵、十六烷基氯化吡啶鎓、十八烷基二甲基苄基氯化铵、双十八烷基二甲基氯化铵、十二烷基氯化吡啶鎓、氯化月桂基吡啶鎓和十四烷基氯化吡啶鎓。
在许多情况下,通过同时使用阴离子和阳离子表面活性剂可以对溶解能力进行优化。也可以类似地加入中性表面活性剂(烷基化的寡聚聚亚烷基二醇、烷基化的多元醇)。
水溶性聚合物普遍已知并且市售可得。这些聚合物可以是天然的、未改性的或改性的聚合物,或是合成的聚合物。所述聚合物是以这样的方式选择的,即选择与表面活性剂相互作用可以形成分子复合物的聚合物。天然聚合物的例子有:可被部分烷基化、羟烷基化或酰化的纤维素;任选酰化的或羟烷基化的淀粉;以及肽类。合成聚合物的例子有:聚酰胺,例如聚赖氨酸或聚(2-乙基-2-噁唑啉);C2-C4链烷二醇的均聚物和共聚物,例如聚乙二醇;以及烯键式不饱和单体的均聚物或共聚物,所述均聚物或共聚物含有足够比例的亲水性烯键式不饱和单体。亲水性单体可以是例如乙烯醇、丙烯酸、甲基丙烯酸、马来酸、任选N-烷基化的丙烯酰胺或甲基丙烯酰胺、任选N-烷基化或酰化的乙烯胺(例如乙烯基吡咯烷酮)。可能的用于水溶性共聚物的疏水性烯键式不饱和单体有例如烯烃、苯乙烯、丙烯酸酯或甲基丙烯酸酯以及乙烯基醚。在本发明的上下文中,具有酸性基团如羧基的聚合物被称为酸性聚合物,具有碱性基团例如胺或酰胺基团的聚合物被称为碱性聚合物。具有-OH基团的水溶性聚合物例如聚链烷二醇、聚乙烯醇、纤维素、淀粉或含有主要呈疏水性并略带酸性的基团的聚合物[例如(甲基)丙烯酸和(甲基)丙烯酸烷基酯或(甲基)丙烯酸羟烷基酯的共聚物]能够更强烈地与阳离子表面活性剂相互作用,并且在本发明上下文中被归类为酸性聚合物。含有主要呈疏水性并略带碱性的基团的聚合物[例如(甲基)丙烯酸酰胺和(甲基)丙烯酸烷基酯或(甲基)丙烯酸羟烷基酯的共聚物]能够更强烈地与阴离子表面活性剂相互作用,并且在本发明上下文中被归类为碱性聚合物,其中同时使用阳离子表面活性剂也是适当的。水溶性聚合物也可以含有酸性和碱性基团,例如(甲基)丙烯酸和任选N-烷基化的(甲基)丙烯酸酰胺的共聚物,因此可以使用阴离子和/或阳离子表面活性剂。
一组优选的水溶性碱性聚合物是那些在重复单元中包含酰胺或胺基团的聚合物,因为这些聚合物与阴离子表面活性剂的相互作用尤其强烈。这种聚合物的例子有聚赖氨酸、聚乙烯吡咯烷酮(例如PVP K90、PVP K30、PVP K25、PVP K17或PVP K12)、任选地部分或全部甲基化的或C1-C6酰基化的聚乙烯胺、聚丙烯酰胺、聚甲基丙烯酰胺、聚-N-甲基-或聚-N-二甲基丙烯酰-或-甲基丙烯酰胺以及聚(2-乙基-2-噁唑啉)。特别优选的是聚乙烯吡咯烷酮。
水溶性聚合物的平均分子量可以是例如2000至2000000道尔顿,并且优选为5000至1000000道尔顿。
本发明特别优选的阴离子表面活性剂和水溶性聚合物的组合的特征在于:选择C6-C18-单烷基硫酸盐和它们的Na+盐或K+盐以及聚乙烯吡咯烷酮。优选的单烷基硫酸盐是十二烷基硫酸钠(SDS)、癸基硫酸钠和辛基硫酸钠。
另一个优选的阴离子表面活性剂和水溶性聚合物的组合的特征在于:选择胆汁酸和它们的Na盐或K盐以及聚乙烯吡咯烷酮。优选的胆汁酸为胆酸、牛磺胆酸、牛磺脱氧胆酸和甘氨胆酸。
水溶性差的药物活性成分本身是已知的。所述活性成分在室温下下优选是固态的。可以提及的一个例子是星形孢菌素及其衍生物。星形孢菌素的生物学效力由D.Fabbro等人在“抗癌药物设计”(2000),15,17-28页(具有抗增殖和抗肿瘤疗效的蛋白激酶抑制剂)中述及。一种优选的星形孢菌素对应于通式
(水溶解度:<0.1mg/l),其在下文中被称为PKC412。
水溶性聚合物与阴离子或阳离子表面活性剂的重量比可以是例如10∶1至1∶1,优选5∶1至1∶1,最优选3∶1至1∶1。使用同时包含组分a)和b)的组合时,可以将所使用的表面活性剂的总量保持在生理可接受的范围内。
本发明的固体组合物中,水溶性差的活性成分的量基于阴离子和/或阳离子表面活性剂和水溶性聚合物可以是以重量计0.01至30%,优选以重量计0.01至20%,最优选以重量计0.1至15%。
本发明的固体组合物可以以粉末、精细分散的颗粒或薄膜的形式存在。
另一方面,本发明提供了用于制备本发明的固体组合物的方法,其包含以下步骤:
a)将组分(a)阴离子表面活性剂和水溶性碱性聚合物或(b)阴离子表面活性剂和水溶性酸性聚合物和(c)至少一种水溶性差的活性成分混合并溶解于水中,
b)除去水直至得到固体组合物,或
c)将组分(a)阴离子表面活性剂和水溶性碱性聚合物或(b)阴离子表面活性剂和水溶性酸性聚合物与(c)至少一种水溶性差的活性成分混合并溶解于有机溶剂中,除去溶剂直至得到固体组合物。
通常,pH值可以为4.5至8.0,例如6至7,例如6.8。
对于混合和溶解步骤,可以单独、成对或合并加入所述组分。在混合并溶解于水中之前,最好通过加入酸、碱液或缓冲剂将水溶液调节至特定的pH值。适宜的缓冲剂是例如磷酸盐缓冲剂和磷酸盐/柠檬酸盐缓冲剂。为了加速饱和溶液的形成,也可以使用过量的组分,随后滤去未溶解的部分。也可以通过加热来加速溶解。溶液优选在约室温至约40℃的温度下形成。
用于方法步骤c)的适宜的惰性溶剂有例如脂肪族、脂环族和芳香族烃类(戊烷、己烷、石油醚、环己烷、甲基环己烷、苯、甲苯、二甲苯)、脂肪族卤代烃类(二氯甲烷、氯仿、二氯乙烷和四氯乙烷)、腈类(乙腈、丙腈、苯甲腈)、醚类(二乙基醚、二丁基醚、叔丁基甲基醚、乙二醇二甲基醚、乙二醇二乙基醚、二乙二醇二甲基醚、四氢呋喃、二恶烷、二乙二醇单甲基醚或单乙基醚)、酮类(丙酮、甲基异丁基酮)、羧酸酯类和内酯类(乙酸乙酯或乙酸甲酯、戊内酯)、N-取代的内酰胺类(N-甲基吡咯烷酮)、甲酰胺类(二甲基酰胺、二甲基甲酰胺)、无环脲类(二甲基咪唑啉)和亚砜类和砜类(二甲基亚砜、二甲基砜、四亚甲基亚砜、四亚甲基砜)和醇类(甲醇、乙醇、丙醇、丁醇、乙二醇单甲基醚、乙二醇单乙基醚、二乙二醇单甲基醚)和水。所述溶剂可以单独使用或以至少两种溶剂的混合物的形式使用。溶剂的混合物也可以包含水和至少一种有机溶剂(例如醚或醇)的混合物。
除去水或有机溶剂可以以已知的方式进行。适宜的方法是任选加热的条件下蒸发、任选加热条件下的真空下蒸发、冻干(冷冻干燥)、喷雾干燥或在流化床中喷洒至载体上。
依照方法步骤c)除去容器中的有机溶剂后,得到薄膜或粉末形式的固体组合物,所述固体组合物在短时间内可完全重新溶解于水或水性缓冲溶液中,并形成在数天内稳定的微乳白色体系。对溶液的检查显示:活性成分可被部分或全部溶解,或被部分溶解并且剩余的活性成分或甚至是全部活性成分可以以直径为亚微米级(纳米至微米)的微粒形式存在。在这种情况下,这些体系是高度分散的体系(分子分散体或胶体分散体),微粒的直径为20nm至5μm,优选30nm至2μm,最优选40nm至1μm。施用后,可以(甚至在高度分散体系的情况下也能够)确保活性成分的吸收,并且其治疗功效完全令人满意。
另一方面,本发明提供了一种溶液,其在水中或有机溶剂中包含:(a)以上所述的阴离子表面活性剂和在此所述的水溶性碱性聚合物的组合,或(b)以上所述的阳离子表面活性剂和在此所述的水溶性酸性聚合物的组合,和
(c)至少一种水溶性差的活性成分。
与每个单独的组分a)和b)相比,组分表面活性剂和聚合物的组合在水和任选地缓冲剂(例如磷酸盐缓冲剂)存在的情况下可以使更多的活性成分溶解。所述溶液光学透明并且稳定,可长期保存。水中的表面活性剂、聚合物和活性成分的量基于水溶液可以是以重量计1至30%,优选5至20%。在有机溶剂中的表面活性剂、聚合物和活性成分的量根据所选溶剂的溶解能力可以相当高;所述的量可以是以重量计1至80%、优选5至50%。
本发明的固体组合物可以在任选缓冲剂存在的情况下重新溶解于水中和/或分散为分子分散体。这些溶液或高度分散体系甚至在胃肠道的生理pH范围内也是稳定的。因此,所述组合物特别适合于制备固体剂型,所述固体剂型含有治疗有效量的水溶性差的药物活性成分、在胃肠道中可以被溶解从而确保获得所需的生物利用度。
本发明的另一个目标是基于药用载体的固体剂型,例如片剂、包衣片、胶囊或栓剂,其含有包含(a)以上所述的阴离子表面活性剂和在此所述的水溶性碱性聚合物的组合或(b)以上所述的阳离子表面活性剂和在此所述的水溶性酸性聚合物的组合以及治疗有效量的水溶性差的活性成分的固体混合物。
剂量取决于活性成分的生理学效力以及所预计的给药时间间隔。通常,活性成分的量可以是0.1至500mg、优选1至100mg。本发明的固体剂型也包括精细分散的粉末,其可以通过雾化器口服或经鼻施用、可以直接填充于胶囊中或可以在溶于水或饮料后口服施用。
用于口服或经直肠施用的药物制剂可以按照已知的方式制备,即通过将本发明的固体组合物(如果需要)与固体载体混合,任选地将混合物制粒,任选地加入适宜的赋形剂,并且将此混合物制成片剂、片芯、胶囊、栓剂或粉末剂。
适宜的载体特别地为填充剂,例如糖(乳糖、蔗糖、甘露醇、山梨醇)、纤维素和纤维素衍生物和/或磷酸钙(磷酸三钙或磷酸氢钙);粘合剂如(例如由玉米、小麦、大米或土豆淀粉制成的)淀粉糊、明胶、黄蓍胶、甲基纤维素、羟丙甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;和崩解剂,例如淀粉、羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂、海藻酸或其盐。所述赋形剂主要是流动调节剂和润滑剂,例如硅酸、滑石粉、硬脂酸和其镁盐或钠盐以及聚乙二醇。对片芯提供适当的、任选是肠溶性的包衣,包衣使用任选包含阿拉伯胶、滑石粉、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛的浓缩糖溶液;或在适宜的有机溶剂中的包衣溶液;或为制备肠溶包衣而使用的纤维素制品(如乙基纤维素邻苯二甲酸酯或羟丙基甲基纤维素邻苯二甲酸酯)的溶液。所述胶囊可以是硬明胶胶囊或由软明胶和增塑剂(例如甘油或山梨醇)制成的密封胶囊。所述硬胶囊可以含有粉末或颗粒形式的本发明的组合物,其中任选可以同时使用填充剂如乳糖、粘合剂如淀粉、润滑剂如滑石粉或硬脂酸镁和/或稳定剂。在软胶囊中,最好将活性成分溶解或悬浮于适合的油性赋形剂如石蜡油或液体聚乙二醇中,其中可以类似地加入稳定剂和/或抗菌剂。片剂、片剂包衣层和胶囊壳中也可以加入染料和/或色素以利于辨认。在制备栓剂的过程中,在将物料压制成最终形状前常常在载体中加入脂类或油类物质或其它润滑剂以增加流动能力。
当用于鼻或眼部使用、用于局部制剂或用于胃肠外施用(例如肌肉内或静脉内施用)时,将水分子(必要时使用雾化器)分散至本发明的胶体分散溶液中是适宜的。优选的是等渗溶液。通常将溶液装在安瓿或小瓶中。可以将载体物质例如甘露醇加入到溶液中。所述溶液可以进行灭菌并可含有赋形剂,例如用于调节渗透压的电解质盐、防腐剂、稳定剂和润湿剂、生理可接受的有机溶剂、增稠剂(如羧甲基纤维素钠、羧甲基纤维素、右旋糖苷、聚乙烯吡咯烷酮和明胶)以及缓冲剂。也可以将本发明的粉末,特别是冻干粉末本身包装在容器中,这样可以在使用前将它们制成水性的和任选的胶体溶液,用于鼻或眼部施用、局部施用,或用于胃肠外施用,例如肌肉内或静脉内施用。
以下仅对本发明的组合物举例进行说明。
A)水溶液和有机溶剂中的溶液的制备
实施例A1:
将10mg/ml的聚乙烯吡咯烷酮(PVP K30,BASF)、10mg/ml的十二烷基硫酸钠和过量的PKC412在25℃下加入到水或磷酸盐缓冲液(pH6.8,溶解于1L水中的13.96g Na2HPO4·2H2O和10.23g NaH2PO4·2H2O)中。将混合物搅拌24小时,使聚合物和表面活性剂完全溶解,随后过滤(注射滤器,0.2μm)混合物。得到的澄清溶液含有4.1mg/ml的PKC412。所述溶液在保存一年后仍然保持不变。
实施例A2-A10:
按照实施例A1的步骤进行。聚合物、表面活性剂及其以mg/ml计的用量列于表1。得到稳定且易于保存的澄清溶液。
表1:
实施例 | 聚合物(含量,mg/ml) | 表面活性剂(含量,mg/ml) | PKC412(溶解量,mg/ml) |
A2 | PVP K30(20) | SDS-Na(10) | (6.1) |
A3 | PVP K30(40) | SDS-Na(10) | (7.1) |
A4 | PVP K12(40) | SDS-Na(20) | (8.4) |
A5 | PVP K17(40) | SDS-Na(20) | (9.6) |
A6 | PVP K25(40) | SDS-Na(20) | (10.8) |
A7 | PVP K30(40) | SDS-Na(20) | (10.8) |
A8 | PVP K90(40) | SDS-Na(20) | (10.8) |
A9 | PVP K30(40) | 十二烷基硫酸钠(20) | (8.8) |
A10 | PVP K30(40) | 辛基硫酸钠(20) | (4.9) |
缩写:PVP是得自BASF的聚乙烯吡咯烷酮。表述K30、K12等指的是平均分子量:K30表示30000道尔顿,K12表示12000道尔顿。
实施例A11:
将40mg/ml的聚乙烯吡咯烷酮(PVP K30,BASF)、20mg/ml的十二烷基硫酸钠和8mg/ml的PKC412在25℃下加入到水中。将混合物搅拌24小时,得到澄清的溶液,并对其进行过滤(注射用滤器,0.2μm)。溶液保存一年后仍然保持不变。
实施例A12-A13:
按照实施例A1的步骤进行。聚合物、表面活性剂和它们以mg/ml计的用量列于表2。得到稳定且可保存的澄清溶液。
表2:
实施例 | 聚合物(含量,mg/ml) | 表面活性剂(含量,mg/ml) | PKC412(溶解量,mg/ml) |
A12 | PVP K30(80) | SDS-Na(20) | (8.0) |
A13 | PVP K30(160) | SDS-Na(20) | (8.0) |
实施例A14:乙醇溶液
在40℃下,将80mg/ml的聚乙烯吡咯烷酮(PVP K30,BASF)、40mg/ml的牛磺胆酸钠和16mg/ml的PKC412于搅拌状态下溶解于乙醇中,得到澄清且稳定的溶液。
实施例A15-A17:
按照实施例A14的步骤进行。聚合物、表面活性剂和它们以mg/ml计的用量列于表3。得到稳定且可保存的澄清溶液。
表3:
实施例 | 聚合物(含量,mg/ml) | 表面活性剂(含量,mg/ml) | PKC412(溶解量,mg/ml) |
A15 | PVP K30(80) | 牛磺胆酸钠(40) | (20.0) |
A16 | PVP K30(80) | 牛磺胆酸钠(40) | (4.0) |
A17 | PVP K30(40) | 牛磺胆酸钠(80) | (16.0) |
B)固体组合物的制备
实施例B1:通过冷冻干燥制备粉末剂
将实施例A11-A13的溶液加入到容器中,灌装高度为约8mm,并依照下面的冻干程序在冻干装置DELTA 1-24KD(GefriertrocknungsanlagenChrist,Osterodeam Harz,德国)中进行冷冻干燥。
冻干程序:
操作 | 温度(℃) | 压力(mbar) | 时间(小时) |
冷冻 | -35 | 非真空 | 1 |
冷冻 | -35 | 非真空 | 3 |
主干燥 | -35 | 1.5 | 1 |
主干燥 | -10 | 1.5 | 1 |
主干燥 | 0 | 1.5 | 20 |
再次干燥 | 0 | 0.4 | 1 |
再次干燥 | 0 | 0.4 | 2 |
再次干燥 | 25 | 0.4 | 1 |
再次干燥 | 25 | 0.4 | 9 |
得到的粉末经轻微振动不超过一分钟可以重新完全溶解于水性介质中。为了进行进一步的处理,将所得到的粉末用平均筛孔尺寸为250μm的筛网过筛。
实施例B2:通过蒸发过程制备粉末剂
首先用装备有水泵的Buchi RE 111旋转蒸发仪(BuchiLaborgerate-Technik,Flawil,瑞士)将大部分溶剂从实施例A14-A17的溶液中除去,然后将共蒸物在40℃下于25-10mbar的真空干燥器(Salvis,Rotkreuz,瑞士)中预干燥约12小时,随后将其用平均筛孔尺寸为500μm的筛网过筛。再次在上述条件下进行最终干燥直至达到恒重。
C)胶囊和片剂的制备
实施例C1:胶囊的制备
使用按照实施例A11制备并随后按照实施例B1干燥的粉末。将含有25mg PKC412的相应量的所述粉末填充至透明、无色的00号硬明胶胶囊(Capsugel,得自比利时的Bornem)中。
实施例C2:胶囊的制备
使用按照实施例A14制备并随后按照实施例B2干燥的粉末。将含有25mg PKC412的相应量的所述粉末填充至透明、无色的1号硬明胶胶囊(Capsugel,得自比利时的Bornem)中。
实施例C3:粉末的预压
预压是用压片机EK 0(Korsch,柏林)进行的。使用片剂检测器6D(Schleuniger,Solothurn,瑞士)对片剂的断裂强度进行了检查。
将按照实施例A11制备、随后按照实施例B1处理的粉末压制成断裂强度约为10至15N的中间体压块,然后将其粉碎过筛,筛网的平均筛孔尺寸为1mm。
实施例C4-C5:片剂的制备
片剂的制备是使用压片机EK 0(Korsch,柏林)进行的。使用片剂检测器6D(Schleuniger,Solothurn,瑞士)对片剂的断裂强度进行了检查。
使用实施例C3的粉末作为含有活性成分的粉末。
用Tubula混合器将表5所示的相应量的含有活性成分的粉末、微晶纤维素和交联聚乙烯吡咯烷酮在50rpm下预混5分钟。随后将混合物通过筛孔尺寸为1mm的筛网。然后加入表5中所列出量的硬脂酸镁并继续搅拌5分钟。将混合物压制成直径为9mm的圆形片,其断裂强度为35-40N,片重为320mg。
表5:PKC412的理论含量为25mg的片剂的组成
实施例 | 含有活性成分的粉末(mg/片) | 微晶纤维素(mg/片) | 交联聚乙烯吡咯烷酮(mg/片) | 硬脂酸镁(mg/片) |
C4 | 212.5 | 104.3 | 0.0 | 3.2 |
C5 | 196.5 | 88.3 | 16.0 | 3.2 |
实施例C6:片剂的制备
单剂量为25mg PKC412的片剂的制备是用压片机EK 0(Korsch,柏林)完成的。使用片剂检测器6D(Schleuniger,Solothurn,瑞士)对断裂强度进行了检查。
所使用的含有活性成分的粉末是依照实施例A14制备、随后依照实施例B2进行处理的粉末。
用Tubula混合器将表6所示的相应量的含有活性成分的粉末、微晶纤维素在50rpm下预混5分钟。随后使混合物通过筛孔尺寸为0.5mm的筛网。然后加入表6中所列出量的硬脂酸镁并再继续搅拌5分钟。将此混合物压制成直径为12mm的圆形片,其断裂强度为35-40N,片重为500mg。
表6:PKC412的理论含量为25mg的片剂的组成
实施例 | 含有活性成分的粉末(mg/片) | 微晶纤维素(mg/片) | 交联聚乙烯吡咯烷酮(mg/片) |
C6 | 212.5 | 282.5 | 5.0 |
D)应用实施例
实施例D1:胶囊的溶解性能
用于溶解性能实验的介质是1升不含表面活性剂的、根据美国药典XXIV(SIFmod)中的“模拟肠液,TS”改进的介质。KH2PO4被NaH2PO4替代。未加入胰液素(pH6.8)。
溶解实验是依照美国药典XXIV中的“桨法”、用Sotax AT6(Sotax,Basle,瑞士)在37℃下、搅拌速度为50rpm时进行的。将胶囊置于聚四氟乙烯包被的沉子(ATN,Pfaffenheim,法国)中以使胶囊保持在溶解容器的底部。基于25mg剂量的未处理的PKC412的可比溶解度小于理论含量的0.4%。
表7中给出了从实施例C1和C2的、含有25mg PKC412的3粒胶囊中释放出的活性成分的平均量占理论含量的百分数。
表7:不同时间间隔后从SIFmod中的含有25mg PKC412的胶囊中释放出的活性成分占理论含量的百分数(n=3)
实施例的胶囊 | 10分钟 | 15分钟 | 20分钟 | 30分钟 | 45分钟 | 60分钟 |
C1 | 23 | 53 | 73 | 92 | 95 | 95 |
C2 | 33 | 65 | 86 | 93 | 93 | 93 |
实施例D2:片剂的溶解性能
溶解性能实验所使用的介质是1升不含表面活性剂的、根据美国药典XXIV(SIFmod)中的“模拟肠液,TS”改进的介质。KH2PO4被NaH2PO4替代。未加入胰液素(pH6.8)。
溶解实验是根按照美国药典XXIV中的“桨法”、用Sotax AT6(Sotax,Basle,瑞士)在37℃下、搅拌速度为50rpm时进行的。加入片剂并测量所释放出的活性成分的量。基于25mg剂量的未处理PKC412的可比溶解度小于理论含量的0.4%。
表8中给出了从实施例C4至C6的含有25mg PKC412的3个片剂中释放出的活性成分的平均量占理论含量的百分数。
表8:不同时间间隔后SIFmod中的含有25mg PKC412的片剂释放出的活性成分占理论含量的百分数(n=3)
实施例的片剂 | 10分钟 | 15分钟 | 20分钟 | 30分钟 | 45分钟 | 60分钟 |
C4 | 32 | 48 | 61 | 80 | 95 | 96 |
C5 | 28 | 39 | 51 | 72 | 93 | 98 |
C6 | 37 | 53 | 67 | 79 | 92 | 95 |
实施例E1:生物利用度实验
在一项相对生物利用度的研究中,测定了实施例C1和C2的胶囊相对于软明胶胶囊中的液状的、可自发分散的制剂(参比)的生物利用度。所述研究使用9只雄性beagle狗(年龄:1-11岁,体重:9-12kg)、采用正交设计进行。
在每只狗的咽部给予每种制剂的两粒胶囊作为单次剂量(相当于50mgPKC412),并用约20ml的去除矿物质的水冲服。在给药前以及给药后的15分钟、30分钟、45分钟、1小时、1.5小时、2小时、4小时、6小时、10小时、24小时、30小时和48小时采集血样并测定血浆中PKC412的浓度。生物利用度研究的结果列于表9。
表9:实施例C1和C2的胶囊相对于软明胶胶囊(参比)中的自发分散制剂的生物利用度研究结果。这些数值是平均值,括号中给出了变异系数(CV%)(n=9)。
(参比) | 实施例C1的胶囊 | 实施例C2的胶囊 | |
剂量(mg/kg) | 4.51(8) | 4.52(9) | 4.50(10) |
AUC(0-48h)[(ng/ml)×h] | 3698(24) | 2435(49) | 3405(31) |
AUC(0-48h)/剂量[(ng/ml)×h/(mg/kg)] | 813(26) | 536(53) | 739(28) |
cmax[ng/mL] | 544(19) | 253(56) | 473(29) |
cmax/剂量[(ng/mL)/(mg/kg)] | 119(23) | 55.5(58) | 102(24) |
tmax[h] | 1.4(27) | 1.8(20) | 1.5(29) |
Frel[%] | 100 | 66.4(45) | 93.2(24) |
Frel范围[%] | 31至127 | 68至132 |
1至2小时(tmax)后,所有制剂的血药浓度都迅速达到最高血药浓度(Cmax)。其它药代动力学参数(Cmax/剂量,AUC(1-48小时)/剂量)显示:实施例C2的胶囊和参比制剂中的PKC412的吸收非常相似,而对于实施例C1的胶囊,PKC412的吸收也较高,但稍低于前两种制剂。此外,实施例C1胶囊的Cmax/剂量或AUC(0-48小时)/剂量的变异性高于其它两种胶囊。三种胶囊制剂的生物利用度的顺序为:
参比制剂
实施例C2的胶囊>实施例C1的胶囊
总之,可以使用各种方法将水溶性差的活性成分PKC412与聚合物和表面活性剂一起制成为固体粉末,并且这些粉末与水性介质接触后能够迅速使活性成分PKC412分散并使其保持溶解形式。所述粉末还可以进一步制成胶囊或片剂,其在体外显示可迅速释放活性成分,并且在狗体内的生物利用度与软明胶胶囊中的自发分散制剂(参比)的生物利用度相当。
Claims (15)
1.固体组合物,其包含
(a)阴离子表面活性剂和水溶性碱性聚合物的组合或(b)阳离子表面活性剂和水溶性酸性聚合物的组合,和
(c)至少一种水溶性差的药物活性成分。
2.权利要求1的组合物,其中的阴离子表面活性剂选自含有疏水取代基的有机酸和其生理可接受的盐,阳离子表面活性剂选自具有长链烃基的生理可接受的鎓盐。
3.权利要求1的组合物,其中的水溶性碱性聚合物的重复单元中包含酰胺或胺基团。
4.权利要求3的组合物,其中的聚合物选自聚赖氨酸、聚乙烯吡咯烷酮、任选地部分或全部甲基化或C1-C6-酰基化的聚乙烯胺、聚丙烯酰胺、聚甲基丙烯酰胺、聚-N-甲基-或聚-N-二甲基丙烯酰-或甲基丙烯酰胺和聚(2-乙基-2-噁唑啉)。
5.权利要求1的组合物,其中的水溶性碱性聚合物为聚乙烯吡咯烷酮。
6.权利要求1的组合物,其中的阴离子表面活性剂为C6-C18-单烷基硫酸盐或其Na+盐或K+盐,水溶性碱性聚合物为聚乙烯吡咯烷酮。
7.权利要求6的组合物,其中水溶性差的药物活性成分是星形孢菌素。
8.权利要求7的组合物,其中水溶性差的活性成分是具有以下通式的星形孢菌素。
9.权利要求1的组合物,其中水溶性聚合物与阴离子或阳离子表面活性剂的重量比为10∶1至1∶1。
10.权利要求1的组合物,其中水溶性差的活性成分的量基于阴离子或阳离子表面活性剂和水溶性聚合物以重量计为0.01至30%。
11.权利要求1的组合物,其以粉末、精细分散的颗粒或薄膜的形式存在。
12.用于制备权利要求1的固体组合物的方法,其包含以下步骤:
a)将组分(a)阴离子表面活性剂和水溶性碱性聚合物或(b)阴离子表面活性剂和水溶性酸性聚合物和(c)至少一种水溶性差的活性成分混合并溶解于水中,
b)除去水直至得到固体组合物,或
c)将组分(a)阴离子表面活性剂和水溶性碱性聚合物或(b)阴离子表面活性剂和水溶性酸性聚合物和(c)至少一种水溶性差的活性成分混合并溶解于有机溶剂中,除去溶剂直至得到固体组合物。
13.一种溶液,其在水中或有机溶剂中包含:
(a)阴离子表面活性剂和水溶性碱性聚合物的组合或(b)阳离子表面活性剂和水溶性酸性聚合物的组合,和
(c)至少一种水溶性差的药物活性成分。
14.权利要求13的水溶液,其用于眼、鼻或胃肠外施用。
15.基于药用载体的固体剂型,其含有固体混合物,所述固体混合物由(a)阴离子表面活性剂和水溶性碱性聚合物的组合或(b)阳离子表面活性剂和水溶性酸性聚合物的组合与治疗有效量的水溶性差的药物活性成分组成。
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CN112739288A (zh) * | 2018-09-24 | 2021-04-30 | 3M创新有限公司 | 具有美容用治疗性水溶液的牙科矫治器 |
CN113797164A (zh) * | 2020-06-17 | 2021-12-17 | 成都瑞沐生物医药科技有限公司 | 一种眼用制剂的载体或辅料及其制备方法和应用 |
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AU2002304784A1 (en) | 2002-10-08 |
CA2439097A1 (en) | 2002-10-03 |
JP4330343B2 (ja) | 2009-09-16 |
US20140303145A1 (en) | 2014-10-09 |
PT1372611E (pt) | 2006-08-31 |
DE60211494D1 (de) | 2006-06-22 |
ES2261671T3 (es) | 2006-11-16 |
HK1061515A1 (en) | 2004-09-24 |
DE60211494T2 (de) | 2006-10-12 |
CN100350911C (zh) | 2007-11-28 |
EP1372611A2 (en) | 2004-01-02 |
US20160287707A1 (en) | 2016-10-06 |
EP1372611B1 (en) | 2006-05-17 |
CY1106159T1 (el) | 2011-06-08 |
US20040077232A1 (en) | 2004-04-22 |
WO2002076432A3 (en) | 2002-12-12 |
JP2004534739A (ja) | 2004-11-18 |
ATE326216T1 (de) | 2006-06-15 |
US20140018346A1 (en) | 2014-01-16 |
BR0208306A (pt) | 2004-03-09 |
US20080287417A1 (en) | 2008-11-20 |
CA2439097C (en) | 2010-10-12 |
WO2002076432A2 (en) | 2002-10-03 |
DK1372611T3 (da) | 2006-09-18 |
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