CN1137689C - 提高甾体化合物稳定性的药物释放组合物 - Google Patents
提高甾体化合物稳定性的药物释放组合物 Download PDFInfo
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- CN1137689C CN1137689C CNB961956941A CN96195694A CN1137689C CN 1137689 C CN1137689 C CN 1137689C CN B961956941 A CNB961956941 A CN B961956941A CN 96195694 A CN96195694 A CN 96195694A CN 1137689 C CN1137689 C CN 1137689C
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Abstract
描述了一种稳定的含3-氧代-4-烯功能基的甾体药物的经皮给药贴剂,其中贴剂包括有效量的不具有酸功能基的甾体药物和载体。该贴剂可进一步含有添加剂如穿透促进剂或赋形剂,条件是这些添加剂也不具有酸功能基。该贴剂既可为基质贴剂也可为贮液贴剂。在基质贴剂中,载体为与甾体药物紧密地混合的生物学上可接受的聚合物粘合剂。该粘合剂优选丙烯酸聚合物或共聚物。在贮液贴剂中,载体为含稀释剂或增稠剂的控制粘度组合物。优选的甾体药物包括某些皮质甾类和性激素,如孕激素和雄激素。也公开了一种在经皮贴剂贮存期间稳定上述甾体药物的方法。
Description
发明背景
总的说来,本发明涉及提高在其A环具有3-氧代-4-烯功能基的甾体药物稳定性的药物释放组合物。更具体地,本发明涉及稳定的透皮释放这类甾体药物的贴剂和提高贮存期间透皮药物释放贴剂中甾体药物稳定性的方法。
具有3-氧代-4-烯功能基的甾体化合物包括某些性激素和某些肾上腺皮质激素(corticosteroids)。肾上腺皮质激素具有很多不同的生理学功能和药理学作用。它们影响碳水化合物,蛋白,脂肪,和嘌吟的代谢,影响电解质和水的平衡;并影响心血管系统,肾脏,骨骼肌,神经系统,和其他器官和组织的功能。治疗学上,肾上腺皮质激素可用来治疗激素不足,炎症,和其他疾病,其中性激素可广泛地用于避孕和激素不足,以及用于其他疾病的治疗。
黄体酮是在月经周期后半段由卵巢,主要是黄体分泌的。该周期结束时从黄体中释放黄体酮的突然减少是月经开始的主要的决定性因素。众所周知,在该周期的黄体阶段黄体酮可导致子宫内膜的变化并产生分泌的子宫内膜。子宫颈内腺体也受黄体酮的影响。另外,在黄体酮的作用下,由雌激素诱导的人类阴道上皮的成熟向妊娠状态改变,并且黄体酮导致与排卵有关的体温升高现象。妊娠期间,逐渐长大的胎盘分泌黄体酮,直到分娩前将分泌出大量黄体酮,而且在妊娠期,少数情况下在月经周期的黄体阶段,黄体酮与雌激素作用,导致乳腺腺体的增生。妊娠结束时,这些腺体充满分泌物,乳腺的脉管系统显著地增大;但是,分娩后雌激素和黄体酮的影响立即停止,泌乳期开始。
孕激素在治疗中用于绝经后激素的替代治疗以中和子宫内膜上雌激素增生作用,用于功能性子宫出血,痛经,经前紧张,子宫内膜异位,以及先兆流产和习惯性流产。诊断学上,孕激素用于卵巢功能的评价。它们也可用于口服避孕药。孕激素可被配制成适用于口服制剂和注射液的剂型,但是,本领域技术人员已知,激素也可通过液体贮器和基质贴剂经皮给药。然而,这些药物在贮存期间的稳定性是一个很重要的问题,下面将更充分的解释这个问题,睾酮。
睾酮在睾丸、卵巢,和肾上腺皮质的控制下正常地合成。众所周知,睾酮的正常功能是在青春期产生显著变化,使男孩成长了一个男人。同样已知雄激素与男性的攻击性和性行为有关。在妇女月经周期已经观察到血浆中睾酮水平的变化。由卵巢和肾上腺皮质分泌的雄激素对妇女很可能具有生理学意义。临床上,睾酮首先被用来治疗男性的性腺机能减退以及促进男性和女性的组成代谢。
药物通过皮,即皮肤和粘膜的释放比其他给药途径具有很多优点。首先经皮给药是一种舒适、方便、和非侵害的给药方式。与口服治疗有关的吸收代谢的可变比率以及其他内在不便如肠胃刺激等均可避免。经皮给药也可提高对任何特定药物的血药浓度的控制程度,这些优点增强了患者的顺应性,提高了药物的安全性和功效。
皮肤是一种结构复杂,厚度较大的膜,从环境进入和通过无损伤的皮肤的分子必须首先穿过角质层和其表面上的任何物质。然后该分子必须穿过能生存的表皮,乳头状真皮,和毛细管壁进入血液或淋巴管。为了实现这样的吸收,分子必须克服不同的阻力,穿过各种类型的组织。因此,通过皮肤膜的转运是一个复杂的现象。但是,表面组合物或给皮给药的药物吸收的主要屏障是角质层。最近人们对使用粘膜作为给药部位很有兴趣,这是因为由于缺乏妨碍穿透的角质层它比皮肤的透过性更高。
经皮给药装置一般为贮液贴剂成基质贴剂。在贮激贴剂中,药物以液体的形式被贮存在一个贮器中,从该处扩散至皮肤。该贴剂包括一个外层,该层可包括速度控制膜以控制药物的释放速率。在基质贴剂中,药物被贮存在聚合物基质中,该基质为一层或多层以贮存药物,控制释放速率,并与皮肤粘附。由于少有如药物与聚合材料的配合禁忌的问题,贮液贴剂比基质贴剂的开发要早。但是,基质贴剂比贮液贴剂更易制造,而且使用更舒适和方便。
释放性激素贮液贴剂在本领域为已知技术。例如,Gerstel等的U.S.专利No.3,964,482,公开了用于经皮给药的药物释放装置,其中包括很多突出和含药物的贮器,其中突出从贮器中伸出,适于贮器中的经皮给药的药物穿过角质层。用于甾体给药的基质贴剂也为本领域的已知技术。例如,Chiang等,在U.S.专利No.5,252,334公开了甾体化合物,优选雌二醇的透皮释放,其中使用了含丙烯酸酯粘合剂,甾体化合物,和非强制性地存在的渗透增强剂和水溶性聚合物的粘附性基质贴剂。Blank的U.S.专利No.5,232,703公开了用于雌二醇经皮给药的非交联的,水不溶性乙烯基吡咯烷酮共聚物基质。Sinnreich等的U.S.专利No.5,019,008公开了用于与桉油醇和N-甲基-2-吡咯烷酮穿透促进剂结合的药物经皮给药的聚异丁烯基质。Chien的U.S.专利No.5,023,084公开了控制生育的孕激素/雌激素经皮给药基质贴剂,其中孕激素和雌激素分散于聚合物粘合剂中。本领域仍未被公开的是含3-氧代-4-烯功能基的甾体化合物,其中包括在含酸功能基的粘合剂,穿透促进剂,赋形剂,和其他贴剂组分存在下不稳定的很多性激素和皮质甾类,这种不稳定性显著降低了在含上述酸功能基的剂量形式中的这些甾体化合物存贮存时的量。
鉴于上述原因,显然提供其中贮存期药物稳定性问题被大大减少的含甾体化合物的药物组合物,特别是含甾体化合物的基质和贮液贮剂在本领域具有明显的进步。
本发明的目的和概要
本发明的一个目的是提供一种含甾体化合物的药物组合物,其中含3-氧代-4-烯功能基的甾体化合物在贮藏期是稳定的。
本发明的另一个目的是提供一种经皮给药的药剂形式,其中含3-氧代-4-烯功能基的甾体化合物在贮藏期是稳定的。
本发明的另一个目的是提供制造及使用用于含3-氧代-4-烯功能基的甾体化合物经皮给药的基质和贮液药剂形式,其中该甾体化合物在该药剂形式贮存期是稳定的。
这些及其他目的可通过提供用于含3-氧代-4-烯功能基的甾体药物的经皮给药的稳定的贴剂而实现,其中甾体药物在该贴剂的长期贮存中保持稳定,该贴剂包含有效量的甾体药物和一种载体,其中载体不含酸功能基并在贮存期间不生成酸功能基。优选地,甾体药物选自性激素,皮质甾类,及其混合物,含3-氧代-4-烯功能基的甾体药物也可与缺乏这样的功能基的甾体化合物,如某些雌激素(如雌二醇),孕激素,雄激素,和皮质甾类混合。稳定的贴剂既可为基质贴剂也可为贮液贴剂。在基质贴剂中,载体包括生物学可相容的聚合物粘合剂,其中甾体药物紧密地混合于其中,如溶于或悬浮于粘合剂中,优选的聚合物粘合剂选自丙烯酸聚合物和共聚物。在贮液贴剂中,载体包括控制粘度的组合物,甾体药物紧密地混入其中。控制粘度的组合物可含有稀释剂或增稠剂。载体中还包括添加剂,如穿透促进剂或赋形剂,条件是该添加剂也不含酸功能基。
在含具有3-氧代-4-烯功能基的甾体药物的经皮给药贴剂的贮存期间稳定该甾体药物的方法包括以下步骤:首先将有效量的甾体药物与有效量的载体紧密地混合,其中载体既不具有酸功能基而且在贮存期间也不形成酸功能基,然后将混合的甾体药物和载体作为甾体药物源混入经皮给药贴剂中。
附图的简要说明
图1显示根据本发明的基质贴剂的用作说明的实例的部分简略的截面图。
图2显示在含:A-无凝胶剂;B-1.5%羟丙基纤维素;C-1.5%交联聚丙烯酸的液体制剂中贮藏后NEA及其降解产物的HPLC分析结果的图解。
图3显示在含A-81%(w/w)Duro TaK 80-1196,4%(w/w)NEA,15%(w/w)脱水山梨醇单油酸酯,B-81%(w/w)TSR,4%(w/w)NEA,15%脱水山梨醇单油酸酯;C-81%(w/w)GEL-VA737,4%(w/w)NEA,15%(w/w)脱水山梨醇单油酸酯的基质制剂中,在室温下贮存114周后NEA及其降解产物的HPLC分析结果的图解。
本发明的详细描述
在本发明稳定的含甾体化合物的贴剂和该贴剂贮存期间稳定该甾体药物的方法公开或被描述之前,应该明白本发明不限于这里所述的特定的加工步骤和材料,有时这些加工步骤和材料可以改变。还应该明白这里使用的术语仅仅用来描述特定的具体方案而不用来限定,因为本发明的范围仅由所附的权利要求及其等同物来限定。
必须注意,除非另外清楚地指出,单数形式“a”,“an”,和“the”包括复数(对原文而言)。因此,例如,概念粘合层合“一个(a)甾体药物”包括两个或两个以上甾体药物的混合物,概念“一种(an)粘附剂”包括一种或多种粘附剂,以及概念“一种(a)穿透促进剂”包括两种或两种以上穿透促进剂的混合物。
在本发明的描述和权利要求中,将根据下列定义使用下列术语。
这里使用的术语“促进”,“穿透促进”,和“渗透促进”指提高生物膜(即皮肤或粘膜)对药物的渗透性,以便提高药物透过该膜的速率。“渗透促进剂”,“促进剂”,“穿透促进剂”或类似的术语表示实现这样的渗透促进的物质。
这里使用的“透皮的”或“经皮的”给药表示药物进入并通过皮肤或粘膜组织的释放。用此除非另外特别指出术语“透皮的”或“透粘膜”可交替使用。同样除非另外特别指出,术语“皮肤”,“-皮肤”(构词成分),“表皮”、“粘膜”,等也可交替使用。
这里使用的“甾体药物”表示在其A环含3-氧代-4-烯功能基的甾体化合物。这样的甾体药物包括某些性激素,包括孕激素和雄激素,以及某些皮质甾类。孕激素的例子包括黄体酮,17-乙炔睾酮(17α-乙炔基睾酮),甲羟孕酮羟孕酮,炔诺酮(17α-乙炔基-19-去甲基睾酮),炔诺酮乙酸酯(17α-乙炔基-19-去甲睾酮乙酸酯),脱氢孕酮(9β10α-孕-4,6-二烯-3,20-二酮),二甲炔睾酮(6α-甲基-17α-[1-丙炔基]-睾酮),氯地孕酮乙酸酯(6-氯-6-去氢-17α-乙酰氧基孕酮),甲基炔诺酮(13β-乙基-)17α-乙炔基-17β-羟基甾-4-烯-3-酮),及其酯和混合物。炔诺酮(NEA)为优选的具有3-氧代-4-烯功能基的孕酮。雄激素的例子包括睾酮,甲基睾酮,氟羟甲睾酮,去氢甲睾酮,诺龙,乙诺酮,及其酯和混合物。睾酮及其酯为优选的具有需要的3-氧代-4-烯功能基的雄激素。皮质甾类的例子包括羟基可的松,可的松,去氧皮甾酮,氟氢可的松,倍他米松,地塞米松,强的松龙,强的松,甲基强的松龙,对氟米松,去尖松,二氟美松,肤轻松,醋酸肤轻松,氟强的松龙,氯氟松,丙酮缩氟氢羟龙,甲基强的松,6α-甲-1-β羟孕酮,及其酯和混合物。
这里使用的“载体”表示经皮给药贴剂的制剂组分,包括但不限于,生物学上可接受的聚合物粘合剂,控制粘度的组合物,穿透促进剂,赋形剂,稀释剂,软化剂,增塑剂,抗刺激剂,遮光剂,等,及其混合物。
这里使用的“基质”,“基质系统”,或“基质贴剂”表示紧密地混合,即溶解成悬浮,于生物学上可接受的聚合物相,优选压力敏感粘合剂的药物,其中也可含有其他组分,或者促进剂也可溶解或悬浮于其中。该定义包括如下具体方案:聚合物相被压成薄片贴于压力敏感的粘合剂上或者使用涂盖层粘合剂。经皮给药领域已知的基质贴剂通常包括压在其聚合物相的外侧表面的非渗透性膜背衬以及,在经皮给药前,聚合物相内表面上的释放里衬。显然,根据本发明的基质贴剂也包括这样的背衬和释放里衬或其功能等同物,而且该部分中也应该无酸功能基。U.S.专利No.5,122,383描述了这样的背衬和里衬,该文献作为参考收编与此。因此,基质系统为聚合物载体中的单剂量形式的药物组合物,并且非强刺性地含有促进剂和其他组分或添加剂,这些成份的配制有利于聚合物层中的药物组合物持续的进行与皮,即皮肤或粘膜有关的药物转运。
术语“贮液贴剂”指紧密地混合于控制粘度的组合物中的药物,并且该药物处于具有非渗透性背衬和由用于经皮给药的渗透膜和粘合剂适当地成型的内表面的闭塞装置中。使用前可剥离的防粘里衬保护着该膜和粘合剂。因此,一个贮液系统为控制粘度组合物中的单剂量形式的药物组合物,它也含有促进剂并且非强制性地含有其他组分,这些成份的配制有利于闭塞装置中的药物组合物持续地进行与皮,即皮肤或粘膜有关的药物转运。使用时,除去可剥离的防粘里衬,将贴剂粘合在皮肤表面。促进剂/药物一起从凝胶或软膏中渗出,跨过该膜和粘合剂,如存在的话,到达皮肤表面,促进剂提高了药物通过皮肤的渗透作用。优选地,贮液贴剂为具有如U.S.专利4,829,224和U.S.专利4,983,395中公开要求保护的粘到皮肤的外周粘合剂环的贮液贴剂,特此将这些文献作为参考收编。
术语“控制粘度组合物”指其中含有甾体药物和促进剂,以及任何其他非强制性地存在的添加剂,如溶剂的,单相或相分离状态的赋形剂或载体,其粘度可通过加入稀释剂或增稠剂控制,从而达到选定的粘度。控制粘度组合物本身可用作溶剂,或者在其中可加入溶剂或共溶剂。这样的控制粘度的组合物可为水-或有机-基的并可含有被适当地凝胶化或增稠化的液体或溶剂的混合物。换句话说,该控制粘度组合物可包括,但不限于,溶液,悬浮液,乳剂,凝胶,软膏,霜剂,糊剂或任何允许选定的甾体药物以及非强制性地存在的促进剂和/或溶剂或其他添加剂向外扩散的其他类似状态。合适的用于控制粘度的增稠剂包括任何适当的材料如矿物油,凡士林,和各种含水凝胶剂和亲水性聚合物如甲基纤维素,羟甲基纤维素,羟丙基纤维素,聚乙烯吡咯烷酮,聚乙烯醇,丙烯酸聚合物增稠剂,(例如AM-SCO 6038ATM;Unocal),低分子量聚合物,等,及其混合物。
这里使用的药物“有效量”指无毒但足以提供选定的效果的药物的量。穿透促进剂的“有效量”指提供选定的膜渗透性的增加值,以及相应地指供选定的穿透深度,给药速率,和药物量的该促进剂的量。
已经发现,在酸功能基的存在下,甾体药物,即含3-氧代-4-烯功能基的甾体化合物是不稳定的,并可被降解。只要存在酸功能基,这种现象出现于任何制剂,口服的,注射的,或经皮给药的。因此,通过使该甾体药物与不含酸功能量的组分,如其他药物,载体,赋形剂,等结合可制备稳定的甾体药物制剂。含有与“甾体药物”混合的非甾体药物或不具有3-氧代-4-烯功能基的甾体化合物的制剂包括于本发明的范围内。这样的混合物可包括与具有3-氧代-4-烯功能基的孕激素,如醋炔诺酮,甲基炔诺酮或黄体酮,或具有3-氧代-4-烯功能基的雄激素,如睾酮及其酯混合的雌二醇或其他雌激素。本发明还包括稳定制济中的上述甾体药物的经皮给药。
通过改变阻力(扩散系数)或动力(扩散梯度)可增加药物通过皮肤或粘膜的流量。通过使用穿过促进剂可提高流量。穿透促进剂包括两类主要的组分,即细胞膜失调化合物和溶剂。本领域已知含两类细胞膜失调化合物的二元体系,例如U.S.专利No.4,863,970,特此作为参考收编。
本领域已知细胞膜失调化合物在表面药剂中很有用处,这些化合物被认为通过使角质层细胞膜的类脂层失调而有助于穿透皮肤。公开于1982年6月13日的欧洲专利公开No.43,738描述了这些化合物的总表,特此将该文献作为参考收编。可以相信,任何细胞膜失调化合物,只要其不含有酸功能基或在贮存或老化过程中不生成酸功能基,都可适用于本发明的目的。优选的细胞膜失调化合物包括十四烷酸异丙酯,十二烷酸甲酯,油醇,单油酸甘油酯,二油酸甘油酯,三油酸甘油酯,单硬脂酸甘油酯,单十二烷酸甘油酯,单十二烷酸丙二醇酯,脱水山梨醇酯及其混合物。
同样,可用于本发明的溶剂应该不含酸功能基。合适的溶剂包括水;二醇,如丙二醇和甘油;单醇,如乙醇,丙醇,和高级醇;DMSO;二甲基甲酰胺;N,N-二甲基乙酰胺;2-吡咯烷酮;N-(2-羟乙基)吡咯烷酮,N-甲基吡咯烷酮,1-十二烷基氮杂环庚烷-2-酮和其他n-取代的-烷基-氮杂环烷基-2-酮(azones)等,及其混合物。
不一定与二元系统有关的其他化学促进剂包括DMSO或DM-SO水溶液。如Hersohler的U.S.专利3,551,554;Hersehler的U.S.专利3,711,602和Herschler的U.S.专利3,711,606所述,以及azones(n-取代的-烷基-氮杂环烷基-2-酮),如Cooper的U.S.专利4,557,943。
某些化学促进剂系统可具有负性副作用如毒性和皮肤刺激。U.S.专利4,855,298公开了使用足够量的具有抗刺激作用的甘油减轻由含具有皮肤刺激性质的组合物的化学促进剂导致的皮肤刺激的组合物。因此,可将抗刺激剂有利地加入本发明的含药组合物中。
经皮给药系统常常不利地发生“爆发作用”,即当经皮给药系统应用于皮肤或粘膜时立即释放高剂量的药物。一段时间后,这种爆发或很高水平的释放降低或拉平,达到血浆中可接受的药物水平。因此,形成一个很不均一的药物释放曲线。共同待审申请序号07/897,269描述了通过从甘油发现的优点解决这个问题,将甘油加入经皮给药制剂时,它有效地降低了药物的最初剂量,同时在未显著降低给药剂量的情况下,在预期的使用期内,使穿透进入血浆中的药物的量更均匀。因此,对抗爆发作用的试剂可有利地加入本发明范围内的药物/促进剂中。
关于图1,根据本发明的基质贴剂的图示具体方案一般如图10所示。贴剂10是适于粘在用药部位的分层的含药聚合物层形式的贴剂。贴剂10的各层包括基本上不渗透药物的背衬14,载有药物的聚合物层18,它适于粘附在皮肤或粘膜上,以及基本上不渗透药物的防粘里衬22。
背衬层14,在使用中,固定在贴剂面向环境的一侧,即远离皮肤或粘膜的一侧。背衬层14的功能是保护贴剂并提供非渗透性的层以防止药物流失到环境,因此,所选用的材料应该对药物基本上无渗透性。优选地,背衬材料可为不透光的,以保护药物在暴露在光线下时不被分解。另外,背衬14应该能结合在贴剂的其他层上并支撑贴剂,而且应该具有柔韧性以适应使用贴剂10的人的运动。在修饰或不修饰的情况下,可使用的材料选自金属箔,金属化的聚合物箔,含聚四氟乙烯(“TEFLON”)一型材料的复合箔或膜或其等同物,聚乙醚酰胺嵌段共聚物(例如,“PEBAX”共聚物),聚氨基甲酸乙酯如′PELLATHANE”或“ESTANE”聚合物,聚编二氯乙烯(Saran),尼龙,硅氧烷弹性体,橡胶基聚异丁烯,苯乙烯,苯乙烯-丁二烯和苯乙烯-异戊二烯共聚物,聚乙烯,聚丙烯,聚酯,以及其他用于经皮给药领域的材料。正如贴剂的其他组分,所选定的背衬材料应该不含酸功能基或在老化过程中不产生酸功能基。
用于形成聚合物/药物复合材料层18的聚合物应该与药物相容并允许所使用的药物流动。聚合物层18的包含的材料优选地为包括不具有酸功能基并在贮存期间不产生酸功能基的药学上可接受的材料的压力敏感的皮肤接触粘合剂。对于经皮给药贴剂所使用的粘合剂应满足的一般标准包括生物相容性,易于使用并易于除去。优选的粘合剂材料应该为药物在其中具有中等扩散性的材料。平衡后,药物将通过粘合剂层18扩散,它有助于释放动力学的调节。因此,通过仔细选择粘合剂18所使用的材料,可调节药物通过整个贴剂10的分布。其他有用的标准包括药物在粘合层10中的适当的溶解度从而提供贮存容量。适用于本发明的粘合剂包括天然和合成的橡胶,其中包括聚异丁烯,氯丁橡胶,聚丁二烯,和聚异戊二烯。其他合适的材料包括聚硅氧烷,聚氨基甲酸酯,增塑剂重量的聚醚酰胺嵌段共聚物(“PEBAX”共聚物),以及某些交联或非交联丙烯酸聚合物和共聚物。交联和非交联的丙烯酸聚合物和共聚物可优选的聚合物粘合剂,因为它们柔韧性高,价格便宜,能提供大面积的粘合制剂,而且可提供比其他粘合剂,如聚异丁烯(“PIB”)粘合剂更好的药物溶解性。两种优选的粘合剂为N-乙烯基吡咯烷酮和2-乙基-己基丙烯酸酯的嵌段共聚物(TSR,Sekisui chemical Co.,Osaka,Japan)和羟基功能基丙烯酸酯粘合剂(GELVA 737,Monsanto Polymer Prod-ucts Co.,St.Louis,Missouri)。尽管优选的聚合物是粘合剂,但非粘合剂的聚合物的使用也应归于本发明的范围内。这种情况下,聚合物层可压制在粘合剂上,或者使用粘合剂贴面。在任何情况下,与药物接触的基质贴剂中的组分都不应含有酸功能基或在老化过程中产生酸功能基。
防粘里衬或可剥离膜22覆盖在贴剂10面向皮肤的或邻近的一面,直到使用贴剂10时。因此防粘里衬或可剥离膜22应该具有与背衬14相似的性质,并优选与其相同的材料。在使用贴剂前,将防粘里衬22除去,暴露出含药物的聚合物层18,使其接触并粘附在皮肤或粘膜表面。因此,防粘里衬应适于从贴剂10上除去。
在含具有3-氧代-4-烯功能基的甾体化合物经皮给药贴剂贮存期间稳定该甾体化合物的方法包括以下步骤:首先使有效量的甾体药物与有效量的载体紧密地混合,其中载体不具有酸功能基并在贮存期间不产生酸功能基,然后将混合的甾体药物和载体作为甾体药物源混入经皮给药贴剂中。根据这个方法,贴剂既可为基质贴剂也可为贮液贴剂,而载体可为任何选自前文所述的适当的载体。该贴剂可按本领域已知的方法制造。
实施例1
将选定量的甘油,甘油单油酸酯(GMO)。十二烷酸甲酯(ML),和乙醇混合得到均相溶液。加入水得到含体积百分比为56/20/20/2/2的乙醇/水/甘油/GMO/ML的储备溶液。将该储备溶液的等分试样(100ml)移到瓶中,并加入NEA使各瓶的最终浓度约为10mg/ml。分析这些含NEA溶液的药物含量,然后将各瓶密封并在室温(RT)或45℃下培养选定的时间,然后再分析NEA的含量。使样品在45℃培养以加速分解,当然在RT下如果时间充足的话分解也会发生。也就是,通过在较高温度下培养可加速分解实验。通过HPLC分析测定NEA含量。该实验的结果如表1所示
表1
时间(周) | RT(mg NEA/ml)a | 45℃(mg NEA/ml)a |
0 | 10.31±0.21 | -- |
12 | 10.34±0.14 | 10.13±0.14 |
a平均±SD,n=4
这些结果说明在不含酸功能基的药物组合物中,NEA在RT或45℃下,在12周内,相当地稳定。
实施例2
除各瓶中加入1.5%重量比的羟丙基纤维素,(KLUCEL HXF,Aqnalon Co.,Wilmington,Delaware)外,按实施例1的步骤进行。通过在广口瓶中放入已知量的凝胶,摇动下用甲醇萃取凝胶过夜,并通过HPLC测定甲醇萃取液等分试样中药物含量而测定前步所得凝胶中的药物含量。该实验的结果如表2所示。
表2
时间(周) | RT(mg NEA/g gel)a | 45℃(mg NEA/g gel)a |
0 | 10.27±0.15 | -- |
12 | 10.17±0.10 | 10.17±0.07 |
a平均±SD,n=4
这些结果说明在不含酸功能基的凝胶化药物/促进剂组合物中,NEA在RT或45℃下,在12周内,相当地稳定。这样的凝胶化组合物可用于贮液贴剂或游离形式的经皮给药系统。
实施例3
除各瓶中加入1.5%重量15的与烯丙基醚交联的聚丙烯酸(CARBOPOL 1342,BF Goodrich Co.,clereland,Ohio)外,按实施例2的步骤进行。由于交联的聚丙烯酸降低药物/促进剂制剂的PH值,因此加入足量2NNaOH调节PH至约5.5,类似于实施例1和2中的药物/促进剂的PH值。该实验的结果如表3所示。
表3
时间(周) | RT(mg NEA/g gel)a | 45℃(mg NEA/g gel)a |
0 | 10.16±0.12 | -- |
12 | 9.92±0.07 | 9.21±0.05 |
a平均±SD,n=4
这些结果说明,在含酸功能基的凝胶中,在45℃贮藏12周后损失了约9%的NEA。这些结果与实施例1和2的结果大不相同,当制剂中不存在酸功能基时,药物没有明显的损失。
HPLC分析显示在含酸功能基的凝胶中存在NEA的降解产物,而无酸功能基的制剂中不存在降解产物。与NEA相比这些分解产物的相对保留时间(RRTS)为0.47和0.52。将这些降解产物从HPLC流出液中收集,减压浓缩,再溶于氯仿,并通过质谱分析。分析结果显示该降解产物为NEA的羟基衍生物。羟基化的位置未确定,但很可能在6,8,和/或10位。该结果证明这些降解产物的形成与酸功能基部分的存在有关。NEA在酸功能基存在下的降解不是对炔诺酮的简单酯水解,而是对NEA分子骨架的素核取代。
实施例4
含NEA的基质经皮给药贴剂按下面所述制备。将少量Duro-Tak80-1196粘合剂溶液(含酸功能基的丙烯酸粘合剂,NationalStarch & Chemical Co.,Bridgewater,N.J.)分配在预称重的铝盘中,并测定其重。在70℃对流烘箱中干燥过夜以蒸发溶剂,然后再对铝盘及其内容物称重。通过干重除以湿重并乘以100而计算固体的百分含量。将已知量的DuroTak 80-1196粘合剂溶液在玻璃瓶中称重。从粘合剂溶液重量和百分固体含量计算溶液中的粘合剂的量。将适量NEA(Schering AG,Berlin,Germang)和脱水山梨醇单油酸酯穿透促进剂(ARLACEL 80,ICI Americas,Wilmington,Delaware)加入,得到含81%DuroTak 80-1196,4%NEA,和15%脱水山梨醇单油酸酯的组合物,所有百分比都按干重计算。然后将各个玻璃瓶盖紧,用实验室膜(PARAFILM“M”,American National Can Co.,Greenwich,CT)密封,并轻摇过夜,直到所有组分完全溶解,溶解变清。
然后将约8ml DuroTak 80-1196/NEA/脱水山梨醇单油酸酯溶液分配在硅烷化的聚酯防粘里衬(Release Technologies.Inc.,W.Chicago,Illinois)上并用10mil间隙的浇注刀浇注。将该浇注混合物在70℃的对流烘箱中干燥15分钟,得到约2mil厚的干膜,然后使用橡胶滚柱将聚乙烯背衬膜(3M Corp.,St.Paul,Minnesota)压制在干燥的粘合剂膜上。该薄膜制品用于快速药物稳定性评价。
按这个实施例配制的基质贴剂中的NEA的稳定性按下述测定。将贴剂(10cm2)从基质薄膜制品上切下,置于白色3×3英寸盒中(SVRLYN薄膜,铝箔,低密度聚乙烯,和纸;WRAPS,Inc.,EastOrange,N.J.),在盒中热封,在室温(RT)或在45℃贮存。在零时间和选定的间隔后分析贴剂样品中药物的含量。在从贴剂上剥离防粘里衬的前后,对在各温度下贮存的三份样品称重。通过对同一面积的贴剂的10份背衬膜样品称重的测定背衬膜的平均重量。通过用除去防贴里衬的贴剂的重量减去背衬膜的重量而计算各贴剂粘合剂的重量。然后在密封容器中用50ml甲醇将剥离的贴剂萃取24小时。通过HPLC分析甲醇萃取液从而测定各贴剂的药物含量。该稳定性快速研究的结果如表4所示。
表4
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 3.88±0.03 | -- |
14 | 3.80±0.02 | 2.5±0.00 |
a平均±SD(n=3)
这些结果显示在含酸功能基的粘合剂的存在下,在45℃贮存14周后,由于分解损失了约36%的NEA。图3显示在酸功能基存在下贮存时的这种药物损失与生成RRTS与实施例3(图2)中降解产物相同的降解产物有关,说明NEA降解的机理与实施例3相同。
实施例5
除粘合剂为不含酸功能基的丙烯酸共聚物(2-乙基己基丙烯酸酯和n-乙烯基-2-吡咯烷酮共聚物;TSR,Sekisui Chemical Co.,Osaka,Japan)外按实施例4的步骤制备含NEA的基质经皮给药贴剂。制得组分干重百分比如下的制剂。81%RST,4%NEA,15%脱水山梨醇单油酸酯。按实施例4的步骤测定这些贴剂的稳定性,其结果如表5所示。
表5
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 4.14±0.04 | -- |
8.5 | 4.08±0.06 | 3.91±0.07 |
a平均±SD(n=3)
这些结果显示不含酸功能基的基质贴剂中的NEA含量在室温或45℃贮存8.5周后仍相当稳定。另外还发现,在不存在酸功能基的情况下,NEA可在室温下稳定地贮存2年以上。与含酸功能基的贴剂比较,NEA由羟基化的降解被抑制(图3)。
实施例6
除粘合剂为不含酸功能基的丙烯酸共聚物(GELVA 737,Mon-santo Polymen Products Co.,St.Louis,Missouri)外,按实施例4的步骤制备含NEA的基质经皮给药贴剂。得到各组分干重百分比如下的制剂:81%(GELVA737,4%NEA,15%脱水山梨醇单油酸酯。测定所制得的贴剂中的NEA的稳定性,其结果如表6所示。
表6
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 3.99±0.06 | -- |
8.5 | 3.87±0.10 | 3.82±0.12 |
a平均±SD
这些结果显示在无酸功能基的情况下,在室温或45℃贮存8周后,NEA没有明显的损失。进一步的研究证明该制剂中的药物可在室温下稳定地贮存2年以上。另外,与含酸功能基的制剂相比NEA降解产物的生成被抑制(图3)。
实施例7
按实施例4的步骤制备含睾酮(TS)的基质经皮给药贴剂。得到各组分干重百分比如下的制剂:83%Duro Tak 80-1196,2%TS,15%脱水山梨醇单油酸酯。测定上述制备的贴剂中的TS的稳定性,结果如表7所示。
表7
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 1.94±0.03 | -- |
4 | 2.05±0.03 | 1.88±0.03 |
12 | 2.05±0.01 | 1.75±0.03 |
26 | 1.98±0.04 | 1.52±0.05 |
a平均±SD
这些结果显示在RT贮存的贴剂和在45℃贮存的贴剂之间在不同的时间内TS含量的明显变化。在含酸功能基的粘合剂中,TS不稳定,与RT样品相比,TS含量在45℃损失了12%和24%。TS含量在DuroTak 80-1196粘合剂中的损失显示其生成了TS降解产物,通过比较降解产物和可靠的6β-OM睾酮的层析的曲线可确定至少一种TS羟基衍生物的生成。该实施例说明甾体药物睾酮在含酸功能基的粘合剂中发生亲核取代机理与在NEA观察到的相似的降解。
实施例8
除用DuroTak 87-2287(一种不含酸功能基的丙烯酸粘合剂)代替DuroTak 80-1196外按实施例7制备含TS的基质经皮给药贴剂。得到各组分干重百分比如下的制剂:88%DuroTak 87-2287.2%TS,10%脱水山梨醇单油酸酯。测定这些贴剂中TS稳定性,其结果如表8所示。
表8
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 2.03±0.02 | -- |
4 | 1.97±0.01 | 2.01±0.02 |
12 | 2.00±0.01 | 2.02±0.01 |
26 | 1.97±0.02 | 1.91±0.02 |
a平均±SD
这些数据显示贴剂在RT和在45℃之间贮存26周后,TS含量无明显不同,该药物在无酸功能基的DuroTak 87-2287粘合剂中,在45℃贮存26周后仍是稳定的。这些结果显示甾体药物睾酮在不含酸功能基的制剂中贮藏时,是稳定的。
实施例9
按实施例4的步骤制备含炔诺酮(NE)的基质经皮给药贴剂。得到各组分干重百分比如下的制剂:88%DuroTak 80-1196,2%NE,10%脱水山梨醇单油酸酯。测定所制备的贴剂中NE的稳定性,其结果如表9所示。
表9
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 1.95±0.06 | -- |
11 | 1.97±0.04 | 1.77±0.05 |
a平均±SD
这些结果显示贴剂在RT贮存和在45℃贮存之间甾体药物含量有明显差别,约11%。因此甾体药物炔诺酮在含酸功能基的粘合剂中是不稳定的。
实施例10
除用不含酸功能基的TSR粘合剂代替DuroTak 80-1196外,按实施例9的步骤制备含NE的基质经皮给药贴剂。得到各组分干重百分比如下的制剂:88%TSR,2%NE,10%脱水山梨醇单油酸酯。测定所得的贴剂中的NE的稳定性,结果如表10所示。
表10
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 1.96±0.07 | -- |
11 | 1.99±0.08 | 1.96±0.03 |
a平均±SD
各时间时的数据的比较显示,贴剂在RT和45℃之间贮存11周后,甾体药物的含量无明显差异,在不含酸功能基的粘合剂中在45℃贮存11周后,甾体药物仍保持稳定。
实施例11
除略去脱水山梨酸单油酸酯外,按实施例9的步骤制备含NE的基质经皮给药贴剂,得到各组分干重百分比如下的制剂:98%DuroTak 80-1196,2%NE。测定所得贴剂中NE的稳定性,其结果如表11所示。
表11
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 1.97±0.02 | -- |
11 | 2.01±0.02 | 1.64±0.03 |
a平均±SD
这些结果显示在RT和45℃之间贮藏11周后NE的含量损失了约14%。因此,甾体药物在含酸功能基的制剂中是不稳定的,甾体药物损失的量与含脱水山梨醇单甘油酯(实施例9)的贴剂大致相等。因此,甾体药物的稳定性与含酸功能基的粘合剂的相互作用有关而与脱水山梨醇单油酸酯无关。
实施例12
按实施例的步骤制备含左旋18-甲基炔诺酮(LVNG)的基质经皮给药贴剂。得到各组分干重百分比如下的制剂:89%DuroTak80-1196,1%LVNG,10%脱水山梨醇单油酸酯。测定所得贴剂中LVNG的稳定性,结果如表12所示。
表12
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 1.94±0.02 | -- |
11 | 0.98±0.01 | 0.84±0.02 |
a平均±SD
这些数据显示在RT和在45℃之间贮存11周后贴剂中LVNG有明显的损失,约14%。因此LVNG在含酸功能基的粘合剂中是不稳定的。
实施例13
除了用不含酸功能基的STR代替DuroTak 80-1196,按实施例12步骤制备含左旋-18-甲基炔诺酮(LVNG)的基质经皮给药贴剂。得到各组分干重百分比如下的制剂:89%TSr,1%LVNG,10%脱水山梨醇单油酸酯。测定所制备的贴剂中的LVNG的稳定性,结果如表13所示。
表13
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 0.91±0.03 | -- |
11 | 0.89±0.02 | 0.89±0.03 |
a平均±SD
各时间的数据的比较显示在RT和在45℃之间贮存11周的贴剂的LVNG含量无明显差异。因此,在45℃贮存11周后,在不含酸功能基的贴剂中的甾体药物仍保持稳定。
实施例14
除了不使用脱水山梨醇单油酸酯外,按实施例12的步骤制备含LVNG的基质经皮给药贴剂。得到各组分干重百分比的制剂:99%DuroTok 80-1196,1%LVNG。测定制得的贴剂中的LVNG稳定性,结果显示于表14中。
表14
时间(周) | RT(%/w/w)a | 45℃(%w/w)a |
0 | 0.98±0.03 | -- |
11 | 0.99±0.02 | 0.85±0.03 |
a平均±SD
这些数据显示,该贴剂在KT和45℃之间贮存11周后,贴剂中LVNG含量有明显的损失,约14%。这说明酸功能基存在下甾体药物是不稳定的。与实施例12比较显示,该不稳定性起源于与粘合剂的相互作用而与制剂中的脱水山梨醇单油酸酯无关。
Claims (33)
1、一种在含具有3-氧代-4-烯功能基的甾体药物及含渗透促进剂的经皮给药贴剂贮存过程中稳定该甾体药物的方法,其中包括以下步骤:首先将有效量的上述甾体药物与有效量的载体紧密地混合,其中所述的载体无酸功能基并在贮存期不产生酸功能基,将有效量的渗透促进剂与药物和载体紧密混合,其中所述渗透促进剂无酸功能基并在贮存期不产生酸功能基,然后将混合的甾体药物,渗透促进剂和载体作为甾体药物源混入上述经皮给药贴剂中,其中所述经皮给药贴剂无酸功能基并在贮存期不产生酸功能基。
2、权利要求1的方法,其中甾体药物选自性激素和皮质甾类。
3、权利要求2的方法,其中贴剂为基质贴剂,而载体包括与甾体药物紧密地混合的生物学上可接受的聚合物粘合剂。
4、权利要求3的方法,其中甾体药物为选自孕激素,雄激素,及其混合物的性激素。
5、权利要求4的方法,其中性激素为孕激素,选自黄体酮,17-乙炔睾酮,甲羟孕酮,羟孕酮,炔诺酮,炔诺酮乙酸酯,脱氢孕酮,二甲炔睾酮,氯地孕酮乙酸酯,甲基炔诺酮,及其酯和混合物。
6、权利要求5的方法,其中孕激素为炔诺酮乙酸酯。
7、权利要求5的方法,其中孕激素为炔诺酮。
8、权利要求5的方法,其中孕激素为左旋18-甲基炔诺酮。
9、权利要求4的方法,其中性激素为雄激素,选自睾酮,甲基睾酮,氟羟甲睾酮,去氢甲睾酮,诺龙,乙诺酮,及其酯和混合物。
10、权利要求9的方法,其中雄激素选自睾酮及其酯。
11、权利要求3的方法,其中甾体药物为皮质甾类,选自羟基可的松,可的松,与氧皮甾酮,氟氢可的松,倍他米松,地塞米松,强的松龙,强的松,甲基强的松龙,对氟米松,去炎松,二氟美松,肤轻松,醋酸肤轻松,氟强的松龙,氯氟松,丙酮缩氟氢羟龙,甲基强的松,6α-甲-11β-羟孕酮,及其酯和混合物。
12、权利要求3的方法,其中聚合物粘合剂选自丙烯酸聚合物和共聚物。
13、权利要求12的方法,其中聚合物粘合剂选自N-乙烯基吡咯烷酮和2-乙基-己基丙烯酸的嵌段共聚物。
14、权利要求1的方法,其中渗透促进剂选自细胞膜失调化合物,溶剂,及其混合物之一。
15、权利要求14的方法,其中细胞膜失调化合物选自十四烷酸异丙酯,十二烷酸甲酯,油醇,单油酸甘油酯,二油酸甘油酯,三油酸甘油酯,单硬脂酸甘油酯,单十二烷酸甘油酯,单十二烷酸丙二醇酯,脱水山梨醇酯及其混合物,而溶剂选自水,二醇,单醇,DMSO,二甲基甲酰胺,N,N-二甲基乙酰胺,2-吡咯烷酮,n-取代的-烷基-氮杂环烷基-2-酮,及其混合物。
16、权利要求3的方法,进一步包括不含3-氧代-4-烯功能基的甾体化合物,该甾体化合物选自雌激素,孕激素,雄激素,和皮质甾类。
17、权利要求16的方法,其中甾体化合物为雌激素。
18、权利要求17的方法,其中雌激素为雌二醇。
19、权利要求3的方法,其中贴剂为贮液贴剂,载体包括与甾体药物紧密地混合的控制粘度的溶液。
20、权利要求19的方法,其中甾体药物为选自孕激素,雄激素,及其混合物的性激素。
21、权利要求20的方法,其中性激素为孕激素,选自黄体酮,17-乙炔睾酮,甲羟孕酮,羟孕酮,炔诺酮,炔诺酮乙酸酯,脱氢孕酮,二甲炔睾酮,氯地孕酮乙酸酯,甲基炔诺酮,及其酯和混合物。
22、权利要求21的方法剂,其中孕激素是炔诺酮乙酸酯。
23、权利要求21的方法,其中孕激素为炔诺酮。
24、权利要求21的方法,其中孕激素为左旋18-甲基炔诺酮。
25、权利要求20的方法,其中性激素为雄激素,选自睾酮,甲基睾酮,氟羟甲睾酮,去氢甲睾酮,诺龙,乙诺酮,及其酯和混合物。
26、权利要求25的方法,其中雄激素选自睾酮及其酯。
27、权利要求19的方法,其中甾体药物为皮质甾类,该皮质甾类选自羟基可的松,可的松,与氧皮甾酮,氟氢可的松,倍他米松,地塞米松,强的松龙,强的松,甲基强的松龙,对氟米松,去炎松,二氟美松,肤轻松,醋酸肤轻松,氟强的松龙,氯氟松,丙酮缩氟氢羟龙,甲基强的松,6α-甲-11β-羟孕酮,及其酯和混合物。
28、权利要求19的方法,其中载体进一步包括选自细胞膜失调化合物,溶剂,及其混合物的穿透促进剂。
29、权利要求28的方法,其中细胞膜失调化合物选自十四烷酸异丙酯,十二烷酸甲酯,油醇,单油酸甘油酯,二油酸甘油酯,三油酸甘油酯,单硬脂酸甘油酯,单十二烷酸甘油酯,单十二烷酸丙二醇酯,脱水山梨醇酯及其混合物,而溶剂选自水,二醇,单醇,DMSO,二甲基甲酰胺,N,N-二甲基乙酰胺,2-吡咯烷酮,n-取代的烷基-氮杂环烷基-2-酮,及其混合物。
30、权利要求19的方法,其中控制粘度的组合物包括选自矿物油,凡士林,羟丙基纤维素,甲基纤维素,羟甲基纤维素,聚乙烯吡咯烷酮,聚乙烯基醇,丙烯酸聚合物增稠剂,低分子量聚合物,及其混合物的增稠剂。
31、权利要求19的方法,进一步包括不含3-氧代-4-烯功能基的甾体化合物,该甾体化合物选自雌激素,孕激素,雄激素,和皮质甾类。
32、权利要求31的方法,其中甾体化合物为雌激素。
33、权利要求32的方法,其中雌激素为雌二醇。
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1995
- 1995-07-20 US US08/504,430 patent/US5780050A/en not_active Expired - Lifetime
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- 1996-06-21 DK DK96921735.5T patent/DK0876131T3/da active
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- 1996-06-21 CN CNB2003101245811A patent/CN100446769C/zh not_active Expired - Fee Related
- 1996-06-21 JP JP50667897A patent/JP3422796B2/ja not_active Expired - Lifetime
- 1996-06-21 EP EP96921735.5A patent/EP0876131B1/en not_active Expired - Lifetime
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- 1996-06-21 DK DK10180180.1T patent/DK2305195T3/en active
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BR9609738A (pt) | 1999-03-16 |
DK0876131T3 (da) | 2014-11-24 |
AU710760B2 (en) | 1999-09-30 |
CN1191475A (zh) | 1998-08-26 |
KR100505171B1 (ko) | 2005-11-22 |
CN100446769C (zh) | 2008-12-31 |
JPH10510548A (ja) | 1998-10-13 |
CN1509718A (zh) | 2004-07-07 |
JP2001072580A (ja) | 2001-03-21 |
HK1017983A1 (en) | 1999-12-10 |
EP2305195A1 (en) | 2011-04-06 |
CA2226425A1 (en) | 1997-02-06 |
EP0876131B1 (en) | 2014-08-13 |
WO1997003629A1 (en) | 1997-02-06 |
DK2305195T3 (en) | 2015-06-29 |
HK1066724A1 (en) | 2005-04-01 |
EP0876131A1 (en) | 1998-11-11 |
JP4344076B2 (ja) | 2009-10-14 |
US5780050A (en) | 1998-07-14 |
MX9800545A (es) | 1998-04-30 |
AU6287496A (en) | 1997-02-18 |
JP3422796B2 (ja) | 2003-06-30 |
CA2226425C (en) | 2009-08-18 |
KR19990028496A (ko) | 1999-04-15 |
EP2305195B1 (en) | 2015-04-22 |
EP0876131A4 (zh) | 1998-12-02 |
ZA965607B (en) | 1997-03-19 |
BR9609738B1 (pt) | 2009-05-05 |
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