CN100569291C - 含有α-2肾上腺素能激动剂的组合物 - Google Patents
含有α-2肾上腺素能激动剂的组合物 Download PDFInfo
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- CN100569291C CN100569291C CNB018073395A CN01807339A CN100569291C CN 100569291 C CN100569291 C CN 100569291C CN B018073395 A CNB018073395 A CN B018073395A CN 01807339 A CN01807339 A CN 01807339A CN 100569291 C CN100569291 C CN 100569291C
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- adrenergic agonist
- component
- composition
- agonist group
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Abstract
本发明涉及用于提高α-2-肾上腺素能激动剂组分的有效性的组合物,其含有载体组分、α-2-肾上腺素能激动剂组分、有助于增溶α-2-肾上腺素能激动剂组分的升高溶解度组分。在一个实施方式中,α-2-肾上腺素能激动剂组分包括α-2-肾上腺素能激动剂。在另一实施方式中,升高溶解度组分包括羧甲基纤维素。
Description
有关申请的交叉参考
本申请请求以2000年7月14日提交的美国临时专利申请60/218,200为优先权。
发明背景
本发明涉及含有α-2-肾上腺素能激动剂组分的组合物。更加具体地,本发明涉及这样的组合物,其中所述的α-2-肾上腺素能激动剂组分在治疗有效浓度下具有增高的溶解度。
α-2-肾上腺素能激动剂包括化学实体,例如化合物、离子、复合物等,其有效作用于或结合α-2-肾上腺素能受体并产生治疗效果。α-2-肾上腺素能激动剂组分是指激动剂本身及其所有前体、其代谢产物和它们的联合形式。含有α-2-肾上腺素能激动剂组分的配制组合物的一种连续刺激可以使此类组分更加有效。例如,α-2-肾上腺素能激动剂在液体组合物中常常因可溶于该组合物的液态载体中而受益。这样的溶解度易于均匀和精确给药。
而且,分配或给予的α-2-肾上腺素能激动剂组分应该优先溶解在生物体系或环境中,例如,用于有效或提高体内经细胞膜或脂质双层的扩散作用。一些具有较高pKa,例如大于约7的α-2-肾上腺素能激动剂组分,倾向于在接近其pKa的pH值下非常容易快速穿过脂质膜,因为在这种环境中它们在中性至碱性生物环境那大多数未电离。然而,一些此类α-2-肾上腺素能激动剂组分在这些至碱性生物pH下不溶解。这种不溶性可以减弱膜扩散性能,致使α-2-肾上腺素能激动剂组分在指定剂量下低效和/或改变其治疗效果。此外,溶解的α-2-肾上腺素能激动剂组分具有其他益处,譬如,减小对与α-2-肾上腺素能激动剂组分相互作用的组织的刺激作用。
始终需要新的含有α-2-肾上腺素能激动剂组分的组合物。
发明概述
已经发现了新的含α-2-肾上腺素能激动剂组分的组合物。本发明的组合物含有某些物质,其有效地至少是协助或者有助于α-2-肾上腺素能激动剂组分增溶到该组合物中,并且优选溶解在组合物所施用或引入的环境中,例如人眼。更加可取地,本发明的α-2-肾上腺素能激动剂组分的增溶作用促进该组合物转运穿过脂质膜。另外,这样的增溶作用适宜为药物的更加可靠和可重现剂型提供了准备。而且,业已发现了含α-2-肾上腺素能激动剂组分的组合物,其含有具有显著优越性的防腐剂,例如降低与α-2-肾上腺素能激动剂组分和/或与施用该组合物的患者之间的相关作用,同时保持防腐有效性。
本发明的组合物优选通过提高α-2-肾上腺素能激动剂组分的表观水溶度来增强α-2-肾上腺素能激动剂组分的有效性,优选在高于中性的pH下。本发明的组合物除了含有肾上腺素能激动剂组分以外,还含有有效量的升高溶解度组分(SECs)以提高α-2-肾上腺素能激动剂组分的溶解度。更加可取地,与不含有SECs的相似组合物比较,α-2-肾上腺素能激动剂组分更加易溶于具有例如pH等于或高于7的本发明组合物中。在另一实施方案中,与α-2-肾上腺素能激动剂组分在不含有SECs的相似组合物对比,本发明组合物的α-2-肾上腺素能激动剂组分更加易溶于中性,优选碱性的,组合物所施用的生物环境中。
在一个实施方式中,α-2-肾上腺素能激动剂组分包括亚氨基-咪唑啉类、咪唑啉类、咪唑类、氮杂卓类、噻嗪类、噁唑啉类、胍类、儿茶酚胺类化合物,它们的生物相容性盐和酯和混合物。更加可取地,α-2-肾上腺素能激动剂组分包括喹喔啉类组分。喹喔啉类组分包括喹喔啉、其生物相容性盐、其酯、其其他衍生物等,和它们的混合物。喹喔啉类衍生物的非限定实例包括(2-咪唑啉(imidozolin)-2-基氨基)喹喔啉、5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉,和其生物相容性盐和其酯,优选5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉的酒石酸盐等,及其混合物。此后,5-溴-6-(2-咪唑啉-2-基氨基)的酒石酸盐被称作“布莫尼定”。
在一个优选的实施方式中,α-2-肾上腺素能激动剂组分,例如上述那些,对α-2A-肾上腺素能受体、α-2B-肾上腺素能受体和/或α-2D-肾上腺素能受体具有特异性。
在一个实施方式中,α-2-肾上腺素能激动剂组分在该组合物中未电离。更加可取地,α-2-肾上腺素能激动剂组分在组合物所施用的生物环境中也未电离。
在一个有效实施方式中,SEC包括多阴离子组分。在此所用的术语“多阴离子组分”是指化学实体,例如,电离带电物质,如电离带电的聚合物,其包括一个以上的离散阴离子电荷,也就是多个离散的阴离子电荷。更加可取地,聚阴离子组分选自具有多阴离子电荷的聚合物,和它们的混合物。
特别有效的多阴离子组分选自:由丙烯酸衍生的阴离子聚合物(是指包括丙烯酸、丙烯酸酯等及其混合物衍生的聚合物),由甲基丙烯酸衍生的阴离子聚合物(是指包括甲基丙烯酸、甲基丙烯酸酯等及其混合物衍生的聚合物),由藻酸衍生的聚合物(是指包括藻酸、藻酸盐等及其混合物),氨基酸的阴离子聚合物(是指包括氨基酸、氨基酸盐等及其混合物的聚合物)等,和它们的混合物。非常有效的多阴离子组分是选自阴离子纤维素类衍生物及其混合物的那些,尤其是羧甲基纤维素。
多阴离子组分适宜具有足够的阴离子以相互作用或者影响,特别是提高α-2-肾上腺素能激动剂组分的溶解度。该相互作用优选足以使α-2-肾上腺素能激动剂组分在治疗有效浓度下基本上完全溶解。SEC在所述组合物中的含量优选是约0.1%(w/v)-约30%(w/v),更优选约0.2%(w/v)-约10%(w/v),并且特别更优选约0.2%(w/v)-约0.6%(w/v)。
该组合物包括载体组分,例如,含水液体载体组分。在一个实施方式中,该组合物具有约7或更高的pH,优选约7-约9,并且是眼科可接受的。
在一个优选实施方式中,提供了一种组合物,其包括有效量的向施用组合物的患者提供至少一种治疗益处的α-2-肾上腺素能激动剂组分、有效量的提高α-2-肾上腺素能激动剂组分的溶解度的阴离子纤维素衍生物和含水液体载体组分。α-2-肾上腺素能激动剂组分优选含有5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉的酒石酸盐。阴离子纤维素衍生物优选含有羧甲基纤维素。阴离子纤维素衍生物在该组合物中的浓度应该是约0.2%(w/v)-约0.6%(w/v)。
在一个优选实施方式中,本发明的组合物是眼科可接受的,例如该组合物不具有有损于施用该组合物的人体或动物的有害或有毒性质。
在本发明的一个广义方面中,在所述组合物中形成复合物。在另一实施方式中,复合物包括由至少一个喹喔啉组分衍生的单体单元。在一个优选实施方式中,本发明的组合物是二聚体。在特别优选的实施方式中,复合物具体是布莫尼定的二聚体的复合物。
在本发明的另一广义方面,提供了含有α-2-肾上腺素能激动剂组分和有效量的至少有助于组合物防腐的防腐剂组分的组合物。优选地,防腐组分包括氧-氯组分,例如化合物、离子、复合物等,它们生物上可接受,化学上稳定并且基本上或者明显没有对组合物中的α-2-肾上腺素能激动剂组分或施用该组合物的患者产生不利影响。所述的组合物适宜基本上在组合物和施用该组合物的患者中不含有环糊精。
本发明所述的任何特征和特征联合包括在本发明的范围内内,条件是任何联合的特征不会相互矛盾和脱离上下文、本说明书和所属领域普通技术人员的常识。
本发明的其他优越性和方面在下面详述和权利要求书中更加清楚。
附图简述
图1是在不同羧甲基纤维素浓度下可溶性布莫尼定对pH的图形。
发明详述
提供含有α-2-肾上腺素能激动剂组分和SECs的组合物。本发明组合物中的α-2-肾上腺素能激动剂组分更加可溶且可以更加有效地作为治疗剂使用。本发明组合物中所用的SECs可以有效地增强电离的α-2-肾上腺素能激动剂组分、非电离的α-2-肾上腺素能激动剂组分或两者的增溶作用。本发明的组合物包括液体载体组分并具有液体的特性,例如,含水液体、溶液。
更加可取地,与不含有SECs的相似组合物中相同α-2-肾上腺素能激动剂组分在相当浓度下比较,α-2-肾上腺素能激动剂组分在pH大于7的本发明组合物中具有增高的溶解度。优选地,与不含SECs的相似组合物中相当浓度的相同α-2-肾上腺素能激动剂组分比较,α-2-肾上腺素能激动剂组分在pH范围为约7-约10的本发明组合物中具有增高的溶解度。
不希望受到任何任何理论或作用机理的限制,可以确信增溶的α-2-肾上腺素能激动剂组分相对于未增溶的α-2-肾上腺素能激动剂组分能够更好地穿过脂质膜。还可以相信,增溶的α-2-肾上腺素能激动剂组分在物理上更小,因此在物理上更加容易渗透或扩散经过脂质膜。
在一个实施方式中,本发明的SECs能够使α-2-肾上腺素能激动剂组分以治疗有效浓度增溶到其所引入的生物环境中。更加可取地,引入本发明组合物的生物环境具有约7-约9的pH范围。譬如,含有SEC和α-2-肾上腺素能激动剂组分的组合物可以施用到眼睛的角膜,其具有约7的pH,其中α-2-肾上腺素能激动剂组分基本上溶解在给药区域。而且,在一个实施方式中,α-2-肾上腺素能激动剂组分通过SECs增溶在给药区域比未经SECs增溶的α-2-肾上腺素能激动剂组分更加容易扩散穿过生物脂质膜。α-2-肾上腺素能激动剂组分的增溶作用适当减少了敏感组织在与α-2-肾上腺素能激动剂组分接触或相互作用时的刺激作用。
本发明所用的α-2-肾上腺素能激动剂组分选自可以受益于SECs的存在的那些。一般地,由于SECs的存在使α-2-肾上腺素能激动剂组分具有增高的表观溶度,优选增高的表观水溶度。
α-2-肾上腺素能激动剂组分的实例包括含胺的分子。优选地,α-2-肾上腺素能激动剂组分是pH大于约7,更优选约7-约9的含胺分子。
α-2-肾上腺素能激动剂组分包括α-2-肾上腺素能激动剂。在此所用的术语“α-2-肾上腺素能激动剂”包括化学实体,例如化合物、离子、复合物等,它们产生净交感神经阻滞反应,导致调节增强,例如通过结合交感神经节后神经末梢上的突触前α-2受体或者结合平滑肌细胞上的神经节后α-2受体。交感神经阻滞反应特征在于抑制、减小或阻止交感神经系统传送的脉冲作用。本发明的α-2-肾上腺素能激动剂组分结合突触前的α-2-肾上腺素能受体,引起负反馈减少神经元去甲肾上腺素的释放。此外,它们还作用于神经节后的α-2-肾上腺素能受体,抑制β-肾上腺素能受体刺激的环AMP的形成,其除了其他细胞内途径上的神经节后α-2-肾上腺素能受体的作用以外,还导致睫状肌松弛。对于神经节前或神经节后α-2-肾上腺素能受体的作用造成肾上腺素影响减弱。减弱的肾上腺素影响导致胆碱能神经支配所致的收缩增强。α-2-肾上腺素能激动剂还包括具有神经保护作用的化合物。例如,5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉是一种α-2-肾上腺素能激动剂,其通过未知机理具有神经保护活性。
本发明不受所列具体基团和化合物的限制,下列是适用于本发明的代表性α-2-肾上腺素能激动剂:亚氨基-咪唑啉类化合物,包括可乐定、阿普尼定;咪唑啉类化合物,包括萘甲唑啉、希美唑啉(xymetazoline)、四氢唑啉和曲马唑啉;咪唑类化合物,包括地托咪定、美托咪定、右美托咪定;氮杂卓类化合物,包括B-HT 920(6-烯丙基-2-氨基-5,6,7,8-四氢-4H-噻唑[4,5-d]-氮杂卓和B-HT 933;噻嗪类化合物,包括赛拉嗪;噁唑啉类化合物,包括利美尼定;胍类化合物,包括胍那苄和胍法辛;儿茶酚胺;等及其衍生物。
特别有效的α-2-肾上腺素能激动剂包括喹喔啉组分。在一个实施方式中,该喹喔啉组分包括喹喔啉、其衍生物及其混合物。更加优选地,喹喔啉的衍生物包括5-卤化物-6-(咪唑啉-2-基氨基)喹喔啉。5-卤化物-6-(2-咪唑啉-2-基氨基)喹喔啉的“卤化物”可以是氟化物、氯化物、碘化物,或者优选溴化物,形成5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉。更加优选,本发明使用的喹喔啉的衍生物包括5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉的酒石酸盐,或者布莫尼定。
其他有效的喹喔啉衍生物是公知的。譬如,有效的喹喔啉衍生物包括Burke等在美国专利号5,703,077中公开的化合物。还参见Danielwicz等的3,890,319。Burke等和Danielwicz各自的内容分别在此引入作为参考。
喹喔啉及其衍生物,例如布莫尼定,含有胺并且优选具有大于7的pKa,优选是7.5-9。
具有α-2-肾上腺素能激动剂作用的上述化合物的类似物也明确地属于本发明范围内。
更加优选地,α-2-肾上腺素能激动剂,例如上述物质,有效激活α-2A-肾上腺素能受体、α-2B-肾上腺素能受体和α-2D-肾上腺素能受体。
在一个实施方式中,α-2-肾上腺素能激动剂,例如布莫尼定,在所述的组合物中基本上未电离。在另一实施方式中,所述的肾上腺素能化合物在其所施用的环境中,例如角膜中,基本上未电离。不希望受到任何理论和作用机理的约束,可以相信,肾上腺素能化合物的未电离形式刺激其穿过膜脂质双层的渗透作用。
本发明可以采用任何适当的SEC。在一个实施方式中,SECs包括吡咯烷酮(pyrrolinidone)组分。吡咯烷酮组分的实例包括聚乙烯吡咯烷酮类化合物及其衍生物。在一个优选实施方式中,SECs包括多阴离子组分。有效的多阴离子组分包括,但不限于,那些可以有效提高难溶α-2-肾上腺素能激动剂组分的表观溶度,优选水溶解度和/或增强α-2-肾上腺素能激动剂组分的稳定性和/或减少α-2-肾上腺素能激动剂组分的不利副作用的物质。此外,优选多阴离子组分在使用浓度下是眼科可接受的。此外,多阴离子组分适宜包括三(3)或多种阴离子(或负)电荷。在多阴离子组分是聚合物的情况中,优选该聚合物的各个重复单元包括离散的阴离子电荷。特别适用的阴离子组分是那些溶于水的阴离子组分,例如,以使用浓度溶解在目前使用的液体含水介质中,例如含有α-2-肾上腺素能激动剂组分的液体含水介质。
优选多阴离子组分具有足够的阴离子与α-2-肾上腺素能激动剂组分相互作用。这种相互作用被希望能够增溶α-2-肾上腺素能激动剂组分和/或保持该α-2-肾上腺素能激动剂组分溶解在载体组分中,例如液体介质中。
多阴离子组分还包括一种或多种具有多个阴离子电荷的聚合物。实例包括:
羧甲基淀粉金属
羧甲基羟乙基淀粉金属,
水解的聚丙烯酰胺和聚丙烯腈
肝素
一种或多种下列的均聚物和共聚物:
丙烯酸和甲基丙烯酸
丙烯酸金属盐和甲基丙烯酸金属盐
藻酸
藻酸金属盐
乙烯磺酸
乙烯磺酸金属盐
氨基酸类,例如天门冬氨酸、谷氨酸等
氨基酸的金属盐
对苯乙烯磺酸
对苯乙烯磺酸金属盐
2-甲基丙烯酰氧基乙基磺酸
2-甲基丙烯酰氧基乙基磺酸金属盐
3-甲基丙烯酰氧基-2-羟丙基磺酸
3-甲基丙烯酰氧基-2-羟丙基磺酸金属盐
2-丙烯酰胺-2-甲基丙烷磺酸
2-丙烯酰胺-2-甲基丙烷磺酸金属盐
烯丙基磺酸
烯丙基磺酸金属盐等。
在另一实施方式中,多阴离子组分包括阴离子多糖,其在较高pH下,例如约7和更高的pH下,倾向于以电离形式存在。下列是本发明可以使用的阴离子多糖的一些实例。
多右旋糖是右旋糖的随机结合的缩合聚合物,哺乳动物只能够代谢其一部分。该聚合物可以含有微量的结合山梨醇、柠檬酸和葡萄糖。
硫酸软骨素也称作硫酸软骨素钠,其是在人体组织的各个部分都可以发现的粘多糖,特别是在软骨、骨骼、腱、韧带和血管壁。从鲨鱼的软骨可以提取和纯化得到这种多糖。
角叉菜胶是一种具有重复半乳糖单元和3,6-脱水半乳糖单元的直链多糖,这两种单元可以硫酸化或者未硫酸化,它们通过交替的1-3和β1-4键连接。角叉菜胶是一种水胶体,从多种红色海藻和角叉菜可以热提取到角叉菜胶。
麦芽糖糊精是水溶性葡萄糖聚合物,其通过淀粉与酸和/或酶在水存在下的反应而形成。
发现适用于本发明的其他阴离子多糖是亲水性胶体物质并且包括天然树胶,例如吉兰糖胶,藻酸盐胶,即藻酸的铵和碱金属盐及其混合物。此外,可以使用壳聚糖,其是脱乙酰壳多糖的常用名。壳多糖是一种含有多-(N-乙酰基-D-葡糖胺)的天然产物。吉兰糖胶是由多沼假单胞菌(pseudomonas elodea)的发酵产生胞外杂多糖来制备的。藻酸盐和壳聚糖可以使用得自Protan,Inc,Commack,N.Y的干粉。吉兰糖胶可以是Kelco Division of Merk & Co.,Inc,San Diego,Calif的产品。
通常,藻酸盐可以是任何水溶性藻酸盐,包括碱金属藻酸盐,例如藻酸的钠、钾、锂、铷和铯盐,和铵盐,和有机碱的可溶性藻酸盐,例如一-、二-或三-乙醇胺藻酸盐,藻酸苯胺盐等。一般地,基于组合物的总重量计,使用约0.2%-约1%(重量)的吉兰糖胶、藻酸盐或壳聚糖离子型多糖来获得本发明的凝胶组合物。
更加可取地,所述的阴离子多糖是环状的。更优选,该环化阴离子多糖包括少于10个单体单元。特别更优选,该环化多糖包括少于6个多糖单元。
在一个实施方式中,特别适用的环化阴离子多糖包括环糊精类。环糊精类的实例包括,但不限于:α-环糊精,α-环糊精的衍生物,β-环糊精,β-环糊精的衍生物,γ-环糊精,γ-环糊精的衍生物,羧甲基-β-环糊精,羧甲基-乙基-β-环糊精,二乙基-β-环糊精,二甲基-β-环糊精,甲基-β-环糊精,无规甲基-β-环糊精、葡糖基-β-环糊精,麦芽糖基-β-环糊精,羟乙基-β-环糊精,羟丙基-β-环糊精,磺丁基醚-β-环糊精等及其混合物。磺丁基醚-β-环糊精是本发明优选的环化阴离子多糖。优选给予包括上述环糊精在内的SEC,其在本发明中在所用的浓度下对哺乳动物、人体无毒,从而抑制这种掺混。在此所用的与环糊精有关的术语“衍生物”是指任何被取代或者改性的化合物,其具有环糊精的特定化学结构足以起到环糊精组分的作用,例如提高活性成分的溶解度和/或稳定性和/或减小活性成分的不良副作用和/或与所述的活性成分形成包合复合物。
虽然环糊精和/或其衍生物可以用作SECs,本发明的一个实施方式可以包括除环糊精和/或其衍生物之外的SECs。
特别适用和优选种类的多阴离子组分包括阴离子纤维素衍生物。阴离子纤维素衍生物包括金属羧甲基纤维素、金属羧甲基羟乙基纤维素和羟丙基甲基纤维素及其衍生物。
本发明的多阴离子组分常常可以未电离状态存在,例如,以固体状态,以伴生或抗衡离子的联合形式,特别是数目上与离散阴离子电荷数相同的多个离散阳离子,使来电离多阴离子组分在电学上呈中性。例如,本发明的未电离多阴离子组分可以以酸形式存在和/或以与一种或多种金属的联合形式存在。由于多阴离子组分优选是眼科可接受的,优选与未电离多阴离子组分关联的金属在所用的浓度下是眼科可接受的。特别适用的金属包括碱金属,如钠和钾;碱土金属,如钙和镁,和它们的混合物。钠非常适合在未电离多阴离子组分中提供抗衡离子。本发明可以使用以未电离态与除H+的阳离子和金属阳离子结合的多阴离子组分。
本发明组合物中的SEC的含量不是十分重要,只要α-2-肾上腺素能激动剂组分的溶解度至少多少有所增高并以生物可接受的量存在。该含量应该有效完成在本发明组合物中和/或给予人体和动物后的预期功能。在一个实施方式中,SEC(优选多阴离子组分)的含量足以与至少大部分量的,并且更优选基本上全部量的,α-2-肾上腺素能激动剂组分复合,在一个实施方案中,本发明组合物中的多阴离子组分的含量是该组合物的约0.1%-约30%(w/v)和更高。优选地,多阴离子组分的含量在约0.2%(w/v)-约10%(w/v)内。更优选,多阴离子组分的含量在约0.2%(w/v)-约0.6%(w/v)内。甚至更优选,多阴离子组分是羧甲基纤维素并以约0.2%(w/v)-约0.6%(w/v)存在于所述组合物中。羧甲基纤维素在本发明组合物的特别有效的浓度是约0.5%。
在一个实施方式中,SECs例如羧甲基纤维素有助于α-2-肾上腺素能激动剂组分增溶在组合物中。虽然SECs能够协助电离的α-2-肾上腺素能激动剂组分的增溶作用,但优选本发明中使用的SECs有助于未电离的α-2-肾上腺素能激动剂组分的增溶作用。譬如,在一个实施方式中,羧甲基纤维素可以协助增溶电离的α-2-肾上腺素能激动剂组分。在另一实施方式中,羧甲基纤维素协助电离的布莫尼定增溶到该组合物中。更优选,羧甲基纤维素有助于未电离的布莫尼定增溶到该组合物中。
在一个实施方式中,所述的组合物还可以含有一种或多种防腐剂组分,其有助于组合物的防腐。选择的防腐剂组分在本发明组合物中是显著且有效的防腐剂,也就是说在多阴离子组分的存在下,当把组合物施用给人体或动物时适宜具有低毒性并且更优选没有毒性。
当在增溶剂存在下使用时药物组合物中常用的防腐剂或有助于组合物防腐的组分常常降低有效性。在某些情况中,通过使用增量的防腐剂可以补偿这种降低了的防腐功效。然而,当涉及敏感或柔弱的机体组织时,这种途径可能不适用,因为防腐剂本身可以在适用该组合物的人体或动物中引起一些副作用或者敏感性。
更加可取地,有助于组合物,特别是其中α-2-肾上腺素能激动剂组分防腐的本发明防腐剂组分,在小于约1%(w/v)或约0.8%(w/v)的浓度下有效并且可以等于或小于500ppm(w/v),例如在约10ppm(w/v)-约200ppm(w/v)的范围内。本发明的防腐剂组分适宜包括,但不限于,那些以小于苯扎氯铵的程度与多阴离子组分形成复合物的防腐剂。
本发明防腐剂组分的非常适用的实例包括,但不限于氧化性防腐组分,如氧-氯组分、过氧化物、过酸盐、过酸等,和它们的混合物。用本发明防腐剂的氧-氯组分的具体实例包括次氯酸盐组分,如次氯酸盐类;氯酸盐组分,例如高氯酸盐;和亚氯酸盐。亚氯酸盐组分的实例包括稳定化的二氧化氯(SCD),次氯酸金属盐,如碱金属和碱土金属次氯酸盐等,和它们的混合物。技术等级(或USP等级)的次氯酸钠是非常有效的防腐组分。人们不十分了解许多次氯酸盐组分如SCD的精确化学组合物。某些次氯酸盐组分的制造或生产描述在McNicholas美国专利3,278,447中,其在此引入作为参考。适用SCD产品的具体实例包括RioLinda Chemical Company,Inc以商标Dura Klor和由InternationalDioxide,Inc.以商标Anthium Dioxide出售的产品。特别适用的SCD是Allergan,Inc.以商标PuriteTM出售的产品。氧化性防腐剂组分的其他实例包括过氧组分。譬如,痕量的过氧组分用过氧化氢稳定剂稳定化,例如二亚乙基三胺五(亚甲基膦酸)或1-羟基乙叉基-1,1-二膦酸,可以作为防腐剂用于眼环境使用的组分内。另外,实际上可以使用任何过氧组分,只要其在水中水解产生过氧化氢,其提供有效量的过氧化氢,包括过硼酸钠十水合物、过氧化钠和过氧化脲。已经发现过乙酸,有机过氧化合物,可能无法用本发明的体系稳定化。例如,参见,Martin等的美国专利号5,725,887,其内容在此全文引入作为参考。
组合物中可以含有除氧化性防腐剂组分以外的防腐剂。防腐剂的选择可能取决于给药的途径。适合组合物的防腐剂通过一种途径给药时可能具有有害性质,但通过另一种途径给药可以排除这种有害性质。对于鼻和眼用组合物,优选防腐剂含有季铵化合物,特别是烷基苄基二甲基铵化合物的混合物并且公知的是“苯扎氯铵”。然而,对于通过吸入给药的组合物,优选的防腐剂是三氯叔丁醇等。其他可以使用的防腐剂,特别是用于直肠给药的组合物的防腐剂,例如是甲基、乙基、丙基、丁基酯和以商品名“Nipastat”出售的产品。
在本发明的另一广义方面,提供的组合物含有α-2-肾上腺素能激动剂组分、有效量的至少有助于防腐的防腐剂组分,优选是有效防腐量。更加可取地,防腐剂组分包括氧-氯组分,如化合物、离子、复合物等,其(1)基本上不或者不显著有损于组合物中的α-2-肾上腺素能激动剂组分或者施用该组合物的患者。和(2)基本上是生物上可接受的和化学上稳定的。本发明的组合物含有α-2-肾上腺素能激动剂组分、氧-氯组分和液体载体组分,并且优选基本上不含有环糊精。
适用于本发明的载体组分选择是对本发明的组合物无毒且基本上没有有害作用。在一个实施方式中,载体组分是液体载体。在一个优选实施方式中,载体组分是液体含水载体组分。特别适用的含水液体载体是由盐水衍生的,例如普通盐水溶液或常规缓冲盐水溶液。该含水液体载体优选pH约6-约9或约10,更优选约6-约8,并且特别优选约7.5。液体介质优选具有眼科可接受的张力水平,例如至少约200mOsmol/g,更优选约200-约400mOsmol/kg。在一个特别适用的实施方式中,载体组分的重量摩尔渗透压浓度或张力基本上相当于眼睛特别是人眼的流体的张力。
在一个实施方式中,含有SECs和α-2-肾上腺素能激动剂组分的载体组分在25℃下可以具有大于0.01厘泊(cps)的粘度,优选在25℃下粘度大于约1cps,甚至更优选在25℃下大于约10cps。在一个优选实施方式中,所述的组合物在25℃下具有约50cps的粘度并含有常规缓冲盐水溶液,羧甲基纤维素和布莫尼定。
为了确保含水液体载体组分的pH,并且由此使组合物的pH,保持在预期范围内,该含水液体载体组分可以含有至少一种缓冲剂组分。虽然任何适当的缓冲剂组分都可以使用,优选选择那些不产生大量二氧化氯或产生大量气体如CO2的组分。优选缓冲剂组分是无机的。本发明优选使用碱金属和碱土金属缓冲剂组分。
可以使用任何一种或多种适当的眼科可接受张力组分,条件是该组分与液体含水载体组分的其他成分相容且不对本发明组合物所施用的人体或动物具有有害或毒性性质。优选张力组分的实例包括氯化钠、氯化钾、甘露醇、右旋糖、甘油、丙二醇及其混合物。在一个实施方式中,张力组分选自无机盐及其混合物。
本发明的组合物一般可以作为溶液或混悬液存在于含水液体或非水液体中,或作为水包油或油包水液体乳液。本发明的组合物可以含有一种或多种附加组分如稀释剂、矫味剂、表面活性剂、增稠剂、润滑剂等,例如,该附加组分是同类型组合物中常用的那些。
水混悬液形式的本发明组合物可以含有适合制备水混悬液的赋形剂。此类赋形剂是助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄芪胶和阿拉伯胶;分散或湿润剂可以是天然磷脂,例如卵磷脂;和环氧乙烷与长链脂族醇如十七碳亚乙基氧基鲸蜡醇的缩聚产物,或者环氧乙烷与由脂肪酸和己糖醇衍生的偏酯的缩聚产物如聚氧化乙烯山梨糖醇一油酸酯,或者环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩聚产物,例如聚氧化乙烯脱水山梨糖醇一油酸酯等及其混合物。此类水混悬液还可以含有一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂,如蔗糖、糖精等及其混合物。
油形式的本发明组合物可以在植物油中配制,例如橄榄油、芝麻油或椰子油,或在矿物油如液体石蜡中。所述的混悬液可以含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可以加入甜味剂,如上述那些,和矫味剂来提供可口的口腔制剂。
本发明的组合物还可以是水包油乳液。油相可以是植物油,例如液体石蜡,等等及其混合物。适当的乳化剂可以是天然树胶,例如阿拉伯胶或黄芪胶,天然磷脂,例如大豆油卵磷脂,和由脂肪酸和己糖醇酐衍生的酯和偏酯,例如脱水山梨糖醇一油酸酯,该乳液还可以含有甜味剂和矫味剂。
糖浆和酏剂形式的本发明组合物可以用甜味剂配制,例如如上所述的。此类制剂还可以含有缓和剂,和矫味剂和着色剂。
任何具体人或动物的具体剂量水平取决于多种因素,包括所用活性成分的活性、年龄、体重、全身健康、性别、饮食、给药时间、给药途径、排泄速率、药物联合形式和被治疗具体病症的严重性。
在本发明的一个广义方面,在本发明组合物中形成复合物。在一个实施方式中,复合物含有至少一种喹喔啉组分的单体单元。喹喔啉组分的实例包括喹喔啉、(2-咪唑啉-2-基氨基)喹喔啉、5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉、其盐、其酯、其其他衍生物等,及其混合物。例如,在一个实施方式中,本发明的复合物可以含有5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉单体单元的偶联物。在另一实施方式中,复合物可以含有5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉单体单元与布莫尼定单体单元的偶联物。
在一个优选实施方式中,本发明的复合物是二聚体。例如,本发明的二聚体可以含有喹喔啉和5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉。优选地,本发明的二聚体包括两个布莫尼定单体单元。
不希望受到任何理论或作用机理的限制,相信任何过氧化物生成剂或者强氧化剂如氧化性防腐剂组分,例如氧-氯组分、过氧化物、过酸盐、过酸类等及其混合物可以促进复合物的形成,更适宜于α-2-肾上腺素能激动剂组分的复合物。譬如,据信布莫尼定单体单元的二聚体在亚氯酸盐,优选稳定化的二氧化氯存在时形成。
而且,相信可以包括单体之间的相互作用,其将单体或单体亚基保持在一起形成复合物,优选低聚物和更优选二聚体,但不限于,共价键、离子键、疏水性键、静电键、氢键、其他化学和/或物理相互作用,等及其联合形式。此类复合物可以在液体中分离,例如,含水液体、介质。在一个实施方式中,单体或单体亚基通过非共价键方式保持在一起。在一个实施方式中,单体或单体亚基通过静电键或力保持在一起。
下列非限定实施例举例说明本发明的某些方面。
实施例1
布莫尼定具有约7.78的pKa。0.5%(w/v)布莫尼定在一种制剂眼科溶液中的pH-溶解度曲线在23℃下建立在约5-约8的范围内。表1。可以相信可以使用非0.5%的肾上腺素能激动剂的浓度,只要它们具有治疗活性。另外,例如温度可以改变,溶解度曲线可以在37℃(98.6°F)下进行。通过首先将聚乙烯醇(PVA)溶解在水中制备制剂赋形剂。将PVA加入到约1/3的所需总量的纯水中同时恒定搅拌。搅拌该浆液20-30分钟且随后加热至80-95℃同时搅拌。在达到80-90℃之后1小时内撤去混合物的热源并且再搅拌10分钟保证均匀性(部分I)。除布莫尼定以外,将眼科溶液的其他组分溶解在含有1/3所需总量的纯水的单独容器内(部分II)。随后用数个漂洗体积的纯水将PVA混合物(部分I)定量转移到部分II中。用纯水调整溶液至最终体积,无需调节pH。
称量布莫尼定的重量且转移到含有5mL上述制剂赋形剂的10mL试管内。各样本的pH随后用稀氢氧化钠和/或稀盐酸调整至预定值。将样本置于搅拌平板的搁物架中且以高速搅拌2天获得均匀混合物;将搁物架于搅拌平板分开防止热量从搅拌平板扩散到样本。通过研究监测试验的温度且发现是23±1℃。
在搅拌2天结束时,测定各个样本的pH值,随后将约1mL的各样本置于微量离心管(聚丙烯)中且在4000rpm下离心10分钟。经1μm过滤单元(Whatman,13mm,PTFE)过滤该上清液。弃去第一个3-4滴;收集其余的滤液且用HPLC流动相定量稀释。稀释样本随后直接注射到HPLC柱(Dupont Zorbax,250mm x 4.6mm,5μm)用于分析布莫尼定,从而定量分析布莫尼定的含量。在pH 6.3-6.5的制剂载体中制备10.05%布莫尼定的对照品并且在分析之前(未处理)和之后(处理过)离心和过滤。由此评估布莫尼定样本制备的两个步骤中的潜在损失。为了确保重现性,连续数天重复进行研究。
表I.含0.5%布莫尼定的眼科溶液
组分 百分比(w/v)
布莫尼定 0.50
苯扎氯铵,NF 0.0050
聚乙烯醇,USP 1.4
氯化钠,USP 0.66
柠檬酸钠,二水合物,USP 0.45
盐酸,NF或
氢氧化钠,NF用于调节pH 5-8
纯水,USP 适量
布莫尼定在制剂赋形剂中的溶解度数据如表II所示。结果表明,布莫尼定的溶解度是高度依赖于pH的且在5-8的pH范围中相差2个数量级以上。溶解度随着pH增高急剧降低。对于处理的和未处理的对照品结果非常接近,表示离心和过滤不会引起任何布莫尼定的显著损失。连续数天获得的磷脂溶解度曲线彼此吻合。
表II.布莫尼定在pH为5-8的眼科溶液中的溶解度
研究1 研究2
样本 pH a 溶解度 e pH a 溶解度 e
1 5.55 ≥164.4b 5.50 ≥200.6b
2 5.92 132.6 5.92 160.8
3 6.14 30.4 6.06 50.1
4 6.57 7.55 6.90 3.19
5 7.00 2.69 7.40 1.19
6 7.45 1.17 7.77 0.63
7 7.83 0.62 7.86 0.58
8 - - 7.88 0.54
对照/
(来处理) - 0.486c - -
对照/
(经处理) - 0.484d - -
a搅拌2天之后且在取样离心和过滤之前测量
b表示基于样本重量的理论浓度。样本溶液澄清表明所有布莫尼定已经溶解。
c 离心和过滤步骤之前对照品中布莫尼定的浓度
d 离心和过滤步骤之后对照品中布莫尼定的浓度
e %w/v
实施例2
测定含有SECs和氧-氯组分的组合物(溶液)中的布莫尼定的pH-溶解度曲线。具体而言,在不同pH条件下测定羧甲基纤维素(CMC)钠。用布莫尼定试验的CMC的不同浓度是0%,0.056%,0.17%,0.5%,1.5%(w/v),表II。
试验样本还含有等渗组分、缓冲剂组分和稳定化的二氧化氯(PuriteTM),表III。羧甲基纤维素钠、氯化钠、氯化钾、氯化钙二水合物和氯化镁六水合物是USP级。硼酸和硼酸钠十水合物是NF级。
表III
样本1 样本2 样本3 样本4 样本5
布莫尼定 0.2% 0.2% 0.2% 0.2% 0.2% (w/v)
CMC 0.0% 0.056% 0.17% 0.5% 1.5% (w/v)
稳定化的二氧化氯a
0.005% 0.005% 0.005% 0.005% 0.005%(w/v)
氯化钠 0.58% 0.58% 0.58% 0.50% 0.58% (w/v)
氯化钾 0.14% 0.14% 0.14% 0.14% 0.14% (w/v)
氯化钙二水合物 0.02% 0.02% 0.02% 0.02% 0.02% (w/v)
氯化镁六水合物 0.006% 0.006% 0.006% 0.006% 0.006%(w/v)
硼酸 0.2% 0.2% 0.2% 0.2% 0.2% (w/v)
四硼酸钠十水合物 0.14 0.14% 0.14% 0.14% 0.14% (w/v)
a Allergan,Inc以商标PuriteTM出售。
各样本(1-5)的pH在约7-约10。将含有样本溶液的瓶子置于实验室旋转器中且放置在室温下平衡15天(~21℃)。用孔径为0.45μm的25mm直径聚砜纤维素乙酸酯注射型滤器过滤钙样本溶液。用过滤的溶液分析布莫尼定。
用常规HPLC和检测技术来检测和测定可溶性布莫尼定的浓度。表IV。在各个CMC浓度下相对于pH绘制溶解度。试验数据点用非线性最小二乘法(Deltagraph 4.0版DeltaPoint,Inc.)与改进的Henderson-Hasselbalch方程吻合,图2。R2值显示试验值和理论方程式之间的吻合的良好性好于0.991。
表IV
布莫尼定的溶解度(%)
0%CMC 0.056%CMC 0.17%CMC 0.5%CMC 1.5%CMC
pH
6.67 0.9302 1.4464
6.68 1.4256 1.4200
6.93 0.7302
7.10 0.3693
7.11 0.2064 0.2828
7.35 0.1904
7.56 0.1451
7.68 0.0786
7.77 0.0721
7.81 0.0735
8.10 0.0498
8.46 0.0313
8.50 0.0286
8.55 0.0328
8.67 0.0311
9.93 0.0234
9.94 0.0250
10.05 0.0241
10.09 0.0218
10.11 0.0222
图1清楚地表明,布莫尼定的溶解度随着CMC浓度的增高而增大。例如,在pH 7.5下,含有0%CMC的样本是布莫尼定为1000ppm;0.056%CMC,1300ppm;0.17%CMC,1300ppm;和0.5%,1600ppm。在pH 7.5下,含1.5%CMC的样本得到约1400ppm,其小于含0.5%CMC的相似溶液。不清楚在这点得到这种观察结果的原因。然而,与不含有CMC的溶液相比,布莫尼定更加易溶于含1.5%CMC的溶液。
CMC也可以有效地使布莫尼定增溶到生物环境中,例如角膜的生物环境。
实施例3
布莫尼定二聚体
将布莫尼定加入到装有含次氯酸盐的组合物的试管内。令试管平衡10天。分析取自试管的样本。观察到一部分的布莫尼定单体单元偶联成为二聚体。
虽然本发明描述了有关的多种具体实施例和实施方式,应理解本发明不受其限制且在下面权利要求书中的范围内可以有不同的实施方式。
Claims (12)
1.一种治疗上有效的含水眼科组合物,含有:
α-2-肾上腺素能激动剂组分,所述组分选自5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉、5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉的盐、5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉的酯及其混合物,
所述组合物包含0.1w/v%-30w/v%的升高溶解度组分,所述的升高溶解度组分选自阴离子纤维素、由丙烯酸衍生的阴离子聚合物、由甲基丙烯酸衍生的阴离子聚合物、由藻酸衍生的阴离子聚合物、由氨基酸衍生的阴离子聚合物及其混合物。
所述组合物的pH为7.0或更高,其中所述组合物基本上不含有环糊精。
2.权利要求1的组合物,其中含有1600ppm的α-2-肾上腺素能激动剂组分。
3.权利要求1的组合物,其中还含有至少有助于组合物防腐的、有效量的防腐剂,所述防腐剂选自氧-氯组分和季铵化合物。
4.权利要求3的组合物,其中所述防腐剂为苯扎氯铵。
5.权利要求3的组合物,其中所述防腐剂为氧-氯组分。
6.权利要求5的组合物,其中所述氧-氯组分为亚氯酸盐。
7.权利要求1-6中任一项的组合物,其中所述的α-2-肾上腺素能激动剂组分为5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉的酒石酸盐。
8.权利要求1-6中任一项的组合物,其中所述α-2-肾上腺素能激动剂组分基本上未电离。
9.权利要求1-6中任一项的组合物,其中所述α-2-肾上腺素能激动剂组分在该组合物所施用的生物环境中基本上未电离。
10.权利要求1-6中任一项的组合物,其中所述的升高溶解度组分是以0.2w/v%-10w/v%的量存在。
11.权利要求1-6中任一项的组合物,其中所述的升高溶解度组分是以0.2w/v%-0.6w/v%的量存在。
12.权利要求1-6中任-项的组合物,其pH为7-9。
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CN200910247188.9A Expired - Lifetime CN101897704B (zh) | 2000-07-14 | 2001-07-09 | 含有α-2肾上腺素能激动剂的组合物 |
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EP (1) | EP1365811A2 (zh) |
JP (3) | JP4927298B2 (zh) |
KR (1) | KR100757656B1 (zh) |
CN (2) | CN100569291C (zh) |
AR (1) | AR033539A1 (zh) |
AU (2) | AU7326901A (zh) |
BR (1) | BR0109317A (zh) |
CA (1) | CA2402405C (zh) |
HK (1) | HK1060519A1 (zh) |
HU (1) | HUP0303197A3 (zh) |
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NZ (1) | NZ521185A (zh) |
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TW (1) | TWI287998B (zh) |
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