CN117482208A - 治疗白内障的超声介导氟碳微乳水凝胶制剂 - Google Patents
治疗白内障的超声介导氟碳微乳水凝胶制剂 Download PDFInfo
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Abstract
本发明属于药物制剂领域,本发明提供了一种治疗白内障的超声介导氟碳微乳水凝胶制剂,该制剂是由还原型谷胱甘肽、肝素钠、硫酸软骨素、泊洛沙姆和氟碳微乳组成,该制剂联合超声波介导技术应用,通过氟碳微乳而产生空化效应和声孔效应,促进还原型谷胱甘肽、肝素钠、硫酸软骨素、泊洛沙姆进入晶状体内部发挥治疗作用,用于治疗各型白内障,特别适于不宜手术的白内障患者的治疗需求。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种治疗白内障的超声介导氟碳微乳水凝胶制剂,特别涉及一种治疗不宜手术的白内障的超声介导氟碳微乳水凝胶制剂。
背景技术
白内障是眼科的常见病和多发病,是全球第一位的致盲性眼病。凡是各种原因如老化,遗传、局部营养障碍、免疫与代谢异常,外伤、中毒、辐射等,都能引起晶状体代谢紊乱,导致晶状体蛋白质变性而发生混浊,称为白内障,此时光线被混浊晶状体阻扰无法投射在视网膜上,导致视物模糊。该疾病多见于40岁以上,且随年龄增长而发病率增多。白内障根据病因可分为老年性白内障、外伤性白内障、并发性白内障、代谢性白内障、中毒性白内障、辐射性白内障、发育性白内障、先天性白内障。
白内障明显的症状是无痛性视力下降,还有对比敏感度下降、屈光改变、单眼复视、眩光、色觉改变等症状。目前治疗主要是药物治疗和手术治疗。药物治疗仅适用于症状轻微、未达到手术标准的患者,或者是身体原因无法接受手术治疗的患者。目前临床上常见的抗白内障药物,如谷胱甘肽滴眼液、吡诺克辛滴眼液、苄达赖氨酸滴眼液等。手术治疗是白内障的主要治疗手段,目前主要采用的手术方式是白内障超声乳化吸除术并人工晶体植入,实现患者的复明。
尽管白内障手术治疗是目前临床上公认的唯一有效方法。但手术治疗需要满足以下条件,且存在一定的安全风险和经济负担。白内障手术的条件分为全身条件和局部条件两部分:局部指眼睛条件;全身条件主要指患者有没有全身疾病,比如高血压、糖尿病、心脏病,以及脑部疾病,还包括有没有意识障碍、精神类的疾病,有没有全身外伤等因素。
由于最常见的白内障是与年龄相关的老年性白内障,而老年人多患有高血压、糖尿病、心脏病和脑部疾病,无法满足白内障手术的全身条件。因此,这类白内障患者只能采用药物治疗。
目前,药物治疗仅适用于白内障早期患者,无法适用于中期和晚期白内障患者。因此,开发能够适用于不宜手术的白内障患者的药物制剂具有十分重大的意义,将为不适宜进行白内障手术的患者复明带来极大的希望,但是目前尚未见到针对不宜手术的白内障(如:老年性白内障、中期和晚期白内障)治疗的药物制剂的任何报道。
为了满足不宜手术的白内障治疗的需要,理想的白内障药物制剂需要符合以下要求:⑴制剂安全性高,不影响组织器官正常功能,不会诱发高血压、糖尿病、心脏病和脑部疾病;⑵给药操作时间短,不易流失,维持药效时间长;⑶能够阻止或逆转晶状体蛋白质变性,防止晶状体混浊,对于各个年龄段的各型白内障(如放射性白内障、老年性白内障、中期和晚期白内障)都具有确切治疗效果;⑷制剂经济成本低,制备方法简便。
目前,尚未见到满足以上所有要求的治疗白内障药物制剂的报道。
发明内容
本发明的目的在于克服现有技术的缺点(即缺乏针对不宜手术的白内障治疗的药物制剂),提供一种超声介导氟碳微乳水凝胶制剂,同时满足理想的白内障药物制剂的各项要求,为各个年龄段的各型白内障(特别是不宜手术的白内障)临床治疗提供安全、高效、便捷、经济的药物制剂。
临床上应用还原型谷胱甘肽制备“临用临配”的谷胱甘肽滴眼液(冻干粉),用于治疗初期老年性白内障、角膜溃疡、角膜上皮剥离、角膜炎,但是该滴眼液无法适用于中期和晚期白内障的治疗。
本发明人发现,还原型谷胱甘肽虽然具有阻止晶状体蛋白质变性和防止白内障进程的作用,但是由于自身的亲水性和分子量,导致其无法有效穿透角膜和晶状体囊膜的两重生物膜屏障,从而无法进入晶状体内部起效。此外,还原型谷胱甘肽稳定性差,因此采用“临用临配”的谷胱甘肽滴眼液冻干粉,不仅增加操作复杂性,而且保存时间短,无法长时间维持药效。
全氟化碳(perfluorocarbon,PFC)安全性高,在水中可以形成微米级乳剂,称为氟碳乳剂。氟碳乳剂在超声波作用下因生成气泡而产生超声空化效应,已被FDA批准作为造影剂。但是氟碳乳剂的表面张力等物理性质与水溶液和蛋白药物有着较大差异,因此,形成的乳剂颗粒不仅粒径大,而且与药物的亲和性低和载药率差,此外,氟碳乳剂在超声波作用下产生的超声空化效应剧烈,可能导致组织、血管的损伤,存在较大的安全隐患。
本发明人经过大量实验发现:(1)泊洛沙姆水凝胶对于还原型谷胱甘肽不仅具有良好的载药能力,并且提升其稳定性,可以制成水性溶液长期保存;(2)肝素对于晶状体蛋白质变性也具有抑制作用,并且因为作用机制不同,能够与谷胱甘肽发挥白内障治疗的协同作用,且可以被泊洛沙姆水凝胶有效携载;(3)本发明人经过大量实验,制备了粒径范围为100~400nm的氟碳微乳泊洛沙姆水凝胶。相比氟碳乳剂,氟碳微乳泊洛沙姆水凝胶具有良好的稳定性和药物携载能力;(4)本发明人制备的氟碳微乳在超声波作用下迅速生成纳米级含气泡,发挥空化效应和声孔作用,有效在角膜和晶状体囊膜上形成可逆性临时孔道,有利于外源性药物进入晶状体发挥治疗作用。
综上发现,本发明人经过大量实验,制备出一种治疗白内障的超声介导氟碳微乳水凝胶制剂及其制备方法和用途。
具体地,通过以下几个方面的技术方案实现了本发明:
在第一个方面中,本发明提供了一种治疗白内障的超声介导氟碳微乳水凝胶制剂,该制剂中包含:还原型谷胱甘肽、肝素钠、硫酸软骨素、泊洛沙姆和氟碳微乳。
上述的还原型谷胱甘肽的质量百分含量为1%~5%、肝素钠的质量百分含量为0.1%~0.3%、硫酸软骨素的质量百分含量为1%~5%、泊洛沙姆的质量百分含量为10%~25%、氟碳微乳的质量百分含量为15%~35%。
上述的氟碳微乳是全氟化碳液体形成的粒径为80~400nm范围内的微乳。
上述的全氟化碳为四氟化碳、全氟己烷、全氟萘烷和全氟三丙胺中的一种或两种组合。
上述的水凝胶制剂联合超声波应用,超声波的频率为6~12MHz,超声波强度为1~4W/m2,持续时间0.5~2min。
上述的水凝胶制剂联合超声波介导技术应用,通过氟碳微乳产生纳米泡的空化效应和声孔效应,促进还原型谷胱甘肽、肝素钠、硫酸软骨素和泊洛沙姆进入晶状体内部发挥治疗作用。
上述的水凝胶制剂用于治疗各型白内障。
上述的水凝胶制剂用于治疗不宜手术的白内障。
优选地,上述的水凝胶制剂中还原型谷胱甘肽的质量百分含量为2.5%,肝素钠的质量百分含量为0.2%,硫酸软骨素的质量百分含量为2.5%,泊洛沙姆的质量百分含量为17%,氟碳微乳的质量百分含量为27%。
优选地,上述的全氟化碳为全氟己烷。
优选地,上述的氟碳微乳粒径为200nm。
优选地,上述的超声波的频率为9MHz,强度为2W/m2,持续时间为1min。
上述的水凝胶制剂中还可以加入其他治疗药物,包括:细胞因子、重组蛋白质药物、抗体、疫苗和寡核苷酸药物的一种或两种以上组合。
上述的水凝胶制剂中还可以加入多元醇、抑菌剂、pH调节剂和渗透压调节剂的一种或两种以上组合。
在第二个方面中,本发明提供了一种上述第一个方面所述的水凝胶制剂的制备方法,所述制备方法包括以下步骤:将泊洛沙姆溶解于蒸馏水中,制成泊洛沙姆溶液,加入还原型谷胱甘肽、肝素钠和硫酸软骨素,充分溶解后,调整温度至-2℃,加入全氟化碳液体,高速均质机中混匀,调整高速均质的时间以调整粒径,得到治疗白内障的超声介导氟碳微乳水凝胶制剂。
优选地,上述的水凝胶制剂的制备方法还包括以下步骤:在所述泊洛沙姆水凝胶制剂中加入其他治疗药物,包括:细胞因子、重组蛋白质药物、抗体、疫苗和寡核苷酸药物的一种或两种以上组合。
在第三个方面中,本发明提供了上述第一个方面所述的水凝胶制剂在制备治疗白内障的药物中的用途。
优选地,所述白内障为各种类型的白内障。
更优选地,所述药物用于治疗不宜手术的白内障。
本发明相对于现有技术,具有以下有益效果:
本发明的治疗白内障的超声介导氟碳微乳水凝胶制剂与现有白内障药物制剂相比,具有以下优点:⑴制剂安全性高,不影响组织器官正常功能,更不会诱发高血压、糖尿病、心脏病和脑部疾病;⑵超声介导的氟碳微乳水凝胶制剂给药的操作时间短,不仅药物起效迅速,且水凝胶具有温敏相变特性,在眼部不易流失,维持药效时间长;⑶还原型谷胱甘肽、肝素钠、硫酸软骨素和泊洛沙姆联合起效,能够阻止和逆转晶状体蛋白质变性,防止晶状体混浊,对于各个年龄段的各型白内障(老年性白内障、中期和晚期白内障)都具有确切治疗效果;⑷制剂经济成本低,制备方法简便。
具体实施方式
下文将详细描述本发明具体实施例。应当注意的是,下述实施例中描述的技术特征或者技术特征的组合不应当被认为是孤立的,它们可以被相互组合,从而达到更好的技术效果。
下面参照具体的实施例对本发明做进一步说明。应当理解,此处所描述的具体实施例仅用于解释本发明,并不用于限定本发明的范围。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为市售产品。
实施例1:超声介导氟碳微乳水凝胶制剂的制备
按照表1的组分比例,配制氟碳微乳水凝胶制剂,实验组的制剂制备:将泊洛沙姆溶解于蒸馏水中,制成泊洛沙姆溶液,加入还原型谷胱甘肽、肝素钠和硫酸软骨素,充分溶解后,调整温度至-2℃,加入全氟化碳液体,高速均质机中混匀,调整高速均质的时间以调整粒径,得到治疗白内障的超声介导氟碳微乳水凝胶制剂。
对照组制剂参考实验组制剂的方法制备,对照组13~15为上市的相关制剂或其组合。
表1氟碳微乳水凝胶制剂组成和超声波介导技术参数
注:“/”代表该项不存在,“*”代表该项指标超出本申请权利要求保护的范围,对照组13和14都是上市的产品,对照组15是对照组13和14滴眼液的混合物。
实施例2:白内障模型大鼠的应用效果
以6个月鼠龄OXYS大鼠作为白内障模型大鼠,选取55~56传代次数6个月鼠龄的OXYS大鼠若干只(雌雄兼备),左右眼的晶状体35%~40%出现混浊,确定为白内障模型大鼠,进行以下实验,每组实验动物不少于5只。
按照表1参数,将实施例1制备的氟碳微乳水凝胶制剂的各个实验组和对照组以同等剂量分别滴注于麻醉后OXYS大鼠左眼部位(翻开眼皮滴注),保持睁眼状态10秒后,合上眼皮,将涂有耦合剂的超声探头紧贴在左眼表外部,按照表1规定的超声参数进行治疗,每日1次,连续14天,于第16天进行观察,以OXYS大鼠自身右眼(未治疗处理)为对照,通过裂隙灯显微镜观察OXYS大鼠左右眼治疗前后晶状体的浑浊程度的改善效果,采用双盲对照方式进行结果判定,将晶状体浑浊的改善效果以各组动物结果的平均值四舍五入取整数后获得的百分值表示,数值越高,代表晶状体浑浊的改善效果越好,同时观察角膜内皮细胞状态,如果角膜内皮细胞形态和完整性如果受到破坏,代表该组治疗产生了严重的副作用,各组评价结果见表2。
表2各组制剂对于白内障模型大鼠的应用效果
从表2结果可见,各实验组制剂对于白内障模型大鼠晶状体浑浊的改善效果较好,维持了角膜内皮细胞正常形态和完整性,说明实验组的技术方案对于白内障治疗均发挥良好的效果,其中以实验组5的效果最佳。
从表2结果可见,对照组12对于白内障模型大鼠晶状体浑浊的改善效果虽然较好,但对于角膜内皮细胞正常形态和完整性影响很大,代表该组治疗产生了严重的副作用,其他对照组制剂对于白内障模型大鼠晶状体浑浊的改善效果均不理想,特别是对照组13~15,应用的是上市的药物滴眼液,效果很差,证明本专利保护的制剂组分和技术参数范围具有创造性,不在本专利保护的制剂组分和技术参数范围内的制剂,无法实现安全、高效、便捷的白内障治疗目的。
上述详细说明是针对发明的可行实施例的具体说明,该实施例并非用以限制本发明的专利范围,凡未脱离本发明的等效实施或变更,均应当包含于本发明的专利范围内。另外,本领域技术人员还可在本发明权利要求公开的范围和精神内做其它形式和细节上的各种修改、添加和替换。当然,这些依据本发明精神所做的各种修改、添加和替换等变化,都应包含在本发明所要求保护的范围之内。
Claims (10)
1.治疗白内障的超声介导氟碳微乳水凝胶制剂,其特征在于:所述制剂包含还原型谷胱甘肽、肝素钠、硫酸软骨素、泊洛沙姆和氟碳微乳;还原型谷胱甘肽的质量百分含量为1%~5%、肝素钠的质量百分含量为0.1%~0.3%、硫酸软骨素的质量百分含量为1%~5%、泊洛沙姆的质量百分含量为10%~25%、氟碳微乳的质量百分含量为15%~35%;所述氟碳微乳是全氟化碳液体形成的粒径为80~400m范围内的微乳;所述全氟化碳为四氟化碳、全氟己烷、全氟萘烷或全氟三丙胺中的一种或两种组合;所述水凝胶制剂联合超声波应用,超声波频率为6~12MHz,超声波强度为1~4W/m2,持续时间0.5~2min;所述水凝胶制剂联合超声波介导技术应用,通过氟碳微乳产生纳米泡的空化效应和声孔作用,促进还原型谷胱甘肽、肝素钠、硫酸软骨素和泊洛沙姆进入晶状体内部发挥治疗作用;所述水凝胶制剂用于治疗各型白内障。
2.根据权利要求1所述的水凝胶制剂,其特征在于:所述水凝胶制剂用于治疗不宜手术的白内障。
3.根据权利要求1所述的水凝胶制剂,其特征在于:所述水凝胶制剂中还原型谷胱甘肽的质量百分含量为2.5%,肝素钠的质量百分含量为0.2%,硫酸软骨素的质量百分含量为2.5%,泊洛沙姆的质量百分含量为17%,氟碳微乳的质量百分含量为27%。
4.根据权利要求1所述的水凝胶制剂,其特征在于:所述全氟化碳为全氟己烷。
5.根据权利要求1所述的水凝胶制剂,其特征在于:所述氟碳微乳粒径为200nm。
6.根据权利要求1所述的水凝胶制剂,其特征在于:所述超声波的频率为9MHz,强度为2W/m2,持续时间为1min。
7.根据权利要求1所述的水凝胶制剂,其特征在于:所述水凝胶制剂还包含治疗药物,包括:细胞因子、重组蛋白质药物、抗体、疫苗或寡核苷酸药物的一种或两种以上组合。
8.根据权利要求1所述的水凝胶制剂,其特征在于:所述水凝胶制剂还包含多元醇、抑菌剂、pH调节剂或渗透压调节剂的一种或两种以上组合。
9.权利要求1~8中任一项所述的水凝胶制剂的制备方法,其特征在于:所述制备方法包括以下步骤:将泊洛沙姆溶解于蒸馏水中,制成泊洛沙姆溶液,加入还原型谷胱甘肽、肝素钠和硫酸软骨素,充分溶解后,调整温度至-2℃,加入全氟化碳液体,高速均质机中混匀,调整高速均质时间以调整粒径,得到治疗白内障的超声介导氟碳微乳水凝胶制剂。
10.权利要求1~8中任一项所述的水凝胶制剂在制备治疗白内障的药物中的用途,其特征在于:所述白内障为各种类型的白内障,优选地,所述药物用于治疗不宜手术的白内障。
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