CN112022808A - 用于治疗眼部疾病的用于递送水飞蓟宾和其他活性成分的纳米结构化制剂 - Google Patents
用于治疗眼部疾病的用于递送水飞蓟宾和其他活性成分的纳米结构化制剂 Download PDFInfo
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- CN112022808A CN112022808A CN202010906336.XA CN202010906336A CN112022808A CN 112022808 A CN112022808 A CN 112022808A CN 202010906336 A CN202010906336 A CN 202010906336A CN 112022808 A CN112022808 A CN 112022808A
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Abstract
本申请涉及用于治疗眼部疾病的用于递送水飞蓟宾和其他活性成分的纳米结构化制剂。描述了包含被掺入到SLN和NLC型脂质纳米颗粒体系、以及基于杯芳烃(calixarene)(可能地粘膜粘附剂)掺入的或者掺入到呈基于两亲性菊粉共聚物的胶束和纳米颗粒体系中的水飞蓟宾(silibinin)或其他活性成分的制剂,所述制剂用于治疗神经变性眼部疾病。还描述了杯芳烃化合物的多功能性,其能够装载和释放待被在眼部疾病的治疗中使用的、特征在于低水溶性、易于化学降解和酶降解、低生物利用度的活性成分,无论其是否是天然来源。
Description
本申请是申请日为2015年10月09日,申请号为201580063444.2,发明名称为“用于治疗眼部疾病的用于递送水飞蓟宾和其他活性成分的纳米结构化制剂”的申请的分案申请。
发明领域
本发明涉及用于治疗眼部疾病的产品的领域以及包含其的制剂。
现有技术
不受控的新血管发生涉及各种疾病的病因,诸如:实体瘤、类风湿性关节炎、牛皮癣以及,在眼部水平上,角膜新血管形成、年龄相关性黄斑变性(ARMD或AMD)、黄斑水肿、早产儿视网膜病变(ROP)、脉络膜新血管形成(CNV)、糖尿病性视网膜病变(DR)和新血管性青光眼。
与许多其他与衰老有关的慢性疾病一样,AMD具有多因素来源,并且其发作是由遗传和生活方式相关的因素的不利组合引起的。
在CNV的治疗中进行的抗-VEGF研究(最初开发用于癌症治疗)导致在CNV的治疗中使用哌加他尼(pegaptanib)(Pfizer)和兰尼单抗(Genentech)。贝伐单抗(Genentech)目前也在AMD的治疗中“标签外(off label)”使用。
还应该考虑,AMD的治疗不仅限于脉络膜新血管形成的治疗(抗VEGF的玻璃体内注射和光动力学治疗),还包括使用多种具有抗氧化、抗炎和神经保护作用的物质,所述物质能够在导致充分发展的疾病的过程的不同水平上起作用并起到预防疾病发作、减缓其进展成晚期形式、减少组织损伤并增强抗VEGF药物的作用。
糖尿病性视网膜病变(DR)是1型和2型糖尿病最严重和频繁的微血管并发症之一,由于黄斑水肿的发作和继发性视网膜玻璃体新血管形成,其常常导致失明而显著影响患者的生活质量。
目前可获得的用于DR的治疗的目的是对比视网膜疾病的血管发生和炎症过程,并且结果是在一些情况下,它们减缓了疾病的进展。
青光眼是引起视神经组织逐渐丧失,使其端部(head)暴露导致视力丧失的视神经病变。葡萄膜炎是由虹膜、睫状体和脉络膜组成的眼中膜(tunica media)(血管)的部分或全部的炎症。
目前可获得的治疗后葡萄膜炎(posterior uveitis)的治疗工具是玻璃体内注射或植入物(Taylor S.R.等人,New developments in corticosteroid therapy foruveitis,Ophthalmologica.2010;224Suppl 1:46-53),并非没有以视觉器官为代价的非常重要的次要效果(眼内炎、视网膜水肿等)。
在过去二十年中,玻璃体内注射已经被认为是非常有价值的,因为与其他施用途径相比,玻璃体内注射通常允许在视网膜和玻璃体中达到更高的浓度。然而,玻璃体内途径与患者的严重风险,诸如视网膜脱离、眼内炎和玻璃体内出血相关。此外,此施用途径需要重复注射药物以确保治疗效果,这通常不被患者良好耐受。
因此,目前可获得的治疗并不令人满意,因为现有的益处/副作用之比不成比例。
使用眼周施用途径(眼球周围(peribulb)、巩膜后部(posterior juxtascleral)、眼球后结膜下膜(retrobulbar subtenon)和结膜下)取得了风险和收益之间的妥协,尽管比玻璃体内效率低,但更加安全。
这些施用途径利用了传统的可注射制剂的使用,并且允许活性成分通过扩散穿过巩膜纤维组织——其形成了不太耐受药物的屏障——达到靶部位(玻璃体和视网膜)。在任何情况下,被注射的药物通过前部(房水的流出)或后部(视网膜和全身循环)途径清除,要求与不良的患者依从性(疼痛、白内障、视网膜脱离、眼内炎和玻璃体出血)相关的多次施用。
因此,目前对眼的后部区段疾病的治疗仅有与不期望的作用相关的药物递送系统。
还已知,当今的纳米颗粒类型的先进药物递送系统是药物递送的最前沿。
脂质性质的纳米颗粒体系诸如固体脂质纳米颗粒(SLN)和纳米结构化脂质体系(NLC)是由生物相容性脂质(纯甘油三酯、甘油酯的复合混合物、蜡)组成的并且用无毒的表面活性剂诸如卵磷脂和泊洛沙姆稳定的胶体系统。它们的尺寸在100nm和500nm之间。在室温下,颗粒处于固态。
已经表明,由于与常规药物形式相比增加的眼前(pre-ocular)保留时间,脂质纳米颗粒提高了几种药物在眼中的生物利用度,从而避免了重复和频繁的滴注(Int.J.Pharm.,238 241-245(2002))。
菊粉是可从多种植物和水果中提取的天然多糖。它是由通过β-(2-1)葡萄糖-呋喃糖苷键键合的D-果糖单元的直链组成的碳水化合物,其偶尔在其还原性末端结合葡萄糖分子。由于菊粉具有许多有利性质的事实(毒性缺乏、生物相容性、在水中的溶解性和对肠道细菌菌群的益生作用),菊粉在无数应用中被使用(Kolida S,Gibson GR.J Nutr2007;137:2503S-2506S;Gocheva等人,Colloids and Surfaces A:Physicochem.Eng.Aspects2011;391:101-104),并且其中许多在生物医学领域。
近期,为了得到新的药物递送系统(DDS)诸如水凝胶、纳米颗粒、大分子生物缀合物和聚合物胶束,无数研究者把他们的注意力投向菊粉的化学改性。
菊粉在侧链中被伯胺化学改性,其已经用于获得与亲水链诸如聚乙二醇(PEG)和与疏水性分子诸如神经酰胺的缀合。
杯芳烃(calixarene)是甚至以低成本易于合成的环状多酚,其特征在于显著的合成多功能性、在不同水平上对其官能化的倾向以及最后,具有低程度的细胞毒性和免疫原性。
近年来,杯[4]芳烃(calix[4]arene)已被作为用于生物医学应用的新的分子平台被认真地研究,其生物医学应用由其衍生物在体外和在体内所示出的低细胞毒性(Int.J.Pharm.2004,273,57)和免疫原性(Bioconjugate Chem.1999,10,613)支持。
杯芳烃骨架的合适官能化提供了具有抗炎、抗肿瘤、抗微生物和疫苗模拟活性的衍生物(Curr.Drug Discov.Technol.2009,6,306;Chem.Soc.Rev.2013,42,366,US 2010/0056482;WO2005123660A2)。
已经提出了将水溶性杯芳烃(对于将药物复合在其疏水性腔内的能力,其与环糊精类似)作为用于制药工业的赋形剂,而能够在水性介质中组装成纳米结构化体系的两亲性杯芳烃是有前景的药物递送系统(J.Sci.Ind.Res.2012,71,21;Chem.Soc.Rev.2013,42,366,EP 1 293 248A1;US2010/0185022A19)。它们中的一些已经被恰当地工程化以根据外部刺激释放药物,该外部刺激诸如氧化还原电势、温度(ACSNANO,2011,5,2880)、pH(Phys.Rev.E,2007,73,051904)、酶活性(RSC Advances,2013,3,8058)的变化,等等。杯芳烃衍生物穿透细胞膜的能力(Chem.Commun.2012,48,1129;J.Am.Chem.Soc.2008,130,2892)以及用识别和结合存在于靶细胞表面上的互补受体的归巢基团(homing group)使杯芳烃骨架官能化的能力,使得杯芳烃也是有前景的用于靶向药物递送的系统(Org.Biomol.Chem.2015,13,3298)。
水飞蓟宾(Silibinin)是水飞蓟(Silybum marianum)中含有的约1:1比例的两种非对映异构体A和B的混合物。
其在临床领域的主要应用是:治疗由酒精引起的肝脏疾病、肝硬化、捕蝇蕈中毒(Amanitapoisoning)、病毒性肝炎和药物诱导的肝脏疾病。
另一方面,已知由于水飞蓟宾在水中的低溶解度(430mg/L),其生物利用度和功效相当有限。
水飞蓟宾似乎是用于预防和治疗人类的恶性胶质瘤的有效的剂(Rana P.Singh,Oncogene,2005)。
此外,在体外和口服施用基于水飞蓟素(silymarin)的制剂之后,已经示出了水飞蓟宾的抗血管发生活性,特别是针对AMD。
鉴于上文,具有可能有利于医师治疗性治疗眼部疾病,特别是神经变性疾病诸如黄斑变性和糖尿病性视网膜病变的新药理学制剂的前景,增加了对化合物诸如水飞蓟宾被官能化以增强其原位利用度的兴趣。
除了用描述的所有纳米结构化体系广泛研究的水飞蓟宾之外,还用这些纳米结构化制剂中的一些研究了天然来源的但不以低水溶性、易于化学降解和酶降解、低生物利用度为特征的其他活性成分,诸如:索拉非尼、姜黄素、拉坦前列素。
索拉非尼(BAY43-9006,Bayer)
是作用于多重靶标(VEGF、PDGF、EGF;其实际上被定义为多激酶抑制剂)的具有普遍存在的抗VEGF作用、具有在肿瘤中被证实的抗血管发生作用(EP 1140840B1,Bayer)的二芳基脲,并且它是在欧洲被批准用于治疗肝细胞癌的第一个抗肿瘤剂(片剂)。
索拉非尼在治疗视网膜疾病中的治疗指数可以通过在眼部水平使用局部施用来增加:以这种方式,可以获得药理作用同时限制全身副作用的发生。此外,局部施用允许使用与经全身施用具有相同作用所需的那些剂量相比有限的剂量,并且从而降低最终产品的成本。
姜黄素(Curcumin)
是从姜黄(Curcuma Longa)的根状茎中提取的黄色多酚(二阿魏酰基甲烷(diferuloylmethane));姜黄是一种用于烹饪行业并且由于其在胆道疾病和一些炎性状况中的治疗性质而用于医学中的亚洲植物。
拉坦前列素(Latanoprost)
是一种活性成分,其如比马前列素(bimatoprost)和曲伏前列素(travoprost)一样是前列腺素类似物的一部分。前列腺素类似物是一类用于局部使用的药物,其近期已被用于治疗开角型青光眼(open-angle glaucoma);最初,由于缺乏关于其长期效果的信息而不被推荐为一线治疗。在与前列腺素的长期治疗相关的副作用中,主要副作用涉及虹膜色素沉着变化、睫毛增厚和延长、黄斑水肿发作(Alexander CL等人,Prostaglandin analogtreatment of glaucoma and ocular hypertension;Ann Pharmacother.,2002)。
发明概述
描述了包含被掺入到SLN和NLC脂质纳米颗粒体系、以及基于杯芳烃(calixarene)(可能地粘膜粘附剂)掺入的或者掺入到基于两亲性菊粉共聚物的胶束和纳米颗粒体系中的水飞蓟宾的用于局部施用的制剂,所述制剂用于治疗神经变性眼部疾病。
本申请提供了以下内容:
项目1.制剂,所述制剂含有选自以下的活性成分:水飞蓟宾或索拉非尼或姜黄素或拉坦前列素,其中所述活性成分可能地在粘膜粘附剂的存在下被掺入到:
(1)SLN,固体脂质纳米颗粒,和NLC,纳米结构化脂质载体,类型的脂质纳米颗粒体系;
(2)基于杯芳烃的纳米结构化体系;
(3)基于两亲性菊粉共聚物的胶束和纳米颗粒体系;
所述制剂用于眼部疾病的局部治疗。
项目2.如项目1所述的制剂,其中所述眼部疾病是神经变性眼部疾病。
项目3.如项目1或2所述的制剂,其中所述脂质纳米颗粒体系由选自以下的脂质组成:甘油三酯、甘油二酯、甘油单酯、脂族醇、脂肪酸(C10-C22);脂肪醇的脂肪酸酯;聚乙二醇化山萮酸的甘油单酯、甘油二酯和甘油三酯的混合物;聚乙二醇化辛酸和聚乙二醇化己酸的甘油单酯、甘油二酯和甘油三酯。
项目4.如项目1或2所述的制剂,其中所述粘膜粘附剂选自:带有氨基基团的菊粉聚合物、低分子量聚合物和阳离子表面活性剂。
项目5.如项目1-4中任一项所述的制剂,其中所述纳米颗粒体系具有在50nm和200nm之间的范围内的平均直径,多分散性指数低于0.5。
项目6.如项目3所述的制剂,其中所述体系掺入在1%w/w和15%w/w之间的范围内的量的选自以下的活性成分:水飞蓟宾、索拉非尼、姜黄素、拉坦前列素。
项目7.如项目1所述的制剂,其中所述神经变性眼部疾病选自:脉络膜新血管形成(CNV)、年龄相关性黄斑变性(AMD)、黄斑水肿、新血管性青光眼、黄斑水肿、早产儿视网膜病变(ROP)、糖尿病性视网膜病变(DR)、葡萄膜炎、眼内炎、视网膜炎、脉络膜炎、脉络膜视网膜炎、全身性疾病的视网膜并发症。
项目8.式(A)的化合物:
其中:
R=CH3、(CH2)XCH3、(CH2)XOH
R1=CH3、(CH2)XCH3、(CH2)XOH
其中
x=1-3
n=4、6、8
m=2-15
并且其中当R=R1=CH3时,m不为2-9。
附图简述
图1示出了与游离水飞蓟宾的溶解曲线相比,由SLN-A在pH 7.4的PBS中释放的水飞蓟宾的百分比作为孵育时间的函数。
图2示出了由被INU-DETA和壳聚糖包被的NLC-B体系在pH 7.4的PBS中释放的水飞蓟宾的百分比作为孵育时间的函数和游离水飞蓟宾的溶解曲线。
图3示出了与游离水飞蓟宾的扩散曲线相比,由INU-C8和INU-C8-PEG的聚合物胶束在pH 7.4的PBS中释放的水飞蓟宾的百分比作为孵育时间的函数。
图4a和4b示出了在不同浓度下培养4小时(4a)和24小时(4b)后,INU-C8和INU-C8-PEG的空胶束在16HBE细胞系上的细胞相容性曲线。
图5A示出了对于用INUC8PEG-索拉非尼体系、用空载体INUC8PEG和用索拉非尼甲苯磺酸酯预处理20小时、然后暴露于H2O2伤害的ARPE-19细胞的影响;定量释放到培养基的LDH。数据的统计学评价通过单因素方差分析(ANOVA)随后是Bonferroni多重比较进行。**p<0.01,对比对照样品(对照);##p<0.01,对比H2O2。
图5B示出了对于用H2O2伤害3小时并用INUC8PEG-索拉非尼体系(C8PEGSor)、用空载体INUC8PEG(C8PEG)和用索拉非尼甲苯磺酸酯(Sor)后处理20小时的ARPE-19细胞的影响;定量释放到培养基的LDH。数据的统计学评价通过单因素方差分析(ANOVA)随后是Bonferroni多重比较进行。**p<0.01,对比对照样品(对照);#p<0.05,##p<0.01,对比H2O2。
图6A示出了对于用INUC8PEG-索拉菲尼体系、用空载体INUC8PEG(C8PEG)和用水飞蓟宾预处理20小时、然后暴露于H2O2伤害的ARPE-19视网膜细胞的影响;定量释放到培养基的LDH。数据的统计学评价通过单因素方差分析(ANOVA)随后是Bonferroni多重比较进行。*p<0.05,对比对照样品(对照);#p<0.05,##p<0.01,对比H2O2。
图6B示出了对于用H2O2伤害3小时并用INUC8PEG-水飞蓟宾体系(C8PEGSib)、用空载体INUC8PEG(C8PEG)和用水飞蓟宾(Sib)后处理20小时的ARPE-19视网膜细胞的影响;定量释放到培养基的LDH。数据的统计学评价通过单因素方差分析(ANOVA)随后是Bonferroni多重比较进行。**p<0.01,对比对照样品(对照);##p<0.01,对比H2O2;δp<0.05,对比用10μM C8PEGSlb处理的样品。
图7示出了在无H2O2(对照,C)或有H2O2(H)并且用INUC8PEG(1μM和10μM)、用INUC8PEGSlb(1μM和10μM)或用Slb(1μM和10μM)处理或不处理的样品上使用抗PARP1 1:800一抗(Cell Signaling)进行的代表性蛋白质印迹。条带的光密度分析(直方图)用β-肌动蛋白归一化。
图8示出了由杯芳烃纳米颗粒在pH 7.4的PBS中释放的水飞蓟宾的百分比作为孵育时间的函数。
图9A示出了对于用杯芳烃-水飞蓟宾体系(CalixSlb)、用空载体(Calix)和用单独的水飞蓟宾预处理20小时、然后暴露于50μM FeSO4的ARPE-19视网膜细胞的影响;定量释放到培养基的LDH。数据的统计学评价通过单因素方差分析(ANOVA)随后是Bonferroni多重比较进行。*p<0.05,**p<0.01,对比对照样品(对照);#p<0.05,##p<0.01,对比FeSO4;δp<0.05,对比用0.1和1μM CalixSlb处理的样品。
图9B示出了对于用FeSO4 50μM处理5小时并用杯芳烃-水飞蓟宾体系(CalixSlb)、用空载体(Calix)和用单独的水飞蓟宾(Sib)后处理20小时的ARPE-19视网膜细胞的影响;定量释放到培养基的LDH。数据的统计学评价通过单因素方差分析(ANOVA)随后是Bonferroni多重比较进行。*p<0.05,**p<0.01,对比对照样品(对照);#p<0.05,##p<0.01,对比FeSO4。
图10A和10B示出了对无FeSO4(CTR)或有FeSO4(Fe)并用Calix(1μM)、用CalixSIb(1μM)或用SIb(1μM)进行处理或不处理的样品进行的代表性蛋白质印迹。使用抗VEGF 1:100一抗(Santa Cruz)(10A),以及对无FeSO4(CTR)或有FeSO4(Fe)并用Calix(0.1μM和1μM)、CalixSIb(0.1μM和1μM)或用SIb(0.1μM和1μM)处理或不处理的样品进行的代表性蛋白质印迹。使用抗组织蛋白酶D1:200一抗(Santa Cruz)。条带的光密度分析(直方图)用β-肌动蛋白归一化(10B)。
图11示出了杯芳烃体系对活性成分姜黄素的保护作用,对此示出了在0.1M PBS和在无血清培养基中30分钟内降解90%以比较。
图12示出了用姜黄素、杯芳烃体系和杯芳烃-姜黄素体系处理后对SIRC角膜细胞的细胞毒性测试的结果。
图13示出了姜黄素、杯芳烃和杯芳烃-姜黄素对J744巨噬细胞的MIT测定的细胞毒性测试的结果。
图14示出了用LPS刺激并预先暴露于用姜黄素、杯芳烃体系和杯芳烃-姜黄素体系处理的J744巨噬细胞的活力。
图15示出了在姜黄素、杯芳烃体系和杯芳烃-姜黄素体系的存在下,受到LPS应激的J744巨噬细胞中组成型蛋白IkBα的降解的减少。
图16示出了在姜黄素、杯芳烃1和杯芳烃-姜黄素的存在下,受到来自LPS应激的J744巨噬细胞中NFkB的减少。
图17示出了在受到LPS应激的J744巨噬细胞中iNO和COX2的表达以及它们在姜黄素、杯芳烃1和杯芳烃-姜黄素的处理的存在下降低。
图18A和18B示出了在葡萄膜炎模型中,在用掺入或未掺入水飞蓟宾的杯芳烃体系、用掺入或未掺入姜黄素的杯芳烃体系处理的动物的房水中的组织学评分和蛋白质测定的结果。在图18A中,***p<0.001,对比模拟;##p<0.01,对比LPS;###p<0.001,对比LPS。在图18B中,##p<0.01,对比LPS;###p<0.001,对比LPS。
图19A和19B示出了在杯芳烃-拉坦前列素体系和含有拉坦前列素的商用产品IOPIZE的单次施用(A)和长期治疗(B)后的张力过高(hypertonia)模型中眼内压降低的趋势。在图19B中,*p≤0.05,对比基线;***p≤0.001,对比基线;单因素方差分析加Dunnett事后检验。
发明详述
本发明用用于局部应用的制剂克服了上文所述的缺点,所述制剂包含掺入到以下中的水飞蓟宾:
(1)SLN(固体脂质纳米颗粒)和NLC(纳米结构化脂质载体)型的脂质纳米颗粒体系;
(2)基于杯芳烃的纳米结构化体系;
(3)基于两亲性菊粉共聚物的胶束和纳米颗粒体系,对于后者提供了对感兴趣的眼部疾病具有使用理论基础的其他活性成分的掺入和释放的实例。
所述制剂能够将治疗有效剂量的活性成分递送至玻璃体或视网膜,用于治疗神经变性眼部疾病如黄斑变性、糖尿病性视网膜病变、青光眼。本发明还涉及如上文定义的掺入水飞蓟宾的纳米颗粒体系的制备方法。
特别地,遵循下文描述的一般方法制备SLN和NLC型体系。
将脂质相(由固体脂质或液体脂质与固体脂质的混合物组成)熔化至高于其熔点约5-10℃。
将水飞蓟宾溶解于乙醇的等分试样中,并然后在磁力搅拌下加至熔化的脂质混合物中。
然后将含有水飞蓟宾的热脂质混合物在含有水、表面活性剂或表面活性剂的混合物的水性溶液中沉淀(沉淀法),或用预先在相同温度下加热的含有水、表面活性剂或表面活性剂的混合物的水性溶液乳化。在后一种情况下,将所得的预乳液:分散于在2℃和5℃之间的温度冷却的水或水性介质中(微乳液法),或进行高压均质化(高压热均质化法)。在所有情况下,允许所得的纳米乳液冷却至室温,然后通过对蒸馏水的彻底透析(COMW12000-14000)纯化。然后,冷冻保护剂被加至纳米颗粒分散体中,所述纳米颗粒分散体可以经受离心(在10℃、4000rpm,持续10分钟)。最后,冷冻干燥后,将固体脂质纳米颗粒回收并储存在冷冻柜中用于随后的表征和/或用粘膜粘附剂聚合物包被。在后一种情况下,将0.1%水性溶液中的INU-EDA和INU-DETA聚合物和壳聚糖加至纳米颗粒悬浮液中,并在室温和磁力搅拌下孵育30分钟。
上述脂质相由脂质组成,所述脂质例如选自:甘油三酯类诸如三硬脂酸甘油酯(tristearin)、三棕榈精(tripalmitin)、辛酸/癸酸甘油三酯(Mygliol);甘油二酯类诸如Precirol ATO 5(二硬脂酸甘油酯);甘油单酯类诸如单硬脂酸甘油酯;脂族醇诸如鲸蜡醇;脂肪酸(C10-C22);脂肪醇的脂肪酸酯诸如棕榈酸鲸蜡醇酯;聚乙二醇化和非山萮酸的甘油单酯、甘油二酯和甘油三酯的混合物诸如Compritol HD-5-ATO(PEG-8山嵛酸酯和三山嵛精(tribehenin))和Compritol 888ATO(山嵛酸单酯、山萮酸二酯和山萮酸三酯的混合物);聚乙二醇化辛酸和聚乙二醇化己酸的甘油单酯、甘油二酯和甘油三酯诸如Accocon CC-6。
在该方法中用作表面活性剂/助表面活性剂的物质可以例如选自:非离子表面活性剂,包括卵磷脂诸如Epikuron 200;聚乙二醇和聚丙二醇嵌段共聚物诸如Pluronic;聚乙二醇化脱水山梨糖醇衍生物诸如吐温;聚乙二醇的脂肪醇醚如Brij;离子表面活性剂,包括胆汁盐诸如牛磺胆酸钠;季胺,包括西吡氯铵和溴化二十八烷基二甲基铵。
在该方法中用作冷冻保护剂的物质可以例如选自:糖类诸如乳糖和海藻糖;聚合物诸如聚乙烯吡咯烷酮(PVP)。
在该方法中用于赋予粘膜粘附性的物质例如选自:含有胺基团的菊粉聚合物(INU-EDA和INU-DETA)、低分子量聚合物(壳聚糖)和阳离子表面活性剂(CCP和DDAB)。
根据进一步的实施方案,本发明涉及包含下式(I)或(II)的基于菊粉的共聚物的眼用制剂,
其中R是-(CH2)p-CH3;其中p在0和19之间的范围内;
其中R是-(CH2)p-CH3;其中p在0和19之间的范围内并且n在9和450之间的范围内,
以及涉及此类共聚物。
上文给出的式(I)和(II)的基于菊粉的共聚物通过用脂族链C8或C8和PEG的链将菊粉官能化获得。
已经证明了这些具有两亲性特征的共聚物能够聚集以形成胶束或纳米颗粒,以掺入灵活(flexible)和不同量的药物并将其以活性形式释放,持续延长且受控的时间,此外,它们是高度生物相容的并且允许容易地制造眼科制剂。
通过向DMF中的聚合物溶液中加入一定量的活性成分(诸如索拉非尼或水飞蓟宾)获得制剂。然后将所得溶液在真空下干燥并通过超声和搅拌循环(10分钟的3个循环)在pH7.4的PBS中分散。此后,将分散体在25℃置于轨道振荡器中持续18小时,然后用具有标称截留值(MWCO)为1000Da的膜对水透析。
最后,将所得分散体冷冻干燥。
根据本发明的进一步的实施方案,其涉及含有基于两亲性杯芳烃的纳米结构化体系的眼用制剂。
在此类体系中,除了赋予粘膜粘附性之外,多个带正电荷的配体单元的存在还可以通过存在于细胞表面上的互补受体的分子识别来协助通过角膜和视网膜上皮。
特别地,本发明涉及用于局部眼用的制剂,其包含被烷氧基胺(包括胆碱)官能化的杯[4]芳烃(Calix[4]arene)衍生物组成的阳离子大分子,以获得通式(A)的新载体,
其中:
R=CH3、(CH2)XCH3、(CH2)XOH
R1=CH3、(CH2)XCH3、(CH2)XOH
其中
x=1-3
n=4、6、8
m=2-15
并且其中当R=R1=CH3时,m不为2-9
除了递送已知的活性成分之外,其还具有可以增强活性成分的生物活性的其自身的生物活性。
可以看出,式A代表形成大环的酚单元数(n=4、6、8)上、在疏水尾部长度(m=2-15,表示CH2的数目)上、在杯芳烃的上缘处存在的极性基团的结构(R和R1=CH3、(CH2)xCH3、(CH2)xOH,其中x=1-3以及其组合)上不同的杯芳烃衍生物。
如上文所述的杯芳烃化合物是新的,并且它们也是本发明的对象;这些化合物在负载和释放待在眼部疾病的治疗中使用的、以低水溶性、易于化学降解和酶降解、低生物利用度为特征的、无论是否是天然来源的活性成分方面表现出极大的多功能性。
作为靶向分子,胆碱引导和促进穿过存在胆碱载体的角膜上皮、血液-视网膜屏障和视网膜上皮(Adv.Drug Deliv.Rev.2006,58,1136)。
并且在此情况下,如同对于上文所述的基于菊粉的共聚物,发现杯芳烃体系已经示出了形成能够掺入和释放水飞蓟宾或其他活性成分诸如姜黄素/拉坦前列素的纳米聚集体的能力。
生物相容性和易于制备是通过以下方式获得的制剂的特征:将杯芳烃衍生物在PBS(pH 7.4)中简单地溶解、加入过量的活性成分(相溶解度法)、超声处理持续15分钟、在25℃下搅拌2-3天、离心并在GHP 0.2μm过滤器上过滤。
在本发明中获得的纳米颗粒体系具有的平均直径在50nm和200nm之间的范围内,多分散性指数低于0.5。药理学上有效量的活性成分被掺入到所述纳米颗粒中。特别地,在本发明中获得的纳米颗粒体系具有的药物载量在1%w/w和15%w/w之间的范围内。
本发明的进一步的特征和优点将从以非限制性实例的方式进行的其一些实施方案的以下描述更清楚地呈现。
SLN(固体脂质纳米颗粒)和NLC(纳米结构化的脂质载体)型的脂质纳米颗粒体系、或基于杯芳烃的纳米结构化体系(无论是否是粘膜粘附性的)、或基于两亲性菊粉共聚物的胶束和纳米颗粒体系中的含有选自水飞蓟宾或索拉非尼或姜黄素或拉坦前列素的活性成分的根据本发明的制剂,允许活性成分的局部施用,用于治疗神经变性眼部疾病诸如:CNV、AMD、黄斑水肿、新血管性青光眼、黄斑水肿、早产儿视网膜病变(ROP)、糖尿病性视网膜病变(DR)、葡萄膜炎、眼内炎、视网膜炎、脉络膜炎、脉络膜视网膜炎、全身性疾病的视网膜并发症。
制剂通常呈冷冻干燥的固体产品的形式,并且除了掺入在上文所述的脂质、聚合物或杯芳烃纳米结构中的活性成分之外,还可以含有组分诸如表面活性剂和/或冷冻保护剂和眼科制剂中经常使用的其他赋形剂。
实施例1
含有水飞蓟宾的SLN(SLN-A)的制备
下文描述了用水飞蓟宾负载用Compritol HD-5-ATO制备的本发明的SLN对象的程序和获得的实验数据。
SLN-A的制备
用高压热均质法制备SLN-A。将200毫克Compritol HD5ATO熔化至高于其熔点约5℃-10℃(65℃-70℃)。将药物(68mg)溶于乙醇的等分试样(0.5mL)中,并然后在磁力搅拌下加至熔化的脂质混合物中。然后将含有药物的热脂质混合物在预先在相同温度下加热的Pluronic F68表面活性剂的水溶液(于100mL中60mg)中乳化。使用Emulsiflex-C5设备(Avestin),将所得的预乳液进行高压均质化(在7500±2500psi下4个循环)、放置在温度为65℃-70℃的热水浴中。允许所得的纳米乳液冷却至室温,然后通过对蒸馏水的透析(COMW12000-14000)进行纯化。此后,将冷冻保护剂海藻糖(脂质:冷冻保护剂重量比=1:1w/w)加入到纳米颗粒分散体中,进行离心(在10℃,4000rpm持续10分钟)。最后,使用Modulyo冷冻干燥机进行冷冻干燥后,将SLN回收并储存在冷冻柜中,用于随后的表征。
SLN-A体系的尺寸确定和ζ电位测量
所制备的SLN-A体系的平均直径和多分散性指数(PDI)通过使用Zetasizer NanoZSP(Malvern Instrument)的光相关光谱法(photo-correlation spectroscopy,PCS)确定。对于分析,将每个样品用0.9%w/w的NaCl水溶液适当地稀释、过滤通过0.2-μm过滤器并以相对于入射光173°的角度进行读数并一式三份地分析。
根据激光多普勒测速法和光散射分析(M3-PALS技术)的原理,使用具有He-Ne激光器、功率=4.0mW、波长=633nm的Zetasizer Nano ZSP(Malvern)测量ζ电位。
获得的平均直径、PDI和ζ电位的结果在表1中给出。
表1
SLN-A体系的平均流体动力学直径、多分散性指数(PDI)、ζ电位。
SLN-A的药物载量(%DL)的确定
为了确定负载于SLN-A样品中的水飞蓟宾的量,将10mg之前进行冷冻干燥的组合物溶解于四氢呋喃(THF)中。然后用甲醇处理有机溶液以沉淀脂质并提取活性成分。然后将所得悬浮液过滤通过0.45μm过滤器并通过HPLC分析。发现关于%DL(表示为负载到SLN中的活性成分的百分比,假设100mg被进行冷冻干燥的材料由脂质+活性成分组成)获得的结果为8.5%w/w。
在pH 7.4,水飞蓟宾从SLN-A的释放
将本发明中描述的体系在体外、在37℃下使用pH 7.4的磷酸盐缓冲液进行释放研究,孵育时间在0小时和12小时之间的范围内。所获得的结果已经示出了本发明的体系在12小时内缓慢地释放药物至最高达7.8%w/w的最大值。在pH 7.4和37℃下孵育后药物的释放和溶解曲线在图1中示出。
所描述的体系是稳定的,即在pH 7.4下将药物非常缓慢地释放到外部介质中,并且这可以是有利的,以便通过包含活性成分的纳米颗粒来优化其在病理部位中的递送。
实施例2
含有水飞蓟宾的NLC(NLC-B)的制备
通过非限制性实例的方式,下文描述了用水飞蓟宾负载用Compritol HD-5-ATO、Gelucire 44/14和Acconon CC-6制备的本发明的NLC对象的程序和获得的实验数据。
NLC-B的制备
用溶剂沉淀-蒸发法制备NLC-B。将Compritol HD5ATO(250mg)熔化至高于其熔点约5℃-10℃(65℃-70℃)并将药物(30mg)加至熔化的脂质中。将Gelucire 44/14(100mg)和Acconon CC-6(100mg)溶解于乙醇(2.0mL)中,然后在磁力搅拌下加至熔化的脂质混合物中。然后将含有药物和表面活性剂的热脂质混合物在预先在相同温度下加热的、包含表面活性剂牛磺胆酸钠的热水溶液(100mL中100mg)中沉淀,并使用Ultra-Turrax均质化(13500rpm)。将仍然在搅拌下的热的纳米颗粒悬浮液置于冰浴中,直到其温度达到10℃的值。然后将所得的纳米颗粒通过对蒸馏水的透析(COMW12000-14000)纯化持续3天,并然后加入冷冻保护剂海藻糖(脂质:冷冻保护剂重量比=1:2w/w)。最后,使用Modulyo冷冻干燥机冷冻干燥后,将NLC回收并储存在冷冻柜中,用于随后用菊粉衍生物(INU-DETA)和壳聚糖包被。在使用INU-DETA包被的情况下,在磁力搅拌下,将9mL经过透析的纳米颗粒悬浮液(浓度为4.3mg/mL)与1mL的0.1%INU-DETA孵育1小时。在用低分子量(5000Mw)壳聚糖包被的情况下,在磁力搅拌下,将含添加的海藻糖的9mL经透析并冷冻干燥的纳米颗粒(浓度为0.165mg/mL)与1mL的0.1%壳聚糖孵育30分钟。然后将经包被的纳米颗粒冷冻干燥并储存为粉末用于随后的表征。
NLC-B体系的尺寸确定和ζ电位测量
通过使用Zetasizer Nano ZSP(Malvern Instrument)的光相关光谱法(photo-correlation spectroscopy,PCS)确定所制备的被INU-EDA和壳聚糖包被的NLC-B体系的平均直径和多分散性指数(PDI)。对于分析,将每个样品用0.9%w/w的NaCl水溶液适当地稀释、过滤通过0.2-μm过滤器并以相对于入射光173°的角度进行读数并一式三份地分析。
根据激光多普勒测速法和光散射分析(M3-PALS技术)的原理,使用具有He-Ne激光器、功率=4.0mW、波长=633nm的Zetasizer Nano ZSP(Malvern)测量ζ电位。
获得的平均直径、PDI和ζ电位的结果在表2中给出。
表2
被INU-DETA和壳聚糖包被的NLC-B的平均流体动力学直径、多分散性指数(PDI)、ζ电位。
用INU-DETA和壳聚糖包被的NLC-B的%DL的确定
为了确定负载在用INU-DETA和壳聚糖包被的NLC-B样品中的水飞蓟宾的量,将2mg之前经历过冷冻干燥的组合物热溶解于8mL乙醇(EtOH)中并超声处理持续3分钟。然后将所得溶液用5.00μm再生纤维素过滤器过滤并用HPLC分析。
发现关于%DL(以负载到NLC中的活性成分的百分比表示,假设100mg经受冷冻干燥的材料由脂质+活性成分组成)获得的结果为,对于被INU-DETA包被的NLC-B,%DL为6.05%w/w,并且对于用壳聚糖包被的NLC-B,%DL为3.07%w/w。
在pH 7.4,活性成分从被INU-DETA和壳聚糖包被的NLC-B的释放
本发明中描述的被INU-DETA和壳聚糖包被的NLC-B体系在体外、37℃下使用pH7.4的磷酸盐缓冲液进行释放研究,孵育时间在0小时和12小时之间的范围内。获得的结果已经示出了,本发明的两个体系缓慢地释放药物,对于用INU-DETA包被的NLC-B,在12小时内最高达50%w/w的最大值,对于用壳聚糖包被的NLC-B,在12小时内最高达30%w/w的最大值。在pH 7.4和在37℃孵育后,药物水飞蓟宾从2个被包被的体系中的释放和溶解曲线在图2中示出。
基于INU-C8和INU-C8-PEG2000的聚合胶束的制备
以非限制性实例的方式,下文描述了用水飞蓟宾或索拉非尼负载基于INU-C8和INU-C8-PEG2000的本发明的聚合物胶束对象的程序和获得的实验数据。
INU-C8和INU-C8-PEG2000共聚物的临界聚集浓度(CAC)的确定
按照文献中已经存在的程序,以良好的收率进行了INU-C8和INU-C8-PEG2000共聚物的生产。
使用芘作为荧光探针,通过荧光光度分析法确定INU-C8和INU-C8-PEG2000共聚物的CAC。将20μL芘的丙酮溶液(6.0×10-5M)置于小瓶中,并在37℃下在轨道振荡器上蒸发至干燥。然后,向含有芘残留物的小瓶中加入2mL具有递增的浓度并且在1×10-5mg/mL和5mg/mL之间的范围内的共聚物水溶液,以获得等于6.0×10-7M的芘的终浓度。在持续搅拌下,将所得到的分散体在37℃保持24小时,以使探针与胶束平衡。分别使用以下波长记录芘的发射和激发光谱:373nm和333nm。结果在表3中示出。
表3
制备的一些共聚物的CAC
负载水飞蓟宾或索拉非尼的INU-C8和INU-C8-PEG的聚合胶束的制备。
通过干式络合法(捏合)制备负载水飞蓟宾和索拉非尼的聚合物胶束。详细地说,使用研钵和研杵将200mg INU-C8或INU-C8-PEG与药物(50mg)干混并在乙醇(5mL)的存在下研磨。然后,将蒸发乙醇后获得的干燥基质(由药物均匀地分散于其中的聚合物形成)缓慢地并且在机械搅拌下水合以促进单体的自聚集和药物掺入于所得胶束的疏水性核中。
将所得分散体进行超声处理和搅拌循环(10分钟的3个循环)。此后,将分散体以2000rpm离心5分钟,并在截留值5μm的注射器式过滤器上过滤以除去未掺入的药物。最后,将所得分散体在液氮中冷冻并冷冻干燥。
INU-C8和INU-C8-PEG2000的聚合物胶束的%DL的确定
将3mg负载水飞蓟宾或负载索拉非尼的胶束分散在甲醇(5mL)中;将分散体超声处理持续10分钟,并然后置于剧烈搅拌4小时。此后,使用截留值0.2μm的注射器式过滤器过滤分散体,并最后将滤液用甲醇(5mL)洗涤以得到10mL的终体积。为了确定从萃取程序获得的600μL甲醇溶液中的水飞蓟宾,加入400μL的1%乙酸(v/v)以符合用于HPLC分析的洗脱剂混合物的组成。因此,通过HPLC分析,使用C6-苯基、1%(v/v)(60:40)甲醇:乙酸柱作为洗脱相确定从胶束提取的药物的量。将流速设定为0.65mL/min并在288nm监测洗脱液。
为了确定索拉非尼,用HPLC直接分析1mL从萃取程序获得的甲醇溶液,以确定被胶束掺入的药物的量。使用C6-苯基、甲醇:水(v/v)(90:10)柱作为洗脱相进行HPLC分析。将流速设定为1mL/min并在266nm监测洗脱液。
结果在表4中示出。INU-C8和INU-C8-PEG的聚合物胶束的平均尺寸和ζ电位的确定
使用Malvern Zetasizer Nano ZS,通过动态光散射测量确定胶束的尺寸分布。这些测量在173°的固定角度和25℃的温度下进行。在过滤通过具有5μm的截留值的纤维素膜过滤器后,分析胶束的水溶液(2mg/mL)。使用相关函数的累积分析获得平均流体动力学直径和多分散性指数(PDI)。通过电泳迁移率并使用Smoluchowsky关系计算ζ电位(mV),假设K·a>>1(其中K和a分别为德拜-休克尔参数和颗粒半径)。结果在表4中示出。可以看出,所有的共聚物能够掺入疏水性药物索拉非尼和水飞蓟宾。
表4
胶束的平均流体动力学直径、多分散性指数(PDI)、ζ电位和药物载量。
a药物载量是指索拉非尼和水飞蓟宾
释放研究
为了评估所得体系释放被掺入的药物的能力,将适量的INU-C8和INU-C8-PEG聚合物胶束(15mg)分散在pH 7.4的PBS(5mL)中并在标称截止量(MWCO)为1kDa的漂浮透析膜Spectra/Por中转移。将含有负载药物的胶束分散体和单独的药物的透析膜浸入pH 7.4的PBS(50mL)中,并在连续搅拌(100rpm)下在Benchtop 808C轨道式振荡恒温器420型中在37℃孵育24小时。在预定的时间间隔,从透析膜外部取出外部介质的等分试样(1mL),并用等量的新鲜介质代替。将取出的样品冷冻干燥、悬浮于甲醇:乙酸1%(v/v)中,并用HPLC分析以确定释放的药物的量。以示例的方式,示出了掺入到体系中的活性成分水飞蓟宾的释放图。将所有释放数据与使用相同程序获得的单独的水飞蓟宾(0.25mg)的扩散曲线进行比较(图3)。考虑到稀释过程,对数据进行了校正。每个实验一式三份地进行并发现结果符合标准误差±5%。从图中可以看出,与游离水飞蓟宾的扩散相比,负载水飞蓟宾的INU-C8和INU-C8-PEG的聚合物胶束示出了非常缓慢的释放动力学(在孵育12小时后,小于5%w/w的水飞蓟宾被释放)。对于活性成分索拉非尼,也获得了相似的释放曲线。
稳定性研究
通过将新鲜冷冻干燥的体系在4℃和25℃下孵育1、2和3个月来评估负载水飞蓟宾或索拉非尼的INU-C8和INU-C8-PEG的胶束的稳定性。特别地,将新鲜制备的样品和冷冻干燥的样品在受控温度储存1、2和3个月。孵育期后,将样品分散在双蒸水(2mg/mL)中,并通过动态光散射测量分析以评价其平均直径、多分散性指数和ζ电位。分别地,将3mg样品分散于甲醇(5mL)中;首先将分散体超声处理持续10分钟并搅拌2小时,并且最后过滤通过具有5μm截留值的注射器式过滤器并用另外5mL甲醇稀释。使用对于确定药物载量所描述的相同程序,通过HPLC分析确定提取的活性成分的量。
获得的结果示出了,制备的胶束和负载的药物都在长期储存时具有良好的物理稳定性。作为一个实例,表5示出了通过动态光散射测量获得的与负载水飞蓟宾或索拉非尼的INU-C8胶束相关的稳定性数据,以评价平均直径、PDI和ζ电位中的变化,以及HPLC分析以评估药物载量和负载的药物的稳定性。
表5
在4℃和25℃储存1、2和3个月后,负载水飞蓟宾/索拉非尼的INU-C8胶束的稳定性。
体外细胞相容性研究
使用商业试剂盒(Cell Titer 96Aqueous One Solution Cell Proliferationassay,Promega),通过MTS测定在人支气管上皮(16HBE)细胞系上评价INU-C8和INU-C8-PEG的空胶束的生物相容性。将细胞以2×104细胞/孔的密度铺板在96孔板上并悬浮于富含10%体积/体积的胎牛血清(FBS)、1%体积/体积抗生素(10mg/mL链霉素、10000U-1mL青霉素)的Dulbecco改良的Eagle培养基(DMEM)中,并在标准条件(95%RH和5%CO2,在37℃)下孵育。孵育24小时后,去除培养基,并用含有浓度等于0.025mg/ml、0.05mg/ml、0.1mg/ml、0.25mg/ml、0.5mg/ml和1mg/ml的INU-C8和INU-C8-PEG的空胶束的200μL新鲜培养基替换。在孵育4和24小时后,去除胶束在DMEM中的分散液、用Dulbecco磷酸盐缓冲盐水(DPBS)洗涤细胞1次,并用100μL新鲜培养基和20μL MTS溶液在37℃孵育2小时。仅与DMEM孵育的细胞被用作阴性对照。结果表示为与对照细胞相比的细胞活力降低的百分比(图4a和4b)。所有实验一式三份地进行。
进行的研究示出,所测试的聚合物胶束具有良好的细胞相容性,并且在体外对人支气管上皮细胞系不表现出细胞毒性作用。此结果使得这些体系潜在地可用作体内药物递送的有效体系。在ARPE-19视网膜细胞和SIRC角膜上皮细胞上也证实了研究的空体系和负载活性成分的体系的生物相容性。
评价与水飞蓟宾或与索拉非尼甲苯磺酸酯缀合的胶束载体INU-C8和INU-C8-PEG对暴露于20小时预处理然后用H2O2伤害以诱导氧化应激的视网膜细胞的保护作用。空的和缀合物INUC8PEG载体示出了比没有PEG的载体更大的保护作用,但是由于PEG的存在,只有较高浓度的与水飞蓟宾或索拉非尼缀合的载体INUC8PEG才能够引起LDH释放的降低。以示例的方式,图5A和图6A分别示出了与活性成分索拉非尼或水飞蓟宾缀合的体系的实验测试数据。
在后处理方案中,被H2O2伤害持续3小时随后被暴露于用与水飞蓟宾或索拉非尼缀合的INU-C8和INU-C8-PEG体系处理的视网膜细胞示出了两种载体恢复伤害诱导的损伤的良好的能力。然而,与任一个活性成分缀合的INUC8PEG体系在抑制H2O2-诱导的应激方面更有效。以示例的方式,图5B和图6B分别示出了与活性成分索拉非尼或水飞蓟宾缀合的体系的实验测试数据。
对于PARP-1蛋白——一种参与响应环境应激的DNA修复的116kDa的聚(ADP-核糖)聚合酶(Calcium Overload Is A Critical Step In Programmed Necrosis Of Arpe-19Cells Induced By High-Concentration H2O2 Guang-Yu Li等人,(2010)Biomedical AndEnvironmental Sciences)——的表达,通过蛋白质印迹分析暴露于用INUC8PEG体系(空的或与水飞蓟宾缀合的)后处理的视网膜细胞的裂解物。在体内和体外,PARP-1由胱天蛋白酶3和胱天蛋白酶7加工,形成24kDa的DNA结合结构域和参与凋亡的89kDa催化结构域(Importance of Poly(ADP-ribose)Polymerase and Its Cleavage in Apoptosis F.JOliver等人,(1998)J.Biol.Chem.)。图7示出了用H2O2处理后PARP-1蛋白的减少,证实了细胞凋亡状态。相反,与游离载体和Slb本身相比,在用缀合载体处理的样品中观察到PARP-1的更高的表达。在用H2O2处理的样品中证实了缀合Slb的INUC8PEG以剂量依赖的方式抑制由氧化损伤诱导的细胞凋亡的能力。使用游离Slb的后处理减少了凋亡过程,然而效率低于缀合载体。
实施例4
杯芳烃纳米颗粒的制备
作为实例,下文描述了用水飞蓟宾、姜黄素或拉坦前列素负载杯[4]芳烃衍生物(化合物1)的程序和获得的实验数据。
制备
调整文献中对于相似衍生物描述的程序,以良好收率合成了两亲性杯[4]芳烃衍生物,其在大环的下边缘具有四个十二烷基脂族链并且在上边缘具有四个胆碱的极性头(化合物1)。化合物通过NMR光谱和质谱表征。
杯芳烃衍生物在纳米聚集体中的组装自发地发生。在PBS(pH 7.4)中简单溶解提供了含有具有表6中示出的尺寸、多分散性指数和ζ电位的纳米聚集体的胶体溶液。
通过向作为底体(bottom body)的胶体溶液中加入过量的药物(摩尔比1:5)进行药物负载。将混合物暴露于超声波持续15分钟,并在振荡器中在25℃、200rpm下搅拌2-3天。随后在4000rpm下离心持续30分钟并在GHP Acrodisc 0.2μm过滤器上过滤提供了负载水飞蓟宾的纳米颗粒的胶体溶液。将此溶液冷冻干燥,不加入冷冻保护剂和使用标准的冷冻干燥器,提供了白色粉末,将该粉末重新悬浮于水时恢复负载药物的纳米颗粒的胶体溶液。胶体溶液在GHP Acrodisc 0.2μm过滤器上的重过滤和随后的确定%DL的HPLC分析示出了,在冷冻干燥后,体系保持掺入的药物载量(表6)。
尺寸确定和ζ电位测量
使用Zetasizer Nano ZS-90(Malvern Instrument)测量负载和不负载水飞蓟宾的杯芳烃纳米颗粒的平均直径、多分散性指数(PDI)和ζ电位,读数是相对于入射光线以90°的角度进行的并且一式三份地分析。获得的平均直径、PDI和ζ电位的结果在表6中给出。
表6
杯芳烃纳米聚集体的平均流体动力学直径、多分散性指数(PDI)、ζ电位。
杯芳烃纳米颗粒的药物载量(%DL)的确定
为了确定负载到含有1mg/mL杯芳烃纳米颗粒的胶体溶液中的水飞蓟宾的量,将溶液的等分试样用甲醇稀释并通过HPLC分析。考虑到水飞蓟宾在288nm处的吸收带,测量药物的量。考虑到PBS中的水飞蓟宾在327nm处的带,还在UV分光计上测量药物的量。
发现关于%DL(以负载的活性成分的重量与负载的活性成分的重量+纳米颗粒的重量之间的百分比表示)获得的结果等于10%-11%。
在pH 7.4的PBS中,水飞蓟宾从杯芳烃NP中的释放
在体外、37℃下、孵育时间在0小时和12小时之间的范围内,通过透析研究水飞蓟宾在pH 7.4的磷酸盐缓冲液中的释放。所得的结果已经表明,该体系在12小时内缓慢释放药物最高达6.5%w/w的最大值(图8)。缓慢释放可能对在病理部位药物递送的目的有利。
负载水飞蓟宾的杯烷烃纳米颗粒在pH 7.4的PBS中的稳定性研究
通过将PBS中的胶体溶液保持在25℃来评估负载水飞蓟宾的杯芳烃纳米颗粒的稳定性。自制备起第7天和第14天的对照示出了尺寸、PDI和%DL值几乎没有变化(表10)。制剂的稳定性是重要的药理学(例如达到眼后部的病理部位)和工业化要求。
表10
杯芳烃纳米颗粒-水飞蓟宾胶体溶液在25℃下7天和14天后的稳定性。
在与水飞蓟宾缀合的杯芳烃-胆碱载体在ARPE-19细胞中的初步研究后,确定了浓度在0.01μM-1μM的范围内并孵育20小时的、游离的或与Slb缀合的载体不引起毒性。然后,使用化合物FeSO4作为氧化伤害,通过细胞氧化还原状态的变化测试缀合体系和空体系的影响。孵育超过24小时后,将细胞预处理20小时,并随后暴露于50μM FeSO4的伤害3小时[“预处理”20小时药物+3小时伤害]。进行的评价毒性和保护免受所研究的载体的损害的活力测试是用来评估培养基中LDH的释放。图9A示出了被50μM FeSO4伤害或不伤害的ARPE细胞中,与Slb缀合的载体(CalixSlb)、空载体(Calix)和单独的水飞蓟宾(Slb)的剂量曲线。注意,Slb降低LDH的释放,而Calix Slb和空Calix不显著改变ARPE-19细胞的LDH释放。相反,当细胞暴露于FeSO4(50μM)时,Calix Slb示出了降低LDH释放的良好潜力,该效果在单独用Calix和Slb处理的样品中未观察到。这些结果表明,calix和Slb可能一起使细胞准备好以防止氧化还原状态的变化。
在随后的实验中,测试了用基于杯芳烃的化合物后处理的效果。因此,细胞用50μMFeSO4处理5小时,并与各种化合物孵育20小时。如图9B中示出的,即使在后处理条件下,CalixSlb仍保护免受伤害,并且该作用被证实为单独地能够保护免受氧化还原状态改变的两种化合物的协同作用。
图10A示出了VEGF的蛋白质印迹分析,其示出了在用FeSO4伤害后可溶性VEGF表达水平的降低,此降低被空Calix、Slb和在1μM Calix Slb的浓度的Calix Slb消除。事实上,Calix Slb本身能够增加VEGF的水平。这些结果与Lin等人报道的观察结果一致:对于缺氧条件下的ARPRE细胞和用药物预处理的ARPRE细胞的VEGF分泌被抑制(Silibinin inhibitsVEGF secretion and age-related macular degeneration in a hypoxia-dependentmanner through the PI-3kinase/Akt/mTOR pathway CH Lin等人,(2013)BritishJournal of Pharmacology)。缺乏分泌导致缺乏不能充当(自分泌信号传导)自身调节物的游离VEGF,伴随血管发生过程的减少。
组织蛋白酶D是一种细胞内天冬氨酰蛋白酶,其在内质网中作为前酶原(pre-pro-enzyme)合成,被加工至产生活性片段。根据其所在的细胞环境,它可以通过不同机制诱导或抑制细胞凋亡。48kDa片段是一种活性中间体形式,从该活性中间体形式产生另外两个活性片段;因此,48kDa片段的降低与蛋白水解过程的活化相关,反之其升高表明了细胞凋亡的抑制。在氧化应激的存在下,组织蛋白酶D的活化可以活化胱天蛋白酶8,其反过来活化胱天蛋白酶3,导致细胞死亡(Regulatory role of cathepsin D in apoptosis,A.Minarowska等人,(2007)Folia Histochemica et Cytobiologica)(Caspase-8-mediated apoptosis induced by oxidative stress is independent of theintrinsic pathway and dependent on cathepsins H.K.Baumgartner等人,(2007)Am JPhysiol Gastrointest Liver Physiol.)。如在图10B中示出的,将细胞暴露于FeSO4导致组织蛋白酶D的48kDa条带的减少。用Calix或Slb后处理增加组织蛋白酶D的表达水平,但在用Calix Slb处理的样品中观察到该蛋白的更大的增加,证实了缀合物关于保护活性的潜在的效果,保护活性被检测为组织蛋白酶D参与其中的凋亡过程的抑制。
杯芳烃载体化合物(1)适于负载多种疏水性分子,作为本发明中的一个实例,除水飞蓟宾以外,它负载姜黄素和拉坦前列素。以上活性成分的特征在于低水溶性、易于化学降解和酶降解、低生物利用度。姜黄素和水飞蓟宾是在从炎症到癌症的多种状况中使用的天然物质,拉坦前列素是用于治疗青光眼(仍然是世界上不可逆转的失明的主要原因的状况)的前列腺素F2α类似物。
并且,对于这些活性成分,活性成分在纳米聚集体化合物(1)中的负载通过相溶解度法发生,药物载量≥10%。活性成分的剂量通过HPLC分析和UV分光光度法进行。
负载活性成分的纳米聚集体(化合物1)由DLS和ζ电位测量表征,其示出了纳米尺寸、多分散性指数和表面负载也适用于药物递送系统(表11)
表11
负载活性成分姜黄素或拉坦前列素的聚集体1的化学和物理化学特征
杯芳烃1将姜黄素以及水飞蓟宾在水性介质中的溶解度增加了至少10倍。
杯芳烃1在作为溶剂的PBS中保护姜黄素,其在0.1M PBS和无血清基质中、在30分钟内示出了80%-90%的降解。(图11)
在室温下超过6个月,杯芳烃1在作为溶剂的PBS中保护拉坦前列素免于降解(表12)。这是一个有趣的结果,因为它允许生产与目前市场上不同的创新制剂,将其从冷链中释放出来并且不含防腐剂。
表12
胶体杯芳烃-拉坦前列素溶液在PBS中、室温下、从制备起最高达4个月的稳定性:尺寸、pdi、拉坦前列素浓度
测试杯芳烃1、负载活性成分的杯芳烃和单独的活性成分的胶体溶液的细胞毒性:SIRC角膜细胞(图12)、J774巨噬细胞(图13)和ARPE视网膜细胞。结果示出了杯芳烃和杯芳烃-活性成分组合对所有测试的细胞类型具有良好的生物相容性。
在体外、在通过用LPS伤害而发生炎症应激的J774细胞上测试杯芳烃1、杯芳烃-姜黄素和单独的姜黄素的胶体溶液的抗炎活性。具体地,用浓度为10μg/mL的脂多糖(LPS)刺激J774细胞24小时,用LPS刺激诱导炎症过程的活化,诸如NFκB核转移和细胞因子产生,如果不同时释放亚硝酸盐和亚硝化应激。然后,在用LPS刺激(10μg/mL持续24小时)和用不同浓度的被研究的递送体系预处理2小时后,评价细胞活力。用LPS刺激后的细胞活力降低了50%,用被检查的物质诸如姜黄素、载体、和与姜黄素缔合的载体处理能够恢复细胞活力,几乎将其恢复到对照水平,除了已经显示对被伤害的细胞有毒性的较高浓度(图14)。然后通过蛋白质印迹分析来评价递送体系的抗炎活性。首先,观察到IκBα的降解(图15)和随之而来的NFκB向核转移(图16),这导致促炎性基因诸如编码细胞因子的那些的产生和活化。结果表明,用LPS刺激(10μg/mL持续30分钟)显著增加IκBα的降解和随后NFκB向核的转移(其水平显著增加,如可在图15中看到的)。相反,用递送系统预处理能够显著降低IκBα的降解和NFκB转移(图15)。NFκB活化涉及蛋白质和炎性介质诸如环加氧酶2(COX-2)和诱导型一氧化氮合酶(iNOS)的产生,从而导致亚硝酸盐的产生增加。通过蛋白质印迹分析,观察到用LPS刺激(10μg/mL持续24小时)显著增加了iNOS和COX-2二者的水平。用姜黄素、载体和与姜黄素缔合的载体预处理显著地并且以剂量-依赖的方式降低iNOS和COX-2的水平(图17)。
杯芳烃衍生物不仅作为载体实现其活性,还对受到LPS的炎性应激的巨噬细胞具有抗炎活性。进行的测试示出了以下抗炎活性:负载姜黄素的杯芳烃>>杯芳烃>>单独的姜黄素。
为了验证负载活性成分的杯芳烃体系对感兴趣的眼部位的有效性,用葡萄膜炎模型在体内进行实验。在160g-180g Lewis大鼠中,通过在后足单次皮下注射200μg在0.2mLpH 7.4的PBS中稀释的来自明尼苏达沙门氏菌(Salmonella Minnesota)的LPS内毒素诱导葡萄膜炎。对照组仅在后足上接受0.2mL PBS。将大鼠分为处理组(杯芳烃体系、杯芳烃-水飞蓟宾、单独的水飞蓟宾、杯芳烃-姜黄素和单独的姜黄素);在诱导葡萄膜炎前,通过局部施用进行预处理,持续三天,然后在处死的点,对于一些动物处死发生在注射内毒素后16小时,对于其他动物,处死发生在注射内毒素后72小时。摘除眼睛进行组织学和免疫组织化学分析。还取出房水用于蛋白质定量。
来自注射过LPS的动物的眼组织的组织学分析示出了伴随中性粒细胞的强渗透的严重葡萄膜炎的迹象。在仅用载体处理的动物中,炎症程度没有降低。用水飞蓟宾处理示出了降低但不显著的眼部炎症,而杯芳烃+水飞蓟宾组合的体系减少了损伤。
然而,用姜黄素,特别是杯芳烃+姜黄素组合处理显著减少了组织学损伤。在模拟组中未观察到眼部炎症。
而且,在16h和72h组之间没有观察到显著差异。以示例的方式,示出了总结为不同组在时间72小时记录的组织学得分的图(图18A)。在注射LPS后16小时和72小时,在注射了LPS的动物的房水中观察到升高的蛋白质水平。仅用载体处理不会导致眼组织中蛋白质水平的降低。水飞蓟宾处理的动物示出了趋势但不显著,而杯芳烃+水飞蓟宾体系组合显著降低了房水中蛋白质的水平。然而,姜黄素和杯芳烃+水飞蓟宾体系组合最有效地确定了眼组织中蛋白质的减少。在16小时和72小时采集的样品示出了所有实验组中类似的趋势,以示例的方式,示出了在时间72小时发现的各处理组的蛋白质剂量的图(图18B)。
为了验证负载拉坦前列素的杯芳烃体系的有效性,用通过巩膜静脉烧灼(EVC)在棕色挪威大鼠中诱导的高眼压模型建立体内实验。
通过滴注12μL/眼(左眼),每天进行一次治疗;对于含活性成分的载体体系的时程,实施方案包括单次施用治疗,在此期间在1小时、3小时、5小时、7小时、24小时、30小时和48小时后进行眼内压(IOP)的测量;和连续7天的长期施用,在此期间在下一次滴注前每24小时评价IOP测量。
对于每个形成的治疗组,其每一个由10只动物组成;将在不同时间点记录的平均IOP测量结果与之前计算的基线的平均值比较。图(图19A和19B)示出了与商购产品(IOPIZE)相比,用Calix+拉坦前列素治疗在时间过程的不同时间点单次施用之后(图19A)和持续七天的长期治疗(图19B)后的降低眼内压(IOP)的趋势。
对于两个治疗,在杯芳烃-拉坦前列素体系的情况和在产品IOPIZE的情况二者中,压力变化的趋势非常相似,在施用后紧接着第1个小时期间观察到拉坦前列素的自相矛盾的效果,并且由IOP的明显上升组成,文献中已知此效果在大鼠中常见(Latanoprost- induced changes in rat intraocular pressure: direct or indirect?Husain S等人JOcul Pharmacol Ther.(2008);Effects of latanoprost on rodent intraocular pressure.Husain S等人Exp Eye Res.(2006)),随后发生压力的逐渐降低,其在仅24小时后达到峰值,然后趋于升高。每24小时施用的长期治疗允许IOP的降低,其在使用杯芳烃-拉坦前列素体系的第4天左右达到其拐弯的最高点。与商购产品相比,杯芳烃体系提供了从冷链释放产品、不使用防腐剂配制产品同时保持活性成分的有效性的优势。
Claims (6)
1.水飞蓟宾或索拉非尼或姜黄素在制备用于眼部疾病的局部治疗的制剂中的用途,其中水飞蓟宾或索拉非尼或姜黄素被掺入到基于杯芳烃的纳米结构化体系中。
3.根据权利要求1或2所述的用途,其中所述眼部疾病是神经变性眼部疾病。
4.根据权利要求1或2所述的用途,其中所述基于杯芳烃的纳米结构化体系具有在50nm和200nm之间的范围内的平均直径和低于0.5的多分散性指数。
5.根据权利要求1或2所述的用途,其中所述体系掺入在1%w/w和15%w/w之间的范围内的量的水飞蓟宾或索拉非尼或姜黄素。
6.根据权利要求2所述的用途,其中所述神经变性眼部疾病选自:脉络膜新血管形成(CNV)、年龄相关性黄斑变性(AMD)、黄斑水肿、新血管性青光眼、黄斑水肿、早产儿视网膜病变(ROP)、糖尿病性视网膜病变(DR)、葡萄膜炎、眼内炎、视网膜炎、脉络膜炎、脉络膜视网膜炎、全身性疾病的视网膜并发症。
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