CN117582396A - 局部眼用制剂的用途 - Google Patents
局部眼用制剂的用途 Download PDFInfo
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- CN117582396A CN117582396A CN202311521053.3A CN202311521053A CN117582396A CN 117582396 A CN117582396 A CN 117582396A CN 202311521053 A CN202311521053 A CN 202311521053A CN 117582396 A CN117582396 A CN 117582396A
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- bosentan
- formulation
- topical ophthalmic
- diabetes
- retinal
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Abstract
本发明涉及局部眼用制剂的用途。更具体地,本发明涉及局部眼用制剂在制备用于预防和/或治疗由糖尿病和/或老龄化诱发的视网膜神经退行性病变的药物中的用途。本发明还涉及局部眼用制剂,该眼用制剂包含至少一种内皮素受体拮抗剂,该拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的组合,最优选波生坦。本发明还涉及局部眼用制剂用于预防和/或治疗由糖尿病和/或老龄化引起的视网膜神经退行性病变的用途,该眼用制剂包含作为活性成分的至少一种内皮素受体拮抗剂,该拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的组合,最优选波生坦。
Description
本申请是申请日为2016年3月22日,申请号为201680018617.3,发明名称为“内皮素受体拮抗剂的局部眼用制剂及其用途”的中国发明专利申请的分案申请。
技术领域
本发明涉及医药领域,并且涉及包含作为活性成分的至少一种内皮素受体拮抗剂的局部眼用制剂,该眼用制剂用于治疗由诸如糖尿病等代谢性疾病和/或老龄化引起的眼部疾病,该内皮素受体的拮抗剂优选地选自:西他生坦(sitaxentan)、安贝生坦(ambrisentan)、阿曲生坦(atrasentran)、波生坦(bosentan)、马西替坦(macitentan)和替唑生坦(tezosentan)或它们的混合物,更优选波生坦。
背景技术
糖尿病是一种慢性病,其以高血糖出现为特征,当身体失去产生足够胰岛素的能力或者失去有效地利用胰岛素的能力时就引起了高血糖。存在两种主要类型的糖尿病:1型和2型。2型糖尿病是通常发生于成年人的最常见类型的糖尿病,但也有越来越多的儿童和青少年病例。
世界范围内患有2型糖尿病的人数正在快速增长。这种增长与经济发展息息相关,这意味着老龄人口的增多和生活方式的改变(不健康的饮食和体力活动减少)。
糖尿病可以导致严重的后期并发症,该并发症分为微血管病变(视网膜病变、神经病变和糖尿病肾病变)和大血管病变(心血管疾病)。
糖尿病视网膜病变(DR)是最常见的糖尿病并发症,并且是发达国家的劳动年龄人口中视敏度下降及失明的主要原因。DR的发生率随着糖尿病发病的时间而升高。因此,90%的1型糖尿病患者和60%的2型糖尿病患者在糖尿病发病20年后都有一定程度的DR。如Yau等人,Meta-Analysis for Eye Disease(META-EYE)Study Group.Global prevalence andmajor risk factors of diabetic retinopathy,Diabetes Care,2012,35,556-64中所描述的,西方国家的DR患病率非常近似且在30%左右,并且10%的DR病例处于严重威胁到视力的晚期。
根据国际糖尿病联合会,Diabetes Atlas(第6版,2014)(http://www.idf.org/diabetesatlas),世界上糖尿病患者的数量会在未来几年呈指数增长:预计糖尿病患者将从2014年的3.87亿人增长至2035年的592,000,000人。因此,患有DR的患者数量也将平行地增长。
严格地控制血糖和血压对于预防和减缓DR发展至关重要。然而,治疗目标难以实现,并且较高比例的患者因此最终患上DR。
目前,针对DR的疗法诸如激光光凝、玻璃体内注射皮质类固醇或血管内皮生长因子的阻滞剂(抗VEGF:兰尼单抗(ranibizumab)、贝伐珠单抗(bevacizumab)、哌加他尼(pegaptanib)和阿柏西普(aflibercept))或者玻璃体视网膜手术都被建议用在非常晚期的疾病中,其效果有限且伴随有显著的副作用。因此,激光疗法会伴随着中度视力丧失、视野缩小、色视觉降低以及对比敏感度降低。玻璃体内注射涉及诸如感染、青光眼和白内障形成等副作用,并且,因为玻璃体内注射需要反复施用,所以副作用发生的风险倍增。抗VEGF剂除了导致局部副作用之外,由于其能够进入体循环,其还会导致全身性并发症。简言之,当前对DR的疗法仅仅适用在疾病的晚期阶段并且伴随有显著的副作用。
DR在传统意义上曾被认为是视网膜的微循环疾病。然而,如Lieth等人,Retinalneurodegeneration.Early pathology in diabetes,Clin.Exper.Ophthalmol.,2000,28:3-8中所描述的,基于神经生理学、心理测量学、组织病理学和生物化学的观察,有越来越多的证据表明视网膜神经退行性病变(retinal neurodegeneration)是DR发病机制中的早期事件,其参与发生在DR中的微循环异常。因此,在没有微血管改变的糖尿病供体的视网膜中检测到了视网膜神经退行性病变的主要特征(凋亡和神经胶质激活(glial activation))。临床上,视网膜神经退行性病变会产生诸如失去辨色力及失去对比敏感度等功能异常。在眼底检查中,这些变化都可以在观察到损伤前在糖尿病患者中检测到。
在综述文章Simó等人,Neurodegeneration in the diabetic eye:new insightsand therapeutic perspectives,Trends Endocrin.Metab.,2014,25,23-33中,公开了以神经保护为基础的疗法开辟了一种预防或阻止DR发展的新途径。此文章中描述了一些处于实验阶段的策略,但是暂时还没有支持这些治疗方法有效性和安全性的临床试验。
在Chou等人,Endothelin Receptor Antagonist-A Attenuates RetinalVascular and neuroretinal Pathology in Diabetic Mice,Invest.Ophthalmol.Vis.,2014,55,2516-2525的文章中,公开了口服阿曲生坦(一种内皮素1的ETA受体的选择性阻滞剂),并且在糖尿病小鼠中观察到了血管和神经视网膜并发症显著减少。这种口服施用的缺点是可能伴随全身性效应。此外,鉴于存在血视网膜屏障(blood-retinal barrier),需要高血清浓度以达到视网膜中的药理学浓度。
US2003/0176356描述了一种包含诸如波生坦等内皮素拮抗剂的药物组合物,但是该药物组合物却用于治疗不同的疾病(诸如青光眼)。该文件公开了尚未证明其可行性(viability)的常规制剂。的确,应用该常规制剂通常声称可以被用于任何内皮素的抑制剂,可是盖伦(galenical)实践已经表明,即使活性成分是属于相同的药物系列,针对特定活性成分开发的相同制剂并不适用于其他活性成分,因为活性成分分子结构中小的变化预示着其药物特征、化学特征和物理特征的改变。在这种情况下,可以说,该文章中所阐释的制剂在没有证明该制剂的正确制备下或者在没有证明该制剂用于眼药应用的活力下,不会允许获得稳定的解决方案并在时间上可行。
尽管现有技术中描述了解决方案,但是存在针对预防和/或治疗DR的新的药物疗法的持续需求,所述新的药物疗法避免全身治疗或者避免玻璃体内注射,以便使潜在的副作用最小化,并能够轻松且长期地施用。
发明内容
本发明的目的是一种局部眼用制剂在制备用于预防和/或治疗由糖尿病和/或老龄化引起的视网膜神经退行性病变的药物中的用途,该眼用制剂包含作为活性成分的至少一种内皮素受体拮抗剂,该内皮素受体拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物,更优选为波生坦;或者,本发明的目的是一种用于预防和/或治疗由糖尿病和/或老龄化引起的视网膜神经退行性病变的局部眼用制剂,该眼用制剂包含作为活性成分的至少一种内皮素受体拮抗剂,该内皮素受体拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物,更优选为波生坦;或者,本发明的目的是一种预防和/或治疗由糖尿病和/或老龄化引起的视网膜神经退行性病变的方法,该方法包括施用治疗有效量的局部眼用制剂,该眼用制剂包含作为活性成分的至少一种内皮素受体拮抗剂,该内皮素受体的拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物,更优选为波生坦。
本发明的另一目的是一种局部眼用制剂,该眼用制剂包含至少一种内皮素受体拮抗剂,该内皮素受体的拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物,更优选为波生坦。
具体实施方式
本发明的目的是一种局部眼用制剂在制备用于预防和/或治疗由糖尿病和/或老龄化引起的视网膜神经退行性病变的药物的用途,该眼用制剂包含作为活性成分的至少一种内皮素受体拮抗剂,该内皮素受体拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物,更优选为波生坦。
该发明进一步涉及一种用于预防和/或治疗由糖尿病和/或老龄化引起的视网膜神经退行性病变的局部眼用制剂,该眼用制剂包含作为活性成分的至少一种内皮素受体拮抗剂,该内皮素受体拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物,更优选为波生坦。
该发明还涉及一种治疗由糖尿病和/或老龄化引起的视网膜神经退行性病变的方法,该方法包括施用治疗有效量的局部眼用制剂,该眼用制剂包含作为活性成分的至少一种内皮素受体拮抗剂,该内皮素受体的拮抗剂根据本文公开的不同实施方式优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物,更优选为波生坦。
术语“治疗有效量”与本文公开的一种或多种活性化合物或组合物的量或者剂量有关,该量或者剂量会引发一种或多种期望的效果,特别是治疗效果。物质的有效量或者治疗有效量可以根据诸如个体的疾病状态、年龄、性别和体重等因素以及物质在该个体中引起期望响应的能力而变化。举例而言,可以施用几个每日分次剂量,或者可以根据治疗状况的紧急性而按比例减少剂量。
本发明的作者发现,令人惊奇的是,一种包含作为活性成分的至少一种内皮素受体拮抗剂(该内皮素受体的拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物,更优选为波生坦)的局部眼用制剂预防了由糖尿病引起的视网膜神经退行性病变,并且其适用于治疗所述神经退行性病变早期阶段的治疗。所述制剂允许活性成分渗入眼黏膜直至抵达视网膜,并在视网膜进行治疗。
尽管局部眼部途径不被认为是治疗DR的合适的给药途径——因为通过此途径施用的药物被认为不会抵达视网膜——但是,所进行的测试显示,本发明的制剂抵达视网膜并且预防视网膜的神经退行性病变。
在本说明书和权利要求书中,除非上下文中明确地以别的方式指出,单数形式的“一个或一种(a)”、“一个或一种(an)”和“该(所述)”包括复数指代。
在本说明书中,除非以别的方式指出,百分比以重量/体积(w/v)百分比表达。
视网膜神经退行性病变
从组织学观点来看,视网膜神经退行性病变是以胶质细胞激活(反应性胶质增生)和神经元(特别是神经节细胞层的神经元)凋亡为特征的。
如由Di Leo等人所著的Presence and further development of retinaldysfunction after 3-year follow up in IDDM patients without angiographicallydocumented vasculopathy,Diabetologia,1994,37,911-916和由Frost-Larsen等人所著的Value of electroretinography and dark adaptation as prognostic tools indiabetic retinopathy,Dev.Ophthalmol.,1981,2,222-234所公开的,视网膜神经退行性病变的主要临床表现为对比敏感度和视野缺陷以及暗适应困难。从临床观点来看,为了开展基于具有神经保护效果的药物的治疗,早期识别神经退行性病变是很重要的。
如前面引用的Simo等人的文章中所描述的,视网膜神经退行性病变的早期阶段可以通过使用频域光学相干断层成像(FD-OCT)或者多焦视网膜电图(mfERG)进行的眼部检查来检测。因为目前没有以神经保护为基础的DR治疗,所以这些针对DR诊断的扫描没有被包括在糖尿病患者定期进行的常规眼检查中。
优选地,局部眼用制剂的用途是用于预防和/或治疗由糖尿病引起的视网膜神经退行性病变,该眼用制剂包含至少一种内皮素受体拮抗剂,该内皮素受体的拮抗剂优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物,更优选为波生坦。
优选地,所述用途是用于预防和/或治疗由糖尿病和/或老龄化引起的视网膜神经退行性病变的早期阶段。
优选地,所述用途是用于预防和/或治疗由糖尿病引起的视网膜神经退行性病变的早期阶段。
局部眼用制剂
本发明的局部眼用制剂可以为液体、半固体或者固体药物形式。液体药物形态例如可以为溶液、悬浮液、流体乳剂、流体凝胶、微乳剂、纳米乳剂或者胶体体系。半固体药物形态例如可以为软膏、乳霜、油膏、胶凝剂或者糊剂。固体药物形式例如可以为眼部植入物、膏状药或者绷带。
在优选的实施方式中,局部眼用制剂为液体药物形式,更优选水溶液。
在进一步优选的实施方式中,局部眼用制剂是水溶液,其包含:
1)作为活性成分的波生坦,
2)药学上可接受的润湿溶剂和/或增溶剂,该润湿溶剂选自由聚乙二醇(PEG)、丙二醇、甘油及它们的混合物组成的组;该增溶剂选自由蓖麻油的聚氧乙烯化衍生物(polyoxyethylenated derivative)(它们可商购获得,例如由BASF供应的名为克列RH40)、聚氧乙烯化硬脂酸盐、聚乙二醇、聚山梨醇酯、泊洛沙姆(poloxamer)、甘油、中链C6-C10甘油三酯及它们的混合物组成的组;
3)药学上可接受的pH缓冲系统,以将水溶液调整在pH 3.5和10.5之间。
所述水溶液包括作为溶剂的水。
活性成分
本发明的活性成分为至少一种内皮素受体拮抗剂,优选地选自西他生坦、安贝生坦、阿曲生坦、波生坦、马西替坦和替唑生坦,或它们的混合物。
更优选地,本发明的制剂中,活性成分为4-(1,1-二甲基乙基)-N-[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)[2,2'-双嘧啶]苯磺酰胺,其对应于波生坦的国际通用名。
在由Hoffmann-La Roche的加拿大专利申请CA-A-2071193中描述了波生坦的制备,并且波生坦是一种内皮素受体拮抗剂,在医学上被用作抗高血压剂,特别是用于治疗肺动脉高血压。
在本发明的上下文中,术语“波生坦”是指波生坦、其水合物和盐,诸如一水合波生坦或者波生坦的钠盐。在本发明的制剂中,优选地使用一水合波生坦。
在本发明的制剂中,波生坦(被表示为波生坦)相对于该制剂的总体积通常是以0.1%到5%(w/v)之间,优选地0.2%到2%之间,甚至更优选地0.5%到1%之间存在。当以一水合物或其他水合物的形式,或者以钠盐或者其他盐的形式使用波生坦时,技术人员可以轻松地计算所对应的量。
在本发明的制剂中,活性成分被发现可以以微粒子、纳米粒子、脂质体或者囊泡(泡囊,niosomes)形式掺入。
在优选的实施方式中,本发明的制剂包含波生坦与另外的活性成分(例如,类固醇、前列腺素、生长因子、抗VEGF因子或者肽)的组合。优选地,波生坦与生长因子组合使用。
润湿溶剂
本发明的制剂包含药学上可接受的润湿溶剂,该润湿溶剂选自由聚乙二醇、丙二醇、甘油及它们的混合物组成的组。
在本发明的上下文中,润湿溶剂为一种具有溶剂性质和润湿性质的化合物。
其中之一为聚乙二醇(PEG),该名称指代由环氧乙烷(ethylene oxide)和水在催化剂存在下缩合而获得的具有不同分子量的一大族聚合物。这些聚合物的分子式可以表示为H(OCH2CH2)nOH,其中n表示氧乙烯基的平均数目。
由于PEG是一种对皮肤基本上无刺激的稳定化合物,所以PEG被广泛地使用在药物组合物中,包括肠胃外的、局部的、眼用的、口服的和直肠的制剂。此外,PEG是一种易溶于水的亲水化合物。
用于本发明制剂的合适的PEG可以具有300到35000、优选600到20000、更优选1000到8000、甚至更优选3000到6000以及还更优选约4000的分子量。不同的PEG通过伴随着术语PEG的数字来指代。因此,PEG 200意味着具有约为200平均分子量的PEG。根据分子量,PEG可以为液体或者固体。因此,具有高至800的平均分子量的PEG在室温下为液体,PEG 1000在温度为37℃到40℃之间熔化,PEG 4000在温度为50℃到58℃之间熔化。环氧乙烷含量越高,PEG的熔点就越高。
PEG可商购获得,例如由Dow Chemical Company(陶氏化学公司)供应的名为Carbowax的。
丙二醇为一种通过水解环氧丙烷而获得的透明、粘稠、无色和几乎无气味的液体。
甘油也是一种无色、透明、粘稠和几乎无气味的具有微甜味的液体。
在本发明的制剂中,PEG和/或丙二醇被用作润湿溶剂,更优选PEG 4000和/或丙二醇,还更优选PEG 4000。
在本发明的制剂中,润湿溶剂的含量通常是相对于制剂的总体积的1%到49%(w/v)之间,优选在5%到40%之间,更优选在10%到30%之间以及甚至更优选在15%到25%之间。
pH缓冲系统
本发明的制剂包含药学上可接受的缓冲系统,用于将水溶液的pH值调节在3.5到10.5之间,优选在4.0到8.5之间,更优选在6.0到8.2之间,更优选在7.0到8.1之间,以及甚至更优选在7.5到8.0之间。
用于获得这种pH的合适的缓冲系统可由本领域的技术人员从用于药物制剂的缓冲系统(诸如,柠檬酸/柠檬酸盐缓冲液、磷酸盐缓冲溶液、硼酸-硼酸盐缓冲溶液以及它们的混合物)中选择。所述缓冲系统可以包括氨基酸和/或胺化物质。
在本发明的制剂中,pH缓冲系统优选地选自由以下组成的缓冲系统:硼酸,甘氨酸和选自由氨丁三醇、精氨酸、赖氨酸、甲基葡萄糖胺以及它们的混合物组成的组中的胺,柠檬酸/柠檬酸盐系统和磷酸盐系统。优选地,pH缓冲系统由以下组成:硼酸,甘氨酸和选自由氨丁三醇、精氨酸、赖氨酸、甲基葡萄糖胺以及它们的混合物组成的组中的胺;或者柠檬酸/柠檬酸盐系统。更优选地,pH缓冲系统由以下组成:硼酸,甘氨酸和选自由氨丁三醇、精氨酸、赖氨酸、甲基葡萄糖胺以及它们的混合物组成的组中的胺;以及更优选地,pH缓冲系统由以下组成:硼酸、甘氨酸和氨丁三醇。
将pH调节至期望值所必需的pH缓冲系统的量对于本领域技术人员而言是不会带来任何困难的常见工作。对于由硼酸、甘氨酸和胺组成的pH缓冲系统而言,通常,硼酸的含量是相对于制剂的总体积的0.1%到10%(w/v)之间,更优选在0.5%到5%之间,以及还更优选在0.75%到1.5%之间;甘氨酸的含量是相对于制剂的总体积的0.5%到20%(w/v)之间,更优选在0.75%到10%之间,以及甚至更优选在1.5%到2.5%之间;并且胺的含量是相对于制剂的总体积的0.1%到25%(w/v)之间,优选在0.5%到10%之间,更优选在0.75%到5%之间,以及甚至更优选在1%到2.5%之间。
其他组分
本发明的局部眼用制剂可以包括其他组分,诸如,例如,表面活性剂、助溶剂、稠化剂、防腐剂、等张剂(isotonizing agent)、等渗剂(isoosmotizing agent)、活性成分的吸收促进剂、黏附聚合物(粘膜粘着聚合物,mucoadhesive polymer)、非黏附聚合物(非粘膜粘着聚合物)、螯合剂、稳定剂、抗氧化剂和它们的混合物。
在表面活性剂中,可以提及的例如有聚乙氧基甘油酯、聚山梨醇酯、泊洛沙姆、十二烷基硫酸钠、磷脂(诸如卵磷脂或者磷脂酰甘油及其衍生物)、聚氧乙烯化氢化蓖麻油(polyoxyethylenated hydrogenated castor oil)、聚氧乙烯化脂肪酸、(可选地,聚氧乙烯化的)脂肪酸的一酸甘油酯、二酸甘油酯和三酸甘油酯的混合物,和它们的混合物。
在助溶剂或者增溶剂中,可以提及的例如有蓖麻油的聚氧乙烯化衍生物(例如,可商购获得的由BASF供应的名为克列RH40)、聚氧乙烯化硬脂酸盐、聚乙二醇、聚山梨醇酯、泊洛沙姆、甘油、中链C6-C10甘油三酯和它们的混合物。
在稠化剂中,可以提及的例如有聚乙烯醇、甲基纤维素、羟丙基甲基纤维素、卡波姆(carbomers)、聚乙二醇和它们的混合物。
在防腐剂中,可以提及的例如有苯扎氯铵、硼酸、苯甲酸、对羟基苯甲酸的C1-C4烷基酯、氯丁醇、苯甲醇、苯乙醇、汞的有机金属衍生物、聚季铵盐(诸如聚季铵盐1),和它们的混合物。
在等张剂和等渗剂中,可以提及的例如有无机盐(诸如氯化钠)、右旋糖(葡萄糖)、海藻糖、甘露醇、氨基酸和它们的混合物。
在活性成分的吸收促进剂中,可以提及的例如有皂素、脂肪酸、脂肪酸的C1-C4烷基酯、吡咯烷酮、聚乙烯吡咯烷酮、丙酮酸、焦谷氨酸和它们的混合物。
在黏附聚合物中,可以提及的例如有透明质酸、聚半乳糖醛酸、聚丙烯酸、羧甲基淀粉、羧甲基甲壳素、硫酸软骨素、甲基纤维素、明胶(gelatine,胶质)、羟甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、黄原胶、壳聚糖、卡波普(carbopol,卡波姆/聚羧乙烯)、聚卡波非(polycarbophil)、结冷胶(gellan gum)、卡拉胶(carrageenan,角叉菜胶)、藻酸盐、胶质(果胶)、泊洛沙姆和它们的混合物。
在非黏附聚合物中,可以提及的例如有聚乙烯醇。
在螯合剂中,可以提及的例如有依地酸二钠(乙二胺四乙酸二钠)和色甘酸二钠(disodium cromoglucate)。
在活性成分的稳定剂中,可以提及的例如有柠檬酸、抗坏血酸、甘氨酸、精氨酸、赖氨酸和它们的混合物。
在抗氧化剂中,可以提及的例如有焦亚硫酸钠、亚硫酸氢钠、乙酰半胱氨酸、抗坏血酸和它们的混合物。
在胶凝剂中,可以提及的例如有卡波姆、甲基纤维素、羟丙基甲基纤维素、泊洛沙姆、聚丙烯酸、藻酸盐、壳聚糖、黄原胶、结冷胶、木葡聚糖(xyloglucan)和它们的混合物。
在用于乳剂和微乳剂的赋形剂中,可以提及的例如有脂肪酸酯和甘油、聚氧乙烯化的醇(polyoxyethylenated alcohols)、聚氧乙烯化脂肪酸、蓖麻油的聚氧乙烯化衍生物、中链C6-C10三酸甘油酯和它们混合物。
在用于软膏和乳霜的赋形剂中,可以提及的例如有石蜡、高分子量聚乙二醇、硅酮(硅氧烷,silicone)和它们的混合物。
用于制备微粒子、纳米粒子、脂质体或者囊泡的化合物例如是聚乳酸、乳酸-乙醇酸共聚物、聚苯乙烯、壳聚糖、清蛋白、明胶、凝集素、氰基丙烯酸酯、聚己内酯、甲基丙烯酸酯、聚丙烯酰胺、藻酸盐、葡聚糖、琼脂糖、聚氧乙烯山梨醇酐衍生物、胆固醇、聚乙氧基脂肪醇、磷酸二鲸蜡酯、卵磷脂和它们的混合物。
即使忽略上述防腐剂,本发明的眼用制剂也可以是无菌的。在这种情况下,无论是通过无菌制备、灭菌过滤,还是对最终制剂进行灭菌,本领域技术人员都可以根据最合适的制药技术来制备该制剂。
在优选的实施方式中,本发明的局部眼用制剂为水溶液,其包含:
1)0.1%到0.5%(w/v)之间、优选0.2%到2%之间以及更优选0.5%到1%之间的波生坦;
2)1%到49%(w/v)之间、优选5%到40%之间、更优选10%到30%之间以及还更优选15%到25%之间的润湿溶剂;所述润湿溶剂选自PEG和/或丙二醇,优选地选自PEG 4000和/或丙二醇;
3)0.1%到10%(w/v)之间、优选0.2%到5%之间以及更优选0.5%到1.5%之间的苯乙醇;
4)0.5%到20%(w/v)之间、优选0.75%到10%之间以及更优选1.5%到2.5%之间的甘氨酸;和
5)0.1%到25%(w/v)之间、优选0.5%到10%之间、更优选0.75%到5%之间以及还更优选1%到2.5%之间的胺;所述胺选自由氨丁三醇、精氨酸、赖氨酸、甲基葡萄糖胺和它们的混合物组成的组,优选氨丁三醇;
其中水溶液的pH被包含在3.5到10.5之间、优选在4.0到8.5之间、更优选在6.0到8.2之间、更优选在7.0到8.1之间以及甚至更优选在7.5到8.0之间;且其中百分比(w/v)是相对于制剂的总体积来表示的。在另外的更优选的实施方式中,本发明的制剂基本上由具有所反映的量并以水溶液形式的上述组分组成。
在另外优选的实施方式中,本发明的局部眼用制剂包含:
1)0.1%到0.5%(w/v)之间、优选0.2%到2%之间、更优选0.5%到1%之间的波生坦;
2)1%到49%(w/v)之间、优选5%到40%之间、更优选10%到30%之间以及还更优选15%到25%之间的增溶剂——蓖麻油的聚氧乙烯化衍生物,优选克列RH40;
3)0.5%到20%(w/v)之间、优选0.75%到10%之间、更优选1.5%到2.5%之间的甘氨酸;和
4)0.1%到25%(w/v)之间、优选0.5%到10%之间、更优选0.75%到5%之间以及还更优选1%到2.5%之间的胺;所述胺选自由氨丁三醇、精氨酸、赖氨酸、甲基葡萄糖胺和它们的混合物组成的组,优选氨丁三醇;
其中水溶液的pH被包含在3.5到10.5之间、优选在4.0到8.5之间、更优选在6.0到8.2之间、更优选在7.0到8.1之间以及甚至更优选在7.5到8.0之间;且其中百分比(w/v)是相对于制剂的总体积来表示的。
在另外优选的实施方式中,本发明的局部眼用制剂包含:
1)0.1%到0.5%(w/v)之间、优选0.2%到2%之间以及更优选0.5%到1%之间的波生坦;
2)1%到49%(w/v)之间、优选5%到40%之间、更优选10%到30%之间以及还更优选15%到25%之间的润湿溶剂;所述润湿溶剂选自PEG和/或丙二醇,优选地选自PEG 4000和/或丙二醇;
3)作为pH缓冲系统的柠檬酸/柠檬酸盐系统;
其中水溶液的pH被包含在3.5到10.5之间、优选在4.0到8.5之间、更优选在6.0到8.2之间、更优选在7.0到8.1之间以及甚至更优选在7.5到8.0之间;且其中百分比(w/v)是相对于制剂的总体积来表示的。在另外更优选的实施方式中,本发明的制剂基本上由具有所反映的量并以水溶液形式的上述组分组成。
制备方法
制备本发明制剂的方法是制药领域中的标准工序。
对于制备水溶液,该方法通常以在反应器中引入一部分水开始,然后于室温在搅拌下相继加入一种或多种润湿溶剂或者一种或多种增溶剂、pH缓冲系统的组分和活性成分。也可以将活性成分与pH缓冲系统的组分穿插加入以促进溶解。建议在每次加入后,搅动反应器内容物直到观察到所加入的组分完全溶解。
对于制备悬浮液、软膏、乳霜和乳剂以及选择合适的赋形剂,可以使用本领域技术人员熟知的公知常识或者制药技术手册,例如《雷明顿:药学的科学与实践》(Rmington:TheScience and Practice of Pharmacy,20th edition,Lippincott,Williams&Wilkins,Philadelphia,2000)或者在Souza等人,Topical ocular delivery of therapeutics:carrier systems and physical methods,J.Pharm.Pharmacol.,2013,66,507-530的综述文章中。
应用测定
如在实施例部分中具体公开的,将本发明的局部眼用制剂直接施用于糖尿病小鼠(db/db)的眼睛中。这些动物在编码瘦蛋白受体的基因中具有突变,并代表了肥胖引起的2型糖尿病的模型,例如在Duval等人Characterization of db/db mice for efficacy/safety pharmacology assessment of antidiabetic drugs,Safety PharmacologySociety Annual Meeting,Phoenix,2012中所描述的。
在14天的时期内施用本发明的制剂,每天两次,并在测试期之后,在用波生坦治疗的被治疗的动物的所有视网膜层中均观察到胶质激活较少且凋亡减少。
胶质激活(或者反应性胶质增生)是胶质细胞(神经元支持细胞)的炎症反应,其在存在损坏视网膜的病因(例如,糖尿病)时发生。经由凋亡的神经元死亡代表了视网膜神经退化过程的最后阶段。
这意味着局部施用波生坦预防了由糖尿病引起的视网膜神经炎症和神经元死亡。
令人惊奇的是,本发明的局部眼用制剂允许波生坦通过眼黏膜抵达视网膜,并且允许其发挥预防和/或治疗视网膜神经退行性病变的治疗效果。
为了阐释本发明,以下包括一些实施例,但是这些实施例不应当视为对本发明的限制。
实施例
用动物测定的相应数据以平均值±标准偏差表示。用配对和不对配的t检验(Student t-test)对连续变量进行比较。用费希尔精确检验(Fisher’s exact test)对分类变量进行比较。将统计显著性的水平设定为p<0.05。
实施例1:局部眼用制剂
在75mL的去离子水中,通过磁力搅拌溶解20g的克列 RH40,并保持搅拌直到完全溶解。然后,加入1.5g的氨丁三醇并搅拌15分钟,达到完全溶解。立刻加入相当于0.5g的波生坦的量的一水合波生坦,并保持搅拌15分钟,达到完全溶解。然后加入2g的甘氨酸和1g的硼酸,并保持搅拌直到完全溶解。
通过加入足够量的去离子水使该溶液的体积达到100mL。通过滤纸过滤溶液,获得pH为8.06的澄明、无色溶液。将溶液装入体积为5mL的滴眼滴管瓶中。
实施例2到7:眼用局部组合物
按照类似于实施例1的工序,制备如表1中描述的眼用局部组合物:
表1
组分的量用克表示,水的量指的是100mL。
在所有情形下,都获得了pH在5到8.5之间的澄明且无色的组合物。
实施例8到25:赋形剂组合
按照类似于实施例1的工序,制备如表2、3和4所描述的眼用局部组合物:
表2
表3
表4
实施例26到30:亲油性软膏
按照标准的工序,制备如表5中所描述的亲油性软膏形式的眼用局部组合物:
表5
实施例31到35:亲水性软膏
按照标准的工序,制备如表6中所描述的亲水性软膏形式的眼用局部组合物:
表6
实施例36到40:水凝胶
按照标准的工序,制备如表7中所描述的水凝胶形式的眼药局部组合物:
表7
实施例41:含有波生坦纳米粒子的眼用局部溶液
通过溶剂挥发(evaporation,蒸发)技术制备纳米粒子。
制备60mL乙酸乙酯中含有120mg PLGA 50:50的溶液。在涡轮搅拌下,在该溶液中掺入含有12mg一水合波生坦和0.5mg聚乙烯醇的50mL水的水溶液。使所得混合物处于连续搅拌和真空下2小时。然后,对所产生的制剂进行超高速离心并进行三次洗涤,以从介质中取出纳米粒子。
在真空炉中将纳米粒子干燥,并且在评估后,将对于0.5mg/100mL的浓度而言足够量的一水合波生坦分散在等渗的水溶液中。
实施例42:含有波生坦囊泡的眼用局部溶液
通过膜水合技术制备囊泡。
在含有10mL氯仿的圆底烧瓶中,将聚氧乙烯化单硬脂酸山梨醇酐酯和20摩尔的环氧乙烷、胆固醇和磷酸二鲸蜡酯以1:0.5:0.1的摩尔比混合。
该混合物在60℃和减压状况下被保持在转速为120rpm的旋转式蒸发器上,直到完全挥发(evaporation,蒸发)。
用pH为7.4的含有5mg一水合波生坦的12mL磷酸缓冲液对烧瓶中形成的膜进行水合。
囊泡悬浮液在4℃下保持冷却12小时,然后通过0.22μm尼龙过滤器进行过滤。
实施例43:用局部眼用制剂进行治疗
在测试中,使用了12只10周龄的雄性db/db小鼠(哈伦实验室公司,(HarlanLaboratories,Inc)),并将其分为两组:这些小鼠中的6只用本发明的制剂来治疗,6只小鼠用氯化钠溶液来治疗,如下所描述的。还使用了6只龄数相匹配的非糖尿病(db/+)小鼠作为对照组。
用注射器将一滴(5μl)实施例1的制剂或一滴载体(5μl的9%w/v氯化钠溶液)直接施用在12只db/db小鼠的每只眼睛的上部角膜表面上,每天两次,持续14天。
在第15天,在尸体剖检前大约1小时,将一滴本发明的制剂或者载体逐步灌入动物的眼中。在进行安乐死后,摘除眼睛。从其中一个眼睛提取神经视网膜,将神经视网膜冷冻在液氮中并储存在-80℃的温度下。将另外一只眼睛用4%的多聚甲醛溶液固定,进行常规处理并包埋在石蜡块中。
实施例44:胶质激活的确定
使用针对GFAP(胶质纤维酸性蛋白)的特异性抗体通过激光扫描共聚焦显微镜来评估胶质激活。在-20℃下,将视网膜切片在酸性甲醇中固定2分钟,紧接着用磷酸盐缓冲液(PBS)洗涤三次,每次5分钟。用含有0.025% X-100的tris缓冲液(TBS)将视网膜切片透化,并在室温下用由10% PBS中含有1% BSA(牛血清清蛋白)和10%羊血清组成的封闭溶液孵育2小时。在4℃和潮湿空气中,将视网膜切片与兔抗GFAP抗体(Abcam有限公司,剑桥,英国;在封闭溶液中按照1:500稀释制备)一起孵育过夜。用PBS溶液洗涤三次(每次5分钟)之后,将视网膜切片与用在封闭溶液中按照1:200稀释制备的二级抗体Alexa 488山羊抗兔(英杰(Invitrogen),加州圣地亚哥,美国)一起孵育。用PBS洗涤视网膜切片三次,用赫斯特(Hoechst)复染,用荧光封固剂(Mounting Medium Fluorescence)(Prolong,Invitrogen)封固,并用盖玻片封固。用奥林巴斯(Olympus)FluoView FV 1000激光扫描共聚焦显微镜,使用相同的亮度和对比度的设置拍摄样品的比较数字图像。
为了评估胶质激活的程度,使用在Anderson等人,Glial and endothelialblood-retinal barrier responses to amyloid-βin the neural retina of the rat,Clin.Ophthalmol.,2008,2,801-816中描述的基于GFAP染色程度的评分系统。该评分系统如下:
-得1分:仅仅米勒(Müller)细胞终足/神经节视网膜细胞层(GCL);
-得2分:米勒细胞终足区域/GCL加上少量近端突起(末端突起,proximalprocesses);
-得3分:米勒细胞终足加上许多突起,但没有延伸至视网膜的外核层(ONL);
-得4分:米勒细胞终足加上遍及ONL中的一些突起;
-得5分:米勒细胞终足加上从GCL到ONL外缘的大量暗突起。
对每只动物的视网膜且每个视网膜最少10个切片进行评估得分。
表8中显示了所示的三种动物(对照;用载体治疗的db/db;和用波生坦治疗的db/db)的胶质激活的程度(GFAP表达的每个得分的百分比):
表8
得分 | 对照(db/+) | 载体(db/db) | 波生坦(db/db) |
1 | 95 | 0 | 85 |
2 | 5 | 0 | 15 |
3 | 0 | 59 | 0 |
4 | 0 | 40 | 0 |
5 | 0 | 1 | 0 |
其显示,正如所预期的,在非糖尿病动物中,GFAP表达主要限制于神经节视网膜细胞层(GCL),因此GFAP得分≤2。
与龄数相匹配的非糖尿病小鼠相比,用载体治疗的糖尿病动物表现出显著的GFAP表达增加。因此,100%的糖尿病动物具有≥3的GFAP得分,这些糖尿病动物中有相当一部分(40%)的得分达到4。施用波生坦两周引起反应性胶质增生显著降低,并且在所有情况下用波生坦治疗的动物的GFAP得分都<3,其中大多数(85%)小于2。
因此,证明了本发明的制剂在降低胶质激活上的功效。
实施例45:用于评估凋亡的免疫组织化学分析
用DeadEnd荧光测定TUNEL系统试剂盒(普洛麦格(Promega),威斯康辛麦迪逊,美国)进行TUNEL(末端转移酶dUTP末端缺口标记)染色,以用免疫组织化学分析来评估凋亡。
通过用0.1% Triton X-100和0.1%柠檬酸钠的新鲜制备的溶液在冰上孵育2分钟使视网膜的冰冻切片透化。二级抗体为Alexa 488山羊抗兔(英杰,加州圣地亚哥,美国)。对于通过激光扫描共聚焦显微镜进行评估,激发波长为488nm,并在与绿色对应的515到565nm范围内进行检测。
对每只动物的视网膜且每个视网膜最少10个切片进行评估。
表9显示了对应于视网膜的不同层中的TUNEL染色阳性细胞的百分比的结果。每层视网膜(外核层,ONL;内核层,INL;神经节细胞层,GCL)百分比的平均值和标准偏差示于括号中:
表9
视网膜层 | 对照(db/+) | 载体(db/db) | 波生坦(db/db) |
ONL | 0.01(0.00) | 30.85(2.16) | 0(0.07) |
INL | 0.01(0.00) | 8.15(2.10) | 0.36(0.31) |
GCL | 0.01(0.00) | 36.49(5.46) | 1.42(0.38) |
这个表格中显示出,用本发明的制剂治疗的所有动物视网膜层中的凋亡率与对照动物(非糖尿病)的凋亡率相似,且显著低于用载体治疗的糖尿病动物。统计学显著性为p<0.001。
因此已经发现,持续两周给糖尿病动物施用本发明的制剂,导致显著地预防了所有视网膜层中的凋亡。
Claims (7)
1.一种局部眼用制剂在制备用于预防和/或治疗由糖尿病和/或老龄化诱发的视网膜神经退行性病变的药物中的用途,其中,所述局部眼用制剂包括:
1)0.1%到0.5%(w/v)之间的波生坦;
2)1%到49%(w/v)之间的蓖麻油聚氧乙烯化衍生物的增溶剂;
3)0.5%到20%(w/v)之间的甘氨酸;和
4)0.1%到25%(w/v)之间的胺,所述胺选自由氨丁三醇、精氨酸、赖氨酸、甲基葡萄糖胺及其混合物组成的组;
其中,百分比(w/v)是相对于所述制剂的总体积来表示的,
其中所述制剂是水溶液,
其中所述水溶液的pH被包括在3.5到10.5之间,
其中所述制剂不包括防腐剂,并且
其中所述制剂被直接局部施用于有需要的受试者的眼睛。
2.根据权利要求1所述的局部眼用制剂的用途,其中所述局部眼用制剂还包括0.1%到10%(w/v)之间的硼酸。
3.根据权利要求2中所述的局部眼用制剂的用途,其中所述胺为氨丁三醇。
4.根据权利要求1-3中任一项所述的局部眼用制剂的用途,其中,所述波生坦以微粒子、纳米粒子、脂质体或者囊泡的形式加入。
5.根据权利要求4所述的用途,用于预防和/或治疗由糖尿病和/或老龄化诱发的早期阶段的视网膜神经退行性病变。
6.根据权利要求4所述的用途,用于预防和/或治疗由糖尿病诱发的视网膜神经退行性病变。
7.根据权利要求5所述的用途,用于预防和/或治疗由糖尿病诱发的早期阶段的视网膜神经退行性病变。
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RU2086544C1 (ru) | 1991-06-13 | 1997-08-10 | Хоффманн-Ля Рош АГ | Бензолсульфонамидные производные пиримидина или их соли, фармацевтическая композиция для лечения заболеваний, связанных с активностью эндотелина |
US6770675B2 (en) * | 1997-03-17 | 2004-08-03 | Novartis Ag | Compositions and methods for reducing ocular hypertension |
US20030176356A1 (en) * | 2001-04-24 | 2003-09-18 | University Of North Texas Health Science Center | Endothelin antagonists and endothelin-converting enzyme inhibitors for the treatment of glaucoma |
JP4725699B2 (ja) * | 2002-04-08 | 2011-07-13 | ライオン株式会社 | 眼科用組成物及び眼科用組成物配合用防腐剤 |
HUE055815T2 (hu) * | 2007-10-05 | 2021-12-28 | Univ Wayne State | Vegyületek nyújtott felszabadítására alkalmas dendrimerek |
EP2564853B1 (en) * | 2007-12-04 | 2019-02-27 | Santen SAS | Compositions comprising corticosteroid prodrug such as dexamethasone palmitate for the treatment of eye disorders |
US8821870B2 (en) * | 2008-07-18 | 2014-09-02 | Allergan, Inc. | Method for treating atrophic age related macular degeneration |
LT2493474T (lt) * | 2009-10-30 | 2019-10-10 | Intratus, Inc. | Būdai ir kompozicijos prolonguotam vaistų įvedimui |
FR2961694B1 (fr) * | 2010-06-29 | 2013-01-25 | Thea Lab | Systeme de delivrance polymerique d'une solution non visqueuse a base de prostaglandine sans conservateur |
EP2567689A1 (en) * | 2011-09-12 | 2013-03-13 | Visiotact Pharma | Ophthtalmic compositions comprising prostaglandin F2 alpha derivatives and hyaluronic acid |
RU2015143521A (ru) * | 2013-03-13 | 2017-04-19 | Илэвэн Байотерапьютикс, Инк. | Лекарственные формы химерных цитокинов для глазной доставки |
TR201808197T4 (tr) * | 2013-03-14 | 2018-07-23 | Eyecro Llc | Mikroemülsiyon topikal dağıtım platformu. |
BR112016027379A2 (pt) * | 2014-05-23 | 2018-06-26 | Ocular Tech Sarl | formulações tópicas e seus usos |
-
2015
- 2015-03-27 ES ES201530409A patent/ES2584534B1/es active Active
-
2016
- 2016-03-22 US US15/561,922 patent/US10716750B2/en active Active
- 2016-03-22 MX MX2017012428A patent/MX2017012428A/es unknown
- 2016-03-22 CN CN201680018617.3A patent/CN107454841A/zh active Pending
- 2016-03-22 EP EP16720451.0A patent/EP3275429A1/en active Pending
- 2016-03-22 WO PCT/ES2016/070197 patent/WO2016156639A1/es active Application Filing
- 2016-03-22 KR KR1020177027527A patent/KR102578102B1/ko active IP Right Grant
- 2016-03-22 CN CN202311521053.3A patent/CN117582396A/zh active Pending
- 2016-03-22 JP JP2018500867A patent/JP6768780B2/ja active Active
- 2016-03-22 BR BR112017019792A patent/BR112017019792A2/pt not_active Application Discontinuation
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JP2018512452A (ja) | 2018-05-17 |
US10716750B2 (en) | 2020-07-21 |
BR112017019792A2 (pt) | 2018-05-22 |
MX2017012428A (es) | 2018-06-19 |
KR102578102B1 (ko) | 2023-09-13 |
KR20170130443A (ko) | 2017-11-28 |
EP3275429A1 (en) | 2018-01-31 |
CN107454841A (zh) | 2017-12-08 |
ES2584534B1 (es) | 2017-03-13 |
ES2584534A1 (es) | 2016-09-28 |
WO2016156639A1 (es) | 2016-10-06 |
JP6768780B2 (ja) | 2020-10-14 |
US20180110728A1 (en) | 2018-04-26 |
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