CN115867264A - 局部眼科组合物和治疗异常血管新生的方法 - Google Patents
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- CN115867264A CN115867264A CN202180047734.3A CN202180047734A CN115867264A CN 115867264 A CN115867264 A CN 115867264A CN 202180047734 A CN202180047734 A CN 202180047734A CN 115867264 A CN115867264 A CN 115867264A
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Abstract
一种局部眼科组合物,其包括作为活性药物成分的多激酶抑制剂和作为液体载剂的全氟己基辛烷(F6H8)。所述多激酶抑制剂抑制血管内皮生长因子受体(VEGFR)。一种治疗眼科病症的方法,其包括:提供含有约0.01‑10%(w/v)的浓度的多激酶抑制剂的局部眼科组合物;并且用所述局部眼科组合物治疗患者以治疗所述眼科病症。
Description
本申请要求2020年6月1日提交的US临时申请号63/032,920的优先权,所述临时申请出于如同完全阐述于本文中的所有目的以引用方式并入。
技术领域
本发明涉及局部眼科组合物以及治疗异常血管新生和纤维化的方法,更具体而言,局部眼科组合物包括作为活性药物成分的多激酶抑制剂和作为液体载剂的全氟己基辛烷(F6H8或CF3(CF2)5(CH2)7CH3),以及治疗具有异常血管新生的眼科病症的方法。
背景技术
多激酶抑制剂是抑制多种激酶的分子。它们往往被用于癌症治疗。这些抑制剂中的许多者靶向酪氨酸激酶受体,诸如血管内皮生长因子受体(VEGFR)。靶向VEGFR的抑制剂可抑制在病情下的新血管形成或异常血管形成。这些抑制剂也以各种效力抑制在血管维护中有作用的血小板源性生长因子受体(PDGFR)。这些抑制剂靶向的另一个激酶家族是可在成纤维细胞生长和纤维化中有作用的成纤维细胞生长因子受体(FGFR)。具有这类靶标特性的抑制剂可用于治疗具有异常血管新生或多血管的疾病,包括许多眼部疾病。它们也可用于治疗具有异常纤维化的疾病。
多激酶抑制剂众所周知是在水或水基载剂中具有非常低溶解度的高度疏水的小分子。因此,需要开发制剂以将足够浓度的多激酶抑制剂递送至靶标部位来实现期望的药理效果。
发明内容
在一个实施方案中,局部眼科组合物包括作为活性药物成分的多激酶抑制剂和作为液体载剂的全氟己基辛烷(F6H8)。多激酶抑制剂抑制血管内皮生长因子受体(VEGFR)。
在另一个实施方案中,多激酶抑制剂抑制VEGFR和成纤维细胞生长因子受体(FGFR)。
在另一个实施方案中,多激酶抑制剂选自由阿西替尼(axitinib)、瑞格菲尼(regorafenib)、帕唑帕尼(pazopanib)、尼达尼布(nintedanib)和其药学上可接受的盐组成的组。
在另一个实施方案中,多激酶抑制剂具有约0.01-0.1%(w/v)、约0.1-1%(w/v)、约1-10%(w/v)、约1.5%-5%(w/v)、约1.5%(w/v)、约2%(w/v)、约2.5%(w/v)、约3%(w/v)、约3.5%(w/v)、约4%(w/v)、约4.5%(w/v)、约5%(w/v)、约6%(w/v)、约7%(w/v)、约8%(w/v)、约9%(w/v)或约9%(w/v)的浓度。
在另一个实施方案中,局部眼科组合物是悬浮液、溶液或乳液的非水基制剂。
在另一个实施方案中,液体载剂不含水。
在另一个实施方案中,局部眼科组合物还包括选自由乙醇、异丙醇、甘油、丙二醇和聚乙二醇组成的组的有机潜溶剂。
在另一个实施方案中,局部眼科组合物由作为活性药物成分的多激酶抑制剂和作为液体载剂的全氟己基辛烷(F6H8)组成。多激酶抑制剂抑制血管内皮生长因子受体(VEGFR)。
在另一个实施方案中,多激酶抑制剂抑制VEGFR和成纤维细胞生长因子受体(FGFR)。
在另一个实施方案中,多激酶抑制剂选自由阿西替尼、瑞格菲尼、帕唑帕尼、尼达尼布和其药学上可接受的盐组成的组。
在另一个实施方案中,多激酶抑制剂具有约0.01-0.1%(w/v)、约0.1-1%(w/v)、约1-10%(w/v)、约1.5%-5%(w/v)、约1.5%(w/v)、约2%(w/v)、约2.5%(w/v)、约3%(w/v)、约3.5%(w/v)、约4%(w/v)、约4.5%(w/v)、约5%(w/v)、约6%(w/v)、约7%(w/v)、约8%(w/v)、约9%(w/v)或约9%(w/v)的浓度。
在另一个实施方案中,治疗眼科病症的方法包括:提供含有约1-10%(w/v)的浓度的多激酶抑制剂的局部眼科组合物;并且用局部眼科组合物治疗患者以治疗眼科病症。多激酶抑制剂抑制血管内皮生长因子受体(VEGFR)。
在另一个实施方案中,多激酶抑制剂抑制VEGFR和成纤维细胞生长因子受体(FGFR)。
在另一个实施方案中,多激酶抑制剂选自由阿西替尼、瑞格菲尼、帕唑帕尼、尼达尼布和其药学上可接受的盐组成的组。
在另一个实施方案中,多激酶抑制剂具有约0.01-0.1%(w/v)、约0.1-1%(w/v)、约1-10%(w/v)、约1.5%-5%(w/v)、约1.5%(w/v)、约2%(w/v)、约2.5%(w/v)、约3%(w/v)、约3.5%(w/v)、约4%(w/v)、约4.5%(w/v)、约5%(w/v)、约6%(w/v)、约7%(w/v)、约8%(w/v)、约9%(w/v)或约9%(w/v)的浓度。
在另一个实施方案中,局部眼科组合物是悬浮液、溶液或乳液的非水基制剂,并且包括全氟己基辛烷(F6H8)作为液体载剂。优选地,F6H8是仅有的液体载剂,并且液体载剂不含水。
在另一个实施方案中,眼科病症选自由以下组成的组:青光眼手术失败,微创青光眼手术失败,新生血管性青光眼,睑板腺功能障碍,干眼病,斯耶格伦(Sjogren)氏综合征,碱烧伤,溃疡,移植物抗宿主病,特应性结膜炎,眼红斑痤疮,瘢痕性类天疱疮,干细胞缺乏,莱尔(Lyell)氏综合征,斯蒂文约翰逊(Steven Johnson)综合征,病毒、细菌、真菌,翼状胬肉,结膜黄斑,角膜移植感染,角膜寄生虫感染,和隐形眼镜诱发的血管再生。
在另一个实施方案中,青光眼手术失败起因于经典小梁切除术、小梁消融术、前房角镜辅助的经腔小梁切开术、准分子激光小梁造瘘术和内窥镜睫状体光凝术;微创青光眼手术失败起因于植入眼滤过器件。
在另一个实施方案中,微创青光眼手术中使用的眼滤过器件选自由结膜下支架、巩膜静脉窦支架和脉络膜上支架组成的组。
应理解,前文的概述和下文的实施方式仅为示例性和解释性的,并意欲提供对所要求的本发明的进一步解释。
附图简要说明
被包括以提供对本发明的进一步理解并且并入本说明书并构成说明书一部分的附图示出了本发明的实施方案,并且与描述一起用来解释本发明的原理。
在附图中:
图1示出组1-组4的成纤维细胞密度评分。组1:载剂对照;组2:MMC阳性对照;组3:第7天至第30天0.3%尼达尼布处理;组4:第1天至第30天0.3%尼达尼布。
具体实施方式
现将详细地提及本发明的实施方案,其实例示于附图中。
多激酶抑制剂(MKI)指的是抑制两种或更多种激酶(包括例如细胞内和/或细胞表面酪氨酸蛋白激酶)的活性的药物化合物(例如小分子)。“小分子”被理解为指代具有小于2,000道尔顿的分子量的化合物。优选这些小分子是有机分子。在某些实施方案中,“小分子”不包括肽或核酸分子。
用于本文所述方法中的示例性多激酶抑制剂展现某些激酶抑制特性,例如多激酶抑制剂具有针对VEGFR(1、2、3)(IC50<100nM)、PDGFRα(IC50<1000nM)和FGFR1(IC50<500nM)的体外IC50的激酶抑制特性。用于本文所述的方法中的示例性多激酶抑制剂包括例如阿法替尼(afatinib)、阿姆伐替尼(amuvatinib)、阿西替尼、卡博替尼(cabozantinib)、卡奈替尼(canertinib)、西地尼布(cediranib)、色瑞替尼(ceritinib)、克莱拉尼(crenolanib)、克唑替尼(crizotinib)、达拉非尼(dabrafenib)、达可替尼(dacomitinib)、达沙替尼(dasatinib)、埃罗替尼(erlotinib)、福瑞替尼(foretinib)、吉非替尼(gefitinib)、戈伐替尼(golvatinib)、依鲁替尼(ibrutinib)、埃克替尼(icotinib)、艾代拉里斯(idelalisib)、伊马替尼(imatinib)、拉帕替尼(lapatinib)、乐伐替尼(lenvatinib)、来那替尼(neratinib)、尼罗替尼(nilotinib)、尼达尼布、帕博西尼(palbociclib)、帕唑帕尼、帕纳替尼(ponatinib)、奎扎替尼(quizartinib)、瑞格菲尼、鲁索替尼(ruxolitinib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、坦度替尼(tandutinib)、替万替尼(tivantinib)、替沃扎尼(tivozanib)、曲美替尼(trametinib)、凡德他尼(vandetanib)、瓦他拉尼(vatalanib)和维罗非尼(vemurafenib);优选阿西替尼、尼达尼布、帕唑帕尼、西地尼布、瑞格菲尼、帕纳替尼、乐伐替尼;且更优选阿西替尼、尼达尼布、帕唑帕尼和瑞格菲尼。优选的例示激酶抑制剂的结构和体外效力示于下方和表1中。
表1.所选激酶抑制剂对关键受体的体外效力
MKI通常被用于治疗癌症。机制是抑制癌症部位的血管新生/血管形成和使癌症组织的营养素供应缺乏而使其生长退行。该机制可适用于具有异常多血管的其他疾病。如此处所列举实例的一些MKI也可抑制FGFR,并且有潜能治疗具有异常纤维化的疾病。本文所描述的组合物和方法可用于治疗患有涉及异常血管新生/多血管或纤维化或两者的在眼睛前部的眼部疾病的患者。
例如,本发明提供使用诸如瑞格菲尼的MKI的所列举实例中的一者的组合物和治疗方法,通过向需要这种治疗的受试者的眼睛施用,而改进青光眼手术(例如青光眼滤过手术)的成功率。一个方面的特征为在受试者中与青光眼手术相关联的辅助治疗的方法,包括向有需要的受试者施用有效量的包含瑞格菲尼或其药学上可接受的盐的组合物。该方法提高了青光眼手术的成功率。青光眼手术包括例如经典小梁切除术法,或选自由小梁消融术、前房角镜辅助的经腔小梁切除术、准分子激光小梁造瘘术和内窥镜睫状体光凝术组成的组的方法。进行的青光眼手术也可用于植入眼滤过器件,其中眼滤过器件是眼支架。例如,眼滤过器件可选自由iStent、Xen凝胶支架、Hydrus和CyPass微支架组成的组。
在另一个方面中,所公开方法通过减弱手术部位的异常多血管和纤维化来减少青光眼手术中的瘢痕形成。在某些方面中,在手术前、与手术结合或在手术后进行所公开的方法以减少青光眼手术的失败。在一些方面中,所施用瑞格菲尼的量有效地使降低眼内压(IOP)的持续时间在手术之后延长至少10天、至少365天或至少3650天。在一些方面中,所施用瑞格菲尼的量有效地延长了滤过泡存活。
材料、方法和实例仅为例示性的而非意图有所限制。
总之,过量多血管和纤维化是导致青光眼手术中过量瘢痕化和失败的关键风险因素。本发明提供利用了抗血管新生和抗纤维化机制的组合物和方法来提高青光眼手术的成功率。
MKI众所周知是在水或水基载剂中具有非常低溶解度的高度疏水的小分子。例如,在中性pH下阿西替尼具有于水中仅0.2mg/ml的溶解度。因而它们难以配制成用于眼部使用的稳定滴眼剂组合物。本发明提供了使用由全氟己基辛烷(F6H8)作为液体载剂组成的稳定制剂中的MKI的组合物和治疗方法,用于治疗具有异常多血管和/或纤维化的眼部疾病。全氟己基辛烷(F6H8)是具有共价结合的两个互不混溶部分(烃段和全氟化段)的两亲性液体。在本发明的组合物中使用的其他相关类似物可为全氟丁基戊烷(F4H5)、全氟丁基己烷(F4H6)、全氟己基丁烷(F6H4)、全氟己基己烷(F6H6)、全氟己基辛烷(F6H8)和全氟己基癸烷(F6H10),优选全氟丁基戊烷(F4H5)、全氟己基己烷(F6H6)和全氟己基辛烷(F6H8),更优选全氟己基辛烷(F6H8)。
F6H8的结构示于下方。
在一些实施方案中,本发明是基于实例中所描述的研究,这些实例显示使用F6H8中配制的瑞格菲尼是治疗本发明中列举的眼部指征的优选的选择。更明确而言,选择该组合以降低青光眼手术的失败率。
实施例1描述了开发尼达尼布的水基制剂所作出的努力。尼达尼布高度不溶于水,报道溶解度低于0.01mg/mL(即0.001%)。测试了各种水基制剂载体和它们的组合以设法将尼达尼布配制为合理高的浓度。因此,发现了能够保持0.3%尼达尼布,具有良好长期稳定性的水基乳液制剂。实施例2描述了在家兔青光眼滤过手术模型中测试于乳液制剂中的0.3%尼达尼布。然而,在该实施例中,发现该制剂不能向手术部位递送足够的药物以具有防止滤过泡失败的预期效果。同时,检测了疗效信号,显示该制剂降低了成纤维细胞密度。因为纤维化是手术成功的失败中的关键步骤,该实施例指示了如果可用更有效的载剂将更多尼达尼布递送至手术部位,则可实现预期的疗效。
因为更高浓度的尼达尼布可能导致有害的副作用,诸如临床中观察到因尼达尼布分子的黄颜色所致的黄色结膜变色,选择了具有与尼达尼布类似的药理特性的无色化合物瑞格菲尼用于进一步的制剂开发和体内动物模型测试。进行了进一步实验以评估各种溶剂,来判定哪种溶剂将对于瑞格菲尼形成局部眼用的高得多浓度的制剂是最好的。在实施例3中,在受测试的所有溶剂之中,F6H8是非水基载剂的优选,以将瑞格菲尼配制成例如约0.01-0.1%(w/v)或约0.1-1%(w/v),优选约1-10%(w/v)、约1.5%-5%(w/v)或约1.5%(w/v)的高浓度,更优选约2%(w/v)、约2.5%(w/v)、约3%(w/v)、约3.5%(w/v)、约4%(w/v)、约4.5%(w/v)、约5%(w/v)、约6%(w/v)、约7%(w/v)、约8%(w/v)、约9%(w/v)或约9%(w/v)。在实施例4中,于F6H8中的2%瑞格菲尼制剂的思考实验将改进狗模型中青光眼手术的成功率。用F6H8配制的MKI的组合物的本公开是将足够浓度多激酶抑制剂递送至靶标部位以实现期望的药理效果的新颖使用。
实施例
实施例1:多激酶抑制剂的乳液制剂
根据以下程序研究了尼达尼布的制剂:
1.扣除1.5mL Eppendorf管的皮重,
2.添加尼达尼布并记录重量,
3.添加增溶剂并记录重量,
4.添加pH 5的水(除了F3和F4)并记录重量,
5.珠磨机混合120秒,
6.置于转动搅拌器上在环境温度下过夜,
7.经过0.2μm SPIN-X离心滤器过滤,
8.测量滤出液的pH,
9.使用CBT-001标准溶液分析滤出液。
尽管所研究增溶剂中的许多者具有类似的结构性质,但对于所研究增溶剂获得了截然不同的结果(参见例如表2和表3)。发现了诸如蓖麻油和聚山梨醇酯80的增溶剂被发现具有针对尼达尼布的高溶解性能。
表2.所筛选组合物(重量%)
重量% | F-1 | F-2 | F-3 | F-4 | F-5 | F-6 | F-7 | F-8 | F-9 | F-10 | F-11 | F-12 |
尼达尼布 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
苄醇 | 1 | |||||||||||
乙醇 | 1 | |||||||||||
蓖麻油 | 99.5 | |||||||||||
矿物油 | 99.5 | |||||||||||
BZK | 1 | |||||||||||
聚山梨醇酯20 | 1 | |||||||||||
聚山梨醇酯80 | 1 | |||||||||||
泊洛沙姆188 | 1 | |||||||||||
泊洛沙姆407 | 1 | |||||||||||
PEG400 | 5 | |||||||||||
PEG8000 | 2 | |||||||||||
丙二醇 | 1 | |||||||||||
WFI | 98.5 | 98.5 | 98.5 | 98.5 | 98.5 | 98.5 | 98.5 | 94.5 | 97.5 | 98.5 |
表3.尼达尼布于各种增溶剂中的溶解度
基于增溶剂结果,各种水基乳液体系被识别以用于研究。发现组合了蓖麻油、聚山梨醇酯80和聚氧乙烯35蓖麻油的水基乳液体系可合适地溶解尼达尼布。如表4中所示,乳液体系中的一者可使尼达尼布溶解至约3-5mg/ml,即0.3%-0.5%的眼科乳液浓度。
表4.尼达尼布于代表性乳液体系中的溶解度
ID | F70批1 | F70批2 |
蓖麻油 | 1 | 1 |
聚山梨醇酯80 | 1 | 1 |
聚氧乙烯35蓖麻油 | 2 | 2 |
水 | 95 | 95 |
尼达尼布溶解度(mg/ml) | 5 | 3.4 |
实施例2:尼达尼布的家兔青光眼滤过手术模型研究
在该实施例中,在家兔青光眼滤过手术模型中测试了0.3%尼达尼布乳液。尼达尼布是可抑制血管新生和纤维化的四种MKI实例中的一者。研究显示出对成纤维细胞密度而非滤过泡存活的阳性疗效信号,表明需要更高的药物含量以潜在可用于实际青光眼手术中。
方法
模型建立:如先前所述地建立青光眼滤过手术模型(Cordeiro等人,1997;Zhong等人,2011)。
阴性对照:从第前7天至第30天载剂BID给药(组1)。
阳性对照:在手术期间丝裂霉素C(MMC)持续5min(组2)。
测试品:从第前7天至第30天(组3)和从第1天至第30天(组4)BID给药的0.3%CBT-001(尼达尼布)。
测量法:IOP,滤过泡评分,成纤维细胞密度组织学,纤维化染色和炎症水平。
时间点:手术后第2、4、7、10、14、21和30天。
动物:24只雌性新西兰白兔(每组6只)。
研究设计示于下表5中。
表5:研究设计
OU=双眼,OD=右眼,OS=左眼,IOP=眼内压,OE=眼部检查,H&E=苏木精和伊红染色,PK=药物动力学
结果和结论
在所有测量法之中,仅成纤维细胞密度显示出疗效信号。结果示于图3中。在组4(用尼达尼布处理30天)中观察到成纤维细胞密度显著降低。在组3(从第前7天至第30天用尼达尼布处理)中也见到非统计学显著的降低趋势。两个处理组中未显示出主要疗效终点、滤过泡存活与载剂对照的任何差异。
从结果推断0.3%尼达尼布乳液在改进滤过泡存活上无效。然而,在成纤维细胞密度中检测到疗效信号。进一步推断当前的0.3%制剂未向手术部位递送足够的药物,但多激酶抑制剂减少青光眼手术失败的机制是有根据的。结果指示如果足够的量可被递送至手术部位,如尼达尼布的具有靶标药理特性的MKI将具有疗效。
实施例3:将瑞格菲尼配制成具有2%浓度的非水基滴眼剂
在该实施例中,进行了实验将瑞格菲尼配制成例如2%的高浓度以用于局部眼用。F6H8被识别为最适合于该目的的非水基载剂。
将400mg的微粒化瑞格菲尼一水合物悬浮于20ml全氟己基辛烷(F6H8)中。通过在室温下搅拌15分钟使悬浮液均化。所测瑞格菲尼浓度为理论浓度的95.4-99.1%。观测到的波动最可能由于在手摇悬浮液后样品的不均匀性。使用下文所述的HPLC法在色谱图中未观测到未识别的降解产物。
测定瑞格菲尼浓度的HPLC法如下:通过用水:乙腈(25/75)将所吸制剂等分试样稀释至100ug/ml的瑞格菲尼终浓度来制备样品。将100的每种样品注入Agilent 1100HPLC系统(Agilent,德国瓦尔德布龙),并且应用1ml/min的流速,在加热(40℃)的Symmetry C18柱(150×4.6mm-粒度3.5um,Waters,德国埃施伯恩)上运行样品。移动相由磷酸钾缓冲液pH2.4(A)和乙腈/乙醇(6/4)(B)的混合物组成。应用如下梯度:0分钟:60%A/40%B,12分钟:20%A/80%B,16分钟:20%A/80%B,16.5分钟:60%A/40%B,20分钟:60%A/40%B。使用DAD检测器在265nm波长下量化瑞格菲尼。瑞格菲尼峰出现在12.5分钟。
实施例4:瑞格菲尼的狗青光眼滤过手术模型研究
在该思考实验实施例中,在青光眼滤过手术的狗模型中测试了于全氟己基辛烷(F6H8)载剂中制备的2%瑞格菲尼制剂。瑞格菲尼是本发明中可抑制血管新生和纤维化的另一个MKI实例。其对VEGFR和FGFR的体外效力是尼达尼布的约两倍多。研究显示出该制剂可改进狗模型中青光眼手术的成功率,并且表明其将潜在可用于人青光眼手术中以降低失败率。
方法
模型建立:如先前所述地建立青光眼滤过手术模型(Kojima等人,2015)。手术后将氧氟沙星软膏涂覆于眼睛。
测试品:于全氟己基辛烷中的2%瑞格菲尼,手术后BID持续4周。
对照:全氟己基辛烷,手术后BID持续4周。
测量法:IOP,滤过泡评分,胶原含量。
时间点:手术后第14天和第28天。
研究设计示于下表6中。
表6:研究设计
OU=双眼,OD=右眼,OS=左眼,IOP=眼内压,OE=眼部检查,H&E=苏木精和伊红染色,PK=药物动力学
结果和结论
如表7中所示,瑞格菲尼处理组显示出与载剂组显著的差异。在第14天和第28天观测到更低的IOP,而载剂中无明显变化。瑞格菲尼组中的滤过泡评分比载剂组更高,并且瑞格菲尼组中的胶原含量更低。
表7:对IOP、滤过泡评分和胶原密度的实施例3结果
a:与基线有显著差异,b:与载剂组有显著差异。
结果显示,全氟己基辛烷(F6H8)中2%的瑞格菲尼制剂可改进狗模型中青光眼滤过手术的成功率。这种或与瑞格菲尼类似的制剂将具有用于人青光眼手术中的潜能以降低随着时间推移的失败率。它还可用于治疗涉及异常多血管和/或纤维化的在眼睛前部的其他眼部疾病。
本领域技术人员将明白的是,可在不脱离本发明的精神或范围的情况下在本发明中作出各种修改和变化。因此,本发明意图涵盖对本发明的修改和变化,前提是它们属于随附权利要求书和其等效物的范围。
Claims (19)
1.一种局部眼科组合物,其包括:
作为活性药物成分的多激酶抑制剂;和
作为液体载剂的全氟己基辛烷(F6H8),
其中所述多激酶抑制剂抑制血管内皮生长因子受体(VEGFR)。
2.根据权利要求1所述的局部眼科组合物,其中所述多激酶抑制剂抑制VEGFR和成纤维细胞生长因子受体(FGFR)。
3.根据权利要求1-2中任一项所述的局部眼科组合物,其中所述多激酶抑制剂选自由阿西替尼、瑞格菲尼、帕唑帕尼、尼达尼布和其药学上可接受的盐组成的组。
4.根据权利要求1-3中任一项所述的局部眼科组合物,其中所述多激酶抑制剂具有约0.01-0.1%(w/v)、约0.1-1%(w/v)、约1-10%(w/v)、约1.5%-5%(w/v)、约1.5%(w/v)、约2%(w/v)、约2.5%(w/v)、约3%(w/v)、约3.5%(w/v)、约4%(w/v)、约4.5%(w/v)、约5%(w/v)、约6%(w/v)、约7%(w/v)、约8%(w/v)、约9%(w/v)或约9%(w/v)的浓度。
5.根据权利要求1-4中任一项所述的局部眼科组合物,其中所述局部眼科组合物是悬浮液、溶液或乳液的非水基制剂。
6.根据权利要求1-5中任一项所述的局部眼科组合物,其中全氟己基辛烷(F6H8)是所述局部眼科组合物的液体载剂。
7.根据权利要求1-6中任一项所述的局部眼科组合物,其还包括选自由乙醇、异丙醇、甘油、丙二醇和聚乙二醇组成的组的有机潜溶剂。
8.一种由以下组成的局部眼科组合物:
作为活性药物成分的多激酶抑制剂;和
作为液体载剂的全氟己基辛烷(F6H8),
其中所述多激酶抑制剂抑制血管内皮生长因子受体(VEGFR)。
9.根据权利要求8所述的局部眼科组合物,其中所述多激酶抑制剂抑制VEGFR和成纤维细胞生长因子受体(FGFR)。
10.根据权利要求8-9中任一项所述的局部眼科组合物,其中所述多激酶抑制剂选自由阿西替尼、瑞格菲尼、帕唑帕尼、尼达尼布和其药学上可接受的盐组成的组。
11.根据权利要求8-10中任一项所述的局部眼科组合物,其中所述多激酶抑制剂具有约0.01-0.1%(w/v)、约0.1-1%(w/v)、约1-10%(w/v)、约1.5%-5%(w/v)、约1.5%(w/v)、约2%(w/v)、约2.5%(w/v)、约3%(w/v)、约3.5%(w/v)、约4%(w/v)、约4.5%(w/v)、约5%(w/v)、约6%(w/v)、约7%(w/v)、约8%(w/v)、约9%(w/v)或约9%(w/v)的浓度。
12.一种治疗眼科病症的方法,其包括:
提供含有约0.01-10%(w/v)的浓度的多激酶抑制剂的局部眼科组合物;并且
用所述局部眼科组合物治疗患者以治疗所述眼科病症,
其中所述多激酶抑制剂抑制血管内皮生长因子受体(VEGFR)。
13.根据权利要求12所述的方法,其中所述多激酶抑制剂抑制VEGFR和成纤维细胞生长因子受体(FGFR)。
14.根据权利要求12-13中任一项所述的方法,其中所述多激酶抑制剂选自由阿西替尼、瑞格菲尼、帕唑帕尼、尼达尼布和其药学上可接受的盐组成的组。
15.根据权利要求12-14中任一项所述的方法,其中所述多激酶抑制剂具有约0.01-0.1%(w/v)、约0.1-1%(w/v)、约1-10%(w/v)、约1.5%-5%(w/v)、约1.5%(w/v)、约2%(w/v)、约2.5%(w/v)、约3%(w/v)、约3.5%(w/v)、约4%(w/v)、约4.5%(w/v)、约5%(w/v)、约6%(w/v)、约7%(w/v)、约8%(w/v)、约9%(w/v)或约9%(w/v)的浓度。
16.根据权利要求12-15中任一项所述的方法,其中所述局部眼科组合物是悬浮液、溶液或乳液的非水基制剂;包含全氟己基辛烷(F6H8)作为液体载剂;并且所述液体载剂不含水。
17.根据权利要求12-16中任一项所述的方法,其中所述眼科病症选自由以下组成的组:青光眼手术失败,微创青光眼手术失败,新生血管性青光眼,睑板腺功能障碍,干眼病,斯耶格伦氏综合征,碱烧伤,溃疡,移植物抗宿主病,特应性结膜炎,眼红斑痤疮,瘢痕性类天疱疮,干细胞缺乏,莱尔氏综合征,斯蒂文约翰逊综合征,病毒、细菌、真菌,翼状胬肉,结膜黄斑,角膜移植感染,角膜寄生虫感染,和隐形眼镜诱发的血管再生。
18.根据权利要求17所述的方法,其中所述青光眼手术失败起因于经典小梁切除术、小梁消融术、前房角镜辅助的经腔小梁切开术、准分子激光小梁造瘘术和内窥镜睫状体光凝术;所述微创青光眼手术失败起因于植入眼过滤器件。
19.根据权利要求18所述的方法,其中所述眼滤过器件选自由结膜下支架、巩膜静脉窦支架和脉络膜上支架组成的组。
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