CN115487301B - Il-13抑制剂在制备延缓或治疗视网膜色素变性的药物中的用途 - Google Patents
Il-13抑制剂在制备延缓或治疗视网膜色素变性的药物中的用途 Download PDFInfo
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Abstract
本发明提供了IL‑13抑制剂在制备延缓或治疗视网膜色素变性的药物中的用途,属于制药领域。本发明首次发现,对视网膜色素变性小鼠施用IL‑13单抗可以达到延缓视网膜色素变性等视网膜退行性病变的进程的作用。包括IL‑13单抗在内的IL‑13抑制剂在制备治疗视网膜色素变性等视网膜退行性病变的药物中具有广泛的应用前景。
Description
技术领域
本发明属于制药领域,具体涉及IL-13抑制剂在制备延缓或治疗视网膜色素变性的药物中的用途。
背景技术
视网膜色素变性(Retinitis pigmentosa,RP))是一种具有高度遗传异质性的视网膜退行性病变,是与光感受器或视网膜色素上皮结构/功能异常相关的一类致盲眼病,其发病率为1/3000-1/7000。该病临床表现一般局限于眼内,但也有20-30%的病人具有全身其他器官的问题,约30余种综合征与该表型有关。RP发病早期表现为夜盲,中期视野进行性缺失,最终可导致全盲。眼科常规检查可见眼底色素沉着,视网膜电图(Electroretinogram,ERG)显著异常或无波型。从细胞层面讲,这与视杆细胞(Rod cell)的功能缺损相关,在疾病后期,视锥细胞(Cone cell)也会受到影响,从而导致全盲,严重影响患者生活质量。
RP具有高度的遗传异质性,根据RETNET数据库报道(https://sph.uth.tmc.edu/retnet/),截止到2019年1月4日,71个基因/位点与RP发病相关。RP发病的机制复杂,如基因突变、自噬缺陷及神经性炎症等导致视网膜退行性病变,Wright AF等把影响光感受器变性的基因按照功能分类,其中睫状体转运缺陷、脂质代谢、光信号传导、离子通道等与之密切相关。
目前RP的治疗方法主要包括4个方向。(1)药物治疗,包括神经保护类、抗凋亡类、抗氧化类及抗炎症类等药物。优点:比较安全,价格便宜;缺点:疗效没有完全被证实,通常用来辅助治疗。(2)基因治疗,主要使用腺相关病毒(Adeno-associated virus,AAV)载体,目前很多基因已进入临床试验。优点:对于基因明确的单纯性RP,可以解决其根本问题;缺点:不适用于病因不明的复杂性RP,价格昂贵,没有办法重生死亡细胞,适用于RP早期治疗。(3)干细胞治疗,包括胚胎干细胞(Embryonic stem cells,ESC)、诱导性多功能干细胞(Induced pluripotent stem cells,iPSC)或其他内源细胞(Endogenous origin)等。优点:可以重生细胞,用于RP晚期阶段;缺点:移植的细胞能否整合进原有的神经环路及安全问题还有待完善。(4)植入视网膜假体。优点:适合在RP最后期使用,临床已证实其安全性和有效性;缺点:只有基本像素画的视觉,需要复杂的手术。
上述每种方法各有优缺点,目前仍需要寻找更加安全和有效的新治疗方法。因此,深入研究RP发病机制,寻找新的治疗靶点,提高诊治和预防水平,降低患者致盲率,提高患者生活质量,具有重要的意义。
发明内容
本发明的目的在于提供IL-13抑制剂(包括IL-13单抗)在制备延缓或治疗视网膜色素变性的药物中的用途。
本发明提供了IL-13抑制剂在制备延缓视网膜退行性病变进程的药物中的用途。
本发明还提供了IL-13抑制剂在制备治疗视网膜退行性病变的药物中的用途。
进一步地,所述视网膜退行性病变为视网膜色素变性。
进一步地,所述IL-13抑制剂为小分子IL-13抑制剂或蛋白多肽类IL-13抑制剂。
进一步地,所述蛋白多肽类IL-13抑制剂为IL-13单抗。
进一步地,所述IL-13单抗Dupilumab、Lebrikizumab或Tralokinumab。
进一步地,所述药物是中和视网膜中IL-13表达,抑制视网膜外核层变薄,减少视网膜神经元细胞凋亡,挽救视杆细胞的丢失,降低视网膜小胶质细胞的活性,和/或减少视网膜外核层小胶质细胞的数量的药物。
进一步地,所述药物是用于视网膜退行性病变初期的药物。
进一步地,所述药物是以IL-13抑制剂为活性成分,加上药学上可接受的辅料制备而成的制剂。
进一步地,所述制剂为口服制剂、注射制剂或经皮给药制剂;所述注射制剂优选为经视网膜下腔注射的制剂或经玻璃体腔注射的制剂,更优选为经玻璃体腔注射的制剂。
白细胞介素13(IL-13)是一种免疫抑制细胞因子,主要由活化的Th2细胞分泌。
IL-13抑制剂指能够靶向抑制/拮抗IL-13功能或表达的药物,抗IL-13单克隆抗体(简称IL-13单抗)是一种已知的IL-13抑制剂。
IL-13单抗能特异性中和IL-13,阻断IL-13介导的炎症反应信号通路,从而发挥作用。
目前已知的人源化IL-13单抗包括赛诺菲公司Dupilumab IL-13单抗(中文商品名:达必妥,通用名:度普利尤单抗),礼来公司Lebrikizumab IL-13单抗(通用名:来瑞组单抗),LEO Pharma公司Tralokinumab IL-13单抗(通用名:曲罗芦单抗)等。
与现有技术相比,本发明取得了以下有益效果:
1.本发明首次发现,对rd1小鼠施用IL-13单抗可以中和rd1小鼠视网膜中的IL-13表达,抑制rd1小鼠视网膜外核层变薄,减少视网膜神经元细胞凋亡,挽救视杆细胞的丢失,降低rd1小鼠视网膜小胶质细胞的活性,减少视网膜外核层小胶质细胞,达到延缓视网膜色素变性等视网膜退行性病变的进程的作用。
2.通过进一步实验发现,采用P7天玻璃体腔注射IL-13单抗的给药方式效果更佳。
总之,包括IL-13单抗在内的IL-13抑制剂在制备延缓视网膜色素变性等视网膜退行性病变的进程,治疗视网膜色素变性等视网膜退行性病变的药物中具有广泛的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1:液相芯片多因子检测结果图。
图2:玻璃体腔注射IL-13单抗对正常wt小鼠视网膜的影响结果图。A.wt小鼠玻璃体腔注射1μl PBS或1μl IL-13单抗后P21眼球冰冻切片DAPI染色图(DAPI:蓝色;ONL:外核层;INL:内核层;GCL神经节细胞层;比例尺50μm);B.wt小鼠玻璃体腔注射1μl PBS或1μlIL-13单抗后P21视网膜外核层厚度统计图。
图3:不同方式注射IL-13单抗对rd1小鼠视网膜形态的影响结果图,具体为rd1小鼠视网膜下腔或玻璃体腔注射1μl IL-13单抗后P21眼球冰冻切片DAPI染色图(DAPI:蓝色;ONL:外核层;INL:内核层;IPL:内丛状层;GCL神经节细胞层;比例尺100μm)。
图4:IL-13单抗对rd1小鼠视网膜ONL厚度的影响结果图。A.分别于P7、P10、P12注射IL-13单抗后P21 rd1小鼠眼球冰冻切片DAPI染色图;B.分别于P7、P10、P12注射IL-13单抗后P21 rd1小鼠视网膜外核层(ONL)厚度统计图(***表示p<0.001,****表示p<0.0001;DAPI:蓝色;ONL:外核层;INL:内核层;GCL神经节细胞层;比例尺50μm)。
图5:rd1组、rd1+IL-13单抗组P14天视网膜IL-13染色图(DAPI:蓝色;IL-13:红色;ONL:外核层;INL:内核层;IPL:内丛状层;GCL神经节细胞层;比例尺50μm)。
图6:IL-13单抗抑制rd1小鼠视网膜外核层细胞凋亡结果图。A.wt组、rd1组、rd1+IL-13单抗组P14视网膜TUNEL染色图(DAPI:蓝色;TUNEL:红色;ONL:外核层;INL:内核层;GCL神经节细胞层;比例尺100μm)。B.wt组、rd1组、rd1+IL-13单抗组P14视网膜TUNEL阳性数量统计图。C.wt组、rd1组、rd1+IL-13单抗组P14天视网膜外核层厚度统计图。**表示p<0.01,***表示p<0.001,****表示p<0.0001。
图7:IL-13单抗抑制rd1小鼠视网膜小胶质细胞激活结果图,具体为wt组、rd1组、rd1+IL-13单抗组P14视网膜Iba-1及Rhodopsin染色图(DAPI:蓝色;Iba-1:绿色;Rhodopsin:红色;ONL:外核层;OPL:外丛状层;INL:内核层;IPL:内丛状层;GCL神经节细胞层;比例尺50μm)。
具体实施方式
如无特别说明,本发明所用原料与设备均为已知产品,通过购买市售产品所得。
以下实施例采用的Pde6brd1(rd1)小鼠为视网膜变性等位基因(Pde6b)突变的纯合小鼠,购自北京维通利华实验动物技术有限公司;对照组采用正常的野生型ICR小鼠,购自成都达硕实验动物有限公司。rd1小鼠是常用的视网膜色素变性小鼠,该小鼠视网膜退行性病变是由磷酸二酯酶6b(Phosphodiesterase 6βsubunit,Pde6b)基因突变引起的,首先引起视杆细胞的变性,继而引发视锥细胞死亡,与人的视网膜色素变性类似。
以下实施例所用实验动物均饲养、繁殖于四川大学华西医院实验动物中心。以下实施例所有实验动物操作流程及步骤均遵循国际视觉与眼科研究协会声明(Associationfor Research in Vision and Ophthalmology,ARVO)同时获得四川大学华西医院动物研究伦理委员会批准。
以下实施例采用的IL-13单抗为Mouse IL-13Antibody(MAB413),购自R&DSystems。
以下实施例中,P7天表示小鼠出生后第7天(对应视网膜色素变性早期阶段),P10天表示小鼠出生后第10天,P12天表示小鼠出生后第12天,P14天表示小鼠出生后第14天(用于模拟视网膜退行性病变进展期),P21天表示小鼠出生后第21天(用于模拟rd1病程中视杆细胞凋亡终末期)。rd1小鼠在P7天开始发生视杆细胞的死亡,P12-14天视杆细胞凋亡到达高峰,到P21天,rd1小鼠视网膜外核层(Outer nuclear layer,ONL)基本消失,仅剩1-2层细胞,视网膜变性进程较快。
实施例1:IL-13在视网膜小胶质细胞中的表达情况
1.实验方法
磁珠分离小胶质细胞及视杆细胞:视网膜使用木瓜蛋白酶(papain)消化15-30分钟,得到单个细胞,加入CD11b抗体和CD73抗体,4℃孵育15min,加入缓冲液,使用免疫磁珠细胞分选仪(MACS,德国美天旎)进行细胞分选,CD11b富集的小胶质细胞,CD73抗体富集的视杆细胞。
液相芯片进行细胞多因子检测:使用Merck Millipore液相芯片试剂盒(MHSTCMAG-70K)对rd1与wt小鼠出生后第14天(视网膜退行性病变进展期)共18个细胞因子进行检测:GM-CSF、IFNγ、IL-1α、IL-1β、IL-2、IL-4、IL-5、IL-6、IL-7、IL-10、IL-12(p70)、IL-13、LIX、IL-17A、KC、MCP-1、MIP-2、TNFα。实验操作依据液相芯片试剂盒所提供实验操作步骤进行。
提取细胞蛋白,加入50μl标准品和质控品到相应孔,加入50μl相应的matrixSolution到背景孔,加入25μL Assay Buffer至样品相应的孔,加入25μL样本到样本孔,每孔加入25μL混合好的磁珠,封板,4℃避光振荡孵育过夜。使用磁力洗板机洗板3次,每次200uL Wash Buffer,需先在磁珠洗板机上静置1min。每孔加入25μL恢复至室温的检测抗体,封板,避光室温振荡孵育1h。每孔加入25μL恢复至室温的Streptavidin-Phycoerythrin,封板,避光室温振荡孵育30min。使用磁力洗板机洗板3次,每次200uL WashBuffer,需先在磁珠洗板机上静置1min。加入150μL读板仪器鞘液,封板,避光室温振荡重悬5分钟,MAGPIX仪器读板,数据导出及结果分析。
2.实验结果
结果发现(图1),相对于wt小鼠,IL-1α和IL-13在rd1小鼠视网膜小胶质细胞中显著上调,尤其是IL-13,说明IL-13与视网膜小胶质细胞活性密切相关,可能参与了rd1小鼠视网膜退行性病变的病理过程,有望作为视网膜退行性病变的治疗靶点。
实施例2:IL-13单抗对视网膜色素变性的影响
1.实验方法
(1)小鼠视网膜下和玻璃体腔注射
IL-13单抗对rd1小鼠视网膜的作用及最佳给药时间研究:将P7、P10、P14天的rd1小鼠随机分为rd1+PBS对照组和rd1+IL-13单抗(0.5μg)组。
IL-13单抗视网膜下注射:使用P10天rd1和ICR小鼠,氯胺酮和甲苯噻嗪按照4:1比例配制的混合麻醉剂,0.01ml/g体重进行腹腔麻醉,双眼复方托吡卡胺滴眼液散瞳。将小鼠置于解剖显微镜下,用32G针头小心在小鼠角巩膜缘刺一小孔(注意避开角巩膜缘血管),以便用于视网膜下注射的钝性针头进入眼内。用33G钝性针头的Hamilton微量注射器吸取IL-13单抗,沿角巩膜缘的小孔斜45度进入眼内,注意避免损伤晶状体和刺破视网膜,当感觉到针尖前进稍有阻力时即到达视网膜下腔,缓缓将1μl IL-13单抗推注到视网膜下腔。当注射者于显微镜下观察到注射部位视网膜有局限性的隆起时,即可判断为视网膜下腔注射成功,而由注射所引起的视网膜的局限性隆起一般可在24-48小时左右自行恢复。对侧眼给予等量PBS注射作为对照,注射完毕后给予抗生素眼膏涂眼,每日观察小鼠情况。若小鼠出现角膜水肿混浊、虹膜出血、白内障或眼内炎等注射并发症,则不予纳入本次研究。每组8-10只小鼠,在P14和P21天收集眼球。
IL-13单抗玻璃体腔注射:小鼠麻醉散瞳后,用33G针头的Hamilton微量注射器吸取IL-13单抗,于小鼠眼球上方赤道部(角巩膜缘后2mm)斜向后下方进针,从瞳孔直视下观察针尖避免损伤晶状体,注射完毕后给予抗生素眼膏涂眼。若小鼠出现角膜水肿混浊、虹膜出血、白内障或眼内炎等注射并发症,则不予纳入本次研究。每组8-10只小鼠,在P14和P21天收集眼球。
(2)小鼠视网膜组织学观察及外核层厚度测量
P21天的IL-13单抗视网膜下腔及玻璃体腔注射后的小鼠,过量麻醉处死小鼠,用弯镊小心快速取出眼球,注意勿挤压眼球;置于4%多聚甲醛中4℃固定过夜后,PBS洗去组织表面多余的多聚甲醛,于30%蔗糖溶液中脱水;OCT包埋后-80℃迅速冷冻,沿角膜-视神经轴向进行冰冻切片,切片厚度为10μm;切片充分干燥后-20℃长期保存,染色前先将切片置于室温30分钟或37℃下10分钟,然后PBS洗片,以充分去除OCT;用免疫组化笔将待染组织圈起来,滴加4’6-二脒基-2-苯基吲哚(DAPI)溶液于组织上,充分覆盖待染组织,室温下避光染色5-15分钟;PBS洗片5分钟×3次,封片;从每个眼球切片中随机选取4张,然后随机选取并测量视神经两侧500到1000μm范围内的4个区域的视网膜外核层(ONL)的厚度,取其平均值。再将随机选取的4张切片所得数据的平均值作为该眼球的视网膜ONL厚度数值。所有上述操作均采用双盲法进行。
(3)TUNEL染色法检测视网膜细胞凋亡
根据罗氏原位细胞死亡检测试剂盒(In Situ Cell Death Detection Kit;RocheDiagnostics,Mannheim,Germany)说明书进行操作:分别取IL-13单抗注射后14天(P14)和21天(P21)过量麻醉处死小鼠,用弯镊小心快速取出眼球,注意勿挤压眼球;置于4%多聚甲醛中4℃固定过夜后,PBS洗去组织表面多余的多聚甲醛,于30%蔗糖溶液中脱水;OCT包埋后-80℃迅速冷冻,沿角膜-视神经轴向进行冰冻切片,切片厚度为10μm,室温晾干15-30min;用免疫组化油笔圈好待染组织后将切片置于PBS中浸泡10min,以充分除去OCT;将切片置于冰上,用0.1% Triton X-100+0,1%柠檬酸钠对其打孔2-5分钟;PBS漂洗3次,每次5分钟;阳性对照加入DNase I,室温处理10分钟;将Enzyme solution和Lable solution按照1:9比例配制成reaction mixture,每个待染组织滴加约50μl reaction mixture,其中阴性对照只滴加Lable solution(注;reaction mixture需现用现配),37℃孵育1小时;PBS漂洗3次,每次5分钟,DAPI复染5-15分钟;PBS漂洗3次,每次5分钟,封片后,荧光显微镜观察结果并拍照;计数整个视网膜ONL内的TUNEL染色阳性细胞数量。每个眼球随机选取4张切片进行计数并取其平均值。所有操作均采用双盲法进行。
(4)视网膜细胞免疫荧光染色
过量麻醉处死小鼠,用弯镊小心快速取出眼球,注意勿挤压眼球;4%多聚甲醛固定,30%蔗糖脱水,OCT(Optimum cutting temperature compound)包埋眼球后进行冰冻切片(Leica CM 1850)。厚度为10μm。将切片风干后用PBS漂洗3次,用含0.5% TritionX-100的0.1% BSA封闭非特异性结合位点30min,一抗4℃过夜孵育。第二天去除一抗,PBS漂洗3次后,二抗室温避光孵育1小时,PBS漂洗3次后,DAPI染色封片,荧光显微镜观察细胞的分布及种类。
(5)统计学分析
本发明中所有用作统计分析的样本数n=4-10,数据以均数±标准差(mean±SD)或均数±标准误(mean±SEM)表示。采用GraphPad Prism 5软件对实验数据进行统计分析。两组独立样本统计采用独立样本非配对t检验,两组以上的独立样本间的比较采用one-wayANOVA单因素方差分析检验并辅以Bonferroni矫正。p<0.05则认为有统计学差异。
2.实验结果
(1)IL-13单抗对正常wt小鼠视网膜的影响
取P10天wt小鼠,给予IL-13单抗玻璃体腔注射,对照组给予等量PBS注射。P21天染色行组织形态学分析,结果发现相较对照组而言,IL-13单抗对正常wt小鼠视网膜形态和外核层的厚度没有明显影响(图2)。
(2)不同方式注射IL-13单抗对rd1小鼠视网膜形态的影响
为探究IL-13单抗是否在rd1的病理过程中发挥作用,本发明使用两种不同的注射方式(视网膜下腔和玻璃体腔)给予IL-13单抗注射,以观察其对rd1小鼠视网膜退行性病变的干预效果。给药后,于P21天(rd1病程中视杆细胞凋亡终末期)收集视网膜,行免疫荧光染色。结果发现两种注射方式都可以抑制rd1小鼠视网膜外核层厚度的减少(图3),但是视网膜下腔给药容易引起视网膜脱离,因此后续的实验都采用玻璃体腔注射的方式。
(3)不同时间点玻璃体腔注射IL-13单抗对rd1小鼠视网膜的影响
为了确定IL-13单抗最佳给药时间,本发明分别于3个不同时间点进行玻璃体腔注射(P7,P10和P12天)。给药后,于P21天(rd1病程中视杆细胞凋亡终末期)收集视网膜,进行免疫荧光染色,结果发现在三个不同的时间点给予IL-13单抗都可以显著抑制rd1小鼠视网膜外核层厚度的减少,其中P7天注射组的保护效果最为明显(图4)。因此后续实验中选择P7天进行IL-13单抗玻璃体腔注射。
(4)IL-13单抗中和rd1小鼠视网膜IL-13表达
P7天玻璃体腔注射IL-13单抗,P14天时,对眼球冰冻切片进行IL-13染色。从图5可以看出,rd1小鼠视网膜IL-13表达在视神经节细胞层,丛状层和光感受器细胞层;而接受IL-13单抗玻璃体腔注射的rd1小鼠,IL-13表达基本被中和,基本没有表达。结果表明,P7天玻璃体腔注射IL-13单抗可以中和rd1小鼠视网膜中的IL-13表达。
(5)IL-13单抗对视网膜神经元凋亡的保护作用
视网膜神经元的凋亡尤其是光感受器细胞的凋亡在RP等视网膜退行性病变中扮演着重要角色,也是导致患者视力丧失的重要原因。在rd1小鼠中,视杆细胞从P8天开始出现凋亡,P14天凋亡到达高峰期,到P21天时视杆细胞几乎丧失殆尽,残存的视锥细胞仍可持续存活1-2个月。因此为进一步验证IL-13单抗对视网膜神经元凋亡的保护作用,本发明于P7天玻璃体腔注射IL-13单抗,并在P14天,rd1小鼠光感受器细胞凋亡的高峰期进行眼球组织冰冻切片TUNEL,以观察视网膜外核层厚度和神经元凋亡的变化情况。
结果如图6所示。P14天时,接受IL-13单抗玻璃体腔注射的rd1小鼠ONL厚度比rd1小鼠厚度增加了将近一倍,差异具有统计学意义。在眼球冰冻切片TUNEL染色中,在对照wt组中没有观察到TUNEL染色阳性细胞,而在P14天时,rd1小鼠视网膜外核层出现大量TUNEL阳性细胞,IL-13单抗治疗后外核层凋亡细胞数量明显减少。
上述结果表明IL-13单抗可以抑制rd1小鼠视网膜外核层变薄,减少视网膜神经元细胞凋亡,挽救视杆细胞的丢失。
(6)IL-13单抗抑制rd1小鼠视网膜小胶质细胞激活
P7天玻璃体腔注射IL-13单抗,P14天收集rd1小鼠视网膜进行冰冻切片及Iba-1免疫荧光染色,发现IL-13单抗可降低rd1小鼠视网膜小胶质细胞的活性。在rd1小鼠P14天,小胶质细胞被激活并迁移至ONL吞噬损伤的视杆细胞,而IL-13单抗处理后,小胶质细胞活化被抑制,ONL小胶质细胞减少,从而起到保护作用(图7)。
综上,上述实验结果表明,对rd1小鼠施用IL-13单抗可以中和rd1小鼠视网膜中的IL-13表达,抑制rd1小鼠视网膜外核层变薄,减少视网膜神经元细胞凋亡,挽救视杆细胞的丢失,降低rd1小鼠视网膜小胶质细胞的活性,减视网膜外核层小胶质细胞,达到延缓视网膜色素变性等视网膜退行性病变的进程的作用。并且,采用P7天玻璃体腔注射IL-13单抗的给药方式效果更佳。
Claims (8)
1.IL-13抑制剂在制备延缓视网膜退行性病变进程的药物中的用途;
所述视网膜退行性病变为视网膜色素变性;
所述IL-13抑制剂为IL-13单抗。
2.IL-13抑制剂在制备治疗视网膜退行性病变的药物中的用途;
所述视网膜退行性病变为视网膜色素变性;
所述IL-13抑制剂为IL-13单抗。
3.根据权利要求1或2所述的用途,其特征在于:所述IL-13单抗为Dupilumab、Lebrikizumab或Tralokinumab。
4.根据权利要求1或2所述的用途,其特征在于:所述药物是中和视网膜中IL-13表达,抑制视网膜外核层变薄,减少视网膜神经元细胞凋亡,挽救视杆细胞的丢失,降低视网膜小胶质细胞的活性,和/或减少视网膜外核层小胶质细胞的数量的药物。
5.根据权利要求1-4任一项所述的用途,其特征在于:所述药物是以IL-13单抗为活性成分,加上药学上可接受的辅料制备而成的制剂。
6.根据权利要求5所述的用途,其特征在于:所述制剂为口服制剂、注射制剂或经皮给药制剂。
7.根据权利要求6所述的用途,其特征在于:所述注射制剂为经视网膜下腔注射的制剂或经玻璃体腔注射的制剂。
8.根据权利要求6所述的用途,其特征在于:所述注射制剂为经玻璃体腔注射的制剂。
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