CN115531302B - 一种用于制备治疗角膜血管新生病症的眼用组合物 - Google Patents
一种用于制备治疗角膜血管新生病症的眼用组合物 Download PDFInfo
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- CN115531302B CN115531302B CN202211193746.XA CN202211193746A CN115531302B CN 115531302 B CN115531302 B CN 115531302B CN 202211193746 A CN202211193746 A CN 202211193746A CN 115531302 B CN115531302 B CN 115531302B
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- Medicinal Preparation (AREA)
Abstract
本发明提供了一种用于制备治疗角膜血管新生病症的眼用组合物，所述眼用组合物包括全氟化碳、半氟化烷。本眼用组合物使用的是全氟化碳与半氟化烷的组合，从角膜缺氧这个角膜血管新生的诱因出发，为角膜乏氧环境提供额外的氧气，并阻断角膜处的炎症反应，为治疗角膜血管新生的药物的制备提供了新的方法。
Description
技术领域
本发明属于药物制备领域，具体涉及一种用于制备治疗角膜血管新生病症的眼用组合物。
背景技术
角膜新生血管是全球最主要的致盲眼病之一。
角膜本身没有血管，角膜细胞不能直接从血液循环中获取氧气。其代谢所需要的氧气，80％来源于空气或者泪膜，15％来自角膜缘血管网，剩下的约5％由房水供给。角膜血管的生成是由促血管生成因子与抗血管生成因子之间的动态平衡控制的。当存在某些感染性因素或非感染性因素时，导致动态平衡被打破，最终角膜里生长出新的血管，导致角膜的透明度受到影响。此外，角膜新生血管是不可逆性眼部疾病。
在角膜血管新生过程中，炎症是诱发血管形成的核心因素。而缺氧是引发炎症的一个关键刺激因子，并伴随血管形成的多个过程。在感染性或非感染性因素的刺激下，角膜发生缺氧、炎症、血管生成等一系列的病理生理改变。(Zeba A.Syed等人，INTERNATIONALOPHTHALMOLOGY CLINICS Volume 57,Number 4,31–38)目前临床上，针对角膜血管新生尚无有效的治疗方式。临床诊疗中对该类患者，常建议进行局部抗炎治疗，包括皮质类固醇激素类或非甾体类抗炎药类。但该类药物本身可能会导致高眼压、后发性白内障诱导、延迟愈合或角膜融解等严重副作用。(Dimitri T Azar，.Trans Am Ophthalmol Soc.(2006)104:264–302)
目前在研多款抗角膜血管新生的局部治疗药物，多聚焦在抗血管内皮生长因子(VEGF)上，如雷珠单抗(Lucentis；Genentech)和贝伐珠单抗(Avastin；Genentech)等。然而，目前的治疗方法仍不够有效，并且部分与显著的不良反应相关。一些患者可能呈现出眼部疾病的恶化，这表明其他一些因素也可能导致眼部血管生成。(Cabral等人,Int.J.Retin.Vitr.(2017)3:31)。
角膜血管新生，很多情况下上是由于角膜缺氧，引起的代偿行为来为角膜补充氧气。而现有的治疗方案，并未有效缓解角膜氧供不足的状况。例如在进行抗VEGF治疗中，不仅抑制血管供氧，并且未缓解缺氧的诱因，因而刺激血管生成的源头——缺氧信号并未得到消除。
在现有的发明专利文件中，WO2020/152046公开了一种包含他克莫司和半氟化烷烃的用于治疗眼部新生血管形成的方法中的药物组合物，该药物组合物主要用于视网膜和/或脉络膜新生血管形成，针对病灶位于眼后节。
WO2020/165132公开了一种包含悬浮在半氟化烷烃中的蛋白粉末制剂和半氟化烷烃，该蛋白粉末是抗血管生成的大分子蛋白，可治疗角膜血管新生。
我们可以看到，现有技术仍然是在阻断炎症发生和抑制血管生长，从而起到治疗血管新生的作用；而本发明主要应用了一种含有全氟化碳和半氟化碳的眼用组合物，目的是利用全氟化碳优秀的携氧、氧气递送能力，缓解角膜缺氧，从而抑制角膜血管生成；同时，全氟化碳具有抗炎特性，可以抑制角膜血管新生过程中的炎症反应。此外，在本发明中，半氟化烷不是作为溶剂，而是为了增加全氟化碳与角膜的亲和力，同时亦使得本发明有额外的药物递送能力。
发明内容
本发明的目的是为了解决现有技术中存在的缺点，提供一种眼用组合物，为眼部角膜新生血管形成提供了创新的、安全且有效的治疗。该种治疗方式从新的发病切入点入手，去阐述和探索治疗/改善角膜血管新生。
本发明采用的技术方案为：一种用于制备治疗角膜血管新生病症的眼用组合物，所述眼用组合物包括全氟化碳和半氟化烷。
进一步地，角膜血管新生病症由感染性因素、遗传或先天营养不良、角膜手术、化学损伤、外伤、长期佩戴接触镜、角膜疾病中的一种或多种所导致的单眼及双眼、轻-重度角膜血管新生。
进一步地，所述感染性因素包括病毒感染、细菌感染、寄生虫感染；所述遗传或先天营养不良包括无虹膜、富氏和Terrien营养不良或圆锥角膜；所述角膜疾病包括干眼症、自身免疫性疾病或角膜结膜炎。
进一步地，所述全氟化碳为全氟代环烷烃、氧杂全氟代环烷烃、氮杂全氟代环烷烃、全氟代链烷烃、氧杂全氟代链烷烃、氮杂全氟代链烷烃中的一种或多种；所述全氟化碳为全氟正丁基呋喃、全氟三丙胺、全氟三丁胺、全氟萘烷、全氟化蒽、全氟化菲、全氟甲基萘烷、全氟异丙基萘烷、全氟正丁基萘烷中的一种或多种。
进一步地，所述半氟化烷是一半为直链或支链烷基、另一半为直链或支链全氟代烷基的饱和氟代烷烃化合物，其分子式为CaH2a+1-CbF2b+1；所述烷基的端碳数a为3至10个，所述全氟代烷基的端碳数b为3至10个。
进一步地，所述半氟化烷是烷基端碳数为6个、全氟代烷基端碳数为4个的半氟化烷、分子式为C6H13-C4F9；烷基端碳数为6个、全氟代烷基端碳数为6个的半氟化烷、分子式为C6H13-C6F13；烷基端碳数为8个、全氟代烷基端碳数为6个的半氟化烷、分子式为C8H17-C6F13、烷基端碳数为10个、全氟代烷基端碳数为6个的半氟化烷、分子式为C10H21-C6F13中的一种或多种。
进一步地，所述全氟化碳与半氟化烷的体积比为1:0.01～100。
进一步地，所述全氟化碳与半氟化烷的体积比为1:0.2～5。
进一步地，该眼用组合物可进一步包含替尼类药物阿帕替尼、乐伐替尼或舒尼替尼中的一种。
进一步地，所述组合物的用量为16～24μL单滴每眼每次，每日至多3次。
本发明获得的有益效果为：本眼用组合物使用的是全氟化碳与半氟化烷的组合，相比于传统的水性眼用组合物，沸点更高，可起到持续润眼和透氧作用；相比于油性眼用组合物，可以有更好的肤感体验，不油腻，同时粘度系数更小，易于使用。
本发明原理：在眼用组合物中，全氟化碳具有优良的携氧和透氧能力，并具有抗炎特性，主要用作氧气递送及渗透制剂，用于为角膜递送和控释氧气，缓解角膜缺氧，抑制炎症反应，从而抑制角膜血管的新生。半氟化烷具有将全氟化碳和细胞膜/药物分子桥接的能力，主要用于增强全氟化碳在角膜的潴留，同时减少水分和全氟化碳的挥发，起到持续润眼和透氧作用。二者相结合时，全氟化碳与半氟化烷的全氟代烷基端亲和，而半氟化烷的烷基端被包裹在中间，形成亲油空腔，从而可以进一步负载活性药物分子。
为了进一步提高血管新生的治疗效果，可以在本眼用组合物中加入用于血管新生治疗的药物，通常是具有抗炎或免疫抑制、或是抗血管新生作用的。优选为替尼类药物，替尼类药物可以抑制血管内皮生长因子受体(VEGFR1、VEGFR2和VEGFR3)，具有抗血管生成作用；最优选的是舒尼替尼、乐伐替尼等具有抑制血管内皮生长因子受体性质的替尼类药物。
此外，在活性药物分子的选择上，也可以使用其他的活性药物分子，用于治疗其他的眼部疾病。例如，可以使用红霉素等抗菌类药物治疗眼部感染的疾病。
附图说明
图1为本发明原理图；
图2为本发明实施例4中实验进行至第10日时不同组小鼠裂隙灯显微图像中的CNV病变；
图3a为本发明每组的平均CNV尺寸表示为与对照非治疗组相比的绝对面积；
图3b为本发明每组的平均CNV尺寸表示为与对照非治疗组相比的减少的百分比；
图4a为本发明实施例4中碱灼烧法诱导的角膜新生血管形成的小鼠模型中造模组的角膜切片图像；
图4b为本发明实施例4中碱灼烧法诱导的角膜新生血管形成的小鼠模型中未造模组的角膜切片图像。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。
如图1-4b所示，一种用于制备治疗角膜血管新生病症的眼用组合物，所述眼用组合物包括全氟化碳和半氟化烷。角膜血管新生病症由感染性因素、遗传或先天营养不良、角膜手术、化学损伤、外伤、长期佩戴接触镜、角膜疾病中的一种或多种所导致的单眼及双眼、轻-重度角膜血管新生。所述感染性因素包括病毒感染、细菌感染、寄生虫感染；所述遗传或先天营养不良包括无虹膜、富氏和Terrien营养不良或圆锥角膜；所述角膜疾病包括干眼症、自身免疫性疾病或角膜结膜炎。
全氟化碳为全氟代环烷烃、氧杂全氟代环烷烃、氮杂全氟代环烷烃、全氟代链烷烃、氧杂全氟代链烷烃、氮杂全氟代链烷烃中的一种或多种；所述全氟化碳为全氟正丁基呋喃、全氟三丙胺、全氟三丁胺、全氟萘烷、全氟化蒽、全氟化菲、全氟甲基萘烷、全氟异丙基萘烷、全氟正丁基萘烷中的一种或多种。所述半氟化烷是一半为直链或支链烷基、另一半为直链或支链全氟代烷基的饱和氟代烷烃化合物，其分子式为CaH2a+1-CbF2b+1；所述烷基的端碳数a为3至10个，所述全氟代烷基的端碳数b为3至10个。所述半氟化烷是烷基端碳数为6个、全氟代烷基端碳数为4个的半氟化烷、分子式为C6H13-C4F9；烷基端碳数为6个、全氟代烷基端碳数为6个的半氟化烷、分子式为C6H13-C6F13；烷基端碳数为8个、全氟代烷基端碳数为6个的半氟化烷、分子式为C8H17-C6F13、烷基端碳数为10个、全氟代烷基端碳数为6个的半氟化烷、分子式为C10H21-C6F13中的一种或多种。
全氟化碳与半氟化烷的体积比为1:0.01～100。优选为，全氟化碳与半氟化烷的体积比为1:0.2～5。
该眼用组合物可进一步包含替尼类药物阿帕替尼、乐伐替尼或舒尼替尼中的一种。组合物的用量为16～24μL单滴每眼每次，每日至多3次。
实施例1
一种用于制备治疗角膜血管新生相关病症的眼用组合物，按体积数计，包括以下组分：全氟萘烷的体积占70％，全氟己基辛烷的体积占30％。
眼用组合物的制备方法，包括如下步骤：按体积比例量取相应的全氟萘烷和全氟己基辛烷，放置于容器中，磁力搅拌或机械搅拌至均匀，即得到眼用组合物。
实施例2
一种用于制备治疗角膜血管新生相关病症的眼用组合物，按体积数计，包括以下组分：全氟萘烷的体积占30％，全氟三乙胺的体积占30％，全氟己基癸烷的体积占40％。
眼用组合物的制备方法，包括如下步骤：按体积比例量取相应的全氟萘烷、全氟三乙胺和全氟己基癸烷，放置于容器中，磁力搅拌或机械搅拌至均匀，即得到眼用组合物。
实施例3
一种用于制备治疗角膜血管新生相关病症的眼用组合物，按体积数计，包括以下组分：全氟三丁胺的体积占50％，全氟己基辛烷的体积占50％，乐伐替尼的添加量为2μg/mL。
眼用组合物的制备方法，包括如下步骤：按体积比例量取相应的全氟三丁胺和全氟己基辛烷，放置于容器中，称取并向其中加入相应量的乐伐替尼，通过机械搅拌、超声处理及高压均质使其完全分散，即得到眼用组合物。
实施例4
在碱灼烧法诱导的角膜新生血管形成(CNV)的小鼠模型中测试处方1和处方2的滴眼液(处方配比见表1)的治疗效果并且分别与0.1％***滴眼液的治疗效果和抗小鼠VEGF的玻璃体内注射进行比较。
材料
用于制备以下列出的处方1和处方2配制品的材料是：全氟萘烷、全氟三丁胺、全氟己基辛烷。
配制品
通过将全氟萘烷和全氟己基辛烷混合得到处方一。
通过将全氟三丁胺和全氟己基辛烷混合得到处方二。
购买***眼用悬浮液0.1％。
购买抗小鼠VEGF抗体。
表1.处方配比
| 全氟萘烷 | 全氟己基辛烷 | 全氟三丁胺 | |
| 处方1 | 60％ | 40％ | / |
| 处方2 | / | 40％ | 60％ |
研究设计
30只C57BL/6小鼠，雌雄各半，6-8周龄，体重18-22g。将所有小鼠进行圈养并且饲养在正常的实验房间内并且暴露于12小时黑暗12小时光照周期中。
碱灼烧法诱导的角膜新生血管形成(CNV)
在小鼠中进行碱灼烧诱导的CNV。简言之，采用阿佛丁50-75mg/kg腹腔注射，0.4％盐酸奥布卡因滴眼液表面麻醉。棉签拭去过多水分，用镊子夹住直径为2mm的单层滤纸片，浸于1M氢氧化钠溶液中，使其饱和，将滤纸片置于小鼠左眼的角膜中央20s，弃掉滤纸，立即用20mL的PBS冲洗烧伤区及结膜囊1min，后给予红霉素眼药膏，每日3次，连续1天。2-3天发展，在第7-12天达到峰值。
治疗方案
此研究包括五个实验组。每组使用六只小鼠(表2)。将小鼠从第0天到第14天每天三次用滴眼液处理，或在CNV诱导后立即玻璃体内注射1μL浓度为1ng/μL的抗VEGF。在滴眼液施用期间，每只眼睛接受20μL滴眼液。
表2.体内治疗组和给药详细信息
| 组别 | n(只) | 处理 | 剂量 | 给药途径 |
| 组1 | 6 | 无 | N/A | N/A |
| 组2 | 6 | 处方1 | 每天三次 | 滴眼液 |
| 组3 | 6 | 处方2 | 每天三次 | 滴眼液 |
| 组4 | 6 | 抗小鼠VEGF(1ng/1μL/只眼睛) | 一次注射 | 玻璃体内 |
| 组5 | 6 | 0.1％*** | 每天三次 | 滴眼液 |
临床检查
在CNV诱导后第2、4、6、8、10、12、14天，使用裂隙灯显微镜对角膜血管新生病变进行临床检查，并通过H-M评分***对角膜血管新生病变进行***评估。
样品收集
在CNV诱导后第14天，将所有小鼠脱颈法处死，并且将眼睛小心移除。使用以下程序制备眼部组织整体铺片。在室温下将所有眼睛固定在4％多聚甲醛中固定。进行石蜡包埋和切片，然后对整体铺片进行进一步处理以进行HE染色和免疫染色。
图像和数据分析
在每次进行临床观察时使用裂隙灯显微镜的拍照***对所有小鼠眼情况进行拍照，并使用H-M评分***对角膜血管新生病变进行***评估(H-M评分***见表3)，记录每只造模眼睛的分数并进行数据汇总。各组中H-M的平均得分情况表示为平均值±SEM。使用Student's t检验(非配对，双尾)来检测处方/***治疗组与相关对照组之间的差异。此外，还使用单向方差分析(ANOVA)土耳其多重比较检验(Turkey’s Multiple ComparisonTest)来检测不同组之间的差异。
表3.本次实验中根据H-M评分***设计的检测评分
临床观察
在CNV诱导后第2、4、6、8、10、12、14天，对来自每组的六只小鼠进行角膜检查。
在图像中检测角膜周围有血管生成，如图2。所有小鼠均产生CNV病变。
免疫组织学结果
表4和图3a-b示出了显微观察的结果。结果显示处方1、2和0.1％***滴眼液治疗显著抑制CNV。
表4.每组CNV结果
| 组别 | n(只) | 处理 | 平均CNV(μm2) |
| 组1 | 6 | 无 | 52011 |
| 组2 | 6 | 处方1 | 27302 |
| 组3 | 6 | 处方2 | 29065 |
| 组4 | 6 | 抗小鼠VEGF(1ng/1μL/只眼睛) | 38901 |
| 组5 | 6 | 0.1％*** | 26403 |
每组中CNV的平均尺寸由染色确定。
H-M评分***结果：表5示出了此实验中每次观察时的各组H-M评分平均结果。结果显示处方1、2和0.1％***滴眼液治疗显著抑制CNV。
表5.各组H-M评分结果
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围之内。
Claims (9)
1.一种眼用组合物在制备治疗角膜血管新生病症的药物中的应用，其特征在于：所述眼用组合物由全氟化碳和半氟化烷组成；所述全氟化碳与半氟化烷的体积比为1:0.01~100；用于为角膜递送和控释氧气，缓解角膜缺氧，抑制炎症反应，从而抑制角膜血管的新生。
2.根据权利要求1所述一种眼用组合物在制备治疗角膜血管新生病症的药物中的应用，其特征在于：角膜血管新生病症由感染因素、非感染性因素、角膜手术、化学损伤、外伤、长期佩戴接触镜、角膜疾病中的一种或多种所导致的单眼及双眼、轻-重度角膜血管新生。
3.根据权利要求2所述一种眼用组合物在制备治疗角膜血管新生病症的药物中的应用，其特征在于：所述非感染性因素包括遗传或先天营养不良，所述角膜血管新生病症包括无虹膜、富氏和Terrien营养不良或圆锥角膜；所述角膜疾病包括干眼症、自身免疫性疾病或角膜结膜炎。
4.根据权利要求1所述一种眼用组合物在制备治疗角膜血管新生病症的药物中的应用，其特征在于：所述全氟化碳为全氟代环烷烃、氧杂全氟代环烷烃、氮杂全氟代环烷烃、全氟代链烷烃、氧杂全氟代链烷烃、氮杂全氟代链烷烃中的一种或多种；所述全氟化碳为全氟正丁基呋喃、全氟三丙胺、全氟三丁胺、全氟萘烷、全氟化蒽、全氟化菲、全氟甲基萘烷、全氟异丙基萘烷、全氟正丁基萘烷中的一种或多种。
5.根据权利要求1所述一种眼用组合物在制备治疗角膜血管新生病症的药物中的应用，其特征在于：所述半氟化烷是一半为直链或支链烷基、另一半为直链或支链全氟代烷基的饱和氟代烷烃化合物，其分子式为CaH2a+1-CbF2b+1；所述烷基的端碳数a为3至10个，所述全氟代烷基的端碳数b为3至10个。
6.根据权利要求5所述一种眼用组合物在制备治疗角膜血管新生病症的药物中的应用，其特征在于：所述半氟化烷是烷基端碳数为6个、全氟代烷基端碳数为4个的半氟化烷、分子式为C6H13-C4F9；烷基端碳数为6个、全氟代烷基端碳数为6个的半氟化烷、分子式为C6H13-C6F13；烷基端碳数为8个、全氟代烷基端碳数为6个的半氟化烷、分子式为C8H17-C6F13、烷基端碳数为10个、全氟代烷基端碳数为6个的半氟化烷、分子式为C10H21-C6F13中的一种或多种。
7.根据权利要求1所述一种眼用组合物在制备治疗角膜血管新生病症的药物中的应用，其特征在于：所述全氟化碳与半氟化烷的体积比为1:0.2~5。
8.根据权利要求1所述一种眼用组合物在制备治疗角膜血管新生病症的药物中的应用，其特征在于：该眼用组合物进一步包含替尼类药物阿帕替尼、乐伐替尼或舒尼替尼中的一种。
9.根据权利要求1所述一种眼用组合物在制备治疗角膜血管新生病症的药物中的应用，其特征在于：所述组合物的用量为16~24μL单滴每眼每次，每日至多3次。
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| A.M.Joussen,et al.Effect of gravity in long-term vitreous tamponade:in vivo investigation using perfluorocarbon liquids and semi-fluorinated alkanes.Graefe’s Arch Clin Exp Ophthalmol.2007,第245卷665-675. * |
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