CN112569224B - 马来酸蒿***胺用于制备眼科制剂的用途 - Google Patents
马来酸蒿***胺用于制备眼科制剂的用途 Download PDFInfo
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- CN112569224B CN112569224B CN201910937864.9A CN201910937864A CN112569224B CN 112569224 B CN112569224 B CN 112569224B CN 201910937864 A CN201910937864 A CN 201910937864A CN 112569224 B CN112569224 B CN 112569224B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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Abstract
本发明涉及马来酸蒿***胺(Aminoarteether Maleate,SM934)用于制备眼科制剂的用途,更具体地,涉及马来酸蒿***胺在制备用于预防或治疗由泪液分泌不足所致眼部炎症损伤的眼科制剂中的用途。
Description
技术领域
本发明涉及马来酸蒿***胺的新用途,本发明具体为马来酸蒿***胺在制备用于治疗泪液分泌不足所致眼部炎症损伤的眼科制剂中的用途。
背景技术
干眼症,又称干性角膜结膜炎,是指由于泪液的质或量的异常或泪液液体动力学异常引起的眼部不适和眼表面损害的一类疾病的总称。临床表现为干涩感、烧灼感、异物感、痒感、畏光、眼红、视物模糊、视力波动及视疲劳等。严重的干眼还可引起角膜炎、角膜血管新生、角膜溃疡等。干眼症主要分为泪液不足型和蒸发过量型,睑板腺功能障碍、干燥综合症、维生素A缺乏症、过敏、怀孕、药物治疗都可引起干眼症的发生。随着社会经济发展和人们生活水平提高,干眼症的发生率有升高且患病群体年轻化的趋势。
目前临床上治疗干眼症的药物分为抗菌类、激素类、人工泪液等,但由于眼部组织较为敏感,且易产生耐药性等问题,对干眼症的治疗效果十分有限。
东莨菪碱氢溴酸盐是一种具有较强外周作用的抗胆碱药,能够阻断M胆碱受体,抑制腺体的分泌[1]。通过皮下注射东莨菪碱诱导大鼠泪液分泌减少,可建立稳定持久的泪液缺乏型干眼症,是公认的泪液生成不足型干眼症动物模型[2-3]。
青蒿素是从中药青蒿(植物黄花蒿Artemisia annua L.)提取的抗疟有效成分,一种罕见的含有过氧基团的倍半萜内酯。它不仅具有卓越的抗疟作用,还发现具有良好的抗炎免疫抑制活性。青蒿素类化合物具有免疫抑制活性,但现有的青蒿素类药物(蒿甲醚、二氢青蒿素、青蒿琥酯等)溶解度差、口服生物利用度低等问题限制了该类药物在免疫***疾病治疗领域的应用推广和研究。马来酸蒿***胺(Aminoarteether Maleate,SM934)是新型水溶性青蒿素衍生物,与上述用于抗疟疾的青蒿素类药物相比,水溶性好,成药性高、制剂方便,易于口服吸收,生物利用度高,免疫抑制活性强,安全性好。
马来酸蒿***胺具有优异的体内、外抑制活性,体外给药能够抑制丝裂原、异基因抗原诱导的小鼠或人淋巴细胞增殖反应,抑制炎症相关细胞因子的产生;体内给药能够显著抑制小鼠的细胞介导免疫反应,即DNFB或SRBC诱导产生的小鼠迟发型超敏反应(DTH);抑制小鼠体液免疫反应,即SRBC诱导的绵羊红细胞溶血反应(QHS);口服给药对阿霉素诱导的大鼠肾病模型具有良好的治疗作用;并在两种经典的国际公认的自发性红斑狼疮小鼠疾病模型(雌性NZB/W F1小鼠和雌性MRL/lpr小鼠)上进一步验证了它的治疗有效性。马来酸蒿***胺具有如下的结构式:
目前尚未有马来酸蒿***胺治疗由于泪液分泌不足所致眼部炎症损伤的应用和报道。
发明内容
本发明人首次发现马来酸蒿***胺对泪液分泌不足所致眼部炎症损伤的治疗作用,并由此完成本发明。
因此,本发明的目的是提供马来酸蒿***胺在制备用于预防或治疗由泪液分泌不足所致眼部炎症损伤的眼科制剂(特别是眼科外用制剂)中的用途。
本发明人发现通过局部给药的方式,可以提高马来酸蒿***胺的疗效和便捷性。
因此,根据一个方面,本发明提供了马来酸蒿***胺在制备用于预防或治疗由泪液分泌不足所致眼部炎症损伤的眼科制剂(特别是眼科外用制剂)中的用途。
本发明中,所述由泪液分泌不足所致眼部炎症损伤包括但不限于,因疾病或用眼过度等原因引起的泪液分泌不足导致的角膜、结膜炎症损伤等眼科疾病。优选地,所述由泪液分泌不足所致眼部炎症损伤为干眼症,特别是泪液不足型干眼症。
本发明中,优选地,所述眼科制剂可以为本领域已知的各种剂型,包括但不限于滴眼液、眼用凝胶、眼用软膏等。
所述眼科制剂可以包括治疗有效量的马来酸蒿***胺和一种或多种药学上可接受的常规辅料。所述药学上可接受的常规辅料可以为赋形剂、填充剂、稀释剂等。
如本文中所使用的,术语“治疗有效量”是指该数量具有治疗性的效果而可用于预防或治疗本文所述的特定疾病、病症或病状。例如,“治疗有效量”可指在接受治疗的个体上提供治疗性或所欲功效所需的数量。如本领域技术人员所知,治疗有效量会因为施用途径、赋形剂的使用以及与其他疗法共用时的可能性而有所变化。
本发明运用东莨菪碱氢溴酸盐诱导大鼠泪液分泌量不足的干眼症模型,研究发现了含有马来酸蒿***胺的眼科外用制剂可以增加泪液分泌量,减小角膜炎症损伤和增加结膜杯状细胞数量,增加黏蛋白分泌,维持结膜屏障功能等,从而治疗大鼠泪液分泌不足导致的眼部疾病,具有良好的临床应用前景。
附图说明
图1显示实施例2中马来酸蒿***胺治疗提高东莨菪碱诱导的大鼠泪液分泌量的结果。其中,图1A为显示治疗周期内各组大鼠泪液分泌量的图;图1B为显示治疗第0天的各组大鼠泪液分泌量的图;图1C为显示治疗第3天的各组大鼠泪液分泌量的图;图1D为显示治疗第5天的各组大鼠泪液分泌量的图;图1E为显示治疗第7天的各组大鼠泪液分泌量的图。其中,各组与模型组比较*=P<0.05,**=P<0.01,***=P<0.001。
图2显示实施例2中马来酸蒿***胺缓解东莨菪碱诱导的大鼠角膜损伤的结果。其中,图2A为显示治疗第3天的各组大鼠角膜荧光素钠染色损伤评分的图;图2B为显示第5天的各组大鼠角膜荧光素钠染色损伤评分的图;图2C为显示治疗第7天的各组大鼠角膜荧光素钠染色损伤评分的图。其中,各组与模型组比较*=P<0.05,**=P<0.01,***=P<0.001。
图3显示实施例2中马来酸蒿***胺缓解东莨菪碱诱导的大鼠角膜损伤代表图。其中,图3A为治疗第3天裂隙灯下观察大鼠角膜荧光素钠染色的图像;图3B为治疗第5天裂隙灯下观察大鼠角膜荧光素钠染色的图像;图3C为治疗第7天裂隙灯下观察大鼠角膜荧光素钠染色的图像。
图4为显示实施例2中治疗7天后,取大鼠结膜组织进行过碘酸希夫(periodicacid Schiff,PAS)染色,并对结膜杯状细胞计数的结果的图。各组与模型组比较*=P<0.05,**=P<0.01,***=P<0.001。
图5为显示实施例2中治疗7天后,取大鼠结膜组织进行过碘酸希夫(periodicacid Schiff,PAS)染色结果的图。
具体实施方式
下面通过具体实施方式进一步说明本发明。在此提供的实施例仅用于说明或解释本发明的实施方式,而不意图限制发明的保护范围。
除非另有说明,否则本申请中所采用的试剂和方法为本领域常规的试剂和方法。
实施例1.马来酸蒿***胺滴眼制剂的制备
马来酸蒿***胺(SM934)的具体制备方法可参照申请人之前的专利(ZL93112454.9)和已发表的论文J.Med.Chem,2000,43:1635-1640.。
SM934:
与马来酸成盐。白色结晶。熔点:139-141℃
元素分析(C21H33NO9):
计算值:C 56.87 H 7.50 N 3.16
实测值:C 56.84 H 7.59 N 3.10
本实施例所述的眼科制剂,为滴眼液,以100ml计,含马来酸蒿***胺0.5g或0.1g、氯化钠0.8g、氯化钾0.02g、十二水合磷酸氢二钠0.2924g、磷酸二氢钾0.02g,pH 7.37。
制备方法:取氯化钠8g、氯化钾0.2g、十二水合磷酸氢二钠2.924g、磷酸二氢钾0.2g,溶于1L蒸馏水中,室温,充分混匀,制得pH7.39溶液,为溶液A。
取马来酸蒿***胺0.5g或0.1g,加入100ml溶液A中,室温,静置,充分溶解后无菌滤膜过滤,制得含量分别为0.5w/v%、0.1w/v%的马来酸蒿***胺滴眼液,pH 5.91或pH6.89。
实施例2.实施例1制备的马来酸蒿***胺滴眼液对东莨菪碱诱导的大鼠泪液分泌不足所致眼部炎症损伤的治疗作用
1.主要实验材料及来源
(1)动物:SPF级SD大鼠,雌性,体重120-150g,由上海杰思捷实验动物有限公司提供,合格证编号:20180004006541。
(2)主要实验药物及试剂
马来酸蒿***胺,性状:白色粉末,按实施例1制成滴眼液(0.5w/v%的马来酸蒿***胺滴眼液,pH 5.91;0.1w/v%的马来酸蒿***胺滴眼液,pH 6.89)。
试剂:东莨菪碱氢溴酸盐,购自国药集团化学试剂有限公司,CAS:6533-68-2,生产批号:#F1713061。以无菌水配制成1.5w/v%、1.75w/v%浓度。玻璃酸钠滴眼液,由参天制药株式会社能登工厂生产,参天制药(中国)有限公司分包装,进口药品注册证小包装证号:H20130583,进口药品注册证大包装证号:H20130584,分包装批准文号:国药准字J20130150。泪液检测酚红棉线,由天津晶明新技术开发有限公司生产,生产许可证号:津食药监械生产许20100040号,注册证号:津食药监械(准)字2014第2410002号,生产批号:20171002。荧光素钠注射液,由广州白云山明兴制药有限公司生产,国药准字H44023401,产品批号170303。
(3)主要仪器
KOWA手持式裂隙灯,型号SL-17,购自上海悠森树生物科技有限公司。滨松病理切片荧光扫描仪(型号:NanoZoomer 2.0HT)。
2.实验方法:
(1)实验分组:在造模前用酚红棉线检测所有大鼠泪液分泌量,并根据泪液分泌量水平进行平均分组,每组10只大鼠,组别分别为:正常对照组,模型对照组,玻璃酸钠对照组,(0.5%,0.1%)滴眼液治疗组。
(2)模型构建
除正常对照组外的其余每只大鼠每日9:00,12:00,15:00点皮下注射浓度1.5w/v%东莨菪碱注射液0.2ml,18:00点皮下注射浓度1.75w/v%东莨菪碱注射液0.2ml,连续注射7天。
(3)治疗方法
正常对照组、模型对照组大鼠不做任何干预,玻璃酸钠对照组大鼠每日4次采用0.1%玻璃酸钠滴眼液滴液(20μl/眼/次),滴眼液治疗组大鼠每天4次分别采用实施例1制得的0.5%、0.1%马来酸蒿***胺滴眼液滴眼(20μl/眼/次)。滴眼时间约为每日9:30,12:30,15:30,18:30,连续进行7天。
1)泪液分泌量检测:分别于治疗第0天、第3天、第5天、第7天用酚红棉线检测各组大鼠泪液分泌量;
2)角膜损伤评分:分别于治疗第3天、第5天、第7天用对角膜进行荧光素钠染色,并用裂隙灯观察角膜染色面积进行损伤评分;
3)结膜杯状细胞计数:实验终点,即于治疗第7天取大鼠左眼结膜组织,置于4%甲醛中室温固定,石蜡切片进行过碘酸希夫(periodic acid Schiff,PAS)染色,每个标本40倍放大范围内取3个视野进行阳性染色杯状细胞计数,其3个视野计数的平均值为该样品的结膜杯状计数结果;
(4)实验结果
1)如图1所示,0.5%及0.1%的马来酸蒿***胺滴眼液能够显著提高大鼠泪液分泌量,且作用优于玻璃酸钠滴眼液;
2)如图2及图3所示,荧光素钠染色大鼠双侧角膜结果表明,0.5%及0.1%的马来酸蒿***胺滴眼液能够显著改善大鼠角膜损伤,且缓解作用优于玻璃酸钠滴眼液;
3)如图4及图5所示,大鼠结膜杯状细胞计数解表表明,0.5%及0.1%的马来酸蒿***胺滴眼液能够维持大鼠结膜的杯状细胞正常数量,且对杯状细胞保护作用优于玻璃酸钠滴眼液。
以上结果表明,马来酸蒿***胺对大鼠泪液分泌不足所致眼部损伤具有显著的治疗作用,能够提高泪液分泌量,改善角膜炎症损伤,维持结膜杯状细胞数量,且效果优于玻璃酸钠滴眼液,可以开发为治疗泪液分泌不足所致眼部炎症损伤的药物。
参考文献
[1]Viau S,Maire MA,Pasquis B,et al.Time course of ocular surface anndlacrimal gland changes in a new scopolamine-induced dry eye model[J].GraefesArch Clin Exp Ophthalmol,2008.246:857-867.
[2]刘会娟,黄悦,张琰,等.大鼠干眼模型的建立及其角膜神经的改变[J].眼科新进展,2014,34(5):422-427.
[3]刘雪,徐雯,高卫萍.硫酸阿托品滴眼液滴眼和氢溴酸东莨菪碱皮下注射制作水液缺乏型干眼兔模型实验研究[J].临床眼科杂志,2015(3):263-266。
Claims (7)
1.马来酸蒿***胺在制备用于预防或治疗由泪液分泌不足所致眼部炎症损伤的眼科制剂中的用途。
2.根据权利要求1所述的用途,其中,所述由泪液分泌不足所致眼部炎症损伤包括因疾病或用眼过度原因引起的泪液分泌不足导致的角膜、结膜炎症损伤的眼科疾病。
3.根据权利要求1所述的用途,其中,所述由泪液分泌不足所致眼部炎症损伤为干眼症。
4.根据权利要求1所述的用途,其中,所述由泪液分泌不足所致眼部炎症损伤为泪液不足型干眼症。
5.根据权利要求1所述的用途,其中,所述眼科制剂包括滴眼液、眼用凝胶或眼用软膏。
6.根据权利要求1所述的用途,其中,所述眼科制剂包括马来酸蒿***胺和一种或多种药学上可接受的辅料。
7.根据权利要求6所述的用途,其中,所述药学上可接受的辅料选自赋形剂、填充剂和稀释剂中的一种或多种。
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