CN112094362B - 烟酰胺核糖或单核苷酸类似物-大分子载体轭合物及制法和应用 - Google Patents
烟酰胺核糖或单核苷酸类似物-大分子载体轭合物及制法和应用 Download PDFInfo
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- CN112094362B CN112094362B CN202011047487.0A CN202011047487A CN112094362B CN 112094362 B CN112094362 B CN 112094362B CN 202011047487 A CN202011047487 A CN 202011047487A CN 112094362 B CN112094362 B CN 112094362B
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Abstract
Description
技术领域
本发明属于生物医药技术领域,具体涉及烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物及制法和应用。
背景技术
烟酰胺核糖(英文缩写NR)是维生素B3的一种衍生物,可以与磷酸、腺嘌呤形成烟酰胺腺嘌呤二核苷酸(辅酶I)和烟酰胺腺嘌呤二核苷酸磷酸(辅酶II),是一种重要辅酶NAD+的前体。
烟酰胺核酸在人体细胞能量生成中扮演重要角色,它参与细胞内NAD(烟酰胺腺嘌呤二核苷酸,细胞能量转化的重要辅酶)的合成。
烟酰胺腺嘌呤二核苷酸(NAD,也称辅酶I)是一种转递质子(更准确来说是氢离子)的辅酶,它出现在细胞很多代谢反应中,参与蛋白质、碳水化合物和脂肪等化合物的分解,如:亮氨酸脱氢酶、甲酸氨脱氢酶、葡萄糖脱氢酶催化的手性还原都需要NAD的帮助来完成整个反应,氧化反应亦是如此。随着细胞的衰老或者病变,NAD的数量就会减少。因此,补充烟酰胺核糖,提高NAD的含量,能够提高细胞的基本代谢活动,从而显著提高细胞活力,提高人体各方面的生理机能。缺乏烟酸,会产生糙皮病,表现为皮炎、舌炎、口咽、腹泻及烦躁、失眠感觉异常等症状。
烟酰胺核糖第一次被人类记载是在1944年,当时被称为流感嗜血杆菌(Haemophilus influenza)的生长因子,也被称为生长因子V。流感嗜血杆菌是生活在血液中并依赖血液生活的细菌。从血液中纯化出来的生长因子V有三种结构:NAD(烟酰胺腺嘌呤二核苷酸),NMN(烟酰胺单核苷酸)和NR(烟酰胺核糖)。后来发现只有烟酰胺核糖(NR)能快速促进这种细菌的生长,而以前被认为是NAD前体的烟酸、烟酰胺、色氨酸和天冬氨酸没有此功能。2000年,酵母Sir2被发现是一种NAD依赖的蛋白质赖氨酸去乙酰化酶,为调节寿命的基因和酶感知NAD的代谢活动。令人惊异是,当NAD合成酶(谷氨酰胺水解酶)从酵母细胞中被删除后,烟酰胺核糖能让酵母细胞生长。因此,科学家克隆了酵母和人类的烟酰胺核糖激动酶,而且在实验室和机体内都证明:通过烟酰胺核糖激动酶,烟酰胺核糖(NR)转化为烟酰胺单核苷酸(NMN)。也证实烟酰胺核糖在牛奶中天然存在,人类可以通过口服烟酰胺核糖,提高血液中NAD的新陈代谢。此后,烟酰胺核糖的研究逐渐成为热点,科学家们发现烟酰胺核糖有许多生物学功能,能显著提高细胞活力,特别是提高衰老细胞的活力。对人体的新陈代谢、免疫力、大脑功能、心血管功能等方面都有明显的改善作用,能够通过整体提升人体机能,让体内细胞处于一种新的活跃状态,达到延缓衰老的目的。
目前,提高机体烟酰胺腺嘌呤二核苷酸代谢水平是以烟酰胺核糖或烟酰胺单核苷酸作为小分子补充剂直接应用。通过实际临床前实验发现,常用的补充烟酰胺核糖或烟酰胺单核苷酸途径是口服或者血管内注射方式,口服会使烟酰胺核糖或烟酰胺单核苷酸进入胃里,在强酸条件下(胃内的pH值大约为2.1),该类物质易水解失活,进而利用率低,活性差;血管内注射的方式虽然可以使烟酰胺核糖或烟酰胺单核苷酸直接进入血液循环,由于其分子量小,代谢快等原因导致药物在体内快速清除,进而利用率低,且给药方式不便于日常补充,因此,如何在不影响烟酰胺核糖或烟酰胺单核苷酸药效的情况下,提高其生物利用度且延长体内半衰期是目前研究的热点。
发明内容
本发明目的之一在于,提供如式I所示的烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物,经合理制剂形式能避免其口服在胃酸内失活,或静脉注射快速代谢消除的问题,有效提高烟酰胺核糖的活性和利用率。
本发明目的之二在于,提供该烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物的制备方法。
本发明目的之三在于,提供该烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物在制备治疗老年退行性疾病的药物中的应用。
为实现上述目的,本发明采用的技术方案如下:
本发明所述的一种烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物,其结构如式I所示:
其中,R1选自H、H2PO3、磷酸盐中的任意一种;
R2为大分子载体化合物基团,优选为多糖、多肽或高分子聚合物;
R3选自H、氟、氯、溴、羟基、甲氧基、三氟甲基、氰基、氨基、甲酰基、甲酰胺基中的一种。
本发明所述烟酰胺核糖或烟酰胺单核苷酸类似物包括:与烟酰胺核糖或烟酰胺单核苷酸的主体结构相同而使其活性相同或相似的物质,例如,对于烟酰胺单核苷酸来说,其磷酸基团其中氢原子被取代基取代形成的物质,取代基可以是无机物(如形成盐),也可以是有机物(如形成共晶)。
本发明的部分实施方案中,为式I化合物药学上可接受上的盐、或共晶。
本发明的载体轭合物在体内通过水解作用释放活性分子,进而可以避免小分子活性物质提前失活和快速代谢消除,使更多的小分子活性物质到达病灶,进而发挥出功效,由此解决现有烟酰胺核糖的活性和利用率低的问题。
本发明的部分实施方案中,所述多糖包括通过酰胺键连接的酸性多糖透明质酸、硫酸软骨素、低分子量肝素或羧甲基壳聚糖中的任意一种或几种,以及通过动态亚胺键连接的壳聚糖;
或/和所述多肽包括通过动态亚多肽包括通过动态亚胺键连接的明胶、聚赖氨酸、聚谷氨酸、胶原蛋白或粘弹蛋白中的任意一种或几种;
或/和所述高分子聚合物包括通过动态亚胺键连接的低分子量聚乙烯亚胺、聚酰胺-胺树状聚合物中的一种或两种。
本发明所述的载体轭合物的制备方法,其特征在于,包括:将大分子载体化合物硼酸化后,再与烟酰胺核糖或烟酰胺单核苷酸反应,生成所述烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物;优选地,采用苯硼酸或其衍生物对大分子载体化合物硼酸化。
本发明的部分实施方案中,包括以下步骤:
S1.配制大分子载体化合物溶液,加入苯硼酸或其衍生物、以及反应助剂,保护气体条件下反应,生成苯硼酸修饰的大分子载体化合物;
S2.将烟酰胺核糖或烟酰胺单核苷酸或其药学上可接受的盐或共晶加入到苯硼酸修饰的大分子载体化合物溶液中,在保护气体条件下反应,生成烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物;
优选地,所述苯硼酸修饰的大分子载体化合物溶液为S1生成的苯硼酸修饰的大分子载体化合物经分离、纯化后,再溶于溶剂制得;或者为S1反应后的溶液。
本发明的部分实施方案中,所述S1中,反应助剂包括1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺中的一种或两种;
所述S1中,反应体系的pH值为5.5-6.5。
本发明的部分实施方案中,
S1中,苯硼酸的用量为大分子载体化合物中可反应羧基摩尔量的10%-40%;所述反应助剂的用量为大分子载体化合物2-5倍摩尔量;
优选地,S1中,大分子载体化合物溶液的质量浓度为1-3%;
优选地,S2中,苯硼酸修饰的大分子载体化合物与烟酰胺核糖或烟酰胺单核苷酸的摩尔比为:1:0.5-5;再优选为1:0.5-2;更优选为1:1;
优选地,S2中,所述溶剂包括缓冲溶液,优选为PBS溶液,更优选为浓度为0.1-0.2M的PBS溶液;
优选地,S2中,S1生成的苯硼酸修饰的大分子载体化合物经分离、纯化后,再溶于溶剂制得质量浓度为1-3%的苯硼酸修饰的大分子化合物溶液;
优选地,S1和S2中的保护气体为均为氮气或惰性气体。
本发明的部分实施方案中,
S1中的反应温度为:25±5℃;反应时间为2-48小时;优选为8-24小时;
S2中的反应温度为:25±5℃;反应时间为0.5-8小时,优选为2-4小时。
本发明的部分实施方案中,还包括烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物的纯化步骤;优选地,将S2制得的烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物经透析纯化,进一步优选的,透析膜的截留分子量为1000-3500。
本发明所述的烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物在制备治疗老年退行性疾病的药物中的应用。
本发明所述的一种药物组合物,其包上述的烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物以及一种或多种药学上可接受的载体;
优选地,所述组合物为口服制剂或注射制剂;
更优选地,所述口服制剂为肠溶口服制剂,包括肠溶口服固体制剂、肠溶口服液体制剂;
再进一步优选地,所述肠溶口服固体制剂包括肠溶胶囊剂、肠溶片剂、肠溶丸剂、肠溶散剂、肠溶颗粒剂;
优选地,注射制剂包括注射液、注射用无菌粉末、注射用浓溶液。
与现有技术相比,本发明具有以下有益效果:
本发明设计科学,构思巧妙,创造性地通过苯硼酸或其衍生物修饰大分子载体化合物,然后与烟酰胺核糖或烟酰胺单核苷酸类似物结合形成药物-大分子载体轭合物,在发生病变的心、脑、眼等器官部位,由于衰老细胞代谢,处于促炎弱酸环境中,pH值大约为6-6.5,在该弱酸环境下,该载体轭合物水解释放小分子烟酰胺核糖或烟酰胺单核苷酸类似物,这样就避免了这些小分子物质失活和流失,进而提高了烟酰胺核糖的活性和利用率。
本发明的制备方法简单,收率高,对环境友好,适宜工业化生产。
附图说明
附图1为实施例1制备的烟酰胺核糖-低分子量肝素轭合物的1H-NMR核磁图谱;
附图2为实施例2制备的烟酰胺核糖-透明质酸轭合物的1H-NMR核磁图谱;
附图3为实施例3制备的烟酰胺核糖-硫酸软骨素轭合物的1H-NMR核磁图谱;
附图4为实施例4制备的烟酰胺烟酰胺核糖-羧甲基壳聚糖轭合物1H-NMR核磁图谱;
附图5为实施例5制备的烟酰胺单核苷酸-壳聚糖轭合物的1H-NMR核磁图谱;
附图6为实施例6制备的烟酰胺单核苷酸-聚乙烯亚胺轭合物的1H-NMR核磁图谱;
附图7为实施例7制备的烟酰胺核糖-明胶轭合物的1H-NMR核磁图谱;
附图8为实施例1、2、3、4所制备的烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物在中性条件下NR的响应性释放行为图;
附图9为实施例1、2、3、4所制备的烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物在酸性条件下NR的响应性释放行为图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
本发明实施例中化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-0(ppm)的单位给出。NMR的测定是用(Bruker Avance III 600和BrukerAvance 400)核磁仪,测定溶剂为氘代二甲基亚砜(D-DMSO),氘代水(D2O),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦126DAD高压液相色谱仪(zorbax SB-C18100×4.6mm)。
实施例1
本实施例公开了本发明的载体轭合物的制备方法,具体为:
称取一定量的低分子量肝素溶于质量浓度为1%MES溶液,配制成质量浓度为2%的低分子量肝素溶液,再分别加入2倍低分子量肝素摩尔量的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS),常温搅拌。然后加入计算量(为低分子量肝素分子中可反应羧基摩尔量的10%)的3-氨基-4-氟苯硼酸,在高纯氮保护条件下避光搅拌,常温反应8小时。产物经去离子水透析(透析膜截留分子量3500)12小时,经冷冻干燥得到苯硼酸修饰的肝素。
称取一定量苯硼酸修饰的肝素溶于0.1M PBS,配制成质量浓度为1%溶液,然后加入与硼酸修饰的肝素等摩尔量的烟酰胺核糖,常温搅拌2小时,产物经去离子水透析(透析膜截留分子量3500)过夜,经冷冻干燥得到烟酰胺核糖-肝素轭合物,收率为74.8%。
经1H-NMR鉴定其结构,其1H-NMR核磁图谱如图1所示。
实施例2
本实施例公开了本发明的载体轭合物的制备方法,具体为:
称取一定量的透明质酸溶于质量浓度为1%MES溶液,配制成质量浓度为2%的透明质酸溶液,再分别加入2.5倍透明质酸摩尔量的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS),常温搅拌。然后加入计算量(为透明质酸分子中可反应基羧基摩尔量的40%)的3-氨基苯硼酸,在高纯氮保护条件下避光搅拌,常温反应24小时。产物经去离子水透析(透析膜截留分子量3500)24小时,经喷雾干燥得到苯硼酸修饰的透明质酸。
称取一定量苯硼酸修饰的透明质酸溶于0.2M PBS,配制成质量浓度为1%溶液,然后加入与苯硼酸修饰的透明质酸等摩尔量的烟酰胺核糖,常温搅拌4小时,产物经去离子水透析(透析膜截留分子量3500)过夜,经喷雾干燥得到烟酰胺核糖-透明质酸轭合物,收率为80.4%。
经1H-NMR鉴定其结构,其1H-NMR核磁图谱如图2所示。
实施例3
本实施例公开了本发明的载体轭合物的制备方法,反应式为:
称取一定量的硫酸软骨素酸溶于质量浓度为1%的MES溶液,配制成质量浓度为2%的硫酸软骨素溶液,分别加入5倍硫酸软骨素酸摩尔量的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺,常温搅拌。然后加入计算量(为硫酸软骨素分子中可反应基羧基摩尔量的30%)的3-氨基苯硼酸,在高纯氮保护条件下避光搅拌,常温反应16小时。产物经去离子水透析(透析膜截留分子量3500)12-24小时,经冷冻干燥得到苯硼酸修饰的硫酸软骨素。
称取一定量苯硼酸修饰的硫酸软骨素溶于0.2M PBS,配制成质量浓度为1%溶液,然后加入与苯硼酸修饰的硫酸软骨素等摩尔量的烟酰胺核糖,常温搅拌4小时,产物经去离子水透析(透析膜截留分子量3500)过夜,经冷冻干燥得到烟酰胺核糖-硫酸软骨素轭合物,收率为68.6%。
经1H-NMR鉴定其结构,其1H-NMR核磁图谱如图3所示。
实施例4
本实施例公开了本发明的载体轭合物的制备方法,反应式为:
称取一定量的羧甲基壳聚糖溶于去离子水配制成质量浓度为1%的溶液,以冰醋酸调节溶液pH至5.5,再分别加入2倍羧甲基壳聚糖摩尔量的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺,常温搅拌。然后加入计算量(为羧甲基壳聚糖分子中可反应基羧基摩尔量的40%)的3-氨基苯硼酸,在高纯氮保护条件下避光搅拌,常温反应24小时。产物经去离子水透析(透析膜截留分子量3500)24小时,经喷雾干燥得到苯硼酸修饰的壳聚糖。
称取一定量苯硼酸修饰的壳聚糖溶于0.1M PBS,配制成质量浓度为1%的溶液,然后加入与苯硼酸修饰的壳聚糖等摩尔量的烟酰胺核糖,常温搅拌3小时,产物经去离子水透析(透析膜截留分子量3500)过夜,经喷雾干燥得到烟酰胺核糖-壳聚糖轭合物,收率为60.5%。
经1H-NMR鉴定其结构,其1H-NMR核磁图谱如图4所示。
实施例5
本实施例公开了本发明的载体轭合物的制备方法,反应式为:
称取一定量的脱乙酰化壳聚糖溶解于质量浓度为0.2%的醋酸溶液,配制成质量浓度为1%的壳聚糖溶液,然后加入计算量(为脱乙酰化壳聚糖分子中可反应氨基摩尔量的20%)的2-甲醛基苯硼酸,在高纯氮保护条件下避光搅拌,常温反应12小时,产物经去离子水透析(透析膜截留分子量3500)15小时,经冷冻干燥得到苯硼酸修饰的壳聚糖。
称取一定量苯硼酸修饰的壳聚糖溶于0.1M PBS溶液,配制成质量浓度为1%的溶液,然后加入与苯硼酸修饰的壳聚糖等摩尔量的烟酰胺单核苷酸,常温避光搅拌2小时。产物经去离子水透析(透析膜截留分子量3500)过夜,经冷冻干燥或者喷雾干燥得到烟酰胺单核苷酸-壳聚糖轭合物,收率为:75.8%。
经1H-NMR鉴定其结构,其1H-NMR核磁图谱如图5所示。
实施例6
本实施例公开了本发明的载体轭合物的制备方法,反应式为:
称取一定量的低分子量聚乙烯亚胺(Mw:1800)溶解于0.1M PBS溶液,制成质量浓度为3%的溶液,然后加入计算量(为低分子量聚乙烯亚胺分子中可反应氨基摩尔量的40%)的2-甲醛基苯硼酸,在高纯氮保护条件下避光搅拌,常温反应16小时,然后加入与低分子量聚乙烯亚胺等摩尔量的烟酰胺单核苷酸,常温继续避光搅拌4小时。产物经去离子水透析(透析膜截留分子量1000)过夜,经冷冻干燥得到烟酰胺单核苷酸-聚乙烯亚胺轭合物,收率为77.2%。
经1H-NMR鉴定其结构,其1H-NMR核磁图谱如图6所示。
实施例7
本实施例公开了本发明的载体轭合物的制备方法,反应式为:
称取一定量的明胶溶解于0.2M PBS溶液,配制成质量浓度为2%的溶液,然后加入计算量(为明胶分子中可反应氨基摩尔量的25%)的2-甲醛基苯硼酸,避光在高纯氮保护条件下搅拌常温反应16小时,然后加入与明胶等摩尔量的烟酰胺核糖,常温继续避光搅拌2-4小时。
产物经去离子水透析(透析膜截留分子量3500)过夜,经冷冻干燥或者喷雾干燥得到烟酰胺核糖-明胶轭合物,收率为88.5%。
经1H-NMR鉴定其结构,其1H-NMR核磁图谱如图7所示。
实施例8
本实施例公开了本发明的载体轭合物的酸响应性释放实验,具体为:
1、实验方法
配制pH 5.5和7.45的0.02M磷酸缓冲液作为释放介质。将36mm的透析袋(MW:3500)置于100℃水浴中活化30min后,精密量取待测样品2mL封装入透析袋,游离药物作为对照组,置于装有20mL释放介质的EP管中,平行三组。将装有透析袋的EP管置于恒温器浴振荡器中连续释放3d(37℃,65rpm),分别取0.5,1,2,4,8,12,48,72h的释放液经高效液相色谱进行药物含量检测。色谱条件为:以十八烷基硅烷键合硅胶为填充剂,以甲醇-0.1wt%庚烷磺酸钠缓冲盐溶液(20:80,v/v)为流动相,其中缓冲盐溶液的pH值为3.5;流速为1mL/min,等度洗脱,柱温为30℃,检测波长为261nm。
计算释放介质中药物的累积释放量占释放总量的百分比。
2、实验结果
实施例1所得烟酰胺核糖-肝素轭合物、实施例2所得烟酰胺核糖-透明质酸轭合物、实施例3所得烟酰胺核糖-硫酸软骨素轭合物、实施例4所得烟酰胺核糖-壳聚糖轭合物以及游离的烟酰胺核糖在体外酸性条件下释放曲线如图8所示,中性条件下释放曲线如图9所示。
由图8可知,本发明的大分子载体轭合物在中性环境下释放量很少,由图9可知,本发明的大分子载体轭合物在酸性条件下释放较好。在发生病变的心、脑、眼等器官部位,由于衰老细胞代谢,处于促炎弱酸环境中,pH值大约为6-6.5。在该弱酸环境下,本发明的大分子载体轭合物水解释放小分子烟酰胺核糖或烟酰胺单核苷酸类似物,这样就避免了这些小分子物质失活和流失,进而提高了烟酰胺核糖的活性和利用率。
实施例9
本实施例公开本发明的大分子载体轭合物对脑损伤动物模型的药效学实验。
动物与分组:
成年雄性SD大鼠50只(购于成都达硕生物科技有限公司),200-250g,随机分为假手术组,模型组,实验1组,实验2组,实验3组(n=10)。
实验组给药剂量(按烟酰胺核糖计)为35mg/kg/天(实验1组采用烟酰胺核糖;实验2组采用按实施例2方法制得的烟酰胺核糖-透明质酸轭合物;实验3组采用按实施例7方法制得的烟酰胺核糖-明胶轭合物,模型组动物给生理盐水)。
各组动物静脉注射给药,连续7天。然后建立大鼠脑缺血再灌注损伤模型:麻醉动物,采用线栓大脑中动脉制备局灶性脑缺血模型,缺血30分钟后,开放再灌注。假手术组仅分离血管,不进线。拔线后,假手术组与模型组尾静脉注射1mL生理盐水;实验1组、2组与3组分别尾静脉注射1mL的对应药物。复灌24h后,处死大鼠,各组取脑组织,部分行2mm冠状切片,TTC染色后,用Image Pro图像分析软件处理分析,计算脑梗死体积;部分行组织匀浆,取上清液,商用SOD和MDA试剂盒测定SOD和MDA的含量。
所有数据都以均数±标准差表示,并行单因素方差分析,P<0.05表示差异有统计学意义。*P<0.05和**P<0.01vs.对照组。实验结果如下:
表1实验结果
由表1数据分析可得,本发明制备的烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物可以降低线栓法MCAO大鼠脑梗死体积,可通过减轻炎症反应和能量再生障碍,对脑卒中后产生的脑损伤具有明显的保护作用。
实施例10
本实施例公开了本发明的烟酰胺核糖或烟酰胺单核苷酸类似物-大分子载体轭合物对眼底黄斑病变的药效学实验。
动物与分组:BALB/C小鼠50只(购于成都达硕生物科技有限公司),18-20g,适应性常规喂养1周后,随机分为对照组,模型组,实验1组,实验2组(n=10)。
实验1组使用烟酰胺核糖;实验2组使用按实施例5方法制得的烟酰胺核糖-壳聚糖轭合物(均经腹腔注射给样,按烟酰胺核糖计50mg/kg),连续预处理7天,对照组、模型组给予等体积生理盐水;随后模型组和实验组小鼠经尾静脉注射碘酸钠(25mg/kg)建立AMD模型,对照组给予等体积生理盐水。造模后实验1组继续使用烟酰胺核糖,实验2组使用烟酰胺核糖-壳聚糖轭合物腹腔注射处理14天,对照组和模型组则给予等体积生理盐水。4周后行眼底荧光血管造影及光相干断层扫描(OCT):小鼠麻醉后,1%荧光素钠注射液0.2ml腹腔注射,注射开始计时行眼底荧光血管造影(FFA)检查双眼并于1s内注射完成。使用30°摄像镜头对准视乳头及周围区域获取后极部视网膜图像,1min内间隔5s连续摄取FFA图像,1~5min内间隔30s,5~10min内间隔1min,共拍摄10min并将图像存盘。OCT在FFA检查完成后加置特制动物镜头再行检查,应用多线扫描模式检查视网膜形态结构。眼底荧光血管造影及光相干断层扫描(OCT)结果如表2所示。影像学检测完成后各组动物分离将眼球,分离视网膜-脉络膜-巩膜,进行病理检测。对视网膜组织形态学进行评价。结果如表3所示。所有数据都以均数±标准差表示,并行单因素方差分析,P<0.05表示差异有统计学意义。*P<0.05和**P<0.01vs对照组。实验结果如下:
表2眼底荧光血管造影及光相干断层扫描(OCT)结果
对照组 | AMD模型组 | 实验1组 | 实验2组 | |
CNV面积(mm<sup>2</sup>) | 0 | 0.52 | 0.49* | 0.21** |
CRT(μm) | 198 | 323.4 | 319.2* | 220.5** |
*CNV choroidal neovascularization脉络膜新生血管;CRT central retinal
thickness视网膜中央厚度。
表3组织石蜡切片HE染色结果表
由表2和表3可知,本发明的烟酰胺核糖-壳聚糖轭合物能有效治疗眼底黄斑病变。
最后应说明的是:以上各实施例仅仅为本发明的较优实施例用以说明本发明的技术方案,而非对其限制,当然更不是限制本发明的专利范围;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围;也就是说,但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色,其所解决的技术问题仍然与本发明一致的,均应当包含在本发明的保护范围之内;另外,将本发明的技术方案直接或间接的运用在其他相关的技术领域,均同理包括在本发明的专利保护范围内。
Claims (8)
2.根据权利要求1所述的应用,其特征在于,所述老年退性疾病包括衰老导致的心脑血管疾病以及年龄相关视网膜疾病。
3.根据权利要求1所述的应用,其特征在于,所述药物还包括一种或多种药学上可接受的载体。
4.根据权利要求1所述的应用,其特征在于,所述药物为口服制剂或注射制剂。
5.根据权利要求4所述的应用,其特征在于,所述口服制剂为肠溶口服制剂,包括肠溶口服固体制剂、肠溶口服液体制剂。
6.根据权利要求5所述的应用,其特征在于,所述肠溶口服固体制剂包括肠溶胶囊剂、肠溶片剂、肠溶丸剂、肠溶散剂、肠溶颗粒剂。
7.根据权利要求4所述的应用,其特征在于,所述注射制剂包括注射液、注射用无菌粉末。
8.根据权利要求4所述的应用,其特征在于,所述注射制剂为注射用浓溶液。
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