CN111281980A - 一种水溶性γ-聚谷氨酸-替米考星复合物及其制备方法 - Google Patents
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Abstract
本发明公开了一种水溶性γ‑聚谷氨酸‑替米考星复合物。以γ‑聚谷氨酸为原料,通过替米考星与γ‑聚谷氨酸成盐反应,将替米考星连接到γ‑聚谷氨酸分子上制备了γ‑聚谷氨酸‑替米考星复合物。所得复合物易溶于水,适口性好,有缓释性能,毒性低,抗菌活性好。
Description
技术领域
本发明涉及一种水溶性γ-聚谷氨酸-替米考星复合物及其制备方法。属于抗菌药物制备领域。
背景技术
替米考星是一种大环内酯类畜禽专用抗菌药,具有抗菌活性强,抗菌谱广,无交叉耐药性的优点,为畜禽细菌感染性疾病治疗的首选药物。已经在澳大利亚、巴西、法国、马来西亚、意大利、西班牙、美国等国家批准上市。但替米考星水溶性很差,限制了其在临床上的应用。
聚谷氨酸是一种水溶性、可生物降解、不含毒性的生物高分子,在医药领域应用较广泛。因其具有良好的生物亲和性和生物降解性,作为药物载体,可实现药物的缓释性、靶向性,提高药物的水溶性,降低药物的毒副作用。叶海峰等以γ-聚谷氨酸作为载体连接顺铂,制备了聚谷氨酸顺铂复合物 (Biomaterials,2006,27(35):5958-5965)。李文娟等制备了γ-聚谷氨酸天冬氨酸-顺铂复合物(中国医药生物技术,2010,5(2):98-104),这些复合物的水溶性和毒性均得到很大改善。本发明将水不溶性的替米考星通过成盐反应连接到γ-聚谷氨酸载体上,制备了水溶性的聚谷氨酸-替米考星复合物。该复合物抗菌活性好。
发明内容
本发明的目的是提供一种水溶性γ-聚谷氨酸-替米考星复合物,该复合物毒性低,载药量高,动物适口性好,具有缓释性能。
本发明的另一目的是提供一种水溶性γ-聚谷氨酸-替米考星复合物的制备方法。
本发明的再一目的是提供一种水溶性γ-聚谷氨酸-替米考星复合物在抗菌领域的应用。
本发明采用的技术方案是:
(1)将γ-聚谷氨酸溶于蒸馏水制成2%左右的溶液,加浓盐酸调pH2-3,在 121℃,0.1MPa条件下水解20min,冰浴冷却后,用1mol/L的NaOH溶液调节pH7-8,蒸馏水透析纯化24h,冷冻干燥,制得小分子γ-聚谷氨酸。
(2)将适量的小分子γ-聚谷氨酸溶于蒸馏水中,将适量的替米考星溶于乙醇中,室温下,将替米考星乙醇溶液慢慢加入到γ-聚谷氨酸水溶液中,搅拌12h,减压蒸除乙醇,剩余溶液用蒸馏水透析24h,除去未反应的替米考星等小分子化合物,冷冻干燥制得γ-聚谷氨酸-替米考星复合物。
所述复合物的分子量为40-70KDa。
所述水溶性γ-聚谷氨酸-替米考星复合物,以离子键形式连接γ-聚谷氨酸与替米考星。
所述的复合物溶于水,载药量高,动物适口性好,有缓释性能,抗菌活性优于替米考星。
附图说明:
图1:本发明的γ-聚谷氨酸-替米考星复合物结构式;
图2:本发明的γ-聚谷氨酸-替米考星复合物在PBS缓冲液中的释放曲线;
图3:本发明的γ-聚谷氨酸-替米考星复合物在人工胃液中的释放曲线。
具体实施方式
下面结合附图和具体的优选实施例来进一步说明本发明的技术方案。
实施例1
将10gγ-聚谷氨酸溶于490mL蒸馏水制成2%的溶液,加浓盐酸调pH2-3,在121℃,0.1MPa条件下水解20min,冰浴冷却后,用1mol/L的NaOH溶液调节 pH7-8,蒸馏水透析纯化24h,冷冻干燥,制得小分子γ-聚谷氨酸。
将1g的小分子γ-聚谷氨酸溶于30mL蒸馏水中,将0.15g替米考星溶于5mL 乙醇中,室温下,将替米考星乙醇溶液慢慢加入到γ-聚谷氨酸水溶液中,搅拌 12h,减压蒸除乙醇,剩余溶液用蒸馏水透析24h,除去未反应的替米考星,冷冻干燥制得γ-聚谷氨酸-替米考星复合物。替米考星载药量32.1%。
实施例2
将1g的小分子γ-聚谷氨酸溶于30mL蒸馏水中,将0.2g替米考星溶于5mL 乙醇中,室温下,将替米考星乙醇溶液慢慢加入到γ-聚谷氨酸水溶液中,搅拌 12h,减压蒸除乙醇,剩余溶液用蒸馏水透析24h,除去未反应的替米考星,冷冻干燥制得γ-聚谷氨酸-替米考星复合物。替米考星载药量33.3%。
实施例3
将1g的小分子γ-聚谷氨酸溶于30mL蒸馏水中,将0.25g替米考星溶于5mL 乙醇中,室温下,将替米考星乙醇溶液慢慢加入到γ-聚谷氨酸水溶液中,搅拌 12h,减压蒸除乙醇,剩余溶液用蒸馏水透析24h,除去未反应的替米考星,冷冻干燥制得γ-聚谷氨酸-替米考星复合物。替米考星载药量33.7%。
实施例4
复合物体外释放研究
将实施例1所制备的γ-聚谷氨酸-替米考星复合物配制成含替米考星浓度为1mg/mL的溶液,放入透析袋中,加5倍量的PBS缓冲液(pH7.4)或加5倍量的人工胃液(pH1.5)混合,37℃恒温震荡箱中放置,分别于不同时间段 (1,2,3,4,5,6,7,8,9,10,12,24,36,48,60,72,84h)取1mL样品保存备用,同时体系再补加1mL新PBS溶液,用HPLC[Waters sysmmtryC18色谱柱(4.6mm ×250mm),流速1.0mL/min,检测波长280nm,柱温30℃,流动相为乙腈:四氢呋喃:磷酸二丁胺缓冲液:水110:55:25:800(体积比)]检测其中释放出来的游离替米考星的量,计算累计释放率(图2-3)。结果显示,在PBS缓冲液中,γ-聚谷氨酸-替米考星复合物释药较缓慢,48h累计释放率达到50%左右。在人工胃液中,γ-聚谷氨酸-替米考星复合物前9小时释药速度较快,之后释放趋于平缓,12h累计释放率达到50%左右。
实施例5
体外抑菌实验
以金黄色葡萄球菌、链球菌、大肠杆菌、沙门氏菌和猪肺炎支原体为试验菌株,培养取对数生长期的菌液,将替米考星和实施例1所制备的γ-聚谷氨酸-替米考星复合物溶解到一定的浓度,采用二倍稀释法进行最小抑菌浓度(MIC) 的测定(表1)。结果显示γ-聚谷氨酸-替米考星复合物对金黄色葡萄球菌、链球菌、大肠杆菌、沙门氏菌的抑制活性优于替米考星。
表1 γ-聚谷氨酸-替米考星复合物体外抗菌活性
实施例6
选30头体重40-50kg的健康猪,随机分成3组,每组10头,前两组分别喂掺本发明实施例3所制备的γ-聚谷氨酸-替米考星复合物和替米考星的饲料,给药剂量以替米考星计200g/吨饲料,第3组为对照组,饲料中不加任何药物,试期为1周,记录每组日平均采食量(表2)。结果显示:喂掺γ-聚谷氨酸 -替米考星复合物饲料组的猪日平均采食量与对照组的猪日平均采食量相当,说明γ-聚谷氨酸-替米考星复合物适口性好,不影响猪采食。
表2采食量的影响
Claims (3)
1.一种水溶性γ-聚谷氨酸-替米考星复合物,所述复合物由γ-聚谷氨酸与替米考星通过成盐反应得到。
2.根据权利要求1所述的一种水溶性γ-聚谷氨酸-替米考星复合物,其特征在于,水溶性γ-聚谷氨酸-替米考星复合物的制备方法包括以下步骤:
(1)将γ-聚谷氨酸溶于蒸馏水制成2%左右的溶液,加浓盐酸调pH2-3,在121℃,0.1MPa条件下水解20min,冰浴冷却后,用1mol/L的NaOH溶液调节pH7-8,蒸馏水透析纯化24h,冷冻干燥,制得小分子γ-聚谷氨酸;
(2)将适量的小分子γ-聚谷氨酸溶于蒸馏水中,再将适量的替米考星溶于乙醇中,室温下,将替米考星乙醇溶液慢慢加入到γ-聚谷氨酸水溶液中,搅拌12h,减压蒸除乙醇,剩余反应液用蒸馏水透析24h,除去未反应的替米考星等小分子化合物,冷冻干燥制得γ-聚谷氨酸-替米考星复合物。
3.根据权利要求1所述的一种水溶性γ-聚谷氨酸-替米考星复合物,其特征在于,所述的复合物溶于水、动物适口性好,有缓释性能、抗菌活性好于替米考星。
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CN112717138A (zh) * | 2021-01-15 | 2021-04-30 | 齐齐哈尔医学院 | γ-聚谷氨酸纳米载体及其制备方法与应用 |
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