CN113663085A - 基于卤代环氧烷烃接枝制备皂苷-壳聚糖衍生物的方法及其应用 - Google Patents
基于卤代环氧烷烃接枝制备皂苷-壳聚糖衍生物的方法及其应用 Download PDFInfo
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- CN113663085A CN113663085A CN202110983593.8A CN202110983593A CN113663085A CN 113663085 A CN113663085 A CN 113663085A CN 202110983593 A CN202110983593 A CN 202110983593A CN 113663085 A CN113663085 A CN 113663085A
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Abstract
本发明公开了一种基于卤代环氧烷烃接枝制备皂苷‑壳聚糖衍生物的方法及其应用,属于生物材料领域。本发明利用卤代环氧烷烃,把中草药中常见的有效成分——皂苷,接枝到壳聚糖衍生物上,得到皂苷‑壳聚糖衍生物,其使皂苷类药物可以随着壳聚糖衍生物的降解而释放,从而达到缓释的效果。将所得皂苷‑壳聚糖衍生物进一步制备成可注射型水凝胶,可应用于骨组织修复。本发明为皂苷药物改性困难、难以达到缓释效果等问题提供了解决方法,使皂苷类药物可以实现缓释,将其作为骨修复材料可以提高骨组织的修复效果。
Description
技术领域
本发明属于生物材料领域,具体涉及一种基于卤代环氧烷烃接枝制备皂苷-壳聚糖衍生物的方法及其应用。
背景技术
骨组织修复分为直接修复和间接修复两种,如果骨折间隙小于0.1 mm,称为直接修复,其在骨折被适当固定的情况下,可以自行愈合;如果骨折间隙小于骨直径的两倍(对长骨而言),称为间接修复,其需通过一系列复杂的生物学过程,形成血管并重塑骨骼,在骨修复材料的作用下可以愈合的较快较好。若骨折间隙大于骨直径的两倍(对长骨而言),在没有骨修复材料的帮助下终身不可能修复。因此,骨修复材料对于较严重的骨折来说非常重要。为加强骨修复材料的性能,负载药物是一种常用的手段。药物负载的同时需要达到药物缓释,且在骨折修复初期持续释放(约1个月),对于水溶性较强的药物来说,微球、囊泡和高分子膜包裹等载药手段都很难达到要求。由于高分子材料在人体内代谢分解较慢,把药物接枝到高分子材料上可有效延长药物释放的时间,达到持续释放的效果。
皂苷广泛存在于中草药中,是大多中草药的有效成分,如川续断皂苷VI是中草药续断的有效成分。现代药理学研究发现,川续断皂苷VI能有效抑制β3-整联蛋白,减少破骨细胞对骨质的吸收,从而促进成骨,且可以通过诱导RUNX2和OCN的表达来刺激脂肪干细胞的成骨分化并有促进钙沉积的效果。然而,皂苷的水溶性较好,植入后容易被体液冲走,且分子结构缺乏氨基、羧基之类容易发生化学反应基团,较难与高分子材料接枝,因此很难达到持续释放的效果。
专利CN 111748053A公开了一种抗凝血共聚物的制备方法及其应用,该共聚物首先由单体A、B、C三种单体按比例加聚形成聚合物,其中,单体A含有双键和磺酸基团,单体B为含有双键和吡咯环的亲水性物质,单体C为含有双键的疏水性物质,然后通过将聚合物侧链的吡咯环打开,通过酯化反应接枝上维生素和薯蓣皂苷元即可制得。该共聚物能对聚氨酯材料表面进行改性,改性后的聚氨酯表面同时具有良好的抗凝血、抗感染、抗蛋白吸附、抗血栓性能,有良好的应用前景。
专利CN 109276762A提供了一种人参皂苷Rg1改性纤维支架,该人参皂苷Rg1改性纤维支架为多孔纤维状,其纤维直径为10nm~100μm,该人参皂苷Rg1改性纤维支架中人参皂苷Rg1负载于基质材料上,基质材料为聚己内酯、聚丙交酯、聚乙交酯、丙交酯-乙交酯共聚物、聚(3-羟基丁酸酯-co-3-羟基戊酸酯)中的至少一种,人参皂苷Rg1的负载量为0.01wt%~1wt%。该人参皂苷Rg1改性纤维支架具有良好的生物活性、生物相容性及生物稳定性,将该支架材料直接植入到缺损部位,可以促进软骨细胞增殖,促进软骨细胞在炎症环境下表型维持能力。
从以上可以看出,至今还没有人把皂苷药物与天然高分子材料接枝制备出可以通过人体代谢持续释放皂苷类药物且适合用于骨组织修复的材料。
壳聚糖是一种从虾蟹等生物体提取的天然多糖材料,由甲壳素脱乙酰化获得,不会造成免疫排斥或跨物种病毒感染,具有较好的生物相容性,有抗炎、抗菌和抗氧化等效果,然而壳聚糖的水溶性较差,只能溶于酸性溶剂,且溶解后氨基被离子化,难以参与化学反应,因此对壳聚糖加入羧基、羟基等基团制备成壳聚糖衍生物,改善壳聚糖的水溶性,可使壳聚糖更容易发生化学反应。
发明内容
本发明为克服现有技术的缺点与不足,提供一种基于卤代环氧烷烃接枝制备皂苷-壳聚糖衍生物的方法及其在骨组织修复上的应用。
为了实现上述目的,本发明采用的技术方案如下:
本发明的目的之一是保护一种基于卤代环氧烷烃接枝制备皂苷-壳聚糖衍生物的方法,其包括以下步骤:
(1)皂苷环氧化改性:把皂苷配成一定浓度的水溶液,调节pH值后,加入一定量的卤代环氧烷烃,加热到一定温度后反应一定时间,然后加入有机溶剂萃取数次,收集水相,得到环氧烃基皂苷溶液;
(2)壳聚糖衍生物接枝皂苷:将步骤(1)得到的环氧烃基皂苷溶液的pH值调到一定值,加入一定量的壳聚糖衍生物,反应一定时间后加入一定量无水乙醇,收集析出物,用无水乙醇清洗至中性,干燥,得到所述皂苷-壳聚糖衍生物。
优选地,步骤(1)中所述皂苷为川续断皂苷VI、三七皂苷R1或人参皂苷Ro;将其配成0.1~100 mg/ml的水溶液。
优选地,步骤(1)中采用氢氧化钠将水溶液的pH值调到8~14。
优选地,步骤(1)中所述卤代环氧烷烃为环氧氯丙烷、4-溴-1,2-环氧丁烷或4-碘-1,2-环氧丁烷,其加入量为所用皂苷摩尔量的0.5~2倍。
优选地,步骤(1)中所述加热的温度为30~90 ℃。
优选地,步骤(1)中所述反应的时间为1~48小时。
优选地,步骤(1)中所述有机溶剂为苯、四氯化碳或乙酰乙酯;其加入量为反应液体积的2~5倍。
优选地,步骤(1)中所述萃取的次数为3~5次。
优选地,步骤(2)中采用氢氧化钠将环氧烃基皂苷溶液的pH值调到8~14。
优选地,步骤(2)中所述壳聚糖衍生物为羧甲基壳聚糖、羟丙基壳聚糖或乙二醇壳聚糖;其用量按每100毫升环氧烃基皂苷溶液加入1-5g进行换算。
优选地,步骤(2)中所述反应的温度为室温,时间为1~48小时。
优选地,步骤(2)中反应后所加入无水乙醇的量为环氧烃基皂苷溶液体积的2~5倍。
本发明的目的之二是保护上述方法制备的皂苷-壳聚糖衍生物。
本发明的目的之三是保护所述皂苷-壳聚糖衍生物在骨组织修复中的应用。
进一步地,其应用方法包括以下步骤:
(1)取一定量的壳聚糖衍生物、皂苷-壳聚糖衍生物和羟基磷灰石混合,加入一定量的生理盐水搅拌成粘稠液体;
(2)配制一定浓度的氧化海藻酸钠溶液,将其按一定比例和步骤(1)得到的粘稠液体混合,搅拌一定时间,即得到可注射的骨修复用水凝胶。
优选地,步骤(1)所述的壳聚糖衍生物为羧甲基壳聚糖、羟丙基壳聚糖或乙二醇壳聚糖。
优选地,步骤(1)中所用壳聚糖衍生物、皂苷-壳聚糖衍生物和羟基磷灰石的质量比为(1-5):(0.1-0.5):(5-20)。
优选地,步骤(1)中所用生理盐水的量为羟基磷灰石质量的0.5~2倍。
优选地,步骤(2)中所述氧化海藻酸钠溶液的浓度为5~20%(w/v),其与粘稠液体混合的体积比为1~5:10;
优选地,步骤(2)中所述搅拌的时间为0.5~2分钟。
皂苷分子一般由数个糖基共价结合甾醇或三萜而成,拥有大量羟基,在碱性条件下可以与环氧氯丙烷的氯原子发生双分子亲核取代反应,使环氧丙基接枝到皂苷分子上;壳聚糖及其衍生物分子链上有大量氨基,在碱性条件下,环氧基可以与氨基发生双分子亲核取代反应,把接有环氧基的皂苷连接到壳聚糖衍生物的分子链上,从而得到皂苷-壳聚糖衍生物。利用皂苷-壳聚糖衍生物制备可注射骨修复水凝胶,将其注射到骨缺损部位后,水凝胶里的氨基和醛基发生缩合反应,使水凝胶凝固成型,水凝胶在骨缺损部位凝固后,细胞逐步迁移至水凝胶内部,溶菌酶使水凝胶降解,皂苷被释放出来,引导细胞分化成骨,最后水凝胶完全降解,新生的骨组织完全填充缺损部位,恢复组织功能。
本发明相对于现有技术具有如下的优点及效果:
(1)本发明利用卤代环氧烷烃把皂苷类药物接枝到天然高分子上,为皂苷药物改性困难、难以达到缓释效果等问题提供了解决方法。
(2)本发明把皂苷类药物接枝到天然高分子上,随着高分子材料的降解,皂苷被缓慢释放出来,因而可以实现皂苷类药物的缓释,为皂苷类药物作为植入材料使用提供了一种解决方法。
(3)本发明把接枝的皂苷-壳聚糖衍生物用于可注射骨修复用水凝胶的制备,可提高骨修复材料对骨组织的修复效果。
附图说明
图1为实施例1所制备羧甲基壳聚糖接枝川续断皂苷VI的分子结构式。
图2为实施例1所制备羧甲基壳聚糖接枝川续断皂苷VI与羧甲基壳聚糖的红外光谱对比图,其中A为羧甲基壳聚糖,B为羧甲基壳聚糖接枝川续断皂苷VI。
图3为实施例1所制备羧甲基壳聚糖接枝川续断皂苷VI与羧甲基壳聚糖、川续断皂苷VI的紫外-可见光光谱对比图,其中A为羧甲基壳聚糖,B为川续断皂苷VI,C为羧甲基壳聚糖接枝川续断皂苷VI。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。下述实施例中所使用的各原料以及试剂,除特别指出的以外,均可由市售获得。
所用氧化海藻酸钠溶液的配制方法“部分氧化海藻酸钠的制备与性能”(参考何淑兰, 张敏, 耿占杰,等,应用化学, 2005(09):85-89)。
实施例1
一种基于卤代环氧烷烃接枝制备皂苷-壳聚糖衍生物的方法,其包括以下步骤:
(1)皂苷环氧化改性
把川续断皂苷VI配成0.1 mg/ml的水溶液,用氢氧化钠将其pH值调到8,加入川续断皂苷VI摩尔数0.5倍的环氧氯丙烷,加热到30 ℃,反应1小时,再加入反应液体积2倍的苯萃取2次,收集水相,得到1,2-环氧丙基-川续断皂苷VI溶液。
(2)壳聚糖衍生物接枝皂苷
取100mL步骤(1)得到的1,2-环氧丙基-川续断皂苷VI溶液,用氢氧化钠将其pH值调到14,然后加入1g的羧甲基壳聚糖,室温反应1小时,加入1,2-环氧丙基-川续断皂苷VI溶液体积2倍的无水乙醇,收集析出物,用无水乙醇清洗至中性,干燥,得到羧甲基壳聚糖接枝川续断皂苷VI,其分子结构式如图1。
图2为羧甲基壳聚糖(A)与所得羧甲基壳聚糖接枝川续断皂苷VI(B)的近红外光谱对比图。由图中可见,羧甲基壳聚糖的光谱中可看到1310、1427、1620 cm-1三个吸收峰,为壳聚糖糖环的吸收峰,3414和3486 cm-1分别为羟基和氨基的的吸收峰。接枝反应后,壳聚糖糖环的吸收峰位移到1320、1403、1582 cm-1,表示糖环受接枝物影响出现变形,导致震动频率改变;3486 cm-1代表氨基的吸收峰消失,表示氨基已经与环氧基反应;1023 cm-1出现C-O-C键合的吸收峰,表示环氧氯丙烷和川续断皂苷VI发生了亲核取代反应;418 cm-1出现碳-碳双键的吸收峰,为川续断皂苷VI的甾醇上的碳-碳双键,表示川续断皂苷VI被成功接枝到羧甲基壳聚糖上。
图3为羧甲基壳聚糖(A)、川续断皂苷VI(B)与所得羧甲基壳聚糖接枝川续断皂苷VI(C)的紫外-可见光光谱对比图。由图中可见,由于糖类对紫外光和可见光都无明显吸收,故羧甲基壳聚糖没有明显的吸收峰;川续断皂苷VI在200 nm有明显的吸收峰,为甾醇的吸收峰;羧甲基壳聚糖接枝川续断皂苷VI在210 nm出现吸收峰,为川续断皂苷VI的甾醇吸收峰受羧甲基壳聚糖分子链极性的影响出现红移,这进一步证明了川续断皂苷VI被成功接枝到羧甲基壳聚糖上。
所得羧甲基壳聚糖接枝川续断皂苷VI用于骨组织修复的具体应用方法包括以下步骤:
(1)把1 g羧甲基壳聚糖、0.1 g羧甲基壳聚糖接枝川续断皂苷VI、5 g羟基磷灰石混合,加入羟基磷灰石质量0.5倍的生理盐水,搅拌成粘稠液体。
(2)配制5%(w/v)的氧化海藻酸钠溶液,将其与步骤(1)得到的粘稠液体按粘稠液体与氧化海藻酸钠溶液的体积比为10:1混合,搅拌0.5分钟,得到可注射骨修复用水凝胶。
(3)把步骤(2)得到的可注射骨修复用水凝胶吸进注射器,注射到患者骨缺损部位。
实施例2
一种基于卤代环氧烷烃接枝制备皂苷-壳聚糖衍生物的方法,其包括以下步骤:
(1)皂苷环氧化改性
把三七皂苷R1配成50 mg/ml的水溶液,用氢氧化钠将其pH值调到11,加入三七皂苷R1摩尔数1.5倍的4-溴-1,2-环氧丁烷,加热到50 ℃,反应24小时,再加入反应液体积1.5倍的四氯化碳萃取3次,收集水相,得到1,2-环氧丁基-三七皂苷R1溶液。
(2)壳聚糖衍生物接枝皂苷
取100mL步骤(1)得到的1,2-环氧丁基-三七皂苷R1溶液,用氢氧化钠将其pH值调到9,然后加入5 g的羟丙基壳聚糖,室温反应24小时,加入1,2-环氧丁基-三七皂苷R1溶液体积3倍的无水乙醇,收集析出物,用无水乙醇清洗至中性,干燥,得到羟丙基壳聚糖接枝三七皂苷R1。
所得羟丙基壳聚糖接枝三七皂苷R1用于骨组织修复的具体应用方法包括以下步骤:
(1)把3 g羟丙基壳聚糖、0.3 g羟丙基壳聚糖接枝三七皂苷R1、10 g羟基磷灰石混合,加入羟基磷灰石质量1.5倍的生理盐水,搅拌成粘稠液体。
(2)配制10%(w/v)的氧化海藻酸钠溶液,将其与步骤(1)得到的粘稠液体按粘稠液体与氧化海藻酸钠溶液的体积比为10:3混合,搅拌1分钟,得到可注射骨修复用水凝胶。
(3)把步骤(2)得到的可注射骨修复用水凝胶吸进注射器,注射到患者骨缺损部位。
实施例3
一种基于卤代环氧烷烃接枝制备皂苷-壳聚糖衍生物的方法,其包括以下步骤:
(1)皂苷环氧化改性
把人参皂苷Ro配成100 mg/ml的水溶液,用氢氧化钠将其pH值调到14,加入人参皂苷Ro摩尔数2倍的4-碘-1,2-环氧丁烷,加热到90 ℃,反应48小时,再加入反应液体积2倍的乙酰乙酯萃取5次,收集水相,得到1,2-环氧丁基-人参皂苷Ro溶液。
(2)壳聚糖衍生物接枝皂苷
取100mL步骤(1)得到的1,2-环氧丁基-人参皂苷Ro溶液,用氢氧化钠把将其pH值调到8,然后加入10 g的乙二醇壳聚糖,室温反应48小时,加入1,2-环氧丁基-人参皂苷Ro溶液体积5倍的无水乙醇,收集析出物,用无水乙醇清洗至中性,干燥,得到乙二醇壳聚糖接枝人参皂苷Ro。
所得乙二醇壳聚糖接枝人参皂苷Ro用于骨组织修复的具体应用方法包括以下步骤:
(1)把5 g乙二醇壳聚糖、0.5 g乙二醇壳聚糖接枝人参皂苷Ro、20 g羟基磷灰石混合,加入羟基磷灰石质量2倍的生理盐水,搅拌成粘稠液体。
(2)配制20%(w/v)的氧化海藻酸钠溶液,将其与步骤(1)得到的粘稠液体按粘稠液体与氧化海藻酸钠溶液的体积比为10:5混合,搅拌2分钟,得到可注射骨修复用水凝胶。
(3)把步骤(2)得到的可注射骨修复用水凝胶吸进注射器,注射到患者骨缺损部位。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (8)
1.一种基于卤代环氧烷烃接枝制备皂苷-壳聚糖衍生物的方法,其特征在于:包括以下步骤:
(1)皂苷环氧化改性:把皂苷配成一定浓度的水溶液,调节pH值后,加入一定量的卤代环氧烷烃,加热到一定温度后反应一定时间,然后加入有机溶剂萃取数次,收集水相,得到环氧烃基皂苷溶液;
(2)壳聚糖衍生物接枝皂苷:将步骤(1)得到的环氧烃基皂苷溶液的pH值调到一定值,加入一定量的壳聚糖衍生物,反应一定时间后加入一定量无水乙醇,收集析出物,用无水乙醇清洗至中性,干燥,得到所述皂苷-壳聚糖衍生物。
2. 根据权利要求1所述的接枝制备皂苷-壳聚糖衍生物的方法,其特征在于:步骤(1)中所述皂苷为川续断皂苷VI、三七皂苷R1或人参皂苷Ro;将其配成0.1~100 mg/ml的水溶液;
采用氢氧化钠将水溶液的pH值调到8~14;
所述卤代环氧烷烃为环氧氯丙烷、4-溴-1,2-环氧丁烷或4-碘-1,2-环氧丁烷,其加入量为所用皂苷摩尔量的0.5~2倍;
所述加热的温度为30~90 ℃;
所述反应的时间为1~48小时;
所述有机溶剂为苯、四氯化碳或乙酰乙酯;其加入量为反应液体积的2~5倍。
3.根据权利要求1所述的接枝制备皂苷-壳聚糖衍生物的方法,其特征在于:步骤(2)中采用氢氧化钠将环氧烃基皂苷溶液的pH值调到8~14;
所述壳聚糖衍生物为羧甲基壳聚糖、羟丙基壳聚糖或乙二醇壳聚糖;其用量按每100毫升环氧烃基皂苷溶液加入1-5g进行换算;
所述反应的温度为室温,时间为1~48小时;
反应后所加入无水乙醇的量为环氧烃基皂苷溶液体积的2~5倍。
4.一种如权利要求1-3任一项方法制备的皂苷-壳聚糖衍生物。
5.一种如权利要求4所述的卤皂苷-壳聚糖衍生物在骨组织修复中的应用。
6.根据权利要求5所述的应用,其特征在于:其应用方法包括以下步骤:
(1)取一定量的壳聚糖衍生物、皂苷-壳聚糖衍生物和羟基磷灰石混合,加入一定量的生理盐水搅拌成粘稠液体;
(2)配制一定浓度的氧化海藻酸钠溶液,将其按一定比例和步骤(1)得到的粘稠液体混合,搅拌一定时间,即得到可注射的骨修复用水凝胶。
7.根据权利要求6所述的应用,其特征在于:步骤(1)所述的壳聚糖衍生物为羧甲基壳聚糖、羟丙基壳聚糖或乙二醇壳聚糖;
所用壳聚糖衍生物、皂苷-壳聚糖衍生物和羟基磷灰石的质量比为(1-5):(0.1-0.5):(5-20);
所用生理盐水的量为羟基磷灰石质量的0.5~2倍。
8.根据权利要求6所述的应用,其特征在于:步骤(2)所述氧化海藻酸钠溶液的浓度为5~20%(w/v),其与粘稠液体混合的体积比为1~5:10;
所述搅拌的时间为0.5~2分钟。
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