新型缓释镇痛药物的构建及其生物学研究
摘要
目的：
1.以壳聚糖为载体制备吗啡、酒石酸布托啡诺镇痛药物缓释系统
2.对吗啡、酒石酸布托啡诺镇痛药物缓释系统进行生物相容性评价
3.对吗啡、酒石酸布托啡诺镇痛药物缓释系统进行药效学评价
方法：
1.用乳化交联法制备壳聚糖微球,并对其表征。将吗啡作为释放镇痛药物,以壳聚糖为载体制备吗啡-壳聚糖缓释微球(MM),并对该微球进行表征,体外释放。
2.用喷雾干燥法制备海藻酸微球、壳聚糖微球,并对上述微球进行自组装支架,测微球间作用力,利用该微球支架为背景载体,利用海藻酸载药,制备酒石酸布托啡诺-海藻酸微球,该微球与壳聚糖微球形成自组装支架。形成酒石酸布托啡诺-海藻酸微球-壳聚糖微球支架药物释放系统(BM),并对该系统进行表征与体外释放。
3.用小鼠胚胎成纤维细胞毒性试验、小白鼠微核实验、大白鼠肌肉埋植实验、兔血溶血实验、小白鼠全身急性反应实验,对BM、MM的进行生物相容性评价。
4.用家兔鼻部填塞用药、大白鼠硬膜外腔用药、大鼠皮下用药,用鼠尾光照测痛法、兔鼻部光照测痛法别对BM、MM的镇痛药效学进行评价。
结果：
1.两种镇痛药物缓释微球成球良好,微球药物释放良好,两种系统有体外镇痛药物缓释效果。
2.两种镇痛药物缓释系统均无毒性,生物相容性良好,细胞毒性0级或1级。微核试验阴性,无遗传学毒性,溶血率<5%,小鼠全身急性试验阴性,小鼠体重稳定增加,无死亡。肌肉埋植试验：局部无组织坏死、无皮肤溃烂、无感染,伤口愈合好,病理显示：埋植药物局部有异物反应,随时间推移,异物反应逐渐减轻,6-8周基本消失,与局部埋植手术丝线相比,BM、MM的局部埋植异物反应轻、消失早。无全身毒性反应。对肝、肾功能及造血功能无影响。
3.BM,MM皮下埋植试验的镇痛效果与生理盐水组、相应的药物水剂组比较有统计学意义,P<0.05。BM,MM的镇痛时间延长,与布托啡诺水剂(BW),吗啡水剂(MW)相比有显著性差异,P<0.05。BM用于兔鼻填塞镇痛试验结果显示BM有镇痛效果,与BW组镇痛效果相比,有统计学意义,P<0.05。MM用于大鼠硬膜外腔镇痛结果显示：MM镇痛时间延长,与MW组的镇痛时间相比有统计学意义,P<0.050
结论：
1.壳聚糖可以用于镇痛缓释药物的缓释药物载体。
2.以壳聚糖为载体的镇痛缓释系统生物相容性好。
3.吗啡-壳聚糖微球缓释系统可以用于大鼠硬膜外腔镇痛,比吗啡水剂的镇痛时间长。
4.酒石酸布托啡诺-海藻酸钙微球-壳聚糖微球可用于兔鼻腔填塞镇痛,比酒石酸布托啡诺水剂的镇痛时间长。
5.吗啡-壳聚糖微球可用于皮下埋植镇痛,比吗啡水剂的镇痛时间长。
6.酒石酸-布托啡诺可以用于大鼠皮下埋植镇痛,比酒石酸布托啡诺水剂的镇痛时间长。
Objectives:
1. To present the preparation of two slow release analgesic systems using Chitosan as carrier with morhphine and butorphanol tartarate as active drugs.
2. To evaluate the biocompatibility of these two analgesic delivery systems.
3. To evaluate the pharmacological effects of these two analgesic delivery systems.
Methods:
1. Using emulsion crosslinking chitosan microspheres were prepared and chitosan-morphine microspheres (MM) were constructed with morphine as the analgesic drug and chitosan as the carrier. Then the characteristics of these MM were studied in vitro.
2. Using spray-dry method alginate micropsheres and chitosan microspheres were prpared and alginate-butorphanol tartarate micospheres were constructed with alginate as the drug carrier. By self-assembly scaffold a drug delivery system with butorphanol-alginate microsphere-chitosan microspere (BM) is formed and the characteristic of this system is studied in vitro.
3. Uisng mouse embryonic fibroblast toxicity test, mouse micronucleus test, rat muscle implantation test, rabbit blood hemolysis test and mice acute systemic reaction test, biocompatibilty of these two drug delivery systems (BM, MM) were studied.
4. With nasal drug administration in rabbit, epidural drug administration in guinea pig, subcutaneous drug administration in rat, the pharmacodynamic effect of BM and MM were evaluated with rat tail flick test and rabbit nose thermal pain test.
Results:
1. The two drug delivery systems so prepared showed good microsphere formation and good drug releasing effect in vitro.
2. Both analgesic drug delivery systems showed good biocompatibility and no toxicity with cell toxicity grading from 0 to 1. The micronucleus test was negative and no teratogenic toxicity shown.. Hemolysis rate was less than 5%. Acute systemic reaction test was negative with steady weight gain and no mortality in mice. Muscle implantation test showed no local tissue necrosis, skin ulceration or infection and wound healing was normal. Pathological examination showed some local foreign body reaction which decreased over time with complete subsidence in 6-8 weeks and was actually less severe when compared to local reaction to implanted surgical silk suture.. There was no abnormalities in hepatic, renal or hemopoietic function observed.
3. The analgesic effect of subcutaneously implanted BM and MM showed statistically significant difference (p<0.05) over the subcutaneous administration of normal saline, or the corresponding active drugs (butorphanol or morphine injectable) with BM and MM producing much longer analgesic effects (p<0.05). When administered nasally in rabbits BM showed signficantly prolonged analgesic effect than injectable butorphanol (p<0.05). When administered epidurally in rats MM showed significantly longer analgesic effect than injectable morphine (p<0.05).
Conclusion:
1.Chitosan can be used as an effective carrier in analgesic drug delivery system.
2. Chitosan show good biocompatibility as carrier in analgesic drug delivery system.
3. Morphine-Chitosan microsphere drug delivery system can be used for epidural analgesia in rats with prolonged analgesic activity.
4. Butorphanol tartarate-alginate microsphere-chitosan microsphere complex can be used for nasal administration in rabbit with signficantly longer duration of analgesia than injectable butorphanol.
5. When subcautaneously implanted, morphine-chitosan microspheres produce prolonged analgesia than injectable morphine.
6. When implanted subcutaneously butorphanol microsphere preparation provides a much longer analgesic effect than injectable butorphanol tartarate.
1.以壳聚糖为载体制备吗啡、酒石酸布托啡诺镇痛药物缓释系统
2.对吗啡、酒石酸布托啡诺镇痛药物缓释系统进行生物相容性评价
3.对吗啡、酒石酸布托啡诺镇痛药物缓释系统进行药效学评价
方法：
1.用乳化交联法制备壳聚糖微球,并对其表征。将吗啡作为释放镇痛药物,以壳聚糖为载体制备吗啡-壳聚糖缓释微球(MM),并对该微球进行表征,体外释放。
2.用喷雾干燥法制备海藻酸微球、壳聚糖微球,并对上述微球进行自组装支架,测微球间作用力,利用该微球支架为背景载体,利用海藻酸载药,制备酒石酸布托啡诺-海藻酸微球,该微球与壳聚糖微球形成自组装支架。形成酒石酸布托啡诺-海藻酸微球-壳聚糖微球支架药物释放系统(BM),并对该系统进行表征与体外释放。
3.用小鼠胚胎成纤维细胞毒性试验、小白鼠微核实验、大白鼠肌肉埋植实验、兔血溶血实验、小白鼠全身急性反应实验,对BM、MM的进行生物相容性评价。
4.用家兔鼻部填塞用药、大白鼠硬膜外腔用药、大鼠皮下用药,用鼠尾光照测痛法、兔鼻部光照测痛法别对BM、MM的镇痛药效学进行评价。
结果：
1.两种镇痛药物缓释微球成球良好,微球药物释放良好,两种系统有体外镇痛药物缓释效果。
2.两种镇痛药物缓释系统均无毒性,生物相容性良好,细胞毒性0级或1级。微核试验阴性,无遗传学毒性,溶血率<5%,小鼠全身急性试验阴性,小鼠体重稳定增加,无死亡。肌肉埋植试验：局部无组织坏死、无皮肤溃烂、无感染,伤口愈合好,病理显示：埋植药物局部有异物反应,随时间推移,异物反应逐渐减轻,6-8周基本消失,与局部埋植手术丝线相比,BM、MM的局部埋植异物反应轻、消失早。无全身毒性反应。对肝、肾功能及造血功能无影响。
3.BM,MM皮下埋植试验的镇痛效果与生理盐水组、相应的药物水剂组比较有统计学意义,P<0.05。BM,MM的镇痛时间延长,与布托啡诺水剂(BW),吗啡水剂(MW)相比有显著性差异,P<0.05。BM用于兔鼻填塞镇痛试验结果显示BM有镇痛效果,与BW组镇痛效果相比,有统计学意义,P<0.05。MM用于大鼠硬膜外腔镇痛结果显示：MM镇痛时间延长,与MW组的镇痛时间相比有统计学意义,P<0.050
结论：
1.壳聚糖可以用于镇痛缓释药物的缓释药物载体。
2.以壳聚糖为载体的镇痛缓释系统生物相容性好。
3.吗啡-壳聚糖微球缓释系统可以用于大鼠硬膜外腔镇痛,比吗啡水剂的镇痛时间长。
4.酒石酸布托啡诺-海藻酸钙微球-壳聚糖微球可用于兔鼻腔填塞镇痛,比酒石酸布托啡诺水剂的镇痛时间长。
5.吗啡-壳聚糖微球可用于皮下埋植镇痛,比吗啡水剂的镇痛时间长。
6.酒石酸-布托啡诺可以用于大鼠皮下埋植镇痛,比酒石酸布托啡诺水剂的镇痛时间长。
Objectives:
1. To present the preparation of two slow release analgesic systems using Chitosan as carrier with morhphine and butorphanol tartarate as active drugs.
2. To evaluate the biocompatibility of these two analgesic delivery systems.
3. To evaluate the pharmacological effects of these two analgesic delivery systems.
Methods:
1. Using emulsion crosslinking chitosan microspheres were prepared and chitosan-morphine microspheres (MM) were constructed with morphine as the analgesic drug and chitosan as the carrier. Then the characteristics of these MM were studied in vitro.
2. Using spray-dry method alginate micropsheres and chitosan microspheres were prpared and alginate-butorphanol tartarate micospheres were constructed with alginate as the drug carrier. By self-assembly scaffold a drug delivery system with butorphanol-alginate microsphere-chitosan microspere (BM) is formed and the characteristic of this system is studied in vitro.
3. Uisng mouse embryonic fibroblast toxicity test, mouse micronucleus test, rat muscle implantation test, rabbit blood hemolysis test and mice acute systemic reaction test, biocompatibilty of these two drug delivery systems (BM, MM) were studied.
4. With nasal drug administration in rabbit, epidural drug administration in guinea pig, subcutaneous drug administration in rat, the pharmacodynamic effect of BM and MM were evaluated with rat tail flick test and rabbit nose thermal pain test.
Results:
1. The two drug delivery systems so prepared showed good microsphere formation and good drug releasing effect in vitro.
2. Both analgesic drug delivery systems showed good biocompatibility and no toxicity with cell toxicity grading from 0 to 1. The micronucleus test was negative and no teratogenic toxicity shown.. Hemolysis rate was less than 5%. Acute systemic reaction test was negative with steady weight gain and no mortality in mice. Muscle implantation test showed no local tissue necrosis, skin ulceration or infection and wound healing was normal. Pathological examination showed some local foreign body reaction which decreased over time with complete subsidence in 6-8 weeks and was actually less severe when compared to local reaction to implanted surgical silk suture.. There was no abnormalities in hepatic, renal or hemopoietic function observed.
3. The analgesic effect of subcutaneously implanted BM and MM showed statistically significant difference (p<0.05) over the subcutaneous administration of normal saline, or the corresponding active drugs (butorphanol or morphine injectable) with BM and MM producing much longer analgesic effects (p<0.05). When administered nasally in rabbits BM showed signficantly prolonged analgesic effect than injectable butorphanol (p<0.05). When administered epidurally in rats MM showed significantly longer analgesic effect than injectable morphine (p<0.05).
Conclusion:
1.Chitosan can be used as an effective carrier in analgesic drug delivery system.
2. Chitosan show good biocompatibility as carrier in analgesic drug delivery system.
3. Morphine-Chitosan microsphere drug delivery system can be used for epidural analgesia in rats with prolonged analgesic activity.
4. Butorphanol tartarate-alginate microsphere-chitosan microsphere complex can be used for nasal administration in rabbit with signficantly longer duration of analgesia than injectable butorphanol.
5. When subcautaneously implanted, morphine-chitosan microspheres produce prolonged analgesia than injectable morphine.
6. When implanted subcutaneously butorphanol microsphere preparation provides a much longer analgesic effect than injectable butorphanol tartarate.
引文
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