丹皮酚-奥扎格雷偶联物长循环脂质体的制备及其体外释放
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摘要
目的:优化丹皮酚-奥扎格雷偶联物(paeonol-ozagrel conjugate,POC)长循环脂质体的制备处方及工艺,测定其体外释放度。方法:采用乙醇注入法制备POC长循环脂质体,并用正交设计优化该脂质体的制备处方及工艺,透射电镜观测其形态,激光粒度仪测定其粒径及电位,透析法考察脂质体的体外释放。结果:最优处方为胆固醇与大豆卵磷脂的质量比为1∶12; DSPE-PEG2000与大豆卵磷脂的质量比为8∶60;有机相与水相的体积比为2∶10;制备的长循环脂质体为近球形结构,包封率大于95%;平均粒径50 nm左右;体外释放实验结果表明制备得到的脂质体具有缓释作用。结论:POC长循环脂质体制备工艺简单、可行、包封率较高,且与原料药相比具有一定的缓释作用。
Objective: To optimize the preparation and formulation of paeonol-ozagrel conjugate( POC)long circulating liposomes and investigate the release rate in vitro. Methods: POC long-circulating liposomes were prepared by ethanol injection method,and orthogonal design was used to optimize the formulation and preparation process of POC long-circulating liposomes. The morphology of liposomes was observed by transmission electron microscopy,the particle size and potential were determined by laser particle size analyzer,and the release of liposomes in vitro was investigated by dynamic dialysis. Results: The optimal formulation was as follows: the mass ratio of cholesterol to soybean lecithin was 1∶ 12,the mass ratio of DSPE-PEG2000 to soybean lecithin was 8∶ 60,and the volume ratio of organic phase to aqueous phase was 2 ∶ 10. The prepared long-circulating liposomes were nearly spherical in structure,the encapsulation efficiency was more than 95%,and the average particle size was about 50 nm. The results of in vitro release experiments showed that the prepared liposomes had a sustained release effect. Conclusion: The preparation process of POC long-circulating liposomes is simple and feasible with high encapsulation efficiency. POC long-circulating liposomes have a certain sustained-release effect compared with the bulk drug.
Objective: To optimize the preparation and formulation of paeonol-ozagrel conjugate( POC)long circulating liposomes and investigate the release rate in vitro. Methods: POC long-circulating liposomes were prepared by ethanol injection method,and orthogonal design was used to optimize the formulation and preparation process of POC long-circulating liposomes. The morphology of liposomes was observed by transmission electron microscopy,the particle size and potential were determined by laser particle size analyzer,and the release of liposomes in vitro was investigated by dynamic dialysis. Results: The optimal formulation was as follows: the mass ratio of cholesterol to soybean lecithin was 1∶ 12,the mass ratio of DSPE-PEG2000 to soybean lecithin was 8∶ 60,and the volume ratio of organic phase to aqueous phase was 2 ∶ 10. The prepared long-circulating liposomes were nearly spherical in structure,the encapsulation efficiency was more than 95%,and the average particle size was about 50 nm. The results of in vitro release experiments showed that the prepared liposomes had a sustained release effect. Conclusion: The preparation process of POC long-circulating liposomes is simple and feasible with high encapsulation efficiency. POC long-circulating liposomes have a certain sustained-release effect compared with the bulk drug.
引文
[1] HOOG J,ACHENBACH S. Summary of the ESC position paper on cancer treatment and cardiovascular toxicity[J]. Herz,2016,41(8):684-689.
[2]高洋,尹伟,刘靖超,等.川芎嗪/查耳酮类杂合物的设计、合成及抗血小板聚集活性[J].中国药科大学学报,2017,48(1):23-30.
[3]郝颖智,王鹏龙,洪缨,等.川芎嗪-原儿茶酸络合物的合成和其抗缺血性脑损伤作用初步研究[J].中药药理与临床,2010,26(5):41-45.
[4] TU JS,ZHONG S,LI PM. Studies on acyclovir-dextran conjugate:synthesis and pharmacokinetics[J]. Drug Dev Ind Pharm,2004,30(9):959-965.
[5]刘敏,章文军,高宁.拼合原理及其在新药设计中的应用[J].化学试剂,2009,31(10):795-797,850.
[6] SATHLER PC,SANTANA M,LOURENO AL,et al. Human thromboxane synthase:comparative modeling and docking evaluation with the competitive inhibitors Dazoxiben and Ozagrel[J]. J Enzyme Inhib Med Chem,2014,29(4):527-531.
[7]杨磊,史朝晖,邱立朋,等.奥扎格雷纳米结构脂质载体的制备及体外评价[J].中国新药杂志,2012,21(11):1301-1305.
[8]董玉红,张淑芹,董世超,等.丹皮酚对高脂血症大鼠降血脂及血管保护作用的实验研究[J].临床和实验医学杂志,2014,13(14):1132-1134.
[9]张涓,张恩户.丹参酮ⅡA与丹皮酚配伍对大鼠脑缺血的保护作用[J].中国医院药学杂志,2013,33(6):458-460.
[10]叶菲菲,代旸,徐缓,等.人参皂苷Rg3脂质体的制备、表征及对黑色素瘤细胞的生长抑制作用[J].中国新药杂志,2014,23(21):2542-2546.
[11]陈颖,叶娟,陈艳婷,等.α-细辛脑脂质体的制备与体外释放药物的考察[J].今日药学,2013,23(1):11-13,22.
[12] ZAKIA B,MAN Y,XIE C,et al. Design of Y-shaped targeting material for liposome-based multifunctional glioblastoma-targeted drug delivery[J]. J Control Release,2017,10(255):132-141.
[13] XING J,LIU D,ZHOU G,et al. Liposomally formulated phospholipid-conjugated novel near-infrared fluorescence probe for particle size effect on cellular uptake and biodistribution in vivo[J]. Colloids Surf B Biointerfaces,2018,161(1):588-596.
[14] MA SY,LI MY,LIU N,et al. Vincristine liposomes with smaller particle size have stronger diffusion ability in tumor and improve tumor accumulation of vincristine significantly[J]. Oncotarget,2017,8(57):87276-87291.
[2]高洋,尹伟,刘靖超,等.川芎嗪/查耳酮类杂合物的设计、合成及抗血小板聚集活性[J].中国药科大学学报,2017,48(1):23-30.
[3]郝颖智,王鹏龙,洪缨,等.川芎嗪-原儿茶酸络合物的合成和其抗缺血性脑损伤作用初步研究[J].中药药理与临床,2010,26(5):41-45.
[4] TU JS,ZHONG S,LI PM. Studies on acyclovir-dextran conjugate:synthesis and pharmacokinetics[J]. Drug Dev Ind Pharm,2004,30(9):959-965.
[5]刘敏,章文军,高宁.拼合原理及其在新药设计中的应用[J].化学试剂,2009,31(10):795-797,850.
[6] SATHLER PC,SANTANA M,LOURENO AL,et al. Human thromboxane synthase:comparative modeling and docking evaluation with the competitive inhibitors Dazoxiben and Ozagrel[J]. J Enzyme Inhib Med Chem,2014,29(4):527-531.
[7]杨磊,史朝晖,邱立朋,等.奥扎格雷纳米结构脂质载体的制备及体外评价[J].中国新药杂志,2012,21(11):1301-1305.
[8]董玉红,张淑芹,董世超,等.丹皮酚对高脂血症大鼠降血脂及血管保护作用的实验研究[J].临床和实验医学杂志,2014,13(14):1132-1134.
[9]张涓,张恩户.丹参酮ⅡA与丹皮酚配伍对大鼠脑缺血的保护作用[J].中国医院药学杂志,2013,33(6):458-460.
[10]叶菲菲,代旸,徐缓,等.人参皂苷Rg3脂质体的制备、表征及对黑色素瘤细胞的生长抑制作用[J].中国新药杂志,2014,23(21):2542-2546.
[11]陈颖,叶娟,陈艳婷,等.α-细辛脑脂质体的制备与体外释放药物的考察[J].今日药学,2013,23(1):11-13,22.
[12] ZAKIA B,MAN Y,XIE C,et al. Design of Y-shaped targeting material for liposome-based multifunctional glioblastoma-targeted drug delivery[J]. J Control Release,2017,10(255):132-141.
[13] XING J,LIU D,ZHOU G,et al. Liposomally formulated phospholipid-conjugated novel near-infrared fluorescence probe for particle size effect on cellular uptake and biodistribution in vivo[J]. Colloids Surf B Biointerfaces,2018,161(1):588-596.
[14] MA SY,LI MY,LIU N,et al. Vincristine liposomes with smaller particle size have stronger diffusion ability in tumor and improve tumor accumulation of vincristine significantly[J]. Oncotarget,2017,8(57):87276-87291.