基于聚乙二醇硬脂酸酯构建的紫杉醇注射用微乳及其溶血性试验
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摘要
目的:以聚乙二醇硬脂酸酯(solutol HS 15,HS 15)为表面活性剂制备紫杉醇注射用微乳,并进行相关体外溶血性试验研究。方法:以《中华人民共和国药典》(ChP) 2015年版第四部以及《化学药物刺激性、过敏性和溶血性研究技术指导原则》为依据进行实验,取不同浓度的HS 15加入2%兔红细胞生理盐水混悬液中,分别采用常规体外试管法和分光光度法来判断溶血和凝聚情况,观察并测定吸光度值,计算溶血率以确定HS 15适用的浓度范围,并在此范围内进行处方筛选,制备紫杉醇注射用微乳,最终进行相关溶血性试验的考察。结果:通过对HS 15的筛选,制备粒径约50 nm的紫杉醇注射用微乳,溶血试验结果表明紫杉醇浓度为1. 2 mg·mL~(-1)的溶血率小于4%,能够达到注射剂上市要求。结论:以HS 15为表面活性剂,能够成功制备紫杉醇注射用微乳,溶血性试验结果达到注射剂上市的要求,为紫杉醇等抗癌药物的新剂型研究开发提供依据。
Objective: To prepare microemulsion for injection using Solutol HS 15( HS 15) as surfactant and conduct hemolysis test in vitro. Methods: According to the fourth part of the 2015 edition of Chinese Pharmacopoeia and Guidelines for the Study of Chemical Drugs on Irritability,Anaphylaxis and Hemolysis,HS 15 of different concentrations were added to 2% rabbit red blood cell physiological saline suspension to determine the hemolysis and agglutination in test tube method and spectrophotometric method. The absorbance value was observed and measured and the hemolysis rate was calculated to determine the applicative concentration range of HS 15,in which the formulation was screened. Paclitaxel was used as a model drug to prepare the microemulsion for injection,and the hemolysis test was carried out in the end. Results: Through the screening of HS 15,paclitaxel microemulsion with particle size of 50 nm was prepared. The hemolysis results showed that the hemolysis ratio of paclitaxel with the concentration of 1. 2 mg·mL~(-1) was less than 4%,which met the requirements of injection marketing. Conclusion:The paclitaxel microemulsion for injection was successfully prepared with HS 15 as surfactant. The results of hemolysistest met the injection marketing requirements. This study may provide the basis for the development of new dosage forms of anti-cancer drugs like paclitaxel.
Objective: To prepare microemulsion for injection using Solutol HS 15( HS 15) as surfactant and conduct hemolysis test in vitro. Methods: According to the fourth part of the 2015 edition of Chinese Pharmacopoeia and Guidelines for the Study of Chemical Drugs on Irritability,Anaphylaxis and Hemolysis,HS 15 of different concentrations were added to 2% rabbit red blood cell physiological saline suspension to determine the hemolysis and agglutination in test tube method and spectrophotometric method. The absorbance value was observed and measured and the hemolysis rate was calculated to determine the applicative concentration range of HS 15,in which the formulation was screened. Paclitaxel was used as a model drug to prepare the microemulsion for injection,and the hemolysis test was carried out in the end. Results: Through the screening of HS 15,paclitaxel microemulsion with particle size of 50 nm was prepared. The hemolysis results showed that the hemolysis ratio of paclitaxel with the concentration of 1. 2 mg·mL~(-1) was less than 4%,which met the requirements of injection marketing. Conclusion:The paclitaxel microemulsion for injection was successfully prepared with HS 15 as surfactant. The results of hemolysistest met the injection marketing requirements. This study may provide the basis for the development of new dosage forms of anti-cancer drugs like paclitaxel.
引文
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[19]DENIHAN NM,WALSH BH,REINKE SN,et al.The effect of haemolysis on the metabolomic profile of umbilical cord blood[J].Clin Biochem,2015,48(7-8):534-537.
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[22]刁兆玉,成朋,王仲妮.表面活性剂溶血作用的研究进展[J].食品与药品,2010,12(3):125-129.
[23]张蕾,訾鹏,高洁,等.非离子型表面活性剂HS 15在药剂中的研究进展[J].药学进展,2015,39(5):370-375.
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[25]崔亚男,王东凯,邱志斌.2种溶血性试验方法在复方参芍注射剂研究中的应用[J].中国药房,2007,18(3):182-183.
[26]NORNOO AO,OSBORNE DW,CHOW DS.Cremophor-free intravenous microemulsions for paclitaxel I:formulation,cytotoxicity and hemolysis[J].Int J Pharm,2008,349(1-2):108-116.
[27]GAO P,RUSH BD,PFUND WP,et al.Development of a supersaturable SEDDS(S-SEDDS)formulation of paclitaxel with improved oral bioavailability[J].J Pharm Sci,2003,92(12):2386-2398.
[28]LI X,DU L,WANG C,et al.Highly efficient and lowly toxic docetaxel nanoemulsions for intravenous injection to animals[J].Pharmazie,2011,6(7):479-483.
[2]FENG S,CHEN K,WANG C,et al.Design,synthesis,and evaluation of water-soluble morpholino-decorated paclitaxel prodrugs with remarkably decreased toxicity[J].Bioorg Med Chem Lett,2016,26(15):3598-3602.
[3]石永辉,余晓霞,吕立,等.HPLC-MS/MS法测定大鼠血浆中紫杉醇的含量[J].今日药学,2017,27(11):735-738.
[4]郑璐,胡静,许权,等.紫杉醇、紫杉醇脂质体和白蛋白结合型紫杉醇在头颈肿瘤中的疗效比较[J].中国现代应用药学,2019,36(11):1391-1394.
[5]HE Z,WAN X,SCHULZ A,et al.A high capacity polymeric micelle of paclitaxel:Implication of high dose drug therapy to safety and in vivo anti-cancer activity[J].Biomaterials,2016,101:296-309.
[6]KADAM AN,NAJLAH M,WAN KW,et al.Stability of parenteral nanoemulsions loaded with paclitaxel:the influence of lipid phase composition,drug concentration and storage temperature[J].Pharm Dev Technol,2014,19(8):999-1004.
[7]BERNABEU E,CAGEL M,LAGOMARSINO E,et al.Paclitaxel:What has been done and the challenges remain ahead[J].Int J Pharmaceut,2017,526(1-2):474-495.
[8]NEHATE C,JAIN S,SANEJA A,et al.Paclitaxel formulations:challenges and novel delivery options[J].Curr Drug Deliv,2014,11(6):666-686.
[9]NAJLAH M,KADAM A,WAN KW,et al.Novel paclitaxel formulations solubilized by parenteral nutrition nanoemulsions for application against glioma cell lines[J].Int J Pharm,2016,506(1-2):102-109.
[10]STINCHCOMBE TE.Nanoparticle albumin-bound paclitaxel:a novel Cremphor-EL-free formulation of paclitaxel[J].Nanomedicine(Lond),2007,2(4):415-423.
[11]LEE SC,HUH KM,LEE J,et al.Hydrotropic polymeric micelles for enhanced paclitaxel solubility:in vitro and in vivo characterization[J].Biomacromolecules,2007,8(1):202-208.
[12]LAWRENCE MJ,REES GD.Microemulsion-based media as novel drug delivery systems[J].Adv Drug Deliver Rev,2012,64:175-193.
[13]DATE AA,NAGARSENKER MS.Parenteral microemulsions:an overview[J].Int J Pharmaceut,2008,355(1-2):19-30.
[14]HRMANN K,ZIMMER A.Drug delivery and drug targeting with parenteral lipid nanoemulsions-a review[J].J Control Release,2016,223:85-98.
[15]CHEN L,CHEN B,DENG L,et al.An optimized two-vial formulation lipid nanoemulsion of paclitaxel for targeted delivery to tumor[J].Int J Pharmaceut,2017,534(1-2):308-315.
[16]KIM JE,PARK YJ.High paclitaxel-loaded and tumor cell-targeting hyaluronan-coated nanoemulsions[J].Colloids Surf BBiointerfaces,2017,50:362-372.
[17]MARANHAO RC,TAVARES ER,PADOVEZE AF,et al.Paclitaxel associated with cholesterol-rich nanoemulsions promotes atherosclerosis regression in the rabbit[J].Atherosclerosis,2008,197(2):959-966.
[18]CHENG Y,LIU M,HU H,et al.Development,optimization,and characterization of pegylated nanoemulsion of prostaglandin E1 for long circulation[J].AAPS Pharmscitech,2016,17(2):409-417.
[19]DENIHAN NM,WALSH BH,REINKE SN,et al.The effect of haemolysis on the metabolomic profile of umbilical cord blood[J].Clin Biochem,2015,48(7-8):534-537.
[20]SUBRAMANIAN S,WILLIAM K.Hemolysis for saponins:a caution[J].Chem Educ,1989,66(12):1058.
[21]校月红,卢婷利,陈涛,等.药物溶血性评价方法的研究进展[J].中国药业,2012,21(17):1-3.
[22]刁兆玉,成朋,王仲妮.表面活性剂溶血作用的研究进展[J].食品与药品,2010,12(3):125-129.
[23]张蕾,訾鹏,高洁,等.非离子型表面活性剂HS 15在药剂中的研究进展[J].药学进展,2015,39(5):370-375.
[24]国家药典委员会.中华人民共和国药典[S].2015年版.四部.北京:中国医药科技出版社,2015:159.
[25]崔亚男,王东凯,邱志斌.2种溶血性试验方法在复方参芍注射剂研究中的应用[J].中国药房,2007,18(3):182-183.
[26]NORNOO AO,OSBORNE DW,CHOW DS.Cremophor-free intravenous microemulsions for paclitaxel I:formulation,cytotoxicity and hemolysis[J].Int J Pharm,2008,349(1-2):108-116.
[27]GAO P,RUSH BD,PFUND WP,et al.Development of a supersaturable SEDDS(S-SEDDS)formulation of paclitaxel with improved oral bioavailability[J].J Pharm Sci,2003,92(12):2386-2398.
[28]LI X,DU L,WANG C,et al.Highly efficient and lowly toxic docetaxel nanoemulsions for intravenous injection to animals[J].Pharmazie,2011,6(7):479-483.
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