GC-51冻干亚微乳剂的制剂学研究及初步药效学评价
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摘要
本课题研究目的是解决Cheliensisin A(GC—51)的静脉给药制剂学问题，并对该药物制剂进行相应的理化性质、稳定性、安全性和体内外抗肿瘤效应进行初步评价。
本文首先测定了GC-51的熔点、溶解性、稳定性、油水分布系数等理化指标，并结合其水溶性很差，不稳定的特点，进行了多种静脉给药剂型的预实验研究，并最终确定GC-51冻干亚微乳剂为最适宜剂型。进而采用单因素和星点设计—效应面优化法相结合的方法筛选出制备GC-51冻干亚微乳剂的最佳处方及工艺，并建立GC-51冻干亚微乳剂的含量测定方法，进行了影响因素实验和长期稳定性实验。对GC-51冻干亚微乳剂进行了溶血性实验、刺激性实验和急性毒性实验，将其作为安全性指标。采用MTT法对体外抗肿瘤细胞活性进行筛选和比较，测定了其浓度依耐性和时间依耐性。建立小鼠肺转移肿瘤模型，并用GC-51冻干亚微乳剂对其进行治疗，以比较小鼠生长状态、抗肿瘤抑制率、生存期等指标初步评价其体内药效学。
结果：制得的GC-51冻干亚微乳剂外观结实平整，加水再分散后，粒径为168±5nm，PDI为0.133±0.070，粘度为水的2.80倍，PH值为7.04，等渗，制剂处方工艺稳定，储存温度在30℃以下，密闭隔绝空气，其物理化学性质很稳定，储存期预期较常规乳剂长；GC-51冻干亚微乳剂几乎不溶血，对家兔几乎无刺激性，小鼠尾静脉注射GC-51冻干亚微乳剂后，无不良反应出现，最大耐受量可达120mL／kg·day，所制得的GC-51冻干亚微乳剂安全性合格，初步实验结果确定可用于静脉给药；体外，GC-51冻干亚微乳剂对HepG2、Hela、A549、CT26四种肿瘤细胞均有较强的抑制作用，且具有一定的时间和浓度的依赖性；与多柔比星、顺铂、五氟尿嘧啶等常规抗肿瘤药物比较，其对该几种肿瘤细胞的增殖抑制作用都较强，具有较广抗瘤谱；体内分布和药代动力学预实验中，体内检测不到GC-51，药物消除很快，半衰期很短，而体外血浆中的稳定性也表明，GC-51极易被生物酶所降解，半衰期很短，机制尚不清楚；体内GC-51冻干亚微乳剂的抗肿瘤效果较顺铂差，但从动物的生长状态、皮毛、饮食及脾脏指数可看出，GC-51冻干亚微乳剂的毒副作用低于顺铂；体内抗肿瘤效果远低于体外，说明体内生物环境对其影响较大，这与前面的实验结论和对体内实验的预测结果一致。
The purpose of this study is to solve the pharmaceutical problems of parenteral administration of Cheliensisin A(GC-51),and to value the physical and chemical characteristics,stability,safety,in vitro and in vivo antitumor effects.
The fusing point,dissolubility,stability,oil/water partition coefficient was firstly measured.Several different kinds of parenteral preparation of GC-51 were examined taking into account of its character of instability and poor dissolubility in water,and Lyophilized submicron emulsion was proved to be the optimal preparation.One factor influence study and central composite design-response surface methodology were combined to optimize the formulation and preparation methods.The content measuring methods was established.Influential test and long term stability test were performed.Hemolysis,stimulation,acute toxicity test were taken,whose results were considered as safety parameters.MTT assay was performed to measure and compare the antitumor character,and its concentration and time dependence were also determined.Mice lung metastasis tumor model was established for the in vivo antitumor effects study. The mice living status,antitumor rate,surviving period,tissue slices were investigated after administrated the GC-51 Lyophilized submicron emulsion in order to determine the therapeutic effects.
The prepared GC-51 Lyophilized submicron emulsion had smooth and tight appearance.Dispersed with water,the size,PDI,viscosity,and pH of the Lyophilized submicron emulsion were 168±5nm,0.133±0.070,2.80 fold of water and 7.04 respectively.The formulation and preparation method were both stable.Under the storage condition,which is below 30℃and avoiding air,the GC-51 Lyophilized submicron emulsion had stable physical and chemical property,and the prospected shelf life could be longer than normal emulsion.The GC-51 Lyophilized submicron emulsion would not cause hemolysis and stimulation to rabbit.Injected this submicron emulsion through the tail vein of mice,no serious side effects was observed,and the max forbearing amount can reach 120 mL/kg-day.The prepared submicron emulsion could reach the safety requirements, therefore could be used for i.v. injection.Compared with common antitumor drugs,such as Doxorubicin,cisplatin,and 5-fluorouracil,GC-51 Lyophilized submicron emulsion was proved to have higher inhibiting effects on HepG2、Hela、A549、CT26 cell lines with in vitro study,with some time and concentration dependence.The in vivo distribution and pharmacokinetics study results indicated that GC-51 was eliminated so quickly that it could hardly be measured in vivo, and the T_(1/2) was extremely short.But the mechanism for that phenomenon was still uncertain.The antitumor effect of GC-51 Lyophilized submicron emulsion was lower than cisplatin,but the side effects of GC-51 Lyophilized submicron emulsion was lower than cisplatin judging from the animal living status,fur appearance,eating,and spleen parameters.The results that the in vivo antitumor effects were much lower than that in vivo indicated the influence of biological environment,which was consistent with the results of former study and the prediction of in vivo study.
本文首先测定了GC-51的熔点、溶解性、稳定性、油水分布系数等理化指标，并结合其水溶性很差，不稳定的特点，进行了多种静脉给药剂型的预实验研究，并最终确定GC-51冻干亚微乳剂为最适宜剂型。进而采用单因素和星点设计—效应面优化法相结合的方法筛选出制备GC-51冻干亚微乳剂的最佳处方及工艺，并建立GC-51冻干亚微乳剂的含量测定方法，进行了影响因素实验和长期稳定性实验。对GC-51冻干亚微乳剂进行了溶血性实验、刺激性实验和急性毒性实验，将其作为安全性指标。采用MTT法对体外抗肿瘤细胞活性进行筛选和比较，测定了其浓度依耐性和时间依耐性。建立小鼠肺转移肿瘤模型，并用GC-51冻干亚微乳剂对其进行治疗，以比较小鼠生长状态、抗肿瘤抑制率、生存期等指标初步评价其体内药效学。
结果：制得的GC-51冻干亚微乳剂外观结实平整，加水再分散后，粒径为168±5nm，PDI为0.133±0.070，粘度为水的2.80倍，PH值为7.04，等渗，制剂处方工艺稳定，储存温度在30℃以下，密闭隔绝空气，其物理化学性质很稳定，储存期预期较常规乳剂长；GC-51冻干亚微乳剂几乎不溶血，对家兔几乎无刺激性，小鼠尾静脉注射GC-51冻干亚微乳剂后，无不良反应出现，最大耐受量可达120mL／kg·day，所制得的GC-51冻干亚微乳剂安全性合格，初步实验结果确定可用于静脉给药；体外，GC-51冻干亚微乳剂对HepG2、Hela、A549、CT26四种肿瘤细胞均有较强的抑制作用，且具有一定的时间和浓度的依赖性；与多柔比星、顺铂、五氟尿嘧啶等常规抗肿瘤药物比较，其对该几种肿瘤细胞的增殖抑制作用都较强，具有较广抗瘤谱；体内分布和药代动力学预实验中，体内检测不到GC-51，药物消除很快，半衰期很短，而体外血浆中的稳定性也表明，GC-51极易被生物酶所降解，半衰期很短，机制尚不清楚；体内GC-51冻干亚微乳剂的抗肿瘤效果较顺铂差，但从动物的生长状态、皮毛、饮食及脾脏指数可看出，GC-51冻干亚微乳剂的毒副作用低于顺铂；体内抗肿瘤效果远低于体外，说明体内生物环境对其影响较大，这与前面的实验结论和对体内实验的预测结果一致。
The purpose of this study is to solve the pharmaceutical problems of parenteral administration of Cheliensisin A(GC-51),and to value the physical and chemical characteristics,stability,safety,in vitro and in vivo antitumor effects.
The fusing point,dissolubility,stability,oil/water partition coefficient was firstly measured.Several different kinds of parenteral preparation of GC-51 were examined taking into account of its character of instability and poor dissolubility in water,and Lyophilized submicron emulsion was proved to be the optimal preparation.One factor influence study and central composite design-response surface methodology were combined to optimize the formulation and preparation methods.The content measuring methods was established.Influential test and long term stability test were performed.Hemolysis,stimulation,acute toxicity test were taken,whose results were considered as safety parameters.MTT assay was performed to measure and compare the antitumor character,and its concentration and time dependence were also determined.Mice lung metastasis tumor model was established for the in vivo antitumor effects study. The mice living status,antitumor rate,surviving period,tissue slices were investigated after administrated the GC-51 Lyophilized submicron emulsion in order to determine the therapeutic effects.
The prepared GC-51 Lyophilized submicron emulsion had smooth and tight appearance.Dispersed with water,the size,PDI,viscosity,and pH of the Lyophilized submicron emulsion were 168±5nm,0.133±0.070,2.80 fold of water and 7.04 respectively.The formulation and preparation method were both stable.Under the storage condition,which is below 30℃and avoiding air,the GC-51 Lyophilized submicron emulsion had stable physical and chemical property,and the prospected shelf life could be longer than normal emulsion.The GC-51 Lyophilized submicron emulsion would not cause hemolysis and stimulation to rabbit.Injected this submicron emulsion through the tail vein of mice,no serious side effects was observed,and the max forbearing amount can reach 120 mL/kg-day.The prepared submicron emulsion could reach the safety requirements, therefore could be used for i.v. injection.Compared with common antitumor drugs,such as Doxorubicin,cisplatin,and 5-fluorouracil,GC-51 Lyophilized submicron emulsion was proved to have higher inhibiting effects on HepG2、Hela、A549、CT26 cell lines with in vitro study,with some time and concentration dependence.The in vivo distribution and pharmacokinetics study results indicated that GC-51 was eliminated so quickly that it could hardly be measured in vivo, and the T_(1/2) was extremely short.But the mechanism for that phenomenon was still uncertain.The antitumor effect of GC-51 Lyophilized submicron emulsion was lower than cisplatin,but the side effects of GC-51 Lyophilized submicron emulsion was lower than cisplatin judging from the animal living status,fur appearance,eating,and spleen parameters.The results that the in vivo antitumor effects were much lower than that in vivo indicated the influence of biological environment,which was consistent with the results of former study and the prediction of in vivo study.
引文
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[4] 韩铭钧等．油性中药抗癌肝动脉栓塞治疗肝癌84倒3年随访报告．临床放射学杂志，1998，17(2)：112-114
[5] Jian You,Fu-de Cui,Qing-po Li,Xu Han,Ying-wei Yu,Ming-shi Yang.A novel formulation design about water-insoluble oily drug:preparation of zedoaryturmeric oil microspheres with self-emulsifying ability and evaluation in rabbits.J.International Journal of Pharmaceutics.288 (2005):315-323
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