齐墩果酸自微乳化制剂的实验研究
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摘要
齐墩果酸(Oleanolic acid,OA)是一种五环三萜类化合物,具有多种药理活性如护肝降酶、抗炎、抗病毒、抗突变、抗癌、降糖、降血脂等,临床用于治疗慢性病毒性肝炎,对症状、体征和肝功能均有明显的改善作用。现在上市的齐墩果酸制剂有片剂和胶囊剂,由于齐墩果酸的溶解性较差,机体难以吸收,致使其生物利用度低,限制了其药理作用的充分发挥,动物实验表明大鼠体内口服生物利用度仅为0.7%。自微乳化给药系统(Self-Microemulsifying Drug DeliverySystem,SMEDDS)能提高难溶性药物溶解度;保护药物在胃肠道内免遭酶解;增强不稳定药物的稳定性;因其粒径小且均匀,可使被包容的药物分散度提高,促进药物在体内的吸收,从而提高药物的生物利用度。本课题研究齐墩果酸的自微乳化制剂,并从体内外全面评价其质量,不仅为齐墩果酸的临床应用提供新的依据,也为实现中药现代化提供新的思路。主要研究工作有以下内容:
1.齐墩果酸SMEDDS的处方工艺研究(1)考察齐墩果酸在不同介质中的饱和溶解度,根据不同油相、表面活性剂的配伍情况以及不同助表面活性剂伪三元相图中微乳区域的大小,确定自微乳化浓缩液的基本处方组成成分为Cremophor EL—无水乙醇—油酸乙酯;(2)绘制了齐墩果酸自微乳液的三元相图,固定油相的质量分数为15%,以齐墩果酸的溶解度和粒径为考察指标进行处方优化,得优化处方:Cremophor EL50%,无水乙醇35%,油酸乙酯15%,其中药物含量的质量分数为1%;(3)以自微乳化速度为指标,考察制备工艺对自微乳液自微乳化能力的影响,确定工艺条件为37℃,400 r·min~(-1)磁力搅拌20min。
2.齐墩果酸SMEDDS的质量评价及体外释放度研究(1)通过对齐墩果酸自微乳液的性状、理化性质参数(粘度、折光率、电导率、Zeta电位)、微观形态、粒径分布和含量的考察,对齐墩果酸自微乳液进行初步质量评价;(2)采用透析袋扩散法对齐墩果酸自微乳和原料药的体外释药行为进行研究,结果表明两者的释药曲线均最符合Weibull方程;(3)考察不同温度、分散介质、稀释倍数对齐墩果酸自微乳液的自微乳化效率的影响;(4)通过影响因素实验和初步稳定性实验证实,齐墩果酸自微乳液稳定性良好。
3.齐墩果酸SMEDDS大鼠在体胃肠吸收研究(1)研究了齐墩果酸微乳及胶束溶液的小肠吸收动力学,两者的吸收呈一级动力学,吸收动力学方程分别为:齐墩果酸微乳溶液:lnX_(剩余)=lnX_0-0.090×t;齐墩果酸胶束溶液:lnX_(剩余)=lnX_0-0.049×t,二者的Ka,t_(1/2)值均存在显著性差异(p＜0.01);(2)考察了低、中、高不同浓度的齐墩果酸微乳溶液的小肠吸收动力学,三者在大鼠小肠的Ka分别为0.100h~(-1)、0.090 h~(-1)和0.103 h~(-1),LnX与时间t呈线性关系,齐墩果酸在肠道内的吸收主要以被动扩散为主;(3)对齐墩果酸微乳溶液在体胃吸收进行了研究,结果表明2h后胃中齐墩果酸吸收百分率平均值为10.92±1.28%,说明药物在胃中吸收较少;(4)研究齐墩果酸微乳溶液的小肠最佳吸收部位,十二指肠、空肠、回肠、结肠的吸收百分率分别为27.52±1.90%、16.81±1.37%、18.83±1.18%、9.69±1.42%,表明十二指肠为主要吸收部位,结肠吸收较少。
4.齐墩果酸SMEDDS在大鼠体内的药物动力学研究(1)建立HPLC—MS法测定齐墩果酸的体内分析方法;(2)以市售齐墩果酸片剂为参比制剂,对齐墩果酸自微乳液进行了大鼠体内药物动力学研究,用DAS ver2.0药代动力学计算机程序处理血药浓度数据,结果表明自微乳液的达峰时间T_(max)为2.0±1.0h,最大血药浓度C_(max)为209.8±47.19 ug·L~(-1);参比片剂的达峰时间T_(max)为2.75±0.50h,最大血药浓度C_(max)为77.6±16.79 ug·L~(-1)。由AUC_(0-8)计算出相对生物利用度Fr为507.03%。可见齐墩果酸自微乳液在体内能快速地吸收,显著地提高口服生物利用度。
Oleanolic acid is a triterpenoid compound possessing many pharmacological activities,such as hepatoprotective,anti-inflammatory,anti-virus,anti-tumor, antidiabetogenic activities,and so on.Oleanolic acid is commonly used in the therapy of hepatitis in clinic and remarkably improve the symptom,physical sign and hepatic function of hepatopath.Now there are only oral tablet and capsule of oleanolic acid in market and because of its poorly solubility in water,the oral administration of oleanolic acid often results in low bioavailability and the oral bioavailability in rat is 0.7%,which limits its therapeutic application.Self-microemulsion drug delivery system(SMEDDS)is a kind of new drug delivery system,which could increase solubility of poorly soluble drugs,protect drugs against enzymolysis in gastrointestinal tract,strengthen stabilities and promote absorption and bioavailability. So it is really a meaningful thing to study the oral oleanolic acid SMEDDS which not only provide new evidence for the clinical application of oleanolic acid,but also offer a new thinking for modernization of traditional Chinese medicine.The main research work was as follows:
1.Foumula and preparation of oleanolic SMEDDS:(1)The basic components of the formulation were determined as Cremophor EL-alcohol-ethyl oleate by investigating the saturated solubility of oleanolic acid in various medium,the interaction between surfactants and oils,the area of microemulsion in the pseudo-ternary phase diagram of different cosurfactants;(2)The quality fraction of oil was determined as 15%by drawing the ternary phase diagram of SMEDDS.The solubility of oleanolic acid and the average particle were selected as the response variables to optimize the SMEDDS formulation and the final formulation(containing Cremophor EL 50%,alcohol 35%,ethyl oleate 15%,with content 1%of drug)had been found;(3)The processing factors that affect the self-microemulsifying ability of SMEDDS had been studied.The final process was stirred with a magnetic stirrer at the speed of 400 r·min~(-1)for 20 minutes at 37℃.
2.Quality evaluation and release of oleanolic acid SMEDDS in vitro:(1)The preliminary quality assessment of oleanilic acid SMEDDS was evaluated by observation of the appearance,the physico-chemical property parameter(such as the viscosity,the refractive index,the conductivity,the Zeta-pontential),the morphology, the particle size and the content;(2)In vitro release studies,the dialysis bag diffusion technique was applied and the release curve of oleanolic acid SMEDDS and crude drug fit well with Weibull equation;(3)The influences of different temperature, disperse medium,dilution ratio on the self-microemulsifying efficiency were also examined;(4)The test of influencing factors and primary stability indicated that the oleanolic acid SMEDDS had a good stability.
3.Absorption kinetics of oleanolic acid SMEDDS in rat stomach and intestine:(1) The intestinal absorption kineticses of oleanolic microemulsion and micelle were investigated and the two absorption processes were both first-process.The absorption kinetics equation of oleanolic microemulsion was lnX_(剩余)=lnX_0-0.090×t,and The absorption kinetics equation of oleanolic micelle was lnX_(剩余)=lnX_0-0.049×t.Ka and t_(1/2)of oleanolic microemulsion and micelle were significantly different;(2)The intestinal absorption kineticses of oleanolic microemulsion with low,middle,high concentrantion were investigated and the Ka were 0.100h~(-1),0.090 h~(-1)和0.103 h~(-1), respectively.So the principal mechanism of oleanolic acid in intestinal absorption conformed to passive diffusion;(3)The gastro in situ was investigated and the absorption percent of oleanolic acid ME was 10.92±1.28%after 2 hours.So oleanolic acid was absorbed poor in the stomach;(4)The test of main segment indicated that the oleanolic acid could be absorbed by all the segments of the intestine, and the absorption percentages of duodenum,jejunum,ileum and colonic were 27.52±1.90%,16.81±1.37%,18.83±1.18%,9.69±1.42%.The oleanolic acid ME was absorbed mainly in duodenum and leastly in colon.
4.Investigation of pharmacokinetic behavior of oleanolic acid SMEDDS in rat in vivo:(1)HPLC-MS method was established to determine the concentration of oleanolic acid in plasma;(2)The pharmacokinetics behavior of oleanolic acid SMEDDS in rats was studied compared with commercial oleanolic acid conventional tablet and the results were treated with DAS ver2.0 procedure.T_(max)of SMEDDS and reference tablet were 2.0±1.0 and 2.75±0.50 h,C_(max)were 209.8±47.19 and 77.6±16.79 ug·L~(-1)respectively.The relative bioavailability Fr was 507.03%by AUC_(0.8).Therefore oleanolic acid SMEDDS could promote the absorption of oleanolic acid and improve the oral bioavailability.
1.齐墩果酸SMEDDS的处方工艺研究(1)考察齐墩果酸在不同介质中的饱和溶解度,根据不同油相、表面活性剂的配伍情况以及不同助表面活性剂伪三元相图中微乳区域的大小,确定自微乳化浓缩液的基本处方组成成分为Cremophor EL—无水乙醇—油酸乙酯;(2)绘制了齐墩果酸自微乳液的三元相图,固定油相的质量分数为15%,以齐墩果酸的溶解度和粒径为考察指标进行处方优化,得优化处方:Cremophor EL50%,无水乙醇35%,油酸乙酯15%,其中药物含量的质量分数为1%;(3)以自微乳化速度为指标,考察制备工艺对自微乳液自微乳化能力的影响,确定工艺条件为37℃,400 r·min~(-1)磁力搅拌20min。
2.齐墩果酸SMEDDS的质量评价及体外释放度研究(1)通过对齐墩果酸自微乳液的性状、理化性质参数(粘度、折光率、电导率、Zeta电位)、微观形态、粒径分布和含量的考察,对齐墩果酸自微乳液进行初步质量评价;(2)采用透析袋扩散法对齐墩果酸自微乳和原料药的体外释药行为进行研究,结果表明两者的释药曲线均最符合Weibull方程;(3)考察不同温度、分散介质、稀释倍数对齐墩果酸自微乳液的自微乳化效率的影响;(4)通过影响因素实验和初步稳定性实验证实,齐墩果酸自微乳液稳定性良好。
3.齐墩果酸SMEDDS大鼠在体胃肠吸收研究(1)研究了齐墩果酸微乳及胶束溶液的小肠吸收动力学,两者的吸收呈一级动力学,吸收动力学方程分别为:齐墩果酸微乳溶液:lnX_(剩余)=lnX_0-0.090×t;齐墩果酸胶束溶液:lnX_(剩余)=lnX_0-0.049×t,二者的Ka,t_(1/2)值均存在显著性差异(p＜0.01);(2)考察了低、中、高不同浓度的齐墩果酸微乳溶液的小肠吸收动力学,三者在大鼠小肠的Ka分别为0.100h~(-1)、0.090 h~(-1)和0.103 h~(-1),LnX与时间t呈线性关系,齐墩果酸在肠道内的吸收主要以被动扩散为主;(3)对齐墩果酸微乳溶液在体胃吸收进行了研究,结果表明2h后胃中齐墩果酸吸收百分率平均值为10.92±1.28%,说明药物在胃中吸收较少;(4)研究齐墩果酸微乳溶液的小肠最佳吸收部位,十二指肠、空肠、回肠、结肠的吸收百分率分别为27.52±1.90%、16.81±1.37%、18.83±1.18%、9.69±1.42%,表明十二指肠为主要吸收部位,结肠吸收较少。
4.齐墩果酸SMEDDS在大鼠体内的药物动力学研究(1)建立HPLC—MS法测定齐墩果酸的体内分析方法;(2)以市售齐墩果酸片剂为参比制剂,对齐墩果酸自微乳液进行了大鼠体内药物动力学研究,用DAS ver2.0药代动力学计算机程序处理血药浓度数据,结果表明自微乳液的达峰时间T_(max)为2.0±1.0h,最大血药浓度C_(max)为209.8±47.19 ug·L~(-1);参比片剂的达峰时间T_(max)为2.75±0.50h,最大血药浓度C_(max)为77.6±16.79 ug·L~(-1)。由AUC_(0-8)计算出相对生物利用度Fr为507.03%。可见齐墩果酸自微乳液在体内能快速地吸收,显著地提高口服生物利用度。
Oleanolic acid is a triterpenoid compound possessing many pharmacological activities,such as hepatoprotective,anti-inflammatory,anti-virus,anti-tumor, antidiabetogenic activities,and so on.Oleanolic acid is commonly used in the therapy of hepatitis in clinic and remarkably improve the symptom,physical sign and hepatic function of hepatopath.Now there are only oral tablet and capsule of oleanolic acid in market and because of its poorly solubility in water,the oral administration of oleanolic acid often results in low bioavailability and the oral bioavailability in rat is 0.7%,which limits its therapeutic application.Self-microemulsion drug delivery system(SMEDDS)is a kind of new drug delivery system,which could increase solubility of poorly soluble drugs,protect drugs against enzymolysis in gastrointestinal tract,strengthen stabilities and promote absorption and bioavailability. So it is really a meaningful thing to study the oral oleanolic acid SMEDDS which not only provide new evidence for the clinical application of oleanolic acid,but also offer a new thinking for modernization of traditional Chinese medicine.The main research work was as follows:
1.Foumula and preparation of oleanolic SMEDDS:(1)The basic components of the formulation were determined as Cremophor EL-alcohol-ethyl oleate by investigating the saturated solubility of oleanolic acid in various medium,the interaction between surfactants and oils,the area of microemulsion in the pseudo-ternary phase diagram of different cosurfactants;(2)The quality fraction of oil was determined as 15%by drawing the ternary phase diagram of SMEDDS.The solubility of oleanolic acid and the average particle were selected as the response variables to optimize the SMEDDS formulation and the final formulation(containing Cremophor EL 50%,alcohol 35%,ethyl oleate 15%,with content 1%of drug)had been found;(3)The processing factors that affect the self-microemulsifying ability of SMEDDS had been studied.The final process was stirred with a magnetic stirrer at the speed of 400 r·min~(-1)for 20 minutes at 37℃.
2.Quality evaluation and release of oleanolic acid SMEDDS in vitro:(1)The preliminary quality assessment of oleanilic acid SMEDDS was evaluated by observation of the appearance,the physico-chemical property parameter(such as the viscosity,the refractive index,the conductivity,the Zeta-pontential),the morphology, the particle size and the content;(2)In vitro release studies,the dialysis bag diffusion technique was applied and the release curve of oleanolic acid SMEDDS and crude drug fit well with Weibull equation;(3)The influences of different temperature, disperse medium,dilution ratio on the self-microemulsifying efficiency were also examined;(4)The test of influencing factors and primary stability indicated that the oleanolic acid SMEDDS had a good stability.
3.Absorption kinetics of oleanolic acid SMEDDS in rat stomach and intestine:(1) The intestinal absorption kineticses of oleanolic microemulsion and micelle were investigated and the two absorption processes were both first-process.The absorption kinetics equation of oleanolic microemulsion was lnX_(剩余)=lnX_0-0.090×t,and The absorption kinetics equation of oleanolic micelle was lnX_(剩余)=lnX_0-0.049×t.Ka and t_(1/2)of oleanolic microemulsion and micelle were significantly different;(2)The intestinal absorption kineticses of oleanolic microemulsion with low,middle,high concentrantion were investigated and the Ka were 0.100h~(-1),0.090 h~(-1)和0.103 h~(-1), respectively.So the principal mechanism of oleanolic acid in intestinal absorption conformed to passive diffusion;(3)The gastro in situ was investigated and the absorption percent of oleanolic acid ME was 10.92±1.28%after 2 hours.So oleanolic acid was absorbed poor in the stomach;(4)The test of main segment indicated that the oleanolic acid could be absorbed by all the segments of the intestine, and the absorption percentages of duodenum,jejunum,ileum and colonic were 27.52±1.90%,16.81±1.37%,18.83±1.18%,9.69±1.42%.The oleanolic acid ME was absorbed mainly in duodenum and leastly in colon.
4.Investigation of pharmacokinetic behavior of oleanolic acid SMEDDS in rat in vivo:(1)HPLC-MS method was established to determine the concentration of oleanolic acid in plasma;(2)The pharmacokinetics behavior of oleanolic acid SMEDDS in rats was studied compared with commercial oleanolic acid conventional tablet and the results were treated with DAS ver2.0 procedure.T_(max)of SMEDDS and reference tablet were 2.0±1.0 and 2.75±0.50 h,C_(max)were 209.8±47.19 and 77.6±16.79 ug·L~(-1)respectively.The relative bioavailability Fr was 507.03%by AUC_(0.8).Therefore oleanolic acid SMEDDS could promote the absorption of oleanolic acid and improve the oral bioavailability.
引文
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