紫杉醇PLGA口服纳米粒的制备及生物利用度的研究
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摘要
紫杉醇(Paclitaxel,TAX)是抗肿瘤药物,在临床上已得到广泛应用,特别是对乳腺癌、卵巢癌的治疗作用明显。由于其水溶性差,临床使用的紫杉醇注射液中的紫杉醇是靠聚氧乙烯蓖麻油(CremophorEL)与无水乙醇以1:1的混合液来稳定和溶解。但聚氧乙烯蓖麻油可促进组胺释放,常引起严重的过敏反应和其他不良反应。为了解决上述问题,研究不含Cremophor EL并能提高紫杉醇生物利用度的制剂成为当前的热点。把紫杉醇制备成口服纳米给药系统后,则不仅能减少毒副作用,增加其稳定性,而且方便储存和运输。本文制备了紫杉醇纳米粒(TAX-NPs),优化了其处方和制备工艺,并对其进行了体内外评价。主要内容和结果如下:
1.建立了紫杉醇样品HPLC测定方法,并对其线性范围、精密度、回收率等进行了验证,结果表明该方法符合分析要求。
以生物可降解聚合物——聚丙交酯乙交酯共聚物(PLGA)为载体,采用乳化-分散法制备了TAX-NPs;以纳米粒的粒径和包封率为评价指标,考察了处方及其工艺因素对制剂质量的影响;对TAX-NPs的基本性质,体外稳定性和释药特征进行了考察;用差示扫描量热法(DSC)及X射线粉末衍射(XRD)分析了紫杉醇在纳米粒中的存在状态,TAX-NPs的平均粒径为(99±7.6)nm,Zeta电位为(78.3±5.87)mV,包封率和载药量分别为(56.99±0.29)%和(7.04±0.13)%。冻干TAX-NPs在4℃放置6个月稳定性良好。DSC及XRD表明TAX以分子形态被有效地包裹在纳米粒中。TAX-NPs在两种不同的pH值PBS释放介质中进行体外释放,以模拟生物体内环境,在pH值越低的条件下,药物释放越快,这对于载药纳米粒在偏酸性的肿瘤环境下发挥抗肿瘤作用非常有利。
2.研究Caco-2细胞对纳米粒的摄取及其影响因素,以评价此种纳米粒作为口服抗肿瘤药物载体的可行性。通过包裹疏水性荧光探针香豆素-6(Coumarin-6,Cou-6)标记纳米粒,采用荧光酶标仪检测细胞内Cou-6的荧光强度,研究粒径,、孵育时间,、纳米粒浓度,、纳米粒的表面性质对Caco-2细胞摄取纳米粒的影响。采用激光共聚焦显微镜观察Caco-2细胞对纳米粒的摄取。与聚乙烯醇(Polyvinyl alcohol,PVA)做乳化剂制备的纳米粒相比,双十二烷基二甲基溴化铵(Didodecyldimethyl ammonium bromide,DMAB)作为乳化剂制备的纳米粒显著增加了Caco-2细胞对纳米粒的摄取率,细胞对粒径为100 nm左右的纳米粒的摄取率最高。结果证明纳米粒可经胃肠道给药吸收入血。
3.利用大鼠在体肠吸收动力学实验,研究了紫杉醇纳米粒及其原料药在肠道的吸收情况,吸收动力学方程分别为:紫杉醇纳米粒lnX_(剩余)=lnX_0-0.154×t;紫杉醇原料药:lnX_(剩余)=lnX_0-0.0023×t,相关系数r分别为0.9460和0.9102。二者的吸收具有显著性差异(P＜0.05),紫杉醇纳米粒在小肠中的吸收速率常数明显大于紫杉醇原料药。
4.建立了紫杉醇的血药浓度测定方法。色谱条件为:色谱柱:Diamonsil C_(18)柱(250mm×4.6mm,5μm);流动相:乙腈/水(47:53,v/v);柱温:30℃;检测波长:227nm;流速:1.0ml/min;进样量:20μl。高、中、低浓度回收率分别为91.23%、92.68%、89.38%。日内RSD分别为3.81%、3.49%、2.89%,日间RSD分别为5.12%、4.59%、3.48%。最低定量浓度为0.02μg/ml。所建立方法适合紫杉醇血药浓度的测定。
以健康的SD大鼠为受试对象,紫杉醇注射液为参比制剂,采用随机对照方法,研究纳米粒在动物体内的生物利用度。实验结果表明紫杉醇纳米粒绝对生物利用度为19.5%,说明用纳米载药系统传输紫杉醇促进了紫杉醇的吸收,提高了其口服生物利用度。
Paclitaxel,as a anticancer drug,has been widely used in clinic, especially for the treatment of breast cancer and ovarian cancer significantly.Since it is poor water solubility,clinically used paclitaxel in the paclitaxel injection is stabilized and dissolved by the mixture of polyoxyethylene castor oil(Cremophor EL) and ethanol(1:1,V/V).But Cremophor EL can promote histamine release,and usually cause severe allergic reactions and other adverse reactions.To solve the above problems, the research on the preparation of paclitaxel does not contain Cremophor EL and can improve the bioavailability become the hot spot.Nanoparticles for oral delivery of paclitaxel could not only reduce side effects and increase its stability,but also profit for storage and transport.Hence, paclitaxel nanoparticles(TAX-NPs) were prepared,the prescription and preparation technology of nanoparticles was optimized.In vivo evaluation of TAX-NPs were carried out.Main contents and results are as follows.
1.In the study,HPLC determination was developed for paclitaxel in vitro and it was validated by characterization of linearity,precision as well as accuracy.
Biodegradable polymer PLGA was used as a drug carrier,and the TAX-NPs were prepared by an emulsification-diffusion method.The effect of formula and technological factors on the quality of preparation was investigated by the estimate index of particle size and encapsulation efficiency of the TAX-NPs.The in vitro stability and release characteristics in vitro of TAX-NPs were investigated,the differential scanning calorimetry(DSC) and X-ray powder diffraction(XRD) were used to analyze existence state of the paclitaxel in the nanoparticles.The average diameter of TAX-NPs was(99±7.6) nm,and Zeta potential was(78.3±5.87) mV.The entrapment efficiency and the content of drug loading of TAX-NPs were(56.99±0.29)%and(7.04±0.13)%,respectively. Freeze-dried TAX-NPs at 4℃for 6 months showed good stability. Differential scanning calorimetry(DSC) and X-ray powder diffraction (XRD) analyses showed TAX was effectively wrapped in the nanoparticles as molecule morphous.TAX-NPs at two different pH values of PBS release medium for in vitro release,to simulate the in vivo environment,the lower the pH value in the condition,the faster the drug release.It is very favorable for TAX-NPs anti-tumor effects for tumor in the acidic environment
2.The Caco-2 cell uptake of nanoparticles and its influencing factors were investigated to evaluate the feasibility of nanoparticles as a carrier of oral anticancer drugs.Nanoparticles were labeled by wrapping hydrophobic fluorescent probe coumarin-6(Cou-6) and fluorescence microplate reader was used to detect fluorescence intensity to investigate the particle size, incubation time,the concentration of nanoparticles and the surface properties of nanoparticles on Caco-2 cell uptake of nanoparticles.The laser confocal scanning microscope was used to observed Caco-2 cell uptake of nanoparticles.Compared with the nanoparticles emulsified by PVA,the nanoparticles emulsified by DMAB showed a significant increase in the Caco-2 cells uptake efficiency,and the uptake efficiency of nanoparticles with particle size of 100 nm was topmost.The results indicate that nanoparticles can be administered via the gastrointestinal tract.
3.The absorption kinetics of free TAX and TAX-NPs were compared by the intestine of rats cannulated in situ recirculation experiment.The absorption kinetics equation of free TAX was lnX_(剩余)=lnX_0-0.154×t.And the absorption kinetics equation of TAX-NPs was lnX_(剩余)=lnX_0-0.0023×t, the correlation coefficient r were 0.9460 and 0.9102,respectively.The absorption of the two significant difference(P＜0.05) and the absorption speed of TAX-NPs was faster than that of free TAX.
4.The analytical method of concentration of paclitaxel in plasma was devoloped.The established chromatographic conditions was as follow:the column was Diamonsil C_(18)(250mm×4.6mm,5μm),a mobile phase was acetonitrile/water(47:53),the temperature of column was 30℃,detective wavelength was 227 nm,flow rate was 1 ml/min and injection volume was 20μl.The recoveries of high,medium and low concentration were 91.23 %、92.68%、89.38%,respectively.Intra-day RSD were 3.81%、3.49% 2.89%,respectively.Inter-day RSD were 5.12%、4.59%、3.48%, respectively.Quantitative minimum concentration was 0.02μg/ml.These results showed that the established method was suitable for determining the plasma concentration of paclitaxel.
Bioavailability in animal vivo was studied by a randomized and controlled study.Healthy SD rats were used as the tested subjects and paclitaxel injection was used as the reference formulation.Experimental results showed that the absolute bioavailability of TAX-NPs was 19.5%. These result showed that the nanoparticles drug delivery system promoted the absorption of paclitaxel to improve their oral bioavailability.
1.建立了紫杉醇样品HPLC测定方法,并对其线性范围、精密度、回收率等进行了验证,结果表明该方法符合分析要求。
以生物可降解聚合物——聚丙交酯乙交酯共聚物(PLGA)为载体,采用乳化-分散法制备了TAX-NPs;以纳米粒的粒径和包封率为评价指标,考察了处方及其工艺因素对制剂质量的影响;对TAX-NPs的基本性质,体外稳定性和释药特征进行了考察;用差示扫描量热法(DSC)及X射线粉末衍射(XRD)分析了紫杉醇在纳米粒中的存在状态,TAX-NPs的平均粒径为(99±7.6)nm,Zeta电位为(78.3±5.87)mV,包封率和载药量分别为(56.99±0.29)%和(7.04±0.13)%。冻干TAX-NPs在4℃放置6个月稳定性良好。DSC及XRD表明TAX以分子形态被有效地包裹在纳米粒中。TAX-NPs在两种不同的pH值PBS释放介质中进行体外释放,以模拟生物体内环境,在pH值越低的条件下,药物释放越快,这对于载药纳米粒在偏酸性的肿瘤环境下发挥抗肿瘤作用非常有利。
2.研究Caco-2细胞对纳米粒的摄取及其影响因素,以评价此种纳米粒作为口服抗肿瘤药物载体的可行性。通过包裹疏水性荧光探针香豆素-6(Coumarin-6,Cou-6)标记纳米粒,采用荧光酶标仪检测细胞内Cou-6的荧光强度,研究粒径,、孵育时间,、纳米粒浓度,、纳米粒的表面性质对Caco-2细胞摄取纳米粒的影响。采用激光共聚焦显微镜观察Caco-2细胞对纳米粒的摄取。与聚乙烯醇(Polyvinyl alcohol,PVA)做乳化剂制备的纳米粒相比,双十二烷基二甲基溴化铵(Didodecyldimethyl ammonium bromide,DMAB)作为乳化剂制备的纳米粒显著增加了Caco-2细胞对纳米粒的摄取率,细胞对粒径为100 nm左右的纳米粒的摄取率最高。结果证明纳米粒可经胃肠道给药吸收入血。
3.利用大鼠在体肠吸收动力学实验,研究了紫杉醇纳米粒及其原料药在肠道的吸收情况,吸收动力学方程分别为:紫杉醇纳米粒lnX_(剩余)=lnX_0-0.154×t;紫杉醇原料药:lnX_(剩余)=lnX_0-0.0023×t,相关系数r分别为0.9460和0.9102。二者的吸收具有显著性差异(P＜0.05),紫杉醇纳米粒在小肠中的吸收速率常数明显大于紫杉醇原料药。
4.建立了紫杉醇的血药浓度测定方法。色谱条件为:色谱柱:Diamonsil C_(18)柱(250mm×4.6mm,5μm);流动相:乙腈/水(47:53,v/v);柱温:30℃;检测波长:227nm;流速:1.0ml/min;进样量:20μl。高、中、低浓度回收率分别为91.23%、92.68%、89.38%。日内RSD分别为3.81%、3.49%、2.89%,日间RSD分别为5.12%、4.59%、3.48%。最低定量浓度为0.02μg/ml。所建立方法适合紫杉醇血药浓度的测定。
以健康的SD大鼠为受试对象,紫杉醇注射液为参比制剂,采用随机对照方法,研究纳米粒在动物体内的生物利用度。实验结果表明紫杉醇纳米粒绝对生物利用度为19.5%,说明用纳米载药系统传输紫杉醇促进了紫杉醇的吸收,提高了其口服生物利用度。
Paclitaxel,as a anticancer drug,has been widely used in clinic, especially for the treatment of breast cancer and ovarian cancer significantly.Since it is poor water solubility,clinically used paclitaxel in the paclitaxel injection is stabilized and dissolved by the mixture of polyoxyethylene castor oil(Cremophor EL) and ethanol(1:1,V/V).But Cremophor EL can promote histamine release,and usually cause severe allergic reactions and other adverse reactions.To solve the above problems, the research on the preparation of paclitaxel does not contain Cremophor EL and can improve the bioavailability become the hot spot.Nanoparticles for oral delivery of paclitaxel could not only reduce side effects and increase its stability,but also profit for storage and transport.Hence, paclitaxel nanoparticles(TAX-NPs) were prepared,the prescription and preparation technology of nanoparticles was optimized.In vivo evaluation of TAX-NPs were carried out.Main contents and results are as follows.
1.In the study,HPLC determination was developed for paclitaxel in vitro and it was validated by characterization of linearity,precision as well as accuracy.
Biodegradable polymer PLGA was used as a drug carrier,and the TAX-NPs were prepared by an emulsification-diffusion method.The effect of formula and technological factors on the quality of preparation was investigated by the estimate index of particle size and encapsulation efficiency of the TAX-NPs.The in vitro stability and release characteristics in vitro of TAX-NPs were investigated,the differential scanning calorimetry(DSC) and X-ray powder diffraction(XRD) were used to analyze existence state of the paclitaxel in the nanoparticles.The average diameter of TAX-NPs was(99±7.6) nm,and Zeta potential was(78.3±5.87) mV.The entrapment efficiency and the content of drug loading of TAX-NPs were(56.99±0.29)%and(7.04±0.13)%,respectively. Freeze-dried TAX-NPs at 4℃for 6 months showed good stability. Differential scanning calorimetry(DSC) and X-ray powder diffraction (XRD) analyses showed TAX was effectively wrapped in the nanoparticles as molecule morphous.TAX-NPs at two different pH values of PBS release medium for in vitro release,to simulate the in vivo environment,the lower the pH value in the condition,the faster the drug release.It is very favorable for TAX-NPs anti-tumor effects for tumor in the acidic environment
2.The Caco-2 cell uptake of nanoparticles and its influencing factors were investigated to evaluate the feasibility of nanoparticles as a carrier of oral anticancer drugs.Nanoparticles were labeled by wrapping hydrophobic fluorescent probe coumarin-6(Cou-6) and fluorescence microplate reader was used to detect fluorescence intensity to investigate the particle size, incubation time,the concentration of nanoparticles and the surface properties of nanoparticles on Caco-2 cell uptake of nanoparticles.The laser confocal scanning microscope was used to observed Caco-2 cell uptake of nanoparticles.Compared with the nanoparticles emulsified by PVA,the nanoparticles emulsified by DMAB showed a significant increase in the Caco-2 cells uptake efficiency,and the uptake efficiency of nanoparticles with particle size of 100 nm was topmost.The results indicate that nanoparticles can be administered via the gastrointestinal tract.
3.The absorption kinetics of free TAX and TAX-NPs were compared by the intestine of rats cannulated in situ recirculation experiment.The absorption kinetics equation of free TAX was lnX_(剩余)=lnX_0-0.154×t.And the absorption kinetics equation of TAX-NPs was lnX_(剩余)=lnX_0-0.0023×t, the correlation coefficient r were 0.9460 and 0.9102,respectively.The absorption of the two significant difference(P＜0.05) and the absorption speed of TAX-NPs was faster than that of free TAX.
4.The analytical method of concentration of paclitaxel in plasma was devoloped.The established chromatographic conditions was as follow:the column was Diamonsil C_(18)(250mm×4.6mm,5μm),a mobile phase was acetonitrile/water(47:53),the temperature of column was 30℃,detective wavelength was 227 nm,flow rate was 1 ml/min and injection volume was 20μl.The recoveries of high,medium and low concentration were 91.23 %、92.68%、89.38%,respectively.Intra-day RSD were 3.81%、3.49% 2.89%,respectively.Inter-day RSD were 5.12%、4.59%、3.48%, respectively.Quantitative minimum concentration was 0.02μg/ml.These results showed that the established method was suitable for determining the plasma concentration of paclitaxel.
Bioavailability in animal vivo was studied by a randomized and controlled study.Healthy SD rats were used as the tested subjects and paclitaxel injection was used as the reference formulation.Experimental results showed that the absolute bioavailability of TAX-NPs was 19.5%. These result showed that the nanoparticles drug delivery system promoted the absorption of paclitaxel to improve their oral bioavailability.
引文
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