苦参碱白蛋白亚微粒给药系统的实验研究
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摘要
苦参碱系从豆科植物苦参、苦豆子及广豆根中分离出来的生物碱，具有抗病毒、抗肝纤维化、抗肿瘤、免疫调节、抗过敏、抗心律失常及消肿利尿等多种药理作用，被广泛应用于临床，抗炎、保肝利胆及免疫抑制的作用成为其治疗急慢性肝炎的药理学基础。
本课题采用现代靶向制剂技术，以苦参碱(matrine，MAT)为模型药物，以安全无毒、无免疫原性、可生物降解、生物相容性好的牛血清白蛋白(bovineserum albumin，BSA)为载体材料，采用去溶剂化—交联法制备苦参碱白蛋白亚微粒(matrine-loaded albumin nanoparticles,MAT-BSA-NP)。实验以包封率为主要考察指标，通过均匀设计法对处方工艺进行了优化，确定最佳处方工艺，并系统的研究了MAT-BSA-NP冻干粉针剂的制备处方和工艺，考察了制剂的体外释放特点以及体内分布和药动学特征。以期通过肝脏靶向分布达到提高MAT治疗肝炎的效果，降低其毒副作用的目的。
通过均匀设计优化的最佳处方工艺为戊二醛／BSA=2.73μg·mg~(-1)，MAT=9.1mg，BSA浓度=2.35％，交联时间=2.4h，转速=700 r·min~(-1)，和静置时间=1.5h。优化工艺操作简单，所制备的MAT-BSA-NP包封率稳定，平均包封率(84.25±0.95)％，载药量为(6.06±0.08)％，成球率为(87.47±0.74)％。透射电镜下观察所得纳米粒为类球形实体，表面光滑不粘连，粒径分布的范围较窄，平均粒径为(323.7±12.5)nnl，Zeta电位为(-16.92±0.39)mV。
以外观、色泽、再分散性为评价指标，将MAT-BSA-NP胶体混悬液制成冻干粉针剂，确定其冻干工艺为：以5％甘露醇作为支架剂，置-80℃的超低温冰箱中冷冻24h，冷冻干燥机中36h。质量评价结果表明冻干过程未影响MAT-BSA-NP的稳定性。对冻干品的DSC和X-射线衍射分析结果表明，制成亚微粒后药物已被载体包裹或吸附，不再是单纯的混合，药物不再以晶体结构存在，即MAT-BSA-NP中形成了新的物相。以MAT-BSA-NP的粒径及分布、包封率和载药量等为指标，评价了MAT-BSA-NP冻干针剂的初步稳定性，结果显示其在3-5℃，20-25℃条件下放置3个月，物理化学稳定性良好。用离心超滤法对MAT-BSA-NP冻干粉针剂的体外释药特性进行了研究，结果表明MAT-BSA-NP的体外释药具有缓释制剂特征，可用双指数方程拟合，方程为100-Q=0.476e~(-0.351t)+0.3253e~(-0.0322t)，r_α=0.9985，r_β=0.9987
本文以MAT溶液为对照组，研究了MAT-BSA-NP冻干粉针剂在小鼠体内的组织分布情况，并选用多种指标评价了该冻干针剂的体内靶向性。结果表明：将MAT制成MAT-BSA-NP后，可明显提高其在肝和脾组织中的浓度分布，肝脾组织中同一时间点的药物浓度均明显高于其普通溶液剂型。同时，MAT-BSA-NP可明显延长药物的作用时间，从而有助于药物疗效的提高，具有重要的临床意义。
血药浓度数据表明，将MAT制成MAT-BSA-NP后，血药浓度更平稳，利用DAS 2.0版实用药代动力学程序对血药浓度数据进行曲线拟合，选择最佳房室模型，并计算主要药物动力学参数。结果表明，MAT溶液和MAT-BSA-NP冻干粉针剂在小鼠体内药物动力学过程可用开放式二室模型来描述。静脉注射MAT溶液后，小鼠体内药物动力学方程为：C=8.096e~(-2.23t)+2.371e~(-0.449t)，分布、消除半衰期及平均滞留时间MRT均很短，分别为T_(1／2α)=0.311h，T_(1／2β)=1.543h，MRT_(0～∞)=1.216h，清除率CLz=4.264 L／h／kg，AUC为9.38 h·μg·ml~(-1)，而静脉注射MAT-BSA-NP冻干粉针剂后，小鼠体内药物动力学有明显改变，其药物动力学方程为：C=4.675e~(0.932t)+0.722e~(-0.07t)，T_(1／2α)、T_(1／2β)、及MRT均显著延长，分别为T_(1／2α)=0.744h，T_(1／2β)=9.866h，MRT_(0～∞)=9.373h，清除率降低，CLz=2.405 L／h／kg，AUC则增至16.632 h·μg·ml~(-1)。由分析结果可知，MAT-BSA-NP能够显著延长MAT在小鼠体内的消除半衰期和体内滞留时间，AUC显著增高，清除率明显降低，说明将MAT制成MAT-BSA-NP后，有助于提高药物的生物利用度，并发挥长效作用。
以苦参碱为模型药物制备肝靶向白蛋白亚微粒的研究目前国内外尚未见报道，本文的研究成果丰富了肝靶向给药系统的研究内容，而且将为探讨和总结苦参碱肝靶向给药系统提供有较高学术价值的参考和借鉴，为乙型肝炎治疗探索一种新的思路和治疗手段。
Matrine(MAT) ,a kind of alkaloid extracted from the well known Chinese herb Sophora Flavescens Ait S.Q lopecuroioles L and S. snbprostrata chun at T. Chon, which has many pharmacologic actions such as anti-virus,anti-hepatic fibrosis, anti-tumor, immunological regulation and so on,and it has been used in the treatment of acute / chronic hepatitis extensively.
As carrier material,bovine serum albumin(BSA) may be very promising because of their biodegradability, lack of toxicity and antigenicity, stability, shelf life, controllable drug-release properties. Therefore, we chose MAT as the model drug and BSA as the drug carrier, and prepared matrine-loaded albumin nanoparticles (MAT-BSA-NP) by a coacervation method and chemical cross-linking with glutaraldehyde in our investigation. The formula and technology for preparing MAT-BSA-NP colloidal solution were optimized by the uniform design method, with the entrapment efficiency as the criterion, and its freeze-dried sample for injection was also systematically studied. The release kinetics in vitro ,characteristics of distribution and Pharmacokinetics in vivo were examined. MAT-BSA-NP were expected to reach the aim of enhancing its therapeutic efficacy of hepatitis through hepatic targeting and decreasing its side effects.
The optimized parameters were as follows: the glutaraldehyde -BSA ratio was 2.73μg·mg~(-1) , the MAT was 9.1mg,the concentration of BSA in water was 2.35%, the cross-linking time was 2.4h, the stirring rate was 700 r·min~(-1),and the standing time was 1.5h. The entrapment efficiency ,actual drug loading and yield of the nanoparticles were (84.25±0.95)%, (6.06±0.08)% and (87.47±0.74) %, respectively. Through the observation of transmission electron microscope, we found that the nanoparticles we prepared were sphere-like and regular. The size distribution of the nanoparticles was narrow, with the average particle diameter of( 323.7 ±12.5 )nm.The Zeta potential was (-16.92±0.39) mV.
The formula of freeze-dried MAT-BSA-NP for injection was established based on the criterious of its appearance,color and redispersibility. The final established freeze-dried method was as follows: the protective agent was manicol with the concentration of 5%, the force-freeze temperature was -80℃, the force-freeze time was 24 h, and the freeze-dried time was 36 h. The comparison between the nanoparticles before and after freeze-dried procedure showed that freeze-drying had little effects on the entrapment efficiency, drug-loading, the particle diameter and Zeta potential of the nanoparticles. It was demonstrated by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) that MAT existed in the form of amorphous in the nanoparticles. The initiatory stability research showed that the freeze-dried MAT-BSA-NP could be stored at 3-5 ℃ or 20-25 ℃ for 3 months.
The in vitro release properties of the freeze-dried MAT-BSA-NP for injection was evaluated by ultrafiltration/centrifugation. The results showed that the drug release pattern was in accord with two phases kinetics equation,having sustained-release character: 100-Q=0.476e~(-0.351t)+0.3253e~(-0.0322t), r_α =0.9985, r_β=0.9987
We utilized the HPLC method to determine and compare the content of MAT in different tissues of mice following the tail intravenous injection of MAT solution and freeze-dried MAT-BSA-NP for injection. The results showed that being packed in nanoparticles, the distribution of MAT in liver and spleen were all enhanced. Moreover, the mean retention time in these tissues was also prolonged. Therefore, MAT-BSA-NP were helpful for MAT to improve its therapertic efficiency and achieve a long-term effect. The results of pharmaceutics showed that, the encapsulation of MAT in MAT-BSA-NP was remarkably effective in prolonging its blood circulation time and possessing a stable blood drug level. Pharmacokinetic parameters and the best compartment method were obtained using the Practical Pharmacokinetic Program-DAS 2.0. The results showed that both preparations' Pharmacokinetics process were conformed to the two-compartment model. The pharmacokinetic equation of MAT solution and freeze-dried MAT-BSA-NP for injection were C=8.096e~(2.23t)+2.371e~(-0.449t) and C=4.675e~(-0.932t)+0.722e~(-0.07t), respectively. The major calculated parameters of the MAT solution group were as follows: T_(1/2α)=0.311h, T_(1/2β)=1.543h, MRT_(0-∞)=1.216h, CLz =4.264 L/h/kg , AUC=9.38h·μg·ml~(-1) , Meanwhile, the major calculated parameters of the freeze-dried MAT-BSA-NP group were as follows: T_(1/2α)=0.744h, T_(1/2β)=9.866h, MRT_(0-∞)=9.373h, CLz =2.405 L/h/kg, AUC =16.632 h·μg·ml~(-1) The results indicated that BSA nanoparticles could be a potential carrier for MAT to prolonged elimination half life and increased bioavailability.
MAT-BSA-NP are novel targeting drug delivery system, which were prepared first time in this research. The results which not only offered reference and experience for hepatic targeting drug delivery system but also brought new ideas to design and develop a new type drug delivery system for hepatitis .
本课题采用现代靶向制剂技术，以苦参碱(matrine，MAT)为模型药物，以安全无毒、无免疫原性、可生物降解、生物相容性好的牛血清白蛋白(bovineserum albumin，BSA)为载体材料，采用去溶剂化—交联法制备苦参碱白蛋白亚微粒(matrine-loaded albumin nanoparticles,MAT-BSA-NP)。实验以包封率为主要考察指标，通过均匀设计法对处方工艺进行了优化，确定最佳处方工艺，并系统的研究了MAT-BSA-NP冻干粉针剂的制备处方和工艺，考察了制剂的体外释放特点以及体内分布和药动学特征。以期通过肝脏靶向分布达到提高MAT治疗肝炎的效果，降低其毒副作用的目的。
通过均匀设计优化的最佳处方工艺为戊二醛／BSA=2.73μg·mg~(-1)，MAT=9.1mg，BSA浓度=2.35％，交联时间=2.4h，转速=700 r·min~(-1)，和静置时间=1.5h。优化工艺操作简单，所制备的MAT-BSA-NP包封率稳定，平均包封率(84.25±0.95)％，载药量为(6.06±0.08)％，成球率为(87.47±0.74)％。透射电镜下观察所得纳米粒为类球形实体，表面光滑不粘连，粒径分布的范围较窄，平均粒径为(323.7±12.5)nnl，Zeta电位为(-16.92±0.39)mV。
以外观、色泽、再分散性为评价指标，将MAT-BSA-NP胶体混悬液制成冻干粉针剂，确定其冻干工艺为：以5％甘露醇作为支架剂，置-80℃的超低温冰箱中冷冻24h，冷冻干燥机中36h。质量评价结果表明冻干过程未影响MAT-BSA-NP的稳定性。对冻干品的DSC和X-射线衍射分析结果表明，制成亚微粒后药物已被载体包裹或吸附，不再是单纯的混合，药物不再以晶体结构存在，即MAT-BSA-NP中形成了新的物相。以MAT-BSA-NP的粒径及分布、包封率和载药量等为指标，评价了MAT-BSA-NP冻干针剂的初步稳定性，结果显示其在3-5℃，20-25℃条件下放置3个月，物理化学稳定性良好。用离心超滤法对MAT-BSA-NP冻干粉针剂的体外释药特性进行了研究，结果表明MAT-BSA-NP的体外释药具有缓释制剂特征，可用双指数方程拟合，方程为100-Q=0.476e~(-0.351t)+0.3253e~(-0.0322t)，r_α=0.9985，r_β=0.9987
本文以MAT溶液为对照组，研究了MAT-BSA-NP冻干粉针剂在小鼠体内的组织分布情况，并选用多种指标评价了该冻干针剂的体内靶向性。结果表明：将MAT制成MAT-BSA-NP后，可明显提高其在肝和脾组织中的浓度分布，肝脾组织中同一时间点的药物浓度均明显高于其普通溶液剂型。同时，MAT-BSA-NP可明显延长药物的作用时间，从而有助于药物疗效的提高，具有重要的临床意义。
血药浓度数据表明，将MAT制成MAT-BSA-NP后，血药浓度更平稳，利用DAS 2.0版实用药代动力学程序对血药浓度数据进行曲线拟合，选择最佳房室模型，并计算主要药物动力学参数。结果表明，MAT溶液和MAT-BSA-NP冻干粉针剂在小鼠体内药物动力学过程可用开放式二室模型来描述。静脉注射MAT溶液后，小鼠体内药物动力学方程为：C=8.096e~(-2.23t)+2.371e~(-0.449t)，分布、消除半衰期及平均滞留时间MRT均很短，分别为T_(1／2α)=0.311h，T_(1／2β)=1.543h，MRT_(0～∞)=1.216h，清除率CLz=4.264 L／h／kg，AUC为9.38 h·μg·ml~(-1)，而静脉注射MAT-BSA-NP冻干粉针剂后，小鼠体内药物动力学有明显改变，其药物动力学方程为：C=4.675e~(0.932t)+0.722e~(-0.07t)，T_(1／2α)、T_(1／2β)、及MRT均显著延长，分别为T_(1／2α)=0.744h，T_(1／2β)=9.866h，MRT_(0～∞)=9.373h，清除率降低，CLz=2.405 L／h／kg，AUC则增至16.632 h·μg·ml~(-1)。由分析结果可知，MAT-BSA-NP能够显著延长MAT在小鼠体内的消除半衰期和体内滞留时间，AUC显著增高，清除率明显降低，说明将MAT制成MAT-BSA-NP后，有助于提高药物的生物利用度，并发挥长效作用。
以苦参碱为模型药物制备肝靶向白蛋白亚微粒的研究目前国内外尚未见报道，本文的研究成果丰富了肝靶向给药系统的研究内容，而且将为探讨和总结苦参碱肝靶向给药系统提供有较高学术价值的参考和借鉴，为乙型肝炎治疗探索一种新的思路和治疗手段。
Matrine(MAT) ,a kind of alkaloid extracted from the well known Chinese herb Sophora Flavescens Ait S.Q lopecuroioles L and S. snbprostrata chun at T. Chon, which has many pharmacologic actions such as anti-virus,anti-hepatic fibrosis, anti-tumor, immunological regulation and so on,and it has been used in the treatment of acute / chronic hepatitis extensively.
As carrier material,bovine serum albumin(BSA) may be very promising because of their biodegradability, lack of toxicity and antigenicity, stability, shelf life, controllable drug-release properties. Therefore, we chose MAT as the model drug and BSA as the drug carrier, and prepared matrine-loaded albumin nanoparticles (MAT-BSA-NP) by a coacervation method and chemical cross-linking with glutaraldehyde in our investigation. The formula and technology for preparing MAT-BSA-NP colloidal solution were optimized by the uniform design method, with the entrapment efficiency as the criterion, and its freeze-dried sample for injection was also systematically studied. The release kinetics in vitro ,characteristics of distribution and Pharmacokinetics in vivo were examined. MAT-BSA-NP were expected to reach the aim of enhancing its therapeutic efficacy of hepatitis through hepatic targeting and decreasing its side effects.
The optimized parameters were as follows: the glutaraldehyde -BSA ratio was 2.73μg·mg~(-1) , the MAT was 9.1mg,the concentration of BSA in water was 2.35%, the cross-linking time was 2.4h, the stirring rate was 700 r·min~(-1),and the standing time was 1.5h. The entrapment efficiency ,actual drug loading and yield of the nanoparticles were (84.25±0.95)%, (6.06±0.08)% and (87.47±0.74) %, respectively. Through the observation of transmission electron microscope, we found that the nanoparticles we prepared were sphere-like and regular. The size distribution of the nanoparticles was narrow, with the average particle diameter of( 323.7 ±12.5 )nm.The Zeta potential was (-16.92±0.39) mV.
The formula of freeze-dried MAT-BSA-NP for injection was established based on the criterious of its appearance,color and redispersibility. The final established freeze-dried method was as follows: the protective agent was manicol with the concentration of 5%, the force-freeze temperature was -80℃, the force-freeze time was 24 h, and the freeze-dried time was 36 h. The comparison between the nanoparticles before and after freeze-dried procedure showed that freeze-drying had little effects on the entrapment efficiency, drug-loading, the particle diameter and Zeta potential of the nanoparticles. It was demonstrated by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) that MAT existed in the form of amorphous in the nanoparticles. The initiatory stability research showed that the freeze-dried MAT-BSA-NP could be stored at 3-5 ℃ or 20-25 ℃ for 3 months.
The in vitro release properties of the freeze-dried MAT-BSA-NP for injection was evaluated by ultrafiltration/centrifugation. The results showed that the drug release pattern was in accord with two phases kinetics equation,having sustained-release character: 100-Q=0.476e~(-0.351t)+0.3253e~(-0.0322t), r_α =0.9985, r_β=0.9987
We utilized the HPLC method to determine and compare the content of MAT in different tissues of mice following the tail intravenous injection of MAT solution and freeze-dried MAT-BSA-NP for injection. The results showed that being packed in nanoparticles, the distribution of MAT in liver and spleen were all enhanced. Moreover, the mean retention time in these tissues was also prolonged. Therefore, MAT-BSA-NP were helpful for MAT to improve its therapertic efficiency and achieve a long-term effect. The results of pharmaceutics showed that, the encapsulation of MAT in MAT-BSA-NP was remarkably effective in prolonging its blood circulation time and possessing a stable blood drug level. Pharmacokinetic parameters and the best compartment method were obtained using the Practical Pharmacokinetic Program-DAS 2.0. The results showed that both preparations' Pharmacokinetics process were conformed to the two-compartment model. The pharmacokinetic equation of MAT solution and freeze-dried MAT-BSA-NP for injection were C=8.096e~(2.23t)+2.371e~(-0.449t) and C=4.675e~(-0.932t)+0.722e~(-0.07t), respectively. The major calculated parameters of the MAT solution group were as follows: T_(1/2α)=0.311h, T_(1/2β)=1.543h, MRT_(0-∞)=1.216h, CLz =4.264 L/h/kg , AUC=9.38h·μg·ml~(-1) , Meanwhile, the major calculated parameters of the freeze-dried MAT-BSA-NP group were as follows: T_(1/2α)=0.744h, T_(1/2β)=9.866h, MRT_(0-∞)=9.373h, CLz =2.405 L/h/kg, AUC =16.632 h·μg·ml~(-1) The results indicated that BSA nanoparticles could be a potential carrier for MAT to prolonged elimination half life and increased bioavailability.
MAT-BSA-NP are novel targeting drug delivery system, which were prepared first time in this research. The results which not only offered reference and experience for hepatic targeting drug delivery system but also brought new ideas to design and develop a new type drug delivery system for hepatitis .
引文
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