斑蝥素及斑蝥提取物的口服缓释制剂研究
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摘要
本文优化和建立了斑蝥素的定量方法,包括高效液相色谱法(HPLC)、气相色谱法(GC)、气相色谱质谱联用方法(GC-MS),考察了斑蝥素及斑蝥提取物中斑蝥素的基本理化性质。利用建立的高灵敏度的GC-MS方法,进行了斑蝥素在比格犬体内的药代动力学研究。制备了斑蝥素及斑蝥提取物两种固体分散体,解决斑蝥素水溶性差和黏膜刺激性问题。并以固体分散体为中间体,以壳聚糖为粘附材料制备了生物粘附缓释颗粒,并对制备的固体分散体进行了黏膜刺激性评价,还考察了制备的缓释颗粒在SD大鼠体内的动态变化,结果显示制备的缓释颗粒在体内具有一定的缓释效果。
首先进行了斑蝥素及斑蝥提取物体外定量方法的研究。本研究优化并建立了HPLC、GC、GC-MS用于不同样品中斑蝥素含量的测定。利用HPLC和GC对斑蝥素及其斑蝥提取物中的斑蝥素溶解性能、表观油/水分配系数、酸稳定性等重要理化参数进行了考察,为斑蝥素的下一步制剂研究提供依据。斑蝥素临床使用剂量小,血药浓度低,本试验建立了高灵敏度的GC-MS方法,采取盐酸酸化,乙酸乙酯萃取的方法处理血浆样品,其萃取率达到了80%以上,最低定量限为2.14ng/mL,可用于斑蝥素的体内评价,为下一步的斑蝥素的体内测定奠定了基础。
其次,目前未见有关斑蝥素体内药代动力学研究,本研究利用建立的高灵敏度的GC-MS对比格犬临床给药剂量下血浆中的微量斑蝥素进行检测,首次得到了斑蝥素比格犬体内的药代动力学参数。结果显示斑蝥素在体内的消除较快,半衰期短,口服生物利用度较低,仅为26.7%。
本研究制备了斑蝥素固体分散体及斑蝥提取物固体分散体,均不同程度的提高了斑蝥素的溶解度,并减轻了对胃黏膜的刺激。体外释放试验证明,二者提高了斑蝥素的释放。以固体分散体为中间体,壳聚糖为生物粘附材料,制备了斑蝥素缓释颗粒及斑蝥提取物缓释颗粒,体外释放考察表明有缓释效果。
最后本研究考察了所制备的斑蝥素及斑蝥提取物制剂在SD大鼠体内的动态变化,结果显示斑蝥素壳聚糖缓释颗粒和斑蝥提取物壳聚糖缓释颗粒在体内的缓释作用良好,且生物利用度较斑蝥素纯品均有明显的提高。
The thesis developed some determination method of cantharidin for different aims, such as HPLC, GC, GC-MS. This thesis studied the basic physicochemical characters of cantharidin and the extract of Mylabris, then studied the pharmacokinetics properties of cantharidin in beagle dogs by GC-MS. Prepared solid dispersion about CA and the extract of Mylabris. Then studied the effect of solid dispersion preparation. Using the chitosan as the bioadhesive material and absorption enhancer, the solid dispersion as the media preparation, prepared the cantharidin and the extract of Mylabris bioadhesive drug delivery systems whose pharmacokinetics parameters were studied in SD rats.
Firstly, the assaying method of CA was established. On one hand, we perfected the HPLC and GC to assay the CA content in vitro; on the other hand, a simple, sensitive and specific GC-MS method was developed, which could assay CA in vivo. HPLC and GC were used to study physicochemical character of cantharidin and the extract of Mylabris to provide the guaidence to preparation. Then the GC-MS was used in the pharmacokinetic study and evaluate in vivo study. One-compartment model best described the blood level data for CA after intravenous administration and oral admintration. It shows CA eliminate quickly in vivo and has a low oral bioavailability 26.7%. The parameters will provide the theoretic basis for the rational use of CA.
Secondly, two kinds of preparations was obtained, used PEG4000 as dispersion carrier which was reported to enhance drug dissolubility and alleviation the stimulatory to gastric mucosa. Then the CA's release curve from two formulations was studied, and it is proved that the effects of the formulation on the release curve of CA were more completely. Then, the bioadhesive particles that using the chitosan as the absorption enhancer and bioadhesive material, the solid dispersion as the media preparation was prepared after the uniform test in order to get the slow release effect.
At last, the bioavailability of bioadhesive particles and the two preparations were evaluated in vivo. In the experiment, the pure CA is reference formulation and the other preparations are test formulation. The plasma concentration-time profiles of CA was studied and assayed by GC-MS method. The result indicated that comparing to the CA, CA bioadhesive patricals and Mylabris extract bioadhesive patricals both showed a significant sustained-release effect in rats.
首先进行了斑蝥素及斑蝥提取物体外定量方法的研究。本研究优化并建立了HPLC、GC、GC-MS用于不同样品中斑蝥素含量的测定。利用HPLC和GC对斑蝥素及其斑蝥提取物中的斑蝥素溶解性能、表观油/水分配系数、酸稳定性等重要理化参数进行了考察,为斑蝥素的下一步制剂研究提供依据。斑蝥素临床使用剂量小,血药浓度低,本试验建立了高灵敏度的GC-MS方法,采取盐酸酸化,乙酸乙酯萃取的方法处理血浆样品,其萃取率达到了80%以上,最低定量限为2.14ng/mL,可用于斑蝥素的体内评价,为下一步的斑蝥素的体内测定奠定了基础。
其次,目前未见有关斑蝥素体内药代动力学研究,本研究利用建立的高灵敏度的GC-MS对比格犬临床给药剂量下血浆中的微量斑蝥素进行检测,首次得到了斑蝥素比格犬体内的药代动力学参数。结果显示斑蝥素在体内的消除较快,半衰期短,口服生物利用度较低,仅为26.7%。
本研究制备了斑蝥素固体分散体及斑蝥提取物固体分散体,均不同程度的提高了斑蝥素的溶解度,并减轻了对胃黏膜的刺激。体外释放试验证明,二者提高了斑蝥素的释放。以固体分散体为中间体,壳聚糖为生物粘附材料,制备了斑蝥素缓释颗粒及斑蝥提取物缓释颗粒,体外释放考察表明有缓释效果。
最后本研究考察了所制备的斑蝥素及斑蝥提取物制剂在SD大鼠体内的动态变化,结果显示斑蝥素壳聚糖缓释颗粒和斑蝥提取物壳聚糖缓释颗粒在体内的缓释作用良好,且生物利用度较斑蝥素纯品均有明显的提高。
The thesis developed some determination method of cantharidin for different aims, such as HPLC, GC, GC-MS. This thesis studied the basic physicochemical characters of cantharidin and the extract of Mylabris, then studied the pharmacokinetics properties of cantharidin in beagle dogs by GC-MS. Prepared solid dispersion about CA and the extract of Mylabris. Then studied the effect of solid dispersion preparation. Using the chitosan as the bioadhesive material and absorption enhancer, the solid dispersion as the media preparation, prepared the cantharidin and the extract of Mylabris bioadhesive drug delivery systems whose pharmacokinetics parameters were studied in SD rats.
Firstly, the assaying method of CA was established. On one hand, we perfected the HPLC and GC to assay the CA content in vitro; on the other hand, a simple, sensitive and specific GC-MS method was developed, which could assay CA in vivo. HPLC and GC were used to study physicochemical character of cantharidin and the extract of Mylabris to provide the guaidence to preparation. Then the GC-MS was used in the pharmacokinetic study and evaluate in vivo study. One-compartment model best described the blood level data for CA after intravenous administration and oral admintration. It shows CA eliminate quickly in vivo and has a low oral bioavailability 26.7%. The parameters will provide the theoretic basis for the rational use of CA.
Secondly, two kinds of preparations was obtained, used PEG4000 as dispersion carrier which was reported to enhance drug dissolubility and alleviation the stimulatory to gastric mucosa. Then the CA's release curve from two formulations was studied, and it is proved that the effects of the formulation on the release curve of CA were more completely. Then, the bioadhesive particles that using the chitosan as the absorption enhancer and bioadhesive material, the solid dispersion as the media preparation was prepared after the uniform test in order to get the slow release effect.
At last, the bioavailability of bioadhesive particles and the two preparations were evaluated in vivo. In the experiment, the pure CA is reference formulation and the other preparations are test formulation. The plasma concentration-time profiles of CA was studied and assayed by GC-MS method. The result indicated that comparing to the CA, CA bioadhesive patricals and Mylabris extract bioadhesive patricals both showed a significant sustained-release effect in rats.
引文
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