| Traditional Chinese medicine Semen Strychni has an excelient effect against rheumatoid arthritis. But its oral toxicity limits its clinical application. The main active ingredients of Semen Strychni are brucine, strychnine and other alkaloids which are also the components of toxicity. In order to reduce the toxicity and enhance the local therapeutic efficacy of Semen Strychni, the application of transdermal drug delivery systems as well as novel drug carrier is of great significance. In this thesis, the pharmacokinetics profile was researched and evaluated of a novel targeted transdermal formulation, noisome gel of Semen Strychni alkaloids extract, which provided not only a basis for further research and development of this formulation but also an idea for clinical application and research of toxic traditional medicine. The main contents are of the following aspects:1, In order to evaluate the rat subcutaneous concentrations of brucine and strychnine in vivo, a dermal microdialysis sampling coupled with LC-MS/MS method was established. The method was validated to be simple and fast and applied to study the rat dermal absorption of brucine and strychnine in8hours after application of noisome gel or conventional gel. It showed that there was no significant difference between the two gel formulations. 2. An LC-MS/MS method was developed and validated for the determination of brucine and strychnine in rat plasma and tissues. Samples were extracted by mixed solvent. It was validated that the selectivity, linear range, recovery of extraction. matrix effect, stability, precision and accuracy of the method met the requirements. It can be used for pharmacokinetics research of brucine and strychnine.3. Concentrations of brucine and strychnine in rat plasma were determined with the method mentioned above. Concentration-time profiles were plotted and the pharmacokinetic parameters were calculated using the non-compartment model. It revealed that there was no significant difference between the AUC within10hours of noisome gel and conventional gel. The times of maximum concentration of noisome gel are (5.17±3.13) h for strychnine and (5.33±3.01) h for brucine, which are longer than those of conventional gel, which are (3.33±0.98) h and (3.00±3.50) h, respectively. In another study, after low, medium or high dose of noisome gel administration, rat plasma concentrations in72hours were determined. The AUC0-72h value of strychnine were (167.47±107.41) ng-h/mL,(112.61±43.47) ng?h/mL and (173.17±145.44) ng?h/mL. The AUC0-72h value of brucine were (227.87±88.39) ng?h/mL,(282.71±73.03) ng?h/mL and (325.29±154.01) ng?h/mL, respectively. It indicated that the levels of the two ingredients in cardiovascular system were low and were not correlated with dose. The inter-subject variability is significant. The plasma concentrations maintained for a long time with MRT valves greater than20hours.4. Tissue distribution was studied in rats after administration of noisome gel of Semen Strychni alkaloids extract. The results showed that the two ingredients distributed widely in rats, mainly in lung, liver, kidney, and intestinal, followed with heart, joint and skin. They accessed the blood-brain barrier but the levels in brain tissue were low. |
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