Sophoridine Alkali Targeted Microsphere Drug Delivery System And Its Pharmacokinetic Preliminary Study

Objective: Sophoridine is one of the main alkaloids extracted from Sopharaalopecuroides. L. The Pharmacological study have showed that it has obvious andvarious antitumor activities. But due to its characteristic of wide distribution and rapidelimination in vivo, its clinic efficiency is limited. This study is trying to promote theantitumor activities of Sophoridine by using targeting particles-microspheres asdelivery carrier. Our investigation emphasize on lung tumor, that mean lung is thetargeting tissue. When such microspheres are administrated by intravenous injection,they will be accumulated in lung and the Sophoridine loaded in them will release fromthem slowly, consequently, there will be higher concentration of SR in lung compare tothe concentrations of it in blood and other tissues. So, the targeting drug deliverysystem(TDDS) will show higher efficient and lower toxic than the common drug deliverysystem(CDDS).Methods: The emulsification-solidification at high temperature method was selected toprepare sophoridine-BSA-microsphere. With particle side and the shape of themicrosphere as the criterion, the influence of different process parameters werestudied by using single factor analysis. Central Composite Design-response surfacemethodology were applied to optimize the parameters of the main factors whichinfluence microspheres formulation obviously with entrapment efficiency, drug loadedamount, particle sides distribution and overall desirability as the criterion.The surface morphology of the microspheres were observed by scanning electronmicroscope. The mean particle size and particle size distribution were caculated byusing optical microscope. The loading efficiency and drug loaded amount ofSR-BSA-MS were determined by visible spectrophotometry. The microspheres werealso characterized by DSC and IR techniques. The primary stability of themicrospheres were studied with loading efficiency and release curves in vitro as thecriterion.The factors which influence the release of the microspheres in vitro were studied.The characteristic of the release curve of the microspheres in vitro were discussed withdifferent release patterns.The concentration of sophoridine in different tissues of mice are determined aftertail intravenous injection of free SR and SR-MS by using HPLC. The results areanalyzed in order to evaluate the targeting efficiency of the microspheres.The concentration of sophoridine in plasma of beagle dog were determined byHPLC after tail iv free SR and SR-MS. The kinetic parameters were calculated by usingDSA ver 1.0 pharmacokinetics program. The kinetic parameters of SR-MS in lung and in plasma of mice also calculated and compared.The effect of SR-CDDS and SR-TDDS to inhibit lewis lung cancer and S180 wereobserved.Results: The result of single -factor experiments showed that the ratio of SR/BSA, thespeed of stirring and the solidification time were the main factors which influencemicrospheres formulation obviously. The optimizing result of Central CompositeDesign-response surface methodology showed that the best conditions of them are theratio of SR/BSA=1:8; the speed of stirring=900rpm; the solidification time=30min. Theprocedure of preparation of the microspheres is as following: 31.5mg Sophoridine isdispersed among 1mL 25% BSA aqueous solution, drop this solution into 40mL oilphase with agitation. Emulsification last for 30min under 30℃, then this emulsion issolidified for 30min under 120℃. Filtration and clean the microspheres with ether, getrid of the ether to get the dry microspheres.Through SEM, the microspheres could be found that they are sphere-like andhave smooth surface, with an average particle size of 12.04μm. The distribution of themicrospheres is narrow, 85% of them are in the range of 8-16μm. The loadingefficiency is 85.60%, the drug loaded amount is 9.52%.There is no SR characteristic peak on the SCD curve and IR gram of SR-BSA-MS.This result reveals that the drug is encapsuled in microsphere. There are no changes inexternal appearance and loading efficiency of the microspheres after being under 40℃and 75%RH, the microspheres are also stable under the light of 4500Lx±500Lx for 10days.The results of SR-BSA-MS release experiment in vitro show that the temparatureof solidification and the time of solidification influence release curve obviously. Therelease kinetics of the microspheres fit to Higuchi equation: y=0.2703 t^1/2+0.0873,r=0.9757.The research on the tissue distribution of Sophoridine after tail iv free SR andSR-MS in mice showed that the microspheres can increase the lung targetingefficiency obviously. There are 1.32% SR distribute to lung after iv free SR, but there38.88% SR in lung after iv SR-MS, while its distribution in the heart and kidney isdescreased.The study of the pharmacokinetics of the SR-CDDS and SR-TDDS in beagle dogsshowed that the concentration-time curve of them both fitted to two-compartmentmodel. The parameters of t_1/2α, t_1/2β, MRT of TDDS are longer than these parameters inCDDS. The kinetic parameters of SR-MS in lung and in plasma of mice are different,that mean, for TDDS, the kinetic parameters of drug in plasma couldn't represent thekinetic parameters of drug in targeting tissue. The inhibition rates to S180 of SR-CDDS and SR-TDDS are 34.1% and 34.6%.The inhibition rates to lewis lung cancer of SR-CDDS and SR-TDDS are 20.9% and35.4%.Conclusion: The stable and high loading efficiency SR-BSA-MS could be prepared byemulsification-solidification at high temperature method. The microspheres couldincrease the concentration of SR in lung and maintain it sustained release in lung. Thatcould improve the efficacy of SR in curing lung cancer. This research is totally new,without any report at home and abroad up to now. The result of this study provide amore efficiency drug delivery system for SR, meanwhile, provide a new example andmethod for applying TDDS technologe to traditional Chinese medicine.