Preparation And In Vitro/in Vivo Release Of The Sustained Release MPEG-PLA Microspheres Loaded With Estradiol

It is the aim that the injectable and biodegradable estradoil(E2)-loaded microspheres, which were prepared by using poly(ethylene glycol) methoxy-poly(D,L-lactic acid) block copolymers(mPEG-PLA) as carrier material, were constructed by the method of O/W emulsion evaporated solvents.We investigated the preparation process of the sustained release mPEG-PLA microspheres loaded with E2. Through the stability of the O/W emulsion was explored, the more effective emulsifier was found out.According as the preparation processes were complex, and there were many independent and dependent variables in the experiments, moreover the dependent variables can effect each other, the central composition design and response surface plots were applied for optimal preparation process. By this way we not only obtained the excellent preparation process of mPEG-PLA microspheres loaded with E2, but also established the approach of optimal and screening preparation process for the complex experiments, which there are many independent and dependent variables in the exploration.To determine the content and in vitro drug release of E2-loaded mPEG-PLA microspheres, the high performance liquid chromatography method was established, and the determining system was checked. The results showed that the measure value was accurate and reliable.In vitro drug release was investigated. Shaker method determined the drug release of E2-loaded mPEG-PLA microspheres which were prepared by optimal preparation process in the condition of simulating physical environment and two kinds of release medium. The relationship between degradation process and drug release process of the E2-loaded mPEG-PLA microspheres was investigated by means of determing dry microspheres weight loss, observing the degradation process of microspheres by the microscopy, and measuring drug release of mPEG-PLA Mw8982, Mw13602, Mw24766E2-loaded microspheres, the kinetics of the drug release was explored as well. The results exhibited that the microspheres showed the better drug release behavior in the condition of the solubilizer-added medium and the drug release behaviors fit to first order equation, the accumulated-percentage drug release of the mPEG-PLA Mw13602E2-loaded microspheres at1,30days were6.56%,85.81%respectively. At the different temperature (45℃,50℃,55℃) the drug release behaviors of mPEG-PLA Mw13602E2-loaded microspheres were researched, and we established the accelerated testing method. The linear regression was used for analysis long-term and accelerated testing.The results showed that the higher the temperature was, the faster the rate of drug release appeared. According to drug release of mPEG-PLA Mw13602E2-loaded microspheres at55℃,the accelerated testing have significant relevance to long-term experiment(R2=0.9971).The results indicated that mPEG-PLA microspheres possessed the characteristic of temperature sensitivity.We can predetermine the drug release of the long-term experiment by the datum of accelerated testing.On the basis of drug release of the mPEG-PLA microspheres in vitro, we chose mPEG-PLA Mw13602E2-loaded microspheres to explore the drug release behavior in vivo. The beagle dogs were the subjects, and the blood concentrations were detected by radioimmunoassay (RIA) method. After intramuscular administration the pharmacokinetics of the mPEG-PLA Mw13602E2-loaded microspheres was investigated. The rosenblueth calculated the pharmacokinetic parameters.The results showed that mPEG-PLA Mw13602microspheres can effectively control drug release in vivo and the formulation was able to keep a little fluctuating blood concentrations during two weeks. Pharmacokinetic parameters AUC,AUMC,MRT were285.042(pg-d/mL);2197.96(pg-d2/mL);7.711(d) respectively.The analysis of the in vivo-in vitro drug release correlations indicated that the accumulated drug release percentage in vitro was significant relevance to the pharmacokinetic parameter AUC according to corresponding time points (R2=0.9930).It is mean that we can use the accumulated drug release percentage in vitro to predict the AUC in order to understand and analyse the drug release behavior in vivo.The mPEG-PLA E2-loaded microspheres drug delivery system was constructed initially in china, which were made of the new copolymer biomaterials and the E2as model drug,it developed the biodegradable sustained-release microspheres for water insoluble drug and achieved long-term drug delivery.The investigation analysed the characteristics of the drug release in vitro and in vivo.The mathematics models of long-term/accelerated testing and in vitro/in vivo drug release correlation were established.We set up the comprehensive technical platform for preparing and assessing injectable and biodegradable sustained-release microspheres loaded with insoluble drug.The mPEG-PLA microspheres drug delivery system have the capability of delivering the insoluble drug safely, effectively and conveniently.The formulation will have the excellent development in the early future.