The Treatment Of Raloxifene Hydrochloride Nanosuspensions On Osteoporisis And Study Of The Mechanism

Raloxifene hydrochloride(RLX)is one of the postmenopausal osteoporosis therapies.RLX belonged to a benzothiophene compound,one of the second generation selective estrogen receptor modulators(SERMs),had a selective effect on exerting estrogen-agonistic actions towards the bone and the cardiovascular system,for example liver,but it also could act as an estrogen-receptor-antagonist in some tissues,such as breast and uterus.However,the bioavailability of the RLX was only 2%due to its poor aqueous solubility.Although other routes for administration were effective,the oral administration was still a convenience route among various routes.Therefore,it is necessary to improve RLX solubility.RLX-NSps is prepared to solve the problem of poor solubility,to improve therapeutic efficacy.The main content of this thesis includes the preparation of RLX-NSps and the pharmacodynamic study on attenuating the bone loss in vivo via oral administration and the study of the mechanism in vitro.The main sections included in this paper were as follow:a.In the study,the optimal formula and technological factors of preparation was investigated by using the estimate index of the particle size,PDI and zeta potential of RLX-NSps.Finally RLX-NSps were successfully prepared using soybean lecithin(SPC)as a stabilizer and 1:2 as drug/stabilizer ratio by means of the Ultrasound method at 25℃.The obtained RLX-NSps had a mean particle size of(91.17±0.73)nm,PDI value of 0.20 ± 0.03 and zeta potential of(36.3±1.80)mv.b.The TEM was used to reveal the size and morphology of RLX-NSps.The results showed RLX-NSps were spherical and evenly distributed.Using the stabilizer could effectively avoid Ostawald aging and improve the stability of RLX-NSps.RLX-NSps was stable in various physiological solutions(artificial intestinal fluid,artificial gastric fluid,PBS,5%isotonic glucose and 0.9%physiological saline)at 12 h.The results of differential scanning calorimetry(DSC)and X-ray powder diffraction(XRD)demonstrated that RLX was in amorphous in the nano suspensions.The optimal lyophilized protective agent of RLX-NSps was 1%sucrose or maltose.By measuring the saturation solubility of RLX in different media,RLX-NSps could persistently release 86%encapsulated drug in the PBS solution with 0.1%Tween80(PH values of 5.5).c.The pharmacodynamic study of RLX-NSps on attenuating the bone loss in vivo was performed by oral administration for 3 and 5 weeks in C57BL/6 mice.The RLX-NSps and RLX solution groups significantly changed on the parameters of BMD and related bone microarchitecture compared with the OVX group(the BV/TV,BS/BV and Tb.Th in the OVX and RLX solution groups:P<0.05,others:P<0.01).And the parameters of BMD and related bone microarchitecture of the RLX-NSps and solution groups had an obvious difference(P<0.05).The results showed that RLX-NSps had a better efficacy compared the solution at the same dose administered.Consistent with the results of oral administration for 3 weeks,RLX-NSps had a better efficacy compared the solution after 5 weeks.d.The mechanism study of RLX-NSps was performed by assessing the biochemical markers in serum and evaluating cell proliferation and the osteogenic differentiation.The results demonstrated that RLX-NSps could attenuated bone loss in the OVX mice by inhibiting the bone resorption and improving the ability of BMSCs proliferation and osteogenic differentiation to some extent.Based on these results,RLX-NSps could attenuated bone loss more effectively than RLX solution in the OVX mice,solved the question of poor aqueous solubility of RLX,and meanwhile could be enhanced the efficacy of oral administration to some extent.