Study And Characterization Of Nimodipine-loaded PLGA Microspheres Prepared With A Modified Method

Nimodipine (NMP) is a calcium antagonist, with a preferential effect on thesmooth muscle of cerebral vascular, which has been the first-choice drug in thetreatment of cerebrovascular disease. However, due to the short half-life and low oralbioavailability of NMP, frequent dosing is necessary, and severe side effects restrictits application. In this study, we produced NMP microspheres to improve its clinicalapplication value.NMP was microencapsulated in the poly (D,L-lactideco-glycolide)(PLGA) viathe emulsion-solvent evaporation/extraction process. Petroleum ether was applied as aco-solvent in the preparation to adjust the solidification rate of the microspheres. Toperform the orthogonal design for the process optimization, several factors such asemulsifier, polymer molecular weight, polymer concentration, and drug/PLGA ratioas well as the ratio of petroleum ether and DCM were evaluated. Microspheresprepared under reduced pressure were also investigated. Moreover, the stability of themicrospheres was inspected.It was indicated that as the increase of the molecular weight and concentration ofthe polymer, the diameter and drug loading of the microspheres would increase andthe initial burst decrease. The drug crystal outside the microspheres caused severeinitial burst when the dosing ratio exceeded1:15. As the ratio of petroleum ether inthe organic phase increased, the solidification rate of microspheres accelerated invarious degree (Vpetroleum ether：VDCM=0,1:10,1:8,1:4, and1:2), affecting the drugloading capability and in vitro release of microspheres. After optimization, theencapsulation efficiency (EE) of microspheres was improved by52.2%, and the initialburst was declined by58.8%. Microspheres with uniform particle size and densifiedsurface were obtained. NMP was released in a more controlled fashion (thecumulative release rate of NMP was about80%at the25thday). The in vitro releasekinetics implied the mechanism of the drug release was the combination of diffusionand erosion. The preparation method had a good reproduction quality. Compared withthe microspheres prepared with DCM alone, the EE of the optimal formulation got alittle improvement. However, the morphology was modified significantly. Theapplication of petroleum ether did not change the physical state of drug and the polymer, but lower the glass transition temperature (Tg) in a little degree.Microspheres prepared at reduced pressure got higher encapsulation efficiency (EE＞50%). However, due to the drug crystals outside the microspheres, the in vitro releaserate was faster (cumulative release rate of NMP was about80%at the18thday). Thestability test showed that NMP microspheres should be stored at subdued light, lowtemperature and humidity.