The Preparation And Evaluation In Vitro And In Vivo Release Of Biodegradable PLGA (9:1) Microspheres Containing Levonorgestrel

The levonorgestrel (LNG) copolymer of lactic and glycolic acid (PLGA) (9:1) microsphere is a new dosage form for parenteral administration of LNG , it was prepared using o/w emulsion organic solvent evaporation at low temperature(0 ~ 5癈) and room temperature(25癱),respectively. The effect of these two kinds of preparation methods on the characteristics of microspheres, such as the surface of microspheres, the molecular weight, the content, the distribution of particle and the loading drug percent, were studied. The results showed that the surface of microspheres prepared by low temperature method was more smooth and compact than that of microspheres prepared by room temperature method, and the content and the loading drug percent were higher than that of room temperature microspheres.The content of PLGA-LNG microspheres was determined by UV spectrophotometer method at 240nm (E1%1cm=544,ethnol), the average recovery was 100.7±1.47%(RSD=1.46%).In order to evaluate on the characteristics of the microspheres prepared by low temperature method in detail, the release in vitroand in vivo was tested, respectively.Pharmacokinetics of levonorgestrel (LNG) in the form of injectable biodegradable PLGA(9:1) microspheres containing LNG was determined in rats by RIA method, the limit of detection(LOD) of this RIA method was 10pg/tube, the average inter-day precision of the assay was 5.15% and the intra-day precision was 6.31%, and the average extraction recovery was more than 90%. The drug release in vitro was determined by UV spectrophotometric method. 25%(v/v) alcohol was used as the media solution. The regression equation wasA=0.0147+0. 0397C(r=0.9999) and the linearity ranges from 0.5 to 6jag/ml. the A max for measurement was set at 248nm.The release profiles of microspheres showed a similar biphasic release pattern between in vitro and in vivo, the first phase of the release was diffusion controlled, and a secondary rise in the drug level due to the onset of degradation of the PLGA. Between the first phase and the secondary phase, there was about 70% steady release in vitro and in vivo. The first phase peak plasma LNG level of the microspheres was low , and its MRT of the microspheres was 65.12d ,the time of lasting action was longer than 168 days. The drug release from PLGA (9:1) microspheres in vitro correlated well with that in vivo. The microspheres have remarkably long-acting control release action.We attempted to correlate the in vitro release datum of low temperature method to fit a recognized mathematical model by computer, the results showed that the release kinetics for LNG from PLGA(9:1) microspheres was approached the Higuchi equation, compared to zero order kinetics pattern and the first order kinetics pattern, the Higuchi equation was Mt/M ?=0. 116t1/2(F=1056. 058, P<0. 001; R=0. 989)In conclusion, the content and the loading drug percent for the microspheres prepared by the low temperature method were higher than that for the room temperature microspheres. Especially, the surface of microspheres made by the low temperature method was more smooth and compact than that of microsphere prepared by the room temperature method, there are many pores on the surface of microsphere prepared by the room temperature method. So, the preparation of microspheres should be used o/w emulsion organic solvent evaporation at low temperature(0 ~ 5 癈). The following parameters such as the loading drug percent, the content , the degree of smooth and compact on microsphere surface, and the characteristics of release in vitro with two peaks and steady drug release area could be used to evaluate and control the quality of PLGA(9:1)-LNG microspheres.