Preparation Of Rifapentine Polylactic Acid Microspheres And Characteristics Of The Drug Release In Both Vitro And Vivo

Objective:study on solubility and stability of rifapentine by preparation of rifapentine polylactic acid microspheres with the L18(37)Orthogonal Experimental Design Method,using UV spectrophotometer to determine its drug release characteristics in vitro and in vivo.Methods:Use UV spectrophotometer to determine equilibrium solubility,apparent oil-water distribution coefficient(1gD)and stability of rifapentine in high humidity,high temperature and lighting environment;use improved double emulsification solvent evaporation procedure to prepare rifapentine polylactic acid microspheres;use biological microscope and scanning electron microscope(SEM)to observe the characteristic of microspheres and measure their average diameter;use ultraviolet spectrophotometry(US)to determine their envelopment rate and drug carried rate;the release characteristics of them were studied in vitro by dissolution method and US.Determine the release quantity at the 0、3、5、7、9、14、21、28、35、42、49、56、63d and then calculate the mean day release rate and the total release rate.Insert rifapentine polylactic acid microspheres,vacant microspheres and crude drug of rifapentine into the 3rd lumbar vertebra of 24 New Zealand White Rabbits separately and determine the concentration of rifapentine at different points in time,then study their release characteristics in vivo on the 3,5,21,35,46,60d by US.Results:The solubility of rifapentine in chloroform,dichloromethane and methanol is good,and the maximum is 13.076 mg·L-1;the solubility of rifapentine in water is bad,that is 3.046 mg·L-1.The compatibilization of Surfactant Tween-80 is the strongest,up to 823 mg·L-1.The apparent oil-water distribution coefficient of rifapentine in N-hexane is 4.778±0.41,in N-octyl alcohol is 17.4412±2.79.Rifapentine in high humidity,high temperature and lighting environment is more stable,which is not susceptible to be damaged and oxidized.Rifapentine polylactic acid microspheres are spherical and their dispersiveness is good,which have no obvious aggregation phenomena.The average diameter of microspheres is 24.4 ± 1.2 μm,75%of diameter of microspheres are distribute in the scope of 20～28μm.The envelopment rate is(79.24 ± 0.18)%and drug-carried rate is(41.06±0.74)%.The results of Drug Release show:in the early 3 days,cumulative release reached 1.4190 ±0.0251mg,about 11.54%of total,averaged 0.4731±0.0124mg per day;7 days later,cumulative release reached 3.3037±0.0016mg,about 3.3037±0.0016mg of total,averaged 0.4719+0.0075mg per day;one month later,cumulative release reached 10.4464±0.203mg,about 84.93%of total,averaged 0.3482±0.0147mg;2 months later,cumulative release reached 11.3751±0.0146mg,about 92.48%of total.Drug Release in vivo show:in 5 days,concentration of rifapentine microspheres in the lumbar vertebra was lower than concentration of crude drug(P<0.01);in 10-60 days,concentration of rifapentine microspheres in the lumbar vertebra was obviously higher than concentr-ation of crude drug(P<0.01),the concentration of rifapentine was continues 110μg/g or more.Concentration of rifapentine in vacant microspheres in the lumbar vertebra was detected consistently below 0.0043μg/g,without statistically significant.Conclusion:Fat-soluble of rifapentine is strong and water-soluble of rifapentine is weak.Rifapentine polylactic acid microsphere has the characteristic of Drug-Release Performance,which is sustained and slow.It can be applied to the tuberculose focus after clearance of focal lesion so as to maintain the effect of anti-tuberculosis.