Solid lipid microparticles for the sustained release of a prodrug of zidovudine obtained by its conjugation with the ursodeoxycholic acid

Purpose: We report a study of encapsulation and release from solid lipid microparticles (SLMs) of a prodrug of zidovudine (AZT), an antiviral agent, obtained by its ester conjugation with a bile acid, the ursodeoxycholic acid (UDCA). We have demonstrate that this prodrug (UDCA-AZT) is able to elude the active efflux systems expressed on physiological barriers. Methods: The microparticles were produced by the conventional hot emulsion technique, using different lipidic carriers (tristearin and stearic acid) and Tween 60 as the surfactant. The SLMs were characterized by scanning electron microscopy, laser diffraction and powder X-ray diffraction analyses. Release studies were performed by incubation of the loaded SLMs in a mixture of water and methanol (70:30 v/v), the % UDCA-AZT released was determined by HPLC. The stability of the free and encapsulated prodrug was evaluated in rat liver homogenates by HPLC analysis after liquid-liquid extraction. Results: The mean diameters of tristearin and stearic acid loaded microparticles were 7 and 14 um, respectively. The shape of the SLMs was spherical and their prodrug loading was 0.57 ±0.03% (tristearin based) and 1.84 ±0.02% (stearic acid based). The tristearin SLMs were able to control the release of the prodrug, whereas the stearic acid SLMs induced a significant increase of the dissolution rate of the free prodrug obtained in the presence of Tween 60. The free prodrug was hydrolyzed in rat liver homogenates with an half life of 2.7 ± 0.14 min, whereas the tristearin SLMs were able to significantly stabilize the prodrug in this physiologic fluid. Conclusions: The developed SLMs represent a good candidate for the local delivery of UDCA-AZT in the nose and its potential uptake in the brain