DESENVOLVIMENTO DE NANOPARTÍCULAS DE POLI(ÁCIDO LÁCTICO) REVESTIDAS COM QUITOSANA CONTENDO ÁCIDO URSÓLICO E AVALIAÇÃO DO PERFIL FARMACOCINÉTICO APÓS ADMINISTRAÇÃO ORAL EM RATOS

Abstract

Ursolic acid (UA) is a pentacyclic triterpenoid derived from several medicinal plants and herbs, and has anti-inflammatory, antioxidant and anti-tumor activities. However, its low water solubility limits its bioavailability, making it impossible to be administered orally. Among the strategies to increase the bioavailability of molecules orally is nanoencapsulation. Polymeric nanoparticles (Nps) promote modified release, protection of the active against degradation, less toxicity, in addition to, the drugs transmitted may have their half-life altered and their bioavailability profile increased. In this work it was developed Nps of poly(lactic acid) (PLA) coated with chitosan (CS) for placement of UA, as a strategy to increase its bioavailability. The Nps were prepared by the solvent emulsification-evaporation technique and had an average diameter of 300 nm, a zeta potential of +28 mV, which confirms the presence of CS on the surface of the particles, and about 90% UA encapsulation. Characterization by scanning electron microscopy showed the spherical shape of the particles and their size homogeneity. Analysis of drug-polymer interaction (X-ray diffraction, infrared spectroscopy, differential scanning calorimetry) showed that the nanoencapsulation process generated amorphization of the UA at Nps and did not cause any type of interaction that would de-characterize the drug. After storage of the lyophilized Nps for 180 days, they did not show tendency to aggregate, however, the suspended Nps had their zeta potential altered when stored for more than 30 days. Stability study of Nps in gastrointestinal fluids showed that Nps coated with QS showed good stability in simulated gastric and intestinal fluid, protecting the drug from pH variations. The in vitro release assay performed demonstrated that after 144 h of assay, about 53% of the UA was released by diffusion of the Nps, following the second order release kinetics. In vitro mucoadhesion studies revealed a high mucoadhesive capacity of Nps coated with CS, when compared to uncoated Nps. Applicability of Nps was assessed by studying the antioxidant potential, and also, by assessing cytotoxicity in erythrocytes and tumor lines (B16-F10 and HEp-2 cells). In relation to the antioxidant study against with hypochlorous acid, the Nps were shown to be as effective as the free drug after 48 h of study. Cytotoxicity on erythrocytes was higher with free UA than with nanoencapsulated. In tumor lines, nanoencapsulated UA was less cytotoxic than free UA, but maintained the cytotoxic action of the drug. Finally, there was a significant improvement in the pharmacokinetic parameters of UA when nanoencapsulated, after oral administration of a single dose in rats. UA bioavailability in Nps was 3.84 times greater than that presented by free UA, and 5.35 times greater than in uncoated particles. Results indicate that the CS coverage is essential for the application of PLA nanoparticles containing UA orally, and that this nanostructured system has potential for antioxidant and anti-tumor treatments.