Desenvolvimento de sistemas autoemulsionáveis sólidos contendo carvedilol por granulação de alto cisalhamento

Abstract

Introduction: The improvement of the biopharmaceutical properties of poorly water-soluble drugs administered orally is of great therapeutic and economic importance. In this sense, the preparation of liquid self-emulsifying drug delivery systems (L-SEDDS) has been highlighted. However, L-SEDDS show some chemical and physical instability and the solidification of these systems can contribute to their future commercial application. Among the potential techniques used in the solidification of L-SEDDS, the high shear granulation should be underscored because of its low processing time and good reproducibility. To date, no study has evaluated the use of this technique to process L-SEDDS containing carvedilol (CARV), a poorly water-soluble drug that shows low oral bioavailability. Objective: The objective of the present study was to obtain solid self-emulsifying delivery system (SSEDDS) a high carvedilol (CARV) load using the high shear granulation technique. Methodology: The selection of the best combination of surfactant, co-solvent and oil was carried out based on the evaluation of the CARV solubility in twelve different mixtures, as well as by the analysis of the self-emulsifying properties and stability of the systems. The selected formulation, containing Solutol® HS15, Transcutol® HP and castor oil, was used as a binder liquid in a high shear granulator containing different mixtures of solid excipients. A combined mixture design was employed to study the effects of formulation factors (different concentrations of crospovidone, L-SEDDS, microcrystalline cellulose, lactose and aerosil) and process (chopper and impeller speeds) on the properties of the obtained solids. Twenty five S-SEDDS were obtained, which were characterized in terms of granulometry, flow (angle of repose, Carr index, Hausner factor), CARV content, in vitro dissolution, X-ray powder diffraction and scanning electron microscopy. Results and Discussion: The selected L-SEDDS was composed of a mixture of Solutol® HS15, Transcutol® HP and castor oil (1:3:1, m/m/m). After dilution (250x) in HCl solution (pH 1.2), the preparation was quickly emulsified giving rise to droplets of average size 253.2 ± 9.50 nm and PdI of 0.352 ± 0.013. This lipid mixture was able to solubilize 124.31 mg of CARV per milliliter of formulation. The incorporation of the liquid formulation in the different powder mixtures using the high shear granulation technique was fast (total processing time less than 23 min) and resulted in high yield (> 99%). Flow analysis showed that most solids showed acceptable flow, which was mainly affected by the concentration of L-SEDDS and lactose in the formulation. In addition, the L-SEDDS concentration was the factor that exerted the greatest influence on the size of the granules, and its increase led to a reduction in the percentage of fines (<63μm). The in vitro release tests allowed to determine that, regardless of the medium (acid or neutral), the release of CARV from S-SEDDS in the first 10 minutes of the test was at least 2 times greater than that observed for the pure drug. In pH 6.8, it was observed a reduction in the release of CARV from the S-SEDDS when compared to the L-SEDDS. Conclusion: The preparation of S-SEDDS containing CARV by high shear granulation was fast and the drug release was superior to that observed for the pure drug. Formulation factors, in particular, the type of diluent and the amount of oil influenced the properties of the obtained granules.