RESUMO
Drug candidate LPSF/FZ4 with promising schistosomicidal properties in vitro was previously synthesized. However, LPSF/FZ4 has limited aqueous solubility (<1⯵g/mL), leading to ineffective dissolution and, therefore, no meaningful in vivo comparative studies could be pursued. This study was aimed to develop a proper amorphous solid dispersion (SD) to enhance the solubility and dissolution rate of LPSF/FZ4 such that its biological activity could be investigated. To better understand its physiological behavior, the pKa of LPSF/FZ4, a monoprotic weak acid with NH group at the imidazolidine ring, was first determined to be 8.13 using an automated SiriusT3. The development of SD systems for LPSF/FZ4 involved the evaluation of various water-soluble polymer carriers such as PVP K-29/32, PVP K-90, HPMC K4M, PVPVA 64 and SOLUPLUS®. The most promising SD systems were selected through in vitro dissolution studies under nonsink conditions, together with physicochemical characterization as well as accelerated stability study. It was shown that SD of 10% LPSF/FZ4 in SOLUPLUS® and PVP K-90 could significantly increase the area-under-the-curve value of the nonsink dissolution profile (AUC values of the SD in SOLUPLUS® and PVP K-90 were 1381.03 and 1342.34⯵L/mL·min, respectively, and that of the pure crystalline drug was 0.02⯵L/mL·min), a useful surrogate for the in vivo bioavailability. Cmax values for the SD in SOLUPLUS® (12.50⯵L/mL) and PVP K-90 (25.86⯵L/mL) were also higher than the one of the crystalline drug (0.02⯵L/mL). The SD system of LPSF/FZ4 in SOLUPLUS® showed a significant increase in schistosomicidal activity in an animal model as compared with the conventional treatment using crystalline drug, consistent with the AUC trend from the nonsink dissolution. Thus this SD system of LPSF/FZ4 could be useful as a potential formulation for treating schistosomiasis.