Enhanced delivery of fixed-dose combination of synergistic antichagasic agents posaconazole-benznidazole based on amorphous solid dispersions.

Autor: Figueirêdo CBM; CAPES scholarship holder, PVE Program, CAPES Foundation, Ministry of Education of Brazil, Brasília, DF 70040-020, Brazil., Nadvorny D; Department of Pharmaceutical Sciences, Universidade Federal de Pernambuco, Avenida Professor Arthur de Sá, SN - Cidade Universitária, Recife, PE 50740-52, Brazil., Vieira ACQM; CAPES scholarship holder, PVE Program, CAPES Foundation, Ministry of Education of Brazil, Brasília, DF 70040-020, Brazil., Schver GCRM; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada., Soares Sobrinho JL; Department of Pharmaceutical Sciences, Universidade Federal de Pernambuco, Avenida Professor Arthur de Sá, SN - Cidade Universitária, Recife, PE 50740-52, Brazil., Rolim Neto PJ; Department of Pharmaceutical Sciences, Universidade Federal de Pernambuco, Avenida Professor Arthur de Sá, SN - Cidade Universitária, Recife, PE 50740-52, Brazil., Lee PI; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada., Soares MFR; Department of Pharmaceutical Sciences, Universidade Federal de Pernambuco, Avenida Professor Arthur de Sá, SN - Cidade Universitária, Recife, PE 50740-52, Brazil. Electronic address: mfs.ufpe@gmail.com.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2018 Jul 01; Vol. 119, pp. 208-218. Date of Electronic Publication: 2018 Apr 19.
DOI: 10.1016/j.ejps.2018.04.024
Abstrakt: Posaconazole (PCZ) and benznidazole (BNZ) are known to show synergetic effect in treating the acute and chronic phases of Chagas disease, a neglected parasitic disease. However, as both compounds are poorly water soluble, the development of amorphous solid dispersions (ASDs) of a PCZ/BNZ fixed-dose combination in a water-soluble polymer becomes an attractive option to increase their apparent solubility and dissolution rate, potentially improving their oral bioavailability. The initial approach was to explore solvent evaporated solid dispertion (SD) systems for a PCZ/BNZ 50:50 (wt%) combination at several total drug loading levels (from SD with 10% to 50% drug loading) in water-soluble carriers, including polyvinylpyrrolidone (PVP K-30) and vinylpyrrolidone-vinyl acetate copolymer (PVPVA 64). Based on comparison of non-sink in vitro dissolution performance, ASD systems based on PVPVA was identified as the most effective carrier for a 50:50 (w/w %) fixed-dose combination of PCZ/BNZ to increase their apparent solubility and dissolution rate, mainly at 10% drug loading, which shows more expressive values of area under the curve (AUC) (7336.04 ± 3.77 min.μL/mL for PCZ and 15,795.02 ± 7.29 min.μL/mL for BNZ). Further characterization with polarized microscopy, powder X-ray diffraction, and thermal analysis reveals that there exists a threshold drug loading level at about 30% PCZ/BNZ, below which ASDs are obtained and above which a certain degree of crystallinity tends to result. Moreover, infrared spectroscopic analysis reveals the lack of hydrogen bonding interactions between the drugs (PCZ and BNZ) and the polymer (PVPVA) in the ASD, this is also confirmed through molecular dynamics simulations. The molecular modeling results further show that even in the absence of meaningful hydrogen bonding interactions, there is a greater tendency for PVPVA to interact preferentially with PCZ and BNZ through electrostatic interactions thereby contributing to the stability of the system. Thus, the present SD system has the advantage of presenting a fixed-dese combination of two synergistic antichagasic agents PCZ and BNZ together in amorphous form stabilized in the PVPVA matrix with enhanced dissolution, potentially improving their bioavailability and therapeutic activity in treating Chagas disease.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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