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Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole

2016; Elsevier BV; Volume: 105; Issue: 9 Linguagem: Inglês

10.1016/j.xphs.2016.03.003

1520-6017

Monica Vialpando, Stefanie Smulders, Scott Bone, Casey Jager, D. Vodak, Michiel Van Speybroeck, Loes Verheyen, Katrien Backx, Peter Boeykens, Marcus E. Brewster, Jens Ceulemans, Héctor Novoa de Armas, Katrien Van Geel, Emma Kesselaers, Vera Hillewaert, Sophie Lachau‐Durand, Greet Meurs, Petros A. Psathas, Ben Van Hove, Geert Verreck, Marieke Voets, Ilse Weuts, Claire Mackie,

Analytical Methods in Pharmaceuticals

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.