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.
amorphous; poorly water soluble drugs; formulation; solid dispersion; flubendazole; spray drying; ordered mesoporous silica; oral absorption; filarial disease.
The structure of FLU and its 2 metabolites, the hydrolyzed and reduced forms, are illustrated in Figure 1. The carbamate group is the main source of FLU’s extremely low aqueous solubility of 5 ng/mL
Citation: Monica Vialpando, Stefanie Smulders, Scott Bone, Casey Jager, David Vodak, Michiel Van Speybroeck, Loes Verheyen, Katrien Backx, Peter Boeykens, Marcus E. Brewster, Jens Ceulemans, Hector Novoa de Armas, Katrien Van Geel, Emma Kesselaers, Vera Hillewaert, Sophie Lachau-Durand, Greet Meurs, Petros Psathas, Ben Van Hove, Geert Verreck, Marieke Voets, llse Weuts, Claire Mackie Evaluation Of Three Amorphous Drug Delivery Technologies To Improve The Oral Absorption Of Flubendazole doi:10.1016/j.xphs.2016.03.003.
Received: 17 December 2015, Revised: 2 March 2016, Accepted: 3 March 2016, Available online: 22 April 2016
Copyright: © 2016 The Authors. Published by Elsevier Inc. on behalf of American Pharmacists Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Results from this study exhibit the process challenges in not only formulating amorphous FLU but also stabilizing it. Formulations from 3 different drug delivery technologies were explored and optimized to improve the dissolution rate and extent of oral absorption. Physicochemical stability and in vitro release in biorelevant media were used to screen all formulations. The 2 emerging drug delivery technologies, an MPSDD 1/9 (wt./wt.) FLU/HPMCAS-M, and 3/7 (wt./wt.) FLU/OMS resulted in superior physical stability compared to the more conventional SSDD approach. Although the OMS technology resulted in the best chemical purity, the use of FA results in high amounts of residual solvent and complicates downstream processability. The heat step during MPSDD increased the amount of hydrolyzed degradant; however, the results showed that this was also dependent on the API-polymer interaction. Plasma concentration profiles from OMS formulations differed due to the mode of administration between the suspension and capsule blend. The 30% wt. loaded suspension resulted in the fastest Tmax, highest Cmax, and exhibited an overall distinctive profile from the other concepts. The 40% wt. loaded capsule blend resulted in the slowest Tmax and highest AUC. Although the OMS illustrated promising in vivo performance, the MPSDD technique will be further explored based on the in vitro data and ease of manufacturing scalability.
This study was made possible through DNDi funded by the Bill and Melinda Gates Foundation Grant number OPP53303, the Federal Ministry of Education and Research (BMBF through KfW), Germany, and Médecins Sans Frontières/Doctors without Borders, International/Norway. Janssen Pharmaceutica would like to thank the late Dr. Marcus E. Brewster for his scientific direction and involvement, and whose warm presence is greatly missed.