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

Abstract

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.

Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi

“…The ASD formulation was selected based on data obtained in rats after testing at least 8 formulations in order to improve the bioavailability of the drug [39]. The selection of formulation took into account the feasibility and stability of the formulation and exposures.…”

Comparison of a Novel Miniaturized Screening Device with Büchi B290 Mini Spray-Dryer for the Development of Spray-Dried Solid Dispersions (SDSDs)

“…The term ASD refers to the formulation technique which consists of the drug amorphization and its dispersion into a hydrophilic polymeric (amorphous) carrier [10]. Nevertheless, inappropriate carrier selection, drug loading (DL), and process conditions/methods can engender phase separation/drug recrystallization after processing that would lead to a reduction in ASD performance [11,12]. In contrast, the formation of a single amorphous phase system, also referred to as "glass solution", where the amorphous drug is molecularly dispersed into the polymeric chain represents the most favorable ASD system in terms of physical stability and solubility enhancement [13].…”

Improving dissolution profile of poorly water-soluble drug using non-ordered mesoporous silica

“…Mesoporous silica as a drug carrier was first evaluated by Vallet-Regi et al [8] Adsorption onto mesoporous silica (MS) is a new enabling technology that improves the performance of poorly water soluble drugs by improving their dissolution rate and solubility and thereby enhancing oral bioavailability [9,10]. A concentrated drug solution is loaded into pores through capillary forces.…”