Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.
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.
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Monica
M
Vialpando
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Stefanie
S
Smulders
Bend Research, Bend, Oregon 97701.
Scott
S
Bone
Bend Research, Bend, Oregon 97701.
Casey
C
Jager
Bend Research, Bend, Oregon 97701.
David
D
Vodak
Formac Pharmaceuticals, Leuven, Belgium.
Michiel
M
Van Speybroeck
Formac Pharmaceuticals, Leuven, Belgium.
Loes
L
Verheyen
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Katrien
K
Backx
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Peter
P
Boeykens
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Marcus E
ME
Brewster
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Jens
J
Ceulemans
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Hector
H
Novoa de Armas
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Katrien
K
Van Geel
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Emma
E
Kesselaers
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Vera
V
Hillewaert
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Sophie
S
Lachau-Durand
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Greet
G
Meurs
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Petros
P
Psathas
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Ben
B
Van Hove
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Geert
G
Verreck
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Marieke
M
Voets
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
Ilse
I
Weuts
Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium. Electronic address: cmackie@its.jnj.com.
Claire
C
Mackie
D000818:Animals; D000969:Antinematodal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003890:Desiccation; D004339:Drug Compounding; D016503:Drug Delivery Systems; D006813:Humidity; D008297:Male; D008463:Mebendazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008747:Methylcellulose / Q000031:analogs & derivatives; D009061:Mouth Mucosa / Q000378:metabolism; D011205:Povidone; D051381:Rats; D017207:Rats, Sprague-Dawley; D013535:Suspensions; D014810:Vitamin E / Q000737:chemistry
D000969:Antinematodal Agents; D013535:Suspensions; D014810:Vitamin E; C048331:hydroxypropylmethylcellulose acetate succinate; D008463:Mebendazole; D008747:Methylcellulose; D011205:Povidone; C018945:flubendazole
amorphous; filarial disease; flubendazole; formulation; oral absorption; ordered mesoporous silica; poorly water soluble drugs; solid dispersion; spray drying