Human bioavailability of propranolol from a matrix-in-cylinder system with a HPMC-Gelucire core.
The bioavailability of propranolol from a matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extruded ethylcellulose pipe surrounding a drug-containing HPMC-Gelucire 44/14 core, was determined. An oral dose of 80 mg propranolol hydrochloride was administered to healthy volunteers (n = 10) in a randomized cross-over study design either as a commercial pellet formulation (Inderal retard mitis) or as a matrix-in-cylinder system. The influence of concomitant food intake on drug release from the matrix-in-cylinder system was also studied. During the first 10 h after administration, the matrix-in-cylinder system resulted in similar plasma levels as the reference formulation Inderal. The concomitant intake of a high-fat, high-calorie breakfast did not cause dose-dumping. Between 10 h and 24 h after administration of the matrix-in-cylinder system, a remarkable increase of the propranolol plasma levels was noticed (compared to Inderal). This effect was even more pronounced under fed conditions. The matrix-in-cylinder system had a relative bioavailability of 156% (fasted conditions) and 222% (fed conditions) compared to the marketed reference product. In order to elucidate the origin of this increased bioavailability, Caco-2 experiments and dog lymph studies were performed. However, none of these experiments was able to provide a conclusive answer.
Mehuys
E
E
Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
Remon
J P
JP
Korst
A
A
Van Bortel
L
L
Mols
R
R
Augustijns
P
P
Porter
C
C
Vervaet
C
C
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000328:Adult; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001693:Biological Transport, Active / Q000502:physiology; D001711:Biotransformation; D018938:Caco-2 Cells; D018592:Cross-Over Studies; D016503:Drug Delivery Systems; D005079:Excipients; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007785:Lactose / Q000031:analogs & derivatives; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives; D008875:Middle Aged; D010078:Oxazines; D011092:Polyethylene Glycols; D011433:Propranolol / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats
D000319:Adrenergic beta-Antagonists; D005079:Excipients; D010078:Oxazines; C104509:gelucire 44-14; D011092:Polyethylene Glycols; D008747:Methylcellulose; C071191:MK 458; D011433:Propranolol; D007785:Lactose