Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations.
Biopharmaceutical evaluation of crystalline celecoxib salts in novel solid formulations, which were designed to simultaneously facilitate dissolution and inhibit precipitation in vitro, showed fast and complete absorption in beagle dogs at doses up to 7.5 mg/kg orally. In contrast, 5 mg/kg celecoxib in the form of Celebrex(R) showed approximately 40% absolute bioavailability in a cross-over experiment. An in vitro-in vivo correlation was observed in dog, and a threshold level of in vitro dissolution needed to maximize in vivo performance was highlighted. Oral bioavailability was limited in the absence of excipient combinations that delayed precipitation of celecoxib free acid as the salt neutralized in the GI fluid. Formulations of crystal forms having high energy (a 'spring'), thus transiently increasing solubility in aqueous solution relative to the free acid, combined with excipients functioning as precipitation inhibitors ('parachutes') were shown to provide both enhanced dissolution and high oral bioavailability.
Guzmán
Héctor R
HR
TransForm Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, Massachusetts 02421, USA. hguzman@TPIUS.JNJ.COM
Tawa
Mark
M
Zhang
Zhong
Z
Ratanabanangkoon
Pasut
P
Shaw
Paul
P
Gardner
Colin R
CR
Chen
Hongming
H
Moreau
Jean-Pierre
JP
Almarsson
Orn
O
Remenar
Julius F
JF
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002214:Capsules; D000068579:Celecoxib; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical; D020650:Combinatorial Chemistry Techniques; D003460:Crystallization; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D004339:Drug Compounding; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013678:Technology, Pharmaceutical / Q000379:methods; D014867:Water / Q000737:chemistry
D002214:Capsules; D052246:Cyclooxygenase 2 Inhibitors; D005079:Excipients; D011720:Pyrazoles; D013449:Sulfonamides; D014867:Water; D000068579:Celecoxib