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Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations.

Authors
  • Guzmán, Héctor R
  • Tawa, Mark
  • Zhang, Zhong
  • Ratanabanangkoon, Pasut
  • Shaw, Paul
  • Gardner, Colin R
  • Chen, Hongming
  • Moreau, Jean-Pierre
  • Almarsson, Orn
  • Remenar, Julius F
Type
Published Article
Journal
Journal of pharmaceutical sciences
Publication Date
Oct 01, 2007
Volume
96
Issue
10
Pages
2686–2702
Identifiers
PMID: 17518357
Source
Medline
License
Unknown

Abstract

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.

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