Formulation of solid dosage forms to overcome gastric pH interaction of the factor Xa inhibitor, BMS-561389.
OBJECTIVE
The purpose of the study was to investigate the specific mechanism by which elevated gastric pH reduces the absorption of BMS-561389, a factor Xa inhibitor, and to develop a solid formulation strategy to overcome this gastric pH interaction.


METHODS
A dissolution method in an acetate buffer at pH 5.5 was used to evaluate the dissolution behavior of the tablet formulation. A precipitation model was used to screen different excipients for their potential to minimize the pH-dependent absorption of BMS-561389. Excipients that showed promise in the precipitation model were incorporated in modified tablet formulations. Dissolution rate of the modified tablets was also determined by the acetate buffer method. A canine model for pH-dependent absorption was subsequently used to evaluate the tablet formulations.


RESULTS
Dissolution studies suggested that the reduced absorption of the original formulation was the result of the precipitation of the poorly water-soluble free base during the initial dissolution of the salt. Modified tablets containing organic acids, sulfobutylether-beta-cyclodextrin, or povidone showed enhanced dissolution as compared with the original formulation. Drug absorption from the tablet containing tartaric acid was substantially independent of gastric pH in the canine model.


CONCLUSIONS
A multitier approach was successful in identifying a solid dosage form that minimizes the pH-dependent absorption of this drug candidate.
Badawy
Sherif I Farag
SI
Pharmaceutical Research Institute, Bristol-Myers Squibb Co., One Squibb Drive, New Brunswick, New Jersey 08903, USA. sherif.badawy@bms.com
Gray
David B
DB
Zhao
Fang
F
Sun
Duxin
D
Schuster
Alan E
AE
Hussain
Munir A
MA
D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D004347:Drug Interactions; D005079:Excipients / Q000737:chemistry; D065427:Factor Xa Inhibitors; D015738:Famotidine / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000494:pharmacology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D007555:Isoxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010418:Pentagastrin / Q000494:pharmacology; D011205:Povidone / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility; D013607:Tablets
D005079:Excipients; D065427:Factor Xa Inhibitors; D005765:Gastrointestinal Agents; D006635:Histamine H2 Antagonists; D007555:Isoxazoles; D011720:Pyrazoles; D013607:Tablets; C500057:razaxaban; D015738:Famotidine; D010418:Pentagastrin; D011205:Povidone