title: Enhancing the oral bioavailability of the poorly soluble drug dicumarol with a bioadhesive polymer.
abstract: This article investigates the effect of particle size and the incorporation of a bioadhesive polymer, poly(fumaric-co-sebacic) anhydride p(FA:SA), on the relative bioavailability of dicumarol. A novel method was used to reduce particle size of the drug, and encapsulated formulations were fabricated using a phase inversion technique to produce nanospheres and microspheres with varying size. Groups of Yorkshire swine were catheterized and gavaged after fasting for 12 h with each formulation in a 50 mg/mL suspension. Blood was collected at different time points, from 0 to 96 h, and pharmacokinetic analysis revealed that formulations incorporating the smaller drug particles showed the highest bioavailability: micronized drug with 7% p(FA:SA) 17:83 polymer had 190% relative bioavailability, and phase inverted p(FA:SA) 17:83 microspheres with 31% (w/w) loading had 198% relative bioavailability to spray dried formulation. Formulations with larger drug particles achieved 71% relative bioavailability. A nonadhesive formulation, fabricated with poly(lactic acid) (PLA), showed 91% relative bioavailability. Both particle size and polymer composition play a role in oral absorption of dicumarol.
authors.affiliation: Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Thanos
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Moses
authors.initials: M
authors.lastname: Goddard
authors.forename: Joshua
authors.initials: J
authors.lastname: Reineke
authors.forename: Nicola
authors.initials: N
authors.lastname: Bailey
authors.forename: Matthew
authors.initials: M
authors.lastname: Cross
authors.forename: Roxanne
authors.initials: R
authors.lastname: Burrill
authors.forename: Edith
authors.initials: E
authors.lastname: Mathiowitz
mesh_terms: D000269:Adhesives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D001728:Dicumarol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility / Q000187:drug effects; D013552:Swine
chemical_list: D000269:Adhesives; D011108:Polymers; D001728:Dicumarol