Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride.
OBJECTIVE
This study was carried out to show the effect of particle size reduction and bioadhesion on the dissolution and relative bioavailability of dicumarol.


METHODS
Formulations were produced by a variety of methods including a novel technique to reduce particle size as well as phase inversion with poly(fumaric-co-sebacic)anhydride p(FA:SA) to create nanospheres. Drug was administered to groups of pigs and rats via oral gavage of a suspension, and dicumarol concentration in the blood was measured using a double extraction technique.


RESULTS
In vitro results showed improved dissolution in both the micronized formulation and the encapsulated p(FA:SA) nanospheres. In vivo, relative bioavailability of a spray-dried formulation was increased by 17% in the rat and 72% in the pig by further reduction in particle size. The bioadhesive p(FA:SA) formulation also improved relative bioavailability over the spray-dried drug, increasing it by 55% in the rat and 96% in the pig. Additionally, the p(FA:SA) formulation prolonged Tmax and decreased Cmax in both species.


CONCLUSIONS
This work demonstrates the importance of particle size and bioadhesion to improve oral bioavailability of ducumarol.
Thanos
C G
CG
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island 02912, USA.
Liu
Z
Z
Reineke
J
J
Edwards
E
E
Mathiowitz
E
E
D000269:Adhesives / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D003652:Decanoic Acids / Q000097:blood / Q000493:pharmacokinetics*; D001728:Dicumarol / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005650:Fumarates / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D010316:Particle Size; D011108:Polymers / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
D000269:Adhesives; D003652:Decanoic Acids; D005650:Fumarates; D011108:Polymers; C473130:poly(fumaric-co-sebacic acid); D001728:Dicumarol