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Improving Relative Bioavailability of Dicumarol by Reducing Particle Size and Adding the Adhesive Poly(Fumaric-Co-Sebacic) Anhydride

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Abstract

Purpose. 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.

Conclusion. This work demonstrates the importance of particle size and bioadhesion to improve oral bioavailability of ducumarol.

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Authors and Affiliations

  1. Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island, 02912

    C. G. Thanos, Z. Liu, J. Reineke, E. Edwards & E. Mathiowitz

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  1. C. G. Thanos
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  2. Z. Liu
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  3. J. Reineke
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  4. E. Edwards
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  5. E. Mathiowitz
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Correspondence to E. Mathiowitz.

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Thanos, C.G., Liu, Z., Reineke, J. et al. Improving Relative Bioavailability of Dicumarol by Reducing Particle Size and Adding the Adhesive Poly(Fumaric-Co-Sebacic) Anhydride. Pharm Res 20, 1093–1100 (2003). https://doi.org/10.1023/A:1024474609667

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