Indomethacin-5-fluorouracil-methyl ester dry emulsion: a potential oral delivery system for 5-fluorouracil.
OBJECTIVE
To produce a combined effect of indomethacin (IDM) and 5-fluorouracil (5FU) for cancer therapy, the side effects of IDM on the gastrointestinal (GI) tract were reduced and the oral adsorption of 5FU was improved. Indomethacin-5-fluorouracil-methyl ester (IFM) dry emulsion was prepared and evaluated as a potential oral delivery system for 5FU.


METHODS
IFM was synthesized by formation of an ester between IDM and 5FU intermediate and then characterized by structure, melting point, solubility, apparent partition coefficient, and incubation with GI tract contents and plasma. Gum acacia and sodium carboxymethyl cellulose (CMC-Na) were applied as the adsorbent and solid carrier to prepare IFM dry emulsion. IFM dry emulsion was then characterized by reconstitution in water and in situ intestinal perfusion experiment.


RESULTS
Physicochemical properties of the new synthesized compound confirmed the formation of IFM. Incubation of IFM in the contents of the GI tract and plasma revealed that IFM was not relatively stable in GI contents during the time period of transit through the GI tract, whereas it was very unstable in plasma and released 5FU rapidly. The IFM dry emulsion could be easily reconstituted in water, and the mean particle size was 2.416 microm. The absorption rate constant (K) for IFM with concentration of 2, 5, and 10 microg/mL in the in situ perfusion experiment were 0.473, 0.423, and 0.433/h, respectively, demonstrating passive diffusion of IFM across the biological membranes.


CONCLUSIONS
This study indicates that the IFM dry emulsion may represent a potentially useful oral delivery system for 5FU.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, PR China. Wang-jing6312@163.com
Jing
J
Wang
Yanchen
Y
Hu
Ling
L
Li
Tongying
T
Jiang
Siling
S
Wang
Fengkui
F
Mo
D000284:Administration, Oral; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D004655:Emulsions; D004952:Esters; D005472:Fluorouracil / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism; D007213:Indomethacin / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D008745:Methylation; D051381:Rats
D004655:Emulsions; D004952:Esters; D005472:Fluorouracil; D007213:Indomethacin