Lymphatic delivery of anticancer drug by lipid microspheres containing prodrug of 5'-deoxy-5-fluorouridine

Lipid microspheres (LM) containing lipophilic prodrug of 5'-deoxy-5-fluorouridine(5'-DFUR), 2', 3'-didecanoyl-5'-deoxy-5-fluorouridine(C 10-5'-DFUR), were prepared. The median diameter of LM containing C 10-5'-DFUR(C 10-5'-DFUR-LM) was about 200 nm, which was unchanged during storage for 1 week at 5°C. We analyzed plasma concentration and cumulative lymphatic transport of drug following oral administration of C 10-5'-DFUR-L to rats, as compared with 5'-DFUR aqueous salutions(5'-DFUR-W) or 5'-DFUR added to LM (5'-DFUR+LM). Effect of simultaneous use of C 10-5'-DFUR and soybean oil or lecithin which is components of LM on lymphatic delivery of drug was also investigated. The plasma concentration of 5'-DFUR rapidly declined following administration of 5'-DFUR-W or 5'-DFUR+LM. In contrast, the plasma concentration of 5'-DFUR was sustained for 24 hr in all cases of formulations containing C 10-5'-DFUR. On the other hand, the cumulative lymphatic transport of the drug following the co-administration of C 10-5'-DFUR and soybean oil or lecithin was higher than 5'-DFUR-W and 5'-DFUR+LM. Especially, in the case of C 10-5'-DFUR-LM, the cumulative lymphatic transport was higher than any other formulation. Those results indicate that administration of lipophilic drug incorporated in LM is effective for directed delivery of the drug to lymph duct, due partly to direct transmucosal passage of the intact LM containing the drug.