A novel mechanism for oral controlled release of drugs by continuous degradation of a phospholipid prodrug along the intestine: In-vivo and in-vitro evaluation of an indomethacin-lecithin conjugate

Purpose: To investigate a novel mechanism for oral controlled release of drugs involving a continuous degradation of a phospholipid prodrug along the intestine. An indomethacin-lecithin conjugate with the drug attached to the sn-2 position of the phospholipid through a 5-carbon linker (DP-155) was used as a model molecule. Methods: The pharmacokinetics of DP-155 and free indomethacin liberated from the prodrug following intravenous, oral or intra-colon administration was investigated in rats, and evaluated in comparison to free indomethacin administration. Degradation by phospholipase A₂ (PLA₂) enzymes was assessed in-vitro. The impact of the linker length was evaluated in comparison to an indomethacin-phospholipid conjugate with a shorter linker (2-carbons). Results: Following oral or intra-colon DP-155 administration, free indomethacin was liberated along the intestine and absorbed into the systemic circulation, resulting in a controlled release profile of indomethacin in the plasma. The shorter linker caused a 20-fold decrease in the subsequent indomethacin absorption. DP-155 in-vitro degradation by PLA₂ was over 60%, while shorter linkers were profoundly less degradable. Conclusions: DP-155 caused a continuous input of free indomethacin into the plasma following degradation by PLA₂ in the gut lumen. Since the rate of drug release is not formulation dependent, the prodrug can be compounded even in a liquid dosage form. The phospholipid-drug conjugate is thus a potential novel mechanism for oral controlled release of drugs.