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

• Published in: Journal of controlled release 2007-05, Vol.119 (1), p.86-93
• Main Authors: Dahan, Arik, Duvdevani, Revital, Dvir, Eran, Elmann, Anat, Hoffman, Amnon
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Biological Availability; Controlled release; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - pharmacokinetics; Drug Evaluation, Preclinical - methods; General pharmacology; Indomethacin; Indomethacin - administration & dosage; Indomethacin - pharmacokinetics; Intestines - drug effects; Intestines - metabolism; Male; Medical sciences; Oral prodrug; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics; Pharmacology. Drug treatments; Phosphatidylcholines - administration & dosage; Phosphatidylcholines - pharmacokinetics; Phospholipase A 2; Phospholipids - administration & dosage; Phospholipids - pharmacokinetics; Phospholipid–drug conjugate; Prodrugs - administration & dosage; Prodrugs - pharmacokinetics; Rats; Rats, Wistar
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2006.12.032

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. 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 A 2 (PLA 2) 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). 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 PLA 2 was over 60%, while shorter linkers were profoundly less degradable. DP-155 caused a continuous input of free indomethacin into the plasma following degradation by PLA 2 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.