title: 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.
abstract: OBJECTIVE
  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 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).
  
  
  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 PLA(2) 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 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.
authors: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Arik
authors: A
authors: Dahan
authors: Revital
authors: R
authors: Duvdevani
authors: Eran
authors: E
authors: Dvir
authors: Anat
authors: A
authors: Elmann
authors: Amnon
authors: A
authors: Hoffman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007213:Indomethacin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D010713:Phosphatidylcholines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010743:Phospholipids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003692:Delayed-Action Preparations; D010713:Phosphatidylcholines; D010743:Phospholipids; D011355:Prodrugs; D007213:Indomethacin