TY - JOUR
T1 - A novel mechanism for oral controlled release of drugs by continuous degradation of a phospholipid prodrug along the intestine
T2 - In-vivo and in-vitro evaluation of an indomethacin-lecithin conjugate
AU - Dahan, Arik
AU - Duvdevani, Revital
AU - Dvir, Eran
AU - Elmann, Anat
AU - Hoffman, Amnon
N1 - Funding Information:
This work is a part of Arik Dahan PhD dissertation. This study was supported by the Israeli Consortium of Pharmalogica. The authors thank Dr. Josh Backon for the constructive comments. A. Hoffman is affiliated with David R. Bloom Center of Pharmacy.
PY - 2007/5/14
Y1 - 2007/5/14
N2 - 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.
AB - 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.
KW - Controlled release
KW - Indomethacin
KW - Oral prodrug
KW - Pharmacokinetics
KW - Phospholipase A
KW - Phospholipid-drug conjugate
UR - http://www.scopus.com/inward/record.url?scp=34147136099&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2006.12.032
DO - 10.1016/j.jconrel.2006.12.032
M3 - Article
C2 - 17382425
AN - SCOPUS:34147136099
VL - 119
SP - 86
EP - 93
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
IS - 1
ER -