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פותח על ידי קלירמאש פתרונות בע"מ -
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
Year:
2007
Source of publication :
Journal of Controlled Release
Authors :
אלמן, ענת
;
.
Volume :
119
Co-Authors:
Dahan, A., Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Jerusalem, Israel
Duvdevani, R., D-Pharm LTD, Rehovot, Israel
Dvir, E., D-Pharm LTD, Rehovot, Israel
Elmann, A., D-Pharm LTD, Rehovot, Israel
Hoffman, A., Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Jerusalem, Israel
Facilitators :
From page:
86
To page:
93
(
Total pages:
8
)
Abstract:
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. © 2007 Elsevier B.V. All rights reserved.
Note:
Related Files :
animal experiment
Animals
animal tissue
Biodegradation
Carbon
enzymes
Male
עוד תגיות
תוכן קשור
More details
DOI :
10.1016/j.jconrel.2006.12.032
Article number:
Affiliations:
Database:
סקופוס
Publication Type:
מאמר
;
.
Language:
אנגלית
Editors' remarks:
ID:
25830
Last updated date:
02/03/2022 17:27
Creation date:
17/04/2018 00:17
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Scientific Publication
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
119
Dahan, A., Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Jerusalem, Israel
Duvdevani, R., D-Pharm LTD, Rehovot, Israel
Dvir, E., D-Pharm LTD, Rehovot, Israel
Elmann, A., D-Pharm LTD, Rehovot, Israel
Hoffman, A., Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Jerusalem, Israel
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. © 2007 Elsevier B.V. All rights reserved.
Scientific Publication
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