Dahan Arik, Duvdevani Revital, Dvir Eran, Elmann Anat, Hoffman Amnon
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
J Control Release. 2007 May 14;119(1):86-93. doi: 10.1016/j.jconrel.2006.12.032. Epub 2007 Feb 1.
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.
研究一种新型的药物口服控释机制，该机制涉及磷脂前药沿肠道的持续降解。以一种通过5个碳原子的连接子将药物连接到磷脂sn-2位的吲哚美辛-卵磷脂缀合物（DP-155）作为模型分子。
在大鼠中研究了DP-155以及前药释放出的游离吲哚美辛经静脉注射、口服或结肠内给药后的药代动力学，并与游离吲哚美辛给药进行比较评估。体外评估了磷脂酶A(2)（PLA(2)）酶的降解情况。与具有较短连接子（2个碳原子）的吲哚美辛-磷脂缀合物相比，评估了连接子长度的影响。
口服或结肠内给予DP-155后，游离吲哚美辛沿肠道释放并吸收进入体循环，导致血浆中吲哚美辛呈现控释特征。较短的连接子使随后的吲哚美辛吸收减少了20倍。DP-155在体外被PLA(2)降解的程度超过60%，而较短连接子的降解性则显著较低。
DP-155在肠腔内被PLA(2)降解后，会导致游离吲哚美辛持续输入血浆。由于药物释放速率不依赖于制剂，前药甚至可以制成液体制剂。因此，磷脂-药物缀合物是一种潜在的新型药物口服控释机制。
