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树枝状大分子前药的合成、表征及稳定性

Synthesis, characterization and stability of dendrimer prodrugs.

作者信息

Najlah Mohammad, Freeman Sally, Attwood David, D'Emanuele Antony

机构信息

School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK.

出版信息

Int J Pharm. 2006 Feb 3;308(1-2):175-82. doi: 10.1016/j.ijpharm.2005.10.033. Epub 2005 Dec 27.

DOI:10.1016/j.ijpharm.2005.10.033
PMID:16384673
Abstract

The design, synthesis and characterization of a series of zero generation (G0) PAMAM dendrimer-based prodrugs for the potential enhancement of drug solubility and bioavailability are described. Naproxen, a poorly water-soluble drug, was conjugated to dendrimers either directly by an amide bond or by ester bonds using either L-lactic acid or diethylene glycol as a linker. All of the prodrugs were more hydrophilic than the parent drug, as evaluated by drug partitioning between 1-octanol and phosphate buffer (pH 7.4). Hydrolysis of the conjugates was measured at 37 degrees C in hydrochloric acid buffer (pH 1.2), phosphate buffer (pH 7.4), borate buffer (pH 8.5) and in 80% human plasma. The amide conjugate and both ester conjugates were chemically stable at all pHs over 48 h of incubation. Naproxen was enzymatically released from both ester conjugates in plasma; the lactic ester conjugate hydrolyzed slowly with only 25% of naproxen released after 24h, the diethylene glycol ester conjugate cleaved rapidly following pseudo first order kinetics (t(1/2) = 51 min). G0 PAMAM dendrimer prodrugs with an appropriate linker (diethylene glycol) show good potential as carriers for oral delivery.

摘要

本文描述了一系列基于零代(G0)聚酰胺-胺(PAMAM)树枝状大分子的前体药物的设计、合成与表征,这些前体药物有望提高药物的溶解度和生物利用度。萘普生是一种水溶性较差的药物,通过酰胺键或使用L-乳酸或二甘醇作为连接基的酯键直接与树枝状大分子偶联。通过测定药物在正辛醇和磷酸盐缓冲液(pH 7.4)之间的分配,评估所有前体药物均比母体药物更具亲水性。在37℃下,于盐酸缓冲液(pH 1.2)、磷酸盐缓冲液(pH 7.4)、硼酸盐缓冲液(pH 8.5)以及80%人血浆中测定偶联物的水解情况。酰胺偶联物以及两种酯偶联物在所有pH值下孵育48小时均化学稳定。萘普生在血浆中可从两种酯偶联物中酶促释放;乳酸酯偶联物水解缓慢,24小时后仅释放25%的萘普生,二甘醇酯偶联物按照准一级动力学快速裂解(半衰期t(1/2) = 51分钟)。具有合适连接基(二甘醇)的G0 PAMAM树枝状大分子前体药物作为口服给药载体显示出良好的潜力。

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