亚胺键形成作为将阿米卡星纳入自乳化药物传递系统（SEDDS）中的工具。
Imine bond formation as a tool for incorporation of amikacin in self-emulsifying drug delivery systems (SEDDS).
机构信息
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens University Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria.
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens University Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria; Department of Pharmaceutical Technology, Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, S.H., Janturan, Warungboto, Umbulharjo, Yogyakarta 55164, Indonesia.
出版信息
Eur J Pharm Biopharm. 2021 May;162:82-91. doi: 10.1016/j.ejpb.2021.03.001. Epub 2021 Mar 16.
AIM
The aim was to develop a self-emulsifying drug delivery system (SEDDS) for amikacin via imine bond formation with hydrophobic aldehydes.
METHODS
Trans-2, cis-6-nonadienal, trans-cinnamaldehyde, citral and benzaldehyde were conjugated to amikacin at pH 8.5. Based on results of precipitation efficiency, Fourier-transform infrared spectroscopy (FTIR) and NMR analysis, amikacin-trans-cinnamaldehyde conjugates were further characterized regarding log P via HPLC. The release of amikacin from the amikacin-trans-cinnamaldehyde conjugates was examined through in vitro incubation with bovine serum albumin (BSA). SEDDS containing the amikacin-trans-cinnamaldehyde conjugates were tested regarding mean droplet size (MDS), polydispersity index (PDI), log D and cell viability.
RESULTS
Trans-cinnamaldehyde formed the most hydrophobic conjugates with amikacin whereas benzaldehyde did not form hydrophobic conjugates at all. Imine bond formation was confirmed by FTIR and NMR analysis. The highest increase in log P was achieved for the amikacin-trans-cinnamaldehyde conjugate in a molar ratio of 1:5, shifting from -8.58 up to 1.59. Incubation of this conjugate with BSA led to the formation of BSA-trans-cinnamaldehyde releasing in turn amikacin. SEDDS based on Capmul MCM, Cremophor EL and propylene glycol containing the conjugate demonstrated a MDS of 61.4 nm and PDI of 0.265. Log D was calculated to be 3.38. Cell viability studies showed very good tolerability of conjugate loaded SEDDS in concentrations of 0.1% - 0.5%.
CONCLUSION
Imine bond formation of amikacin with trans-cinnamaldehyde and the incorporation of the resulting conjugate into SEDDS represents a promising strategy for oral delivery of amikacin.
目的
通过与疏水醛形成亚胺键，开发一种阿米卡星自乳化药物传递系统（SEDDS）。
方法
在 pH 8.5 下，将反式-2，顺式-6-壬二烯醛、反式肉桂醛、柠檬醛和苯甲醛与阿米卡星共轭。基于沉淀效率、傅里叶变换红外光谱（FTIR）和 NMR 分析的结果，通过 HPLC 进一步对阿米卡星-反式肉桂醛轭合物的 log P 进行了表征。通过与牛血清白蛋白（BSA）体外孵育来检查阿米卡星从阿米卡星-反式肉桂醛轭合物中的释放。对含有阿米卡星-反式肉桂醛轭合物的 SEDDS 进行了平均液滴大小（MDS）、多分散指数（PDI）、log D 和细胞活力测试。
结果
反式肉桂醛与阿米卡星形成最疏水的轭合物，而苯甲醛根本没有形成疏水轭合物。FTIR 和 NMR 分析证实了亚胺键的形成。在 1:5 的摩尔比下，阿米卡星-反式肉桂醛轭合物的 log P 增加最大，从-8.58 增加到 1.59。将该轭合物与 BSA 孵育会导致 BSA-反式肉桂醛的形成，从而释放出阿米卡星。基于 Capmul MCM、Cremophor EL 和丙二醇的 SEDDS 含有该轭合物，其 MDS 为 61.4nm，PDI 为 0.265。计算的 log D 为 3.38。细胞活力研究表明，浓度为 0.1%-0.5%的载有轭合物的 SEDDS 具有非常好的耐受性。
结论
阿米卡星与反式肉桂醛形成亚胺键，以及将所得轭合物纳入 SEDDS，代表了一种有前途的阿米卡星口服传递策略。
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