Imine bond formation as a tool for incorporation of amikacin in self-emulsifying drug delivery systems (SEDDS)

Abstract

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_{octanol/water} 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_{SEDDS/release medium} 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_{SEDDS/release medium} 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.

Keywords: Amikacin; Hydrophobic aldehydes; Imine; Peptide; SEDDS.