The extrapolation of the curve shows that the concentration of netilmicin on the ocular surface can be effective against microorganisms more than 120 minutes after eye drop instillation.
The synthetic antimicrobial peptide SET-M33 is being developed as a possible new antibacterial candidate for the treatment of multi-drug resistant bacteria. SET-M33 is a branched peptide featuring higher resistance and bioavailability than its linear analogues. SET-M33 shows antimicrobial activity against different species of multi-resistant Gram-negative bacteria, including clinically isolated strains of Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumanii and Escherichia coli. The secondary structure of this 40 amino acid peptide was investigated by NMR to fully characterize the product in the framework of preclinical studies. The possible presence of helixes or β-sheets in the structure had to be explored to predict the behavior of the branched peptide in solution, with a view to designing a formulation for parenteral administration. Since the final formulation of SET-M33 will be strictly defined in terms of counter-ions and additives, we also report the studies on a new salt form, SET-M33 chloride, that retains its activity against Gram-negative bacteria and gains in solubility, with a possible improvement in the pharmacokinetic profile. The opportunity of using a chloride counter-ion is very convenient from a process development point of view and did not increase the toxicity of the antimicrobial drug.
Aerobic biodegradation tests of three blends representative of the most commonly marketed aliphatic alcohol polyethoxylates (AE) and a commercial polyethylene glycols (PEG) mixture were run under standard test conditions (Organization for Economic Cooperation and Development, Paris, France [OECD] 301 E protocol). The test liquors were investigated using a 400-MHz proton-nuclear magnetic resonance (1H-NMR) spectrometer in order to elucidate the biodegradation mechanism. Diagnostic signals for both linear and branched AE homologs were identified by bidimensional homocorrelated spectroscopy (COSY) and by double quantum filter correlated spectroscopy (DQFCOSY). The 1H-NMR allowed individually monitoring the fate of the alkyl and polyethoxyl fragments of the parent compounds and distinguishing between oxidative and nonoxidative polyethoxyl depolymerization, which could not be performed by other reported techniques such as high-peformance liquid chromatography (HPLC) or mass spectrometry (MS) or FAB spectroscopy. The AE biodegradation time profiles showed that under the test conditions, both alkyl and polyethoxyl chains of the linear and oxo-AE were biodegraded quite readily. The removal of the multibranched AE was slower when compared to that of linear and oxo-AE, while PEG exhibited a time profile characterized by a biodegradation rate significantly slower than that of PEG released by the microbial attack of linear and oxo-AE. In the case of linear AE, the alkyl chain was biodegraded much faster than the polyethoxyl chain, while in the case of oxo- and multibranched AE, both the alkyl and the polyethoxyl chains were biodegraded at similar rates.
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