Pharmaceutica Analytica Acta

Abstracto

Application of ¹⁹F NMR Spectroscopy Using a Novel a-Tocopherol Derivative as a ¹⁹F NMR Probe for a Pharmacokinetic Study of Lipid Nano-Emulsions in Mice

Takegami S, Katsumi H, Asai K, Fujii D, Fujimoto T, Kawakami H, Tokuyama T, Konishi A, Yamamoto A and Tatsuya Kitade

Objective: The aim of our study was to demonstrate the usefulness of 19F nuclear magnetic resonance (NMR) spectroscopy as an analytical technique applicable for the pharmacokinetic studies of lipid nano-emulsions (LNEs) using a mixture of soybean oil, phosphatidylcholine and sodium palmitate as drug carriers. Methods: A α−tocopherol derivative, 19F-TP, in which a 4-(trifluoromethyl) benzoyl group was introduced to the hydroxyl group of α-tocopherol was newly synthesized as a 19F NMR probe. Three different LNEs containing 19F-TP, denoted 19F-TP-LNEs (Small-LNE, Large-LNE, and polyethylene glycol-modified LNE (PEG-LNE)) were prepared by the sonication method and characterized using a dynamic light-scattering method and zeta potential analysis. The concentrations of the three 19F-TP-LNEs in the blood, liver and kidneys of mice were periodically evaluated based on the 19F NMR signal intensity ratio of 19F-TP using 0.1 mM of trifluoromethane sulfonic acid sodium salt as an internal reference. Results: 19F-TP was easily synthesized with a high yield of 96% in a one-step procedure. Small-LNE, Large- LNE and PEG-LNE had the mean particle sizes of 58, 157 and 174 nm and zeta potentials of –34, –53 and –32 mV, respectively. A single signal attributable to 19F-TP in 19F-TP-LNEs was observed at 15.4 ppm in the 19F NMR spectra of biological samples, but was observed to decrease over time. From the change of 19F NMR signal of 19F-TP in biological samples, it was shown that three 19F-TP-LNEs had different pharmacokinetic characteristics because of their droplet sizes and surface physical properties. Conclusion: Based on these results, the 19F NMR method was confirmed to be a convenient and useful tool for assessing the pharmacokinetics of LNEs without the need for complicated pretreatment procedures such as the deproteination of the matrix and extraction of the target compound before the 19F NMR measurements.