Abstract:

In this paper we report on the solubilization of desmopressin, as a model for peptide drugs, into reverse hexagonal (HII) liq. crystals. Concn.- and temp.-induced interactions of desmopressin, as well as the conformation of the peptide, were studied using small-angle X-ray scattering, ATR-FTIR spectroscopy, SD-NMR, and rheol. measurements. A considerable increase (up to 6 \AA) in the lattice parameter of the mesophases was obtained upon incorporation of the peptide. According to the ATR-FTIR anal., the chaotropic effect of peptide embedment was assigned to its interactions with hydroxyls of monoglyceride in the outer interface region. These interactions had only a minor influence on the conformation of the peptide; weakening or opening the $\gamma$-turns resulted in partial binding of the peptides free carbonyls to monoolein. Temp.-dependent SAXS measurements displayed a chaotropic destabilizing effect of desmopressin on the structure, shifting toward the lower temp. HII-L2 structural transition. Temp. increase resulted in an increase of the domain size in the presence of the peptide, in contrast to the trend obsd. in the empty mesophase. SD-NMR anal. enabled distinguishing between two factors impeding the diffusion of the peptide: the restriction of motion due to the geometrical constrain of diffusion within the water tubes, and the interactions of the guest mol. with monoglyceride. The onset of the crit. behavior at 45 °C was found to be significant, indicating considerable weakening of the monoglyceride and desmopressin interactions and the destabilizing effect of the peptide on the mesophase above this temp. Similar temp.-dependent behavior was revealed by rheol. measurements displaying the same onset of the crit. behavior. It was demonstrated by Franz diffusion cell measurements that hexagonal mesophases can potentially be used as delivery vehicles for sustained delivery of desmopressin. [on SciFinder(R)]