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Abstract

\The therapeutic use of peptides has aroused growing interest over the past twenty years. The major problem incurred following oral administration of the peptides is significant enzymatic degradation in the gastrointestinal tract. The nasal cavity presents excellent characteristics for the systemic administration of peptides. From a therapeutic point of view, it would therefore be preferable to adopt another strategy based on the use of a bioadhesive system thus avoiding rapid mucociliary elimination and damage to epithelial cells. Poloxamer 407 is a surfactant with a molecular weight of approximately 12,000, consisting of 30% polyoxypropylene and 70% polyoxyethylene (EPE copolymer). Thanks to its excellent biocompatibility, its low toxicity and its micellar and gelling properties, poloxamer 407 has already been the subject of detailed studies with a view to various pharmaceutical applications. We have chosen as a model peptide the natriuretic factor of the atria (ANF, 28 amino acids, molecular weight 3060). Recently, it has been reported that ANF in saline solution is absorbed gradually after nasal administration in rats, while causing an increase in diuresis and natriuresis for about fifty minutes. With a view to developing a mucoadhesive system, it seemed important to us to verify whether the thermorheological behavior is affected by the presence of the active principle or the excipients used. The $\sp{13}$C NMR analysis shows no interaction between the ions and the poloxamer. The release kinetics of the peptide were evaluated in vitro in order to determine the diffusion coefficient as a function of various factors such as the polymer concentration, the presence of additives and the temperature variation. These studies indicate that the presence of poloxamer 407 strongly slows the diffusion of ANF, which suggested a controlled release in vivo. We also evaluated the influence of these same factors on the adhesion of the gel to mucus (ileal segment of dogs) in vitro. Following this study, we hypothesized that the mucoadhesion mechanism of poloxamer gel is based on its thermorheological properties. The fluidity at low temperature (5$\sp\circ$ to 10$\sp\circ$C) would facilitate the application and allow the solution to penetrate and spread in the irregularities of the mucosa. After application of the gel, the viscosity of the poloxamer solution increases at a temperature below body temperature. The results under different storage conditions suggest that the presence of poloxamer 407 does not modify the stability of the peptide. The pharmacokinetics of radioiodine ANF was studied after nasal administration in a 20% poloxamer 407 gel in rabbits. Finally, poloxamer 407 would protect the unchanged ANF from enzymatic degradation by endopeptidase 24.11 in the nasal cavity and allow its passage through the nasal mucosa according to a mechanism to be defined. (Abstract shortened by UMI.)

Authors

Juhasz, Julianna

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