INTRANASAL DELIVERY OF HUMAN GROWTH-HORMONE - OPTIMIZATION OF FORMULATION

Ten different formulations of recombinant human growth hormone (hGH) and a permeation enhancer of the nasal mucosa, sodium tauro-24,25-dihydrofusidate (STDHF) were administered intranasally (i.n.) to ten patients with classical GH deficiency. The formulations contained three variables: the hGH content (2, 4.1, or 6.3 mg = 4, 8.25, or 12.5 IU), the concentration of STDHF (0.75, 1, or 1.25%) and the spray volume (2 x 35, 2 x 53, or 2 x 70 mu l). The influence of these variables on the bioavailability of hGH after i.n. administration and the local (nasal) irritation were assessed. The bioavailability was measured as the plasma concentration of hGH obtained by blood sampling, prior to and at frequent intervals for up to 5 h after administration. The effects on the nasal mucosa were evaluated by nasal inspections before and after each administration and also by using a self-rating protocol to estimate the nasal sensations for each dose. The influences of the three variables (hGH content, STDHF concentration, and spray volume) on the bioavailability of hGH were analyzed by analysis of variance and multivariate statistical analysis being a useful way to evaluate multiple factors in pharmaceutical preparations with a limited number of observations in early clinical trials. This study demonstrates that formulations with low spray volumes (2 x 35 CLI) resulted in a lower uptake of hGH and somewhat less inter-individual variability compared to larger volumes (2 x 53, 2 x 70 mu l) and that the concentrations of STDHF (0.75, 1, or 1.25%) had no significant effect on the bioavailability. The higher concentrations of STDHF were accompanied by more intense nasal sensations even if none of the formulations resulted in any damage of the nasal mucosa as determined by nasal inspections. (C) 1995 Wiley-Liss, Inc.