PURPOSE: A low-viscosity formulation for pulmonary delivery of rh-insulin as model peptide drugs was developed using a solution of sodium hyaluronate. METHOD: The effects of different concentrations and pH values of low-viscosity solutions of hyaluronate on the pulmonary absorption of rh-insulin were examined after intratracheal administration in rats. The permeation of fluorescein isothiocyanate (FITC)-dextran (molecular weight 4300; FD-4) and insulin through excised rat trachea in vitro were also examined. RESULTS: The hyaluronate (2140 kDa) solutions (0.1% and 0.2% w/v) at pH 7.0 significantly enhanced the pharmacological availability (PAB) of insulin compared to the aqueous solution of insulin at pH 7.0. The absorption-enhancing effect at a concentration of 0.1% w/v hyaluronate was greater than that at a concentration of 0.2% w/v hyaluronate. Furthermore, the greatest absorption-enhancing effect was obtained, regardless of the molecular weight of hyaluronate, when the concentration of hyaluronate was adjusted to 0.47 microM. Absorption-enhancing effects were consistent with the effect of a 0.1 w/v hyaluronate preparation at pH 4.0 and 7.0 on the permeation of FITC-dextran and insulin through excised rat trachea in vitro. CONCLUSION: Low-viscosity hyaluronate preparation was shown to be a useful vehicle for pulmonary delivery of peptide drugs.
PURPOSE: A low-viscosity formulation for pulmonary delivery of rh-insulin as model peptide drugs was developed using a solution of sodium hyaluronate. METHOD: The effects of different concentrations and pH values of low-viscosity solutions of hyaluronate on the pulmonary absorption of rh-insulin were examined after intratracheal administration in rats. The permeation of fluorescein isothiocyanate (FITC)-dextran (molecular weight 4300; FD-4) and insulin through excised rat trachea in vitro were also examined. RESULTS: The hyaluronate (2140 kDa) solutions (0.1% and 0.2% w/v) at pH 7.0 significantly enhanced the pharmacological availability (PAB) of insulin compared to the aqueous solution of insulin at pH 7.0. The absorption-enhancing effect at a concentration of 0.1% w/v hyaluronate was greater than that at a concentration of 0.2% w/v hyaluronate. Furthermore, the greatest absorption-enhancing effect was obtained, regardless of the molecular weight of hyaluronate, when the concentration of hyaluronate was adjusted to 0.47 microM. Absorption-enhancing effects were consistent with the effect of a 0.1 w/v hyaluronate preparation at pH 4.0 and 7.0 on the permeation of FITC-dextran and insulin through excised rat trachea in vitro. CONCLUSION: Low-viscosity hyaluronate preparation was shown to be a useful vehicle for pulmonary delivery of peptide drugs.