Time dependent effects of two absorption enhancers on the nasal absorption of growth hormone in rabbits

Abstract

Enhancer-based drug preparations allow absorption of peptide drugs. We investigated the reversibility with time of nasal absorption of human growth hormone (hGH) induced by the absorption enhancers didecanoylphosphatidylcholine (DDPC) and α-cyclodextrin (α-CD). Rabbits were dosed intranasally with enhancer in the absence of hGH at time − 3, − 1, − 0.5 and 0 h. At time zero the same groups of rabbits were dosed with a hGH powder devoid of the enhancers. Values for plasma hGH AUC and C max were estimated in order to measure the degree of absorption, and rabbits receiving hGH together with enhancers were used as positive references. With an enhancer preparation of 8% DDPC and 30% α-CD, the hGH AUC and C max values showed a significant time-dependent decrease after enhancer administration. This may indicate recovery of the enhancer-induced mucosal leakiness as well as clearance of the enhancers from the tissue. Similar findings were obtained with α-CD alone, whereas a preparation containing only DDPC showed no recovery of leakiness. The effect of α-CD was also investigated in vitro in rabbit nasal mucosa mounted in Ussing chambers. Incubation for 15 min with 1, 3 and 8% α-CD induced a concentration-dependent decrease of the potential difference, the short circuit current and the resistance suggesting impaired sodium transport and loosening of tight junctions. After washout of α-CD, this effect was completely reversible for the low concentrations of α-CD, but not for the 8% α-CD. These results show that α-CD alone, or in combination with DDPC, has properties as a reversible enhancer for nasal absorption of hGH in vivo.