Improvement of pulmonary absorption of cyclopeptide FK224 in rats by co-formulating with beta-cyclodextrin.

FK224 is a cyclopeptide drug with a low aqueous solubility. Following oral administration to rats, poor absorption was observed due to proteolysis in the gastrointestinal tract. The objective of this study was to investigate the effect of the pulmonary route on the systemic absorption of FK224 in comparison with other administration routes, and to determine the bioavailability (BA) of FK224 following pulmonary administration in rats using various dosage forms. From absorption studies on the Polyethylene Glycol 400 solution given by various routes (intranasal, subcutaneous, intratracheal and intravenous as reference), it was shown that pulmonary administration was a potentially attractive route for FK224. In the pulmonary absorption studies, after administration of the aqueous suspension, the BA was reduced to 2.7% compared with 16.8% for the solution. However, beta-cyclodextrin (beta-CyD) was found to be an effective additive as far as improving the solubility of FK224 was concerned. The BA of the aqueous suspension containing beta-CyD was increased to 19.2%. Pressurized metered dose inhalers were prepared by formulating beta-CyD with various molar ratios of 1:0, 1:1 and 1:7 (FK224/beta-CyD), and the resulting BAs were 4.3%, 29.0% and 91.2%, respectively. It was observed that both the C(max) and AUC of FK224 were increased as the amount of beta-CyD increased. The plasma profiles showed sustained absorption. In conclusion, we have seen that the lung is a suitable route for absorption of FK224, and beta-CyD is an extremely effective additive as far as improving the pulmonary absorption of FK224 is concerned. beta-CyD or derivatives with various degrees of aqueous solubility are potential drug carriers for controlling pulmonary absorption. Copyright 2002 Elsevier Science B.V.