Vasoactive intestinal peptide (VIP) exerts a relaxing action on tracheal smooth muscle which is mediated through interaction with
VIP receptors. The deficiency of VIP in the airways has been implicated in the pathogenesis of
asthma. Thus, the administration of VIP may be useful for the
therapy of
pulmonary diseases. However, the therapeutic application of VIP is largely limited by its rapid degradation in addition to the systemic adverse effects due to the wide distribution of
VIP receptors. To overcome these problems, we succeeded to synthesize a novel VIP derivative of VIP, [R15, 20, 21, L17]-VIP-GRR (
IK312532), and to prepare its dry
powder for the
topical administration to the lung. The physicochemical properties of dry
powder were evaluated by
laser diffraction and cascade impactor. The
laser diffraction analysis indicated that the carrier and fine particles had median diameter of 65.6 and 4.5 microm, respectively, and the air flow at the pressure of 0.15 MPa or higher resulted in the high dispersion and significant separation of fine particle containing
peptide from the carrier molecule. The cascade impactor analysis clearly showed the high emission of dry
powder from
capsule and the deposition of
peptide on stages 3 of the cascade impactor. The intratracheal administration of
dry powder inhaler (DPI) of VIP or
IK312532 brought about a significant decrease of maximal number of binding sites (Bmax) for [125I]VIP in anterior and posterior lobes of rat right lung, suggesting a significant occupancy of lung
VIP receptors. This effect by IK312532-DPI compared with VIP-DPI lasted for a longer period. Thus, IK312532-DPI may be a pharmacologically useful drug delivery system for the VIP
therapy of
pulmonary diseases such as
asthma.