Ohmori Yuki, Onoue Satomi, Endo Kosuke, Matsumoto Asami, Uchida Shinya, Yamada Shizuo
Department of Pharmacokinetics and Pharmacodynamics and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
Life Sci. 2006 Jun 6;79(2):138-43. doi: 10.1016/j.lfs.2005.12.049. Epub 2006 Feb 3.
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.
血管活性肠肽（VIP）对气管平滑肌具有舒张作用，该作用通过与VIP受体相互作用介导。气道中VIP的缺乏与哮喘的发病机制有关。因此，给予VIP可能对肺部疾病的治疗有用。然而，除了由于VIP受体广泛分布导致的全身不良反应外，VIP的快速降解在很大程度上限制了其治疗应用。为了克服这些问题，我们成功合成了一种新型的VIP衍生物，[R15, 20, 21, L17]-VIP-GRR（IK312532），并制备了其干粉用于肺部局部给药。通过激光衍射和多级撞击器对干粉的物理化学性质进行了评估。激光衍射分析表明，载体和细颗粒的中值直径分别为65.6和4.5微米，在0.15 MPa或更高压力下的气流导致含肽细颗粒与载体分子的高分散和显著分离。多级撞击器分析清楚地显示了干粉从胶囊中的高发射以及肽在多级撞击器第3级的沉积。气管内给予VIP或IK312532的干粉吸入器（DPI）导致大鼠右肺前叶和后叶中[125I]VIP的最大结合位点（Bmax）显著降低，表明肺VIP受体被显著占据。与VIP-DPI相比，IK312532-DPI的这种作用持续时间更长。因此，IK312532-DPI可能是一种对哮喘等肺部疾病进行VIP治疗的药理学上有用的药物递送系统。
