Abstract
The objective of this study is to investigate the potential use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) as a biocompatible solubilizer for a lipophilic absorption enhancer, 1-[2-(decylthio)-ethyl] azacyclopentane-2-one (HPE-101) involved in the nasal preparation of insulin. The solubility of HPE-101 in water increased in a linear fashion as a function of HP-β-CyD concentration : the apparent stability constant of the complex was estimated to be 4300 M-1 at 25°C. When bovine insulin was administered nasally to rats, a simultaneous use of HPE-101 solubilized in HP-β-CyD showed a prominent increase in serum immunoreactive insulin levels and a marked hypoglycemia. The proteolysis of insulin in rat nasal homogenates was slightly inhibited by the solubilized HPE-101, and appeared to be of minor importance of the nasal absorption enhancement. HPE-101 enhanced the nasal permeability, as indicated by the transport of inulin, an inert and membrane impermeable marker from the nasal cavity into systemic circulation. This enhancing effect was potentiated by the solubilization of HPE-101 in HP-β-CyD, probably through the facilitated transfer of HPE-101 into the nasal mucosa. These results suggest that a combination of HPE-101 and HP-β-CyD is useful for designing the nasal delivery systems of peptide and protein drugs.
