Improvement of Stability and Nasal Absorption of Peptide/Protein Drugs by Cyclodextrin Derivatives

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Nasal absorption of peptide/protein drugs such as insulin has been severely restricted by the presystemic elimination due to mucociliary clearance or enzymatic degradaion and by the limited mucosal membrane permeability. The objective of this study, therefore, is to investigate the potential use of hydrophilic cyclodextrin (CyD) derivatives in the nasal preparation of insulin, and prevention of insulin self-association and surface adsorption. The results obtained were as follows.(1) Methylated cyclodextrins were found to be more potent absorption enhancers than parent and hydroxypropylated CyDs. Spectroscopic observations indicated that the scope of inclusion complexation of insulin with cyds appeared to be of minor importance in the nasal absorption enhancement. CyDs increased the permeability of rat nasal mucosa, perhaps through the interaction with lipids and/or divalent cations on the membrane surface. In addition, the enzymatic degradation of insulin in- rat nasal homogenates was … More suppressed by CyDs. Multiple regression analysis suggested that the increased nasal membrane permeability and reduced proteolysis contributed synergistically to the absorption enhancement of insulin.(2) Possible use of 2-hydroxypropyl- beta -cyclodextrin (2-HP- beta -CYD) was preliminarily investigated in designing nasal preparation of insulin involving lipophilic absorption enhancer 1-[2- (decylthio) -ethyl]azacyclopentane-2-one (HPE-101). When insulin was administered nasally to rats, a simultanqp. . u's use of HPE-101 solubilized in 2-HP- beta-CyD showed a prominent increase in serum immunoreacive insulin levels and a marked hypoglycemia, probably through the facilitated transfer cit HPE-101 into the nasal mucosa. These results suggest that a combination of HPE-101 and hydrophilic CyDs is useful for designing mote effective and safer nasal delivery system of peptide/protein drugs.(3) Since insulin is biologically active mainly in the monomeric state, this study also attempted to overcome the insulin self-association and surface adsorption phenomena by the addition of CyDs. It was found that the hydrophilic CyDs such as maltosyl-beta-CyD and 2-HP-beta-CyD to insulin solution significantly reduced both insulin self-association and adsorption onto glass and polymeric surfaces. The analysis of circular dichroic (CD) behavior of insulin solution indicated that CyD may facilitate the conformational transition of insulin from some higher aggregates to monomeric state, decreasing antiparallel beta-structure of insulin. Less