Absorption enhancers in nasal insulin delivery and their influence on nasal ciliary functioning
Schipper, N.G.M.; Verhoef, J.; Romeijn, S.G.; Merkus, F.W.H.M.
Journal of Controlled Release 21(1-3): 173-186
ISSN/ISBN: 0168-3659 DOI: 10.1016/0168-3659(92)90019-n
A major drawback in current insulin therapy is the lack of an efficient non-parenteral delivery system. Among other routes nasal administration of insulin has extensively been investigated as an alternative route for delivery. Insulin is poorly absorbed from the nasal mucosa, and it is necessary to use an absorption enhancing compound to facilitate its absorption. Many enhancers of widely differing chemical structure have been investigated in this respect. Recently, it was demonstrated that the cyclodextrin derivative, dimethyl--cyclodextrin (DMCD), at a concentration of 5% (w/v) strongly improved nasal insulin absorption in rats. In the present study the effect of different concentrations of DMCD on the absorption of intranasally administered insulin in rats was studied. Administration of 2 IU/kg insulin with 5% (w/v) DMCD resulted in a bioavailability of approx. 100%. The minimal concentration of DMCD required to improve the insulin absorption was 2% (w/v). Increasing the concentration to 3, 4, and 5% (w/v) resulted in a more pronounced insulin absorption, but the area under the serum concentration-time curve measured up to 1 h post administration was not significantly different from 2% DMCD. DMCD decreased the ciliary beat frequency of both chicken embryo trachea and human adenoid tissue in vitro. The effect was concentration dependent. For 2% DMCD the ciliary activity was still 40% of the initial frequency at 60 min incubation in both ciliated tissue models. In conclusion, DMCD is a potent enhancer of nasal insulin absorption in rats, already effective at concentrations that show a mild effect on in vitro ciliary movement.