Effect of addition of hyaluronic acid to highly concentrated insulin on absorption from the conjunctiva in conscious diabetic dogs.

Insulin absorption from the conjunctiva was investigated in five pancreatectomized diabetic mongrel dogs, with the nasolacrimal ducts occluded by micro plugs to prevent insulin absorption from nasolacrimal membrane. In the anaesthetized state, highly concentrated porcine insulin (1000 units mL-1, pH 7.4) was absorbed rapidly and significantly from the conjunctiva. Plasma immunoreactive insulin concentrations increased significantly up to 3 h after insulin administration to conjunctival membranes. Plasma glucose concentration decreased significantly compared with saline control experiments after insulin administration (10 units kg-1) at 3 h (8.3 +/- 0.1 vs 15.6 +/- 0.6 mmol, P < 0.01). However, in the conscious state, there was no significant increase in the plasma insulin levels after topical insulin administration. To improve insulin absorption in the conscious state, we examined the effect of increasing viscosity of insulin preparation with hyaluronic acid. In anaesthetized experiments, there were no significant changes in the bioavailability of insulin after addition of hyaluronate (0.84 +/- 0.11 vs 0.87 +/- 0.05%). In the conscious state, with addition of hyaluronic acid, the area under the curve of plasma insulin concentration was significantly increased (1842 +/- 383 vs 75 +/- 24 m units min L-1, P < 0.01). The bioavailability of insulin absorption was significantly increased after addition of hyaluronate (0.68 +/- 0.14 vs 0.03 +/- 0.01%, P < 0.01). From this study we could demonstrate that the conjunctiva is a potential route for insulin administration, and increased viscosity by the addition of hyaluronate was found effective in increasing the bioavailability of insulin absorption from conjunctival membrane in the conscious state.