Two-layered dissolving microneedles formulated with intermediate-acting insulin

Two-layered dissolving microneedles (DMs) containing intermediate-acting insulin, protamine sulfate insulin (PSI), were prepared. Then a pharmacodynamic study was performed to evaluate the prolonged hypoglycemic effects in rats. The DMs were approximately 497 +/- 5 mu m long, with 303 +/- 3 mu m diameter at their base. The length of the insulin loaded space was 182 +/- 4 mu m. PSI contents in DMs were 0.51 +/- 0.02 IU. A three-month stability study showed that 99.9 +/- 1.4% of PSI was recovered at 4 degrees C. As the temperature increased to 40 degrees C, recovery decreased to 97.5 +/- 2.0%. PSI was released within 5 min from DMs. Hypoglycemic effects of PSI DMs were evaluated in rats where subcutaneous injection preparations were used as references. Total area above the plasma glucose level (% of the pre-dose level) vs. time curve as an index of hypoglycemic effect was 144.0 +/- 16.0% h and 243.3 +/- 8.5% h for PSI DMs at 1.46 and 3.28 IU/kg. The relative pharmacologic availability of PSI from DMs were 100.2 +/- 9.8% and 91.4 +/- 4.1%. No significant difference of hypoglycemic curves was found between DMs and injection solutions, which suggests the usefulness of two-layered DMs of PSI for the displacement therapy of sc injection preparation. (c) 2012 Elsevier B.V. All rights reserved.