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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 μm long, with 303 ± 3 μm diameter at their base. The length of the insulin loaded space was 182 ± 4 μm. 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 °C. As the temperature increased to 40 °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.