Prolonged hypoglycemic effects obtained by two-layered dissolving microneedles containing insulin glargine

Two-layered dissolving microneedles (DMs) containing the long-acting insulin analog, insulin glargine (IG), were prepared and a pharmacodynamic study was performed to evaluate the prolonged hypoglycemic effects of IG DMs in rats. DMs were approximately 487 ± 16 ßm (n = 8) in length and 293 ± 8 ßm (n = 8) in diameter at their base. The length of the insulin-loaded space was approximately 225 ± 21 ßm (n = 8). The level of IG in DMs was 3.96 ± 0.33 U (n = 8). In a one-month stability study, 98.2 ± 1.7 % (n = 8) of IG was recovered at 40 °C. A dissolution study revealed that 82.7 ± 10.3 % (n = 5) of IG was released within 2 min. The hypoglycemic effects of IG DMs were evaluated in rats in which subcutaneous injection preparations were used as the positive control. Decreased plasma glucose levels were maintained for 10 h. The total area above the plasma glucose level (AAG, % of the pre-dose level) vs. time curve as an index of the hypoglycemic effect was 147.5 ± 34.0 %-h (n = 5). AAG increased to 194.3 ± 20.6 %-h (n = 5) when the dose of IG was increased to 5.87 ± 0.85 U (n = 5). The relative pharmacological availabilities of IG from DMs were 79.1 ± 18.3 % (n = 5) and 85.3 ± 9.0 % (n = 5). A pharmacokinetic study showed that plasma IG levels were maintained between 100 and 200 ßU/mL for 9 h. These results clearly demonstrated the usefulness of DM in obtaining long-term hypoglycemic effects in rats.