Incidence of low bioavailability of leuprolide acetate after percutaneous administration to rats by dissolving microneedles

Two-layered dissolving microneedles of which acral portion contained leuprolide acetate (LA) as solid dispersion were prepared with sodium chondroitin sulfate as the base and the systemic absorption efficiency of LA was studied in rats after administration to their abdominal skin. A patch contained 100 dissolving microneedles of which length and basement diameter were 469.8 ± 4.7 μm and 284.5 ± 9.8 μm, where LA content was 14.3 ± 1.6 μg. In vitro dissolution experiment showed that LA was released from dissolving microneedle patch within 3 min. LA was stable in the patch, % recoveries for 3 months were 102.2 ± 1.9–95.3 ± 1.9%. One and half-patch of LA dissolving microneedles were administered to the rat skin and plasma LA concentrations were measured by LC–MS/MS. Plasma LA concentrations increased immediately after administration, and reached to the maximum level at 15 min, where Cmax were 6.0 ± 0.7 and 16.4 ± 0.9 μg/ml, respectively. The AUC were 5.8 ± 0.8 and 14.5 ± 0.4 μg h/ml and BA were 33.8 ± 4.3% and 31.7 ± 0.8%. When LA solution was subcutaneously (s.c.) injected to rats, 50 μg/kg, the BA was 32.0 ± 2.1%. Relative BA of LA from dissolving microneedles against s.c. solution was 105.6 ± 13.5%. The degradation rate of LA in the rat skin tissue homogenate was very fast where the half-life was 16.3 ± 5.7 min. The degradation of LA in the skin tissue was the cause of the low BA of LA after percutaneous administration to rats.

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