Transdermal drug delivery systems (TDDS) have drawbacks such as poor absorption, low blood concentration, and delayed effects. Dissolving microneedle has sharp tips and short length, which overcome patients' pain and improve transdermal efficiency but has low mechanical strength and drug loading capacity. This study thereby proposes a microemulsion-encapsulated and long-time-released transdermal microneedle (MN) delivery system with estradiol (Es) as the model drug. The microemulsion (ME) was optimized by utilizing the pseudo-ternary phase diagram and D-optimal mixture design. The estradiol microemulsion-encapsulated microneedle (Es-ME-MN) was optimized by Box-Behnken design and prepared by freeze-thaw method. The Es-ME-MN obtained was characterized and evaluated through a large variety of studies. Es-ME-MN had sufficient mechanical strength to pierce skin and was safe enough, the length of which was 600 μm, and the Es content was 177.12 ± 0.72 μg/patch without drug-excipient chemical interaction. In vitro permeation study showed that Es-ME-MN has a higher transdermal efficiency and lower retention capacity than commercial estradiol patch and conventional MN. Es plasma concentration began to increase at 3 h and remained at 12.98-23.52 ng/mL until 72 h by pharmacokinetic experiments in the Es-ME-MN group. Es-ME-MN rapidly achieves effective blood concentrations through needle puncture and microemulsion delivery and maintains blood concentrations through the baseplate long-time release. Microemulsion-encapsulated, organic solvent-free, and long-time-released transdermal microneedle will make progress and provide a new idea for transdermal delivery of lipophilic drugs.
Keywords: Box–Behnken design; D-optimal mixture design; In vitro permeation; Long-time release; Microemulsion-encapsulated microneedle.
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