Biphasic dissolving microneedles with cyclodextrin inclusion complexes for enhanced delivery of poorly soluble drugs

Abstract

Dissolving microneedles (DMNs) have been widely investigated for transdermal drug delivery, yet their clinical translation and commercialization remain limited, primarily due to insufficient drug-loading capacity. To address this challenge, we developed a high capacity platform by integrating hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion technology with a biphasic microneedle design for the delivery of flurbiprofen (FB), a model poorly soluble drug. Comprehensive characterization evaluated the morphology, mechanical strength, and ex vivo studies of FB/HP-β-CD DMNs, while in vivo pharmacokinetic studies in rats compared their performance with a commercial flurbiprofen gel patch under single- and multiple-dose regimens. The fabricated microneedles exhibited sufficient mechanical strength, with a single needle fracture force of 0.58 ± 0.10 N, adequate for reliable stratum corneum penetration. Each microneedle patch (100 needles) achieved a drug loading of 2.67 ± 0.11 mg, significantly higher than previously reported DMNs. Ex vivo permeation studies using a Franz diffusion cell setup using rat skin and phosphate-buffered saline (PBS, pH 7.4) as the receptor medium at 37 °C showed that more than 95% of the drug was released within 24 hours. In vivo single-dose studies demonstrated that the DMNs achieved a Tmax of 2 h, compared to 8 h for the commercial gel patch, and a Cmax of 124.4 ± 11.4 µg mL−1, resulting in a 2.6-fold increase in bioavailability (AUC0→24h of 1247.6 ± 240.7 µg h mL−1 for DMNs versus 485.0 ± 63.0 µg h mL−1 for the commercial gel patch). Multiple-dose studies confirmed flexible modulation of the pharmacokinetic profile by adjusting dosing frequency. In conclusion, the FB/HP-β-CD inclusion biphasic DMN system offers an effective approach for transdermal delivery of poorly soluble drugs.