Transdermal codelivery system of resveratrol nanocrystals and fluorouracil@ HP-13-CD by dissolving microneedles for cutaneous melanoma treatment

Cutaneous melanoma is a serious malignant tumor. In recent years, the morbidity and mortality rate of this disease have been continuously and rapidly increasing. Codelivery of natural product resveratrol (RES) and chemical synthetic drug fluorouracil (Fu) is beneficial to achieve reduced toxicity and increased efficacy effects for melanoma therapeutic. However, the poor solubility and bioavailability of the two drugs resulted in deficient effective and systemic toxicity due to high dose administration. Furthermore, these shortcomings also lead to drug resistance and unsatisfactory patient compliance. In this study, a codelivery dissolvable microneedle (DMN) patch was designed by carrying RES nanocrystals and Fu@hydroxypropyl-beta-cyclodextrin (HP-13-CD) for a synergistic effect. The RES nanocrystals exhibited satisfied solubility and dissolution properties in vitro, and the Fu inclusion compound with HP-13-CD resulted in satisfactory drug loading. Laser confocal fluorescence microscopy demonstrated uniform distribution of both drugs in the DMN. Mechanical tests and in vitro and in vivo puncture tests of the DMN exhibited great mechanical and insertion properties. The DMN in the Franz diffusion cell test released 84.13 +/- 5.19 % of the RES and 90.65 +/- 18.23 % of the Fu at 12 h. Additionally, for in vivo release, the DMN released 81.24 +/- 5.23 % of the RES and 72.48 +/- 7.82 % of the Fu. All excipients of the DMN presented high biosafety. In conclusion, codelivery of RES nanocrystals and Fu@HP-13-CD by the DMN presented an excellent pharmaceutical and biological properties and satisfied potential clinical application prospects for cutaneous melanoma treatment.