Development of alpha-arbutin and resveratrol-loaded dissolving microneedles for skin depigmentation

Abstract

In this study, polymeric dissolving microneedles (DMNs) were developed to enhance the transdermal delivery of skin depigmentation agents into the melanocytes where melanin is synthesized. Alpha-arbutin (AA) is a well-known skin depigmentation agent due to its tyrosinase inhibition activity, whereas resveratrol (Res) possesses potent antioxidant and melanin inhibition activities. However, poor permeability of AA and poor solubility with chemical instability of Res limit their use in skin applications. Therefore, AA- and/or Res-loaded DMNs were prepared with HPMC/PVP-K90, PAMA/PVA, Eudragit E100/PVP-K90, Eudragit RS100/PVP-K90, and Eudragit RL100/PVP-K90 to overcome these issues. The results revealed that AA and/or Res were successfully incorporated into DMNs, which were characterized and evaluated in vitro and in vivo. All needles of 8% AA-loaded DMNs, 5% Res-loaded DMNs, and 10% AA and 2% Res-loaded DMNs were dissolved entirely within 45 min, 30 min, and 15 min, respectively. In vitro skin permeation of 8% AA-loaded HPMC/PVP-K90 DMNs and PAMA/PVA DMNs showed delivery of AA approximately 8.5 and 4.5 times compared with their gel formulations, whereas 3.7 and 2.8 times in comparison to commercial AA cream (p<0.05). In the case of 5% Res-loaded Eudragit E/PVP-K90 DMNs and Eudragit RS/PVP-K90 DMNs, Res permeation significantly increased about 3.4 and 3.8 folds compared to their gel formulations (p<0.05). The percentage of melanin contents after treatment of AA (2000 µg/mL) or Res (20 µg/mL) was significantly decreased as compared with control group (p<0.01). The best synergistic effect on melanogenesis was obtained at the weight ratio of AA and Res at 5:1 which represented the lowest CI value (0.58). Therefore, it was selected for fabricating 10% AA and 2% Res-loaded Eudragit RL/PVP-K90 DMNs. The high cumulative amount of AA (1265.93 µg/cm2) and Res (45.24 µg/cm2) was delivered at 24 h following the application of 10% AA and 2% Res-loaded DMNs compared to 10% AA and 2% Res combination cream (85.69 µg/cm2 of AA delivered and 3.98 µg/cm2 of Res delivered). In vivo studies also indicated that AA- and/or Res-loaded DMNs provided more AA and/or Res into the mice's skin than commercial cream and combination cream. The mice's skin can reseal naturally without any damage after removing DMNs. Moreover, 10% AA and 2% Res-loaded DMNs remained highly stable in DMNs formulations at 25±2ºC, 60±5% RH for 6 months. In a clinical study, DMNs demonstrated the safety in human. Although using DMNs slightly decreased melanin index for skin depigmentation, there was no significant difference between before and after applied DMNs for 24 h. Accordingly, 10% AA and 2% Res-loaded DMNs were would be a promising platform for cosmetic applications.

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