Fabrication of nanosponges for topical delivery of retinoic acid for skin acne

Abstract

Acne is a skin disease that causes physical and psychosocial impact for those that are affected. It is perceived as a common condition among adolescents, yet the prevalence in adulthood remains high. All-trans retinoic acid (ATRA) has high efficacy against acne but is insoluble in water, unstable in the presence of light, heat and air; and may cause side effect on the skin such as dryness, peeling and pruritus. Nanosponge with its porous structure can entrap ATRA and maybe able to enhance the solubility and stability of ATRA, improving its delivery while reducing side effects. Hence the objective of this study is to formulate a stable, safe and effective ATRA loaded nanosponge gel-cream formulation for the treatment of acne. Nanosponge was prepared with β-cyclodextrin (BCD) as the polymer and carbonyldiimidazole (CDI) as the cross-linker. ATRA was loaded into the nanosponge with varying ratios where the solubilization and entrapment efficiency was assessed. The final loaded nanosponge was then characterized through particle size and zeta potential analysis, surface morphology assessment, Attenuated Total Reflectance Fourier Transform Infra-Red (ATR-FTIR) spectroscopy, and Differential Scanning Calorimetric (DSC) analysis. The loaded nanosponge was then incorporated into a gel-cream formulation. A stability study was conducted for 12 weeks where the organoleptic properties, pH, zeta potential, particle size, polydispersity index (PDI), ATRA content and microbial limit were tested. Franz diffusion cell study with rat skin and an animal model weekly skin assessment, irritation and histology study were also conducted. Formulation was applied once daily for 21 days. Weekly skin tests to assess the trans-epidermal water loss (TEWL), hydration and erythema was done with Dermalab Combo® equipment. Human study involving 15 participants were done with nanosponge and commercial formulation with weekly skin assessment similar to animal study. Formulations were applied separately on different arms at the volar area of the forearm for 4 weeks. The ATRA nanosponge showed desirable characteristics with particle size of below 300 nm, polydispersity index below 0.5 and zeta potential value of -26.17 mV. Encapsulation efficiency obtained was 73.90% which is optimal as it is above 60%. Both ATR-FTIR and DSC study confirmed inclusion of ATRA in the cyclodextrin. The gel-cream formulation which ATRA loaded nanosponge was incorporated into remained stable in both real-time and accelerated chamber with small particle size and PDI, highly negative zeta potential, acidic pH and no phase separation nor physical changes. Animal study results show that the commercial formulation group caused significant increase in trans-epidermal water loss (TEWL) and erythema which is parallel to the physical observation whereby skin became dry, flaky, and developed wounds. Nanosponge group did show a slight increase in TEWL overtime, but it was not significant. The observation with Draize skin score and histology study further proved the irritation caused by commercial formulation and the ability of nanosponge to reduce such reactions. The results for human study also showed signs of skin barrier dysfunction similar to the findings in animal study. Reports from participants validated the findings as more participants experienced side effects with commercial formulation. As a conclusion the fabrication of ATRA loaded nanosponge gel cream that is safe, stable and effective was successful.