Clinical Effectiveness of a Novel Caffeine Nano-Cream for Cellulite Reduction: A Randomised Double-Blind Trial

Background: Caffeine (CAF), whether extracted from plants or synthesised as a chemical compound, is considered the safest among other xanthine alkaloids. Novel nano-cream formulations have been successfully developed and evaluated to increase the potential of caffeine as a skin cosmeceutical, targeting the minimisation of cellulite appearance. Methods: Nano-cream formulations were prepared through a process of hot-temperature emulsification, in a variety of homogeniser combinations. Results: When chemical penetration enhancers (CPEs) (lanolin, transcutol, and propylene glycol), either alone or in combination, were incorporated into the nano-cream formulations, the permeation of CAF through skin increased. All nano-cream formulations achieved sustained delivery of CAF into and through the skin over 8 h (IVPT). Quantification of CAF from skin tissues was achieved using high-performance liquid chromatography (HPLC). The nano-cream formulation containing lanolin (LAN) showed the highest CAF permeation (8.829 ± 1.472 µg/cm²/h) through the skin compared to CAF in an aqueous solution (2.533 ± 0.480 µg/cm²/h) and a commercial CAF cellulite product with the same CAF concentration (2.827 ± 0.555 µg/cm²/h). Therefore, 2% CAF nano-cream formulation containing LAN was chosen for clinical testing. A double-blind, randomised, placebo-controlled paired trial was conducted, in which each volunteer applied active and placebo creams to the upper thighs twice daily for 12 weeks. The effect of the cream on skin appearance was monitored over 12 weeks. The primary outcome measures were reduced cellulite scores from 3.96 (95% CI: 3.16-4.76) to 2.50 (95% CI: 1.70-3.30) (active) compared with placebo from 3.88 (95% CI: 3.08-4.67) to 2.83 (95% CI: 2.03-3.63). The effect sizes (E.S.) indicated a moderate effect for the active CAF nano-cream formulation (E.S. = 0.475), while the placebo (E.S. = 0.286) had a small effect. Conclusion: We concluded that our optimised 2% CAF nano-cream formulation containing LAN offered an effective formulation strategy for enhancing skin penetration in the IVPT study. The LAN nano-cream formulation demonstrated efficacy and tolerability, both objectively and subjectively, in a human clinical trial.