Nanostructured Lipid Carriers Enhances The Safety Profile of Tretinoin: In Vitro and Healthy Human Volunteers’ Studies

Abstract

Aim: To enhance the tretinoin (TRE) safety profile through the encapsulation in nanostructured lipid carriers (NLC). Materials & methods: NLC-TRE was developed using a 23 experimental factorial design, characterized (HPLC, dynamic light scattering, differential scanning calorimetry, x-ray diffraction analysis, transmission electron microscopy, cryo-transmission electron microscopy) and evaluated by in vitro studies and in healthy volunteers. Results: The NLC-TRE presented spherical structures, average particle size of 130 nm, zeta potential of 24 mV and encapsulation efficiency of 98%. The NLC-TRE protected TRE against oxidation (p < 0.0001) and promoted epidermal targeting (p < 0.0001) compared with the marketed product, both 0.05% TRE. The in vitro assay on reconstructed human epidermis and the measurement of transepidermal water loss in healthy volunteers demonstrated an enhanced safety profile in comparison to the marketed product (p < 0.0002). Conclusion: The NLC-TRE enhances the epidermal targeting and safety profile of TRE, representing a potential safer alternative for the topical treatment of skin disorders using TRE.

Stepwise Protocols for Preparation and Use of Porcine Ear Skin for in Vitro Skin Permeation Studies Using Franz Diffusion Cells

“…(2020) and Lima et al. (2021). In both studies, porcine ears skin and static 20‐mm Franz diffusion cells with a diffusion area of 3.14 cm 2 and receptor volume of 10 ml (PermeGear Inc. #4G‐01‐00‐20‐10, USA) were used.…”

“…In the fluconazole study (Ayub et al., 2007), it was possible to quantify the drug in the collected samples. However, for retinoids (Lima et al., 2021; Rodrigues et al., 2020), no drug was detected in the samples collected at different time intervals.…”

“…In our studies with fluconazole (Ayub et al., 2007), ∼10% and ∼5%‐11% of the applied dose was quantified in the epidermis and dermis, respectively, for the different emulsions evaluated. In studies with tretinoin (Lima et al., 2021), ∼0.6% and ∼20.5% of the applied dose was quantified in the epidermis and dermis, respectively; and in studies with adapalene (Rodrigues et al., 2020), ∼1.2% and ∼16.4% of the applied dose was quantified in the epidermis and dermis, respectively. The dose applied to each membrane is calculated by subtracting from the average dose (determined during dose standardization) the amount of formulation retained on the glass swab.…”

“…If, under normal conditions of use, the formulation remains on the skin for ∼8 hr, permeation should be evaluated for at least 8 hr. In our studies (Ayub et al., 2007; Lima et al., 2021; Rodrigues et al., 2020), drug permeation was evaluated for 8 hr, with sample collection from the receptor compartment performed at 2, 4, 6, and 8 hr. In the fluconazole study (Ayub et al., 2007), it was possible to quantify the drug in the collected samples.…”

“…After the excess emulsion is removed from the membrane surfaces using the solution described above, the membranes were carefully removed from the Franz cell supports and, using needles, were fixed (dermis faces downwards) on a corkboard covered with plastic film (see Basic Protocol 2) and then dried with a cotton swab. In studies with solid lipid nanoparticles (Rodrigues et al., 2020) and nanostructured lipid carriers (Lima et al., 2021), in each case dispersed in a hydrophilic hydroxyethyl cellulose gel, excess formulation was easily removed by gentle wiping with three successive cotton swabs soaked in PBS, pH 7.4, followed by drying with a dry cotton swab. In this process, the use of a light box and a magnifying glass facilitates the visualization of the complete removal of the formulation from the membrane surface.…”