Reconstructed Human Epidermis: An Alternative Approach for In Vitro Bioequivalence Testing of Topical Products

Abstract

The use of in vitro human skin permeation tests is of value when addressing the quality and equivalence of topical drug products in Europe and the US. Human skin is the membrane of choice for these studies. The use of human skin as a membrane is hindered by limited access, high variability of results, and limited applicability for drugs with low skin permeability. Reconstructed human epidermis (RhE) models are validated as skin surrogates for safety tests and have been explored for percutaneous absorption testing. Clotrimazole poorly permeates human skin and is widely available for topical treatments. In this study, clotrimazole creams were used to test the ability of RhE to be used as biological membrane for bioequivalence testing, based on the Draft Guideline on Quality and Equivalence of Topical Products (CHMP/QWP/708282/2018) using a discriminative and modified in vitro permeation test (IVPT). To fulfill the validation of a discriminatory method, Canesten® 10 mg/g cream was compared with a test product with the same drug strength, along with two “negative controls” dosed at a 50% and 200% drug strength. Products were compared in finite dose conditions, regarding maximal flux (Jmax) and the total amount of drug permeated (Atotal). The results showed the discriminatory power of the method among the three drug strengths with no interference of the placebo formulation. The study design and validation complied with the requirements established in the guideline for a valid IVPT. This new test system allowed for the equivalence comparison between test and comparator product. Higher permeability of the RhE compared to human skin could be observed. This arose as a strength of the model for this modified IVPT bioequivalence testing, since comparing permeation profiles among products is envisaged instead of drawing absolute conclusions on skin permeation extent. These results may support the acceptance of RhE as biological membranes for modified IVPT in bioequivalence testing of topical products.

A versatile, bioengineered skin reconstruction device designed for use in austere environments

“…The results of this study show that our custom MN arrays can fully and efficiently penetrate the tough epidermis and even break though the underlying polycarbonate membrane of the cell culture inserts used in the in vitro epidermis model. Although this study utilized in vitro epidermis models commonly used for preliminary drug permeation and skin barrier assessments ( Agonia et al, 2022 ) and SF MN have been previously shown to be effective in animal models ( Tsioris et al, 2012 ; Stinson et al, 2017 ), future in vivo or skin explant studies are required to confirm efficacy of this device’s MN array. We also show that the MN array with adhesive coating more than doubles drug delivery across the epidermis relative to the scaffold alone.…”

Exploring the efficacy of AHA–BHA infused nanofiber skin masks as a topical treatment for acne vulgaris

“…Several alternative testing methods have been developed as substitutes for animal skin research 9 . These include living skin equivalents, such as reconstructed human epidermis (RHE), 10 reconstructed full‐thickness (FT) human skin, 11 and skin organ culture (SOC) models 12 . These alternative models offer a way to comply with animal testing bans while expanding our understanding of skin biology 13 .…”