TESTING
Skin penetration: next generation in vitro testing
Dr Massimo Alberti - Revivo BioSystems
Percutaneous absorption of molecules is a critical step in the design and development of novel formulations in skincare and pharmaceutical research. Skin permeation can be conducted in vitro for evaluating topical formulations and dermal or transdermal drug delivery systems, to verify the bioavailability of active ingredients and estimate their effectiveness. In vitro skin absorption and dermal
penetration tests use human skin explants (ex vivo models), advanced cell-based equivalents reconstructed in specialized laboratories (in vitro models) or synthetic membranes. The traditional technology for these studies is the diffusion cell: in it, a skin tissue or simulant is placed in between an acceptor chamber - in which the test sample is applied -, and a receptor chamber, where the compound of interest diffuses to after penetrating the membrane/skin. Diffusion cells are also widely used for in
vitro release testing (IVRT) for quality control and benchmarking purposes. Different types of diffusion cells are available, such as vertical diffusion cells, jacketed diffusion cells, side-by- side cells and flow-through cells. In vitro skin absorption and penetration is used in skincare research and for transdermal delivery studies of topical cosmetic and pharmaceutical formulations. It provides information on absorption of a test substance applied to the surface of a skin sample. Infinite or finite doses can be used to better understand the transport properties of such substance and to mimic human exposure, respectively. The penetration of a molecule during a given
A
period (e.g. 24 hours) is measured by analyzing the receptor fluid at different time points. OECD 428 provides a validated guideline for in vitro skin absorption. Excised human or animal skin tissues are the ideal models for these studies. However, when native skin is not readily available, skin substitutes like reconstructed skin equivalents and synthetic membranes can be employed. In Vitro Release Testing (IVRT) is a test
required by FDA to comply with SUPAC-SS requirements for supporting post-approval manufacturing changes (quality and performances evaluation) of topical semisolid formulations.
B This technique can also be used to
compare brand products during topical generic drug development and during research and development stages of topical drugs, as a screening tool for prototype formulations. For IVRT, synthetic membranes are normally employed in a diffusion cell setup.
Diffusion cells A diffusion cell may be either a static or a flow-through set up. Jacketed vertical Franz Diffusion cells (FDCs), developed by T.J. Franz in 1975, have since then been considered the gold standard. A jacketed vertical FDC consists of two primary chambers, usually made of glass: a top chamber (donor compartment) and a lower chamber (receptor compartment) with a heating jacket. Excised skin tissues or skin substitutes are sandwiched between the donor and the receptor chambers (Figure 1a). The receptor compartment is filled with a receiving vehicle – such as Phosphate Buffered Saline or an organic solvent depending on the water solubility of the molecule of interest - while the test sample is applied topically to the skin tissue via the donor compartment. If the molecule of interest penetrates the
200mm = 3 Franz cells
Figure 1: Franz Diffusion Cell Apparatus vs REVex chip. An example of a diffusion cells apparatus with three franz diffusion cells (a) and of a three-chamber microfluidic diffusion device (b).
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skin and reaches the receptor chamber, it dissolves in the receiver vehicle. The receptor solution is continuously agitated with magnetic stirrers so that sink conditions can be maintained. In the receptor compartment, a sampling
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