Dermal and transdermal drug therapy is increasing in importance nowadays in drug development. To completely utilize the potential of this administration route, it is necessary to optimize the drug release and skin penetration measurements. This review covers the most well-known and up-to-date methods for evaluating the cutaneous penetration of drugs in vitro as a supporting tool for pharmaceutical research scientists in the early stage of drug development. The aim of this article is to present various experimental models used in dermal/transdermal research and summarize the novel knowledge about the main in vitro methods available to study skin penetration. These techniques are: Diffusion cell, skin-PAMPA, tape stripping, two-photon microscopy, confocal laser scanning microscopy, and confocal Raman microscopic method.

The aim of this research was to investigate the stability of a lidocaine-loaded nanostructured lipid carrier dispersion at different temperatures, formulate a nanostructured lipid carrier gel, and test the penetration profile of lidocaine from the nanostructured lipid carrier gel using different skin penetration modeling methods. The formulations were characterized by laser diffraction, rheological measurements and microscopic examinations. Various in vitro methods were used to study drug release, diffusion and penetration. Two types of vertical Franz diffusion cells with three different membranes, including cellulose, Strat-M®, and heat separated human epidermis were used and compared to the Skin-parallel artificial membrane permeability assay (PAMPA) method. Results indicated that the nanostructured lipid carrier dispersion had to be gelified as soon as possible for proper stability. Both the Skin-PAMPA model and Strat-M® membranes correlated favorably with heat separated human epidermis in this research, with the Strat-M® membranes sharing the most similar drug permeability profile to an ex vivo human skin model. Our experimental findings suggest that even when the best available in vitro experiment is selected for modeling human skin penetration to study nanostructured lipid carrier gel systems, relevant in vitro/in vivo correlation should be made to calculate the drug release/permeation in vivo. Future investigations in this field are still needed to demonstrate the influence of membranes and equipment from other classes on other drug candidates.

PurposePapaverine hydrochloride (PaHCl) is an old, well-known drug with spasmolytic activity but it has therapeutic effect in erectile dysfunction, too. As an intracavernous injection, it is not used in urologic clinics today because the side effects of the injection are pain, scarring or priapism. Our aim was to develop and test a topical semi-solid preparation containing PaHCl that would provide an alternative administration option by eliminating the undesirable side effects of the injection.Materials and methodsLyotropic liquid crystal (LLC) systems were formulated as a semi-solid preparation with different concentrations of PaHCl. The characterization of the LLC structure was performed by polarization microscopy using a Leica image analyzer and rheological measurements. The drug diffusion and penetration tests were performed with in vitro synthetic membrane and an ex vivo human epidermis, using Franz diffusion cell to test the skin penetration of PaHCl. Human skin was investigated by Raman microscope to visualize the Active Pharmaceutical Ingredient (API) in different skin layers.ResultsThe results of diffusion and penetration showed reverse concentration dependency. The in vitro and ex vivo studies correlated with each other and the results of Raman microscopy. The LLC structure influenced the penetration results, the lower viscosity and lamellar structure increased penetration through the skin.ConclusionBased on our results, a PaHCl containing topically used LLC formulation may be a suitable and effective alternative to the injectable formulation.

The human skin is marked as a standard by the regulatory agencies in the permeation study of dermal formulations. Artificial membranes can substitute human skin to some extent. Academicians and pharmaceutical corporations are focusing their efforts on developing standardized protocols and safe, reliable options to substitute human skin for carrying out permeability studies. Our research aim was to study the applicability of new techniques in the case of different types of dermal formulations. The skin parallel artificial membrane permeability assay (PAMPA) method and Raman mapping were compared to the gold-standard Franz cell method. A hydrogel and two types of creams were investigated as the most generally used dermal preparations. The values of the diffused drug were closer to each other in PAMPA and Franz cell measurement. The diffused amount of drug showed the same order for the different formulations. These results correlate well with the results of Raman mapping. Our conclusions suggest that all early screening examinations can be performed with model tools such as skin PAMPA supplemented with methods like Raman mapping as a semi-quantitative method.

In recent years, the study of dermal preparations has received increased attention. There are more and more modern approaches to evaluate transdermal formulations, which are crucial in proving the efficacy of a formulation. The aim of this study was to compare permeation across innovative synthetic membranes (Strat-M and Skin PAMPA membranes) and heat-separated human epidermis (HSE, gold standard membrane) using four different dermal formulations. The Strat-M and Skin PAMPA membranes were designed to mimic the stratum corneum layer of the human epidermis. There have also been some publications on their use in dermal formulation development, but further information is needed. Drug permeation was measured using formulations containing diclofenac sodium (two hydrogels and two creams). The HSE, Strat-M, and Skin PAMPA membranes proved to be significantly different, but based on the results, the Strat-M membrane showed the greatest similarity to HSE. The permeation data of the different formulations across different membranes showed good correlations with formulations similar to these four, which allows the prediction of permeation across HSE using these synthetic membranes. In addition, Strat-M and Skin PAMPA membranes have the potential to select and differentiate a dermal formulation containing diclofenac sodium as an early screening model.

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