Supervisors info:
Παρασκευάς Δάλλας, Επίκουρος Καθηγητής, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
Transdermal drug delivery systems offer clear pharmacological advantages over conditional routes of administration. A crucial step in pharmaceutical drug development is the preclinical safety testing of new drug candidates, which include risk assessment of chemicals and the therapeutic assessment of topical drug delivery systems, and range from in vivo systems to simple in vitro methods. The establishment of an in vitro-in vivo correlation that is able to reliably and accurately predict the in vivo bioavailability through the in vitro release of drug is critical in determining the pharmacological, pharmacokinetic and toxicological effect of the drug and ensuring product quality. Indeed, in cases where there is a clear correlation between in vitro and in vivo data, the in vitro experiments may replace the in vivo tests in bioequivalence studies.
The in vitro methods, as a part of a hierarchical strategy of trials, are commonly used prior to in vivo human or animal studies. The diffusion cells are considered as the most valid in vitro model for the assessment of percutaneous absorption, and usually, isolated human skin is the membrane of choice in in vitro permeation experiments. However, human cadaver skin presents a number of drawbacks, such as limited availability, high cost, storage limitations and high variability results. Therefore, the discovery of a commercial synthetic membrane that mimics human skin has become increasingly important in the evaluation of local or transdermal drug penetration behavior.
The focus of this study was the evaluation of the artificial Strat-M membrane (Merck Milipore, USA) as an alternative to human skin in in vitro diffusion studies of commercial transdermal therapeutic systems of nitroglycerin and nicotine, as well as an establishment of in vitro–in vivo correlation. In this context, permeation experiments were conducted in modified Franz cells using Strat-MTM membrane and human stratum corneum as barrier. The latter was obtained from whole skin by the heat-separation technique. The experimental data showed that there is a linear correlation, with satisfying correlation coefficient R2, between the permeation results of Strat-MTM membrane and human skin. However, a significant higher flux was achieved using the Strat-MTM, compared to the excised skin, and the in vitro transdermal permeation of both nicotine and nitroglycerin was overestimated. With
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regard to the establishment of the in vitro-in vivo correlation, the in vitro permeation results were associated with the in vivo absorption profiles, after transdermal application, obtained using the deconvolution method. The in vitro skin and Strat-MTM permeation results had a linear correlation, with satisfying correlation coefficients R2, with the in vivo data, and hence, it may be possible to assess the in vivo absorption of drugs through the in vitro permeation experiments with the use of human skin and the synthetic membrane Strat-MTM, as well as establishing the in vitro-in vivo correlation in bioequivalence studies.
Keywords:
Transdermal administration, Nicotine, Nitroglycerin, in vitro permeation, human stratum corneum, Strat-MTM membrane, in vitro-in vivo correlation
