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Comparing confocal Raman spectroscopy and tape stripping concerning the demonstration of bioequivalence of topical formulations

Affiliation
University of Tuebingen, Department of Pharmaceutical Technology, Auf der Morgenstelle 8, 72076 Tuebingen, Germany
Gaiser, Annette;
Affiliation
University of Tuebingen, Department of Pharmaceutical Technology, Auf der Morgenstelle 8, 72076 Tuebingen, Germany
Lunter, Dominique Jasmin

According to the EMA the draft guideline on quality and equivalence of topical products and the guideline on the investigation of bioequivalence, bioequivalence in skin penetration research is defined as achieved if the 90 % confidence interval of the amount of drug that penetrates the skin from the generic product falls within 80 – 125 % of the amount that penetrates from the reference product. Currently, the most used technique for assessing the skin penetration in terms of bioequivalence of different formulations is tape stripping, which is destructive to the stratum corneum. The goal of our investigation was to show that confocal Raman spectroscopy (CRS), as a non-destructive technology, is a suitable alternative for establishing bioequivalence of topical drug products. Effekton, an on-the-market gel containing ketoprofen, was selected as the reference formulation. Bioequivalence was investigated by testing Effekton against itself. By diluting Effekton 1:2 with carbomer gel, a non-bioequivalent model formulation was produced and tested for validation purposes as required by the EMA.

Both formulations were applied to the skin and incubated for 3 hours to test during the invasion phase. A 785 nm-wavelength NIR laser was used to perform CRS measurements. The concentration of ketoprofen was measured up to 50 μm into the skin using a 3 sec accumulation time and a spectrum captured every μm. Afterwards, tape stripping was performed and the tapes, after peeling off, sonicated in methanol to extract ketoprofen. The ketoprofen content of the resulting solutions was then quantified by HPLC. Both methods were conducted on the same skin samples in order to demonstrate a direct association between tape stripping and CRS.

It was found that the two methods achieved the same relative ratios between the different formulations and thus a direct correlation was successfully demonstrated.

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