Complying with the Guideline for Quality and Equivalence for Topical Semisolid Products: The Case of Clotrimazole Cream

Abstract

Semisolids constitute a significant proportion of topical pharmaceutical dosage forms available on the market, with creams being considered profitable systems for releasing active substances into the skin. This work aimed at the development of a generic Clotrimazole topical cream, based on the assumptions that assist the development of such formulations. First, the critical parameters to obtain a final formulation as similar as possible to the reference product were defined. Then, the percentages of cetyl palmitate and octyldodecanol were identified as critical variables and chosen for optimization in further studies. A “quality by design” approach was then used to identify the effect of process variability on the structural and functional similarity (Q3) of the generic product qualitatively (Q1) and quantitatively (Q2). A two-factor central composite orthogonal design was applied and eleven different formulations were developed and subjected to physicochemical characterization and product performance studies. The results were used to estimate the influence of the two variables in the variation of the responses, and to determine the optimum point of the tested factors, using a design space approach. Finally, an optimized formulation was obtained and analysed in parallel with the reference. The obtained results agreed with the prediction of the chemometric analysis, validating the reliability of the developed multivariate models. The in vitro release and permeation results were similar for the reference and the generic formulations, supporting the importance of interplaying microstructure properties with product performance and stability. Lastly, based on quality targets and response constraints, optimal working conditions were successfully achieved.

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

“…There is a consensus that reconstructed epidermis models are more permeable to test substances than excised human skin due to its incomplete barrier function [ 27 ], and a prediction model should, in fact, be the next step for development [ 13 , 28 ]. Regardless of all efforts in the introduction of RhE models to permeation studies [ 13 , 27 , 29 , 30 ], there are no current conclusions regarding the use of these models in bioequivalence studies for IVPT with the intent to compare test formulations with comparator ones and to establish a degree of equivalence.…”

“…Therefore, this study aimed to investigate the suitability of RhE models as test systems for bioequivalence studies of topical formulations, according to the requirements of study design and method validation described on the Draft Guideline on Quality and Equivalence of Topical Products (CHMP/QWP/708282/2018) [ 3 ]. The clotrimazole 1% test and reference topical products were selected for this study due to limited extension of skin permeation of this lipophilic drug [ 29 ] and to high variability encountered in in vitro human skin permeation testing with clotrimazole products [ 30 , 31 , 32 , 33 ].…”