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.
Highlights
Semisolids constitute a significant proportion of pharmaceutical dosage forms.Semisolids for cutaneous application may be distinguished according to the following categories: ointments, creams, gels, pastes, medicated plasters, or cutaneous patches.According to their structure, ointments, creams, and gels generally show viscoelastic behaviour and are non-Newtonian [1]
In 2018, the European Medicines Agency (EMA) released a draft guideline on the quality and equivalence of topical products, stating that the bioequivalence and pharmaceutical equivalence of the generic drug must be ensured during the drug development process, before reaching the stage of therapeutic equivalence studied in clinical trials
A whole path was followed along the guideline on quality and equivalence of topical products in which the first step was demonstrating the quality of the product and the equivalence
Summary
Semisolids constitute a significant proportion of pharmaceutical dosage forms.Semisolids for cutaneous application may be distinguished according to the following categories: ointments, creams, gels, pastes, medicated plasters, or cutaneous patches.According to their structure, ointments, creams, and gels generally show viscoelastic behaviour and are non-Newtonian [1]. Semisolids constitute a significant proportion of pharmaceutical dosage forms. Semisolids for cutaneous application may be distinguished according to the following categories: ointments, creams, gels, pastes, medicated plasters, or cutaneous patches. According to their structure, ointments, creams, and gels generally show viscoelastic behaviour and are non-Newtonian [1]. Among the different topical dosage forms available in the market, cream formulations continue to receive growing attention as profitable systems to deliver drugs and cosmetic agents into the skin [2]. Pharmaceutical equivalence of a reference-listed drug (RLD) and a generic product means that their active pharmaceutical ingredient(s) (API)(s), dosage form, route of administration, and strength are the same.
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