Publicação
Development of Generic Topical Corticosteroid Formulation using the Quality by Design Approach
| Resumo: | Semi-solids are the most frequently used topical pharmaceutical dosage forms. Among the diverse formulations, creams continue to be the most extensively researched and developed as viable systems for delivering drugs to the skin. The primary goals of this study were the pharmaceutical development and characterization of a generic topical formulation containing betamethasone dipropionate (0.064 wt.%), with qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance (Q4) equivalence with Diprosone cream, the reference-listed drug. To meet the quality objectives of the generic product, the Quality by Design (QbD) approach was implemented. The critical material and process parameters are directly related to the critical quality attributes of the product. By developing a comprehensive understanding of both the product and the process, it is possible to significantly reduce the inherent variability, thereby improving quality, reducing risk and enhancing productivity. Following a risk assessment of the main factors that affect the critical quality attributes of the cream, a central composite design (CCD) was implemented with 17 experimental runs with triplicate centre points, to assess the influence of the emulsifier, emollient A and emollient B on the quality of the final product. The Design of Experiments (DoE) formulations were characterized in terms of physicochemical properties (droplet size, pH and rheology) and product performance (drug release) regarding the reference batches. The experimental data were analysed using Design-Expert v13 software, which assessed the influence of the factors on the responses and generated three-dimensional response surface plots for all the interactions. Four optimal formulations were achieved using the Response Surface Methodology (RSM) approach to determine the content of the independent variables (liquid paraffin, petrolatum and cetomacrogol 1000) and equally analysed against the reference product batches. The In Vitro Release Test (IVRT) revealed a similarity factor of 92.4 between the drug release profiles of the reference formulation (RF) and formulation FIII (liquid paraffin (5.0 wt.%), petrolatum (19.81 wt.%), and cetomacrogol 1000 (1.0 wt.%)), resulting in a bioequivalent formulation. Moreover, formulation FIII demonstrated an apparent viscosity of 11.4 Pa.s (at 2.3 s⁻¹), a hysteresis area of 14068 Pa/s, a droplet size of 30.09 μm, and exhibited solid-like behaviour (G’ > G’’). A generic formulation with equivalent properties to the reference formulation (RF), based on betamethasone dipropionate, was successfully obtained according to the rheological and stability evaluation. Additionally, the formulation demonstrated bioequivalence in in vitro studies. |
|---|---|
| Autores principais: | Saloio, Marisa |
| Assunto: | Semi-solid cream formulation generic product Quality by Design bioequivalent |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Semi-solids are the most frequently used topical pharmaceutical dosage forms. Among the diverse formulations, creams continue to be the most extensively researched and developed as viable systems for delivering drugs to the skin. The primary goals of this study were the pharmaceutical development and characterization of a generic topical formulation containing betamethasone dipropionate (0.064 wt.%), with qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance (Q4) equivalence with Diprosone cream, the reference-listed drug. To meet the quality objectives of the generic product, the Quality by Design (QbD) approach was implemented. The critical material and process parameters are directly related to the critical quality attributes of the product. By developing a comprehensive understanding of both the product and the process, it is possible to significantly reduce the inherent variability, thereby improving quality, reducing risk and enhancing productivity. Following a risk assessment of the main factors that affect the critical quality attributes of the cream, a central composite design (CCD) was implemented with 17 experimental runs with triplicate centre points, to assess the influence of the emulsifier, emollient A and emollient B on the quality of the final product. The Design of Experiments (DoE) formulations were characterized in terms of physicochemical properties (droplet size, pH and rheology) and product performance (drug release) regarding the reference batches. The experimental data were analysed using Design-Expert v13 software, which assessed the influence of the factors on the responses and generated three-dimensional response surface plots for all the interactions. Four optimal formulations were achieved using the Response Surface Methodology (RSM) approach to determine the content of the independent variables (liquid paraffin, petrolatum and cetomacrogol 1000) and equally analysed against the reference product batches. The In Vitro Release Test (IVRT) revealed a similarity factor of 92.4 between the drug release profiles of the reference formulation (RF) and formulation FIII (liquid paraffin (5.0 wt.%), petrolatum (19.81 wt.%), and cetomacrogol 1000 (1.0 wt.%)), resulting in a bioequivalent formulation. Moreover, formulation FIII demonstrated an apparent viscosity of 11.4 Pa.s (at 2.3 s⁻¹), a hysteresis area of 14068 Pa/s, a droplet size of 30.09 μm, and exhibited solid-like behaviour (G’ > G’’). A generic formulation with equivalent properties to the reference formulation (RF), based on betamethasone dipropionate, was successfully obtained according to the rheological and stability evaluation. Additionally, the formulation demonstrated bioequivalence in in vitro studies. |
|---|