Continuous manufacturing of a topical hydrogel with clobetasol propionate-loaded liposomes using QbD methodology.

An increasing number of published studies have highlighted the benefits of continuous manufacturing technologies for producing topical pharmaceuticals. In light of this, the present study aimed to investigate the development of a topical pharmaceutical hydrogel containing clobetasol propionate encapsulated liposomes using a continuous manufacturing system. By applying the Quality-by-Design (QbD) concept, the desired quality target profile of clobetasol propionate-loaded liposomes (CPLs) for topical use was initially determined, in which the drug entrapment concentration, encapsulation efficiency, particle size, and polydispersity index (PDI) were investigated as critical quality attributes (CQAs). Critical material attributes and process parameters were determined through cause and effect and failure modes effect analysis (FMEA) tools. The completion of a four-factor with three levels, D-optimal experimental design enabled the determination of a design space in which CPLs had particle size of 102.4 ± 0.4 nm, a PDI of 0.24 ± 0.01, a drug entrapment concentration of 3810 ± 6.9 μg/mL and an encapsulation efficiency of 80.1 ± 0.2 %, which were all within the specified target ranges. The optimum CPLs were used to continuously manufacture clobetasol propionate liposomal gels (CPLGs), produced at homogenisation speeds of 500, 1000 and 1500 rpm. CPLGs with a pH of 6.0 and incorporated CPLs with CQAs within the desired specifications were produced regardless of the varied mixing speeds. Additionally, compared to a commercial clobetasol propionate gel 0.05 %, rotational and oscillatory rheological measurements demonstrated that CPLGs had greater cohesiveness under deformation with higher viscosity and mechanical stability 'at rest' conditions, as well as higher resistance to structural breakage. Thus, this study demonstrates the successful development of topical CP-liposomal hydrogels and the feasibility of continuously processing nano-drug carriers into a semi-solid formulation using a flexible continuous mixing line. Importantly, these findings support a translational manufacturing pathway toward the fully continuous end-to-end manufacturing of nano-based semi-solids.