Digkas Tryfon, Tefas Lucia Ruxandra, Porfire Alina Silvia, Tomuta Ioan, Beer Thomas De
Laboratory of Pharmaceutical Process Analytical Technology (LPPAT), Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, "Iuliu Hatieganu" University of Medicine and Pharmacy, 41 Victor Babes Street, 400012 Cluj-Napoca, Romania.
Int J Pharm. 2025 Sep 15;682:125964. doi: 10.1016/j.ijpharm.2025.125964. Epub 2025 Jul 15.
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.
越来越多已发表的研究强调了连续制造技术在生产局部用药物方面的优势。有鉴于此，本研究旨在探讨使用连续制造系统开发一种含有丙酸氯倍他索包封脂质体的局部用药物水凝胶。通过应用质量源于设计（QbD）理念，最初确定了用于局部使用的载丙酸氯倍他索脂质体（CPLs）的期望质量目标概况，其中研究了药物包封浓度、包封效率、粒径和多分散指数（PDI）作为关键质量属性（CQAs）。通过因果分析和失效模式效应分析（FMEA）工具确定了关键物料属性和工艺参数。完成了一个三水平四因素的D - 最优实验设计，从而确定了一个设计空间，在此空间中CPLs的粒径为102.4 ± 0.4 nm，PDI为0.24 ± 0.01，药物包封浓度为3810 ± 6.9 μg/mL，包封效率为80.1 ± 0.2%，所有这些均在规定的目标范围内。使用最佳的CPLs以500、1000和1500 rpm的均质速度连续制造丙酸氯倍他索脂质体凝胶（CPLGs）。无论混合速度如何变化均生产出pH为6.0且包含符合期望规格CQAs的CPLs的CPLGs。此外，与市售的0.05%丙酸氯倍他索凝胶相比，旋转和振荡流变学测量表明，CPLGs在变形时具有更高的内聚性，在“静止”条件下具有更高的粘度和机械稳定性，以及更高的抗结构破坏能力。因此，本研究证明了局部用CP - 脂质体水凝胶的成功开发以及使用灵活的连续混合生产线将纳米药物载体连续加工成半固体制剂的可行性。重要的是，这些发现支持了一条向基于纳米的半固体全连续端到端制造的转化制造途径。
