Srishti Sanjida Ahmed, Pinky Paromita Paul, Taylor Ryan, Guess Jacob, Karlik Natasha, Janjic Jelena M
School of Pharmacy, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
Pharmaceutics. 2024 Nov 21;16(12):1487. doi: 10.3390/pharmaceutics16121487.
Skin inflammation represents a hallmark of many skin conditions, from psoriasis to eczema. Here, we present a novel microemulsion formulation for delivering a low dose of potent immunosuppressant, tacrolimus, to the skin for local inflammation control. The efficacy of topically delivered tacrolimus in controlling skin inflammation can be enhanced by packaging it into microemulsions. Microemulsions are small-size, thermodynamically stable, and surfactant-rich emulsions that can enhance tissue penetration and local tissue retention of poorly soluble drugs, which can reduce dosing frequency and potentially improve patient compliance. We present a novel approach for microemulsion manufacturing that uses a combination of both low and high-energy methods. The microemulsion composition and manufacturing parameters were optimized by adopting Quality by Design methodologies. The FMECA (Failure, Mode, Effects, Criticality Analysis)-based risk assessment, D-optimal Design of Experiment (DoE), and statistical analysis of parameters impacting responses through the multiple linear regression (MLR) was implemented for identifying critical formulation and process parameters. Through QbD strategy, a stable microemulsion with optimized drug loading that met all critical quality attributes (CQAs) was identified. The optimal microemulsion candidate was successfully scaled up three-fold with retained CQAs. The presented microemulsion showed a slow and extended drug release profile in vitro. Presented findings suggest that microemulsions are a promising novel approach for tacrolimus delivery to the skin. Further, we also demonstrated that a combination of low-energy emulsification and microfluidization processes can produce stable and robust microemulsions with small droplet size that can be implemented in drug delivery of poorly soluble anti-inflammatory drugs. To the best of our knowledge, this is the first report of QbD-driven optimization of microemulsion manufacturing by microfluidization.
皮肤炎症是许多皮肤疾病的一个标志，从银屑病到湿疹皆是如此。在此，我们展示了一种新型微乳制剂，用于将低剂量的强效免疫抑制剂他克莫司递送至皮肤，以控制局部炎症。将他克莫司局部给药用于控制皮肤炎症的疗效可通过将其包装入微乳中来提高。微乳是小尺寸、热力学稳定且富含表面活性剂的乳剂，可增强难溶性药物的组织渗透和局部组织滞留，这可减少给药频率并潜在地提高患者依从性。我们提出了一种新型的微乳制备方法，该方法结合了低能和高能方法。通过采用质量源于设计方法对微乳组成和制备参数进行了优化。实施了基于FMECA（失效模式、影响、关键性分析）的风险评估、D-最优实验设计（DoE）以及通过多元线性回归（MLR）对影响响应的参数进行统计分析，以确定关键的制剂和工艺参数。通过质量源于设计策略，确定了一种具有优化载药量且满足所有关键质量属性（CQAs）的稳定微乳。最佳微乳候选物成功放大了三倍，同时保留了关键质量属性。所展示的微乳在体外呈现出缓慢且持续的药物释放曲线。所呈现的研究结果表明，微乳是一种有前景的将他克莫司递送至皮肤的新方法。此外，我们还证明，低能乳化和微流化工艺相结合可产生具有小液滴尺寸的稳定且耐用的微乳，可用于难溶性抗炎药物的药物递送。据我们所知，这是第一篇关于通过微流化进行质量源于设计驱动的微乳制备优化的报告。
