Almuqbil Rashed M, Sreeharsha Nagaraja, Nair Anroop B
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia.
Department of Pharmaceutics, Vidya Siri College of Pharmacy, Off Sarjapura Road, Bangalore 560035, India.
Pharmaceutics. 2022 Jul 6;14(7):1419. doi: 10.3390/pharmaceutics14071419.
As regulatory and technical landscapes for pharmaceutical formulation development are rapidly evolving, a risk-management approach using multivariate analysis is highly essential for designing a product with requisite critical quality attributes (CQA). Efinaconazole, a newly approved poorly water-soluble antifungal triazole drug has poor permeability. Spanlastics, new-generation surfactant nanovesicles, being fluidic, help improve the permeability of drugs. Therefore, we optimized efinaconazole spanlastics using the concepts of Formulation-by-Design (FbD) and explored the feasibility of transungual delivery for the management of onychomycosis. Using the Ishikawa fishbone diagram, the risk factors that may have an impact on the CQA of efinaconazole spanlastic vesicles were identified. Application of the Plackett-Burman experimental design facilitated the screening of eight different formulation and process parameters influencing particle size, transmittance, relative deformability, zeta potential, entrapment efficiency, and dissolution efficiency. With the help of Pareto charts, the three most significant factors were identified, viz., vesicle builder (Span), edge activator (Tween), and mixing time. The levels of these three critical variables were optimized by FbD to reduce the particle size and maximize the transparency, relative deformability, encapsulation efficiency, and dissolution efficiency of efinaconazole spanlastic nanovesicles. Bayesian and Lenth's analysis and mathematical modeling of the experimental data helped to quantify the critical formulation attributes required for getting the formulation with optimum quality features. The optimized efinaconazole-loaded spanlastic vesicles had a particle size of 197 nm, transparency of 91%, relative deformability of 12.5 min, and dissolution efficiency of 81.23%. The spanlastic formulation was incorporated into a gel and explored ex vivo for transungual delivery. This explorative study provides an example of the application of principles of risk management, statistical multivariate analysis, and the FbD approach in developing efinaconazole spanlastic nanovesicles.
随着药物制剂开发的监管和技术环境迅速演变，采用多变量分析的风险管理方法对于设计具有必要关键质量属性（CQA）的产品至关重要。艾氟康唑是一种新批准的水溶性差的抗真菌三唑类药物，其渗透性较差。新一代表面活性剂纳米囊泡Spanlastics具有流动性，有助于提高药物的渗透性。因此，我们运用设计理念（FbD）优化了艾氟康唑Spanlastics，并探讨了经皮给药治疗甲癣的可行性。使用石川鱼骨图，确定了可能影响艾氟康唑Spanlastics囊泡CQA的风险因素。Plackett-Burman实验设计的应用有助于筛选影响粒径、透光率、相对变形性、zeta电位、包封率和溶解效率的八个不同的制剂和工艺参数。借助帕累托图，确定了三个最显著的因素，即囊泡形成剂（Span）、边缘活化剂（吐温）和混合时间。通过FbD优化这三个关键变量的水平，以减小粒径并最大化艾氟康唑Spanlastics纳米囊泡的透明度、相对变形性、包封效率和溶解效率。对实验数据的贝叶斯分析和Lenth分析以及数学建模有助于量化获得具有最佳质量特征的制剂所需的关键制剂属性。优化后的载艾氟康唑Spanlastics囊泡的粒径为197nm，透明度为91%，相对变形性为12.5分钟，溶解效率为81.23%。将Spanlastics制剂制成凝胶，并进行了经皮给药的体外研究。这项探索性研究提供了一个在开发艾氟康唑Spanlastics纳米囊泡中应用风险管理原则、统计多变量分析和FbD方法的实例。
