Jin Xuping, Alavi Seyed Ebrahim, Shafiee Abbas, Leite-Silva Vania Rodrigues, Khosrotehrani Kiarash, Mohammed Yousuf
Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia.
School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia.
Pharmaceutics. 2023 Jun 11;15(6):1707. doi: 10.3390/pharmaceutics15061707.
When developing topical semisolid products, it is crucial to consider the metamorphosis of the formulation under the "in use" condition. Numerous critical quality characteristics, including rheological properties, thermodynamic activity, particle size, globule size, and the rate/extent of drug release/permeation, can be altered during this process. This study aimed to use lidocaine as a model drug to establish a connection between the evaporation and change of rheological properties and the permeation of active pharmaceutical ingredients (APIs) in topical semisolid products under the "in use" condition. The evaporation rate of the lidocaine cream formulation was calculated by measuring the weight loss and heat flow of the sample using DSC/TGA. Changes in rheological properties due to metamorphosis were assessed and predicted using the Carreau-Yasuda model. The impact of solvent evaporation on a drug's permeability was studied by in vitro permeation testing (IVPT) using occluded and unconcluded cells. Overall, it was found that the viscosity and elastic modulus of prepared lidocaine cream gradually increased with the time of evaporation as a result of the aggregation of carbopol micelles and the crystallization of API after application. Compared to occluded cells, the permeability of lidocaine for formulation F1 (2.5% lidocaine) in unoccluded cells decreased by 32.4%. This was believed to be the result of increasing viscosity and crystallization of lidocaine instead of depletion of API from the applied dose, which was confirmed by formulation F2 with a higher content of API (5% lidocaine) showing a similar pattern, i.e., a 49.7% reduction of permeability after 4 h of study. To the best of our knowledge, this is the first study to simultaneously demonstrate the rheological change of a topical semisolid formulation during volatile solvent evaporation, resulting in a concurrent decrease in the permeability of API, which provides mathematical modelers with the necessary background to build complex models that incorporate evaporation, viscosity, and drug permeation in the simulation once at a time.
在开发局部用半固体制剂时，考虑制剂在“使用中”条件下的变化至关重要。在此过程中，许多关键质量特性，包括流变学性质、热力学活性、粒径、液滴大小以及药物释放/渗透的速率/程度，都可能发生改变。本研究旨在以利多卡因为模型药物，建立在“使用中”条件下局部用半固体制剂中溶剂蒸发、流变学性质变化与活性药物成分（API）渗透之间的联系。通过使用差示扫描量热法/热重分析法（DSC/TGA）测量样品的重量损失和热流来计算利多卡因乳膏制剂的蒸发速率。使用Carreau-Yasuda模型评估和预测因变化导致的流变学性质变化。通过使用封闭和未封闭细胞的体外渗透试验（IVPT）研究溶剂蒸发对药物渗透性的影响。总体而言，发现制备的利多卡因乳膏的粘度和弹性模量随着蒸发时间的增加而逐渐增加，这是由于卡波姆胶束聚集和涂抹后API结晶所致。与封闭细胞相比，制剂F1（2.5%利多卡因）在未封闭细胞中的利多卡因渗透性降低了32.4%。据信这是利多卡因粘度增加和结晶的结果，而非给药剂量中API的消耗，这一点通过具有更高API含量（5%利多卡因）的制剂F2显示出类似模式得到证实，即在研究4小时后渗透性降低49.7%。据我们所知，这是第一项同时证明局部用半固体制剂在挥发性溶剂蒸发过程中流变学变化导致API渗透性同时降低的研究，这为数学建模人员提供了必要的背景，以便构建一次纳入蒸发、粘度和药物渗透的复杂模拟模型。
