This study aimed to optimize, by means of an experimental design multivariate strategy, a liposomal formulation for topical delivery of the local anaesthetic agent benzocaine. The formulation variables for the vesicle lipid phase uses potassium glycyrrhizinate (KG) as an alternative to cholesterol and the addition of a cationic (stearylamine) or anionic (dicethylphosphate) surfactant (qualitative factors); the percents of ethanol and the total volume of the hydration phase (quantitative factors) were the variables for the hydrophilic phase. The combined influence of these factors on the considered responses (encapsulation efficiency (EE%) and percent drug permeated at 180 min (P%)) was evaluated by means of a D-optimal design strategy. Graphic analysis of the effects indicated that maximization of the selected responses requested opposite levels of the considered factors: For example, KG and stearylamine were better for increasing EE%, and cholesterol and dicethylphosphate for increasing P%. In the second step, the Doehlert design, applied for the response-surface study of the quantitative factors, pointed out a negative interaction between percent ethanol and volume of the hydration phase and allowed prediction of the best formulation for maximizing drug permeation rate. Experimental P% data of the optimized formulation were inside the confidence interval (P < 0.05) calculated around the predicted value of the response. This proved the suitability of the proposed approach for optimizing the composition of liposomal formulations and predicting the effects of formulation variables on the considered experimental response. Moreover, the optimized formulation enabled a significant improvement (P < 0.05) of the drug anaesthetic effect with respect to the starting reference liposomal formulation, thus demonstrating its actually better therapeutic effectiveness.

中文翻译：

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使用实验设计优化苯佐卡因脂质体的配方变量

本研究旨在通过实验设计多变量策略优化用于局部递送局部麻醉剂苯佐卡因的脂质体制剂。囊泡脂质相的配方变量使用甘草酸钾 (KG) 作为胆固醇的替代品，并添加阳离子（硬脂胺）或阴离子（磷酸二乙酯）表面活性剂（定性因素）；乙醇的百分比和水合相的总体积（定量因素）是亲水相的变量。这些因素对所考虑的反应（包封效率 (EE%) 和 180 分钟时药物渗透百分比 (P%)）的综合影响通过 D 最优设计策略进行评估。效果的图形分析表明，所选响应的最大化需要不同水平的考虑因素：例如，KG 和硬脂胺更适合增加 EE%，胆固醇和磷酸二乙酯更适合增加 P%。在第二步中，Doehlert 设计应用于定量因素的响应面研究，指出乙醇百分比与水合相体积之间的负相互作用，并允许预测最佳制剂以最大化药物渗透率。优化配方的实验 P% 数据位于围绕响应预测值计算的置信区间 (P < 0.05) 内。这证明了所提出的方法适用于优化脂质体制剂的组成和预测制剂变量对所考虑的实验响应的影响。此外，与起始参考脂质体制剂相比，优化的制剂能够显着提高药物麻醉效果（P < 0.05），从而证明其实际上具有更好的治疗效果。