Development of a nanogel formulation for transdermal delivery of tenoxicam: a pharmacokinetic-pharmacodynamic modeling approach for quantitative prediction of skin absorption
Development of a nanogel formulation for transdermal delivery of tenoxicam: a pharmacokinetic-pharmacodynamic modeling approach for quantitative prediction of skin absorption
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DOI：
10.1080/03639045.2016.1268153
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发表时间：
2017-01-01
影响因子：
3.4
通讯作者：
Ali, Ahmed M. A.
中科院分区：
文献类型：
--
作者：
Elkomy, Mohammed H.;El Menshawe, Shahira F.;Ali, Ahmed M. A.
本研究探讨了固体脂质纳米颗粒（SLN）凝胶经皮给药替诺昔康（TNX）的潜力，并描述了一种用于预测皮肤浓度-时间分布的药代动力学-药效学（PK-PD）建模方法。采用23因子设计研究配方因素对SLN性能的影响，确定最佳配方。采用家兔皮肤刺激试验研究了sln -凝胶的耐受性。采用角叉菜胶诱导大鼠足跖水肿试验评价其抗炎活性。已发表的体外抑制COX-2酶的Hill模型与水肿抑制数据相拟合。皮肤中的浓度用线性样条函数表示，系数用非线性回归估计。使用蒙特卡罗模拟评估了预测浓度的不确定性。优化后的SLN为球形囊泡（58.1 +/- 3.1 nm），包封效率为69.6 +/- 2.6%。sln -凝胶制剂耐受性良好。使TNX活性和皮肤水平分别提高40 +/- 13.5%和227 +/- 116%。模型预测的平均Cmax和AUC（0-24）分别比体外渗透性数据计算的相应值高2倍和3.6倍。sln -凝胶是一种安全有效的TNX跨皮肤载体，用于炎症性疾病的治疗。从PD活性数据中间接定量皮肤沉积，PK-PD模型是一种很有前途的方法。
This study investigates potentials of solid lipid nanoparticles (SLN)-based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach for predicting concentration-time profile in skin. A 23 factorial design was adopted to study the effect of formulation factors on SLN properties and determine the optimal formulation. SLN-gel tolerability was investigated using rabbit skin irritation test. Its anti-inflammatory activity was assessed by carrageenan-induced rat paw edema test. A published Hill model for in vitro inhibition of COX-2 enzyme was fitted to edema inhibition data. Concentration in skin was represented as a linear spline function and coefficients were estimated using non-linear regression. Uncertainty in predicted concentrations was assessed using Monte Carlo simulations. The optimized SLN was spherical vesicles (58.1 +/- 3.1 nm) with adequate entrapment efficiency (69.6 +/- 2.6%). The SLN-gel formulation was well-tolerated. It increased TNX activity and skin level by 40 +/- 13.5, and 227 +/- 116%, respectively. Average Cmax and AUC(0-24) predicted by the model were 2- and 3.6-folds higher than the corresponding values computed using in vitro permeability data. SLN-gel is a safe and efficient carrier for TNX across skin in the treatment of inflammatory disorders. PK-PD modeling is a promising approach for indirect quantitation of skin deposition from PD activity data.