Tiered Testing Strategy for Assessing Thermal Effects on Transdermal Products

许多透皮系统受温度的影响，并标有防热警告 应用程序.例如，热可以增加皮肤渗透性。热可影响药物在制剂中的溶解度 和药物（和赋形剂）从透皮系统中释放。热也可以增加皮肤清除率， 通过血管网络的全身药物吸收。不同透皮贴剂的热效应可能不同 运载系统。在FDA的审查过程中，当参考产品的标签上有防热警告时， 在临床应用中，仿制药对热的敏感性不得高于参比药。不同热 透皮产品之间的效果可能是由于不同的药物释放（和制剂释放） 产品.此外，由于在加热下释放的不同制剂，这些制剂可以发挥不同的作用。 对皮肤渗透性的影响。不同的制剂释放和渗透到真皮中也可以影响 全身药物吸收的皮肤清除率。本项目的目的是（a）研究体外 用于鉴定热对透皮递送的影响的释放试验条件，和（B）开发体外试验 透皮产品审查中使用的流程，以确保仿制药不会引入任何 额外的安全风险。我们将评估加热对贴剂药物释放速率的影响 使用USP溶出装置的体外释放测试（第1层），药物和制剂经皮肤的渗透 使用Franz扩散池（第2层），以及使用现有的最先进皮肤进行皮肤清除率分析 扩散模型，以确定真皮浓度和药物吸收到真皮中的血管网络中 (tier 3）。假设这种分层体外试验策略将产生基于科学的决策树， 支持ANDA批准透皮产品的热效应评估。

Many transdermal systems are affected by temperature and are labeled with a warning against heat application. For example, heat can increase skin permeability. Heat can affect drug solubility in a formulation and drug (and excipient) release from the transdermal system. Heat can also increase dermal clearance and systemic drug absorption via the vascular network. Heat effects can be different among different transdermal delivery systems. In the FDA review process, when the reference product has a label warning against heat application, the generic product cannot be more sensitive to heat than the reference product. Different heat effects among transdermal products can be due to different drug release (and formulation release) from the products. In addition, due to the different formulation release under heat, these formulations can exert different effects on skin permeability. The different formulation release and penetration into the dermis can also affect dermal clearance for systemic drug absorption. The objectives of this project are to (a) investigate the in vitro release test conditions for identifying heat effects on transdermal delivery and (b) develop an in vitro test process to be used in the reviews of transdermal products to ensure that generic products do not introduce any additional safety risks. We will evaluate the influence of heat upon the rate of drug release from the patch using in vitro release testing of USP dissolution apparatus (tier 1), drug and formulation permeation across skin using Franz diffusion cells (tier 2), and dermal clearance analyses using an existing, state-of-the-art, skin diffusion model to determine dermis concentration and drug absorption into the vascular network in the dermis (tier 3). It is hypothesize that this tiered in vitro testing strategy will yield a scientifically-based decision tree to support the evaluation of thermal effects for ANDA approvals of transdermal products.