Tiered Testing Strategy for Assessing Thermal Effects on Transdermal Products

许多透皮系统会受到温度的影响，并标有防暑的警告。 申请。例如，高温会增加皮肤的渗透性。热会影响药物在制剂中的溶解度 药物(和赋形剂)从透皮系统释放。高温还可以增加皮肤的清除量， 通过血管网络的全身性药物吸收。不同透皮方式的热效应可能不同 传输系统。在FDA审查过程中，当参考产品有防热警告的标签时 应用中，非专利产品不能比参比产品对热更敏感。不同热度 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，由于不同的配方在加热下释放，这些配方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也会影响 全身药物吸收的皮肤清除。本项目的目标是(A)研究体外培养的 确定透皮给药热效应的释放试验条件和(B)开发体外试验 用于透皮产品审查的过程，以确保仿制药不会引入任何 额外的安全风险。我们将评估热对贴剂药物释放速率的影响 使用USP溶出仪(一级)的体外释放试验，药物和制剂经皮渗透 使用Franz扩散池(第2层)，以及使用现有的、最先进的皮肤进行真皮清除分析 确定真皮浓度和药物在真皮血管网络中吸收的扩散模型 (第3级)。假设这种分层的体外测试策略将产生一个科学的决策树，以 支持对ANDA批准的透皮产品进行热效应评估。

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.