Heat Effect on Generic Transdermal Drug Delivery Systems

摘要 药物从不同的经皮给药系统（TDDS）中释放受许多因素控制 包括：皮肤状况、闭塞、暴露于热、不同的非活性成分、汗液、年龄和贴片 设计（储药器与基质）。特别是，暴露于热已被充分记录，以增加峰值 包括尼古丁在内的许多药物的血浆浓度和血浆浓度曲线下面积， 芬太尼、硝酸甘油、可乐定、水杨酸甲酯、雌二醇和睾酮，带来了严重的安全问题。 大多数报道的研究都是有限的，因为它们集中于研究热对参比或仿制TDDS的影响 根据文献，几乎没有一个文献直接比较了热效应对 体内参比品和仿制品。当参考产品有禁止加热的警告时， 通用产品将具有相同的警告而不管它们之间可能存在的不同（即， 非活性成分或TDDS类型的差异）。很可能同一种药物的释放速率不同 从不同的TDDS产品响应于热，以及皮肤渗透被修改，由于 增强剂和助溶剂的不同释放速率。有一个未满足的需要，以表征热效应对 体外和体内仿制药与参比产品，以开发体外/体内相关性，可用于 ANDA赞助商预测其仿制产品在热应用时的性能。这将确保 在加热性能方面，仿制药与参比产品没有区别 并将确保通用TDDS使用者没有额外的关键安全问题。的 本提案的目的是确定最佳体外试验条件，以确定热对 储库和基质尼古丁和芬太尼贴剂的渗透特性。尼古丁芬太尼贴剂 分别在没有处方和有处方的情况下提供。它们是全球使用最多的补丁之一 并且它们可以从不同的制造商以基质和储存器的形式获得。该项目将： 研究热效应对健康人体内参比和仿制尼古丁和芬太尼TDDS的影响 志愿者，研究体外可变测试条件对FDA批准的尼古丁和芬太尼的影响 TDDS在正常和升高的温度下，开发体外/体内相关性，并评估 对FDA批准的仿制药的加热（无可用的热效应研究）及其各自的参考 使用我们优化的体外测试条件生产产品。这些研究的结果将有助于FDA决定 ANDA申办者在评价时必须考虑的体外试验条件和研究设计 其仿制产品的性能，以确保其产品的热效应等同于 各自的参考产品。该项目的未来几年可能包括检查热效应 在特殊患者人群和屏障受损的皮肤上使用额外的药物贴剂。

ABSTRACT Drug release from different transdermal drug delivery systems (TDDS) is governed by a number of factors including: skin condition, occlusion, exposure to heat, different inactive ingredients, sweat, age and patch design (reservoir vs. matrix). In particular, exposure to heat has been well documented to increase the peak plasma concentration and area-under the plasma concentration curve for many drugs including nicotine, fentanyl, nitroglycerine, clonidine, methyl salicylate, estradiol and testosterone, imposing critical safety issues. Most of the reported studies are limited as they focused on studying heat effect on reference or generic TDDS and almost none, according to the literature, provided direct comparison of the influence of heat effect on reference and generic products in vivo. When a reference product has a warning against applying heat, the generic product will have the same warning regardless of the dissimilarity that may exist between them (i.e., differences in inactive ingredients or type of TDDS). It is likely that the release rate of the same drug differs from different TDDS products in response to heat, as well as the skin permeation being modified due to different release rates of enhancers and cosolvents. There is an unmet need to characterize heat effects on generic vs. reference products in vitro and in vivo to develop in vitro/in vivo correlation which can be used by ANDA sponsors to predict the performance of their generic products upon heat application. This will ensure that generic products are no different than reference products with respect to their performance upon heat application and will ensure that there are no additional critical safety issues for users of generic TDDS. The objective of this proposal is to determine the best in vitro test conditions that identify the influence of heat on the permeation properties of reservoir and matrix nicotine and fentanyl patches. Nicotine and fentanyl patches are available without and with prescriptions, respectively. They are among the most used patches worldwide and they are available in both matrix and reservoir forms from different manufacturers. This project will: investigate the influence of heat effects on reference and generic nicotine and fentanyl TDDS in healthy human volunteers, investigate the influence of variable test conditions in vitro on FDA approved nicotine and fentanyl TDDS at normal and elevated temperatures, develop in vitro/in vivo correlation, and evaluate the influence of heat on FDA-approved generic products (with no available heat effect studies) and their respective reference products using our optimized in vitro test conditions. Results from these studies will help the FDA decide on which in vitro test conditions and study design ANDA sponsors will have to consider in evaluating the performance of their generic product to ensure that heat effect on their products is equivalent to that on the respective reference product. Future years of this project could include examination of the heat effect on additional drug patches, on special patient populations, and on skin with compromised barrier.