Heat Effect on Generic Transdermal Drug Delivery Systems

摘要 不同的经皮给药系统(TDDS)的药物释放受多种因素的影响 包括：皮肤状况，遮挡，暴露在高温下，不同的非活性成分，汗水，年龄和贴片 设计(蓄水池与基质)。特别是，暴露在高温下会增加高峰期，这一点已经有很好的记录。 血浆浓度和面积-包括尼古丁在内的许多药物的血浆浓度曲线下， 芬太尼、硝酸甘油、可乐定、水杨酸甲酯、雌二醇和睾酮，造成严重的安全问题。 大多数报道的研究都是有限的，因为它们集中在研究热对参考或普通TDDS的影响 而且，根据文献，几乎没有人直接比较热效应对 体内的参比和仿制药。当参考产品出现禁止加热的警告时， 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)。很可能同一药物的释放率不同 来自不同的TDDS产品对热的响应，以及由于以下原因而被修改的皮肤渗透性 促进剂和助溶剂的释放速率不同。有一种尚未得到满足的需求来表征热效应 体外和体内仿制药与参比产品的体外/体内相关性研究 ANDA赞助商预测他们的仿制药在热应用时的性能。这将确保 仿制药在受热性能方面与参比产品没有区别 并将确保通用TDDS的用户不会遇到其他严重的安全问题。这个 这项建议的目的是确定最佳的体外试验条件，以确定热的影响 尼古丁和芬太尼贴片的渗透性。尼古丁和芬太尼贴片 分别在没有处方和有处方的情况下提供。它们是世界上使用最多的补丁之一 它们有基质和储罐两种形式，可从不同制造商获得。该项目将： 热效应对健康人参比烟碱和芬太尼TDDS的影响 志愿者，研究不同的体外试验条件对FDA批准的尼古丁和芬太尼的影响 在常温和高温下的TDDS，发展体外/体内相关性，并评价 FDA批准的仿制药的热效应(没有可用的热效应研究)及其各自的参考 产品采用我们优化的体外试验条件。这些研究的结果将帮助FDA决定 哪些体外试验条件和研究设计以及ANDA赞助商在评估 他们的仿制产品的性能，以确保其产品上的热效应与 各自的参考产品。该项目未来几年可能包括对热效应的检查 额外的药物贴片，适用于特殊患者群体，以及屏障受损的皮肤。

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.