体外试验在确定咽喉局部用药特性中的作用:氟比洛芬的应用

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Vit Perlik, Hafsa Ali, Jean M Cardot, Anuradha Kulasekaran
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引用次数: 0

摘要

背景/目的:对于局部应用、局部起效的非专利药产品,由于血浆浓度较低,不能充分反映作用部位的局部暴露情况,因此通常无法根据全身暴露情况与原研药产品进行比较。如果存在经过验证的 PD 模型,则可以在健康受试者中进行比较临床研究;如果没有替代终点,则需要招募相关适应症的患者,并考虑所有可能导致缺乏敏感性的相关因素。尽管业界和监管机构都承认需要替代体外方法,但体内给药过程的复杂性使得指导文件的制定尤为困难。我们的目标是介绍不常用的体外方法,并解决所选测试的体内相关性问题。方法:本文分析了欧洲和美国目前的监管方法,并以本地应用的氟比洛芬的各种制剂为例,强调了体外测试在灵敏度、可靠性、可重复性和体内相关性方面的主要优势。结果:体外食管滞留(IVOR)模型表明,使用不同氟比洛芬制剂后的前 6-10 分钟对它们的比较非常重要,而且使用浓度-时间曲线下的部分面积(pAUCs)与体内数据的相关性最好。流变学评估进一步证明,凝胶喷雾制剂的粘附特性是基于与粘蛋白的相互作用。结论设计相关的体外试验需要充分评估药物物质、药物产品、给药条件和给药过程的复杂性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Role of In Vitro Tests in the Characterisation of Locally Applied, Locally Acting Drugs in the Throat: Application to Flurbiprofen.

Background/Objectives: For locally applied, locally acting generic drug products, comparison to an originator product based on systemic exposure is usually not feasible due to low plasma concentrations and inadequate reflection of local exposure at the site of action. Where a validated PD model exists, a comparative clinical study can be performed in healthy subjects; where no surrogate endpoint is available, patients with the relevant indication need to be enrolled, with all the associated factors which could result in lack of sensitivity. Even though the need for alternative in vitro approaches has been acknowledged by both industry and regulatory bodies, the complexity of in vivo drug delivery processes makes the development of guidance documents particularly difficult. Our objective was to present in vitro approaches less classically used and to address in vivo relevance of the selected tests. Methods: This article analyses current regulatory approaches in Europe and the U.S., and highlights the key advantages of in vitro tests in terms of their sensitivity, reliability, reproducibility and in vivo relevance using locally applied flurbiprofen in various formulations. Results: The in vitro esophageal retention (IVOR) model demonstrates that the first 6-10 min after application of different flurbiprofen formulations is important for their comparison and also offers the best correlation with in vivo data using the partial area under the concentration-time curves (pAUCs). Rheological evaluations further demonstrated that the mucoadhesive properties of the gel spray formulation are based on interaction with mucin. Conclusions: Designing a relevant in vitro test requires adequate evaluation of the complexity of the drug substance, drug product, dosing conditions and delivery processes.

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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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