Assessing the skin pharmacokinetics of topical drugs, and the bio(in)equivalence of topical drug products, using non-invasive techniques

使用非侵入性技术评估外用药物的皮肤药代动力学以及外用药品的生物等效性

• 批准号: 10469997
• 负责人: RICHARD H GUY
• 金额: $ 24.99万
• 依托单位: UNIVERSITY OF BATH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469997
• 关键词: Assessing; skin; pharmacokinetics; topical; drugs

The quantitative determination of the bioavailability (BA) of a topically applied drug at its site of action in the skin represents an unmet regulatory need. The majority of dermatological drug targets are found in the epidermis and upper dermis (including appendages such as hair follicles and sebaceous glands), beneath the principal skin barrier, the stratum corneum (SC). While some alternative methods to clinical endpoint BA and bioequivalence (BE) studies have been identified, the evaluation of other surrogate approaches is a ‘work-in-progress’. The central hypothesis of the research strategy proposed is that spectroscopic (in particular, Raman) imaging is able to provide a non-invasive, accurate, sensitive and reproducible determination of the rate and extent to which a topically administered drug becomes available at its site of action below the SC (and, specifically, the viable epidermis). The initial goal is to establish experimental methods, combining Raman and mass spectrometry imaging, to prove this hypothesis ex vivo; subsequently, the objective is to develop Raman imaging in vivo, and to calibrate the approach using complementary techniques. The project has the following specific aims: (a) to conceive strategies by which unambiguous Raman spectroscopic analysis of a drug in the skin can be achieved despite the potential for significant, background signal interference; (b) to evolve a robust approach to correct for drug signal attenuation as a function of increasing depth of measurement in the skin; (c) to demonstrate that continuous, real- time Raman imaging after topical application of a formulation can measure the drug’s “input kinetics” into the viable epidermis ex vivo; (d) to correlate and validate Raman spectroscopic assessment of drug input with parallel, high-sensitivity mass spectroscopic analysis and imaging; (e) to develop Raman imaging to quantify drug input kinetics into the viable epidermis in vivo and to calibrate the method using SC sampling and reverse iontophoresis, another non-invasive method, in combination with mathematical modelling; (f) to demonstrate that the refined spectroscopic tool can characterise the epidermal BA of a topically applied drug and distinguish correctly between formulations that are BE and those that are not; and (g) to apply spatio-temporal mathematical modelling to identify the mechanistic processes underlying the observed results, to explore the impact of drug properties on those mechanisms, and to estimate and validate key metrics of topical bioavailability. In summary, therefore, the proposed project combines different, but synergistic, approaches to assess topical BA/BE with novel spectroscopic imaging strategies to demonstrate that the routine, facile and noninvasive measurement of drug pharmacokinetics in the skin in vivo is an attainable objective with considerable potential for application in regulatory science and decision-making.

定量测定外敷药物在作用部位的生物利用度

项目成果

Quantification of Chemical Uptake into the Skin by Vibrational Spectroscopies and Stratum Corneum Sampling.

• DOI: 10.1021/acs.molpharmaceut.2c01109
• 发表时间: 2023-05-01
• 期刊: MOLECULAR PHARMACEUTICS
• 影响因子: 4.9
• 作者: Tabosa, M. Alice Maciel;Vitry, Pauline;Zarmpi, Panagiota;Bunge, Annette L.;Belsey, Natalie A.;Tsikritsis, Dimitrios;Woodman, Timothy J.;White, K. A. Jane;Delgado-Charro, M. Begona;Guy, Richard H.
• 通讯作者: Guy, Richard H.

Visualisation of drug distribution in skin using correlative optical spectroscopy and mass spectrometry imaging.

使用相关光谱和质谱成像可视化皮肤中的药物分布。

• DOI: 10.1016/j.jconrel.2023.10.026
• 发表时间: 2023
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Belsey,NatalieA;Dexter,Alex;Vorng,Jean-Luc;Tsikritsis,Dimitrios;Nikula,ChelseaJ;Murta,Teresa;Tiddia,Maria-Vitalia;Zhang,Junting;Gurdak,Elzbieta;Trindade,GustavoF;Gilmore,IanS;Page,Leanne;Roper,CliveS;Guy,RichardH;Bettex,
• 通讯作者: Bettex,

Reverse Iontophoresis: Noninvasive Assessment of Topical Drug Bioavailability.

• DOI: 10.1021/acs.molpharmaceut.3c00791
• 发表时间: 2024-01-01
• 期刊: MOLECULAR PHARMACEUTICS
• 影响因子: 4.9
• 作者: Moore, Kieran;Gregoire, Sebastien;Eilstein, Joan;Delgado-Charro, M. Begona;Guy, Richard H.
• 通讯作者: Guy, Richard H.

Confocal Raman Spectroscopic Characterization of Dermatopharmacokinetics Ex Vivo.

• DOI: 10.1021/acs.molpharmaceut.3c00755
• 发表时间: 2023-11-06
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Zarmpi P;Tabosa MAM;Vitry P;Bunge AL;Belsey NA;Tsikritsis D;Woodman TJ;Delgado-Charro MB;Guy RH
• 通讯作者: Guy RH