Adaptive perfusion: An in vitro release test (IVRT) for complex drug products

JOURNAL OF CONTROLLED RELEASE

卷:333

Article

Patel, Deval^1,2  Zhang, Ying^1,3  Dong, Yixuan⁴  Qu, Haiou¹  Kozak, Darby³  Ashraf, Muhammad¹  Xu, Xiaoming¹ 

[1] US FDA, Off Testing & Res, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

[2] US FDA, Off Qual Surveillance, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

[3] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

[4] US FDA, Off Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

关键词: Nanoemulsions;    Adaptive perfusion;    Tangential flow filtration;    Globule size;    Drug release;   

DOI  :  10.1016/j.jconrel.2021.03.024

来源: Elsevier

【 摘 要 】

In this work, adaptive perfusion, a pressure-driven separation method based on the principle of tangential flow filtration (TFF) was developed for investigating the rate and extent of drug release from drug products containing particulates, such as emulsions, suspensions, liposomes, drug-protein complexes. The TFF filters were preconditioned with unique conditioning solutions and processes to improve the fiber reproducibility and robustness. The adaptive perfusion method achieved size-based separation of the particulates with simultaneous analysis of the released drug as well as remaining drug. By contrast to conventional dialysis methods, the adaptive perfusion method can be used to measure the rate and extent of the drug release from drug solution, drug loaded micelles and nanoemulsions via adjustment of the filter molecular weight cutoff, feed flow rate or back-pressure. Notably, the adaptive perfusion method provided discriminatory drug release profiles for drug in solution, in micelles, and in small, medium, and large globule size nanoemulsions. The drug release profile obtained using adaptive perfusion method was found significantly faster (e.g., minutes rather than hours) and higher (e.g., >60%) than the release obtained using dialysis method. The IVRT method presented here is free from the constraints of rate-limiting factors, such as diffusion through dialysis membrane, and has potential to be extended further to examine the impact of manufacturing process on drug distribution and release characteristics of other challenging complex drug products.

【 授权许可】

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