An NMR Protocol for In Vitro Paclitaxel Release from an Albumin-Bound Nanoparticle Formulation
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Research Article An NMR Protocol for In Vitro Paclitaxel Release from an Albumin-Bound Nanoparticle Formulation Min Sung Suh,1 Sharadrao M. Patil,1 Darby Kozak,2 Eric Pang,2 Stephanie Choi,2 Xiaohui Jiang,2 Jason D. Rodriguez,3 David A. Keire,4 and Kang Chen1,5
Received 7 January 2020; accepted 26 March 2020 Abstract. The paclitaxel protein-bound particles for injectable suspension (marketed under the brand name Abraxane®) contains nanosized complexes of paclitaxel and albumin. The molecular interaction between paclitaxel and albumin within the higher-order nanostructure is analytically challenging to assess, as is any correlation of differences to differences in therapeutic effect. However, because the higher-order nanostructures may affect the paclitaxel release, a suitable in vitro assay to detect potential differences in paclitaxel release between comparator lots and products is desirable. Herein, solution NMR spectroscopy with a T2-filtering technique was developed to detect paclitaxel signal while suppressing albumin signals to follow the released paclitaxel in the NMR tube upon dilution. The non-invasive nature of NMR allows for precise measurement of a full range of dilutioninduced drug release percentage from 14 to 92% without any sample extraction. The critical concentration of the drug product (DP) at 50% of release was 0.63 ± 0.04 mg/mL in PBS buffer. In addition, 2D diffusion ordered NMR spectroscopy (DOSY) results revealed that the released paclitaxel experiencing slightly slowed diffusion rates than free paclitaxel, which was attributed to paclitaxel in equilibrium with albumin-bound states. Collectively, the dilution-based NMR method offered an analytical approach to investigate physicochemical attributes of complex injectable products with minimal needed sample preparation and perturbation to nanoparticle formulation. KEY WORDS: T2-filtering; DOSY; non-invasive; dilution.
INTRODUCTION
Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12249-020-01669-1) contains supplementary material, which is available to authorized users. 1
Division of Complex Drug Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993, USA. 2 Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drug, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993, USA. 3 Division of Complex Drug Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St. Louis, Missouri 63110, USA. 4 Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St. Louis, Missouri 63110, USA. 5 To whom correspondence should be addressed. (e–mail: [email protected])
Paclitaxel (PTX) is a chemotherapeutic agent that has been used for canc
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