Natural deep eutectic solvents as a storage medium for human interferon-α2: a green and improved strategy for room-temperature biologics

Min Sang Lee; Kyuri Lee; Min Woo Nam; Kyung Min Jeong; Jung Eun Lee; Nak Won Kim; Yue Yin; Su Yeon Lim; Da Eun Yoo; Jeongmi Lee; Ji Hoon Jeong

Journal of Industrial and Engineering Chemistry, Vol.65, 343-348, September, 2018

DOI10.1016/j.jiec.2018.05.005 Export Citation

Natural deep eutectic solvents as a storage medium for human interferon-α2: a green and improved strategy for room-temperature biologics

Min Sang Lee, Kyuri Lee, Min Woo Nam, Kyung Min Jeong, Jung Eun Lee, Nak Won Kim, Yue Yin, Su Yeon Lim, Da Eun Yoo, Jeongmi Lee^†, and Ji Hoon Jeong^†

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea

E-mail:,

The inherent vulnerability of protein biologics to high temperature is the origin of their limited use in clinical settings where proper storage and handling systems are not available. Herein, we demonstrate he first application of natural deep eutectic solvents (NADES) as a temperature-stable storage medium for a real therapeutic protein, human interferon-alpha 2 (IFN-α2). A formulation of IFN-α2 based on a NADES composed of choline chloride and fructose at a 1:1 molar ratio (CCl:Fru) had no influence on the activity of IFN-α2. The NADES provided an appropriate environment for effective protection of IFN-α2 from thermal denaturation at mid (37 °C) and high (70 °C) temperatures during long-term (90 days) and short-term (2 h) storage. Protein stability in the presence of CCl:Fru was demonstrated by orthogonal or complementary methods, including in vitro activity assay, circular dichroism spectroscopy and extrinsic fluorescence spectroscopy. In view of their biocompatibility, customizable properties, and the simplicity of synthesis and use, NADESs are suggested as a green and improved short-term and long-term storage medium that could facilitate the development of room-temperature biologics.

Keywords:Green solvent;Protein stabilization;Room temperature storage;Natural deep eutectic solvent;Designer solvent

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[6] Ammann C, AAPS PharmSciTech, 12, 1264 (2011)

[7] Tan LJ, Group SVDW, Vaccine, 32, 2389 (2014)

[8] Cheyne J, Rev. Infect. Dis., 11, S617 (1989)

[9] Wolfson LJ, Gasse F, Lee-Martin SP, Lydon P, Magan A, Tibouti A, Johns B, Hutubessy R, Salama P, Okwo-Bele JM, Bull. World Health Organ., 86, 27 (2008)

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[14] Capelle MA, Gurny R, Arvinte T, Eur. J. Pharm. Biopharm., 65, 131 (2007)

[15] Maa YF, Hsu CC, Int. J. Pharm., 140, 155 (1996)

[16] Griebenow K, Klibanov AM, Proc. Natl. Acad. Sci. U. S. A., 92, 10969 (1995)

[17] Klibanov AM, Nature, 409, 241 (2001)

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[19] Gross G, Terzo SD, Kumar SK, Stabilized interferon alpha solutions, Google Patents (1998).

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[21] Ruiz L, Reyes N, Duany L, Franco A, Aroche K, Rando EH, Int. J. Pharm., 264, 57 (2003)

[22] Zhang J, Pritchard E, Hu X, Valentin T, Panilaitis B, Omenetto FG, Kaplan DL, Proc. Natl. Acad. Sci. U. S. A., 109, 11981 (2012)

[23] Pena-Pereira F, Namiesnik J, ChemSusChem, 1784 (2014).

[24] Dai Y, van Spronsen J, Witkamp GJ, Verpoorte R, Choi YH, Anal. Chim. Acta, 766, 61 (2013)

[25] Dai Y, van Spronsen J, Witkamp GJ, Verpoorte R, Choi YH, J. Nat. Prod., 76, 2162 (2013)

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[27] Mondal D, Sharma M, Mukesh C, Gupta V, Prasad K, Chem. Commun., 49, 9606 (2013)

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[37] Mahon FX, Faberes C, Pueyo S, Cony-Makhoul P, Salmi R, et al., Blood, 92, 4059 (1998)

[38] Opravil M, Hirschel B, Bucher HC, Luthy R, Study SHC, Int. J. Std. Aids, 10, 369 (1999)

[39] Gutierrez MC, Ferrer ML, Mateo CR, del Monte F, Langmuir, 25(10), 5509 (2009)

[40] Nam MW, Zhao J, Lee MS, Jeong JH, Lee J, Green Chem., 17, 1718 (2015)

[41] Semisotnov GV, Rodionova NA, Razgulyaev OI, Uversky VN, Gripas AF, Gilmanshin RI, Biopolymers, 31, 119 (1991)

[42] Stryer L, J. Mol. Biol., 13, 482 (1965)

[43] Hawe A, Sutter M, Jiskoot W, Pharm. Res. Dordr., 25, 1487 (2008)

[44] Sharma VK, Kalonia DS, Pharm. Res. Dordr., 20, 1721 (2003)

[45] Fujita K, MacFarlane DR, Forsyth M, Chem. Commun., 4804 (2005).