Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm In vivo biocompatibility, pharmacokinetics, antitumor efficacy, and hypersensitivity evaluation of ionic liquid-mediated paclitaxel formulations Md. Raihan Chowdhury a , Rahman Md Moshikur a , Rie Wakabayashi a,b , Yoshiro Tahara a , Noriho Kamiya a,c , Muhammad Moniruzzaman d , Masahiro Goto a,b, ⁎ a Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan b Advanced Transdermal Drug Delivery System Center, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan c Division of Biotechnology, Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan d Chemical Engineering Department, Universiti Teknologi PETRONAS, 32610 Seri Iskandar, Perak, Malaysia ARTICLE INFO Keywords: Biocompatibility Ionic liquid Paclitaxel Pharmacokinetics Hypersensitivity ABSTRACT In order to prevent common hypersensitivity reactions to paclitaxel injections (Taxol), we previously reported an ionic liquid-mediated paclitaxel (IL-PTX) formulation with small particle size and narrow size distribution. The preliminary work showed high PTX solubility in the IL, and the formulation demonstrated similar antitumor activity to Taxol, while inducing a smaller hypersensitivity effect in in vitro cell experiments. In this study, the stability of the IL-PTX formulation was monitored by quantitative HPLC analysis, which showed that IL-PTX was more stable at 4 °C than at room temperature. The in vivo study showed that the IL-PTX formulation could be used in a therapeutic application as a biocompatible component of a drug delivery system. To assess the in-vivo biocompatibility, IL or IL-mediated formulations were administered intravenously by maintaining physiological buffered conditions (neutral pH and isotonic salt concentration). From in vivo pharmacokinetics data, the IL-PTX formulation was found to have a similar systemic circulation time and slower elimination rate compared to cremophor EL mediated paclitaxel (CrEL-PTX). Furthermore, in vivo antitumor and hypersensitivity experiments in C57BL/6 mice revealed that IL-PTX had similar antitumor activity to CrEL-PTX, but a significantly smaller hypersensitivity effect compared with CrEL-PTX. Therefore, the IL-mediated formulation has potential to be an effective and safe drug delivery system for PTX. 1. Introduction Paclitaxel (PTX) has long been considered an excellent naturally derived chemotherapeutic agent against different types of cancer such as ovarian, lung, and breast cancer, as well as acute leukemia, head and neck carcinoma, and AIDS-related Kaposi’s sarcoma (Jordan and Wilson, 2004; Kavallaris, 2010; Rowinsky et al., 1990). However, low aqueous solubility (< 4.0 μg/mL) and poor permeability across biolo- gical membranes are the main barriers to its widespread application (Khmelnitsky et al., 1997; Sparreboom et al., 1997). The current most commonly administered clinical formulation (Taxol, Bristol-Myers Squibb, New York, NY, USA) consists of a vehicle system of Cremophor EL (polyethoxylated castor oil, CrEL) and dehydrated ethanol (EtOH) in a 50:50 ratio (1:1, v/v) to enhance its solubility and stability in water/ saline (0.9% NaCl)/dextrose (5.0% glucose) solution during in- travenous (IV) infusion/injection (Singla et al., 2002). The use of a large amount of CrEL in this formulation is often associated with var- ious side effects such as hypersensitivity (minor reaction: flushing and rash in 41%–44% of patients, and major reaction: potentially life threatening in 1.5%–3% of patients), abnormal lipoproteins, aggrega- tion of erythrocytes, neuropathy, vasodilation, dyspnea, and hypoten- sion (Dorr, 1994; Gelderblom et al., 2001; Szebeni et al., 1998; Weiss et al., 1990). As a preventive action, continuous administration of an- tihistamines and corticosteroids at high doses is required throughout the treatment/pretreatment, resulting in significant patient non- compliance (Wang et al., 2013). Numerous strategies have been in- vestigated for developing drug delivery systems without CrEL, in- cluding formation of albumin, nanoparticle, emulsion, prodrug, https://doi.org/10.1016/j.ijpharm.2019.05.020 Received 2 March 2019; Received in revised form 22 April 2019; Accepted 8 May 2019 Abbreviations: AUC, area under curve; CrEL, cremophor EL (polyethoxylated castor oil); C 0 , concentration at time zero; C max , maximum concentration; CL, clearance; EtOH, ethanol, anhydrous; IL, ionic liquid; PK, pharmacokinetics; PTX, paclitaxel; T-80, tween-80 (polyoxyethylene 20 sorbitan monooleate); t 1/2 , elimination half life; V d , volume of distribution ⁎ Corresponding author at: Graduate School of Engineering, Kyushu University, 744 Motooka, 819-0395 Fukuoka, Japan. E-mail address: m-goto@mail.cstm.kyushu-u.ac.jp (M. Goto). International Journal of Pharmaceutics 565 (2019) 219–226 Available online 08 May 2019 0378-5173/ © 2019 Elsevier B.V. All rights reserved. T