Contents lists available at ScienceDirect Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst Nanostructured lipid carriers containing ondansetron hydrochloride by cold high-pressure homogenization method: Preparation, characterization, and pharmacokinetic evaluation Van-An Duong, Thi-Thao-Linh Nguyen, Han-Joo Maeng, Sang-Cheol Chi * College of Pharmacy, Gachon University, Incheon, South Korea ARTICLE INFO Keywords: Nanostructured lipid carriers Ondansetron hydrochloride Homogenization Entrapment efficiency Sustained-release Pharmacokinetic ABSTRACT Nanostructured lipid carriers (NLCs) loaded with ondansetron hydrochloride, a water-soluble drug, were de- veloped for sustained-release delivery. A modified cold high-pressure homogenization method was used, and the pH-dependent solubility of the drug was exploited to obtain NLCs with an enhanced entrapment efficiency. The conditions for cold high-pressure homogenization were optimized at 500 bars for 6 cycles. The pH of the aqueous phase was 7.4, which led to an improvement of the entrapment efficiency to approximately 90%. Certain variables of the formulation composition were evaluated for their influences on ondansetron hydrochloride- loaded NLCs. The transformation of the drug to an amorphous state in NLCs was indicated by differential scanning calorimetry and X-ray powder diffraction. The optimized formulation consisted of tristearin: Phosal® 53MCT: drug (60:40:15, w/w) with 0.5% Tween® 80 (w/v). This formulation exhibited a sustained-release characteristic of the drug in vitro. After single subcutaneous injections in rats, the optimized ondansetron hy- drochloride-loaded NLCs prolonged the drug release for up to 96 h with an extended mean resident time and enhanced systemic exposure compared to the drug solution. The developed NLCs might be an efficient approach to prolong the therapeutic effect of ondansetron hydrochloride for the management of chemotherapy- and radiotherapy-induced emesis. 1. Introduction Ondansetron hydrochloride (OSH) is an antagonist of serotonin (5- hydroxytryptamine) subtype 3 receptor. It is currently used in neo- plastic patients for the management of nausea and vomiting induced by chemotherapy and radiotherapy [1–3]. Oral and intravenous dosage forms of OSH are commercially available. However, there are some drawbacks relating to the clinical use of the current formulations. Following oral administration, the absolute bioavailability of the drug is approximately 60% due to the first-pass metabolism and the half-life is relatively short (3–3.5 h) [4,5]. It should be administered at least 30 min prior to chemotherapy. Furthermore, the drug tends to be dis- charged by vomiting after oral administration, which can lead to a re- markable reduction in its therapeutic effects [6]. When administered intravenously, the drug shows noticeable side effects such as headache, constipation, and diarrhea due to the quick increase in the drug con- centration in the blood [7]. For the prevention of nausea and vomiting induced by chemotherapy and radiotherapy, the drug needs to be administered several times a day throughout therapy. It can cause fa- tigue and displeasure for neoplastic patients. Therefore, OSH sustained- release drug delivery systems were developed to prolong the ther- apeutic effects of the drug and reduce dosing frequency, thereby in- creasing patient compliance [8–10]. Previously, OSH-loaded solid lipid nanoparticles (SLNs) were prepared as sustained-release formulations for nasal delivery. However, entrapment efficiency (EE) of the drug was relatively low (16–57%) due to the good water-solubility of OSH [5,11]. Furthermore, nasal delivery remains certain limitation, such as irritation of the nasal mucosa, mucociliary clearance, and low drug retention time that requires repeated administration. SLNs loaded with drugs could be used for subcutaneous application [12]. This approach, as a potential alternative to nasal delivery of OSH-loaded SLNs, needs considerable investigation. SLNs and nanostructured lipid carriers (NLCs) are colloidal lipid nanoparticles, which have attracted many scientists [11,13,14]. They can potentially contribute to the bioavailability improvement of various drugs due to the biodegradability and physicochemical diversity of the https://doi.org/10.1016/j.jddst.2019.101185 Received 5 February 2019; Received in revised form 3 July 2019; Accepted 28 July 2019 * Corresponding author. College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea. E-mail addresses: anduong@gachon.ac.kr (V.-A. Duong), linhnguyen@gachon.ac.kr (T.-T.-L. Nguyen), hjmaeng@gachon.ac.kr (H.-J. Maeng), scchi@gachon.ac.kr (S.-C. Chi). Journal of Drug Delivery Science and Technology 53 (2019) 101185 Available online 31 July 2019 1773-2247/ © 2019 Elsevier B.V. All rights reserved. T