Contents lists available at ScienceDirect Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst QBD-based systematic development of BosentanSNEDDS: Formulation, characterization and pharmacokinetic assessment Kahnu Charan Panigrahi * , Jayashree Jena, Goutam Kumar Jena, Ch. Niranjan Patra, M.E. Bhanoji Rao Roland Institute of Pharmaceutical Sciences (Affiliated to Biju Patnaik University of Technology, Odisha), Berhampur, 760010, India ARTICLE INFO Keywords: Bosentan Self-emulsifying drug delivery system Quality by design Central composite design Pharmacokinetic study ABSTRACT The aim of this study was to develop self-nanoemulsifying drug delivery system (SNEDDS) of bosentan using quality by design (QBD) approach with better bioavailability. The major component of the formulation vis-à-vis lipid (Capmul MCM), surfactant (LABRASOL) and co-surfactant (PEG 600) were selected on the basis of sa- turation solubility. Mixture of LABRASOL and PEG 600 in the ratio of 1:1 showed better nano emulsifying region as depicted by pseudo ternary phase diagram. The optimum mixture of Capmul MCM, LABRASOL and PEG 600 were selected by using response surface method (RSM) with central composite design (CCD). Pharmacokinetic study was conducted to determine various critical parameters. The optimized formulation showed 98.5% drug release in 15 min, globule size of 62.5 nm, emulsification time of 12 s and PDI of 0.146. TEM study revealed the drug entrapment within the oil globules of nano size range. Pharmacokinetic study of optimized formulation indicated faster dissolution and absorption which was evidenced from significantly higher C max , larger AUC and lower T max than pure drug bosentan. Thus the present study confirms potential of SNEDDS in enhancing the oral bioavailability of bosentan. 1. Introduction Self-emulsifying drug delivery systems (SEDDS) are isotropic mix- ture of oils and surfactants and co-solvent or co-surfactant which un- dergoes self-emulsification in gastrointestinal tract (GIT) [1]. The peristaltic movement of stomach and intestine render the agitation re- quired for self-emulsification [2,3]. These formulations when exposed to GIT fluid form oil in water nanoemulsion [4]. The process of self- emulsification was spontaneous as the free energy required is either low positive or negative [5]. The presence of endogenous materials such as bile salts, phospholipids and cholesterol in the intestinal lumen in- stigate an alteration in lipid composition and results in the formation micelles, vesicles, and liquid crystalline phases leading to improvement in solubilisation capacity and subsequent absorption of drug [6,7]. The solubilisation and absorption of drug depend on the lipid composition [8]. The nanoemulsions can be defined as thermodynamically stable, transparent (or translucent) dispersions having the globule size in the range of 10–100 nm [9]. The major advantage of nanoemulsion include very low interfacial tension and large oil in water (o/w) interfacial area. Nanoemulsion has exhibited enormous possibilities in nanoformulation of various inorganic substances [10]. Drugs with high lipophillicity (log P > 2), low melting point, low bioavailability and poor solubility in water are suitable for SEDDS [11,12]. The mechanism of action of bosentan is dual endothelin re- ceptor antagonist which acts by blocking the action of endothelin mo- lecules. It has particular action on narrowing of the blood vessels and lead to high blood pressure. Hence Bosentan is used for the treatment of pulmonary artery hypertension (PAH) [13]. The absolute bioavail- ability of bosentan is approximately 50% and food does not affect ab- sorption. Terminal elimination half-life is about 5 h in healthy adult subjects. The marketed product of bosentan are available in the dose of 62.5 mg and 125 mg. Bosentan has high lipophillicity (log P = 4.94), low melting point (1040C) and is categorized under BCS II drug. Based on the above criteria bosentan qualifies for selection as drug for SNEDDS [14]. A step wise approach to formulation development of SEDDS has to be followed when more than two excipients are used. The ternary phase diagram was used for optimizing the ratio of surfactant and co-surfac- tant in order to achieve large area of micro or nano emulsifying region [15,16]. HLB coupled with response surface methodology (RSM) ap- proach was adopted for optimization of SEDDS [17]. The pharmaceu- tical Quality by Design (QbD) can be defined as a systematic develop- ment of dosage form that start with predefined objectives considering product and process control based on quality risk management [18]. https://doi.org/10.1016/j.jddst.2018.06.021 Received 6 May 2018; Received in revised form 15 June 2018; Accepted 25 June 2018 * Corresponding author. Roland Institute of Pharmaceutical Sciences (Affiliated to Biju Patnaik University of Technology, Odisha), Berhampur, 760010, India. E-mail address: kanhu.pharma@gmail.com (K.C. Panigrahi). Journal of Drug Delivery Science and Technology 47 (2018) 31–42 Available online 26 June 2018 1773-2247/ © 2018 Elsevier B.V. All rights reserved. T