Lecithin/TPGS-based spray-dried self-microemulsifying drug delivery systems: In vitro pulmonary deposition and cytotoxicity Rania A.H. Ishak, Rihab Osman * Ain Shams University, Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Abbassyia, Cairo, Egypt A R T I C L E I N F O Article history: Received 28 January 2015 Received in revised form 6 March 2015 Accepted 10 March 2015 Available online 12 March 2015 Pubchem: Atorvastatin calcium (Pubmed CID: 60823) Vitamin E TPGS (Alpha-tocopheryl polyethylene glycol 1000 succinate) (Pubmed CID: 71406) Polyethylene glycol 6000 (Pubmed CID: 174) L-leucine (Pubmed CID: 6106) Dextran (Pubmed CID: 5460037) Mannitol (Pubmed CID: 6251) Keywords: Atorvastatin Spray drying SMEDDS Lecithin TPGS Pulmonary deposition Cytotoxicity A B S T R A C T The aim of the present work was to develop a new solid self-microemulsifying drug delivery system (SMEDDS) for the pulmonary delivery of the poorly water-soluble anti-cancer drug atorvastatin (AVT). Microemulsion (ME) was first developed using isopropyl myristate (IPM), a combination of 2 biocompatible surfactants: lecithin/D-a-tocopheryl polyethylene glycol succinate (TPGS) and ethanol as co-surfactant. Two types of lecithin with different phosphatidylcholine (PC) contents were compared. Phase diagram, physico-chemical characterization and stability studies were used to investigate ME region. Solid SMEDDS were then prepared by spray-drying the selected ME using a combination of carriers composed of sugars, leucine as dispersibility enhancer with or without polyethylene glycol (PEG) 6000. Yield, flow properties, particle size and in vitro pulmonary deposition were used to characterize the spray-dried powders. Reconstituted MEs were characterized in terms of morphology, particle size and size distribution. In vitro cytotoxicity study was undertaken on lung cancer cell line for the selected MEs and SD-SMEDDS formulae. Results showed that the most satisfactory MEs properties were obtained with 1:3 lecithin/TPGS, 1:1 lecithin/oil and 1:1 surfactant/co-surfactant ratios. A larger ME area was obtained with lecithin containing 100% PC compared to the less expensive lecithin containing 20% PC. By manipulating spray drying parameters, carrier composition and ratio of ME lipids to carrier, microparticles with more than 70% of respirable fraction could be prepared. The ME was efficiently recovered in simulated lung fluid even after removal of alcohol. The concurrent delivery of AVT with TPGS in solid SMEDDS greatly enhanced the cytotoxic activity on lung cancer cells. ã 2015 Elsevier B.V. All rights reserved. 1. Introduction Targeted pulmonary delivery using dry powder inhalers (DPIs) has the potential of increased solid-state stability, improved pulmonary receptor occupancy and reduced systemic side effects for drugs treating pulmonary diseases (Hickey and Mansour, 2009; Park et al., 2013). Atorvastatin (AVT), an inhibitor of 3-hydroxy-3- methylglutaryl CoA (HMG-CoA) reductase, is a synthetic statin commonly used in the treatment of hypercholesterolemia (Rodde et al., 2014). HMG-CoA reductase activity was found to increase in various types of tumors including lung carcinoma, the second most common cause of cancer related mortality (Rosell et al., 2004; Lu et al., 2008; Chen et al., 2012; Gill et al., 2012). Hence, the anticancer activity of statins in various cancer cells had been investigated (Khurana et al., 2007; McFarlane et al., 2002; Corcos and Jossic-Corcos, 2013). AVT is a BCS Class II with log P of 6 and a bioavailability of only 12% attributed to its poor water solubility and high presystemic clearance (>80%) (Rodde et al., 2014). The use of lipid based carriers, among which micro- emulsions (MEs) and self-microemulsifying drug delivery systems (SMEDDS), could overcome its solubility problem (Narang et al., 2007). Tailoring these SMEDDS to suit lung delivery would avoid unnecessary drug distribution to other organs enhancing drug efficacy in treatment of lung cancer. MEs require high surfactants (SAA)/co-surfactant (co-SAA) concentration to reduce the surface tension between oil and water phases achieving zero interfacial tension, leading thus to increased toxicity (Lawrence and Rees, 2000). From this perspec- tive, lecithin MEs are especially desirable since lecithin is a naturally occurring nontoxic biological SAA (Yuan et al., 2008), being one of the major components of lung SAA (Mitra et al., 2001). Unfortunately, due to the highly lipohophilic character of lecithin and its tendency to form liquid crystalline phases, either alcohol or considerable amounts of other SAA such as Brij 96 1 , Tween 80 1 * Corresponding author. Tel.: +20 1221022566. E-mail address: rihabosman@pharma.asu.edu.eg (R. Osman). http://dx.doi.org/10.1016/j.ijpharm.2015.03.019 0378-5173/ ã 2015 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 485 (2015) 249–260 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsev ier.com/locate /ijpharm