Please cite this article in press as: Waddad, A.Y., et al., Formulation, characterization and pharmacokinetics of Morin hydrate niosomes prepared from various non-ionic surfactants. Int J Pharmaceut (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.08.040 ARTICLE IN PRESS G Model IJP 13591 1–13 International Journal of Pharmaceutics xxx (2013) xxx–xxx Contents lists available at ScienceDirect International Journal of Pharmaceutics j o ur nal ho me page: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Formulation, characterization and pharmacokinetics of Morin hydrate niosomes prepared from various non-ionic surfactants Ayman Y. Waddad a,b,∗ , Sarra Abbad a , Fan Yu a , Were L.L. Munyendo a , Q1 Wang Jing a , Huixia Lv a,∗ , Jianping Zhou a,∗ a Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China b Department of Pharmaceutics, Faculty of Pharmacy, University of Gezira, Wad Medani P.O. Box 20, Sudan a r t i c l e i n f o Article history: Received 8 April 2013 Received in revised form 9 August 2013 Accepted 25 August 2013 Available online xxx Keywords: Morin hydrate Niosomes Orthogonal array Drug delivery Pharmacokinetics Molecular modeling a b s t r a c t Morin hydrate (MH), a bioflavonoid with antioxidant and anticancer activity as well as the ability to improve the bioavailability of other drugs on their concurrent use. Three differently optimized niosomal formulations using three different non-ionic surfactants (Span 60, Span 80 and Tween 60) were achieved by (L 9 (3 4 )) Taguchi orthogonal array (TOA). The analysis of TOA revealed that Tween 60 Niosomes had the highest entrapment efficiency (93.4%) compared to other optimized Niosomal formulations (71–79%). In terms of MH remaining %, Tween 60 Niosomes were found to be the most stable (89%) at 4 ◦ C over one month compared to Span 60 (56%) and Span 80 (57%) Niosomes. The release pattern in all Niosomal formulations was found to follow the Weibull model and Tween 60 Niosomes had the highest release rate. The molecular modeling simulation explained the binding of MH to the human serum albumin (HSA) by hydrogen bonds during the in vitro release process. As for the bioavailability, the AUC 0–8 showed 1.3–2.7 fold increase compared to the MH solution. Ex vivo images of the excised organs showed that MH could accumulate in brain which indicates that MH-Tween 60 Niosomes might be a possible candidate to deliver hydrophobic drugs and overcome the blood–brain barrier (BBB) penetration. © 2013 Published by Elsevier B.V. 1. Introduction Morin hydrate (3,5,7,2 ′ ,4 ′ -pentahydroxyflavone, Fig. 5), one of the bioflavonoid has been identified in a number of fruits, veg- etables, and herbs of the Moraceae family (Zhang et al., 2010c, 2011). Several studies showed that Morin has neuroprotective action in Parkinson’s disease (Zhang et al., 2010c). It induces apo- ptosis in hepatocellular carcinogenesis model (Sivaramakrishnan and Devaraj, 2010), inhibits the growth of HL-60 cells and breast cancer resistance protein (ABCG2)-mediated transport (Hsiu-Maan Kuo et al., 2007; Shuzhong Zhang et al., 2004) in addition to its dual action as a hypouricemic agent and xanthine oxidase inhibitor (Yu et al., 2006). On concurrent use Morin also has been proved to alter the pharmacokinetics of some drugs by improving their oral bioavailability in rats (Choi et al., 2006; Li et al., 2007; Sang-Chul Shin and Choi, 2008). Due to the unique chemical structure, MH easily chelates with metal ions specifically divalent and trivalent ions (Panhwar et al., 2010) subsequently forming complexes that exhibit fluorescence properties (Yumin Song et al., 2000). ∗ Corresponding authors. Tel.: +86 25 83271272; fax: +86 25 83301606. E-mail addresses: aymanwaddad@hotmail.com (A.Y. Waddad), lvhuixia@163.com (H. Lv), iamzhoujianping@163.com (J. Zhou). Niosomes were first reported in the 1970s as a feature of the cos- metic industry (Uchegbu and Vyas, 1998). They are formed by the self-assembly of non-ionic amphiphiles in aqueous media result- ing in close concentric bilayer which has the same conformation of liposomes but lack the phospholipids component in their bilayer structure (Manosroi et al., 2008a). As an analog to liposomes, nio- somes have the ability to entrap both hydrophilic and hydrophobic drugs in their core and between the bilayers, respectively (Hong et al., 2009). Their greater chemical stability, high purity, content uniformity, low cost, the availability of various types of non-ionic surfactants and convenient storage overcome the drawbacks asso- ciated with liposomes (Hao and Li, 2011). Different methods of preparation and types of surfactants are usually used in formula- tion of niosomes, giving rise to different types of non-ionic vesicles in terms of their shape, number of layers, size, entrapment effi- ciency and stability (Uchegbu, 1999). Non-ionic surfactant vesicles have variously been investigated as potential drug delivery system for anticancer payload (Azmin et al., 1985; Bayindir and Yuksel, 2010; Uchegbu et al., 1996), peptides (Arunothayanun et al., 1999; Huang et al., 2008; Pardakhty et al., 2007), anti-inflammatory and anti-infective agents (Baillie et al., 1986; El-Ridy et al., 2011; Manosroi et al., 2008b; Mehta et al., 2011; Zidan et al., 2011), ocu- lar (Abdelbary and El-Gendy, 2008), and transdermal drug delivery (Manosroi et al., 2011; Muzzalupo et al., 2011; Rungphanichkul et al., 2011). 0378-5173/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ijpharm.2013.08.040 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65