International Journal of Pharmaceutics 387 (2010) 272–277 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Inclusion of poorly soluble drugs in highly ordered mesoporous silica nanoparticles M.J.K. Thomas a , I. Slipper a , A. Walunj a , A. Jain a , M.E. Favretto b , P. Kallinteri b , D. Douroumis a,∗ a Medway School of Science, Department of Pharmaceutical Sciences, University of Greenwich, Central Avenue, Chatham Maritime ME4 4TB, Kent, United Kingdom b Medway School of Pharmacy, Universities of Kent/Greenwich, Chatham Maritime ME4 4TB, Kent, United Kingdom article info Article history: Received 17 September 2009 Received in revised form 7 December 2009 Accepted 9 December 2009 Available online 16 December 2009 Keywords: Mesoporous silica SBA-16 Antiepileptic drugs Loading Cytotoxicity abstract Silica nanoparticles (MSNs) with a highly ordered mesoporous structures (103 Å) with cubic Im ¯ 3m have been synthesized using triblock copolymers with high poly(alkylene oxide) (EO) segments in acid media. The produced nanoparticles displayed large specific surface area (∼765 cm 2 /g) with an average particles size of 120 nm. The loading efficiency was assessed by incorporating three major antiepileptic active sub- stances via passive loading and it was found to varying from 17 to 25%. The state of the adsorbed active agents was further analyzed using differential scanning calorimetry (DSC) and X-ray powder diffrac- tion (XRPD). Dissolution studies revealed rapid release profiles within the first 3 h. The viability of 3T3 endothelial cells was not affected in the presence of MSNs indicating negligible cytotoxicity. © 2009 Elsevier B.V. All rights reserved. 1. Introduction In recent years, mesoporous silica nanoparticles (MSNs) have attracted increasing consideration as a dynamic drug carrier sys- tem (Slowing et al., 2008; Liong et al., 2008; Vallet-Regi et al., 2007). These materials were discovered by Mobil scientists (Kresge et al., 1992; Beck et al., 1992) know as MCM-41 or MCM-48 and used as molecular sieves. It was firstly Vallet-Regi et al. (2001) who proposed the use of MSNs as drug delivery system by loading ibuprofen into the mesoporous MCM-41 material. MSNs possess several features that render them excellent candidates as drug delivery systems such as the ordered pore network, with very homogeneous size that controls the drug load and release kinetics. In addition the high pore volume and the high surface area facilitate the adsorption of high active substances amounts. By adjusting also the pore size slightly larger than the dimension of the drug molecule MSNs can serve as a versatile host of various substances. Finally, the silanol-containing surface can be functionalized to induce better control over drug loading and release properties. MSNs are synthesized though either the alkaline route (Beck et al., 1992) or the acid route (Huo et al., 1994) both using amphiphiles as templates. The acid catalysis accelerates the hydrolysis versus the condensation rate and promotes mainly condensation at the ends of silica polymers to form linear silicate ions. On the other ∗ Corresponding author. Tel.: +44 0208 8331 8440; fax: +44 0208 8331 9805. E-mail address: D.Douroumis@gre.ac.uk (D. Douroumis). hand, the alkaline catalysis favors both hydrolysis and condensa- tion. Two main synthetic pathways have been proposed so far to enlighten the formation of the mesoporous structure. The first one, known as the “liquid-crystal template mechanism”, suggests that the hexagonal, liquid-crystal surfactant phase exists in the solution prior the addition of the silica precursors. The silica framework pre- cipitates around this template, forming a mesoporous structure. The surfactants are then removed by calcination, thus creating a porous structure with a high surface area. In the latter, the surfac- tants are aggregated as single, rod-like micelles before the addition of the silica precursors. The addition of silica enables these species to interact with the surface of the surfactant micelles, which sets off the surfactant rods to assemble into a hexagonal array. Administration of MSNs can take place through parenteral and oral route. One of the main advantages is the ability to increase the solubility of poorly water soluble drugs while they can also be used for hydrophilic active agents. Thus high drug loading can be achieved with loading capacities normally varying from 10 to 34% (Qu et al., 2006) or up to 60% in extreme cases (Heikkilä et al., 2007). They have been also used for controlled release and drug targeting providing sustained release for 16 h (Wen et al., 2006). Carbamazepine (CBZ), oxcarbazepine (OXC) and rufinamide (RFN) are three major antiepileptic drugs classified by the Bio- pharmaceutics Classification System (BCS) as Class II active pharmaceutical ingredients (Amidon et al., 1995; Amidon and Löbenberg, 2000) because they present low solubility and high per- meability. They are poorly water soluble drugs and the dissolution is the rate-limiting factor for absorption. Thus it is important to 0378-5173/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2009.12.023