European Journal of Pharmaceutical Sciences 24 (2005) 411–419 Pegylated nanoparticles based on poly(methyl vinyl ether-co-maleic anhydride): preparation and evaluation of their bioadhesive properties Krassimira Yoncheva a,1 , Elena Lizarraga b , Juan M. Irache a,∗ a Centro Gal´ enico, Dep. Farmacia y Tecnolog´ ıa Farmac´ eutica, Universidad de Navarra, Apartado 177, Irunlarrea, 31080 Pamplona, Spain b Departamento de Quimica Organica y Farmaceutica, CIFA, Universidad de Navarra, 31080 Pamplona, Spain Received 3 September 2004; received in revised form 1 December 2004; accepted 10 December 2004 Available online 2 February 2005 Abstract Pegylated nanoparticles based on poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) were prepared by simple solvent displacement method, in the absence of catalysts or specific chemical conditions. Pegylation efficiency increased with the increasing of molecular weight and bulk concentration of poly(ethylene glycols) (PEGs) investigated. In fact, the use of PEG with molecular weight less than 1000 Da did not lead to its attachment. 1 H NMR spectroscopy was performed in order to estimate the conformation state of PEG-chains and to predict the nanoparticle structure. Pegylation with PEG 2000 gave surface modified nanoparticles (“brush” conformation), while the chains of PEG 1000 were distributed either in the core or physically adsorbed on the nanoparticle surface. The capacity of nanoparticles to adsorb mucin at pH 7.4 was significantly higher for PEG 1000-NP than for PEG 2000-NP. The “brush” layer seemed to decrease the interaction between PEG 2000-NP and mucin, which facilitated their penetration through the mucus gel. As a consequence, PEG 2000-NP displayed higher capacity to develop adhesive interactions with rat intestinal mucosa in vivo. Independent on the weaker bioadhesive potential of PEG 1000-NP, both types of pegylated nanoparticles demonstrated very high affinity to the intestinal mucosa rather than to the stomach wall, which could be established for drug targeting to the small intestine. © 2004 Elsevier B.V. All rights reserved. Keywords: Poly(ethylene glycol); Pegylated nanoparticles; Bioadhesion; Oral delivery 1. Introduction Colloidal nanoparticles are widely investigated as carriers for oral delivery of drugs over the last years. When nanoparti- cles are administered by oral route, only a small portion of the given dose appears to reach the gastrointestinal mucosa since they have to avoid eventual interactions with proteins or food components in the lumen and then to overcome the mucus barrier layer. Nanoparticles which interact with the mucus compounds could be entrapped in the mucus gel and sub- sequently removed by the normal mucus-turnover (Ponchel and Irache, 1998). If nanoparticles are able to diffuse through ∗ Corresponding author. Tel.: +33 948 425600; fax: +33 948 425649. E-mail address: jmirache@unav.es (J.M. Irache). 1 Department of Pharmaceutical Technology, Faculty of Pharmacy, 2 Dunav Str., 1000 Sofia, Bulgaria. the mucus network, they may adhere to the cell surface and, in some cases, to be taken up and translocated (Florence and Hussain, 2001). Despite of these phenomena, it has been clearly demon- strated the efficacy of particulate carriers to improve the oral bioavailability and activity of a number of drugs. The enhanced bioavailability can be related to the capacity of nanoparticles to interact strongly with the upper regions of the gut, including chitosan (Chen et al., 2004), poly(lactic acid) (PLA) (Florence and Hussain, 2001), gliadin (Arangoa et al., 2001) and poly(methyl vinyl ether-co-maleic anhy- dride) (Arbos et al., 2002a) nanoparticles. However, the de- sign of nanoparticulate systems able to adhere to the small intestine mucosa and/or to target specific areas within the gut appears to be more difficult. During the last years, dif- ferent strategies have been developed including the use of surfactants (Jung et al., 2000), lectins (Hussain et al., 1997), 0928-0987/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2004.12.002