International Journal of Pharmaceutics 411 (2011) 10–17 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Design and synthesis of a novel cationic thiolated polymer Deni Rahmat a,b , Duangkamon Sakloetsakun c , Gul Shahnaz a , Glen Perera a , Reinhard Kaindl d , Andreas Bernkop-Schnürch a,∗ a Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 52, Josef Möller Haus, 6020 Innsbruck, Austria b Department of Pharmaceutical Technology, Faculty of Pharmacy, Pancasila University, Srengseng Sawah, Jagakarsa 16240, Jakarta Selatan, Indonesia c Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand d Institute of Mineralogy and Petrography, Faculty of Geo- and Atmospheric Sciences, University of Innsbruck, Innrain 52, 6020 Innsbruck, Austria article info Article history: Received 18 January 2011 Received in revised form 23 February 2011 Accepted 25 February 2011 Available online 4 March 2011 Keywords: Hydroxyethyl cellulose Cysteamine Thiomer Mucoadhesive properties Permeation enhancing properties abstract The purpose of this study was to design and characterize a novel cationic thiolated polymer. In this regard a hydroxyethylcellulose-cysteamine conjugate (HEC-cysteamine) was synthesized. Oxidative ring opening with periodate and reductive amination with cysteamine were performed in order to immobilize free thiol groups to HEC. The resulting HEC-cysteamine displayed 2035 ± 162 mol immobilized free thiol groups and 185 ± 64 mol disulfide bonds per gram of polymer being soluble in both acidic and basic conditions. Unlike the unmodified HEC, in case of HEC-cysteamine, a three-fold increase in the viscosity was observed when equal volumes of the polymer were mixed with mucin solution. Tablets based on HEC-cysteamine remained attached on freshly excised porcine mucosa for 80 h and displayed increased disintegration time of 2 h. Swelling behavior of HEC-cysteamine tablets in 0.1 M phosphate buffer pH 6.8 indicated swelling ratio of 19 within 8 h. In contrast, tablets comprising unmodified HEC detached from the mucosa within few seconds and immediately disintegrated. In addition, they did not exhibit swelling behavior. The transport of rhodamine 123 across freshly excised rat intestine enhanced by a value of approximately 1.6-fold (p-value = 0.0024) in the presence of 0.5% (m/v) HEC-cysteamine as compared to buffer control. Result from cytotoxicity test of HEC-cysteamine applied to Caco-2 cells in concentration of 0.5% (m/v) revealed 82.4 ± 4.60% cell viability. According to these results, HEC-cysteamine seems to be a promising polymer for various pharmaceutical applications especially for intestinal drug delivery. © 2011 Published by Elsevier B.V. 1. Introduction Polymeric excipients can be classified as non-ionic, cationic and anionic. Among cationic polymers, poly(l-lysine), polyethylen- imine (PEI), polyamidoamine (PAMAM) dendrimers and chitosan seem to be the most commonly used. These polymers have been shown to have a significant application in gene and oligonucleotide delivery against tumors. Polymers based on PEI effectively complex DNA molecules leading to homogeneous spherical particles with a size ≤ 100 nm. These homogenous particles can transfect cells effi- ciently in vitro and in vivo. The higher charge density and more efficient complexation of DNA and/or oligonucleotides afford sig- nificantly enhanced protection against degradation by nucleases when compared to other polycations like poly(l-lysine). Chitosan polymers in the molecular weight range of 30–170 kDa have been shown to provide gene expression levels similar to PEI (Merdan et al., 2002; Jevprasesphant et al., 2003). On the other end, PAMAM dendrimers can mimic globular proteins and biological lipid bilayer ∗ Corresponding author. Tel.: +43 512 507 5371; fax: +43 512 507 2933. E-mail address: andreas.bernkop@uibk.ac.at (A. Bernkop-Schnürch). membranes. The DNA–PAMAM dendrimer complexes have been reported to show high stability, as well as enhanced gene expres- sion during in vitro transfections (Esfand and Tomalia, 2001; Tang et al., 1996). While PEI, poly(l-lysine) and PAMAM dendrimers exhibit high cytotoxicity, chitosan shows a significantly better biocompatibil- ity (Merdan et al., 2002; Jevprasesphant et al., 2003; Tang and Szoka, 1997). Many studies described the usage of chitosan for various drug delivery systems such as oral, parenteral and nasal administration because it demonstrates permeation enhancing and mucoadhesive properties (Dodane and Vilivalam, 1998). Recently, it has been demonstrated that the introduction of thiol groups on chitosan can lead to even further improved mucoadhesive, cohesive and permeation enhancing properties. The permeation enhanc- ing and the mucoadhesive properties effect of thiolated chitosans are approximately 80-fold and 140-fold higher, respectively, in comparison to unmodified chitosan (Sakloetsakun and Bernkop- Schnürch, 2010; Roldo et al., 2004). However, chitosan and subsequently thiolated chitosans bear the disadvantage of precipitation in aqueous media of pH above 6.5. Consequently, they do not reach their full potential as permeation enhancer on mucosal membranes where pH is above 6.5 (Kotzé 0378-5173/$ – see front matter © 2011 Published by Elsevier B.V. doi:10.1016/j.ijpharm.2011.02.063