Functionalized chitosan/NIPAM (HEMA) hybrid polymer networks as inserts for ocular drug delivery: Synthesis, in vitro assessment, and in vivo evaluation Liliana Verestiuc, 1 Oana Nastasescu, 1 Eugen Barbu, 2 Indrajeetsinh Sarvaiya, 2 Keith L. Green, 2 John Tsibouklis 2 1 Faculty of Medical Bioengineering, University of Medicine and Pharmacy”Gr.T. Popa”, 16 Universitatii St., Iasi, 700115, Romania 2 School of Pharmacy and Biomedical Sciences, University of Portsmouth, St. Michael’s Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom Received 5 September 2005; revised 3 November 2005; accepted 8 November 2005 Published online 22 March 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.30668 Abstract: A series of hybrid polymeric hydrogels, pre- pared by the reaction of acrylic acid-functionalized chitosan with either N-isopropylacrylamide or 2-hydroxyethyl methacrylate monomers, were synthesized, pressed into minitablets, and investigated for their ability to act as con- trolled release vehicles for ophthalmic drug delivery. For comparison, interpolymeric complex analogues synthesized using the same monomers and pure, unfunctionalized chi- tosan were examined by means of an identical characteriza- tion protocol. The effects of network structure and compo- sition upon the swelling properties, adhesion behavior, and drug release characteristics were investigated. Comparative in vitro studies employing chloramphenicol, atropine, nor- floxacin, or pilocarpine informed the selection of drug-spe- cific carrier compositions for the controlled delivery of these compounds. In addition, in vivo (rabbit model) experiments involving the delivery of pilocarpine indicated that chitosan- based hybrid polymer networks containing 2-hydroxyethyl methacrylate are useful carriers for the delivery of this ther- apeutic agent. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res 77A: 726 –735, 2006 Key words: functionalized chitosan; N-isopropylacrylam- ide; 2-hydroxyethyl methacrylate; ophthalmic drug deliv- ery; minitablets INTRODUCTION As a biocompatible and biodegradable material that also shows good release characteristics, chitosan pos- sesses many of the desired properties for safe use as a pharmaceutical excipient. 1–4 Consequently, much re- search has concentrated on the use of chitosan (CS) as a vehicle for the controlled and targeted release of therapeutic agents, 5–9 with many recent publications highlighting the need for chemical functionalization as the key to optimal carrier properties. 10 –15 The hy- droxyl moieties and the primary amino group of the d-glucosamine unit represent two readily accessible sites for the attachment of pendent functionalities. 16,17 Such structural modifications not only impact upon the physicochemical and biological properties of the material but also allow the manipulation of its mor- phology. 13 The covalent crosslinking of chitosan affords three- dimensional networks that exhibit desirable drug-dif- fusion characteristics. Examples of agents that have been used to effect crosslinking include alde- hydes, 18 –22 itaconic acid, 23 naturally-occurring geni- pin, 24 diisocyanates, 25 diepoxides, 26 and gelatin 27 ; thermal crosslinking has also been demonstrated. 28 An alternative crosslinking strategy involves the for- mation of direct covalent bonds between chitosan and other biocompatible polymers (Fig. 1). This approach offers the opportunity for further refinements to the properties of the drug carrier (e.g., mechanical strength, pH, and temperature sensitivity), by combin- ing the advantages of the chitosan molecule with those of the partner polymer. While full- or semi-interpen- etrating polymer networks (IPN) combining chitosan with synthetic macromolecules have received consid- erable attention as controlled release systems, 29 –33 lit- tle is known about the drug-carrier capabilities of analogous hybrid polymer networks (HPN), with re- Correspondence to: J. Tsibouklis; e-mail: john.tsibouklis@ port.ac.uk © 2006 Wiley Periodicals, Inc.