Oral insulin delivery using P(MAA-g-EG) hydrogels: effects of network morphology on insulin delivery characteristics Koji Nakamura a , Robert J. Murray a , Jeffrey I. Joseph b , Nicholas A. Peppas c , Mariko Morishita d , Anthony M. Lowman a, * a Department of Chemical Engineering, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA b The Artificial Pancreas Center, Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA, USA c Departments of Chemical and Biomedical Engineering, University of Texas, Austin, TX, USA d Department of Pharmaceutics, Hoshi University, Tokyo, Japan Received 9 September 2003; accepted 31 December 2003 Abstract Hydrogels of poly(methacrylic acid-g-ethylene glycol) were prepared using different reaction water contents in order to vary the network mesh size, swelling behavior and insulin loading/release kinetics. Gels prepared with greater reaction solvent contents swelled to a greater degree and had a larger network mesh size. All of the hydrogels were able to incorporate insulin and protected it from release in acidic media. At higher pH (7.4), the release rates increased with reaction solvent content. Using a closed loop animal model, all of the insulin loaded formulations produced significant insulin absorption in the upper small intestine combined with hypoglycemic effects. In these studies, bioavailabilities ranged from 4.6% to 7.2% and were dependent on reaction solvent content. D 2004 Elsevier B.V. All rights reserved. Keywords: Hydrogels; Complexation; Oral protein delivery; Insulin 1. Introduction Generally, peptides and proteins such as insulin cannot be administered via the oral route because of the degradation by the proteolytic enzymes in the gastrointestinal tract and the extremely slow rate of transport across the mucosal membrane. In order to overcome these hurdles to effective oral protein de- livery, several strategies have been employed, such as the use of absorption enhancers [1–3], enzyme inhib- itors [4,5], enteric coatings [6,7], and nanoparticle delivery [8]. Recently, nanoparticlulate delivery sys- tems have been studied because the incorporated protein and peptide-drugs could be protected from degradation in the gastrointestinal mucosa, and the attachment of ligands such as lectin on their surface provided for targeted delivery to specific GI segments (for absorption) because the lectin specifically inter- acts with the mucus layer, particularly glycoproteins [9,10]. However, the permeation of nanoparticles across the mucosa was still small (less than 10%), resulting in poor bioavailibility of the drug and plasma drug levels below the therapeutic levels [11,12]. The use of protease inhibitors [4,5] and absorption 0168-3659/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2003.12.022 * Corresponding author. Tel.: +1-215-895-2228; fax: +1-215- 895-5837. E-mail address: alowman@drexel.edu (A.M. Lowman). www.elsevier.com/locate/jconrel Journal of Controlled Release 95 (2004) 589 – 599