Synthesis and Characterization of pH Sensitive Poly(PEGDMA-MAA) Copolymeric Microparticles for Oral Insulin Delivery Amit Kumar, 1 Sitanshu S. Lahiri, 2 Supriya Punyani, 1 Harpal Singh 1 1 Centre for Biomedical Engineering, Indian Institute of Technology-Delhi 110016, India 2 Experimental Animal Facility, Institute of Nuclear Medicine and Allied Sciences, Delhi 110052, India Received 13 March 2006; accepted 11 January 2007 DOI 10.1002/app.26181 Published online 27 September 2007 in Wiley InterScience (www.interscience.wiley.com). ABSTRACT: Poly(ethylene glycol) dimethacrylates (PEGDMA) were synthesized by esterification reaction of different molecular weight poly(ethylene glycol) with methacrylic acid in presence of acid catalyst. Their degrees of acrylation were found to be in the range of 93–95% using nuclear magnetic resonance (NMR) spec- troscopy. PEG dimethacrylates of molecular weight rang- ing from 400 to 4000 and methacrylic acid were further copolymerized to obtain pH sensitive crosslinked hydro- gel microparticles. The diameters of poly(PEGDMA- MAA) microparticles increased with increasing molecular weight of the poly(ethylene glycol) dimethacrylates and was found to be in the range of 0.4–2.7 mm at pH 7.4 and 5.2–25.3 mm at pH 2.5 in aqueous solution. Surface mor- phology of various polymeric samples were observed using SEM, which showed partial aggregation of par- ticles at pH 2.5 but microparticles coalesce with each other and appeared like a continuous film at pH 7.4. In vitro insulin release studies were performed by simulat- ing the condition of gastrointestinal tract, which showed only 18–25% insulin release into the aqueous medium at pH 2.5 in 90 min, while significantly higher release was observed at pH 7.4. In studies with diabetic rabbits, the blood glucose levels were lower for animals that received the insulin loaded hydrogel microparticles and the effect lasted for 8–10 h. Ó 2007 Wiley Periodicals, Inc. J Appl Polym Sci 107: 863–871, 2008 Key words: oral drug delivery; insulin; diabetes; hydrogel microparticles; poly(ethylene glycol) INTRODUCTION Oral delivery of proteins/peptides still remains a challenge for scientific community, because of bar- riers such as loss of activity during formulation and storage conditions, acidic environment of stomach, enzymatic degradation, and low epithelial permeability in gastro intestinal tract. 1,2 To benefit from the advantages of oral delivery, a number of studies have been carried out to develop oral insu- lin formulations. Actually, orally administered in- sulin is delivered first to the liver through portal circulation, similar to the physiological route of in- sulin secretion in nondiabetic individuals. Further- more, potential benefits from this route include improved disease management, enhanced patient compliance, and reduction of long term complica- tions of diabetes. 3–6 Polymeric systems attempted for oral insulin delivery include enteric coated dos- age forms and microencapsulations. 7,8 Various co- polymers, comprised either of methacrylic acid or acrylic acid for their pH-sensitive nature and methoxytermenated poly(ethylene glycol) for its ability to stabilize and protect insulin, have also been used for oral insulin delivery. 9–13 Some of the disadvantages with this approach include exposure of the proteins to the harsh possessing conditions, long processing times to prepare the micropar- ticles, rapid release (2 h) and the lower encapsula- tion efficiencies (as low as 40%). Some investiga- tors have also used absorption enhancers to in- crease the intestinal permeability. 14–16 Studies have proved that polymers containing carboxylic acid groups have the ability to protect insulin from pro- tease enzymes like trypsin and chymotrypsin. Binding of divalent cations (calcium and zinc) by these polymers was proposed to be the major rea- son for their enzyme inhibitory effect. 17,18 Further- more, reduction of extracellular divalent ion con- centration can result in opening of tight junctions and improves the paracellular peptide transport across the intestinal epithelium. 19 Moreover, mu- coaddhesive properties exhibited by these poly- mers increases the residence time of oral doses forms at the epithelial surface and improves drug absorption. 20 The present work is devoted towards the devel- opment of a pH sensitive polymeric formulation with high insulin loading efficiency, sustained, and Correspondence to: H. Singh (harpal2000@yahoo.com). Journal of Applied Polymer Science, Vol. 107, 863–871 (2008) V V C 2007 Wiley Periodicals, Inc.