Development, optimization and biological evaluation of chitosan scaffold formulations of new xanthine derivatives for treatment of type-2 diabetes mellitus Florentina Geanina Lupascu a , Mamoni Dash b , Sangram Keshari Samal c , Peter Dubruel b , Catalina Elena Lupusoru d , Raoul-Vasile Lupusoru d , Oana Dragostin a , Lenuta Profire a,⇑ a University of Medicine and Pharmacy ‘‘Grigore T. Popa’’, Faculty of Pharmacy, University 16, 700115 Iasi, Romania b Polymer Chemistry & Biomaterials Research Group, Ghent University, Krijgslaan 281, S4-Bis, B-9000 Ghent, Belgium c Laboratory of General Biochemistry and Physical Pharmacy, Centre for Nano- and Biophotonics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium d University of Medicine and Pharmacy ‘‘Grigore T. Popa’’, Faculty of Medicine, University 16, 700115 Iasi, Romania article info Article history: Received 16 April 2015 Received in revised form 4 June 2015 Accepted 12 June 2015 Available online 12 June 2015 Keywords: Diabetes mellitus Chitosan Microparticles Xanthine derivative Drug delivery abstract New xanthine derivatives as antidiabetic agents were synthesized and new chitosan formulations have been developed in order to improve their biological and pharmacokinetic profile. Their physicochemical properties in terms of particle size, morphology, swelling degree, crystalline state, the loading efficiency as well as in vitro release and biodegradation rate were evaluated. According to the results the opti- mized formulations have a high drug loading efficiency (more than 70%), small particle size, a good release profile in the simulated biological fluids (the percentage of cumulative release being more than 55%) and improved biodegradation rate in reference with chitosan microparticles. The presence of xanthine derivatives (6, 7) in chitosan microparticles was demonstrated by means of FTIR analysis. The X-ray diffraction (XRD) proved that xanthine derivatives present a crystalline state. The biological evaluation assays confirmed the antioxidant and antidiabetic effects of the xanthine derivatives (6, 7) and their chitosan formulations (CS-6, CS-7). Xanthine derivative 6 showed a high antiradical scaveng- ing effect (DPPH remaining = 41.78%). It also reduced the glucose blood level with 59.30% and recorded level of glycosylated hemoglobin was 4.53%. The effect of its chitosan formulation (CS-6) on the level of blood glucose (114.5 mg/dl) was even more intense than the one recorded by pioglitazone (148.5 mg/dl) when used as standard antidiabetic drug. These results demonstrated the potential application of xan- thine derivative 6 and its chitosan formulation (CS-6) in the treatment of the diabetes mellitus syndrome. Ó 2015 Elsevier B.V. All rights reserved. 1. Introduction Diabetes mellitus type 2 (T2DM) is the most common form of diabetes, which is strongly associated with a sedentary life style and obesity (Dandona and Aljada, 2004). T2DM is a complex meta- bolic syndrome affecting more than 100 millions of people from all over the world, being considered one of the five causes of world mortalities (Shanmugam et al., 2011). There are two factors that are strongly related to hyperglycemia: insulin resistance in the liver, the adipose tissue and the skeletal muscles and insulin defi- ciency caused by the pancreatic b-cell dysfunction (Jin et al., 2008). Current antidiabetic therapy include four classes of drugs: sulpho- nyureas and glinides, biguanides, thiazolidinediones and a-glucosidase inhibitors. Unfortunately, all current drugs, are fre- quently associated with several side effects as weight gain, edema, anemia, heart failure, fracture of bones and gastrointestinal intol- erance (Cariou et al., 2012; Quin et al., 2008). The newly discovered incretin effect has provided a new path of treatment which is able to reduce the hyperglycemia with minimal side effects. The incretin hormones called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) increase glucose-dependent stimulation of insulin secretion, suppress abnormally elevated glucagon secretion from pancreatic http://dx.doi.org/10.1016/j.ejps.2015.06.008 0928-0987/Ó 2015 Elsevier B.V. All rights reserved. ⇑ Corresponding author. E-mail addresses: lupascu.geanina@yahoo.com (F.G. Lupascu), mamoni.dash@ ugent.be (M. Dash), sangramkeshari.samal@ugent.be (S.K. Samal), peter.dubruel@ ugent.be (P. Dubruel), celupusoru@yahoo.com (C.E. Lupusoru), rvlupusoru@yahoo. com (R.-V. Lupusoru), oana.dragostin@umfiasi.ro (O. Dragostin), lenuta.profire@ umfiasi.ro (L. Profire). European Journal of Pharmaceutical Sciences 77 (2015) 122–134 Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps