Dramatic improvement in pharmacokinetic and pharmacodynamic effects of sustain release curcumin microparticles demonstrated in experimental type 1 diabetes model

Abstract

ABSTRACT Curcumin (cur) is a well known plant flavonoid with pleiotropic pharmacological activities. However, due to its poor bioavailability those therapeutic benefits are still out of reach for patient community. The main aim of our study was to prepare sustained release cur microparticles (CuMPs) with Poly (lactic‐co‐glycolic acid) (PLGA), an FDA approved biodegradable polymer and to assess their pharmacological potential in multiple low doses streptozotocin (MLD‐STZ) induced type 1 diabetes mellitus (T1DM). CuMPs were formulated and characterized for size (12.71±4.20&mgr;m) and encapsulation efficiency (85.10±2.33%) with 28% drug loading. In vitro release and in vivo pharmacokinetics studies showed promising results of sustained release of cur from CuMPs. With this here we report a strategy that single administration of CuMPs may fill the therapeutic window that is missing from free drug repeated administration and low bioavailability of cur. Moving forward with this concept, we compared the therapeutic effects of CuMPs (equivalent to 7.5mg/kg cur with free cur orally (100mg/kg) and intraperitoneally (7.5mg/kg) administered daily in MLD‐STZ challenged animals). CuMPs exhibited superior effects compared to daily administration free drug given either orally or i.p. in terms of lowering the blood glucose levels, improved glucose clearance as evident from results of i.p. glucose tolerance test (IPGTT). Interestingly, we observed a remarkable reduction in diabetes incidence in CuMPs groups (only one out of six animals i.e. 16.6%). Moreover, plasma and tissue levels of insulin indicated superior effect of CuMPs. In addition, immunohistochemical analysis of insulin in pancreatic &bgr;‐cells further confirmed the improved therapeutic benefit with significant increase in insulin signal with CuMPs. Amelioration of oxidative stress and inflammation of CuMPs was observed as the molecular mechanism behind the observed superior pharmacological effects with CuMPs. Cumulatively, our sustained release CuMPs formulation may serve as a bridge in overcoming the poor pharmacokinetics issues associated with cur and may hasten the clinical translation of cur.