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Frontiers of Chemical Science and Engineering >> 2013, Volume 7, Issue 1 doi: 10.1007/s11705-013-1306-9

Overcoming oral insulin delivery barriers: application of cell penetrating peptide and silica-based nanoporous composites

1. School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; 2. Department of Pharmaceutics, School of Pharmacy, Fudan University; Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Shanghai 201203, China; 3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 4. School of Environmental Science and Engineering, State Key Laboratory of Engines, Tianjin University, Tianjin 300072, China; 5. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; 6. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Michigan 48109-1065, USA

Available online: 2013-03-05

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Abstract

Oral insulin delivery has received the most attention in insulin formulations due to its high patient compliance and, more importantly, to its potential to mimic the physiologic insulin secretion seen in non-diabetic individuals. However, oral insulin delivery has two major limitations: the enzymatic barrier that leads to rapid insulin degradation, and the mucosal barrier that limits insulin’s bioavailability. Several approaches have been actively pursued to circumvent the enzyme barrier, with some of them receiving promising results. Yet, thus far there has been no major success in overcoming the mucosal barrier, which is the main cause in undercutting insulin’s oral bioavailability. In this review of our group’s research, an innovative silica-based, mucoadhesive oral insulin formulation with encapsulated-insulin/cell penetrating peptide (CPP) to overcome both enzyme and mucosal barriers is discussed, and the preliminary and convincing results to confirm the plausibility of this oral insulin delivery system are reviewed. In vitro studies demonstrated that the CPP-insulin conjugates could facilitate cellular uptake of insulin while keeping insulin’s biologic functions intact. It was also confirmed that low molecular weight protamine (LMWP) behaves like a CPP peptide, with a cell translocation potency equivalent to that of the widely studied TAT. The mucoadhesive properties of the produced silica-chitosan composites could be controlled by varying both the pH and composition; the composite consisting of chitosan (25 wt-%) and silica (75 wt-%) exhibited the greatest mucoadhesion at gastric pH. Furthermore, drug release from the composite network could also be regulated by altering the chitosan content. Overall, the universal applicability of those technologies could lead to development of a generic platform for oral delivery of many other bioactive compounds, especially for peptide or protein drugs which inevitably encounter the poor bioavailability issues.

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