Tricalcium phosphate delayed release formulation for oral delivery of insulin: a proof-of-concept study

Several attempts have been made for delivering insulin orally utilizing several polymers with varying degrees of effectiveness. A major obstacle associated with polymeric delivery system for protein or polypeptide drugs is the poor retention of the structure and its biological activity of encapsulated proteins particularly for the unstable insulin. Calcium phosphate ceramic is considered highly compatible to protein or peptide drugs, particularly insulin. Therefore, an attempt has been made to load insulin in tricalcium phosphate (TCP) microspheres and coat with pH sensitive polymer of methacrylate derivative, and to study the stability and conformational variations of loaded insulin, and finally the biological activity of the formulation in diabetic rats. TCP microspheres were prepared by a standard procedure. Human insulin was loaded in to these porous microspheres by diffusion filling and coated with Eudragit S100. This was subjected to in vitro release studies in simulated fluids and the stability and conformational variations of the released insulin were studied using photon correlation spectroscopy and circular dichroism (CD). Biological activity of the formulation was studied on induced diabetic rats. Insulin released in the intestinal fluid (SIF) maintained the native conformation without showing any aggregation. A dose dependent reduction of blood glucose level (BGL) was achieved in streptozotocin induced diabetic Wistar rats, demonstrating its biological activity. It has been established from this preliminary study that insulin loaded in to TCP microspheres is highly compatible with no degradation or loss of biological activity of loaded insulin. The TCP microsphere based delayed release formulation of insulin has effected a decrease in elevated glucose level in induced diabetic rats, establishing its feasibility towards the development of a noninvasive delivery device.