Oral insulin delivery is projected to provide both physiologic and technical benefits, and has been the focus of rigorous research efforts in recent years. The ORMD-0801 oral insulin formulation relies on the activities of both protease inhibitors and an absorption enhancer to ensure insulin integrity and bioavailability. In efforts to further improve its efficacy, a recombinant protease inhibitor (rPI), identical in sequence to its naturally sourced (nsPI) counterpart, was cloned and expressed in Pichia pastoris. The enzymatic activity of the isolated and purified protein was then tested in vitro. In addition, the glucose-lowering effect of ORMD-0801 formulated with various doses of rPI was assessed in 8 healthy, fasting pigs administered the preparation directly to the duodenum. rPI effectively inhibited its standard substrate in a dose-dependent manner and demonstrated >2.5-fold higher activity as compared to nsPI. When integrated in the ORMD-0801 formulation, pigs treated with the formulation containing 25 mg rPI experienced a 20% greater change from baseline serum glucose concentrations as compared to those treated with the PI-free formulation (AUC: -6369 mg/dL vs. -2201 mg/dL, respectively). In parallel, the duration of its effect (140±33 minutes) was 75% longer than the duration of the effect of the PI-free formulation (80±37 minutes). Further calibrations of the rPI-supplemented ORMD-0801 formulation promise to enhance oral insulin bioavailability and its salutary effects, subsequently improving its clinical potential and value.


R. Nagaraju: None. S. Madan: None. K. Arora: None. N.M. Arora: None. P.K. Kundu: None. Y. Greenberg-Shushlav: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc. A. Hershko: Advisory Panel; Self; Oramed Pharmaceuticals, Inc..

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