Oral delivery of Exenatide using solid nano-in-micro-particles - ICRS 2018 The 11th Meeting of The Israel Chapter of the Controlled Release Society

Liat Soudry-Kochavi ¹ Natalya Naraykin ¹ Rosanna Di Paola ² Enrico Gugliandolo ² Alessio Peritore ² Salvatore Cuzzocrea ² Ehud Ziv ³ Taher Nassar ¹ Simon Benita ¹

¹The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
²Pharmacology Department, University of Messina, Messina, Italy
³Diabetes Unit, Division of Internal Medicine, Hadassah Ein Kerem Hospital, Jerusalem, Israel

Exenatide (4.1kDa) is a glucagon-like peptide-1 agonist, a regulator of glucose metabolism and insulin secretion, approved for type 2 diabetes treatment by subcutaneous injection. To overcome the low oral bioavailability of exenatide and address adherence issues of patients following daily injections, we incorporated exenatide into nanoparticles (NPs) composed of cross-linked dextran and albumin and further encapsulated into gastro-resistant microparticles (MPs). The physicochemical character and morphology of various NPs and MPs were evaluated. Two leading formulations, differing in dextran amount, DX-50 and DX-150, elicited a relatively high oral bioavailability of 77% and 46%, respectively, compared to SC injection of Byetta™ (commercial exenatide formulation). DX-50 oral formulation showed similar efficacy to that of Byetta®, in a well-established diabetic rodent model of ob/ob mice. Over thirty days experiment, DX-50 succeeded in lowering blood glucose levels over time (BGL AUC) by 600mg*h/dL, which did not differ significantly from the AUC value achieved by SC injection of Byetta™ (p<0.01). Both oral formulations raised insulin levels significantly but not to the same extent as of Byetta™. DX-50 elicited a larger decrement in glycated hemoglobin (HbA 1C ) than DX-150 (1.8 versus 1%). In the ob/ob groups treated by DX-50, DX-150 or Byetta™, no significant increase in weight was recorded, as oppose to negative control groups (i.e. blank MPs).

An attempt to elucidate the absorption processs of the NPs and their incorporated macromolecules was made using fluorescent probes bound to either exenatide or albumin. The results suggested that both albumin (NPs) and exenatide penetrated in the enterocytes while microencapsulated in the MPs. The potential of this technique to encapsulate other macromolecules such as insulin (5.8kDa), salmon calcitonin (3.4kDa) or liraglutide (3.7kDa) was also evaluated. It was found that this novel delivery system is suitable for linear peptides, with molecular weight of less than 6kDa and not soluble in acetone.