In vitro and in vivo evaluation of a novel oral insulin formulation.
OBJECTIVE
To develop a stable self-emulsifying formulation for oral delivery of insulin.


METHODS
Caco-2 cell line and diabetic beagles were used as in vitro and in vivo models to study the absorption mechanism and the hypoglycemic efficacy of the formulation. In addition, various physicochemical parameters of the formulation such as droplet size, insulin encapsulation efficiency and stability were evaluated.


RESULTS
This formulation enabled changes in barrier properties of Caco-2 monolayers, as referred by transepithelial electrical resistance (TEER) and apparent permeability coefficients (P(app)) of the paracellular marker ranitidine (20-fold greater than control) but not transcellular marker propranolol, suggesting that the opening of tight junctions was involved. In diabetic beagle dogs, the bioavailability of this formulation was up to 15.2% at a dose of 2.5 IU/kg in comparison with the hypoglycemic effect of native insulin (0.5 IU/kg) delivered by subcutaneous injection.


CONCLUSIONS
This formulation, recently approved by the China State Food and Drug Administration to enter clinical trials, was stable, degradation-protected and absorption-enhanced, and provided a promising formulation for oral insulin delivery.
Ma
Er-li
EL
State Key Laboratory of Bio-membrane and Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China.
Ma
Hong
H
Liu
Zheng
Z
Zheng
Ghang-xue
GX
Duan
Ming-xing
MX
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D003651:Decanoates; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004285:Dogs; D004338:Drug Combinations; D016503:Drug Delivery Systems; D004355:Drug Stability; D017097:Electric Impedance; D004655:Emulsions; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D011092:Polyethylene Glycols; D021381:Protein Transport; D011899:Ranitidine / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
D001786:Blood Glucose; D003651:Decanoates; D004338:Drug Combinations; D004655:Emulsions; D007328:Insulin; D011092:Polyethylene Glycols; D011899:Ranitidine