Diabetes Correction in Pancreatectomized Canines by Orally Absorbable Insulin−Deoxycholate Complex

Abstract

Oral insulin therapy has great potential benefits over conventional therapy for diabetic patients as well as mimicking the physiological fate of insulin. Here we evaluated the characteristics of insulin and deoxycholate-based synthetic N(alpha)-deoxycholyl-L-lysyl-methylester (DCK) complex, and diabetes correction in pancreatectomized canines after oral administration. After the insulin/DCK complexation was made, the insulin's folding structure, stability against digestive enzymes, lipophilicity and permeability to Caco-2 monolayer were evaluated in vitro. Diabetic canines were kept under fasting conditions, and Eudragit-coated gelatin capsules containing insulin or insulin/DCK powder were singly or triply administered. Evaluation of glucodynamics, pharmacokinetics, oral glucose tolerance test (OGTT) and reproducibility were carried out. After complexation with DCK, the folding structure of insulin did not become denatured and the resistance against digestive enzymes was powerfully improved. The lipophilicity and permeability of insulin/DCK (coupling ratio up to 1:10) were also highly increased. The insulin/DCK complex, administered orally into diabetic canines at the doses of 21, 42, and 81 IU/kg, reduced the plasma glucose levels by about 28%, 44% and 67%, respectively, while the plasma insulin concentrations increased. During OGTT, insulin/DCK nearly maintained the normoglycemic state in the diabetic canines, whereas the hyperglycemic state of placebo-treated controls was not corrected. During oral administration of insulin/DCK, it repetitively showed similar therapeutic efficacy in diabetic canines for 3 days. The therapeutic efficacy of insulin/DCK was exhibited in its digestive enzyme resistance, deoxycholate-based lipophilicity for enhancing permeability and intact insulin delivery without chemical modification, providing potential oral therapeutic remedy as an alternative to injectable insulin medication.

Intestinal permeation enhancers for oral peptide delivery

“…Korea [345]) in a 1:10 molar ratio increased the Log P METHYLENE CHLORIDE:WATER by 146-fold from 0.08 to 11.64 and increased transcellular flux across Caco-2 monolayers by 15-fold versus the native peptide [337]. Oral delivery of the insulin:DCK complex improved oral insulin absorption in rats by 6-fold [346].…”

“…route albeit at a higher dose [337]. DCK has also been shown to hydrophobise other drugs including ceftriaxone [347], heparin [348], and risedronate [349].…”

Absorption Mechanism of a Physical Complex of Monomeric Insulin and Deoxycholyl-l-lysyl-methylester in the Small Intestine

“…It is noteworthy to mention that the oral administration of DCK alone could not be attributed to glucose lowering effects or alter plasma insulin level. 11,12 However, the focus of our previous study was the physiological properties and also the biological activities of orally administered insulin. Despite demonstrating the promise of insulin/DCK as a substrate for the bile acid transporter in the ileum, the previous study had failed to generate any supportive data that confirms uptake of oral insulin through the ASBT.…”

Facilitated permeation of insulin across TR146 cells by cholic acid derivatives-modified elastic bilosomes

“…30,31 It has also been reported that SGC-lipo was the most superior in protecting gastrointestinal tract against enzymatic degradation, and this property was the main mechanism in enhancing the oral bioavailability of insulin. 32,33 Furthermore, the enhanced oral bioavailability of insulin, 34,35 cyclosporine A, 18 and itraconazole 36 has been demonstrated by employing liposomes containing bile salts. Similarly, bilosomes incorporating various drugs have shown their efficient applicability toward a transdermal route such as insulin, 37 methotrexate, 28 and tenoxicam.…”