A new drug carrier, Nalpha-deoxycholyl-L: -lysyl-methylester, for enhancing insulin absorption in the intestine.
OBJECTIVE
The development of an orally active insulin formulation will offer great advantages over conventional injectable insulin therapy in the treatment of patients with diabetes mellitus. Since insulin absorption in the intestine is restricted by the natural physiological characteristics of insulin, we developed a small synthetic compound, Nalpha-deoxycholyl-L: -lysyl-methylester (DCK), as an insulin carrier to enhance oral delivery.


METHODS
Streptozotocin-induced diabetic rats orally received single doses of insulin (42 U/kg) or insulin/DCK formulation (10, 21, 30 and 42 U/kg) under fasting conditions. Blood glucose levels and plasma insulin concentrations were measured for 6 h following the administration of the agents. An OGTT was also performed immediately after the administration of the oral insulin/DCK formulation.


RESULTS
The administration of 21, 30 and 42 U/kg (based on insulin activity) of insulin/DCK formulation reduced plasma glucose levels by up to 33.0% (median; range 30.6-70.2%), 78.5% (39.4-86.8%) and 75.2% (67.0-87.4%), respectively, compared with baseline levels. Furthermore, plasma insulin concentrations were observed to rapidly increase. In the OGTT, the insulin/DCK formulation reduced the AUC0-240 for glucose by 30.8% (22.3-54.9%) (p<0.01), and stabilized glycaemia for up to 4 h.


CONCLUSIONS
The results of this study demonstrate that the insulin/DCK formulation can be absorbed in the intestine and that it is biologically efficacious. We therefore suggest that this oral formulation could be used as an alternative to injectable insulin with enhanced clinical effects.
Lee
S
S
Center for Cell and Macromolecular Therapy, Department of Materials Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, South Korea.
Lee
J
J
Lee
D Y
DY
Kim
S K
SK
Lee
Y
Y
Byun
Y
Y
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004337:Drug Carriers / Q000138:chemical synthesis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007408:Intestinal Absorption; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; C504125:deoxycholyl-L-lysyl-methylester; D002635:Chenodeoxycholic Acid; D008239:Lysine
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