Effect of Different Bile Salts on the Relative Hypoglycemia of Witepsol W35 Suppositories Containing Insulin in Diabetic Beagle Dogs

Abstract

Insulin suppositories were formulated using Witepsol W35 as a base to investigate the effect of various bile salts/acids on the plasma glucose concentration of diabetic beagle dogs. Comparison of the effect of these formulations was made with that produced by insulin subcutaneous injections. Of the bile salts/acids studied, incorporation of 100 mg of deoxycholic acid (DCA), sodium cholate (NaC), or sodium deoxycholate (NaDC) with insulin (10 U/Kg) showed that suppositories containing NaDC produced the highest area under the curve (AUC) and relative hypoglycemia (RH) of 290 +/- 83 mg%h and 28% +/- 8.1%, respectively. To study the optimum amount of NaDC in insulin suppositories to produce the highest RH, 50-200 mg/suppository were used, and we found that 150 mg NaDC produced 35% +/- 13% RH. We also studied the influence of different doses of insulin (5-20 U/kg) in the presence of NaDC (100 mg). It was found that increase of the insulin dose was accompanied by an increase in AUC and maximum reduction in plasma glucose level Cmax. A combination of NaDC (100 mg) and NaC (50 mg) produced an AUC of 252 +/- 13mg%h and an RH of 49% +/- 2.6%, which were higher than produced by either of its individual components (NaC 50 mg or NaDC 100 mg) when used alone or when compared with an equivalent amount of NaDC (150 mg). When the effect of sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC) was studied, it was found that an insulin suppository containing 100 mg of either NaTC or NaTDC produced an RH equivalent to that produced previouslY with a mixture of NaDC (100 mg) and NaC (50 mg). On the other hand, NaC (50 mg) did not improve the hypoglycemic effect of NaTC any further. In conclusion, a relative hYpoglycemia of about 50% can be reached using insulin suppositories containing Witepsol W35 as a base and NaDC plus NaC (100 mg plus 50 mg, respectively), NaTDC (100mg), or NaTC (100 mg) as rectal absorption enhancers of insulin. A desirable hypoglycemia, expressed as Cmax, and/or AUC can be reached by adjusting the insulin dose in the formulation according to the degree of hyperglycemia.

Routes of administration of insulin

“…A relative decrease in blood glucose level of about 50% was attained using this formulation in vivo [53].…”

Novel noninvasive techniques in management of diabetes

“…Use of DCA, NaC, and NaDC as rectal absorption enhancers of insulin is promising approach in rectal insulin delivery. [214] Insulin suppositories containing sodium salicylate (50 mg) and polyoxyethylene-9-lauryl ether (1%) showed relative hypoglycemia of 49% ± 12% and 55% ± 11% relative to subcutaneous injection of insulin (4 U/kg). [215] Further research in this area leads to the development of thermo-reversible insulin liquid suppository composed of poloxamer P 407, P 188, polycarbophil and sodium salicylate, which undergoes a phase transition to bioadhesive gels at body temperature and ultimately enhances the bioavailability of insulin.…”