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.