Effect of bioadhesive polymers, sodium salicylate, polyoxyethylene-9-lauryl ether, and method of preparation on the relative hypoglycemia produced by insulin enteric-coated capsules in diabetic beagle dogs.

The hypoglycemic effect of oral insulin capsules coated with pH-dependent Eudragit S100 and containing various absorption promoters was studied in hyperglycemic beagle dogs. The absorption enhancers used were bioadhesive polymers, sodium salicylate, and non-ionic surfactants. A comparative study of the bioadhesive polymers, polycarbophil (PC), hydroxypropyl methylcellulose (HPMC), and carbopol 934 in insulin-coated capsules revealed no significant difference between the insulin capsules containing these polymers, giving relative hypoglycemia (RH) values ranging from 4.3 +/- 2.3% to 6.5 +/- 5.1%. It was also found that the method of preparation of the mixture of the bioadhesive polymer with insulin either by physical mixing or freeze-drying did not affect the RH values obtained. Sodium salicylate, when used in insulin enteric-coated capsules (50 mg) mixed with insulin as a physical mixture, or prepared by wet granulation using 10% polyvinyl pyrollidone (PVP), or by freeze-drying, produced RH values ranging from 7.3 +/- 2.9% to 9.4 +/- 3.7%. When sodium salicylate (100 mg) was used with insulin in freeze-dried granules an RH value of 10 +/- 2.6% was produced. As the dose of insulin increased from 6 to 9 U/kg, the area under curve (AUC) of the enteric-coated capsules containing 50 mg sodium salicylate increased from 73.2 +/- 27.8% to 121.4 +/- 102.7% reduction, but the RH did not change significantly. Insulin capsules containing polyoxyethylene-9-lauryl ether (POELE) used in its optimum concentration (2%), found in these experiments, produced RH of 9.5 +/- 6.8% when prepared as granules by wetting with a few drops of absolute alcohol in the presence of PC (50 mg). Insulin capsules containing lower (1%) or higher (3%) concentrations of POELE and prepared with PC, 50 mg by wet granulation produced lower RH of about 6%. The enteric-coated oral insulin capsules containing insulin (6 or 9 U/kg) and sodium salicylate (50 mg) as an absorption promoter, together with the bioadhesive polymer polycarbophil (50 mg), and prepared either by wet granulation using ethanol or by freeze-drying, are the best formulations to be used. They achieved a reduction in plasma glucose levels of about 25-30% and RH of about 10%. Also insulin (9 U/kg) capsules containing 2% POELE produced a 28% reduction in plasma glucose levels and RH of 9.6 +/- 6.8%.

Effect of bio-adhesive polymers, sodium salicylate, polyoxyethylene-9-lauryl ether and method of preparation on the relative hypoglycemia produced by insulin enteric coated capsules in diabetic beagle dogs.

The hypoglycemic effect of oral insulin capsules coated with pH-dependent Eudragit S100 and containing various absorption promoters was studied in hyperglycemic beagle dogs. The absorption enhancers used were bio-adhesive polymers, sodium salicylate and non-ionic surfactants. A comparative study of the bio-adhesive polymers, polycarbophil (PC), hydroxypropyl methylcellulose (HPMC) and carbopol 934 in insulin coated capsules, revealed no significant difference between the insulin capsules containing these polymers giving a relative hypoglycemia (RH) values ranged from 4.3 +/- 2.3% to 6.5 +/- 5.1%. It was also found that the method of preparation of the mixture of the bio-adhesive polymer with insulin either by physical mixing or freeze-drying did not affect the RH values obtained. Sodium salicylate, when used in insulin enteric coated capsules (50 mg) mixed with insulin as a physical mixture or prepared by wet granulation using 10% polyvinyl pyrollidone (PVP) or by freeze drying, produced RH values ranged from 7.3 +/- 2.9 to 9.4 +/- 3.7%. When sodium salicylate (100 mg) was used with insulin in freeze-dried granules an RH value of 10 +/- 2.6% was produced. As the dose of insulin increased from 6 to 9 U/kg, the AUC of the enteric coated capsules containing 50 mg sodium salicylate increased from 73.2 +/- 27.8 to 121.4 +/- 102.7% reduction but the RH id not significantly change. Insulin capsules containing polyoxyethylene-9-lauryl ether (POELE) used in its optimum concentration (2%), found in these experiments, produced a RH of 9.5 +/- 6.8% when prepared as granules by wetting with few drops of absolute alcohol in presence of PC (50 mg). Insulin capsules containing lower (1%) or higher (3%) concentrations of POELE and prepared with PC, 50 mg by wet granulation produced lower RH of about 6%. The enteric coated oral insulin capsules containing insulin (6 or 9 U/kg) and sodium salicylate (50 mg) as an absorption promoter together with the bioadhesive polymer polycarbophil (50 mg) and prepared either by wet granulation using ethanol or by freeze drying are the best formulations to be used. They achieved a reduction in plasma glucose levels of about 25-30% and RH of about 10%. Also insulin (9 U/kg) capsules containing 2% POELE produced 28% reduction in plasma glucose levels and RH of 9.6 +/- 6.8%.

Relative hypoglycemic effect of insulin suppositories in diabetic beagle dogs: optimization of various concentrations of sodium salicylate and polyoxyethylene-9-lauryl ether.

The effect of insulin suppositories containing different amounts and concentrations of sodium salicylate (50, 100 mg) and polyoxyethylene-9-lauryl ether (POELE 1, 3, 4%), respectively, on the plasma glucose concentration of diabetic beagle dogs was investigated after rectal administration. Comparison of the effects of these formulations was made with that produced after subcutaneous insulin injections. Insulin suppositories containing sodium salicylate (50 mg) produced a maximum reduction of plasma glucose concentration (Cmax) of 55 +/- 11%, an area under the curve (AUC) of 252 +/- 59% reduction h; and a relative hypoglycemia (RH) of 49 +/- 12% relative to subcutaneous injection of insulin (4 U/kg). Increasing sodium salicylate to 100 mg/suppository did not improve the hypoglycemic effect of insulin suppositories further. Investigation of the influence of insulin suppositories containing different concentrations of the nonionic surfactant POELE (1, 3, 4%) showed that; the suppositories containing the lowest concentration (1%) produced the highest hypoglycemic effect with a Cmax of 68%, AUC of 332 +/- 67% reduction h, and RH of 55 +/- 11%. Incorporation of sodium salicylate 50mg in insulin suppositories containing 1% POELE did not improve further the effects found with these suppositories. In conclusion, a relative hypoglycemic effect of about 50-55% can be achieved using insulin suppositories containing Witepsol W35 as a base, insulin (5 U/kg), and sodium salicylate (50 mg) or POELE (1%) as rectal absorption enhancers.

Effect of different bile salts on the relative hypoglycemia of witepsol W35 suppositories containing insulin in diabetic Beagle dogs.

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.

Ascorbate as an induction inhibitor of beta-lactamase in a strain of Enterobacter cloacae.

The effect of ascorbate and anaerobiosis of beta-lactamase content (constitutive and inducible) in relation to the susceptibility of a standard strain of Enterobacter cloacae to ampicillin was studied. Enterobacter cloacae ATCC 13047 showed increasing susceptibility to ampicillin when incubated anaerobically in the presence of increasing concentrations of ascorbic acid. The inducible beta-lactamase activity in the cell-free extracts of Ent. cloacae decreased when the bacterium was grown aerobically in the presence of ascorbic acid. Under anaerobic growth conditions, however, ascorbic acid abrogated the induction of the enzyme completely. On the other hand, the constitutive enzymatic activity was markedly decreased as the bacterium was grown anaerobically. Thus under these growth conditions ascorbate-anaerobiosis, the total beta-lactamase level in the presence of ampicillin as inducer fell below the basal constitutive activity observed in the absence of ampicillin.

Hypoglycemic activity of oral hypoglycemics with increased hydrophilicity.

The effect of increasing the hydrophilicity of acetohexamide and tolbutamide with hydroxypropyl methylcellulose and methylcellulose on drug dissolution and hypoglycemic activity in rats was examined. The dissolution rate of both drugs was increased according to the type and concentration of the polymer. The oral absorption of both drugs was improved, as indicated by potentiation of the reduction in blood glucose in rats. The efficiency of the polymer in increasing the dissolution rates of of the drugs correlated with hydrophilicity of the polymer.