• Significant Hypoglycemic Effect of a Perorally-delivered Insulin in the Treatment of Streptozocin-induced Diabetic Rats
• Signifcant Enhancement of Triglyceride-lowering Effect by Intraduodenum-delivered Oral Insulin, Simavastatin and Pravastatin, formulated with Coremed s drug delivery system, in comparison to Atrovastatin in rats
• Glucose Responses to Food Intake in Non-diabetic Rats Treated with Per-orally Delivered Insuln (Musulin)

Frank K Leung, Jiang Li, Lanqui Huang and Emily Leung

The effectiveness of an oral insulin (Musulin) in streptozocin-treated diabetic rats was evaluated by a single-dose or multiple-doses algorithm method,administered perorally. Experimental and control groups were performed concurrently and matched with comparable weight(230 gm),age(4-5 months) and initial glucose levels (330 mg/ml). The differences in these parameters were statistically insignificant between these two groups. Statistical analysis was performed using SAS 8.0.Experiment 1 (single-dose, 0.4u/gm): Glucose was sampled from the Jugular vein at time: 0, 15, 30, 60, 120, 180, 300, 360, 420, 480 min. Results of normalized glucose - Control group (N=4): 100, 106, 114, 105, 102, 89, 86, 75, 77, 55, 57. Musulin-treated group (N=4): 100, 101, 95, 61, 45, 37, 29, 32, 33, 36. Sustained statistically significant hypoglycemia occurred at 60, 120, 180, 300 min. ( p<0.025, 0.009, 0.004, 0.02 )and glucose was lowered by 44.8 - 57.4%. Experiment 2 (algorithm method): Glucose was sampled from the tails at 9 AM and 4 PM daily for 3 weeks. No insulin was given if the glucose was at or below 150 mg/ml. Musulin was administered perorally at 0.05 unit for each 1 mg/ml glucose rose above 150 mg/ml in week 1, the dose was increased to 0.1 unit in week 2 and then, to 0.2 unit in week 3. Statistical analysis was performed by SAS 8.0, compound symmetry of within covariance matrix and repeated measures of ANOVA. Results of glucose levels - Week 1: AM glucose difference between control (N=8) and Musulin group (N=12) was 100.63 (S.E. 35.33), P<0.01; PM difference was 123.87 (S.E. 37.4), P<0.004. Week 2: AM difference was 107.63 (S.E. 40.94), P<0.01 and PM difference was 135.98 ( S.E. 38.92), P<0.0026. In Week 2, 4 control and 9 Musulin survived. 2 Musulin rats died of hypoglycemia.In Week 3, 2 control and 9 Musulin survived.Conclusion: 1) Musulin is effective in lowering glucose levels, delivered perorally as a single dose or multiple doses by algorithm method in diabetic rats.2) Hypoglycemia occurred within 60 min. 3) More diabetic rats survived when treated with Musulin than control over a 3 weeks period.

Frank K Leung, Jiang Li, Lanqui Huang and Emily Leung

In human studies of primary hypercholesterolemia and Type IV hypertriglyceridemia, atrovastatin (A) performs better than simavastatin(S) and pravastatin(P)in its cholesterol- and triglyceride-lowering efficacy. In rats, these drugs also have significant triglyceride-lowering effect which correlates positively with the cholesterol-lowering action in human study. The current study compared the triglyceride-lowering effect of S, P and oral insulin formulated with Coremed s drug delivery system which is designed for intraduodenal delivery to A with Lipitor (Pfizer) formulation ( not formualted with Croemed s drug delivery system ) and placebo. After 12 hours fast, a surgical incision was made in the abdoment, a group of 5 rats (250-300 gm) each was given 5 mg of S, or 5 mg of P or oral insulin (Intesulin 0.2 u/gm) intraduodenally with a 30 gauge syringe. Control group consisted of 5 rats each was given placebo intraduodenally or 5 mg of A intragastrically. Jugular vein blood was sampled and pooled for triglyceride measurements hourly for 8 hours. In the oral insulin and placebo groups, blood was also sampled at 24, 36 and 48 hours. Results: The nadir in the oral insulin group occurred at 24 hours. For other groups, the low point occurred at 8th hour. In comparison to the placebo, A lowered triglyceride by -15.3%, S by -44.7%, P by -83.7% and oral insulin by -60% at the lowest point respectively. In conclusion, our preliminary data suggested that intraduodenal-delivered simavastatin and pravastatin formulated with Coremed s drug delivery system performed much better than atrovastatin in lowering triglyceride levels.Coremed s oral insulin has triglyceride-lowering efficacy comparable to the inhibitors of HMG CoA reductase with sustained action lasting over 24 hours.

Jing Li, Frank K Leung, Emily Leung and Shao-Ling Soo.

We have previously demosntrated the efficacy of high dose oral insulin. This study is to evaluate the effects of food intake on the glucose responses in non-diabetic rats treated with lower dose Musulin at 0.02 unit/gram or 20 units/kg, delivered per-orally as one single dose. Procedures and materials: Study was concurrent. All were non-diabetic rats with average weight 292 gm. Average baseline line glucose was 72 mg/dl after 12 hours fast.. Placebo control (C ): n=4. Musulin: n=4. Musulin concentration: 250 units/ml. Dose: 0.02 unit/gm. Food intake was given as two ml of D50W per-orally at 30 minutes of the experiment. Average dosing volume: 0.02ml given as one single administration at time 0. Blood glucose was sampled from the tails at time 0, 15, 30, 45, 60, 120, 240, 300, 360. Data and results: Glucose was normalized as percentage of the baseline glucose at time 0. Glucose of C: 100%, 102%, 109%, 150%, 171%, 182%, 180%, 175%, 163%, 143%. Glucose of Musulin group: 100%, 100%, 96.3%, 113.8%, 126.8%, 132.5%, 125%, 117%, 108%, 92%. Statistical analysis: SAS 8.01. Significance is at 5%. Percent glucose-lowering effects of Musulin compared to C: 0%, 2%, 12%, 24%, 26%, 28%, 31%, 33%, 34%, 36%. Significant glucose-lowering effect occurred at 30 minutes. Compared to control, Glucose was lowered by 12% just before food intake. 36% at time 360 minutes. At 360 mintues, the Musulin group returned to the baseline glucose levels, whereas the Control group glucose were still 42.5% above their baseline levels. Conclusion: Musulin has onset of action at 30 minutes with a dose of 0.02 u/gm delivered per-orally. Musulin lowers pre-meal and post-meal glucose significantly, and has a sustained long action over 360 minutes.