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2001 Endocrine Society 83rd Annual Meeting |
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A new intestinal transmucosal insulin formulation
(Intesulin) - its glucose responses and insulin pharmacokinetics in
diabetic rats and in comparison to subcutaneous insulin injection
F.K. Leung, J. Li, E.C. Leung and L. Huang.
Purpose: To evaluate the insulin pharmacokinetics and glucose
responses of an intestinal transmucosal insulin
(Intesulin,concentration:25 u. insulin/ml) in diabetic rats and in
comparison to Humalog™ (U100,Eli Lilly) subcutaneous injection.
Methods: All diabetic rats aged 2-21/2 months. Diabetes was induced
by Streptozotocin. Group 1(control, placebo): 4 rats; Group
2(Intesulin,0.2u/gm): 8 rats; Group 3(Humalog,0.2 u/gm): 4 rats;
Group 4 (Intesulin, 0.2 u/gm):5 rats; Group 5(Humalog,0.2 u/gm):5
rats. Protocol: All animals received same amount of insulin by
weight. After 12 hrs fast, the abdominal wall was dissected. At time
0, Intesulin or placebo was injected through a 30 gauge needle
syringe into the duodenum. Insulin was sampled and pooled from the
hepatic portal vein, followed by jugular vein from Group 4,5 at
0,5,15,30,60,90,120 min. Glucose was sampled from jugular vein in
Group 1,2,3 without insulin sampling at time 0, 5, 15, 30, 60, 120,
180, 240, 300, 360, 420,480,540,600 min. Study was terminated with
D50W feeding when glucose was 80 mg/ml or lower. Statistical
Analysis: SAS system,v6.12: non-compartmental calculation of Pk
parameters, Dunnett's t for multiple comparisons, repeated measures
analysis of slope. Data and Summary: 1)Significant hypoglycemia
onset: Group 3:15 min., Group 2:60 min. 2)Glucose reduction slope:
Group 3:-40.9% per hour, Group 2: -12.2% per hour.3) Glucose Nadir:
Group 3: 20% of time 0 at 120 min., Group 2: 20% of time 0 at 540
min. 4)Hepatic portal vein insulin peak absorption: Group 2: 1728
min/ml at 5 min.5)Glucose AUC_average over time mean: Group 1:80.1
(min.45.6,max.114.1);Group 2:59.4 (min.42.2,max.89.2); Group 3:61.2
(min.44.6,max.76.2) At 120 min., Intesulin achieved 41.3% of glucose
reduction by Humalog injection. Conclusion: Intesulin lowers glucose
in diabetic rats in a linear slope from time 0 to 540 min. It has an
extremely rapid insulin absorption at 5 min. and increased by 23351%
from time 0. Although Humalog has a quicker onset of action,
intesulin achieved the same end point as Humalog and its AUC_glucose
is the same as the latter, suggesting of comparable and sustained
efficacy as in Humalog injection. |
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A new intragastric transmucosal insulin (Gastrisulin)
- its glucose responses in non-diabetic rats and in comparison to
its Azone (Laurocapram) formulation.
F.K. Leung, J. Li, L. Huang and E. C. Leung,
Purpose: To evaluate the glucose reponses between Gastrisulin-C (intragastric
oral insulin delivery) and subcutaneous Humalog™ injections in
non-diabetic rats and in comparison to its Azone formulation.
Methods: All rats aged between 1 1/2-2 months. Group 1(control,
placebo):5 rats,Group 2 (Gastrisulin-C, 12.5u):5 rats, Group 3 (Humalog,
12.5u): 4 rats,Group 4 (Gastrisulin-Azone, 25 u):5 rats. Protocol:
After fasting for 12 hrs, blood glucose was sampled and measured
from the jugular vein in Group 1,2,3,4 at
time:0,5,10,15,30,60,90,120,150,180,210,240,270,300 min. Ether was
used for anesthesia. At time 0, the abdominal wall was opened,
Gastrisulin-C, or Gastrisulin-Azone or Placebo was injected into the
superior antrum of the stomach by a 30 gauge syringe. The junction
between the stomach and duodenum was gently clamped to prevent
leakage of content into the intestine. Group 3 rats received
identical surgical procedure and Humalog injection subcutaneous in
the abdominal wall. The surgical wound was immediately closed after
drug or placebo administration. Statistical Analysis: SAS
system,v6.12:non-compartmental calculation of Pk parameters,
Dunnett's t for multiple comparisons, repeated measures analysis
slope. Data and Summary:1) Blood Glucose at time 0,15,60,120,180
min.: Control 100%,150%, 160%,175%,160%.Gastrisulin-C
-100%,88%,75%,78%,70%. Gastrisulin-Azone-100%,105%,85%, 78%,75%.
Humalog -100%,21%,18%,18%,15%. 2) Significant hypoglycemia:
Gastrisulin-C or -Azone: 15 min., Humalog - 5 min. 3) AUC_mean:
Gastrisulin-C or -Azone: 90, Humalog -25.013, Control -164.091.
4)Gastrisulin-C at 12.5 u has similar hypoglycemic efficacy as
Gastrisulin-Azone at 25 u. 5) Gastrisulin-C achieves 61.7% of the
Humalog hypoglycemic efficacy at 120 min. Conclusion: Gastrisulin-C
is a very effective transmucosal insulin formulation even when it is
given intragastrically. Adding Azone (Laurocapram), a transdermal
enhancer, does not improve the Gastrisulin efficacy. Gastrisulin-C
has a rapid onset and sustained hypoglycemic action over 3-5 hours. |
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A new oral insulin formulation (Musulin) - its
glucose responses and insulin pharmacokinetics in non-diabetic rats
and in comparison to subcutaneous insulin injection.
J. Li, F.K. Leung, L. Huang and E.C. Leung.
Purpose: To evaluate the glucose reponses and insulin
pharmacokinetics between Musulin (25 u insulin/ml) and subcutaneous
Humalog ™ (Eli Lilly, U100) injections in non-diabetic rats.
Methods: All rats aged 11/2-2 months. Group 1 (control, placebo): 5
rats, Group 2 (Musulin, 12.5 u): 4 rats, Group 3 (Humalog, 12.5 u):
4 rats, Group 4 (Musulin, 12.5 u): 5 rats. Group 5 (Humalog,12.5u):5
rats. Protocol: After 12 hours fast, blood glucose was sampled from
jugular veins in Group 1,2,3 at time:
0,5,15,30,60,90,120,150,180,210, 240,300 minutes. Musulin or placebo
was fed perorally in Group 1,2,4 at time 0. Humalog was injected
subcutaneously in the abdomen of Group 3,5 at time 0. Insulin was
measured from jugular veins and pooled in Group4,5 at time
0,15,30,60,120,300,480 minutes. Statistical Analysis: SAS
system,v6.12:non- compartmental calculation of Pk parameters,
Dunnett's t for multiple comparison and repeated measures analysis
of slope. Data and Summary:1)% glucose reduction at time
0,30,60,120,150 min.- Control: 100%,119%,125%,140%,116%; Musulin
group:100%, 95%, 88%,78%62%; Humalog group:100%,28%,
28%,22%,17%.2)Significant hypoglycemia: Musulin: 15 min., Humalog: 5
min..3)Peak insulin absorption: Musulin - 15 min., Humalog - 60
min.4) Cmax insulin: Musulin - 229 min/ml, Humalog - 9260
min/ml.5)Total insulin bioavailablity: 3.2%(AUC_Tauc), 2.2% (AUC_infinity),0.95%
(AUC_average). 6)Insulin half life: Musulin- 99.66 min., Humalog -
38.56 min.,7)Hypoglycemic efficacy (AUC_average Glucose divided by
AUC_average Insulin absorbed):Musulin - 112.405/55.24=2.0348,Humalog
- 24.013/5803.33 = 0.00413 8) Relative insulin potency ( Musulin
divided by Humalog hypoglycemic potency): 2.0348/0.00413 =
491.77.Conclusion: 1)Musulin has a quick onset action and peak
insulin absorption at 15 min. 2)Musulin achieves 42.3 -45.6% of the
Humalog injection hypoglycemic efficacy between 60-120 min. 3)Its
total insulin bioavailability is 0.95% (AUC_average). However, it is
much more potent than Humalog injection when considered its
hypoglycemic action per unit insulin absorbed. Musulin is a
relatively potent and efficacious form of oral insulin with
sustained hypoglycemic action over 3-5 hours. |
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