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2001 American Diabetes Association 61st
Scientific Sessions |
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A New Transmucosal Insulin Formulation -Findings
of Superior and Better Insulin Absorption in Diabetic Rats by 686%
in Comparison to Non-diabetic controls
Frank k Leung, Jing Li, Lanqi Huang and Emily Leung.
Purpose: To evaluate the insulin pharmacokinetics and
hypoglycemia efficacy of a transmucosal insulin (Intesulin-B,25u
insulin/ml, Coremed)in diabetic rats comparing to subcutaneous
injection and non-diabetic controls. Methods: All rats aged
2-21/2months.Diabetes was induced by Streptozotocin. Group1
(Control, diabetic): 4 rats; Group 2(Control, non-diabetic):5 rats;
Group 3(Diabetic,Intesulin-B,0.2u/gm):5 rats; Group
4(Diabetic,Intesulin-B, 0.2u/gm):8 rats; Group 5(Diabetic, Humalog
injection,0.2u/gm):4 rats and Group 6(Diabetic, Humalog
injection,0.2u/gm) 5 rats. Protocol: Intesulin-B was injected
directly into duodenum by 30 gauge syringe. Insulin was pooled and
sampled from the hepatic portal vein, followed by jugular vein from
Group 2,3,5 at 0,5,15,30,60,90,120 min. Group 1,4,6 had glucose
measured from jugular vein without insulin samplings at 0, 5, 15,
30, 60, 120, 180, 240, 300, 360, 420, 480,540,600 min. Statistical
Analysis: SAS System Version 8.0.,known compartmental calculation of
PK parameters, Dunnett's t and "Mixed Procedure". Data and Summary:
1) Significant onset of hypoglycemia: Group 6 at 15 min., Group 4 at
60 min. 2) Slope of glucose reduction from time 0: Group 6 at -40.9%
per hours, Group 4 at -12.2% per hours.3 Slope of Group 4 was linear
from time 0 and mean glucose declined by 80% at 540 min.4) Hepatic
portal vein insulin: AUC-average over time for Group 2: 134.39,
Group 3:921.81 Cmax for Group 2:430 miu/ml, Group 3:1728 miu/ml.
Tmax for Group 2 and 3: 5 min. 5) Total insulin bioavailability:
Group 3 compared to injection: 15.9% (portal vein), 12.8% (jugular
vein) 6) Half life: Group 3: 22.72 min. (portal vein), 60.13 min.
(jugular vein).Conclusion: Intesulin-B has extremely rapid insulin
peak absorption at 5 min. in both diabetic and non-diabetic rats. It
lowered glucose linearly over many hours and has profound
hypoglycemic action. One surprise finding is that diabetic rats have
685.9% better absorption than non-diabetic control, suggesting the
excellence of Intesulin-B in treating diabetic rats. |
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A New Transmucosal Insulin Formulation - Findings of
Its Insulin Pharmacokinetics Superiority Which Surpass Results in
Subcutaneous Insulin Injection in Non-diabetic Rats
Frank k Leung, Jing Li, Lanqi Huang and Emily Leung.
Purpose: To evaluate the insulin pharmacokinetics and
hypoglycemia efficacy between a transmucosal insulin (Intesulin-A,
25 units insulin/ml, Coremed) and subcutaneous Humalog injection
(injection) in non-diabetic rats. Methods: All rats aged 1-11/2
months. Group 1(control,placebo):6 rats, Group 2(Intesulin-A, 12.5
u):5 rats, Group 3(Intesulin-A,6.25 u):5 rats, Group 4(injection,
12.5u):5 rats, Group 5(Intesulin-A, 12.5u):4 rats, Group
6(Intesulin-A, 6.25u): 5 rats, Group 7(injection, 12.5u):5
rats.Protocol: After fasting for 12 hrs, blood glucose was measured
from Group 1,2,3,4 Jugular veins at time, 0,5,10,15,30,60,90, 120,
150, 180, 210, 240, 270, 300 min. Insulin was pooled and measured
from Group 5,6,7 hepatic portal veins at time 0,5,15,30,60, 90 min
and followed by jugular vein samplings. Statistical Analysis: SAS
sytem, Version 8.0.1) Known compartmental calculation of PK
parameters, Dunnett's t and "Mixed Procedure." Data and Summary:
1)At 30 min., glucose in Group 2 declined by 90% and 100% at 90 min.
Group 4 had 4 died of hypoglycemia and one survived. 2) Significant
onset of hypoglycemia: Group 4:5 min. and Group 2,3: 15 min..3)
Percent glucose reduction slope (Mean + standard error at
95%confidence interval): Group 1 (0.59562 s.e. 0.1643),Group 2
(-0.5950 s.e.0.4070), Group3 (-0.0853 s.e.0.1257) and Group
4(-0.1084 s.e.0.1257) 4)Insulin Peak Absorption time: Group 5,6: 5
min.,Group 7:60 min.5)Total Insulin Bioavailability (AUC of
Inteuslin-A divided by AUC Injection): AUC_t: 4.12% (portal vein),4%
(Jugular vein); AUC_infinity:2.6% (Portal vein), 2.6% (Jugualr
vein); AUC_average over time: 4% (portal and Jugular
veins).6)Hypoglycemic Potency (AUC average Glucose divided by AUC
average Insulin): Intesulin-A (12.5u):0.2823,Injection
(12.5u):000518.7)Relative hypoglycemia potency (Intesulin-A/injection):
54.5 times. Conclusion: Intesulin-A has an extremely rapid insulin
peak absorption at 5 min. and does not have sustained
hyperinsulinemia as in injection group. Intesulin-A (12.5u) is 54.5
times more potent in its hypoglycemic action per unit insulin
absorbed than subcutaneous Humalog injection. |
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A New Transdermal Insulin Formulation - Results of
Insulin Pharmacokinetics and Hypoglycemic Efficacy in Comparison to
Azone and Subcutaneous Insulin Inejctions in Non-diabetic Rats
Frank k Leung, Jing Li, Lanqi Huang and Emily Leung
Purpose: To evaluate the hypoglycemic efficacy and insulin
pharmacokineitcs between a transdermal insulin (Dermulin, Coremed ,
subcutaneous injection and an Azone Dermulin formulation in
non-diabetic rats. Methods: All rats aged 1-1/2 months. Group 1
(control-placebo): 6 rats, Group 2 (Dermulin, 12.5u): 4 rats, Group
3 (Dermulin, 25 u):5 rats,Group 4 (Azone 12.5u): 5 rats, Group 5 (Azone
25u):5 rats, Group 6 (injection,12.5u):4 rats,Group 7 (Dermulin,
12.5u) and Group 8 (Injection,12.5u).Protocol:All rats were fasted
12 hrs. Jugular vein was exposed and blood was drawn at
0,5,10,15,30,60,120,150,180,210,240, 270,300 minutes for glucose
measurements.Insulin was pooled and measured from Group 7,8 jugular
vein at 0,15,30,60,90,120,240 min. Statistical Analysis: SAS System,
Version 8.0 :1)Simultaneous comparison of multiple groups by
Dunnett;s test at 5% significance level. 2)Comparison of slopes of
the glucose reduction rate by repeated measures analysis of variance
method by the "Mixed Procedure." Data:1)Significant onset of action:
Group 6 at 5 min., Group 3,5 at 15 min. and Group 2,4 at 30min. 2)
Significant hypoglycemia lasted 3-5 hrs.3) Percent of glucose
reduction compared to initial time 0 at 60,120,180,300 min were:
Group1:124 (s.d.20.8),116.5 (s.d.29.6),98.2 (s.d.28),98.2 (s.d.28);
Group2:74 (s.d.24.8),57.5 (s.d.21.8),55.3 (s.d.15.5),58.5
(s.d.23.5), Group3:53.4(s.d.16.7),34.2 (s.d.17.4),51.1
(s.d.22.7),54.5 (s.d.10.3); Group6: 28 (s.d.13.4),21.9 (s.d.13),
17.2(s.d.14.1), 0 (s.d.0). Insulin Pharmacokinetics: The total
insulin bioavailablity in Group 7 compared to 8 is 0.57%. Half life
of Dermulin in 219.69 min. Tmax is 30 min.. Cmax of insulin
absorption is 241 min/ml at 30 min.. Conclusion: Dermulin produced
marked hypoglycemia and the glucose declined by 59.3% to 82.3%
compared to placebo group at 120min., it has a rapid onset of action
at 15-30 min. The calculated efficacy of Dermulin compared to the
identical dose by subcutaneous injection is 60-70% and has similar
action as its Azone formulations. Dermulin has an excellent
transdermal insulin absorption. |
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A New Oral Insulin Formulation - Results of Long-term
Daily Glucose Control of Diabetic Rats
Frank k Leung, Jing Li, Lanqi Huang Emily Leung, Chang Zhang Xue
and Rose Wang
Purpose: To evaluate the use of a new oral insulin (Musulin, 25 u
of insulin/ml, Coremed ) in long-term daily glucose control of
diabetic rats. Methods: All rats aged 2-3 months, diabetes-induced
by Streptozotocin with fasting glucose 250 mg/ml or more. Group 1
(Control diabetic, placebo):5 rats, Group 2 (Diabetic, Musulin):9
rats.Protocol:Blood glucose was measured at 10am and 4pm daily after
2 hrs fasting. Musulin or Placebo was fed perorally through a
plastic pipet according to the algorithm sliding scale for glucose
rising above 150 mg/ml. Week 1: 0.05 unit of Musulin per 1 mg/ml
glucose; week 2: 0.1 u per 1mg/ml glucose; week 3: 0.15 u/1mg/ml
glucose. End-point:1) No more Musulin was given after glucose was
successfully maintained at 150 mg/ml for 1 week. 2)Glucose was
measured for an additional week after the study was terminated.
Data: Mean glucose levels in mg/ml (n=9): 297, 166, 179, 160, 182,
163, 177, 154, 179, 162, 225, 167, 190, 161, 159, 139, 160, 92, 135,
92, 168, 132, 111, 106, 129, 154, 160, 147, 144, 174, 167, 132, 160,
217,159,198,138,156,189,127,106. Statistical Analysis: SAS System,
version 8.0. Dunnett's t and " Mixed Procedure" method. Results:
1)Significant decrease in mean glucose levels occurred within 24
hours.2)Number of rats achieving glucose control of 150mg/ml: 2 rats
required 0.05 u/mg/ml dose, 4 rats required 0.1 u/mg/ml, 2 rats
required 0.15 u/mg/ml 3)Group 2: 4 rats died of hypoglycemia, 2 rats
had severe hypoglycemia less than 25 mg/ml and were revived. 4)After
study was terminated, mean glucose level rose slightly but remained
significantly below pre-treatment and control. Conclusion: Musulin
is effective in lowering blood glucose in diabetic rats over
sustained period of time. |
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