|
|
 |
|
|
2005 American Diabetes Association 65th
Scientific Sessions |
|
|
|
Glucose Responses of Pulmonary-delivered Alveair
Formulated with Unmodified Chinese-made Analog Insulin in Normal
Rats Frank K Leung, M.D., Jing Li, M.D., Yirong Song,
B.Parm, Sieting Wong, Ph.D., Wayne Hornig, Ph.D., Emily Leung, B.A.
and ShaoLing Soo, M.D. Lake Bluff, Illinois, United States.
Purpose: The present study is to evaluate the glucose efficacy in
normal rats treated with inhalable Alveair insulin formulated with
unmodified Chinese-made analog insulin (GT) compared to unmodified
Aspart (Novo Nordsk). Methods and materials: Group 1 - Alveair
formulated with Chinese-made analog monomer insulin was given to 5
normal rats through intra-trachea. Group 2 - Alveair formulated with
Aspart was administered with identical procedures to 4 normal rats.
Tail glucose was measured at time 0, 5 ,15, 30, 60, 120, 180, 240,
300, 360, 420, 480 minutes with an Accuchek monitor. Results:
Percent of initial glucose levels: Group 1: 100, 101,, 87, 78, 60,
44,35, 38, 35, 38, 42. Group 2: 100, 111, 89, 59, 37, 33, 35, 34,
39, 48, 51.The glucodynamic profiles of these two formualtions
overlapped with each other. The glucose nadir occurred between 120
minutes ( Tmax). The maximal glucose reduction was 65% in group 1
and 65% in group 2. The onset of action was 30 minutes in both
groups. The glucodynamic profiles between these two drugs overlapped
with each other with comparable Cmin and Tmax and AUCs.
Conclusion: Inhalable Alveair insulin formulated with the
Chinese-made analog monomer insulin and Aspart have similar and
comparable glucose responses and efficacy. |
|
|
|
Glucodynamic Profile and Glucose Dose-Responses of
Alveair (Pulmonary-delivered) in Comparison to Aspart (Subcutaneous
Injection) in Normal Rats with Food Intake Frank K Leung,
M.D., Jing Li, M.D., Yirong Song, B.Sc., Sieting Wong, Ph.D., Wayne
Hornig, Ph.D., Emily Leung, B.A. and Shaoling Soo, M.D.
Lake Bluff, Illinois, United States.
Purpose: The glucodynamic profile of Aspart is well established. The
present study is to compare intratrachea-delivered Alveair
(formulated with unmodified analog insulin) to subcutaneously
injected Aspart in normal rats with food intake.
Method and Materials: Group 1 has 5 rats received Alveair at 0.5
u/kg dose. Group 2 has 4 rats received Alveair at 1 u/kg dose. Group
3 has 4 rats treated with Aspart at 0.5 u/kg dose. Group 4 has 4
rats treated with Aspart at 1 u/kg dose. Group 5 has 4 rats received
placebo. All rats received the insulin or placebo followed by
immediate gavage delivery of 2 ml of Boost (20% protein, 14% CHO, 6%
Fat). Tail glucose was measured by Accuchek monitor at time 0, 5,
15, 30, 60, 120, 180,240, 300, 360, 420, 480 minutes.
Results and analysis: Percent of initial glucose levels Group 1:
100, 108,109,101,91,86,80,84,95, 84,95,89,89,90.
Group2:100,108,102,96,85,74,74,89,96,108,116,116. Group 3: 100, 103,
116, 104, 96,79,75,78,82,87,88,89. Group 4: 100,
99,98,81,72,64,65,73,81,89,95,92 Group 5:
100,109,119,123,123,126,127,128,131,101,97,102. . Statistical
analysis was performed with SAS 8.01. The glucose nadir (C min) was
at 120 minutes (T max) in group 1,2,3,4. The AUC average is the
comparable between groups 1 and 3; group 2 and 4. Groups 2 and 4
which received high dosage had great glucose reduction than groups 1
and 2.
Conclusion: The present study directly compared inhalable Alveair
to Aspart s.c. in normal rats with food intake, their glucodynamic
profiles and glucose dose-responses are similar and comparable. This
experiment showed that inhalable Alveair efficacy and performance is
similar to subcutaneously injected Aspart. |
|
|
|
Improved Efficacy of Intesulin (Oral Insulin)
Formulated with Unmodified Regular Insulin in Normal Rats
Frank K Leung, M.D., Jing Li, M.D., Yirong Song, B.Parm, Sieting
Wong, Ph.D., Wayne Hornig, Ph.D. and Emily Leung, B.A.
Lake Bluff, Illinois, United States.
Purpose: We have previously demonstrated the efficacy of Intesulin
in streptozocin-induced diabetic rats at dosages below 10 units/kg,
but failed to show similar results in normal rats with the exception
of normal guinea pigs. Previous Intesulin formulation was based on
unmodified analog insulin. The present study is to evaluate an
improved Intesulin (Coremeds 2004 formulation) based on unmodified
regular insulin in normal rats at 10 units/kg dosage.
Methods and materials: Concurrent study was performed in 8 normal
rats and 4 placebo controls. Intesulin or placebo was delivered to
the stomach with a gavage needle ( Harvard Apparatus). Tail glucose
was measured with an Accuchek monitor at time 0, 15, 30, 60, 120,
180, 240, 300, 360, 420, and 480 minuets. Statistical analysis was
performed with SAS 8.01
Results: Placebo percent of initial glucose levels 100, 101, 102,
100, 100, 97, 88, 84, 79, 77, 76. Intesulin 100, 91, 89, 79, 70, 62,
58, 59, 62, 67, 65. AUC mean, AUC min, AUC max, Tmaxmean, Tmaxmin,
Tmaxmax, Cmaxmean, Cmaxmin, Cmaxmax: Placebo: 85.8471, 71, 118.7907,
60, 30, 120, 105.75, 86, 134. Intesulin: 64.0736, 50.6042, 82.109,
41.25, 30, 120, 89.25, 82, 130. Statistical significance at 5%
confidence occurred At 30, 60, 120, 180, 240, 300 minutes.
Conclusion: Our previous experiments had shown that Intesulin is
more efficacious in streptozocin-induced diabetic than normal rats.
The current 2004 Intesulin formulation at 10 units/kg dosage
delivered by gavage method is effective in lowering glucose levels
in normal, non-diabetic rats, a significant improvement over our
previous older formulation. This study has shown that unmodified
regular insulin can be used to formulate an effective oral insulin. |
|
|
|
Insulin Bioavailability and pK Estimates of
Intravenous Alveair Formulation Frank K Leung, M.D., Jing
Li, M.D., Yirong Song, B.Parm, Sieting Wong, Ph.D., Wayne Hornig,
Ph.D. and Emily Leung, B.A.
Lake Bluff, Illinois, United States.
Purpose: In order to study the insulin profiles of Alveair in the
blood, this experiment is to evaluate the insulin bioavailability
and pK estimates of Alveair (t.m.) formulation (analog based)
administered intravenously, and compared to Aspart (Novolog)
formulation.
Methods and materials: Alveair (2.7 u/ml) was formulated with
Aspart. Normal rats were given dosages at 0.15, 0.5 and 1 unit/kg
intravenously through the Jugular vein. Control of Aspart (Novolog)
was given at 0.5, 1 unit/kg with identical procedures. Aspart was
diluted with phosphate buffer at pH 7.0 such that Aspart was given
with same dosing volung and insulin concentration. Insulin was
determined by a commercial kit (ALCO) and performed at Coremeds
laboratory. Insulin was sampled through the Jugular vein at tome 0,
5, 15, 30, 60, 120, 180, 240, 300 minutes.
Results in microi.u./ml:
Time 0 5 15 30 60 120 180 240 300
Alveair 1 u/kg 0 879 540 787 454 131 41.7 14.1 5.5
Alveair 0.5 u/kg 0 636 648 610 244 38 11 4 0
Alveair 0.15 u/kg 0 414 422 211 42 48 11 0 0
Novolog 1 u/kg 0 618 649 633 618 55 34 1.7 0
Novolog 0.5 u/kg 0 239 330 472 452 236 5.4 10 0
pK estimates ( SAS 8.01):
Tmax Cmax AUC_t AUC_ave
Alveair 1 u/kg 5 879 62853 209.51
Alveair 0.5 u/kg 15 648 40635 169.313
Alveair 0.15 u/kg 15 422 18227.5 101.264
Novolog 1 u/kg 15 649 30191 250.796
Novolog 0.5 u/kg 30 472 51661.5 215.256
Conclusion: At dosages of 0.5 and 1 unit/kg, intravenous.Alveair
achieved comparable and slightly better Cmax and AUC_t than Aspart
formulation. Alveair also has a faster Tmax time than Aspart. |
|
|
|
Comparison of Insulin Bioavailability and pK
Estimates of Alveair Formulation Administered by Pulmonary and
Intravenous Routes Frank K Leung, M.D., Jing Li, M.D.,
Yirong Song, B.Parm, Sieting Wong, Ph.D., Wayne Hornig, Ph.D. and
Emily Leung, B.A.
Lake Bluff, Illinois, United States.
Purpose: This study is to evaluate the insulin bioavailability
and pK estimates of Alveair formulation administered by different
routes and its comparison to intravenous Aspart injection, which is
considered 100% bioavailability.
Methods and materials: Alveair (2.7 u/ml) was formulated with
unmodified Aspart. Normal rats were given dosages at 1 unit/kg
intravenously through the Jugular vein or via intratrachea. Control
Aspart (Novolog) was given at 1 unit/kg with identical intravenous
procedures. Aspart was diluted with phosphate buffer at pH 7.0 such
that Aspart was given with same dosing volume and insulin
concentration. Insulin was determined at the Quest Diagnostic Lab
(60% cross reactivity with analog). Insulin was sampled through the
Jugular vein at tome 0, 5, 15, 30, 60, 120, 180, 240, 300 minutes.
Results in micro i.u./ml:
Time (minutes) 0 5 15 30 60 120 180 240 300
Novolog i.v. 5.2 197 270 303 202 42 16.9 16.9 7.8
Alveair i.v. 5 382 275 373 103 29.5 17.5 4.8 4.8
Alveair (pulmonary) 7 36.2 121 162.7 317.5 170.6 117.5 31 7.1
Statistical Analysis with SAS 8.01:
Tmax Cmax AUC_t AUC_ave
Novolog i.v. 30 303 25555 85.183
Alveair i.v. 5 to 30 382 22594 75.315
Alveair (pulmonary) 60 317 39108.75 130.363
Conclusion: At 1 unit/kg dose delivered by pulmonary route,
Alveair achieved comparable and greater AUC than intravenously
injected Aspart and it has delayed Tmax. Intravenously injected
Alveair has a broader Cmax peak compared to Aspart. |
|
|
|
Insulin Bioavailability and pK Estimates of Alveair
Formulated with Unmodified Regular Insulin Frank K Leung,
M.D., Jing Li, M.D., Yirong Song, B.Parm, Sieting Wong, Ph.D., Wayne
Hornig, Ph.D. and Emily Leung, B.A.
Lake Bluff, Illinois, United States.
Purpose: Regular insulin is readily available world-wide. It has
a lower manufacturing cost. Previous Alveair formulation was based
on unmodified analog monomer insulin. This study is to evaluate
Alveair formulated with regular insulin (Novolin-regular) for its
bioavailability and pK estimates in normal rats.
Methods and materials: Normal rats were given dosages at 0.5, 1
and 2 units/kg via intratrachea. Control plain regular insulin was
given at 1 unit/kg with identical procedures. Control regular
insulin was diluted with phosphate buffer at pH 7.0 such that the
control was given with same dosing volume and insulin concentration.
Insulin was determined at the ARUP (Associated Regional University
Pathologists, Salt Lake City, Utah). Insulin was sampled through the
Jugular vein at time 0, 5, 15, 30, 60, 120, 180, 240, 300 minutes.
Results in micro i.u./ml:
Time 0 5 15 30 60 120 180
Alveair-reg at 0.5 u/kg 1 13 40 33 44 1 1
Alveair-reg at 1u/kg 6.7 205 196 158 46 32 21
Alveair-reg at 2 u/kg 1 70 104 501 317 13 12
Control regular 1.9 7.8 7.8 6.3 8.4 4.2 0
Statistical analysis with SAS 8.01. Results of pK estimates:
Tmax Cmax AUC_t AUC_ave
Alveair-reg at 0.5 u/kg 15 to 60 44 3412.5 18.958
Alveair-reg at 1u/kg 5 to 30 205 12179.25 67.663
Alveair-reg at 2 u/kg 30 501 28505 158.361
Control regular 60 8.4 806 6.721
Conclusion: Pulmonary-delivered Alveair which was formulated with
unmodified regular insulin achieved therapeutic level of blood
insulin at 0.5 unit/kg or higher. Control plain regular at 1 unit/kg
has minimal and sub-therapeutic level of insulin absorption.
Signifcant amount of unmodified regular insulin in the Alveair
formulation is absorbed via pulmonary delivery. |
|
|
|
Unmodified Inhalable Regular Insulin (Alveair-R) Has
Same Glucodynamic Profile and Effectiveness as Compared to Inhalable
Analog Monomer insulins Frank K Leung, M.D., Jing Li,
M.D., Yirong Song, B.Parm, Sieting Wong, Ph.D., Wayne Hornig, Ph.D.,
Emily Leung, B.A. and Shaoling Soo, M.D.
Lake Bluff, Illinois, United States.
Purpose: Modified inhalable insulin has been shown to induce
antibodies which can potentially result in side-effects such as
attenuation of clinical efficacy. Regular insulin is available
world-wide and is lower in manufacturing costs. The present study is
to evaluate unmodified inhalable insulin (Alveair) formulated with
the Chinese-made regular(WB), Chinese-made analog insulin (GT), as
compared to Aspart (Novo Nordsk).
Methods and materials: Group 1 - Alveair formulated with
Chinese-made analog monomer insulin was given to 4 normal rats
through intra-trachea. Group 2 Alveair formulated with Chinese-made
regular insulin was given to 5 normal rats with identical
procedures. Group 3 - Alveair formulated with Aspart was
administered with identical procedures to 4 normal rats. Tail
glucose was measured at time 0, 15, 30, 60, 120, 180, 240, 300, 360,
420, 480 minutes with an Accuchek monitor.
Results: Percent of initial glucose levels: Group 1:
100,99,85,75,56,41,35,37,35,37,41. Group 2:
100,95,89,74,52,42,35,33,32,35,35 Group 3: 100, 111, 89, 59, 37, 33,
35, 34, 39, 48, 51.The glucodynamic profiles of these three
formualtions practically overlapped with each other. The glucose
nadir occurred around 120 minutes ( Tmax). The maximal glucose
reduction (Nadir) was 65% in group 1 , 68% in group 2, 65% in group
3. The onset of action was within 30 minutes in all groups. The
glucodynamic profiles between these three drugs overlapped with each
other with identical Cmin and Tmax and AUCs.
Conclusion: Alveair formulated with the unmodified Chinese WB
regular insulin has identical glucose responses and efficacy as the
analog monomer insulins by Chinese GT and by Novo Nordsk. |
|
|
|
Intesulin (Oral Insulin) Hepatic Vein Cmax insulin
levels in Streptozocin-induced Diabetic Rats by Gavage Delivery
Frank K Leung, M.D., Jing Li, M.D., Yirong Song, B.Parm, Sieting
Wong, Ph.D., Wayne Hornig, Ph.D. and Emily Leung, B.A.
Lake Bluff, Illinois, United States.
Purpose: Insulin level in the hepatic vein measures mostly the
amount of oral insulin absorption through the gastrointestinal
tract. The Cmax value also predicts the therapeutic efficacy of the
formulation from our experience. The present study is to measure the
hepatic vein insulin Cmax of Intesulin by gavage delivery.
Methods and materials: The same dosing volume of 0.2 ml Intesulin
was delivered directly into the stomach with a gavage needle
(Harvard Apparatus) to each animal weighing around 300 grams. The
calculated dosage of Intesulin delivered based on the weight of the
individual animal was between 2-3 units per kg. Blood was sampled
for insulin measurements at time 0, 60, 120, 240 minutes from the
hepatic veins. Experiment 1 consisted of 4 streptozocin-induced
diabetic rats. Experiment 2 was a repeat of experiment 1 and
consisted of 3 streptozocin-induced diabetic rats. Insulin was
measured at Quest Diagnostic Laboratory.
Results: The Cmax of experiment 1 was 78 micro i.u./ml at 120
minutes, and 48 micro i.u./ml for experiment 2.
Discusssion and conclusion: The results of the present study
indicated that Intesulin (Coremeds 2003 oral insulin formulation) at
2-3 units/kg dosage achieves therapeutic insulin levels in
streptozocin-induced diabetic rats. At this stage of development,
Intesulins effective dosage is about ten to twenty times of the
injection. |
|
|
