Insulin Delivery Approaches Jay S' Skyler, M'D' Presented at Diabetes Advances at Bedside and Bench

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Insulin Delivery ApproachesJay S. Skyler,
M.D.Presented at Diabetes Advances at Bedside
and Bench Symposium October 1, 2005
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Insulin Pens
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Jet Injectors
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Basal/Bolus Insulin Absorption Pattern Standard
Insulin Preparations
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Breakfast
Lunch
Dinner
50
Plasma Insulin µU/ml)
25
NPH/Lente
400
1600
2000
2400
400
800
1200
800
Time
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Basal-Bolus Treatment Program withRapid Acting
Long Acting Analogues
Breakfast
Lunch
Dinner
Plasma Insulin
Glargine or Detemir
400
1600
2000
2400
400
800
1200
800
Time
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Continuous Subcutaneous Insulin Delivery (CSII)
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History of Pumps
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Latest Pump Technology
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US Pump Usage Total Patients Using Insulin Pumps
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Continuous Subcutaneous Insulin Infusion (CSII)
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CSII Inserter
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Continuous Subcutaneous Insulin Infusion (CSII)
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Paradigm and Paradigm Link
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Disposable Pump

• Disposable pump for basal infusion
• Simple one-step application
• Non-programmable 3- day continuous delivery
• Pre-set daily infusion choices

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Future Micropump
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Insulet OmniPod Disposable Pump
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Variable Basal Rate Continuous Subcutaneous
Insulin Infusion (CSII) Program
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Breakfast
Lunch
Dinner
50
Plasma Insulin µU/ml)
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400
1600
2000
2400
400
800
1200
800
Time
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Insulin Lispro in CSII Double-Blind, Cross-Over
Study
Glucose Profiles



Glucose (mmol/l)
Breakfast
Lunch
Supper
HS
0200
Zinman Diabetes 199746 440-3
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Pulmonary Insulin Delivery
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Inhalation of Systemically Active Pharmaceuticals
Rationale the lung offers an absorption area of
100-140 m2
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Pulmonary Insulin DeliveryEpithelial Comparison
Human Terminal Bronchioles 0.5-1 µm diameter
Human Bronchi 3-5 µm diameter
Human Alveoli 250 µm diameter
8 µm
58 µm
3 µm
0.07 µm fluid
10 µm
0.1-0.2 µm
Ciliated Cell
Basal Cell
Type I Cell
Goblet Cell
Basement Membrane
Brush Cell
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Inhaled Insulin Not a New Idea
Klinische Wochenschrift, January 1925, p.71
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Pfizer / Aventis / Nektar Exubera Pulmonary
Insulin Delivery System
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Novo-Nordisk / Aradigm AERx iDMS Pulmonary
Insulin Delivery System
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Lilly / Alkermes AIR Particle TechnologyPulmonar
y Insulin Delivery System
Large, Porous Particles
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MannKind TechnosphereTMPulmonary Insulin
Delivery System
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Kos Breath Actuated Inhaler Pulmonary Insulin
Delivery System
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Pharmacokinetics of 3 mg Exubera Inhaled Insulin
versus 10 units SC Regular Insulin
(N 16, 3-way crossover)

SC Insulin 0.15 U/kg (10U)
Inhaled Insulin (1 mg x 3)
Median Rise (mU/ml)
Inhaled Insulin (3 mg x 1)

Time (min)
Cefalu et al Ann Int Med 2001 134203-7
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Plasma Glucose Response to 3 mg Inhaled Insulin
versus 10 units SC Regular Insulin
(N 16, 3-way crossover)
Inhaled Insulin (3 mg x 1)
mg/dl
SC Insulin 0.15 U/kg (10 U)
Inhaled Insulin (1 mg x 3)

-30
0
30
60
90
120
150
180
210
240
270
300
330
360
Time (min)
Cefalu et al Ann Int Med 2001 134203-7
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Time-Action Profile of Inhaled Insulin
glucose infusion rates (mg/kg/min)
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Data from different studies
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Pfizer/Aventis/Nektar
Lilly/AIR/Alkermes
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Aerogen
KOS
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GIR
Novo Nordisk/Aradigm
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2
15 U Lispro s.c.
0
0
1
2
3
4
5
6
7
8
9
10
time (h)
Br J Diab Vasc Dis 20044295-301
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Time-Action Profile of Inhaled Insulin
glucose infusion rates (mg/kg/min)
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Data from different studies
MannKind
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Pfizer/Aventis/Nektar
Lilly/AIR/Alkermes
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Aerogen
KOS
6
GIR
Novo Nordisk/Aradigm
4
2
15 U Lispro s.c.
0
0
1
2
3
4
5
6
7
8
9
10
time (h)
Br J Diab Vasc Dis 20044295-301
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Plasma Glucose Concentration Before and After
3-Months Treatment with Inhaled vs SC Insulin
Regimen in Patients With Type 1 Diabetes (Mean
SD)
Week 12
Week 0
500
500
400
400
)
dL
l
l
l
l
300
n
300
l
n
l
n
l
n
l
l
n
n
BG (mg/
n
n
n
l
l
n
n
n
200
200
l
l
n
n
100
100
0
0
3-Hour
Fasting
3-Hour
Fasting
Postprandial
Postprandial
n
Inhaled Insulin
l
SC
Skyler JS et al. Lancet 2001 357331335
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Phase III Exubera in Type 1 DiabetesChange in
A1c Intensive Rx
Skyler et al, Diabetes Care 2005 28 1630-1635
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Basal-Bolus Treatment Program with Inhaled
Insulin Long Acting Analogue
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Breakfast
Lunch
Dinner
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Inhaled Inhaled Inhaled
Plasma Insulin µU/ml)
Detemir or Glargine
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400
1600
2000
2400
400
800
1200
800
Time
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Transdermal insulin
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Reservoir (formulated drug / vaccine)
Porator (array of metallic filaments)
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Application
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Delivery of Insulin in a Phase 1 Clinical Study
using a Basal Insulin Skin Patch
Patch Off
U-1000 Insulin Concentration 12 hour
Application Mean S.E. n 8
C-Peptide Adjusted Insulin Concentration /
Euglycemic Glucose Clamp Study
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Glucodynamics (Clamp) in a Phase 1 Clinical Study
using a Basal Insulin Skin Patch
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Phase 1 Dose Proportionality Study Using a Basal
Insulin Skin Patch
Steady State Serum Insulin Concentration as a
Function of Insulin Concentration in the Patch
Reservoir (8 Hour Application)
Css (2-8 hr) Mean S.E. n 8 (n 4 for U1000)
Serum Insulin Concentration (uU/mL)
Linear Regression r2 0.989
Insulin Concentration in Reservoir (Units/mL)
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Oral Insulin Delivery
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Oral Insulin Players

• Nobex HIM2
• Emisphere eligen insulin
• Valentis Flemington - Oralgen - Polymasc Pharma
  (PEG insulin)
• Coremed USA - Macrolin Intestulin
• Purdue University Hydrogel formulation
• Hadassah Hospital insulin caprylate (SNAC)
• Oral insulin formulation DTY001
• iMEDD microfabricated insulin
• BioSante Pharmaceuticals CAPIC (calcium
  phosphate insulin)
• Transgene Biotek Ltd (India) nanoparticle oral
  insulin

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Oral Insulin Polymer (Nobex HIM2)
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Plasma Insulin Levels After Oral Insulin (Nobex
HIM2)
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Plasma Glucose Levels After Oral Insulin (Nobex
HIM2)
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Emisphere Oral Insulin
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Oral Insulin Pharmacokinetics
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Oral Insulin Pharmacodynamics
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Peritoneal Insulin Delivery
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Peritoneal Insulin Absorption

• Absorption following 1 u/kg IP injection
• Double tracer method in dogs
• Portal Peripheral
• Peak Absorption 20 min 28 min
• Proportion
• Absorbed 51 49

Radziuk et al Am J Physiol 1994 266E750-E759
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Implantable Insulin Pump External Controller
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Implantable Pumps
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Basal Insulin by Implantable Pump in Type 2
Diabetes

Rupp et al NEJM 1982 307265-270
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Glycemic Control with Implantable Insulin Pumps
French Multicenter Study
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Hypoglycemia with Implantable Insulin
PumpsFrench Multicenter Study
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Hypoglycemia with Implantable Insulin PumpsUS
Infusaid Multicenter Study - Type 1 DM
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Benefits of Peritoneal Insulin

• Less hypoglycemia
• Less weight gain
• Effective glucose control

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Closed-Loop Insulin Delivery
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Biostator Glucose Controlled Insulin Infusion
System
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Merging of Technologies
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External Closed-Loop Setup for Canine Studies
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Closed Loop Glucose Regulation with CSII
Subcutaneous Glucose Sensor
Pancreatectomized Canine
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Medtronic Minimed Closed Loop System
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Moon The First Implantable Closed Loop System
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Closed Loop Glucose Regulation with Implanted
Pump Implanted Glucose Sensor
Pancreatectomized Canine
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• 15 sensors 10 pts 5m/5f age 44-65 dm dur 7-50
• Cum exp 11.8 pt-yrs avg 287 (89-431) dd
• No clotting incident or venous trauma
• SMBG comp avg 1738 (599-4524) r0.85 (0.73-0.90)
• Clark AB 95.8 (88.7-98.3)
• Mean absolute deviation 18.1 (15.4-33.0)
• Fully automated closed loop x 48 h reduced time
• lt70 from 18 to 6
• gt240 from 17 to 2
• Added premeal bolus kept all values 70-240

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First Human Closed Loop Results