Protein Delivery from Mechanical

Devices
Challenges and Opportunities

Bill Van Antwerp and Poonam

Gulati
The Protein Formulation and
Testing Group
Medtronic Minimed

FDA Workshop
July 2003
 Why Protein Drugs in Devices

• Protein/peptide drugs are

increasingly important
• Diabetes (Insulin, Symlin, Exendin, Somatokine)
• Cancer (Interferon, Monoclonal Antibodies, Vaccines)
• Cardiovascular Drugs (Natrecor, GPIIB
receptor, Protein G receptor)
• Inflammation (TNF-a, IL1-RA)
• HIV/AIDS (Somatostatin, T20, T1249, IL-2,
Interferon)

FDA Workshop
July 2003
 Why Use Pumps?

• Proteins and peptides need delivery

• Poor oral bioavailability
• Protein denaturation in the digestive
system
• Acid hydrolysis in the stomach
• Enzymatic degradation
• Poor adsorption due to size
• Poor adsorption due to polar/charge
distribution

FDA Workshop
July 2003
 Advantages of Continuous Infusion
for Protein Drugs
6

Side Effects
5
Plasma Drug Concentration

Enzyme Activation
P450 Activation Wasted Drug
14 x CSI
4

1 Therapeutic
Bolus Injection
Range Continuous Infusion

0
0 4 8 12 16 20 24

FDA Workshop Time (hours)

July 2003
 Parenteral Delivery Today

• IV administration
• Subcutaneous injection
• Continuous Subcutaneous Infusion
(Pumps)
• Continuous Intraperitoneal Infusion
• Subcutaneous Depot (leuprolide etc)
• PLGA microspheres
• PEG attached peptides
• Microemulsions
• Intrathecal, Intraparenchymal

FDA Workshop
July 2003
 Pump Challenges, Old and New

• Formulation
• Chemical Stability
• Clearance
• Physical Stability
• PK/PD Therapeutic Range and
Toxicity (localized site
reactions)

FDA Workshop
July 2003
 Regulatory Hurdles
Let’s Not Re-invent the Wheel

• Device Physics
• Drug Chemistry
• Drug Packaging
• Pump/Drug Interactions (in-vitro)
• Drug Physical Stability (in-vitro)

FDA Workshop
July 2003
 Stability in Pumps

• Chemical and physical stability can

determine clinical efficacy
• Physical stability is difficult to measure
• Wide variety of measurements
• Turbidity
• Concentration Changes
• Fluorescence
• CD/Microcalorimetry/Denaturation Kinetics

FDA Workshop
July 2003
 Chemical Stability

• Chemical stability is
determined by the molecule
and by the formulation
• Relatively simple formulation
changes can affect stability
• Pump chemical stability, in
general, is the same as in
primary packaging

FDA Workshop
July 2003
 Physical Interactions

• Protein physical stability in devices

• Materials of contact
• Teflon/Titanium/Polyolefin/Silicone Oil
• Pumping mechanism physics, shear and
compliance can lead to denaturation
• Agitation in device
• Body temperature storage

FDA Workshop
July 2003
 Physical Interactions with Devices

• Protein adsorption to the device

• Protein denaturation after adsorption
• Partially unfolded intermediates
dominate physical stability of protein
formulations
• Protein aggregation on surface
• Protein aggregation in solution

Uversky, V. N. Lee , H. J., Li, J., Fink, A. L. & Lee, S. J. (2001) Stabilization of Partially Folded
Conformation During a-Synuclein Oligomerization in Both Purified and Cytosolic
Preparations. J. Biol. Chem. 276, 43495-43498.

FDA Workshop
July 2003
 Proposed Aggregation Mechanism

Surface P
P2 2P surf Psurfden Partially
Unfolded Intermediate

autocatalytic
Pagg I + Pagg Psoln.den.
P = Protein
P soln.den. = denatured protein
P surf = surface bound protein
in solution
P surfden = surface bound
P agg = Protein aggregates
denatured
protein
FDA Workshop
July 2003
 Curve Fit Results to Autocatalytic Model
800

Value
700 m1 734.57
m2 1.6383
m3 0.00016847
600
Chisq 4.5331e+05
R 0.99755
500

400

300

200

100

0
-20 0 20 40 60 80 100

Time (hr)

FDA Workshop
July 2003
 Effect of Contact Material on
Aggregation Rate (Insulin/Tris)
150
Glass
Titanium
% survival

100 Polyethylene
Teflon

50

0
0 50 100 150 200
Time to Fixed Fluorescence

FDA Workshop
July 2003
 Formulation and Drug
Substance Effects
GLP-1
100
% survival

75
Standard Drug Substance
50
Standard Sub. Low pH
New Drug Substance
25
New Drug Low pH
0
0 25 50 75 100 125 150

Time to Reach Fixed

Fluorescence
FDA Workshop
July 2003
 Proteins in Pumps

• Formulation is the beginning of successful

drug delivery
• Multiple potential interactions between
the protein and the pump
• Control of the material interface is most
important
• Device design and formulation need to
work together and be regulated together

FDA Workshop
July 2003
FDA Workshop
July 2003
 Conclusions

• Pump/Drug interactions need to be

managed and understood
• Formulation and pump design need
to work together
• Combination product components
can be evaluated separately and
historical data used for regulatory
approval with proper attention to
drug/device interactions

FDA Workshop
July 2003
FDA Workshop
July 2003