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

Plasma Drug Concentration

Side Effects

Enzyme Activation
P450 Activation

Wasted Drug
14 x CSI

FDA Workshop
July 2003

Therapeutic
Range
0

Bolus Injection
Continuous Infusion

12

Time (hours)

16

20

24

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
Lets Not Re-invent the Wheel
Device Physics
Drug Chemistry
Drug Packaging
Pump/Drug Interactions (invitro)
Drug Physical Stability (invitro)
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

FDA Workshop
July 2003

Turbidity
Concentration Changes
Fluorescence
CD/Microcalorimetry/Denaturation Kinetics

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
2P
surf

P2

Psurf den Partially

Unfolded Intermediate

autocatalytic
Pagg
P = Protein

I + Pagg

Psoln. den.

P surf = surface bound protein

P soln. den. = denatured protein

in solution

P surf den= surface bound

denatured
protein

P agg = Protein aggregates

FDA Workshop
July 2003

Curve Fit Results to Autocatalytic Model

800
700
600
500

m1
m2
m3
Chisq
R

Value
734.57
1.6383
0.00016847
4.5331e+05
0.99755

400
300
200
100
0
-20

20

40
Time (hr)

FDA Workshop
July 2003

60

80

100

Effect of Contact Material on

Aggregation Rate (Insulin/Tris)
150

Glass

% survival

Titanium
Polyethylene
Teflon

100

50

0
0

50

100

150

Time to Fixed Fluorescence

FDA Workshop
July 2003

200

Formulation and Drug

Substance Effects
GLP-1
% survival

100

75

Standard Drug Substance

50

Standard Sub. Low pH

New Drug Substance

25

New Drug Low pH

0
0

25

50

75

100

125

Time to Reach Fixed

Fluorescence
FDA Workshop
July 2003

150

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