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Protein Delivery from Mechanical Devices Challenges and Opportunities. Bill Van Antwerp and Poonam Gulati The Protein Formulation and Testing Group Medtronic Minimed. Why Protein Drugs in Devices. Protein/peptide drugs are increasingly important

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protein delivery from mechanical devices challenges and opportunities

Protein Delivery from Mechanical DevicesChallenges and Opportunities

Bill Van Antwerp and Poonam Gulati

The Protein Formulation and Testing Group

Medtronic Minimed

why protein drugs in devices
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)
why use pumps
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
slide4

Advantages of Continuous Infusion

for Protein Drugs

6

Side Effects

Enzyme Activation

P450 Activation

5

Wasted Drug

14 x CSI

4

Plasma Drug Concentration

3

2

1

Therapeutic

Range

Bolus Injection

Continuous Infusion

0

0

4

8

12

16

20

24

Time (hours)

parenteral delivery today
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
pump challenges old and new
Pump Challenges, Old and New
  • Formulation
  • Chemical Stability
  • Clearance
  • Physical Stability
  • PK/PD Therapeutic Range and Toxicity (localized site reactions)
regulatory hurdles let s not re invent the wheel
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)
stability in pumps
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
chemical stability
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
physical interactions
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
physical interactions with devices
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.

slide12

Proposed Aggregation Mechanism

Surface

P surf

P2

2 P

Psurf den Partially Unfolded Intermediate

autocatalytic

Pagg

I +

Pagg

Psoln. den.

P = Protein

P soln. den. = denatured protein

in solution

P surf = surface bound protein

P surf den= surface bound

denatured protein

P agg = Protein aggregates

slide13

Curve Fit Results to Autocatalytic Model

800

700

600

500

400

300

200

100

0

-20

0

20

40

60

80

100

Time (hr)

Value

m1

734.57

m2

1.6383

m3

0.00016847

Chisq

4.5331e+05

R

0.99755

slide14

Effect of Contact Material on

Aggregation Rate (Insulin/Tris)

150

Glass

Titanium

Polyethylene

100

Teflon

% survival

50

0

0

50

100

150

200

TimetoFixed Fluorescence

slide15

Formulation and Drug

Substance Effects

GLP-1

100

75

Standard Drug Substance

% survival

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

proteins in pumps
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
conclusions
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
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