Mani

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

6

Side Effects

5

Enzyme Activation P450 Activation

Wasted Drug 14 x CSI

4

3

2

1

0

FDA Workshop July 2003

Therapeutic Range 0

4

Bolus Injection Continuous Infusion

8

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 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 • • • •

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

Psurfden

Partially

Unfolded Intermediate

autocatalytic Pagg P = Protein

I + Pagg

P surf = surface bound protein P surfden = surface bound denatured protein

FDA Workshop July 2003

Psoln.den. P soln.den.

= denatured protein in solution

P agg = Protein aggregates

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

0

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