# Presentation: 060020

## 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**
**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?

**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**

## Advantages of Continuous Infusion 

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 0

- 4

- 8

- 12

- 16

- 20

- 24

***Advantages of Continuous Infusion ***
***for Protein Drugs***

- Bolus Injection

- Continuous Infusion

**Time (hours)**

- Therapeutic
- Range

- Side Effects
- Enzyme Activation
- P450 Activation

- Wasted Drug
- 14 x CSI

**Plasma Drug Concentration**

## 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

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

## 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

**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 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

**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

**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*.*

## Proposed Aggregation Mechanism

- P2

- 2 P

- Surface

- P surf

- Psurf den Partially Unfolded Intermediate

- Psoln. den.

- Pagg

- I +

- autocatalytic

- P = Protein

- P surf = surface bound protein

- P surf den= surface bound
-               denatured protein

- P soln. den. = denatured protein
- 	     in solution

- P agg = Protein aggregates

- Pagg

## Value

- 734.57

- m1

- 1.6383

- m2

- 0.00016847

- m3

- 4.5331e+05

- Chisq

- 0.99755

- R

## Effect of Contact Material on

- Aggregation Rate (Insulin/Tris)

- 0

- 50

- 100

- 150

- 200

- 0

- 50

- 100

- 150

- Polyethylene

- Teflon

- Titanium

- Glass

- Time to Fixed Fluorescence

**% survival**

## Formulation and Drug

**Formulation and Drug**

**Substance Effects**

**GLP-1**

- 0

- 25

- 50

- 75

- 100

- 125

- 150

- 0

- 25

- 50

- 75

- 100

- New Drug Substance

- Standard Drug Substance

- New Drug Low pH

- Standard Sub. Low pH

**Time to Reach Fixed**

**Fluorescence**

**% survival**

## 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**

## Slide 17

## 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**

## Slide 19