protein delivery from mechanical devices.ppt

8/9/2019 Protein Delivery from Mechanical Devices.ppt

1/19

FDA WorkshopJuly 2003

Protein Delivery from MechanicalDevices

Challenges and Opportunities

Bill Van Antwerp and PoonamGulatiThe Protein Formulation and

Testing Group

Medtronic Minimed


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Why Protein Drugs in Devices

• Protein/peptide drugs areincreasingly important

• Diabetes ( nsulin! "ymlin! #$endin! "omato%ine&• 'ancer ( nter eron! Monoclonal Antibodies!Vaccines&• 'ardio)ascular Drugs (*atrecor! GP B

receptor! Protein G receptor&•

n+ammation (T*F,a! -., A&• 0 V/A D" ("omatostatin! T12! T.134! -,1!nter eron&


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Why Use Pumps?

• Proteins and peptides needdeli)ery

• Poor oral bioa)ailability•

Protein denaturation in the digesti)esystem• Acid hydrolysis in the stomach• #n5ymatic degradation• Poor adsorption due to si5e• Poor adsorption due to polar/charge

distribution


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0

1

2

3

4

5

6

0 4 8 12 16 20 24

Advantages of Continuous Infusionfor Protein Drugs

Bolus InjectionContinuous Infusion

Time (hours)

TherapeuticRange

Side EffectsEn y!e Acti"ation#$%0 Acti"ation Wasted Drug

&$ ' (S)

P l a s m a

D r u g

C o n c e n

t r a

t i o n


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Parenteral Delivery Today

• V administration• "ubcutaneous in6ection• 'ontinuous "ubcutaneous n usion

(Pumps&• 'ontinuous ntraperitoneal n usion• "ubcutaneous Depot (leuprolide etc&

• P-GA microspheres• P#G attached peptides• Microemulsions

• ntrathecal! ntraparenchymal


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Pump Challenges Old and !e"

• Formulation• 'hemical "tability•

'learance• Physical "tability• P7/PD Therapeutic ange and

To$icity (locali5ed sitereactions&


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#egulatory $urdles%et&s !ot #e'invent the Wheel

• De)ice Physics• Drug 'hemistry•

Drug Pac%aging• Pump/Drug nteractions ( in-vitro &

•

Drug Physical "tability ( in-vitro &


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ta ility in Pumps

• 'hemical and physical stability candetermine clinical e8cacy

• Physical stability is di8cult to

measure• 9ide )ariety o measurements• Turbidity• 'oncentration 'hanges•

Fluorescence• 'D/Microcalorimetry/Denaturation 7inetics


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Chemical ta ility

• 'hemical stability is determinedby the molecule and by the

ormulation• elati)ely simple ormulation

changes can a:ect stability• Pump chemical stability! in

general! is the same as inprimary pac%aging


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Physical *nteractions

• Protein physical stability in de)ices• Materials o contact

• Te+on/Titanium/Polyole;n/"ilicone


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Physical *nteractions "ith Devices

• Protein adsorption to the de)ice• Protein denaturation a ter

adsorption• Partially un olded intermediates

dominate physical stability oprotein ormulations

•

Protein aggregation on sur ace• Protein aggregation in solution

Uversky, V. . !ee , ". #., !i, #., $ink, %. !. & !ee, '. #. (2001) 't*+ili *tion of -*rti*lly $ol e Confor/*tion urin * 'ynuclein li o/eri *tion in Bot -urifie *n Cytosolic-re *r*tions. J. Biol. Chem. 2 6, 43475 43478 .


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Proposed +ggregation Mechanism

# 2 2 #Surface # surf # surf den #artially

*nfolded )nter!ediate

# soln+ den+# agg) ,

autocatalytic

# - #rotein

# surf - surface .ound protein

# surf den - surface .ounddenatured

protein

# soln+ den+- denatured proteinin solution

# agg - #rotein aggregates

# agg


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0

100

200

300

400

500

600

00

800

20 0 20 40 60 80 100

Curve ,it #esults to +utocatalytic Model

i/e ( r)

V*lue34.5/1

1.6383/20.0001684/34.5331e905C is:

0.77 55;


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ris)

0 50 100 150 2000

50

100

150

-olyet yleneeflon

it*niu/?l*ss

i/e to $i@e $luorescence

- s u

r v i v a

l


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,ormulation and Drugu stance .ffects

/%P'0

0 25 50 5 100 125 1500

25

50

5

100

eA ru 'u+st*nce

't*n *r ru 'u+st*nce

eA ru !oA "

't*n *r 'u+. !oA "

Time to #each ,i1ed,luorescence

- s

u r v

i v a

l


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Proteins in Pumps

• Formulation is the beginning osuccess ul drug deli)ery

• Multiple potential interactions

between the protein and the pump• 'ontrol o the material inter ace is

most important• De)ice design and ormulation need

to wor% together and be regulatedtogether


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Conclusions

• Pump/Drug interactions need to bemanaged and understood

• Formulation and pump design need

to wor% together• 'ombination product components

can be e)aluated separately andhistorical data used or regulatoryappro)al with proper attention todrug/de)ice interactions


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FDA WorkshopJ l 2003

protein delivery from mechanical devices.ppt

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