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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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FDA WorkshopJuly 2003
Why Protein Drugs in Devices
• Protein/peptide drugs areincreasingly important
• Diabetes ( nsulin! "ymlin! #$endin! "omato%ine&• 'ancer ( nter eron! Monoclonal Antibodies!Vaccines&• 'ardio)ascular Drugs (*atrecor! GP B
receptor! Protein G receptor&•
n+ammation (T*F,a! -., A&• 0 V/A D" ("omatostatin! T12! T.134! -,1!nter eron&
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FDA WorkshopJuly 2003
Why Use Pumps?
• Proteins and peptides needdeli)ery
• Poor oral bioa)ailability•
Protein denaturation in the digesti)esystem• Acid hydrolysis in the stomach• #n5ymatic degradation• Poor adsorption due to si5e• Poor adsorption due to polar/charge
distribution
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FDA WorkshopJuly 2003
0
1
2
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0 4 8 12 16 20 24
Advantages of Continuous Infusionfor Protein Drugs
Bolus InjectionContinuous Infusion
Time (hours)
TherapeuticRange
Side EffectsEn y!e Acti"ation#$%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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FDA WorkshopJuly 2003
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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FDA WorkshopJuly 2003
Pump Challenges Old and !e"
• Formulation• 'hemical "tability•
'learance• Physical "tability• P7/PD Therapeutic ange and
To$icity (locali5ed sitereactions&
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FDA WorkshopJuly 2003
#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 &
8/9/2019 Protein Delivery from Mechanical Devices.ppt
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FDA WorkshopJuly 2003
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
8/9/2019 Protein Delivery from Mechanical Devices.ppt
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FDA WorkshopJuly 2003
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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FDA WorkshopJuly 2003
Physical *nteractions
• Protein physical stability in de)ices• Materials o contact
• Te+on/Titanium/Polyole;n/"ilicone
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FDA WorkshopJuly 2003
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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FDA WorkshopJuly 2003
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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FDA WorkshopJuly 2003
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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FDA WorkshopJuly 2003
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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FDA WorkshopJuly 2003
,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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FDA WorkshopJuly 2003
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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FDA WorkshopJuly 2003
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FDA WorkshopJuly 2003
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
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