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The Science Behind Taxus
Advanced Angioplasty 2004
Christian Vander Velde, Boston Scientific Europe, Marketing
TAXUS Technology
Paclitaxel
•
•
•
Binds tubulin
Microtubular dynamics
Multifunctional
Polymer
•
• Uniformity
• Durability
• Biphasic Controlled Release
•
Kinetics
Platform
Express™ Stent
Tandem Architecture
Flexibility
Maverick™ Balloon
Deliverability
TAXUS Technology - Paclitaxel
Restenotic Cascade
Platelet
Aggregation
The Ideal
Pharmaceutical
Should Control
Inflammatory Cells
SMC Proliferation
SMC Migration
ECM
The Ideal
Pharmaceutical
Should Promote
Endothelialization
0–2
2–4
4–10
Days
Days
Days
Table adapted from the experimental models by Ferns et al.
10–14
Days
2–4
Weeks
TAXUS Technology - Paclitaxel
Paclitaxel selectively impacts smooth muscle cells, platelets, and
white blood cell activity without affecting endothelial cells
– Paclitaxel is a multi-functional drug which
Restenosis
effectively:
•
•
•
•
Inhibits proliferation
Inhibits migration
Inhibits inflammation
Inhibits secretion
Prevents
– Paclitaxel enables healing by selectively
impacting the cells that cause restenosis
while allowing healthy healing of
endothelial cells
• TAXUS shows similar healing between
Endothelialization
Promotes
control bare metal stent and paclitaxel
Axel et al, AHA 1997, Karsch et al, SIC 1998
Endothelialization of a paclitaxel-eluting stent in
a porcine coronary artery
Polymer Carrier Considerations
Chemical/Physical and Biological
Biocompatible
Formulate/
process
Coating
Integrity
Sterilization
Drug Loading
Drug release
Vascular
compatible
Coating Integrity
BSC Carrier- TransluteTM
Coated, Loaded, Sterilized, Expanded
40x
200x
• Smooth, Uniform Coverage
• No Cracking, Flaking or Delaminating
Uniform PTx Content Along Stents
of Different Lengths
(15, 24, 32 mm stents -- 1ug/mm2)
Uniformity of Paclitaxel Distribution Along Stent
Comparison of % Paclitaxel Recovery from Consecutive 4cm Segments Along Stent
140
15mm NIR (85ug)
24 mm Express WH (151ug)
32 mm Express WH (209ug)
Paclitaxel % Recovery ( [HPLC/gravimetric] x 100%)
120
100
80
60
40
20
0
1
2
3
4
5
6
Stent Segment (Approximately 4cm length per each segment)
7
8
Uniform PTx Release From ExpressTM
Stents of Different Lengths
% Cumulative Paclitaxel Release
% Cumulative Paclitaxel Release
4.0%
4.0%
1.0 ug/mm2, Slow release
16 mm
1.0 ug/mm2, Slow Release
24 mm
% Paclitaxel Released
3.0%
2.0%
1.0%
0.0%
2.0%
1.0%
0.0%
0
2
4
6
8
10
12
0
2
4
TIME (Days)
6
TIME (Days)
% Cumulative Paclitaxel Release
4.0%
1.0 ug/mm2, Slow Release
32 mm
3.0%
% Paclitaxel Released
% Paclitaxel Released
3.0%
2.0%
1.0%
0.0%
0
2
4
6
TIME (Days)
8
10
12
8
10
12
Polymer-based Clinical Data
TRIAL
TAXUS I
TAXUS II
TAXUS II
TAXUS IV
DOSE OF PTx
1.0ug/mm2 SR
1.0ug/mm2 SR
1.0ug/mm2 MR
1.0ug/mm2 SR
LATE LOSS mm
0.36 +/- 0.48
0.31 +/- 0.39
0.30 +/- 0.39
0.39 +/- 0.50
Confirmed by IVUS analysis (TAXUS II - Circulation
January 20, 2004)
In Vivo Considerations for
Polymers and Drugs
• Animal Model
–
In Vivo Studies,
#&@% !!!!
–
–
–
Rat
Rabbit
Swine
Canine
• Implant Time
• Implant Location
–
–
–
–
Sub Q
IM
Iliac
Coronary
• Other
Polymer Carriers
Vascular Compatibility
Failed candidates
(normal porcine coronary model)
Bare Stent
Polyurethane-coated Stent
(2 months)
Sub-optimal drug carriers can cause severe inflammatory
response
In Collaboration w/Drs. Rogers and Edelman,MIT
Effect of Animal Model and Implant Site
Rat Subcutaneous Implant Model
28 day Implant - H&E Staining
Bare Stent
Polyurethane-coated Stent
Effect of Animal Model and Implant Site
Porcine Coronary 28 day
Bare Stent
Polyurethane-coated Stent
In Collaboration w/Drs. Rogers and Edelman,MIT
Effect of Animal Model and Implant Site
Rabbit Iliac Artery
28 day PLA/PCL
coated stent
56 day PLA/PCL coated stent
In Collaboration w/Drs. Rogers and Edelman, MIT
Effect of Animal Model and Implant Site
Porcine Coronary Artery
35 day PLA/PCL
In Collaboration w/Drs. Rogers and Edelman, MIT
Vascular Compatibility
TransluteTM
90D Bare
control
180D Bare
control
90D polymer 180D polymer
coated
coated
In collaboration with Dr. Rob Schwartz Mayo Clinic
and Dr. Greg Wilson Sick Children’s-Toronto
Translute Polymer
Long term (180 days) vascular compatibility
Lumen Area
180 day
12
10
8
2
mm 6
4
2
0
Bare Control
Translute only
Express stent
Translute Coated
• Good safety profile
• Polymer similar to control
• Reproduced from lot to lot
In collaboration with Dr. Rob Schwartz Mayo Clinic
and Dr. Greg Wilson Sick Children’s-Toronto
28
Days
90
Days
Vascular Compatibility
TransluteTM
Endothelial coverage
(PECAM 1, 0-5)
% Luminal Stenosis
100
80
60
40
20
0
5
4
3
2
1
0
0
60
120
180
0
60
120
180
Inflammation
(CD45, 0-4)
Bare
Polymer-coated
4
3
2
No significant differences
1
0
0
60
120
180
In Collaboration w/Drs. Rogers and Edelman,MIT
TAXUS Technology - Translute™ Polymer
Polymer-based matrices provide:
• ease of handling
• uniform dose along stent and dosing in a controlled manner =
•
consistency
a matrix by which drug release can be manipulated to achieve a
desired biological response
With greater opportunities come greater challenges
TransluteTM Polymer stability
TransluteTM coating integrity was maintained in 10-year
equivalency tests*
The TransluteTM polymer has shown remarkable stability
out to two years in an animal model*
Harsh conditions (alcohol storage, mild heat, agitation)
fail to degrade the polymer*
Tests have shown that following physical abrasion of
the polymer, the release is not markedly increased*
* data on file
Thank You !