U.S. patent application number 10/725698 was filed with the patent office on 2005-06-02 for temperature controlled crimping.
Invention is credited to Pacetti, Stephen D..
Application Number | 20050118344 10/725698 |
Document ID | / |
Family ID | 34620322 |
Filed Date | 2005-06-02 |
United States Patent
Application |
20050118344 |
Kind Code |
A1 |
Pacetti, Stephen D. |
June 2, 2005 |
Temperature controlled crimping
Abstract
This disclosure describes a method for crimping a stent with a
polymer coating onto a catheter for percutaneous transluminal
coronary angioplasty or other intraluminal interventions. The
method comprises crimping the stent onto a catheter when the
polymer coating is at a target temperature other than ambient
temperature. The polymer coating can optionally comprise
drug(s).
Inventors: |
Pacetti, Stephen D.; (San
Jose, CA) |
Correspondence
Address: |
Cameron Kerrigan
Squire, Sanders & Dempsey L.L.P.
Suite 300
One Maritime Plaza
San Francisco
CA
94111
US
|
Family ID: |
34620322 |
Appl. No.: |
10/725698 |
Filed: |
December 1, 2003 |
Current U.S.
Class: |
427/422 |
Current CPC
Class: |
B29K 2023/083 20130101;
B29K 2055/02 20130101; A61L 31/10 20130101; Y10T 29/49865 20150115;
Y10T 428/3154 20150401; B29C 66/71 20130101; B29K 2033/08 20130101;
B29K 2023/00 20130101; B29K 2075/00 20130101; B29K 2031/00
20130101; A61F 2/9526 20200501; B29C 66/91941 20130101; B29K
2001/00 20130101; B29C 66/9121 20130101; A61F 2/9524 20200501; B29K
2029/00 20130101; B29C 66/91921 20130101; B29K 2033/20 20130101;
B29C 65/56 20130101; B29C 66/91641 20130101; B29C 65/76 20130101;
B29C 66/91431 20130101; B29K 2063/00 20130101; B29C 66/919
20130101; B29K 2077/00 20130101; B29K 2001/12 20130101; B29K
2083/00 20130101; Y10T 428/24942 20150115; Y10T 428/31544 20150401;
A61F 2/9522 20200501; A61F 2/958 20130101; B29C 66/73117 20130101;
B29C 2035/0822 20130101; B29C 2071/022 20130101; A61L 31/06
20130101; A61L 31/14 20130101; B29K 2027/08 20130101; B29B 13/024
20130101; B29K 2023/086 20130101; B29C 66/91945 20130101; B29K
2027/06 20130101; Y10T 428/31855 20150401; B29L 2031/7542 20130101;
B29K 2027/16 20130101; B29C 66/71 20130101; B29K 2083/00 20130101;
B29C 66/71 20130101; B29K 2079/08 20130101; B29C 66/71 20130101;
B29K 2077/00 20130101; B29C 66/71 20130101; B29K 2071/00 20130101;
B29C 66/71 20130101; B29K 2069/00 20130101; B29C 66/71 20130101;
B29K 2067/04 20130101; B29C 66/71 20130101; B29K 2067/00 20130101;
B29C 66/71 20130101; B29K 2063/00 20130101; B29C 66/71 20130101;
B29K 2059/00 20130101; B29C 66/71 20130101; B29K 2055/02 20130101;
B29C 66/71 20130101; B29K 2033/20 20130101; B29C 66/71 20130101;
B29K 2033/12 20130101; B29C 66/71 20130101; B29K 2033/08 20130101;
B29C 66/71 20130101; B29K 2027/16 20130101; B29C 66/71 20130101;
B29K 2027/08 20130101; B29C 66/71 20130101; B29K 2025/08 20130101;
B29C 66/71 20130101; B29K 2023/18 20130101; B29C 66/71 20130101;
B29K 2023/086 20130101; B29C 66/71 20130101; B29K 2023/083
20130101; B29C 66/71 20130101; B29K 2023/08 20130101; B29C 66/71
20130101; B29K 2023/00 20130101; A61L 31/06 20130101; C08L 67/04
20130101 |
Class at
Publication: |
427/422 |
International
Class: |
B05D 001/02 |
Claims
What is claimed is:
1. A method of making a medical device comprising a coated piece
wherein the coated piece comprises a coating, which optionally
comprises a polymer or polymer combination and drug(s), wherein the
method comprises: a) adjusting the temperature of the coating to a
target temperature followed by a crimping step; b) adjusting the
temperature of the coating to a target temperature during a
crimping step; c) adjusting the temperature of the coating to a
target temperature and maintaining the temperature of the coating
within plus or minus 5.degree. C. of the target temperature during
a crimping step; d) adjusting the temperature of the coating to a
target temperature followed by crimping such that the temperature
of the coating remains within plus or minus 10.degree. C. of the
target temperature during a crimping step; or e) adjusting the
temperature of the coating to a temperature other than ambient
towards a target temperature and continuing to adjust the
temperature of the coating towards the target temperature during a
crimping step.
2. The method of claim 1 wherein the crimping step comprises the
steps of closing the crimper, adjusting the temperature of the
coating to a second temperature, and opening the crimper wherein
the second temperature is greater than or less than target
temperature.
3. The method of claim 1 wherein the device further comprises a
catheter and wherein the crimping step attaches the coated piece to
the catheter.
4. The method of claim 1 wherein the coating comprises a polymer or
polymer combination.
5. The method of claim 4 wherein the polymer or polymer combination
comprises a polymer with Tg below ambient temperature.
6. The method of claim 4 wherein the polymer or polymer combination
comprises a polymer with Tg above ambient temperature.
7. The method of claim 4 wherein the polymer or polymer combination
comprises a polymer that is one of or any combination of poly(ester
amides); ABS resins; acrylic polymers and acrylic copolymers;
acrylonitrile-styrene copolymers; alkyd resins; cellulose ethers;
celluloses; copoly(ether-esters); copolymers of polycarboxylic
acids and poly-hydroxycarboxylic acids; copolymers of vinyl
monomers with each other and olefins; cyanoacrylates; epoxy resins;
ethylene vinyl alcohol copolymer; ethylene-.alpha.-olefin
copolymers; ethylene-methyl methacrylate copolymers; ethylene-vinyl
acetate copolymers; poly(amino acids); poly(anhydrides); poly(imino
carbonates); poly(iminocarbonate); poly(orthoesters); poly(tyrosine
arylates); poly(tyrosine derive carbonates); polyacrylates;
polyacrylic acid; polyacrylic acids; polyacrylonitrile;
polyalkylene oxalates; polyamides; polyamino acids; polyanhydride;
polyanhydrides; polycarbonates; polycarboxylic acids;
polycyanoacrylates; polyesters; polyethers; poly-hydroxycarboxylic
acids; polyimides; polyisobutylene and ethylene-.alpha.-olefin
copolymers; polyketones; polymethacrylates; polyolefins;
polyorthoester; polyorthoesters; polyoxymethylenes;
polyphosphazenes; polyphosphoester; polyphosphoester urethane;
polyphosphoesters; polyphosphoesters-urethane; polyurethane;
polyurethanes; poly(ether-urethanes), poly(ester-urethanes),
poly(silicone-urethanes), polyvinyl alcohol; polyvinyl aromatics;
polyvinyl esters; polyvinyl ethers; polyvinyl ketones;
poly(vinylidene fluoride), poly(vinylidene chloride),
poly(vinylidene fluoride-co-hexafluoropropene), poly(vinylidene
fluoride-co-chlorotrifluoroethylene), poly(vinyl fluoride),
poly(vinyl chloride), polyvinylidene halides; silicones; starches;
vinyl copolymers vinyl-olefin copolymers; vinyl halide polymers and
copolymers; and vinyl halide polymers vinyl halide polymers
copolymers
8. The method of claim 4 wherein the polymer or polymer combination
comprises a polymer that is one of or any combination of starch,
sodium alginate, rayon-triacetate, rayon, polyvinylidene fluoride,
polyvinylidene chloride, polyvinyl pyrrolidone, polyvinyl methyl
ether, polyvinyl chloride, polyvinyl acetate, polystyrene,
polyisocyanate, polyisobutylene, polyethylene glycol,
polydioxanone, polycaprolactone, polycaprolactam,
polyacrylonitrile, poly(trimethylene carbonate), poly(L-lactic
acid), poly(lactide-co-glycolide), poly(hydroxyvalerate),
poly(hydroxybutyrate-co-valerate),
poly(hydroxybutyrate-co-hydroxyvalerat- e), poly(hydroxybutyrate),
poly(glycolide), poly(glycolic acid),
poly(D,L-lactide-co-L-lactide), poly(D,L-lactide-co-glycolide),
poly(D,L-lactide), poly(4-hydroxybutyrate),
poly(3-hydroxybutyrate), poly(3-hydroxy valerate), Nylon 66,
hyaluronic acid, fibrinogen, fibrin, elastin-collagen, collagen,
cellulose propionate, cellulose nitrate, cellulose butyrate,
cellulose acetate butyrate, cellulose acetate, cellulose,
cellophane, carboxymethyl cellulose, or poly(2-hydroxyethyl
methacrylate).
9. The method of claim 1 wherein the coated piece is selected from
self-expandable stents, balloon-expandable stents, and
stent-grafts.
10. The method of claim 1 wherein the coating comprises drug(s)
selected from antiproliferative, antineoplastic, antiinflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,
antibiotic, antioxidants, or their combinations.
11. The method of claims 1-10 wherein the target temperature is a)
within or below the range defined by definition 1, definition 2,
definition 3, definition 4, definition 5, definition 6, or
definition 7 of the Tg range of the polymer or polymer combination;
b) within or above the range defined by definition 1, definition 2,
definition 3, definition 4, definition 5, definition 6, or
definition 7 of the Tg range of the polymer or polymer combination;
c) below ambient temperature; d) below room temperature; e) above
ambient temperature; f) above room temperature; g) at or below
-40.degree. C.; h) between ambient temperature and upper Tg of the
Tg range; i) between ambient temperature and lower Tg of the Tg
range; j) between -40.degree. C. and upper Tg of the Tg range; k)
between -40.degree. C. and lower Tg of the Tg range; l) between
-40.degree. C. and ambient temperature; m) at or above 80.degree.
C.; n) between 80.degree. C. and upper Tg of the Tg range; o)
between 80.degree. C. and lower Tg of the Tg range; or p) between
80.degree. C. and ambient temperature.
12. The method of claim 11 wherein the target temperature is
limited to a temperature below the temperature at which therapeutic
agents present in the coating substantially decompose.
13. The method of claim 11 wherein the target temperature is
limited to a temperature below the temperature at which drug(s)
present in the coating become substantially unsatisfactory for
their intended use.
14. The method of claim 11 wherein the target temperature is chosen
to simultaneously minimize deformation- and delamination-based
failure during crimping.
15. The method of claim 11 wherein Tg range of the polymer or
polymer combination excludes ambient temperature.
16. The method of claim 11 wherein Tg range of the polymer or
polymer combination excludes ambient temperature plus or minus
1.degree. C.
17. The method of claim 11 wherein Tg range of the polymer or
polymer combination excludes ambient temperature plus or minus
5.degree. C.
18. The method of claim 11 wherein target temperature is chosen to
yield a change in shore hardness wherein: a) the change is plus
50%; or b) the change is minus 50%.
19. The method of claim 18 wherein: a) the change is plus 20%; or
b) the change is minus 20%.
20. The method of claim 11 wherein the target temperature is a) for
polymers which have a shore hardness of 60A to 80D; predominately
exhibit deformation-based failures during crimping; have a Tg above
room temperature; or have a Tg above ambient temperature: i) within
or below the range defined by definition 1, definition 2,
definition 3, definition 4, definition 5, definition 6, or
definition 7 of the Tg range of the polymer or polymer combination;
ii) below ambient temperature; iii) below room temperature; iv) at
or below -40.degree. C.; v) between ambient temperature and upper
Tg of the Tg range; vi) between ambient temperature and lower Tg of
the Tg range; vii) between -40.degree. C. and upper Tg of the Tg
range; viii) between -40.degree. C. and lower Tg of the Tg range;
ix) between -40.degree. C. and ambient temperature; b) for polymers
which have a shore hardness of 60D to 95D; predominately exhibit
delamination-based failure during crimping; have a Tg above room
temperature; or have a Tg below ambient temperature: i) within or
above the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; ii) above ambient
temperature; iii) above room temperature; iv) at or above
80.degree. C.; v) between 80.degree. C. and upper Tg of the Tg
range; vi) between 80.degree. C. and upper Tg of the Tg range; vii)
between 80.degree. C. and lower Tg of the Tg range; viii) between
80.degree. C. and lower Tg of the Tg range; or ix) between
80.degree. C. and ambient temperature.
21. The method of claim 20 wherein for polymers that have a shore
hardness of 60A to 80D the target temperature is: a) within or
below the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) below ambient
temperature; c) below room temperature; d) at or below -40.degree.
C.; e) between ambient temperature and upper Tg of the Tg range; f)
between ambient temperature and lower Tg of the Tg range; g)
between -40.degree. C. and upper Tg of the Tg range; h) between
-40.degree. C. and lower Tg of the Tg range; i) between -40.degree.
C. and ambient temperature;
22. The method of claim 20 wherein for polymers that have a shore
hardness of 60D to 95D the target temperature is: a) within or
above the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) above ambient
temperature; c) above room temperature; d) at or above 80.degree.
C.; e) between ambient temperature and upper Tg of the Tg range; f)
between ambient temperature and lower Tg of the Tg range; g)
between 80.degree. C. and upper Tg of the Tg range; h) between
80.degree. C. and lower Tg of the Tg range; or i) between
80.degree. C. and ambient temperature.
23. The method of claim 20 wherein for polymers that predominately
exhibit deformation-based failures during crimping the target
temperature is: a) within or below the range defined by definition
1, definition 2, definition 3, definition 4, definition 5,
definition 6, or definition 7 of the Tg range of the polymer or
polymer combination; b) below ambient temperature; c) below room
temperature; d) at or below -40.degree. C.; e) between ambient
temperature and upper Tg of the Tg range; f) between ambient
temperature and lower Tg of the Tg range; g) between -40.degree. C.
and upper Tg of the Tg range; h) between -40.degree. C. and lower
Tg of the Tg range; i) between -40.degree. C. and ambient
temperature;
24. The method of claim 20 wherein for polymers that predominately
exhibit delamination-based failure during crimping the target
temperature is: a) within or above the range defined by definition
1, definition 2, definition 3, definition 4, definition 5,
definition 6, or definition 7 of the Tg range of the polymer or
polymer combination; b) above ambient temperature; c) above room
temperature; d) at or above 80.degree. C.; e) between ambient
temperature and upper Tg of the Tg range; f) between ambient
temperature and lower Tg of the Tg range; g) between 80.degree. C.
and upper Tg of the Tg range; h) between 80.degree. C. and lower Tg
of the Tg range; or i) between 80.degree. C. and ambient
temperature.
25. The method of claim 20 wherein for polymers that have a Tg
above room temperature the target temperature is: a) within or
below the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) below ambient
temperature; c) below room temperature; d) at or below -40.degree.
C.; e) between ambient temperature and upper Tg of the Tg range; f)
between ambient temperature and lower Tg of the Tg range; g)
between -40.degree. C. and upper Tg of the Tg range; h) between
-40.degree. C. and lower Tg of the Tg range; i) between -40.degree.
C. and ambient temperature;
26. The method of claim 20 wherein for polymers that have a Tg
above room temperature the target temperature is: a) within or
above the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) above ambient
temperature; c) above room temperature; d) at or above 80.degree.
C.; e) between ambient temperature and upper Tg of the Tg range; f)
between ambient temperature and lower Tg of the Tg range; g)
between 80.degree. C. and upper Tg of the Tg range; h) between
80.degree. C. and lower Tg of the Tg range; or i) between
80.degree. C. and ambient temperature.
27. The method of claim 20 wherein for polymers that have a Tg
above ambient temperature the target temperature is: a) within or
below the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) below ambient
temperature; c) below room temperature; d) at or below -40.degree.
C.; e) between ambient temperature and upper Tg of the Tg range; f)
between ambient temperature and lower Tg of the Tg range; g)
between -40.degree. C. and upper Tg of the Tg range; h) between
-40.degree. C. and lower Tg of the Tg range; i) between -40.degree.
C. and ambient temperature.
28. The method of claim 20 wherein for polymers that have a Tg
below ambient temperature the target temperature is: a) within or
above the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) above ambient
temperature; c) above room temperature; d) at or above 80.degree.
C.; e) between ambient temperature and upper Tg of the Tg range; f)
between ambient temperature and lower Tg of the Tg range; g)
between 80.degree. C. and upper Tg of the Tg range; h) between
80.degree. C. and lower Tg of the Tg range; or i) between
80.degree. C. and ambient temperature.
29. The method of claim 20 wherein for polymers that have a shore
hardness of 60A to 80D the target temperature is within or below
the range defined by definition 1, definition 2, definition 3,
definition 4, definition 5, definition 6, or definition 7 of the Tg
range of the polymer or polymer combination.
30. The method of claim 20 wherein for polymers that have a shore
hardness of 60A to 80D the target temperature is below ambient
temperature.
31. The method of claim 20 wherein for polymers that have a shore
hardness of 60A to 80D the target temperature is at or below
-40.degree. C.
32. The method of claim 20 wherein for polymers that have a shore
hardness of 60A to 80D the target temperature is between
-40.degree. C. and lower Tg of the Tg range.
33. The method of claim 20 wherein for polymers that have a shore
hardness of 60D to 95D the target temperature is within or above
the range defined by definition 1, definition 2, definition 3,
definition 4, definition 5, definition 6, or definition 7 of the Tg
range of the polymer or polymer combination.
34. The method of claim 20 wherein for polymers that have a shore
hardness of 60D to 95D the target temperature is above ambient
temperature.
35. The method of claim 20 wherein for polymers that have a shore
hardness of 60D to 95D the target temperature is at or above
80.degree. C.
36. The method of claim 20 wherein for polymers that have a shore
hardness of 60D to 95D the target temperature is between 80.degree.
C. and upper Tg of the Tg range.
37. The method of claim 20 wherein for polymers that predominately
exhibit deformation-based failures during crimping the target
temperature is within or below the range defined by definition 1,
definition 2, definition 3, definition 4, definition 5, definition
6, or definition 7 of the Tg range of the polymer or polymer
combination.
38. The method of claim 20 wherein for polymers that predominately
exhibit deformation-based failures during crimping the target
temperature is below ambient temperature.
39. The method of claim 20 wherein for polymers that predominately
exhibit deformation-based failures during crimping the target
temperature is at or below -40.degree. C.
40. The method of claim 20 wherein for polymers that predominately
exhibit deformation-based failures during crimping the target
temperature is between ambient temperature and upper Tg of the Tg
range.
41. The method of claim 20 wherein for polymers that predominately
exhibit deformation-based failures during crimping the target
temperature is between -40.degree. C. and upper Tg of the Tg
range.
42. The method of claim 20 wherein for polymers that predominately
exhibit delamination-based failure during crimping the target
temperature is within or above the range defined by definition 1,
definition 2, definition 3, definition 4, definition 5, definition
6, or definition 7 of the Tg range of the polymer or polymer
combination.
43. The method of claim 20 wherein for polymers that predominately
exhibit delamination-based failure during crimping the target
temperature is above ambient temperature.
44. The method of claim 20 wherein for polymers that predominately
exhibit delamination-based failure during crimping the target
temperature is at or above 80.degree. C.;
45. The method of claim 20 wherein for polymers that predominately
exhibit delamination-based failure during crimping the target
temperature is between 80.degree. C. and upper Tg of the Tg
range.
46. The method of claim 20 wherein the target temperature is chosen
to minimize deformation- or delamination-based failure during
crimping.
47. The method of claim 46 wherein Tg range of the polymer or
polymer combination excludes ambient temperature.
48. The method of claim 46 wherein Tg range of the polymer or
polymer combination excludes ambient temperature plus or minus
1.degree. C.
49. The method of claim 46 wherein Tg range of the polymer or
polymer combination excludes ambient temperature plus or minus
5.degree. C.
50. The method of claim 46 wherein target temperature is chosen to
yield a change in shore hardness wherein: a) the change is plus
50%; or b) the change is minus 50%.
51. The method of claim 50 wherein: a) the change is plus 20%; or
b) the change is minus 20%.
52. The method of claim 11 wherein adjusting the temperature
comprises disposing the coating or coated piece in thermal contact
with a heat sink or heat source.
53. The method of claim 52 wherein adjusting the temperature
comprises: a) thermally contacting the coating or coated piece with
a heat sink or heat source; b) directing a heated or cooled gas at
the coating or coated piece; c) placing the coating or coated piece
near a heated or cooled surface for emitting thermal or infrared
radiation to or absorbing thermal or infrared radiation from the
coating or coated piece; d) placing the coating or coated piece
near a heated or cooled surface to enable convection to or from the
coating or coated piece to the surface; e) i) heating or cooling
the jaws of the crimper; and ii) thermally contacting the coating
or coated piece with the crimper jaws; f) for crimper jaws that
allow the passage of infrared radiation, bathing the stent on
catheter with infrared radiation; or g) heating the stent on
catheter in an incubator or oven, or cooling the stent on catheter
in a refrigerator to pre-equilibrate the stent on catheter to the
desired temperature before crimping.
54. The method of claim 53 wherein adjusting the temperature
comprises disposing the coating or coated piece in thermal contact
with a heat sink or heat source.
55. The device of claim 53 wherein the heat sink or heat source is
integrated with a crimping device.
56. The method of claim 21 wherein the heat sink or heat source is
integrated with a crimping device.
57. A method of crimping a stent onto a delivery catheter or a
balloon of the delivery catheter comprising: a) positioning the
stent on the catheter or the balloon; and b) crimping the stent on
the catheter or a balloon wherein crimping is done at a target
temperature, wherein the target temperature is other than ambient
temperature.
58. The method of claim 1 wherein the target temperature is a)
within or below the range defined by definition 1, definition 2,
definition 3, definition 4, definition 5, definition 6, or
definition 7 of the Tg range of the polymer or polymer combination;
b) within or above the range defined by definition 1, definition 2,
definition 3, definition 4, definition 5, definition 6, or
definition 7 of the Tg range of the polymer or polymer combination;
c) below ambient temperature; d) below room temperature; e) above
ambient temperature; f) above room temperature; g) at or below
-40.degree. C.; h) between ambient temperature and upper Tg; i)
between ambient temperature and lower Tg; j) between -40.degree. C.
and upper Tg; k) between -40.degree. C. and lower Tg; 1) between
-40.degree. C. and ambient temperature; m) at or above 80.degree.
C.; n) between 80.degree. C. and upper Tg; o) between 80.degree. C.
and lower Tg; or p) between 80.degree. C. and ambient
temperature.
59. The method of claim 58 wherein the target temperature is a) for
polymers which have a shore hardness of 60A to 80D; predominately
exhibit deformation-based failures during crimping; have a Tg above
room temperature; or have a Tg above ambient temperature: i) within
or below the range defined by definition 1, definition 2,
definition 3, definition 4, definition 5, definition 6, or
definition 7 of the Tg range of the polymer or polymer combination;
ii) below ambient temperature; iii) below room temperature; iv) at
or below -40.degree. C.; v) between ambient temperature and upper
Tg; vi) between ambient temperature and lower Tg; vii) between
-40.degree. C. and upper Tg; viii) between -40.degree. C. and lower
Tg; ix) between -40.degree. C. and ambient temperature; b) for
polymers which have a shore hardness of 60D to 95D; predominately
exhibits delamination-based failure during crimping; have a Tg
above room temperature; or have a Tg below ambient temperature: i)
within or above the range defined by definition 1, definition 2,
definition 3, definition 4, definition 5, definition 6, or
definition 7 of the Tg range of the polymer or polymer combination;
ii) above ambient temperature; iii) above room temperature; iv) at
or above 80.degree. C.; v) between 80.degree. C. and upper Tg; vi)
between 80.degree. C. and upper Tg; vii) between 80.degree. C. and
lower Tg; viii) between 80.degree. C. and lower Tg; or ix) between
80.degree. C. and ambient temperature.
60. The method of claim 59 wherein for polymers that have a shore
hardness of 60A to 80D the target temperature is: a) within or
below the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) below ambient
temperature; c) below room temperature; d) at or below -40.degree.
C.; e) between ambient temperature and upper Tg; f) between ambient
temperature and lower Tg; g) between -40.degree. C. and upper Tg;
h) between -40.degree. C. and lower Tg; i) between -40.degree. C.
and ambient temperature;
61. The method of claim 59 wherein for polymers that have a shore
hardness of 60D to 95D the target temperature is: a) within or
above the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) above ambient
temperature; c) above room temperature; d) at or above 80.degree.
C.; e) between ambient temperature and upper Tg; f) between ambient
temperature and lower Tg g) between 80.degree. C. and upper Tg; h)
between 80.degree. C. and lower Tg; or i) between 80.degree. C. and
ambient temperature.
62. The method of claim 59 wherein for polymers that predominately
exhibit deformation-based failures during crimping the target
temperature is: a) within or below the range defined by definition
1, definition 2, definition 3, definition 4, definition 5,
definition 6, or definition 7 of the Tg range of the polymer or
polymer combination; b) below ambient temperature; c) below room
temperature; d) at or below -40.degree. C.; e) between ambient
temperature and upper Tg; f) between ambient temperature and lower
Tg; g) between -40.degree. C. and upper Tg; between -40.degree. C.
and lower Tg; i) between -40.degree. C. and ambient
temperature;
63. The method of claim 59 wherein for polymers that predominately
exhibit delamination-based failure during crimping the target
temperature is: a) within or above the range defined by definition
1, definition 2, definition 3, definition 4, definition 5,
definition 6, or definition 7 of the Tg range of the polymer or
polymer combination; b) above ambient temperature; c) above room
temperature; d) at or above 80.degree. C.; e) between ambient
temperature and upper Tg; f) between ambient temperature and lower
Tg g) between 80.degree. C. and upper Tg; h) between 80.degree. C.
and lower Tg; or i) between 80.degree. C. and ambient
temperature.
64. The method of claim 59 wherein for polymers that have a Tg
above room temperature the target temperature is: a) within or
below the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) below ambient
temperature; c) below room temperature; d) at or below -40.degree.
C.; e) between ambient temperature and upper Tg; f) between ambient
temperature and lower Tg; g) between -40.degree. C. and upper Tg;
h) between -40.degree. C. and lower Tg; i) between -40.degree. C.
and ambient temperature;
65. The method of claim 59 wherein for polymers that have a Tg
above room temperature the target temperature is: a) within or
above the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) above ambient
temperature; c) above room temperature; d) at or above 80.degree.
C.; e) between ambient temperature and upper Tg; f) between ambient
temperature and lower Tg g) between 80.degree. C. and upper Tg; h)
between 80.degree. C. and lower Tg; or i) between 80.degree. C. and
ambient temperature.
66. The method of claim 59 wherein for polymers that have a Tg
above ambient temperature the target temperature is: a) within or
below the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) below ambient
temperature; c) below room temperature; d) at or below -40.degree.
C.; e) between ambient temperature and upper Tg; f) between ambient
temperature and lower Tg; g) between -40.degree. C. and upper Tg;
h) between -40.degree. C. and lower Tg; i) between -40.degree. C.
and ambient temperature.
67. The method of claim 59 wherein for polymers that have a Tg
below ambient temperature the target temperature is: a) within or
above the range defined by definition 1, definition 2, definition
3, definition 4, definition 5, definition 6, or definition 7 of the
Tg range of the polymer or polymer combination; b) above ambient
temperature; c) above room temperature; d) at or above 80.degree.
C.; e) between ambient temperature and upper Tg; f) between ambient
temperature and lower Tg g) between 80.degree. C. and upper Tg; h)
between 80.degree. C. and lower Tg; or i) between 80.degree. C. and
ambient temperature.
68. The method of claim 60-67 wherein the target temperature is
chosen to minimize deformation- or delamination-based failure
during crimping.
69. The method of claim 68 wherein Tg range of the polymer or
polymer combination excludes ambient temperature plus or minus
5.degree. C.
70. The method of claim 68 wherein Tg range of the polymer or
polymer combination excludes ambient temperature.
71. The method of claim 68 wherein Tg range of the polymer or
polymer combination excludes ambient temperature plus or minus
1.degree. C.
72. The method of claim 68 wherein target temperature is chosen to
yield a change in shore hardness wherein: a) the change is plus
50%; or b) the change is minus 50%.
73. The method of claim 68 wherein: a) the change is plus 20%; or
b) the change is minus 20%.
74. A coating for a medical device made using the method of claim
11.
75. A device for crimping stents onto delivery catheters or
balloons that has a crimping means wherein the improvement
comprises a heating or cooling means integral with or adjacent to
the crimping means.
Description
BACKGROUND
[0001] Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease. A surgeon introduces a
catheter assembly having a balloon portion percutaneously into the
cardiovascular system of a patient via the brachial or femoral
artery. The surgeon advances the catheter assembly through the
coronary vasculature until the balloon portion crosses the
occlusive lesion. Once in position, the surgeon inflates the
balloon to radially compress the atherosclerotic plaque of the
lesion and remodel the vessel wall. The surgeon then deflates the
balloon to remove the catheter.
[0002] An advance on PTCA involved using an intravascular stent.
Mechanically, stents act as scaffoldings, physically holding open
and, if desired, expanding the vessel wall. Typically, stents
compress for insertion through small vessels and then expand to a
larger diameter once in position. U.S. Pat. No. 4,733,665, issued
to Palmaz; U.S. Pat. No. 4,800,882, issued to Gianturco; and U.S.
Pat. No. 4,886,062, issued to Wiktor disclose examples of PTCA
stents.
[0003] Before this procedure can occur, equipment for the procedure
must be manufactured. Stent crimping is a critical step in
manufacturing this equipment in that stent retention depends on it.
Generally, stent crimping is the act of affixing the stent to the
delivery catheter or delivery balloon so that it remains affixed to
the catheter or balloon until the physician desires to deliver the
stent at the treatment site. Current stent crimping technology is
sophisticated. A short time ago, one process used a roll crimper.
This damaged many polymer coatings due to its inherent shearing
action. Next came the collet crimper; in it, metal jaws are mounted
into what is essentially a drill chuck. The jaws move in a purely
radial direction. This movement was not expected to shear the
coating, because it applied forces only normal to the stent
surface. But some stent geometries require that stent struts
scissor together during crimping. In those geometries, even if the
crimper imposes only normal forces, the scissor action of the stent
struts imparts shear. Finally, the iris or sliding-wedge crimper
imparts mostly normal forces with some amount of tangential
shear.
[0004] To use a roll crimper, first the stent is slid loosely onto
the balloon portion of the catheter. This assembly is placed
between the plates of the roll crimper. With an automated roll
crimper, the plates come together and apply a specified amount of
force. They then move back and forth a set distance in a direction
that is perpendicular to the catheter. The catheter rolls back and
forth under this motion, and the diameter of the stent is reduced.
The process can be broken down into more than one step, each with
its own level of force, translational distance, and number of
cycles. With regard to a stent with a drug eluting coating, this
process imparts a great deal of shear to the stent in a direction
perpendicular to the catheter or catheter wall. Furthermore, as the
stent is crimped, there is additional relative motion between the
stent surface and the crimping plates. As a result, this crimping
process tends to damage the drug eluting stent coating.
[0005] The collet crimper is equally conceptually simple. A
standard drill-chuck collet is equipped with several
pie-piece-shaped jaws. These jaws move in a radial direction as an
outer ring is turned. To use this crimper, a stent is loosely
placed onto the balloon portion of a catheter and inserted in the
center space between the jaws. Turning the outer ring causes the
jaws to move inward. An issue with this device is determining or
designing the crimping endpoint. One scheme is to engineer the jaws
so that when they completely close, they touch and a center hole of
a known diameter remains. Using this approach, turning the collet
onto the collet stops crimps the stent to the known outer diameter.
While this seems ideal, it can lead to problems. Stent struts have
a tolerance on their thickness. Additionally, the process of
folding non-compliant balloons is not exactly reproducible.
Consequently, the collet crimper exerts a different amount of force
on each stent in order to achieve the same final dimension. Unless
this force, and the final crimped diameter, is carefully chosen,
the variability of the stent and balloon dimensions can yield stent
coating or balloon damage.
[0006] Furthermore, although the collet jaws move in a radial
direction, they move closer together as they crimp. This action,
combined with the scissoring motion of the struts, imparts
tangential shear on the coatings that can also lead to damage.
Lastly, the actual contact surfaces of the collet crimper are the
jaw tips. These surfaces are quite small, and only form a
cylindrical surface at the final point of crimping. Before that
point, the load being applied to the stent surface is
discontinuous.
[0007] In the sliding wedge or iris crimper, adjacent
pie-piece-shaped sections move inward and twist, much like the
leaves in a camera aperture. This crimper can be engineered to have
two different types of endpoints. It can stop at a final diameter,
or it can apply a fixed force and allow the final diameter to
float. From the discussion on the collet crimper, there are
advantages in applying a fixed level of force as variabilities in
strut and balloon dimension will not change the crimping force. The
sliding wedges impart primarily normal forces, which are the least
damaging to stent coatings. As the wedges slide over each other,
they impart some tangential force. But the shear damage is
frequently equal to or less than that of the collet crimper.
Lastly, the sliding wedge crimper presents a nearly cylindrical
inner surface to the stent, even as it crimps. This means the
crimping loads are distributed over the entire outer surface of the
stent.
[0008] All current stent crimping methods were developed for
all-metal stents. Stent metals, such as stainless steel, are
durable and can take abuse. When crimping was too severe, it
usually damaged the underlying balloon, not the stent. But
polymeric coatings present different challenges.
[0009] In the drug eluting stent arena, drugs are commonly placed
on the stent in combination with a polymer. This placement
typically coats all stent surfaces. Then the stent is crimped onto
the catheter. In general, polymer coatings are softer, weaker, and
less durable than the underlying stent material. Upon crimping with
a sliding wedge crimper, and following crimp protocols for the
particular stent, coating damage is frequently seen. FIGS. 1 and 2
show an Elasteon 80A (a polyurethane) coating on
poly(ethylene-co-vinyl alcohol) (EVAL) after crimp, grip, and the
wet expansion test.
[0010] Grip is a process conducted after crimping to further
increase stent retention. An outer sleeve restrains the crimped
stent. Simultaneously, pressure and heat are applied to the
stent-balloon section. Under this action, the balloon material
deforms slightly, moving in between the struts. In a wet expansion
test, the final stent-on-catheter assembly is immersed in deionized
water at 37.degree. C. for 30 seconds. Then the balloon is inflated
according to the device instructions to at least a nominal pressure
(8 atmospheres). After holding this pressure for 30 seconds, the
balloon is deflated, and the stent slides off. After drying, the
stent can be examined by optical microscopy or scanning electron
microscopy for coating damage.
[0011] The primary purpose of the polymer in the stent coating is
to contain the drug and control its release at a desired rate.
Other obvious specifications for the polymer are a high level of
vascular biocompatibility and the ability to flex and elongate to
accommodate stent expansion without cracking or peeling. Meeting
all of these objectives, while also possessing a high level of
toughness and strength to withstand conventional crimping process,
can be challenging.
[0012] A crimping process that minimizes damage to the polymer
coatings of stents is needed.
SUMMARY
[0013] The current invention comprises several embodiments, some of
which relate to extracorporeal methods of making medical devices or
implantable medical devices. These devices can comprise portions
with coatings. In some embodiments, the coating comprises a polymer
or polymer combination or drug(s). The piece comprising the coating
is crimped onto another part of the device or onto a separate
device. In some embodiments, crimping is done at non-ambient
temperatures. Sometimes non-ambient-temperature crimping comprises
changing the temperatures of the coating, the piece comprising the
coating, the medical device, the crimping device, or any
combination of these. Likewise, medical devices made using these
methods and devices for implementing these methods are also part of
this invention.
[0014] Specific heating and cooling profiles are used in different
invention embodiments. For instance, embodiments of crimping
methods include adjusting the temperature of the coating to a
target temperature followed by a crimping step; adjusting the
temperature of the coating to a target temperature during a
crimping step; adjusting the temperature of the coating to a target
temperature and maintaining the temperature of the coating within
plus or minus 5.degree. C. of the target temperature during a
crimping step; adjusting the temperature of the coating to a target
temperature followed by crimping such that the temperature of the
coating remains within plus or minus 10.degree. C. of the target
temperature during a crimping step; and adjusting the temperature
of the coating to a temperature other than ambient towards a target
temperature and continuing to adjust the temperature of the coating
towards the target temperature during a crimping step.
Alternatively, the temperature of the coating can first be adjusted
to a target temperature with the crimper jaws then closing. After
that, the temperature can be adjusted to a second temperature,
followed by opening the crimper jaws.
[0015] Embodiments in which the target temperature takes values
based on Tg and intervals around Tg are described, with the goal of
some embodiments being to simultaneously minimize deformation- and
delamination-based failure during crimping. In some embodiments,
the target temperature ultimately depends on the predominate
failure mode of the polymer coating, Tg of the coating, shore D
hardness of the polymer coating at ambient temperature, and shore
hardness of the polymer coating at the target temperature, among
other factors.
[0016] In some embodiments, invention methods relate to making
medical devices comprising at least one coated piece wherein the
coated piece can comprise a coating. In some embodiments, the
coating comprises a polymer or polymer combination and drug(s). A
typical method comprises choosing a target temperature based on the
mechanical behavior of the coating material, sometimes the behavior
during crimping. The method further comprises juxtaposing the
closing of the crimping jaws with adjusting the temperature of the
coating in any combination. For instance, the following heating or
cooling regimes are practical:
[0017] adjusting the temperature of the coating to a target
temperature followed by a crimping step;
[0018] adjusting the temperature of the coating to a target
temperature during a crimping step;
[0019] adjusting the temperature of the coating to a target
temperature and maintaining the temperature of the coating within
plus or minus 5.degree. C. of the target temperature during a
crimping step;
[0020] adjusting the temperature of the coating to a target
temperature followed by crimping such that the temperature of the
coating remains within plus or minus 10.degree. C. of the target
temperature during a crimping step; and
[0021] adjusting the temperature of the coating to a temperature
other than ambient towards a target temperature and continuing to
adjust the temperature of the coating towards the target
temperature during a crimping step.
[0022] In these embodiments or others the heating or cooling regime
can comprise closing the crimper, adjusting the temperature of the
coating to a second temperature, and opening the crimper wherein
the second temperature is greater than or less than the target
temperature. Some medical devices further comprise a catheter. In
those devices, the crimping step of invention methods can be used
to attach the coated piece to the catheter.
[0023] Invention methods can be used on a variety of coating
materials including polymeric materials characterized as having Tg
above or below ambient temperature. In some embodiments the methods
act on coatings comprising poly(ester amides); ABS resins; acrylic
polymers and acrylic copolymers; acrylonitrile-styrene copolymers;
alkyd resins; cellulose ethers; celluloses; copoly(ether-esters);
copolymers of polycarboxylic acids and poly-hydroxycarboxylic
acids; copolymers of vinyl monomers with each other and olefins;
cyanoacrylates; epoxy resins; ethylene vinyl alcohol copolymer;
ethylene-.alpha.-olefin copolymers; ethylene-methyl methacrylate
copolymers; ethylene-vinyl acetate copolymers; poly(amino acids);
poly(anhydrides); poly(imino carbonates); poly(iminocarbonate);
poly(orthoesters); poly(tyrosine arylates); poly(tyrosine derive
carbonates); polyacrylates; polyacrylic acid; polyacrylic acids;
polyacrylonitrile; polyalkylene oxalates; polyamides; polyamino
acids; polyanhydride; polyanhydrides; polycarbonates;
polycarboxylic acids; polycyanoacrylates; polyesters; polyethers;
poly-hydroxycarboxylic acids; polyimides; polyisobutylene and
ethylene-.alpha.-olefin copolymers; polyketones; polymethacrylates;
polyolefins; polyorthoester; polyorthoesters; polyoxymethylenes;
polyphosphazenes; polyphosphoester; polyphosphoester urethane;
polyphosphoesters; polyphosphoesters-urethane; polyurethane;
polyurethanes; poly(ether-urethanes), poly(ester-urethanes),
poly(silicone-urethanes), polyvinyl alcohol; polyvinyl aromatics;
polyvinyl esters; polyvinyl ethers; polyvinyl ketones;
poly(vinylidene fluoride), poly(vinylidene chloride),
poly(vinylidene fluoride-co-hexafluoropropene), poly(vinylidene
fluoride-co-chlorotrifluoroethylene), poly(vinyl fluoride),
poly(vinyl chloride), polyvinylidene halides; silicones; starches;
vinyl copolymers vinyl-olefin copolymers; vinyl halide polymers and
copolymers; and vinyl halide polymers vinyl halide polymers
copolymers.
[0024] Specific examples of useful polymers for some embodiments
include the following polymers: starch, sodium alginate,
rayon-triacetate, rayon, polyvinylidene fluoride, polyvinylidene
chloride, polyvinyl pyrrolidone, polyvinyl methyl ether, polyvinyl
chloride, polyvinyl acetate, polystyrene, polyisocyanate,
polyisobutylene, polyethylene glycol, polydioxanone,
polycaprolactone, polycaprolactam, polyacrylonitrile,
poly(trimethylene carbonate), poly(L-lactic acid),
poly(lactide-co-glycolide), poly(hydroxyvalerate),
poly(hydroxybutyrate-co-valerate),
poly(hydroxybutyrate-co-hydroxyvalerat- e), poly(hydroxybutyrate),
poly(glycolide), poly(glycolic acid),
poly(D,L-lactide-co-L-lactide), poly(D,L-lactide-co-glycolide),
poly(D,L-lactide), poly(4-hydroxybutyrate),
poly(3-hydroxybutyrate), poly(3-hydroxy valerate), Nylon 66,
hyaluronic acid, fibrinogen, fibrin, elastin-collagen, collagen,
cellulose propionate, cellulose nitrate, cellulose butyrate,
cellulose acetate butyrate, cellulose acetate, cellulose,
cellophane, carboxymethyl cellulose, or poly(2-hydroxyethyl
methacrylate).
[0025] Some invention methods operate on drug-containing coatings.
In some of these embodiments, the drugs are selected from the
following types: antiproliferative, antineoplastic,
antiinflammatory, antiplatelet, anticoagulant, antifibrin,
antithrombin, antimitotic, antibiotic, antioxidants, or their
combinations.
[0026] The target temperature can be chosen in a number of ways.
For instance, the target temperature can be
[0027] within or below the range defined by definition 1,
definition 2, definition 3, definition 4, definition 5, definition
6, or definition 7 of the Tg range of the polymer or polymer
combination;
[0028] within or above the range defined by definition 1,
definition 2, definition 3, definition 4, definition 5, definition
6, or definition 7 of the Tg range of the polymer or polymer
combination;
[0029] below ambient temperature;
[0030] below room temperature;
[0031] above ambient temperature;
[0032] above room temperature;
[0033] at or below -40.degree. C.;
[0034] between ambient temperature and upper Tg of the Tg
range;
[0035] between ambient temperature and lower Tg of the Tg
range;
[0036] between -40.degree. C. and upper Tg of the Tg range;
[0037] between -40.degree. C. and lower Tg of the Tg range;
[0038] between -40.degree. C. and ambient temperature;
[0039] at or above 80.degree. C.;
[0040] between 80.degree. C. and upper Tg of the Tg range;
[0041] between 80.degree. C. and lower Tg of the Tg range; or
[0042] between 80.degree. C. and ambient temperature.
[0043] Some invention embodiments choose the target temperature to
avoid ambient temperature or a window around ambient temperature.
Other embodiments choose the target temperature such that
therapeutic agents present in the coating avoid substantial
decomposition.
[0044] Some invention embodiments choose the target temperature to
simultaneously minimize deformation- and delamination-based failure
during crimping. Some invention embodiments choose the target
temperature to yield an improvement in shore hardness.
[0045] Different invention embodiments use a variety of methods for
achieving the temperature adjustment of the coating. For instance,
the following ways of changing the temperature are all within the
scope of the current invention:
[0046] contacting the coating or coated piece with a heat sink or
heat source.
[0047] directing a heated or cooled gas at the coating or coated
piece;
[0048] placing the coating or coated piece near a heated or cooled
surface for emitting thermal or infrared radiation to or absorbing
thermal or infrared radiation from the coating or coated piece;
[0049] placing the coating or coated piece near a heated or cooled
surface to enable convection to or from the coating or coated piece
to the surface;
[0050] heating or cooling the jaws of the crimper and thermally
contacting the coating or coated piece with the crimper jaws;
[0051] for crimper jaws that allow the passage of infrared
radiation, bathing the stent on catheter with infrared
radiation;
[0052] heating the stent on catheter in an incubator or oven, or
cooling the stent on catheter in a refrigerator to pre-equilibrate
the stent on catheter to the desired temperature before
crimping.
[0053] For some invention devices useful in practicing invention
methods, the heat sink or heat source is integrated with a crimping
device. In some embodiments, the coated piece is selected from
self-expandable stents, balloon-expandable stents, and
stent-grafts.
BRIEF DESCRIPTION OF FIGURES
[0054] FIG. 1 shows a coating as prepared in Example 1, which is an
Elasteon 80A coating on EVAL after crimp, grip, and the wet
expansion test.
[0055] FIG. 2 shows another coating as prepared in Example 1, which
is Elasteon 80A coating on EVAL after crimp, grip, and the wet
expansion test.
[0056] FIG. 3 shows a topcoat of Solef 21508 on EVAL made using the
procedures of Example 3.
[0057] FIG. 4 shows another topcoat of Solef 21508 on EVAL, also
made using the procedures of Example 3.
[0058] FIG. 5 shows the tensile stress at yield of polypropylene as
a function of temperature.
[0059] FIG. 6 shows how the stress-strain curve of a thermoplastic
polymer changes with temperature.
[0060] FIG. 7 plots heat capacity versus temperature for a typical
thermoplastic polymer.
DETAILED DESCRIPTION
[0061] FIGS. 1 and 2 show that the coating on the outer surface of
the stent, in one case, has been pinched or wrinkled over, while in
the other, has been smeared off. Similarly, FIGS. 3 and 4 show a
topcoat of Solef 21508 on EVAL. Solef 21508 is the softest
poly(hexafluoropropene-co- -vinylidene fluoride) thermoplastic
polymer commercially available.
[0062] FIGS. 3 and 4 show dents in the high spots of the strut
arms. Most high spots of these two stents show similar damage. For
these reasons, polymer coatings made of lower durometer (80A for
example) polymers frequently fail quality assurance tests. EVAL, a
hard plastic, seems to hold up to standard crimping, but it has a
hardness of 85 shore D. For comparison, the low-density
polyethylene used in milk containers is 47-55 shore D.
[0063] A crimp process in which the coated stent is held at a
target temperature, which may be different from ambient, is
disclosed. A temperature below ambient can be used to increase
polymer coating hardness to avoid, shearing, tearing, pinching, and
denting damage. This strategy would be particularly effective for
polymers with glass transition temperatures (Tg) at or below
ambient or temperature. Additionally, invention processes are
suited for polymer mixtures in which the Tg of a polymer or polymer
mixture is at or below ambient temperature. Temperatures above
ambient can be used in cases where the Tg is above ambient or room
temperature and greater coating ductility is desired. For purposes
of this disclosure, ambient temperature is the temperature of the
crimper or coating when the crimper or coating has not been
purposely heated or cooled. Typically, this temperature will be
close to room temperature or the temperature surrounding the
crimping equipment or the coating. Similarly, for purposes of this
disclosure, a target temperature is a temperature numerically
different from ambient temperature brought about by purposely
heating or cooling the crimper, stent, balloon, polymer coating, or
any combination of these. For purposes of this disclosure,
"polymer", "polymer combination" and "polymer mixture" are
synonymous, meaning a composition of one polymer or, when more than
one polymer, a mixture of, a blend of, a copolymerization of, or
any other combination of more than one polymer. The combination can
occur after the more than one polymer was polymerized or can occur
during the polymerization of monomer into one or more polymers.
1 Durometer Temperature Temperature Hardness Range for Range for
Polymer Tg .degree. C. Shore D Greater Hardness Ductility Solef
21508 -29 60 -62 to 10 Ambient to 60 Elasteon 80A -100, 0 30-35
-110 to -10 Ambient to 60 Elasteon 55D -100, 0 55 -110 to -10
Ambient to 60 EVAL-E151 55 85 Zero to Ambient 50 to 100 Kynar-Flex
-30 65-70 -62 to 10 Ambient to 60 2800 Butvar B-90 72-78 85-90 Zero
to Ambient Ambient to 100 Kynar 710 -30 76-80 -62 to 10 Ambient to
60 Poly(n-butyl 20 NA -30 to 15 Ambient to 60 methacrylate)
[0064] A representative method includes heating or cooling a
polymer coating on a medical device to or towards a target
temperature. Next, either after the target temperature has been
reached or while the coating is changing temperature towards the
target temperature, the portion of the medial device containing the
coating is crimped onto another portion of the medical device or
onto another medical device. Crimping is done in a temperature
region designed to minimize both cohesive and adhesive failure (or
deformation- and delamination-based failure) caused by local
pressure from the jaws or surfaces of the crimping device, and
deformation of the stent caused by reducing its diameter. For
instance, a polymer-coated stent can be heated with a stream of air
and crimped onto a delivery catheter with an iris crimper.
[0065] Heating and cooling are generically discussed as "adjusting"
the temperature of the coating, the crimper, or the medical device.
Adjusting the temperature comprises placing the object that is to
have its temperature adjusted into thermal contact with a heat sink
or heat source. For purposes of this disclosure, thermal contact
with a heat sink means heat sink arrangement vis a vis the object
so that energy would flow or be carried from the object to the heat
sink. For purposes of this disclosure, thermal contact with a heat
source means heat source arrangement vis a vis the object so that
energy would flow or be carried from the heat source to the object.
Thermal contact is a generic term at least encompassing an
arrangement of the object such that radiation, conduction, or
convection to or from the heat sink or heat source would transfer
energy. In some embodiments, thermal contact is defined to exclude
any of radiation, conduction, convection, or any combination of
these.
[0066] Different invention embodiments employ different heating or
cooling profiles. For instance, when the heating profile calls for
softening the polymer by choosing a target temperature above some
temperature value, the coating is adjusted to the target
temperature before crimping and then crimping occurs (with or
without some amount of cooling before crimping); alternatively, the
coating is adjusted to the target temperature before crimping and
maintained at or near the target temperature during crimping;
alternatively, crimping is started, the coating is adjusted to the
target temperature, and crimping is completed. For purposes of this
disclosure, "maintained near the target temperature" means that the
temperature of the coating at the instant of contact with the
crimper is the target temperature plus or minus 20.degree. C.,
15.degree. C., 10.degree. C., 5.degree. C., 2.degree. C. or
1.degree. C. In some embodiments, "maintained near the target
temperature" means that the temperature of the coating at the
instant of contact with the crimper is the target temperature plus
or minus 10.degree. C.
[0067] Similarly, if a cooling profile calls for hardening a
polymer by choosing a target temperature below some temperature
value, the coating is adjusted to the target temperature before
crimping and then crimping occurs (with or without some amount of
warming before crimping); alternatively, the coating is adjusted to
the target temperature before crimping and maintained at or near
the target temperature during crimping; alternatively, crimping is
started, the coating is adjusted to be target temperature, and
crimping is completed.
[0068] Polymers on crimped stents exhibit adhesive and cohesive
failure as two main failure modes. In adhesive failure, the coating
is sheared off the stent due to poor adhesion to the metal stent or
underlying polymer layers. This is a failure of the polymer layer
due to poor interaction between polymer molecules and the surface
of the stent. Since at higher temperatures, particularly those
above Tg, polymeric materials are softer, a higher temperature
crimp process could assist in preventing adhesive failure at the
polymer-stent surface interface. Adhesive failure is sometimes
referred to as an adhesive-based failure or delamination-based
failure. When a polymer coating on a stent exhibits adhesive
failure, that polymer becomes a candidate for crimping above Tg of
the polymer. Adhesive failure is also caused by a build-up of
stress at the polymer-metal interface. Heating the polymer above
its Tg lowers its modulus and decreases the stress build-up at the
interface. When stents are crimped, certain portions of the stent
pattern undergo elongation. If this degree of elongation exceeds
the elongation of the coating, the coating will crack. The ultimate
elongation of polymers is a temperature function, and heating the
polymer above its Tg can increase the ultimate elongation, thereby
preventing coating failure. If the polymer coating exhibits a
cohesive failure due to insufficient elongation, it is also a
candidate for crimping above the Tg of the polymer.
[0069] In cohesive failure, the topmost polymer layer is
mechanically dented, deformed, or torn. This is a failure of the
polymer layer due to poor interaction between polymer molecules.
Since at lower temperatures, particularly those below Tg, polymeric
materials are harder, a low temperature crimp process can be suited
to preventing cohesive damage to the polymer surface. Cohesive
failure is sometimes referred to as a cohesive-based failure or a
deformation-based failure. When a polymer coating on the stent
exhibits cohesive failure due to compressive loads, that polymer
becomes a candidate for crimping below Tg of the polymer.
[0070] FIG. 5 shows tensile stress at yield of polypropylene as a
function of temperature. This property is not the same as hardness,
but correlates with it. Both involve the stress needed to
permanently deform the polymer. For thermoplastics in general, a
lower temperature leads to greater hardness. FIG. 6 shows how a
thermoplastic's stress-strain curve changes with temperature.
[0071] For some embodiments of this invention, the target
temperature is selected in relation to Tg of the coating. Tg is the
temperature at which the amorphous domains of a polymer change from
a brittle vitreous state to a plastic state at atmospheric
pressure. In other words, Tg corresponds to the temperature where
the onset of segmental motion in the chains of the polymer occurs,
and it is discernible in a heat-capacity-versus-temperature graph
for a polymer, as is depicted in FIG. 7. When an amorphous or
semicrystalline polymer is heated, its coefficient of expansion and
heat capacity both increase as the temperature rises, indicating
increased molecular motion. As the temperature rises, the sample's
actual molecular volume remains constant. Therefore, a higher
coefficient of expansion points to a free volume increase of the
system and increased freedom of movement for the molecules. The
increasing heat capacity corresponds to increasing heat dissipation
through movement.
[0072] Tg of a given polymer can be dependent on the heating rate
and can be influenced by the thermal history of the polymer.
Furthermore, polymer chemical structure heavily influences Tg by
affecting polymer mobility. Generally, flexible main-chain
components lower Tg and bulky side groups raise Tg. Similarly,
increasing flexible-side-group length lowers Tg and increasing
main-chain polarity increases Tg. Additionally, the presence of
crosslinks can increase the observed Tg for a given polymer, and
the presence of a drug or therapeutic agent can alter the Tg of a
polymer due to plasticization effects. The magnitude of these
plasticization effects depends on the miscibility and compatibility
of the drug and polymer and the loading of drug in the polymer.
[0073] By way of illustration, when a semicrystalline polymer is
heated, the polymer crystallinity begins to increase as temperature
reaches Tg. At or above Tg, the increased molecular motion allows
the polymer chains to adopt a more thermodynamically stable
relationship, and thereby increases polymer crystallinity. In FIG.
7, Tg is shown on the first curve, 60, which is the temperature at
which half of the increase in heat capacity has occurred. The
crystallinity then increases rapidly after Tg and reaches a maximum
at Tc (the apex of second curve, 62).
[0074] As can be seen in FIG. 7, Tg is somewhat arbitrarily placed
on the temperature versus heat capacity curve. For purposes of this
disclosure, the Tg range is defined in several different ways for a
polymer or polymer combination. Some invention embodiments can be
predicated on any one of these Tg range definitions.
[0075] Tg Range Definition 1
[0076] For this definition, Tg range is greater than or equal to
the initial point on the polymer's (or polymer combination's)
temperature-versus-heat-capacity curve showing a drop in heat
capacity, indicated as Tg1 (100) on FIG. 7 (this point is defined
as lower Tg for definition 1). Tg range is less than or equal to Tc
(110) on the curve in FIG. 7 (this point is defined as upper Tg for
definition 1). This Tg range is referred to in this disclosure as
Tg range definition 1. Those of ordinary skill in the art recognize
that the specific curvature and temperature points in FIG. 7 depend
upon the nature of the polymer or polymer combination. Therefore,
the indication of a point on FIG. 7 is meant to communicate a point
corresponding to the FIG. 7 point on a similar graph for the
particular polymer or polymer combination being used.
[0077] A target temperature is within Tg range definition 1 if it
is above or equal to Tg1 and below or equal to Tg2. A target
temperature is below Tg range definition 1 if it is below or equal
to Tg2. A target temperature is above Tg range definition 1 if it
is above or equal to Tg1. A target temperature is between a higher
temperature and a lower temperature if it is above or equal to the
lower temperature and below or equal to the higher temperature.
These concepts hold for all temperatures and ranges throughout this
disclosure.
[0078] Tg Range Definition 2
[0079] For this definition, the Tg range is greater than or equal
to the point Tg1 (100) on FIG. 7 (lower Tg for definition 2) and
less than or equal to point 140 on FIG. 7 (upper Tg for definition
2). This range is referred to in this disclosure as Tg range
definition 2. Point 140 corresponds to the onset of the
crystallization phase transition for the material.
[0080] Tg Range Definitions 3, 4, 5, and 6
[0081] For definition 3, the Tg range is the conventionally
measured Tg (180) for the polymer (or combination) plus 40.degree.
C. (upper Tg for definition 3) and minus 40.degree. C. (lower Tg
for definition 3).
[0082] For definition 4, the Tg range is the conventionally
measured Tg for the polymer (or combination) plus 20.degree. C.
(upper Tg for definition 4) and -20.degree. C. (lower Tg for
definition 4).
[0083] For definition 5, the Tg range is the conventionally
measured Tg for the polymer (or combination) plus 10.degree. C.
(upper Tg for definition 5) and minus 10.degree. C. (lower Tg for
definition 5).
[0084] For definition 6, the Tg range is the conventionally
measured Tg for the polymer (or combination) plus 5.degree. C.
(upper Tg for definition 6) and minus 5.degree. C. (lower Tg for
definition 6).
[0085] Tg Range Definition 7
[0086] For this definition, the Tg range is greater than or equal
to the point Tg1 (100) on FIG. 7 (lower Tg for definition 7) and
less than or equal to point 160 on FIG. 7 (upper Tg for definition
7). This range is referred to in this disclosure as Tg range
definition 7. Point 160 corresponds to the tail off or end of the
glass phase transition for the material.
[0087] These embodiments also include embodiments in which the Tg
range specifically excludes ambient temperature, ambient
temperature + or -1.degree. C. or ambient temperature + or
-5.degree. C. Also, in some embodiments the target temperature has
a maximum at or below the temperature at which any included
therapeutic agents substantially decompose. For purposes of this
disclosure, "substantially decompose" means decomposition to the
extent that one of ordinary skill in the art would conclude that
the decomposition would reduce the efficacy of the therapeutic
substance too much. In other words, decomposition would reduce the
efficacy enough that one of ordinary skill in the art would reject
the heated or cooled, crimped composition for use in vivo.
[0088] Based on the shore hardness of the coating or the failure
mode of the coating, several embodiments can be described. For
coatings that are too soft, that exhibit cohesive or deformation
failures, that have Tg below ambient or room temperature, or that
have a shore hardness of shore 60A to 80D (alternatively, shore 80A
to 60D), the polymer can be improved by causing the polymer to be
harder during crimping. This can be accomplished by choosing a
target temperature less than upper Tg. (When this disclosure speaks
of upper Tg or lower Tg, but does not specify which definition of
Tg range is being used, this disclosure is intended to cover upper
and lower Tg for each range definition). Alternatively, the polymer
can be hardened during crimping by choosing a target temperature
below lower Tg. Alternatively, choosing a target temperature below
ambient temperature can harden the polymer. Alternatively, choosing
a target temperature below -30.degree. C., -40.degree. C.,
-50.degree. C., or -60.degree. C. can harden the polymer. In some
embodiments, the target temperature is between ambient temperature
and upper Tg; ambient temperature and lower Tg; or -30.degree. C.,
-40.degree. C., -50.degree. C., or -60.degree. C. and upper Tg;
-30.degree. C., -40.degree. C., -50.degree. C., or -60.degree. C.
and lower Tg; or -30.degree. C., -40.degree. C., -50.degree. C., or
-60.degree. C. and ambient temperature.
[0089] In addition to choosing the target temperature based on the
Tg range definitions discussed above, various embodiments can be
described otherwise. For coatings that are too soft, that exhibit
cohesive or deformation failures, that have Tg below ambient or
room temperature, or that have a shore hardness of shore 60A to 80D
(alternatively, shore 80A to 60D), the polymer can be improved by
causing the polymer to be harder during crimping. Therefore, an
improvement in cohesive or deformation failures can be achieved by
choosing a target temperature that yields a 50% increase in shore
hardness, alternatively, a 40%, 30%, 20%, or 10% increase in shore
hardness.
[0090] Medical devices that use outermost coatings with shore
hardness of shore 60A to 60D frequently experience cohesive failure
during crimping. Invention medical devices prepared with invention
crimping methods allow the use of outermost coatings with shore D
hardness as low as 30 to 80, or 35 to 60. Alternatively, invention
medical devices prepared with invention crimping methods allow the
use of outermost coatings with shore D hardness less than or equal
to 45, 40, 35, or 30.
[0091] For coatings that are too hard, that exhibit adhesive
failures, have insufficient elongation, or that have Tg above
ambient or room temperature, or that have a shore hardness of 60D
to 95D (alternatively, 65D to 90D), the polymer can be improved by
causing the polymer to be softer during crimping. This can be
accomplished by choosing a target temperature greater than upper
Tg. Alternatively, the polymer can be softened during crimping by
choosing a target temperature above lower Tg. Alternatively,
choosing a target temperature above ambient temperature can soften
the polymer. Alternatively, choosing a target temperature above
70.degree. C., 80.degree. C., 90.degree. C., or 100.degree. C. can
soften the polymer. In some embodiments, the target temperature is
between ambient temperature and upper Tg; ambient temperature and
lower Tg; between 70.degree. C., 80.degree. C., 90.degree. C., or
100.degree. C. and upper Tg; between 70.degree. C., 80.degree. C.,
90.degree. C., or 100.degree. C. and lower Tg; or between
70.degree. C., 80.degree. C., 90.degree. C., or 100.degree. C. and
ambient temperature.
[0092] In addition to choosing the target temperature based on the
Tg range definitions discussed above, various embodiments can be
described otherwise. For coatings that are too hard, that exhibit
adhesive failures, that have Tg above ambient or room temperature,
or that have a shore hardness of 60D to 95D (alternatively, 65D to
90D), the polymer can be improved by causing the polymer to be
softer during crimping. Therefore, an improvement in adhesive
failure can be achieved by choosing a target temperature that
yields a 50% decrease in shore hardness, alternatively, a 40%, 30%,
20%, or 10% decrease in shore hardness.
[0093] Medical devices that use outermost coatings with shore
hardness of shore 60D to shore 90D frequently experience adhesive,
or elongational failure during crimping. Invention medical devices
prepared with invention crimping methods allow the use of outermost
coatings with shore hardness as high as 60D to 90D, or 65D to 85D.
Alternatively, invention medical devices prepared with invention
crimping methods allow the use of outermost coatings with shore
hardness greater than or equal to 60D, 70D, 80D, or 90D.
[0094] When EVAL is crimped at ambient temperature, it is in a
glassy state (FIG. 6, curve A). By crimping at a temperature above
its glass transition temperature (Tg) (55.degree. C.), the ultimate
elongation becomes higher (FIG. 6, curve B). This should reduce
cracking in the tensile regions on the outside of stent junctions.
For PBMA, Tg of 20.degree. C., crimping at a low temperature of
0.degree. or less should reduce crimping damage from shear and
compression. Similarly, for KYNAR (a polymer consisting of
poly(vinylidene fluoride) and available from Atofina of
Philadelphia, Pa.), Tg of -30.degree. C., crimping at a temperature
of -40.degree. C. should also reduce denting and shearing
damage.
[0095] Devices for crimping medical devices are well known in the
art. In some embodiments, the device is designed to crimp the
polymer-coated stent onto the balloon portion of a catheter for
PTCA. For crimpers such as the sliding wedge design, the
temperature may be controlled by passage of a stream of dry air, or
inert gas through the bore. This air can be heated or cooled by
first passing it through a tube heater or chilled heat exchanger.
The stent is loosely placed onto the catheter, and then the
assembly is inserted into the bore of the crimper. The passage of
air would rapidly equilibrate the stent delivery system (SDS) to
the crimp temperature. Continuously heated or cooled airflow would
bring the crimping jaws to the desired temperature.
[0096] Alternative ways include heating or cooling the jaws of the
crimper itself. Electrical heating elements can be installed into
the crimper jaws. By appropriate placement of thermocouples and
feedback controls, an elevated temperature can be maintained.
Cooling of the crimper jaws can be accomplished by rendering them
with passageways through which a cooling medium is pumped. This may
also be used to heat the crimping jaws. If the jaws were composed
of an electrically conductive material, application of an
oscillating electric field can heat them via eddy currents. If the
jaws were made of an IR transparent material, the stent on catheter
can be thermostated by infrared radiation.
[0097] If the crimper is at ambient temperature, but the jaws
themselves are of a material with low thermal conductivity, then
processes can be considered where the stent loosely applied to the
catheter is pre-equilibrated to a non-ambient temperature before
crimping. As the DES system is small, with a high surface area to
volume ratio, the DES system would have to be rapidly moved from
the controlled temperature environment to the crimper to maintain
the desired temperature. Heating in an incubator or oven, or
cooling in a refrigerator can pre-equilibrate the DES system to the
desired temperature before crimping.
[0098] Processes of the current invention provide medical devices.
These medical devices contain a piece or portion that is coated, in
some embodiments, with polymer(s). In some embodiments, the
crimping device used in invention crimping steps can be heated or
cooled before it is used to crimp the coated piece or portion onto
the remainder of the medical device or onto another medical device.
This heating or cooling causes the temperature of the coating
material to change so that the crimping effectively occurs at a
target temperature other than ambient temperature. Other ways of
modifying the temperature of the coating include heating or cooling
the substrate of the medical device or heating or cooling the
coating directly with forced air, among other methods.
[0099] Some invention embodiments select medical devices to be
those adapted for placement in arterial, venous, neurovascular,
urethral, biliary, prostate, intravascular, ureteral, bronchial,
esophageal, fallopial, tracheal, laryngeal, gastrointestinal,
lymphatic, eustachiaic, pancreatic, cerebral, other genitourinary,
other gastrointestinal, or other respiratory lumens or
passages.
[0100] Representative examples of polymer families that can be used
to coat a medical device in accordance with the present invention
include poly(ester amides); ABS resins; acrylic polymers and
acrylic copolymers; acrylonitrile-styrene copolymers; alkyd resins;
cellulose ethers; celluloses; copoly(ether-esters) (e.g. PEO/PLA);
copolymers of polycarboxylic acids and poly-hydroxycarboxylic
acids; copolymers of vinyl monomers with each other and olefins;
cyanoacrylates; epoxy resins; ethylene vinyl alcohol copolymer;
ethylene-.alpha.-olefin copolymers; ethylene-methyl methacrylate
copolymers; ethylene-vinyl acetate copolymers; poly(amino acids);
poly(anhydrides); poly(imino carbonates); poly(orthoesters);
poly(tyrosine arylates); poly(tyrosine derive carbonates);
polyacrylates; polyacrylic acid; polyacrylic acids;
polyacrylonitrile; polyalkylene oxalates; polyamides; polyamino
acids; polyanhydride; polyanhydrides; polycarbonates;
polycarboxylic acids; polycyanoacrylates; (mentioned above);
polyesters; polyethers; poly-hydroxycarboxylic acids; polyimides;
polyisobutylene and ethylene-.alpha.-olefin copolymers;
polyketones; polymethacrylates; polyolefins; polyorthoester;
polyorthoesters; polyoxymethylenes; polyphosphazenes;
polyphosphoester; polyphosphoester urethane; polyphosphoesters;
polyphosphoesters-urethane; poly(ether-urethanes),
poly(ester-urethanes), poly(silicone-urethanes), polyurethane;
polyurethanes; polyvinyl alcohol; polyvinyl aromatics; polyvinyl
esters; polyvinyl ethers; polyvinyl ketones; poly(vinylidene
fluoride), poly(vinylidene chloride), poly(vinylidene
fluoride-co-hexafluoropropene)- , poly(vinylidene
fluoride-co-chlorotrifluoroethylene), poly(vinyl fluoride),
poly(vinyl chloride), polyvinylidene halides; silicones; starches;
vinyl copolymers vinyl-olefin copolymers; vinyl halide polymers and
copolymers; and vinyl halide polymers vinyl halide polymers
copolymers.
[0101] Representative examples of polymers that can be used to coat
a medical device in accordance with the present invention include
starch, sodium alginate, rayon-triacetate, rayon, polyvinylidene
fluoride, polyvinylidene chloride, polyvinyl pyrrolidone,
poly(iminocarbonate), polyvinyl methyl ether, polyvinyl chloride,
polyvinyl acetate, polystyrene, polyisocyanate, polyisobutylene,
polyethylene glycol, polydioxanone, polycaprolactone,
polycaprolactam, polyacrylonitrile, poly(trimethylene carbonate),
poly(L-lactic acid), poly(lactide-co-glycolide),
poly(hydroxyvalerate), poly(hydroxybutyrate-co-valerate),
poly(hydroxybutyrate-co-hydroxyvalerat- e), poly(hydroxybutyrate),
poly(glycolide), poly(glycolic acid),
poly(D,L-lactide-co-L-lactide), poly(D,L-lactide-co-glycolide),
poly(D,L-lactide), poly(4-hydroxybutyrate),
poly(3-hydroxybutyrate), poly(3-hydroxy valerate), Nylon 66,
hyaluronic acid, fibrinogen, fibrin, elastin-collagen, collagen,
cellulose propionate, cellulose nitrate, cellulose butyrate,
cellulose acetate butyrate, cellulose acetate, cellulose,
cellophane, carboxymethyl cellulose, and 2-hydroxyethyl
methacrylate.
[0102] The polymer coating for use with this invention can comprise
a mixture of polymers, such as an intimate mixture of polymer
molecules, or can use a combination of polymers arranged in a
layered structure. One of ordinary skill in the art will recognize
that the optimal target temperature can be chosen based on the
overall thermal behavior of the polymers or combination of
polymers.
[0103] In some embodiments, the crimping process operates on
polymers or mixtures of polymers comprising a drug that can inhibit
vascular smooth muscle cell activity. More specifically, the drug
activity can aim at inhibiting abnormal or inappropriate migration
or proliferation of smooth muscle cells to prevent, inhibit,
reduce, or treat restenosis. The drug can also include any
substance capable of exerting a therapeutic or prophylactic effect
in the practice of the present invention. Examples of such active
agents include antiproliferative, antineoplastic, antiinflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,
antibiotic, and antioxidant substances as well as their
combinations. An example of an antiproliferative substance is
actinomycin D, or derivatives and analogs thereof (manufactured by
Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233;
or COSMEGEN available from Merck). Synonyms of actinomycin D
include dactinomycin, actinomycin IV, actinomycin I1, actinomycin
X1, and actinomycin C1. Examples of antineoplastics include
paclitaxel and docetaxel. Examples of antiplatelets,
anticoagulants, antifibrins, and antithrombins include aspirin,
sodium heparin, low molecular weight heparin, hirudin, argatroban,
forskolin, vapiprost, prostacyclin and prostacyclin analogs,
dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist, recombinant hirudin, thrombin inhibitor (available from
Biogen), and 7E-3B.RTM. (an antiplatelet drug from Centocor).
Examples of antimitotic agents include methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, Adriamycin, and mutamycin.
Examples of cytostatic or antiproliferative agents include
angiopeptin (a somatostatin analog from Ibsen), angiotensin
converting enzyme inhibitors such as Captopril (available from
Squibb), Cilazapril (available from Hoffman-LaRoche), or Lisinopril
(available from Merck & Co., Whitehouse Station, N.J.), calcium
channel blockers (such as Nifedipine), colchicine, fibroblast
growth factor (FGF) antagonists, histamine antagonist, Lovastatin
(an inhibitor of HMG-CoA reductase, a cholesterol lowering drug
from Merck & Co.), monoclonal antibodies (such as PDGF
receptors), nitroprusside, phosphodiesterase inhibitors,
prostaglandin inhibitor (available from Glazo), Seramin (a PDGF
antagonist), serotonin blockers, thioprotease inhibitors,
triazolopyrimidine (a PDGF antagonist), and nitric oxide. Other
useful drugs may include alpha-interferon, genetically engineered
epithelial cells, dexamethasone, estradiol, clobetasol propionate,
cisplatin, insulin sensitizers, receptor tyrosine kinase
inhibitors, and carboplatin. Exposure of the composition to the
drug should not adversely alter the drug's composition or
characteristic. Accordingly, drug-containing embodiments choose
drugs that are compatible with the blended composition. Rapamycin
is a suitable drug. Additionally, 40-O-(2-hydroxy)ethyl-rapamycin,
or a functional analog or structural derivative thereof, is
suitable, as well. Examples of analogs or derivatives of
40-O-(2-hydroxy)ethyl-rapamycin include, among others,
40-O-(3-hydroxy)propyl-rapamycin and
40-O-2-(2-hydroxy)ethoxyethyl-rapamycin. Those of ordinary skill in
the art know of various methods and coatings for advantageously
controlling the release rate of drugs, such as
40-O-(2-hydroxy)ethyl-rapamycin.
[0104] Some embodiments choose the drug such that it does not
contain at least one of or any combination of antiproliferative,
antineoplastic, antiinflammatory, antiplatelet, anticoagulant,
antifibrin, antithrombin, antimitotic, antibiotic, or antioxidant
substances. Some invention embodiments choose the drug such that it
does not contain at least one of or any combination of actinomycin
D, derivatives and analogs of Actinomycin D, dactinomycin,
actinomycin IV, actinomycin I1, actinomycin X1, actinomycin C1,
paclitaxel, docetaxel, aspirin, sodium heparin, low molecular
weight heparin, hirudin, argatroban, forskolin, vapiprost,
prostacyclin, prostacyclin analogs, dextran,
D-phe-pro-arg-chloromethylke- tone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist, recombinant hirudin, thrombin inhibitor and 7E-3B,
methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,
adriamycin, mutamycin, angiopeptin, angiotensin converting enzyme
inhibitors, Captopril, Cilazapril, or Lisinopril, calcium channel
blockers, Nifedipine, colchicine, fibroblast growth factor (FGF)
antagonists, histamine antagonist, Lovastatin, monoclonal
antibodies, PDGF receptors, nitroprusside, phosphodiesterase
inhibitors, prostaglandin inhibitor, Seramin, PDGF antagonists,
serotonin blockers, thioprotease inhibitors, triazolopyrimidine,
nitric oxide, alpha-interferon, genetically engineered epithelial
cells, dexamethasone, estradiol, clobetasol propionate, cisplatin,
insulin sensitizers, receptor tyrosine kinase inhibitors,
carboplatin, Rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, or a
functional analogs of 40-O-(2-hydroxy)ethyl-rapamycin, structural
derivative of 40-O-(2-hydroxy)ethyl-rapamycin,
40-O-(3-hydroxy)propyl-rapamycin, and
40-O-2-(2-hydroxy)ethoxyethyl-rapamycin.
[0105] Some embodiments comprise polymers combined with other
polymers in multilayer arrangements. For example, one polymer can
under- or over-lay another polymer such as a polymer coated on a
device, a medical device, an implantable medical device, or a
stent. The polymer can be used neat in this regard, or it can first
be mixed with another polymer.
[0106] Examples of implantable devices useful in the present
invention include self-expandable stents, balloon-expandable
stents, and stent-grafts. The underlying structure of the device
can be of virtually any design. The device can comprise a metallic
material or an alloy such as, but not limited to, cobalt chromium
alloy (ELGILOY), stainless steel (316L), high nitrogen stainless
steel, e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N,"
"MP20N," ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,
platinum-iridium alloy, gold, magnesium, or combinations thereof.
"MP35N" and "MP20N" are trade names for alloys of cobalt, nickel,
chromium, and molybdenum available from Standard Press Steel Co.,
Jenkintown, Pa. "MP35N" consists of 35% cobalt, 35% nickel, 20%
chromium, and 10% molybdenum. "MP20N" consists of 50% cobalt, 20%
nickel, 20% chromium, and 10% molybdenum. Of course, one of
ordinary skill in the art recognizes that the invention method is
only useful for medical devices that use a crimping step in their
production.
[0107] Various, specialized tests are used to assay the integrity
of a drug eluting stent coating. In all of them, completed units
are tested which have been though all stent-catheter assembly
processes, including crimping and any heat-pressure processes. One
test is inspection of the coated stents by scanning electron
microscopy. This can be done on the completed units by cutting the
stent-balloon section from the catheter, or the stent can be
removed from the catheter by dry expansion in air or wet expansion
in aqueous solution. Under SEM, the fraction of compromised coating
surface area can be estimated. Compromised coating is coating that
has been deformed, torn, or removed. When this fraction of surface
area exceeds 5-10%, the drug-release-rate properties, and total
drug content can be affected. Another measure of coating integrity,
which is tied to crimping damage, is the number and size of
particles shed when the stent is expanded in aqueous solution. The
stent is deployed in a solution of previously filtered water and
the particles shed are counted by one of several available
particle-counting instruments. Example instruments would be those
produced by Malvern that work by light scattering, instruments that
work by light obscuration, such as the Hiac-Royco, or the Coulter
counter which works by electrical conductivity. Elevated numbers,
and sizes, of particles shed are indicative of coating failure,
which is affected by crimping damage either in the form of coating
pieces that are completely shorn off, or cracks in the coating
which propagated during stent expansion to liberate particles. Yet
another approach to measuring the effects of coating crimping
damage is by acute thrombogenicity testing, one example of which is
that detailed by Sukavaneshvar et al. ASAIO Journal, Aug. 11, 2000,
p 301 and ASIAO Journal, Jul. 5, 2000, p M393, which approach
subjected stents deployed in tubing to a flow of bovine blood in
which the platelets have been radiolabeled. Accumulation of
platelets and thrombus is a measure of the acute thrombogenicity.
The effect of coating cracks and defect can be compared to uncoated
stents, or to stents where the coatings have fewer, or no cracks
and coating defects.
EXAMPLES
Example 1
Used to Make Stents for FIGS. 1 & 2
[0108] A first composition was prepared by mixing the following
components:
[0109] (a) 2.0 mass % of poly(ethylene-co-vinyl alcohol) (EVAL)
EC-151A and
[0110] (b) the balance, dimethylacetamide
[0111] The first composition was applied onto the surface of bare
13 mm TETRA stents (available from Guidant Corporation), which were
first pre-expanded by passing them over a 0.071 inch, tapered
mandrel. Coating was sprayed and dried to form a primer layer. A
spray coater was used having a 0.046 fan nozzle maintained at about
60C with a feed pressure 2.5 psi (0.17 atm) and an atomization
pressure of about 15 psi (1.02 atm). Coating was applied at 10
.mu.g per pass, in between which the stent was dried for 10 seconds
in a flowing air stream at 60C. Approximately 70 .mu.g of wet
coating was applied. The stents were baked at 140C for one hour,
yielding a primer layer composed of approximately 50 .mu.g of
EVAL.
[0112] A simulated reservoir layer was applied onto the primer
layer, using the same spraying technique, equipment, and
formulation used for the applying the primer. In this case,
approximately 340 .mu.g of wet coating is applied, followed by
drying, e.g., baking at 50C for about two hours, yielding about 300
.mu.g of simulated drug-polymer reservoir layer.
[0113] A second composition can be prepared by mixing the following
components:
[0114] (a) 2.0 mass % of Elast-Eon 80A and
[0115] (b) the balance dimethylacetamide.
[0116] The second composition can be applied onto the dried
simulated drug reservoir layer to form a topcoat layer. Using the
same spraying technique and equipment used for applying the
simulated drug reservoir layer. Approximately 340 .mu.g of wet
topcoat is applied followed by baking at 80C for two hours,
yielding a 300 .mu.g Elast-Eon 80A topcoat layer.
[0117] Using a sliding wedge crimper, the stents were crimped onto
13 mm Tetra catheters (available from Guidant Corporation). The
stents were expanded in deionized water at 37C with a balloon
deployment pressure of 12 atm. Examination by SEM yielded FIGS. 1
& 2.
Example 2
Used to Make Stents for FIG. 3
[0118] A first composition was prepared by mixing the following
component
[0119] (a) 4.0 mass % of poly(ethylene-co-vinyl alcohol) (EVAL)
EC-151A and
[0120] (b) the balance, an 80/20 weight blend of dimethylacetamide
and pentane.
[0121] The first composition was applied onto the surface of bare
13 mm TETRA stents (available from Guidant Corporation), which were
first pre-expanded by passing them over a 0.071 inch, tapered
mandrel. Coating was sprayed and dried to form a primer layer. A
spray coater was having a 0.046 fan nozzle maintained at about 60C
with a feed pressure 2.5 psi (0.17 atm) and an atomization pressure
of about 15 psi (1.02 atm). Coating was applied at 10 .mu.g per
pass, in between which the stent was dried for 10 seconds in a
flowing air stream at 60C. Approximately 65 .mu.g of wet coating
was applied. The stents were baked at 140C for one hour, yielding a
primer layer composed of approximately 60 .mu.g of EVAL.
[0122] A simulated reservoir layer was applied onto the primer
layer, using the same spraying technique, equipment, and
formulation used for the applying the primer. In this case
approximately 340 .mu.g of wet coating is applied, followed by
drying, e.g., baking at 80C for about two hours, yielding about 315
.mu.g of a simulated drug-polymer reservoir layer.
[0123] A second composition can be prepared by mixing the following
components:
[0124] (a) 2.0 mass % of Solef 21508 and
[0125] (b) the balance a 50/25/25, by weight, blend of acetone,
cyclohexanone, and AMS Defluxer.
[0126] AMS Defluxer is a blend of dichloropentafluoropropanes and
methanol available from Tech Spray Inc. of Amarillo Tex.
[0127] The second composition can be applied onto the dried
simulated drug reservoir layer to form a topcoat layer. Using the
same spraying technique and equipment used for applying the
simulated drug reservoir layer. Approximately 345 .mu.g of wet
topcoat is applied followed by baking at 50C for two hours,
yielding a 325 .mu.g Solef 21508 topcoat layer.
[0128] Using a sliding wedge crimper, the stents were crimped onto
13 mm Tetra catheters (available from Guidant Corporation). After
this, they were subjected to a heat and pressure process wherein
the balloon was restrained by a sheath, air pressure was applied to
the catheter, and heat was applied to the balloon. Units were
packaged and sterilized by electron beam radiation at a dose of 35
KGy. The stent coating performance was evaluated in an apparatus
where a guiding catheter was connected to flexible silicone tubing
embedded in a block with three gradual 90-degree bends. Deionized
water at 37C was recirculated through the guiding catheter. The
stents were passed through a rotating hemostatic valve attached to
the guiding catheter, through the guiding catheter, through the
tortuous silicone tubing, and deployed at a pressure of 12
atmospheres. After the stents were removed from the tubing,
examination by SEM yielded FIGS. 3 & 4.
[0129] Appropriate standards for the measurement of durometer
hardness are ASTM D2240 or ISO868.
[0130] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from the embodiments of this invention in its broader
aspects and, therefore, the appended claims are to encompass within
their scope all such changes and modifications as fall within the
true spirit and scope of the embodiments of this invention. All
patents, test procedures, and other documents cited in this
specification are fully incorporated by reference to the extent
that this material is consistent with this specification and for
all jurisdictions in which such incorporation is permitted.
* * * * *