U.S. patent application number 11/888940 was filed with the patent office on 2009-02-05 for polymers for implantable devices exhibiting shape-memory effects.
Invention is credited to Michael Ngo, John Stankus, Mikael Trollsas.
Application Number | 20090035350 11/888940 |
Document ID | / |
Family ID | 40266039 |
Filed Date | 2009-02-05 |
United States Patent
Application |
20090035350 |
Kind Code |
A1 |
Stankus; John ; et
al. |
February 5, 2009 |
Polymers for implantable devices exhibiting shape-memory
effects
Abstract
The present invention is directed to polymeric compositions
comprising a biodegradable copolymer that possesses shape-memory
properties and implantable devices (e.g., drug-delivery stents)
formed of materials (e.g., a coating) containing such compositions.
The polymeric compositions can also contain at least one
non-fouling moiety, at least additional biocompatible polymer, at
least one biobeneficial material, at least one bioactive agent, or
a combination thereof. The polymeric compositions are formulated to
possess good mechanical, physical and biological properties.
Moreover, implantable devices formed of materials comprising such
compositions can be delivered to the treatment site in a
conveniently compressed size and then can expand to dimensions
appropriate for their medical functions.
Inventors: |
Stankus; John; (Campbell,
CA) ; Trollsas; Mikael; (San Jose, CA) ; Ngo;
Michael; (San Jose, CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA, SUITE 300
SAN FRANCISCO
CA
94111
US
|
Family ID: |
40266039 |
Appl. No.: |
11/888940 |
Filed: |
August 3, 2007 |
Current U.S.
Class: |
424/424 ;
424/145.1; 514/1.1; 514/54; 514/57; 523/113; 528/45; 528/59;
528/61; 528/65; 604/531; 623/1.19 |
Current CPC
Class: |
C08G 2230/00 20130101;
C08G 2280/00 20130101; A61L 27/34 20130101; A61L 27/54 20130101;
A61L 2400/16 20130101; A61L 27/18 20130101; C08L 75/04
20130101 |
Class at
Publication: |
424/424 ; 528/61;
528/65; 528/59; 528/45; 523/113; 514/12; 514/57; 514/54; 424/145.1;
623/1.19; 604/531 |
International
Class: |
A61K 9/00 20060101
A61K009/00; C08G 18/32 20060101 C08G018/32; C08G 18/00 20060101
C08G018/00; A61F 2/00 20060101 A61F002/00; A61F 2/94 20060101
A61F002/94; A61K 38/17 20060101 A61K038/17; A61K 31/715 20060101
A61K031/715; A61K 39/395 20060101 A61K039/395 |
Claims
1. A composition comprising a biodegradable copolymer comprising at
least two segments A and B, wherein: the A segment has a T.sub.g or
T.sub.m in the range from about 50.degree. C. to about 300.degree.
C. and is made from at least one diisocyanate and at least one
diol, diamine or dithiol chain extender; the B segment has a
T.sub.g or T.sub.m in the range from about 30.degree. C. to about
100.degree. C. and is derived from a polymer containing at least
one hydroxyl, amino or thiol end group; the T.sub.g or T.sub.m of
the A segment is at least about 20.degree. C. greater than the
T.sub.g or T.sub.m of the B segment; and the A and B segments each
independently have a polymer number-average molecular weight
(M.sub.n) from about 0.4 kDa to about 500 kDa; and wherein: the
composition displays at least one shape-memory effect, and a
permanent shape of the composition is obtained when the temperature
of the composition is equal to or greater than the T.sub.g or
T.sub.m of the B segment.
2. The composition of claim 1, wherein the A segment has a T.sub.g
or T.sub.m in the range from about 70.degree. C. to about
260.degree. C. and the B segment has a T.sub.g or T.sub.m in the
range from about 35.degree. C. to about 70.degree. C.
3. The composition of claim 2, wherein the T.sub.g or T.sub.m of
the B segment is in the range from about 35.degree. C. to about
40.degree. C.
4. The composition of claim 1, wherein the T.sub.g or T.sub.m of
the A segment is at least about 40.degree. C. greater than the
T.sub.g or T.sub.m of the B segment.
5. The composition of claim 1, wherein the B segment is derived
from a polymer comprising from one to four different types of
monomer, wherein each type of monomer has from about 5 to about
5,000 monomer units.
6. The composition of claim 1, wherein the A segment is made from
one to four different polycondensation reactions involving a
diisocyanate and a diol, diamine or dithiol chain extender, wherein
each polycondensation reaction: occurs from about 5 to about 5,000
times, and involves a diisocyanate and a diol, diamine or dithiol
chain extender that may be the same as or different than any other
diisocyanate(s) and any other diol, diamine or dithiol chain
extender(s) involved in any other polycondensation reaction(s).
7. The composition of claim 1, wherein the biodegradable copolymer
further comprises a third segment A', and wherein the A' segment:
is made from at least one diisocyanate and at least one diol,
diamine or dithiol chain extender; has an M.sub.n from about 0.4
kDa to about 500 kDa; may be attached to the B segment or the A
segment; and may be the same as or different than the A
segment.
8. The composition of claim 7, wherein the A' segment is made from
one to four different polycondensation reactions involving a
diisocyanate and a diol, diamine or dithiol chain extender, wherein
each polycondensation reaction: occurs from about 5 to about 5,000
times, and involves a diisocyanate and a diol, diamine or dithiol
chain extender that may be the same as or different than any other
diisocyanate(s) and any other diol, diamine or dithiol chain
extender(s) involved in any other polycondensation reaction(s).
9. The composition of claim 7, wherein the A' segment is attached
to the B segment.
10. The composition of claim 7, wherein the A' segment is attached
to the A segment.
11. The composition of claim 7, wherein the A and A' segments are
the same.
12. The composition of claim 7, wherein the A and A' segments are
different.
13. The composition of claim 12, wherein the A' segment has a
T.sub.g or T.sub.m in the range from about -70.degree. C. to about
100.degree. C.
14. The composition of claim 13, wherein the A' segment has a
T.sub.g or T.sub.m in the range from about -20.degree. C. to about
35.degree. C.
15. The composition of claim 1, wherein the B segment is derived
from a polyester containing at least one hydroxyl end group.
16. The composition of claim 15, wherein the polyester containing
at least one hydroxyl end group is selected from the group
consisting of polycaprolactone (PCL) diol,
poly(.beta.-hydroxy-alkanoate-diol),
poly([R]-3-hydroxybutyrate-diol), poly(L-lactide) (PLLA) diol,
poly(D,L-lactide) diol, polyglycolic acid, polyglycolide (PGA)
diol, poly(trimethylene carbonate) (PTMC) diol, polydioxanone diol,
polyvalerolactone diol, polypropiolactone diol and
hydroxyl-terminated random or block copolymers thereof.
17. The composition of claim 16, wherein the hydroxyl-terminated
random or block copolymer is selected from the group consisting of
poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide),
poly(L-lactide-co-caprolactone-co-L-lactide),
poly(L-lactide-co-D,L-lactide-co-glycolide-co-L-lactide),
poly(glycolide-co-trimethylene carbonate),
poly(glycolide-co-caprolactone), poly(caprolactone-co-trimethylene
carbonate), poly(glycolide-co-trimethylene
carbonate-co-caprolactone), and any variations in the arrangement
of the monomers thereof.
18. The composition of claim 1, wherein the B segment further
comprises at least one non-fouling moiety.
19. The composition of claim 18, wherein the at least one
non-fouling moiety is selected from the group consisting of
polyethylene glycol (PEG), polypropylene glycol, Pluronic.TM.
surfactants, poly(2-hydroxyethyl methacrylate) (PHEMA), poly(vinyl
alcohol) (PVA), polyalkene oxides, poly(n-propylmethacrylamide),
poly(N-vinyl-2-pyrrolidone) (PVP), sulfonated polystyrene, dextran,
sulfonated dextran, dextrin, hyaluronic acid, sodium hyaluronate,
and derivatives thereof.
20. The composition of claim 1, wherein the A segment is made from
at least one aliphatic diisocyanate.
21. The composition of claim 20, wherein the at least one aliphatic
diisocyanate is selected from the group consisting of
1,2-diisocyanatoethane, 1,3-diisocyanatopropane,
1,4-diisocyanatobutane, 1,5-diisocyanatopentane,
1,6-diisocyanatohexane, 1,4-diisocyanatocubane, and lysine
diisocyanate.
22. The composition of claim 1, wherein the A segment is made from
at least one diol, diamine or dithiol chain extender selected from
the group consisting of ethylene glycol, 1,3-propanediol,
1,2-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol,
1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol,
1,11-undecanediol, 1,12-dodecanediol, 1,2-cyclohexanedimethanol,
1,4-cyclohexanedimethanol, the corresponding diamine and dithiol
analogs thereof, lysine ethyl ester, arginine ethyl ester,
p-alanine-based diamine, and random or block copolymers made from
at least one diisocyanate and at least one diol, diamine or dithiol
chain extender.
23. The composition of claim 1, wherein the B segment is immiscible
with the A segment.
24. The composition of claim 1, wherein the copolymer is
thermoplastic.
25. The composition of claim 1, wherein the copolymer is
thermoset.
26. The composition of claim 1, further comprising at least one
additional biocompatible polymer.
27. The composition of claim 26, wherein the at least one
biocompatible polymer is selected from the group consisting of
poly(ethylene glycol) (PEG); polypropylene; poly(propylene glycol)
(PPG); poly(N-vinyl pyrrolidone) (PVP); poly(N-vinyl
pyrrolidone-co-vinyl acetate) (Copovidone); poly(ester amides)
(PEA); acrylic acid (AA); polyacrylates; acrylamides; fluorinated
polymers or copolymers; poly(hydroxyvalerate); poly(L-lactic
acid)/polylactide (PLLA); poly(E-caprolactone);
poly(lactide-co-glycolide) (PLGA); poly(hydroxybutyrate);
poly(hydroxyvalerate); poly(hydroxybutyrate-co-valerate);
polydioxanone; polyorthoesters; polyanhydrides; poly(glycolic
acid)/polyglycolide (PGA); poly(D,L-lactic acid) (PLA);
poly(glycolic acid-co-trimethylene carbonate); polyphosphoesters;
polyurethanes; polyureas; polyurethane(ureas); poly(amino acids);
cyanoacrylates; poly(trimethylene carbonate);
poly(iminocarbonates); co-poly(ether-esters); polyalkylene
oxalates; polyphosphazenes; silicones; polyesters; polyolefins;
polyisobutylene and ethylene-.alpha.-olefin copolymers; vinyl
halide polymers and copolymers; polyvinyl ethers; polyvinylidene
chloride; polyacrylonitrile; polyvinyl ketones; polyvinyl
aromatics; polyvinyl esters; copolymers of vinyl monomers with each
other; olefins; poly(vinyl alcohol) (PVA); acrylonitrile butadiene
(ABS) resins; ethylene-vinyl acetate copolymers; polyamides; alkyl
resins; polycarbonates; polyoxymethylenes; polyimides; polyethers;
epoxy resins; rayon; rayon-triacetate; and combinations and
co-polymers thereof.
28. The composition of claim 1, further comprising at least one
biobeneficial material.
29. The composition of claim 28, wherein the at least one
biobeneficial material is selected from the group consisting of
fibrin; fibrinogen; cellulose and cellulose derivatives; starch;
pectin; chitosan; elastin, gelatin; alginate and conjugates
thereof; collagen and conjugates thereof; hyaluronan and
derivatives thereof; hyaluronic acid; sodium hyaluronate; and
self-assembled peptides (SAP).
30. The composition of claim 1, further comprising at least one
biologically active agent selected from the group consisting of
antiproliferative, antineoplastic, anti-inflammatory, antiplatelet,
anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,
antiallergic and antioxidant substances.
31. The composition of claim 30, wherein the at least one
biologically active agent is selected from the group consisting of
paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, bioactive RGD, CD-34 antibody, abciximab (REOPRO),
progenitor cell-capturing antibodies, prohealing drugs, prodrugs
thereof, co-drugs thereof, and a combination thereof.
32. A coating comprising the composition of claim 1.
33. A coating comprising the composition of claim 30.
34. A coating comprising the composition of claim 31.
35. An implantable device formed of a material comprising the
composition of claim 1.
36. The implantable device of claim 35, wherein the material is a
coating disposed over the device.
37. The implantable device of claim 35, which is selected from the
group consisting of stents, grafts, stent-grafts, catheters, leads
and electrodes, clips, shunts, closure devices and valves.
38. An implantable device formed of a material comprising the
composition of claim 30.
39. The implantable device of claim 38, wherein the material is a
coating disposed over the device.
40. The implantable device of claim 38, which is selected from the
group consisting of stents, grafts, stent-grafts, catheters, leads
and electrodes, clips, shunts, closure devices and valves.
41. An implantable device formed of a material comprising the
composition of claim 31.
42. A method of preparing the composition of claim 1, comprising:
performing polycondensation of a diisocyanate and a diol, diamine
or dithiol chain extender with a B segment polymer containing at
least one hydroxyl, amino or thiol end group, and optionally
performing additional polycondensation reaction(s) with additional
diisocyanate(s) and additional diol, diamine or dithiol chain
extender(s).
43. A method of fabricating an implantable device, comprising
forming the device of a material comprising the composition of
claim 1.
44. A method of fabricating an implantable device, comprising
forming the device of a material comprising the composition of
claim 30.
45. A method of treating or preventing a condition or disorder in a
patient, comprising implanting in the patient an implantable device
formed of a material comprising the composition of claim 1, wherein
the condition or disorder is selected from the group consisting of
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection, vascular perforation, vascular aneurysm, vulnerable
plaque, chronic total occlusion, patent foramen ovale,
claudication, anastomotic proliferation for vein and artificial
grafts, arteriovenous anastamoses, bile duct obstruction, ureter
obstruction and tumor obstruction.
46. The method of claim 45, wherein the condition or disorder is
selected from atherosclerosis, thrombosis, restenosis, and
vulnerable plaque.
47. The method of claim 45, further comprising providing a thermal
stimulus to the device if the T.sub.g or T.sub.m of the B segment
is greater than body temperature.
48. The method of claim 45, wherein the composition further
comprises at least one biologically active agent selected from the
group consisting of antiproliferative, antineoplastic,
anti-inflammatory, antiplatelet, anticoagulant, antifibrin,
antithrombin, antimitotic, antibiotic, antiallergic and antioxidant
substances.
49. The method of claim 48, wherein the at least one biologically
active agent is selected from the group consisting of paclitaxel,
docetaxel, estradiol, nitric oxide donors, super oxide dismutases,
super oxide dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, bioactive RGD, CD-34 antibody, abciximab (REOPRO),
progenitor cell-capturing antibodies, prohealing drugs, prodrugs
thereof, co-drugs thereof, and a combination thereof.
50. The method of claim 45, wherein the implantable device is
selected from the group consisting of stents, grafts, stent-grafts,
catheters, leads and electrodes, clips, shunts, closure devices and
valves.
Description
BACKGROUND
[0001] 1. Field of the Invention
[0002] The present invention is directed to polymeric materials
comprising biodegradable copolymers that exhibit shape-memory
effects and implantable devices (e.g., drug-delivery stents) formed
of such polymeric materials.
[0003] 2. Description of the State of the Art
[0004] An implantable device that exists in a compressed size and
then changes to a shape suitable for a particular medical need upon
its deployment would have numerous medical applications (e.g., as a
stent). Such a device should exhibit mechanical properties (e.g.,
strength, rigidity, toughness and flexibility) appropriate for its
medical functions. To prevent inflammatory responses to the device
and side reactions caused by harmful breakdown products of the
device, the device should also biodegrade into biocompatible
substances after it accomplishes its medical functions.
[0005] As an example, stents are often used in the treatment of
atherosclerotic stenosis in blood vessels. To reduce the occlusion
of the artery by the collapse of arterial lining and to reduce the
chance of thrombosis and restenosis following angioplasty in the
vascular system, a stent can be implanted in the lumen to reinforce
the blood vessel and maintain the vascular patency. It would be
useful if stents are made of a material that allows the stents to
exist in a compressed shape, so that they can be inserted through
small vessels via catheters, and then allows the stents to
self-expand to the desired diameter once they are deployed at the
treatment site. To act effectively as a scaffolding, i.e.,
physically holding open and, if desired, expanding the wall of a
passageway, stents must possess good strength, rigidity, toughness
and flexibility.
[0006] Stents are also used as a vehicle for providing biological
therapy. Biological therapy can be achieved by medicating the
stents. Medicated stents provide for the local administration of a
therapeutic substance at the diseased site, thereby possibly
avoiding side effects associated with systemic administration of
such substance. One method of medicating stents involves the use of
a polymeric carrier coated onto the surface of a stent, where a
therapeutic substance is impregnated in the polymeric carrier.
[0007] Late stent thrombosis has emerged as a concern for
drug-delivery stents. The incidence of late stent thrombosis
appears to be higher with drug-delivery stents than with the
corresponding bare metal stents. One potential cause of late
thrombosis with drug-delivery stents is a chronic inflammatory or
hypersensitivity response to the polymeric coating on the
stent.
[0008] The present invention is directed to biodegradable polymeric
materials that exhibit shape-memory effects. Used for making
implantable devices (e.g., stents), the polymeric materials enable
the devices to adopt the appropriate shape upon deployment in the
body, perform their mechanical and therapeutic functions more
effectively, and avoid adverse effects such as late stent
thrombosis.
SUMMARY OF THE INVENTION
[0009] The biodegradable polymeric materials of the invention
exhibit shape-memory effects, and thus allow implantable devices
made therefrom to exist in desired shapes before and after
deployment in the body. The inventive polymeric materials are also
configured to completely or substantially completely erode after
the devices accomplish their intended functions (e.g., acting as a
scaffolding, promoting tissue regeneration, maintaining vascular
patency and/or locally delivering drugs), thereby avoiding adverse
effects such as inflammatory responses and late stent thrombosis.
Other advantages of the polymeric materials include, among others,
good mechanical properties (e.g., strength, rigidity, toughness,
flexibility and recoverability), biocompatibility, control of
drug-release rates, and enhanced adhesion to metal surfaces. The
physical and chemical properties of the polymeric materials can be
tuned by appropriate selection of the monomer components, the
ratios and numbers of the monomers, the molecular weight and length
of the various monomer sections, and the arrangement of the various
monomers.
[0010] Some embodiments of the invention are directed to a
composition comprising a biodegradable copolymer comprising at
least two segments A and B, wherein: [0011] the A segment has a
T.sub.g or T.sub.m in the range from about 50.degree. C. to about
300.degree. C. and is made from at least one diisocyanate and at
least one diol, diamine or dithiol chain extender; [0012] the B
segment has a T.sub.g or T.sub.m in the range from about 30.degree.
C. to about 100.degree. C. and is derived from a polymer containing
at least one hydroxyl, amino or thiol end group; [0013] the T.sub.g
or T.sub.m of the A segment is at least about 20.degree. C. greater
than the T.sub.g or T.sub.m of the B segment; and [0014] the A and
B segments each independently have a polymer number-average
molecular weight (M.sub.n) from about 0.4 kDa to about 500 kDa; and
wherein: [0015] the composition displays at least one shape-memory
effect, and [0016] a permanent shape of the composition is obtained
when the temperature of the composition is equal to or greater than
the T.sub.g or T.sub.m of the B segment.
[0017] The copolymer may be thermoplastic or thermoset, and the B
segment may be miscible or immiscible with the A segment.
[0018] In another embodiment, the biodegradable copolymer further
comprises a third segment A', wherein the A' segment: [0019] is
made from at least one diisocyanate and at least one diol, diamine
or dithiol chain extender; [0020] has an M.sub.n from about 0.4 kDa
to about 500 kDa; [0021] may be attached to the B segment or the A
segment; and [0022] may be the same as or different than the A
segment. In an embodiment, the A' segment has a T.sub.g or T.sub.m
in the range from about -70.degree. C. to about 100.degree. C.
[0023] In yet another embodiment, the A and B segments (and the A'
segment, if applicable) each independently comprise a polymer
comprising from one to four different types of monomer, wherein
each type of monomer has from about 5 to about 5,000 monomer
units.
[0024] In one embodiment, the B segment is derived from a polyester
containing at least one hydroxyl end group. In another embodiment,
the B segment further comprises at least one non-fouling moiety. In
still another embodiment, the A segment (and the A' segment, if
applicable) is made from at least one aliphatic diisocyanate.
[0025] In a further embodiment, at least one dihydroxyaryl group is
conjugated to the polymer ends of the biodegradable copolymer to
enhance adhesion of the copolymer to metal surfaces.
[0026] In another embodiment, the composition of the invention
further comprises at least one additional biocompatible
polymer.
[0027] In yet another embodiment, the composition further comprises
at least one biobeneficial material.
[0028] In some embodiments, the composition further comprises at
least one biologically active agent. In an embodiment, the at least
one biologically active agent is selected from antiproliferative,
antineoplastic, anti-inflammatory, antiplatelet, anticoagulant,
antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and
antioxidant substances.
[0029] According to another embodiment, the at least one
biologically active agent is selected from paclitaxel, docetaxel,
estradiol, nitric oxide donors, super oxide dismutases, super oxide
dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, bioactive RGD, CD-34 antibody, abciximab (REOPRO),
progenitor cell-capturing antibodies, prohealing drugs, prodrugs
thereof, co-drugs thereof, and a combination thereof.
[0030] Other embodiments of the invention are directed to a coating
comprising any combination of embodiments of the inventive
composition.
[0031] Yet other embodiments of the invention are directed to an
implantable device formed of a material comprising any combination
of embodiments of the inventive composition. In an embodiment, the
material comprises any combination of embodiments of the inventive
coating, which is disposed over the implantable device. In another
embodiment, the implantable device is a stent, graft, stent-graft,
catheter, lead, electrode, clip, shunt, closure device, or
valve.
[0032] Still other embodiments of the invention are directed to a
method of preparing any combination of embodiments of the inventive
composition by performing polycondensation with the corresponding
diisocyanate(s) and the corresponding diol, diamine and/or dithiol
chain extender(s) for the A segment (and the A' segment, if
applicable).
[0033] Further embodiments of the invention are directed to a
method of fabricating an implantable device. In one embodiment, the
method comprises forming the implantable device of a material
comprising any combination of embodiments of the inventive
composition. In another embodiment, the method comprises depositing
any combination of embodiments of the inventive coating over at
least a portion of the implantable device. In certain embodiments,
the implantable device is a stent, graft, stent-graft, catheter,
lead, electrode, clip, shunt, closure device, or valve.
[0034] Still further embodiments of the invention are directed to a
method of treating or preventing a condition or disorder in a
patient, comprising implanting in the patient any combination of
embodiments of the inventive implantable device. In certain
embodiments, the method further comprises providing a thermal
stimulus to the implantable device to induce formation of the
permanent shape of the device in cases where the T.sub.g or T.sub.m
of the B segment is greater than the body temperature of the
particular patient. In an embodiment, the condition or disorder is
selected from atherosclerosis, thrombosis, restenosis, hemorrhage,
vascular dissection, vascular perforation, vascular aneurysm,
vulnerable plaque, chronic total occlusion, patent foramen ovale,
claudication, anastomotic proliferation of vein and artificial
grafts, arteriovenous anastamoses, bile duct obstruction, ureter
obstruction and tumor obstruction. In a more specific embodiment,
the condition or disorder is selected from atherosclerosis,
thrombosis, restenosis, and vulnerable plaque.
[0035] Various embodiments of the invention are described in
further detail below.
DETAILED DESCRIPTION OF THE INVENTION
Terms and Definitions
[0036] The following definitions apply:
[0037] The terms "biologically degradable" (or "biodegradable"),
"biologically erodable" (or "bioerodable"), "biologically
absorbable" (or "bioabsorbable"), and "biologically resorbable" (or
"bioresorbable"), in reference to polymers and coatings, are used
interchangeably and refer to polymers and coatings that are capable
of being completely or substantially completely degraded,
dissolved, and/or eroded over time when exposed to physiological
conditions and can be gradually resorbed, absorbed and/or
eliminated by the body, or that can be degraded into fragments that
can pass through the kidney membrane of an animal (e.g., a human),
e.g., fragments having a molecular weight of about 40,000 Daltons
(40 kDa) or less. The process of breaking down and eventual
absorption and elimination of the polymer or coating can be caused
by, e.g., hydrolysis, metabolic processes, oxidation, enzymatic
processes, bulk or surface erosion, and the like. Conversely, a
"biostable" polymer or coating refers to a polymer or coating that
is not biodegradable.
[0038] Whenever the reference is made to "biologically degradable,"
"biologically erodable," "biologically absorbable," and
"biologically resorbable" stent coatings or polymers forming such
stent coatings, it is understood that after the process of
degradation, erosion, absorption, and/or resorption has been
completed or substantially completed, no coating or substantially
little coating will remain on the stent. Whenever the terms
"degradable," "biodegradable," or "biologically degradable" are
used in this application, they are intended to broadly include
biologically degradable, biologically erodable, biologically
absorbable, and biologically resorbable polymers or coatings.
[0039] "Complete" degradation of a polymer or a polymeric material
(e.g., a polymeric coating) means that the polymer or the polymeric
material loses at least about 95% of its mass over a period of
time.
[0040] "Substantially complete" degradation of a polymer or a
polymeric material (e.g., a polymeric coating) means that the
polymer or the polymeric material loses at least about 75% of its
mass over a period of time. In certain embodiments, "substantially
complete" degradation of a polymer or a polymeric material can mean
that the polymer or the polymeric material loses at least about 80%
of its mass, or at least about 85% of its mass, or at least about
90% of its mass, or at least about 95% of its mass over a period of
time.
[0041] As used herein, a "biocompatible" polymer refers to a
polymer that is capable of enhancing the biological compatibility
of the composition, material (e.g., coating) or structure (e.g.,
implantable device) containing it by not causing injury or toxicity
to, or an immunological reaction in, living tissue.
[0042] A "biobeneficial" material refers to a material that
benefits a treatment site (e.g., by enhancing the biocompatibility
of the medical device containing such material) by being
non-fouling, hemocompatible, non-thrombogenic, and/or
anti-inflammatory, etc., without depending on the release of a
pharmaceutically or therapeutically active agent.
[0043] A "non-fouling moiety" refers to a portion of a composition
of this invention that provides an implantable device fabricated
from or coated with the composition with the ability to resist
(i.e., to prevent, delay, or reduce the amount of) build-up of a
denatured layer of protein on its surface, which is caused by the
body's reaction to foreign material and can lead to protein
fouling. Protein fouling occurs when proteins aggregate on the
surface of the material. Protein aggregation can occur due to
hydrophobic interactions and when a protein is reversibly or
irreversibly denatured when hydrophobic regions of the protein are
exposed due to interaction with the material. Protein aggregation
can also result from oxidation of thiol groups on proteins to form
covalent aggregates.
[0044] The adsorption of proteins on the surface of an implanted
device constitutes the first step of several biological responses,
including the activation of the coagulation cascade. Following
protein adsorption, cell adhesion occurs, which could lead to
impairment of the device's functioning as well as adverse side
effects on the patient. For example, thrombi formation could occur
after adsorption and activation of platelets.
[0045] "Physiological conditions" refer to conditions to which an
implant is exposed within the body of an animal (e.g., a human).
Physiological conditions include, but are not limited to, "normal"
body temperature for that species of animal (approximately
37.degree. C. for a human) and an aqueous environment of
physiologic ionic strength, pH and enzymes. In some cases, the body
temperature of a particular animal may be above or below what would
be considered "normal" body temperature for that species of animal.
For example, the body temperature of a human may be above or below
approximately 37.degree. C. in certain cases. The scope of the
present invention encompasses those cases where the physiological
conditions (e.g., body temperature) of an animal are not considered
"normal".
[0046] In the context of a blood-contacting implantable device, a
"prohealing" drug or agent refers to a drug or agent that has the
property that it promotes or enhances re-endothelialization of
arterial lumen to promote healing of the vascular tissue.
[0047] As used herein, a "co-drug" is a drug that is administered
concurrently or sequentially with another drug to achieve a
particular pharmacological effect. The effect may be general or
specific. The co-drug can exert an effect different from that of
the other drug, or it can promote, enhance or potentiate the effect
of the other drug.
[0048] As used herein, the term "prodrug" refers to an agent
rendered less active by a chemical or biological moiety, which
metabolizes into or undergoes in vivo hydrolysis to form a drug or
an active ingredient thereof. The term "prodrug" can be used
interchangeably with terms such as "proagent", "latentiated drugs",
"bioreversible derivatives", and "congeners". N.J. Harper, Drug
latentiation, Prog Drug Res., 4: 221-294 (1962); E. B. Roche,
Design of Biopharmaceutical Properties through Prodrugs and
Analogs, Washington, D.C.: American Pharmaceutical Association
(1977); A. A. Sinkula and S. H. Yalkowsky, Rationale for design of
biologically reversible drug derivatives: prodrugs, J. Pharm. Sci.,
64: 181-210 (1975). Use of the term "prodrug" usually implies a
covalent link between a drug and a chemical moiety, though some
authors also use it to characterize some forms of salts of the
active drug molecule. Although there is no strict universal
definition of a prodrug itself, and the definition may vary from
author to author, prodrugs can generally be defined as
pharmacologically less active chemical derivatives that can be
converted in vivo, enzymatically or nonenzymatically, to the
active, or more active, drug molecules that exert a therapeutic,
prophylactic or diagnostic effect. Sinkula and Yalkowsky, above; V.
J. Stella et al., Prodrugs: Do they have advantages in clinical
practice?, Drugs, 29: 455-473 (1985).
[0049] The terms "polymer" and "polymeric" refer to compounds that
are the product of a polymerization reaction. These terms are
inclusive of homopolymers (i.e., polymers obtained by polymerizing
one type of monomer), copolymers (i.e., polymers obtained by
polymerizing two or more different types of monomers), terpolymers,
etc., including random, alternating, block, graft, dendritic,
crosslinked and any other variations thereof.
[0050] The terms "block copolymer" and "graft copolymer" are
defined in accordance with the terminology used by the
International Union of Pure and Applied Chemistry (IUPAC). "Block
copolymer" refers to a copolymer containing a linear arrangement of
blocks. The block is defined as a portion of a polymer molecule in
which the monomer units have at least one constitutional or
configurational feature absent from the adjacent portions. "Graft
copolymer" refers to a polymer composed of macromolecules with one
or more species of block connected to the main chain as side
chains, these side chains having constitutional or configurational
features that differ from those in the main chain.
[0051] As used herein, an "implantable device" can be any suitable
substrate that can be implanted in a human or non-human animal.
Examples of implantable devices include, but are not limited to,
self-expandable stents, balloon-expandable stents, coronary stents,
peripheral stents, stent-grafts, catheters, other expandable
tubular devices for various bodily lumen or orifices, grafts,
vascular grafts, arterio-venous grafts, by-pass grafts, pacemakers
and defibrillators, leads and electrodes for the preceding,
artificial heart valves, anastomotic clips, arterial closure
devices, patent foramen ovale closure devices, and cerebrospinal
fluid shunts. The stents can be intended for any vessel in the
body, including neurological, carotid, vein graft, coronary,
aortic, renal, iliac, femoral, popliteal vasculature, and urethral
passages.
[0052] An implantable device can be designed for the localized
delivery of a therapeutic agent. A medicated implantable device can
be constructed in part, e.g., by coating the device with a coating
material containing a therapeutic agent. The body of the device can
also contain a therapeutic agent.
[0053] An implantable device can be fabricated with a coating
containing partially or completely a
biodegradable/bioabsorbable/bioerodable polymer, a biostable
polymer, or a combination thereof. An implantable device itself can
also be fabricated partially or completely from a
biodegradable/bioabsorbable/bioerodable polymer, a biostable
polymer, or a combination thereof.
[0054] As used herein, a "portion" of an implantable device can be
any portion of the device. For example, a portion can be a portion
of the body of the device. As another example, a portion can be a
portion of the surface of the device, or the whole surface of the
device. As a further example, a portion can refer to an area of
material in the body or over the surface of the device, e.g., a
layer, film or coating disposed over the device.
[0055] As used herein, a material that is described as a layer or a
film (e.g., a coating) "disposed over" an indicated substrate
(e.g., an implantable device) refers to, e.g., a coating of the
material deposited directly or indirectly over at least a portion
of the surface of the substrate. Direct depositing means that the
coating is applied directly to the exposed surface of the
substrate. Indirect depositing means that the coating is applied to
an intervening layer that has been deposited directly or indirectly
over the substrate.
[0056] In the context of a stent, "delivery" refers to introducing
and transporting the stent through a bodily lumen to a region, such
as a lesion, in a vessel that requires treatment. "Deployment"
corresponds to the expanding of the stent within the lumen at the
treatment region. Delivery and deployment of a stent are
accomplished by positioning the stent about one end of a catheter,
inserting the end of the catheter through the skin into a bodily
lumen, advancing the catheter in the bodily lumen to a desired
treatment location, expanding the stent at the treatment location,
and removing the catheter from the lumen.
[0057] In the case of a balloon-expandable stent, the stent is
mounted about a balloon disposed on the catheter. Mounting the
stent typically involves compressing or crimping the stent onto the
balloon. The stent is then expanded by inflating the balloon. The
balloon can then be deflated and the catheter withdrawn. In the
case of a self-expanding stent, the stent can be secured to the
catheter via a constraining member such as a retractable sheath or
a sock. When the stent is in a desired bodily location, the sheath
can be withdrawn, which allows the stent to self-expand.
[0058] The "glass transition temperature", T.sub.g, is the
temperature at which the amorphous domains of a polymer change from
a brittle, glassy, vitreous state to a solid deformable, ductile or
rubbery state at atmospheric pressure. In other words, the T.sub.g
corresponds to the temperature where the onset of segmental motion
in the chains of the polymer occurs. When an amorphous or
semicrystalline polymer is exposed to an increasing temperature,
the coefficient of expansion and the heat capacity of the polymer
both increase as the temperature is raised, indicating increased
molecular motion. As the temperature is raised, the actual
molecular volume in the sample remains constant, and so a higher
coefficient of expansion points to an increase in free volume
associated with the system and therefore increased freedom for the
molecules to move. The increasing heat capacity corresponds to an
increase in heat dissipation through movement. The T.sub.g of a
given polymer can be dependent on the heating rate and can be
influenced by the thermal history of the polymer. Furthermore, the
chemical structure of the polymer heavily influences the glass
transition by affecting chain mobility.
[0059] The "melting temperature", T.sub.m, is the temperature at
which the crystalline domains of a polymer lose their short- and
long-term order, changing from a regular, ordered structure of
chain packing to that of a disordered structure, resembling an
amorphous polymer. The disappearance of the polymer crystalline
phase is accompanied by changes in physical properties of the
polymer. The material becomes a viscous solid, with discontinuous
changes in the density, refractive index, heat capacity,
transparency, and other properties. The T.sub.m of a given polymer
occurs over a finite temperature range. The breadth of the
transition is dependent on the size and perfection of the polymer
crystallites, as well as their homogeneity and purity. By thermal
analytical techniques, the T.sub.m of a semi-crystalline polymer is
an endothermic transition when the heating rate is positive. The
ability of the polymer chains to pack into an ordered, repeating
structure is heavily influenced by the chemical structure of the
polymer.
[0060] "Stress" refers to force per unit area, as in the force
acting through a small area within a plane. Stress can be divided
into components, normal and parallel to the plane, called normal
stress and shear stress, respectively. True stress denotes the
stress where force and area are measured at the same time.
Conventional stress, as applied to tension and compression tests,
is force divided by the original gauge length.
[0061] "Strength" refers to the maximum stress along an axis which
a material will withstand prior to fracture. The ultimate strength
is calculated from the maximum load applied during the test divided
by the original cross-sectional area.
[0062] "Modulus" can be defined as the ratio of a component of
stress or force per unit area applied to a material divided by the
strain along an axis of applied force that results from the applied
force. For example, a material has both a tensile and a compressive
modulus. A material with a relatively high modulus tends to be
stiff or rigid. Conversely, a material with a relatively low
modulus tends to be flexible. The modulus of a material depends on
the molecular composition and structure, temperature of the
material, amount of deformation, and the strain rate or rate of
deformation. For example, below its T.sub.g, a polymer tends to be
brittle with a high modulus. As the temperature of a polymer is
increased from below to above its T.sub.g, its modulus
decreases.
[0063] "Strain" refers to the amount of elongation or compression
that occurs in a material at a given stress or load.
[0064] "Elongation" can be defined as the increase in length in a
material which occurs when subjected to stress. It is typically
expressed as a percentage of the original length.
[0065] "Toughness" is the amount of energy absorbed prior to
fracture, or equivalently, the amount of work required to fracture
a material. One measure of toughness is the area under a
stress-strain curve from zero strain to the strain at fracture.
Thus, a brittle material tends to have a relatively low
toughness.
[0066] The terms "alkyl" and "aliphatic group" refer to an
optionally substituted, straight-chain or branched, saturated or
unsaturated hydrocarbon moiety that may contain one or more
heteroatoms selected from O, S, and N. If unsaturated, the alkyl or
aliphatic group may contain one or more double bonds and/or one or
more triple bonds. The alkyl or aliphatic group may be monovalent
(i.e., --R) or divalent (i.e., --R--) in terms of its attachment to
the rest of the compound. Examples of alkyl and aliphatic groups
include, but are not limited to, methyl, ethyl, ethylenyl, ethynyl,
n-propyl, isopropyl, propenyl, propynyl, n-butyl, isobutyl,
sec-butyl, tertiary-butyl, butenyl, butynyl, n-pentyl, isopentyl,
pentenyl, and pentynyl.
[0067] The terms "heteroalkyl" and "heteroaliphatic group" refer to
an alkyl or aliphatic group that contains at least one heteroatom
selected from O, S and N, in the main portion and/or the branch(es)
of the hydrocarbon moiety. Examples of heteroalkyl and
heteroaliphatic groups include, but are not limited to, alcohols,
ethers, oxo compounds, ketones, aldehydes, esters, carbonates,
thioesters, thiols, sulfides, sulfoxides, sulfones, sulfonamides,
amino compounds, amines, nitriles, N-oxides, imines, oximes,
amides, carbamates, ureas, and thioureas.
[0068] The terms "cycloalkyl" and "cycloaliphatic group" refer to
an optionally substituted, saturated or unsaturated, mono- or
polycyclic hydrocarbon moiety that may contain one or more
heteroatoms selected from O, S, and N. If unsaturated, the
cycloalkyl or cycloaliphatic group may contain one or more double
bonds and/or one or more triple bonds in and/or off of one or more
rings of the cyclic moiety. The cycloalkyl or cycloaliphatic group
may be monovalent (i.e., -Cyc) or divalent (i.e., -Cyc-) in terms
of its attachment to the rest of the compound. Examples of
cycloalkyl and cycloaliphatic groups include, but are not limited
to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cyclohexenyl, decahydronaphthyl, and
octahydroindyl.
[0069] The terms "heterocycloalkyl" and "heterocycloaliphatic
group" refer to a cycloalkyl or cycloaliphatic group in which at
least one ring in the cyclic moiety contains one or more
heteroatoms selected from O, S, and N. Examples of heterocycloalkyl
and heterocycloaliphatic groups include, but are not limited to,
aziridinyl, oxiranyl, oxolanyl, thiolanyl, pyrrolidinyl,
3-pyrrolinyl, dioxalanyl, 1,3-dithiolanyl, oxazolidinyl,
imidazolidinyl, oxanyl, piperidinyl, piperazinyl, 1,3-dioxanyl,
1,4-dioxanyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,
octahydrobenzofuryl, octahydrobenzothiophene, octahydrochromenyl,
and decahydroquinolinyl.
[0070] The terms "aryl" and "aromatic group" refer to an optionally
substituted mono- or polycyclic aromatic moiety in which at least
one ring in the moiety is aromatic. The ring(s) in the moiety may
be carbocyclic or may contain one or more heteroatoms selected from
O, S, and N. The ring(s) in the moiety may be aromatic or
non-aromatic (saturated or unsaturated), but at least one ring in
the moiety is aromatic. An aryl or aromatic group may be monovalent
(i.e., --Ar) or divalent (i.e., --Ar--) in terms of its attachment
to the rest of the compound. Examples of aryl and aromatic groups
include, but are not limited to, phenyl, indolinyl, isoindolinyl,
2,3-dihydrobenzofuryl, 2,3-dihydrobenzothiophene, chromanyl,
1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,
naphthyl, indenyl, and indanyl.
[0071] The terms "heteroaryl" and "heteroaromatic group" refer to
an aryl or aromatic group in which at least one ring (aromatic or
non-aromatic) in the aromatic moiety contains one or more
heteroatoms selected from O, S, and N. Examples of heteroaryl and
heteroaromatic groups include, but are not limited to, pyrrolyl,
pyrazolyl, imidazolyl, furyl, isoxazolyl, oxazolyl, thiophenyl,
thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,
tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
1,3,5-triazinyl, indolyl, isoindolyl, benzofuranyl,
benzothiophenyl, indazolyl, benzimidazolyl, benzothiazolyl,
[1,7]naphthyridinyl, chromenyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, purinyl,
pyridazinyl, quinolinyl, imidazo[4,5-c]pyridinyl,
pyrido[2,3-d]pyrimidinyl, pyrimido[3,2-c]pyrimidinyl, and
pyrrolo[2,3-d]pyrimidinyl.
[0072] The alkyl, aliphatic, heteroalkyl, heteroaliphatic,
cycloalkyl, cycloaliphatic, heterocycloalkyl, heterocycloaliphatic,
aryl, aromatic, heteroaryl and heteroaromatic groups may be
substituted or unsubstituted. If substituted, they may contain from
1 to 5 substituents. The substituents include, but are not limited
to: optionally substituted carbon-containing groups, e.g., alkyl,
cycloalkyl and aryl (e.g., benzyl); halogen atoms (i.e., F, Cl, Br
and I) and optionally substituted halogen-containing groups, e.g.,
haloalkyl (e.g., trifluoromethyl); optionally substituted
oxygen-containing groups, e.g., oxo, alcohols (e.g., hydroxyl,
hydroxyalkyl, aryl(hydroxyl)alkyl), and ethers (e.g., alkoxy,
aryloxy, alkoxyalkyl, aryloxyalkyl); optionally substituted
carbonyl-containing groups, e.g., aldehydes (e.g., carboxaldehyde),
ketones (e.g., alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,
arylalkylcarbonyl, arycarbonylalkyl), carboxy acids (e.g., carboxy,
carboxyalkyl), esters (e.g., alkoxycarbonyl, alkoxycarbonylalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl), carbonates, thioesters,
amides (e.g., aminocarbonyl, mono- or dialkylaminocarbonyl,
aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl,
arylaminocarbonyl, alkylarylaminocarbonyl), carbamates (e.g.,
alkoxycarbonylamino, arloxycarbonylamino, aminocarbonyloxy, mono-
or dialkylaminocarbonyloxy, arylaminocarbonyloxy,
alkylarylaminocarbonyloxy), and ureas (e.g., mono- or
dialkylaminocarbonylamino, arylaminocarbonylamino,
alkylarylaminocarbonylamino); optionally substituted groups
containing carbonyl derivatives, e.g., imines, oximes, and
thioureas; optionally substituted nitrogen-containing groups, e.g.,
amines (e.g., amino, mono- or dialkylamino, mono- or diarylamino,
alkylarylamino, aminoalkyl, mono- or dialkylaminoalkyl), azides,
nitriles (e.g., cyano, cyanoalkyl) and nitro; optionally
substituted sulfur-containing groups, e.g., thiols, sulfides,
thioethers, sulfoxides, sulfones and sulfonamides (e.g. sulfhydryl,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl,
arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl);
and optionally substituted aromatic or non-aromatic heterocyclic
groups containing one or more heteroatoms selected from O, S and N
(e.g., thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,
thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,
aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl,
pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl,
piperazinyl, morpholinyl, thianaphthyl, benzofuranyl,
isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl,
indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl,
quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl,
quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl,
chromanyl, isochromanyl, phthalazinyl, carbolinyl).
Shape-Memory Characteristics
[0073] A polymeric material displaying shape-memory effects can
have two or more phases or segments. If the polymer has two
segments, the "harder" segment with the higher T.sub.g or T.sub.m
acts as the crosslink and is responsible for the permanent shape of
the material. Crosslinks to provide the permanent shape can be
physical (e.g., microphase separation, hydrogen bonding, or
crystalline melting temperature) or covalent (crosslinking).
Thermoplastic polymers tend to have physical crosslinks, while
thermoset polymers tend to have covalent crosslinks. The harder
segment provides strength and rigidity to the material. At a
temperature at or above the T.sub.g or T.sub.m of the harder
segment, the material loses its permanent shape and becomes
amorphous or fluid-like.
[0074] The other, "softer" segment is responsible for the temporary
shape of the material at a temperature below the T.sub.g or T.sub.m
of this segment. At a temperature at or above the T.sub.g or
T.sub.m of the softer segment, the material transitions to its
permanent shape. In other words, the transition, or switching,
temperature of the material is the melting temperature, T.sub.m (if
the segment is crystalline), or the glass transition temperature,
T.sub.g (if the segment is partially crystalline, glassy,
non-crystalline, or amorphous), of the softer segment. The softer
segment tends to be more flexible and elastic than the harder
segment so that the former can facilitate the transition from the
temporary shape to the permanent shape.
[0075] If the shape-memory polymer contains three segments, an
article formed of such a polymer can have one permanent shape and
two temporary shapes. The third, "softest" segment would be
responsible for a second temporary shape, and the article would
switch to its first temporary shape at a temperature at or above
the T.sub.g or T.sub.m of the softest segment.
[0076] In summary, an article formed of a two-segment, shape-memory
polymer can have one permanent shape and one temporary shape. If a
temporary shape was never created, the permanent shape of the
article exists at a temperature below the T.sub.g or T.sub.m of the
harder segment. If a temporary shape was created, the temporary
shape exists at a temperature below the T.sub.g or T.sub.m of the
softer segment, and the permanent shape is recovered in the
temperature range from, and including, the T.sub.g or T.sub.m of
the softer segment to below the T.sub.g or T.sub.m of the harder
segment.
[0077] If the shape-memory polymer contains a third, "softest"
segment, then the article can have a second temporary shape. If a
second temporary shape was never created, the (first) temporary
shape exists at a temperature below the T.sub.g or T.sub.m of the
softer segment. If a second temporary shape was created, the second
temporary shape exists at a temperature below the T.sub.g or
T.sub.m of the softest segment, and the first temporary shape
exists in the temperature range from, and including, the T.sub.g or
T.sub.m of the softest segment to below the T.sub.g or T.sub.m of
the softer segment. Again, the permanent shape is recovered in the
temperature range from, and including, the T.sub.g or T.sub.m of
the softer segment to below the T.sub.g or T.sub.m of the harder
segment.
Embodiments of the Invention
[0078] Composition and Polymer
[0079] Some embodiments of the present invention are directed to a
polymeric composition that displays shape-memory effects and is
designed to possess properties suitable for implantable devices.
The degradation rate of a polymer can be enhanced by the
appropriate selection of monomers and ratio thereof for the
"harder" and "softer" segments of the polymer. The relatively high
T.sub.g or T.sub.m of the "harder" segment, above body temperature
(e.g., above about 50.degree. C.), increases the strength and
rigidity of the polymer. Further, the fracture toughness,
flexibility and drug permeability of the polymer can be increased
by incorporation, with the harder segment polymer, of a "softer"
segment polymer having a T.sub.g or T.sub.m less than the T.sub.g
or T.sub.m of the harder segment polymer.
[0080] The softer segment can be designed to have a T.sub.g or
T.sub.m of around body temperature or greater, depending upon the
particular needs. If the softer segment has a T.sub.g or T.sub.m of
around body temperature, then the permanent shape of the polymeric
composition, and hence that of the implantable device (e.g., a
stent) formed thereof, will be obtained when the device is deployed
at the desired bodily location. The softer segment can also be
designed to have a T.sub.g or T.sub.m above body temperature for
various reasons (e.g., so that the permanent shape is not recovered
during sterilization of the device at elevated temperature). In
such a case, the permanent shape of the composition can be obtained
by providing a thermal stimulus to the composition (e.g., via a
catheter). The harder segment can be designed to have a T.sub.g or
T.sub.m sufficiently greater (e.g., at least about 20.degree. C.
greater) than the T.sub.g or T.sub.m of the softer segment so that
the composition, and thus the device, does not lose its desired
permanent shape after being deployed in the body.
[0081] Accordingly, some embodiments of the present invention,
optionally in combination with one or more other embodiments
described herein, are directed to a composition comprising a
biodegradable copolymer comprising at least two segments A and B,
wherein: [0082] the A segment has a T.sub.g or T.sub.m in the range
from about 50.degree. C. to about 300.degree. C. and is made from
at least one diisocyanate and at least one diol, diamine or dithiol
chain extender; [0083] the B segment has a T.sub.g or T.sub.m in
the range from about 30.degree. C. to about 100.degree. C. and is
derived from a polymer containing at least one hydroxyl, amino or
thiol end group; [0084] the T.sub.g or T.sub.m of the A segment is
at least about 20.degree. C. greater than the T.sub.g or T.sub.m of
the B segment; and [0085] the A and B segments each independently
have a polymer number-average molecular weight (M.sub.n) from about
0.4 kDa to about 500 kDa; and wherein: [0086] the composition
displays at least one shape-memory effect, and [0087] a permanent
shape of the composition is obtained when the temperature of the
composition is equal to or greater than the T.sub.g or T.sub.m of
the B segment.
[0088] In some cases, the harder A segment might not have a T.sub.m
and its T.sub.g may be broad. For example, the A segment may be
semi-crystalline or non-crystalline and may not have a T.sub.m. A
more amorphous A segment may also have a broad T.sub.g that
overlaps with the T.sub.g or T.sub.m of the B segment. The scope of
the present invention also encompasses those cases where the harder
A segment has no T.sub.m and exhibits a broad T.sub.g.
[0089] In one embodiment, the A segment has a T.sub.g or T.sub.m in
the range from about 50.degree. C. to about 300.degree. C. when the
A segment is hydrated, and the B segment has a T.sub.g or T.sub.m
in the range from about 30.degree. C. to about 100.degree. C. when
the B segment is hydrated. In another embodiment, the A segment has
a T.sub.g or T.sub.m in the range from about 50.degree. C. to about
300.degree. C. when the A segment is not hydrated, and the B
segment has a T.sub.g or T.sub.m in the range from about 30.degree.
C. to about 100.degree. C. when the B segment is not hydrated.
[0090] The B segment may or may not be miscible with the A segment.
In one embodiment, optionally in combination with one or more other
embodiments described herein, the B segment is partially or
completely miscible with the A segment. In another embodiment,
optionally in combination with one or more other embodiments
described herein, the B segment is partially or completely
immiscible with the A segment. Moreover, the A and/or B segments of
the biodegradable copolymer can comprise other polymer(s) that may
be partially or completely miscible or immiscible with the B and/or
A segments, respectively.
[0091] The copolymer exhibiting shape-memory effects can be
thermoplastic or thermoset depending on, e.g., the functionality of
the monomer components. In one embodiment, the copolymer is
thermoplastic. A thermoplastic copolymer can derive desirable
mechanical properties from, e.g., microphase separation of the
harder and softer segments. In another embodiment, the copolymer of
the invention is thermoset. The permanent shape of a material
formed of a thermoset copolymer typically is supported by covalent
crosslinking between the segments.
[0092] The biodegradable copolymer of the invention can comprise
elastomeric polymer(s) and/or non-elastomeric polymer(s). In one
embodiment, the copolymer comprises at least one elastomeric
polymer and no non-elastomeric polymer. In another embodiment, the
copolymer comprises at least one non-elastomeric polymer and no
elastomeric polymer. In yet another embodiment, the copolymer
comprises at least one elastomeric polymer and at least one
non-elastomeric polymer.
[0093] The segmented nature of the inventive copolymer containing
urethane, urea and/or "thiourethane" (i.e., RHNC(O)SR') linkages
makes the copolymer suitable for shape-memory programming. For
example, the T.sub.m of the harder A segment, if crystalline, can
serve as the permanent memory temperature below which the permanent
shape memory is set, and the T.sub.g or T.sub.m of the softer B
segment can serve as the transition temperature at or above which
the permanent shape is recovered. The physical and mechanical
properties (e.g., modulus and transition temperature) of the
copolymer can be tuned by adjusting various factors, e.g., the
length of each segment and the ratio of the monomers of the
segments. As an example, a longer harder A segment and a greater
ratio of diisocyanate(s) and chain extender(s) of the A segment to
the polymer of the softer B segment can lead to a higher modulus
and a higher transition temperature.
[0094] The softer B segment provides elasticity, allowing the
polymeric composition to transition from a temporary shape to the
permanent shape when the temperature of the composition is at or
above the T.sub.g or T.sub.m of the B segment. On the other hand,
the harder A segment provides strength and rigidity for, and thus
gives form to, the permanent shape of the composition. Because the
A segment is created by at least one polycondensation reaction
involving at least one diisocyanate and at least one diol, diamine
or dithiol chain extender, the A segment is rich in hydrogen bonds
involving the resulting carbamate (or urethane), urea and/or
thiourethane linkages. These hydrogen bonds act as virtual
crosslinks to give strength and structure to the permanent shape of
the composition.
[0095] To provide strength and rigidity, and to ensure that the
composition, and hence the implantable device formed thereof, does
not lose its desired permanent shape under intended or potential
conditions of application, the A segment is formulated so that its
T.sub.g or T.sub.m is above body temperature. In one embodiment,
optionally in combination with one or more other embodiments
described herein, the T.sub.g or T.sub.m of the A segment is in the
range from about 50.degree. C. to about 300.degree. C. The T.sub.g
or T.sub.m of the A segment can be tuned to a desired value by
appropriate selection of component monomers and adjustment of their
numbers, ratio and arrangement. In certain embodiments, optionally
in combination with one or more other embodiments described herein,
the T.sub.g or T.sub.m of the A segment ranges from about
50.degree. C. to about 300.degree. C., or from about 60.degree. C.
to about 280.degree. C., or from about 70.degree. C. to about
260.degree. C., or from about 80.degree. C. to about 240.degree.
C., or from about 90.degree. C. to about 220.degree. C., or from
about 100.degree. C. to about 200.degree. C.
[0096] The permanent shape of the polymeric composition, and hence
that of the implantable device formed thereof, is recovered when
the temperature of the composition is at or above the T.sub.g or
T.sub.m of the B segment. The T.sub.g or T.sub.m of the B segment
should be in a range suitable for the expected conditions of the
storage, sterilization and application of the device. In one
embodiment, optionally in combination with one or more other
embodiments described herein, the T.sub.g or T.sub.m of the B
segment is in the range from about 30.degree. C. to about
100.degree. C. The lower end of the range, about 30.degree. C.,
allows for the recovery of the permanent shape, without an
additional thermal stimulus, in a patient whose body temperature is
significantly below "normal" body temperature. Further, this lower
end avoids the obtainment of the permanent shape when the device is
at room temperature. The higher end of the range, about 100.degree.
C., should allow for the safe provision of a thermal stimulus for
recovering the permanent shape. Exposure of a biological structure
(e.g., tissues) to a heat source at about 100.degree. C. should
present little risk of damage to that biological structure so long
as the thermal stimulus is provided within a short time period
(i.e., several seconds).
[0097] Provision of a thermal stimulus can also be made safe by
appropriate thermal shielding of the implantable device or another
article that delivers the device and provides the thermal stimulus.
For example, a stent can be delivered through a catheter that
contains an outer insulating or cooling component to shield the
blood and tissues from the catheter compartment providing the
thermal stimulus.
[0098] The T.sub.g or T.sub.m of the B segment can be tuned to a
desired value by appropriate selection of component monomers and
adjustment of their numbers, ratio and arrangement. In certain
embodiments, optionally in combination with one or more other
embodiments described herein, the T.sub.g or T.sub.m of the B
segment ranges from about 30.degree. C. to about 100.degree. C., or
from about 40.degree. C. to about 90.degree. C., or from about
50.degree. C. to about 80.degree. C. In a particular embodiment,
the B segment has a T.sub.g or T.sub.m in the range from about
35.degree. C. to about 70.degree. C. In another specific
embodiment, the B segment has a T.sub.g or T.sub.m around body
temperature, so that the permanent shape of the polymeric
composition is recovered when the implantable device formed thereof
is deployed in the body. Thus, in an embodiment, the T.sub.g or
T.sub.m of the B segment is in the range from about 35.degree. C.
to about 40.degree. C.
[0099] In another embodiment, the B segment has a T.sub.g or
T.sub.m significantly greater than body temperature to provide for
greater radial strength of the implantable device after its
expansion to its permanent shape. In certain embodiments, the B
segment has a T.sub.g or T.sub.m that is 5.degree. C., or
10.degree. C., or 15.degree. C., or 20.degree. C., or 25.degree.
C., or 30.degree. C., or 35.degree. C. greater than body
temperature.
[0100] Various terminal sterilization processes are available for
sterilizing implantable devices (e.g., drug-delivery stents). Many
of these processes, such as electron beam and gamma irradiation,
can cause degradation of a drug incorporated with an implantable
device. Ethylene oxide gas (EOG) tends to cause less drug
degradation. EOG sterilization typically transpires at around
40-45.degree. C. Even if an implantable device formed of a
shape-memory polymeric composition is sterilized using EOG at about
40-45.degree. C., the transition temperature of the composition can
still be around body temperature. For example, the device (e.g., a
stent) can be held in a compressed shape by surrounding the device
with, e.g., a sheath or a sock, to avoid recovering the permanent
shape of the device during sterilization at elevated
temperature.
[0101] High rigidity and strength may be important for an
implantable device formed of a polymeric material, e.g., for a
stent so that the stent can support the walls of a vessel. However,
the polymeric material should also possess sufficient toughness and
flexibility for the range of applications intended for the device.
If the device is also intended to deliver a therapeutic agent, the
polymeric material should also have sufficient drug permeability to
be able to control drug-release rates at reasonable drug-to-polymer
ratios. To increase fracture toughness and flexibility and to
improve drug-release control, the softer B segment of the
biodegradable copolymer can be formulated to have a T.sub.g or
T.sub.m less than the T.sub.g or T.sub.m of the harder A
segment.
[0102] The softer B segment can have greater flexibility, a lower
modulus, and higher fracture toughness than the harder A segment at
physiological conditions. Examples of biodegradable polymers having
a relatively high fracture toughness at body temperature include,
but are not limited to, polycaprolactone (PCL), poly(trimethylene
carbonate) (PTMC), polydioxanone, poly(propiolactone),
poly(valerolactone) and polyacetal. Accordingly, some embodiments
of the B segment can include caprolactone (CL), trimethylene
carbonate (TMC), dioxanone, propiolactone, valerolactone or acetal
monomer units, or a combination thereof.
[0103] The A segment can be designed to have a T.sub.g or T.sub.m
sufficiently greater than the T.sub.g or T.sub.m of the B segment
so that the polymeric composition, and hence the implantable device
formed thereof, does not lose its permanent shape under the
expected conditions of deployment and application in the body. In
certain embodiments, optionally in combination with one or more
other embodiments described herein, the T.sub.g or T.sub.m of the A
segment is greater than the T.sub.g or T.sub.m of the B segment by
at least about 20.degree. C., or by at least about 30.degree. C.,
or by at least about 40.degree. C., or by at least about 50.degree.
C., or by at least about 60.degree. C., or by at least about
70.degree. C.
[0104] The mechanical properties (e.g., rigidity, strength,
toughness, flexibility and shape-memory recoverability),
degradation rate and drug permeability of the inventive copolymer,
as well as the T.sub.g or T.sub.m of the segments, can be tuned by
appropriate selection of the monomer units of the harder and softer
segments, the ratio of the monomers within the segments, the length
or molecular weight of the segments, the weight ratio of the
segments, and any other substance(s) chemically or non-chemically
incorporated with the copolymer.
[0105] Any biocompatible polymer that contains at least one
hydroxyl, amino or thiol end group and is capable of reacting with
a diisocyanate can be used to form the B segment. To enhance the
biodegradation of the inventive copolymer, the B segment can be
formulated to contain hydrolytically labile bonds. For example, the
B segment polymer can be derived from monomer(s) that have a
relatively high degradation rate due to their hydrophilic and/or
hydrolytically active nature, e.g., poly(glycolide) (PGA) or a
glycolide-containing copolymer {e.g., poly(D,L-lactide-co-glycolide
(PLGA) and poly(glycolide-co-trimethylene carbonate)
(P(GA-co-TMC))}. Thus, if the B segment comprises a
glycolide-containing copolymer, the degradation rate of the B
segment, and hence that of the polymeric composition, can be
increased by augmenting the fraction of GA in the B segment. In
exemplary embodiments, a glycolide-containing copolymer of the B
segment (e.g., poly(GA-co-CL) or poly(GA-co-TMC)) can have greater
than 1 wt %, 5 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt %,
60 wt %, 70 wt % or 80 wt % GA units.
[0106] Moreover, the B segment can contain monomer units that have
acidic or hydrophilic degradation products. Since the rate of the
hydrolysis reaction tends to increase as the pH decreases, acidic
degradation products can increase the degradation rate of the
polymeric material, and hence that of the device formed thereof.
For example, glycolide units have acidic degradation products that
can increase the degradation rate of a glycolide-containing
polymeric material.
[0107] In some embodiments, the softer B segment can include
toughness-enhancing units and fast degrading units. In more
specific embodiments, the B segment can include glycolide (GA),
caprolactone (CL), trimethylene carbonate (TMC), valerolactone,
propiolactone or acetal units, or a combination thereof. The B
segment can have alternating or random GA, CL, TMC, valerolactone,
propiolactone and acetal units. For example, the B segment can be
poly(GA-co-CL), poly(GA-co-TMC), poly(CL-co-TMC), or
poly(GA-co-TMC-co-CL).
[0108] The flexibility, toughness and degradation rate of the
softer B segment can also be adjusted by the ratio of fast
degrading and toughness-enhancing units. For example, as the ratio
of CL increases in poly(GA-co-CL), the segment copolymer becomes
more flexible and tougher.
[0109] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the B segment is
derived from a polyester containing at least one hydroxyl end
group. In one embodiment, the polyester containing at least one
hydroxyl end group is selected from polycaprolactone (PCL) diol,
poly(.beta.-hydroxy-alkanoate-diol),
poly([R]-3-hydroxybutyrate-diol), poly(L-lactide) (PLLA) diol,
poly(D,L-lactide) diol, polyglycolic acid, polyglycolide (PGA)
diol, poly(trimethylene carbonate) (PTMC) diol, polydioxanone diol,
polyvalerolactone diol, polypropiolactone diol, and
hydroxyl-terminated random or block copolymers thereof. In a
particular embodiment, the hydroxyl-terminated random or block
copolymer is selected from poly(D,L-lactide-co-glycolide),
poly(L-lactide-co-glycolide),
poly(L-lactide-co-caprolactone-co-L-lactide),
poly(L-lactide-co-D,L-lactide-co-glycolide-co-L-lactide),
poly(glycolide-co-trimethylene carbonate),
poly(glycolide-co-caprolactone), poly(caprolactone-co-trimethylene
carbonate), poly(glycolide-co-trimethylene
carbonate-co-caprolactone), and any variations in the arrangement
of the monomers thereof.
[0110] The B segment can also be derived from other types of
polymers. Non-limiting examples of other types of polymers that can
be suitable for forming the B segment include carboxyl-terminated
poly(anhydrides), polythioesters and polyacetals.
[0111] Moreover, the B segment can comprise at least one
non-fouling moiety. In one embodiment, the B segment comprises at
least one non-fouling moiety as a main component of the segment. In
another embodiment, the B segment comprises at least one
non-fouling moiety as an additional component of the segment.
[0112] Examples of non-fouling moieties include, without
limitation, poly(ethylene glycol) (PEG), poly(propylene glycol),
polyethylene oxide, PLURONIC.TM. surfactants (polypropylene
oxide-co-PEG), PEO-PPO surfactants (PLURONIC.TM. polyols,
poly(ethylene oxide-co-propylene oxide)), poly(tetramethylene
glycol), amino-terminated PEG, hydroxy functionalized poly(vinyl
pyrrolidone), dextran, dextrin, sulfonated dextran, dermatan
sulfate, silk-elastin block copolymers, sodium hyaluronate,
hyaluronic acid, poly(2-hydroxyethyl methacrylate), dihydroxy
poly(styrene sulfonate), poly(3-hydroxypropyl methacrylate),
poly(3-hydroxypropyl methacrylamide), poly(alkoxy methacrylates),
poly(alkoxy acrylates), polyarginine peptides (PAP) (e.g., R7),
phosphoryl choline, heparin, chondroitan sulfate,
glycosaminoglycans, chitosan, and derivatives thereof.
[0113] Silk and elastin both are natural proteins. Silk possesses
strength and elastin high flexibility. Their combination in a block
copolymer makes the non-fouling moiety very strong and, at the same
time, very flexible. Silk-elastin blockcopolymer can be obtained
from Protein Polymer Technologies, Inc. of San Diego, Calif.
[0114] In a specific embodiment, the at least one non-fouling
moiety is selected from polyethylene glycol (PEG), polypropylene
glycol, Pluronic.TM. surfactants (polypropylene oxide-co-PEG),
poly(2-hydroxyethyl methacrylate) (PHEMA), poly(vinyl alcohol)
(PVA), polyalkene oxides, poly(n-propylmethacrylamide),
poly(N-vinyl-2-pyrrolidone) (PVP), sulfonated polystyrene, dextran,
sulfonated dextran, dextrin, hyaluronic acid, sodium hyaluronate,
and derivatives thereof.
[0115] In some embodiments, optionally in combination with one or
more other embodiments described herein, the B segment specifically
cannot comprise one or more of any of the polymers or substances
described herein.
[0116] The maximum molecular weight of the non-fouling moiety or,
if the non-fouling moiety itself is biodegradable, the maximum
molecular weight of the largest fragment formed should be low
enough so that it is small enough to pass through the kidneys.
Thus, in certain embodiments, the molecular weight of the
non-fouling moiety or its largest fragment is 40 kDa or less, or 30
kDa or less, or 20 kDa or less.
[0117] Both the at least one diisocyanate and the at least one
chain extender used to make the A segment independently can contain
an optionally substituted aliphatic, heteroaliphatic,
cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic
group, or a combination thereof. To increase the hydrolytic
lability and bioresorbability of a polymer containing urethane,
urea and/or thiourethane linkages, appropriate diisocyanates (e.g.,
aliphatic diisocyanates) and chain extenders (e.g.,
enzyme-sensitive chain extenders) can be used. Employing aliphatic
diisocyanates may have the additional advantage of avoiding
potential toxicity associated with aromatic diamine degradation
products of aromatic diisocyanates. Therefore, in an embodiment,
optionally in combination with one or more other embodiments
described herein, the A segment is made from at least one aliphatic
diisocyanate.
[0118] Non-limiting examples of aliphatic diisocyanates that can be
used to make biodegradable polyurethanes, polyureas or
polythiourethanes that degrade into biocompatible products include:
[0119] 1,2-diisocyanatoethane, which hydrolytically degrades into
non-carcinogenic ethylene diamine; [0120] 1,4-diisocyanatobutane
(BDI), which degrades into 1,4-butanediamine (putrescine), a
biocompatible mediator of cell growth and differentiation; [0121]
1,4-diisocyanatocubane; [0122] 1,5-diisocyanatopentane, which
degrades into cadaverene, a biological substance found in
decomposing tissues; [0123] 1,6-diisocyanatohexane, which degrades
into 1,6-hexanediamine; and [0124] lysine diisocyanate, which
degrades into the amino acid lysine. Accordingly, in an embodiment,
optionally in combination with one or more other embodiments
described herein, the A segment is made from at least one aliphatic
diisocyanate selected from 1,2-diisocyanatoethane,
1,3-diisocyanatopropane, 1,4-diisocyanatobutane,
1,5-diisocyanatopentane, 1,6-diisocyanatohexane,
1,4-diisocyanatocubane, and lysine diisocyanate.
[0125] Other types of diisocyanates can also be utilized to make
the A segment. For example, diisocyanates incorporating labile
ester bonds can be used to render the A segment more
biodegradable.
[0126] Various types of diol, diamine and/or dithiol chain
extenders can be employed to make the A segment more biodegradable
and provide it with strength and shape-memory recoverability. In
one embodiment, optionally in combination with one or more other
embodiments described herein, the A segment is made from at least
one chain extender selected from ethylene glycol, 1,3-propanediol,
1,2-propanediol, 1,4-butanediol (BDO), 1,5-pentanediol,
1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol,
1,10-decanediol, 1,11-undecanediol, 1,12-dodecanediol,
1,2-cyclohexanedimethanol, 1,4-cyclohexanedimethanol, the
corresponding diamine and dithiol analogs thereof, lysine ethyl
ester, arginine ethyl ester, and p-alanine-based diamine.
[0127] In another embodiment, optionally in combination with one or
more other embodiments described herein, the at least one chain
extender includes random or block copolymers made from at least one
diisocyanate and at least one diol, diamine or dithiol chain
extender. For example, BDO-BDI-BDO and BDI-BDO-BDI-BDO-BDI can be
employed to prevent transesterification reactions from causing too
much polydispersity within the harder A segment.
[0128] Other types of chain extenders can also be utilized to make
the A segment. For example, chain extenders incorporating labile
ester bonds can be used to render the A segment more
biodegradable.
[0129] In some embodiments, optionally in combination with one or
more other embodiments described herein, the A segment specifically
cannot be made from one or more of any of the diisocyanates or from
one or more of any of the chain extenders described herein.
[0130] For forming certain types of material (e.g., films), the
entire polymer may need to have sufficient molecular weight.
Accordingly, in some embodiments, optionally in combination with
one or more other embodiments described herein, the copolymer of
the invention has a polymer number-average molecular weight
(M.sub.n) of at least about 20 kDa. In other embodiments, the
copolymer has an M.sub.n of at least about 40 kDa.
[0131] In an embodiment, optionally in combination with one or more
other embodiments described herein, the copolymer of the invention
ranges in M.sub.n from about 20 kDa to about 1,000 kDa. In another
embodiment, the copolymer ranges in M.sub.n from about 20 kDa to
about 500 kDa. A polymer with an M.sub.n from about 20 kDa to about
500 kDa may be more amenable to being processed into a coating. In
yet another embodiment, the copolymer ranges in M.sub.n from about
40 kDa to about 500 kDa.
[0132] For the segments to form discrete phases which are
indicative of an immiscible system, they need to be of a certain
minimal size. When a two-phase system forms, each phase is
saturated with the other phase, although these saturated
concentrations may be very small. Accordingly, in some embodiments,
the A and B segments each independently have an M.sub.n of at least
about 0.4 kDa. In certain embodiments, optionally in combination
with one or more other embodiments described herein, the A and B
segments each independently range in M.sub.n from about 0.4 kDa to
about 500 kDa, or from about 1 kDa to about 500 kDa, or from about
10 kDa to about 400 kDa, or from about 20 kDa to about 300 kDa, or
from about 30 kDa to about 200 kDa, or from about 40 kDa to about
100 kDa.
[0133] In addition, varying the ratio of softer to harder segments
allows one to tune/modify the properties of the polymeric material,
e.g., the strength, rigidity, toughness, flexibility,
recoverability, drug permeability and biodegradation rate of the
material. Accordingly, in certain embodiments, optionally in
combination with one or more other embodiments described herein,
the ratio of the molecular weight of the A segment to the B segment
is between about 20:1 and about 1:20, or between about 10:1 and
about 1:10, or between about 5:1 and about 1:5.
[0134] In other embodiments, optionally in combination with one or
more other embodiments described herein, the weight fraction of the
A segment with respect to the total copolymer of the invention is
from about 1% to about 99%, or from about 10% to about 90%, or from
about 20% to about 80%, or from about 30% to about 70%, of from
about 40% to about 60%. In yet other embodiments, the inventive
copolymer can contain about 1-50 wt %, or about 5-40 wt %, or about
10-30 wt % of the B segment, and about 50-99% wt %, or about 60-95
wt %, or about 70-90 wt % of the A segment.
[0135] In further embodiments, optionally in combination with one
or more other embodiments described herein, the A and B segments
each independently comprise a polymer comprising from one to four
different types of monomer, wherein each type of monomer has from
about 5 to about 5,000 monomer units. In narrower embodiments, each
type of monomer in the polymer of the A or B segment independently
has from about 10 to about 4,500 monomer units, or from about 20 to
about 4,000 monomer units, or from about 30 to about 3,500 monomer
units, or from about 40 to about 3,000 monomer units, or from about
50 to about 2,500 monomer units.
[0136] In another embodiment, optionally in combination with one or
more other embodiments described herein, the A segment is made from
one to four different polycondensation reactions involving a
diisocyanate and a diol, diamine or dithiol chain extender, wherein
each polycondensation reaction: [0137] occurs from about 5 to about
5,000 times, and [0138] involves a diisocyanate and a diol, diamine
or dithiol chain extender that may be the same as or different than
any other diisocyanate(s) and any other diol, diamine or dithiol
chain extender(s) involved in any other polycondensation
reaction(s).
[0139] Adhesion of a polymeric material (e.g., a coating) to a
metal surface (e.g., a stent) can be promoted by appropriate (e.g.,
chemical) modification of the polymer. Such modification could lead
to a single polymer, which could be used as a drug reservoir, with
no primer. In the case of a polymer that does not have any inherent
adhesion to metal surfaces, a primer of that pure polymer may have
to be used to achieve optimum adhesion to metal stents.
[0140] To improve adhesion of the inventive copolymer to metal
surfaces, at least one dihydroxyaryl group could be conjugated to
the ends of the copolymer. The dihydroxyaryl group(s) can contain a
dihydroxyphenyl moiety. Ortho-dihydroxyphenyl groups in
3,4-dihydroxyphenyl alanine have been shown to be responsible for
the bonding of mussel adhesive proteins to a variety of metallic
substrates. B. P. Lee et al., Biomacromolecules, 3: 1038-1047
(2002). Other 3,4-dihydroxyphenyl-containing compounds that can be
conjugated to the ends of the copolymer to increase its adhesion to
metal surfaces include, e.g., dopamine and
3,4-dihydroxyhydrocinnamic acid.
[0141] Accordingly, in some embodiments, optionally in combination
with one or more other embodiments described herein, at least one
dihydroxyaryl group is conjugated to the ends of the copolymer of
the invention. In an embodiment, the at least one dihydroxyaryl
group contains an ortho-dihydroxyphenyl moiety. In one embodiment,
the at least one dihydroxyaryl group contains a 1,2-dihydroxyphenyl
moiety. In another embodiment, the at least one dihydroxyaryl group
contains a 3,4-dihydroxyphenyl moiety.
3,4-Dihydroxyphenyl-containing compounds that could be conjugated
to the ends of the copolymer include, e.g., dopamine and
3,4-dihydroxyhydrocinnamic acid.
[0142] As explained earlier, if a shape-memory polymer contains
three segments, it can have one permanent shape and two temporary
shapes. The permanent shape would be recovered upon deployment of
the implantable device formed of that polymer, with the provision
of a thermal stimulus, if necessary. A first temporary shape may be
desired, e.g., for handling of the device at room temperature and
for delivery of the device to the treatment site in the body. A
second temporary shape may be also be desired, e.g., for storage of
the device at cold temperature.
[0143] Accordingly, in some embodiments, the biodegradable
copolymer of the invention comprises a third segment. In an
embodiment, optionally in combination with one or more other
embodiments described herein, the copolymer further comprises a
third segment A', wherein the A' segment: [0144] is made from at
least one diisocyanate and at least one diol, diamine or dithiol
chain extender; [0145] has an M.sub.n from about 0.4 kDa to about
500 kDa; [0146] may be attached to the B segment or the A segment;
and [0147] may be the same as or different than the A segment.
[0148] The description herein, including the various embodiments,
relating to the A segment may also apply to the A' segment, as
appropriate. For example, in one embodiment, optionally in
combination with one or more other embodiments described herein,
the A' segment is made from one to four different polycondensation
reactions involving a diisocyanate and a diol, diamine or dithiol
chain extender, wherein each polycondensation reaction: [0149]
occurs from about 5 to about 5,000 times, and [0150] involves a
diisocyanate and a diol, diamine or dithiol chain extender that may
be the same as or different than any other diisocyanate(s) and any
other diol, diamine or dithiol chain extender(s) involved in any
other polycondensation reaction(s).
[0151] The A' segment may be attached to the B segment or the A
segment. In an embodiment, the A' segment is attached to the B
segment. In another embodiment, the A' segment is attached to the A
segment.
[0152] Further, the A' segment may be the same as or different than
the A segment. In one embodiment, the A and A' segments are the
same. In another embodiment, the A and A' segments are
different.
[0153] The A' segment, rather than the B segment, may serve as the
segment responsible for switching the polymeric composition to the
permanent shape. Alternatively, the A' segment may be responsible
for a second temporary shape for various reasons, e.g., for storage
of the implantable device at cold temperature. Accordingly, in one
embodiment, optionally in combination with one or more other
embodiments described herein, the A' segment has a T.sub.g or
T.sub.m in the range from about -70.degree. C. to about 100.degree.
C. In narrower embodiments, the T.sub.g or T.sub.m of the A'
segment is in the range from about -50.degree. C. to about
80.degree. C., or from about -30.degree. C. to about 60.degree. C.,
or from about -10.degree. C. to about 40.degree. C. In a particular
embodiment, the A' segment has a T.sub.g or T.sub.m in the range
from about -20.degree. C. to about 35.degree. C.
[0154] Although both the A and A' segments independently are made
from at least one polycondensation reaction involving at least one
diisocyanate and at least one diol, diamine or dithiol chain
extender, they can possess different physical and mechanical
properties. The physical and mechanical properties (e.g., the
T.sub.g or T.sub.m) of the A' segment can be tuned by appropriate
selection of the diisocyanate(s) and chain extender(s) (including
any functional groups in these compounds), the ratio and
arrangement of the monomers within the segment, the length or
molecular weight of the segment, and any other substance(s)
chemically or non-chemically incorporated with the segment.
[0155] Biocompatible Polymer
[0156] Another embodiment of the invention, optionally in
combination with one or more other embodiments described herein, is
drawn to a composition comprising a biodegradable copolymer of the
invention and at least one additional biologically compatible (or
"biocompatible") polymer. The biocompatible polymer provides the
inventive copolymer with biological, e.g., blood, compatibility.
The at least one additional biocompatible polymer can be
biodegradable or nondegradable. In an embodiment, the biocompatible
polymer is biodegradable. The at least one additional biocompatible
polymer can be selected in such a way as to make the entire
inventive copolymer biologically degradable. In another embodiment,
the biocompatible polymer is nondegradable. Moreover, the at least
one additional biocompatible polymer may be blended, grafted,
co-polymerized or incorporated with the polymers of the A and/or B
segments (or any additional segments).
[0157] Examples of suitable biocompatible polymers include, but are
not limited to, poly(ester amides), ethylene vinyl alcohol
copolymer (commonly known by the generic name EVOH or by the trade
name EVAL), poly(hydroxyvalerate), poly(L-lactic acid),
polycaprolactone, poly(lactide-co-glycolide),
poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),
polydioxanone, polyorthoesters, polyanhydrides, poly(glycolic
acid), poly(D,L-lactic acid), poly(D,L-lactide-co-glycolide)
(PDLLAGA), poly(glycolic acid-co-trimethylene carbonate),
polyphosphoesters, polyphosphoester urethanes, poly(amino acids),
polycyanoacrylates, poly(trimethylene carbonate),
poly(iminocarbonates), polyurethanes, polyphosphazenes, silicones,
polyesters, polyolefins, polyisobutylene and
ethylene-.alpha.-olefin copolymers, acrylic polymers and
copolymers, vinyl halide polymers and copolymers (e.g., polyvinyl
chloride), polyvinyl ethers (e.g., polyvinyl methyl ether),
polyvinylidene halides (e.g., vinylidene fluoride based home or
copolymer under the trade name Solef.TM. or Kynar.TM., e.g.,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride), polyacrylonitrile, polyvinyl ketones,
polyvinyl aromatics (e.g., polystyrene), polyvinyl esters (e.g.,
polyvinyl acetate), copolymers of vinyl monomers with each other
and olefins (e.g., ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl
acetate copolymers), polyamides (e.g., Nylon 66 and
polycaprolactam), alkyd resins, polycarbonates, polyoxymethylenes,
polyimides, polyethers, poly(glyceryl sebacate), poly(propylene
fumarate), epoxy resins, polyurethanes, rayon, rayon-triacetate,
poly(N-acetylglucosamine) (Chitin), Chitosan, biomolecules (e.g.,
fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic
acid), cellulose derivatives (e.g., cellulose acetate, cellulose
butyrate, cellulose acetate butyrate, cellophane, cellulose
nitrate, cellulose propionate, cellulose ethers and carboxymethyl
cellulose), and combinations and copolymers thereof.
[0158] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the at least one
additional biocompatible polymer is selected from poly(ethylene
glycol) (PEG); polypropylene; poly(propylene glycol) (PPG);
poly(N-vinyl pyrrolidone) (PVP); poly(N-vinyl pyrrolidone-co-vinyl
acetate) (Copovidone); poly(ester amides) (PEA); acrylic acid (AA);
polyacrylates (e.g., poly(methyl methacrylate) (PMMA), poly(butyl
methacrylate), poly(ethyl methacrylate), hydroxyethylmethacrylate
(HEMA), poly(ethyl methacrylate-co-butyl methacrylate) (P(MMA-co
BMA)), ethyl glycol dimethacrylate, (EGDMA), and ethylene-methyl
methacrylate copolymers); acrylamides (e.g., N,N-dimethyl
acrylamide, diacetone acrylamide, and acrylamide-methyl-propane
sulfonate (AMPS)); fluorinated polymers or copolymers (e.g.,
poly(vinylidene fluoride) and poly(vinylidene
fluoride-co-hexafluoro propene)); poly(hydroxyvalerate);
poly(L-lactic acid)/polylactide (PLLA);
poly(.epsilon.-caprolactone); poly(lactide-co-glycolide) (PLGA);
poly(hydroxybutyrate); poly(hydroxyvalerate);
poly(hydroxybutyrate-co-valerate); polydioxanone; polyorthoesters;
polyanhydrides; poly(glycolic acid)/polyglycolide (PGA);
poly(D,L-lactic acid) (PLA); poly(glycolic acid-co-trimethylene
carbonate); polyphosphoesters; polyurethanes (e.g.,
polyphosphoester urethanes); polyureas; polyurethane(ureas);
poly(amino acids); cyanoacrylates; poly(trimethylene carbonate);
poly(iminocarbonates); co-poly(ether-esters) (e.g., PEO/PLA);
polyalkylene oxalates; polyphosphazenes; silicones; polyesters;
polyolefins; polyisobutylene and ethylene-.alpha.-olefin
copolymers; vinyl halide polymers and copolymers (e.g., polyvinyl
chloride (PVC)); polyvinyl ethers (e.g., polyvinyl methyl ether);
polyvinylidene chloride; polyacrylonitrile; polyvinyl ketones;
polyvinyl aromatics (e.g., polystyrene, styrene sulfonate, and
acrylonitrile-styrene copolymers); polyvinyl esters (e.g.,
polyvinyl acetate); copolymers of vinyl monomers with each other
(e.g., divinyl benzene (PVB)); olefins (e.g.,
poly(ethylene-co-vinyl alcohol) (EVAL)); poly(vinyl alcohol) (PVA);
acrylonitrile butadiene (ABS) resins; ethylene-vinyl acetate
copolymers; polyamides (e.g., Nylon 66 and polycaprolactam); alkyl
resins; polycarbonates; polyoxymethylenes; polyimides; polyethers;
epoxy resins; rayon; rayon-triacetate; and combinations and
co-polymers thereof.
[0159] In another embodiment, optionally in combination with one or
more other embodiments described herein, the at least one
additional biocompatible polymer includes at least one polyester.
Non-limiting examples of suitable polyesters include PLA, PLGA,
PGA, PHA, poly(3-hydroxybutyrate) (PHB),
poly(3-hydroxybutyrate-co-3-hydroxyvalerate),
poly((3-hydroxyvalerate), poly(3-hydroxyhexanoate),
poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),
poly(4-hydroxyhexanoate), and polycaprolactone (PCL).
[0160] In some embodiments, optionally in combination with one or
more other embodiments described herein, the at least one
additional biocompatible polymer specifically cannot be one or more
of any of the biocompatible polymers described herein.
[0161] The molecular weight of the at least one additional
biocompatible polymer may be chosen to be 40 kDa or less to ensure
renal clearance of the compound, e.g., between about 300 and about
40,000 Daltons, or between about 8,000 and about 30,000 Daltons
(e.g., about 15,000 Daltons).
[0162] The biocompatible polymer can provide a controlled release
of a bioactive agent, if incorporated with a polymeric material of
which an implantable device is formed. Controlled release and
delivery of a bioactive agent using a polymeric carrier has been
extensively researched. See, e.g., Mathiowitz, Ed., Encyclopedia of
Controlled Drug Delivery, C.H.I.P.S. (1999). The release rate of
the bioactive agent can be controlled by various means, e.g.,
selection of a particular type of biocompatible polymer, which can
provide a desired release profile of the bioactive agent. The
release profile of the bioactive agent can be further controlled by
selecting the molecular weight of the biocompatible polymer and/or
the ratio of the biocompatible polymer to the bioactive agent. One
of ordinary skill in the art can readily select a carrier system
using a biocompatible polymer to provide a controlled release of
the bioactive agent.
[0163] Biobeneficial Materials
[0164] A further embodiment of the invention, optionally in
combination with one or more other embodiments described herein, is
directed to a composition comprising a biodegradable copolymer of
the invention and at least one biobeneficial material. The
biobeneficial material may be a polymeric material or a
non-polymeric material, and may be biodegradable or non-degradable.
In certain embodiments, the at least one biobeneficial material is
flexible, biodegradable, biocompatible, non-toxic, non-antigenic
and/or non-immunogenic. The biobeneficial material may be blended,
grafted, co-polymerized or incorporated with the polymers of the A
and/or B segments (or any additional segments).
[0165] The biobeneficial material, if polymeric, may have a
relatively low T.sub.g, e.g., a T.sub.g below or significantly
below that of the biocompatible polymer. In an embodiment, the
T.sub.g of the biobeneficial material is below body temperature.
This attribute would, e.g., render the biobeneficial material
relatively soft as compared to the biocompatible polymer and allow,
e.g., a layer of coating containing the biobeneficial material to
fill any surface damages that may arise with an implantable device
coated with a layer comprising the biocompatible polymer. For
example, during radial expansion of a stent, a more rigid
biocompatible polymer can crack or have surface fractures. A softer
biobeneficial material can fill in the crack and fractures.
[0166] The biobeneficial material may also be hydrophlic.
Hydrophicility of, e.g., the coating material would affect the
drug-release rate of a drug-delivery coating and, if the coating
material is biodegradable, would affect the degradation rate of the
coating material. Generally, the more hydrophilic the coating
material, the greater the drug-release rate of the drug-delivery
coating and the greater the degradation rate of the coating if it
is biodegradable.
[0167] Examples of biobeneficial materials include, but are not
limited to, polyethers (e.g., poly(ethylene glycol) (PEG));
poly(ether esters); co-poly(ether-esters) (e.g. PEO/PLA);
polyalkylene oxides (e.g., poly(ethylene oxide) and poly(propylene
oxide)); polyalkylene oxalates; polyphosphazenes; phosphoryl
choline; choline; poly(aspirin); polymers and co-polymers of
hydroxyl bearing monomers such as hydroxyethyl methacrylate (HEMA),
hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide,
poly (ethylene glycol)acrylate (PEGA), PEG methacrylate,
2-methacryloyloxyethylphosphorylcholine (MPC) and N-vinyl
pyrrolidone (VP); carboxylic acid bearing monomers such as
methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate,
alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate (TMSPMA);
copolymers of PEG such as poly(styrene-isoprene-styrene)-PEG
(SIS-PEG), polystyrene-PEG, polyisobutylene-PEG,
polycaprolactone-PEG (PCL-PEG), PLA-PEG, poly(methyl
methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG
(PDMS-PEG), and poly(vinylidene fluoride)-PEG (PVDF-PEG);
PLURONIC.TM. surfactants (polypropylene oxide-co-polyethylene
glycol); poly(tetramethylene glycol); biomolecules such as fibrin,
fibrinogen, cellulose, starch, collagen, dextran, dextrin,
hyaluronic acid, fragments and derivatives of hyaluronic acid,
heparin, fragments and derivatives of heparin, glycosamino glycan
(GAG), GAG derivatives, polysaccharides, elastin, chitosan, and
alginate; silicones; and combinations and copolymers thereof.
[0168] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the at least one
biobeneficial material is selected from fibrin; fibrinogen;
cellulose and cellulose derivatives (e.g., cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellophane,
cellulose nitrate, cellulose propionate, cellulose ethers, and
carboxymethyl cellulose); starch; pectin; chitosan; elastin;
gelatin; alginate and conjugates thereof (e.g., alginate-gelatin,
alginate-collagen, alginate-laminin, alginate-elastin,
alginate-collagen-laminin and alginate-hyaluronic acid); collagen
and conjugates thereof; hyaluronan and derivatives thereof (e.g.,
methacrylate-modified hyaluronan and NHS ester-modified
hyaluronan); hyaluronic acid; sodium hyaluronate; and
self-assembled peptides (SAP) (e.g., AcN-RARADADARARADADA-CNH.sub.2
(RAD 16-II), VKVKVKVKV-PP-TKVKVKVKV-NH.sub.2 (MAX-1), and
AcN-AEAEAKAKAEAEAKAK-CNH.sub.2 (EAK 16-II)).
[0169] In another embodiment, the biobeneficial material is a block
copolymer having flexible poly(ethylene glycol) and poly(butylene
terephthalate) blocks (PEG/PBT) (e.g., PolyActive.TM.).
PolyActive.TM. is intended to include AB, ABA, and BAB copolymers
having such segments of PEG and PBT (e.g., poly(ethylene
glycol)-block-poly(butylene terephthalate)-block-poly(ethylene
glycol) (PEG-PBT-PEG)).
[0170] In some embodiments, optionally in combination with one or
more other embodiments described herein, the at least one
biobeneficial material specifically cannot be one or more of any of
the biobeneficial materials described herein.
[0171] Biologically Active Agents
[0172] Another embodiment of the invention, optionally in
combination with one or more other embodiments described herein, is
directed to a composition comprising a biodegradable copolymer of
the invention and at least one biologically active (or "bioactive")
agent. The at least one biologically active agent can include any
substance capable of exerting a therapeutic, prophylactic or
diagnostic effect for a patient.
[0173] Examples of suitable bioactive agents include, but are not
limited to, synthetic inorganic and organic compounds, proteins and
peptides, polysaccharides and other sugars, lipids, and DNA and RNA
nucleic acid sequences having therapeutic, prophylactic or
diagnostic activities. Nucleic acid sequences include genes,
antisense molecules that bind to complementary DNA to inhibit
transcription, and ribozymes. Some other examples of other
bioactive agents include antibodies, receptor ligands, enzymes,
adhesion peptides, blood clotting factors, inhibitors or clot
dissolving agents such as streptokinase and tissue plasminogen
activator, antigens for immunization, hormones and growth factors,
oligonucleotides such as antisense oligonucleotides and ribozymes
and retroviral vectors for use in gene therapy. The bioactive
agents could be designed, e.g., to inhibit the activity of vascular
smooth muscle cells. They could be directed at inhibiting abnormal
or inappropriate migration and/or proliferation of smooth muscle
cells to inhibit restenosis.
[0174] In an embodiment, optionally in combination with one or more
other embodiments described herein, the inventive composition
comprises at least one biologically active agent selected from
antiproliferative, antineoplastic, antimitotic, anti-inflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic,
antiallergic and antioxidant substances.
[0175] An antiproliferative agent can be a natural proteineous
agent such as a cytotoxin or a synthetic molecule. Examples of
antiproliferative substances include, but are not limited to,
actinomycin D or derivatives and analogs thereof (manufactured by
Sigma-Aldrich, or COSMEGEN available from Merck) (synonyms of
actinomycin D include dactinomycin, actinomycin IV, actinomycin II,
actinomycin X.sub.1, and actinomycin C.sub.1); all taxoids such as
taxols, docetaxel, and paclitaxel and derivatives thereof; all
olimus drugs such as macrolide antibiotics, rapamycin, everolimus,
structural derivatives and functional analogues of rapamycin,
structural derivatives and functional analogues of everolimus,
FKBP-12 mediated mTOR inhibitors, biolimus, perfenidone, prodrugs
thereof, co-drugs thereof, and combinations thereof. Examples of
rapamycin derivatives include, but are not limited to,
40-O-(2-hydroxy)ethyl-rapamycin (trade name everolimus from
Novartis), 40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus, manufactured by Abbott Labs.), prodrugs thereof,
co-drugs thereof, and combinations thereof.
[0176] An anti-inflammatory drug can be a steroidal
anti-inflammatory drug, a nonsteroidal anti-inflammatory drug
(NSAID), or a combination thereof. Examples of anti-inflammatory
drugs include, but are not limited to, alclofenac, alclometasone
dipropionate, algestone acetonide, alpha amylase, amcinafal,
amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra,
anirolac, anitrazafen, apazone, balsalazide disodium, bendazac,
benoxaprofen, benzydamine hydrochloride, bromelains, broperamole,
budesonide, carprofen, cicloprofen, cintazone, cliprofen,
clobetasol, clobetasol propionate, clobetasone butyrate, clopirac,
cloticasone propionate, cormethasone acetate, cortodoxone,
deflazacort, desonide, desoximetasone, dexamethasone, dexamethasone
acetate, dexamethasone dipropionate, diclofenac potassium,
diclofenac sodium, diflorasone diacetate, diflumidone sodium,
diflunisal, difluprednate, diftalone, dimethyl sulfoxide,
drocinonide, endrysone, enlimomab, enolicam sodium, epirizole,
etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac,
fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort,
flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin
meglumine, fluocortin butyl, fluorometholone acetate, fluquazone,
flurbiprofen, fluretofen, fluticasone propionate, furaprofen,
furobufen, halcinonide, halobetasol propionate, halopredone
acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen
piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen,
indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam,
ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol
etabonate, meclofenamate sodium, meclofenamic acid, meclorisone
dibutyrate, mefenamic acid, mesalamine, meseclazone,
methylprednisolone suleptanate, momiflumate, nabumetone, naproxen,
naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,
orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,
pentosan polysulfate sodium, phenbutazone sodium glycerate,
pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine,
pirprofen, prednazate, prifelone, prodolic acid, proquazone,
proxazole, proxazole citrate, rimexolone, romazarit, salcolex,
salnacedin, salsalate, sanguinarium chloride, seclazone,
sermetacin, sudoxicam, sulindac, suprofen, talmetacin,
talniflumate, talosalate, tebufelone, tenidap, tenidap sodium,
tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol
pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate,
zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid),
salicylic acid, corticosteroids, glucocorticoids, tacrolimus,
pimecorlimus, prodrugs thereof, co-drugs thereof, and combinations
thereof.
[0177] Alternatively, the anti-inflammatory agent may be a
biological inhibitor of pro-inflammatory signaling molecules.
Anti-inflammatory biological agents include antibodies to such
biological inflammatory signaling molecules.
[0178] In addition, the bioactive agents can be other than
antiproliferative or anti-inflammatory agents. The bioactive agents
can be any agent that is a therapeutic, prophylactic or diagnostic
agent. In some embodiments, such agents can be used in combination
with antiproliferative or anti-inflammatory agents. These bioactive
agents can also have antiproliferative and/or anti-inflammatory
properties or can have other properties such as antineoplastic,
antimitotic, cystostatic, antiplatelet, anticoagulant, antifibrin,
antithrombin, antibiotic, antiallergic, and/or antioxidant
properties.
[0179] Examples of antineoplastics and/or antimitotics include, but
are not limited to, paclitaxel (e.g., TAXOL.RTM. available from
Bristol-Myers Squibb), docetaxel (e.g., Taxotere.RTM. from
Aventis), methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin.RTM. from
Pfizer), and mitomycin (e.g., Mutamycin.RTM. from Bristol-Myers
Squibb).
[0180] Examples of antiplatelet, anticoagulant, antifibrin, and
antithrombin agents that may also have cytostatic or
antiproliferative properties include, but are not limited to,
heparin, sodium heparin, low molecular weight heparins,
heparinoids, hirudin, recombinant hirudin, thrombomodulin,
flavonoids, salicylate (aspirin), argatroban, forskolin, vapiprost,
prostacyclin and prostacyclin analogues, dextran, atrial
natriuretic peptide (ANP), D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist antibody, thrombin inhibitors
such as ANGIOMAX (from Biogen), calcium channel blockers (e.g.,
nifedipine), colchicine, fibroblast growth factor (FGF)
antagonists, fish oil (e.g., omega 3-fatty acid), histamine
antagonists, lovastatin (a cholesterol-lowering drug that inhibits
HMG-CoA reductase, brand name Mevacor.RTM. from Merck), monoclonal
antibodies (e.g., those specific for platelet-derived growth factor
(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,
prostaglandin inhibitors, suramin, serotonin blockers, steroids,
thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist),
nitric oxide or nitric oxide donors, super oxide dismutases, super
oxide dismutase mimetics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
estradiol, anticancer agents, dietary supplements such as various
vitamins, and a combination thereof.
[0181] Examples of cytostatic substances include, but are not
limited to, angiopeptin, angiotensin converting enzyme inhibitors
such as captopril (e.g., Capoten.RTM. and Capozide.RTM. from
Bristol-Myers Squibb), cilazapril and lisinopril (e.g.,
Prinivil.RTM. and Prinzide.RTM. from Merck).
[0182] Examples of antiallergic agents include, but are not limited
to, permirolast potassium. Examples of antioxidant substances
include, but are not limited to,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO).
[0183] Other bioactive agents can include anti-infectives such as
antiviral agents; analgesics and analgesic combinations; anorexics;
antihelmintics; antiarthritics, antiasthmatic agents;
anticonvulsants; antidepressants; antidiuretic agents;
antidiarrheals; antihistamines; antimigrain preparations;
antinauseants; antiparkinsonism drugs; antipruritics;
antipsychotics; antipyretics; antispasmodics; anticholinergics;
sympathomimetics; xanthine derivatives; cardiovascular preparations
including calcium channel blockers and beta-blockers such as
pindolol and antiarrhythmics; antihypertensives; diuretics;
vasodilators including general coronary vasodilators; peripheral
and cerebral vasodilators; central nervous system stimulants; cough
and cold preparations, including decongestants; hypnotics;
immunosuppressives; muscle relaxants; parasympatholytics;
psychostimulants; sedatives; tranquilizers; naturally derived or
genetically engineered lipoproteins; and restenoic reducing
agents.
[0184] Other biologically active agents that can be used include
alpha-interferon, genetically engineered epithelial cells,
tacrolimus and dexamethasone.
[0185] A "prohealing" drug or agent, in the context of a
blood-contacting implantable device, refers to a drug or agent that
has the property that it promotes or enhances re-endothelialization
of arterial lumen to promote healing of the vascular tissue. The
portion(s) of an implantable device (e.g., a stent) containing a
prohealing drug or agent can attract, bind and eventually become
encapsulated by endothelial cells (e.g., endothelial progenitor
cells). The attraction, binding, and encapsulation of the cells
will reduce or prevent the formation of emboli or thrombi due to
the loss of the mechanical properties that could occur if the stent
was insufficiently encapsulated. The enhanced re-endothelialization
can promote the endothelialization at a rate faster than the loss
of mechanical properties of the stent.
[0186] The prohealing drug or agent can be dispersed in the body of
the bioabsorbable polymer substrate or scaffolding. The prohealing
drug or agent can also be dispersed within a bioabsorbable polymer
coating over a surface of an implantable device (e.g., a
stent).
[0187] "Endothelial progenitor cells" refer to primitive cells made
in the bone marrow that can enter the bloodstream and go to areas
of blood vessel injury to help repair the damage. Endothelial
progenitor cells circulate in adult human peripheral blood and are
mobilized from bone marrow by cytokines, growth factors, and
ischemic conditions. Vascular injury is repaired by both
angiogenesis and vasculogenesis mechanisms. Circulating endothelial
progenitor cells contribute to repair of injured blood vessels
mainly via a vasculogenesis mechanism.
[0188] In some embodiments, the prohealing drug or agent can be an
endothelial cell (EDC)-binding agent. In certain embodiments, the
EDC-binding agent can be a protein, peptide or antibody, which can
be, e.g., one of collagen type 1, a 23 peptide fragment known as
single chain Fv fragment (scfv A5), a junction membrane protein
vascular endothelial (VE)-cadherin, and combinations thereof.
Collagen type 1, when bound to osteopontin, has been shown to
promote adhesion of endothelial cells and modulate their viability
by the down regulation of apoptotic pathways. S. M. Martin, et al.,
J. Biomed. Mater. Res., 70A:10-19 (2004). Endothelial cells can be
selectively targeted (for the targeted delivery of immunoliposomes)
using scFv A5. T. Volkel, et al., Biochimica et Biophysica Acta,
1663:158-166 (2004). Junction membrane protein vascular endothelial
(VE)-cadherin has been shown to bind to endothelial cells and down
regulate apoptosis of the endothelial cells. R. Spagnuolo, et al.,
Blood, 103:3005-3012 (2004).
[0189] In a particular embodiment, the EDC-binding agent can be the
active fragment of osteopontin,
(Asp-Val-Asp-Val-Pro-Asp-Gly-Asp-Ser-Leu-Ala-Try-Gly). Other
EDC-binding agents include, but are not limited to, EPC (epithelial
cell) antibodies, RGD peptide sequences, RGD mimetics, and
combinations thereof.
[0190] In further embodiments, the prohealing drug or agent may be
a substance or agent that attracts and binds endothelial progenitor
cells. Representative substances or agents that attract and bind
endothelial progenitor cells include antibodies such as CD-34,
CD-133 and vegf type 2 receptor. An agent that attracts and binds
endothelial progenitor cells can include a polymer having nitric
oxide donor groups.
[0191] The foregoing biologically active agents are listed by way
of example and are not meant to be limiting. Other biologically
active agents that are currently available or that may be developed
in the future are equally applicable. Moreover, useful bioactive
agents include prodrugs and co-drugs of the agents and drugs
described herein.
[0192] In a more specific embodiment, optionally in combination
with one or more other embodiments described herein, the
composition of the invention comprises at least one biologically
active agent selected from paclitaxel, docetaxel, estradiol, nitric
oxide donors, super oxide dismutases, super oxide dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, bioactive RGD, CD-34 antibody, abciximab (REOPRO),
progenitor cell-capturing antibodies, prohealing drugs, prodrugs
thereof, co-drugs thereof, and a combination thereof. In a
particular embodiment, the bioactive agent is everolimus. In
another specific embodiment, the bioactive agent is clobetasol.
[0193] In some embodiments, optionally in combination with one or
more other embodiments described herein, the at least one
biologically active agent specifically cannot be one or more of any
of the bioactive drugs or agents described herein.
[0194] The dosage or concentration of the at least one bioactive
agent required to produce a favorable therapeutic effect should be
less than the level at which the bioactive agent produces toxic
effects and greater than the level at which non-therapeutic results
are obtained. The dosage or concentration of the bioactive agent
required to, e.g., inhibit the target cellular activity of the
vascular region can depend upon various factors such as the
particular circumstances of the patient, the nature of the trauma,
the nature of the therapy desired, the time over which the
administered agent resides at the vascular site, and if other
active agents are employed, the nature and type of the substance or
combination of substances. Therapeutically effective concentrations
or dosages can be determined empirically, e.g., by infusing vessels
from suitable animal model systems and using immunohistochemical,
fluorescent or electron microscopy methods to detect the agent and
its effects, or by conducting suitable in vitro studies. Standard
pharmacological test procedures to determine concentrations or
dosages are understood by one of ordinary skill in the art.
[0195] Material and Coating
[0196] The inventive composition comprising the biodegradable
copolymer can be used to make a material of which an implantable
device is formed. Such a material can comprise any combination of
embodiments of the inventive composition described herein.
[0197] Accordingly, an embodiment of the invention, optionally in
combination with one or more other embodiments described herein, is
drawn to a material containing any combination of embodiments of
the composition comprising the biodegradable copolymer. For
example, the composition forming the material can optionally
contain a third segment A', at least one non-fouling moiety, at
least one additional biocompatible polymer, at least one
biobeneficial material, at least one bioactive agent, or a
combination thereof.
[0198] The material of the invention can be used to make a portion
of an implantable device or the whole device itself. For example,
the material can be used to make a coating that is disposed over at
least a portion of an implantable device.
[0199] Accordingly, an embodiment of the invention, optionally in
combination with one or more other embodiments described herein, is
directed to a coating containing any combination of embodiments of
the composition comprising the biodegradable copolymer. For
example, the composition forming the coating can optionally contain
a third segment A', at least one non-fouling moiety, at least one
additional biocompatible polymer, at least one biobeneficial
material, at least one bioactive agent, or a combination
thereof.
[0200] The coating can have a range of thickness and biodegradation
rates. In some embodiments, optionally in combination with one or
more other embodiments described herein, the coating has a
thickness of .ltoreq.about 30 micron, or .ltoreq.about 20 micron,
or .ltoreq.about 10 micron. In a particular embodiment, the coating
has a thickness of .ltoreq.about 10 micron. In further embodiments,
optionally in combination with one or more other embodiments
described herein, the coating completely or substantially
completely degrades within about 24 months, or within about 18
months, or within about 12 months, or within about 6 months, or
within about 3 months, or within about 2 months, or within about 1
month (i.e., 30 days). In a specific embodiment, the coating
completely or substantially completely degrades within about 12
months.
[0201] Implantable Device
[0202] The inventive material containing any combination of
embodiments of the composition comprising the biodegradable
copolymer can be used to form an implantable device. Accordingly,
one embodiment of the invention, optionally in combination with one
or more other embodiments described herein, is directed to an
implantable device formed of a material containing any combination
of embodiments of the composition comprising the biodegradable
copolymer. For example, the implantable device can be formed of a
material comprising a composition that optionally contains a third
segment A', at least one non-fouling moiety, at least one
additional biocompatible polymer, at least one biobeneficial
material, at least one bioactive agent, or a combination
thereof.
[0203] A portion of the implantable device or the whole device
itself can be formed of the material containing any combination of
embodiments of the composition comprising the biodegradable
copolymer. For example, at least a portion of the implantable
device can be coated by a coating containing any combination of
embodiments of the composition comprising the biodegradable
copolymer.
[0204] Accordingly, an embodiment of the invention, optionally in
combination with one or more other embodiments described herein, is
directed to an implantable device formed of a coating containing
any combination of embodiments of the composition comprising the
biodegradable copolymer. For example, the implantable device can be
formed of a coating comprising a composition that optionally
contains a third segment A', at least one non-fouling moiety, at
least one additional biocompatible polymer, at least one
biobeneficial material, at least one bioactive agent, or a
combination thereof.
[0205] The implantable device can be formed of a coating that can
have a range of thickness and biodegradation rates. In some
embodiments, optionally in combination with one or more other
embodiments described herein, the implantable device is formed of a
coating that has a thickness of .ltoreq.about 30 micron, or
.ltoreq.about 20 micron, or .ltoreq.about 10 micron. In a
particular embodiment, the device is formed of a coating that has a
thickness of .ltoreq.about 10 micron. In further embodiments,
optionally in combination with one or more other embodiments
described herein, the implantable device is formed of a coating
that completely or substantially completely degrades within about
24 months, or within about 18 months, or within about 12 months, or
within about 6 months, or within about 3 months, or within about 2
months, or within about 1 month (i.e., 30 days). In a specific
embodiment, the device is formed of a coating that completely or
substantially completely degrades within about 12 months.
[0206] The present invention also encompasses implantable devices
formed of bioabsorbable and/or biostable polymers. In some
embodiments, optionally in combination with one or more other
embodiments described herein, a portion of the device (e.g., a
coating disposed over the device) or the whole device itself can be
formed of such polymers and any other substances described
herein.
[0207] Any implantable device can be formed of the inventive
material containing any combination of embodiments of the
composition comprising the biodegradable copolymer. Examples of
implantable devices include, but are not limited to, stents (e.g.,
coronary stents and peripheral stents), grafts (e.g., aortic
grafts, arterio-venous grafts, vascular grafts and by-pass grafts),
stent-grafts, catheters, guidewires, leads and electrodes for
pacemakers and defibrillators, endocardial leads (e.g., FINELINE
and ENDOTAK, available from Abbott Vascular, Santa Clara, Calif.),
clips (e.g., anastomotic clips), shunts (e.g., cerebrospinal fluid
and axius coronary shunts), closure devices (e.g., arterial and
patent foramen ovale closure devices), valves (e.g., artificial
heart valves), ventricular assist devices, artificial heart, and
blood oxygenators. Furthermore, the inventive material containing
any combination of embodiments of the composition comprising the
biodegradable copolymer can be used to make other types of
substrates including, e.g., sustained-release small molecule or
protein formulations, microspheres and nanofibers.
[0208] In an embodiment, optionally in combination with one or more
other embodiments described herein, the implantable device is
selected from stents, grafts, stent-grafts, catheters, leads and
electrodes, clips, shunts, closure devices, and valves. In a more
specific embodiment, optionally in combination with one or more
other embodiments described herein, the implantable device is a
stent. The stent may be balloon-expandable or self-expandable.
Moreover, the stent can be intended for any vessel in the body,
e.g., neurological, carotid, vein graft, coronary, aortic renal,
iliac, femoral, popliteal vasculature and urethral passages.
[0209] The underlying structure of the implantable device can be of
virtually any design. A portion of the device, or the whole device
itself, can be made of a metallic material, an alloy, a polymeric
material, any other type of material, or a combination thereof, as
is known in the art. For example, a polymeric material comprising
any combination of embodiments of the inventive composition can be
used to make a portion of the implantable device or the whole
device itself.
[0210] Non-limiting examples of metallic materials and alloys
suitable for fabricating implantable devices include
cobalt-chromium alloys (e.g., ELGILOY), "L-605", stainless steel
(316L), "MP35N," "MP20N," ELASTINITE (Nitinol), tantalum,
tantalum-based alloys, nickel-titanium alloys, platinum,
platinum-based alloys (e.g., platinum-iridium alloy), iridium,
gold, magnesium, titanium, titanium-based alloys, zirconium-based
alloys, or combinations thereof. "L-605" is a trade name for an
alloy of cobalt, chromium, tungsten, nickel and iron available as
Haynes 25 from Haynes International (Kokomo, Ind.). "L-605"
consists of 51% cobalt, 20% chromium, 15% tungsten, 10% nickel and
3% iron. "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.
[0211] If a polymeric material is used to make a portion (e.g., a
coating) of the implantable device or the whole device itself, the
polymeric material can comprise any combination of embodiments of
the inventive composition, e.g., the biodegradable copolymer of the
invention, a blend of different types of polymers, a blend of
polymer(s) and additional substance(s), or a combination thereof.
Further, additional polymer(s) and/or additional substance(s) can
be attached to the underlying copolymer forming the device or a
portion thereof. The additional polymer(s) and/or additional
substance(s) that may be attached to, grafted to, blended with,
co-polymerized with, or incorporated with the underlying polymer
can include, but are not limited to, biocompatible polymers,
bioabsorbable polymers, biocompatible moieties, non-fouling
moieties, biobeneficial substances and materials, and bioactive
agents. To enhance the mechanical characteristics (e.g., strength
and rigidity) of an implantable device made substantially of a
polymeric material, the device can be supported by additional
structure(s) (e.g., struts in the case of stents made substantially
of a polymeric material).
[0212] Structure of Coating
[0213] According to some embodiments of the invention, optionally
in combination with one or more other embodiments described herein,
a coating disposed over an implantable device (e.g., a stent) can
be a multi-layer structure that can include any of the following
four layers or combination thereof: [0214] (1) a primer layer;
[0215] (2) a drug-polymer layer (also referred to as a "reservoir"
or "reservoir layer") or, alternatively, a polymer-free drug layer;
[0216] (3) a topcoat layer; and/or [0217] (4) a finishing coat
layer.
[0218] Each layer of a stent coating can be disposed over the stent
by dissolving the polymer or a blend of polymers in a solvent, or a
mixture of solvents, and disposing the resulting polymer solution
over the stent by spraying or immersing the stent in the solution.
After the solution has been disposed over the stent, the coating is
dried by allowing the solvent to evaporate. The process of drying
can be accelerated if the drying is conducted at an elevated
temperature. The complete stent coating can be optionally annealed
at a temperature between about 40.degree. C. and about 150.degree.
C. for a period of time between about 5 minutes and about 60
minutes, if desired, to improve the thermodynamic stability of the
coating.
[0219] To incorporate a bioactive agent (e.g., a drug) into the
reservoir layer, the drug can be combined with the polymer solution
that is disposed over the stent as described above. Alternatively,
if it is desirable to have the stent coating with a fast
drug-release rate, a polymer-free reservoir can be made. To
fabricate a polymer-free reservoir, the drug can be dissolved in a
suitable solvent or mixture of solvents, and the resulting drug
solution can be disposed over the stent by spraying or immersing
the stent in the drug-containing solution.
[0220] Instead of introducing a drug via a solution, the drug can
be introduced as a colloid system, such as a suspension in an
appropriate solvent phase. To make the suspension, the drug can be
dispersed in the solvent phase using conventional techniques used
in colloid chemistry. Depending on a variety of factors, e.g., the
nature of the drug, those having ordinary skill in the art can
select the solvent to form the solvent phase of the suspension, as
well as the quantity of the drug to be dispersed in the solvent
phase. Optionally, a surfactant can be added to stabilize the
suspension. The suspension can be mixed with a polymer solution and
the mixture can be disposed over the stent as described above.
Alternatively, the drug suspension can be disposed over the stent
without being mixed with the polymer solution.
[0221] The drug-polymer layer can be applied directly or indirectly
over at least a portion of the stent surface to serve as a
reservoir for at least one bioactive agent (e.g., drug) that is
incorporated into the reservoir layer. The optional primer layer
can be applied between the stent and the reservoir to improve the
adhesion of the drug-polymer layer to the stent. The optional
topcoat layer can be applied over at least a portion of the
reservoir layer and serves as a rate-limiting membrane that helps
to control the rate of release of the drug. In one embodiment, the
topcoat layer can be essentially free from any bioactive agents or
drugs. If the topcoat layer is used, the optional finishing coat
layer can be applied over at least a portion of the topcoat layer
for further control of the drug-release rate and for improving the
biocompatibility of the coating. Without the topcoat layer, the
finishing coat layer can be deposited directly on the reservoir
layer.
[0222] The process of the release of a drug from a coating having
both topcoat and finishing coat layers includes at least three
steps. First, the drug is absorbed by the polymer of the topcoat
layer at the drug-polymer layer/topcoat layer interface. Next, the
drug diffuses through the topcoat layer using the void volume
between the macromolecules of the topcoat layer polymer as pathways
for migration. Next, the drug arrives at the topcoat
layer/finishing layer interface. Finally, the drug diffuses through
the finishing coat layer in a similar fashion, arrives at the outer
surface of the finishing coat layer, and desorbs from the outer
surface. At this point, the drug is released into the blood vessel
or surrounding tissue. Consequently, a combination of the topcoat
and finishing coat layers, if used, can serve as a rate-limiting
barrier. The drug can be released by virtue of the degradation,
dissolution, and/or erosion of the layer(s) forming the coating, or
via migration of the drug through non-degradable polymeric layer(s)
into a blood vessel or tissue.
[0223] In one embodiment, any or all of the layers of the stent
coating can be made of biologically
degradable/erodable/absorbable/resorbable polymer(s),
non-degradable/biostable polymer(s), or a combination thereof. In
another embodiment, the outermost layer of the coating can be
limited to biodegradable polymer(s), biostable polymer(s), or a
combination thereof.
[0224] To illustrate in more detail, in a stent coating having all
four layers described above (i.e., the primer, the reservoir layer,
the topcoat layer and the finishing coat layer), the outermost
layer is the finishing coat layer, which can be made of
biodegradable polymer(s), biostable polymer(s), or a combination
thereof. The remaining layers (i.e., the primer, the reservoir
layer and the topcoat layer) optionally can also be fabricated of
biodegradable polymer(s), biostable polymer(s), or a combination
thereof. The polymer(s) in a particular layer may be the same as or
different than those in any of the other layers.
[0225] If a finishing coat layer is not used, the topcoat layer can
be the outermost layer and can be made of biodegradable polymer(s),
biostable polymer(s), or a combination thereof. In this case, the
remaining layers (i.e., the primer and the reservoir layer)
optionally can also be fabricated of biodegradable polymer(s),
biostable polymer(s), or a combination thereof. The polymer(s) in a
particular layer may be the same as or different than those in any
of the other layers.
[0226] If neither a finishing coat layer nor a topcoat layer is
used, the stent coating could have only two layers--the primer and
the reservoir. In such a case, the reservoir is the outermost layer
of the stent coating and can be made of biodegradable polymer(s),
biostable polymer(s), or a combination thereof. The primer
optionally can also be fabricated of biodegradable polymer(s),
biostable polymer(s), or a combination thereof. The two layers may
be made from the same or different polymers.
[0227] Increased rate of degradation, erosion, absorption and/or
resorption of biologically degradable, erodable, absorbable and/or
resorbable polymer(s) can lead to an increased rate of release of a
drug due to the gradual disappearance of the polymer(s) that form
the reservoir, the topcoat layer, and/or the finishing coat layer.
Through appropriate selection of biodegradable polymer(s),
biostable polymer(s) or a combination thereof, a stent coating can
be engineered to provide either fast or slow release of a drug, as
desired. Those having ordinary skill in the art can determine
whether a stent coating having slow or fast drug-release rate is
advisable for a particular drug. For example, fast release may be
recommended for stent coatings loaded with antimigratory drugs,
which often need to be released within 1 to 2 weeks. For
anti-proliferative and anti-inflammatory drugs, slower release may
be desired, e.g., up to 30-day and 60-day release times,
respectively.
[0228] Any layer of a stent coating can contain any amount of a
bioabsorbable polymer and/or a biocompatible polymer, or a blend of
more than one such polymer. Non-limiting examples of bioabsorbable
polymers and biocompatible polymers include polyacrylates, e.g.,
poly(butyl methacrylate), poly(ethyl methacrylate), poly(ethyl
methacrylate-co-butyl methacrylate), poly(acrylonitrile),
poly(ethylene-co-methyl methacrylate),
poly(acrylonitrile-co-styrene) and poly(cyanoacrylates);
fluorinated polymers and/or copolymers, e.g., poly(vinylidene
fluoride) and poly(vinylidene fluoride-co-hexafluoro propylene);
poly(N-vinyl pyrrolidone) (PVP); poly(N-vinyl pyrrolidone-co-vinyl
acetate) (Copovidone); polydioxanone; polyorthoesters;
polyanhydrides; poly(glycolic acid); poly(glycolic
acid-co-trimethylene carbonate); polyphosphoesters;
polyphosphoester urethanes; poly(amino acids); poly(trimethylene
carbonate); poly(iminocarbonates); co-poly(ether-esters);
polyalkylene oxalates; polyphosphazenes; biomolecules, e.g.,
fibrin, fibrinogen, cellulose, cellophane, starch, collagen,
hyaluronic acid, and derivatives thereof (e.g., cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellulose nitrate,
cellulose propionate, cellulose ethers, and carboxymethyl
cellulose); polyurethanes; silicones; polyesters; polyolefins;
polyisobutylene and ethylene-alphaolefin copolymers; vinyl halide
polymers and copolymers, e.g., polyvinyl chloride; polyvinyl
ethers, e.g., polyvinyl methyl ether; polyvinylidene chloride;
polyvinyl ketones; polyvinyl aromatics, e.g., polystyrene;
polyvinyl esters, e.g., polyvinyl acetate; copolymers of vinyl
monomers with each other and olefins, e.g., poly(ethylene-co-vinyl
alcohol) (EVAL); ABS resins; poly(ethylene-co-vinyl acetate);
polyamides, e.g., Nylon 66 and polycaprolactam; alkyd resins;
polycarbonates; polyoxymethylenes; polyimides; polyethers, epoxy
resins; polyurethanes; rayon; rayon-triacetate; and copolymers
thereof.
[0229] Any layer of a stent coating can also contain any amount of
a non-degradable polymer, or a blend of more than one such polymer.
Non-limiting examples of non-degradable polymers include
methylmethacrylate, ethylmethacrylate, butylmethacrylate,
2-ethylhexylmethacrylate, laurylmethacrylate, hydroxyl ethyl
methacrylate, polyethylene glycol (PEG) acrylate, PEG methacrylate,
2-methacryloyloxyethylphosphorylcholine (MPC) and N-vinyl
pyrrolidone, methacrylic acid, acrylic acid, hydroxypropyl
methacrylate, hydroxypropylmethacrylamide, 3-trimethylsilylpropyl
methacrylate, and copolymers thereof.
[0230] Method of Fabricating Implantable Device
[0231] Other embodiments of the invention, optionally in
combination with one or more other embodiments described herein,
are drawn to a method of fabricating an implantable device. In one
embodiment, the method comprises forming the implantable device of
a material containing any combination of embodiments of the
composition comprising the biodegradable copolymer. For example,
the method comprises forming the implantable device of a material
comprising a composition that optionally contains a third segment
A', at least one non-fouling moiety, at least one additional
biocompatible polymer, at least one biobeneficial material, at
least one bioactive agent, or a combination thereof.
[0232] Under the method, a portion of the implantable device or the
whole device itself can be formed of the material containing any
combination of embodiments of the composition comprising the
biodegradable copolymer. Moreover, the method can comprise
depositing, or disposing, over at least a portion of the
implantable device a coating containing any combination of
embodiments of the composition comprising the biodegradable
copolymer.
[0233] Accordingly, in an embodiment, the method comprises
disposing over at least a portion of an implantable device a
coating containing any combination of embodiments of the
composition comprising the biodegradable copolymer. For example,
the method comprises disposing over at least a portion of an
implantable device a coating comprising a composition that
optionally contains a third segment A', at least one non-fouling
moiety, at least one additional biocompatible polymer, at least one
biobeneficial material, at least one bioactive agent, or a
combination thereof. The coating can be disposed over the
implantable device by any of various methods known in the art, such
as dip coat, syringe drip coat, spray coat, etc.
[0234] The method of the invention can deposit a coating having a
range of thickness over an implantable device. In certain
embodiments, the method deposits over at least a portion of the
implantable device a coating that has a thickness of .ltoreq.about
30 micron, or .ltoreq.about 20 micron, or .ltoreq.about 10 micron.
In a particular embodiment, the method deposits a coating that has
a thickness of .ltoreq.about 10 micron.
[0235] According to an embodiment, the method is used to fabricate
an implantable device selected from stents, grafts, stent-grafts,
catheters, leads and electrodes, clips, shunts, closure devices,
and valves. In a specific embodiment, the method is used to
fabricate a stent.
[0236] In general, representative examples of polymers that can be
used to fabricate an implantable device include, but are not
limited to, poly(N-acetylglucosamine) (Chitin), Chitosan,
poly(hydroxyvalerate), poly(lactide-co-glycolide),
poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),
polyorthoester, polyanhydride, poly(glycolic acid),
poly(glycolide), poly(L-lactic acid), poly(L-lactide),
poly(D,L-lactic acid), poly(L-lactide-co-glycolide),
poly(D,L-lactide), poly(caprolactone), poly(trimethylene
carbonate), polyethylene amide, polyethylene acrylate,
poly(glycolic acid-co-trimethylene carbonate),
co-poly(ether-esters) (e.g., PEO/PLA), polyphosphazenes,
biomolecules (e.g., fibrin, fibrinogen, cellulose, starch, collagen
and hyaluronic acid), polyurethanes, silicones, polyesters,
polyolefins, polyisobutylene and ethylene-alphaolefin copolymers,
acrylic polymers and copolymers other than polyacrylates, vinyl
halide polymers and copolymers (e.g., polyvinyl chloride),
polyvinyl ethers (e.g., polyvinyl methyl ether), polyvinylidene
halides (e.g., polyvinylidene chloride), polyacrylonitrile,
polyvinyl ketones, polyvinyl aromatics (e.g., polystyrene),
polyvinyl esters (e.g., polyvinyl acetate), acrylonitrile-styrene
copolymers, ABS resins, polyamides (e.g., Nylon 66 and
polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,
polyethers, polyurethanes, rayon, rayon-triacetate, cellulose and
derivates thereof (e.g., cellulose acetate, cellulose butyrate,
cellulose acetate butyrate, cellophane, cellulose nitrate,
cellulose propionate, cellulose ethers, and carboxymethyl
cellulose), and copolymers thereof.
[0237] Additional representative examples of polymers that may be
well suited for fabricating an implantable device include ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(butyl methacrylate), poly(vinylidene
fluoride-co-hexafluoropropylene) (e.g., SOLEF 21508, available from
Solvay Solexis PVDF of Thorofare, N.J.), polyvinylidene fluoride
(otherwise known as KYNAR, available from ATOFINA Chemicals of
Philadelphia, Pa.),
poly(tetrafluoroethylene-co-hexafluoropropylene-co-vinylidene
fluoride), ethylene-vinyl acetate copolymers, and polyethylene
glycol.
[0238] The copolymer of the invention, and any other desired
substances and materials, can be formed into a polymer construct,
such as a tube or sheet that can be rolled or bonded to form a
construct such as a tube. A tube can be formed from melt extrusion
of the copolymer or from wet extrusion of the copolymer in a
solvent conventionally, by electrospinning, or by other methods
such as thermally induced phase separation.
[0239] An implantable device can then be fabricated from the
polymer construct. For example, a stent can be fabricated from a
tube by laser machining a pattern into the tube. In another
embodiment, the polymer construct can be formed from the polymeric
material of the invention using an injection-molding apparatus.
[0240] In an exemplary method of fabricating an implantable device
possessing shape-memory properties, polymeric tubes of the
inventive copolymer are extruded or processed from the melt and
elongated to the desired final dimensions (e.g., diameter) of the
device at a temperature at or above the T.sub.g or T.sub.m of the
harder A segment. The tubes are then cooled to a temperature below
the T.sub.g or T.sub.m of the A segment while being held at the
final implant dimensions, and laser cut to create the design of the
implant (e.g., a stent). Next, the stent is heated to a temperature
at or above the T.sub.g or T.sub.m of the softer B segment, crimped
to the delivery size (the temporary shape), and then cooled to a
temperature below the T.sub.g or T.sub.m of the B segment while
being held at the delivery size. The stent can also be inserted in
a sheath or a sock and then sterilized at elevated temperature
(e.g., 40-45.degree. C.), which avoids recovering the permanent
shape of the stent even if the transition temperature is around
body temperature.
[0241] Method of Treating or Preventing Disorders
[0242] An implantable device formed of a material containing any
combination of embodiments of the composition comprising the
biodegradable copolymer can be used to treat, prevent or diagnose a
variety of conditions or disorders. The material can form a portion
of the device (e.g., a coating disposed over the device) or the
whole device. Examples of such conditions or disorders include, but
are not limited to, atherosclerosis, thrombosis, restenosis,
hemorrhage, vascular dissection, vascular perforation, vascular
aneurysm, vulnerable plaque, chronic total occlusion, patent
foramen ovale, claudication, anastomotic proliferation of vein and
artificial grafts, arteriovenous anastamoses, bile duct
obstruction, ureter obstruction and tumor obstruction.
[0243] An implantable device formed of a material comprising the
inventive copolymer is particularly suitable for the treatment or
prevention of conditions or disorders that are sensitive to high
pressure. For example, use of the inventive device displaying
shape-memory effects avoids the high pressure associated with the
inflation of a balloon during the deployment of a
balloon-expandable stent. The high pressure associated with
balloon-expansion of a stent could potentially rupture a vulnerable
plaque, causing formation of a blood clot that could completely
block an artery and result in adverse coronary events such as a
heart attack.
[0244] Accordingly, an embodiment of the invention, optionally in
combination with one or more other embodiments described herein, is
drawn to a method of treating, preventing or diagnosing a condition
or disorder in a patient, comprising implanting in the patient an
implantable device formed of a material containing any combination
of embodiments of the composition comprising the biodegradable
copolymer. For example, the implantable device can be formed of a
material comprising a composition that optionally contains a third
segment A', at least one non-fouling moiety, at least one
additional biocompatible polymer, at least one biobeneficial
material, at least one bioactive agent, or a combination thereof. A
portion of the device, or the whole device itself, can be formed of
the inventive material. Moreover, the material can be a coating
disposed over the device.
[0245] In an embodiment, the condition or disorder treated,
prevented or diagnosed by the implantable device is selected from
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection, vascular perforation, vascular aneurysm, vulnerable
plaque, chronic total occlusion, patent foramen ovale,
claudication, anastomotic proliferation of vein and artificial
grafts, arteriovenous anastamoses, bile duct obstruction, ureter
obstruction and tumor obstruction. In a more specific embodiment,
the condition or disorder is selected from atherosclerosis,
thrombosis, restenosis and vulnerable plaque.
[0246] In one embodiment, the implantable device employed in the
method is formed of a material containing at least one biologically
active agent selected from antiproliferative, antineoplastic,
anti-inflammatory, antiplatelet, anticoagulant, antifibrin,
antithrombin, antimitotic, antibiotic, antiallergic and antioxidant
substances. In a more specific embodiment, the at least one
bioactive agent is selected from paclitaxel, docetaxel, estradiol,
nitric oxide donors, super oxide dismutases, super oxide dismutase
mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, bioactive RGD, CD-34 antibody, abciximab (REOPRO),
progenitor cell-capturing antibodies, prohealing drugs, prodrugs
thereof, co-drugs thereof, and a combination thereof.
[0247] In some embodiments, the at least one biologically active
agent delivered by the implantable device specifically cannot be
one or more of any of the bioactive drugs or agents described
herein.
[0248] In an embodiment, the implantable device used in the method
is selected from stents, grafts, stent-grafts, catheters, leads and
electrodes, clips, shunts, closure devices, and valves. In a
specific embodiment, the implantable device is a stent.
[0249] After delivery of the device (e.g., a stent) to the
treatment site in the body, deployment of the device under
physiological conditions, including provision of a thermal stimulus
to the device if the transition temperature of the polymeric
composition is above body temperature, leads to recovery of the
permanent shape of the device (its initial extruded size). As an
example, exposure of a stent to a temperature at or above the
transition temperature triggers the self-expansion of the stent to
a diameter appropriate for the target vessel.
[0250] If the B segment is the switching segment and has a T.sub.g
or T.sub.m greater than body temperature, then a thermal stimulus
would be needed to trigger the recovery of the permanent shape of
the implantable device formed of the inventive polymeric
composition. In such cases, the method of treatment or prevention
further comprises providing a thermal stimulus to the implantable
device such that the temperature of the composition is at or above
the T.sub.g or T.sub.m of the B segment but below the T.sub.g or
T.sub.m of the A segment.
[0251] The thermal stimulus can be provided by any of various
sources and means known in the art, e.g., by laser, ultrasonic
wave, high frequency wave, infrared radiation, hot air stream or
hot water. In a particular embodiment, the thermal stimulus is
provided by a catheter. For example, a catheter attached to a stent
and containing a suitable thermal stimulus within its lumen or
other internal compartment can provide the thermal stimulus to the
stent after the stent is delivered to the treatment site. When
deployed or unsheathed upon removal of the stress maintaining the
stent's compact, temporary shape, the stent can recover immediately
to the desired permanent shape.
[0252] As explained earlier, a thermal stimulus can be provided
safely within a short period of time (e.g., within several seconds)
or by appropriate thermal shielding of the implantable device or
another article that delivers the device and provides the thermal
stimulus. For example, a stent can be delivered through a catheter
that contains an outer insulating or cooling component to shield
the blood and tissues from the catheter compartment providing the
thermal stimulus.
Synthesis of Copolymers of Invention
[0253] The biodegradable copolymers of the invention can be
prepared by any method of polymerization known in the art. Methods
of polymerization include, but are not limited to, solution-based
polymerization and melt-phase polymerization. In solution-based
polymerization, all the reactive components involved in the
polymerization reaction are dissolved in a solvent.
[0254] The copolymers of the invention can be synthesized in bulk
or in solution through polycondensation of a hydroxyl-, amino- or
thiol-containing polymer (the B segment) with one or more
diisocyanates and one or more diol, diamine and/or dithiol chain
extenders to form the A segment (and the A' segment, if desired).
The reaction may be one-step, with all components added, or
multi-step. A traditional approach is two-step, wherein the
hydroxyl-, amino- or thiol-containing B segment polymer first
reacts with a diisocyanate, followed by chain extension upon
addition of a diol, diamine or dithiol chain extender.
[0255] The polycondensation reaction can be catalyzed by an organic
or inorganic acid (e.g., a Lewis acid), an organic (e.g., a
tertiary amine base) or inorganic base (e.g., a Lewis base), an
organometallic reagent, and/or heat, if necessary and if compatible
with the reactants and product(s) of the reaction. Typical
catalysts are Lewis acid salts and tertiary amines. Tin catalysts
(e.g., stannous octoate and tin triflates) are particularly
suitable for use with aliphatic diisocyanates.
[0256] The inventive copolymers can be synthesized various ways, as
is known in the art. For example, the A segment can be generated as
a block by repeating a polycondensation reaction of a particular
diisocyanate and a particular diol, diamine or dithiol chain
extender a desired number of times, optionally performing another
polycondensation reaction of another diisocyanate and another diol,
diamine or dithiol chain extender a desired number of times, and so
on. The A segment can also be synthesized as an alternating
copolymer by alternating the various polycondensation reactions as
desired. Moreover, the A segment can be synthesized in a random
fashion by conducting a polycondensation reaction involving at
least two different diisocyanates and a particular chain extender,
or a particular diisocyanate and at least two different chain
extenders, or at least two different diisocyanates and at least two
different chain extenders in the same pot, and optionally
performing other polycondensation reaction(s) involving different
diisocyanate(s) and/or different chain extender(s) in the same pot.
The mechanical properties (e.g., strength, rigidity, toughness,
flexibility, deformation and recovery) and physical properties
(e.g., T.sub.g or T.sub.m, the temperature range of the thermal
transitions, degradation rate and drug-release rate) of the
copolymer can all vary based on the amount of randomness.
[0257] One method of preparing an AB disegment copolymer is to
conduct polycondensation of a diisocyanate and a diol, diamine or
dithiol chain extender with a B segment polymer containing at least
one hydroxyl, amino or thiol end group, and optionally performing
additional polycondensation reaction(s) with additional
diisocyanate(s) and additional diol, diamine or dithiol chain
extender(s), wherein the same or different diisocyanates and chain
extenders may be employed in the various polycondensation
reactions. The same procedure can be used to synthesize an ABA'
trisegment copolymer in which the same A and A' segments are
copolymerized with a B segment polymer containing two hydroxyl,
amino or thiol end groups.
[0258] Likewise, an A-B-A' trisegment copolymer, in which the A and
A' segments are different, can be synthesized by: [0259] performing
polycondensation of a diisocyanate and a diol, diamine or dithiol
chain extender with a B segment polymer containing a free hydroxyl,
amino or thiol end group and a protected hydroxyl, amino or thiol
end group; [0260] optionally performing additional polycondensation
reaction(s) with additional diisocyanate(s) and additional diol,
diamine or dithiol chain extender(s); [0261] protecting the
functional group formed at the polymer end of the A segment; [0262]
deprotecting the protected hydroxyl, amino or thiol end group of
the B segment; [0263] performing polycondensation of a diisocyanate
and a diol, diamine or dithiol chain extender with the deprotected
hydroxyl, amino or thiol end group of the B segment; [0264]
optionally performing additional polycondensation reaction(s) with
additional diisocyanate(s) and additional diol, diamine or dithiol
chain extender(s); and [0265] optionally deprotecting the protected
functional group at the polymer end of the A segment. The same or
different diisocyanates and chain extenders may be employed in the
various polycondensation reactions to make the A and/or A'
segments. A similar procedure can be used to synthesize an A'-A-B
trisegment copolymer, except that the polycondensation reaction(s)
to make the A' segment are initiated with the functional group
formed at the polymer end of the A segment and the protected end
group of the B segment remains protected during the formation of
the A' segment.
[0266] Various embodiments of the inventive composition comprising
a biodegradable copolymer can be prepared by optionally: [0267]
conjugating at least one dihydroxyaryl group to the polymer ends of
the copolymer; [0268] blending or attaching at least one
non-fouling moiety with or to the copolymer; [0269] blending or
attaching at least one additional biocompatible polymer with or to
the copolymer; [0270] blending or attaching at least one
biobeneficial material with or to the copolymer; and/or [0271]
incorporating at least one biologically active agent.
[0272] The at least one dihydroxyaryl group conjugated to the
polymer ends can contain, e.g., an ortho-dihydroxyphenyl moiety
such as 1,2-dihydroxyphenyl and 3,4-dihydroxyphenyl.
3,4-Dihydroxyphenyl-containing compounds include, e.g., dopamine
and 3,4-dihydroxyhydrocinnamic acid. Dopamine could be conjugated
to, e.g., hydroxyl end groups of a copolymer via coupling with
1,1'-carbonyldiimidazole. 3,4-Dihydroxy-hydrocinnamic acid could be
conjugated to hydroxyl end groups by conversion of the cinnamic
acid to the N-succidimyl ester or by use of
dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridinium
(DPTS). Alternatively, conjugation of the cinnamic acid could be
effected via a Mitsunobu reaction using triphenylphosphine and
diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate
(DIAD). Conjugation of a dihydroxyaryl group to an active end group
(e.g., a hydroxyl, amino or thiol group) could also be effected
using other reagents and methods, as is known in the art.
Manufacture of Implantable Device Displaying Shape-Memory
Effects
[0273] If an article (e.g., an implantable device) is formed of a
two-segment copolymer possessing shape-memory properties, the
permanent shape of the article can be created by: [0274] (1)
heating the article to a temperature at or above the T.sub.g or
T.sub.m of the "harder" segment into a melt; [0275] (2)
mechanically stressing and melt-molding the article into the
desired permanent shape at the elevated temperature; and then
[0276] (3) cooling the article below the T.sub.g or T.sub.m of the
harder segment while the article remains under stress and held in
the permanent shape.
[0277] Similarly, the temporary shape of the article can be formed
by: [0278] (1) heating the article to a temperature at or above the
T.sub.g or T.sub.m of the "softer" segment, but below the T.sub.g
or T.sub.m of the harder segment, to fluidize the softer segment;
[0279] (2) mechanically stressing and molding the article into the
desired temporary shape at the elevated temperature; and then
[0280] (3) cooling the article below the T.sub.g or T.sub.m of the
softer segment while the article remains under stress and held in
the temporary shape.
[0281] If the article is formed of a shape-memory copolymer
containing three segments, the article can have one permanent shape
and two temporary shapes. The third, "softest" segment would be
responsible for a second temporary shape. Likewise, the second
temporary shape of the article can be formed by: [0282] (1) heating
the article to a temperature at or above the T.sub.g or T.sub.m of
the softest segment, but below the T.sub.g or T.sub.m of the softer
segment, to fluidize the softest segment; [0283] (2) mechanically
stressing and molding the article into the desired second temporary
shape at the elevated temperature; and then [0284] (3) cooling the
article below the T.sub.g or T.sub.m of the softest segment while
the article remains under stress and held in the second temporary
shape.
[0285] Other methods can be used to form the permanent shape or the
temporary shape(s) of the article. For example, the permanent shape
of the article can also be created by heating or forming a
pre-polymer solution to the desired permanent shape and then
covalently crosslinking while the article remains under stress to
hold the permanent shape.
[0286] As another example, the permanent shape or the temporary
shape(s) of the article can be created via a solvent extrusion
method by: [0287] (1) dissolving the article in a solvent or a
mixture of solvents, evaporating off the solvent(s), and heating
the article to a temperature at or above the T.sub.g or T.sub.m of
the harder segment (to create the permanent shape) or the softer
segment (to create the temporary shape); [0288] (2) mechanically
stressing and molding the article into the desired permanent shape
or temporary shape at the elevated temperature; and then [0289] (3)
cooling the article below the T.sub.g or T.sub.m of the harder
segment or the softer segment while the article remains under
stress and held in the permanent shape or the temporary shape.
[0290] 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 thereto without
departing from the invention in its broader aspects. 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 present invention.
Sequence CWU 1
1
4116PRTArtificial SequenceSynthetic peptide 1Arg Ala Arg Ala Asp
Ala Asp Ala Arg Ala Arg Ala Asp Ala Asp Ala1 5 10
15220PRTArtificial SequenceSynthetic peptide 2Val Lys Val Lys Val
Lys Val Lys Val Pro Pro Thr Lys Val Lys Val1 5 10 15Lys Val Lys
Val20316PRTArtificial SequenceSynthetic peptide 3Ala Glu Ala Glu
Ala Lys Ala Lys Ala Glu Ala Glu Ala Lys Ala Lys1 5 10
15413PRTArtificial SequenceSynthetic peptide 4Asp Val Asp Val Pro
Asp Gly Asp Ser Leu Ala Tyr Gly1 5 10
* * * * *