U.S. patent application number 14/602617 was filed with the patent office on 2015-05-14 for dioxanone-based copolymers for implantable devices.
The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Ni Ding.
Application Number | 20150134048 14/602617 |
Document ID | / |
Family ID | 52443589 |
Filed Date | 2015-05-14 |
United States Patent
Application |
20150134048 |
Kind Code |
A1 |
Ding; Ni |
May 14, 2015 |
DIOXANONE-BASED COPOLYMERS FOR IMPLANTABLE DEVICES
Abstract
The present invention is directed to polymeric materials
comprising biodegradable, dioxanone-based copolymers and
implantable devices (e.g., drug-delivery stents) formed of such
materials. The polymeric materials can also contain at least one
additional biocompatible moiety, at least one non-fouling moiety,
at least one biobeneficial material, at least one bioactive agent,
or a combination thereof. The polymeric materials are designed to
improve the mechanical, physical and biological properties of
implantable devices formed thereof.
Inventors: |
Ding; Ni; (San Jose,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
52443589 |
Appl. No.: |
14/602617 |
Filed: |
January 22, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11888808 |
Aug 1, 2007 |
8952123 |
|
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14602617 |
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60835287 |
Aug 2, 2006 |
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Current U.S.
Class: |
623/1.46 ;
514/291; 524/108; 524/110; 524/111; 524/21; 524/22; 524/27; 524/29;
524/377; 524/47; 524/54; 524/58; 524/599; 524/86; 525/190;
525/326.7; 525/328.5; 525/328.8; 525/329.4; 525/410; 525/413;
525/54.2; 525/54.21; 525/54.24; 525/56; 525/61; 528/354 |
Current CPC
Class: |
C08G 63/78 20130101;
C08G 63/64 20130101; A61F 2250/0067 20130101; C08G 63/664 20130101;
A61F 2/82 20130101; C08G 63/66 20130101; A61K 31/436 20130101; A61L
31/06 20130101 |
Class at
Publication: |
623/1.46 ;
528/354; 524/377; 524/86; 524/111; 524/110; 524/108; 525/190;
524/54; 525/410; 525/413; 524/58; 524/27; 525/54.2; 524/29;
525/326.7; 525/328.5; 525/328.8; 525/56; 525/61; 525/329.4; 524/22;
524/21; 524/47; 525/54.24; 525/54.21; 524/599; 514/291 |
International
Class: |
A61L 31/06 20060101
A61L031/06; A61K 31/436 20060101 A61K031/436; A61F 2/82 20060101
A61F002/82; C08G 63/66 20060101 C08G063/66 |
Claims
1. A composition comprising a biodegradable copolymer, wherein the
copolymer: is derived from dioxanone and at least one additional
ester-, carbonate- or ether-based monomer; has a crystallinity of
about 80% or less; has a T.sub.g from about -100.degree. C. to
about 100.degree. C.; has a polymer number-average molecular weight
(M.sub.n) from about 10 kDa to about 1,500 kDa; and completely or
substantially completely degrades within about 24 months.
2. The composition of claim 1, wherein the copolymer: has a
crystallinity from about 5% to about 70%; has a T.sub.g from about
-60.degree. C. to about 60.degree. C.; has an M.sub.n from about 20
kDa to about 1,000 kDa; and completely or substantially completely
degrades within about 12 months.
3. The composition of claim 2, wherein the copolymer: has a
crystallinity from about 10% to about 60%; has a T.sub.g from about
-30.degree. C. to about 30.degree. C.; has an M.sub.n from about 30
kDa to about 700 kDa; and completely or substantially completely
degrades within about 6 months.
4. The composition of claim 1, wherein the copolymer is derived
from dioxanone and one to five additional ester-based monomers,
carbonate-based monomers, ether-based monomers, or a combination
thereof.
5. The composition of claim 1, wherein dioxanone and the at least
one additional ester-, carbonate- or ether-based monomer each
independently have from about 5 to about 5,000 monomer units.
6. The composition of claim 1, wherein the at least one additional
ester-, carbonate- or ether-based monomer is selected from
glycolide (GA), D-lactide (DLA), L-lactide (LLA), D,L-lactide
(DLLA), C.sub.3-C.sub.12 .beta.-lactone, C.sub.4-C.sub.12
.gamma.-lactone, .alpha.-bromo-.gamma.-butyrolactone,
.alpha.-bromo-.gamma.-valerolactone, homoserine lactone
C.sub.2-C.sub.14 amide, C.sub.5-C.sub.14 .delta.-lactone,
mevalonolactone, C.sub.6-C.sub.16 .epsilon.-lactone,
1,3-dioxolan-2-one, 4-methyl-1,3-dioxolan-2-one,
4-methoxymethyl-1,3-dioxolan-2-one, 4-chloro-1,3-dioxolan-2-one,
4-phenyl-1,3-dioxolan-2-one, 4-vinyl-1,3-dioxolan-2-one,
trimethylene carbonate (TMC), ethylene oxide (EO), and propylene
oxide (PPO).
7. The composition of claim 6, wherein the at least one additional
ester-, carbonate- or ether-based monomer is selected from GA, DLA,
LLA, DLLA, .beta.-propiolactone (PL), .beta.-butyrolactone (BL),
.delta.-valerolactone (VL), .epsilon.-caprolactone (CL), TMC, EO,
and PPO.
8. The composition of claim 7, wherein the copolymer is derived
from dioxanone (DS) and one to three additional ester-based
monomers, carbonate-based monomers, ether-based monomers or a
combination thereof, and wherein the individual units of each
different type of monomer can be arranged in any manner.
9. The composition of claim 8, wherein the copolymer is selected
from P(DS-GA), P(DS-DLA), P(DS-LLA), P(DS-DLLA), P(DS-PL),
P(DS-BL), P(DS-VL), P(DS-CL), P(DS-TMC), P(DS-EO), P(DS-PPO),
P(DS-GA-DLA), P(DS-GA-LLA), P(DS-GA-DLLA), P(DS-GA-VL),
P(DS-GA-CL), P(DS-GA-TMC), P(DS-GA-EO), P(DS-GA-PPO),
P(DS-DLA-LLA), P(DS-DLA-DLLA), P(DS-DLA-VL), P(DS-DLA-CL),
P(DS-DLA-TMC), P(DS-DLA-EO), P(DS-DLA-PPO), P(DS-LLA-DLLA),
P(DS-LLA-VL), P(DS-LLA-CL), P(DS-LLA-TMC), P(DS-LLA-EO),
P(DS-LLA-PPO), P(DS-DLLA-VL), P(DS-DLLA-CL), P(DS-DLLA-TMC),
P(DS-DLLA-EO), P(DS-DLLA-PPO), P(DS-VL-CL), P(DS-VL-TMC),
P(DS-VL-EO), P(DS-VL-PPO), P(DS-CL-TMC), P(DS-CL-EO), P(DS-CL-PPO),
P(DS-GA-DLLA-CL), P(DS-GA-DLLA-TMC), P(DS-GA-DLLA-EO),
P(DS-GA-CL-TMC), P(DS-GA-CL-EO), P(DS-GA-TMC-EO),
P(DS-DLLA-CL-TMC), P(DS-DLLA-CL-EO), P(DS-DLLA-TMC-EO), and
P(DS-CL-TMC-EO).
10. The composition of claim 1, further comprising at least one
additional biocompatible moiety.
11. The composition of claim 10, wherein the at least one
additional biocompatible moiety is selected from poly(ethylene
oxide), polypropylene glycol), poly(tetramethylene glycol),
poly(ethylene oxide-co-propylene oxide), .epsilon.-caprolactone,
.beta.-butyrolactone, .delta.-valerolactone, glycolide,
poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic
acid) and salts thereof, poly(styrene sulfonate), sulfonated
dextran, polyphosphazenes, poly(orthoesters), poly(tyrosine
carbonate), sialic acid, hyaluronic acid and derivatives thereof,
copolymers of poly(ethylene glycol) (PEG) with hyaluronic acid or
derivatives thereof, heparin, copolymers of PEG with heparin, graft
copolymers of poly(L-lysine) and PEG, and copolymers thereof.
12. The composition of claim 1, further comprising at least one
non-fouling moiety.
13. The composition of claim 12, wherein the at least one
non-fouling moiety is selected from polyethylene glycol,
polypropylene glycol, Pluronic.TM. surfactants, poly(2-hydroxyethyl
methacrylate), poly(vinyl alcohol), polyalkene oxides,
poly(n-propylmethacrylamide), poly(N-vinyl-2-pyrrolidone),
sulfonated polystyrene, dextran, sulfonated dextran, dextrin,
hyaluronic acid, sodium hyaluronate, and derivatives thereof.
14. The composition of claim 1, further comprising at least one
biobeneficial material.
15. The composition of claim 14, wherein the at least one
biobeneficial material is selected from fibrin, fibrinogen,
cellulose and derivatives thereof, 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.
16. The composition of claim 1, further comprising at least one
biologically active agent selected from antiproliferative,
antineoplastic, antimitotic, anti-inflammatory, antiplatelet,
anticoagulant, antifibrin, antithrombin, antibiotic, antiallergic
and antioxidant substances.
17. The composition of claim 16, wherein 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-hydroxyl)ethyl-rapamycin (everolimus),
40-O-(2-ethoxyl)ethyl-rapamycin (biolimus),
40-O-(3-hydroxyl)propyl-rapamycin,
40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, progenitor cell-capturing antibodies, prohealing drugs,
prodrugs thereof, co-drugs thereof, and a combination thereof.
18. A coating comprising the composition of claim 1.
19. The coating of claim 18, which has a thickness of .ltoreq.about
10 micron and completely or substantially completely degrades
within about 12 months.
20. (canceled)
21. (canceled)
22. (canceled)
23. (canceled)
24. An implantable device formed of a material comprising the
composition of claim 1.
25. The device of claim 24, wherein the material is a coating
disposed over at least a portion of the device.
26. The device of claim 25, wherein the coating has a thickness of
.ltoreq.about 10 micron and completely or substantially completely
degrades within about 12 months.
27. The device of claim 24, which is selected from stents, grafts,
stent-grafts, catheters, leads and electrodes, clips, shunts,
closure devices, valves, and particles.
28. The device of claim 27, which is a stent.
29. (canceled)
30. (canceled)
31. (canceled)
32. (canceled)
33. (canceled)
34. A method of preparing the composition of claim 1, comprising
performing ring-opening polymerization (ROP) reactions with an
initiator, dioxanone and at least one additional ester-, carbonate-
or ether-based monomer, wherein: the initiator has one or two
active hydroxyl, amino or thiol end groups.
35. A method of fabricating an implantable device, comprising
forming the device of a material comprising the composition of
claim 1.
36. The method of claim 35, comprising depositing the material as a
coating over at least a portion of the implantable device.
37. 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 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.
38. The method of claim 37, wherein the composition further
comprises at least one additional biocompatible moiety.
39. The method of claim 37, wherein the composition further
comprises at least one non-fouling moiety.
40. The method of claim 37, wherein the composition further
comprises at least one biobeneficial material.
41. The method of claim 37, wherein the composition further
comprises at least one biologically active agent selected from
antiproliferative, antineoplastic, antimitotic, anti-inflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic,
antiallergic and antioxidant substances.
42. The method of claim 41, wherein 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-hydroxyl)ethyl-rapamycin (everolimus),
40-O-(2-ethoxyl)ethyl-rapamycin (biolimus),
40-O-(3-hydroxyl)propyl-rapamycin,
40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, progenitor cell-capturing antibodies, prohealing drugs,
prodrugs thereof, co-drugs thereof, and a combination thereof.
43. The method of claim 37, wherein the material is a coating
disposed over at least a portion of the implantable device.
44. The method of claim 37, wherein the implantable device is
selected from stents, grafts, stent-grafts, catheters, leads and
electrodes, clips, shunts, closure devices, valves, and
particles.
45. The method of claim 44, wherein the implantable device is a
stent.
Description
CLAIM OF PRIORITY UNDER 35 U.S.C. .sctn.119
[0001] The present Application for Patent claims priority to
Provisional Application Ser. No. 60/835,287, entitled
"Polydioxanone-Based Copolymer Stent Coating" and filed on Aug. 2,
2006, which is assigned to the assignee hereof and expressly
incorporated by reference in its entirety herein.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The present invention is directed to polymeric materials
comprising biodegradable copolymers, implantable devices (e.g.,
drug-delivery stents) formed of such materials, and therapeutic
methods using such devices.
[0004] 2. Description of the State of the Art
[0005] Angioplasty is a well-known procedure for treating heart
disease. A problem associated with angioplasty includes formation
of intimal flaps or torn arterial linings which can collapse and
occlude the conduit after the balloon is deflated. Moreover,
thrombosis and restenosis of the artery may develop over several
months after angioplasty, which may require another angioplasty
procedure or a surgical by-pass operation. "Stenosis" refers to a
narrowing or constriction of the diameter of a bodily passage or
orifice, and "restenosis" refers to the reoccurrence of stenosis in
a blood vessel or heart valve after it has been treated (as by
balloon angioplasty, stenting, or valvuloplasty) with apparent
success.
[0006] Stents are often used in the treatment of atherosclerotic
stenoses in blood vessels. To reduce the partial or total 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
body vessels and maintain the vascular patency. A "lumen" refers to
a cavity of a tubular organ such as a blood vessel. As a mechanical
intervention, stents act as scaffoldings, functioning to physically
hold open and, if desired, to expand the wall of a passageway,
e.g., a blood vessel, urinary tract or bile duct.
[0007] 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 medication. One method of medicating stents involves the use
of a polymeric carrier coated over the surface of a stent, wherein
a therapeutic substance is impregnated in the polymeric
carrier.
[0008] 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.
[0009] The present invention addresses late stent thrombosis and
offers other advantageous features.
SUMMARY OF THE INVENTION
[0010] The present invention is directed to biodegradable polymeric
materials used for implantable devices (e.g., stents) that enable
the devices to perform their functions more effectively and avoid
adverse effects. The polymeric materials are configured to
completely or substantially completely erode after the devices
accomplish their intended functions (e.g., maintaining vascular
patency and locally delivering drugs), thereby avoiding adverse
effects such as late stent thrombosis. Other advantages of the
biodegradable polymeric materials include, among others, good
mechanical properties (e.g., toughness and flexibility), control of
drug-release rates, and enhanced adhesion to metal surfaces.
[0011] Some embodiments of the invention are directed to a
composition comprising a biodegradable copolymer, wherein the
copolymer: [0012] is derived from dioxanone and at least one
additional ester-, carbonate- or ether-based monomer; [0013] has a
crystallinity of about 80% or less; [0014] has a T.sub.g from about
-100.degree. C. to about 100.degree. C.; [0015] has a polymer
number-average molecular weight (M.sub.n) from about 10 kDa to
about 1,500 kDa; and [0016] completely or substantially completely
degrades within about 24 months.
[0017] In one embodiment, the at least one additional ester-,
carbonate- or ether-based monomer is selected from glycolide (GA),
D-lactide (DLA), L-lactide (LLA), D,L-lactide (DLLA),
C.sub.3-C.sub.12 .beta.-lactone, C.sub.4-C.sub.12 .gamma.-lactone,
.alpha.-bromo-.gamma.-butyrolactone,
.alpha.-bromo-.gamma.-valerolactone, homoserine lactone
C.sub.2-C.sub.14 amide, C.sub.5-C.sub.14, .delta.-lactone,
mevalonolactone, C.sub.6-C.sub.16 .delta.-lactone,
1,3-dioxolan-2-one, 4-methyl-1,3-dioxolan-2-one,
4-methoxymethyl-1,3-dioxolan-2-one, 4-chloro-1,3-dioxolan-2-one,
4-phenyl-1,3-dioxolan-2-one, 4-vinyl-1,3-dioxolan-2-one,
trimethylene carbonate (TMC), ethylene oxide (EO), and propylene
oxide (PPO). In a particular embodiment, the at least one
additional ester-, carbonate- or ether-based monomer is selected
from GA, DLA, LLA, DLLA, .beta.-propiolactone (PL),
.beta.-butyrolactone (BL), .delta.-valerolactone (VL),
s-caprolactone (CL), TMC, EO, and PPO.
[0018] In an embodiment, the copolymer is derived from dioxanone
(DS) and one to three additional ester-based monomers,
carbonate-based monomers, ether-based monomers or a combination
thereof, and the individual units of each different type of monomer
can be arranged in any manner. In a more specific embodiment, the
copolymer is selected from P(DS-GA), P(DS-DLA), P(DS-LLA),
P(DS-DLLA), P(DS-PL), P(DS-BL), P(DS-VL), P(DS-CL), P(DS-TMC),
P(DS-EO), P(DS-PPO), P(DS-GA-DLA), P(DS-GA-LLA), P(DS-GA-DLLA),
P(DS-GA-VL), P(DS-GA-CL), P(DS-GA-TMC), P(DS-GA-EO), P(DS-GA-PPO),
P(DS-DLA-LLA), P(DS-DLA-DLLA), P(DS-DLA-VL), P(DS-DLA-CL),
P(DS-DLA-TMC), P(DS-DLA-EO), P(DS-DLA-PPO), P(DS-LLA-DLLA),
P(DS-LLA-VL), P(DS-LLA-CL), P(DS-LLA-TMC), P(DS-LLA-EO),
P(DS-LLA-PPO), P(DS-DLLA-VL), P(DS-DLLA-CL), P(DS-DLLA-TMC),
P(DS-DLLA-EO), P(DS-DLLA-PPO), P(DS-VL-CL), P(DS-VL-TMC),
P(DS-VL-EO), P(DS-VL-PPO), P(DS-CL-TMC), P(DS-CL-EO), P(DS-CL-PPO),
P(DS-GA-DLLA-CL), P(DS-GA-DLLA-TMC), P(DS-GA-DLLA-EO),
P(DS-GA-CL-TMC), P(DS-GA-CL-EO), P(DS-GA-TMC-EO),
P(DS-DLLA-CL-TMC), P(DS-DLLA-CL-EO), P(DS-DLLA-TMC-EO), and
P(DS-CL-TMC-EO).
[0019] In some embodiments, the composition further comprises at
least one additional biocompatible moiety, at least one non-fouling
moiety, at least one biobeneficial material, at least one
biologically active agent, or a combination thereof.
[0020] Other embodiments are drawn to coatings comprising the
inventive composition and implantable devices formed of a material
comprising the inventive composition. In an embodiment, the
material is a coating disposed over at least a portion of the
implantable device.
[0021] In certain embodiments, the implantable device is selected
from stents, grafts, stent-grafts, catheters, leads and electrodes,
clips, shunts, closure devices, valves, and particles. In a
particular embodiment, the implantable device is a stent.
[0022] 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 an implantable device
formed of a material comprising the inventive composition, wherein
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 one embodiment, the material is a coating disposed
over at least a portion of the implantable device.
[0023] Various embodiments of the invention are described in
further detail below.
DETAILED DESCRIPTION OF THE INVENTION
Terms and Definitions
[0024] The following definitions apply:
[0025] 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.
[0026] 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.
[0027] "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.
[0028] "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.
[0029] As used herein, a "biocompatible moiety" refers to a moiety
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.
[0030] 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.
[0031] A "non-fouling moiety" refers to a moiety that provides an
implantable device fabricated from or coated with a material
comprising the moiety 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 could lead to protein fouling. 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.
[0032] "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 such cases where the physiological
conditions (e.g., body temperature) of an animal are not considered
"normal".
[0033] 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.
[0034] 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 may exert an effect different from that of
the other drug, or it may promote, enhance or potentiate the effect
of the other drug.
[0035] 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, DC: 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).
[0036] 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.
[0037] 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.
[0038] 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, cerebrospinal fluid
shunts, and particles (e.g., drug-delivery particles,
microparticles and nanoparticles). 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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 may then be deflated and the catheter withdrawn. In the
case of a self-expanding stent, the stent may 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
may be withdrawn, which allows the stent to self-expand.
[0045] 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.
[0046] 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.
[0047] "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.
[0048] "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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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).
Embodiments of the Invention
Composition and Polymer
[0056] The polymeric materials of the present invention are
designed to possess certain advantages over conventional
biodegradable polymers used to make implantable devices. The
mechanical properties (e.g., strength, rigidity, fracture toughness
and flexibility) and physical properties (e.g., T.sub.g,
degradation rate and drug permeability) of a polymer can be tuned
by the appropriate selection of monomers and ratio and arrangement
thereof. To improve the biological properties of an implantable
device formed of a material comprising the polymer, at least one
additional biocompatible moiety, at least one non-fouling moiety,
at least one biobeneficial material and/or at least one bioactive
agent can be physically or chemically attached to, blended with, or
incorporated with the polymer. Finally, adhesion of a polymeric
coating to a metal surface 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.
[0057] Dioxanone would make a suitable monomer component for a
polymer that needs to be biodegradable and flexible, e.g., a
polymer used to make a coating disposed over an implantable device.
Polydioxanone (PDS.RTM.), which is synthesized via ring opening
polymerization of dioxanone (DS), is completely or substantially
completely absorbed in vivo within about 6 months. It has from
about 30% to about 50% crystallinity and a T.sub.g from about
-16.degree. C. to about 0.degree. C. These physical properties make
PDS relatively elastic compared to, e.g., polyglycolide (PGA) and
poly(D-lactide) (PDLA). Depending on various other factors (e.g.,
the identity and ratio of other monomer components), a DS-based
copolymer can exhibit suitable elasticity to be used in forming an
implantable device that changes its shape (e.g., a stent that is
crimped during delivery but expands during deployment).
[0058] 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, wherein the copolymer: [0059] is derived
from dioxanone and at least one additional ester-, carbonate- or
ether-based monomer; [0060] has a crystallinity of about 80% or
less; [0061] has a T.sub.g from about -100.degree. C. to about
100.degree. C.; [0062] has a polymer number-average molecular
weight (M.sub.n) from about 10 kDa to about 1,500 kDa; and [0063]
completely or substantially completely degrades within about 24
months.
[0064] In a narrower embodiment, optionally in combination with one
or more other embodiments described herein, the copolymer: [0065]
has a crystallinity from about 5% to about 70%; [0066] has a
T.sub.g from about -60.degree. C. to about 60.degree. C.; [0067]
has an M.sub.n from about 20 kDa to about 1,000 kDa; and [0068]
completely or substantially completely degrades within about 12
months.
[0069] In an even narrower embodiment, optionally in combination
with one or more other embodiments described herein, the
copolymer:
[0070] has a crystallinity from about 10% to about 60%; [0071] has
a T.sub.g from about -30.degree. C. to about 30.degree. C.; [0072]
has an M.sub.n from about 30 kDa to about 700 kDa; and [0073]
completely or substantially completely degrades within about 6
months.
[0074] In an embodiment, optionally in combination with one or more
other embodiments described herein, the copolymer is derived from
dioxanone (DS) and one to five additional ester-based monomers,
carbonate-based monomers, ether-based monomers or a combination
thereof, and the individual units of each different type of monomer
can be arranged in any manner. In other embodiments, the copolymer
is derived from DS and one to four, or one to three, or one to two,
additional ester-based monomers, carbonate-based monomers,
ether-based monomers, or a combination thereof. Dioxanone can be
1,4-dioxanone or 1,3-dioxanone, and thus the scope of the present
invention encompasses copolymers derived from 1,4-dioxanone and/or
1,3-dioxanone.
[0075] In one embodiment, the copolymer is derived from DS and at
least one additional ester-based monomer. In another embodiment,
the copolymer is derived from DS and at least one carbonate-based
monomer. In yet another embodiment, the copolymer is derived from
DS and at least one ether-based monomer. In a further embodiment,
the copolymer is derived from DS and any combination of ester-based
monomers, carbonate-based monomers, and ether-based monomers.
[0076] The dioxanone monomer, ester-based monomers, carbonate-based
monomers, and ether-based monomers described herein can optionally
be substituted with one to five substituents. The optional
substituents can be straight-chain or branched, saturated or
unsaturated, cyclic or acyclic, aromatic or nonaromatic, and can
contain one or more of the heteroatoms O, N and/or S. The optional
substituents can also contain one or more groups that may be
straight-chain or branched, saturated or unsaturated, cyclic or
acyclic, aromatic or nonaromatic, and that may contain one or more
of the heteroatoms O, N and/or S. Non-limiting examples of the
optional substituents include: halogens; nitrile; C.sub.1-C.sub.12
alkyl; C.sub.2-C.sub.12 alkenyl; C.sub.2-C.sub.12 alkynyl;
C.sub.1-C.sub.12 haloalkyl; C.sub.1-C.sub.12 heteroalkyl;
C.sub.1-C.sub.12 alkoxy; C.sub.1-C.sub.12 ethers; C.sub.1-C.sub.12
sulfides; C.sub.1-C.sub.12 thioethers; C.sub.1-C.sub.12 sulfones;
C.sub.1-C.sub.12 secondary amines; C.sub.2-C.sub.24 tertiary
amines; C.sub.1-C.sub.12 ketones; C.sub.1-C.sub.12.degree. C.- and
O-linked esters; C.sub.1-C.sub.12 S- and N-linked secondary
sulfonamides; C.sub.2-C.sub.24 S- and N-linked tertiary
sulfonamides; C.sub.1-C.sub.12 C- and N-linked secondary amides;
C.sub.2-C.sub.24 C- and N-linked tertiary amides; C.sub.1-C.sub.12
O- or N-linked secondary carbamates; C.sub.2-C.sub.24 O- or
N-linked tertiary carbamates; C.sub.3-C.sub.6 cycloalkyl;
C.sub.3-C.sub.6 heterocycloalkyl; C.sub.5-C.sub.14 aryl; and
C.sub.5-C.sub.14 heteroaryl.
[0077] In one embodiment, the copolymer has the specified T.sub.g
ranges when it is hydrated. In another embodiment, the copolymer
has the specified T.sub.g ranges when it is not hydrated. It should
be understood that in some cases, the copolymer may have a T.sub.m
rather than a T.sub.g, and the scope of the present invention
encompasses those cases where the copolymer has a T.sub.m rather
than a T.sub.g.
[0078] The T.sub.g of the copolymer can be tuned to a desired value
by appropriate selection of component monomers and adjustment of
their number, ratio and arrangement. A higher T.sub.g can increase
strength and rigidity. Strength and rigidity may be important for
an implantable device formed of a polymeric material in certain
applications, e.g., for a stent so that the stent can support the
walls of a vessel.
[0079] On the other hand, a lower T.sub.g can enhance the fracture
toughness and flexibility of the copolymer and improve drug-release
control. Toughness and flexibility may be important for a range of
aggressive applications of an implantable device, e.g., for a
coated stent, such as overlapped stents, stent through stent
delivery, and bifurcations. Polymers (e.g., certain glassy,
semicrystalline polymers) with too high a T.sub.g may be brittle
under physiological conditions and fracture during the application
of the device, exhibiting little or no plastic deformation prior to
failure.
[0080] For a polymer with low permeability of a drug, a high
drug/polymer ratio must be employed to get the drug to release.
However, a high drug/polymer ratio can lead to a drug-release
profile in which most of the drug is released as a burst, and the
remaining portion of the drug is released very slowly. On the other
hand, a low drug/polymer ratio may result in no drug release at
all. A higher drug permeability can allow better control of
drug-release rates at reasonable drug-to-polymer ratios, e.g.,
where the amount of polymer is greater than 50% by weight.
[0081] The copolymer of the invention can have any T.sub.g value
within the range from about -100.degree. C. to about 100.degree. C.
The T.sub.g of the copolymer can be tuned to a desired value
depending on the particular applications of the copolymer. In
narrower embodiments, the copolymer can have a T.sub.g from about
-80.degree. C. to about 80.degree. C., or from about -60.degree. C.
to about 60.degree. C., or from about -40.degree. C. to about
40.degree. C., or from about -20.degree. C. to about 20.degree. C.,
or from about -10.degree. C. to about 10.degree. C. The copolymer
can also have a T.sub.g in the lower or higher end of the range.
For example, in some embodiments, the copolymer can have a T.sub.g
from about -100.degree. C. to about 0.degree. C., or from about
-80.degree. C. to about -20.degree. C., or from about -60.degree.
C. to about -40.degree. C., or from about -60.degree. C. to about
0.degree. C., or from about -40.degree. C. to about 0.degree. C.,
or from about -20.degree. C. to about 0.degree. C. In other
embodiments, the copolymer can have a T.sub.g from about 0.degree.
C. to about 100.degree. C., or from about 20.degree. C. to about
80.degree. C., or from about 40.degree. C. to about 60.degree. C.,
or from about 0.degree. C. to about 60.degree. C., or from about
0.degree. C. to about 40.degree. C., or from about 0.degree. C. to
about 20.degree. C.
[0082] The mechanical properties of a polymer can also be
influenced by the identity of its monomer components. For example,
poly(glycolide) (PGA), poly(D-lactide) (PDLA), poly(L-lactide)
(PLLA), and poly(D,L-lactide) (PDLLA) tend to be stronger and more
rigid. Thus, in one embodiment, monomer units of glycolide (GA),
D-lactide (DLA), L-lactide (LLA), D,L-lactide (DLLA), or a
combination thereof are used to increase the strength and rigidity
of the inventive copolymer.
[0083] On the other hand, non-limiting examples of biodegradable
polymers having a relatively high fracture toughness and
flexibility at body temperature include polycaprolactone (PCL),
poly(trimethylene carbonate) (PTMC), polydioxanone (PDS),
poly(propiolactone), poly(valerolactone) and polyacetal. Therefore,
to enhance the toughness and flexibility of the copolymer, some
embodiments of the copolymer can include caprolactone (CL),
trimethylene carbonate (TMC), propiolactone, valerolactone or
acetal monomer units, or a combination thereof, in addition to
dioxanone (DS) units.
[0084] The identity of the monomer components of a polymer can also
influence its degradation rate. For example, the copolymer of the
invention can include monomer units that are hydrophilic and/or
hydrolytically active. These two characteristics increase the
moisture content of the copolymer, which increases its degradation
rate. The copolymer can also 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
copolymer.
[0085] Non-limiting examples of polymers that degrade rapidly
include PDS, PGA, PDLA, PLLA and PDLLA. PDS generates about
0.98.times.10.sup.-2 moles of acid per gram when it fully degrades,
comparable to PGA (about 1.7.times.10.sup.-2 moles of acid per
gram) and PDLA and PLLA (about 1.4.times.10.sup.-2 moles of acid
per gram). The monofilaments of PDS lose about 50% of their initial
strength after about 3 weeks as a consequence of degradation, and
PDS is completely or substantially completely absorbed in vivo
within about 6 months. Accordingly, for faster degradation, some
embodiments of the copolymer can include monomer units of GA, DLA,
LLA, DLLA, or a combination thereof in addition to DS units.
[0086] As a particular example, for faster degradation the
copolymer of the invention can contain GA units. When incorporated
into a polymer, glycolic acid hydrolyzes faster than L-lactic acid
or D-lactic acid, for the ester bond formed from glycolic acid is
less sterically hindered than that formed from lactic acid.
Further, glycolide units have acidic degradation products that can
increase the degradation rate of a GA-containing polymer. Moreover,
glycolic acid is a low molecular weight monomer, so that an
appreciable level of glycolic acid means that there is a
substantial number of ester bonds formed from glycolic acid in a
GA-containing polymer, any or all of which can hydrolyze. For
example, a fast degrading polymer is poly(glycolide-co-trimethylene
carbonate) (P(GA-co-TMC)).
[0087] Incorporation of a hydrophilic component or polymer in the
inventive copolymer can also enhance its drug permeability as well
as its degradation rate and improve control of drug-release rates.
Increased water penetration and content in the copolymer owing to
the hydrophilic component or polymer increases the permeability of
the copolymer to a drug. Non-limiting examples of hydrophilic
components or polymers include carboxylic acid-bearing monomers
(e.g., methacrylic acid (MA) and acrylic acid (AA)),
hydroxyl-bearing monomers (e.g., hydroxyethyl methacrylate (HEMA),
hydroxypropyl methacrylate (HPMA), hydroxypropyl methacrylamide,
and 3-trimethylsilylpropyl methacrylate (TMSPMA)), polyalkylene
oxide, poly(ethylene glycol) (PEG), poly(propylene glycol), PEG
acrylate (PEGA), PEG methacrylate, copolymers of
2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl
pyrrolidone (VP), hydroxy functional poly(vinyl pyrrolidone) (PVP),
SIS-PEG (SIS is polystyrene-polyisobutylene-polystyrene block
copolymer), polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG
(PLA is polylactic acid), PMMA-PEG (PMMA is poly(methyl
methacrylate)), PDMS-PEG (PDMS is polydimethyloxanone), PVDF-PEG
(PVDF is polyvinylidene fluoride), PLURONIC.TM. surfactants
(polypropylene oxide-co-polyethylene glycol), poly(tetramethylene
glycol), poly(L-lysine-g-ethylene glycol) (PLL-g-PEG),
poly(L-lysine-g-hyaluronic acid) (PLL-g-HA),
poly(L-lysine-g-phosphoryl choline) (PLL-g-PC),
poly(L-lysine-g-vinyl pyrrolidone) (PLL-g-PVP),
poly(ethylimine-g-ethylene glycol) (PEI-g-PEG),
poly(ethylimine-g-hyaluronic acid) (PEI-g-HA),
poly(ethylimine-g-phosphoryl choline) (PEI-g-PC),
poly(ethylimine-g-vinyl pyrrolidone) (PEI-g-PVP), PLL-co-HA,
PLL-co-PC, PLL-co-PVP, PEI-co-PEG, PEI-co-HA, PEI-co-PC,
PEI-co-PVP, dextran, dextrin, sodium hyaluronate, hyaluronic acid,
elastin, chitosan, acrylic sulfate, acrylic sulfonate, acrylic
sulfamate, methacrylic sulfate, methacrylic sulfonate, methacrylic
sulfamate, polymers and copolymers thereof, and polymers and
copolymers of combinations thereof.
[0088] In some embodiments, the copolymer of the invention can
include toughness-enhancing units and fast degrading units. In more
specific embodiments, the copolymer can include GA, CL, TMC,
valerolactone, propiolactone or acetal units, or a combination
thereof, in addition to DS units. The copolymer can have block,
alternating or random GA, CL, TMC, valerolactone, propiolactone
and/or acetal units, or any other variations in their arrangement.
For example, the copolymer can be poly(DS-co-GA-co-CL),
poly(DS-co-GA-co-TMC), or poly(DS-co-GA-co-TMC-co-CL).
[0089] The flexibility, toughness and degradation rate of the
copolymer can also be tuned by adjusting the ratio of fast
degrading and toughness-enhancing units. For example, as the ratio
of CL increases and that of GA decreases in poly(DS-co-GA-co-CL),
the copolymer becomes more flexible and tougher and less rigid. As
another example, the degradation rate of the copolymer can be
enhanced by increasing the fraction of GA in poly(DS-co-GA-co-CL)
relative to CL. In exemplary embodiments, a DS-based copolymer
containing glycolide units 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.
[0090] The degradation rate of the inventive copolymer can also be
influenced by its physical state. Since the diffusion rate of
fluids through an amorphous structure is generally faster than
through a crystalline structure, the copolymer can be configured to
have a higher degree of amorphousness to increase its degradation
rate. The faster degrading units or sections of the copolymer
increase water penetration and content in those units or sections.
The increased water penetration and content causes an increase in
the degradation rate of the copolymer.
[0091] The physical state of the copolymer can also influence its
mechanical properties. A more crystalline copolymer can be stronger
and more rigid. On the other hand, a more amorphous copolymer can
be tougher and more flexible. A more amorphous copolymer can be
more "elastomeric" or "rubbery" in that it can exhibit elastic
deformation through a greater range of deformation. This
characteristic may be desirable when the structure of an
implantable device is anticipated to deform during the device's
applications, e.g., when a stent that is crimped during delivery
expands upon deployment.
[0092] In an embodiment, optionally in combination with one or more
other embodiments described herein, the copolymer of the invention
can have any degree of crystallinity from about 0% to about 80%. In
narrower embodiments, the copolymer can have a crystallinity from
about 2% to about 75%, or from about 5% to about 70%, or from about
10% to about 65%, or from about 15% to about 60%, or from about 20%
to about 55%, or from about 25% to about 50%.
[0093] For greater strength and rigidity, the copolymer can have a
degree of crystallinity at the higher end of the range. In certain
embodiments, optionally in combination with one or more other
embodiments described herein, the copolymer can have a
crystallinity from about 30% to about 80%, or from about 35% to
about 75%, or from about 40% to about 70%, or from about 45% to
about 65%.
[0094] To increase its toughness, flexibility, degradation rate and
drug permeability, the copolymer can be configured to be more
amorphous, i.e., be less crystalline. In some embodiments,
optionally in combination with one or more other embodiments
described herein, the copolymer can have a crystallinity from about
0% to about 60%, or from about 5% to about 55%, or from about 10%
to about 50%, or from about 15% to about 45%, or from about 20% to
about 40%. In other embodiments, the copolymer can be substantially
or completely amorphous. For example, the copolymer can have a
degree of crystallinity of about 10% or less, or about 7.5% or
less, or about 5% or less.
[0095] Depending on the intended applications of an implantable
device formed of a polymeric material, the copolymer of the
invention can have a wide range of degradation rates. For example,
it may be desirable for the copolymer to have a slow degradation
rate (e.g., substantially complete degradation over a period of
about 2 years) if the device is intended to act as a structural
scaffold for an extended period of time. Conversely, faster
degradation of the copolymer (e.g., substantially complete
degradation over a period of about 6 months or less) may be desired
in cases where the device is intended to accomplish its functions
within a shorter period of time, e.g., locally delivering a drug up
to about 6 months or less. Faster degradation of the copolymer may
be advantageous in, e.g., avoiding or minimizing the body's immune
response to the polymeric material forming the device, which may be
a cause of adverse side effects such as late stent thrombosis.
[0096] In an embodiment, optionally in combination with one or more
other embodiments described herein, the copolymer of the invention
completely or substantially completely degrades within about 24
months. In narrower embodiments, the copolymer completely or
substantially completely degrades 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).
[0097] The mechanical properties (e.g., strength, rigidity,
toughness and flexibility) and physical properties (e.g., T.sub.g,
crystallinity, degradation rate and drug permeability) of the
inventive copolymer can be tuned by appropriate selection of
monomer components; the number, ratio, and arrangement of the
monomer components; the length or molecular weight, weight ratio,
and arrangement of any sections of particular monomer component(s)
within the copolymer; and any other substances physically or
chemically attached to, blended with, or incorporated with the
copolymer.
[0098] In some embodiments, optionally in combination with one or
more other embodiments described herein, the biodegradable
copolymer of the invention is derived from dioxanone (DS) and at
least one additional ester-, carbonate- or ether-based monomer
selected from glycolide (GA), D-lactide (DLA), L-lactide (LLA),
D,L-lactide (DLLA), C.sub.3-C.sub.12 .beta.-lactone,
C.sub.4-C.sub.12 .gamma.-lactone,
.alpha.-bromo-.gamma.-butyrolactone,
.alpha.-bromo-.gamma.-valerolactone, homoserine lactone
C.sub.2-C.sub.14 amide, C.sub.5-C.sub.14 .delta.-lactone,
mevalonolactone, C.sub.6-C.sub.16 .epsilon.-lactone,
1,3-dioxolan-2-one, 4-methyl-1,3-dioxolan-2-one,
4-methoxymethyl-1,3-dioxolan-2-one, 4-chloro-1,3-dioxolan-2-one,
4-phenyl-1,3-dioxolan-2-one, 4-vinyl-1,3-dioxolan-2-one,
trimethylene carbonate (TMC), ethylene oxide (EO), and propylene
oxide (PPO). In a particular embodiment, the at least one
additional ester-, carbonate- or ether-based monomer is selected
from GA, DLA, LLA, DLLA, .beta.-propiolactone (PL),
.beta.-butyrolactone (BL), .delta.-valerolactone (VL),
.epsilon.-caprolactone (CL), TMC, EO, and PPO.
[0099] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the copolymer is
derived from DS and one to three additional ester-based monomers,
carbonate-based monomers and/or ether-based monomers selected from
GA, DLA, LLA, DLLA, PL, BL, VL, CL, TMC, EU and PPO, wherein the
individual units of each different type of monomer can be arranged
in any manner (e.g., block, graft, random, alternating, etc.). In a
more specific embodiment, the copolymer is selected from P(DS-GA),
P(DS-DLA), P(DS-LLA), P(DS-DLLA), P(DS-PL), P(DS-BL), P(DS-VL),
P(DS-CL), P(DS-TMC), P(DS-EO), P(DS-PPO), P(DS-GA-DLA),
P(DS-GA-LLA), P(DS-GA-DLLA), P(DS-GA-VL), P(DS-GA-CL),
P(DS-GA-TMC), P(DS-GA-EO), P(DS-GA-PPO), P(DS-DLA-LLA),
P(DS-DLA-DLLA), P(DS-DLA-VL), P(DS-DLA-CL), P(DS-DLA-TMC),
P(DS-DLA-EO), P(DS-DLA-PPO), P(DS-LLA-DLLA), P(DS-LLA-VL),
P(DS-LLA-CL), P(DS-LLA-TMC), P(DS-LLA-EO), P(DS-LLA-PPO),
P(DS-DLLA-VL), P(DS-DLLA-CL), P(DS-DLLA-TMC), P(DS-DLLA-EO),
P(DS-DLLA-PPO), P(DS-VL-CL), P(DS-VL-TMC), P(DS-VL-EO),
P(DS-VL-PPO), P(DS-CL-TMC), P(DS-CL-EO), P(DS-CL-PPO),
P(DS-GA-DLLA-CL), P(DS-GA-DLLA-TMC), P(DS-GA-DLLA-EO),
P(DS-GA-CL-TMC), P(DS-GA-CL-EO), P(DS-GA-TMC-EO),
P(DS-DLLA-CL-TMC), P(DS-DLLA-CL-EO), P(DS-DLLA-TMC-EO), and
P(DS-CL-TMC-EO).
[0100] In some embodiments, optionally in combination with one or
more other embodiments described herein, the copolymer of the
invention specifically cannot be derived from one or more of any of
the monomers described herein. In certain embodiments, the
copolymer specifically cannot be any particular one of the polymers
or copolymers described herein.
[0101] For forming certain types of material (e.g., films,
coatings, etc.), the entire polymer may need to have sufficient
molecular weight. Accordingly, in one embodiment, 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 5 kDa. In other
embodiments, the copolymer has an M.sub.n of at least about 10 kDa,
or at least about 20 kDa, or at least about 30 kDa, or at least
about 40 kDa.
[0102] The copolymer of the invention can have a wide range of
M.sub.n depending on its intended applications. In an embodiment,
optionally in combination with one or more other embodiments
described herein, the copolymer has an M.sub.n from about 10 kDa to
about 1,5000 kDa. In other embodiments, the copolymer has an
M.sub.n from about 15 kDa to about 1,250 kDa, or from about 20 kDa
to about 1,000 kDa, or from about 25 kDa to about 750 kDa, or from
about 30 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. Thus, in one embodiment, the inventive copolymer
has an M.sub.n from about 20 kDa to about 500 kDa. In another
embodiment, the polymer has an M.sub.n from about 40 kDa to about
500 kDa.
[0103] As stated previously, the mechanical and physical properties
of the inventive copolymer can be influenced by the number of units
of the monomer components and the ratio thereof. In some
embodiments of the copolymer, optionally in combination with one or
more other embodiments described herein, dioxanone and the at least
one additional ester-, carbonate- or ether-based monomer each
independently have from about 5 to about 5,000 monomer units. In
narrower embodiments, each type of monomer of the copolymer 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.
[0104] Some polymers cannot adhere to metal surfaces. For 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.
[0105] 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.
[0106] 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 inventive
copolymer. 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.
[0107] Copolymer Containing Blocks or Segments
[0108] The copolymer of the invention can also be configured to
contain one or more blocks or segments. In certain embodiments,
optionally in combination with one or more other embodiments
described herein, the copolymer is composed of two blocks or
segments, or three blocks or segments, or four blocks or segments,
or five blocks or segments. Certain blocks or segments can be the
same as one another or different than other blocks or segments. The
monomer components can be arranged in any manner (e.g., block,
graft, random, alternating, etc.) within each of the blocks or
segments.
[0109] In some embodiments, optionally in combination with one or
more other embodiments described herein, at least one of the blocks
or segments of the copolymer is derived from dioxanone, and each of
the blocks or segments is independently derived from one to four
different types of monomer selected from dioxanone, ester-based
monomers, carbonate-based monomers, ether-based monomers or a
combination thereof. In one embodiment, optionally in combination
with one or more other embodiments described herein, each type of
monomer in a block or segment has from about 5 to about 5,000
monomer units. In narrower embodiments, each type of monomer in a
block or 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.
[0110] The mechanical properties (e.g., strength, rigidity,
toughness and flexibility) and physical properties (e.g.,
T.sub.g/T.sub.m, crystallinity, degradation rate and drug
permeability) of a copolymer containing one or more blocks or
segments can be tuned by appropriate selection of monomer
components; the number, ratio, and arrangement of the monomer
components; the length or molecular weight, weight ratio, and
arrangement of the blocks or segments; and any other substances
physically or chemically attached to, blended with, or incorporated
with the copolymer. [0111] For greater strength and rigidity and a
higher T.sub.g/T.sub.m, a particular block or segment can be
enriched in certain types of monomers, e.g., GA, DLA, LLA, DLLA or
a combination thereof. Likewise, for greater toughness and
flexibility and a lower T.sub.g/T.sub.m, a particular block or
segment can contain a greater ratio of other types of monomers,
e.g., DS, CL, TMC, propiolactone, valerolactone, acetal or a
combination thereof. Similarly, the degradation rate of a
particular block or segment can be enhanced if it is enriched in
certain types of monomers, e.g., DS, GA, DLA, LLA, DLLA or a
combination thereof.
[0112] To provide greater strength and rigidity, one or more blocks
or segments of the copolymer can be formulated to have a higher
T.sub.g or T.sub.m. In a specific embodiment, the "harder" block or
segment has a T.sub.g or T.sub.m above body temperature. In certain
embodiments, optionally in combination with one or more other
embodiments described herein, the T.sub.g or T.sub.m of the harder
block or segment ranges from about 30.degree. C. to about
300.degree. C., or from about 40.degree. C. to about 250.degree.
C., or from about 50.degree. C. to about 200.degree. C., or from
about 60.degree. C. to about 150.degree. C., or from about
70.degree. C. to about 100.degree. C.
[0113] To increase fracture toughness, flexibility, degradation
rate and drug permeability, one or more blocks or segments of the
copolymer can be designed to have a lower T.sub.g or T.sub.m. The
"softer" block or segment has a T.sub.g or T.sub.m less than the
T.sub.g or T.sub.m of the harder block or segment. In some
embodiments, optionally in combination with one or more other
embodiments described herein, the T.sub.g of the softer block or
segment ranges from about -200.degree. C. to about 100.degree. C.,
or from about -150.degree. C. to about 75.degree. C., or from about
-100.degree. C. to about 50.degree. C., or from about -50.degree.
C. to about 30.degree. C., or from about -20.degree. C. to about
10.degree. C. In a particular embodiment, the softer block or
segment has a T.sub.g below body temperature. It should be
understood that in some cases, the softer block or segment may have
a T.sub.m rather than a T.sub.g, and the scope of the present
invention encompasses cases where the softer block or segment has a
T.sub.m rather than a T.sub.g.
[0114] The blocks or segments of the copolymer may or may not be
miscible with each other. In one embodiment, the blocks or segments
are partially or completely miscible with each other. In another
embodiment, the blocks or segments are partially or completely
immiscible with one another.
[0115] For the blocks or 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 blocks or segments of the copolymer each independently have an
M.sub.n of at least about 1 kDa, or at least about 5 kDa, or at
least about 10 kDa. In certain embodiments, optionally in
combination with one or more other embodiments described herein,
the blocks or segments each independently range in M.sub.n from
about 1 kDa to about 500 kDa, or from about 5 kDa to about 450 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.
[0116] In further embodiments, optionally in combination with one
or more other embodiments described herein, the ratio of the
molecular weight of a harder block or segment to a softer block or
segment is between about 20:1 and about 1:20, or between about 15:1
and about 1:15, or between about 10:1 and about 1:10, or between
about 5:1 and about 1:5, or between about 2:1 and 1:2.
[0117] In other embodiments, optionally in combination with one or
more other embodiments described herein, the weight fraction of a
harder block with respect to the total copolymer 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%, or from about 40% to
about 60%. In yet other embodiments, the copolymer can contain
about 1-50 wt %, or about 5-40 wt %, or about 10-30 wt % of a
harder block or segment, and about 50-99% wt %, or about 60-95 wt
%, or about 70-90 wt %, respectively, of a softer block or
segment.
[0118] Biocompatible Moieties
[0119] Besides increasing toughness, flexibility, degradation rate
and drug permeability, dioxanone enhances the biocompatibility of a
copolymer composed of DS units. For example, a PDS-based suture
elicits little or no foreign body reaction (i.e., immune response)
to it, and is more biocompatible than a PGA-based suture.
[0120] To further improve its biocompatibility, the inventive
copolymer can comprise at least one additional biologically
compatible ("biocompatible") moiety. Accordingly, in some
embodiments, optionally in combination with one or more other
embodiments described herein, the inventive composition comprises
the biodegradable, dioxanone-based copolymer and at least one
additional biocompatible moiety. The at least one additional
biocompatible moiety can be physically or chemically attached to,
blended with, or incorporated with the copolymer. The at least one
additional biocompatible moiety can be selected in such a way as to
adjust the biodegradability of the copolymer (e.g., to make the
entire copolymer biologically degradable).
[0121] Examples of suitable biocompatible moieties include, but are
not limited to, poly(alkylene glycols), e.g., poly(ethylene glycol)
(PEG), poly(ethylene oxide), poly(propylene glycol) (PPG),
poly(tetramethylene glycol) and poly(ethylene oxide-co-propylene
oxide); lactones and lactides, e.g., .epsilon.-caprolactone,
.beta.-butyrolactone, .delta.-valerolactone and glycolide;
poly(N-vinyl pyrrolidone); poly(acrylamide methyl propane sulfonic
acid) and salts thereof (AMPS and salts thereof); poly(styrene
sulfonate); sulfonated dextran; polyphosphazenes;
poly(orthoesters); poly(tyrosine carbonate); sialic acid;
hyaluronic acid; hyaluronic acid having a stearoyl or palmitoyl
substitutent group; copolymers of PEG with hyaluronic acid,
hyaluronic acid-stearoyl or hyaluronic acid-palmitoyl; heparin;
copolymers of PEG with heparin; a graft copolymer of poly(L-lysine)
and PEG; and copolymers thereof. To ensure its renal clearance, the
molecular weight of a polymeric biocompatible moiety may be 40 kDa
or less, 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.
[0122] In one embodiment, optionally in combination with one or
more other embodiments described herein, the at least one
additional biocompatible moiety is selected from poly(ethylene
oxide), poly(propylene glycol), poly(tetramethylene glycol),
poly(ethylene oxide-co-propylene oxide), .epsilon.-caprolactone,
.beta.-butyrolactone, .delta.-valerolactone, glycolide,
poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic
acid) and salts thereof, poly(styrene sulfonate), sulfonated
dextran, polyphosphazenes, poly(orthoesters), poly(tyrosine
carbonate), sialic acid, hyaluronic acid and derivatives thereof,
copolymers of poly(ethylene glycol) (PEG) with hyaluronic acid or
derivatives thereof, heparin, copolymers of PEG with heparin, graft
copolymers of poly(L-lysine) and PEG, and copolymers thereof.
[0123] In some embodiments, optionally in combination with one or
more other embodiments described herein, the at least one
additional biocompatible moiety specifically cannot be one or more
of any of the biocompatible moieties described herein.
[0124] Non-Fouling Moieties
[0125] The body's reaction to foreign material could lead to
adsorption of proteins on the surface of an implantable device,
which could ultimately impair the device's functioning and result
in adverse side effects such as thrombosis. A non-fouling moiety
provides an implantable device with the ability to resist protein
adsorption on its surface. Accordingly, some embodiments of the
inventive composition, optionally in combination with one or more
other embodiments described herein, comprise the biodegradable,
dioxanone-based copolymer and at least one non-fouling moiety. The
at least one non-fouling moiety can be physically or chemically
attached to, blended with, or incorporated with the copolymer.
[0126] 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.
[0127] Silk and elastin both are natural proteins. Silk possesses
great 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.
[0128] In a specific embodiment, optionally in combination with one
or more other embodiments described herein, 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.
[0129] In some embodiments, optionally in combination with one or
more other embodiments described herein, the at least one
non-fouling moiety specifically cannot be one or more of any of the
non-fouling moieties described herein.
[0130] The maximum molecular weight of the at least one 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
of an animal (e.g., a human). 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.
[0131] Biobeneficial Materials
[0132] To improve the biological properties of an implantable
device (e.g., enhance its biocompatibility and reduce protein
adsorption on its surface), the device can be formed of a material
comprising a biobeneficial material. Therefore, some embodiments of
the inventive composition, optionally in combination with one or
more other embodiments described herein, comprise the
biodegradable, dioxanone-based copolymer 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 can be physically or chemically attached to,
blended with, or incorporated with the copolymer.
[0133] The biobeneficial material, if polymeric, may have a
relatively low T.sub.g, e.g., a T.sub.g less than or significantly
less than that of the inventive copolymer. In an embodiment, the
T.sub.g of the biobeneficial material is below body temperature.
Having a T.sub.g below or significantly below that of the
copolymer, the biobeneficial material would be relatively soft as
compared to the copolymer. This attribute would, e.g., allow 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 copolymer. For example, during radial
expansion of a stent, a more rigid copolymer can crack or have
surface fractures. A softer biobeneficial material can fill in the
crack and fractures.
[0134] The biobeneficial material can 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.
[0135] 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.
[0136] 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)).
[0137] 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)).
[0138] 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.
[0139] Biologically Active Agents
[0140] Further embodiments of the invention, optionally in
combination with one or more other embodiments described herein,
are directed to a composition comprising the biodegradable,
dioxanone-based copolymer and at least one biologically active
("bioactive") agent. The at least one bioactive agent can include
any substance capable of exerting a therapeutic, prophylactic or
diagnostic effect for a patient.
[0141] 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.
[0142] In certain embodiments, 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.
[0143] 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
I.sub.l, 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-hydroxyl)ethyl-rapamycin (trade name everolimus
from Novartis), 40-O-(2-ethoxyl)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxyl)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.
[0144] 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.
[0145] Alternatively, the anti-inflammatory agent can be a
biological inhibitor of pro-inflammatory signaling molecules.
Anti-inflammatory biological agents include antibodies to such
biological inflammatory signaling molecules.
[0146] 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-inflammmatory
properties or can have other properties such as antineoplastic,
antimitotic, cystostatic, antiplatelet, anticoagulant, antifibrin,
antithrombin, antibiotic, antiallergic, and/or antioxidant
properties.
[0147] 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).
[0148] Examples of antiplatelet, anticoagulant, antifibrin, and
antithrombin agents that can also have cytostatic or
antiproliferative properties include, but are not limited to,
sodium heparin, low molecular weight heparins, heparinoids,
hirudin, argatroban, forskolin, vapiprost, prostacyclin and
prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist antibody, recombinant
hirudin, 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.
[0149] 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).
[0150] 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).
[0151] Other bioactive agents 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.
[0152] Other biologically active agents that can be used include
alpha-interferon, genetically engineered epithelial cells,
tacrolimus and dexamethasone.
[0153] 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.
[0154] 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).
[0155] "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.
[0156] 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).
[0157] 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.
[0158] In further embodiments, the prohealing drug or agent can 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.
[0159] 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.
[0160] 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-hydroxyl)ethyl-rapamycin (everolimus),
40-O-(2-ethoxyl)ethyl-rapamycin (biolimus),
40-O-(3-hydroxyl)propyl-rapamycin,
40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, 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.
[0161] 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.
[0162] Material and Coating
[0163] The inventive composition comprising the biodegradable,
dioxanone-based 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.
[0164] Accordingly, some embodiments of the invention, optionally
in combination with one or more other embodiments described herein,
are drawn to a material containing any combination of embodiments
of the composition comprising the biodegradable, dioxanone-based
copolymer. For example, the composition forming the material can
optionally have at least one dihydroxyaryl group conjugated to the
ends of the copolymer and can optionally contain at least one
additional biocompatible moiety, at least one non-fouling moiety,
at least one biobeneficial material, at least one biologically
active agent, or a combination thereof.
[0165] 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 the device.
[0166] Accordingly, some embodiments of the invention, optionally
in combination with one or more other embodiments described herein,
are directed to a coating containing any combination of embodiments
of the composition comprising the biodegradable, dioxanone-based
copolymer. For example, the composition forming the coating can
optionally have at least one dihydroxyaryl group conjugated to the
ends of the copolymer and can optionally contain at least one
additional biocompatible moiety, at least one non-fouling moiety,
at least one biobeneficial material, at least one biologically
active agent, or a combination thereof.
[0167] The coating can have a range of thickness and degradation
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, or .ltoreq.about 5 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).
[0168] Implantable Device
[0169] The inventive material containing any combination of
embodiments of the composition comprising the biodegradable,
dioxanone-based copolymer can be used to form an implantable
device. Accordingly, some embodiments of the invention, optionally
in combination with one or more other embodiments described herein,
are drawn to an implantable device formed of a material containing
any combination of embodiments of the composition comprising the
biodegradable, dioxanone-based copolymer. For example, the
implantable device can be formed of a material comprising a
composition that can optionally have at least one dihydroxyaryl
group conjugated to the ends of the copolymer and can optionally
contain at least one additional biocompatible moiety, at least one
non-fouling moiety, at least one biobeneficial material, at least
one biologically active agent, or a combination thereof.
[0170] 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,
dioxanone-based copolymer. For example, a coating containing any
combination of embodiments of the composition comprising the
biodegradable, dioxanone-based copolymer can be disposed over at
least a portion of the implantable device.
[0171] Accordingly, certain embodiments of the invention,
optionally in combination with one or more other embodiments
described herein, are directed to an implantable device formed of a
coating containing any combination of embodiments of the
composition comprising the biodegradable, dioxanone-based
copolymer. The coating is disposed over at least a portion of the
device. For example, the implantable device can be formed of a
coating comprising a composition that can optionally have at least
one dihydroxyaryl group conjugated to the ends of the copolymer and
can optionally contain at least one additional biocompatible
moiety, at least one non-fouling moiety, at least one biobeneficial
material, at least one biologically active agent, or a combination
thereof.
[0172] The implantable device can be formed of a coating that can
have a range of thickness and degradation 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, or
.ltoreq.about 5 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).
[0173] The present invention also encompasses implantable devices
formed of bioabsorbable polymers, biostable polymers, or a
combination thereof. 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.
[0174] Any implantable device can be formed of the inventive
material or coating containing any combination of embodiments of
the composition comprising the biodegradable, dioxanone-based
copolymer. Non-limiting examples of implantable devices include
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., nanofibers,
sustained-release small molecule or protein formulations,
microspheres, and particles (e.g., drug-delivery particles,
microparticles and nanoparticles).
[0175] In certain embodiments, 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, valves and particles.
In a specific embodiment, 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, synthetic graft, arteriovenous
anastamosis, coronary, aortic renal, iliac, femoral, popliteal
vasculature and urethral passages.
[0176] 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.
[0177] 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," "MP2 ON," 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 "MP2 ON" 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. "MP2 ON" consists of 50% cobalt,
20% nickel, 20% chromium and 10% molybdenum.
[0178] 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 physically or chemically attached to the underlying copolymer
forming the device or a portion thereof. The additional polymer(s)
and/or additional substance(s) that can be physically or chemically
attached to, blended 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).
[0179] Structure of Coating
[0180] 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: [0181] (1) a primer layer;
[0182] (2) a drug-polymer layer (also referred to as a "reservoir"
or "reservoir layer") or, alternatively, a polymer-free drug layer;
[0183] (3) a topcoat layer; and/or [0184] (4) a finishing coat
layer.
[0185] 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.
[0186] 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.
[0187] 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.
[0188] 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.
[0189] 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.
[0190] 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.
[0191] 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.
[0192] 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.
[0193] 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.
[0194] 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.
[0195] 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); 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.
[0196] 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.
[0197] Method of Fabricating Implantable Device
[0198] 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, dioxanone-based
copolymer. For example, the method comprises forming the
implantable device of a material comprising a composition that can
optionally have at least one dihydroxyaryl group conjugated to the
ends of the copolymer and can optionally contain at least one
additional biocompatible moiety, at least one non-fouling moiety,
at least one biobeneficial material, at least one biologically
active agent, or a combination thereof.
[0199] 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. For example, the method can comprise
depositing over at least a portion of the implantable device a
coating containing any combination of embodiments of the
composition comprising the biodegradable copolymer.
[0200] Accordingly, in one 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, dioxanone-based
copolymer. For example, the method comprises depositing over at
least a portion of an implantable device a coating comprising a
composition that can optionally have at least one dihydroxyaryl
group conjugated to the ends of the copolymer and can optionally
contain at least one additional biocompatible moiety, at least one
non-fouling moiety, at least one biobeneficial material, at least
one biologically active agent, or a combination thereof.
[0201] The method 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 Shout .ltoreq.30 micron, or about
.ltoreq.20 micron, or about .ltoreq.10 micron, or .ltoreq.about
.ltoreq.5 micron.
[0202] In certain embodiments, the method is used to fabricate an
implantable device selected from stents, grafts, stent-grafts,
catheters, leads and electrodes, clips, shunts, closure devices,
valves, and particles. In a specific embodiment, the method is used
to fabricate a stent.
[0203] 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. An implantable device can then be
fabricated from the construct. For example, a stent can be
fabricated from a tube by laser machining a pattern into the tube.
In another embodiment, a polymer construct can be formed from the
polymeric material of the invention using an injection-molding
apparatus.
[0204] Non-limiting examples of polymers that can be used to
fabricate an implantable device include 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.
[0205] Additional representative examples of polymers that may be
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.
[0206] Method of Treating or Preventing Disorders
[0207] An implantable device formed of a material or coating
containing any combination of embodiments of the composition
comprising the biodegradable, dioxanone-based copolymer can be used
to treat, prevent or diagnose various conditions or disorders.
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. A portion of the implantable
device or the whole device itself can be formed of the material, as
described herein. For example, the material can be a coating
disposed over at least a portion of the device.
[0208] Accordingly, some embodiments of the invention, optionally
in combination with one or more other embodiments described herein,
are 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 or coating
containing any combination of embodiments of the composition
comprising the biodegradable, dioxananone-based copolymer. For
example, the implantable device can be formed of a material or
coating comprising a composition that can optionally have at least
one dihydroxyaryl group conjugated to the ends of the copolymer and
can optionally contain at least one additional biocompatible
moiety, at least one non-fouling moiety, at least one biobeneficial
material, at least one biologically active agent, or a combination
thereof.
[0209] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the inventive method
treats, prevents or diagnoses a condition or disorder 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 particular embodiment, the
condition or disorder is atherosclerosis, thrombosis, restenosis or
vulnerable plaque.
[0210] In one embodiment of the method, optionally in combination
with one or more other embodiments described herein, the
implantable device is formed of a material or coating containing 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-hydroxyl)ethyl-rapamycin (everolimus),
40-O-(2-ethoxyl)ethyl-rapamycin (biolimus),
40-O-(3-hydroxyl)propyl-rapamycin,
40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, progenitor cell-capturing antibodies, prohealing drugs,
prodrugs thereof, co-drugs thereof, and a combination thereof.
[0211] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the implantable device
used in the method is selected from stents, grafts, stent-grafts,
catheters, leads and electrodes, clips, shunts, closure devices,
valves, and particles. In a specific embodiment, the implantable
device is a stent.
Examples
[0212] The examples set forth below are shown for the sole purpose
of further illustrating embodiments of the present invention and
are in no way meant to limit the invention. The following prophetic
examples are given to aid in understanding the invention, but it is
to be understood that the invention is not limited to the
particular materials or procedures of the examples.
[0213] Synthesis of Dioxananone-Based Copolymers
[0214] The biodegradable, dioxananone-based copolymer 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 partially or completely
dissolved in a solvent.
[0215] The copolymer of the invention can be synthesized by
standard methods known to those having ordinary skill in the art,
e.g., by ring-opening polymerization (ROP) with the corresponding
monomers of the copolymer and using an initiator. ROP 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. For example, zirconium catalysts such as zirconium
acetylacetone, zinc catalysts such as diethylzinc and zinc
L-lactate, and tin catalysts such as stannous octoate and tin
triflates are particularly suitable for the synthesis of
biodegradable polyesters.
[0216] In some embodiments, the initiator employed in the synthesis
of the copolymer has at least one active end group that is a
hydroxyl, amino or thiol group. If the initiator has only one
active end group, then the polymer grows only at one end. On the
other hand, if the initiator has two active end groups, then a
polymerization reaction occurs at both ends of the polymer. In an
embodiment, the initiator is a diol, in which one of the hydroxyl
end groups may optionally be protected. In another embodiment, the
initiator is a diamine, in which one of the amino end groups may
optionally be protected. In yet another embodiment, the initiator
is a dithiol, in which one of the thiol end groups may optionally
be protected. In further embodiments, the dihydroxy, diamino or
dithiol initiator is C.sub.2-C.sub.24 and contains an optionally
substituted aliphatic, heteroaliphatic, cycloaliphatic,
heterocycloaliphatic, aromatic or heteroaromatic group, or a
combination thereof. In other embodiments, the initiator is a diol
selected from 1,2-ethanediol, 1,3-propanediol, 1,4-butanediol,
1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol,
diethylene glycol, triethylene glycol, tetraethylene glycol,
poly(ethylene glycol), poly(propylene glycol), poly(tetramethylene
glycol), and poly(caprolactone) diol.
[0217] Accordingly, some embodiments of the invention are directed
to a method of preparing the inventive composition, comprising
performing ring-opening polymerization (ROP) reactions with an
initiator, dioxanone and at least one additional ester-, carbonate-
or ether-based monomer, wherein:
[0218] the initiator has one or two active hydroxyl, amino or thiol
end groups; [0219] the initiator can do the initial ROP reaction
with dioxanone or a different ester-, carbonate- or ether-based
monomer; [0220] the ROP reaction with each different type of
monomer can occur in any order and for any number of times; and
[0221] a particular ROP reaction can occur in the presence of only
one type of monomer or in the presence of two or more different
types of monomers.
[0222] The various embodiments of the inventive composition
comprising the biodegradable, dioxanone-based copolymer can be
prepared by optionally: [0223] conjugating at least one
dihydroxyaryl group to the ends of the copolymer; [0224] blending
or physically or chemically attaching at least one additional
biocompatible moiety with or to the copolymer; [0225] blending or
physically or chemically attaching at least one non-fouling moiety
with or to the copolymer; [0226] blending or physically or
chemically attaching at least one biobeneficial material with or to
the copolymer; and/or [0227] incorporating at least one
biologically active agent with the copolymer.
[0228] One example of the synthesis of a biodegradable,
dioxanone-based copolymer of the invention is the synthesis of
P(DS-GA-DLLA-TMC) via ROP in Scheme 1. In this example,
mono-protected 1,6-hexanediol is the initiator. It initiates ROP
with dioxanone (DS) to form PDS. The hydroxyl end group of PDS then
initiates ROP with glycolide (GA) to generate P(DS-GA). Similarly,
the hydroxyl end group of P(DS-GA) in turn initiates ROP with
D,L-lactide (DLLA) to furnish P(DS-GA-DLLA). Finally, the hydroxyl
end group of P(DS-GA-DLLA) initiates ROP with trimethylene
carbonate (TMC) to produce P(DS-GA-DLLA-TMC).
[0229] In the example illustrated in Scheme 1, it should be
understood that a particular ROP reaction with a particular type of
monomer can occur any number of times. Therefore, the variables m,
n, p and q can be any integer For example, each of these variables
can independently be 1 to 10,000, or 5 to 5,000, or 10 to 4,000, or
20 to 3,000, or 30 to 2,000, or 40 to 1,000, or 50 to 500. The
order of ROP reactions depicted in Scheme 1 is merely illustrative.
The ROP reactions involving the four different types of monomer can
occur in any order. Moreover, a particular ROP reaction can be
random by being performed in the presence of two or more different
types of monomers.
[0230] If a particular ROP reaction with a particular type of
monomer occurs multiple times, a block or segment derived from that
monomer can be created. The block or segment can be a certain
length or molecular weight, and can alternate with another block or
segment derived from another type of monomer. Further, a block or
segment can be derived from two or more different types of
monomers, wherein each type of monomer undergoes a particular ROP
reaction a certain number of times. These ROP reactions can also
alternate in forming a block or segment. In addition, a random
block or segment can be created by conducting an ROP reaction in
the presence of two or more different types of polymers any number
of times, optionally conducting another ROP reaction in the
presence of two or more other types of polymers any number of
times, and so on.
[0231] If desired, the protected "left" end of the copolymer in
Scheme 1 can remain protected after the polymerization reactions
have been completed, and the hydroxyl group at the "right" end can
be functionalized in any desired manner. Alternatively,
deprotection of the left end of the copolymer allows this end to be
functionalized in any desired fashion, with appropriate
pre-protection of the right end group, if desired. The use of
protecting (or blocking) groups in organic synthesis is well known
in the art.
[0232] For example, both hydroxyl end groups can be conjugated to a
dihydroxyaryl group to enhance the adhesion of the copolymer to
metal surfaces. The at least one dihydroxyaryl group 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 the hydroxyl end groups of the
copolymer via coupling with 1,1'-carbonyldiimidazole.
3,4-Dihydroxy-hydrocinnamic acid could be conjugated to the
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.
[0233] As another example, either the left or the right hydroxyl
end group, or both end groups, independently can be attached to a
biocompatible moiety, a non-fouling moiety, a biobeneficial
material, and/or a bioactive agent. Alternatively, monomers
different than those shown in Scheme 1 and bearing a protected side
group can be used in synthesizing the copolymer. After completion
of the polymerization reactions, the side groups can be deprotected
and functionalized as desired, e.g., by attaching them to a
biocompatible moiety, a non-fouling moiety, a biobeneficial
material, and/or a bioactive agent.
[0234] Protection of the right end of the copolymer in Scheme 1 and
deprotection of the left end permit the left end to be elaborated
in further polymerization reactions. The polymerization reactions
occurring at the left end can involve any types of monomers, can
transpire any number of times, and can occur in any order and
manner, as desired. Alternatively, the 1,6-hexanediol initiator in
Scheme 1 can initiate ROP as an unprotected diol. In this case,
both the right and left ends of the polymer would be elaborated in
the same way in the polymerization reactions.
##STR00001##
[0235] Drug-Coated Stent
[0236] The copolymer illustrated in Scheme 1 is dissolved in
hexafluoroisopropanol at 2% w/w. Everolimus is added to the
solution at a drug-to-polymer ratio of 1:1. Vision stent at
3.times.18 mm is mounted on a mandrel. The solution is spray-coated
on the stent with multiple passes. The solvent is then removed by
baking the stent at 50.degree. C. for 2 hours.
[0237] 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.
[0238] It should be understood that if a substance can have more
than one stereochemistry and/or regiochemistry at one or more
stereocenters and/or regiocenters and the stereochemistry and/or
regiochemistry of the substance at the one or more stereocenters
and/or regiocenters are not indicated, the scope of the present
invention encompasses all possible stereoisomers (e.g.,
enantiomers, diastereomers, etc.) and/or regioisomers of that
substance.
* * * * *