U.S. patent application number 11/528891 was filed with the patent office on 2007-08-23 for coatings including an antioxidant.
Invention is credited to Leslie Coleman, Ni Ding.
Application Number | 20070198080 11/528891 |
Document ID | / |
Family ID | 37679362 |
Filed Date | 2007-08-23 |
United States Patent
Application |
20070198080 |
Kind Code |
A1 |
Ding; Ni ; et al. |
August 23, 2007 |
Coatings including an antioxidant
Abstract
A coating including an antioxidant or a combination of
antioxidant and another bioactive agent on a medical device is
described.
Inventors: |
Ding; Ni; (San Jose, CA)
; Coleman; Leslie; (Redwood City, CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY L.L.P.
1 MARITIME PLAZA, SUITE 300
SAN FRANCISCO
CA
94111
US
|
Family ID: |
37679362 |
Appl. No.: |
11/528891 |
Filed: |
September 27, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11189216 |
Jul 25, 2005 |
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11528891 |
Sep 27, 2006 |
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Current U.S.
Class: |
623/1.38 ;
424/426; 427/2.1; 623/1.42 |
Current CPC
Class: |
A61L 31/10 20130101;
Y10T 428/1307 20150115 |
Class at
Publication: |
623/001.38 ;
427/002.1; 623/001.42; 424/426 |
International
Class: |
A61L 33/00 20060101
A61L033/00; B05D 3/00 20060101 B05D003/00; A61F 2/06 20060101
A61F002/06; A61F 2/02 20060101 A61F002/02; A61F 2/82 20060101
A61F002/82 |
Claims
1. A medical device comprising a coating, the coating comprising an
antioxidant selected from natural antioxidants, synthetic
antioxidants, or combinations thereof, wherein the synthetic
antioxidant is not butylated hydroxytoluene (BHT) or butylated
hydroxyanisole (BHA), and wherein the natural antioxidant is not
Vitamin E.
2. The medical device of claim 1, wherein the antioxidant is
selected from ascorbic acid, folic acid and b vitamins, beta
carotene, flavonoids, a super-oxide dismutase mimetic (SODm),
polyphenol antioxidants, apigenin or combinations thereof.
3. The medical device of claim 2, wherein the SODm is attached to
the surface of the coating.
4. The medical device of claim 3, wherein the SODm is attached to a
polymer in the coating.
5. The medical device of claim 1, wherein the coating further
comprises a bioactive agent.
6. The medical device of claim 1, wherein the coating further
comprises heparin.
7. The medical device of claim 5, wherein the bioactive agent is
selected from the group consisting of paclitaxel, docetaxel,
estradiol, nitric oxide donors, super oxide dismutases, super oxide
dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor cell capturing antibody, prohealing drugs, prodrugs
thereof, co-drugs thereof, or a combination thereof.
8. The medical device of claim 1, which is a stent.
9. The medical device of claim 1, which is a bioabsorbable
stent.
10. The medical device of claim 1, wherein the SODm comprises a
Mn(II) coordinated in a macrocyclic pentamine ring.
11. A bioabsorbable medical device comprising an antioxidant
selected from natural antioxidants, synthetic antioxidants, or
combinations thereof, wherein the synthetic antioxidant is not
butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA),
and wherein the natural antioxidant is not Vitamin E.
12. The bioabsorbable medical device of claim 11, wherein the
antioxidant is selected from ascorbic acid, folic acid and b
vitamins, beta carotene, flavonoids, a super-oxide dismutase
mimetic (SODm), polyphenol antioxidants, apigenin or combinations
thereof.
13. The bioabsorbable medical device of claim 11, wherein the SODm
is attached to the surface of the bioabsorbable medical device.
14. The bioabsorbable medical device of claim 11, wherein the
bioabsorbable medical device further comprises a bioactive
agent.
15. The bioabsorbable medical device of claim 11, wherein the
bioabsorbable medical device further comprises heparin.
16. The medical device of claim 14, wherein the bioactive agent is
selected from the group consisting of paclitaxel, docetaxel,
estradiol, nitric oxide donors, super oxide dismutases, super oxide
dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor cell capturing antibody, prohealing drugs, prodrugs
thereof, co-drugs thereof, or a combination thereof.
17. The bioabsorbable medical device of claim 11, which is a
stent.
18. The bioabsorbable medical device of claim 11, wherein the SODm
comprises a Mn(II) coordinated in a macrocyclic pentamine ring.
19. A method comprising applying to a medical device a formulation
comprising an antioxidant selected from natural antioxidants,
synthetic antioxidants, or combinations thereof, and forming a
coating of the formulation on the medical device, wherein the
synthetic antioxidant is not butylated hydroxytoluene (BHT) or
butylated hydroxyanisole (BHA), wherein the synthetic antioxidant
is not butylated hydroxytoluene (BHT) or butylated hydroxyanisole
(BHA), and wherein the natural antioxidant is not Vitamin E.
20. The method of claim 19, wherein the antioxidant is selected
from ascorbic acid, folic acid and B vitamins, beta carotene,
flavonoids, a super-oxide dismutase mimetic (SODm), polyphenol
antioxidants, apigenin or combinations thereof.
21. The method of claim 20, wherein the SODm is attached to the
surface of the coating.
22. The method of claim 20, wherein the SODm is attached to a
polymer in the coating.
23. The method of claim 19, wherein the formulation further
comprises a bioactive agent.
24. The method of claim 19, wherein the formulation further
comprises heparin.
25. The method of claim 24, wherein the bioactive agent is selected
from the group consisting of paclitaxel, docetaxel, estradiol,
nitric oxide donors, super oxide dismutases, super oxide dismutases
mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate; midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor cell capturing antibody, prohealing drugs, prodrugs
thereof, co-drugs thereof, or a combination thereof.
26. The method of claim 19, wherein the medical device is a
stent.
27. The method of claim 19, wherein the medical device is a
bioabsorbable stent.
27. The method of claim 19, wherein forming the coating comprises
baking the coating, and sterilizing the coating.
28. The method of claim 27, wherein the baking or sterilizing are
conducted at a temperature between about 25.degree. C. and about
55.degree. C.
29. The method of claim 20, wherein the SODm comprises a Mn(II)
coordinated in a macrocyclic pentamine ring.
30. A method comprising implanting the medical device of claim 1
into a human being in need of treatment for atherosclerosis,
thrombosis, restenosis, hemorrhage, vascular dissection or
perforation, vascular aneurysm, vulnerable plaque, chronic total
occlusion, claudication, anastomotic proliferation (for vein and
artificial grafts), bile duct obstruction, ureter obstruction,
tumor obstruction, or combinations of these.
31. A method, comprising implanting the medical device of claim 7
to the human being, into a human being in need of treatment for
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection or perforation, vascular aneurysm, vulnerable plaque,
chronic total occlusion, claudication, anastomotic proliferation
(for vein and artificial grafts), bile duct obstruction, ureter
obstruction, tumor obstruction, or combinations of these.
32. A method comprising implanting the medical device of claim 8
into a human being in need of treatment for atherosclerosis,
thrombosis, restenosis, hemorrhage, vascular dissection or
perforation, vascular aneurysm, vulnerable plaque, chronic total
occlusion, claudication, anastomotic proliferation (for vein and
artificial grafts), bile duct obstruction, ureter obstruction,
tumor obstruction, or combinations of these.
33. A medical device comprising a coating, the coating comprising
at least two antioxidants, wherein one antioxidant is selected from
BHT, BHA, Vitamin E, a SODm or a combination thereof.
34. The medical device of claim 33, wherein the other antioxidant
is selected from ascorbic acid, folic acid and b vitamins, beta
carotene, flavonoids, polyphenol antioxidants, apigenin or
combinations thereof.
35. The medical device of claim 33, wherein the SODm is attached to
the surface of the coating.
36. The medical device of claim 35, wherein the SODm is attached to
a polymer in the coating.
37. The medical device of claim 33, wherein the coating further
comprises a bioactive agent.
38. The medical device of claim 33, wherein the coating further
comprises heparin.
39. The medical device of claim 37, wherein the bioactive agent is
selected from the group consisting of paclitaxel, docetaxel,
estradiol, nitric oxide donors, super oxide dismutases, super oxide
dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor cell capturing antibody, prohealing drugs, prodrugs
thereof, co-drugs thereof, or a combination thereof.
40. The medical device of claim 33, which is a stent.
41. The medical device of claim 33, which is a bioabsorbable
stent.
42. The medical device of claim 33, wherein the SODm comprises a
Mn(II) coordinated in a macrocyclic pentamine ring.
43. A bioabsorbable medical device comprising at least two
antioxidants, wherein one antioxidant is selected from BHT, BHA,
Vitamin E, a SODm or a combination thereof.
44. The bioabsorbable medical device of claim 43, wherein the
antioxidant is selected from ascorbic acid, folic acid and b
vitamins, beta carotene, flavonoids, a super-oxide dismutase
mimetic (SODm), polyphenol antioxidants, apigenin or combinations
thereof.
45. The bioabsorbable medical device of claim 43, wherein the SODm
is attached to the surface of the bioabsorbable medical device.
46. The bioabsorbable medical device of claim 43, wherein the
bioabsorbable medical device further comprises a bioactive
agent.
47. The bioabsorbable medical device of claim 43, wherein the
bioabsorbable medical device further comprises heparin.
48. The medical device of claim 46, wherein the bioactive agent is
selected from the group consisting of paclitaxel, docetaxel,
estradiol, nitric oxide donors, super oxide dismutases, super oxide
dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor cell capturing antibody, prohealing drugs, prodrugs
thereof, co-drugs thereof, or a combination thereof.
49. The bioabsorbable medical device of claim 43, which is a
stent.
50. The bioabsorbable medical device of claim 43, wherein the SODm
comprises a Mn(II) coordinated in a macrocyclic pentamine ring.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This is a continuation-in-part application of U.S.
application Ser. No. 11/189,216, filed on Jul. 25, 2005, the
teachings of which are incorporated hereto by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention generally relates to a method of providing an
antioxidant to a coating on a medical device such as a
drug-delivery stent.
[0004] 2. Description of the Background
[0005] Blood vessel occlusions are commonly treated by mechanically
enhancing blood flow in the affected vessels, such as by employing
a stent. Stents are used not only for mechanical intervention but
also as vehicles for providing biological therapy. To effect a
controlled delivery of an active agent in stent medication, the
stent can be coated with a biocompatible polymeric coating. The
biocompatible polymeric coating can function either as a permeable
layer or a carrier to allow a controlled delivery of the agent.
[0006] Although stents work well mechanically, the chronic issues
of restenosis and, to a lesser extent, stent thrombosis remain.
Pharmacological therapy in the form of a drug delivery stent
appears to be a feasible means to tackle these issues. Subacute
thrombosis and neointimal hyperplasia are considered to be the
leading complications after stenting. Various factors are believed
to be involved in the process. Methods for reducing thrombosis and
restenosis have been previously proposed. However, those methods
are less satisfactory for reducing thrombosis or restenosis
associated with stenting.
[0007] The embodiments disclosed herein address the above described
problems.
SUMMARY OF THE INVENTION
[0008] Provided herein is a coating that includes an antioxidant
for a medical device. The coating includes a polymer matrix, an
antioxidant, and optionally heparin or a bioactive agent. In some
embodiments, the coating can include a biobeneficial material. The
coating can be biodegradable or nondegradable. In some embodiments,
the medical device can be a stent. In some embodiments, the stent,
itself, can be a polymeric biodegradable, bioerodable or
bioabsorbable stent, terms which are used interchangeably unless
specifically indicated, which can include the bioactive agent
embedded in the body of the stent or coating in the stent.
[0009] In some embodiments, the antioxidant can be embedded within
the coating of the body of the medical device. In some embodiments,
the antioxidant can be attached to the surface of the coating or
surface of the medical device.
[0010] In some embodiments, a coating or device can include two ore
more antioxidants, at least one of the antioxidant can be butylated
hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Vitamin E, a
super-oxide dismutase mimetic (SODm), or combinations thereof.
[0011] Some examples of the bioactive agent that can be included in
the coating or medical device include, but are not limited to,
paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor cell capturing antibody, prohealing drugs, prodrugs
thereof, co-drugs thereof, or a combination thereof.
[0012] The medical device having the features described herein can
be used for treating, preventing, or ameliorating a medical
condition such as atherosclerosis, thrombosis, restenosis,
hemorrhage, vascular dissection or perforation, vascular aneurysm,
vulnerable plaque, chronic total occlusion, claudication,
anastomotic proliferation (for vein and artificial grafts), bile
duct obstruction, ureter obstruction, tumor obstruction, or
combinations of these.
DETAILED DESCRIPTION
[0013] Provided herein is a coating that includes an antioxidant
for a medical device. The coating includes a polymer matrix, an
antioxidant, and optionally heparin or a bioactive agent. In some
embodiments, the coating can include a biobeneficial material. The
coating can be biodegradable or nondegradable. In some embodiments,
the medical device can be a stent. In some embodiments, the stent,
itself, can be a polymeric biodegradable, bioerodable or
bioabsorbable stent, terms which are used interchangeably unless
specifically indicated, which can include the bioactive agent
embedded in the body of the stent or coating in the stent.
[0014] In some embodiments, the antioxidant can be embedded within
the coating of the body of the medical device. In some embodiments,
the antioxidant can be attached to the surface of the coating or
surface of the medical device.
[0015] In some embodiments, a coating or device can include two ore
more antioxidants, at least one of the antioxidant can be BHT, BHA,
Vitamin E, a SODm, or combinations thereof.
[0016] Some examples of the bioactive agent that can be included in
the coating or medical device include, but are not limited to,
paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor cell capturing antibody, prohealing drugs, prodrugs
thereof, co-drugs thereof, or a combination thereof.
[0017] The medical device having the features described herein can
be used for treating, preventing, or ameliorating a medical
condition such as atherosclerosis, thrombosis, restenosis,
hemorrhage, vascular dissection or perforation, vascular aneurysm,
vulnerable plaque, chronic total occlusion, claudication,
anastomotic proliferation (for vein and artificial grafts), bile
duct obstruction, ureter obstruction, tumor obstruction, or
combinations of these.
Antioxidants
[0018] As used herein, the term "antioxidant" refers to a substance
that is capable of inhibiting, preventing, reducing or ameliorating
oxidative reactions on another substance (e.g., a polymer, a
bioactive agent or a therapeutic substance) when the antioxidant is
used in a system (e.g., coating) that includes such other
substances. An example of such "antioxidant" is oxygen
scavenger.
[0019] The antioxidant useful in the present invention can be any
volatile or non-volatile antioxidant, which can be natural or
synthetic. Natural antioxidant refers to an antioxidant derived
from a natural source, with or without modification. Synthetic
antioxidant refers to any antioxidant that is not a natural
antioxidant. For example, ascorbic acid (Vitamin C) can be a
natural antioxidant. BHT, BHA, or a SODm can be a synthetic
antioxidant.
[0020] In some embodiments, the antioxidant includes, but is not
limited to, BHT, BHA, ascorbic acid (Vitamin C), folic acid, b
vitamins, beta carotene, flavonoids, SODm, polyphenol antioxidants
such as apigenin or combinations thereof.
[0021] In some embodiments, the term "antioxidant" can specifically
exclude an antioxidant described above. For example, the term
"antioxidant" can specifically exclude BHT, BHA or a SODm. In some
embodiments, the term "antioxidant" can specifically exclude
Vitamin E. In some embodiments, the term "antioxidant" can
specifically exclude a super-oxide dismutase mimetic (SODm). In
still some embodiments, the antioxidant can specifically exclude
one of folic acid, b vitamins, beta carotene, flavonoids,
polyphenol antioxidants such as apigenin or combinations
thereof.
Super-Oxide Dismutase Mimetic
[0022] In some embodiments, a coating or device can include a
super-oxide dismutase (SOD) mimetic (SODm). In some embodiments,
the SODm can be attached to the surface of a coating or device. The
SODm can be attached to the surface of a coating or device via
covalent bonding or non-covalent bonding. Non-covalent bonding can
be, e.g., ionic interaction, hydrogen bonding, or an
interpenetrating network (IPN).
[0023] As used herein, the term SODm refers to any super-oxide
dismutase (SOD) mimetic. SOD can have important effects on vascular
pathophysiology. For example, SOD1-deficient mice have been found
to produce more superoxide than their wild-type controls and have
decreased endothelium-dependent and -independent vasodilation. SOD1
overexpression in mice causes a decrease in VSMC proliferation in
response to EGF but no change in the aortic hypertrophic response
to Angiotensin II. A separate study with mice overexpressing SOD1
on the apoE.sup.-/- background showed no significant effect on
aortic atherosclerotic lesion area. Total SOD2 deficiency is lethal
in mice, and although partial SOD2 deficiency has been shown to
cause an increase in atherosclerotic lesion formation at arterial
branch points, there was no effect on vasomotor responses to
serotonin, PGF2.alpha., or acetylcholine at baseline or after
inhibition of SOD1 and SOD3 with diethyldithiocarbamate. The second
most abundant SOD isoform in blood vessels is SOD3, which is
predominantly produced by VSMCs, but because of its location in the
interstitium between ECs and VSMCs, it is thought to be essential
for endothelial-dependent vasodilation by protecting NO as it
diffuses from the ECs to the VSMCs. These differences in the
regulation of vascular tone or in the formation of atherosclerotic
lesions indicate the potential importance of the subcellular
localization of antioxidant systems in the modulation of local
oxidant signaling.
[0024] Some examples of SODm include, but are not limited to, low
molecular weight SOD synzymes having a Mn(II) coordinated in a
macrocyclic pentamine ring (Ref: Riley D P, Weiss R H. JACS 1994;
116:387-388). In some embodiments, a coating or device can
specifically exclude a SODm described above.
[0025] A SODm can be included in the coating or device or attached
to the surface of a coating or device with or without a spacer.
Attaching a SODm to the surface of a coating or device can be
achieved by, for example, attaching the SODm to a polymer on the
surface of the coating or the device via coupling of the reactive
group in the SODm molecule to the polymer. In some embodiments,
attaching a SODm to the polymer can be achieved by photo or
thermally initiated radical coupling, which are well known in the
art. In some embodiments, covalent attachment of a SODm to a
polymer in the coating can be accomplished for example by reacting
isocyanate group on the polymer chain with amino group on SODm
(ref. Udipi, K, et al. J. biomaterial Mater. Res., 51, 549-560,
2000).
[0026] In some embodiments, attachment of a SODm to the polymer can
be induced via photo activation. For example, photo-reactive
chemical(s) (PRC) can extract hydrogen on the surface in the form
of C--H or Si--H bonds, and covalently couple directly to the
surface. If the PRC contains chemically reactive groups, a SODm,
can be bound to the PRC. As a result, a SODm can be covalently
grafted to the carbon surface.
[0027] Examples of photo-reactive chemicals are from the
benzophenone family, i.e. benzophenone tetracarboxylic dianhydride,
benzoylbenzoic acid, benzoyl benzoyl chloride, 4-benzoylbenzoic
acid N-hydroxysuccinimide ester, benzoyl benzoyl amine, or from
azide family, i.e. substituted phenyl azide and substituted acyl
azide.
[0028] The hydrogen extraction can be initiated by UV exposure of
the PRC entity. The linking reaction between PRC to the SODm will
be dependent on the specific structure of the molecule but can be
readily carried out by an ordinary artisan. For example, an amine
functional group on SODm can react with an anhydride or acyl
chloride of substituted benzophenone. The PRC can be coupled to the
carbon surface first and then coupled with the SODm, or vice
versa.
[0029] In some embodiments, a SODm can be attached to a polymer to
form a SODm/polymer conjugate. The SODm/polymer conjugate can then
be included in a formulation for forming a coating or a device. The
SODm/polymer conjugate can have a covalent bond or non-covalent
bond between the SODm and the polymer.
[0030] In some embodiments, antioxidants can be susceptible to
oxidation or chemical changes under certain conditions. For
example, BHT and BHA at an elevated temperature can compromise the
molecular integrity of the antioxidant or cause an volatile
antioxidant to evaporate. Therefore, the conditions in the coating
process or device forming process can affect the content of the
antioxidant to minimize the reduction of the level of
antioxidant.
[0031] In some embodiments, the loss of antioxidant(s) in the
coating or device forming process can be reduced by controlling the
processing conditions. Such control of processing conditions can
be, e.g., duration of the process, exclusion of air or oxygen using
inert atmosphere or lowering the processing temperature. In some
embodiments, the sterilization process can be conducted at a low
temperature. A low temperature of sterilization refers to a
temperature from about 25.degree. C. to about 55.degree. C., e.g.,
from about 30.degree. C. to about 45.degree. C. In some
embodiments, the baking process can be conducted at a low
temperature or in vacuum. A low temperature of baking refers to a
temperature from about 25.degree. C. to about 55.degree. C. with
and without vacumm. The procedure or process of coating or forming
a medical device including stent is well documented in the art.
[0032] In some embodiments, the content of the antioxidant in a
coating or device can be maintained or enhanced by adding an
additional amount of the antioxidant (e.g., BHT or BHA) in the
formulation forming the coating or device. Such additional amount
depends from the chemical, physical or physiological nature of the
antioxidant. For example, in the coating formulation, the BHT level
can be increased up to about 60 wt %. Other types of antioxidant
such as vitamin C can have a level from about 60 wt %. If a coating
already contains an active agent, the antioxidant can be added as a
second active agent in the coating at an amount that can be up to
about 50 wt %. The active agent can be, e.g., paclitaxel,
docetaxel, estradiol, nitric oxide donors, super oxide dismutases,
super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor-cell-capturing antibody, or combinations thereof.
Biocompatible Polymers
[0033] A coating or device having an antioxidant described herein
can include one or more biocompatible polymer(s). The biocompatible
polymer can be biodegradable (bioerodable or bioabsorbable) or
nondegradable. Representative biocompatible polymers include, but
are not limited to, poly(ester amide), polyhydroxyalkanoates (PHA),
poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),
poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),
poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) and
poly(3-hydroxyoctanoate), poly(4-hydroxyalkanaote) such as
poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),
poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),
poly(4-hydroxyoctanoate) and copolymers including any of the
3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein
or blends thereof, poly(D,L-lactide), poly(L-lactide),
polyglycolide, poly(D,L-lactide-co-glycolide),
poly(L-lactide-co-glycolide), polycaprolactone,
poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),
poly(dioxanone), poly(ortho esters), poly(anhydrides),
poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine
ester) and derivatives thereof, poly(imino carbonates),
poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,
polyphosphoester urethane, poly(amino acids), polycyanoacrylates,
poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes,
polyphosphazenes, silicones, polyesters, polyolefins,
polyisobutylene and ethylene-alphaolefin copolymers, acrylic
polymers and copolymers, vinyl halide polymers and copolymers, such
as polyvinyl chloride, polyvinyl ethers, such as polyvinyl methyl
ether, polyvinylidene halides, such as polyvinylidene chloride,
polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, such as
polystyrene, polyvinyl esters, such as polyvinyl acetate,
copolymers of vinyl monomers with each other and olefins, such as
ethylene-methyl methacrylate copolymers, polycarbonates,
polyoxymethylenes, polyimides, polyethers, poly(glyceryl sebacate),
poly(propylene fumarate), poly(n-butyl methacrylate),
poly(sec-butyl methacrylate), poly(isobutyl methacrylate),
poly(tert-butyl methacrylate), poly(n-propyl methacrylate),
poly(isopropyl methacrylate), poly(ethyl methacrylate), poly(methyl
methacrylate), epoxy resins, polyurethanes, rayon,
rayon-triacetate, cellulose acetate, cellulose butyrate, cellulose
acetate butyrate, cellophane, cellulose nitrate, cellulose
propionate, cellulose ethers, carboxymethyl cellulose, polyethers
such as poly(ethylene glycol) (PEG), copoly(ether-esters) (e.g.
PEO/PLA), polyalkylene oxides such as poly(ethylene oxide),
poly(propylene oxide), poly(ether ester), polyalkylene oxalates,
polyphosphazenes, phosphoryl choline, choline, poly(aspirin),
polymers and co-polymers of hydroxyl bearing monomers such as HEMA,
hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG
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),
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), poly(vinylidene
fluoride)-PEG (PVDF-PEG), PLURONIC.TM. surfactants (polypropylene
oxide-co-polyethylene glycol), poly(tetramethylene glycol), hydroxy
functional poly(vinyl pyrrolidone), biomolecules such as collagen,
chitosan, alginate, fibrin, fibrinogen, cellulose, starch,
collagen, dextran, dextrin, fragments and derivatives of hyaluronic
acid, heparin, fragments and derivatives of heparin, glycosamino
glycan (GAG), GAG derivatives, polysaccharide, elastin, chitosan,
alginate, or combinations thereof. In some embodiments, the coating
or device described herein can exclude any one of the
aforementioned polymers.
[0034] As used herein, the terms poly(D,L-lactide),
poly(L-lactide), poly(D,L-lactide-co-glycolide), and
poly(L-lactide-co-glycolide) can be used interchangeably with the
terms poly(D,L-lactic acid), poly(L-lactic acid), poly(D,L-lactic
acid-co-glycolic acid), or poly(L-lactic acid-co-glycolic acid),
respectively.
[0035] In some embodiments, the coating or device can include a
fluoropolymer such as a Solef.TM. polymer (e.g., PVDF-HFP).
[0036] In some embodiments, the coating or device can further
include a biobeneficial material. The biobeneficial material can be
polymeric or non-polymeric. The biobeneficial material is
preferably substantially non-toxic, non-antigenic and
non-immunogenic. A biobeneficial material is one that enhances the
biocompatibility of a device by being non-fouling, hemocompatible,
actively non-thrombogenic, or anti-inflammatory, all without
depending on the release of a pharmaceutically active agent.
[0037] Representative biobeneficial materials include, but are not
limited to, polyethers such as poly(ethylene glycol),
copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxides such as
poly(ethylene oxide), poly(propylene oxide), poly(ether ester),
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),
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), poly(vinylidene
fluoride)-PEG (PVDF-PEG), PLURONIC.TM. surfactants (polypropylene
oxide-co-polyethylene glycol), poly(tetramethylene glycol), hydroxy
functional poly(vinyl pyrrolidone), 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, polysaccharide, elastin, chitosan,
alginate, silicones, PolyActive.TM., and combinations thereof. In
some embodiments, the coating or device can exclude any one of the
aforementioned polymers.
[0038] The term PolyActive.TM. refers to a block copolymer having
flexible poly(ethylene glycol) and poly(butylene terephthalate)
blocks (PEGT/PBT). PolyActive.TM. is intended to include AB, ABA,
BAB copolymers having such segments of PEG and PBT (e.g.,
poly(ethylene glycol)-block-poly(butyleneterephthalate)-block
poly(ethylene glycol) (PEG-PBT-PEG).
[0039] In a preferred embodiment, the biobeneficial material can be
a polyether such as poly(ethylene glycol) (PEG) or polyalkylene
oxide.
[0040] Above listed polymers can be used as a drug carrier for
active agents or topcoat to control the drug release.
Alternatively, one active agent (such as antioxidant) can be
imbedded in one biocompatible coating and another active agent
(anti-proliferative agent) can be coated with the polymer on the
top of the layer or vice versa.
Bioactive Agents
[0041] In some embodiments, the coating or device having the
features described herein can include one or more bioactive agents.
The bioactive agents can be any bioactive agent that is
therapeutic, prophylactic, or diagnostic. These agents can have
anti-proliferative or anti-inflammatory properties or can have
other properties such as antineoplastic, antiplatelet,
anti-coagulant, anti-fibrin, antithrombonic, antimitotic,
antibiotic, antiallergic, and antioxidant properties. These agents
can be cystostatic agents, agents that promote the healing of the
endothelium such as NO releasing or generating agents, agents that
attract endothelial progenitor cells, or agents that promote the
attachment, migration and proliferation of endothelial cells (e.g.,
natriuretic peptide such as CNP, ANP or BNP peptide or an RGD or
cRGD peptide), while quenching smooth muscle cell proliferation.
Examples of suitable therapeutic and prophylactic agents include
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. Examples of anti-proliferative agents include
rapamycin and its functional or structural derivatives,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus), and its functional or
structural derivatives, paclitaxel and its functional and
structural derivatives. Examples of rapamycin derivatives include
methyl rapamycin (ABT-578), 40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin. Examples of paclitaxel derivatives
include docetaxel. Examples of antineoplastics or antimitotics
include methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin.RTM. from
Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.
Mutamycin.RTM. from Bristol-Myers Squibb Co., Stamford, Conn.).
Examples of such antiplatelets, anticoagulants, antifibrin, and
antithrombins include 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 Ib/IIIa platelet membrane receptor
antagonist antibody, recombinant hirudin, thrombin inhibitors such
as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channel
blockers (such as nifedipine), colchicine, fibroblast growth factor
(FGF) antagonists, fish oil (omega 3-fatty acid), histamine
antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a
cholesterol lowering drug, brand name Mevacor.RTM. from Merck &
Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such
as 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 mimetic,
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. Examples of anti-inflammatory
agents including steroidal and non-steroidal anti-inflammatory
agents include tacrolimus, dexamethasone, clobetasol, combinations
thereof. Examples of such cytostatic substance include angiopeptin,
angiotensin converting enzyme inhibitors such as captopril (e.g.
Capoten.RTM. and Capozide.RTM. from Bristol-Myers Squibb Co.,
Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil.RTM. and
Prinzide.RTM. from Merck & Co., Inc., Whitehouse Station,
N.J.). An example of an antiallergic agent is permirolast
potassium. Other therapeutic substances or agents that may be
appropriate include alpha-interferon, pimecrolimus, imatinib
mesylate, midostaurin, bioactive RGD, and genetically engineered
endothelial cells. The foregoing substances can also be used in the
form of prodrugs or co-drugs thereof. The foregoing substances also
include metabolites thereof or prodrugs of the metabolites. The
foregoing substances are listed by way of example and are not meant
to be limiting. Other active agents that are currently available or
that may be developed in the future are equally applicable.
[0042] The dosage or concentration of the bioactive agent required
to produce a favorable therapeutic effect should be less than the
level at which the bioactive agent produces toxic effects and
greater than the level at which non-therapeutic results are
obtained. The dosage or concentration of the bioactive agent can
depend upon factors such as the particular circumstances of the
patient, the nature of the trauma, the nature of the therapy
desired, the time over which the ingredient administered resides at
the vascular site, and if other active agents are employed, the
nature and type of the substance or combination of substances.
Therapeutic effective dosages can be determined empirically, for
example by infusing vessels from suitable animal model systems and
using immunohistochemical, fluorescent or electron microscopy
methods to detect the agent and its effects, or by conducting
suitable in vitro studies. Standard pharmacological test procedures
to determine dosages are understood by one of ordinary skill in the
art.
Examples of Medical Device
[0043] As used herein, a medical device may be any suitable medical
substrate that can be implanted in a human or veterinary patient.
Examples of such medical devices include self-expandable stents,
balloon-expandable stents, stent-grafts, grafts (e.g., aortic
grafts), heart valve prostheses, cerebrospinal fluid shunts,
pacemaker electrodes, catheters, and endocardial leads (e.g.,
FINELINE and ENDOTAK, available from Guidant Corporation, Santa
Clara, Calif.), anastomotic devices and connectors, orthopedic
implants such as screws, spinal implants, and electro-stimulatory
devices. The underlying structure of the device can be of virtually
any design. The device can be made of a metallic material or an
alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),
stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR
108, cobalt chrome alloy L-605, "MP35N," "MP20N," ELASTINITE
(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,
gold, magnesium, or combinations thereof. "MP35N" and "MP20N" are
trade names for alloys of cobalt, nickel, chromium and molybdenum
available from Standard Press Steel Co., Jenkintown, Pa. "MP35N"
consists of 35% cobalt, 35% nickel, 20% chromium, and 10%
molybdenum. "MP20N" consists of 50% cobalt, 20% nickel, 20%
chromium, and 10% molybdenum. Devices made from bioabsorbable
(e.g., bioabsorbable stent) or biostable polymers could also be
used with the embodiments of the present invention.
Method of Use
[0044] Preferably, the medical device is a stent. The stent
described herein is useful for a variety of medical procedures,
including, by way of example, treatment of obstructions caused by
tumors in bile ducts, esophagus, trachea/bronchi and other
biological passageways. A stent having the above-described coating
is particularly useful for treating diseased regions of blood
vessels caused by lipid deposition, monocyte or macrophage
infiltration, or dysfunctional endothelium or a combination
thereof, or occluded regions of blood vessels caused by abnormal or
inappropriate migration and proliferation of smooth muscle cells,
thrombosis, and restenosis. Stents may be placed in a wide array of
blood vessels, both arteries and veins. Representative examples of
sites include the iliac, renal, carotid and coronary arteries.
[0045] For implantation of a stent, an angiogram is first performed
to determine the appropriate positioning for stent therapy. An
angiogram is typically accomplished by injecting a radiopaque
contrasting agent through a catheter inserted into an artery or
vein as an x-ray is taken. A guidewire is then advanced through the
lesion or proposed site of treatment. Over the guidewire is passed
a delivery catheter that allows a stent in its collapsed
configuration to be inserted into the passageway. The delivery
catheter is inserted either percutaneously or by surgery into the
femoral artery, radial artery, brachial artery, femoral vein, or
brachial vein, and advanced into the appropriate blood vessel by
steering the catheter through the vascular system under
fluoroscopic guidance. A stent having the above-described coating
may then be expanded at the desired area of treatment. A
post-insertion angiogram may also be utilized to confirm
appropriate positioning.
[0046] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this 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 this invention.
* * * * *