U.S. patent application number 11/356696 was filed with the patent office on 2007-08-23 for nitric oxide generating medical devices.
Invention is credited to Paul Consigny, Thierry Glauser, Stephen D. Pacetti.
Application Number | 20070196428 11/356696 |
Document ID | / |
Family ID | 38283651 |
Filed Date | 2007-08-23 |
United States Patent
Application |
20070196428 |
Kind Code |
A1 |
Glauser; Thierry ; et
al. |
August 23, 2007 |
Nitric oxide generating medical devices
Abstract
Medical devices having a catalyst capable of catalyzing the
generation of nitric oxide attached to the medical device and
methods of treating a vascular condition using the devices are
provided.
Inventors: |
Glauser; Thierry; (Redwood
City, CA) ; Pacetti; Stephen D.; (San Jose, CA)
; Consigny; Paul; (San Jose, CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA
SUITE 300
SAN FRANCISCO
CA
94111
US
|
Family ID: |
38283651 |
Appl. No.: |
11/356696 |
Filed: |
February 17, 2006 |
Current U.S.
Class: |
424/426 ;
514/184; 514/185 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 35/00 20180101; A61L 31/16 20130101; A61L 31/08 20130101; A61K
33/00 20130101; A61L 29/16 20130101; A61L 31/10 20130101; A61L
31/148 20130101; A61P 9/08 20180101; A61P 7/04 20180101; A61L
2300/114 20130101; A61L 2300/606 20130101; A61P 9/10 20180101; A61P
7/02 20180101 |
Class at
Publication: |
424/426 ;
514/184; 514/185 |
International
Class: |
A61K 31/555 20060101
A61K031/555; A61F 2/02 20060101 A61F002/02 |
Claims
1. A medical device comprising a polymer and a metal complex
attached to the polymer wherein the metal complex catalyzes the in
vivo generation of nitric oxide
2. The medical device of claim 1 wherein in vivo generation of
nitric oxide is nitric oxide generation in the blood stream or
tissue adjacent to the medical device.
3. The medical device of claim 1 further comprising a coating for
the medical device wherein the coating comprises the polymer.
4. The medical device of claim 1 wherein the medical device is a
bioabsorbable stent comprising the polymer.
5. The medical device of claim 1 wherein the metal complex
comprises copper.
6. The medical device of claim 1 wherein the metal complex
comprises Cyclen, Cyclam, DTTCT, or a bipyridine ligand.
7. The medical device of claim 1 where in the metal complex
comprises copper and at least one of Cyclen, Cyclam, DTTCT, or a
bipyridine ligand.
8. The medical device of claim 1 wherein the metal complex attaches
to the polymer via a spacer.
9. The medical device of claim 7 wherein the metal complex attaches
to the polymer via a spacer.
10. The medical device of claim 8, wherein the spacer is a short
chain alkyl group, phenyl group, aryl group, or poly(ethylene
glycol).
11. The medical device of claim 1 wherein the metal complex
comprises a metal selected from the group consisting of Cu, Co, Ni,
Zn, Mn, Al, or Fe.
12. The medical device of claim 1 wherein the metal complex
comprises an ion selected from the group consisting of Cu.sup.2+,
Co.sup.2+, Ni.sup.2+, Zn.sup.+2+, Mn.sup.2+, Al.sup.3+, or
Fe.sup.3+.
13. The medical device of claim 1 further comprising a drug adapted
to be released from the device.
14. The medical device of claim 1 additionally including a coating
having a drug.
15. The medical device of claim 14 wherein the coating includes the
polymer.
16. The medical device of claim 1, which is a stent.
17. The medical device of claim 1 which is a bioabsorbable
stent.
18. The medical device of claim 1 wherein the nitric oxide is
released from a nitrosylated biomolecule present in the blood
stream or tissue adjacent to the medical device.
19. The medical device of claim 1 wherein the nitric oxide is
released from a nitrosylated protein or S-nitrosothiols present in
the blood stream or a tissue adjacent to the medical device.
20. A medical device comprising a metal complex, wherein the metal
complex attaches to a surface of the medical device or a coating on
the medical device, and wherein the metal complex catalyzes the
generation of nitric oxide in the blood stream or a tissue adjacent
to the medical device.
21. The medical device of claim 20, wherein the nitric oxide is
released from a nitrosylated biomolecule present in the blood
stream or a tissue adjacent to the medical device.
22. The medical device of claim 20, wherein the nitric oxide is
released from a nitrosylated protein or S-nitrosothiol present in
the blood stream or a tissue adjacent to the medical device.
23. The medical device of claim 20, wherein the metal complex is a
copper complex.
24. The medical device of claim 20, wherein the metal complex
comprises Cyclen, Cyclam, DTTCT, or a bipyrridine liand.
25. The medical device of claim 20, wherein the metal complex is
attached to the surface of the medical device or the coating via a
spacer.
26. The medical device of claim 25, wherein the spacer is a short
chain alkyl group, phenyl group, aryl group, or poly(ethylene
glycol).
27. The medical device of claim 20, wherein the metal complex
comprises an ion selected from the group consisting of Cu.sup.2+,
Co.sup.2+, Ni.sup.2+, Zn.sup.+2+, Mn.sup.2+, Al.sup.3+, or
Fe.sup.3+.
28. The medical device of claim 20 which is a bioabsorbable polymer
stent.
29. The medical device of claim 20 which is a biodurable polymer
stent.
30. A medical device comprising a coating wherein the coating
comprises: a polymer, and a metal complex that catalyzes the in
vivo generation of nitric oxide in the blood stream or tissue
adjacent to the medical device, wherein the metal complex comprises
an ion selected from the group consisting of Cu.sup.2+, Co.sup.2+,
Ni.sup.2+, Zn.sup.+2+, Mn.sup.+2, Al.sup.3+, or Fe.sup.3+; and a
ligand selected from Cyclen, Cyclam, DTTCT, or a bipyridine
ligand.
31. The medical device of claim 30 wherein the metal complex
attaches to the polymer via a spacer that is at least one of a
short chain alkyl group, phenyl group, aryl group, or poly(ethylene
glycol).
32. The medical device of claim 30 further comprising a drug.
33. The medical device of claim 30 wherein the coating further
comprises a drug.
34. The medical device of claim 30 in which the medical device is
an endovascular stent.
35. A medical device comprising: a polymer, and a metal complex
that catalyzes the in vivo generation of nitric oxide in the blood
stream or tissue adjacent to the medical device, wherein the metal
complex comprises an ion selected from the group consisting of
Cu.sup.2+, Co.sup.2+, Ni.sup.2+, Zn.sup.+2+, Mn.sup.2+, Al.sup.3+,
or Fe.sup.3+; and a ligand selected from Cyclen, Cyclam, DTTCT, or
a bipyridine ligand.
36. The medical device of claim 35 wherein the metal complex
attaches to the polymer via a spacer that is at least one of a
short chain alkyl group, phenyl group, aryl group, or poly(ethylene
glycol).
37. The medical device of claim 35 further comprising a coating on
the polymer wherein the coating comprises the metal complex.
38. The medical device of claim 35 further comprising a drug.
39. The medical device of claim 37 wherein the coating further
comprises a drug.
40. The medical device of claim 35 in which the medical device is a
bioabsorbable stent.
41. A method of treating a disorder in a patient comprising
implanting in the patient the medical device of claim 1 wherein the
disorder is selected from the group consisting of 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, diabetic vascular disease, and combinations
thereof.
42. A method of treating a disorder in a patient comprising
implanting in the patient the medical device of claim 20, wherein
the disorder is selected from the group consisting of
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, diabetic vascular disease, and
combinations thereof.
Description
FIELD OF THE INVENTION
[0001] This invention is generally related to medical devices
capable of in vivo generation of nitric oxide.
DESCRIPTION OF THE STATE OF THE ART
[0002] Stents are used not only as a mechanical intervention in
vascular conditions but also as a vehicle for providing biological
therapy. As a mechanical intervention, stents act as scaffoldings,
functioning to physically hold open and, if desired, to expand the
wall of the passageway. Typically, stents are capable of being
compressed, so that they can be inserted through small vessels via
catheters, and then expanded to a larger diameter once they are at
the desired location. Examples in patent literature disclosing
stents that have been applied in PTCA procedures include stents
illustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat.
No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062
issued to Wiktor.
[0003] Biological therapy can be achieved by medicating the stents.
Medicated stents provide for the local administration of a
therapeutic substance at the diseased site. In order to provide an
efficacious concentration to the treated site, systemic
administration of such medication often produces adverse or toxic
side effects on the patient. Local delivery is a preferred method
of treatment in that smaller total levels of medication are
administered in comparison to systemic dosages, but are
concentrated at a specific site. Local delivery thus produces fewer
side effects and achieves more favorable results.
[0004] In many patients, especially diabetic patients, stentable
lesions are focal manifestations of widespread vascular disease.
The advent of drug eluting stents has brought relief from
restenosis of the treated lesion, but leaves progression of
regional vascular disease unaddressed.
[0005] Nitric oxide (NO) has numerous physiologic and
pathophysiologic functions. For example, NO can inhibit the
inflammatory process by lowering cytokine synthesis and
inactivating nuclear factor (NF)-.kappa.B,3 as several cytokines
contain a binding site for NF-.kappa.B in their promoter regions.
It has been reported that blood level NO can inhibit platelet
adhesion and aggregation, inflammation, and smooth muscle cell
migration and proliferation and can stimulate endothelial cell
migration and proliferation. In addition, NO has vasorelaxant
effect and can regulate smooth muscle contractility and platelet
reactivity (see, e.g., Lindberg, L., et al., Nitric Oxide gives
maximal response after coronary artery bypass surgery. J.
Cardiothorac Vasc. Anesth. 8:182-87 (1994)).
[0006] Therefore, the present invention provides means of
generating nitric oxide to cure the deficiencies of a conventional
drug eluting stent.
SUMMARY
[0007] A medical device is provided comprising a polymer and a
metal complex attached to the polymer, wherein the metal complex
catalyzes the generation of nitric oxide in the blood stream or in
tissue adjacent to the medical device. In some embodiments, the
polymer is included in a coating for the medical device. In some
embodiments, the medical device is a bioabsorbable stent made from
at least the polymer. The metal complex can be a copper complex.
The metal complex can comprise Cyclen, Cyclam, DTTCT, or a
bipyridine ligand. The metal complex can be attached to the polymer
with a spacer. The spacer can be a short-chain alkyl group, phenyl
group, an aryl group, or poly(ethylene glycol). In some
embodiments, the metal complex comprises a metal selected from the
group consisting of Cu.sup.2+, Co.sup.2+, Ni.sup.2+, Zn.sup.+2+,
Mn.sup.2+, Al.sup.3+, or Fe.sup.3+. The medical device can include
a drug adapted to be released from the device. The drug can be
included in a coating. The coating can be made from the polymer to
which the complex is attached. The nitric oxide can be released
from a nitrosylated biomolecule present in the blood stream or a
tissue adjacent to the medical device. The nitric oxide can be
released from a nitrosylated protein or S-nitrosothiols present in
the blood stream or in tissue adjacent to the medical device.
[0008] In accordance with another aspect of the invention, a
medical device comprising a metal complex is provided, wherein the
metal complex is attached to the surface of the medical device or a
coating on the medical device, and wherein the metal complex
catalyzes the generation of nitric oxide in the blood stream or in
tissue adjacent to the medical device.
DETAILED DESCRIPTION
[0009] The present invention provides methods for generating NO in
blood. According to embodiments of the present invention, NO can be
released from a nitric oxide source present in the blood stream or
a tissue when the nitric oxide source meets a metal catalyst in the
blood stream or the tissue. The metal catalyst can be attached to a
coating (e.g., a topcoat) on a medical device with a spacer. Upon
exposure to the blood stream or the tissue, the metal catalyzes the
release of NO from the NO source. The nitric oxide source can
comprise nitrosylated biomolecules such as nitrosylated proteins
(e.g., S-nitrosothiols).
[0010] NO has numerous physiologic and pathophysiologic functions.
For example, NO can inhibit the inflammatory process by lowering
cytokine synthesis and inactivating nuclear factor (NF)-.kappa.B,3
as several cytokines contain a binding site for NF-.kappa.B in
their promoter regions. It has been reported that blood level NO
can inhibit platelet adhesion and aggregation, inflammation, and
smooth muscle cell migration and proliferation and can stimulate
endothelial cell migration and proliferation. In addition, NO has
vasorelaxant effect and can regulate smooth muscle contractility,
and platelet reactivity.
[0011] The metal catalyst includes a metal, which can be a metal
ion or a metal atom, and one or more ligands. The ligand can have
two or more coordination sites. Preferably, the ligand has four
nitrogen atoms that serve as coordination sites in the ligand. The
metal catalyst can be formed prior to the ligand's attachment to a
polymer coating or after the ligand's attachment to the polymer
coating. Preferably, the catalyst is formed after the ligand's
attachment to the coating.
[0012] In some embodiments, a coating including the metal complex
described herein can be formed directly on the surface of a medical
device or on top of a layer of a coating that includes a
biocompatible polymer. In some embodiments, the coating can be
formed on top of a drug reservoir, which can be a layer of neat or
pure drug(s) or a layer that includes a biocompatible polymer
combined with a drug or combination of drugs.
[0013] In some embodiments, the medical device itself can be
bioabsorbable (e.g., a bioabsorbable stent) and the catalyst can be
attached directly to the surface of the device. In some
embodiments, the catalyst can also be attached to a coating of the
bioabsorbable device.
[0014] The medical device having the catalyst described herein can
include one or more biocompatible polymer(s) and optionally one or
more biobeneficial material(s). In some embodiments, the coating
can include a bioactive agent such as a drug. Some examples of the
bioactive agents 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, bioactive RGD, CD-34 antibody,
abciximab (REOPRO), progenitor cell capturing antibody, prohealing
drugs, prodrugs thereof, co-drugs thereof, or a combination
thereof.
[0015] The medical device including a catalyst described herein can
be used to treat, prevent, or ameliorate a vascular 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
thereof.
Metal Complexes
[0016] Copper complexes have been shown to generate biologically
relevant levels of NO for up to 6 hours (see, e.g., Oh, B. K. and
Meyerhoff, M. E., Biomaterials 25:283-293 (2005)). NO generation
occurs as long as the copper catalyst is present and a nitrosylated
biomolecule (e.g., nitrosylated proteins or S-nitrosothiols) in the
blood reaches the copper catalyst (see, e.g., Oh, B. H., Meyerhoff,
M. E., J. Amer. Chem. Soc., 125(32):9552-53) (2003). NO generation
can be achieved when a metal ion (e.g., copper or zinc) is bound to
a ligand such as Cyclen (see Scheme I), Cyclan (see Scheme I), or
macrocycles having four nitrogen groupings. One such macrocycle
ligand is
dibenzo[e,k]-2,3,8,9-tetraphenyl-1,4,7,10-tetraaza-cyclododeca-1,3,7,9-te-
traene (DTTCT). The electronic and steric environment provided by
the ligands influences the metal ion's reactivity and selectivity.
Therefore, it is important not to significantly modify the
structure of the macrocycle in attaching the ligand to a polymer in
the coating on a medical device.
[0017] The metal catalyst can be any metal complex capable of
catalyzing the generation of nitric oxide in the blood stream or
the tissue. In some embodiments, the metal complex is a copper
complex. In some embodiments, the metal complex contains a metal
such as Co.sup.2+, Ni.sup.2+, Zn.sup.+2+, Mn .sup.2+, Al.sup.3+, or
Fe.sup.3+.
[0018] The metal complex can be formed by mixing a metal compound
and the ligand described herein and allowing the ligand to complex
with the metal. Methods for forming a metal complex are well
documented in the art. Some references can be found in A. B. P.
Lever, Editor-in-Chief, Coordination Chemistry Reviews, published
by Elsevier.
[0019] Ligands useful for forming the metal complex described
herein are chelating ligands having multiple coordination sites.
The ligands can have at least two coordination sites, preferably
three coordination sites, more preferably four coordination sites.
In some embodiments, the ligand is an N4 macrocycle ligand (a
ligand having four nitrogen coordination sites). Some
representative N4 ligands include, but are not limited to, Cyclen,
Cyclam, and DTTCT.
[0020] In some embodiments, the ligand can have two coordination
sites. Two or more equivalents of the ligands can complex to a
metal to form a metal complex. For example, two equivalents of an
N2 ligand (ligand having two nitrogen coordination sites) can
complex to a metal such as copper to form a metal complex having
four nitrogen coordination sites. Some representative N2 ligands
are, for example, 2,2'-bipyridine ligands.
[0021] Standard procedures can be used to introduce the metal
(e.g., a metal ion) into the macrocycle.
[0022] To have a local generation of NO, in some embodiments, the
metal complex described herein is attached to the surface of a
medical device or a coating on the device through a spacer. The
spacer can be, for example, an alkyl chain or a poly(ethylene
glycol) (PEG) chain. The spacer has a length of at least two carbon
atoms or longer. This can allow the copper complex to be at the
blood polymer interface and have the active center accessible to
nitrosylated biomolecules (e.g., nitrosylated proteins or
nitrosothiols) in the blood. The metal complex can either be
coupled to the spacer and then to the polymer or coupled to a
spacer that is already attached to the polymer. The order of the
reactions is dictated by the compatibility of the chemistry, which
can be readily appreciated by one of ordinary skill in the art.
[0023] Exemplary spacers that can be used in the present invention
include, but are not limited to, PEG, poly(alkylene oxide) such as
poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), C2-C20
alkyls, and short peptides. In some embodiments, the spacer can be
a biocompatible polymer or oligomer.
Synthesis and/or Functionalization of Ligands
[0024] Attachment of a spacer to ligands can be achieved by
functionalizing the ligand and then coupling the functionalized
ligand to a spacer. Functionalization of the ligand can be carried
out using standard procedures in organic synthesis. To illustrate,
Cyclen and Cyclam, both having N--H groups in their molecules, can
be coupled to a spacer that has a leaving group such as a halo
group and a reactive group R, which can be any reactive group such
as carboxyl, hydroxyl, thiol, or amine groups (Scheme I). The
reactive group can be used to attach Cyclen or Cyclam to the
reactive groups available on the polymer. ##STR1## In some
embodiments, the free reactive groups on a ligand (such as N--H
groups on Cyclam) can be selectively protected by a protective
group such as t-bock. The remaining reactive group can then be used
to attach the ligand to a spacer. Other N4 macrocycles, such as
DTTCT, can be synthesized to bear functional groups by selecting
functionalized starting materials. As shown in Scheme II, two
molecules of a diamine with an R1 group, which can have a protected
functional group such as hydroxyl, amine or carboxylic acid group,
can react with two molecules of a diketone having R2 groups to form
a N4 macrocycle (Scheme II). ##STR2## In Scheme II, where the
diamine is 1,2-di-amine-benzene and the R2 group of the diketone is
a phenyl group, the N4 macrocycle is DTTCT, which can form a copper
complex as shown below: ##STR3##
[0025] Other methods for functionalizating macrocyclic ligands are
well documented. For example, acylations of phenyls can be done by
a Friedel-Crafts reaction (Bryce-Smith D. J.; J. Chem. Soc., 1963,
5983, and Benkeser et al. J. Am. Chem. Soc. 1963, 85, 3984). Acyl
halides (Byce-Smith D. J. et al., J. Chem. Soc. 1954, 2743 and
Pocker Y. et al. J. Am. Chem. Soc. 1968, 90, 6764) are the most
common reagents, but carboxylic acids, anhydrides and ketenes can
also be used. For example an acid chloride (RCOCl) can attack the
hydrogen on the phenyl (R2 in Scheme II=phenyl) to yield ROCR2.
Alternatively, a Suzuki coupling (Miyaura N. and Suzuki A. Chem.
Rev. 1995, 95, 2457) can be performed between an organo-boronic
acid and halides using a palladium catalyst. It is noteworthy that
the Suzuki coupling is a milder reaction. In some embodiments,
reactive groups on the ligand or the polymer may need to be
protected (t-BOC, etc.) to avoid undesirable side reactions. In
some embodiments, to obtain a single attachment point, less than 1
equivalent of acid chloride can be added. Subsequent purification
can be needed.
Coupling of Spacer to Polymer
[0026] Coupling of spacers to a polymer in a coating or on the
surface of a medical device can be achieved using two mechanisms.
In some embodiments, the metal complex can be coupled to a polymer
and then sprayed as a coating onto the medical device. In some
embodiments, the polymer can be applied to the medical device and
the metal complex can be subsequently coupled to the polymer
coating. This approach can generate a coating having a higher
surface density of the metal complex. The polymer should have
reactive side groups such as hydroxyls, carboxylic acids, amines,
etc. In some embodiments the medical device, such as a
bioabsorbable polymer stent, can be made to include the metal
complex.
[0027] In some embodiments, the polymer (e.g., coating or the
device surface) has mildly reactive hydroxyl groups. The spacer
should have reactive groups such as a carboxylic acid,
N-hydroxysuccinimide (NHS), an acid halide (e.g., acid chloride) or
equivalent thereof, or a vinyl sulphone. A carboxylic acid or NHS
can be readily coupled to a hydroxyl group in the presence of
N,N'-carbonyldiimidazole or dicyclohexylcarbodiimide (DCC), which
are commercially available.
[0028] In some embodiments, the spacer can be poly(ethylene glycol)
(PEG). PEG can be readily functionalized using acryloyl chloride to
bear an acryloyl chloride end group. This end group can serve to
couple PEG to the reactive groups on the polymer.
[0029] In some embodiments, the spacer can comprise vinyl sulphone,
which can be readily coupled to the polymer under acidic
conditions. Vinyl sulphone is commercially available.
[0030] As an example, Scheme III shows coupling of a copper complex
to a hydroxyl functional methacrylate via a PEG spacer.
##STR4##
Biocompatible Polymers
[0031] A biocompatible polymer can be applied to a device and then
coupled to the metal complex so as to form a coating. In some
embodiments, the biocompatible polymer can be coupled with the
metal complex, and afterwards be sprayed onto a device as a
coating.
[0032] The biocompatible polymer can be biodegradable (either
bioerodable or bioabsorbable or both) or nondegradable and can be
hydrophilic or hydrophobic. 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),
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, acrylonitrile-styrene
copolymers, ABS resins, and ethylene-vinyl acetate copolymers,
polyamides, such as Nylon 66 and polycaprolactam, alkyd resins,
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. poly(ethylene oxide-co-lactic
acid) (PEO/PLA)), polyalkylene oxides such as poly(ethylene oxide),
poly(propylene oxide), poly(ether ester), polyalkylene oxalates,
phosphoryl choline, choline, poly(aspirin), polymers and
co-polymers of hydroxyl bearing monomers such as 2-hydroxyethyl
methacrylate (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, dextran,
dextrin, hyaluronic acid, fragments and derivatives of hyaluronic
acid, heparin, fragments and derivatives of heparin, glycosamino
glycan (GAG), GAG derivatives, polysaccharide, elastin, or
combinations thereof. In some embodiments, the topcoat can exclude
any one of the aforementioned polymers.
[0033] 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.
Bioactive Agents
[0034] The medical device having the metal complex described herein
can include one or more bioactive agent(s), which can be
therapeutic, prophylactic, or diagnostic agent(s). These agents can
have anti-proliferative or anti-inflammatory properties or can have
other properties such as antineoplastic, antiplatelet,
anti-coagulant, anti-fibrin, antithrombogenic, antimitotic,
antibiotic, antiallergic, and antioxidant. The 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, agents that promote the
attachment, migration and proliferation of endothelial cells (e.g.,
natriuretic peptides such as CNP, ANP or BNP peptide or an RGD or
cRGD peptide), while impeding 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. Some other examples of the bioactive agent 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
40-epi-(N1-tetrazolyl)-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 and/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 IIb/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, or
combinations thereof. Examples of cytostatic substances 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 which
may be appropriate include alpha-interferon, pimecrolimus, imatinib
mesylate, midostaurin, bioactive RGD, SIKVAV peptides, elevating
agents such as cANP or cGMP peptides, 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 and/or prodrugs of the metabolites. The
foregoing substances are listed by way of example and are not meant
to be limiting. Other active agents which are currently available
or that may be developed in the future are equally applicable.
[0035] 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 non-therapeutic levels. 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 administered
ingredient resides at the vascular site, and if other active agents
are employed, the nature and type of the substance or combination
of substances. Therapeutically effective 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
[0036] 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,
electrodes, pacemaker electrodes, catheters, sensors, 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 or biostable polymers could also be used with the
embodiments of the present invention.
[0037] In some embodiments, the device is a bioabsorbable stent,
with or without a coating, such that the complex is attached to the
coating or the surface of the device itself.
Method of Use
[0038] In accordance with embodiments of the invention, a medical
device having the metal complex described herein can be used for
the generation of nitric oxide in the blood stream or tissue
adjacent to the medical device.
[0039] 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. In some embodiments, the
device described herein can be in dialysis, as grafts, or
fistulae.
[0040] Representative examples of sites include the iliac, renal,
carotid and coronary arteries.
[0041] 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 which 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, 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 features may then be expanded at
the desired area of treatment. A post-insertion angiogram may also
be utilized to confirm appropriate positioning.
[0042] I would like you to add some prophetic examples including
producing a stent with an NO-generating coating.
[0043] 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.
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