U.S. patent application number 14/085476 was filed with the patent office on 2014-03-20 for coatings of acrylamide-based copolymers.
This patent application is currently assigned to Abbott Cardiovascular Systems Inc.. The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Thierry Glauser, Syed Faiyaz Ahmed Hossainy, Mikael O. Trollsas.
Application Number | 20140079743 14/085476 |
Document ID | / |
Family ID | 39434170 |
Filed Date | 2014-03-20 |
United States Patent
Application |
20140079743 |
Kind Code |
A1 |
Hossainy; Syed Faiyaz Ahmed ;
et al. |
March 20, 2014 |
COATINGS OF ACRYLAMIDE-BASED COPOLYMERS
Abstract
An implantable device including a conjugate formed of an
acrylamide-based copolymer and a bioactive agent is provided.
Inventors: |
Hossainy; Syed Faiyaz Ahmed;
(Hayward, CA) ; Glauser; Thierry; (Redwood City,
CA) ; Trollsas; Mikael O.; (San Jose, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
Abbott Cardiovascular Systems
Inc.
Santa Clara
CA
|
Family ID: |
39434170 |
Appl. No.: |
14/085476 |
Filed: |
November 20, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13677115 |
Nov 14, 2012 |
8591934 |
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14085476 |
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13206417 |
Aug 9, 2011 |
8333984 |
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13677115 |
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11639860 |
Dec 15, 2006 |
8017141 |
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13206417 |
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Current U.S.
Class: |
424/400 |
Current CPC
Class: |
A61K 47/65 20170801;
A61L 31/16 20130101; A61L 31/10 20130101; A61F 2/82 20130101; A61K
47/6957 20170801; C08L 33/26 20130101; A61K 47/32 20130101; A61L
2300/00 20130101; A61K 45/06 20130101; A61L 31/10 20130101 |
Class at
Publication: |
424/400 |
International
Class: |
A61K 47/32 20060101
A61K047/32; A61K 45/06 20060101 A61K045/06 |
Claims
1. An implantable device comprising a coating, the coating
comprising: a bioactive agent; a linker; wherein the linker
comprises poly(ethylene glycol) (PEG), poly(alkylene oxide), C1-C12
alkyl, C1-C12 cycloalkyl, C1-C12 aryl, a peptide, a peptide
sequence, an alkyl chain, a protein, an oligomer of amino acids,
succinic anhydride, glutaric anhydride, dimethyl succinic
anhydride, methyl glutaric anhydride, a thioester, a disulfide
bond, a PLA-oligomer, a PLGA-oligomer, a PCL-oligomer, an ester
linkage, or an anhydride linkage; and a copolymer of Formula II:
##STR00006## wherein R.sub.5 and R.sub.6 are independently CH.sub.3
or H; wherein R.sub.7 is a straight or branched C.sub.1-C.sub.12
alkyl, aryl, cycloalkyl, or heterocyclic group; wherein n and m are
independently mole ratios from about 0.01 to about 0.99, with a
proviso that n+m=1; and wherein the linker conjugates the bioactive
agent to the copolymer.
2. The implantable device of claim 1, wherein the linker comprises
succinic anhydride, glutaric anhydride, dimethyl succinic
anhydride, methyl glutaric anhydride, a thioester, a disulfide
bond, a PLA-oligomer, a PLGA-oligomer, a PCL-oligomer, an ester
linkage, or an anhydride linkage.
3. The implantable device of claim 1, wherein the linker comprises
succinic anhydride, glutaric anhydride, dimethyl succinic
anhydride, or methyl glutaric anhydride.
4. The implantable device of claim 1, wherein the linker comprises
poly(ethylene glycol) (PEG), an alkyl chain, or a peptide
sequence.
5. The implantable device of claim 4, wherein the peptide sequence
comprises glycine-phenylalinine-leucine-glycine.
6. The implantable device of claim 1, wherein the linker comprises
poly(ethylene glycol) (PEG), poly(alkylene oxide), C1-C12 alkyl,
C1-C12 cycloalkyl, or C1-C12 aryl.
7. The implantable device of claim 1, wherein the copolymer is
poly[N-(2-hydroxypropyl) methacrylamide-co-methoxyethyl
methacrylate] (HPMA-co-MOEMA).
8. The implantable device of claim 1, wherein the copolymer is a
random or block copolymer.
9. The implantable device of claim 1, which is a stent.
10. The implantable device of claim 1, wherein the bioactive agent
is selected from the group consisting of halofuginone, paclitaxel,
docetaxel, estradiol, 17-beta-estradiol, a nitric oxide donor,
super oxide dismutase, a super oxide dismutase mimic,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, a rapamycin derivative,
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), .gamma.-hiridun, clobetasol, mometasone, pimecrolimus,
imatinib mesylate, or midostaurin, or a prodrugs, co-drugs, or
combination of these.
11. The implantable device of claim 9, wherein the bioactive agent
is selected from the group consisting of halofuginone, paclitaxel,
docetaxel, estradiol, 17-beta-estradiol, a nitric oxide donor,
super oxide dismutase, a super oxide dismutase mimic,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, a rapamycin derivative,
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), .gamma.-hiridun, clobetasol, mometasone, pimecrolimus,
imatinib mesylate, or midostaurin, or a prodrugs, co-drugs, or
combination of these.
12. The implantable device of claim 1, wherein the coating
comprises a layer of matrix comprising the copolymer, linker and
the bioactive agent.
13. The implantable device of claim 1, wherein the coating
comprises a topcoat comprising the copolymer, linker and the
bioactive agent.
14. The implantable device of claim 1, wherein the coating further
comprises one or more biocompatible polymers selected from the
group consisting of poly(ester amide), polyhydroxyalkanoates (PHA),
poly(3-hydroxyalkanoates), poly(4-hydroxyalkanaote),
poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),
poly(tyrosine carbonates), poly(tyrosine ester), polyphosphoester,
polyphosphoester urethane, polycyanoacrylates,
poly(iminocarbonate), polyurethanes, silicones, polyesters,
polyolefins, polyisobutylene and ethylene-alphaolefin copolymers,
acrylic polymers and copolymers, polyvinyl chloride, polyvinyl
ethers, polyvinyl methyl ether, polyvinylidene halides,
polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl
esters, ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, polyamides, polycaprolactam,
polycarbonates, polyimides, 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),
polyurethanes, rayon, rayon-triacetate, cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellophane,
cellulose nitrate, cellulose propionate, cellulose ethers,
carboxymethyl cellulose, poly(propylene oxide), poly(aspirin),
2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate
(HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG
methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and
n-vinyl pyrrolidone (VP), methacrylic acid (MA), acrylic acid (AA),
alkoxymethacrylate, alkoxyacrylate, 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), polypropylene
oxide-co-polyethylene glycol, poly(tetramethylene glycol), hydroxy
functional poly(vinyl pyrrolidone), 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, and alginate.
15. The implantable device of claim 14, wherein the one or more
biocompatible polymers are selected from the group consisting of
polyhydroxyalkanoates (PHA), poly(3-hydroxyalkanoates),
poly(4-hydroxyalkanaotes), vinyl halide polymers and copolymers,
polyvinyl ethers, polyvinylidene halides, polyvinyl ketones,
polyvinyl aromatics, polyamides and polyvinyl esters.
16. The implantable device of claim 14, wherein the one or more
biocompatible polymers are selected from the group consisting of
poly(3-hydroxypropanoate), poly(3-hydroxybutyrate),
poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),
poly(3-hydroxyheptanoate), poly(3-hydroxyoctanoate),
poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),
poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),
poly(4-hydroxyoctanoate), hydroxyethyl methacrylate (HEMA),
hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG
acrylate (PEGA), PEG-methacrylate,
2-methacryloyloxyethylphosphorylcholine (MPC), n-vinyl pyrrolidone
(VP), polyvinyl chloride, polyvinyl methyl ether, polyvinylidene
chloride, polyacrylonitrile, polystyrene, polycaprolactam and
polyvinyl acetate.
17. A method of treating or ameliorating a medical condition,
comprising implanting into a blood vessel the implantable device of
claim 9.
18. A method of forming a coating on an implantable device,
comprising: providing a copolymer of Formula II: ##STR00007##
providing a bioactive agent; providing a linker; conjugating the
bioactive agent to the copolymer with the linker; and forming a
coating comprising the conjugate on the implantable device; wherein
R.sub.5 and R.sub.6 are independently CH.sub.3 or H; wherein
R.sub.7 is a straight or branched C.sub.1-C.sub.12 alkyl, aryl,
cycloalkyl, or heterocyclic group; and wherein n and m are
independently mole ratios from about 0.01 to about 0.99, with a
proviso that n+m=1; wherein the linker comprises poly(ethylene
glycol) (PEG), poly(alkylene oxide), C1-C12 alkyl, C1-C12
cycloalkyl, C1-C12 aryl, a peptide, a protein, an oligomer of amino
acids, succinic anhydride, glutaric anhydride, dimethyl succinic
anhydride, methyl glutaric anhydride, a thioester, a disulfide
bond, a PLA-oligomer, a PLGA-oligomer, a PCL-oligomer, an ester
linkage, or an anhydride linkage.
19. The method of claim 18, wherein the linker comprises succinic
anhydride, glutaric anhydride, dimethyl succinic anhydride, methyl
glutaric anhydride, a thioester, a disulfide bond, a PLA-oligomer,
a PLGA-oligomer, a PCL-oligomer, an ester linkage, or an anhydride
linkage.
20. The method of claim 18, wherein the linker comprises succinic
anhydride, glutaric anhydride, dimethyl succinic anhydride, or
methyl glutaric anhydride.
21. The method of claim 18, wherein the linker comprises
poly(ethylene glycol) (PEG), an alkyl chain, or a peptide
sequence.
22. The method of claim 21, wherein the peptide sequence comprises
glycine-phenylalinine-leucine-glycine.
23. The method of claim 18, wherein the linker comprises
poly(ethylene glycol) (PEG), poly(alkylene oxide), C1-C12 alkyl,
C1-C12 cycloalkyl, or C1-C12 aryl.
24. The method of claim 18, wherein the coating further comprises
one or more biocompatible polymers selected from the group
consisting of poly(ester amide), polyhydroxyalkanoates (PHA),
poly(3-hydroxyalkanoates), poly(4-hydroxyalkanaote),
poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),
poly(tyrosine carbonates), poly(tyrosine ester), polyphosphoester,
polyphosphoester urethane, polycyanoacrylates,
poly(iminocarbonate), polyurethanes, silicones, polyesters,
polyolefins, polyisobutylene and ethylene-alphaolefin copolymers,
acrylic polymers and copolymers, polyvinyl chloride, polyvinyl
ethers, polyvinyl methyl ether, polyvinylidene halides,
polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl
esters, ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, polyamides, polycaprolactam,
polycarbonates, polyimides, 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),
polyurethanes, rayon, rayon-triacetate, cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellophane,
cellulose nitrate, cellulose propionate, cellulose ethers,
carboxymethyl cellulose, poly(propylene oxide), poly(aspirin),
2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate
(HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG
methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and
n-vinyl pyrrolidone (VP), methacrylic acid (MA), acrylic acid (AA),
alkoxymethacrylate, alkoxyacrylate, 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), polypropylene
oxide-co-polyethylene glycol, poly(tetramethylene glycol), hydroxy
functional poly(vinyl pyrrolidone), 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, and alginate.
25. The method of claim 24, wherein the one or more biocompatible
polymers are selected from the group consisting of
polyhydroxyalkanoates (PHA), poly(3-hydroxyalkanoates),
poly(4-hydroxyalkanaotes), vinyl halide polymers and copolymers,
polyvinyl ethers, polyvinylidene halides, polyvinyl ketones,
polyvinyl aromatics, polyamides and polyvinyl esters.
26. The method of claim 24, wherein the one or more biocompatible
polymers are selected from the group consisting of
poly(3-hydroxypropanoate), poly(3-hydroxybutyrate),
poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),
poly(3-hydroxyheptanoate), poly(3-hydroxyoctanoate),
poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),
poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),
poly(4-hydroxyoctanoate), hydroxyethyl methacrylate (HEMA),
hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG
acrylate (PEGA), PEG-methacrylate,
2-methacryloyloxyethylphosphorylcholine (MPC), n-vinyl pyrrolidone
(VP), polyvinyl chloride, polyvinyl methyl ether, polyvinylidene
chloride, polyacrylonitrile, polystyrene, polycaprolactam and
polyvinyl acetate.
Description
FIELD OF THE INVENTION
[0001] This invention generally relates to acrylamide-based
copolymers for coating an implantable device such as a drug
delivery stent.
DESCRIPTION OF THE BACKGROUND
[0002] 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.
[0003] The existing polymeric coating on a stent can have different
types of limitations. For example, some poly(ester amide) based
coatings can have poor mechanical properties so as to compromise
coating integrity, and coating based on hydrophobic polymers can
have problems in controlling release of a hydrophilic drug.
[0004] Therefore, there is a need for new carrier materials for
controlled delivery of an agent.
[0005] The polymer and methods of making the polymer disclosed
herein address the above described problems.
SUMMARY OF THE INVENTION
[0006] Poly(HPMA) is a hydrophilic polymer which has been used to
conjugate a bioactive agents such as drugs, peptides and proteins.
This conjugation can lead to increased circulation time in the
bloodstream of these bioactive agents as well as these agents'
uptake by the cellular endoplasm (Ulbrich K., et al., Advance in
Experimental Medicine and Biology: Polymer Drugs in the Clinical
Stage, 519:125-143 (2003).
[0007] Accordingly, provided in this invention is a coating on an
implantable device, the coating comprising a acrylamide-based
copolymer that can conjugate to a bioactive agent. The polymer can
have a chosen degree of hydrophilicity by virtue of the presence of
the hydroxy groups on the polymer backbone. The coating can have a
topcoat or a drug matrix that includes the acrylamide-based
copolymer described herein. In some embodiments, the
acrylamide-based copolymer includes poly[N-(2-hydroxypropyl)
methacrylamide] (poly(HPMA)).
[0008] The bioactive active agent can be conjugated to the
acrylamide-based copolymer via a labile linker. The bioactive agent
can be conjugated to the polymer by conjugation to functional
groups (e.g., hydrophilic groups) on the copolymer. In some
embodiments, the bioactive agent can be conjugated to the
acrylamide-based copolymer via hydrophilic groups on the
acrylamide-based copolymer.
[0009] The bioactive agents can be any drugs, peptides, proteins,
or combinations thereof. Some examples of the bioactive agent
include, but are not limited to, halofuginone, 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, bioactive RGD, CD-34 antibody, abciximab
(REOPRO), progenitor cell capturing antibody, prohealing drugs,
prodrugs thereof, co-drugs thereof, or a combination thereof.
[0010] An implantable device having a coating described herein can
be used to treat, prevent, or ameliorate a vascular medical
condition. Some exemplary vascular medical conditions include
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, urethra
obstruction, tumor obstruction, and combinations thereof. For
example, the implantable device can be planted within a tissue of a
human being, e.g., in the blood vessel.
[0011] In some embodiments, the present invention provides a method
of forming a coating on the implantable device. The method
comprises
[0012] providing a copolymer that comprises units derived from at
least one acrylamide monomer,
[0013] providing a bioactive agent,
[0014] forming a conjugate of the bioactive agent and the
copolymer, and
[0015] forming a coating comprising the conjugate on the
implantable device.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Poly[N-(2-hydroxypropyl) methacrylamide] (Poly(HPMA)) is a
hydrophilic polymer which has been used to conjugate a bioactive
agents such as drugs, peptides and proteins. This conjugation can
lead to increased circulation time in the bloodstream of these
bioactive agents as well as these agents' uptake by the cellular
endoplasm (Ulbrich K., et al., Advance in Experimental Medicine and
Biology: Polymer Drugs in the Clinical Stage, 519:125-143
(2003).
[0017] Accordingly, provided in this invention is a coating on an
implantable device, the coating comprising a acrylamide-based
copolymer that can conjugate to a bioactive agent. The polymer can
have a chosen degree of hydrophilicity by virtue of the presence of
the hydroxy groups on the polymer backbone. The coating can have a
topcoat or a drug matrix that includes the acrylamide-based
copolymer described herein. In some embodiments, the
acrylamide-based copolymer includes poly(HPMA).
[0018] The bioactive active agent can be conjugated to the
acrylamide-based copolymer via a labile linker. The bioactive agent
can be conjugated to the polymer by conjugation to functional
groups (e.g., hydrophilic groups) on the copolymer. In some
embodiments, the bioactive agent can be conjugated to the
acrylamide-based copolymer via hydrophilic groups on the
acrylamide-based copolymer.
[0019] The bioactive agents can be any drugs, peptides, proteins,
or combinations thereof. Some examples of the bioactive agent
include, but are not limited to, halofuginone, 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, bioactive RGD, CD-34 antibody, abciximab
(REOPRO), progenitor cell capturing antibody, prohealing drugs,
prodrugs thereof, co-drugs thereof, or a combination thereof.
[0020] An implantable device having a coating described herein can
be used to treat, prevent, or ameliorate a vascular medical
condition. Some exemplary vascular medical conditions include
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, urethra
obstruction, tumor obstruction, and combinations thereof. For
example, the implantable device can be planted within a tissue of a
human being, e.g., in the blood vessel.
[0021] In some embodiments, the present invention provides a method
of forming a coating on the implantable device. The method
comprises providing a copolymer that comprises units derived from
at least one acrylamide monomer,
[0022] providing a bioactive agent,
[0023] forming a conjugate of the bioactive agent and the
copolymer, and
[0024] forming a coating comprising the conjugate on the
implantable device.
Acrylamide-Based Copolymer
[0025] The acrylamide-based copolymer can be formed of an
acrylamide or methacrylamide monomer having a hydrophilic group.
Preferably, the hydrophilic group is --OH, --SH, --NRH, --COOH,
--COO.sup.-Na.sup.+, or --COO.sup.-K.sup.+.
[0026] In some embodiments, the acrylamide monomer forming the
acrylamide-based copolymer can be an acrylamide or methacrylamide
having the structure of formula I:
##STR00001##
wherein R.sub.1 is CH.sub.3 or H, and R.sub.2 can be any group
having at least one hydroxyl, thiol, amino or carboxyl group.
Examples of R.sub.2 can be short chain hydroxyalkyl groups, a
peptide sequence, an alkyl chain, or a linker.
[0027] The acrylamide-based copolymer can have different molar
ratios of monomers. Such molar ratios of monomers can be designated
as n and m. These molar ratios can independently range from about
0.01 to about 0.99 and the total values of molar ratios n+m=1. Some
examples of the molar ratios are about 0.05, about 0.1, about 0.2,
about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8,
about 0.9, or about 0.95. Note, molar ratios of the monomers can
affect the hydrophobicity of the copolymer. A higher ratio of
hydrophobic monomers can result in a more hydrophobic copolymer,
and vice versa. The hydrophobic nature of the copolymer can
influence the release of a drug embedded, admixed, dissolved, or
otherwise included in a matrix or coating including the
copolymer.
[0028] The acrylamide-based copolymer can be formed by any
established method of polymerization (see, e.g., Polymer Handbook,
by Eric A. Grulke, Akihiro Abe, Daniel R. Bloch, and J. Brandrup
(Eds), J&W Wiley, 2003). For example, the acrylamide-based
copolymer can be formed by standard free radical copolymerization
and controlled radical polymerization such as ATRP (T. E. Patten
and K. Matyjaszewski, Adv. Mater. 10, (1998) pp. 901; K.
Matyjaszewski and J. Xia, Chem. Rev. 101 (2001) pp. 2921; M.
Kamigaito, T. Audo and M. Sawamoto Chem. Rev. 101 (2001) pp. 3689.
and RAFT (reversible addition-fragmentation chain transfer) J.
Krstina et al., Macromolecules 28 (1995) pp. 5381; G. Moad et al.,
WO 96/15157 (1996); T. P. Le et al., WO 9801478/A1 (1998); J.
Chiefari et al., Macromolecules 31 (1998) pp. 5559 The
polymerization or copolymerization can be carried out sequentially
to yield a block copolymer of concurrently to yield a random
copolymer, depending on the desired properties of the copolymer. A
general scheme of forming the acrylamide-based copolymer is shown
in Scheme I:
##STR00002##
In Scheme I, R.sub.1 and R.sub.2 are defined as those in Formula I.
R.sub.3 is CH.sub.3 or H. R.sub.4 is a straight or branched C1-C12
alkyl, aryl, cycloalkyl, or heterocyclic group. R.sub.4 can bear
functional groups such as hydroxyl, alkoxy such as methoxy or
ethoxy, thiol, carboxyl, NH, or other groups. Some examples of
R.sub.4 are CH.sub.3, ethyl, propyl, 2-hydroxyethyl, butyl, or
methoxyethyl. N and m are molar ratios of the two monomers and are
independently from about 0.01 to about 0.99 and the total values of
molar ratios n+m=1. Some examples of n and m are about 0.05, about
0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about
0.7, about 0.8, about 0.9, or about 0.95. Z can be O or NH.
[0029] In some embodiments, the acrylamide monomer is N-(2-hydroxy
propyl) methacrylamide (HPMA). HPMA can easily polymerize alone or
copolymerize with other monomers such as acrylamide, acrylate or
methacrylate monomers to form a HPMA copolymer. Therefore, HPMA can
be used as a monomer to introduce a chosen degree of hydrophilicity
into the backbone of the acrylamide-based copolymer by forming a
copolymer(s) with other monomers. A general scheme forming the HPMA
copolymer can be illustrated by the reaction in Scheme II
below:
##STR00003##
forming a HPMA-based copolymer having the general formula II
##STR00004##
In Scheme II and Formula II, n and m are molar ratios of the two
monomers forming the copolymer and can independently range from
about 0.01 to about 0.99. Some examples of n and m values are about
0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about
0.6, about 0.7, about 0.8, about 0.9, or about 0.95. R.sub.5 and
R.sub.6 are independently CH.sub.3 and H. R.sub.7 is a straight or
branched C1-C12 alkyl, aryl, cycloalkyl, or heterocyclic group.
R.sub.7 can bear functional groups such as hydroxyl, alkoxy such as
methoxy or ethoxy, thiol, carboxyl, NH, or other groups. Some
examples of R.sub.7 are CH.sub.3, ethyl, propyl, 2-hydroxyethyl,
butyl, or methoxyethyl. An example of the HPMA-based copolymer of
formula II is where R.sub.5 and R.sub.6 are CH.sub.3, and R.sub.7
is methoxyethyl. This polymer is poly[N-(2-hydroxypropyl)
methacrylamide-co-methoxyethyl methacrylate] (HPMA-co-MOEMA), which
can be a random or block copolymer.
Linkers
[0030] Any biocompatible linker can be used to conjugate a
bioactive agent to the hydrophilic group on a monomer forming the
poly(HPMA)-based polymer or on the poly(HPMA)-based polymer itself.
In some embodiments, the linker can be any linker having about 40
atoms or less. In some embodiments, the linker can include
poly(ethylene glycol) (PEG), poly(alkylene oxide), C1-C12 short
chain alkyl, C1-C12 short chain cycloalkyl, C1-C12 aryl, peptide,
protein, oligomer of amino acids or combinations thereof. In some
embodiments, the linker is a labile linker. For example, such
labile linker can include, e.g., a peptide sequence such as
glycine-phenylalinine-leucine-glycine. Some other labile linkers
include, but are not limited to, succinic anhydride, glutaric
anhydride, dimethyl succinic anhydride, methyl glutaric anhydride,
thioesters, disulfide bonds, PLA-, PLGA-, PCL-oligomers and other
ester and anhydride linkages.
[0031] In some embodiments, the linker can include a vinyl group
and can polymerize with HPMA or other monomers forming a
poly(HPMA)-based copolymer having pendant linker molecules. The
linker includes a free hydrophilic group (e.g., OH) for conjugation
to a bioactive agent. Scheme III shows the formation of an example
of a linker having PEG and a methacrylate group.
##STR00005##
As shown in Scheme III, a linker, such as PEG, a peptide sequence
or an alkyl chain, can include two functional groups (e.g., a free
amine, hydroxyl, thiol, carboxyl), one functional group being
reactive and the other one being protected by a protective group
such as benzyl group. The reactive group can react with a reactive
vinyl group (e.g., acryloyl halide or methacryloyl halide) to form
a vinyl group terminated PEG. The protective group can subsequently
be removed by a process such as hydrogenation (H.sub.2 gas and
Pd/C) to yield a free functional group. This linker vinyl molecule
with a reactive terminal group can readily copolymerize with other
acrylate, methacrylate or acrylamide monomers to form an
acrylamide-based copolymer according to Scheme I, above.
[0032] Other examples of useable linkers include, but are not
limited to, any biocompatible linker can be used to conjugate a
bioactive agent to the hydrophilic group on a monomer forming the
poly(HPMA)-based polymer or on the poly(HPMA)-based polymer itself.
In some embodiments, the linker can be any linker having about 40
atoms or less. In some embodiments, the linker can include
poly(ethylene glycol) (PEG), poly(alkylene oxide), C1-C12 short
chain alkyl, C1-C12 short chain cycloalkyl, C1-C12 aryl, peptide,
protein, oligomer of amino acids or combinations thereof. In some
embodiments, the linker is a labile linker. For example, such
labile linkers can include, e.g., a peptide sequence such as
glycine-phenylalinine-leucine-glycine. Some other labile linkers
include, but are not limited to, succinic anhydride, glutaric
anhydride, dimethyl succinic anhydride, methyl glutaric anhydride,
thioesters, disulfide bonds, PLA-, PLGA-, PCL-oligomers and other
ester and anhydride linkages.
Conjugation of Bioactive Agents
[0033] Any bioactive agent can be conjugated to the
acrylamide-based copolymer. Conjugation can be achieved by binding
force of any nature, e.g., hydrogen bonding, ionic interaction
(e.g., ion pairs), interpenetrating network, or covalent chemical
bonding. Preferably, the binding force between the bioactive agent
and the acrylamide-based copolymer is covalent chemical
bonding.
[0034] Conjugation of the bioactive agent to the acrylamide-based
copolymer by chemical bonding can be carried out using any
established coupling chemistry. For example, where the
acrylamide-based copolymer or a linker attached thereto bears
hydrophilic groups such as hydroxyl, amino or carboxylic groups,
coupling the bioactive group and the hydrophilic groups can be
readily achieved using EDC chemistry (see, e.g., Olde Damink L. H.,
et al., Biomaterials. 17(8):765-73 (1996)). Some other examples of
coupling the bioactive agent to the hydrophilic groups via chemical
bonding are described in U.S. patent application Ser. No.
10/857,141, the teaching of which is incorporated hereto in its
entirety by reference.
Coating Construct
[0035] The acrylamide-based copolymer described herein can be used
with or without a bioactive agent conjugated thereto. In some
embodiments, the acrylamide-based copolymer can be used as a matrix
including a bioactive agent or a topcoat on an implantable device
to control the release of the bioactive agent (e.g., a drug) from
the implantable device. In some embodiments, the acrylamide-based
copolymer can form a topcoat on an implantable device as surface
functionalization of the implantable device. The acrylamide-based
copolymer can include a bioactive agent permanently bound thereto,
the bioactive agent imparting beneficial surface biological
properties to the implantable device. The matrix or topcoat can
further include a biocompatible polymer other than the
acrylamide-based copolymer ("biocompatible polymer") described
herein.
[0036] Release of the bioactive agent from the matrix or topcoat of
the implantable device can proceed via several mechanisms, which
vary according to the nature of the binding force between the
bioactive agent and the acrylamide-based copolymer. For example,
where the binding force between bioactive agent and the
acrylamide-based copolymer is not covalent chemical bonding, the
bioactive agent can diffuse out of the matrix or topcoat so as to
release into the blood stream or a tissue of a human being who
receives an implantable device having a matrix or topcoat described
herein. Where the nature of binding between a bioactive agent and
the acrylamide-based copolymer is covalent bonding via a labile
linker, release of the bioactive agent can be achieved by
degradation or disruption of the labile linker to cause the
bioactive agent to release into the blood stream or a tissue of a
human being who receives an implantable device having a matrix or
topcoat described herein. Degradation or disruption of the labile
linker can be achieved by enzymedic degradation or hydrolytic
degradation of the labile linker.
Biocompatible Polymers
[0037] The acrylamide-based copolymer described herein can be used
with other biocompatible polymers. 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 containing polymer, 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, methacrylate polymers containing
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), molecules 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, elastin
protein mimetics, or combinations thereof. Some examples of elastin
protein mimetics include (LGGVG).sub.n, (VPGVG).sub.n,
Val-Pro-Gly-Val-Gly, or synthetic biomimetic
poly(L-glytanmate)-b-poly(2-acryloyloxyethyllactoside)-b-poly(1-glutamate-
) triblock copolymer. Note, the term "mimetic" can be used
interchangeably with the term "mimic."
[0038] In some embodiments, the polymer can be
poly(ethylene-co-vinyl alcohol), poly(methoxyethyl methacrylate),
poly(dihydroxylpropyl methacrylate), polymethacrylamide, aliphatic
polyurethane, aromatic polyurethane, nitrocellulose, poly(ester
amide benzyl), co-poly-{[N,N'-sebacoyl-bis-(L-leucine)-1,6-hexylene
diester].sub.0.75-[N,N'-sebacoyl-L-lysine benzyl ester].sub.0.25}
(PEA-Bz), co-poly-{[N,N'-sebacoyl-bis-(L-leucine)-1,6-hexylene
diester].sub.0.75-[N,N'-sebacoyl-L-lysine-4-amino-TEMPO
amide].sub.0.25} (PEA-TEMPO), aliphatic polyester, aromatic
polyester, fluorinated polymers such as poly(vinylidene
fluoride-co-hexafluoropropylene), poly(vinylidene fluoride) (PVDF),
and Teflon.TM. (polytetrafluoroethylene), a biopolymer such as
elastin mimetic protein polymer, star or hyper-branched SIBS
(styrene-block-isobutylene-block-styrene), or combinations thereof.
In some embodiments, where the polymer is a copolymer, it can be a
block copolymer that can be, e.g., di-, tri-, tetra-, or
oligo-block copolymers or a random copolymer. In some embodiments,
the polymer can also be branched polymers such as star
polymers.
[0039] In some embodiments, a coating having the features described
herein can exclude any one of the aforementioned polymers.
[0040] 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
[0041] Bioactive agents that can form a conjugation with the
acrylamide-based copolymer 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,
antifibrotic, 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 or
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, small interfering RNA (siRNA), small hairpin RNA
(shRNA), aptamers, 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, as well as halofuginone which also has
anti-fibrotic activity. 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, mometasone,
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
can 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.
[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 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 Implantable Device
[0043] As used herein, an implantable device can be any suitable
medical substrate that can be implanted in a human or veterinary
patient. Examples of such implantable 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 or bioabsorbable metals such as
magnesium could also be used with the embodiments of the present
invention. In some embodiments, the device is a bioabsorbable
stent.
Method of Use
[0044] In accordance with embodiments of the invention, an
implantable device having a coating that includes the
acrylamide-based copolymer described herein can be used for
treating, preventing or ameliorating a medical condition.
Preferably, the implantable 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 can 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.
[0045] Representative examples of sites include the iliac, renal,
carotid and coronary arteries.
[0046] 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 can then be expanded at
the desired area of treatment. A post-insertion angiogram can also
be utilized to confirm appropriate positioning.
[0047] 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.
* * * * *