U.S. patent application number 14/308412 was filed with the patent office on 2014-12-11 for elastin-based copolymers.
The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Thierry Glauser, Syed F.A. Hossainy, Yiwen Tang, Mikael Trollsas.
Application Number | 20140363563 14/308412 |
Document ID | / |
Family ID | 38722714 |
Filed Date | 2014-12-11 |
United States Patent
Application |
20140363563 |
Kind Code |
A1 |
Hossainy; Syed F.A. ; et
al. |
December 11, 2014 |
ELASTIN-BASED COPOLYMERS
Abstract
A copolymer comprising a block of an elastin pentapeptide and
method of making and using the copolymer are provided.
Inventors: |
Hossainy; Syed F.A.;
(Hayward, CA) ; Trollsas; Mikael; (San Jose,
CA) ; Glauser; Thierry; (Redwood City, CA) ;
Tang; Yiwen; (Sunnyvale, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
38722714 |
Appl. No.: |
14/308412 |
Filed: |
June 18, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11449896 |
Jun 9, 2006 |
8778376 |
|
|
14308412 |
|
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|
|
Current U.S.
Class: |
427/2.25 ;
427/2.1 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
1/00 20180101; A61P 7/02 20180101; A61K 38/39 20130101; A61P 13/02
20180101; A61P 7/04 20180101; A61L 27/54 20130101; B05D 3/007
20130101; Y10T 428/3154 20150401; A61L 31/047 20130101; A61P 9/10
20180101; A61L 31/10 20130101; A61L 2420/02 20130101; A61L 2300/25
20130101; A61L 29/085 20130101; C08H 1/00 20130101; A61L 31/16
20130101; A61P 35/00 20180101; Y10T 428/31909 20150401; A61P 29/00
20180101; A61K 38/08 20130101; A61L 27/34 20130101; C07K 14/001
20130101; A61L 27/227 20130101; A61P 13/00 20180101 |
Class at
Publication: |
427/2.25 ;
427/2.1 |
International
Class: |
A61L 31/10 20060101
A61L031/10; B05D 3/00 20060101 B05D003/00 |
Claims
1.-40. (canceled)
41. A method of forming a coating comprising an elastin-based
copolymer on a medical device, comprising providing a solution
comprising the elastin-based copolymer, applying the solution to
the medical device to form a layer of the solution on the medical
device, and treating the medical device with heat at a temperature
about 15.degree. C. to about 30.degree. C. above the lower critical
solution temperature (LCST) of the elastin-based copolymer to form
the coating.
42. The method of claim 41, wherein the solution comprises about 5%
to about 30% the elastin-based copolymer.
43. The method of claim 41, wherein the solution comprises about
10% to about 20% the elastin-based copolymer.
44. The method of claim 41, wherein the solution comprises a
solvent selected from the group consisting of water,
dimethylformamide (DMF), dimethyl suloxide (DMSO), dimethyl
acetamide (DMAC), methyl ethyl ketone (MEK), ethylene glycol,
triflouroethanol (TFE), and combinations thereof.
45. The method of claim 41, wherein the solution comprises a
bioactive agent.
46. The method of claim 45, wherein the bioactive agent is selected
from the group consisting of paclitaxel, docetaxel, estradiol,
17-beta-estradiol, nitric oxide donors, super oxide dismutases,
super oxide dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), .gamma.-hiridun, clobetasol, mometasone, pimecrolimus,
imatinib mesylate, midostaurin, and combinations thereof.
47. The method of claim 41, wherein the block copolymer comprising
a block comprising an elastin pentapeptide (A) and a hydrophilic
block (B), wherein the elastin pentapeptide is VGVPG (SEQ ID NO:
1).
48. The method of claim 47, wherein the block copolymer is an ABA
type triblock copolymer.
49. The method of claim 47, wherein the hydrophilic block comprises
lysine.
50. The method of claim 47, wherein the hydrophilic block comprises
a synthetic polymer.
51. The method of claim 47, wherein the hydrophilic block comprises
a natural polymer.
52. The method of claim 47, wherein the hydrophilic block is a
variant of the VGVPG (SEQ ID NO: 1).
53. The method of claim 49, further comprising a phosphoryl choline
(PC) or poly(ethylene glycol) (PEG) pendant group, wherein the PC
or PEG is conjugated to the block copolymer via lysine in the
hydrophilic block.
54. The method of claim 50, wherein the synthetic polymer is
selected from the group consisting of PEG, PVP
(polyvinylpyrrolidinone), polyacrylamide, poly(PEG acrylate),
poly(HEMA), poly(acrylic acid), and combinations thereof.
55. The method of claim 51, wherein the natural polymer is selected
from the group consisting of collagen or collagen derivative,
hyaluronic acid, alginate, and combinations thereof.
56. The method of claim 47, wherein the block copolymer further
comprises a sequence that promotes proliferation and/or migration
of endothelial cells.
57. The method of claim 56, wherein the sequence is selected from
the group consisting of RGD, cRGD, SIKVAV (SEQ ID NO: 2), CNP,
YIGSRG (SEQ ID NO: 3), mimetics thereof, and combinations of
thereof.
58. The method of claim 47, wherein the block copolymer further
comprises a biodegradable linkage between the A and B blocks.
59. The method of claim 58, wherein the biodegradable linkage is
selected from the group consisting of poly(lactic acid) (PLA),
poly(glycolic acid) (PLGA), polycaprolactone (PCL),
poly(3-hydroxybutyric acid (PHB), poly(4-hydroxybutyrate (P4HB),
and combinations thereof.
60. The method of claim 41, wherein the medical device is a
stent.
61. The method of claim 60, wherein the stent is a bioabsorbable
stent.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional application of U.S.
application Ser. No. 11/449,896 filed Jun. 9, 2006, the teaching of
which is incorporated by reference herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention generally relates to elastin-based copolymers
for coating an implantable device such as a drug delivery stent or
for forming a composition as cell therapy carrier.
[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] 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.
[0007] Therefore, there is a need for new carrier materials for
controlled delivery of an agent. There is a further need for
coating materials for coating a medical device.
[0008] The polymer and methods of making the polymer disclosed
herein address the above described problems.
SUMMARY OF THE INVENTION
[0009] Described in this invention is an elastin-based copolymer.
The copolymer can be used to form a coating on a medical device. In
some embodiments, the coating can further include a polymer, a
biobeneficial material, a bioactive agent, or combinations of
these. Some examples of the bioactive agent 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, bioactive RGD, CD-34 antibody, abciximab
(REOPRO), progenitor cell capturing antibody, prohealing drugs,
prodrugs thereof, co-drugs thereof, or a combination thereof.
[0010] A medical 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.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Described in this invention is an elastin-based copolymer.
The copolymer can be used to form a coating on a medical device. In
some embodiments, the coating can further include a polymer, a
biobeneficial material, a bioactive agent, or combinations of
these. Some examples of the bioactive agent 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, bioactive RGD, CD-34 antibody, abciximab
(REOPRO), progenitor cell capturing antibody, prohealing drugs,
prodrugs thereof, co-drugs thereof, or a combination thereof.
[0012] A medical 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.
Elastin-Based Polymer
[0013] Elastin is a protein that is found in the walls of arteries,
in lungs, intestines and skin in the body of an animal. Elastin
imparts elasticity to the body. Working in partnership with
collagen, elastin allows the body organs to stretch and relax.
Thus, while collagen provides rigidity, elastin allows the blood
vessels and heart tissues, for example, to stretch and then revert
to their original positions.
[0014] Elastin is found to contain short peptides. The most
frequent pentapeptide sequence is valyl-glycyl-valyl-prolyl-glycine
(VGVPG). VGVPG is found to exhibit elastin-like properties (see,
e.g., Reiersen, H., et al., J. Mol. Biol. 283:255-264 (1998)).
[0015] In some embodiments, the elastin-based polymer described
herein can be an ABA or BAB type polymer, where A represents a unit
that includes the pentapeptide sequence VGVPG and B represents a
unit which can be a peptide sequence or a unit derived from a
monomer. The copolymer can be a block or random copolymer.
[0016] In some embodiments, the elastin-based copolymer is an ABA
triblock copolymer, where A is a block comprising the VGVPG
sequence and B is a block derived from a peptide or monomer(s). In
some embodiments, B can be a hydrophilic variant of the VGVPG
peptide. The term "variant" refers to any form of VGVPG
modification. For example, an amino acid in the peptide can be
replaced with another amino acid. In some embodiments, the sequence
of VGVPG can be varied so as to form a variant of the VGVPG
peptide. In some embodiments, the VGVPG peptide can be modified to
include lysine (lysine block). This lysine block can be used as the
middle block to form the ABA triblock copolymer with the VGVPG
pentapeptide. In these embodiments, the lysine block can be
modified to conjugate a molecule or polymer such as phosphoryl
choline (PC), poly(ethylene glycol) (PEG), or a bioactive moiety
such as nitric oxide generating catalyst or TEMPO as pendant
groups. These pendant groups can impart different physical,
chemical, or biological properties to the elastin-based
polymer.
[0017] As one of the properties for the natural elastin materials
are usually non-degradable or very slow degradation, degradable
linkages can be formed between the peptide blocks so that the newly
formed elastin-based materials could be degradable. Any
biodegradable polymers described below can be used as the linkage.
Some examples of these degradable linkages are poly(lactic acid)
(PLA), poly(glycolic acid) (PLGA), polycaprolactone (PCL),
poly(3-hydroxybutyric acid (PHB), poly(4-hydroxybutyrate (P4HB), or
combinations of these.
[0018] In some embodiments, the elastin-based copolymer is an ABA
triblock copolymer where A is a block comprising the VGVPG peptide
and B is a hydrophilic synthetic polymer. Such a synthetic polymer
can be, for example, a hydrophilic polymer such as PEG, PVP (poly
vinylpyrrolidinone), polyacrylamide, poly(PEG acrylate),
poly(HEMA), poly(acrylic acid) or combinations of these
polymers.
[0019] In some embodiments, the elastin-based copolymer is an ABA
triblock copolymer where A is a block comprising the VGVPG peptide
and B is a hydrophilic natural polymer such as protein or peptide.
In some embodiments, such a hydrophilic natural polymer can be, for
example, collagen or collagen derivative, hyaluronic acid, alginate
or combinations of these.
[0020] In some embodiments, the elastin-based polymer can include a
peptide sequence that promotes proliferation and/or migration of
endothelial cells (ECs). Such peptide sequence can be, for example,
RGD, cRGD, or EC specific sequences such as SIKVAV, CNP, YIGSRG,
mimetics of these sequences, or combinations of these.
Composition of Elastin-Based Polymer
[0021] In some embodiments, the elastin-based polymer can be used
in a composition for cell therapy carrier. For example, the
composition can include the elastin-based polymer, cells such as
stem cells and optionally other materials and agents. The
composition can be delivered to a dysfunctional part of the body
(e.g., an organ such as heart or blood vessel) while the cells are
still viable. In some embodiments, the composition can include a
pharmaceutically acceptable carrier.
[0022] Delivery of the composition can be achieved by any
established modes of delivery. Preferably, the delivery can be
injection or delivery through catheter. In some embodiments, the
composition can also be delivered using surgical method such as
creating a depot within the muscle and releasing the pharmaceutical
agent(s) out of the depot.
Other Biocompatible Polymers
[0023] The elastin-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.
[0024] 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. In
some embodiments, a coating having the features described herein
can exclude any one of the aforementioned polymers.
[0025] 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.
Biobeneficial Material
[0026] The elastin-based copolymer can be optionally used with a
biobeneficial material. The biobeneficial material can be a
polymeric material or non-polymeric material. The biobeneficial
material is preferably non-toxic, non-antigenic and
non-immunogenic. A biobeneficial material is one which enhances the
biocompatibility of the particles or device by being non-fouling,
hemocompatible, actively non-thrombogenic, or antiinflammatory, all
without depending on the release of a pharmaceutically active
agent.
[0027] 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), molecules 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, a coating described herein can exclude any one of
the aforementioned polymers. 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).
[0028] In a preferred embodiment, the biobeneficial material can be
a polyether such as poly(ethylene glycol) (PEG) or polyalkylene
oxide.
Bioactive Agents
[0029] The elastin-based copolymer can form a coating on a medical
device. The coating 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. 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.
[0030] 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.
Coating of Elastin-Based Polymer
[0031] The elastin-based polymer can be coated on a medical device
such as a stent according to an established coating process such as
dipping, spray or other processes.
[0032] In some embodiments, the coating can be formed by dipping in
an aqueous solution of the elastin-based polymer. For example, in
some embodiments, a solution of an elastin-based polymer described
here can be provided. A medical device such as a stent can be
dipped in (rinsed) the solution at a temperature below ambient
temperature (e.g., 4.degree. C.). The rinsed medical device can be
subject to heat treatment at a temperature in the range of about
15.degree. C.-30.degree. C. higher than the lower critical solution
temperature (LCST) of the elastin-based polymer to generate a
coating with biomimcry effect.
[0033] A solution of the elastin-based polymer can have a
concentration of the polymer ranging from about 1 wt % to about 50
wt %. Preferably, the solution has a concentration of the
elastin-based polymer in the range between about 5 wt % and about
30%, for example, about 10 wt %, about 15 wt %, about 20 wt % or
about 25 wt %. The solution can include a solvent such as water or
a biocompatible organic solvent such as dimethylformamide (DMF),
dimethyl suloxide (DMSO), dimethyl acetamide (DMAC), methyl ethyl
ketone (MEK), ethylene glycol or combinations of these.
[0034] In some embodiments, the solvent can be triflouroethanol
(TFE). TFE has a boiling temperature of about 80.degree. C., making
the solvent a good solvent for use in coating a medical device. The
concentration can be varied and determined according to the
molecular weight of the elastin-based polymer for forming the
coating. For example, with a elastin-based polymer with a weight
average molecular weight about 160K Daltons, a solution of the
polymer of about 2 wt % in TFE can be used to form a coating on a
medical device using spray coating method at room temperature.
[0035] In some embodiments, the solution can be an acidic solution
having a pH lower than 7. Where an acidic solution of the
elastin-based polymer is used to form the coating on a medical
device, medical device rinsed or sprayed with the acidic solution
shall be rinsed (or sprayed) with a solution of basic pH (>7)
buffered solution. Upon pH increase, the elastin-based polymer will
come out of the solution and result in a coating on the medical
device. The basic buffered solution can be any basic buffer
solution in the art.
[0036] The mechanical property of the film cast from elastin-based
polymer depends on the solution used in the cast. For example, for
elongation of the film, generally a pH>7 coating system will
lead to a higher elongation than a neutral or acidic water coating
system, and a neutral or acidic water coating system will lead to a
higher elongation than a TFE coating system.
Examples of Medical Device
[0037] As used herein, a medical device can 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. "MP2ON" 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
[0038] In accordance with embodiments of the invention, a medical
device having a coating that includes the elastin-based polymer
described herein can be used for treating, preventing or
ameliorating a medical condition. 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 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.
[0039] Representative examples of sites include the iliac, renal,
carotid and coronary arteries.
[0040] 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.
[0041] 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.
Sequence CWU 1
1
615PRTArtificial Sequencesynthetic peptide 1Val Gly Val Pro Gly 1 5
26PRTArtificial Sequencesynthetic peptide 2Ser Ile Lys Val Ala Val
1 5 36PRTArtificial Sequencesynthetic peptide 3Tyr Ile Gly Ser Arg
Gly 1 5 45PRTArtificial Sequencesynthetic peptide 4Leu Gly Gly Val
Gly 1 5 55PRTArtificial Sequencesynthetic peptide 5Val Pro Gly Val
Gly 1 5 65PRTArtificial Sequencesynthetic peptide 6Val Pro Gly Val
Gly 1 5
* * * * *