U.S. patent application number 15/063375 was filed with the patent office on 2016-06-30 for prohealing piezoelectric coatings.
The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Syed Faiyaz Ahmed Hossainy, Lothar Walter KLEINER, Mikael TROLLSAS.
Application Number | 20160184494 15/063375 |
Document ID | / |
Family ID | 52019412 |
Filed Date | 2016-06-30 |
United States Patent
Application |
20160184494 |
Kind Code |
A1 |
Hossainy; Syed Faiyaz Ahmed ;
et al. |
June 30, 2016 |
PROHEALING PIEZOELECTRIC COATINGS
Abstract
Provided herein is a prohealing piezoelectric coating and the
method of making and using the same.
Inventors: |
Hossainy; Syed Faiyaz Ahmed;
(Hayward, CA) ; TROLLSAS; Mikael; (San Jose,
CA) ; KLEINER; Lothar Walter; (Los Altos,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
52019412 |
Appl. No.: |
15/063375 |
Filed: |
March 7, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14476597 |
Sep 3, 2014 |
9302030 |
|
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15063375 |
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11890904 |
Aug 7, 2007 |
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14476597 |
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Current U.S.
Class: |
427/2.1 |
Current CPC
Class: |
C08F 214/28 20130101;
B05D 3/14 20130101; A61L 2300/416 20130101; C08F 114/22 20130101;
C08F 214/22 20130101; A61L 31/10 20130101; A61L 2420/04 20130101;
A61L 31/16 20130101; C08F 14/22 20130101; A61L 2420/02
20130101 |
International
Class: |
A61L 31/16 20060101
A61L031/16; B05D 3/14 20060101 B05D003/14; A61L 31/10 20060101
A61L031/10 |
Claims
1. A method of generating piezoelectric polarization in a coating
on an implantable device, comprising: forming the coating
comprising a piezoelectric polymer(s) onto the implantable device,
providing solvent vapor to the coating, subjecting the coating to
high electric voltage to generate polarization of the piezoelectric
polymer(s), and removing the solvent vapor from the coating and
causing the coating to dry, thereby fixing the polarization of the
piezoelectric polymer(s) in the coating.
2. The method of claim 1, wherein the piezoelectric polymer
comprises units derived from fluoro vinyl monomers.
3. The method of claim 1, wherein the piezoelectric polymer is
selected from PVDF, PVDF-TrFE, PVDF-TFE, or combinations
thereof.
4. The method of claim 1, wherein the piezoelectric polymer
comprises PVDF-HFP.
5. The method of claim 1, wherein the solvent is acetone.
6. The method of claim 1, wherein the coating further comprises at
least one bioactive agent.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional application of U.S.
application Ser. No. 14/476,597, filed on Sep. 3, 2014, which is a
divisional application of U.S. application Ser. No. 11/890,904,
filed on Aug. 7, 2007--both of which are incorporated by reference
herewith. U.S. application Ser. No. 14/476,597 published as US
2014-0370072 A1 on Dec. 18, 2014.
BACKGROUND
[0002] 1. Field of the Invention
[0003] This invention is generally related to coatings for
implantable medical devices, such as drug delivery vascular
stents.
[0004] 2. Description of the State of the Art
[0005] Percutaneous coronary intervention (PCI) is a procedure for
treating heart disease. A catheter assembly having a balloon
portion is introduced percutaneously into the cardiovascular system
of a patient via the brachial or femoral artery. The catheter
assembly is advanced through the coronary vasculature until the
balloon portion is positioned across the occlusive lesion. Once in
position across the lesion, the balloon is inflated to a
predetermined size to radially compress the atherosclerotic plaque
of the lesion to remodel the lumen wall. The balloon is then
deflated to a smaller profile to allow the catheter to be withdrawn
from the patient's vasculature.
[0006] Problems associated with the above procedure include
formation of intimal flaps or torn arterial linings which can
collapse and occlude the blood conduit after the balloon is
deflated. Moreover, thrombosis and restenosis of the artery may
develop over several months after the procedure, which may require
another angioplasty procedure or a surgical by-pass operation. To
reduce the partial or total occlusion of the artery by the collapse
of the arterial lining and to reduce the chance of thrombosis or
restenosis, a stent is implanted in the artery to keep the artery
open.
[0007] Drug delivery stents have reduced the incidence of in-stent
restenosis (ISR) after PCI (see, e.g., Serruys, P. W., et al., J.
Am. Coll. Cardiol. 39:393-399 (2002)), which has plagued
interventional cardiology for more than a decade. However, ISR
still poses a significant problem given the large volume of
coronary interventions and their expanding use. The
pathophysiological mechanism of ISR involves interactions between
the cellular and acellular elements of the vessel wall and the
blood. Damage to the endothelium during PCI constitutes a major
factor for the development of ISR (see, e.g., Kipshidze, N., et
al., J. Am. Coll. Cardiol. 44:733-739 (2004)).
[0008] The embodiments of the present invention address these
concerns as well as others that are apparent to one having ordinary
skill in the art.
SUMMARY
[0009] Provided herein is a piezoelectric coating and the method of
making the same. The piezoelectric coating includes a piezoelectric
polymer or material. The piezoelectricity of the coating provides
enhanced endothelization of the coating and imparts to the coating
enhanced prohealing properties.
[0010] In some embodiments, the piezoelectric coating can include a
piezoelectric polymer. The piezoelectric polymer can be any
polymers that are piezoelectric.
[0011] As used herein, the term piezoelectric or piezoelectricity
refers to the attributes of a polymer to generate a charge in
response to applied mechanical stress. If the material is not
short-circuited, the applied charge induces a voltage across the
material.
[0012] In some embodiments, the piezoelectric polymer is a poled
fluoropolymer. The fluoropolymer can be any polymer that includes
fluoro grouping or atoms. In some embodiments, the fluoropolymer is
poly(vinylidene fluoride) (PVDF), poly(vinylidene
fluoride-co-hexafluoropropylene) (PVDF-HFP), poly(vinylidene
fluoride-co-trifluoroethylene) (PVDF-TrFE), poly(vinylidene
fluoride-co-tetrafluoroethylene) (PVDF-TFE), other co-polymers
based on PVDF or polymers which can have piezoelectric properties,
or combinations thereof.
[0013] In some embodiments, the prohealing piezoelectric coating
can include a chemo-attractant for endothelial cells. Release of
the chemo-attractant can recruit endothelial cells to the coating.
In some embodiments, the coating can include one or more polymers
that are capable of controlling the chemo-attractant's release. The
chemo-attractant can diffuse through the polymer coating, through a
layer of absorbed proteins and cells (acute phase after
implantation), and through the neo-intima (long-term phase) to the
lumen surface in an amount sufficient to recruit endothelial cells
or endothelial progenitor cells to the surface.
[0014] In some embodiments, the piezoelectric coating can include a
bioactive agent other than the chemo-attractant for endothelial
cells described above. Any bioactive agent can be included in a
coating with the chemo-attractant described herein. Some examples
of the bioactive agent include siRNA and/or other oligoneucleotides
that inhibit endothelial cell migration. The bioactive agent can
also be lysophosphatidic acid (LPA) or sphingosine-1-phosphate
(S1P). LPA is a "bioactive" phospholipid able to generate growth
factor-like activities in a wide variety of normal and malignant
cell types. LPA plays an important role in normal physiological
processes such as wound healing, and in vascular tone, vascular
integrity, or reproduction. Some other exemplary bioactive agents
are paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric
oxide donors, super oxide dismutases, super oxide dismutases
mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), biolimus, 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), .gamma.-hiridun, clobetasol, pimecrolimus, imatinib
mesylate, midostaurin, prodrugs thereof, co-drugs thereof, and
combinations thereof
[0015] The coating can be formed on an implantable device such as a
stent, which can be implanted in a patient to treat, prevent,
mitigate, or reduce a vascular medical condition, or to provide a
pro-healing effect. Examples of these 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, ureter
obstruction, tumor obstruction, or combinations of these.
DETAILED DESCRIPTION
[0016] Provided herein is a piezoelectric coating and the method of
making the same. The piezoelectric coating includes a piezoelectric
polymer or material. The piezoelectricity of the coating provides
enhanced endothelization of the coating and imparts to the coating
enhanced prohealing properties.
[0017] In some embodiments, the piezoelectric coating can include a
piezoelectric polymer. The piezoelectric polymer can be any
polymers that are piezoelectric.
[0018] As used herein, the term piezoelectric or piezoelectricity
refers to the attributes of a polymer to generate a charge in
response to applied mechanical stress. If the material is not
short-circuited, the applied charge induces a voltage across the
material.
[0019] In some embodiments, the piezoelectric polymer is a poled
fluoropolymer. The fluoropolymer can be any polymer that includes
fluoro grouping or atoms. In some embodiments, the fluoropolymer is
poly(vinylidene fluoride) (PVDF), poly(vinylidene
fluoride-co-hexafluoropropylene) (PVDF-HFP), poly(vinylidene
fluoride-co-trifluoroethylene) (PVDF-TrFE), poly(vinylidene
fluoride-co-tetrafluoroethylene) (PVDF-TFE), other co-polymers
based on PVDF or polymers which can have piezoelectric properties,
or combinations thereof In some embodiments, a fluoropolymer is a
polymer of any polymer including units derived from fluoro vinyl
monomers.
[0020] The term "poled" refers to the molecules of a polymer being
oriented toward a direction.
[0021] In some embodiments, the prohealing piezoelectric coating
can include a chemo-attractant for endothelial cells. Release of
the chemo-attractant can recruit endothelial cells to the coating.
In some embodiments, the coating can include one or more polymers
that are capable of controlling the chemo-attractant's release. The
chemo-attractant can diffuse through the polymer coating, through a
layer of absorbed proteins and cells (acute phase after
implantation), and through the neo-intima (long-term phase) to the
lumen surface in an amount sufficient to recruit endothelial cells
or endothelial progenitor cells to the surface.
[0022] In some embodiments, the piezoelectric coating can include a
bioactive agent other than the chemo-attractant for endothelial
cells described above. Any bioactive agent can be included in a
coating with the chemo-attractant described herein. Some examples
of the bioactive agent include siRNA and/or other oligoneucleotides
that inhibit endothelial cell migration. The bioactive agent can
also be lysophosphatidic acid (LPA) or sphingosine-1-phosphate
(S1P). LPA is a "bioactive" phospholipid able to generate growth
factor-like activities in a wide variety of normal and malignant
cell types. LPA plays an important role in normal physiological
processes such as wound healing, and in vascular tone, vascular
integrity, or reproduction. Some other exemplary bioactive agents
are paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric
oxide donors, super oxide dismutases, super oxide dismutases
mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), biolimus, 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), .gamma.-hiridun, clobetasol, pimecrolimus, imatinib
mesylate, midostaurin, prodrugs thereof, co-drugs thereof, and
combinations thereof
[0023] The coating can be formed on an implantable device such as a
stent, which can be implanted in a patient to treat, prevent,
mitigate, or reduce a vascular medical condition, or to provide a
pro-healing effect. Examples of these 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, ureter
obstruction, tumor obstruction, or combinations of these.
Piezoelectric Coating
[0024] The piezoelectric coating described herein can include any
piezoelectric polymer or material. In some embodiments, the coating
can include a piezoelectric polymer. In some embodiments, the
coating can include a piezoelectric material that is not a polymer,
such as a piezoelectric ceramic, or a piezoelectric polymer-ceramic
composite.
Piezoelectric polymer
[0025] The piezoelectric polymer that can be included in a
piezoelectric coating described herein can be any piezoelectric
polymer. In some embodiments, the piezoelectric polymer is a
fluoropolymer. Some examples of fluoropolymers include Solef.TM.
polymers. One example of Solef.TM. polymers is PVDF. In some
embodiments, the piezoelectric polymer is a copolymer comprising
PVDF-HFP.
[0026] Polyvinylidene fluoride (PVDF)--PVDF exhibits
piezoelectricity several times larger than quartz. Unlike ceramics,
where the crystal structure of the material creates the
piezoelectric effect, in polymers the intertwined long-chain
molecules attract each and repel other when an external force is
applied. The desired morphology of PVDF is known as the .beta.
phase or Form I, in which the predominantly "head to tail" polymer
chains have an all-trans extended planar zig-zag form with the
dipoles of adjacent chains parallel to one another. This .beta.
phase can be formed from the more common alpha phase (Form II),
which is nonpolar, by mechanical deformation followed by electrical
polarization. In practice, both uniaxial and biaxial mechanical
orientation is used which, after poling, gives a different balance
of piezo/pyro-electric properties.
[0027] The process of transforming a piezoelectric material from
the nonpolar alpha phase to the dipolar .beta. phase is well known
in the art. An exemplary process is described in U.S. Pat. No.
4,427,609.
[0028] Other piezoelectric polymers include, but are not limited
to, polyvinylidene fluoride (PVDF) and copolymers films of PVDF,
which possess the highest values of piezoelectric constants of any
known polymer.
[0029] In some embodiments, the piezoelectric coating can
specifically exclude any of the above listed piezoelectric polymer
or polymers.
Piezoelectric Material
[0030] The piezoelectric material other than the piezoelectric
polymer described above that can be included in a piezoelectric
coating can be any piezoelectric material. In some embodiments, the
piezoelectric material is a piezoelectric ceramic compound. Some
examples of the piezoelectric material include, but are not limited
to, lead zirconium titanate (PZT), lead scandium tantalate, barium
strontium titanate, lead magnesium niobate, or combinations
thereof. Some further examples of piezoelectric materials include,
but are not limited to, Pb(xZr,(1-x)Ti)O.sub.3, BaTiO.sub.3,
PbZrO.sub.3, PbTiO.sub.3, PbNb.sub.2O.sub.6, (Pb,Ca)TiO.sub.3,
(Pb,Sm)TiO.sub.3, Pb(NbO.sub.2).sub.2/PbTiO.sub.3,
(1-x)Pb(Mg.sub.1/3Nb.sub.2/3)O.sub.3-xPbTiO.sub.3,
(1-x-y)Pb(Zn.sub.1/3Nb.sub.2/3)O.sub.3-xPbTiO.sub.3-yBaTiO.sub.3,
and
(1-x-y)Pb(Zn.sub.1/3Nb.sub.2/3)O.sub.3-xBaTiO.sub.3-yPbTiO.sub.3,
xPZN-(1-x)PMN, xPMN-(1-x)PZT, PNN-PZ-PT, xPZN-(1-x)PZT, or
combinations thereof.
[0031] Other piezoelectric materials that can be included in a
piezoelectric coating include, but are not limited to,
polymer-ceramic composites, which can be a blend or multi-layer
composites. Generally, a polymer-ceramic composite includes a
piezoelectric phase and a non-piezoelectric phase. The
piezoelectric phase includes at least one piezoelectric material,
and the non-piezoelectric phase includes a binder material which
can be, e.g., a polymer. An example of such a multi-layer composite
contains a PVDF and a piezoelectric ceramic. Some other examples of
such polymer-ceramic composites or multi-layer composites are
described in U.S. Pat. Nos. 5,505,870; and 5,796,207, the teachings
of which are incorporated herein in its entirety by reference.
[0032] In some embodiments, the piezoelectric coating can
specifically exclude any of the above listed piezoelectric material
or materials.
Polarization
[0033] The piezoelectric coating described herein can be formed
onto an implantable device (e.g., a stent) and then subjected to
high electric voltage. The high electric voltage can pole the
piezoelectric polymer or material to orient the polymer(s) or
material(s), resulting in polarization of the piezoelectric
polymer(s) or material(s).
[0034] Generally, the piezoelectric coating receiving a high
electric voltage treatment will be in a condition that is capable
of allowing the piezoelectric polymer(s) or material to re-orient
or to polarize. Such condition can include, e.g., solvated or
wetted condition. In some embodiments, such condition can be, e.g.,
heating the coating to a temperature at or above glass transition
temperature (T.sub.g) of the coating.
[0035] Polarization of the piezoelectric polymer(s) or material(s)
in the coating can be fixed or frozen in the coating by causing the
coating to solidify from a less solidified condition by, e.g.,
evaporation of solvent in the coating or cooling the coating from a
temperature above, e.g., T.sub.g of the coating to a temperature
below T.sub.g of the coating. Following implant of an implantable
device comprising the piezoelectric coating, the cyclic motion of
the vessel will induce faster healing for that the coronary artery
behaves like a peristaltic pump, oscillations in charge are induced
due to pulsatile flow. This pulsatile flow promotes vascular
healing.
[0036] As used herein, the term high voltage refers to a direct
current (DC) having a voltage at about (e.g., 100 V) or above. The
term low voltage refers to a DC current having a voltage at about
10V or below, e.g. 3V.
[0037] Some examples of treating the piezoelectric coating by a
high electric voltage are described below: [0038] a) A
piezoelectric coating comprising a piezoelectric polymer or
material can be subjected to high electric voltage before the
coating is dried (e.g., in a convection oven). The high electric
voltage can pole and orient the piezoelectric polymer or material
and cause the polarization to fix when the coating is dried. For
example, a coating comprising PVDF can be subjected to the
treatment of a high electric voltage in this fashion. [0039] b) A
piezoelectric coating formed on an implantable device comprising a
piezoelectric polymer(s) or material(s) can be exposed to a solvent
vapor (e.g., acetone vapor) and simultaneously or subsequently
subjected to the treatment of a high electric voltage to re-orient
to generate polarization of the piezoelectric polymer(s) or
material(s). Removal of the solvent vapor and dry the coating,
which may take in some solvent as the result of exposure to the
solvent vapor, can cause the piezoelectric polymer(s) or
material(s) to fix the polarization. The solvent for forming the
solvent vapor is chosen on the condition that such solvent can
solvate or wet the piezoelectric coating subjected to the treatment
of high electric voltage. A person of ordinary skill in the art can
readily chosen a solvent to form a solvent vapor based on the
chemical nature of the piezoelectric coating. For example, for a
piezoelectric coating comprising PVDF, acetone or any other solvent
that can solvate or wet PVDF can be used to form the solvent vapor.
[0040] c) Immediately after each coating pass, a high voltage pulse
can be delivered to a piezoelectric coating thus formed comprising
a piezoelectric polymer(s) or material(s). The pulses are so
synchronized so that the polarization relaxation time of the
piezoelectric polymer(s) or material(s) exceeds the drying time so
that the polarization is fixed or frozen in the coating. Generally,
the high voltage pulses can have a voltage as described above and a
duration of approximately ten second or less, about one second or
less, or about 0.1 second or less. The pulses can be synchronized,
and a person of ordinary skill in the art can readily appreciate
the ways to synchronize the pulses to cause the polarization
relaxation time of the piezoelectric polymer(s) or material(s) to
exceed the drying time so that the polarization is fixed or frozen
in the coating. [0041] d) During coating a composition comprising a
piezoelectric polymer(s) or material(s) onto an implantable device,
a high voltage pulse can be delivered to the coating. The pulses
are so synchronized so that the polarization relaxation time of the
piezoelectric polymer(s) or material(s) exceeds the drying time so
that the polarization is fixed or frozen in the coating. Generally,
the high voltage pulses can have a voltage as described above and a
duration of approximately ten second or less, about one second or
less, or about 0.1 second or less. The pulses can be synchronized,
and a person of ordinary skill in the art can readily appreciate
the ways to synchronize the pulses to cause the polarization
relaxation time of the piezoelectric polymer(s) or material(s) to
exceed the drying time so that the polarization is fixed or frozen
in the coating.
[0042] The methods of coating an implantable device are well
documented in the art. Generally, the method includes (a) providing
a coating composition and (b) applying the coating composition onto
an implantable medical device to form a coating on the implantable
medical device. The coating composition can include any polymer(s),
material(s), bioactive agent(s) for forming the piezoelectric
coating described herein.
Biocompatible Polymers
[0043] The piezoelectric coating described herein can include one
or more biocompatible polymer other than the piezoelectric
polymer(s) or material(s) described above. The biocompatible
polymer can be biodegradable (both bioerodable or bioabsorbable) or
nondegradable and can be hydrophilic or hydrophobic.
[0044] Representative biocompatible polymers include, but are not
limited to, poly(ester amide), polyhydroxyalkanoates (PHA),
poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),
poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),
poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) and
poly(3-hydroxyoctanoate), poly(4-hydroxyalkanaote) such as
poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),
poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),
poly(4-hydroxyoctanoate) and copolymers including any of the
3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein
or blends thereof, poly(D,L-lactide), poly(L-lactide),
polyglycolide, poly(D,L-lactide-co-glycolide),
poly(L-lactide-co-glycolide), polycaprolactone,
poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),
poly(dioxanone), poly(ortho esters), poly(anhydrides),
poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine
ester) and derivatives thereof, poly(imino carbonates),
poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,
polyphosphoester urethane, poly(amino acids), polycyanoacrylates,
poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes,
polyphosphazenes, silicones, polyesters, polyolefins,
polyisobutylene and ethylene-alphaolefin copolymers, acrylic
polymers and copolymers, vinyl halide polymers and copolymers, such
as polyvinyl chloride, polyvinyl ethers, such as polyvinyl methyl
ether, polyvinylidene halides, such as polyvinylidene chloride,
polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, such as
polystyrene, polyvinyl esters, such as polyvinyl acetate,
copolymers of vinyl monomers with each other and olefins, such as
ethylene-methyl methacrylate copolymers, 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/poly(lactic
acid) (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
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), PLURONIC.TM. surfactants
(polypropylene oxide-co-polyethylene glycol), poly(tetramethylene
glycol), hydroxy functional poly(vinyl pyrrolidone), biomolecules
such as chitosan, alginate, fibrin, fibrinogen, cellulose, starch,
dextran, dextrin, fragments and derivatives of hyaluronic acid,
heparin, fragments and derivatives of heparin, glycosamino glycan
(GAG), GAG derivatives, polysaccharide, chitosan, alginate, or
combinations thereof In some embodiments, the copolymer described
herein can exclude any one or more of the aforementioned
polymers.
[0045] 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.
Biologically Active Agents
[0046] The implantable device described herein can optionally
include at least one biologically active ("bioactive") agent. The
at least one bioactive agent can include any substance capable of
exerting a therapeutic, prophylactic or diagnostic effect for a
patient.
[0047] Examples of suitable bioactive agents include, but are not
limited to, synthetic inorganic and organic compounds, proteins and
peptides, polysaccharides and other sugars, lipids, and DNA and RNA
nucleic acid sequences having therapeutic, prophylactic or
diagnostic activities. Nucleic acid sequences include genes,
antisense molecules that bind to complementary DNA to inhibit
transcription, and ribozymes. Some other examples of other
bioactive agents include antibodies, receptor ligands, enzymes,
adhesion peptides, blood clotting factors, inhibitors or clot
dissolving agents such as streptokinase and tissue plasminogen
activator, antigens for immunization, hormones and growth factors,
oligonucleotides such as antisense oligonucleotides and ribozymes
and retroviral vectors for use in gene therapy. The bioactive
agents could be designed, e.g., to inhibit the activity of vascular
smooth muscle cells. They could be directed at inhibiting abnormal
or inappropriate migration and/or proliferation of smooth muscle
cells to inhibit restenosis.
[0048] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the implantable device
can include at least one biologically active agent selected from
antiproliferative, antineoplastic, antimitotic, anti-inflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic,
antiallergic and antioxidant substances.
[0049] An antiproliferative agent can be a natural proteineous
agent such as a cytotoxin or a synthetic molecule. Examples of
antiproliferative substances include, but are not limited to,
actinomycin D or derivatives and analogs thereof (manufactured by
Sigma-Aldrich, or COSMEGEN available from Merck) (synonyms of
actinomycin D include dactinomycin, actinomycin IV, actinomycin
I.sub.1, actinomycin X.sub.1, and actinomycin C.sub.1); all taxoids
such as taxols, docetaxel, and paclitaxel and derivatives thereof;
all olimus drugs such as macrolide antibiotics, rapamycin,
everolimus, structural derivatives and functional analogues of
rapamycin, structural derivatives and functional analogues of
everolimus, FKBP-12 mediated mTOR inhibitors, biolimus,
perfenidone, prodrugs thereof, co-drugs thereof, and combinations
thereof. Examples of rapamycin derivatives include, but are not
limited to, 40-O-(2-hydroxy)ethyl-rapamycin (trade name everolimus
from Novartis), 40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus, manufactured by Abbott Labs.), prodrugs thereof,
co-drugs thereof, and combinations thereof. An anti-inflammatory
drug can be a steroidal anti-inflammatory drug, a nonsteroidal
anti-inflammatory drug (NSAID), or a combination thereof. Examples
of anti-inflammatory drugs include, but are not limited to,
alclofenac, alclometasone dipropionate, algestone acetonide, alpha
amylase, amcinafal, amcinafide, amfenac sodium, amiprilose
hydrochloride, anakinra, anirolac, anitrazafen, apazone,
balsalazide disodium, bendazac, benoxaprofen, benzydamine
hydrochloride, bromelains, broperamole, budesonide, carprofen,
cicloprofen, cintazone, cliprofen, clobetasol, clobetasol
propionate, clobetasone butyrate, clopirac, cloticasone propionate,
cormethasone acetate, cortodoxone, deflazacort, desonide,
desoximetasone, dexamethasone, dexamethasone acetate, dexamethasone
dipropionate, diclofenac potassium, diclofenac sodium, diflorasone
diacetate, diflumidone sodium, diflunisal, difluprednate,
diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab,
enolicam sodium, epirizole, etodolac, etofenamate, felbinac,
fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone,
fentiazac, flazalone, fluazacort, flufenamic acid, flumizole,
flunisolide acetate, flunixin, flunixin meglumine, fluocortin
butyl, fluorometholone acetate, fluquazone, flurbiprofen,
fluretofen, fluticasone propionate, furaprofen, furobufen,
halcinonide, halobetasol propionate, halopredone acetate, ibufenac,
ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap,
indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole,
isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole
hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate
sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid,
mesalamine, meseclazone, methylprednisolone suleptanate,
momiflumate, nabumetone, naproxen, naproxen sodium, naproxol,
nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin,
oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate
sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam,
piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate,
prifelone, prodolic acid, proquazone, proxazole, proxazole citrate,
rimexolone, romazarit, salcolex, salnacedin, salsalate,
sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,
suprofen, talmetacin, talniflumate, talosalate, tebufelone,
tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine,
tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,
triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin
(acetylsalicylic acid), salicylic acid, corticosteroids,
glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof,
co-drugs thereof, and combinations thereof.
[0050] Alternatively, the anti-inflammatory agent can be a
biological inhibitor of pro-inflammatory signaling molecules.
Anti-inflammatory biological agents include antibodies to such
biological inflammatory signaling molecules.
[0051] In addition, the bioactive agents can be other than
antiproliferative or anti-inflammatory agents. The bioactive agents
can be any agent that is a therapeutic, prophylactic or diagnostic
agent. In some embodiments, such agents can be used in combination
with antiproliferative or anti-inflammatory agents. These bioactive
agents can also have antiproliferative and/or anti-inflammmatory
properties or can have other properties such as antineoplastic,
antimitotic, cystostatic, antiplatelet, anticoagulant, antifibrin,
antithrombin, antibiotic, antiallergic, and/or antioxidant
properties.
[0052] Examples of antineoplastics and/or antimitotics include, but
are not limited to, paclitaxel (e.g., TAXOL.RTM. available from
Bristol-Myers Squibb), docetaxel (e.g., Taxotere.RTM. from
Aventis), methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin.RTM. from
Pfizer), and mitomycin (e.g., Mutamycin.RTM. from Bristol-Myers
Squibb).
[0053] Examples of antiplatelet, anticoagulant, antifibrin, and
antithrombin agents that can also have cytostatic or
antiproliferative properties include, but are not limited to,
sodium heparin, low molecular weight heparins, heparinoids,
hirudin, argatroban, forskolin, vapiprost, prostacyclin and
prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist antibody, recombinant
hirudin, thrombin inhibitors such as ANGIOMAX (from Biogen),
calcium channel blockers (e.g., nifedipine), colchicine, fibroblast
growth factor (FGF) antagonists, fish oil (e.g., omega 3-fatty
acid), histamine antagonists, lovastatin (a cholesterol-lowering
drug that inhibits HMG-CoA reductase, brand name Mevacor.RTM. from
Merck), monoclonal antibodies (e.g., those specific for
platelet-derived growth factor (PDGF) receptors), nitroprusside,
phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,
serotonin blockers, steroids, thioprotease inhibitors,
triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric
oxide donors, super oxide dismutases, super oxide dismutase
mimetics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), estradiol, anticancer agents, dietary supplements
such as various vitamins, and a combination thereof.
[0054] Examples of cytostatic substances include, but are not
limited to, angiopeptin, angiotensin converting enzyme inhibitors
such as captopril (e.g., Capoten.RTM. and Capozide.RTM. from
Bristol-Myers Squibb), cilazapril and lisinopril (e.g.,
Prinivil.RTM. and Prinzide.RTM. from Merck).
[0055] Examples of antiallergic agents include, but are not limited
to, permirolast potassium. Examples of antioxidant substances
include, but are not limited to,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO). Other
bioactive agents include anti-infectives such as antiviral agents;
analgesics and analgesic combinations; anorexics; antihelmintics;
antiarthritics, antiasthmatic agents; anticonvulsants;
antidepressants; antidiuretic agents; antidiarrheals;
antihistamines; antimigrain preparations; antinauseants;
antiparkinsonism drugs; antipruritics; antipsychotics;
antipyretics; antispasmodics; anticholinergics; sympathomimetics;
xanthine derivatives; cardiovascular preparations including calcium
channel blockers and beta-blockers such as pindolol and
antiarrhythmics; antihypertensives; diuretics; vasodilators
including general coronary vasodilators; peripheral and cerebral
vasodilators; central nervous system stimulants; cough and cold
preparations, including decongestants; hypnotics;
immunosuppressives; muscle relaxants; parasympatholytics;
psychostimulants; sedatives; tranquilizers; naturally derived or
genetically engineered lipoproteins; and restenoic reducing
agents.
[0056] Other biologically active agents that can be used include
alpha-interferon, genetically engineered epithelial cells,
tacrolimus and dexamethasone.
[0057] A "prohealing" drug or agent, in the context of a
blood-contacting implantable device, refers to a drug or agent that
has the property that it promotes or enhances re-endothelialization
of arterial lumen to promote healing of the vascular tissue. The
portion(s) of an implantable device (e.g., a stent) containing a
prohealing drug or agent can attract, bind and eventually become
encapsulated by endothelial cells (e.g., endothelial progenitor
cells). The attraction, binding, and encapsulation of the cells
will reduce or prevent the formation of emboli or thrombi due to
the loss of the mechanical properties that could occur if the stent
was insufficiently encapsulated. The enhanced re-endothelialization
can promote the endothelialization at a rate faster than the loss
of mechanical properties of the stent.
[0058] The prohealing drug or agent can be dispersed in the body of
the bioabsorbable polymer substrate or scaffolding. The prohealing
drug or agent can also be dispersed within a bioabsorbable polymer
coating over a surface of an implantable device (e.g., a
stent).
[0059] "Endothelial progenitor cells" refer to primitive cells made
in the bone marrow that can enter the bloodstream and go to areas
of blood vessel injury to help repair the damage. Endothelial
progenitor cells circulate in adult human peripheral blood and are
mobilized from bone marrow by cytokines, growth factors, and
ischemic conditions. Vascular injury is repaired by both
angiogenesis and vasculogenesis mechanisms. Circulating endothelial
progenitor cells contribute to repair of injured blood vessels
mainly via a vasculogenesis mechanism.
[0060] In some embodiments, the prohealing drug or agent can be an
endothelial cell (EDC)-binding agent. In certain embodiments, the
EDC-binding agent can be a protein, peptide or antibody, which can
be, e.g., one of collagen type 1, a 23 peptide fragment known as
single chain Fv fragment (scFv A5), a junction membrane protein
vascular endothelial (VE)-cadherin, and combinations thereof.
Collagen type 1, when bound to osteopontin, has been shown to
promote adhesion of endothelial cells and modulate their viability
by the down regulation of apoptotic pathways. S. M. Martin, et al.,
J. Biomed. Mater. Res., 70A:10-19 (2004). Endothelial cells can be
selectively targeted (for the targeted delivery of immunoliposomes)
using scFv A5. T. Volkel, et al., Biochimica et Biophysica Acta,
1663:158-166 (2004). Junction membrane protein vascular endothelial
(VE)-cadherin has been shown to bind to endothelial cells and down
regulate apoptosis of the endothelial cells. R. Spagnuolo, et al.,
Blood, 103:3005-3012 (2004).
[0061] In a particular embodiment, the EDC-binding agent can be the
active fragment of osteopontin,
(Asp-Val-Asp-Val-Pro-Asp-Gly-Asp-Ser-Leu-Ala-Try-Gly). Other
EDC-binding agents include, but are not limited to, EPC (epithelial
cell) antibodies, RGD peptide sequences, RGD mimetics, and
combinations thereof.
[0062] In further embodiments, the prohealing drug or agent can be
a substance or agent that attracts and binds endothelial progenitor
cells. Representative substances or agents that attract and bind
endothelial progenitor cells include antibodies such as CD-34,
CD-133 and vegf type 2 receptor. An agent that attracts and binds
endothelial progenitor cells can include a polymer having nitric
oxide donor groups.
[0063] The foregoing biologically active agents are listed by way
of example and are not meant to be limiting. Other biologically
active agents that are currently available or that may be developed
in the future are equally applicable.
[0064] In a more specific embodiment, optionally in combination
with one or more other embodiments described herein, the
implantable device of the invention comprises at least one
biologically active agent selected from paclitaxel, docetaxel,
estradiol, nitric oxide donors, super oxide dismutases, super oxide
dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, progenitor cell-capturing antibodies, prohealing drugs,
prodrugs thereof, co-drugs thereof, and a combination thereof. In a
particular embodiment, the bioactive agent is everolimus. In
another specific embodiment, the bioactive agent is clobetasol.
[0065] In some embodiments, optionally in combination with one or
more other embodiments described herein, the at least one
biologically active agent specifically cannot be one or more of any
of the bioactive drugs or agents described herein.
[0066] The dosage or concentration of the bioactive agent required
to produce a favorable therapeutic effect should be less than the
level at which the bioactive agent produces toxic effects and
greater than the level at which non-therapeutic results are
obtained. The dosage or concentration of the bioactive agent can
depend upon factors such as the particular circumstances of the
patient, the nature of the trauma, the nature of the therapy
desired, the time over which the ingredient administered resides at
the vascular site, and if other active agents are employed, the
nature and type of the substance or combination of substances.
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 those of ordinary skill in
the art.
Examples of Implantable Device
[0067] 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 prosthesis (e.g.,
artificial heart valves) or vascular graft, cerebrospinal fluid
shunts, pacemaker electrodes, catheters, endocardial leads (e.g.,
FINELINE and ENDOTAK, available from Guidant Corporation, Santa
Clara, Calif.), and devices facilitating anastomosis such as
anastomotic connectors. 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 "MP2ON" 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 could also be used with the
embodiments of the present invention. The device can be, for
example, a bioabsorbable stent.
Method of Use
[0068] In accordance with embodiments of the invention, a
chemo-attractant can be included in an implantable device or
prosthesis, e.g., a stent. For a device including one or more
active agents, the agent will retain on the device such as a stent
during delivery and expansion of the device, and released at a
desired rate and for a predetermined duration of time at the site
of implantation.
[0069] Preferably, the 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 the
bile ducts, esophagus, trachea/bronchi and other biological
passageways. A stent having the above-described coating is
particularly useful for treating occluded regions of blood vessels
caused by abnormal or inappropriate migration and proliferation of
smooth muscle cells, thrombosis, and restenosis. Stents may be
placed in a wide array of blood vessels, both arteries and veins.
Representative examples of sites include the iliac, renal, and
coronary arteries.
[0070] For implantation of a stent, an angiogram is first performed
to determine the appropriate positioning for stent therapy. An
angiogram is typically accomplished by injecting a radiopaque
contrasting agent through a catheter inserted into an artery or
vein as an x-ray is taken. A guidewire is then advanced through the
lesion or proposed site of treatment. Over the guidewire is passed
a delivery catheter that allows a stent in its collapsed
configuration to be inserted into the passageway. The delivery
catheter is inserted either percutaneously or by surgery into the
femoral artery, brachial artery, femoral vein, or brachial vein,
and advanced into the appropriate blood vessel by steering the
catheter through the vascular system under fluoroscopic guidance. A
stent having the above-described coating may then be expanded at
the desired area of treatment. A post-insertion angiogram may also
be utilized to confirm appropriate positioning.
[0071] 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.
* * * * *