U.S. patent application number 14/081876 was filed with the patent office on 2014-03-13 for coating of fast absorption or dissolution.
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 Syed Faiyaz Ahmed Hossainy, Lothar W. Kleiner, Bozena Zofia Maslanka, Michael Huy Ngo, Mikael O. Trollsas.
Application Number | 20140074224 14/081876 |
Document ID | / |
Family ID | 39312925 |
Filed Date | 2014-03-13 |
United States Patent
Application |
20140074224 |
Kind Code |
A1 |
Trollsas; Mikael O. ; et
al. |
March 13, 2014 |
COATING OF FAST ABSORPTION OR DISSOLUTION
Abstract
A coating of fast absorption or fast dissolution on an
implantable device and methods of making and using of the coating
are provided.
Inventors: |
Trollsas; Mikael O.; (San
Jose, CA) ; Ngo; Michael Huy; (San Jose, CA) ;
Maslanka; Bozena Zofia; (Aptos, CA) ; Hossainy; Syed
Faiyaz Ahmed; (Hayward, CA) ; Kleiner; Lothar W.;
(Los Altos, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
Abbott Cardiovascular Systems
Inc.
Santa Clara
CA
|
Family ID: |
39312925 |
Appl. No.: |
14/081876 |
Filed: |
November 15, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11638780 |
Dec 13, 2006 |
8597673 |
|
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14081876 |
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Current U.S.
Class: |
623/1.38 ;
428/334 |
Current CPC
Class: |
A61P 35/00 20180101;
A61L 31/16 20130101; A61P 9/10 20180101; A61L 27/54 20130101; A61P
1/16 20180101; A61L 2300/606 20130101; A61P 13/12 20180101; A61P
7/02 20180101; A61F 2/82 20130101; A61L 27/34 20130101; A61P 13/02
20180101; A61L 2300/416 20130101; A61P 9/00 20180101; A61P 7/04
20180101; A61L 27/58 20130101; C09D 143/02 20130101; A61L 31/148
20130101; A61L 31/10 20130101; Y10T 428/263 20150115 |
Class at
Publication: |
623/1.38 ;
428/334 |
International
Class: |
A61L 31/10 20060101
A61L031/10; A61F 2/82 20060101 A61F002/82 |
Claims
1. A coating on an implantable device, the coating comprising a
soluble or fast absorption polymer or material, and between about
1% and about 20% of a low molecular weight polymer, wherein the low
molecular weight polymer has a weight-average weight (M.sub.w)
below 5,000 Daltons and is hydrophilic, and wherein the coating has
a thickness from about 1 .mu.m to about 100 .mu.m and about 50 wt %
or more of the coating can absorb or dissolve within 24 hours after
implantation.
2. (canceled)
3. The coating of claim 1, wherein the low molecular weight polymer
comprises acidic or basic pendant groups.
4. The coating of claim 1, wherein the soluble or fast absorption
polymer or material comprises an ionic or non-ionic polymer.
5. The coating of claim 1, wherein the soluble or fast absorption
polymer or material comprises poly(ethylene glycol) (PEG),
poly(vinyl alcohol) (PVA), hyaluronic acid, hydroxyl cellulose, CMC
(carboxymethyl cellulose), hydroxy propyl methyl cellulose (HPMC),
hydroxy propyl methacrylamide (HPMA), poly(butylene
terephthalate-co-poly(ethylene glycol) (PBT-PEG), poly(butylene
terephthalate-co-carboxy methyl cellulose) (PBT-co-CMC),
polysaccharide, phosphoryl choline polymer, chitosan, collagen,
PLA, PLGA, PEA, polyacylate, polymethacrylate or a combination
thereof.
6. The coating of claim 1, wherein the soluble or fast absorption
polymer or material has a M.sub.w of 10,000 Daltons to about
150,000 Daltons.
7. (canceled)
8. The coating of claim 1 wherein the soluble or fast absorption
polymer comprises a phosphoryl choline polymer.
9. The coating of claim 8, wherein the phosphoryl choline polymer
comprises units derived from a vinyl monomer comprising phosphoryl
choline.
10. The coating of claim 8, wherein phosphoryl choline polymer has
the formula of ##STR00002## where n and m independently range from
about 0.01 to about 0.99.
11. The coating of claim 10 where some or all butyl groups can be
replaced by methyl, ethyl, other alkyl groups, or a combination
thereof.
12. The coating of claim 11, wherein n and m are about 0.5.
13. The coating of claim 10, wherein the phosphoryl choline polymer
is random or block copolymer.
14. The coating of claim 11, wherein the phosphoryl choline polymer
is a random or block copolymer.
15. The coating of claim 12, wherein the phosphoryl choline polymer
is a random or block copolymer.
16. The coating of claim 8, wherein the phosphoryl choline polymer
comprises at least one phosphoryl choline moiety and at least one
moiety derived from a biocompatible polymer.
17. The coating of claim 16, wherein the biocompatible polymer
comprises poly(ester amide), poly(lactic acid), poly(glycolic
acid), poly(caprolactone), poly(dioxanone), or poly(ester
amide-2,2,6,6-tetramethyl-1-piperidinyloxy) (PEA-TEMPO).
18. The coating of claim 1, wherein the implantable device is
stent.
19. The coating of claim 8, wherein the implantable device is
stent.
20. The coating of claim 1, further comprising a bioactive
agent.
21. The coating of claim 8, further comprising a bioactive
agent.
22. The coating of claim 1, further comprising an agent selected
from the group consisting of paclitaxel, docetaxel, estradiol,
nitric oxide donors, super oxide dismutases, 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), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor cell capturing antibody, prohealing drugs, prodrugs
thereof, or a combination thereof.
23. The coating of claim 8, further comprising an agent selected
from the group consisting of paclitaxel, docetaxel, estradiol,
nitric oxide donors, super oxide dismutases, 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), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, CD-34 antibody, abciximab (REOPRO),
progenitor cell capturing antibody, prodrugs thereof, or a
combination thereof.
24. A method of treating a human being by implanting in the human
being an implantable device comprising the coating of claim 22,
wherein the disorder is selected from the group consisting of
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection or perforation, vascular aneurysm, vulnerable plaque,
chronic total occlusion, claudication, anastomotic proliferation
for vein and artificial grafts, bile duct obstruction, ureter
obstruction, tumor obstruction, and combinations thereof.
25. A method of treating a human being by implanting in the human
being an implantable device comprising the coating of claim 23,
wherein the disorder is selected from the group consisting of
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection or perforation, vascular aneurysm, vulnerable plaque,
chronic total occlusion, claudication, anastomotic proliferation
for vein and artificial grafts, bile duct obstruction, ureter
obstruction, tumor obstruction, and combinations thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation application of U.S.
application Ser. No. 11/638,780 filed on Dec. 13, 2006, the
teaching of which is herein incorporated by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention generally relates to a coating of fast
dissolution or absorption on an implantable device.
[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 affect a
controlled delivery of an active agent in stent based therapy, 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. A
continuing challenge in the art of implantable stents is to provide
a coating that possesses good biobeneficial properties, which refer
to good biocompatibilities in both the acute and chronic
timeframes.
[0006] Generally, a polymer forming a coating composition for an
implantable device has to be at least biologically benign.
Additionally, the polymer could have a therapeutic effect either
additively or synergistically with the bioactive agent. The polymer
is preferably biocompatible. To provide for a coating that is
biologically benign, various compositions have been used with
limited success. For example, coating compositions containing
poly(ethylene glycol) have been described (see, for example, U.S.
Pat. No. 6,099,562). One of the needs in the art is to provide for
a stent that has favorable long-term biological properties.
However, under certain circumstances, it is documented that polymer
and remaining drugs on the stents are major factors in causing late
clinical effects such as late stent thrombosis, in stent
artherosclerosis, and late stent malapposition.
[0007] The various embodiments described below address the above
described problems.
SUMMARY OF THE INVENTION
[0008] Provided herein is a coating of fast absorption or
dissolution. The coating includes a polymer or material of fast
absorption or dissolution. By "fast absorption" or "fast
dissolution" it is meant that the coating can quickly absorb or
dissolve by degradation or solvation. For example, in some
embodiments, about 50 weight percents of the coating can absorb or
dissolve within about 24 hours after deployment of the implantable
device. As used herein, the term absorption or dissolution is
independent of location. In some embodiments, the absorption or
dissolution occurs in a tissue. In some embodiments, the absorption
or dissolution can occur in a blood vessel, for example, arteries
or veins. In some further embodiments, the absorption or
dissolution can occur in a disease site in need of treatment by the
implantable device described herein. The type of fluid causing the
absorption or dissolution described herein can be any body fluid.
In some embodiments, the body fluid is a physiological fluid in a
body tissue. In some embodiments, the body fluid is blood.
[0009] In some embodiments, the polymers or materials for forming
the coating shall have a hydrophilicity that renders the polymers
or materials soluble in the blood stream or have a molecular weight
sufficiently low so that it can readily dissolve or degrade in the
blood stream or a tissue. In some embodiments, the polymers or
materials can have a weight average molecular weight (M.sub.w) of
about 100,000 Daltons or below, about 50,000 Daltons or below
(e.g., about 45,000 Daltons), about 10,000 Daltons or below, about
5,000 Daltons or below, or about 2,000 Daltons or below (e.g.,
about 1,000 Daltons).
[0010] Such polymer or material can be ionic or non-ionic. In some
embodiments, the polymer or material can bear a positive or
negative charge(s). In some embodiments, the polymer or materials
can include a polymer poly(ethylene glycol) (PEG), poly(vinyl
alcohol) (PVA), hyaluronic acid, hydroxyl cellulose, CMC
(carboxymethyl cellulose), hydroxy propyl methyl cellulose (HPMC),
hydroxy propyl methacrylamide (HPMA), poly(butylene
terephthalate-co-poly(ethylene glycol) (PBT-PEG), poly(butylene
terephthalate-co-carboxy methyl cellulose) (PBT-co-CMC),
polysaccaride, a phosphoryl choline polymer, chitosan, collagen, or
combinations thereof.
[0011] In some embodiments, the dissolution or absorption rate can
be increased by blending a small amount of low molecular weight
polymer into the coating. In some embodiments, polymers with basic
or acidic pendant groups can be included in a coating to increase
the dissolution or absorption rate of the coating.
[0012] The thickness of the coating relates to the rate of
dissolution or absorption if the dissolution or absorption of the
coating is by a mechanism that includes surface erosion. In some
embodiments, the coating can have various thicknesses. The coating
can have a thickness ranging from about 10 nm to about 1 mm. In
some embodiments, the coating can have a thickness of about 1
.mu.m, about 3 .mu.m, about 5 .mu.m, about 10 .mu.m, about 20 .mu.m
or about 50 .mu.m. In some embodiments, the coating can have a
thickness ranging from about 2 .mu.m to about 10 .mu.m.
[0013] In some embodiments, the coating includes a therapeutic
substance. The therapeutic substance can have a release rate that
is substantially the same as the absorption rate of the coating if
release of the therapeutic substance is by a mechanism that
includes surface erosion. In some embodiments, the therapeutic
substance can have a release rate that is faster than the
absorption rate of the coating.
[0014] In some embodiments, the therapeutic substance can have a
release rate that is slower the absorption rate of the coating. For
example, where a coating includes a layer without the therapeutic
substance on top of a reservoir layer including the therapeutic
substance, the release rate of the therapeutic substance can be
slower than the absorption rate of the coating.
[0015] The coating described herein can be formed on an implantable
device such as a drug delivery stent. The coating may optionally
include one or more bioactive agents. Some examples of the
bioactive agent that can be included in the coating or implantable
device include, but are not limited to, paclitaxel, docetaxel,
estradiol, nitric oxide donors, super oxide dismutases, super oxide
dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,
40-O-(2-hydroxy)ethyl-rapamycin(everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, statins, CD-34 antibody, abciximab
(REOPRO), progenitor cell capturing antibody, prohealing drugs,
prodrugs thereof, co-drugs thereof, or a combination thereof.
[0016] The implantable device having the coating described herein
can be used for treating, preventing, or ameliorating a medical
condition such as atherosclerosis, thrombosis, restenosis,
hemorrhage, vascular dissection or perforation, vascular aneurysm,
vulnerable plaque, diabetes, chronic total occlusion, claudication,
anastomotic proliferation (for vein and artificial grafts), bile
duct obstruction, ureter obstruction, tumor obstruction, or
combinations of these.
BRIEF DESCRIPTION OF DRAWINGS
[0017] FIG. 1 is the scanning electron microscopy (SEM) image of a
coating on a stent including a phosphoryl choline polymer before
simulated use. The coating has a drug/polymer ratio of 1:5.
[0018] FIG. 2 is the SEM image of the coating in FIG. 1 after the
simulated use.
[0019] FIG. 3 shows the release rate of everolimus from a
poly(ester amide) (PEA) coating, a PEA-TEMPO coating, and a coating
of phosphoryl choline polymer, respectively.
DETAILED DESCRIPTION
[0020] Provided herein is a coating of fast absorption or
dissolution. The coating includes a polymer or material of fast
absorption or dissolution. By "fast absorption" or "fast
dissolution" it is meant that the coating can quickly absorb or
dissolve by degradation or solvation. For example, in some
embodiments, about 50 weight percents of the coating can absorb or
dissolve within about 24 hours after deployment of the implantable
device. As used herein, the term absorption or dissolution is
independent of location. In some embodiments, the absorption or
dissolution occurs in a tissue. In some embodiments, the absorption
or dissolution can occur in a blood vessel, for example, arteries
or veins. In some further embodiments, the absorption or
dissolution can occur in a disease site in need of treatment by the
implantable device described herein. The type of fluid causing the
absorption or dissolution described herein can be any body fluid.
In some embodiments, the body fluid is a physiological fluid in a
body tissue. In some embodiments, the body fluid is blood.
[0021] In some embodiments, the polymers or materials for forming
the coating shall have a hydrophilicity that renders the polymers
or materials soluble in the blood stream or have a molecular weight
sufficiently low so that it can readily dissolve or degrade in the
blood stream or a tissue. For example, the polymers or materials
can have a weight-average molecular weight (M.sub.w) ranging from
about 1,000 Daltons to about 150,000 Daltons, e.g., from about
10,000 Dalton to about 150,000 Daltons or from about 50,000 Daltons
to about 100,000 Daltons. In some embodiments, the polymers or
materials can have a M.sub.w of about 100,000 Daltons or below,
about 50,000 Daltons or below (e.g., about 45,000 Daltons), about
10,000 Daltons or below, about 5,000 Daltons or below, or about
2,000 Daltons or below (e.g., about 1,000 Daltons).
[0022] Such polymer or material can be ionic or non-ionic. In some
embodiments, the polymer or material can bear a positive or
negative charge(s). In some embodiments, the polymer or materials
can include a polymer poly(ethylene glycol) (PEG), poly(vinyl
alcohol) (PVA), hyaluronic acid, hydroxyl cellulose, CMC
(carboxymethyl cellulose), hydroxy propyl methyl cellulose (HPMC),
hydroxy propyl methacrylamide (HPMA), poly(butylene
terephthalate-co-poly(ethylene glycol) (PBT-PEG), poly(butylene
terephthalate-co-carboxy methyl cellulose) (PBT-co-CMC),
polysaccaride, a phosphoryl choline polymer, chitosan, collagen, or
combinations thereof.
[0023] In some embodiments, the dissolution or absorption rate can
be increased by blending a small amount of low molecular weight
polymer into the coating. In some embodiments, polymers with basic
or acidic pendant groups can be included in a coating to increase
the dissolution or absorption rate of the coating. The term "low
molecular weight" generally refers to a weigh-average molecular
weight ("M.sub.w") below about 45,000 Daltons, e.g., below about
30,000 Daltons, below about 20,000 Daltons, below about 10,000
Daltons, below about 5,000 Daltons, or below about 1,000 Daltons.
In some embodiments, the term "low molecular weight" can be in a
range between about 300 and about 5,000 Daltons, e.g., between
about 1,000 Daltons to about 5,000 Daltons. The term "small amount"
refers to a weight percentage of about 1% to about 10%, about 1% to
about 5%, or about 5% to about 10%. In some embodiments, the term
"small amount" can refer to a weight percentage of below about 1%.
In some embodiments, the term "small amount" can refer to a weight
percentage of above 10%, e.g., about 15% or about 20%.
[0024] The thickness of the coating relates to the rate of
dissolution or absorption if the dissolution or absorption of the
coating is by a mechanism that includes surface erosion. In some
embodiments, the coating can have various thicknesses. The coating
can have a thickness ranging from about 10 nm to about 1 mm. In
some embodiments, the coating can have a thickness of about 1
.mu.m, about 3 .mu.m, about 5 .mu.m, about 10 .mu.m, about 20 .mu.m
or about 50 .mu.m. In some embodiments, the coating can have a
thickness ranging from about 2 .mu.m to about 10 .mu.m.
[0025] In some embodiments, the coating includes a therapeutic
substance. The therapeutic substance can have a release rate that
is substantially the same as the absorption rate of the coating if
release of the therapeutic substance is by a mechanism that
includes surface erosion. In some embodiments, the therapeutic
substance can have a release rate that is faster than the
absorption rate of the coating.
[0026] In some embodiments, the therapeutic substance can have a
release rate that is slower the absorption rate of the coating. For
example, where a coating includes a layer without the therapeutic
substance on top of a reservoir layer including the therapeutic
substance, the release rate of the therapeutic substance can be
slower than the absorption rate of the coating.
[0027] The coating described herein can be formed on an implantable
device such as a drug delivery stent. The coating may optionally
include one or more bioactive agents.
[0028] Some examples of the bioactive agent that can be included in
the coating or implantable device include, but are not limited to,
paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,
40-O-(2-hydroxy)ethyl-rapamycin(everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, mometasone, statins, CD-34 antibody, abciximab
(REOPRO), progenitor cell capturing antibody, prohealing drugs,
prodrugs thereof, co-drugs thereof, or a combination thereof.
[0029] The implantable device having the coating described herein
can be used for treating, preventing, or ameliorating a medical
condition such as atherosclerosis, thrombosis, restenosis,
hemorrhage, vascular dissection or perforation, vascular aneurysm,
vulnerable plaque, diabetes, chronic total occlusion, claudication,
anastomotic proliferation (for vein and artificial grafts), bile
duct obstruction, ureter obstruction, tumor obstruction, or
combinations of these.
[0030] The scanning electron microscopy (SEM) image of a coating on
a stent including a phosphoryl choline polymer before simulated use
is shown in FIG. 1. The coating has a drug/polymer ratio of
1:5.
Coating Modulation
[0031] The absorption rate or dissolution rate of a coating can be
modulated by modulating several parameters of the coating. Some of
the factors are, e.g., (1) hydrophilicity of the coating
(hydrophilic/hydrophobic ratio) (2) charge (pKa) or isoelectric
point (polymers/proteins pH dependent solubility) , (3) thickness
of the coating, (4) coating morphology, or (5) ingredients of the
composition forming the coating. Hydrophilicity of the coating
pertains to water uptake of the coating and therefore relates to
the absorption rate or dissolution rate of the coating. Generally,
the more hydrophilic the coating, the more absorbable or
dissolvable of the coating. Thickness of the coating is also
related to the absorption or dissolution of the coating. While the
relationship of the rate of absorption or dissolution of a
particular coating with respect to the thickness of the coating
depends on mechanism of absorption or dissolution, a thicker
coating can dissolve or absorb slower than a thinner coating.
Coating morphology relates to the rate of absorption or dissolution
in that an amorphous coating generally dissolves or dissolves
faster than a crystalline coating. Therefore, to control the rate
of absorption or dissolution of a coating, one can tailor the above
parameters according to a desired rate of absorption or
dissolution.
[0032] In some embodiments, one can tailor the rate of dissolution
or absorption of coating by blending a small amount of low
molecular weight hydrophilic polymer into the coating matrix. Low
molecular weight polymer can mean any hydrophilic polymers, such as
poly(ethylene glycol) (PEG), vinyl alcohol polymer or copolymers
(e.g., EVAL) having a molecular weight below about, e.g., 5,000
Daltons, below about 1,000 Daltons, or below about 500 Daltons. In
some embodiments, the coating matrix can include a small amount
unpolymerized monomer or comonomer. In some embodiments, the low
molecular hydrophilic polymer can include acidic or basic end
groups, etc. Such acidic groups can be, for example, carboxylic
acid group, sulfonic acid group, or phosphonic acid group. Such
basic groups, can be, for example, amino group or a salt of the
carboxylic acid, sulfonic acid, or phosphonic acid groups.
[0033] In some embodiments, the coating can be formed to have a
thickness so that renders the coating capable of fast absorption or
dissolution. For example, the coating can have a thickness ranging
from about 10 nm to about 1 mm. In some embodiments, the coating
can have a thickness of about 1 .mu.m, about 5 .mu.m, about 10
.mu.m, about 20 .mu.m or about 50 .mu.m. In some embodiments, the
coating can have a thickness ranging from about 2 .mu.m to about 10
.mu.m, e.g., about 3 .mu.m.
Phosphoryl Choline Polymers
[0034] Phosphoryl choline (PC) is a zwitterionic functionality that
mimics the outer surface of a lipid bilayer. It has good
hemocompatibility, non-thrombogenicity, arterial tissue acceptance
and long-term in-vivo stability. It has been used to increase the
biocompatibility of polymers, especially of acrylic copolymers. As
used herein, the term "phosphoryl choline polymer" refers to any
polymer that includes at least one phosphoryl choline moiety. The
phosphoryl choline polymer can be a block copolymer or a random
copolymer. The phosphoryl choline polymer can have a molecular
weight or hydrodynamic volume low enough to clear from the kidneys
or degrade into species or fragments of a molecular weight or
hydrodynamic volume low enough to clear from the kidneys. For
example, the phosphoryl choline polymer can have or degrade into
species or fragments that have a molecular weight below about
45,000 Daltons, e.g., about 40,000 Daltons, about 30,000 Daltons,
about 20,000 Daltons, about 10,000 Daltons, about 5,000 Daltons, or
about 1,000 Daltons. As used herein, the term hydrodynamic volume
refers to the volume of a polymer coil when it is in solution,
which can vary for a polymer depending on how well it interacts
with the solvent, and the polymer's molecular weight.
[0035] In some embodiments, the phosphoryl choline polymer can be
formed by polymerizing a phosphoryl choline bearing monomer and
optionally monomers without phosphoryl choline. The phosphoryl
choline polymer can have different molecular weight, degree of
polymerization (DP), or distributions or molar ratios of monomers
that have no phosphoryl choline to monomers that bear phosphoryl
choline.
[0036] In another embodiment, the biocompatible polymer useful as
moiety of the copolymer comprising phosphoryl choline is a
non-degradable polymer. Representative biocompatible,
non-degradable polymers include, but are not limited to, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), polyurethanes, silicones, polyesters,
polyolefins, polyisobutylene and ethylene-alphaolefin copolymers,
styrene-isobutyl-styrene triblock copolymers, acrylic polymers and
copolymers, vinyl halide polymers and copolymers such as
poly(vinyldifluoride-co-hexafluoropropane),
poly(chlorotrifluoroethylene-co-hexafluoropropane), polyvinyl
ethers such as polyvinyl methyl ether, polyvinylidene halides such
as polyvinylidene fluoride and polyvinylidene chloride,
polyfluoroalkenes, polyperfluoroalkenes, 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, polyoxymethylenes,
polyimides, polyethers, epoxy resins, rayon, rayon-triacetate,
polyurethanes, silk, silk-elasitn, polyphosphazenes and
combinations thereof. In some embodiments, the phosphoryl choline
polymer can specifically exclude any of the above polymers.
[0037] In a further embodiment, the copolymer described herein
comprises one or more of the following hydrophobic monomers:
methylmethacrylate (MMA), ethylmethacrylate (EMA),
butylmethacrylate (BMA), 2-ethylhexylmethacrylate,
laurylmethacrylate (LMA), or combinations thereof. By varying the
copolymer's content of the hydrophobic monomers, mechanical
properties such as elasticity and toughness can be modulated. For
example, a monomer having a relatively long side chain would
enhance the flexibility of a coating comprising the copolymer. In
contrast, a monomer having a relatively short side chain would
enhance the rigidity and toughness of a coating comprising the
copolymer.
[0038] In a further embodiment, the copolymer described herein
comprises one or more of the following hydrophilic monomers:
non-fouling monomers such as hydroxyl ethyl methacrylate (HEMA),
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), hydroxyl bearing monomers
such as HEMA, hydroxypropyl methacrylate (HPMA),
hydroxypropylmethacrylamide, 3-trimethylsilylpropyl methacrylate
(TMSPMA), and combinations thereof. The carboxylic acid bearing
monomers or hydroxyl bearing monomers can be used to crosslink the
copolymer once it is applied to the substrate to coat. This will
hinder a very hydrophilic coating from dissolving away.
[0039] In some embodiments, the phosphoryl choline polymer can
specifically exclude any units derived from the above-identified
monomer(s).
[0040] In some embodiments, the phosphoryl choline polymer can be a
block copolymer. The block copolymer can be formed by coupling a
biocompatible polymer and a phosphoryl choline moiety.
Representative biodegradable polymers include, but are not limited
to, polyesters, polyhydroxyalkanoates (PHAs), poly(ester amides)
that may optionally contain alkyl, amino acid, PEG and/or alcohol
groups, polycaprolactone, poly(L-lactide), poly(D,L-lactide),
poly(D,L-lactide-co-PEG) block copolymers,
poly(D,L-lactide-co-trimethylene carbonate), polyglycolide,
poly(lactide-co-glycolide), polydioxanone (PDS), polyorthoester,
polyanhydride, poly(glycolic acid-co-trimethylene carbonate),
polyphosphoester, polyphosphoester urethane, poly(amino acids),
polycyanoacrylates, poly(trimethylene carbonate),
poly(iminocarbonate), polycarbonates, polyurethanes,
copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates,
polyphosphazenes, PHA-PEG, and combinations thereof. The PHA may
include poly(.alpha.-hydroxyacids), poly(.beta.-hydroxyacid) such
as poly(3-hydroxybutyrate) (PHB),
poly(3-hydroxybutyrate-co-valerate) (PHBV),
poly(3-hydroxyproprionate) (PHP), poly(3-hydroxyhexanoate) (PHH),
or poly(4-hydroxyacid) such as poly poly(4-hydroxybutyrate),
poly(4-hydroxyvalerate), poly(4-hydroxyhexanoate),
poly(hydroxyvalerate), poly(tyrosine carbonates), poly(tyrosine
acrylates).
[0041] In some embodiments, the phosphoryl choline polymer can
specifically exclude any of the above polymers. In some
embodiments, the phosphoryl choline block copolymer comprises
poly(ester amide) (PEA-PC).
Methods of phosphoryl choline polymers
[0042] The copolymer described herein can be synthesized by
introducing phosphoryl choline into a polymer or by introducing
phosphoryl choline into a monomer to form a phosphoryl choline
monomer and then polymerizing the phosphoryl choline monomer to
form the phosphoryl choline polymer.
[0043] In some embodiments, the phosphoryl choline can be
introduced into the polymer via a reactive functionality, which can
be, for example, hydroxyl groups, amino groups, halo groups,
carboxyl groups, thiol groups, aldehyde, N-hydroxysuccinimide
(NHS). Alternatively, phosphoryl choline can be introduced into a
monomer such as an oxirane. Polymerization of the monomers can
generate a phosphoryl choline polymer.
[0044] Monomers bearing phosphoryl choline can polymerize alone or
with other comonomers by means known in the art e.g., catalytic
polymerization, chemical reaction, or free radical polymerization,
to form respective polymers bearing phosphoryl choline
moiety(ies).
[0045] In some embodiments, the phosphoryl choline polymer can be a
copolymer. The copolymer can be formed of a monomer bearing no
phosphoryl choline and another monomer bearing phosphoryl choline.
In some embodiments, the monomer bearing no phosphoryl choline can
be a vinyl monomer. An example of the phosphoryl choline polymer
can be formed according to scheme I.
##STR00001##
[0046] The monomers forming the phosphoryl choline polymer can have
different molar percentage. Generally, the molar percentage of the
monomers can independently range from 0 to 100. For example, the
molar percentage of the monomers can independently be about 1,
about 5, about 10, about 20, about 30, about 40, about 50, about
60, about 70, about 80, about 90, about 95, or about 99. For
example, in the polymer of scheme I, n and m, which represent the
molar percentages of the two monomers forming the phosphoryl
choline polymer in the scheme, can be about 50 and 50. In some
embodiments, n and m can be expressed as molar ratios of the
monomers forming a phosphoryl choline copolymer. For example, n and
m can independently range from about 0.01 to about 0.99. In some
embodiments, n and m can be about 0.5.
[0047] Various methods of forming a phosphoryl choline polymer has
been described in U.S. application Ser. No. 10/807,362, filed on
Nov. 26, 2003, the teachings of which are incorporated herein in
their entirety by reference.
Coating Construct
[0048] The coating described herein can have any suitable coating
construct. For example, the polymer or material of fast absorption
or dissolution can be included in the coating as a top-coat over a
reservoir layer or matrix that includes a therapeutic substance. In
some embodiments, the fast absorption polymer or material can form
the coating alone or with another polymer. In some embodiments, the
fast absorption polymer or material can include at least one
therapeutic substance(s) (e.g., a drug or drugs).
[0049] In some embodiments, the coating including a polymer or
material of fast absorption can have a multilayer construct. For
example, the coating can have multiple layer of coating matrix. As
used herein, the term "coating matrix" or "matrix coating" refers a
layer of coating different from a topcoat or a primer layer of the
coating.
Bioactive Agents
[0050] In some embodiments, the coating or device having the
features described herein can include one or more bioactive agents.
The bioactive agents can be any bioactive agent that is
therapeutic, prophylactic, or diagnostic. These agents can have
anti-proliferative or anti-inflammatory properties or can have
other properties such as antineoplastic, antiplatelet,
anti-coagulant, anti-fibrin, antithrombonic, antimitotic,
antibiotic, antiallergic, and antioxidant properties. These agents
can be cystostatic agents, agents that promote the healing of the
endothelium such as nitric oxide releasing or generating agents,
agents that attract endothelial progenitor cells, or agents that
promote the attachment, migration and proliferation of endothelial
cells (e.g., natriuretic peptide such as CNP, ANP or BNP peptide or
an RGD or cRGD peptide), while quenching smooth muscle cell
proliferation. Examples of suitable therapeutic and prophylactic
agents include synthetic inorganic and organic compounds, proteins
and peptides, polysaccharides and other sugars, lipids, and DNA and
RNA nucleic acid sequences having therapeutic, prophylactic or
diagnostic activities. Nucleic acid sequences include genes,
antisense molecules that bind to complementary DNA to inhibit
transcription, and ribozymes. Some other examples of other
bioactive agents include antibodies, receptor ligands, enzymes,
adhesion peptides, blood clotting factors, inhibitors or clot
dissolving agents such as streptokinase and tissue plasminogen
activator, antigens for immunization, hormones and growth factors,
oligonucleotides such as antisense oligonucleotides and ribozymes
and retroviral vectors for use in gene therapy. Examples of
anti-proliferative agents include rapamycin and its functional or
structural derivatives,
40-O-(2-hydroxy)ethyl-rapamycin(everolimus), and its functional or
structural derivatives, paclitaxel and its functional and
structural derivatives. Examples of rapamycin derivatives include
methyl rapamycin (ABT-578), 40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin. Examples of paclitaxel derivatives
include docetaxel. Examples of antineoplastics or antimitotics
include methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin.RTM. from
Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.
Mutamycin.RTM. from Bristol-Myers Squibb Co., Stamford, Conn.).
Examples of such antiplatelets, anticoagulants, antifibrin, and
antithrombins include sodium heparin, low molecular weight
heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,
prostacyclin and prostacyclin analogues, dextran,
D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein 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,
combinations thereof. Examples of such cytostatic substance include
angiopeptin, angiotensin converting enzyme inhibitors such as
captopril (e.g. Capoten.RTM. and Capozide.RTM. from Bristol-Myers
Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g.
Prinivil.RTM. and Prinzide.RTM. from Merck & Co., Inc.,
Whitehouse Station, N.J.). An example of an antiallergic agent is
permirolast potassium. Other therapeutic substances or agents that
may be appropriate include alpha-interferon, pimecrolimus, imatinib
mesylate, midostaurin, bioactive RGD, and genetically engineered
endothelial cells. The foregoing substances can also be used in the
form of prodrugs or co-drugs thereof. The foregoing substances also
include metabolites thereof or prodrugs of the metabolites. The
foregoing substances are listed by way of example and are not meant
to be limiting. Other active agents that are currently available or
that may be developed in the future are equally applicable such as
statins and their derivatives or analogues.
[0051] The dosage or concentration of the bioactive agent required
to produce a favorable therapeutic effect should be less than the
level at which the bioactive agent produces toxic effects and
greater than the level at which non-therapeutic results are
obtained. The dosage or concentration of the bioactive agent can
depend upon factors such as the particular circumstances of the
patient, the nature of the trauma, the nature of the therapy
desired, the time over which the ingredient administered resides at
the vascular site, and if other active agents are employed, the
nature and type of the substance or combination of substances.
Therapeutic effective dosages can be determined empirically, for
example by infusing vessels from suitable animal model systems and
using immunohistochemical, fluorescent or electron microscopy
methods to detect the agent and its effects, or by conducting
suitable in vitro studies. Standard pharmacological test procedures
to determine dosages are understood by one of ordinary skills in
the art.
Examples of Medical Devices
[0052] As used herein, a medical device may be any suitable medical
substrate that can be implanted in a human or veterinary patient.
Examples of such medical devices include self-expandable stents,
balloon-expandable stents, stent-grafts, grafts (e.g., aortic
grafts), heart valve prostheses, cerebrospinal fluid shunts,
pacemaker electrodes, catheters, and endocardial leads (e.g.,
FINELINE and ENDOTAK, available from Guidant Corporation, Santa
Clara, Calif.), anastomotic devices and connectors, orthopedic
implants such as screws, spinal implants, and electro-stimulatory
devices. The underlying structure of the device can be of virtually
any design. The device can be made of a metallic material or an
alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),
stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR
108, cobalt chrome alloy L-605, "MP35N," "MP20N," ELASTINITE
(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,
gold, magnesium, or combinations thereof. "MP35N" and "MP20N" are
trade names for alloys of cobalt, nickel, chromium and molybdenum
available from Standard Press Steel Co., Jenkintown, Pa. "MP35N"
consists of 35% cobalt, 35% nickel, 20% chromium, and 10%
molybdenum. "MP20N" consists of 50% cobalt, 20% nickel, 20%
chromium, and 10% molybdenum. Devices made from bioabsorbable
(e.g., bioabsorbable stent) or biostable polymers could also be
used with the embodiments of the present invention.
Method of Use
[0053] Preferably, the medical device is a stent. The stent
described herein is useful for a variety of medical procedures,
including, by way of example, treatment of obstructions caused by
tumors in bile ducts, esophagus, trachea/bronchi and other
biological passageways. A stent having the above-described coating
is particularly useful for treating diseased regions of blood
vessels caused by lipid deposition, monocyte or macrophage
infiltration, or dysfunctional endothelium or a combination
thereof, or occluded regions of blood vessels caused by abnormal or
inappropriate migration and proliferation of smooth muscle cells,
thrombosis, and restenosis. Stents may be placed in a wide array of
blood vessels, both arteries and veins. Representative examples of
sites include the iliac, renal, carotid and coronary arteries.
[0054] For implantation of a stent, an angiogram is first performed
to determine the appropriate positioning for stent therapy. An
angiogram is typically accomplished by injecting a radiopaque
contrasting agent through a catheter inserted into an artery or
vein as an x-ray is taken. A guidewire is then advanced through the
lesion or proposed site of treatment. Over the guidewire is passed
a delivery catheter that allows a stent in its collapsed
configuration to be inserted into the passageway. The delivery
catheter is inserted either percutaneously or by surgery into the
femoral artery, radial artery, brachial artery, femoral vein, or
brachial vein, and advanced into the appropriate blood vessel by
steering the catheter through the vascular system under
fluoroscopic guidance. A stent having the above-described coating
may then be expanded at the desired area of treatment. A
post-insertion angiogram may also be utilized to confirm
appropriate positioning.
[0055] The implantable device can be implanted in any mammal, e.g.,
an animal or a human being. In some embodiments, the implantable
device can be implanted in a patient in need of treatment by the
implantable device. The treatment can be angioplasty or other type
of treatments involving an implantable device.
[0056] A patient who receives the implantable device described
herein can be male or female under normal body condition (e.g.,
normal weight) or abnormal body condition (e.g., underweight or
overweight). The patient can be in any age, preferably, the patient
is in an age ranging from about 40 to 70 years. An index for
measuring the body condition of a patient is BMI (body mass index).
A patient can have a BMI ranging from about 18 to about 30 or
above.
[0057] The implantable device described herein can be used to treat
or ameliorate a medical condition such as atherosclerosis,
thrombosis, restenosis, hemorrhage, vascular dissection or
perforation, vascular aneurysm, vulnerable plaque, chronic total
occlusion, claudication, type-II diabetes, anastomotic
proliferation for vein and artificial grafts, bile duct
obstruction, ureter obstruction, tumor obstruction, or combinations
thereof.
[0058] FIG. 1 shows an SEM image of a drug delivery stent spray
coated with a poly(phosphoryl choline-co-butyl methacrylate) (NOF,
Japan) and everolimus (Novartis, Switzerland) solution at a
polymer/drug ratio of 5:1. The ratio of the phosphoryl choline to
butyl monomers were 50/50 and the Mw of the polymer was
approximately 100,000 Daltons as measured by GPC using RI-detector.
The solid concentration used for spraying were 2% using a mixture
of solvents (CH2Cl2 50% (w/w), CH3OH 25% (w/w), DMAc 25% (w/w)).
FIG. 2 is the SEM image of the coating in FIG. 1 after simulated
use. The simulated use were performed in synthetic artery made from
PVA using PBS saline buffer. The stent were tested for one hour
before being removed and analyzed by SEM at which it was observed
that all polymer had been removed FIG. 3 shows the release rate of
everolimus from a poly(ester amide) (PEA) coating, a PEA-TEMPO
coating, and a coating made of the above mentioned phosphoryl
choline polymer, respectively. The total content of the various
drug delivery stents were determined and used to calculate the
remaining amount of drug in the coating after immersing in porcine
serum for 24, and 72 h respectively. As expected the drug was
completely release at 24 h for the bioabsorbable or soluble
phosphorylcholine coating.
[0059] 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 they fall within the true spirit and
the scope of this invention.
* * * * *