U.S. patent application number 10/116647 was filed with the patent office on 2003-10-16 for processes for producing polymer coatings through surface polymerization.
Invention is credited to Dayton, Peter L., Herrmann, Robert A., Naimark, Wendy, Strickler, Frederick H..
Application Number | 20030195610 10/116647 |
Document ID | / |
Family ID | 28789846 |
Filed Date | 2003-10-16 |
United States Patent
Application |
20030195610 |
Kind Code |
A1 |
Herrmann, Robert A. ; et
al. |
October 16, 2003 |
Processes for producing polymer coatings through surface
polymerization
Abstract
A medical device with a therapeutic agent-releasing polymer
coating. The medical device is provided by a method that comprises:
(a) attaching at least one reactive species to a medical device
surface, which reactive species leads to chain growth
polymerization in the presence of monomer; (b) contacting the
reactive species with at least one monomer species, thereby forming
a polymer coating on the surface of the medical device; and (c)
providing at least one therapeutic agent within the polymer
coating. The therapeutic agent may be incorporated during formation
of the polymer coating or after formation of the polymer coating.
The at least one reactive species can comprise, for example, a free
radical species, a carbanion species, a carbocation species, a
Ziegler-Natta polymerization complex, a metallocene complex, and/or
an atom transfer radical polymerization initiator. Alternatively,
the medical device is provided by a process comprising: (a)
immobilizing least one polymerization catalyst at a medical device
surface, which polymerization catalyst leads to polymerization in
the presence of monomer; (b) contacting the medical device surface
with at least one monomer species, thereby forming a polymer
coating at the surface of the medical device; and (c) providing at
least one therapeutic agent within the polymer coating.
Inventors: |
Herrmann, Robert A.;
(Boston, MA) ; Strickler, Frederick H.; (Marlboro,
MA) ; Naimark, Wendy; (Cambridge, MA) ;
Dayton, Peter L.; (Brookline, MA) |
Correspondence
Address: |
MAYER, FORTKORT & WILLIAMS, PC
251 NORTH AVENUE WEST
2ND FLOOR
WESTFIELD
NJ
07090
US
|
Family ID: |
28789846 |
Appl. No.: |
10/116647 |
Filed: |
April 4, 2002 |
Current U.S.
Class: |
623/1.15 |
Current CPC
Class: |
A61L 2300/606 20130101;
A61L 31/16 20130101; A61L 31/10 20130101 |
Class at
Publication: |
623/1.15 |
International
Class: |
A61F 002/06 |
Claims
In the claims:
1. A method of providing a medical device with a therapeutic
agent-releasing polymer coating comprising: (a) attaching at least
one reactive species to a medical device surface, said reactive
species leading to chain growth polymerization in the presence of
monomer; (b) contacting said reactive species with at least one
monomer species, thereby forming a polymer coating on the surface
of the medical device; and (c) providing at least one therapeutic
agent within said polymer coating.
2. The method of claim 1, wherein at least one therapeutic agent is
incorporated during formation of the polymer coating.
3. The method of claim 1, wherein at least one therapeutic agent is
incorporated after formation of the polymer coating.
4. The method of claim 1, wherein the medical device is an
implantable or insertable medical device.
5. The method of claim 4, wherein the medical device is a
stent.
6. An implantable or insertable medical device made by the method
of claim 1.
7. The method of claim 1, wherein said at least one monomer species
comprises an unsaturated monomer.
8. The method of claim 1, wherein said polymer is selected from
polyalkylenes and derivatives, vinyl polymers and derivatives,
acrylic acid polymers and derivatives, and copolymers thereof.
9. The method of claim 1, wherein said polymer is selected from
ethylene vinyl acetate and styrene-isobutylene copolymers.
10. The method of claim 1, wherein said at least one reactive
species comprises a free radical species.
11. The method of claim 10, wherein the free radical species is
provided by a process comprising (a) covalently attaching a
free-radical initiator molecule to the surface or (b) covalently
attaching a species that acquires a free-radical upon exposure to a
free radical initiator molecule.
12. The method of claim 1, wherein said at least one reactive
species comprises a carbanion species.
13. The method of claim 12, wherein the carbanion species is
provided by a process comprising (a) covalently attaching an
anionic initiator molecule to the surface or (b) covalently
attaching a species that acquires a carbanion upon exposure to an
anionic initiator molecule.
14. The method of claim 1, wherein said at least one reactive
species comprises a carbocation species.
15. The method of claim 14, wherein the carbocation species is
provided by a process comprising covalently attaching a species
that develops a carbocation upon exposure to a cationic initiator
molecule.
16. The method of claim 1, wherein said at least one reactive
species comprise a Ziegler-Natta polymerization complex.
17. The method of claim 1, wherein said at least one reactive
species comprises a metallocene complex.
18. The method of claim 1, wherein said at least one reactive
species comprises an atom transfer radical polymerization
initiator.
19. The method of claim 18, wherein the at least one reactive
species is provided by a process comprising (a) covalently
attaching an atom transfer radical polymerization initiator
molecule to the surface or (b) covalently attaching a species that
acquires a free-radical upon exposure to an atom transfer radical
polymerization initiator and an atom transfer radical
polymerization catalyst.
20. The method of claim 1, wherein the at least one reactive
species is formed from a derivatized monomer that is covalently
bonded to the surface of the medical device.
21. The method of claim 1, wherein the at least one reactive
species is formed from a derivatized initiator compound that is
covalently bonded to the surface of the medical device.
22. A method of providing a medical device with a therapeutic
agent-releasing coating comprising: (a) immobilizing least one
polymerization catalyst at a medical device surface, said
polymerization catalyst leading to polymerization in the presence
of monomer; (b) contacting the medical device surface with at least
one monomer species, thereby forming a polymer coating at the
medical device surface; and (c) providing at least one therapeutic
agent within said polymer coating.
23. The method of claim 22, wherein the at least one polymerization
catalyst is immobilized by covalently bonding it to said
surface.
24. The method of claim 22, wherein the at least one polymerization
catalyst is immobilized by physically embedding it in said
surface.
25. The method of claim 22, wherein the medical device surface is
at least partially covered by a metal catalyst.
26. The method of claim 22, further comprising cross-linking said
polymer coating.
27. The method of claim 22, wherein the at least one monomer
species comprises a dendrimer.
28. The method of claim 22, wherein at least one therapeutic agent
is provided within the polymer coating during formation of the
polymer coating.
29. The method of claim 22, wherein at least one therapeutic agent
is provided within the polymer coating after formation of the
polymer coating.
30. The method of claim 22, wherein the medical device is an
implantable or insertable medical device.
31. The method of claim 30, wherein the medical device is a
stent.
32. An implantable or insertable medical device made by the method
of claim 22.
33. The method of claim 22, wherein said polymer is selected from
ethylene vinyl acetate copolymers, poly(.epsilon.-caprolactone),
styrene-isobutylene copolymers and silicone.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to medical devices with
polymeric coatings and more particularly to medical devices having
polymer coatings that release therapeutic agent.
[0003] 2. Brief Description of the Background Art
[0004] Local delivery of therapeutic agents is an important adjunct
to mechanical treatment of diseases. For example, local delivery of
restenosis-inhibiting therapeutic agents has been proposed in
connection with the insertion of a coronary stent after
percutaneous transluminal coronary angioplasty, as the presence of
the stent can exacerbate neointimal hyperplasia, which is believed
to be a significant causative factor in the restenosis of the
vessel.
[0005] One common method of local therapeutic agent delivery is to
allow the therapeutic agent to diffuse from a polymer matrix. In
this connection, controlling release is an important aspect in
providing effective therapy. Furthermore, controlling the
manufacture of the polymer matrix is an important factor in
determining the ultimate release rate.
SUMMARY OF THE INVENTION
[0006] The present invention provides a method of producing a
polymer on a medical device in which polymer chains are grown at
the surface of the medical device to provide a polymer coating.
[0007] According to one aspect of the presenting invention, a
medical device with a therapeutic agent-releasing polymer coating
is provided by a method that comprises: (a) attaching at least one
reactive species to a medical device surface, which reactive
species leads to chain growth polymerization in the presence of
monomer; (b) contacting the reactive species with at least one
monomer species, thereby forming a polymer coating on the surface
of the medical device; and (c) providing at least one therapeutic
agent within the polymer coating.
[0008] The therapeutic agent may be incorporated during formation
of the polymer coating or after formation of the polymer
coating.
[0009] In certain embodiments, the reactive species is formed from
a derivatized monomer that is covalently bonded to the surface of
the medical device.
[0010] In certain other embodiments, the reactive species is formed
from a derivatized initiator compound that is covalently bonded to
the surface of the medical device.
[0011] The reactive species can comprise, for example, a free
radical species, a carbanion species, a carbocation species, a
Ziegler-Natta polymerization complex, a metallocene complex, and/or
an atom transfer radical polymerization initiator.
[0012] Where a free radical species is used, it can be provided,
for example, by a process comprising (a) covalently attaching a
free-radical initiator molecule to the surface or (b) covalently
attaching a species that acquires a free-radical upon exposure to a
free radical initiator molecule.
[0013] Where a carbanion species is used, it can be provided, for
example, by a process comprising (a) covalently attaching an
anionic initiator molecule to the surface or (b) covalently
attaching a species that acquires a carbanion upon exposure to an
anionic initiator molecule.
[0014] Where a carbocation species used, it can be provided, for
example, by a process comprising covalently attaching a species
that develops a carbocation upon exposure to a cationic initiator
molecule.
[0015] Where atom transfer radical polymerization is used the at
least one reactive species can be provided, for example, by a
process comprising: (a) covalently attaching an atom transfer
radical polymerization initiator molecule to the surface or (b)
covalently attaching a species that acquires a free-radical upon
exposure to an atom transfer radical polymerization initiator and
an atom transfer radical polymerization catalyst.
[0016] According to another aspect of the present invention, a
medical device with a therapeutic agent-releasing coating is
provided by a process comprising: (a) immobilizing least one
polymerization catalyst at a medical device surface, which
polymerization catalyst leads to polymerization in the presence of
monomer; (b) contacting the medical device surface with at least
one monomer species, thereby forming a polymer coating at the
surface of the medical device; and (c) providing at least one
therapeutic agent within the polymer coating.
[0017] One advantage of the present invention is that a process is
provided that allows for controlled manufacture of drug delivery
polymer coatings on medical device surfaces.
[0018] Another advantage of the present invention is that a process
is provided, which allows many medical devices to be coated at the
same time, improving manufacturing efficiency and cost
effectiveness.
[0019] The above and other embodiments and advantages of the
present invention will be readily understood by those of ordinary
skill in the art upon review of the Detailed Description and Claims
to follow.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Methods for providing medical devices having
therapeutic-agent-releasing polymer coatings are provided below in
accordance with various embodiments of the invention.
[0021] Preferred medical devices for use in conjunction with the
present invention are implantable or insertable medical devices,
including catheters (for example, urinary catheters or vascular
catheters), guide wires, balloons, filters (e.g., vena cava
filters), stents (including coronary vascular stents, cerebral,
urethral, ureteral, biliary, tracheal, gastrointestinal and
esophageal stents), stent grafts, cerebral aneurysm filler coils
(including GDC--Guglilmi detachable coils--and metal coils),
vascular grafts, myocardial plugs, patches, pacemakers and
pacemaker leads, heart valves, biopsy devices or any polymer coated
substrate (which can be, for example, metallic, polymeric or
ceramic) for use in the human body, either for procedural use or as
an implant.
[0022] The medical devices contemplated for use in connection with
the present invention include drug delivery medical devices that
are used for either systemic treatment or for the treatment of any
mammalian tissue or organ. Non-limiting examples of tissues and
organs include the heart, coronary or peripheral vascular system,
lungs, trachea, esophagus, brain, liver, kidney, bladder, urethra
and ureters, eye, intestines, stomach, pancreas, ovary, and
prostate; skeletal muscle; smooth muscle; breast; cartilage; and
bone.
[0023] Medical devices made in accordance with the present
invention can be placed in a wide variety of bodily locations for
contact with bodily tissue and/or fluid. Some preferred placement
locations include the coronary vasculature or peripheral vascular
system (referred to collectively herein as "the vasculature"),
gastrointestinal tract, esophagus, trachea, colon, biliary tract,
urinary tract, prostate and brain.
[0024] In some embodiments of the present invention, a polymer
coating is provided by first attaching one or more reactive species
to at least a portion of the surface of a medical device.
Subsequent contact with a monomer-containing liquid leads to
chain-growth polymerization at the site of the attached species. In
this manner, a polymer coating is produced that is attached to the
surface of the medical device.
[0025] A "monomer" is a polymerizable molecule. For example,
monomers may be small molecules, such as those listed below; or
they may be larger molecules containing polymerizable groups, for
example, polymers containing >C.dbd.C< groups. A "polymer" is
composed of two or more monomers, and includes dimers, trimers,
tetramers, etc.
[0026] Preferred monomers for embodiments of the invention that
utilize chain-growth polymerization (e.g., addition polymerization)
are unsaturated monomers, including, for example: (a) alkylene
monomers and derivatives, such as ethylene, propylene, butylenes
(e.g., isobutylene), and fluorinated alkylene monomers (e.g.,
tetrafluoroethylene); (b) vinyl monomers and derivatives, such as
styrene, vinyl chloride, vinyl pyrrolidone, acrylonitrile, vinyl
alcohol, and vinyl acetate; and (d) acrylic acid monomers and
derivatives, such as methyl acrylate, methyl methacrylate, acrylic
acid, methacrylic acid, acrylamide, hydroxyethyl acrylate,
hydroxyethyl methacrylate, glyceryl acrylate, glyceryl
methacrylate, methacrylamide and ethacrylamide.
[0027] Polymerization can proceed via essentially any known
chain-growth polymerization mechanism, including free-radical
polymerization, cationic polymerization, anionic polymerization,
Ziegler-Natta polymerization, metallocene polymerization, and atom
transfer radical polymerization.
[0028] In some chain-growth polymerization reactions, including
several of the reactions discussed below, an initiator molecule
becomes incorporated into the polymer that is formed. In some
cases, the initiator molecule is attached to the medical device
surface. A polymer is then formed by exposing the attached
initiator to monomer, along with any desired auxiliary species
(e.g., co-initiators, catalysts, co-catalysts, electron donors,
accelerators, sensitizers, etc.) under any desired reaction
conditions (for example, irradiation and/or heat). Examples of
initiators include free radical initiators, anionic initiators,
cationic co-initiators and atom transfer radical polymerization
initiators. For example, the medical device can be formed from a
material that provides chemically reactive groups or the surface of
the medical device can be treated with a reagent that places
chemically reactive groups on the device surface or with a coating
that supplies such groups. These groups are then reacted with
groups that are either inherently found on the initiator molecule
or are supplied to the initiator molecule (i.e., a derivatized form
of the initiator is used). Covalent attachment may be carried out
using numerous known reaction chemistries.
[0029] In other embodiments of the invention, a transformable
molecule is attached to the medical device surface, which is
transformed into a reactive species upon interaction with an
initiator or catalyst molecule. The chain growth occurs at the site
of the reactive species upon exposure to an appropriate monomer
under the appropriate conditions.
[0030] The transformable molecule is typically an unsaturated
molecule, and more typically a monomer that is derivatized for
attachment to the device surface.
[0031] To avoid the initiation of polymer chains not attached to
the surface, it is preferred, for example, to either (a) limit the
quantity of initiator or catalyst added or (b) remove excess
initiator or catalyst before the introduction of monomer.
[0032] As with the initiator molecule, attachment of the
transformable molecule can be covalent. For example, in the case
where the transformable molecule is a monomer, attachment typically
occurs through groups that are either inherently found on the
monomer or are supplied to the monomer (e.g., a derivatized form of
the monomer is used).
[0033] Specific examples include the following: (a) interaction
between an attached unsaturated molecule and a free-radical
initiator can be used to generate an attached free radical species,
which leads to chain growth in the presence of monomer, (b)
interaction between an attached unsaturated molecule and a cationic
initiator can be used to generate an attached carbocationic
species, which leads to chain growth in the presence of monomer,
(c) interaction between an attached unsaturated molecule and an
anionic initiator can be used to generate an attached carbanion
species, which leads to chain growth in the presence of monomer,
(d) interaction between an attached unsaturated molecule and a
Ziegler-Natta catalyst/co-catalyst system can be used to generate
an attached reactive species, which leads to chain growth in the
presence of monomer, (e) interaction between an attached
unsaturated molecule and a metallocene catalyst can be used to
generate an attached reactive species, which leads to chain growth
in the presence of monomer, and (f) interaction between an attached
unsaturated molecule and an atom transfer radical polymerization
initiator system can be used to generate an attached reactive
species, which leads to chain growth in the presence of
monomer.
[0034] Suitable free radical initiator compounds for use in
connection with free-radical polymerization embodiments of the
present invention include hydroperoxide, peroxide, di-tert-butyl
peroxide, di-benzoyl peroxide, and azo compounds, such as
azobis(isobutyronitrile), tertiary butyl perbenzoate, di-cumyl
peroxide and potassium persulfate.
[0035] According to a specific exemplary embodiment of the
invention, a substrate surface is provided, which contains free
hydroxyl groups. Subsequently a molecule including a vinyl group is
covalently bonded to the surface. For example,
vinyltrimethoxysilane can be reacted with the --OH groups on the
surface, leaving a vinyl group attached to the surface for
subsequent polymerization (e.g., free-radical polymerization) with
a number of monomeric species.
[0036] According to another a specific exemplary embodiment of the
invention, a free radical polymerization of methyl methacrylate is
conducted to provide a polymeric coating on the surface of a
medical device. Initially, a methyl methacrylate derivative is
covalently attached to the medical device surface 1
[0037] as shown, where R is an organic radical, typically a
hydrocarbon chain. A free radical initiator such as a peroxide
compound is added, generating a free radical species within the
attached molecule. Subsequently, methyl methacrylate monomer is
added to commence chain growth polymerization, which proceeds from
the attached molecule. The result is a medical device with a
covalently attached polymethylmethacrylate coating. Where R is an
initiator molecule attached to the surface, polymerization would
occur through the illustrated double bond.
[0038] In related embodiments, the attachment of the methacrylate
derivative can occur through the ester group. For example, a
functionalized methacrylate, such as glycidyl methacrylate, hydroxy
ethyl methacrylate, methacrylic acid, can initially be attached to
the surface. The initiator then generates the free-radicals, and
methyl methacrylate monomer is added to start polymer
formation.
[0039] Metallocene catalysts are coordination compounds that are
cyclopentadienyl derivatives of metal-containing ions (e.g.,
transition metal ions or transition metal halide ions). Examples of
metallocene catalysts for use in metallocene polymerization
embodiments of the present invention include ferrocene and
bis-chlorozirconocene. Their use in the polymerization of
unsaturated monomers is well known.
[0040] Ziegler-Natta catalysts are also well known. Typical
Ziegler-Natta catalysts for use in Ziegler-Natta polymerization
embodiments of the present invention include a transition metal
compound, for example, titanium halides such as TiCl.sub.3 or
TiCl.sub.4, in combination with an organo aluminum compound, for
example, a trialkyl aluminum or dialkylaluminum halide such as
Al(CH.sub.2H.sub.5).sub.2Cl or Al(C.sub.2H.sub.5).sub.3. An
electron donor is also typically included.
[0041] In an atom transfer radical polymerization process, one or
more radically polymerizable monomers are polymerized in the
presence of an initiator and a catalyst, which includes a
transition metal complexed by one or more ligands. The transition
metal is any transition metal compound that can participate in a
redox cycle with the initiator and the growing polymer chain.
Transition metal catalysts include those represented by the
following general formula TM.sup.n+X.sub.n, where TM is the
transition metal, n is the formal charge on the transition metal
having a value of from 0 to 7, and X is a counterion or covalently
bonded component. Examples of the transition metal (TM) include,
but are not limited to, Cu, Fe, Au, Ag, Hg, Pd, Pt, Co, Mn, Ru, Mo,
Nb and Zn. Examples of X include, but are not limited to, halide,
hydroxy, oxygen, C.sub.1-C.sub.6 alkoxy, cyano, cyanato,
thiocyanato and azido. A preferred transition metal is Cu(I) and X
is preferably halide. Ligands include compounds having one or more
nitrogen, oxygen, phosphorus and/or sulfur atoms, which can
coordinate to the transition metal catalyst compound, such as
unsubstituted and substituted pyridines and bipyridines;
porphyrins; cryptands; crown ethers; polyamines; alkylene glycols;
carbon monoxide; as well as coordinating monomers, for example,
styrene, acrylonitrile and hydroxyalkyl (meth)acrylates. Initiators
that may be used include organic compounds, such as aliphatic
compounds, cycloaliphatic compounds, aromatic compounds, polycyclic
aromatic compounds, heterocyclic compounds, sulfonyl compounds,
sulfenyl compounds, esters of carboxylic acids, nitrites, ketones,
phosphonates and combinations thereof, having one or more radically
transferable groups such as, for example, cyano, cyanato,
thiocyanato, azido, halide groups and combinations thereof.
Preferably, the radically transferable groups of the monomeric
initiator are selected from halide groups (e.g., chloride, bromide
and iodide). Additional information can be found, for example, in
U.S. Pat. Nos. 5,807,937 and 6,326,420, which are hereby
incorporated by reference.
[0042] According to a specific embodiment of the invention, an atom
transfer radical polymerization process is conducted to provide a
polymeric coating on the surface of a medical device. Initially, an
alky halide initiator molecule is attached to the medical device
surface, to yield, for example, 2
[0043] where R is an organic radical, such as a hydrocarbon chain.
A transition metal catalyst, such as Cu(I)Cl, and a monomer, such
as styrene (as noted above, coordinating monomers such as styrene
can be used as a ligand), are introduced to commence chain growth
polymerization, which proceeds from the initiator molecule. The
result is a medical device with a covalently attached polystyrene
coating.
[0044] Suitable anionic initiators for use in anionic
polymerization embodiments of the present invention include alkyl
metal compounds, such as methyl lithium, ethyl lithium, methyl
sodium, isopropyl lithium, n-butyl lithium, sec-butyl lithium,
tert-butyl lithium, n-dodecyllithium, cyclohexyllithium,
4-cyclohexyllithium butyl sodium, lithium naphthalene, sodium
naphthalene, potassium naphthalene, cesium naphthalene, phenyl
sodium, phenyl lithium, benzyl lithium, cumyl sodium, cumyl
potassium, methyl potassium, ethyl potassium, and so forth.
[0045] Cationic initiators for use in cationic polymerization
embodiments the present invention are generally of the Lewis acid
type, for example, aluminum trichloride, boron trifluoride, boron
trifluoride etherate complexes, titanium tetrachloride and the
like. If desired, a cationic co-initiator can be added. Suitable
cationic co-initiators include tertiary alkyl halides (e.g.,
t-butylchloride), tert-ester, tert-ether, tert-hydroxyl and
tert-halogen containing compounds, such as cumyl esters of
hydrocarbon acids, alkyl cumyl ethers, cumyl halides and cumyl
hydroxyl compounds and hindered versions of the same. Also,
electron pair donors such as dimethyl acetamide, dimethyl
sulfoxide, or dimethyl phthalate can be added, as can
proton-scavengers that scavenge water, such as
2,6-di-tert-butylpyridine, 4-methyl-2,6-di-tert-butylpyridine,
1,8-bis(dimethylamino)-naphthalene, or diisopropylethyl amine.
[0046] In one preferred embodiment, the reaction is commenced by
removing a tert-ester, tert-ether, tert-hydroxyl or tert-halogen
group from a co-initiator molecule that has been covalently
attached to the surface of a medical device by reacting it with the
Lewis acid initiator in a suitable solvent system (e.g., a mixture
of polar and non-polar solvents such as methyl chloride and
hexanes) in the presence of an electron pair donor. In place of the
tert-leaving groups is a quasi-stable or "living" cation, which is
stabilized by the surrounding tertiary carbons as well as the polar
solvent system and electron pair donors. Monomer, such as
isobutylene, is introduced, which cationically propagates or
polymerizes from each cation on the attached co-initiator molecule.
Because the initiator complex is unstable, the monomer (e.g.,
isobutylene) is commonly added to the reaction before the addition
of the Lewis acid initiator (e.g., TiCl.sub.4). If desired, an
additional monomer such as styrene can subsequently added to form a
block copolymer. In this connection, it is noted that a
mono-functional initiator produces a diblock copolymer (e.g.,
polyisobutylene-polystyrene) and a di-functional initiator attached
to the surface is used to create a triblock copolymer (e.g.,
polystyrene-polyisobutylene-polystyrene). The reaction can be
terminated by adding a termination molecule such as methanol, water
and the like. Further information can be found, for example, in
U.S. Pat. No. 5,741,331 and U.S. Pat. No. 4,946,899, which are
hereby incorporated by reference.
[0047] In the embodiments discussed above, a polymer coating is
provided by attaching one or more species to the surface of a
medical device, followed by contact with a monomer, leading to
chain-growth polymerization at the site of the attached species. In
other embodiments, however, the surface is provided either
completely or in part with a catalyst that is used to cause the
polymerization reaction at the surface. Subsequently, the medical
device exposed to monomer, which then polymerizes in the vicinity
of the immobilized catalyst. The catalyst can be immobilized, for
example, by covalently bonding it to the surface(including, for
example, a coating surface), by physically embedding it in the
surface, by plating it onto the surface, by adsorbing it onto the
surface, by absorbing it into the surface, and so forth. As the
reaction progresses, polymer merges into polymer and thus the
integrity of the coating is created by the continuity of the
polymer.
[0048] For example, the catalyst can be covalently bonded by, for
example, treating the surface of the medical device with a reagent
that places chemically reactive groups on the device surface or
with a coating that supplies such groups. These groups are then
reacted with groups that are either inherently found on the
catalyst or are supplied to the catalyst (i.e., a derivatized form
of the catalyst is used). Covalent attachment of the catalyst may
be carried out using numerous known reaction chemistries.
[0049] As another example, the surface of the medical device such
as a stent can be at least partially covered by a metallic
catalyst, for instance, by plating the medical device with a
platinum group catalyst. The platinum group metal is subsequently
used to catalyze a polymerization reaction, for example, the
polymerization of silicone.
[0050] The polymerization rates in this embodiment are preferably
much greater than the rate at which the formed polymer diffuses
away from the surface. Therefore, a polymer is formed that is not
covalently attached to the surface of the device, but is
concentrated at that surface.
[0051] In some embodiments, crosslinking is used to change the
properties of the resulting polymer coating. Crosslinking can also
provide stronger interaction with the medical device surface, for
example, by improving the ability of the polymer to form a unitary
mass that surrounds the medical device. Crosslinking strategies are
known in the art and include providing the monomer with functional
groups that are crosslinkable, e.g., using a crosslinking agent or
via photoreaction.
[0052] Where chain-growth polymerization reactions are employed,
immobilized catalysts include metallocene catalysts, Ziegler-Natta
catalysts, atom transfer radical and polymerization catalysts.
Where a multi-component catalyst is used, one component of the
system may be immobilized. Numerous preferred chain-growth polymers
are listed above.
[0053] Where step-growth polymerization reactions (typically
condensation polymerization reactions) are employed, preferred
monomers include terephthalic acid, butanediol, ethylene glycol,
toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI),
polyether polyols, hexamethylene diamine, adipic acid, bis-phenol
A, diphenyl carbonate (see, e.g., U.S. Pat. No. 6,323,304, which is
hereby incorporated by reference), while preferred catalysts for
immobilization include the previously discussed platinum group
metals, as well as dibutyl tin dilaurate and stannous octoate.
[0054] In some step-growth embodiments, dendrimers can be used,
allowing branched polymers to be formed.
[0055] In all of the above embodiments, polymerization proceeds
upon contact with a liquid that contains the selected monomer, as
well any other desired components, such as initiators,
co-initiators, catalysts, co-catalysts, electron donors and so
forth. However, the liquid preferably does not contain sufficient
components to cause initiation not attached to the surface.
Instead, polymerization preferably occurs at or near the surface
upon interaction with species that are provided at the device
surface (e.g., initiator, catalyst, etc.).
[0056] The monomer containing liquid also typically includes an
appropriate solvent system. However, in certain embodiments,
polymerization can also be conducted in the absence of solvent
(i.e., via a "neat" or "bulk" polymerization process).
[0057] The monomer containing liquid can be applied to the medical
device (for example, by spraying or rinsing the medical device with
the liquid) or, more preferably, the medical device can be immersed
in the monomer containing liquid. In these embodiments, multiple
medical devices can be produced concurrently.
[0058] The thickness of the coating that is formed on the medical
device can be controlled in a number of ways, including limiting
the amount of monomer that is present, terminating the reaction
after a sufficient coating thickness is a achieved, or separating
the medical device from the monomer containing liquid after a
sufficient coating is a achieved.
[0059] Using the above techniques, a wide variety of polymeric
coatings can be created. Polymers include (a) polyalkylenes and
derivatives such as polyethylenes, polypropylenes,
poly-4-methyl-pen-1-eness, polybutylenes (including polybut-1-enes
and polyisobutylenes), and fluorinated polyalkylenes (including
polytetrafluoroethylenes); (b) polyvinyl polymers and derivatives,
such as polystyrenes, polyvinyl chlorides, polyvinyl pyrrolidones,
polyacrylonitriles, polyvinyl alcohols, polyvinyl ethers, polyvinyl
pyridines, and polyvinyl acetates; and (d) acrylic acid polymers
and derivatives, such as methylacrylate polymers, methyl
methacrylate polymers, acrylic acid polymers, methacrylic acid
polymers, acrylamide polymers, hydroxyethyl acrylate polymers,
hydroxyethyl methacrylate polymers, glyceryl acrylate polymers,
glyceryl methacrylate polymers, methacrylamide polymers and
ethacrylamide polymers, (e) step-growth polymers such as
poly(esters), nylons, poly(urethanes), poly(carbonates), and (f)
ring-opening polymerization products, such as
poly(.epsilon.-caprolactone) (e.g., nylon 6), poly(L-lactide),
poly(glycolide) and poly(p-dioxanone). Also included are copolymers
(e.g., block and random copolymers) of the above, including
styrene-butadiene copolymers, acrylonitrile-styrene copolymers,
acrylonitrile-butadiene-styrene copolymers, styrene-isobutylene
copolymers, ethylene-alpha-olefin copolymers, ethylene-methacrylic
acid copolymers, ethylene-acrylic acid copolymers, ethylene-methyl
methacrylate copolymers and ethylene-vinyl acetate copolymers,
ethylene-tetrafluoroethylene copolymers, anhydride functionalized
copolymers, such as styrene-maleic anhydride,
methylvinylether-maleic anhydride, ring opening copolymers such as
copolymers of poly(glycolides), poly(lactides), poly(caprolactones)
and poly(p-dioxanone), copolymers of polyamides and ethers, and
copolymers of esters and ethers. Random copolymers can be made, for
example, by exposing the medical device to a mixture of monomers,
while block copolymers can be made, for example, by sequential
exposure to different monomers.
[0060] The polymer coatings of the present invention are preferably
biocompatible for their intended purpose. This means, for example,
that the coatings typically do not lead to severe, long-lived or
escalating adverse biological responses (which are distinguished,
for instance, from the mild, transient inflammation that
accompanies implantation of essentially all foreign objects into a
living organism).
[0061] After the polymer coating is formed, the medical device may
be washed in an appropriate solvent to remove unreacted monomer (as
well as any other residual species, including initiators,
co-initiators, catalysts, co-catalysts and so forth).
[0062] A therapeutic agent is preferably provided within the
polymer coating on the medical device surface. In some instances,
the therapeutic agent can be provided within the polymer coating
concurrently with polymer formation (for example, by including the
therapeutic agent in the monomer containing liquid). In other
instances, the therapeutic agent is incorporated after polymer
formation. For example, the therapeutic agent can be dissolved or
dispersed within a liquid medium, and the liquid medium contacted
with the polymer coating, for example by applying the liquid to the
polymer coating (e.g., by spraying or rinsing) or by immersing at
least a portion of the medical device within the liquid.
[0063] Where the polymer is covalently attached to the medical
device surface, the polymer can be contacted with a solvent that
would otherwise dissolve the attached polymer. In this way, the
polymer can be solubilized, without being removed from the device
surface. For example, such a solvent can be used to remove
unreacted monomer and/or other residual species from the polymer
coating, with diffusion of species out of the polymer being
enhanced by the fact that the polymer is solubilized.
Alternatively, a solvent of this type can be used to
dissolve/disperse a therapeutic agent, which is then contacted with
the coating. Analogous to species removal, diffusion of species (in
this case, therapeutic agent) into the polymer coating is increased
by solubilizing the polymer. Once the solvent is removed, the
therapeutic agent is trapped within the polymer.
[0064] Therapeutic agents useful in connection with the present
invention include essentially any therapeutic agent that is
compatible with the selected polymeric coating (e.g., is not
adversely affected by the polymeric coating and can be released
from the polymeric coating). Therapeutic agents may be used singly
or in combination.
[0065] "Therapeutic agents", "pharmaceutically active agents",
"pharmaceutically active materials", "drugs" and other related
terms may be used interchangeably herein and include genetic
therapeutic agents, non-genetic therapeutic agents and cells.
[0066] Exemplary non-genetic therapeutic agents include: (a)
anti-thrombotic agents such as heparin, heparin derivatives,
urokinase, and PPack (dextrophenylalanine proline arginine
chloromethylketone); (b) anti-inflammatory agents such as
dexamethasone, prednisolone, corticosterone, budesonide, estrogen,
sulfasalazine and mesalamine; (c)
antineoplastic/antiproliferative/anti-mitotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, angiopeptin, monoclonal
antibodies capable of blocking smooth muscle cell proliferation,
and thymidine kinase inhibitors; (d) anesthetic agents such as
lidocaine, bupivacaine and ropivacaine; (e) anti-coagulants such as
D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing
compound, heparin, hirudin, antithrombin compounds, platelet
receptor antagonists, anti-thrombin antibodies, anti-platelet
receptor antibodies, aspirin, prostaglandin inhibitors, platelet
inhibitors and tick antiplatelet peptides; (f) vascular cell growth
promoters such as growth factors, transcriptional activators, and
translational promotors; (g) vascular cell growth inhibitors such
as growth factor inhibitors, growth factor receptor antagonists,
transcriptional repressors, translational repressors, replication
inhibitors, inhibitory antibodies, antibodies directed against
growth factors, bifunctional molecules consisting of a growth
factor and a cytotoxin, bifunctional molecules consisting of an
antibody and a cytotoxin; (h) protein kinase and tyrosine kinase
inhibitors (e.g., tyrphostins, genistein, quinoxalines); (i)
prostacyclin analogs; (j) cholesterol-lowering agents; (k)
angiopoietins; (l) antimicrobial agents such as triclosan,
cephalosporins, aminoglycosides and nitrofurantoin; (m) cytotoxic
agents, cytostatic agents and cell proliferation affectors; (n)
vasodilating agents; and (o)agents that interfere with endogenous
vasoactive mechanisms.
[0067] Exemplary genetic therapeutic agents include anti-sense DNA
and RNA as well as DNA coding for: (a) anti-sense RNA, (b) tRNA or
rRNA to replace defective or deficient endogenous molecules, (c)
angiogenic factors including growth factors such as acidic and
basic fibroblast growth factors, vascular endothelial growth
factor, epidermal growth factor, transforming growth factor .alpha.
and .beta., platelet-derived endothelial growth factor,
platelet-derived growth factor, tumor necrosis factor .alpha.,
hepatocyte growth factor and insulin-like growth factor, (d) cell
cycle inhibitors including CD inhibitors, and (e) thymidine kinase
("TK") and other agents useful for interfering with cell
proliferation. Also of interest is DNA encoding for the family of
bone morphogenic proteins ("BMP's"), including BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11,
BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferred
BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These
dimeric proteins can be provided as homodimers, heterodimers, or
combinations thereof, alone or together with other molecules.
Alternatively, or in addition, molecules capable of inducing an
upstream or downstream effect of a BMP can be provided. Such
molecules include any of the "hedgehog" proteins, or the DNA's
encoding them.
[0068] Vectors of interest for delivery of genetic therapeutic
agents include (a) plasmids, (b) viral vectors such as adenovirus,
adenoassociated virus and lentivirus, and (c) non-viral vectors
such as lipids, liposomes and cationic lipids.
[0069] Cells include cells of human origin (autologous or
allogeneic), including stem cells, or from an animal source
(xenogeneic), which can be genetically engineered if desired to
deliver proteins of interest.
[0070] A number of the above therapeutic agents and several others
have also been identified as candidates for vascular treatment
regimens, for example, as agents targeting restenosis. Such agents
are appropriate for the practice of the present invention and
include one or more of the following: (a) Ca-channel blockers
including benzothiazapines such as diltiazem and clentiazem,
dihydropyridines such as nifedipine, amlodipine and nicardapine,
and phenylalkylamines such as verapamil, (b) serotonin pathway
modulators including: 5-HT antagonists such as ketanserin and
naftidrofuryl, as well as 5-HT uptake inhibitors such as
fluoxetine, (c) cyclic nucleotide pathway agents including
phosphodiesterase inhibitors such as cilostazole and dipyridamole,
adenylate/guanylate cyclase stimulants such as forskolin, as well
as adenosine analogs, (d) catecholamine modulators including
.alpha.-antagonists such as prazosin and bunazosine,
.beta.-antagonists such as propranolol and
.alpha./.beta.-antagonists such as labetalol and carvedilol, (e)
endothelin receptor antagonists, (f) nitric oxide donors/releasing
molecules including organic nitrates/nitrites such as
nitroglycerin, isosorbide dinitrate and amyl nitrite, inorganic
nitroso compounds such as sodium nitroprusside, sydnonimines such
as molsidomine and linsidomine, nonoates such as diazenium diolates
and NO adducts of alkanediamines, S-nitroso compounds including low
molecular weight compounds (e.g., S-nitroso derivatives of
captopril, glutathione and N-acetyl penicillamine) and high
molecular weight compounds (e.g., S-nitroso derivatives of
proteins, peptides, oligosaccharides, polysaccharides, synthetic
polymers/oligomers and natural polymers/oligomers), as well as
C-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds and
L-arginine, (g) ACE inhibitors such as cilazapril, fosinopril and
enalapril, (h) ATII-receptor antagonists such as saralasin and
losartin, (i) platelet adhesion inhibitors such as albumin and
polyethylene oxide, (j) platelet aggregation inhibitors including
aspirin and thienopyridine (ticlopidine, clopidogrel) and GP
IIb/IIIa inhibitors such as abciximab, epitifibatide and tirofiban,
(k) coagulation pathway modulators including heparinoids such as
heparin, low molecular weight heparin, dextran sulfate and
.beta.-cyclodextrin tetradecasulfate, thrombin inhibitors such as
hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone)
and argatroban, FXa inhibitors such as antistatin and TAP (tick
anticoagulant peptide), Vitamin K inhibitors such as warfarin, as
well as activated protein C, (l) cyclooxygenase pathway inhibitors
such as aspirin, ibuprofen, flurbiprofen, indomethacin and
sulfinpyrazone, (m) natural and synthetic corticosteroids such as
dexamethasone, prednisolone, methprednisolone and hydrocortisone,
(n) lipoxygenase pathway inhibitors such as nordihydroguairetic
acid and caffeic acid, (o) leukotriene receptor antagonists, (p)
antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 and
ICAM-1 interactions, (r) prostaglandins and analogs thereof
including prostaglandins such as PGE1 and PGI2 and prostacyclin
analogs such as ciprostene, epoprostenol, carbacyclin, iloprost and
beraprost, (s) macrophage activation preventers including
bisphosphonates, (t) HMG-CoA reductase inhibitors such as
lovastatin, pravastatin, fluvastatin, simvastatin and cerivastatin,
(u) fish oils and omega-3-fatty acids, (v) free-radical
scavengers/antioxidants such as probucol, vitamins C and E,
ebselen, trans-retinoic acid and SOD mimics, (w) agents affecting
various growth factors including FGF pathway agents such as bFGF
antibodies and chimeric fusion proteins, PDGF receptor antagonists
such as trapidil, IGF pathway agents including somatostatin analogs
such as angiopeptin and ocreotide, TGF-.beta. pathway agents such
as polyanionic agents (heparin, fucoidin), decorin, and TGF-.beta.
antibodies, EGF pathway agents such as EGF antibodies, receptor
antagonists and chimeric fusion proteins, TNF-.alpha. pathway
agents such as thalidomide and analogs thereof, Thromboxane A2
(TXA2) pathway modulators such as sulotroban, vapiprost, dazoxiben
and ridogrel, as well as protein tyrosine kinase inhibitors such as
tyrphostin, genistein and quinoxaline derivatives, (x) MMP pathway
inhibitors such as marimastat, ilomastat and metastat, (y) cell
motility inhibitors such as cytochalasin B, (z)
antiproliferative/antineoplastic agents including antimetabolites
such as purine analogs(6-mercaptopurine), pyrimidine analogs (e.g.,
cytarabine and 5-fluorouracil) and methotrexate, nitrogen mustards,
alkyl sulfonates, ethylenimines, antibiotics (e.g., daunorubicin,
doxorubicin), nitrosoureas, cisplatin, agents affecting microtubule
dynamics (e.g., vinblastine, vincristine, colchicine, paclitaxel
and epothilone), caspase activators, proteasome inhibitors,
angiogenesis inhibitors (e.g., endostatin, angiostatin and
squalamine), rapamycin, cerivastatin, flavopiridol and suramin,
(aa) matrix deposition/organization pathway inhibitors such as
halofuginone or other quinazolinone derivatives and tranilast, (bb)
endothelialization facilitators such as VEGF and RGD peptide, and
(cc) blood rheology modulators such as pentoxifylline.
[0071] Several of the above and numerous additional therapeutic
agents appropriate for the practice of the present invention are
also disclosed in U.S. Pat. No. 5,733,925 assigned to NeoRx
Corporation, the entire disclosure of which is incorporated by
reference.
[0072] A wide range of therapeutic agent loadings can be used in
connection with the above polymeric coatings, with the amount of
loading being readily determined by those of ordinary skill in the
art and ultimately depending upon the condition to be treated, the
nature of the therapeutic agent itself, the avenue by which the
therapeutic-agent-loade- d polymeric coating is administered to the
intended subject, and so forth. The loaded polymeric coating will
frequently comprise from 1% or less to 70 wt % or more therapeutic
agent.
[0073] Although various embodiments are specifically illustrated
and described herein, it will be appreciated that modifications and
variations of the present invention are covered by the above
teachings and are within the purview of the appended claims without
departing from the spirit and intended scope of the invention.
* * * * *