U.S. patent application number 14/643576 was filed with the patent office on 2015-07-02 for coatings for implantable medical devices.
The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Syed F.A. Hossainy, Eugene T. Michal, Ashok Shah.
Application Number | 20150182672 14/643576 |
Document ID | / |
Family ID | 36574532 |
Filed Date | 2015-07-02 |
United States Patent
Application |
20150182672 |
Kind Code |
A1 |
Michal; Eugene T. ; et
al. |
July 2, 2015 |
COATINGS FOR IMPLANTABLE MEDICAL DEVICES
Abstract
The present application teaches a coating having a biologically
compatible compound conjugated to, or blended with, a polymer,
wherein the polymer includes at least one olefin-derived unit and
at least one unit derived from a vinyl alcohol, an allyl alcohol,
or derivatives thereof.
Inventors: |
Michal; Eugene T.; (San
Francisco, CA) ; Hossainy; Syed F.A.; (Hayward,
CA) ; Shah; Ashok; (San Jose, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
36574532 |
Appl. No.: |
14/643576 |
Filed: |
March 10, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14044693 |
Oct 2, 2013 |
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14643576 |
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11338058 |
Jan 23, 2006 |
8563025 |
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14044693 |
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10104769 |
Mar 20, 2002 |
7919075 |
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11338058 |
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Current U.S.
Class: |
514/21.1 ;
514/182; 514/291; 514/449; 523/105 |
Current CPC
Class: |
A61K 31/337 20130101;
C09D 151/06 20130101; C08F 2810/50 20130101; A61L 2300/43 20130101;
C08F 8/34 20130101; C09D 151/08 20130101; C09D 151/06 20130101;
A61L 2300/416 20130101; C08G 18/6212 20130101; C09D 151/06
20130101; C09D 151/08 20130101; C09D 151/003 20130101; C08F 8/30
20130101; A61K 31/56 20130101; C09D 151/08 20130101; A61L 31/16
20130101; C08F 2800/10 20130101; C09D 151/003 20130101; A61L
2300/606 20130101; C08F 8/32 20130101; C09D 151/003 20130101; A61L
31/10 20130101; C08F 8/00 20130101; C08F 8/30 20130101; C08F 8/32
20130101; C09D 151/08 20130101; C08F 8/14 20130101; C08G 18/711
20130101; C08F 210/02 20130101; C09D 151/06 20130101; C09D 175/04
20130101; C08F 8/32 20130101; C08F 8/00 20130101; C09D 151/003
20130101; A61K 31/4745 20130101; C08L 2666/04 20130101; C08F 8/32
20130101; C08L 2666/04 20130101; C08F 210/02 20130101; C08L 2666/02
20130101; C08F 210/02 20130101; C08F 216/06 20130101; C08L 2666/02
20130101; C08F 216/06 20130101; C08F 216/06 20130101; C08F 216/06
20130101; C08F 8/14 20130101; C08L 2666/02 20130101; C08L 2666/14
20130101; C08F 216/06 20130101; C08F 210/02 20130101; C08L 2666/04
20130101; C08F 8/34 20130101; C08L 2666/14 20130101; C08L 2666/14
20130101 |
International
Class: |
A61L 31/10 20060101
A61L031/10; A61L 31/16 20060101 A61L031/16 |
Claims
1. A coating for a medical device, wherein the coating comprises: a
biologically compatible compound blended with a polymer, wherein
the polymer comprises at least one unit (I) --CH.sub.2--CH.sub.2--
(I) and at least one unit (II) ##STR00013## wherein, R.sup.1
comprises a component selected from a group consisting of a
carboxy, an ester, an ether, an amide, a urethane, an amine, a
toluenesulfoester, a 2,2,2-trifluoroethylsulfoester, an epoxy, and
a glycidyl group; and R.sup.2 comprises a component selected from a
group consisting of a hydrogen and an alkyl group.
2. The coating of claim 1, wherein the polymer comprises:
##STR00014## wherein, R.sup.1 comprises a component selected from a
group consisting of a carboxy, an ester, an ether, an amide, a
urethane, an amine, a toluenesulfoester, a
2,2,2-trifluoroethylsulfoester, an epoxy, and a glycidyl group;
R.sup.2 comprises a component selected from a group consisting of a
hydrogen and an alkyl group; the molecular weight of R.sup.1 or
R.sup.2 ranges from about 1 to about 30,000 Daltons; and, the total
of m+n is an integer ranging from about 50 to about 7,000.
3. The coating of claim 1, wherein the molecular weight of R.sup.1
or R.sup.2 ranges from about 1 to about 30,000 Daltons; and, the
total of m+n is an integer ranging from about 50 to about
7,000.
4. The coating of claim 1, wherein the molecular weight of R.sup.1
is about 5000 Daltons.
5. The coating of claim 1, wherein the alkyl is methyl.
6. The coating of claim 1, wherein the polymer comprises
##STR00015## and, the total of m+n is an integer ranging from about
50 to about 7,000.
7. The coating of claim 1, wherein the biologically compatible
compound comprises a poly(alkylene glycol), a poly(alkylene glycol)
derivative, a protein, a polysaccharide, a superoxide dismutase
mimetic, a diazenium diolate, or a combination thereof.
8. The coating of claim 1, wherein the biologically compatible
compound comprises poly(ethylene glycol).
9. The coating of claim 1, wherein the biologically compatible
compound is conjugated to a protein or to a polysaccharide.
10. The coating of claim 9, wherein the protein comprises
albumin.
11. The coating of claim 9, wherein the polysaccharide comprises a
component selected from a group consisting of hyaluronic acid,
heparin, heparin derivatives containing a hydrophobic counter-ion
and chitosan.
12. The coating of claim 7, wherein the diazenium diolate comprises
a component selected from a group consisting of 1,3-propanediamine,
N-{4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]butyl}-diazen-1-ium--
1,2-diolate and
1-{N-methyl-N-[6-(N-methylammonio)hexyl]amino}diazen-1-ium-1,2-diolate.
13. The coating of claim 7, wherein the superoxide dismutase
mimetic comprises manganese(II)dichloro-aminoethylthiolated
pentaazatetracyclohexacosatriene.
14. The coating of claim 1, further comprising a therapeutic
substance.
15. The coating of claim 14, wherein the therapeutic substance
comprises actinomycin D, estradiol, paclitaxel, docetaxel, or
rapamycin.
16. The coating of claim 1, wherein the medical device comprises a
stent.
Description
CROSS REFERENCE
[0001] This application is a divisional application of U.S.
application Ser. No. 14/044,693 filed on Oct. 2, 2013, which is a
divisional application of U.S. application Ser. No. 11/338,058
filed on Jan. 23, 2006 and issued as U.S. Pat. No. 8,563,025, which
is a continuation application of U.S. application Ser. No.
10/104,769 filed on Mar. 20, 2002 and issued as U.S. Pat. No.
7,919,075, which are hereby incorporated by reference in their
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to the field of medical devices, more
particularly, to coatings for devices such as stents.
[0004] 2. Description of the Background
[0005] In the field of medical technology, there is frequently a
necessity to administer drugs locally. To provide an efficacious
concentration to the treatment site, systemic administration of
medication often produces adverse or toxic side effect for the
patient. Local delivery is a preferred method in that smaller total
levels of medication are administered in comparison to systemic
dosages but are concentrated at a specific site. Thus, local
delivery produces fewer side effects and achieves more effective
results.
[0006] One commonly applied technique for local delivery of a drug
is through the use of a polymeric matrix. A polymer impregnated
with a drug can be formed into particles or can be coated on
implantable medical devices such as stents. Subsequent to the
implantation of the particle or the device, the drug slowly elutes
from the polymer. A variety of well known polymers have suitable
biocompatible properties which allow the polymers to serve as
suitable hosts for local drug delivery. A selected group of these
polymers can also form a film layer or a coating for implantable
devices such as stents. One example of a polymer that serves the
dual function of being very biocompatible and capable of forming a
coating for devices is a copolymer of ethylene and vinyl alcohol,
also known as poly(ethylene-co-vinyl alcohol) or EVOH.
Poly(ethylene-co-vinyl alcohol) is also known under the trade name
EVAL and is distributed commercially by Aldrich Chemical Company of
Milwaukee, Wis. EVAL is also manufactured by EVAL Company of
America of Lisle, Ill. Other polymers which can be used to coat
stents include a copolymer of ethylene and acrylic acid (EAA) and a
copolymer of ethylene and glycidyl methacrylate (EGMA).
[0007] EVAL is a product of hydrolysis and contains ethylene-vinyl
acetate copolymers. EVAL may also be a terpolymer and may include
up to 5% (molar) units derived from styrene, propylene and other
suitable unsaturated monomers. EVAL can be described as being
hydrophobic and thus is essentially insensitive to moisture. EAA
and EGMA, likewise, are hydrophobic and relatively impermeable to
gases. The ethylene fragments of EVAL, EAA and EGMA provide
hydrophobicity and barrier properties, while functional fragments
of each copolymer (hydroxyl groups, carboxyl groups, and glycidyl
groups, respectively) provide at least limited solubility in
organic solvents.
[0008] While EVAL, EAA and EGMA are inert and biocompatible
polymers which are quite suitable for use as a drug delivery
matrix, and more particularly when used in conjunction with medical
devices, some of the properties of these polymers can be improved.
In particular, the polymers are prone to protein fouling, which may
significantly inhibit the polymers' lifetime in vivo efficacy.
[0009] There is a need for polymeric carriers suitable for the
delivery of drugs, and more particularly for coating medical
devices used as a means for drug delivery. Suitable characteristics
of the polymeric materials should be significantly impermeable to
oxygen, high degree of hydrophobicity and long term
biocompatibility with minimum protein fouling effects.
SUMMARY
[0010] The present application generally encompasses a coating
having a biologically compatible compound conjugated to, or blended
with, a polymer, wherein the polymer includes at least one
olefin-derived unit and at least one unit derived from a vinyl
alcohol, an allyl alcohol, or derivatives thereof. In some
embodiments, the invention includes a coating for a medical device,
wherein the coating includes a modified polymer comprising a
biologically compatible compound conjugated to a polymer. The
modified polymer comprises at least one unit (I)
--CH.sub.2--CH.sub.2-- (I)
and at least one unit (II)
##STR00001##
wherein, R.sup.1 comprises a component selected from a group
consisting of an ester, an ether, an amine, an amide, a urethane,
and a combination thereof; and R.sup.2 comprises a component
selected from a group consisting of a hydrogen and an alkyl group.
In some embodiments, the biologically compatible compound is
blended with the polymer.
[0011] In some embodiments, the present invention includes a method
of fabricating a medical device comprising forming a coating on the
device, wherein the coating comprises a modified polymer comprising
a biologically compatible compound conjugated to a polymer. The
modified polymer comprises at least one unit (I)
--CH.sub.2--CH.sub.2-- (I)
and at least one unit (II)
##STR00002##
wherein, R.sup.1 comprises a component selected from a group
consisting of an ester, an ether, an amine, an amide, a urethane,
and a combination thereof; and R.sup.2 comprises a component
selected from a group consisting of a hydrogen and an alkyl group.
In some embodiments, the forming comprises reacting the polymer
with the biologically compatible compound to create the modified
polymer, and depositing the modified polymer on the medical device.
In some embodiments, the forming comprises depositing the polymer
on the medical device to produce a coating, and reacting the
coating with a biologically compatible compound to create a
modified coating.
DETAILED DESCRIPTION
[0012] The present invention provides for a modification of
polymers to be used for the local delivery of therapeutic
substances or drugs. The polymers can also be used as coatings for
implantable medical devices such as stents. The polymers can be
referred to herein as "modified polymers," "polymers to be
modified," or "polymers subject to modification."
[0013] The polymers can be characterized by the presence of a
polyolefin backbone, pendant on which are alkyl, hydroxyl, and/or
carboxyl groups. EVAL is one example of a polymer that can be
modified according to this invention. Other examples of polymers
that can be modified include a copolymer of ethylene and acrylic
acid (EAA) and a copolymer of ethylene and glycidyl methacrylate
(EGMA). EVAL, EAA, and EGMA have relatively high oxygen-barrier
properties and are resistant to water vapor; however, the polymers'
long-term biocompatibility is somewhat limited due to protein
fouling effects. Modification of the polymers by covalent
conjugation to biologically active materials will enhance the
polymers' in vivo behavior, thus providing better long-term
results.
[0014] EVAL, EAA and EGMA can be modified by biologically active
compounds, hereinafter also referred to as "modifiers" or
"modifying compounds." Modification can be accomplished by covalent
conjugation of the polymer to one or more modifiers. The functional
groups of the polymers, such as the hydroxyl groups in EVAL, the
carboxyl groups in EAA, and the glycidyl groups in EGMA, can be
used as the target sites for the conjugation. The modification of
the polymer can be conducted directly on the stent or the polymer
can be modified first, and the modified product can then applied to
the stent.
[0015] In one embodiment, the modifiers include poly(ethylene
glycol) (PEG) and PEG's functionalized derivatives. More
particularly, representative examples include PEG, PEG-isocyanate,
PEG-epoxide, and amino-terminated PEG. In accordance with another
embodiment of the invention, the modifier can be an intracellular
enzyme, for example, oxidoreductases containing seven-coordinate
complexes of manganese, which is also known as superoxide dismutase
mimics (SODm). In yet another embodiment, the modifier can include
diazenium diolate type nitric oxide donors. In yet another
embodiment, the modifier can include hyaluronic acids. In yet
another embodiment of the invention, the modifying compound(s) can
be conjugated to proteins or polysaccharides followed by
cold-blending of the conjugates with the matrix polymer such as
EVAL.
[0016] A therapeutic substance or a drug can be incorporated in the
modified polymer. The therapeutic substance can include any
compound that exerts a therapeutic or prophylactic effect for the
patient. The substance can be for inhibiting the migration and/or
proliferation of smooth muscle cells or for the treatment of
restenosis and can include small molecule drugs, peptides,
proteins, oligonucleotides, or DNA. Examples of the drugs include
antiproliferative substances such as actinomycin D, or derivatives
and analogs thereof. Synonyms of actinomycin D include
dactinomycin, actinomycin IV, actinomycin I.sub.1, actinomycin
X.sub.1, and actinomycin C.sub.1. The substance can also fall under
the genus of antineoplastic, anti-inflammatory, antiplatelet,
anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,
antiallergic and antioxidant substances. Examples of such
antineoplastics and/or antimitotics include paclitaxel, docetaxel,
methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,
doxorubicin hydrochloride, and mitomycin. 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, and thrombin. Examples of such cytostatic or
antiproliferative agents include angiopeptin, angiotensin
converting enzyme inhibitors such as captopril, cilazapril or
lisinopril, 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),
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), and nitric oxide. An example of an antiallergic agent
is permirolast potassium. Other therapeutic substances or agents
which may be appropriate include alpha-interferon, genetically
engineered epithelial cells, rapamycin, rapamycin derivatives and
analogs, and dexamethasone.
[0017] The coating of the present invention can be used in
conjunction with a balloon-expandable or self-expandable stent. The
application of the coating is not limited to stents and the coating
can also be used with a variety of other medical devices. Examples
of other implantable medical device include stent-grafts, grafts
(e.g., aortic grafts), artificial heart valves, cerebrospinal fluid
shunts, pacemaker electrodes, axius coronary shunts and endocardial
leads (e.g., FINELINE and ENDOTAK, available from Guidant
Corporation). The underlying structure of the device can be of
virtually any design.
[0018] The device can be made of a metallic material or an alloy
such as, but not limited to, cobalt-chromium alloys (e.g.,
ELGILOY), stainless steel (316L), "MP35N," "MP20N," ELASTINITE
(Nitinol), tantalum, tantalum-based alloys, nickel-titanium alloy,
platinum, platinum-based alloys such as, e.g., platinum-iridium
alloy, iridium, gold, magnesium, titanium, titanium-based alloys,
zirconium-based alloys, or combinations thereof. Devices made from
bioabsorbable or biostable polymers can also be used with the
embodiments of the present invention. "MP35N" and "MP20N" are trade
names for alloys of cobalt, nickel chromium and molybdenum,
available from Standard Press Steel Co. of 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.
[0019] The following examples illustrate various embodiments for
the modified polymers.
1. Modification of EVAL
[0020] In one embodiment of the invention, EVAL
(--[CH.sub.2--CH.sub.2].sub.m--[CH.sub.2--CH(OH)].sub.n--)
manufactured by EVALCA Corp., Lisle, Ill., has an m:n ratio of
44:56. Those having ordinary skill in the art will understand that
EVAL with higher or lower ethylene content can be modified by the
same methods as those discussed below. In accordance with some of
the embodiments of this invention, EVAL is modified as shown in the
following examples.
EXAMPLE 1
Modifier: poly(ethylene glycol)
[0021] Poly((ethylene glycol) (PEG) is a highly biologically
compatible product. Due to the presence of hydroxyl groups, PEG is
capable of entering reactions of condensation with EVAL. The
reaction may need to be catalyzed by a suitable acidic or basic
catalyst. PEG can be in an oligomeric or polymeric form and can
have a molecular weight within a range of between about 500 and
about 30,000 Daltons. The conditions under which this reaction is
conducted can be determined by one having ordinary skill in the
art. EVAL can be firmly bonded to the biologically compatible PEG.
Thus, EVAL is modified by PEG and the modified EVAL can have an
enhanced long-term biocompatibility.
EXAMPLE 2
Modifier: poly(ethylene glycol)-isocyanate
[0022] Poly(ethylene glycol)-isocyanate (hereinafter, PEG-ISO) is a
PEG based product having the isocyanate fragments --N.dbd.C.dbd.O.
An example of a PEG-ISO suitable as a modifier for EVAL is a
methoxylated PEG-ISO. The PEG-ISO has a general formula
CH.sub.3--[O--CH.sub.2--CH.sub.2].sub.p--N.dbd.C.dbd.O. This
modifier, manufactured by Shearwater Corp. of Huntsville, Ala., has
a molecular weight of about 5,000 which corresponds to the value of
the integer "p" of about 112. Due to the presence of the isocyanate
groups, PEG-ISO is chemically very active and readily reacts with
EVAL in solution. The --N.dbd.C.dbd.O group of PEG-ISO, having
strong electron accepting properties, reacts with the nucleophilic
hydroxyl group of EVAL, as illustrated by reaction scheme (I):
##STR00003##
[0023] The conditions under which reaction scheme (I) is conducted
can be determined by one having ordinary skill in the art. As a
result, EVAL is firmly bonded to the biologically compatible
PEG-ISO to form the urethane product of reaction scheme (I). Thus,
EVAL, modified by PEG-ISO, can have an enhanced long-term
biocompatibility.
EXAMPLE 3
Modifier: poly(ethylene glycol)-epoxide
[0024] Poly(ethylene glycol)-epoxide (hereinafter, PEG-EPO) is a
PEG-based product having epoxy fragments. An example of a PEG-EPO
suitable as a modifier for EVAL is a methoxylated PEG-EPO, such as
methoxy-PEG-glycidyl ether and has the following general
formula
##STR00004##
The PEG-EPO has a molecular weight of about 5,000, which
corresponds to the value of the integer "p" of about 112, and is
manufactured by Shearwater Corp. of Huntsville, Ala.
[0025] Epoxy groups in PEG-EPO are reactive, and PEG-EPO easily
reacts with EVAL in solution. The epoxy group of PEG-EPO can react
with the nucleophilic hydroxyl group of EVAL, via the nucleophilic
substitution reaction S.sub.N2. Normally, the proton of the
hydroxyl group attacks the less substituted .alpha.-carbon atom of
the epoxy group. The .beta.-carbon is less accessible due to the
steric hindrances. As a result of the proton attack on the
.alpha.-carbon atom, the ring opens, and the modified EVAL is
formed according to a reaction that can be shown as reaction scheme
(II):
##STR00005##
[0026] Reaction scheme (II) is carried out more effectively in the
presence of electron acceptors, because the electron acceptors
facilitate electrophilic polarization of the C--O bond of the epoxy
ring, thus making the subsequent attack by the proton of the
hydroxyl group of EVAL easier. Accordingly, modification of EVAL
with PEG-EPO is facilitated in the presence of electrophilic
ring-opening catalysts, for instance, aprotonic acids such as
amine-boron trifluoride products or tertiary amines. The use of any
ring-opening catalyst is optional. The conditions under which this
reaction is conducted can be determined by one having ordinary
skill in the art.
EXAMPLE 4
Modifier: Hyaluronic Acid
[0027] Hyaluronic acid is a linear polysaccharide composed of
disaccharide units of N-acetylglucosamine and D-glucoronic acid. In
hyaluronic acid, uronic acid and the aminosugar are linked by
alternating .beta.-1,4 and .beta.-1,3 glucosidic bonds. Hyaluronic
acid has hydroxymethyl groups and secondary amino groups. EVAL can
be modified by these groups. In order to facilitate the
condensation reaction of either the hydroxymethyl groups or the
secondary amino groups of hyaluronic acid with the hydroxyl groups
of EVAL, an appropriate catalyst may be needed. Alternatively, the
modification of EVAL by hyaluronic acid can be carried in the
presence of 1-ethyl-3(3-dimethylaminopropyl) carbodiimide, also
known as carbodiimide or EDC, having the formula
CH.sub.3--CH.sub.2--N.dbd.C.dbd.N--CH.sub.2--CH.sub.2--CH.sub.2--N(CH.sub-
.3).sub.2. EDC is manufactured by Pierce Corp., Rockford, Ill.
Instead of EDC, 1,3-dicyclohexylcarbodiimide (DCC) having the
formula
##STR00006##
can be used. As a result, EVAL is firmly bonded to the biologically
compatible hyaluronic acid for enhanced long-term
biocompatibility.
EXAMPLE 5
Modifier: Protein and/or Polysaccharide Products
[0028] As a first step, a biologically active agent is conjugated
to a protein or a polysaccharide, or to a combination of the
protein and the polysaccharide. Albumin (also known as albumen or
the egg white protein) can be used as the protein, and heparin,
heparin derivatives, including the derivatives containing
hydrophobic counter-ions, hyaluronic acid or chitosan can be used
as polysaccharides. PEG is one example of the biologically active
agent to be conjugated to the protein or polysaccharide, or to a
combination of the protein and the polysaccharide. Other
biologically active agents that can be used include superoxide
dismutase-mimetics (SOD-mimetics or SODm) and diazenium diolate
type nitric oxide donors.
[0029] Superoxide dismutase-mimetics are oxidoreductase-based
complexes that contain cations of copper, iron, or manganese.
SOD-mimetics are major intracellular enzymes that protect the cell
against oxygen toxicity by dismutating the radical oxygen
superoxide, .O.sub.2, to oxygen and hydrogen peroxide.
[0030] Manganese-based SODm,
manganese(II)dichloro-aminoethylthiolated
pentaazatetracyclohexacosatriene (SOD-40470) manufactured by
Metaphore Pharmaceuticals, Inc., St. Louis, Mo. is one example of a
SODm that can be used to conjugate to the protein or
polysaccharide. Those having ordinary skill in the art can also
select other types of SODm. Due to the presence of the primary
amino ligands, SOD-40470 is chemically quite active and can be
easily conjugated to the protein or the polysaccharide, or to a
combination of the protein and the polysaccharide.
[0031] Diazenium diolate type nitric oxide donors are products of
nitric oxide (NO) with nucleophilic amines. Diazenium diolates also
known as NONOates are highly biologically compatible and possess
valuable medicinal properties. In slightly acidic medium they
spontaneously release NO which has excellent therapeutic
properties. One example of a diazenium diolate that can be used to
conjugate to the protein or polysaccharide is spermine diazenium
diolate (SDD).
[0032] An aliphatic NONOate, SDD, or 1,3-propanediamine,
N-{4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]butyl}-diazen-1-ium--
1,2-diolate has the formula
NH.sub.2--(CH.sub.2).sub.3--N[N.sup.+(O)--(N--OH)]--(CH.sub.2).sub.4--NH--
-(CH.sub.2).sub.3--NH.sub.2 and is manufactured by Molecular
Probes, Inc., Eugene, Oreg. Alternatively, other diazenium
diolate-type NO donors can be used. One example of a suitable
alternative diazenium diolate-type NO donor can be
1-{N-methyl-N-[6-(N-methylammonio)hexyl]amino}diazen-1-ium-1,2-diolate
having the formula
CH.sub.3--N.sup.+H.sub.2--(CH.sub.2).sub.6--N(CH.sub.3)--N.sup.+(O.sup.-)-
.dbd.N--O.sup.- (MAHMA-NO). Another example of a suitable
alternative NONOate can be
Z-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate
having the formula
O.sup.---N.sup.+[N(CH.sub.2--CH.sub.2--NH.sub.2)CH.sub.2--CH.sub.2--N.sup-
.+H.sub.3].dbd.N--O.sup.- (DETA-NO). MAHMA-NO and DETA-NO can be
obtained from Cayman Chemical Co., Ann Arbor, Mich.
[0033] Due to the presence of amino groups, both SDD, MAHMA-NO and
DETA-NO are easily conjugated to the above-mentioned proteins
and/or polysaccharides, or to a combination thereof. The conditions
under which the reaction of conjugation of PEG, SODm or diazenium
diolates to the protein or polysaccharide, or a combination
thereof, is conducted can be determined by those having ordinary
skill in the art.
[0034] As a second step, the product of conjugation of PEG, SODm or
diazenium diolates to the protein or polysaccharide, or a
combination thereof, is cold-blended with EVAL. As a result, EVAL
is modified with a product having high biocompatibility.
2. Polymer Subject to Modification is an EVAL Derivative
[0035] EVAL can be preliminarily derivatized by tosylation
(treatment with tosyl chloride), or alternatively by tresylation
(by reacting with tresyl chloride). Tosyl chloride is a derivative
of toluene, p-toluene sulfonyl chloride having the formula
CH.sub.3--C.sub.6H.sub.4--SO.sub.2Cl (TsCl). The process of EVAL
derivatization can be conducted directly on the stent. The
following process of tosylation can be used.
[0036] A 2% (mass) solution of EVAL in dimethylacetamide (DMAC) can
be sprayed on the stent and dried for 10 minutes at 80.degree. C.,
and then again for 1 hour at 140.degree. C. A 3% (mass) of TsCl in
dry xylene can be prepared and the coated EVAL stent can be shaken
for 1 minute with 1.4 ml of the TsCl solution. 0.25 ml of 33%
(mass) of pyridine in dry xylene can be added, followed by shaking
for 4 hours in a desiccator. The stent can be then rinsed with
acetone and twice with 1 mM solution of HCl to remove the excess
TsCl. As a result, EVAL can be tosylated according to reaction
scheme (III) and the tosyl group is attached to the EVAL backbone
via a hydroxy group to yield the toluenesulfoester:
##STR00007##
[0037] Alternatively, tresyl chloride
(2,2,2-trifluoroethanesulphonyl chloride) can be used to
derivatrize EVAL according to reaction scheme (IV), and the tresyl
group is attached to the EVAL backbone via hydroxy group:
##STR00008##
EXAMPLE 6
Modifier: poly(ethylene glycol)-amine product
[0038] Poly(ethylene glycol)-amine product (hereinafter,
PEG-NH.sub.2) is a PEG-based product having amino groups NH.sub.2.
An example of a PEG-NH.sub.2 that can be used as a modifier for the
tosylated or tresylated EVAL is a methoxylated PEG-NH.sub.2 product
having a general formula
CH.sub.3--[O--CH.sub.2--CH.sub.2].sub.p--O--CH.sub.2--CH.sub.2--N-
H.sub.2. This product, manufactured by Shearwater Corp.,
Huntsville, Ala., has a molecular weight of about 5,000 which
corresponds to the value of the integer "p" of about 113.
[0039] Due to the presence of the amino groups, PEG-NH.sub.2 is
chemically active and is readily alkylated with the tosylated or
tresylated EVAL in solution. Typically, compared with the hydroxyl
group of EVAL, the amino group of PEG-NH.sub.2 is more reactive
with alkylating agents such as tosylated or tresylated agents.
[0040] In addition, since toluenesulfonic acid is known to be a
very strong acid, on par with sulfuric or hydrochloric acids, its
anion, CH.sub.3--C.sub.6H.sub.4--SO.sub.3.sup.-, is an excellent
leaving group in the nucleophilic substitution alkylation reaction
of a primary amine; it is much better than the hydroxyl group of an
underivatized EVAL. Accordingly, the tosylated EVAL obtained as
described above, readily reacts with PEG-NH.sub.2 as schematically
shown by the alkylation reaction scheme (V):
##STR00009##
[0041] The conditions under which this reaction are conducted can
be determined by those having ordinary skill in the art. The
reaction of tresylated EVAL and PEG-NH.sub.2 is similar to reaction
scheme (V). As a result, EVAL is firmly bonded to the biologically
compatible PEG-NH.sub.2 to form the secondary amine product of
reaction (V).
EXAMPLE 7
Modifier: SOD-Mimetic
[0042] SOD-mimetics are highly biocompatible and can be used for
modifying tosylated or tresylated EVAL. In particular, SOD-40470
can be used as a modifying agent with the tosylated or tresylated
EVAL. Due to the presence of the primary amino ligands, SOD-40470
is chemically active and is readily alkylated with the tosylated or
tresylated EVAL in solution. Alternatively, other SOD-mimetics can
be used so long as they have amino groups. The mechanism of the
tosylation or tresylation is via a reaction of alkylation of the
amino group of SODm and is similar to reaction scheme (V) discussed
above. The conditions under which this reaction is conducted will
be determined by those having ordinary skill in the art. As a
result, EVAL is firmly bonded to the biologically compatible amino
ligand-containing SODm to form the secondary amine product.
EXAMPLE 8
Modifier: Spermine Diazenium Diolate
[0043] Tosylated or tresylated EVAL can be modified by binding to a
NONOate. Spermine diazenium diolate, SDD, can be used as a
modifying agent for the tosylated or tresylated EVAL. Due to the
presence of two primary and one secondary amino groups, SDD is
easily alkylated with the tosylated or tresylated EVAL in solution.
The mechanism of such tosylation or tresylation includes alkylation
of the amino group of SDD and is similar to reaction scheme (V)
discussed above. Alternatively, other diazenium diolate-type NO
donors can be used, so long as they have amino groups, for example,
MAHMA-NO or DETA-NO. The mechanism of binding of the tosylated or
tresylated EVAL to MAHMA-NO or DETA-NO is the same as the mechanism
of binding to SDD.
[0044] The conditions under which the tosylated or tresylated EVAL
is bound to SDD, or the alternative diazenium diolate-type NO
donors, can be determined by those having ordinary skill in the
art. As a result, EVAL is firmly bonded to the biologically
compatible diazenium diolate-type NO donors to form the secondary
amine product. Since the modified product will be able to release
NO having valuable medicinal properties, the stent coating will
acquire additional therapeutical properties.
3. The Polymer Subject to Modification is a Copolymer of Ethylene
with Acrylic Acid (EAA)
[0045] EAA has the general formula
--[CH.sub.2--CH.sub.2].sub.m--[CH.sub.2--CH(COOH)].sub.n--. In one
embodiment of this invention, 25% (by mass) aqueous,
ammonia-neutralized dispersion of EAA manufactured by Michelman,
Inc., Cincinnati, Ohio is used. In some of the embodiments of this
invention, EAA is modified as illustrated in the following
examples.
EXAMPLE 9
Modifier: PEG-NH.sub.2
[0046] Due to the presence of the amino groups, PEG-NH.sub.2 is
chemically active and readily acylated with the carboxyl groups of
EAA. Accordingly, EAA readily reacts with PEG-NH.sub.2. The
reaction is carried out in the presence of EDC. EAA reacts with EDC
and forms an O-acylisourea, an amine-reactive intermediate. This
intermediate is unstable in an aqueous environment and immediately
reacts with PEG-NH.sub.2 utilizing PEG-NH.sub.2's amino groups.
[0047] The path of the reaction is via a nucleophilic attack of the
carbon of the carboxyl group of EAA by the electron-rich nitrogen
of the amino group of PEG-NH.sub.2, followed by the formation of
the peptide bond --NH--CO--. Water is the by-product. The process
is schematically shown by the acylation reaction scheme (VI):
##STR00010##
EXAMPLE 10
Modifier: SOD-Mimetic
[0048] SOD-40470 can be used as a modifying agent of EAA. Due to
the presence of the primary amino ligands, SOD-40470 is chemically
active and readily couples with EAA. As in the case of modification
with PEG-NH.sub.2, the reaction is carried out in the presence of
EDC. The mechanism of the reaction is via acylation of the amino
group of SOD-40470 and is similar to reaction scheme (VI). Other
SOD-mimetics can be used so long as they have amino groups. EAA can
be firmly bonded to the biologically compatible amino
ligand-containing SOD-40470 to form the peptide-type product.
EXAMPLE 11
Modifier: Spermine Diazenium Diolate
[0049] SDD can be used as a modifying agent for EAA. Due to the
presence of the amino groups, SDD is chemically active and readily
couples with EAA. As in the case of modification with PEG-NH.sub.2
and SOD-40470, the reaction is carried out in the presence of EDC.
The mechanism of the reaction is via acylation of the amino group
of SDD and is similar to reaction scheme (VI). Other diazenium
diolate-type NO donors can be used, so long as they have amino
groups, for example, MAHMA-NO or DETA-NO. The mechanism of the
coupling of EAA to MAHMA-NO or to DETA-NO is the same as the
mechanism of coupling EAA to SDD. The conditions under which the
reaction of binding EAA to SDD or the alternative diazenium
diolate-type NO donors is conducted can be determined by those
having ordinary skill in the art. As a result, EAA is firmly bonded
to the biologically compatible diazenium diolate-type NO donors to
form the peptide-type product. The modified product will be able to
release NO.
4. Polymer Subject to Modification is a Copolymer of Ethylene with
Glycidyl Methacrylate (EGMA)
[0050] EGMA has the general formula
##STR00011##
wherein m and n are integers.
[0051] A brand of EGMA having about 80% (by mass) of the units
derived from ethylene can be used for modification. EGMA is an
aliphatic epoxy oligomer with relatively high contents of epoxy
functionality. Due to the presence of the epoxy groups, EGMA is
chemically reactive and can be modified via these epoxy groups,
particularly, by reacting EGMA with substances containing amino-,
carboxyl-, and/or hydroxyl groups. In accordance with some of the
embodiments of this invention, EGMA is modified as shown in the
following examples.
EXAMPLE 12
Modifier: PEG-NH.sub.2
[0052] As mentioned above, PEG-NH.sub.2 is chemically active and
its amino group easily reacts with the epoxy group of EGMA. The
path of the reaction is via the S.sub.N2 nucleophilic attack of the
epoxy group of EGMA by the electron-rich nitrogen of the amino
group of PEG-NH.sub.2. As a result, the oxirane ring of EGMA opens
and a hydroxyl group forms. The process is schematically shown by
reaction scheme (VII):
##STR00012##
[0053] Reaction scheme (VII) may then continue and, depending on
the amounts of EGMA and PEG-NH.sub.2, the second proton of the
amino group of the product can attack the second molecule of EGMA
by the same nucleophilic mechanism. As a result, a cross-linked
oligomer may form. The conditions under which reaction (VII) is
conducted can be determined by those having ordinary skill in the
art. Irrespective of whether the reaction stops at a stage shown by
reaction (VII) or continues through the formation of the
cross-linked tri-dimensional oligomeric network, EGMA is firmly
bonded to the biologically compatible PEG-NH.sub.2.
EXAMPLE 13
Modifier: SOD-Mimetic
[0054] SOD-40470 can be used as a modifying agent of EGMA. Due to
the presence of the primary amino ligands, SOD-40470 is chemically
active and readily couples with EGMA. The mechanism of the reaction
is via nucleophilic bonding of the amino group of SOD-40470 to the
oxirane group of EGMA and is similar to the reaction (VII)
discussed above. Alternatively, other SOD-mimetics can be used so
long as they have amino groups. EGMA can be firmly bonded to the
biologically compatible amino ligand-containing SOD-40470 to form a
linear or cross-linked oligomer, depending on the conditions of the
reaction of modification.
EXAMPLE 14
Modifier: Spermine Diazenium Diolate
[0055] SDD can be used as a modifying agent of EGMA. Due to the
presence of the amino groups, SDD is chemically active and readily
couples with EGMA according to the mechanism similar to reaction
scheme (VII). Other diazenium diolate-type NO donors can be used,
so long as they have amino groups, for example, MAHMA-NO or
DETA-NO. The mechanism of coupling of EAA to MAHMA-NO or DETA-NO is
the same as the mechanism of coupling to SDD. The conditions under
which the reaction of binding EGMA to SDD, or the alternative
diazenium diolate-type NO donors, is conducted can be determined by
those having ordinary skill in the art. EGMA can be firmly bonded
to the biologically compatible diazenium diolate-type NO
donors.
EXAMPLE 15
Modifier: Hydroxyl-Terminated Methoxy-PEG
[0056] Hydroxyl-terminated methoxy-PEG is a PEG-based product
having hydroxyl groups. An example of a hydroxyl-terminated
methoxy-PEG suitable as a modifier for EGMA is a monomethyl ether
of PEG, a methoxylated PEG product having a general formula
CH.sub.3O--[CH.sub.2--CH.sub.2--O].sub.p--CH.sub.2--CH.sub.2--OH,
known as a low-diol mPEG. The product is manufactured by Shearwater
Corp., Huntsville, Ala., and, like PEG-ISO or PEG-EPO, has a
molecular weight of about 5,000 which corresponds to "p" being an
integer of about 112. The low-diol mPEG is a strong nucleophilic
agent and bonds with EGMA via a nucleophilic substitution reaction
of its nucleophilic hydroxyl group with the oxirane ring of EGMA.
The mechanism of that reaction is similar to the mechanism
illustrated schematically by reaction (II).
[0057] Naturally, modification of EGMA by the low diol mPEG is
carried out more effectively in the presence of the electron
acceptors, which facilitate the nucleophilic attack of the epoxy
group of EGMA by the proton of the hydroxyl group of the low diol
mPEG. Accordingly, modification of EGMA with the low diol mPEG is
facilitated in the presence of ring-opening catalysts that include
either amines or electrophilic agents which can be, for example,
aprotonic acids such as amine-boron trifluoride products. The use
of any ring-opening catalysts is optional.
[0058] The conditions under which this reaction is conducted can be
determined by those having ordinary skill in the art. As a result,
EGMA is firmly bonded to the biologically compatible low diol mPEG
to form the product similar to the product of reaction (II).
EXAMPLE 16
Modifier: Carboxyl-Terminated Methoxy-PEG
[0059] Carboxyl-terminated methoxy-PEG is a PEG-based product
having carboxyl groups. An example of a carboxyl-terminated
methoxy-PEG suitable as a modifier for EGMA is methoxy-PEG
propionic acid, a methoxylated PEG-based product having a general
formula
CH.sub.3O--[CH.sub.2--CH.sub.2--O].sub.p--CH.sub.2--CH.sub.2COOH,
known as PA-PEG. The product, manufactured by Shearwater Corp.,
Huntsville, Ala., has a molecular weight of about 5,000 which
corresponds to the value of the integer "p" of about 111.
[0060] Like low diol mPEG, PA-PEG is a strong nucleophilic agent
which can react with the epoxy group of EGMA. The mechanism of this
reaction is similar to the mechanism illustrated schematically by
reaction (II), except a proton of carboxyl group carries out the
nucleophilic attack instead of the alcohol proton illustrated by
the reaction (II). EGMA can be firmly bonded to the biologically
compatible PA-PEG to form a product similar to the product of the
reaction (II).
[0061] Modification of the EVAL, tosylated or tresylated EVAL, EAA
and EGMA discussed in Examples 1-16 can be recapitulated as shown
in Table 1.
TABLE-US-00001 TABLE 1 Example The modified polymer The modifying
agent 1 EVAL PEG 2 EVAL PEG-ISO 3 EVAL PEG-EPO 4 EVAL Hyaluronic
acid 5 EVAL PEG or SODm or diazenium diolate + albumin or heparin
or chitosan 6 Tosylated or tresylated EVAL PEG-NH.sub.2 7 Tosylated
or tresylated EVAL SODm 8 Tosylated or tresylated EVAL SDD 9 EAA
PEG-NH.sub.2 10 EAA SODm 11 EAA SDD 12 EGMA PEG-NH.sub.2 13 EGMA
SODm 14 EGMA SDD 15 EGMA Low diol mPEG 16 EGMA PA-PEG
[0062] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *