U.S. patent application number 11/400433 was filed with the patent office on 2006-08-10 for stent with coatings containing self-assembled monolayers.
Invention is credited to Ni Ding.
Application Number | 20060177482 11/400433 |
Document ID | / |
Family ID | 36780222 |
Filed Date | 2006-08-10 |
United States Patent
Application |
20060177482 |
Kind Code |
A1 |
Ding; Ni |
August 10, 2006 |
Stent with coatings containing self-assembled monolayers
Abstract
A medical device with a coating, particularly a drug eluting
stent, is described. The coating includes a self-assembled
monolayer.
Inventors: |
Ding; Ni; (San Jose,
CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA
SUITE 300
SAN FRANCISCO
CA
94111
US
|
Family ID: |
36780222 |
Appl. No.: |
11/400433 |
Filed: |
April 6, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10255911 |
Sep 26, 2002 |
|
|
|
11400433 |
Apr 6, 2006 |
|
|
|
Current U.S.
Class: |
424/426 ;
514/291 |
Current CPC
Class: |
A61L 31/16 20130101;
B82Y 40/00 20130101; Y10T 428/24 20150115; A61L 2300/416 20130101;
A61L 31/10 20130101; B82Y 30/00 20130101; A61K 31/4745
20130101 |
Class at
Publication: |
424/426 ;
514/291 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; A61F 2/00 20060101 A61F002/00 |
Claims
1. An implantable medical device comprising a coating, the coating
including a polymeric layer disposed on at least a portion of an
implantable medical device, and a self-assembled monolayer of
molecules of an organic or elemento-organic substance disposed on
the polymeric layer.
2. The device of claim 1, wherein the device is a stent.
3. The device of claim 1, wherein the self-assembled monolayer is
chemically bonded to the polymeric layer.
4. The device of claim 1, further comprising a therapeutic
substance incorporated in the coating.
5. The device of claim 4, wherein the therapeutic substance is
rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin,
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or
40-O-tetrazole-rapamycin.
6. The device of claim 1, wherein the self-assembled monolayer is
prepared out of a substance having a methylene-based chain or a
silicone-based chain.
7. The device of claim 6, wherein the substance further includes at
least one reactive substitutent.
8. The device of claim 7, wherein the reactive substitutent is
selected from a group consisting of hydroxyl, carboxyl, vinyl,
anhydride, acyl chloride, sulfonyl, isocyanate, epoxy, amino,
thiol, and acrylic.
9. The device of claim 1, further comprising a biocompatible agent
chemically bonded to the self-assembled monolayer.
10. The device of claim 9, wherein the biocompatible agent is
selected from a group consisting of polypeptides, heparin,
hyaluronic acid, and superoxide dismutase mimics.
11. The device of claim 1, wherein the polymer of the polymeric
layer includes at least one reactive substitutent.
12. The device of claim 11, wherein the reactive substitutent is
selected from a group consisting of hydroxyl, amino, aldehyde, and
isocyanate.
Description
CROSS REFERENCE
[0001] This is a divisional application of U.S. Ser. No.
10/255,911, which was filed on Sep. 26, 2002.
BACKGROUND
[0002] 1. Field of the Invention
[0003] This invention is directed to coatings for implantable
medical devices, such as drug eluting vascular stents.
[0004] 2. Description of the State of the Related Art
[0005] Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease. A catheter assembly having a
balloon portion is introduced percutaneously into the
cardiovascular system of a patient via the brachial or femoral
artery. The catheter assembly is advanced through the coronary
vasculature until the balloon portion is positioned across the
occlusive lesion. Once in position across the lesion, the balloon
is inflated to a predetermined size to radially compress against
the atherosclerotic plaque of the lesion to remodel the lumen wall.
The balloon is then deflated to a smaller profile to allow the
catheter to be withdrawn from the patient's vasculature.
[0006] A problem associated with the above procedure includes
formation of intimal flaps or torn arterial linings which can
collapse and occlude the conduit after the balloon is deflated.
Moreover, thrombosis and restenosis of the artery may develop over
several months after the procedure, which may require another
angioplasty procedure or a surgical by-pass operation. To reduce
the partial or total occlusion of the artery by the collapse of
arterial lining and to reduce the chance of the development of
thrombosis and restenosis, a stent is implanted in the lumen to
maintain the vascular patency.
[0007] Stents are used not only as a mechanical intervention but
also as a vehicle for providing biological therapy. As a mechanical
intervention, stents act as scaffoldings, functioning to physically
hold open and, if desired, to expand the wall of the passageway.
Typically, stents are capable of being compressed, so that they can
be inserted through small vessels via catheters, and then expanded
to a larger diameter once they are at the desired location.
Examples in patent literature disclosing stents which have been
applied in PTCA procedures include stents illustrated in U.S. Pat.
No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to
Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor.
[0008] Biological therapy can be achieved by medicating the stents.
Medicated stents provide for the local administration of a
therapeutic substance at the diseased site. In order to provide an
efficacious concentration to the treated site, systemic
administration of such medication often produces adverse or toxic
side effects for the patient. Local delivery is a preferred method
of treatment in that smaller total levels of medication are
administered in comparison to systemic dosages, but are
concentrated at a specific site. Local delivery thus produces fewer
side effects and achieves more favorable results. One proposed
method for medicating stents involves the use of a polymeric
carrier coated onto the surface of a stent. A solution which
includes a solvent, a polymer dissolved in the solvent, and a
therapeutic substance dispersed in the blend is applied to the
stent. The solvent is allowed to evaporate, leaving on the stent
surface a coating of the polymer and the therapeutic substance
impregnated in the polymer.
[0009] To the extent that the mechanical functionality of stents
has been optimized in recent years, it has been determined that
continued improvements could be done by means of pharmacological
therapies. For the purposes of pharmacological therapy, it is
important to maintain the concentration of the drug at a
therapeutically effective level for an acceptable period of time.
Hence, controlling a rate of release of the drug from the stent is
important.
[0010] In view of the foregoing, coatings for reducing the rate of
release a therapeutic substance from implantable devices, such as
stents, are desired. The coatings should prolong the residence time
of the drug in the patient.
SUMMARY
[0011] According to one embodiment of the present invention, an
implantable medical device including a coating is provided, the
coating comprises a polymeric reservoir layer disposed on at least
a portion of the device, and a self-assembled monolayer of
molecules of an organic or elemento-organic substance disposed on
the reservoir layer. The self-assembled monolayer can be chemically
bonded to the reservoir layer. A therapeutic substance, for
example, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin,
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or
40-O-tetrazole-rapamycin can be incorporated into the coating. An
active agent, for example, polypeptide, heparin, hyaluronic acid,
or superoxide dismutase mimics, can be optionally bonded to the
self-assembled monolayer.
[0012] According to another embodiment of the present invention, a
method for coating an implantable medical device is provided, the
method comprises applying a polymeric reservoir layer on at least a
portion of the device, and forming a self-assembled monolayer of
molecules of an organic or elemento-organic substance on the
reservoir layer.
DETAILED DESCRIPTION
[0013] A coating for an implantable medical device, such as a
stent, can include a drug-polymer layer (also referred to as a
"reservoir layer") or a drug layer free from any polymer, a topcoat
layer, and a primer layer. The drug-polymer layer can serve as a
reservoir for a therapeutically active agent or drug which is
incorporated into the drug-polymer layer. The drug-polymer layer or
the drug layer can be applied directly onto the stent surface. The
topcoat layer can be applied over the reservoir layer or the drug
layer. With the use of the drug layer free from any polymer, the
use of a topcoat layer is needed.
[0014] The optional primer layer can be applied between the stent
and the reservoir layer or the drug layer to improve the adhesion
of the reservoir layer or the drug layer to the stent.
[0015] The topcoat layer, which can be essentially free from any
therapeutic substances or drugs, serves as a rate limiting membrane
which further controls the rate of release of the drug. By forcing
the agent to diffuse through an additional coating layer prior to
its release from the stent, the release of the active agent may be
slowed.
[0016] The topcoat layer can be made of a self-assembled monolayer
(SAM). For the purposes of this invention, SAM is defined as a thin
film of an ordered monolayer of molecules of an organic or
elemento-organic substance. The ordered film forms on the substrate
surface when SAM molecules are attached to the substrate. The
thickness of a SAM can be between about 10 and 40 .ANG..
[0017] Examples of suitable SAMs include substances having a
general formula (I) R-A-R' (I) such as substances where A
represents a methylene chain or a silicone-based chain.
[0018] SAM can be prepared by applying substance (I) on a stent
having reservoir layer or a drug layer deposited over at least a
portion of the stent. For the purposes of the present invention,
substance (I) is referred to as a "SAM-forming substance." Any
suitable SAM-fabrication technique known to those having ordinary
skill in the art can be used. For example, a SAM-forming substance
can be dissolved in an appropriate solvent, such as hexane. The
solvent used to dissolve a SAM-forming substance should be
incompatible with the drug and the polymer in the reservoir layer,
so as to avoid extraction of the drug from the reservoir to the
surface, and to avoid dissolving the polymer of the reservoir
layer. The concentration of the SAM-forming substance in the
solution can be typically between 0.01 mass % and 100 mass %. The
stent can then be immersed into the solution, usually for a period
of time which can be between a few minutes and several hours, for
example, between about 1 hour and 72 hours, to allow the
SAM-forming substance enough time to bond to the reservoir
layer.
[0019] According to one embodiment of the present invention,
methylene chain-based SAMs can be used to form the topcoat layer.
For the methylene chain-based SAMs, "A" in formula (I) is the
methylene group --CH.sub.2--. Thus, the methylene chain-based SAM
comprises a methylene chain having functional groups on one end or
both ends of the chain. The structure of a substance forming a SAM
can be represented by a general formula (II)
R--(CH.sub.2).sub.n--R', (II) where the substitutents are the same
(R=R') or different (R.noteq.R'). Methylene chains can typically
include between 10 and 50 carbon atoms (n=10-50). R and/or R' can
usually include hydrogen, methyl, vinyl, anhydride, acyl chloride,
hydroxyl, carboxyl, sulfonyl, acetate, trifluoro acetate, benzoate,
isocyanate, epoxy, amino, thiol, succinimidal derivatives, or
acrylic groups. At least one of R and R' can be a reactive group.
For example, if R is methyl (a non-reactive group), R' will usually
be a reactive group, e.g., hydroxyl, isocyanate or epoxy group.
[0020] SAM can be chemically bonded to the reservoir layer to form
a topcoat layer. One way to bond the SAM is by forming covalent
bonds between the SAM and the reservoir layer using the
functionalities present in the SAM-forming substance and in the
polymer forming the reservoir layer.
[0021] One example of a polymer having functional groups that can
be used for bonding to a SAM is poly(ethylene-co-vinyl alcohol)
having a general formula
--[CH.sub.2--CH.sub.2].sub.p--[CH.sub.2--CH(OH)].sub.q--.
Poly(ethylene-co-vinyl alcohol) is known under the trade name EVAL
and is manufactured by EVAL Company of America of Lisle, Ill., and
can be obtained from Aldrich Chemical Co. of Milwaukee, Wis.
[0022] EVAL is a product of hydrolysis of ethylene-vinyl acetate
copolymers. Those having ordinary skill in the art of polymer
chemistry will understand that EVAL may also be a terpolymer and
may include up to 5% (molar) units derived from styrene, propylene
and other suitable unsaturated monomers. The hydroxyl functionality
of EVAL can be used for chemical bonding to a SAM. Instead of EVAL,
other polymers having hydroxyl groups can be utilized for preparing
the reservoir layer. One example of such polymers is poly(methyl
methacrylate-co-2-hydroxyethyl methacrylate) (PMMA-HEMA) having the
formula ##STR1##
[0023] Other polymers having hydroxyl groups that can be used
include poly(ethyl methacrylate-co-2-hydroxyethyl methacrylate)
(PEMA-HEMA) and poly(butyl methacrylate-co-2-hydroxyethyl
methacrylate) (PBMA-HEMA).
[0024] According to one embodiment, an isocyanate-terminated
SAM-forming substance can be bonded to a polymer forming the
reservoir layer containing hydroxyl groups. In the
isocyanate-terminated SAM-forming substance, at least one of R and
R' in formula (I) is the isocyanate group --N.dbd.C.dbd.O. Due to
the presence of the isocyanate groups, isocyanate-terminated
SAM-forming substance is chemically very active and readily reacts
with EVAL. The isocyanate group, having strong electron accepting
properties, reacts with nucleophilic hydroxyl group of EVAL, as
illustrated by reaction scheme (III): ##STR2##
[0025] The conditions under which reaction (III) is conducted can
be determined by those having ordinary skill in the art. Since the
isocyanate group easily becomes inactive as a result of hydrolysis,
reaction (III) is conducted in water- and moisture-free
environment. If desired, EVAL can be replaced with another
acceptable polymer containing hydroxyl groups. For example,
isocyanate-terminated SAM-forming substance can be bonded to
PMMA-HEMA utilizing hydroxyl groups of the HEMA component of
PMMA-HEMA. As a result, SAM is firmly bonded to EVAL or another
acceptable hydroxyl-containing polymer to form the urethane product
of reaction (III).
[0026] According to another embodiment, an epoxy-terminated
SAM-forming substance can be bonded to a polymer forming the
reservoir layer containing hydroxyl groups. In the epoxy-terminated
SAM-forming substance, at least one of R and R' in formulae (I) or
(II) is the epoxy group ##STR3##
[0027] Epoxy groups in an epoxy-terminated SAM-forming substance
are reactive, and can easily react with EVAL. The epoxy group can
react with nucleophilic hydroxyl group of EVAL, via the
nucleophilic substitution reaction S.sub.N2. The ring opens and the
epoxy-terminated SAM-forming substance is bonded to EVAL according
to reaction scheme (IV): ##STR4##
[0028] Reaction (IV) can be carried out more effectively in the
presence of electron acceptors which 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, bonding of the epoxy-terminated SAM-forming
substance to EVAL can be facilitated in the presence of
electrophilic ring-opening catalysts, for instance, tertiary amines
or aprotonic acids such as amine-boron trifluoride adducts. 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. Again, other hydroxyl-containing
polymers, such as PMMA-HEMA can be used instead of EVAL if
desired.
[0029] According to another embodiment, an anhydride or acyl
chloride group-terminated SAM-forming substance can be bonded to a
polymer forming the reservoir layer containing hydroxyl groups. For
example, in the anhydride-terminated SAM-forming substance, at
least one of R and R' in formulae (I) or (II) is the anhydride
group. Example of suitable anhydride-terminated and acyl
chloride-terminated SAM-forming substances include lauric anhydride
(also known as dodecanoic anhydride) having the formula
[CH.sub.3----(CH.sub.2).sub.10--CO].sub.2O and lauroyl chloride
(also known as dodecanoyl chloride) having the formula
CH.sub.3--(CH.sub.2).sub.10--CO--Cl. Anhydride or acyl chloride
groups can react with hydroxyl groups of the reservoir layer. For
example, in case of lauroyl chloride the reaction can be
illustrated by reaction scheme (V): ##STR5##
[0030] Reaction (V) is a typical reaction of esterification that
can be accelerated by an acidic or basic catalyst, if desired.
[0031] According to yet another embodiment, an amino
group-terminated SAM-forming substance can be bonded to a polymer
forming the reservoir layer containing reactive groups such as
hydroxyl groups or alternatively aldehyde or isocyanate groups. In
the amino-terminated SAM-forming substance, at least one of R and
R' in formulae (I) or (II) is the amino group --NH.sub.2. Examples
of a suitable amino-terminated SAM-forming substances include
C.sub.12-C.sub.17 aliphatic amines, such as, laurylamine
C.sub.12H.sub.24NH.sub.2 available from Aldrich Chemical
Company.
[0032] Amino-terminated SAM-forming substance can be conjugated to
the hydroxyl-containing polymer forming the reservoir layer such as
EVAL or PMMA-HEMA. To conjugate, as a first step EVAL can be
preliminarily derivatized by tosylation (treatment with tosyl
chloride), or alternatively by tresylation (by reacting with tresyl
chloride). Tosyl chloride (TsCl) is a sulfonyl derivative of
toluene, p-toluenesulfonyl chloride, having the formula
CH.sub.3--C.sub.6H.sub.4--SO.sub.2Cl. Tresyl chloride or
2,2,2-trifluoroethanesulphonyl chloride (TrCl) is an aliphatic
derivative of sulfonic acid having the formula
CF.sub.3--CH.sub.2--SO.sub.2Cl.
[0033] The process of EVAL derivatization can be conducted directly
on the stent. In case of tosylation, the following process can be
used. 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 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 (VI) and
tosyl group is attached to the EVAL backbone via hydroxy group to
yield the toluenesulfoester: ##STR6##
[0034] Alternatively, if tresylation is used to derivatrize EVAL,
the process can be illustrated as shown by reaction scheme (VII)
and as a result the tresyl group is attached to the EVAL backbone
via hydroxy group: ##STR7##
[0035] As a second step of conjugating, an amino-terminated
SAM-forming substance is reacted with the derivatized EVAL. 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--, is an excellent leaving group
in the nucleophilic substitution alkylation reaction of a primary
amine, much better than hydroxyl group of underivatized EVAL.
Accordingly, the tosylated EVAL (the product of reaction (VI))
readily reacts with the amino-terminated SAM-forming substance as
schematically shown by the alkylation reaction shown by reaction
scheme (VIII): ##STR8##
[0036] 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 the amino-terminated SAM-forming
substance is similar to reaction (VIII). As a result, the
amino-terminated SAM-forming substance is bonded to EVAL to form
the secondary amine product of reaction (VIII).
[0037] Alternatively, other hydroxyl-containing polymers, such as
PMMA-HEMA can be used instead of EVAL to bond the amino-terminated
SAM-forming substance if desired. Those having ordinary skill in
the art will appreciate that the chemistry of conjugating PMMA-HEMA
or other suitable hydroxyl-containing polymers is similar to the
processes described by reactions (V)-(VIII).
[0038] As another alternative, the alkylation of amines technique
can be used to bond SAM-forming substance to the reservoir layer
made of a polymer containing amino groups such as a poly(amino
acid). In this case, the functions of the components are
reversed--the SAM-forming substance provides the hydroxyl
functionality and the reservoir polymer provides the amino
functionality. The SAM-forming substance can be a
hydroxyl-terminated compound, such as a long-chained aliphatic
alcohol or diol. The chemistry of bonding the hydroxyl-terminated
SAM-forming substance to an amino group-containing polymer of the
reservoir layer is similar to the processes described by reactions
(V)-(VIII).
[0039] Instead of the hydroxyl-terminated SAM-forming substance, a
carboxyl-terminated SAM-forming substance can be used, for example
a carbonic acid. In such a case, the carboxyl-terminated
SAM-forming substance can be conjugated to the amino
group-containing polymer of the reservoir layer to form an amide,
under conditions to be determined by those having ordinary skill in
the art.
[0040] If desired, the SAM-forming substance can be additionally
modified. To modify, a biologically active reactive agent can be
bonded to one terminus of the SAM-forming substance, while the
functional group pendant on the other terminus can be used for
bonding the SAM-forming substance to the polymer of the reservoir
layer. Examples of biologically active reactive agents that can be
bonded to the SAM-forming substance include polypeptides, heparin,
hyaluronic acid, and oxidoreductases containing seven-coordinate
complexes of manganese, also known as superoxide dismutase mimics
(SODm).
[0041] Examples of suitable polypeptides include polymers and/or
oligomers of L-arginine. L-arginine, also known as
2-amino-5-guanidinovaleric acid, is an amino acid having a formula
NH.dbd.C(NH.sub.2--NH--CH.sub.2--CH.sub.2--CH.sub.2--CH(NH.sub.2)--COOH.
Polymers and/or oligomers of L-arginine that can be used comprise a
plurality of repeating monomeric amino acid units connected with
peptide bonds, with a general formula H[NH--CHX--CO].sub.p--OH,
where "p" can be within a range of 5 and 1,000, typically, within a
range of between 6 and 20, and X is 1-guanidinopropyl radical
having the chemical structure
--CH.sub.2--CH.sub.2--CH.sub.2--NH--C(NH.sub.2).dbd.NH. For
example, a heptamer (designated R7), having p=7, can be used.
[0042] One example of bonding of a biologically active reactive
agent is by using R7 and an amino group-terminated SAM-forming
substance, for example a diamine having the formula
NH.sub.2--(CH.sub.2).sub.n--NH.sub.2. Grafting R7 to the amino
group-terminated SAM-forming substance can be accomplished
according to the following procedure. First, the non-protonated,
non-terminal primary amino groups of R7 are protected by reaction
with 9-fluorenylmethyl chloroformate in aqueous dioxane as shown by
reaction scheme (IX). 9-fluorenylmethyl chloroformate also known as
9-fluorenylmethyloxycarbonylchloride or FMOC-chloride, has the
formula ##STR9## and is designated below as Q-O--C(O)--Cl.
##STR10## where Q is 9-fluoreneylmethyl group. Alternatively, the
amino groups of R7 can be protected using tert-BOC (di-tert-butyl
dicarbonate) instead of FMOC-chloride.
[0043] Next, the protected R7 is reacted with an amino
group-terminated SAM-forming substance to form amide derivatives.
One example of a possible path of such reaction can be illustrated
by reaction scheme (X), which can be carried in the presence of the
equimolar or greater amount 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. of Rockford, Ill.
##STR11##
[0044] Finally, the product of reaction (X) can be cleaved by 50%
morpholine or other appropriate amine. As a result, the
9-fluoreneylmethyl group is removed and R7 is tethered to the
SAM-forming substance by the amide bond, as shown by the formula
(XI): ##STR12##
[0045] Alternatively, the protected R7 can be conjugated to the
SAM-forming substance by the reaction of direct esterification,
which can be carried in the presence of
1,3-dicyclohexylcarbodiimide or dimethylamino pyridine. Regardless
of which method of conjugation is selected, the final product (XI)
is the same. The reactions described above are conducted under the
standard conditions known to those having ordinary skill in the
art.
[0046] The SAM-forming substance having R7 conjugated to it can
then be bonded to the hydroxyl-containing polymer forming the
reservoir layer according to the procedure described by reactions
(V)-(VIII). As a result, the stent coating includes the SAM bonded
to the polymer of the reservoir layer and R7 bonded to the SAM.
Those having ordinary skill in the art will incorporate heparin,
hyaluronic acid and other biologically active reactive agents into
the stent coating using similar procedures, taking into account
their chemical structures and choosing an appropriate synthesis
accordingly.
[0047] The above-described embodiments discuss reservoir layers
made of polymers that include a reactive group, such as hydroxyl,
amino, or isocyanate group. Polymers not having the reactive groups
can be pre-treated to generate the reactive groups so as to enable
the bonding of the SAM-forming substance to the polymer of the
reservoir layer.
[0048] For example, hydroxyl groups can be generated on the surface
of a reservoir layer not originally containing hydroxyl groups by
partially oxidizing the polymer forming the reservoir layer. The
partial oxidation can be accomplished using low energy surface
treatments known to those having ordinary skill in the art. The
examples of such treatments include oxidative gas plasma treatment,
corona discharge and electron beam treatment, oxidative gas
treatments using, for example, ozone or a mixture of fluorine and
oxygen, and chemical etching treatments using, for example, nitric
acid or chromic acid.
[0049] In another embodiment, amino groups can be introduced on the
surface of a reservoir layer not originally containing amino
groups. For example, the surface of the reservoir polymer can be
treated with ammonium and hydrogen gas plasma to generate amino
groups. Alternatively, the surface of the reservoir polymer can be
treated by oxygen plasma to generate aldehyde or ketone groups on
the surface. The aldehyde or ketone groups can react directly with
an amine-terminated SAM-forming substance to form a Schiff base,
which can be optionally reduced to a secondary amine. Another
alternative can be to react the aldehyde or ketone groups with
hydroxylamine H.sub.2NOH followed by reduction to yield amino
groups on the surface of the reservoir polymer.
[0050] The polymers not having reactive groups can be also used to
make the reservoir layer. For instance, the SAM can be incorporated
into the stent coating using UV-radiation curing techniques, for
example by using the acrylate- or vinyl-terminated SAM-forming
substance, described by formulae (I) or (II), where at least one of
R and R' in formula (I) is the acrylic group or the vinyl group.
Examples of suitable acrylate-terminated SAM-forming substances
include lauryl acrylate (also known as dodecyl acrylate) having the
formula CH.sub.2.dbd.CH--COO--(CH.sub.2).sub.11--CH.sub.3 and
lauryl methacrylate (also known as dodecyl methacrylate) having the
formula CH.sub.2.dbd.C(CH.sub.3)--COO--(CH.sub.2).sub.11--CH.sub.3.
One example of a suitable vinyl-terminated SAM-forming substance is
vinyl decanoate having the formula
CH.sub.3--(CH.sub.2).sub.8--COO--CH.dbd.CH.sub.2.
[0051] The acrylate- or vinyl-terminated SAM-forming substance can
be polymerized on the surface of the reservoir layer, for example,
by UV-polymerization in the presence of a suitable photoinitiator
such as benzophenone. The reservoir layer in this embodiment need
not have functional groups as long as it has extractable hydrogen.
The conditions under which the reaction of UV-polymerization is
conducted can be determined by those having ordinary skill in the
art.
[0052] The polymer of the reservoir layer can be any polymer
otherwise suitable for making coatings for implantable medical
devices such as stents. In addition to EVAL, PMMA-HEMA, PEMA-HEMA,
PBMA-HEMA and poly(amino acids) discussed above, representative
examples of polymers that can be used to fabricate the reservoir
layer include poly(hydroxyvalerate), poly(L-lactic acid),
polycaprolactone, poly(lactide-co-glycolide),
poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),
polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid),
poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene
carbonate), polyphosphoester, polyphosphoester urethane,
cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),
co-poly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates,
polyphosphazenes, biomolecules (such as fibrin, fibrinogen,
cellulose, starch, collagen and hyaluronic acid), polyurethanes
(such as BIONATE available from Polymer Technology Group of
Berkeley, Calif., or ELASTEON available from AorTech Biomaterials
Co. of Chatswood, Australia), silicones, polyesters, polyolefins,
polyisobutylene and ethylene-alphaolefin copolymers, acrylic
polymers and copolymers (such as poly(butyl methacrylate),
poly(ethyl methacrylate) or poly(hydroxyethyl methacrylate)), vinyl
halide polymers and copolymers (such as polyvinyl chloride),
polyvinyl ethers other than polyacetals, polyvinylidene halides
(such as polyvinylidene fluoride and polyvinylidene chloride),
polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as
polystyrene), polyvinyl esters (such as polyvinyl acetate,
acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl
acetate copolymers), polyamides (such as Nylon 66 and
polycaprolactam), alkyd resins, polycarbonates, polyoxymethylenes,
polyimides, polyethers, epoxy resins, polyurethanes, rayon,
rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate,
cellulose acetate butyrate, cellophane, cellulose nitrate,
cellulose propionate, cellulose ethers, and carboxymethyl
cellulose. The selected polymer can have reactive groups. The
presence of the reactive groups is however optional.
[0053] The drug-containing reservoir layer can be formed on the
stent in any suitable manner. For example, a coating composition
including a solvent, a polymer, and the drug can be applied to the
stent by immersing the stent in the coating composition or by
spraying the coating composition onto the stent. Following
evaporation of the solvent, a reservoir layer of the polymer and
the drug incorporated in the polymer is formed on the stent.
[0054] Alternatively, a polymeric reservoir layer, free from drugs,
can be formed on the stent by any suitable method. The drug can
then be introduced into the reservoir layer, for example, by
placing the coated stent into a reaction flask containing the drug,
allowing the agent to diffuse across the concentration gradient
into the reservoir layer, and drying the stent to form a
drug-containing reservoir layer on the stent.
[0055] The drug can include any substance capable of exerting a
therapeutic or prophylactic effect for a patient. The drug may
include small molecule drugs, peptides, proteins, oligonucleotides,
and the like. The drug could be designed, for example, to inhibit
the activity of vascular smooth muscle cells. It can be directed at
inhibiting abnormal or inappropriate migration and/or proliferation
of smooth muscle cells to inhibit restenosis.
[0056] Examples of drugs include antiproliferative substances such
as actinomycin D, or derivatives and analogs thereof (manufactured
by Sigma-Aldrich of Milwaukee, Wis., or COSMEGEN available from
Merck). Synonyms of actinomycin D include dactinomycin, actinomycin
IV, actinomycin I.sub.1, actinomycin X.sub.1, and actinomycin
C.sub.1. The active agent 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 (e.g. TAXOL.RTM. by Bristol-Myers
Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere.RTM., from
Aventis S. A., Frankfurt, Germany) 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).
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 antithromb in),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist antibody, recombinant hirudin, and thrombin inhibitors
such as Angiomax.TM. (Biogen, Inc., Cambridge, Mass.). Examples of
such cytostatic or antiproliferative agents 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.); 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), 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, tacrolimus, dexamethasone, and
rapamycin and structural derivatives or functional analogs thereof,
such as 40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of
EVEROLIMUS available from Novartis),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin.
[0057] The coating of the present invention has been described in
conjunction with a stent. However, the coating can also be used
with a variety of other medical devices. Examples of the
implantable medical device that can be used in conjunction with the
embodiments of this invention include stent-grafts, grafts (e.g.,
aortic grafts), artificial heart valves, cerebrospinal fluid
shunts, pacemaker electrodes, 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. 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.
EXAMPLES
[0058] Some embodiments of the present invention are further
illustrated by the following example.
Example 1
[0059] A first composition can be prepared by mixing the following
components:
[0060] (a) about 0.4 g of PBMA-HEMA, having a number average
molecular weight of about 207,000 and a weight average molecular
weight of about 378,000, with the molar ratio between the
butylmethacrylate-derived units and the hydrbxyethyl
methacrylate-derived units of about 3:1;
[0061] (b) about 11.568 g of acetone;
[0062] (c) about 7.712 g of xylene; and
[0063] (d) about 0.32 g of EVEROLIMUS.
[0064] The first composition can be applied onto the surface of a
13 mm TETRA stent (available from Guidant Corp.) by spraying and
dried to form a drug-polymer layer. A spray coater having an EFD
7803 spray valve with 0.014 inch fan nozzle with a VALVEMATE 7040
control system, manufactured by EFD, Inc. of East Providence, R.I.
can be used. The feed pressure can be about 0.2 atm (about 3 psi)
and an atomization pressure can be about 1.35 atm (about 20 psi).
The drug-polymer layer can be baked at about 80.degree. C. for
about one hour.
[0065] The drug-polymer layer-coated stent can be immersed into
about 1 g of lauroyl chloride for about 1 hour, maintaining the
temperature at about 50.degree. C., under a nitrogen blanket to
avoid moisture. The stent can then be removed, rinsed in
cyclohexane to wash off the excess of lauroyl chloride, and dries
at room temperature.
[0066] 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.
* * * * *