U.S. patent application number 10/304360 was filed with the patent office on 2003-04-17 for methods of forming a coating for a prosthesis.
Invention is credited to Guruwaiya, Judy, Harish, Sameer, Hossainy, Syed Faiyaz Ahmed, Pacetti, Stephen, Sanders Millare, Deborra, Wu, Steven.
Application Number | 20030072868 10/304360 |
Document ID | / |
Family ID | 25023075 |
Filed Date | 2003-04-17 |
United States Patent
Application |
20030072868 |
Kind Code |
A1 |
Harish, Sameer ; et
al. |
April 17, 2003 |
Methods of forming a coating for a prosthesis
Abstract
Methods of forming a coating onto an implantable device or
endoluminal prosthesis, such as a stent, are provided. The coating
may be used for the delivery of an active ingredient. The coating
may have a selected pattern of interstices for allowing a fluid to
seep through the coating in the direction of the pattern
created.
Inventors: |
Harish, Sameer; (Fremont,
CA) ; Wu, Steven; (Santa Clara, CA) ; Sanders
Millare, Deborra; (San Jose, CA) ; Guruwaiya,
Judy; (San Jose, CA) ; Pacetti, Stephen; (San
Jose, CA) ; Hossainy, Syed Faiyaz Ahmed; (Fremont,
CA) |
Correspondence
Address: |
Paul J. Meyer, Jr.
Squire, Sanders & Dempsey L.L.P.
Suite 300
One Maritime Plaza
San Francisco
CA
94111
US
|
Family ID: |
25023075 |
Appl. No.: |
10/304360 |
Filed: |
November 25, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10304360 |
Nov 25, 2002 |
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09751691 |
Dec 28, 2000 |
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6503556 |
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Current U.S.
Class: |
427/2.24 |
Current CPC
Class: |
A61L 31/10 20130101;
A61L 31/16 20130101; A61L 2300/606 20130101; A61L 2300/602
20130101; A61L 2300/416 20130101 |
Class at
Publication: |
427/2.24 |
International
Class: |
A61L 002/00 |
Claims
What is claimed is:
1. A method of forming a coating for a prosthesis, comprising:
depositing a polymeric sheath over at least a portion of a
prosthesis, said prosthesis having a plurality of interconnected
struts separated by gaps and a longitudinally extending central
bore for allowing a fluid to travel through said prosthesis; and
exposing said polymeric sheath to a temperature not greater than
about the melting temperature of the polymer to form a coating for
said prosthesis.
2. A coated stent produced in accordance with the method of claim
1.
3. The method of claim 1, wherein said coating covers said gaps
underlying said sheath.
4. The method of claim 1, wherein said method further comprises:
removing a portion of said coating positioned over some of said
gaps to form a pattern of interstices dispersed between said struts
for allowing a fluid that flows through said central bore to seep
through said coating.
5. The method of claim 4, wherein said removing is performed by
applying a laser discharge to said portion of said coating to form
a preselected pattern of interstices.
6. The method of claim 1, wherein said temperature is above the
glass transition temperature for the polymer.
7. The method of claim 1, wherein said coating is made from an
ethylene vinyl alcohol copolymer.
8. The method of claim 1, wherein said coating is impregnated with
an active ingredient for the sustained release of said active
ingredient when said prosthesis is implanted in a biological
passageway, and wherein said active ingredient is selected from a
group of antiproliferative, antineoplastic, antiinflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,
antibiotic, antioxidant substances and combinations thereof.
9. The method of claim 8, wherein said method further comprises:
forming a rate limiting membrane over said coating.
10. The method of claim 1, wherein said coating contains
actinomycin D, docetaxel, or paclitaxel.
11. The method of claim 1, wherein said coating contains a material
selected from a group of radioactive isotopes and radiopaque
elements.
12. The method of claim 1, wherein said method further comprises:
forming a second coating onto said coating on said prosthesis,
wherein said second coating is impregnated with an active
ingredient for the sustained release of said active ingredient when
said prosthesis is implanted in a biological passageway.
13. A method for increasing an amount of a polymeric coating on a
stent having struts separated by gaps, without increasing the
thickness of the coating, comprising the acts of: inserting a stent
having a plurality of interconnected struts separated by gaps into
a polymeric sheath; and exposing said polymeric sheath to a
temperature not greater than about the melting temperature of the
polymer to form a coating for said stent, wherein said coating
covers said struts and said gaps between said struts so as to
increase the quantity of said polymeric coating supported by said
stent without increasing the thickness of said coating on said
stent.
14. The method of claim 13, further comprising: removing a portion
of said coating deposited over at least one of said gaps to create
an opening in said coating, wherein the size of said opening is
smaller than the size of said gap, and wherein said opening allows
a fluid to travel through said coating from within said stent.
15. The method of claim 14, wherein said act of removing comprises:
applying a laser discharge to a portion of said coating deposited
over at least one of said gaps to create said opening in said
coating.
16. The method of claim 13, wherein said polymeric coating
comprises an active ingredient to inhibit restenosis.
17. The method of claim 13, wherein said temperature is not less
than about the glass transition temperature of the polymer.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to implantable devices or endoluminal
prostheses, such as stents, and methods of coating such
devices.
[0003] 2. Description of the Background
[0004] 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 press against the
atherosclerotic plaque of the lesion for remodeling of the vessel
wall. The balloon is then deflated to a smaller profile to allow
the catheter to be withdrawn from the patient's vasculature.
[0005] 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.
Vasospasms and recoil of the vessel wall also threaten vessel
closure. Moreover, thrombosis and restenosis of the artery may
develop over several months after the procedure, which may
necessitate 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, an expandable,
intraluminal prosthesis, one example of which is a stent, is
implanted in the lumen to maintain the vascular patency.
[0006] 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 cavities via catheters, and then expanded
to a larger diameter once they are at the desired location.
Examples in the patent literature disclosing stents that have been
applied in PTCA procedures include 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. Mechanical intervention via
stents has reduced the rate of restenosis as compared to balloon
angioplasty. Yet, restenosis is still a significant clinical
problem with rates ranging from 20-40%. When restenosis does occur
in the stented segment, its treatment can be challenging, as
clinical options are more limited as compared to lesions that were
treated solely with a balloon.
[0007] Stents are used not only for mechanical intervention but
also as vehicles for providing biological therapy. 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 even 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.
[0008] One method of medicating a stent involves the use of a
polymeric carrier coated onto the surface of the stent. A
composition including a solvent, a polymer dissolved in the
solvent, and a therapeutic substance dispersed in the blend is
applied to the stent by immersing the stent in the composition or
by spraying the composition onto the stent. The solvent is allowed
to evaporate, leaving on the stent strut surfaces a coating of the
polymer and the therapeutic substance impregnated in the
polymer.
[0009] Depending on the physiological mechanism targeted, the
therapeutic substance may be required to be released at an
efficacious concentration for an extended duration of time.
Increasing the quantity of the therapeutic substance in the
polymeric coating can lead to poor coating mechanical properties,
inadequate coating adhesion, and overly rapid rate of release.
Increasing the quantity of the polymeric compound by producing a
thicker coating can perturb the geometrical and mechanical
functionality of the stent, as well as limit the procedure for
which the stent can be used.
[0010] It is desirable to increase the residence time of a
substance at the site of implantation, at a therapeutically useful
concentration, without the application of a thicker coating. It is
also desirable to be able to increase the quantity of the
therapeutic substance carried by the polymeric layer without
perturbing the mechanical properties of the coating, such as
adhesion of the polymer to the stent substrate.
SUMMARY OF THE INVENTION
[0011] The present invention provides a method of forming a coating
for a prosthesis, e.g., a stent. The method includes depositing a
polymeric sheath over at least a portion of a prosthesis. The
prosthesis has a plurality of interconnected struts separated by
gaps and a longitudinally extending central bore for allowing a
fluid to travel through the prosthesis. The method further includes
exposing the polymeric sheath to a temperature not greater than
about the melting temperature of the polymer to form a coating for
the prosthesis. The method can further include removing a portion
of the coating positioned over some of the gaps to form a pattern
of interstices dispersed between the struts for allowing a fluid
that flows through the central bore to seep through the
coating.
[0012] In one embodiment, the coating contains an active
ingredient. In other embodiments, the coating contains radiopaque
elements or radioactive isotopes.
[0013] Also provided is a method for increasing an amount of a
polymeric coating on a stent having struts separated by gaps,
without increasing the thickness of the coating. The method
includes inserting a stent having a plurality of interconnected
struts separated by gaps into a polymeric sheath. The method
further includes exposing the polymeric sheath to a temperature not
greater than about the melting temperature of the polymer to form a
coating for the stent. The coating covers the struts and the gaps
between the struts so as to increase the quantity of the coating
supported by the stent without increasing the thickness of the
coating on the stent. The method can also include removing a
portion of the coating deposited over at least one of the gaps to
create an opening in the coating. The size of the opening is
smaller than the size of the gap. The opening allows a fluid, such
as blood, to travel through the coating from within the stent.
BRIEF DESCRIPTION OF THE FIGURES
[0014] FIG. 1 illustrates a side view of an implantable device;
[0015] FIG. 2 illustrates a side view of a sheath;
[0016] FIG. 3 illustrates the implantable device of FIG. 1 after
the sheath of FIG. 2 has been deposited thereon;
[0017] FIG. 4 illustrates the implantable device of FIG. 3
following a heat treatment to form a coating thereon;
[0018] FIG. 5A illustrates the implantable device of FIG. 4 after a
pattern of interstices has been created within the coating;
[0019] FIG. 5B illustrates an enlarged view of region 5B of the
implantable device in FIG. 5A; and
[0020] FIG. 6 illustrates exemplary paths of blood flow through
interstices within the implantable device of FIG. 5A as employed in
a blood vessel.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0021] Some of the various embodiments of the present invention are
illustrated by FIGS. 1-6. The Figures have not been drawn to scale,
and the size of the various regions have been over or under
emphasized for illustrative purposes.
Examples of the Prosthesis
[0022] The device or prosthesis used in conjunction with the
compositions described below may be any suitable device used for
the release of an active ingredient or for the incorporation of
radiopaque or radioactive materials, examples of which include
self-expandable stents, balloon-expandable stents, grafts, and
stent-grafts. Referring to FIG. 1, a body of a stent 10 is formed
from a plurality of struts 12. Struts 12 are separated by gaps 14
and may be interconnected by connecting elements 16. Struts 12 can
be connected in any suitable configuration and pattern. Stent 10 is
illustrated having an outer surface (tissue-contacting surface) and
an inner surface. A hollow, central bore 18 extends longitudinally
from a first end 20 to a second end 22 of stent 10.
[0023] Stent 10 can be made of a metallic material or an alloy such
as, but not limited to, stainless steel (316L), "MP35N," "MP20N,"
ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,
platinum-iridium alloy, gold, magnesium, or combinations thereof.
"MP35N" and "MP20N" are trade names for alloys of cobalt, nickel,
chromium and molybdenum available from standard Press Steel Co.,
Jenkintown, Pa. "MP35N" consists of 35% cobalt, 35% nickel, 20%
chromium, and 10% molybdenum. "MP20N" consists of 50% cobalt, 20%
nickel, 20% chromium, and 10% molybdenum. Stent 10 made from
bioabsorbable or biostable polymers could also be used with the
embodiments of the present invention. A polymeric device should be
compatible with the selected compositions described below.
Composition for Forming a Sheath
[0024] The embodiments of the composition for forming a sheath are
prepared by conventional methods wherein all components are
combined, then blended. More particularly, in accordance with one
embodiment, a predetermined amount of a polymeric compound is added
to a predetermined amount of a mutually compatible solvent. The
polymeric compound can be added to the solvent at ambient pressure
and, if applicable, under anhydrous atmosphere. If necessary,
gentle heating and stirring and/or mixing can be employed to effect
dissolution of the polymer into the solvent, for example 12 hours
in a water bath at about 60.degree. C.
[0025] "Polymer," "poly," and "polymeric" are defined as compounds
that are the product of a polymerization reaction and are inclusive
of homopolymers, copolymers, terpolymers etc., including random,
alternating, block, and graft variations thereof. Particular care
should be taken to ensure that the polymer employed in the
composition will not be adversely affected by the heat treatment
applied to the sheath formed from the composition as described
below. The polymer chosen should be a polymer that is
biocompatible. The polymer may be bioabsorbable or biostable.
Bioabsorbable polymers that may be used 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, poly(amino acids), cyanoacrylates,
poly(trimethylene carbonate), poly(iminocarbonate),
copoly(ether-esters) (e.g., PEO/PLA), polyalkylene oxalates,
polyphosphazenes and biomolecules such as fibrin, fibrinogen,
cellulose, starch, collagen and hyaluronic acid. In addition,
biostable polymers with a relatively low chronic tissue response
such as polyurethanes, silicones, and polyesters may be used. Other
polymers may also be used if they can be dissolved and cured or
polymerized on stent 10 such as polyolefins, polyisobutylene and
ethylene-alphaolefin copolymers; acrylic polymers and copolymers;
vinyl halide polymers and copolymers, such as polyvinyl chloride;
polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene
halides, such as polyvinylidene fluoride and polyvinylidene
chloride; polyacrylonitrile; polyvinyl ketones; polyvinyl
aromatics, such as polystyrene; polyvinyl esters, such as polyvinyl
acetate; copolymers of vinyl monomers with each other and olefins,
such as ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl
acetate copolymers; polyamides, such as Nylon 66 and
polycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes;
polyimides; polyethers; epoxy resins; polyurethanes; rayon;
rayon-triacetate; cellulose; cellulose acetate; cellulose butyrate;
cellulose acetate butyrate; cellophane; cellulose nitrate;
cellulose propionate; cellulose ethers; and carboxymethyl
cellulose.
[0026] Ethylene vinyl alcohol is functionally a very suitable
choice of polymer. The copolymer adheres well to metal surfaces,
such as stainless steel, and has illustrated the ability to expand
with a stent without any significant detachment of the copolymer
from the surface of the stent. Ethylene vinyl alcohol copolymer,
commonly known by the generic name EVOH or by the trade name EVAL,
refers to copolymers comprising residues of both ethylene and vinyl
alcohol monomers. One of ordinary skill in the art understands that
ethylene vinyl alcohol copolymer may also be a terpolymer so as to
include small amounts of additional monomers, for example less than
about five (5) mole percentage of styrenes, propylene, or other
suitable monomers. In a useful embodiment, the copolymer comprises
a mole percentage of ethylene of from about 27% to about 47%.
Typically, 44 mole percent ethylene is suitable. Ethylene vinyl
alcohol copolymers are available commercially from companies such
as Aldrich Chemical Company, Milwaukee, Wis., or EVAL Company of
America, Lisle, Ill., or can be prepared by conventional
polymerization procedures that are well known to one of ordinary
skill in the art.
[0027] The solvent should be capable of placing the polymer into
solution at the concentration desired in the composition. Examples
of solvents include, but are not limited to, dimethylsulfoxide
(DMSO), chloroform, acetone, water (buffered saline), xylene,
acetone, methanol, ethanol, 1-propanol, tetrahydrofuran,
1-butanone, dimethylformamide, dimethylacetamide, cyclohexanone,
and N-methyl pyrrolidinone. With the use of low ethylene content,
e.g., 29 mol %, ethylene vinyl alcohol copolymer, a suitable
solvent is iso-propylalcohol (IPA) admixed with water (e.g.,
1:1).
[0028] By way of example, the polymer can comprise from about 15%
to about 34%, more narrowly from about 20% to about 25% by weight
of the total weight of the composition, and the solvent can
comprise from about 66% to about 85%, more narrowly from about 75%
to about 80% by weight of the total weight of the composition.
[0029] In another embodiment, sufficient amounts of an active
ingredient are dispersed in the blended composition of the polymer
and the solvent. The active ingredient may be in true solution or
saturated in the blended composition. If the active ingredient is
not completely soluble in the composition, operations including
mixing, stirring, and/or agitation can be employed to effect
homogeneity of the residues. The active ingredient may be added so
that the dispersion is in fine particles. The mixing of the active
ingredient can be conducted at ambient pressure, at room
temperature, and if applicable in an anhydrous atmosphere, such
that supersaturating the active ingredient is not desired.
[0030] As with the selection of the polymer, particular care should
be taken to ensure that the active ingredient employed in the
composition will not be adversely affected by the heat treatment
applied to the sheath formed from the composition as described
below. Otherwise, the active ingredient may be any substance
capable of exerting a therapeutic or prophylactic effect in the
practice of the present invention. Examples of such active
ingredients include antiproliferative, antineoplastic,
antiinflammatory, antiplatelet, anticoagulant, antifibrin,
antithrombin, antimitotic, antibiotic, and antioxidant substances
as well as combinations thereof.
[0031] A suitable example of an antiproliferative substance is
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. Examples of
suitable antineoplastics include paclitaxel and docetaxel. Examples
of suitable antiplatelets, anticoagulants, antifibrins, and
antithrombins include sodium heparin, low molecular weight heparin,
hirudin, argatroban, forskolin, vapiprost, prostacyclin and
prostacyclin analogs, dextran, D-phe-pro-arg-chloromethy- lketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist, recombinant hirudin,
thrombin inhibitor (available from Biogen), and 7E-3B.RTM. (an
antiplatelet drug from Centocore). Examples of suitable antimitotic
agents include methotrexate, azathioprine, vincristine,
vinblastine, fluorouracil, adriamycin, and mutamycin. Examples of
suitable cytostatic or antiproliferative agents include angiopeptin
(a somatostatin analog from Ibsen), angiotensin converting enzyme
inhibitors such as CAPTOPRIL (available from Squibb), CILAZAPRIL
(available from Hoffman-LaRoche), or LISINOPRIL (available from
Merck); calcium channel blockers (such as Nifedipine), colchicine,
fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty
acid), histamine antagonist, LOVASTATIN (an inhibitor of HMG-CoA
reductase, a cholesterol lowering drug from Merck), monoclonal
antibodies (such as PDGF receptors), nitroprusside,
phosphodiesterase inhibitors, prostaglandin inhibitor (available
form Glazo), Seramin (a PDGF antagonist), serotonin blockers,
steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF
antagonist), and nitric oxide. Other therapeutic substances or
agents which may be appropriate include alpha-interferon,
genetically engineered epithelial cells, and dexamethasone.
Exposure of the composition to the active ingredient is not
permitted to adversely alter the active ingredient's composition or
characteristic. Accordingly, the particular active ingredient is
selected for mutual compatibility with the blended polymer-solvent
composition.
[0032] The dosage or concentration of the active ingredient
required to produce a favorable therapeutic effect should be less
than the level at which the active ingredient produces toxic
effects and greater than the level at which non-therapeutic results
are obtained. The dosage or concentration of the active ingredient
required can depend upon factors such as the particular
circumstances of the patient; the nature of the trauma; the nature
of the therapy desired; the time over which the ingredient
administered resides at the treatment site; and if other bioactive
substances are employed, the nature and type of the substance or
combination of substances. Therapeutic effective dosages can be
determined empirically, for example by infusing vessels from
suitable animal model systems and using immunohistochemical,
fluorescent or electron microscopy methods to detect the agent and
its effects, or by conducting suitable in vitro studies. Standard
pharmacological test procedures to determine dosages are understood
by one of ordinary skill in the art.
[0033] By way of example, the polymer can comprise from about 14%
to about 33%, more narrowly from about 20% to about 25% by weight
of the total weight of the composition, the solvent can comprise
from about 33% to about 85%, more narrowly from about 50% to about
70% by weight of the total weight of the composition, and the
active ingredient can comprise from about 1% to about 50%, more
narrowly from about 10% to about 25% by weight of the total weight
of the composition. More than 40% by weight of the active
ingredient could adversely affect characteristics that are
desirable in the polymeric coating, such as controlled release of
the active ingredient. Selection of a specific weight ratio of the
polymer and solvent is dependent on factors such as, but not
limited to, the material from which the device is made, the
geometrical structure of the device, and the type and amount of the
active ingredient employed. The particular weight percentage of the
active ingredient mixed within the composition depends on factors
such as duration of the release, cumulative amount of release, and
release rate that is desired.
[0034] In accordance with another embodiment, the polymeric
composition includes radiopaque elements or radioactive isotopes.
Examples of radiopaque elements include, but are not limited to,
gold, tantalum, and platinum. An exemplary radioactive isotope is
P.sup.32. Sufficient amounts of radiopaque elements or radioactive
isotopes may be dispersed in the composition. By dispersed it is
meant that the substances are not present in the composition as
agglomerates or flocs. In some compositions, certain substances
will disperse with ordinary mixing. Otherwise, the substances can
be dispersed in the composition by high shear processes such as
ball mill, disc mill, sand mill, attritor, rotor stator mixer, or
ultrasonication--all such high shear dispersion techniques being
well known to one of ordinary skill in the art. Biocompatible
dispersing agents in the form of surfactants, emulsifiers, or
stablilizers may also be added to the composition to assist in
dispersion.
Forming a Sheath from the Composition
[0035] Referring now to FIG. 2, a sheath 24 is formed from the
embodiments of the above-described composition, which may contain
an active ingredient. The inner diameter of sheath 24 should be
slightly larger than the outer diameter of stent 10 to allow sheath
24 to be fitted over stent 10 as described below. Sheath 24 can
have any suitable thickness so long as the thickness does not
compromise properties that are critical for achieving optimum
performance. Such properties include low susceptibility to defects
or tearing, the ability to be deposited on stent 10, good
flexibility, and the ability to allow stent 10 to expand for
engagement against the vessel wall. By way of example and not
limitation, the thickness can be in the range of about 0.001 inch
to about 0.002 inch, or about 25.4 microns to about 50.8
microns.
[0036] Sheath 24 may be formed using any suitable method known to
one of ordinary skill in the art. By example, and not limitation,
sheath 24 may be extruded in the form of a generally tubular
structure using conventional extrusion techniques, which are well
known to those of ordinary skill in the art. Alternatively, a flat
sheet of uniform thickness may be formed from the composition
using, for example, a casting blade, then rolled into a generally
tubular structure, and sealed at its ends to form sheath 24.
Formation of a Coating for a Stent
[0037] Referring to FIG. 3, sheath 24 is fitted over stent 10 and
exposed to a heat treatment. Heat may be applied to stent 10 via a
convection oven, a heat gun, or by any other suitable heat
source.
[0038] With the use of the above-described thermoplastic polymers
such as ethylene vinyl alcohol copolymer, polycaprolactone,
poly(lactide-co-glycolide), and poly(hydroxybutyrate), sheath 24
should be exposed to a heat treatment at a temperature range
greater than about the glass transition temperature (T.sub.g) and
less than about the melting temperature (T.sub.m) of the selected
polymer. Unexpected results have been discovered with treatment of
the composition under this temperature range, specifically strong
adhesion or bonding of the polymeric coating to the metallic
surface of a stent. Stent 10 should be exposed to the heat
treatment for any suitable duration of time that will allow for the
polymer to take on a somewhat sticky consistency without complete
liquefaction. Particular care should be exercised to ensure that an
active ingredient contained in sheath 24 is not exposed to a
temperature that may adversely alter the active ingredient's
composition or characteristic.
[0039] Table 1 lists the T.sub.g and T.sub.m for some of the
polymers used in the embodiments of the composition for forming
sheath 24 and, ultimately, coating 26. T.sub.g and T.sub.m of
polymers are attainable by one of ordinary skill in the art. The
cited exemplary temperature is provided by way of illustration and
is not meant to be limiting.
1TABLE 1 Exemplary Polymer T.sub.g (.degree. C.) T.sub.m (.degree.
C.) Temperature (.degree. C.) EVOH 55 165 70 polycaprolactone -60
60 50 ethylene vinyl 36 63 45 acetate (e.g., 33% vinyl acetate
content) Polyvinyl 75-85* 200-220* 75 alcohol *Exact temperature
depends on the degree of hydrolysis which is also known as the
amount of residual acetate.
[0040] The above-described heat treatment allows the polymeric
material of sheath 24 to adhere to struts 12 of stent 10 to form a
coating 26, as illustrated in FIG. 4. Vacuum 10 conditions may be
employed to ensure that coating 26 adheres uniformly to stent 10.
Coating 26 covers struts 12 as well as gaps 14 between struts
12.
[0041] As mentioned above, conventional coating methods coat the
struts of a stent, leaving voids in the coating over the gaps
between the struts. By forming coating 26 to cover struts 12 as
well as gaps 14 between struts 12, the present invention allows an
increased amount of the polymeric coating to be present on stent 10
without increasing the thickness of the coating. Accordingly, the
amount of therapeutic substance is increased concomitantly.
Formation of an Optional Primer Layer
[0042] An optional primer layer can be formed on the outer surface
of stent 10 prior to the insertion of stent 10 within sheath 24.
The presence of an active ingredient in a polymeric matrix
typically interferes with the ability of the matrix to adhere
effectively to the surface of the device. An increase in the
quantity of the active ingredient reduces the effectiveness of the
adhesion. High drug loadings of, for example, 10-40% by weight in
the coating may significantly hinder the retention of the coating
on the surface of the device. The primer layer serves as a
functionally useful intermediary layer between the surface of the
device and an active ingredient-containing sheath. The primer layer
provides for an adhesive tie between sheath 24 and stent 10--which,
in effect, would also allow for the quantity of the active
ingredient in coating 26 formed from sheath 24 to be increased
without compromising the ability of coating 26 to be effectively
contained on stent 10 during delivery and, if applicable, expansion
of stent 10.
[0043] To form an optional primer layer, the surfaces of stent 10
should be clean and free from contaminants that may be introduced
during manufacturing. However, the surfaces of stent 10 require no
particular surface treatment to retain the applied coating.
Metallic surfaces of stents can be, for example, cleaned by an
argon plasma process as is well known to one of ordinary skill in
the art. A primer layer may be formed on stent 10 by applying a
primer composition to stent 10 and then removing the solvent from
the applied primer composition to form the desired primer layer on
stent 10.
[0044] The primer composition typically includes a polymer
dissolved in a solvent. Suitable polymers and solvents were
described above with reference to the composition for forming
sheath 24 and are equally applicable here. Application of the
primer composition can be accomplished by any conventional method,
such as by spraying the primer composition onto stent 10 or
immersing stent 10 in the primer composition. Such application
methods are understood by one of ordinary skill in the art.
[0045] The solvent is removed from the primer composition by
allowing the solvent to evaporate. The evaporation can be induced
by heating stent 10 at a predetermined temperature for a
predetermined period of time. For example, stent 10 can be heated
at a temperature of about 60.degree. C. for about 12 hours to about
24 hours. The heating can be conducted in an anhydrous atmosphere
and at ambient pressure. The heating can, alternatively, be
conducted under a vacuum condition. It is understood that
essentially all of the solvent will be removed from the primer
composition but traces or residues can remain. Upon removal of the
solvent from the primer composition, a primer layer is formed on
stent 10.
Patterning the Coating to Form Interstices Therein
[0046] As illustrated in FIGS. 5A and 5B, coating 26 may be
patterned such that portions of coating 26 positioned over at least
some of gaps 14 are removed to yield a pattern of interstices 28
dispersed between struts 12. Such patterning of coating 26 may be
accomplished, for example, by exposing designated portions of
coating 26 to the discharge of a laser, such as an excimer laser.
Application of a laser discharge to form patterns can be performed
by one of ordinary skill in the art.
[0047] Interstices 28 may be of any suitable size and shape and are
typically smaller than the gap 14 in which they are created.
Interstices 28 may be interspersed between struts 12 in any
pattern. The pattern of interstices 28 created depends, in part, on
the application for which stent 10 is to be utilized.
[0048] As depicted in FIG. 6, interstices 28 allow a fluid, such as
blood, which flows through central bore 18 to seep through coating
26. Interstices 28 can be selectively patterned to direct the flow
of blood in a selected direction, for example in a direction 30 to
make contact with a vessel wall 34 of a targeted vessel 32. Such
contact between blood and the vessel wall 34 may be required to
allow vessel wall 34 to acquire essential nutrients from red blood
cells. Alternatively, interstices 28 can be selectively patterned
to direct the flow of blood in a direction 36 and into a side
vessel 38. In this manner, the creation of interstices 28 allows
branching side vessels 38 to remain patent during treatment of
targeted vessel 32 with stent 10.
Optional Topcoat
[0049] In some embodiments, a second polymeric coating, or topcoat,
is formed onto at least a portion of coating 26 on stent 10. In one
such embodiment, the topcoat may function as a rate limiting
membrane with respect to an active ingredient contained within
coating 26. In another embodiment the topcoat itself may be
impregnated with an active ingredient, while coating 26 functions
as a primer layer to aid the adhesion of the
active-ingredient-containing topcoat to stent 10.
Methods of Use
[0050] In accordance with the above-described methods, an active
ingredient can be applied to a device, e.g., a stent, retained on
the stent during delivery and expansion of the stent, and released
at a desired control rate and for a predetermined duration of time
at the site of implantation. A stent having the above-described
coating is useful for a variety of medical procedures, including,
by way of example, treatment of obstructions caused by tumors in
bile ducts, esophagus, trachea/bronchi and other biological
passageways. A stent having the above-described coating is
particularly useful for treating occluded regions of blood vessels
caused by abnormal or inappropriate migration and proliferation of
smooth muscle cells, thrombosis, or restenosis. Stents may be
placed in a wide array of blood vessels, both arteries and veins.
Representative examples of sites include the iliac, renal, and
coronary arteries.
[0051] Briefly, an angiogram is first performed to determine the
appropriate positioning for stent therapy. Angiography is typically
accomplished by injecting a radiopaque contrast agent through a
catheter inserted into an artery or vein as an x-ray is taken. A
guidewire is then advanced through the lesion or proposed site of
treatment. Over the guidewire is passed a delivery catheter that
allows a stent in its collapsed configuration to be inserted into
the passageway. The delivery catheter is inserted either
percutaneously or by surgery into the femoral artery, brachial
artery, femoral vein, or brachial vein, and advanced into the
appropriate blood vessel by steering the catheter through the
vascular system under fluoroscopic guidance. A stent having the
above-described coating may then be expanded at the desired area of
treatment. A post insertion angiogram may also be utilized to
confirm appropriate positioning.
[0052] 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 and,
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.
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