U.S. patent application number 12/088000 was filed with the patent office on 2009-01-01 for stent and method for fabricating the same.
Invention is credited to Ikuo Komura, Koji Mori, Tatsuyuki Nakatani, Keishi Okamoto, Shuzo Yamashita.
Application Number | 20090005862 12/088000 |
Document ID | / |
Family ID | 51690517 |
Filed Date | 2009-01-01 |
United States Patent
Application |
20090005862 |
Kind Code |
A1 |
Nakatani; Tatsuyuki ; et
al. |
January 1, 2009 |
Stent and Method For Fabricating the Same
Abstract
A stent includes a tubular stent body 11, a diamond-like carbon
film 12 formed on the surface of the stent body 11 and having an
activated surface, and a polymer layer 13 immobilized on the
surface of the diamond-like carbon film. The polymer layer 13
contains a drug 14 having an effect to prevent restenosis, and the
drug 14 is gradually released from the polymer layer 13.
Inventors: |
Nakatani; Tatsuyuki;
(Hiroshima, JP) ; Okamoto; Keishi; (Hiroshima,
JP) ; Yamashita; Shuzo; (Okayama, JP) ;
Komura; Ikuo; (Okayama, JP) ; Mori; Koji;
(Okayama, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
51690517 |
Appl. No.: |
12/088000 |
Filed: |
January 15, 2007 |
PCT Filed: |
January 15, 2007 |
PCT NO: |
PCT/JP2007/050415 |
371 Date: |
July 18, 2008 |
Current U.S.
Class: |
623/1.49 ;
623/1.15; 623/1.44; 623/1.46 |
Current CPC
Class: |
A61L 31/084 20130101;
A61F 2250/0067 20130101; A61L 31/16 20130101; A61L 2420/08
20130101; A61L 31/10 20130101; A61L 2300/606 20130101; A61L
2300/416 20130101; A61L 33/025 20130101; A61F 2/91 20130101 |
Class at
Publication: |
623/1.49 ;
623/1.44; 623/1.46; 623/1.15 |
International
Class: |
A61F 2/06 20060101
A61F002/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 30, 2006 |
JP |
2006-020926 |
Claims
1. A stent comprising: a tubular stent body; a diamond-like carbon
film formed on a surface of the stent body and having an activated
surface; and a polymer that is immobilized on the surface of the
diamond-like carbon film, contains an anti-restenosis drug and
gradually releases the drug.
2. The stent of claim 1, wherein the diamond-like carbon film has a
thickness not less than 10 nm and not more than 300 nm.
3. The stent of claim 1, further comprising an intermediate layer
formed between the stent body and the diamond-like carbon film,
wherein the intermediate layer is made of an amorphous film
including at least one of silicon and carbon as a principal
component.
4. The stent of claim 3, wherein the intermediate layer has a
thickness not less than 5 nm and not more than 100 nm.
5. The stent of claim 1, wherein the stent body is made of one of a
metal material, a ceramic material and a polymeric material, or is
a complex made of at least two of a metal material, a ceramic
material and a polymeric material.
6. The stent of claim 1, wherein a surface portion of the
diamond-like carbon film has a hydrophilic functional group.
7. The stent of claim 1, wherein the polymer is immobilized on the
surface of the diamond-like carbon film through ionic
interaction.
8. The stent of claim 1, wherein the polymer is a biocompatible
polymer.
9. The stent of claim 8, wherein the biocompatible polymer is at
least one polymer or an ester of a polymer selected from the group
consisting of polyurethane, polyacrylamide, polyethylene oxide,
polyethylene carbonate, polyethylene, polyethylene glycol,
polypropylene carbonate, polyamide, fibrin, a polymer of
phospholipid, a hydrophobic/hydrophilic microphase-separated
polymer, a polymer or a copolymer of hydroxyethyl methacrylate, a
polymer or a copolymer of vinyl pyrrolidone, a polymer or a
copolymer of a fluorine-containing monomer, a polymer or a
copolymer of a Si-containing monomer, and a polymer or a copolymer
of vinyl ether.
10. The stent of claim 1, wherein the polymer is a biodegradable
polymer.
11. The stent of claim 10, wherein the biodegradable polymer is at
least one polymer selected from the group consisting of polylactic
acid, polyglycolic acid, a copolymer of polylactic acid and
polyglycolic acid, collagen, gelatin, chitin, chitosan, hyaluronic
acid, polyamino acid, starch, poly-.epsilon.-caprolactone,
polyethylene succinate and poly-.beta.-hydroxylalkanoate.
12. The stent of claim 11, wherein the biodegradable polymer
includes a plasticizing agent.
13. The stent of claim 1, wherein the drug is at least one drug
selected from the group consisting of an antiplatelet drug, an
anticoagulant, an antifibrin, an antithrombin, an antiproliferative
agent, an anticancer agent, an inhibitor of HMG-CoA reductase,
alfa-interferon and genetically modified epithelial cells.
14. A method for fabricating a stent comprising: a diamond-like
carbon film forming step of forming a diamond-like carbon film on a
surface of a stent body; a surface activation step of producing
reactive sites in a surface portion of the diamond-like carbon
film; and a polymer layer forming step of immobilizing a polymer
containing a drug onto a surface of the diamond-like carbon film
after the surface activation step.
15. The method for fabricating a stent of claim 14, further
comprising, before the diamond-like carbon film forming step, an
intermediate layer forming step of forming an amorphous film
including silicon and carbon as principal components on the surface
of the stent body.
16. The method for fabricating a stent of claim 14, wherein the
surface activation step is plasma irradiation step of irradiating
the surface of the diamond-like carbon film with plasma.
17. The method for fabricating a stent of claim 16, wherein the
plasma is plasma of one gas or a mixed gas of two or more gases
selected from the group consisting of argon, xenon, neon, helium,
krypton, nitrogen, oxygen, ammonia, hydrogen, steam, chain or
cyclic hydrocarbon, an organic compound including oxygen and an
organic compound including nitrogen.
18. The method for fabricating a stent of claim 14, further
comprising, between the surface activation step and the polymer
layer forming step, a surface treatment step of introducing
hydroxyl groups onto the surface portion of the diamond-like carbon
film by reacting between the reactive sites and molecules including
oxygen.
19. The method for fabricating a stent of claim 14, wherein the
polymer is a biocompatible polymer or a biodegradable polymer.
Description
TECHNICAL FIELD
[0001] The present invention relates to a stent and a method for
fabricating the same, and more particularly, it relates to a drug
release stent and a method for fabricating the same.
BACKGROUND ART
[0002] In accordance with recent westernization in the lifestyle,
ischemic heart diseases (including angina pectoris and cardiac
infarction) are rapidly increasing in Japan. An ischemic heart
disease is caused principally when coronary thrombosis or coronary
twitch is caused additionally to an arteriosclerotic disease of a
thick coronary artery extending on the heart surface.
[0003] As a treatment method for angiostenosis, angioplasty (PTA,
PTCA or the like) in which a small balloon is expanded within a
blood vessel for the treatment is widely employed as a minimally
invasive treatment. In employing this treatment method, however,
stenosis (restenosis) is repeatedly caused in high probability. As
a method for reducing the ratio of the restenosis, a stent
placement technique is being rapidly spreading these days.
[0004] Since a stent is used to be indwelled in a body, it is
required to have durability against biological materials and
compatibility with an organism. As a method for providing a medical
material such as a stent with durability, a method in which the
surface of the medical material is coated with a diamond-like
carbon film (a DLC film) is known (see, for example, Patent
Document 1). Since a DLC film is a very smooth and chemically inert
film, it is characterized by being minimally reactive with biogenic
components. Accordingly, when the surface of a base material of a
stent is coated with a DLC film, a stent with high durability and
good biocompatibility can be obtained.
[0005] On the other hand, it has been reported that the restenosis
occurs at frequency of approximately 20% through 30% also in
employing the stent indwelling technique. In the case where the
restenosis occurs, it is necessary to perform the PTCA again, and
it is a global problem of great urgency to establish methods for
preventing and treating the restenosis.
[0006] As a method for preventing the restenosis, an attempt has
been made to coat the base material of a stent with a drug for
restricting the occurrence of occlusion. For example, Patent
Document 2 discloses a method for coating a stent by spraying a
polymer solution including a drug over the surface of the stent or
by immersing the stent in the polymer solution. Thus, a stent from
which an anti-restenosis drug is gradually released can be
realized.
[0007] Patent Document 1: Japanese Laid-Open Patent Publication No.
10-248923
[0008] Patent Document 2: National Publication of Translated
Version No. 2005-531332
[0009] Patent Document 3: National Publication of Translated
Version No. 2002-517285
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0010] However, a conventional stent has a problem that it is
difficult to continuously release the drug because the coated
polymer is peeled off. Since a stent is largely physically deformed
in use, when the base material is physically coated with the
polymer by, for example, spraying the polymer solution over the
surface of the base material, cracks are caused so that the polymer
can be easily peeled off.
[0011] In particular, in the case where the surface of the base
material is covered with a DLC film, since the surface of the DLC
film is inert and smooth, the physical interaction between the
polymer and the DLC film is so small that the polymer is more
easily peeled off. Therefore, the anti-restenosis drug cannot be
continuously released from the stent, and hence, the restenosis
cannot be effectively prevented.
[0012] On the other hand, a method in which biogenic molecules are
chemically immobilized on the surface of a DLC film by using a
linker molecule is known (see, for example, Patent Document 3), but
it is difficult in this case to gradually release the biogenic
molecules. Also, since it is necessary to use a linker molecule,
there are problems that it is complicated to immobilize the
biogenic molecules and that the kinds of biogenic molecules to be
immobilized are limited.
[0013] An object of the present invention is solving the
aforementioned conventional problems for realizing a stent
including a base material not degraded by a biogenic component and
capable of continuously releasing a drug for preventing the
restenosis.
Means for Solving Problems
[0014] In order to achieve the object, in the stent of this
invention, a drug release polymer is immobilized on the surface of
a DLC film with a functional group introduced into a surface
portion of the DLC film.
[0015] Specifically, the stent of this invention includes a tubular
stent body; a diamond-like carbon film formed on a surface of the
stent body and having an activated surface; and a polymer that is
immobilized on the surface of the diamond-like carbon film,
contains an anti-restenosis drug and gradually releases the
drug.
[0016] Since the stent of this invention includes the diamond-like
carbon film formed on the surface of the stent body and having the
activated surface, a base material of the stent is minimally
degraded. Also, since the polymer can be tightly immobilized, even
when the stent is largely deformed in use, the polymer gradually
releasing the drug is never peeled off from the surface of the
stent. Accordingly, the drug can be continuously released from the
stent, and hence the restenosis is minimally caused.
[0017] In the stent of this invention, the diamond-like carbon film
preferably has a thickness not less than 10 nm and not more than
300 nm. Thus, the diamond-like carbon film can be prevented from
peeling off from the stent body, so that the stent can be used for
a long period of time.
[0018] The stent of this invention preferably further includes an
intermediate layer formed between the stent body and the
diamond-like carbon film, and the intermediate layer is preferably
made of an amorphous film including at least one of silicon and
carbon as a principal component. Thus, the adhesiveness between the
diamond-like carbon film and the stent is improved, so as to
definitely prevent the degradation of the base material.
[0019] In this case, the intermediate layer preferably has a
thickness not less than 5 nm and not more than 100 nm.
[0020] In the stent of this invention, the stent body is preferably
made of one of a metal material, a ceramic material and a polymeric
material, or preferably is a complex made of at least two of a
metal material, a ceramic material and a polymeric material.
[0021] In the stent of this invention, a surface portion of the
diamond-like carbon film preferably has a hydrophilic functional
group. Thus, the biocompatibility of the surface of the
diamond-like carbon film can be improved.
[0022] In the stent of this invention, the polymer is preferably
immobilized on the surface of the diamond-like carbon film through
ionic interaction. Thus, the polymer can be definitely prevented
from peeling off from the surface of the diamond-like carbon
film.
[0023] In the stent of this invention, the polymer is preferably a
biocompatible polymer.
[0024] In this case, the biocompatible polymer is preferably at
least one polymer or an ester of a polymer selected from the group
consisting of polyurethane, polyacrylamide, polyethylene oxide,
polyethylene carbonate, polyethylene, polyethylene glycol,
polypropylene carbonate, polyamide, fibrin, a polymer of
phospholipid, a hydrophobic/hydrophilic microphase-separated
polymer, a polymer or a copolymer of hydroxyethyl methacrylate, a
polymer or a copolymer of vinyl pyrrolidone, a polymer or a
copolymer of a fluorine-containing monomer, a polymer or a
copolymer of a Si-containing monomer, and a polymer or a copolymer
of vinyl ether.
[0025] In the stent of this invention, the polymer is preferably a
biodegradable polymer.
[0026] In this case, the biodegradable polymer is preferably at
least one polymer selected from the group consisting of polylactic
acid, polyglycolic acid, a copolymer of polylactic acid and
polyglycolic acid, collagen, gelatin, chitin, chitosan, hyaluronic
acid, polyamino acid, starch, poly-.epsilon.-caprolactone,
polyethylene succinate and poly-.beta.-hydroxylalkanoate.
[0027] In this case, the biodegradable polymer preferably includes
a plasticizing agent. Thus, the decomposition of the biodegradable
polymer in vivo is accelerated, so as to improve the efficiency in
releasing the drug.
[0028] In the stent of this invention, the drug is preferably at
least one drug selected from the group consisting of an
antiplatelet drug, an anticoagulant, an antifibrin, an
antithrombin, an antiproliferative agent, an anticancer agent, an
inhibitor of HMG-CoA reductase, alfa-interferon and genetically
modified epithelial cells.
[0029] The method for fabricating a stent of this invention
includes a diamond-like carbon film forming step of forming a
diamond-like carbon film on a surface of a stent body; a surface
activation step of producing reactive sites in a surface portion of
the diamond-like carbon film; and a polymer layer forming step of
immobilizing a polymer containing a drug onto a surface of the
diamond-like carbon film after the surface activation step.
[0030] Since the method for fabricating a stent of this invention
includes the activation step of producing the reactive sites in the
surface portion of the diamond-like carbon film, the degradation of
the stent body is prevented as well as the polymer containing the
drug can be tightly immobilized on the surface of the diamond-like
carbon film. Accordingly, even when the stent is largely deformed
in use, the polymer can be prevented from peeling off. As a result,
a stent minimally degraded in its base material and capable of
continuously releasing the drug can be realized.
[0031] The method for fabricating a stent of this invention
preferably further includes, before the diamond-like carbon film
forming step, an intermediate layer forming step of forming an
amorphous film including silicon and carbon as principal components
on the surface of the stent body. Thus, the adhesiveness between
the diamond-like carbon film and the stent body can be
improved.
[0032] In the method for fabricating a stent of this invention, the
surface activation step is preferably plasma irradiation step of
irradiating the surface of the diamond-like carbon film with
plasma. In this case, the plasma is preferably plasma of one gas or
a mixed gas of two or more gases selected from the group consisting
of argon, xenon, neon, helium, krypton, nitrogen, oxygen, ammonia,
hydrogen, steam, chain or cyclic hydrocarbon, an organic compound
including oxygen and an organic compound including nitrogen. Thus,
a functional group can be definitely introduced into the surface
portion of the diamond-like carbon film.
[0033] The method for fabricating a stent of this invention
preferably further includes, between the surface activation step
and the polymer layer forming step, a surface treatment step of
introducing hydroxyl groups onto the surface portion of the
diamond-like carbon film by reacting between the reactive sites and
molecules including oxygen.
[0034] In the method for fabricating a stent of this invention, the
polymer is preferably a biocompatible polymer or a biodegradable
polymer.
Effect of the Invention
[0035] According to the present invention, a stent including a base
material not degraded by a biogenic component and capable of
continuously releasing a drug for preventing restenosis can be
realized.
BRIEF DESCRIPTION OF DRAWINGS
[0036] FIGS. 1A and 1B are diagrams of a stent according to an
embodiment of the invention, and FIG. 1A is a perspective view of
the whole stent and FIG. 1B is a cross-sectional view thereof taken
on line Ib-Ib of FIG. 1A.
[0037] FIG. 2 is a schematic diagram of an ionization evaporation
system used in a fabrication method for a stent according to an
example of the invention.
[0038] FIG. 3 is a schematic diagram of a plasma irradiation system
used in the fabrication method for a stent according to the example
of the invention.
DESCRIPTION OF REFERENCE NUMERALS
[0039] 10 stent [0040] 11 stent body [0041] 12 diamond-like carbon
film [0042] 13 polymer layer [0043] 14 drug [0044] 21 plasma
generator [0045] 22 material [0046] 31 chamber [0047] 32 vacuum
pump [0048] 33 electrode [0049] 34 electrode [0050] 35
radiofrequency power supply [0051] 36 matching network
BEST MODE FOR CARRYING OUT THE INVENTION
[0052] A stent according to an embodiment of the invention will now
be described with reference to the accompanying drawings. FIGS. 1A
and 1B show the stent of this embodiment, and FIG. 1A shows the
schematic shape of the stent and FIG. 1B shows the cross-sectional
structure thereof taken on line Ib-Ib of FIG. 1A.
[0053] As shown in FIGS. 1A and 1B, the stent 10 of this embodiment
includes a diamond-like carbon film (DLC film) 12 formed on the
surface of a stent body 11 made of a metal or the like. The surface
of the DLC film 12 has been subjected to activation. The activation
is performed by plasma irradiation, ultraviolet (UV) irradiation,
ozonization or the like as described later.
[0054] The surface of the DLC film 12 having been subjected to the
activation is coated with a polymer layer 13. Since the surface of
the DLC film 12 has been subjected to the activation, the polymer
layer 13 is tightly immobilized onto the surface of the DLC film
12. The polymer layer 13 contains a drug 14 for prevention of
restenosis, and the drug 14 is gradually released from the polymer
layer 13. Thus, a stent capable of continuously releasing the drug
for a long period of time can be realized.
[0055] Now, the respective components of the stent will be
described in detail.
[0056] Stent Body
[0057] The stent body 11 is not particularly specified and may be
made of any of generally known materials. For example, it is
obtained by cutting with laser, into a stent design, a metal tube
made of stainless steel, a nickel titanium (Ni--Ti) alloy, a copper
aluminum manganese (Cu--Al--Mn) alloy, tantalum, a cobalt chromium
(Co--Cr) alloy, iridium, iridium oxide, niobium or the like and
electrolytic polishing the resultant. Alternatively, it may be
obtained by a method in which a metal tube is etched, a method in
which a metal plate is cut with laser to be rolled into a cylinder
and welded, a method in which a metal wire is knit, or the
like.
[0058] Also, the material for the stent body 11 is not limited to
the metal material, but a polymeric material such as polyorefin,
polyorefin elastomer, polyamide, polyamide elastomer, polyurethane,
polyurethane elastomer, polyester, polyester elastomer, polyimide,
polyamide-imide or polyether ether ketone, or an inorganic material
such as ceramics or hydroxy-apatite may be used. A method for
processing such a polymeric or inorganic material into a stent does
not affect the effects of the invention, and a processing method
appropriate for each material may be arbitrarily selected.
[0059] Formation of Diamond-Like Carbon Film
[0060] The diamond-like carbon film (DLC film) 12 is a thin film of
carbon similar to diamond and is so dense and digit that biogenic
components cannot permeate through the DLC film 12. Therefore, when
the surface of the stent body 11 is covered with the DLC film 12,
the degradation of the stent body 11 otherwise caused by biogenic
components can be prevented.
[0061] Furthermore, there are micro-scale or nano-scale
irregularities on the material surface of the stent body 11. These
irregularities can be a starting point of adhesion of a biogenic
component, and the adhesion of a biogenic component onto the stent
body 11 may cause thrombus or the like. However, when the stent
body 11 is covered with the DLC film 12, the irregularities are
smoothed. The stent body 11 covered with the smooth and inert DLC
film 12 is minimally interacted with a biogenic component so that
the adhesion of the biogenic component onto the stent can be
reduced.
[0062] In this embodiment, the DLC film 12 can be formed on the
stent body 11 by any of known methods such as sputtering, DC
magnetron sputtering, RF magnetron sputtering, chemical vapor
deposition (CVD), plasma CVD, plasma ion implantation, superposed
RF plasma ion implantation, ion plating, arc ion plating, ion beam
evaporation or laser abrasion.
[0063] The thickness of the DLC film 12 is preferably large from
the viewpoint of preventing the degradation of the stent body 11 by
a biogenic component. However, since the stent is largely deformed
in use, if the thickness of the DLC film 12 is too large, a crack
may be caused in the deformation, which leads to a problem of
peeling of the DLC film. Accordingly, the thickness of the DLC film
12 is not less than 10 nm and not more than 30 nm and is preferably
not less than 20 nm and not more than 80 nm.
[0064] Although the DLC film may be directly formed on the surface
of the stent body 11, an intermediate layer may be provided between
the stent body 11 and the DLC film 12 for more tightly adhering the
DLC film 12 onto the stent body 11.
[0065] The intermediate layer can be made of any of various
materials in accordance with the material of the stent body 11 and
may be made of a known material such as an amorphous film of
silicon (Si) and carbon (C), titanium (Ti) and carbon (C) or
chromium (Cr) and carbon (C).
[0066] Since the intermediate layer should be uniformly formed on
the stent body 11, it needs to have a given thickness. When the
thickness is too large, however, it takes a long time to form it,
which lowers the productivity. Accordingly, the thickness of the
intermediate layer is not less than 5 nm and not more than 100 nm
and is preferably not less than 10 nm and not more than 40 nm.
[0067] The intermediate layer may be formed by any of known
methods, such as the sputtering, the CVD, the plasma CVD, spray
coating, the ion plating or the arc ion plating.
[0068] Activation of Diamond-Like Carbon Film
[0069] Since the surface of the DLC film 12 is smooth and inert as
described above, when the surface of the DLC film 12 is directly
coated with a polymer, the polymer is peeled off soon.
[0070] On the other hand, when the surface of the DLC film 12 is
irradiated with plasma or the like, part of diamond (carbon-carbon)
bonds formed on the surface can be cleaved. Thus, free radicals or
ion seeds can be produced in a surface portion of the DLC film 12.
When the free radicals or ion seeds are used, easily reactive
functional groups such as carboxyl groups or hydroxyl groups can be
easily introduced into the surface portion of the DLC film 12, and
these functional groups can be replaced with another functional
groups.
[0071] When the surface of the DLC film 12 is activated through the
introduction of the functional groups, the surface of the DLC film
12 can be tightly coated with any of various polymers.
[0072] The carbon-carbon bonds of the DLC film 12 may be cleaved by
exposing the DLC film to plasma generated from a gas of, for
example, argon (Ar), neon (Ne), helium (He), krypton (Kr), xenon
(Xe), nitrogen (N.sub.2), oxygen (O.sub.2), ammonia (NH.sub.4),
hydrogen (H.sub.2) or steam (H.sub.2O). One of such gases may be
singly used or a mixture thereof may be used. Alternatively, the
carbon-carbon bonds may be cleaved through irradiation with
ultraviolet or irradiation with ultraviolet in an ozone
atmosphere.
[0073] Since a cleaved carbon-carbon bond is easily reacted with
water, a hydroxyl group or a carboxyl group can be easily
introduced into the surface portion of the DLC film 12. Also, a
hydroxyl group or a carboxyl group once introduced can be easily
replaced with another functional group. For example, a hydroxyl
group introduced into the surface portion of the DLC film 12 can be
easily replaced with an amino group, a carboxyl group, an
isocyanate group or a vinyl group through a reaction with a
functional alkoxysilane derivative such as 3-aminopropyl
trimethoxysilane, a functional carboxylic acid derivative such as
2-mercaptoacetic acid, a diisocyanate derivative, 2-methacryloyloxy
ethyl isocyanate, 2-acryloyloxy ethyl isocyanate, N-methacryloyl
succinimide, N-acryloyl succinimide or the like.
[0074] When hydroxyl groups or carboxyl groups are introduced into
the surface portion of the DLC film 12, the hydrophilic property of
the surface of the DLC film 12 is improved. Thus, the
biocompatibility of the DLC film 12 itself is preferably improved.
In this case, even when the groups are replaced with another
functional groups, a part of hydroxyl groups or carboxyl groups are
not replaced but remain, and therefore, the effect to improve the
biocompatibility of the DLC film 12 itself can be retained.
[0075] In the case where chain or cyclic hydrocarbon, an organic
compound including oxygen or an organic compound including nitrogen
is used as the gas corresponding to the plasma source, the
carbon-carbon bonds are not only cleaved but also reacted with ion
seeds included in the plasma, and functional groups in accordance
with the gas seed can be directly introduced into the surface
portion of the DLC film 12.
[0076] The kind of functional groups to be introduced into the
surface portion of the DLC film 12 is appropriately selected in
accordance with the kind of polymer used for the polymer layer 13
to be immobilized onto the DLC film 12. For example, when the
functional group to be introduced into the surface portion of the
DLC film 12 is an ionic functional group such as a carboxyl group,
an amino group or a phosphoric acid group, a polymer can be
immobilized onto the surface of the DLC film 12 through ionic
interaction (ion bonding) by using an ionic functional group
included in the polymer.
[0077] Alternatively, when a hydrophobic functional group is
introduced, a polymer can be physically immobilized by increasing
the physical interaction with the polymer.
[0078] Furthermore, in the case where a polymer includes, in its
molecule, a functional group of an isocyanate group or a trialkyl
oxysilane group such as trimethoxysilane or trimethoxysilane, when
a functional group to be introduced into the surface portion of the
DLC film 12 is an amino group, the functional groups can be
covalent bonded with each other. Alternatively, a bifunctional
reagent may be used for bonding a functional group introduced into
the surface portion of the DLC film 12 and a functional group
included in a polymer, and in this case, the kind of functional
group to be introduced into the surface portion of the DLC film 12
is selected in accordance with the kind of bifunctional
reagent.
[0079] Polymer Layer
[0080] The polymer layer 13 is formed by immobilizing a polymer
onto the surface of the DLC film 12. The polymer to be immobilized
on the surface of the DLC film 12 is preferably a polymer that is
immobilizable onto the activated DLC film 12, contains a drug
therein and is capable of releasing the drug at a given speed.
Furthermore, a polymer onto which a blood platelet is minimally
adhered and which is not stimulative against a tissue is
preferred.
[0081] Examples of the polymer are biodegradable polymers such as
polyglycolic acid, a copolymer of lactic acid and glycolic acid,
poly(DL-lactic acid) (DL-PLA), poly(L-lactic acid) (L-PLA),
lactide, polycaprolactone (PCL), collagen, gelatin, chitin,
chitosan, hyaluronic acid, polyamino acid such as poly(L-glutamic
acid) or poly-L-lysine, poly-.epsilon.-caprolactone, polyethylene
succinate and poly-.beta.-hydroxyalkanoate. Furthermore, a polar
functional group may be introduced into the terminal of polylactic
acid, polyglycolic acid or a copolymer of polylactic acid and
polyglycolic acid.
[0082] In addition, any biodegradable polymer can be used as far as
it is enzymatically or nonenzymatically decomposed in vivo, a
decomposition product thereof does not exhibit toxicity and it is
capable of releasing a drug.
[0083] Furthermore, a plasticizing agent may be added for
accelerating the decomposition in vivo and for efficiently
releasing the drug. As the plasticizing agent, for example, a
plasticizing ester of tartaric acid, malic acid or citric acid, or
another plasticizing agent having been confirmed in the safety
against organism may be used.
[0084] Alternatively, a non-decomposable polymer with
biocompatibility may be used. For example, parylene, Parylast.RTM.,
polyethylene, polyethylene terephthalate, ethylene vinyl acetate,
silicon, polyethylene oxide (PEO), polybutyl methyl acrylate,
polyacrylamide, polycarbonate such as polyethylene carbonate or
polypropylene carbonate, polyurethane such as segmented
polyurethane, or a synthetic polymer such as a blend or a block
copolymer of polyether type polyurethane and dimethyl silicon may
be used. Alternatively, a natural polymer such as fibrin may be
used.
[0085] It is noted that a functional group or the like may be
introduced if necessary for immobilizing the polymer onto the DLC
film.
[0086] Drug
[0087] The drug to be contained in the polymeric material may be
any drug as far as it exhibits the anti-restenosis effect. For
example, an antiplatelet drug, an anticoagulant, an antifibrin, an
antithrombin, a thrombolytic drug, an antiproliferative agent, an
anticancer agent, an immunosuppressive agent, an antibiotic, an
anti-inflammatory drug or the like can be used. Specific examples
of the drug will now be described, which are merely illustratively
mentioned and do not limit the invention.
[0088] Examples of the antiplatelet drug, the anticoagulant, the
antifibrin and the antithrombin are heparin sodium, low molecular
weight heparin, hirudin, argatroban, forskolin, sarpogrelate
hydrochloride, vapiprost, prostacyclin, prostacyclin homologues,
dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dypyridamole, a glycoprotein IIb/IIIa platelet membrane receptor
antibody, a vitronectin receptor antagonist and thrombin
inhibitors.
[0089] Examples of the thrombolytic drug are a tissue plasminogen
activator, streptokinase and urokinase.
[0090] Examples of the antiproliferative agent are angiotensin
converting enzyme inhibitors such as angiopeptin, captopril,
cilazapril and lisinopril, a calcium channel blocker antibody,
colchicine, a fibroblast growth factor (FGF) antagonist, fish oil
(omega 3-fatty acid), a histamine antagonist, lovastatin (an
inhibitor of HMG-CoA reductase), methotrexate, nitroprusside, a
phosphodiesterase inhibitor, a prostaglandin inhibitor, seramin (a
PDGF antagonist), a serotonin blocker antibody, steroid, a
thioprotease inhibitor, triazolopyrimidine (a PDGF antagonist),
nitrogen oxide, all-trans retinoic acid, 13-cisretinoic acid and
9-cisretinoic acid (alitretinoin).
[0091] Alternatively, any of antiproliferative antimitotic
alkylating drugs such as nitrogen mustards (including
mechlorethamine, cyclophosphamide and an analogue thereof,
melphalan, chlorambucil and the like), ethyleneimine,
methylmelamine (including hexamethylmalamine, thiotepa and the
like), a sulfonic acid alkyl-busulfan complex, nitrosoureas
(including carmustine (BCNU), a BCNU analogue, sutreptozocin and
the like) and a trazenes-dacarbazine (DTIC) complex may be
used.
[0092] Alternatively, any of pyrimidine analogues (such as
fluorouracil, floxuridine and cytarabine), purine analogues (such
as mercaptopurine, thioguanine, pentostatin and
2-chlorodeoxyadenosine) and other inhibitors may be used. Any of
antiproliferative antimitotic metabolic antagonists such as
platinum coordination complexes (such as cisplatinum and
carboplatin), procarbazine, hydroxyurea, mitotane,
aminoglutethimide and hormones (including estrogen and the like)
may be used. An enzyme such as L-asparaginase that systemically
metabolizes L-asparagine for depriving various cells not having a
function to autogenously synthesize asparagine may be used.
[0093] Examples of the anticancer agent are alkaloids such as
taxol, taxotere and Topotecin, antibiotics such as Adriacin and
Bleo, metabolic antagonists such as 5-FU and natural products such
as vinca alkaloids (such as vinblastine, vincristine and
vinorelbine).
[0094] Examples of the immunosuppressive agent are cyclospolin,
tacrolimus (FK-506), sirolimus (rapamycin), azathioprine and
mycophenolate mofetil. Examples of the antibiotic are dactinomycin
(actynomycin D), daunorubicin, doxorubicin, idarubicin,
anthracycline, mitozantrone, bleomycin, plicamycin (mithramycin)
and mitomycin.
[0095] Examples of the anti-inflammatory drug are aspirin,
dipyridamole, ticlopidine, clopidogrel, abciximab, antimigratory,
an antisecretory agent (breveldin), adrenocortical steroids (such
as cortisol, cortisone, fludrocortisone, prednisone, prednisolone,
6.alpha.-methylprednisolone, triamcinolone, betamethasone and
dexamethazone), non-steroidal drugs (such as a salicylic acid
derivative, namely, aspirin, and a paraaminophenol derivative,
namely, acetaminophen), indole acetic acid and indene acetic acid
(such as imdomethacin, sulindac and etodalac), heteroarylacetic
acid (such as tolmetin, diclofenac and ketorolac), arylpropionic
acid (such as ibuprofen and a derivative thereof), anthranilic acid
(such as mefenamate and meclofenamate), enolic acid (such as
piroxicam, tenoxicam, phenylbutazone and oxyphenthatrazone),
nabumetone and gold compounds (such as auranofin, gold thioglucose
and sodium aurothiomalate).
[0096] Alternatively, alfa-interferon, an angiogenic agent, a
vascular endothelical growth factor (VEGF), an angiotensin receptor
blocking agent, a nitrogen oxide donor, antisense oligonucleotides
and a combination of them, a cell cycle inhibitor, a mTOR
inhibitor, a growth factor signal transduction kinase inhibitor,
retenoid, a cyclin/CDK inhibitor, an HMG coenzyme reductase
inhibitor (statins), a protease inhibitor or the like can be
used.
[0097] Furthermore, one of the aforementioned drugs may be singly
used or a plurality of them may be used together. Moreover, instead
of the drug, epithelial cells having genes engineered for
discharging various drugs by the gene engineering technique may be
used.
[0098] The drug having the effect to prevent the restenosis may be
held in the polymer by any of known methods. For example, the drug
can be held in the polymer by mixing the polymer in the form of a
gel and the drug in a given concentration. In this case, the drug
is held in the polymer through the physical interaction or the
ionic interaction. Alternatively, depending upon the kind of
polymer to be used, the drug may be subsumed by the
three-dimensional structure of the polymer. When a solution or the
like obtained by mixing the polymer and the drug is used for
immobilizing the polymer onto the DLC film, the drug can be held in
the polymer at the same time as the polymer is immobilized onto the
DLC film.
[0099] Immobilization of Polymer
[0100] The polymer is immobilized onto the surface of the DLC film
12 by immersing, in a polymer solution, the stent body 11 having
the activated DLC film 12 or by spraying or dropping a polymer
solution over the stent body 11 having the activated DLC film 12.
When the immersion is employed in particular, the polymer can be
efficiently immobilized on the stent because the inner surface
easily comes into contact with the polymer solution.
[0101] As a solvent of the polymer solution used in the dipping or
spraying, an arbitrary solvent with solubility in the polymer can
be selected. A mixed solvent including two or more solvents can be
used in order to adjust the volatility of the solvent.
Alternatively, it is not necessary to dissolve the polymer in the
solvent but the solution may be a suspension or dispersion.
Furthermore, when a liquid polymer is used, the polymer can be used
as it is without using a solvent. Alternatively, the polymer may be
placed in a melted state for use.
[0102] The concentration of the polymer solution is not
particularly specified and is determined in consideration of the
surface characteristic of the polymer layer 13, the necessary
amount of drug to be held, the releasing behavior of the held drug
and the like.
[0103] The ultimate thickness of the polymer layer 13 needs to be
large from the viewpoint of the thickness uniformity of the polymer
layer 13 on the stent surface, but if it is too large, a crack may
be caused during the use of the stent. Therefore, the thickness is
not less than 0.1 .mu.m and not more than 200 .mu.m and is
preferably not less than 1 .mu.m and not more than 100 .mu.m.
[0104] Alternatively, the polymer layer 13 may include a plurality
of layers. In this case, the drug may be contained in merely some
of the layers. Alternatively, the respective layers may include
different kinds of polymers. For example, an undercoat layer in
contact with the DLC film may include a polymer with high
adhesiveness to the DLC film, and a topcoat layer in contact with
blood may include a biocompatible material such as silicon resin or
a biodegradable polymer such as polylactic acid. Instead, a polymer
including an antithrombotic material such as heparin may be used.
In this case, a polymer included in the topcoat layer may be
selected in consideration of an esthetic effect such as a color and
luster.
EXAMPLE
[0105] The stent of the present invention will now be described in
detail by describing a specific example. In this example, a Co--Cr
alloy stent having a length of 19 mm, a diameter of 1.5 mm and a
cell thickness of 75 .mu.m was used as the stent body 11.
[0106] FIG. 2 schematically shows an ionization evaporation system
used in this example, and this is a general ionization evaporation
system in which a DLC film is solidified and deposited on a target
22 by colliding, against the target 22 biased to a negative
voltage, plasma generated by introducing Ar and benzene
(C.sub.6H.sub.6) gases corresponding to ion sources into a DC arc
discharge plasma generator 21 provided within a vacuum chamber.
[0107] A stent body 11 was set within the chamber of the ionization
evaporation system of FIG. 2, and bombardment cleaning, in which Ar
ions are produced by discharging after introducing an argon gas
(Ar) into the chamber so as to attain a pressure of 10.sup.-1 Pa
through 10.sup.-3 Pa (10.sup.-3 Torr through 10.sup.-5 Torr) and
the thus produced Ar ions are collided against the surface of the
stent body, was performed for approximately 30 minutes.
[0108] Subsequently, tetramethylsilane (Si(CH.sub.3).sub.4) was
introduced into the chamber for 3 minutes, so as to form an
amorphous intermediate layer with a thickness of 20 nm including
silicon (Si) and carbon (C) as principal components.
[0109] After forming the intermediate layer, a C.sub.6H.sub.6 gas
was introduced into the chamber, and the gas pressure was set to
10.sup.-1 Pa. C.sub.6H.sub.6 was ionized by causing discharge while
continuously introducing the C.sub.6H.sub.6 into the chamber at a
rate of 30 ml/min., and the ionization evaporation was performed
for approximately 2 minutes, so as to form a DLC film 12 with a
thickness of 30 nm on the surface of the stent body 11.
[0110] In forming the DLC film 12, a substrate voltage was set to
1.5 kV, a substrate current was set to 50 mA, a filament voltage
was set to 14 V, a filament current was set to 30 A, an anode
voltage was set to 50 V, an anode current was set to 0.6 A, a
reflector voltage was set to 50 V and a reflector current was set
to 6 mA. Also, the temperature of the stent body attained in the
formation is approximately 160.degree. C.
[0111] The intermediate layer is provided for improving the
adhesiveness between the stent body 11 and the DLC film 12, and
therefore, it may be omitted if sufficient adhesiveness is attained
between the stent body 11 and the DLC film 12.
[0112] Although a single gas of C.sub.6H.sub.6 was used as a carbon
source in this example, another hydrocarbon material or a mixed gas
of a hydrocarbon material including C.sub.6H.sub.6 and a flon gas
such as CF.sub.4 may be used, so as to form a DLC film 12 including
fluorine on the surface of the stent body 11.
[0113] Next, the DLC film 12 formed on the surface of the stent
body 11 was irradiated with plasma so as to introduce functional
groups into a surface portion of the DLC film 12. FIG. 3
schematically shows a plasma irradiation system used in this
example.
[0114] As shown in FIG. 3, the plasma irradiation system is a
general plasma irradiation system, in which an electrode 33 and an
electrode 34 are provided respectively on the bottom and in the
middle of a chamber 31 connected to a vacuum pump 32 and capable of
exchanging gases included therein. When high-frequency waves are
applied from a radio-frequency power supply 35 through a matching
network 36 to the electrode 33 and the electrode 34, plasma is
generated within the chamber 31.
[0115] First, the stent body 11 having the DLC film 12 was set
within the chamber 31 of the plasma irradiation system, and
acetylene was allowed to flow so as to attain an internal pressure
of the chamber of 133 Pa. Subsequently, high-frequency waves of 50
W were applied to the electrodes 33 and 34 by using the
radio-frequency power supply 35 (manufactured by Adtec Plasma
Technology Co., Ltd.; AX-300; with a frequency of 13.56 MHz), so as
to generate plasma within the chamber 31. The stent having the DLC
film was irradiated with the plasma for approximately 30 seconds,
so as to produce functional groups in a surface portion of the DLC
film 12.
[0116] Alternatively, the DLC film can be activated by producing
radicals in the surface portion of the DLC film by using an Ar or
oxygen gas in this example.
[0117] Next, a polymer layer 13 was formed by immobilizing a
polymer containing a drug 14 on the surface of the DLC film 12 into
which the functional groups had been introduced. As the polymer,
poly(DL-lactic acid) was used, and rapamycin was used as the drug
14. Immediately after the plasma processing, a liquid containing
the polymer and the drug was sprayed all over the surface of the
stent at a rate of 0.02 ml/min. for 8 minutes while rotating the
stent at a rate of 120 rpm. For immobilizing the polymer, a
solution prepared by mixing 1.5 wt % of poly(DL-lactic acid), 0.5
wt % of rapamycin and 98 wt % of chloroform was used. After
completing the spraying, the stent was dried with nitrogen airflow
for 10 minutes and further dried at room temperature under reduced
pressure for twenty-four hours.
[0118] After completing the drying, the weight of the stent was
measured, resulting in confirming that the amount of immobilized
polymer was 0.54 mg. When the stent was observed with a
stereoscopic microscope with a magnifying power of 400 times, it
was found that the polymer layer 13 was uniformly coated on the
surface of the stent, and no cracks and no defects such as peeling
was observed. Next, the stent was mounted on a balloon catheter,
and the diameter of the stent was expanded to 3.0 mm by expanding
the balloon. At this point, the maximum strain of the stent was 40%
at the maximum. After the expansion, the catheter was drawn off and
the polymer layer 13 was observed, but no crack was found in the
polymer layer 13 and no peeling of the polymer layer 13 off from
the stent body 11 was observed.
[0119] In this manner, in the stent of this example, the polymer
containing the drug capable of preventing arterial intimal
thickening is tightly immobilized onto the surface of the stent
covered with the DLC film. Therefore, even if the stent is largely
deformed, the polymer layer suffers from no cracks and is never
peeled off from the surface of the stent. As a result, it is
possible to realize a stent in which the drug can be continuously
released and a base material is minimally degraded.
INDUSTRIAL APPLICABILITY
[0120] According to the stent and the method for fabricating the
same of this invention, it is possible to realize a stent that is
not degraded in its base material by a biogenic component and
continuously releases a drug for preventing restenosis, and the
invention is useful particularly as a drug release stent and a
method for fabricating the same.
* * * * *