U.S. patent application number 10/363668 was filed with the patent office on 2003-09-25 for stent.
Invention is credited to Ishii, Naoki, Togawa, Hideyuki.
Application Number | 20030181975 10/363668 |
Document ID | / |
Family ID | 19042762 |
Filed Date | 2003-09-25 |
United States Patent
Application |
20030181975 |
Kind Code |
A1 |
Ishii, Naoki ; et
al. |
September 25, 2003 |
Stent
Abstract
A stent capable of stably loading a biologically/physiologically
active substance, without causing its decomposition or
deterioration, and permitting it to release itself slowly over a
long period of time without being rapidly released in a short
period, after being implanted in a lesion. The stent (1) comprises
a cylindrical stent main body (2) having an opening on each end and
extending in axial direction between the two openings, and a
sustained release coating formed on the surface of said stent main
body from which a biologically/physiologically active substance is
released, and wherein said sustained release coating is composed of
a layer of a biologically/physiologically active substance (3)
which covers the surface of said stent main body, and a polymer
layer (4) which covers said layer of a biologically/physiologically
active substance (3) on said layer of a
biologically/physiologically active substance (3), and said layer
of a biologically/physiologically active substance (3) contains at
least one kind of fat-soluble biologically/physiologically active
substance, and said polymer layer (4) contains a polymer miscible
with said biologically/physiologically active substance and fine
particles (5) equal to or smaller than 5 .mu.m in particle diameter
dispersed in the polymer.
Inventors: |
Ishii, Naoki; (Kanagawa,
JP) ; Togawa, Hideyuki; (Kanagawa, JP) |
Correspondence
Address: |
BURNS DOANE SWECKER & MATHIS L L P
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Family ID: |
19042762 |
Appl. No.: |
10/363668 |
Filed: |
March 6, 2003 |
PCT Filed: |
July 4, 2002 |
PCT NO: |
PCT/JP02/06767 |
Current U.S.
Class: |
623/1.42 |
Current CPC
Class: |
A61L 2300/602 20130101;
A61L 31/16 20130101; A61L 31/10 20130101; A61L 2300/608
20130101 |
Class at
Publication: |
623/1.42 |
International
Class: |
A61F 002/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 6, 2001 |
JP |
2001206665 |
Claims
What is claimed is:
1. A stent to be implanted in a duct of a living body, comprising:
a cylindrical stent main body having an opening on each end and
extending in axial direction between the two openings and a
sustained release coating formed on the surface of said stent main
body from which a biologically/physiologically active substance is
released; wherein said sustained release coating composed of: a
layer of a biologically/physiologically active substance which
covers the surface of said stent main body; and a polymer layer
which covers said layer of a biologically/physiologically active
substance on said layer of a biologically/physiologically active
substance, said layer of a biologically/physiologically active
substance containing at least one kind of fat-soluble
biologically/physiologically active substance, said polymer layer
containing a polymer miscible with said
biologically/physiologically active substance and fine particles
equal to or smaller than 5 .mu.m in particle diameter dispersed in
the polymer.
2. The stent as defined in claim 1, wherein the stent main body is
formed from a metallic material.
3. The stent as defined in claim 1, wherein the stent main body is
formed from a polymeric material.
4. The stent as defined in any of claims 1 to 3, wherein the layer
of a biologically/physiologically active substance is composed
solely of a biologically/physiologically active substance.
5. The stent as defined in any of claims 1 to 4, wherein the
biologically/physiologically active substance is any of
antineoplastic agent, immunosuppressor, antibiotic, antirheumatic,
antilipemic agent, ACE inhibitor, calcium antagonist, antiallergic
agent, retinoid, antioxidant, and anti-inflammatory agent.
6. The stent as defined in any of claims 1 to 5, wherein the
biologically/physiologically active substance is one which has a
molecular weight not higher than 600.
7. The stent as defined in any of claims 1 to 6, wherein the
polymer is a silicone polymer.
8. The stent as defined in any of claims 1 to 7, wherein the fine
particles are those of a low-molecular-weight water-soluble salt
having a molecular weight not higher than 1000.
9. The stent as defined in claim 8, wherein the
low-molecular-weight salt is sodium chloride.
10. The stent as defined in any of claims 1 to 7, wherein the fine
particles are those of a water-insoluble substance.
11. The stent as defined in claim 10, wherein the water-insoluble
substance is a silica filler.
12. The stent as defined in claim 10, wherein the water-insoluble
substance is polytetrafluoroethylene.
Description
TECHNICAL FIELD
[0001] The present invention relates to a stent which is designed
to be implanted in a stenotic or occluded lesion that has occurred
in such ducts of a living body as blood vessel, bile duct, trachea,
esophagus, and urethra, thereby keeping the lesion open. More
particularly, the present invention relates to a stent which slowly
releases from its surface over a long period of time a
biologically/physiologically active substance effective in
preventing restenosis, thereby keeping open the lesion over a long
period of time.
BACKGROUND ART
[0002] The following provides some background to the present
invention with reference to angioplasty applied to ischemic heart
disease.
[0003] The diffusion of westernized diets in Japan has steeply
increased patients suffering from ischemic heart diseases (angina
pectoris, cardiac infarction). Among new remedies against such
heart diseases is percutaneous transluminal coronary angioplasty
(PTCA), which is gaining general acceptance rapidly. It has matured
technically and is now applied to more cases than before. PTCA was
originally applied to a circumscribed lesion (with short lesion
length) or a single vessel lesion (with the stenosis only at one
vessel). Its application has been extended to a lesion which is
distal, eccentric, or calcified, or a multivessel lesion (with the
stenosis at two or more vessels).
[0004] PTCA is a procedure which consists of making a small
incision in an artery of a patient's arm or leg, indwelling an
introducer sheath in the incision, inserting a long tube called
guide catheter into the blood vessel through the sheath, with a
guide wire preceding, after the tube reaches the entrance of the
coronary artery, withdrawing the guide wire, passing another guide
wire and a balloon catheter through the guide catheter, advancing
the balloon catheter under the X-ray radiography, with the guide
wire preceding, to the lesion, namely the stenotic or occluded
lesion in the coronary artery, and inflating the balloon once or
more times at a prescribed pressure for 30 to 60 seconds. The
result of this procedure is that the blood vessel at the lesion
expands and remains open, thereby allowing more blood to flow in
the blood vessel. The disadvantage of this procedure is that there
is a possibility of the catheter damaging the vascular wall. In
fact, it has been reported that restenosis occurs in a ratio of 30
to 40% by the growth of the vascular inner membrane which heals the
damaged vascular wall.
[0005] Although no method for preventing restenosis has been firmly
established yet, there is a promising one which employs such
devices as stent and atherectomy catheter. The term "stent" used
herein denotes a medical device in hollow cylindrical shape,
usually made of metallic or polymeric material. It is used to cure
various diseases resulting from stenosis or occlusion in blood
vessels or other ducts. When in use, it expands the lesion, namely
the stenotic or occluded lesion and is implanted there so as to
keep open the blood vessel or duct. A variety of stents have been
proposed so far. For example, one is a hollow cylindrical body
having pores formed in the side wall thereof which is made of
metallic or polymeric material, and another is a cylindrical body
which is woven from metal wires or polymer fibers. The object of
the implanted stent is to prevent or reduce the possibility of
restenosis occurring after PTCA. However, it has turned out that
any stent used alone cannot effectively prevent restenosis.
[0006] Nowadays, attempts are being made to reduce the possibility
of restenosis in such a way that the stent is loaded with a
biologically/physiologically active substance such as anticancer
drug which locally and slowly releases itself in the implanted
lesion. For example, JP 8-33718 A proposes a stent wherein a
mixture composed of a therapeutical substance (a
biologically/physiologically active substance) and a polymer is
coated on the surface of the stent main body, and JP 9-99056 A
proposes a stent wherein a layer of a bioactive material (a layer
of a biologically/physiologically active substance) is formed on
the surface of the stent main body, and a polymeric porous material
layer is formed on the surface of the layer of the bioactive
material.
[0007] Regrettably, the stent proposed in JP 8-33718 A has the
disadvantage that the therapeutical substance
(biologically/physiological- ly active substance) incorporated in
the polymer is decomposed or deteriorated by chemical reactions
between them. The problem with chemical instability of the
biologically/physiologically active substance is explained below
with reference to an example in which the polymer is polylactic
acid. Because of its decomposability in a living body, polylactic
acid permits the biologically/physiologically active substance to
release itself efficiently. On the other hand, because of its
tendency to liberate an acid upon decomposition, polylactic acid
deteriorates the biologically/physiologically active substance
which might have a weak acid resistance. Moreover, when a readily
biodegradable polymer is selected, it permits the
biologically/physiologically active substance to release itself in
a short period (several days after implanted), resulting in making
the stent unable to prevent restenosis sufficiently. In other
words, the stent proposed in JP 8-33718 A, which is so designed as
to prevent the biologically/physiologically active substance from
decomposition and deterioration and to permit the
biologically/physiologi- cally active substance to release itself
over a long period of time (several weeks to several months after
implanted), has the disadvantage that the range of selection of the
biologically/physiologically active substance is limited by
combination with the polymer.
[0008] The stent proposed in JP 9-99056 A has no problems with the
bioactive material (the biologically/physiologically active
substance) being decomposed and deteriorated by the polymer because
the biologically/physiologically active substance exists in a layer
which is separated from the polymer layer. Nevertheless, it still
has a drawback resulting from the fact that the layer of the
biologically/physiologicall- y active substance is covered with a
porous polymer layer. In other words, the
biologically/physiologically active substance remains exposed to
the atmosphere surrounding the stent (the atmosphere outside the
polymer layer) throughout the period from production to insertion
into a living body, because the polymer layer has passages
penetrating through it. Therefore, the stent of such structure
would permit the biologically/physiologically active substance to
release itself through the passages in the porous polymer layer
before it is implanted at the lesion. Moreover, it is liable to
cause the phenomenon that biologically/physiologically active
substance is released rapidly in a short period (several days after
implanted) after it has been implanted at the lesion, namely the
initial burst. Thus, the above-mentioned stent presents
difficulties in permitting the biologically/physiologically active
substance to release itself slowly over a long period of time
(several weeks to several months after implanted).
DISCLOSURE OF INVENTION
[0009] It is an object of the present invention to provide a stent
capable of stably loading a biologically/physiologically active
substance, without causing its decomposition and deterioration, and
permitting it to release itself slowly over a long period of time
without being rapidly released in a short period, after implanted
in a lesion.
[0010] The present invention to achieve the above-mentioned object
includes the following aspects (1) to (12).
[0011] (1) A stent to be implanted in a duct of a living body,
comprising:
[0012] a cylindrical stent main body having an opening on each end
and extending in axial direction between the two openings and
[0013] a sustained release coating formed on the surface of said
stent main body from which a biologically/physiologically active
substance is released; wherein
[0014] said sustained release coating composed of:
[0015] a layer of a biologically/physiologically active substance
which covers the surface of said stent main body; and
[0016] a polymer layer which covers said layer of a
biologically/physiologically active substance on said layer of a
biologically/physiologically active substance,
[0017] said layer of a biologically/physiologically active
substance containing at least one kind of fat-soluble
biologically/physiologically active substance,
[0018] said polymer layer containing a polymer miscible with said
biologically/physioiogically active substance and fine particles
equal to or smaller than 5 .mu.m in particle diameter dispersed in
the polymer.
[0019] (2) The stent as defined in (1) above wherein the stent main
body is formed from a metallic material.
[0020] (3) The stent as defined in (1) above wherein the stent main
body is formed from a polymeric material.
[0021] (4) The stent as defined in any of (1) to (3) above wherein
the layer of a biologically/physiologically active substance is
composed solely of a biologically/physiologically active
substance.
[0022] (5) The stent as defined in any of (1) to (4) above wherein
the biologically/physiologically active substance is any of
antineoplastic agent, immunosuppressor, antibiotic, antirheumatic,
antilipemic agent, ACE inhibitor, calcium antagonist, antiallergic
agent, retinoid, antioxidant, and anti-inflammatory agent.
[0023] (6) The stent as defined in any of (1) to (5) above wherein
the biologically/physiologically active substance is one which has
a molecular weight not higher than 600.
[0024] (7) The stent as defined in any of (1) to (6) above wherein
the polymer is a silicone polymer.
[0025] (8) The stent as defined in any of (1) to (7) above wherein
the fine particles are those of a low-molecular-weight
water-soluble salt having a molecular weight not higher than
1000.
[0026] (9) The stent as defined in (8) above wherein the
low-molecular-weight salt is sodium chloride.
[0027] (10) The stent as defined in any of (1) to (7) above wherein
the fine particles are those of a water-insoluble substance.
[0028] (11) The stent as defined in (10) above wherein the
water-insoluble substance is a silica filler.
[0029] (12) The stent as defined in (10) above wherein the
water-insoluble substance is polytetrafluoroethylene.
BRIEF DESCRIPTION OF DRAWINGS
[0030] FIG. 1 is a side view showing one embodiment of the stent
according to the present invention.
[0031] FIG. 2 is an enlarged transverse cross-sectional view taken
along line A-A in FIG. 1.
[0032] FIG. 3 is a partially enlarged vertical cross-sectional view
taken along line B-B in FIG. 1.
[0033] FIG. 4 is identical with FIG. 3 except that the fine
particles in the polymer layer are dispersed in a different
manner.
[0034] FIG. 5 is a schematic diagram showing the apparatus used in
Example to measure the rate at which simvastatin passes through the
polymer layer.
BEST MODE FOR CARRYING OUT THE INVENTION
[0035] The invention will be described in more detail with
reference to the preferred embodiments in conjunction with the
accompanying drawings.
[0036] The stent according to the present invention includes a
stent main body and a sustained release coating which covers the
surface of the stent main body.
[0037] FIG. 1 is a side view showing one embodiment of the stent
according to the present invention. FIG. 2 is an enlarged
transverse cross-sectional view taken along line A-A in FIG. 1.
FIG. 3 is a partially enlarged vertical cross-sectional view taken
along line B-B in FIG. 1.
[0038] As FIGS. 2 and 3 show, in the stent 1 according to the
present invention, a layer 3 of biologically/physiologically active
substance covers a fibrous member 2 on the surface of the fibrous
member 2 constituting the stent main body , and a polymer layer 4
covers the layer 3 of biologically/physiologically active substance
on the layer 3 of biologically/physiologically active substance. It
is not always necessary that the layer 3 of
biologically/physiologically active substance entirely covers the
fibrous member 2 constituting the stent main body, but it is only
necessary that the layer 3 of biologically/physiologically active
substance partly covers the fibrous member 2 constituting the stent
main body. Thus the stent may vary in the way the layer 3 of
biologically/physiologically active substance covers the fibrous
member 2. For example, the layer 3 of biologically/physiologically
active substance may cover only that part of the fibrous member 2
which forms the outer surface of the stent main body which is
cylindrical body. Conversely, the layer 3 of
biologically/physiologically active substance may cover only that
part of the fibrous member 2 which forms the inner surface of the
stent main body. On the other hand, the layer 3 of
biologically/physiologically active substance should always be
covered with the polymer layer 4.
[0039] A more detailed mention is made below of the components
constituting the stent 1 according to the present invention.
[0040] The stent main body is an cylindrical body having an opening
on each end and extending in axial direction between these
openings. The wall of the cylindrical body has a large number of
holes passing across it between the outer surface and the inner
surface. The cylindrical body is constructed such that it expands
or contracts in its radial direction as the holes deform. It
retains its shape while it is implanted in a duct of a living body
such as blood vessel and bile duct.
[0041] The stent main body shown in FIG. 1 is constituted of an
elastic fibrous material 2 and composed of basic units 11 having a
rhombic hole. A plurality of the basic units 11 arranged and
connected to one another in the circumferential direction form an
annular unit 12. One annular unit 12 joins to its adjacent ones
through a linear elastic material 13. Thus a plurality of annular
units 12 are continuously arranged in the axial direction with
partial connection to one another. The stent main body (stent) 1
constructed in this manner forms an cylindrical body having an
opening on each end and extending in axial direction between these
openings. Moreover, the stent main body (stent) 1 has rhombic
holes, so that it expands or contracts in its radial direction as
the holes deform.
[0042] The stent main body according to the present invention is
not limited to that shown in FIG. 1, however, it may include the
one which is an cylindrical body having an opening on each end and
extending in axial direction between these openings and has a large
number of holes passing across its wall between the outer surface
and the inner surface, so that the cylindrical body expands or
contracts in its radial direction as the holes deform.
[0043] Examples of the stent main body that expands or contract in
its radial direction are found in the following disclosures.
[0044] JP 9-215753 A and JP 7-529 A propose a stent main body in a
cylindrical shape consisting of a plurality of coils of elastic
wires joined together. Gaps between the elastic wires function as
holes.
[0045] JP 8-502428 A and JP 7-500272 A propose a stent main body in
a cylindrical shape consisting of zigzag elastic wires joined
together. Gaps between the elastic wires function as holes.
[0046] JP 2000-501328 and JP 11-221288 A propose a stent main body
in a cylindrical shape consisting of winding elastic wires in a
helical form. Gaps between the elastic wires function as holes.
[0047] JP 10-503676 proposes a stent main body in mesh structure
having meanderingly arranged holes unlike the stent main body shown
in FIG. 1.
[0048] JP 8-507243 proposes a stent main body in a cylindrical
shape formed with a coiled flat member. Gaps between adjacent coils
function as holes.
[0049] JP 4-68939 B propose a variation of stent main body
including two cylindrical bodies, one being formed with a helically
wound elastic flat member and having gaps functioning as holes
between adjacent coils, and the other being formed with braded
elastic wires and having gap functioning as holes between elastic
wires. The stent main body of the present invention may be in any
form like coiled leaf spring, multiple coil, odd-shape tube, and so
on. In addition, the stent main body of the present invention may
also be something similar to the one shown in FIGS. 2(a) and 2(b)
in JP 4-68939 B. It is a cylindrical body formed with a coiled
elastic flat member. The cylindrical body has no holes in its side
wall but expands and contracts in its radial direction. Citations
from the above-mentioned literature and patent application
constitute a part of this specification.
[0050] No specific restrictions are imposed on the method of
expanding the stent main body which has been implanted in a lesion.
The stent main body may be of self-expansive type, that is, it
expands in its radial direction by its own restoring force when it
is released from the force to fold it small. Alternatively, the
stent main body may be of ballon-expandable type, that is, it is
expanded in its radial direction by an external force as the
balloon placed therein is inflated.
[0051] The stent main body may be formed from a polymeric material,
metallic material, carbon fiber, ceramics, or the like. These
materials are not specifically restricted so long as they have a
certain degree of stiffness and elasticity. However, those which
are compatible with a living body are preferable.
[0052] Typical examples of the materials are listed below.
[0053] Polymeric materials: polyolefins such as polyethylene and
polypropylene, polyesters such as polyethylene terephthalate,
cellulosic polymers such as cellulose acetate and cellulose
nitrate, and fluoroplastics such as poly-tetrafluoroethylene,
tetrafluoroethylene-ethy- lene copolymer.
[0054] Metallic materials: stainless steel, tantalum, titanium,
nickel-titanium alloy, tantalum-titanium alloy, nickel-aluminum
alloy, Inconel, gold, platinum, iridium, tungsten, and cobalt
alloy. In some variation of stainless steel, SUS316L is desirable
because of its outstanding corrosion resistance.
[0055] The stent main body may be formed as desired from any of the
above-mentioned materials which is selected according to the lesion
to which the stent is applied or the means by which the stent is
expanded. A stent formed from a metallic material ensures being
implanted in the lesion on account of the high strength of metal. A
stent formed from a polymeric material permits easy delivery to the
lesion on account of the good flexibility of polymer.
[0056] A stent of self-expansive type should preferably be formed
from a highly elastic alloy such as titanium-nickel alloy so that
it has a sufficient restoring force. A stent of balloon-expandable
type should preferably be formed from stainless steel so that it
will not return to its original shape after expansion.
[0057] A stent made of carbon fiber is desirable because of its
high strength, good flexibility, and high safety in a living
body.
[0058] The size of the stent main body should be determined
according to the lesion to which the stent is applied. It should
preferably be in the range of 1.0 to 3.0 mm in outside diameter and
in the range of 5 to 50 mm in length before expansion, if the stent
is to be applied to the coronary artery.
[0059] In the case of a stent main body made of a fibrous member,
the widthwise length of the fibrous member constituting holes
should be in the range of 0.01 to 0.5 mm, preferably in the range
of 0.05 to 0.2 mm.
[0060] The method of producing the stent main body is not
specifically restricted; an ordinary one may be employed according
to the structure and material of the stent.
[0061] In the stent according to the present invention, a layer 3
of biologically/physiologically active substance covers the surface
of the fibrous member 2 constituting the above-mentioned stent main
body. In the case of a stent main body formed from other
constituent besides the fibrous member, for example, a sheet
member, a layer 3 of biologically/physiologically active substance
covers the surface of the constituent like the sheet member.
[0062] The layer 3 of biologically/physiologically active substance
should contain at least one kind of fat-soluble
biologically/physiologically active substance, which is not
specifically restricted so long as it is effective in preventing
restenosis while the stent is implanted in the lesion. It includes,
for example, antineoplastic agent, immunosuppressor, antibiotics,
antilipemic agent, ACE inhibitor, calcium antagonist, antiallergic
agent, retinoid, antioxidant, and anti-inflammatory agent.
[0063] Preferred antineoplastic agents include, for example,
irinotecan hydrochloride, paclitaxel, docetaxel hydrate, and
methotrexate.
[0064] Preferred immunosuppressors include, for example, sirolimus,
tacrolimus hydrate, azathioprine, ciclosporin, and mycophenolate
mofetil.
[0065] Preferred antibiotics include, for example, mitomycin C,
doxorubicin hydrochloride, actinomycin D, idarubicin hydrochloride,
and pirarubicin hydrochloride.
[0066] Preferred antilipemic agents include, for example, probucol
and HMG-CoA reductase inhibitor such as cerivastatin, simvastatin,
and lobastatin.
[0067] Preferred ACE inhibitors include, for example, trandolapril,
cilazapril, temocapril hydrochloride, delapril hydrochloride, and
enalapril maleate.
[0068] Preferred calcium antagonists include, for example,
nilvadipine, benidipin hydrochloride, and nisoldipine.
[0069] Preferred antiallergic agents include, for example,
tranilast.
[0070] Preferred retinoids include, for example, all-trans retinoic
acid.
[0071] Preferred antioxidants include, for example,
epigallocatechin gallate.
[0072] Preferred anti-inflammatory agents include, for example,
aspirin and steroids such as dexamethazone and prednisolone.
[0073] The biologically/physiologically active substance should
desirably be a low-molecular-weight one which has a molecular
weight not higher than 600. Such a biologically/physiologically
active substance passes through the polymer layer at a relatively
high rate if fine particles are not dispersed in the polymer layer.
However, it releases itself slowly if fine particles are dispersed
in the polymer layer.
[0074] Of the biologically/physiologically active substances
illustrated above, typical examples having a molecular weight not
higher than 600 include cerivastatin, simvastatin, and
lobastatin.
[0075] The layer of biologically/physiologically active substance
may contain only one kind of the biologically/physiologically
active substance illustrated above, or alternatively ,more than one
kind of the biologically/physiologically active substances of the
combination adequately selected from the
biologically/physiologically active substances illustrated above
according to need.
[0076] The layer 3 of biologically/physiologically active substance
is formed on the surface of the fibrous member 2 constituting the
stent main body, as mentioned above. The method for this step is
not specifically restricted so long as it permits the layer 3 of
biologically/physiologica- lly active substance to be formed
uniformly on the surface of the fibrous member 2 constituting the
stent main body. One possible way is to apply the
biologically/physiologically active substance in a molten state to
the surface of the fibrous member 2 constituting the stent main
body. Another way is to dip the stent main body into the
biologically/physiologically active substance in a molten state,
followed by pulling out and cooling. It is also possible to coat
the fibrous member constituting the stent main body with the layer
of the biologically/physiologically active substance by dissolving
the biologically/physiologically active substance in an adequate
solvent and then dipping the stent main body into the resulting
solution, followed by pulling up and drying for solvent removal, or
spraying the stent main body with the resulting solution, followed
by drying for solvent removal.
[0077] In the case where the biologically/physiologically active
substance alone does not form its layer on the surface of the
fibrous member 2 constituting the stent main body due to its
insufficient adhering force, it is desirable to add an additional
component for imparting adhesion to the solution. Examples of such
an additional component include low-molecular-weight higher fatty
acid with a molecular weight not higher than 1000 such as fish oil
and vegetable oil, and fat-soluble vitamins such as vitamin A and
vitamin E. If the additional component has a melting point low
enough not to harm the biologically/physiologically active
substance, then it is possible to heat the coating film above the
melting point of the mixture so that the layer of the
biologically/physiologically active substance firmly adheres to the
surface of the fibrous member 2 constituting the stent main
body.
[0078] The layer of the biologically/physiologically active
substance can be formed most easily and simply by dipping or
spraying if there exists an adequate solvent for the
biologically/physiologically active substance and the resulting
solution alone can form a layer on the surface of the fibrous
member 2 constituting the stent main body.
[0079] The biologically/physiologically active substance may vary
in amount in its layer depending on the shape and size of the
stent. An desirable amount ranges from 100 to 1,000 .mu.g/cm2. An
adequate amount should be established so that the
biologically/physiologically active substance fully produces its
effect without adversely affecting the performance of the stent
main body (such as ability to be delivered to the lesion and
freedom from stimulant action on vascular walls).
[0080] In the stent according to the present invention, a polymer
layer 4 covers the layer 3 of the biologically/physiologically
active substance. The polymer layer 4 is composed of a polymer
miscible with the biologically/physiologically active substance,
and fine particles equal to or smaller than 5 .mu.m in particle
diameter are dispersed in the polymer layer 4.
[0081] Being miscible with the biologically/physiologically active
substance, the polymer constituting the polymer layer 4 dissolves
the biologically/physiologically active substance at the interface
between the polymer layer 4 and the layer 3 of the
biologically/physiologically active substance. The dissolved
biologically/physiologically active substance passes through the
polymer layer 4 and releases itself to the outside of the sustained
release coating. If the polymer layer 4 is composed only of a
polymer miscible with the biologically/physiologically active
substance, it would permit the biologically/physiologically active
substance to pass through the polymer layer 4 and release itself to
the outside of the polymer layer 4 rapidly in a short period
However, this is not the case with the stent of the present
invention, in which the polymer layer 4 contains fine particles 5
equal to or smaller than 5 .mu.m in particle diameter dispersed
therein which control the rate at which the
biologically/physiologically active substance releases itself. In
other words, the fine particles 5 dispersed in the polymer layer 4
function as obstacles to the biologically/physiologically active
substance passing through the polymer layer 4, thereby retarding
and controlling the passage of the biologically/physiologically
active substance. As the result, the biologically/physiologically
active substance releases itself from the polymer layer 4 slowly
over a long period of time without being rapidly released in a
short period.
[0082] The polymer from which the polymer layer 4 is formed is not
specifically restricted so long as it is misclible with the
biologically/physiologically active substance forming the layer 3
of the biologically/physiologically active substance. Therefore, it
should be selected according to the biologically/physiologically
active substance used. It is usually fat-soluble because the
biologically/physiologically active substance is fat-soluble.
[0083] The polymer for the polymer layer 4 should have high
stability in a living body and low stimulation to tissues in view
of the fact that it is used for the stent implanted in a duct of a
living body. Examples of such a polymer include silicone polymer
such as silicone elastomer, cellulosic plastics, polyurethane,
polyester, vinyl polymer, acrylic polymer, and thermoplastic
elastomer. Of these examples, silicone elastomer is most
desirable.
[0084] A silicone elastomer denotes any elastomer composition
composed mainly of straight-chain or branched-chain
dialkylpolysiloxane. The dialkylpolysiloxane may have its alkyl
groups partly replaced by vinyl groups, amino groups, hydrogen
atoms, chlorine atoms, and so on, although more than 90% of alkyl
groups are methyl groups. The silicone elastomer should have a
viscosity not lower than 500 cps before curing and a durometer
hardness (Shore A) of 20 to 80 after curing. Incidentally, a
silicone elastomer of two-pack system is preferable because of its
good workability in forming the polymer layer 4. Silicone
elastomers meeting the above-mentioned conditions are commercially
available under a trade name of, for example, "Silastic" (Dow
Corning Corporation) and "Silicone Elastomer MED-4211" (Nusil).
[0085] The above-mentioned polymer may contain additional
components such as plasticizer and filler in an amount not harmful
to the effect of the present invention.
[0086] No specific restrictions are imposed on the method for
covering the layer 3 of biologically/physiologically active
substance with the polymer layer 4 and the method for dispersing
the fine particles 5 in the polymer layer 4, so long as the layer 3
of biologically/physiologically active substance is covered
completely with the polymer layer 4 and the fine particles 5 are
uniformly or unevenly as mentioned later dispersed in the polymer
layer 4. One method may consist of dissolving a polymer and the
fine particles in a solvent and dipping the stent main body covered
with the layer of biologically/physiologically active substance in
the resulting solution, followed by drying. The other method may
consist of spraying the resulting solution onto the fibrous member
constituting the stent main body, the fibrous member being
previously covered with the layer of biologically/physiologically
active substance, followed by drying.
[0087] As in the case of the layer 3 of
biologically/physiologically active substance, the thickness of the
polymer layer 4 should be established in an adequate range which is
not harmful to the performance of the stent main body 2 such as
easy delivery to the lesion and non stimulus to the vascular wall.
The thickness of the polymer layer 4 should preferably be in the
range of 1 to 75 .mu.m, more preferably in the range of 10 to 50
.mu.m, and most desirably in the range of 20 to 30 .mu.m. With a
thickness smaller than 1 .mu.m, the polymer layer 4 does not
completely cover the layer 3 of biologically/physiologically active
substance because the diameter of the fine particles contained
therein are relatively larger than the thickness of the polymer
layer 4. Conversely, with a thickness larger than 75 .mu.m, the
polymer layer makes the outside diameter of the stent itself
excessively large, thereby reducing the ease with which the stent
is delivered to the lesion.
[0088] The fine particles 5 to be dispersed in the polymer layer 4
should preferably be those of water-soluble substance, particularly
a low-molecular-weight water-soluble salt having a molecular weight
not higher than 1000. The term "low-molecular-weight water-soluble
salt" denotes an ionic compound formed by neutralization of an acid
and a base. The fine particles 5 of the water-soluble substance
absorb water or water vapor which has entered the polymer layer 4,
thereby forming water particles scattered in the polymer layer 4.
The water or water vapor which enters the polymer layer 4 is the
one which exists in a duct of a living body while the stent 1 is
implanted in the lesion. The water vapor is formed as the result of
evaporation of humor such as blood present in the duct of the
living body. The water particles resulting from the water-soluble
substance absorbing water or water vapor function as an obstacle to
the passage of the fat-soluble biologically/physiologically active
substance through the polymer layer 4, thereby retarding and
controlling the rate at which the biologically/physiologically
active substance releases itself from the sustained release
coating.
[0089] For the reason mentioned above, in the case where the fine
particles 5 are those of a water-soluble salt, the polymer layer 4
should be permeable to water or water vapor.
[0090] According to the present invention, the fine particles 5 to
be dispersed in the polymer layer 4 should preferably be those of
an inactive substance composed of an inorganic substance or an
organic substance insoluble in water and fat. Such an inactive
substance is hardly decomposable and inactive to a living body.
When dispersed in the polymer layer 4, it functions as an obstacle
to the passage of the biologically/physiologically active substance
through the polymer layer 4, thereby controlling the rate at which
the biologically/physiologically active substance releases itself.
Examples of such an inactive substance include silicon compounds
such as silica filler, carbon allotrope such as graphite, carbon
black, fullerene, and carbon nanotube, and fluoroplastics such as
polytetrafluoroethylene (PTFE). Of these examples, silica filler
and PTFE are desirable because of their good appearance and low
price.
[0091] These inactive substances may undergo surface treatment
without any adverse effect on their inactiveness. The surface
treatment improves dispersibility into the polymer layer 4.
[0092] The concentration of the fine particles 5 should preferably
be in the range of 0.0001 to 1 mass % of the polymer constituting
the polymer layer 4 in the case where they are those of a
low-molecular-weight water-soluble salt such as sodium chloride. On
the other hand, the concentration of the fine particles 5 should
preferably be in the range of 10 to 100 mass % of the polymer
constituting the polymer layer 4 in the case where they are those
of an inactive substance.
[0093] The fine particles 5 used more than the above-mentioned
range might greatly impair the mechanical properties of the polymer
layer 4. Alternatively, the fine particles 5 used less than the
above-mentioned range do not fully function as an obstacle in the
polymer layer 4 and hence they fail to control the rate at which
the biologically/physiologic- ally active substance diffuses from
the biologically/physiologically active substance layer 3 into the
polymer layer 4 and releases itself from the stent.
[0094] In the stent of the present invention, no specific
restrictions are imposed on how the fine particles 5 are dispersed
in the polymer layer 4. It is not always necessary that the fine
particles 5 should be uniformly dispersed in the polymer layer 4 as
shown in FIG. 3. The fine particles 5 may be dispersed unevenly in
the polymer layer 4 as shown in FIG. 4. FIG. 4 is the same partial
cross-sectional views as FIG. 3. FIG. 4 shows that the fine
particles 5 are not uniformly dispersed in the polymer layer 4 and
there is a layer-like part with a high concentration of the fine
particles 5 held between layer-like parts with a low concentration
of the fine particles 5. The uneven distribution of the fine
particles 5 in the polymer layer 4 permits the high-concentration
part to prevent the passage of the biologically/physiologically
active substance. Nevertheless, the fine particles 5 dispersed in
this manner do not impair the mechanical properties of the polymer
layer 4 unlike the case in which the concentration of the fine
particles is high throughout the polymer layer 4, because the
concentration of the fine particles 5 is not necessarily high
throughout the polymer layer 4. In the case of uneven distribution
as mentioned above, it is possible to increase the concentration of
the fine particles partially in excess of 100 mass % without any
adverse effect on the mechanical properties of the polymer layer
4.
[0095] The fine particles 5 to be added to the polymer layer 4 are
not specifically restricted in particle diameter so long as they
are small enough not to roughen the surface of the polymer layer 4.
The particle diameter should be in the range of 0.01 to 5 .mu.m,
preferably in the range of 0.03 to 3 .mu.m, most desirably in the
range of 0.05 to 1 .mu.m, in view of the thickness of the polymer
layer 4.
[0096] Incidentally, the polymer for the polymer layer 4 and the
fine particles 5 are not specifically restricted in kind so long as
the fine particles 5 are dispersible in the polymer layer 4 and are
capable of functioning as an obstacle in the polymer layer 4. A
desirable combination is as follows.
[0097] In the case of a water-soluble substance as the fine
particles 5, sodium chloride having a particle diameter of 0.01 to
1 .mu.m should be dispersed in the silicone elastomer mentioned
above in an amount of 0.0001 to 1 mass %.
[0098] In the case of an inactive substance as the fine particles
5, silica filler or PTFE having a particle diameter of 0.01 to 1
.mu.m should be dispersed in the silicone elastomer mentioned above
in an amount of 10 to 100 mass %.
EXAMPLES
[0099] The invention will be described in more detail with
reference to the following examples, which are not intended to
restrict the scope thereof.
[0100] (1) Test for Permeation of the Biologically/Physiologically
Active Substance through the Polymer Film
Example 1
[0101] A polymer film having a thickness of 30 .mu.m was prepared
by casting in a petri dish from a hexane solution of two-pack
silicone elastomer (10 wt % in concentration) incorporated with
PTFE fine particles (not larger than 1 .mu.m in particle diameter).
The two-pack silicone elastomer is "Q7-4840 Silastic" (from Dow
Corning Corporation) consisting of solution-A and solution-B in
equal quantities. The amount of the PTFE is 30 wt % on the total
amount of the polymer in the silicone elastomer and the PTFE fine
particles.
[0102] The thus obtained polymer film was placed at the
intermediate part 6 of two chambers 7 and 8 of the apparatus shown
in FIG. 5. One chamber 7 of the apparatus was filled with an
aqueous solution of simvastatin (SVS) which had been filtered off
through a 0.45 .mu.m thick membrane filter made by Advantec. The
aqueous solution contains 50 .mu.g/ml conc. of SVS and 2 wt % of
surfactant ("Tween 20" from Nikko Chemical Co, . Ltd.). The other
chamber 8 was filled with reverse osmosis (RO) water containing 2
wt % of surfactant ("Tween 20"). The apparatus was allowed to stand
in a thermostat at 37.degree. C. in order to measure the rate
(cm/sec) at which SVS permeates through the polymer film. The rate
of permeation was measured in the following manner. The solution in
the chamber 8 is sampled (1 ml each) at prescribed time intervals:
Each sample is measured for absorbance at a wavelength of 238 nm by
using a spectrophotometer (UV-2400PC made by Shimadzu Corporation).
The readings of absorbance are converted into the amount of
permeation of SVS by using a previously prepared calibration curve.
The amount of permeation is further converted into the amount per
unit time and unit area of the polymer film. The results of the
test are shown in Table 1.
Example 2
[0103] A polymer film having a thickness of 30 .mu.m was prepared
by casting in a petri dish from a hexane solution of two-pack
silicone elastomer (10 wt % in consentration) incorporated with
sodium chloride fine particles (not larger than 1 .mu.m in particle
diameter). The two-pack silicone elastomer is "Q7-4840 Silastic"
(from Dow Corning Corporation) consisting of solution-A and
solution-B in equal quantities. The amount of sodium chloride is
0.25 wt % on the total amount of the polymer in the silicone
elastomer and the sodium chloride fine particles. The thus obtained
polymer film was measured for the rate of permeation of SVS in the
same way as in Example 1. The results of the test are shown in
Table 1.
Comparative Example 1
[0104] A polymer film having a thickness of 30 .mu.m was prepared
by casting in a petri dish from a hexane solution of two-pack
silicone elastomer (10 wt % in concentration) which is not
incorporated with PTFE or sodium chloride fine particles. The
two-pack silicone elastomer is "Q7-4840 Silastic" (from Dow Corning
Corporation) consisting of solution-A and solution-B in equal
quantities. The thus obtained polymer film was measured for the
rate of permeation of SVS in the same way as in Example 1. The
results of the test are shown in Table 1.
1TABLE 1 Rate of permeation of SVS through polymer film (cm/sec)
Example 1 2.713E-05 Example 2 2.244E-05 Comparative Example 1
3.697E-05
[0105] It is noted from Table 1 that the polymer film in Examples 1
and 2 which contains PTFE or sodium chloride fine particles reduces
the rate of permeation of SVS through it.
[0106] (2) Measurement of the Rate of Sustained Release of
Biologically/Physiologically Active Substance
Example 3
[0107] A stent sample was prepared in the following manner from a
stent main body which is in a cylindrical shape (1.8 mm in outside
diameter and 15 mm long, having approximately rhombic holes) and is
composed of fibrous members (0.1 mm in diameter) of stainless steel
(SUS 316L), as shown in FIG. 1. This stent main body was sprayed
with a hexane solution of SVS (5 wt % in concentration) by using a
hand spray (HP-C made by Iwata Corporation). It was confirmed that
the surface of the fibrous members constituting the stent main body
was coated with about 200 .mu.g of SVS. Upon complete solvent
(hexane) removal by evaporation, there was formed a layer of SVS
(biologically/physiologically active substance) on the surface of
the fibrous members constituting the stent main body.
[0108] The coated stent main body was sprayed with a hexane
solution of two-pack silicone elastomer incorporated (2 wt % in
concentration) with PTFE fine particles (not larger than 1 .mu.m in
particle diameter). The two-pack silicone elastomer is "Q7-4840
Silastic" (from Dow Corning Corporation) consisting of solution-A
and solution-B in equal quantities. The solution of two-pack
silicone elastomer is composed of 1 g each of solution-A and
solution-B and 98 g of hexane. The amount of PTFE fine particles is
30 wt % on the total amount of the polymer in the silicone
elastomer and the PTFE fine particles. The solution was applied to
the stent main body by using a hand spray such that the layer of
biologically/physiologically active substance is completely covered
with the polymer layer. The polymer layer was cured by heating at
80.degree. C. for 1 hour in an oven. The resulting polymer layer
was found to have an average thickness of about 30 .mu.m. The thus
obtained stent sample was measured for the rate at which SVS
releases itself.
[0109] Measurement was carried out in the following manner. The
stent sample is immersed in RO water containing 2 wt % of
surfactant (Tween 20) which is held in a thermostat at 37.degree.
C. The RO water is sampled (1 ml each) at prescribed time
intervals, and the amount of SVS in each sample is determined in
the same way as in Example 1 and the rate of sustained release of
SVS is calculated. The results are shown in Table 2. The values in
Table 2 denote the ratio (%) of the amount of SVS released to the
amount of SVS applied to the fibrous members constituting the stent
main body.
Example 4
[0110] The same stent main body as used in Example 3 was sprayed
with a hexane solution of SVS (5 wt % in concentration) by using a
hand spray. It was confirmed that the surface of the fibrous
members constituting the stent main body was coated with about 200
.mu.g of SVS. Upon complete solvent (hexane) removal by
evaporation, there was formed a layer of SVS. The coated stent main
body was sprayed with a hexane solution of two-pack silicone
elastomer (2 wt % in concentration) incorporated with sodium
chloride fine particles (not larger than 1 .mu.m in particle
diameter). The two-pack silicone elastomer is "Q7-4840 Silastic"
(from Dow Corning Corporation) consisting of solution-A and
solution-B in equal quantities. The solution of two-pack silicone
elastomer is composed of 1 g each of solution-A and solution-B and
98 g of hexane. The amount of sodium chloride fine particles is
0.25 wt % on the total amount of the polymer in the silicone
elastomer and the sodium chloride fine particles. The solution was
applied to the stent main body by using a hand spray such that the
layer of biologically/physiologically active substance is
completely covered with the polymer layer. The polymer layer was
cured by heating at 80.degree. C. for 1 hour in an oven. The
resulting polymer layer was found to have an average thickness of
about 30 .mu.m. The thus obtained stent sample was measured for the
rate at which SVS releases itself.
[0111] Measurement was carried out in the same way as in Example 3.
The results are shown in Table 2. The values in Table 2 denote the
ratio (%) of the amount of SVS released to the amount of SVS
applied to the fibrous members constituting the stent main
body.
Comparative Example 2
[0112] The same stent main body as used in Example 3 was sprayed
with a hexane solution of SVS (5 wt % in concentration) by using a
hand spray. It was confirmed that the surface of the fibrous
members constituting the stent main body was coated with about 200
.mu.g of SVS. Upon complete solvent (hexane) removal by
evaporation, there was formed a layer of SVS. The coated stent main
body was sprayed with a hexane solution of two-pack silicone
elastomer (2 wt % in concentration) which is not incorporated with
sodium chloride or PTFE fine particles. The two-pack silicone
elastomer is "Q7-4840 Silastic" (from Dow Corning Corporation)
consisting of solution-A and solution-B in equal quantities. The
solution of two-pack silicone elastomer is composed of 1 g each of
solution-A and solution-B and 98 g of hexane. The solution was
applied to the stent main body by using a hand spray such that the
layer of biologically/physiologi- cally active substance is
completely covered with the polymer layer. The polymer layer was
cured by heating at 80.degree. C. for 1 hour in an oven. The
resulting polymer layer was found to have an average thickness of
about 30 .mu.m. The thus obtained stent sample was measured for the
rate at which SVS releases itself.
[0113] Measurement was carried out in the same way as in Example 3.
The results are shown in Table 2. The values in Table 2 denote the
ratio (%) of the amount of SVS released to the amount of SVS
applied to the fibrous members constituting the stent main
body.
2TABLE 2 Ratio (%) of sustained release of SVS 0 h 23 h 72 h 240 h
Example 3 0.0 4.3 11.1 36.4 Example 4 0.0 2.9 9.7 27.4 Comparative
0.0 4.5 13.9 56.7 Example 2
[0114] Values in Table 2 denote the ratio (%) of the amount of SVS
released to the amount of SVS applied to the fibrous members
constituting the stent main body.
[0115] It is noted from Table 2 that the stent samples in which the
polymer layer is incorporated with PTFE or sodium chloride fine
particles permit SVS to release itself slowly.
INDUSTRIAL APPLICABILITY
[0116] As mentioned above, the present invention relates to a stent
to be implanted in a duct of a living body. The stent comprises a
cylindrical stent main body having an opening on each end and
extending in axial direction between the two openings, and a
sustained release coating formed on the surface of said stent main
body from which a biologically/physiologically active substance is
released, and wherein said sustained release coating is composed of
a layer of a biologically/physiologically active substance which
covers the surface of said stent main body, and a polymer layer
which covers said layer of a biologically/physiologically active
substance on said layer of a biologically/physiologically active
substance, and said layer of a biologically/physiologically active
substance contains at least one kind of fat-soluble
biologically/physiologically active substance, and said polymer
layer contains a polymer miscible with said
biologically/physiologically active substance and fine particles
equal to or smaller than 5 .mu.m in particle diameter dispersed in
the polymer. The stent constructed in this way stably loads the
biologically/physiologically active substance on the stent main
body without decomposition and degradation. In addition, after
being implanted in a lesion, it permits the
biologically/physiologically active substance to release itself
slowly over a long period of time without rapid release in a short
period.
[0117] The stent main body may be formed from a metallic material.
In this case, the stent will be implanted certainly in the lesion
because the metallic material has high strength.
[0118] The stent main body may be formed from a polymeric material.
In this case, the stent will be easily delivered to the lesion
because the polymeric material has good flexibility.
[0119] The layer of a biologically/physiologically active substance
may be composed solely of a biologically/physiologically active
substance. In this case, it is possible to form the layer of
biologically/physiological- ly active substance in a simple
way.
[0120] The biologically/physiologically active substance may be any
of antineoplastic agent, immunosuppressor, antibiotic,
antirheumatic, antilipemic agent, ACE inhibitor, calcium
antagonist, antiallergic agent, retinoid, antioxidant, and
anti-inflammatory agent. Any of these biologically/physiologically
active substance prevents restenosis while the stent is implanted
in the lesion.
[0121] The polymer layer may be formed from a silicone polymer. In
this case, the stent exhibits outstanding safety to the living
body.
[0122] The fine particles may be those of a low-molecular-weight
water-soluble salt having a molecular weight not higher than 1000
which is one of the salts present in a living body. In this case,
the stent is highly safe because the salt has a low level of
stimulus to a living body.
[0123] The low-molecular-weight water-soluble salt may be sodium
chloride. In this case, the stent is much safer because sodium
chloride is present in a high ratio in a living body.
[0124] The fine particles may be an inactive substance such as
silica filler and PTFE. In this case, such fine particles are
inactive to a living body. In addition, it can be made readily
dispersible into or miscible with the polymer layer by surface
treatment in various ways.
* * * * *