U.S. patent application number 12/767289 was filed with the patent office on 2010-08-19 for intraluminal device with a coating containing a therapeutic agent.
This patent application is currently assigned to ZISCOAT N.V.. Invention is credited to Ivan De Scheerder, Maria Dhont, Pierre Jacobs, Johan Martens.
Application Number | 20100209473 12/767289 |
Document ID | / |
Family ID | 27224430 |
Filed Date | 2010-08-19 |
United States Patent
Application |
20100209473 |
Kind Code |
A1 |
Dhont; Maria ; et
al. |
August 19, 2010 |
INTRALUMINAL DEVICE WITH A COATING CONTAINING A THERAPEUTIC
AGENT
Abstract
The invention relates to an intraluminal device, in particular
an intraluminal prosthesis, shunt, catheter or local drug delivery
device, provided with at least one coating containing a therapeutic
agent comprised in a matrix which sticks to the intraluminal
device, characterised in that said matrix is formed by a
biocompatible oil or fat, which oil or fat is a chemically hardened
oil or fat.
Inventors: |
Dhont; Maria; (Nazareth,
BE) ; De Scheerder; Ivan; (Herent, BE) ;
Jacobs; Pierre; (Gooik, BE) ; Martens; Johan;
(Huldenberg, BE) |
Correspondence
Address: |
CLARK & ELBING LLP
101 FEDERAL STREET
BOSTON
MA
02110
US
|
Assignee: |
ZISCOAT N.V.
Lubbeek
BE
|
Family ID: |
27224430 |
Appl. No.: |
12/767289 |
Filed: |
April 26, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11140811 |
May 31, 2005 |
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12767289 |
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10494892 |
Mar 25, 2005 |
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PCT/BE02/00166 |
Nov 8, 2002 |
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11140811 |
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Current U.S.
Class: |
424/423 ;
604/265; 604/8; 623/23.64 |
Current CPC
Class: |
A61L 29/16 20130101;
A61L 2300/22 20130101; A61L 31/08 20130101; A61L 27/54 20130101;
A61L 31/10 20130101; A61K 31/20 20130101; A61L 31/16 20130101 |
Class at
Publication: |
424/423 ;
623/23.64; 604/8; 604/265 |
International
Class: |
A61F 2/04 20060101
A61F002/04; A61F 2/00 20060101 A61F002/00; A61M 27/00 20060101
A61M027/00; A61M 25/00 20060101 A61M025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 8, 2001 |
EP |
01870237.3 |
Mar 28, 2002 |
EP |
02447048.6 |
Apr 26, 2002 |
EP |
02447075.9 |
Claims
1. An intraluminal device, in particular an intraluminal
prosthesis, shunt, catheter or local drug delivery device, provided
with at least one coating containing a therapeutic agent comprised
in a matrix which sticks to the intraluminal device, characterised
in that said matrix is formed by a biocompatible oil or fat, which
oil or fat is a chemically hardened oil or fat.
2. The device according to claim 1, characterized in that said
chemically hardened oil or fat is a partially hydrogenated oil or
fat.
3. The device according to claim 1, characterised in that said
chemically hardened oil or fat comprises unsaturated fatty acid
chains but is substantially free of trans isomers of unsaturated
fatty acid chains.
4. The device according to claim 1, characterized in that said
chemically hardened oil or fat is obtained by a method involving
removal of trans isomers of said hardened oil or fat.
5. The device according to claim 1, characterised in that said
therapeutic agent comprises at least one therapeutic agent selected
from the group consisting of immunosuppressants,
anti-inflammatories, anti-proliferatives, anti-migratory agents,
anti-fibrotic agents, proapoptotics, calcium channel blockers,
anti-neoplastics, antibodies, anti-thrombotics, anti-platelet
agents, IIb/IIIa blockers, antiviral agents, anti-cancer agents,
chemotherapeutics, thrombolytics, vasodilators, antibiotics, growth
factor antagonists, free radical scavengers, radiopaque agents,
anti-angiogenesis agents, angiogenesis drugs, cyclooxygenase
inhibitors, phosphodiesterase inhibitors, cytokine inhibitors,
nitrogen oxide donors, and cytokine activators.
6. A device according to claim 1, characterised in that said oil or
fat comprises fatty acids and/or one or more derivatives
thereof.
7. The device according to claim 1 wherein said oil or fat
comprises one or more triglycerides composed of glycerol and one or
more fatty acids.
8. The device according to claim 6, characterised in that said
fatty acids comprise omega-3 fatty acids.
9. The device according to claim 8, characterised in that said
fatty acids comprise eicosapantaenoic acid and/or decosahexaenoic
acid.
10. The device according to claim 1, characterised in that said
device is an endovascular prosthesis.
11. An intraluminal device, comprising: At least one coating
containing a therapeutic agent comprised in a therapeutic matrix
which covers at least a portion of the device, said therapeutic
matrix disposed to deliver the therapeutic agent to tissue of a
patient upon implantation in said patient, and said therapeutic
matrix formed by a chemically hardened oil or fat, wherein the
chemically hardened oil or fat matrix comprises triglycerides in an
amount of more than 70% by weight, wherein the triglycerides
comprise unsaturated omega-3 fatty acids in an amount of more than
15% by weight.
Description
[0001] The present invention relates to an intraluminal device, in
particular an intraluminal prosthesis, shunt, catheter or local
drug delivery device, provided with at least one coating containing
a therapeutic agent comprised in a matrix which sticks to the
intraluminal device.
[0002] Several trials with systematically (oral or intravenous)
administered anti-restenotic therapeutic agents after dilatation of
narrowed lumina (for example of a coronary arterial atherosclerotic
narrowing) failed in consequence of a too limited therapeutic agent
concentration on the place where the therapeutic agent has to act
and due to the systemic therapeutic agent's side effects when
higher doses are administered. For this reason therapeutic agents
were applied locally, at the place of the organ to be treated. For
example in the treatment of coronary stenoses using special
catheters, therapeutic agents were injected into the vessel wall.
Disadvantages of this approach are the limited efficiency of the
so-called local treatment (less than 5% of the administered
therapeutic agent reaches the target organ) and the increased
damage to the target organ due to the local drug
administration.
[0003] Another method is the coverage of an endoluminal prosthesis
with a polymer coating and the impregnation of the polymer with a
therapeutic agent (EP-A-0623354, . . . ). The disadvantages of this
method are the limited drug capacity of the coating and the too
fast release of the therapeutic agent because of the large contact
area. Furthermore, polymers need a quite aggressive polymerisation
step that can result in inactivation of the therapeutic agent and
most polymers are not very bio-compatible and induce a foreign body
inflammatory response, resulting in even more hyperplasia and
restenosis.
[0004] The object of the present invention is therefore to provide
a new intraluminal device which is provided with a coating which
does not need an aggressive polymerisation step, which is
bio-compatible and which enables to obtain a sustained local
release of the therapeutic agent.
[0005] To achieve this object, the intraluminal device according to
the invention is characterised in that the matrix which comprises
the therapeutic agent is formed by a bio-compatible oil or fat.
[0006] It has been found rather surprisingly that an oil or fat
adheres sufficiently strongly to the intraluminal device so that
most of the coating remains on the intraluminal device when
inserting it in the lumen. The oil or fat matrix further slows down
the release of the therapeutic agent once inserted in the body
lumen. Due to the selection of a bio-compatible oil or fat, the
coating reduces the foreign body inflammatory response induced by
the intraluminal device. A further advantage of an oil or fat
coating is that it has a lubricating effect so that no further
lubricants have to be used which may reduce the bio-compatibility
of the intraluminal device.
[0007] By bio-compatible oil or fat is meant is the present
specification that the oil or fat does not have any intolerable
adverse effect on the lumen structure wherein the intraluminal
device is to be applied.
[0008] The term "oil or fat" is further used to designated
substances which have the physical characteristics of an oil or a
fat, a fat differing only in one respect from an oil, a fat being
solid at room temperature whilst an oil is liquid at room
temperature. In liquid state, i.e. at a sufficiently high
temperature, oils and fats have a viscous consistency and a
characteristic unctuous feel. They are moreover lighter than water
and insoluble in it.
[0009] Due to their fatty, viscous consistency, fats and oils are
able to stick sufficiently strongly to the intraluminal device.
Moreover, since they are not soluble in water, they are able to
provide for a prolonged release of the therapeutic agent in the
body lumen.
[0010] As oil or fat different products can be used. First of all,
although some mineral oils may be bio-compatible, animal or
vegetable oils are suitable, in particular edible oils such as fish
oil, olive oil, linseed oil, sunflower oil, corn oil and/or palm or
palmnut oil. Good effects have been demonstrated experimentally for
cod-liver oil and olive oil. The oils do not need to be used in
their natural form but the chemical structure thereof can be
modified. The natural, biological oils can in particular be
hydrogenated (preferably only partially so that they still contain
unsaturated fatty acids) resulting in an increased melting point.
Further, it is possible to produce synthetic oils or fats having a
composition similar to the composition of the natural oils or to
the composition of particular components thereof, in particular
triglycerides.
[0011] In the above mentioned preferred embodiment, the oils
comprise triglycerides composed of glycerol and one or more fatty
acids. Preferably, they comprise more than 20% by weight, and most
preferably more than 70% by weight of triglycerides. These amounts
are either present in the natural oils or they can be achieved by
adding triglycerides or by further purifying the oils. In other
embodiments of the present invention, it is however possible to
substitute other trihydroxy or polyhydroxy compounds for the
glycerol. A special preference is given to cod-liver oil which is
purified so that it contains more than 90% of triglycerides.
[0012] The oils or fats may also contain free fatty acids (having a
free --COOH group) but this preferably in an amount of less than
50% by weight and more preferably only in minor proportions, e.g.
less than about 10% by weight free fatty acids. The oils or fats
can further be composed of, or may comprise other fatty acid
derivatives, in particular methyl or ethyl esters of fatty
acids.
[0013] An example of a further "oily" or "fatty" substance which
can be used as bio-compatible oil or fat is alfa-tocopherol and/or
a derivative thereof such as alfa-tocopherol acetate. The
alfa-tocopherol and/or a derivative thereof may either be a
component of the oil or fat or the oil or fat may consist
substantially entirely of this compound.
[0014] As disclosed already in EP-A-0 623 354 tocopherol (vitamin
E) is a therapeutic agent. In general, in accordance with the
present invention, the oil or fat forming the matrix which sticks
to the intraluminal device may thus be formed partially or
completely by the therapeutic agent when this therapeutic agent is
an oil or a fat. Of course one or more further therapeutic agents
can be incorporated in the thus formed oil or fat matrix.
[0015] The present inventors have found that alfa-tocopherol and/or
derivatives thereof are preferably used in combination with an oil
or fat comprising fatty acids and/or derivatives thereof, in
particular one or more triglycerides. They have found more
particularly that coatings containing this combination showed a
very good bio-compatibility to vascular tissue. The observed
effects on the decrease on the inflammation score, and especially
on the decrease of the area stenosis and of the neointimal
hyperplasia, indicating the occurrence of synergetic effects. The
alfa-tocopherol and/or the derivatives thereof are preferably mixed
with the oil or fat comprising fatty acids and/or derivatives
thereof to achieve such synergetic effects but a top coat of the
alfa-tocopherol and/or the derivatives thereof on a first oil or
fat coating appeared to provide also good results. Such a top coat
comprises preferably said alfa-tocopherol and/or said derivative
thereof in an amount of at least 90% by weight and most preferably
in an amount of at least 95% by weight. When being a component of
the oil or fat of the coating, this oil or fat comprises the
alfa-tocopherol, and/or the derivative thereof, preferably in an
amount of between 20 and 80% by weight, more preferably in an
amount of between 30 and 70% by weight.
[0016] Instead of being a component of the oil or fat, the
therapeutic agent may also be chemically bonded to the oil or fat
by any chemical bonding technique. When the oil or fat comprises
for example triglycerides, the therapeutic agent may for example be
chemically bound to the fatty acid groups or to the glycerol group.
On the other hand, the fatty acid groups themselves may be formed
by fatty acids which may be therapeutic agents. Such fatty acids
are in particular unsaturated fatty acids, more particularly
omega-3 fatty acids. In view of their therapeutic effect, the fatty
acids are preferably formed by more than 5%, more preferably by
more than 10% and most preferably by more than 15% by weight of
unsaturated fatty acids. Most preferably these unsaturated fatty
acids comprise eicosapantaenoic acid (EPA) and optionally
decosahexaenoic acid (DHA). Experiments have shown in particular
for cod-liver oil and for olive oil that a coating consisting only
of such an oil, i.e. without added therapeutic agents, has already
a beneficial effect on the healing response resulting in an
improved patency of the prosthesis. The beneficial effect of
bio-compatible oils like cod-liver oil and olive oil may be
explained by their anti-oxidant and anti-inflammatory effect, in
particular the anti-oxidant effect of their unsaturated fatty
acids. This anti-oxidant effect can be increased by added or
naturally present vitamin E or derivatives thereof having an
anti-oxidant effect (for example when the oil or fat has been
hydrogenated partially). Furthermore bio-compatible oils inhibit
smooth muscle cell proliferation in cell culture experiments.
[0017] In the device according to the present invention, the
therapeutic agent may also be mixed with the oil or fat. When
soluble in the oil or fat, the therapeutic agent can be dissolved
therein or, when it is not soluble in the oil or fat, it can be
dispersed therein, more particularly emulsified or suspended
depending on the fact whether the therapeutic agent is a liquid or
a solid.
[0018] The therapeutic agent may be selected from the group
consisting of vinblastine, sirolimus, mitoxantrone, tacrolimus,
paclitaxel, cytochalasin, latrunculin, and everolimus, a particular
preference being given to everolimus. It can also be selected from
the group consisting of deferoxamine, geldanamycin, nigericin,
penitrem, paxilline, verruculogen, KT5720, KT5823, Anisomycin,
chelerythrine chloride, genistein, parthenolide, trichostatin A, T2
toxin, Zearalenone, Interferon, epithalon-D, Ca-ionophore, 4 bromo
Ca lonophore, Aflatoxins, aphidicolin, brefeldin A, cerulenin,
chromomycin A3, citrinin, cyclopiazonic acid, forsokolin,
fumagillin, fumonisins B1, B2, hypericin, K252, mycophenolic acid,
ochratoxin A, and oligomycin or further from the group consisting
of mycophenolic acid, mycophenolate mofetil, mizoribine,
methylprednisolone, dexamethasone and other corticosteroids,
Certican.TM., Tritolide.TM., Methotrexate.TM., Benidipine.TM.,
Ascomycin.TM., Wortmannin.TM., LY 294002, Camptothecin.TM.,
Topotecan.TM., hydroxyurea, cyclophosphamide, cyclosporin,
daclizumab, azathioprine, Gemcitabine.TM., and derivatives and
analogues thereof. As therapeutic agents genes, coding for certain
substances (proteins), having either anti-thrombotic and/or
anti-restenotic action, can be used as well.
[0019] The therapeutic agent may have different effects and may in
this respect be selected amongst immunosuppressants,
anti-inflammatories, anti-proliferatives, anti-migratory agents,
anti-fibrotic agents, proapoptotics, calcium channel blockers,
anti-neoplastics, antibodies, anti-thrombotics, anti-platelet
agents, IIb/IIIa blockers, antiviral agents, anti-cancer agents,
chemotherapeutics, thrombolytics, vasodilators, antibiotics, growth
factor antagonists, free radical scavengers, radiopaque agents,
anti-angiogenesis agents, angiogenesis drugs, cyclooxygenase
inhibitors, phosphodiesterase inhibitors, cytokine inhibitors,
nitrogen oxide donors, and cytokine activators.
[0020] The coating provided on the intraluminal device in
accordance with the present invention may comprise other substances
in addition to the therapeutic agent and the oil or fat. It is for
example possible to add some substances, in particular some natural
or synthetic polymeric substances, binders, thickening agents, etc.
to the coating in order to stabilise it. The amount of such
substances is however preferably kept below 30%, more preferably
below 85% and most preferably below 95% by weight in order to
maintain the improved bio-compatibility of the oil or fat coating
as much as possible. This means that the coating comprises
preferably at least 70% by weight, more preferably at least 85% by
weight and most preferably at least 95% by weight of the oil or fat
and the therapeutic agent. The oil or fat content of the coating is
preferably at least 50% by weight, more preferably at least 70% by
weight, and most preferably at least 80% by weight, a particular
preference being given to an oil or fat content of at least 90% by
weight.
[0021] In order to control or tailor the release of the therapeutic
agent out of the coating, a top coat can be applied on top of this
coating, in particular a top coat of the same or a different
bio-compatible oil or fat. The rate at which the therapeutic agent
is delivered can further be controlled by the ratio of therapeutic
agent to oil or fat in the coating or by providing multiple
coatings with varying drug concentrations. In the device according
to the present invention the release of therapeutic agent can
further be controlled by the selection of an appropriate
bio-compatible oil or fat having a certain stability level and
melting point.
[0022] The oil or fat has preferably a melting point lower than
100.degree. C. and more preferably lower than 80.degree. C. so that
the therapeutic agent can be mixed with the oil or fat in the
molten state thereof without having a deleterious effect on the
therapeutic agent. The melting temperature is preferably even lower
than 60.degree. C., more preferably lower than 40.degree. C., so
that a mixture can be made of the therapeutic agent, the oil or fat
in its molten state and a volatile solvent such a ethanol.
[0023] In view of the fact that the release of the therapeutic
agent may be too slow from the oil or fat matrix in the solid state
thereof, the melting point of the oil or fat is preferably lower or
equal to 37.degree. C. so that the oil or fat will be in the molten
state once inserted in the body lumen.
[0024] The oil or fat may be an oil at room temperature. The above
mentioned natural oils are for example liquid at room temperature,
except palm oil and palm nut oil. Linseed oil, sunflower oil, corn
oil; olive oil and cod-liver oil have a melting point lower or
equal to about 0.degree. C. Experiments have shown that even with
such a low melting point, these oils are able to stick sufficiently
strongly to the intraluminal device. However, in order to have a
more stable coating, these unsaturated oils can be further
stabilised by a partial hydrogenation resulting in an increase of
their melting point. The melting point can be raised to a melting
point higher than 10, 15, 20 or 30.degree. C. depending on the
desired stability (viscosity) of the oil or fat and the release
properties thereof.
[0025] When use is made of a chemically hardened oil or fat which
still comprises unsaturated fatty acid chains, the hardened oil or
fat is preferably free of trans isomers of unsaturated fatty acid
chains. Natural oils are normally free of such trans isomers.
During the usual hardening processes, trans isomers are however
formed. Since such trans isomers may have negative effects, they
are preferably removed, for example in accordance with the
technique described in WO 98/54275.
[0026] The present invention also relates to a method for providing
an intraluminal device, in particular an intraluminal prosthesis,
shunt, catheter or local drug delivery device, with at least one
coating containing a therapeutic agent comprised in a matrix which
sticks to the intraluminal device. In accordance with the
invention, the matrix is formed by a bio-compatible oil or fat,
which comprises said therapeutic agent, and which is applied in a
flowable state onto the device.
[0027] When the oil or fat has a sufficiently low viscosity
(optionally after heating), it can be applied in a molten state
onto the device. Usually, use is however preferably made of a
solvent which is mixed with the oil or fat before applying the oil
or fat onto the device and, after having applied the mixture of
solvent and oil or fat onto the device, the solvent is allowed to
evaporate. The solvent is normally an organic solvent, in
particular an alcohol such as ethanol.
[0028] When the oil or fat is soluble in the solvent, a solution of
the oil or fat in the solvent can first be made after which the
therapeutic agent, when not yet comprised in the oil or fat, can be
added. When the oil or fat is not soluble, a homogeneous mixture is
first made, in particular an emulsion. Alternatively, the
therapeutic agent can first be dissolved or dispersed in the
solvent before mixing it with the oil or fat.
[0029] A typical method according to a preferred embodiment of the
present invention comprises the following steps: [0030] a)
Cleaning, degreasing and drying of the prosthesis [0031] b) Dipping
of the prosthesis in an deoxidative solution and airdrying it
[0032] c) Making an emulsion or solution of the bio-compatible oil
or fat and a solvent, preferably in a liquid state of the oil or
fat [0033] d) In this emulsion/solution a therapeutic agent is
dissolved when the oil or fat did not yet contain a therapeutic
agent or an additional therapeutic agent is dissolved when the oil
or fat did already contain a therapeutic agent. The therapeutic
substance needs only to be dispersed throughout the solvent/oil
emulsion or solution so that it may be either in a true solution
with the solvent/oil emulsion or solution or dispersed in fine
particles in the solvent/oil emulsion or solution. [0034] e)
Stirring of the obtained solution until achievement of a homogenous
mixture/solution [0035] f) Applying to the prosthesis body of the
therapeutic agent containing oil/solvent emulsion or solution using
dipcoating or spraycoating or any other coating method [0036] g)
Airdry till the solvent is evaporated. [0037] h) Optionally repeat
the previous steps multiple times, eventually using different
therapeutic agents. [0038] i) Further airdry the prosthesis in a
sterile laminar flow.
[0039] Prior to step c, a therapeutic agent could already be added
to the solvent or to the oil or fat. The oil or fat could for
example be enriched with EPA and optionally DHA. It is also
possible to add alfa-tocopherol and/or a derivative thereof to the
oil or fat. Moreover, an oil or fat can be selected which comprises
already groups which are therapeutically active, such as
unsaturated fatty acid groups, or a therapeutic agent can be bonded
to the oil or fat using any chemical bonding technique. When the
oil or fat is already provided in this way with a therapeutic
agent, it is not necessary any more to add a therapeutic agent
although it is still possible to add further therapeutic agents.
This is for example the case when the oil is formed by
alfa-tocopherol or a derivative thereof or when the oil comprises
alfa-tocopherol or a derivative thereof.
[0040] After drying a topcoat, consisting of a bio-compatible oil
or fat, in particular a natureal edible oil or alfa-tocopherol (or
an derivative thereof) or a combination thereof can be using
dipcoating, spraycoating or any other coating method.
[0041] After drying, the obtained coated prosthesis can be used as
such or further dried and sterilised. Light-protection of the
obtained coated prosthesis is advisable to maintain the
bio-compatible characteristics when stored.
[0042] The inclusion of a bio-compatible, in particular a
biological oil or fat in intimate contact with a drug covering the
prosthesis allows the drug to be retained in the prosthesis in a
resilient matrix during expansion of the prosthesis and also slows
the administration of drug following implantation. Furthermore,
depending on the melting point of the biological oil used the oil
can become a fat, retaining the drug and resulting in a more stable
surface coating. Furthermore by addition of certain chemical
substances (bicarbonate) or by hydrogenation the coating can be
further stabilised resulting in a very stable drug containing
coating. The method of the invention can be used whether the
prosthesis has a metallic or polymeric surface. The method is also
an extremely simple one since it can be effected by simply
immersing the prosthesis into the solution (emulsion) or by
spraying the solution (emulsion) onto the prosthesis. The amount of
drug to be included onto the prosthesis can be readily controlled
by using different drug concentrations and or different coating
application methods. The rate at which the drug is delivered can be
controlled by the selection of an appropriate bio-compatible oil or
fat at a certain stability level and melting point and by the ratio
of drug to oil in the solution. The release rate can be further
controlled by using additional barrier coatings or multiple layers
of coating with varying drug concentrations. Furthermore this
system allows the use of different therapeutic agents. In
operation, prosthesis made according to the present invention can
deliver drugs to a body lumen by introducing the prosthesis
transluminally into a selected portion of the body lumen and
radially expanding the prosthesis into contact with the body lumen.
The transluminal delivery can be accomplished by a catheter
designed for the delivery of the prostheses and the radial
expansion can be accomplished by balloon expansion of the
prosthesis, by self-expansion of the prosthesis or a combination of
self-expansion and balloon expansion.
[0043] Thus the present invention provides a prosthesis which may
be delivered and expanded in a selected body lumen or conduit
without losing a therapeutically significant amount of a drug or
gene applied thereto. It also provides a drug or gene containing
prosthesis which allows for a sustained release of the drug or gene
to luminal or conduit tissue.
[0044] The underlying structure of the prosthesis used according to
the invention can be virtually any prosthesis design, for example
of the self-expanding type or of the balloon expandable type, and
of metal or polymeric material. Thus metal prosthesis designs such
as those disclosed in U.S. Pat. No. 4,733,665 (Palmaz) and U.S.
Pat. No. 5,603,721 (Lau) could be used in the present invention.
Also prosthesis with special surface treatments or special designs
to optimise local drug delivery are especially suitable for this
invention (for example: DE199 16 086 A1, EP 0 950 386 A2, EP 1 132
058 A1, WO 01/66036 A2, WO 98/23228, U.S. Pat. No. 5,902,266, U.S.
Pat. No. 5,843,172, . . . ). The surface of the prosthesis could in
particular be provided with perforating holes or pits which can be
filled with the coating material to increase the load of
therapeutic agent and/or to slow down the release. After having
applied the coating, the surface of the prosthesis next to the
holes or pits can be wiped off or cleaned to remove the coating
material. The present invention therefore does not only embrace
continuous coatings covering the entire prosthesis but also
discontinuous local coatings or combinations of local coatings and
continuous top coatings applied thereover. The coating further does
not need to be applied on the surface of the prosthesis. When using
for example porous prostheses, the coating may be located within
the pores of the prosthesis. The prosthesis could be made of
virtually any bio-compatible material having physical properties
suitable for the design. For example, tantalum, nitinol and
stainless steel have been proven suitable for many such designs and
could be used in the present invention. Also, prostheses made of
biostable or bioabsorbable polymers such as poly(ethylene
terephthalate), polyacetal, poly(lactic acid), poly(ethylene
oxide)/poly(butylene terephthalate) copolymer could be used in the
present invention. Although the prosthesis surface should be clean
and free from contaminants that may be introduced during
manufacturing, the prosthesis surface requires no particular
surface treatment in order to retain the coating applied in the
present invention.
[0045] The oil or fat chosen should be bio-compatible and minimise
irritation to the vessel wall when the prosthesis is implanted. The
ratio of therapeutic substance to the oil/solvent emulsion in the
solution will depend on the efficacy of the oil or fat in securing
the therapeutic substance onto the prosthesis and the rate at which
the coating is to release the therapeutic substance to the tissue
of the blood vessel or body conduit. More oil or fat may be needed
if it has relatively poor efficacy in retaining the therapeutic
substance on the prosthesis and more oil may be needed in order to
provide an elution matrix that limits the elution of a very soluble
therapeutic substance. A wide ratio of therapeutic substance to
oil/solvent emulsion could therefore be appropriate, in particular
a weight ratio ranging from about 100:1 to 1:100.
[0046] Experimental Work with this New Coating Method.
The biological coatings are based upon: [0047] 1) biological
dissolvable oils (fish oil, olive oil and other biological oils),
[0048] 2) alfa tocoferol (Vit E oil solution) and mixtures of these
components (50/50) either used in a single layer or used in
multiple layers. All coating solutions were shaken well until
homogenous solutions were achieved.
Stent and Stent Coating
[0049] Balloon mounted stainless steel balloon-expandable coronary
stents, 16 mm long, were used for these studies. The bare stents
were sterile and dipped in a bicarbonate solution and air-dried,
then dipcoated in the oil coating solution. The coated stents were
air-dried or sterilized with ethylene oxide before implantation in
porcine coronary arteries. The surface characteristics of the
coated stents were examined by light and scanning electron
microscopy (SEM).
Stent Implantation
[0050] Domestic cross bred pigs of both sexes, weighing 20-25 kg
were used. They were fed with a standard natural grain diet without
lipid or cholesterol supplementation throughout the study. All
animals were treated and cared for in accordance with the Belgium
National Institute of Health Guidelines for care and use of
laboratory animals.
Acute Study
[0051] In this study control bare stents and oil coated stents
(cod-liver oil (CLO), alfa-tocopherol oil solution (VIT E), CLO+VIT
E, in each group 5 stents) were randomly implanted in the coronary
arteries of pigs. Pigs were sacrificed after 5 days to evaluate
acute inflammatory response and thrombus formation.
Chronic Study
[0052] In this study control bare stents (n=16) and oil coated
stents (CLO n=13, VIT E n=16, CLO+VIT E n=3) were implanted
randomly in the coronary arteries of pigs. Pigs were sacrificed
after 4 weeks to evaluate peri-strut inflammation and neointimal
hyperplasia.
Surgical procedures and stent implantation in the coronary arteries
were performed according to the method described by De Scheerder et
al in "Local angiopeptin delivery using coated stents reduces
neointimal proliferation in overstretched porcine coronary
arteries." J. Inves. Cardiol. 8:215-222; 1996, and in "Experimental
study of thrombogenicity and foreign body reaction induced by
heparin-coated coronary stents." Circulation 95:1549-1553; 1997.
The guiding catheter was used as a reference to obtain an
oversizing from 10 to 20%.
Tissue Processing for Histomorphometric Analysis
[0053] At 5 days or 4 weeks follow-up, the pigs were sacrificed and
the stented coronary arteries were perfused with a 10% formalin
solution at 80 mmHg. Artery segments were carefully dissected
together with minimum a 1 cm vessel segment both proximal and
distal to the stent. The segments were furthermore fixed in a 10%
formalin solution. Each segment was cut into a proximal, middle and
distal stent segment for histomorphometric analysis. Tissue
specimens were embedded in a cold-polymerizing resin (Technovit
7100, Heraus Kulzer GmbH, and Wehrheim, Germany). Sections, 5
microns thick, were cut with a rotary heavy duty microtome HM 360
(Microm, Walldorf, Germany) equipped with a hard metal knife, and
stained with hematoxylin-eosin, masson's trichrome, elastic stain
and a phosphotungstic acid hematoxylin stain. Light microscopic
examination was performed blinded to the type of stent used. Injury
of the arterial wall due to stent deployment was evaluated for each
stent filament site and graded as described by Schwartz et al in
"Restenosis and the proportional neointimal response to coronary
artery injury: results in a porcine model." J. Am. Coll. Cardiol.
1992:19(2):267-74. Inflammatory reaction at every stent filament
site was carefully examined searching for inflammatory cells, and
scored as followed: [0054] 1=sparsely located histiolymphocytic
infiltrate around the stent filament; [0055] 2=more densely located
histiolymphocytic infiltrate covering the stent filament, but no
foreign body granuloma or giant cells; [0056] 3=diffusely located
inflammatory cells and/or giant cells, also invading the media.
Appearance of thrombus was evaluated for every stent filament on
the phosphotungstic acid hematoxylin stained slides and graded as
follows: [0057] 1=small thrombus adjacent to the stent filament;
[0058] 2=more pronounced, covering the stent filament; [0059] 3=big
thrombus resulting in an area stenosis of <50%; [0060] 4=big
thrombus resulting in an area stenosis>50%. The mean score was
calculated as the sum of scores for each filament/number of
filament present. Morphometric analysis of the coronary segments
harvested was performed on 3 slices (proximal, middle and distal
stent part) by using a computerized morphometry program (Leitz CBA
8000). The areas of respectively the arterial lumen, the area
inside the internal elastic lamina (IEL), and the area inside the
external elastic lamina (EEL) were measured. Furthermore, the area
stenosis (1-lumen area/IEL area) and the area of neointimal
hyperplasia (IEL area-lumen area) were calculated.
Statistics
[0061] For comparison among different groups, the non-paired t-test
is used. Data are presented as mean value.+-.SD. A p value
.ltoreq.0.05 was considered as statistically significant.
Results
SEM Images of the Coated Stents
[0062] The thickness of coating covering the stent filaments was 10
.mu.m. The stent surface was smooth.
Histopathologic Findings (Table 1)
[0063] At 5 days follow-up, the bare and all CLO coated stents
induced an identical histopathological response. The stent
filaments showed a good alignment to the vascular wall. Internal
elastic membrane was beneath the stent filaments and the media was
compressed. Arterial injury induced by stent implantation was not
significant different among the groups. A thin fibrin layer
covering the stent filaments was observed. A few inflammatory cells
trapped within a thrombotic meshwork covering the stent struts were
observed. No significant different inflammatory score and thrombus
score of CLO coated stents and bare stents were observed. At 4
weeks follow-up, histopathological examination learned that the
lumen surface of the CLO coated stents and bare stents were covered
completely with endothelial cells. A few inflammatory cells were
found adjacent to the stent struts. A peri-strut inflammation score
more than 2 was rare. The mean inflammation scores of all CLO
coated stents were lower than the bare stents, although only VIT E
coated stents showed a significantly decreased inflammation score
(1.10.+-.0.29 vs 1.00.+-.0.01, P<0.05). Lacerated internal
elastic lamina and media were observed. Comparing to bare stents,
the arterial injury scores of CLO coated (0.28.+-.0.39 vs
0.19.+-.0.19, P>0.05) and CLO+VIT E coated stents (0.28.+-.0.39
vs 0.21.+-.0.16, P>0.05) were decreased.
Morphometry
[0064] At 4 weeks follow-up, the neointima of all CLO coated and
bare stents was well organized which consisted of extracellular
matrix and SMC's. The lumen area of bare stents was significantly
larger than the VIT E coated stents (5.17.+-.1.19 vs 4.19.+-.0.93,
P<0.001), but smaller than CLO+VIT E coated stents (5.17.+-.1.19
vs 6.37.+-.0.97, P<0.01). The neointimal hyperplasia of bare
stents was comparable to VIT E stents, but higher than CLO coated
stents (1.50.+-.0.76 vs 1.25.+-.0.61, P>0.05) and CLO+VIT E
coated stents (1.50.+-.0.76 vs 0.96.+-.0.20, P<0.05).
TABLE-US-00001 TABLE 1 Histomorphometric response to the coated
stents at 4 weeks follow-up Lumen Area Hyperplasia Area Stenosis
Inflammation Injury Stents n (mm.sup.2) (mm.sup.2) (%) Score Score
Bare 48 5.17 .+-. 1.19 1.50 .+-. 0.76 23 .+-. 13 1.10 .+-. 0.29
0.28 .+-. 0.39 CLO 39 5.59 .+-. 1.39 1.25 .+-. 0.61 19 .+-. 10 1.02
.+-. 0.07 0.19 .+-. 0.19 VIT E 48 4.19 .+-. 0.93*** 1.60 .+-. 0.66
28 .+-. 12 1.00 .+-. 0.01* 0.31 .+-. 0.26 CLO + VIT E 9 6.37 .+-.
0.97** 0.96 .+-. 0.20* 13 .+-. 3* 1.00 .+-. 0.00* 0.21 .+-. 0.16
Comparing to bare stents, *P < 0.05, **P < 0.01, ***P <
0.001
CONCLUSION
[0065] All three coated and bare stents elicited a similar tissue
response at 5 days follow-up. No additional inflammatory response
and increased thrombus formation were observed with coated stents
at that time point. At 4 weeks follow-up, all coated stents showed
a mild inflammatory response. The inflammatory scores of coated
stents were lower than the bare stents, especially using the VIT E
coating. CLO and CLO+VIT E coated stents showed a decreased
neointimal hyperplasia compared to the bare stents. The decreased
lumen area of VIT E coated stents may be caused by smaller selected
stented arteries as the neointimal hyperplasia of VIT E coated
stents was comparable to bare stents. In conclusion, all CLO, VIT E
and CLO+VIT E coatings showed an excellent bio-compatibility to
vascular tissue and could therefore serve as a vehicle for local
drug delivery. The best results were obtained with the CLO+VIT E
combination.
Olive Oil Coatings
[0066] In addition to the tests with cod-liver oil and vit. E oil,
similar tests have been done with olive oil. The results of these
tests are shown in Table 2. In this table it can be seen that,
compared to the results for the bare stents given in Table 1, a
coating consisting of only olive oil has beneficial effects on the
lumen area, the neointimal hyperplasia and the area stenosis.
TABLE-US-00002 TABLE 2 Histomorphometric response to the olive oil
coated stents at 4 weeks follow-up EEL IEL Dia.- Lum. eq. IEL- EEL-
IELa- Area Dia.- Lum. a. peri. dia. a. peri. eq.dia. a. peri.
eq.dia. Lum.a. Dia.Ste. Ste. Lum.Dia. Dia. Prox 5.59 9.05 2.67 6.94
10.08 2.97 8.74 11.08 3.34 1.35 10% 19% 0.30 0.67 Mid 4.82 8.86
2.48 6.05 9.40 2.78 7.82 10.59 3.15 1.23 11% 20% 0.30 0.67 Dis 5.42
8.73 2.63 6.33 9.48 2.84 7.69 10.22 3.13 0.91 7% 14% 0.21 0.50 Prox
4.32 7.77 2.34 5.45 8.82 2.63 7.03 9.98 2.99 1.13 11% 21% 0.29 0.65
Mid 5.37 8.53 2.61 6.22 9.48 2.81 7.57 10.11 3.11 0.85 7% 14% 0.20
0.50 Dis 4.63 7.97 2.43 5.92 9.15 2.75 7.29 9.92 3.05 1.29 12% 22%
0.32 0.62 Mean 5.03 8.49 2.53 6.15 9.40 2.80 7.69 10.32 3.13 1.13
10% 18% 0.27 0.60 .+-.SD 0.51 0.51 0.13 0.49 0.42 0.11 0.59 0.44
0.12 0.21 0.02 0.03 0.05 0.08
Tacrolimus Loaded into the Biological Oil
[0067] To evaluate this new coating method use was made as
endoluminal prosthesis of a commercial available balloonexpandable
coronary stent (V-Flex Plus, 16 mm/3.0 mm, William Cook Europe). As
drug we used Tacrolimus, a calcineurin inhibitor, which blocks IL-2
mediated T-cell proliferation and possesses anti-inflammatory and
anti-proliferative activity.
[0068] Tacrolimus (1 mg) was dissolved in an emulsion of 50% highly
purified eicosapentaenoic (EPA) enriched oil and 50% pure ethanol.
After intense stirring during 5 min a homogeneous solution was
obtained. Stents were cleaned and degreased and dried. They were
dipped in a Sodium bicarbonate solution during 30 seconds,
air-dried and than dipped in the Tacrolimus/eicosapentaenoic (EPA)
enriched oil/ethanol emulsion.
[0069] The stents were air-dried in a warm laminar flow to let
evaporate the ethanol and a thin, homogeneous coating layer was
obtained. Stents were repeatedly (3.times.) dipped and dried.
Thereafter the stents were immerced in an alfa-tocopherol/ethanol
solution and again airdried.
[0070] Total Tacrolimus amount obtained on one stent was 800
.mu.g.
[0071] In vitro drug release showed a progressive release of the
drug over 4 weeks.
[0072] In vivo experiments using a porcine coronary model revealed
perfect biocompatibility of the coating system. No inflammatory
response was seen at 5, 10 days, and 4 and 8 weeks after stent
inplantation. Using the coating without the drug an unexpected 20%
reduction of in-stent neointimal hyperplasia compared with
non-coated bare stents was observed at 4 and 8 weeks. Adding
tacrolimus, the neointimal hyperplasia could be further
decreased.
* * * * *