U.S. patent application number 09/991235 was filed with the patent office on 2003-04-24 for stent coatings containing hmg-coa reductase inhibitors.
Invention is credited to Akella, Rama, Pathak, Chandrashekhar, Ranieri, John.
Application Number | 20030077310 09/991235 |
Document ID | / |
Family ID | 25537014 |
Filed Date | 2003-04-24 |
United States Patent
Application |
20030077310 |
Kind Code |
A1 |
Pathak, Chandrashekhar ; et
al. |
April 24, 2003 |
Stent coatings containing HMG-CoA reductase inhibitors
Abstract
Stents with coatings comprising a combination of a restenosis
inhibitor comprising an HMG-CoA reductase inhibitor and a carrier.
Also provided are methods of coating stents with a combination of
an HMG-CoA reductase inhibitor and a carrier. A preferred example
of a restenosis inhibitor is cerivastatin. The stent coatings have
been shown to release restenosis inhibitors in their active
forms.
Inventors: |
Pathak, Chandrashekhar;
(Austin, TX) ; Akella, Rama; (Austin, TX) ;
Ranieri, John; (Atlanta, GA) |
Correspondence
Address: |
SULZER MEDICA USA INC.
Suite 1600
3 East Greenway Plaza
Houston
TX
77046
US
|
Family ID: |
25537014 |
Appl. No.: |
09/991235 |
Filed: |
October 22, 2001 |
Current U.S.
Class: |
424/423 ;
604/500 |
Current CPC
Class: |
A61L 31/049 20130101;
A61F 2230/0013 20130101; A61L 2300/434 20130101; A61F 2250/0067
20130101; A61L 2300/606 20130101; A61L 31/06 20130101; A61L 31/125
20130101; A61L 2300/802 20130101; A61F 2/82 20130101; A61F 2/91
20130101; A61L 2300/416 20130101; A61L 31/10 20130101; A61L 2/16
20130101; A61L 31/08 20130101; A61L 2300/602 20130101; A61L 31/16
20130101; A61L 2420/04 20130101; A61L 2/28 20130101; A61L 31/048
20130101 |
Class at
Publication: |
424/423 ;
604/500 |
International
Class: |
A61M 031/00 |
Claims
1.) a coated stent comprising: a) a stent and b) a coating
composition comprising: 1) an HMG-CoA reductase inhibitor in an
amount effective to inhibit proliferation of smooth muscle cells in
a body lumen of a patient, and 2) a carrier.
2. The coated stent of claim 1 wherein the carrier is a
nonpolymeric carrier.
3. The coated stent of claim 1 wherein the carrier is a polymeric
carrier.
4. The coated stent of claim 1 wherein the carrier is a liquid at
body temperature.
5. The coated stent of claim 4 wherein the carrier is a solid at
room temperature.
6. The coated stent of claim 1 wherein the carrier is polymeric and
the HMG-CoA reductase inhibitor is physically bound to the
carrier.
7. The coated stent of claim 1 wherein the carrier is polymeric and
the HMG-CoA reductase inhibitor is chemically bound to the
carrier.
8. The coated stent of claim 1 wherein the coating composition is a
liquid at body temperature.
9. The coated stent of claim 8 wherein the coating composition is a
solid at room temperature.
10. The coated stent of claim 1 wherein the coating composition
further comprises: a. a solvent and wherein the coating composition
is a liquid at body temperature.
11. The coated stent of claim 1 wherein the coating composition is
a solid at body temperature.
12. The coated stent of claim 1 wherein the coating composition
comprises from about 1 wt % to about 50 wt % HMG-CoA reductase
inhibitor, based on the total weight of the coating
composition.
13. The coated stent of claim 1 wherein the coating composition
comprises from about 5 wt % to about 30 wt % HMG-CoA reductase
inhibitor, based on the total weight of the coating
composition.
14. The coated stent of claim 1 wherein the coating composition
comprises from about 10 wt % to about 20 wt % HMG-CoA reductase
inhibitor, based on the total weight of the coating
composition.
15. The coated stent of claim 1 wherein the HMG-CoA reductase
inhibitor is selected from the group consisting of cerivastatin,
atorvastatin, simvastatin, fluvastatin, lovastatin, and
pravastatin.
16. The coated stent of claim 1 wherein the HMG-CoA reductase
inhibitor is cerivastatin.
17. The coated stent of claim 1 wherein the coating composition
further comprises: a) a restenosis inhibitor which is not an
HMG-CoA reductase inhibitor.
18. The coated stent of claim 1 wherein the carrier is non-reactive
with the HMG-CoA reductase inhibitor.
19. The coated stent of claim 1 wherein the carrier comprises a
polymer having no functional group that is reactive with the
HMG-CoA reductase inhibitor.
20. The coated stent of claim 1 wherein the carrier comprises a
biodegradable polymer.
21. The coated stent of claim 1 wherein the carrier comprises a
polymer selected from the group consisting of polyhydroxy acids,
polyanhydrides, polyphosphazenes, polyalkylene oxalates,
biodegradable polyamides, polyorthoesters, polyphosphoesters,
polyorthocarbonates, and blends or copolymers thereof.
22. The coated stent of claim 1 wherein the carrier comprises a
biostable polymer.
23. The coated stent of claim 1 wherein the carrier comprises a
polymer selected from the group consisting of polyurethanes,
silicones, acrylates, polyesters, polyalkylene oxides,
polyalcohols, polyolefins, polyvinyl chlorides, cellulose and its
derivatives, fluorinated polymers, biostable polyamides, and blends
or copolymers thereof.
24. A method of coating a stent comprising: a) providing a stent;
b) providing a coating composition comprising 1) an HMG-CoA
reductase inhibitor in an amount effective to inhibit proliferation
of smooth muscle cells in a body lumen of a patient; and 2) a
carrier; and c) applying the coating composition to the stent.
25. The method of claim 24, wherein said step of providing the
coating composition comprises mixing the HMG-CoA reductase
inhibitor, the carrier, and a solvent under conditions such that
the HMG-CoA reductase inhibitor does not chemically react to any
substantial degree with the carrier.
26. The method of claim 24, wherein said step of providing the
coating composition comprises mixing the HMG-CoA reductase
inhibitor, the carrier, and a solvent at a temperature of from
about 20.degree. C. to about 30.degree. C.
27. The method of claim 24, further comprising: a) expanding the
stent before applying the coating composition to the stent.
28. The method of claim 24, wherein said step of applying comprises
spraying the coating composition onto the stent.
29. The method of claim 24, wherein said step of applying comprises
immersing the stent in the coating composition.
30. The method of claim 24, further comprising: a) drying the stent
after the coating composition is applied to the stent.
31. The method of claim 24, wherein said step of providing
comprises forming the coating composition into a film, and said
step of applying comprises wrapping the film around the stent.
32. The method of claim 24, further comprising: a) drying the stent
after the coating composition is applied to the stent and b)
applying a second coating composition comprising a polymer to the
dried stent.
33. The method of claim 24, further comprising: a) drying the stent
after the coating composition is applied to the stent; and b)
applying a second coating composition comprising a polymer and a
substantially unreacted HMG-CoA reductase inhibitor to the dried
stent.
34. The method of claim 24, wherein said step of providing
comprises mixing the HMG-CoA reductase inhibitor, a polymer
carrier, and a solvent.
35. The method of claim 24, wherein said step of providing
comprises providing said HMG-CoA reductase inhibitor at from about
1 wt % to about 50 wt %, based on the total weight of the coating
composition.
36. The method of claim 24, wherein the carrier is nonreactive with
the HMG-CoA reductase inhibitor.
37. The method of claim 24, wherein the carrier comprises a
biodegradable polymer.
38. The method of claim 24, wherein the polymer includes a
biostable polymer.
39. The method of claim 24, wherein the HMG-CoA reductase inhibitor
is selected from the group consisting of cerivastatin,
atorvastatin, simvastatin, fluvastatin, lovastatin, and
pravastatin.
40. The method of claim 24, wherein the HMG-CoA reductase inhibitor
is cerivastatin.
41. A method of treating restenosis, comprising a) providing a
coated stent comprising 1) a stent, and 2) a coating composition,
coupled to said stent, comprising an HMG-CoA reductase inhibitor
and a carrier, b) delivering said coating stent to an occluded body
lumen, and c) expanding said stent to provide support to said body
lumen.
Description
BACKGROUND
[0001] 1. Field of the Invention
[0002] The present invention generally relates to stent coatings
that include bioactive compounds that inhibit restenosis.
[0003] 2. Description of the Related Art
[0004] Stents are often used in the treatment of atherosclerosis, a
disease of the vascular system in which arteries become partially,
and sometimes completely, occluded with substances that may include
lipids, cholesterol, calcium, and various types of cells, such as
smooth muscle cells and platelets. Atherosclerosis is a very common
disease that can be fatal, and methods of preventing the
accumulation of occluding compounds in arteries are being
investigated.
[0005] Percutaneous transluminal angioplasty (PTA) is a commonly
used procedure to break up and/or remove already formed deposits
along arterial walls. PTA can also be used to treat vascular
occlusions not associated with atherosclerosis. During PTA, a
catheter is threaded through a patient's arteries until the
occluded area to be treated is reached. A balloon attached to the
end of the catheter is then inflated at the occluded site. The
expanded balloon breaks up the mass of occluding substances,
resulting in a more open arterial lumen. However, there is a risk
that the artery may re-close within a period of from one day to
approximately six months of the procedure. This re-closure is known
as restenosis. Accordingly, a balloon-only angioplasty procedure
often does not result in a permanently reopened artery. To prevent
restenosis, scaffolding devices called stents are deployed in the
lumen of the artery as a structural support to maintain the lumen
in an open state. Unlike the balloon and the catheter used in an
angioplasty procedure, the stent usually remains in the artery as a
permanent prosthesis. Although technically feasible, removal of the
stent from the artery is generally avoided.
[0006] Stents are typically elongated structures used to keep open
lumens (e.g., openings in the body) found in various parts of the
body so that the parts of the body containing those lumens may
function properly. Stents are usually implanted at their site of
use in the body by attaching them in a compressed state to a
catheter that is directed through the body to the site of stent
use. The stent can be expanded to a size which enables it to keep
the lumen open by supporting the walls of the lumen once it is
positioned at the desired site.
[0007] The lumens of blood vessels are common sites of stent
deployment. Vascular stents are frequently used in blood vessels to
open the vessel and provide improved blood flow. The stents are
typically hollow, cylindrical structures made from struts or
interconnected filaments. Vascular stents can be collapsed to
reduce their diameter so that the stent can be guided through a
patient's arteries or veins to reach the site of deployment. Stents
are typically either coupled to the outside of the balloon for
expansion by the expanding balloon or are self-expanding upon
removal of a restraint such as a wire or sleeve maintaining the
stent in its collapsed state.
[0008] The stent is allowed to expand at the desired site to a
diameter large enough to keep the blood vessel open. Vascular
stents are often made of metal to provide the strength necessary to
support the occluded arterial walls. Two of the preferred metals
are Nitinol alloys of nickel and titanium, and stainless steel.
Other materials that can be used in fabricating stents are
ceramics, polymers, and plastics. Stents may be coated with a
substance, such as a biodegradable or biostable polymer, to improve
the biocompatibility of the stent, making it less likely to cause
an allergic or other immunological response in a patient. A coating
substance may also add to the strength of the stent. Some known
coating substances include organic acids, their derivatives, and
synthetic polymers that are either biodegradable or biostable.
Biostable coating substances do not degrade in the body,
biodegradable coating substances can degrade in the body. A problem
with known biodegradable and biostable stent coatings is that both
types of coatings are susceptible to breaking and cracking during
the temperature changes and expansion/contraction cycles
experienced during stent formation and use.
[0009] Stents located within any lumen in the body may not always
prevent partial or complete restenosis. In particular, stents do
not always prevent the re-narrowing of an artery following PTA. In
fact, the introduction and presence of the stent itself in the
artery or vein can create regions of trauma such as, e.g., tears in
the inner lining of the artery, called the endothelium. It is
believed that such trauma can trigger migration of vascular smooth
muscle cells, which are usually separated from the arterial lumen
by the endothelium, into the arterial lumen, where they proliferate
to create a mass of cells that may, in a matter of days or weeks,
occlude the artery. Such re-occlusion, which is sometimes seen
after PTA, is an example of restenosis. Coating a stent with a
substance to make the surface of the stent smoother and to minimize
damage to the endothelium has been one method used to create stents
that are less likely to contribute to restenosis.
[0010] Currently, drug therapy for restenosis primarily consists of
the systemic administration of drugs. However, delivering drugs in
this manner may result in undesirable side effects in other areas
of the body unrelated to the vascular occlusion. Also, the
administered dose of a drug that is delivered systemically is less
effective in achieving the desired effect in the local area of the
body in which it is needed. For example, an anti-restenosis drug
delivered systemically may be sequestered or metabolized by other
parts of the body, resulting in only a small amount of the drug
reaching the local area in which it is needed.
[0011] Stents with bioactive compounds or drugs in or on their
coatings can be used. One class of drugs that can be used in stent
coatings is restenosis inhibitors. There remains a need for
coatings that can be shown to actually release the restenosis
inhibiting compounds in their active forms. Further, there is a
need for stents that can carry drugs and release them in a
sufficient concentration to produce the desired effect. In
particular, there is a need for such stents that can inhibit
restenosis.
SUMMARY OF INVENTION
[0012] Broadly, the invention relates to coated stents, methods of
making coated stents and methods of using coated stents. In one
aspect, the invention can include a coated stent comprising a stent
and a coating comprising a substantially unreacted HMG-CoA
reductase inhibitor. It is preferred that the coating also comprise
a carrier for the HMG-CoA reductase inhibitor. In a specific
embodiment, the HMG-CoA reductase inhibitor is provided in a
nonpolymeric carrier. In another embodiment, the HMG-CoA reductase
inhibitor is provided in a polymeric carrier, which may be
physically bound to the polymer, chemically bound to the polymer,
or both. The coating composition can be a liquid solution at room
and/or body temperature, which may include the HMG-CoA reductase
inhibitor and the polymeric or nonpolymeric carrier, and which may
additionally include a solvent which later may be removed, e.g., by
drying. Alternatively, the coating composition may be a solid at
room and body temperature.
[0013] The coating composition preferably includes an effective
amount of the HMG-CoA reductase inhibitor. More particularly, the
coating composition preferably includes an amount of the HMG-CoA
reductase inhibitor that is sufficient to be therapeutically
effective for inhibiting regrowth of plaque or inhibiting
restenosis. In one embodiment, the coating composition may include
from about 1 wt % to about 50 wt % HMG-CoA reductase inhibitor,
based on the total weight of the coating composition. In another
embodiment, the coating composition includes from about 5 wt % to
about 30 wt % HMG-CoA reductase inhibitor. In yet another
embodiment, the coating composition includes from about 10 wt % to
about 20 wt % HMG-CoA reductase inhibitor. Any HMG-CoA reductase
inhibitor may be used, but the HMG-CoA reductase inhibitor is
preferably selected from the group consisting of cerivastatin,
atorvastatin, simvastatin, fluvastatin, lovastatin, and
pravastatin. More preferably, the HMG-CoA reductase inhibitor is
cerivastatin. In another embodiment, the coating composition
comprises more than one HMG-CoA reductase inhibitor. In another
embodiment, the coating composition includes a restenosis inhibitor
that is not an HMG-CoA reductase inhibitor.
[0014] In one embodiment, the coating composition comprises an
effective amount of a polymeric carrier, e.g., an amount sufficient
to provide a polymer matrix or support for the inhibitor. The
polymer is preferably non-reactive with the HMG-CoA reductase
inhibitor, i.e., no chemical reaction occurs when the two are
mixed. The polymer may be a polymer having no functional groups.
Alternatively, the polymer may be one having functional groups, but
none that are reactive with the HMG-CoA reductase inhibitor. The
polymer may include a biodegradable polymer. For example, the
polymer may include a polymer selected from the group consisting of
polyhydroxy acids, polyanhydrides, polyphosphazenes, polyalkylene
oxalates, biodegradable polyamides, polyorthoesters,
polyphosphoesters, polyorthocarbonates, and blends or copolymers
thereof. The polymer may also include a biostable polymer, alone or
in combination with a biodegradable polymer. For example, the
polymer may include a polymer selected from the group consisting of
polyurethanes, silicones, polyacrylates, polyesters, polyalkylene
oxides, polyalcohols, polyolefins, polyvinyl chlorides, cellulose
and its derivatives, fluorinated polymers, biostable polyamides,
and blends or copolymers thereof.
[0015] In another embodiment, the coating composition comprises an
effective amount of a non-polymeric carrier. In a particular
embodiment, the non-polymeric carrier comprises a fatty acid. The
non-polymeric carrier may alternatively comprise a biocompatible
oil, wax, or gel. In a yet further embodiment, the non-polymeric
carrier may comprise a mixture of one or more of a fatty acid, an
oil, a wax, and/or a gel.
[0016] In another aspect, the invention can include a method of
coating a stent. In a specific embodiment, the method includes
providing a coating composition comprising a blend of a
substantially unreacted HMG-CoA reductase inhibitor and a polymeric
or nonpolymeric carrier, and applying the coating composition to
the stent. Providing the coating composition may include mixing the
HMG-CoA reductase inhibitor and a nonpolymeric liquid carrier. In
one embodiment, the nonpolymeric liquid carrier comprises a C-6 to
C-18 fatty acid. In another embodiment, providing the coating
composition may include mixing the HMG-CoA reductase inhibitor and
a polymeric liquid carrier. In a further embodiment, providing the
coating composition may include mixing the HMG-CoA reductase
inhibitor, a polymer, and a solvent under conditions such that the
HMG-CoA reductase inhibitor does not chemically react with the
polymer, or does not react to any substantial extent. Providing the
coating composition may also include mixing the HMG-CoA reductase
inhibitor, a polymer, and a solvent at a temperature of from about
20.degree. C. to about 30.degree. C., preferably at about
25.degree. C. The method of coating the composition may further
comprise removing the solvent by, e.g., drying. In another
embodiment, providing a coating composition may include providing a
solid coating comprising an HMG-CoA reductase inhibitor and a
polymer.
[0017] In another embodiment, a method of coating a stent may
further comprise expanding the stent to an expanded position before
applying the coating composition to the stent. The coating
composition may be applied to the stent by any number of ways,
e.g., by spraying the coating composition onto the stent, by
immersing the stent in the coating composition, or by painting the
stent with the coating composition. Other coating methods, such as
electrodeposition can also be used. In one embodiment, excess
coating composition is allowed to drain from the stent. In another
embodiment, the stent is dried after the coating composition is
applied to the stent to provide a solid coating composition. The
coating composition may be formed into a solid film that is then
applied to the stent by wrapping the film around the stent.
[0018] In another aspect, the invention includes a method of
treating an occluded artery comprising providing a stent, providing
a coating composition comprising a nonpolymeric or polymeric
carrier and a HMG-CoA reductase inhibitor in an amount effective to
prevent or substantially reduce restenosis, applying the coating
composition to the stent, and deploying the stent in the occluded
artery at the site of occlusion. Providing a coating composition
may comprise dissolving or suspending an amount of the HMG-CoA
reductase inhibitor effective to prevent or substantially reduce
restenosis in a nonpolymeric carrier that is a liquid at room
and/or body temperature. In another embodiment, providing a coating
composition may comprise dissolving in a polymeric carrier that is
a liquid at room and/or body temperature an amount of the HMG-CoA
reductase inhibitor effective to prevent or substantially reduce
restenosis in an occluded vascular lumen. In alternative
embodiments, the nonpolymeric or polymeric carrier may be a solid
at room and body temperature. Where a polymeric carrier is
provided, the HMG-CoA reductase inhibitor may be physically bound
to the polymer, chemically bound to the polymer, or both. The
coating composition may be a solution which includes the HMG-CoA
reductase inhibitor, the polymer, and a solvent. The solvent may be
removed by, e.g., drying the stent or other methods known in the
art to yield a stent having a solid polymeric carrier for the
HMC-CoA reductase inhibitor. The coating composition may include an
amount of the HMG-CoA reductase inhibitor that is therapeutically
effective for inhibiting regrowth of plaque or inhibiting
restenosis. More particularly, the coating composition may include
from about 1 wt % to about 50 wt % HMG-CoA reductase inhibitor,
based on the total weight of the coating composition.
[0019] In another aspect, the invention can include a method of
treating restenosis, comprising inserting a coated stent into a
body lumen, the coated stent comprising a stent and a coating
composition comprising a substantially unreacted HMG-CoA reductase
inhibitor and a nonpolymeric or polymeric carrier, which may be a
liquid at room and body temperature, a solid at room and body
temperature, or a solid at room temperature and a liquid at body
temperature. In one embodiment, the coated stent releases the
HMG-CoA reductase inhibitor in an amount sufficient to inhibit or
reduce the regrowth of plaque. In another embodiment, the coated
stent releases the HMG-CoA reductase inhibitor in an amount
sufficient to inhibit or reduce restenosis.
[0020] In another aspect, the invention can include a method of
localized delivery of an HMG-CoA reductase inhibitor, comprising
inserting a coated stent into a body lumen, the coated stent
comprising a stent and a coating composition comprising a
substantially unreacted HMG-CoA reductase inhibitor and a polymeric
or nonpolymeric carrier. In one embodiment, the coated stent
releases the HMG-CoA reductase inhibitor in an amount effective to
inhibit the regrowth of plaque. In another embodiment, the coated
stent releases the HMG-CoA reductase inhibitor in an amount
effective to inhibit restenosis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is a cross-section of an artery experiencing
restenosis in the presence of an uncoated stent.
[0022] FIG. 2 is a cross-section of an artery containing a coated
stent.
[0023] FIG. 3 is a stent of a type suitable for use in connection
with the present invention.
[0024] FIG. 4 is a UV-VIS spectra of cerivastatin released from a
stent coating.
[0025] FIG. 5 is a release profile of cerivastatin released from a
stent coating of EVA film.
[0026] FIG. 6 is a release profile of cerivastatin released from a
stent coating of polycaprolactone film.
[0027] FIG. 7 is a release profile of cerivastatin released from a
stent coated with silicone.
[0028] FIG. 8 is a release profile of cerivastatin released from a
stent coated with liquid vitamin.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0029] An exemplary artery 10 experiencing restenosis is shown in
FIG. 1. The endothelium 12 normally serves as a solid barrier
between the layer of smooth muscle cells 14 and the arterial lumen
20. Small tears 16 in the endothelium 12 can expose smooth muscle
cells 14, which can then migrate into the arterial lumen 20 and
hyperproliferate into a mass 18 which can partially or completely
occlude the lumen 20 even though an uncoated stent 21 is placed,
during a procedure such as angioplasty, in the artery 10 to keep
the arterial lumen 20 open.
[0030] An artery 10 containing a coated stent 22 prepared according
to an embodiment herein is shown in FIG. 2. The stent has a coating
24 containing a polymer and a bioactive compound that inhibits
restenosis. By using a stent having this coating 24, the tears 16
shown in FIG. 1 in the endothelium 12 may be reduced or eliminated.
Additionally, the mass 18 created by a proliferation of smooth
muscle cells 14, as shown in FIG. 1, is eliminated or substantially
reduced.
[0031] FIG. 3 illustrates a stent 21 suitable for use in connection
with the present invention. In one embodiment, the stent 21
comprises a hollow reticulated tube. The tubular body of stent 21
is defined by a number of filaments or struts 25 which surround
open cells 26. The stent 21 comprises an inner surface 27 facing
the interior of the stent and an outer surface 28 facing the
exterior. In a preferred embodiment, a coating (now shown) covers
both the inner surface 27 and the outer surface 28. In alternative
embodiments, the coating may cover only the inner surface, only the
outer surface, or portions of one or both of the inner and outer
surfaces. The coating may aggregate at the intersection of
filaments. In a preferred embodiment, the coated stent 22 (FIG. 2)
is made out of a metal or metal alloy, such as titanium, tantalum,
stainless steel, or nitinol. In a preferred embodiment, the coating
24 is made by mixing together an HMG-CoA reductase inhibitor, and a
carrier in which both the HMG-CoA reductase inhibitor is soluble.
In a particularly preferred embodiment, the carrier is a liquid oil
that adheres to the inner and outer surfaces 27, 28 of the stent
22. In other embodiments, the carrier comprises a polymer dissolved
in a solvent, which is then removed, e.g., by drying, to yield a
solid coating composition comprising the polymer and the HMG-CoA
reductase inhibitor.
[0032] As discussed, the coated stent of this invention includes a
stent and a coating composition. The coating composition is
preferably a blend of HMG-CoA reductase inhibitor and a liquid oil
capable of adhering to the inner surface 27 and/or the outer
surface 28 of the stent 22. In another embodiment, the coating
composition comprises a blend of HMG-CoA reductase inhibitor and a
polymer. These two ingredients are preferably blended, e.g., mixed
thoroughly but not chemically reacted to any substantial degree.
Preferably the HMG-CoA reductase inhibitor is "substantially
unreacted." The term "substantially unreacted," when referring to
the HMG-CoA reductase inhibitor, means that the inhibitor does not
chemically react with the oil, the polymer or any other component
of the coating or the stent, to any degree that substantially
reduces its biological activity, such as inhibiting restenosis by,
e.g., inhibiting the proliferation of smooth muscle cells 14. Where
the coating comprises a polymer, the reductase inhibitor is
physically bound to the polymer and/or to the stent, but is not
chemically bound to any significant degree. In a preferred
embodiment, the carrier, whether liquid or solid, polymeric or
nonpolymeric, is incapable of reacting chemically with the
inhibitor, i.e., is totally non-reactive (inert) with respect to
the inhibitor.
[0033] The HMG-CoA reductase inhibitor should remain active even
after being coupled to the carrier to form the coating composition
and even after the coating composition is applied to the stent and
the device is sterilized. Preferably, the reductase inhibitor
remains active when the coated stent is introduced into the body of
a patient, e.g., through a lumen, and is also still active when it
is released from the stent. An "effective amount" of the HMG-CoA
reductase inhibitor means an amount that is sufficient, when
delivered to a localized area in the body lumen of a patient, to
inhibit the proliferation of smooth muscle cells in a body lumen of
a patient. An "effective amount" of the carrier means an amount of
carrier sufficient to provide an amount of the coating composition
to substantially coat the portion of the stent that is desired to
be coated, preferably the entire stent. Preferably, the carrier has
no functional groups that react with the HMG-CoA reductase
inhibitor under the conditions of forming the blend of the HMG-CoA
reductase inhibitor and the carrier. The term "biodegradable" is
applied herein to any carrier, whether polymeric or nonpolymeric,
and whether liquid or solid, that breaks down in the body. The term
"biostable" is applied herein to any carrier, whether polymeric or
nonpolymeric, and whether liquid or solid, that does not break down
in the body. The term "biocompatible" describes any material that
is not harmful to and does not cause an immunological response in a
body, e.g., a human being.
[0034] In accordance with methods and compositions described
herein, restenosis may be prevented or lessened using localized
delivery of HMG-CoA reductase inhibitors from a stent placed in a
body lumen. Preferably, metal stents are coated with a
biocompatible coating composition comprising a carrier containing
an effective amount of an HMG-CoA reductase inhibitor. The coated
stent can be deployed during any conventional percutaneous
transluminal angioplasty (PTA) procedure. Controlled delivery from
a stent of the active HMG-CoA reductase inhibitor, using a stent
such as that described herein, in an effective amount, can inhibit
the regrowth of plaque and prevent restenosis. While the stents
shown and described in the various embodiments are vascular stents,
any type of stent suitable for deployment in a body lumen of a
patient may be used with the coatings described herein.
[0035] An important aspect of this invention is the carrier used to
form the coating composition. The coating composition may comprise
more than one compound in a liquid carrier. The coating composition
may alternatively comprise more than one solid compound in a solid
carrier. The coating composition may further comprise both a liquid
carrier and a solid carrier. In a still further aspect, the coating
composition may also comprise more than one type of nonpolymeric or
polymeric compound in the carrier, and may further comprise both a
polymeric material and a nonpolymeric material in a solid or liquid
carrier. In a yet further aspect of the invention, the coating
composition may comprise more than one type of HMG-CoA reductase
inhibitor. In coatings created by this method, the HMG-CoA
reductase inhibitors are preferably physically bound to the carrier
but not chemically bound thereto. Accordingly, the chemical or
molecular structure of the HMG-CoA reductase inhibitor is
preferably unchanged when they are mixed with the polymers to form
the coating. Therefore, when the HMG-CoA reductase inhibitor is
released from the coating, it remains in the desired active
form.
[0036] In order to create coatings in which HMG-CoA reductase
inhibitors are physically rather than chemically bound to the
polymers in the coatings, HMG-CoA reductase inhibitors and carriers
are chosen such that they will not have functional groups that will
react with each other under the compounding conditions of to form
the coating solution.
[0037] The carriers in the coating composition may be either
biodegradable or biostable. Biodegradable polymers are often used
in synthetic biodegradable sutures. These polymers include
polyhydroxy acids. Polyhydroxy acids suitable for use in the
present invention include poly-L-lactic acids, poly-DL-lactic
acids, polyglycolic acids, polylactides including homopolymers and
copolymers of lactide (including lactides made from all stereo
isomers of lactic acids, such as D-, L-lactic acid and meso lactic
acid), polylactones, polycaprolactones, polyglycolides,
polyparadioxanone, poly 1,4-dioxepan-2-one, poly
1,5-dioxepan-2-one, poly 6,6-dimethyl-1,4-dioxan-2-one,
polyhydroxyvalerate, polyhydroxybuterate, polytrimethylene
carbonate polymers, and blends of the foregoing. Polylactones
suitable for use in the present invention include polycaprolactones
such as poly(e-caprolactone), polyvalerolactones such as
poly(d-valerolactone), and polybutyrolactones such as
poly(?-butyrolactone). Other biodegradable polymers that can be
used are polyanhydrides, polyphosphazenes, biodegradable polyamides
such as synthetic polypeptides such as polylysine and polyaspartic
acid, polyalkylene oxalates, polyorthoesters, polyphosphoesters,
and polyorthocarbonates. Copolymers and blends of any of the listed
polymers may be used. Polymer names that are identical except for
the presence or absence of brackets represent the same
polymers.
[0038] Biostable polymers that are preferred are biocompatible.
Biostable polymers suitable for use in the present invention
include, but are not limited to polyurethanes, silicones such as
polyalkyl siloxanes such as polydimethyl siloxane and copolymers,
acrylates such as polymethyl methacrylate and polybutyl
methacrylate, polyesters such as poly(ethylene terephthalate),
polyalkylene oxides such as polyethylene oxide or polyethylene
glycol, polyalcohols such as polyvinyl alcohols and polyethylene
glycols, polyolefins such as polyethylene, polypropylene,
poly(ethylene-propylene) rubber and natural rubber, polyvinyl
chloride, cellulose and modified cellulose derivatives such as
rayon, rayon-triacetate, cellulose acetate, cellulose acetate
butyrate, cellophane, cellulose nitrate, cellulose propionate,
cellulose ethers such as carboxymethyl cellulose and hydroxyalkyl
celluloses, fluorinated polymers such as polytetrafluoroethylene
(Teflon), and biostable polyamides such as Nylon 66 and
polycaprolactam. Fixed animal tissues such as glutaraldehyde fixed
bovine pericardium can also be used. Polyesters and polyamides can
be either biodegradable or biostable. Ester and amide bonds are
susceptible to hydrolysis, which can contribute to biodegradation.
However, access to water, and thus, hydrolysis, can be prevented by
choosing certain neighboring chemical structures.
[0039] In a preferred embodiment, the polymer used to form the
coating composition is polycaprolactone. Polycaprolactone is
biocompatible, and it has a low glass transition temperature, which
gives it flexibly and allows it to withstand the temperature
changes stents often experience during their formation and use. For
example, nitinol stents are preferably cooled to a temperature of
about -50.degree. C. so that they become flexible and can be
compressed and fitted onto a catheter. A sheath placed over the
stent (or another restraint such as a wire binding the ends of the
stent), prevents the stent from expanding as it is introduced into
a patient's body at a higher temperature. The sheath or other
restraint is removed at the site of the stent's use, and the stent
re-expands to the size at which it is coated with a composition
that includes polycaprolactone. Polycaprolactone, unlike some other
stent coating materials, does not become brittle and crack
throughout these fluctuations in stent temperature and size.
Preferably, the polycaprolactone has a molecular weight between
about 20,000 and 2,000,000, and provides a stronger and more
uniform coating than lower molecular weight polymers.
[0040] Generally, the HMG-CoA reductase inhibitor is released from
the stent by diffusion of the HMG-CoA reductase inhibitor out of
the carrier. If the carrier comprises a biodegradable polymer, the
HMG-CoA reductase inhibitor is preferably released from the stent
by the degradation of the polymer. A controlled release of the
HMG-CoA reductase inhibitor from the coating can be achieved with a
carrier comprising both a liquid and a solid through the relatively
rapid release of the diffusion of the HMG-CoA reductase inhibitor
from the liquid and a slower release from the solid. In a still
further embodiment, a highly controlled delivery of the HMG-CoA
reductase inhibitor can be achieved by a carrier comprising a
liquid, a biodegradable (preferably solid) polymer, and a biostable
(preferably solid) polymer. An initial release of the HMG-CoA
reductase inhibitor from the liquid may be followed by a slower
release from the biodegradable solid, and a still slower release
from the biostable solid.
[0041] The diffusion rate of the HMG-CoA reductase inhibitor from
the carrier can be determined by release studies and the dose of
the HMG-CoA reductase inhibitor can be adjusted to deliver the drug
at a desired rate. In one embodiment, a higher dose of an HMG-CoA
reductase inhibitor can be delivered over a short period of time by
using a liquid that releases a known amount of the inhibitor within
one to three days. In another embodiment, a higher dose of an
HMG-CoA reductase inhibitor can be delivered over a short period of
time by using a nonpolymeric liquid carrier such as vitamin E. In
another embodiment, the inhibitor can be delivered via a
biodegradable polymer that degrades within a few days, e.g., low
molecular weight polyglycolic acid, releasing the HMG-CoA reductase
inhibitor by both diffusion and/or coating degradation. In another
embodiment, a biodegradable polymer which delivers an HMG-CoA
reductase inhibitor primarily through diffusion is used. An example
of such a polymer is polycaprolactone, which degrades after several
years in the body.
[0042] Advantageously, the rate of release of a HMG-CoA reductase
inhibitor from a coating can be more easily predicted and is more
consistent than the rate of release of a drug from other coatings
in which the drug is chemically bound to the coating. With the
coatings described herein, the HMG-CoA reductase inhibitors are
preferably physically released from the coatings, and thus, not
dependent on a chemical step, such as hydrolysis, whose rate could
vary in different patients as well as within the same patient.
[0043] The coating composition comprising the carrier and the
HMG-CoA reductase inhibitor can be applied to a stent in a number
of different ways. Preferably, a stent is coated in its expanded
form so that a sufficient amount of coating will be applied to coat
the expanded stent. In a preferred embodiment, the coating
composition is at least initially applied to the stent as a liquid.
Where the coating composition comprises a solid polymer, the
polymer is preferably dissolved in a suitable solvent to form a
polymer solution and the stent is sprayed with the solution in
order to coat the stent struts. Alternatively, the polymer solution
may be painted on the stent or applied by other means known in the
art, such as electrodeposition, dipping, casting or molding. The
solvent may then be dried to yield a solid coating composition
comprising the polymer. In a preferred embodiment, the stent is
dried at from 20.degree. C. to 30.degree. C. or ambient temperature
for a period of time sufficient to remove the solvent. The drying
temperature should not be high as to cause the polymer to react
chemically with the HMG-CoA reductase inhibitor.
[0044] Multiple layers of the polymer solution may be applied to
the stent. Preferably, each layer is allowed to dry before the next
coating is applied. While an HMG-CoA reductase inhibitor is
included in at least one layer of the coating, the coating solution
in the other layers may optionally also contain the same or a
different HMG-CoA reductase inhibitor. The polymer solution for
each layer may contain the same or different polymers. The number
of layers and the polymers in the layers can be chosen to deliver
an HMG-CoA reductase inhibitor in a controlled manner because the
rate of diffusion of the HMG-CoA reductase inhibitor through a
known thickness of polymers can be estimated or measured
directly.
[0045] In one embodiment, a first layer of the polymer solution,
e.g., a primer layer, may be applied to improve the adhesion of the
coating composition to the stent surface. Generally, coating a
stent by completely encapsulating the struts of the stent is
preferred. Complete encapsulation typically provides uniform
distribution of a drug along the surfaces of the stent. A
completely encapsulated coated stent is also more resistant than a
partially coated stent to peeling and other mechanical stresses
encountered during stent deployment. In certain specific
embodiments, a top layer of the polymer solution without a drug may
be applied on the coating. The top coating may be used to control
the diffusion of the drug from the stent. The thickness of the
coating is preferably 0.1 microns to 2 mm. More preferably, the
thickness of the coating is from 1 to 50 microns. Most preferably,
the thickness of the coating is from 10 to 30 microns. Accordingly,
specific embodiments of the invention include a stent with multiple
coatings or layers, e.g., films. For example, a stent with three or
more coatings or layers can be provided, where the first layer
(contacting the stent) comprises a first carrier material having
substantially no HMG-CoA reductase inhibitor, the second layer
(applied to the outer surface of the first layer) includes the
HMG-CoA reductase inhibitor in a second carrier material, and the
third layer (applied to the second layer) comprises a third carrier
material having substantially no HMG-CoA reductase inhibitor.
[0046] In another embodiment, the polymer solution can be formed
into a film and the film then applied to the stent. Any of a
variety of conventional methods of forming films can be used. For
example, the polymer, HMG-CoA reductase inhibitor and solvent are
preferably mixed into solution and then poured onto a smooth, flat
surface such that a coating film is formed after the solution is
dried to remove the solvent. The film can then be cut to fit the
stent on which it is to be used. The film may then be mounted, such
as by wrapping, on the outer surface of a stent.
[0047] As used herein, the term "solvent" is defined according to
its broadest recognized definition and includes any material into
which the polymer and the HMG-CoA reductase inhibitor can dissolve,
fully or partially, at room temperature or from 20.degree. C. to
40.degree. C. Methylene chloride is a preferred solvent. Methylene
chloride's low boiling point facilitates removal from the polymer
and the HMG-CoA reductase inhibitor at ambient temperatures by
evaporation. However, it is contemplated that virtually any organic
solvent that dissolves the polymer can be used. Solvents that can
cause corrosion, such as highly acidic or basic aqueous solutions,
are not preferred. Organic solvents that are biocompatible, have
low boiling points and high flash points, are preferred. Other
solvents that may be used include chloroform, toluene, cyclohexane,
acetone, methylethyl ketone, ethyl formate, ethyl acetate,
acetonitrile, n-methyl pyrrolidinone, dimethyl sulfoxide,
n,n-dimethylacetamide, n,n-dimethyl formamide, ethanol, methanol,
acetic acid, and supercritical carbon dioxide.
[0048] In a particularly preferred embodiment, the coating
composition comprises a nonpolymeric liquid that remains a liquid
after it is applied to the stent and the stent is deployed within
the body of a patient, i.e., the coating liquid has a melting point
below body temperature (37.degree. C.), preferably below 30.degree.
C., more preferably below room temperature (22.degree. C.), more
preferably below 20.degree. C., still more preferably below
10.degree. C. The liquid is preferably a viscous liquid that
adheres to at least a portion of the external surface 28 of the
stent 22 in sufficient quantity to deliver a therapeutically
effective amount of the HMG-CoA reductase inhibitor upon expansion
in the body of the patient. Although the viscous liquid may be
hydrophilic, in a preferred embodiment the viscous liquid is
hydrophobic. Specifically, the carrier may comprise liquid Vitamin
E.
[0049] In another preferred embodiment, the viscous, hydrophobic
liquid comprises a C4-C36 fatty acid or mixtures of such fatty
acids, such as oleic acid or stearic acid, by way of nonlimiting
example. In yet another preferred embodiment, the viscous,
hydrophobic liquid comprises an oil. Exemplary oils suitable for
use in the present invention include peanut oil, cottonseed oil,
mineral oil, low molecular weight (C4-C36), and other viscous
organic compounds that behave as oils such as, by way of
nonlimiting example, 1,2 octanediol and other low molecular weight
alcohols and polyols. Spraying the stent with the liquid carrier
results in a coating of uniform thickness on the struts of the
stent. In another embodiment, the stent may be dip coated or
immersed in the solution, such that the solution completely coats
the struts of the stent. Alternatively, the stent may be painted
with the solution, such as with a paint brush. In each of these
coating applications, the entirety of both the outer and inner
surfaces of the stent are preferably coated, although only portions
of either or both surfaces may be coated in some embodiments.
[0050] In yet a further embodiment of the present invention the
coating composition comprises a nonpolymeric compound that is a
solid at room temperature but becomes a liquid at or near body
temperature. In particular, the coating composition comprises low
molecular weight waxes and derivatives having a melting point at
between about 30.degree. C. and 40.degree. C., more particularly
from about 35.degree. C. to 40.degree. C. and more particularly
about 36.degree. C. to about 38.degree. C. In preferred
embodiments, the low melting solid is applied to the stent by
heating the solid to above its melting point, then sprayed,
painted, dipped, molded, or otherwise applied to the stent as a
liquid and allowing the liquid to resolidify upon cooling. The
stent may then be deployed in the body lumen, whereupon the coating
composition re-liquifies.
[0051] In a preferred embodiment, the HMG-CoA reductase inhibitor
used in the coating composition is cerivastatin. Cerivastatin is a
very potent HMG-CoA reductase inhibitor. For example, when it is
administered systemically, a therapeutic dose of cerivastatin is
less than 1 mg per day, while other HMG-CoA reductase inhibitors
must be administered in 50 mg doses. A thinner stent coating can be
used if cerivastatin is the chosen HMG-CoA reductase inhibitor
instead of other HMG-CoA reductase inhibitors because less coating
is needed. For example, a stent coating preferably has a thickness
of about 10-100 .mu.m. If less drug and less coating to carry the
drug are required, a stent coating having a preferable thickness of
10-25 .mu.m can be used. A thinner stent coating may be preferred
because it leaves more of the arterial lumen open for blood flow.
Thinner coatings are also useful in preserving sidebranch access.
Sidebranches are small blood vessels that branch out from the
coronary artery and provide blood to some part of the heart.
[0052] Cerivastatin has other properties, in addition to its
ability to inhibit the proliferation of smooth muscle cells that
can contribute to restenosis, making it a desirable component of
stent coatings. For example, cerivastatin has anti-thrombotic
activity. Stents can often be sites of thrombus formation in the
body because of the immunologically-triggered aggregation of
different cell types and blood components at the site of a foreign
object in the body. Thus, including cerivastatin in a stent coating
may help prevent thrombus formation at the site of the stent.
Cerivastatin also promotes endothelialization, or the repair of the
endothelium 12 after it is damaged, such as by the delivery and
expansion of the stent in an artery or other body lumen. It is
contemplated that the endothelialization triggered by cerivastatin
can help repair the endothelium, and thus reduce tears in the
endothelium through which smooth muscle cells and other cell types
can migrate into the arterial lumen and proliferate, leading to
restenosis.
[0053] Other HMG-CoA reductase inhibitors may be used in these
stent coatings. For example, atorvastatin, simvastatin,
fluvastatin, lovastatin, and pravastatin may be used. While these
compounds are known for their antihypercholesterolemic properties,
it is believed that they may have other beneficial activities, such
as restenosis inhibition or inhibition of cell proliferation, when
they are delivered in a localized manner, such as from a stent
coating.
[0054] In one embodiment, the coating compositions described herein
may include more than one type of HMG-CoA reductase inhibitor. For
example, a coating composition may include cerivastatin and
lovastatin. In other specific embodiments, the stent coatings
described herein may include one or more drugs or bioactive
compounds that inhibit restenosis and are not HMG-CoA reductase
inhibitors. These drugs include, but are not limited to, rapamycin,
paclitaxel, actinomycin D, nicotine, and bioactive derivatives,
analogues, and truncates of the foregoing. It is contemplated that
combining these drugs with an HMG-CoA reductase inhibitor will
provide a more effective coating composition for inhibiting
restenosis than a coating composition containing only one
restenosis inhibiting agent. However, the foregoing may also be
used without an HMG-CoA reductase inhibitor.
EXAMPLES
[0055] The following examples are included to demonstrate different
illustrative embodiments or versions of the invention. However,
those skilled in the art will, in light of the present disclosure,
appreciate that many changes can be made in the specific
embodiments which are disclosed and still obtain a like or similar
result without departing from the spirit and scope of the
invention.
[0056] Coronary stents were provided by Baylor Medical School and
Sulzer Intratherapeutics. Poly(lactic acid)-co-poly(glycolic acid)
(PLGA) polymer was purchased from Boehringer Ingelheim. Methylene
chloride was purchased from Aldrich. Poly(ethylene-co-vinyl
acetate) (EVA) copolymer was purchased from Aldrich or Polymer
Sciences. Sulzer Carbomedics, Inc. provides medical grade silicone
rubber.
[0057] Example 1. One hundred (100) mg PCL (poly caprolactone)
polymer and 10 mg of cerivastatin were dissolved in 10 ml methylene
chloride solution at room temperature. The solution was poured onto
a glass plate and the solvent was allowed to evaporate for 12-24
hours. After almost complete removal of the solvent, the
cerivastatin-loaded PCL film was removed from the glass plate and
was cut to 1.5 cm by 1.5 cm size. The film was mounted on a
Palmaz-Schatz coronary endovascular stent. Control PCL films were
prepared in the following manner: 100 mg PCL (poly caprolactone)
polymer was dissolved in 10 ml methylene chloride solution at room
temperature. The solution was poured onto a glass plate and the
solvent was allowed to evaporate for 12-24 hours. After almost
complete removal of the solvent, the control PCL film was removed
from the glass plate and was cut to 1.5 cm by 1.5 cm size. The
control film was mounted on a Palmaz-Schatz coronary endovascular
stent. Release profiles were obtained for the coated stents as
shown in FIG. 6.
[0058] Example 2. 100 mg EVA (ethylene-vinyl acetate) polymer and
10 mg of cerivastatin were dissolved in 10 ml methylene chloride
solution at room temperature. The solution was poured onto a glass
plate and the solvent was allowed to evaporate for 12-24 hours.
After almost complete removal of the solvent, the
cerivastatin-loaded EVA film was removed from the glass plate and
was cut to 1.5 cm by 1.5 cm size. The film was mounted on a
Palmaz-Schatz coronary endovascular stent. Control EVA films were
prepared in the following manner: 100 mg EVA (ethylene-vinyl
acetate) polymer was dissolved in 10 ml methylene chloride solution
at room temperature. The solution was poured onto a glass plate and
the solvent was allowed to evaporate for 12-24 hours. After almost
complete removal of the solvent, the control EVA film was removed
from the glass plate and was cut to 1.5 cm by 1.5 cm size. The
control film was mounted on a Palmaz-Schatz coronary endovascular
stent. Release profiles were obtained for the coated stents as
shown in FIG. 5.
[0059] Example 3. A 0.6% solution of polycaprolactone dissolved in
methylene chloride was prepared at room temperature. The solution
was sprayed onto a Sulzer Intratherapeutics nitinol Protege model
endovascular stent (6 mm.times.20 mm) using a semi-automated
nebulizer apparatus. The nebulizer spray system provided a means of
rotating and traversing the length of the stent at a controlled
rate. The traversing component of the apparatus contained a glass
nebulizer system that applied nebulized polycaprolactone solution
to the stent at a rate of 3 ml per minute. Once applied, the 10 mg
polymer coating was "reflowed" by application of 60.degree. C.
heated air for approximately 5 seconds. The process of reflowing
the polymer provides better adherence to the stent surface. A
drug-loaded polymer coating can be provided using this technique by
first preparing a 1%-20% cerivastatin/polymer solution in methylene
chloride with subsequent application to the stent surface using the
same nebulizer coating system.
[0060] Example 4. A 1% solution of uncured two-part silicone rubber
dissolved in trichloroethylene was applied to a "Protege" nitinol
stent in the manner described in Example 3. The coated stent was
dried at room temperature for 15 minutes to allow the
trichloroethylene to evaporate. Once 10 mg of silicone was coated
onto the stent, the composite device containing both uncured
polymer and nitinol was heated in a vacuum oven for a period of
four hours in order to crosslink the silicone coating. After the
coated stents were removed from the oven and allowed to cool for a
period of 1 hour, cerivastatin was loaded into the silicone coating
by the following method. Three mg of cerivastatin was dissolved in
300 .mu.l of methylene chloride at room temperature. A volume of
100 .mu.l of methylene chloride was applied to the silicone coating
of each stent in dropwise fashion. In this manner, each stent was
loaded with 1 mg cerivastatin, for a final concentration of 10%
w/w. The crosslinked silicone absorbed the drug/solvent solution,
where the solvent subsequently evaporated at room temperature,
leaving behind the drug entrapped within the silicone. By this
method, a diffusion-based release system for cerivastatin was
created. A release profile was obtained for the coated stent as
shown in FIG. 7.
[0061] Example 5. A 10% w/w solution of cerivastatin in vitamin E
was created by the following method. Four mg of cerivastatin was
dissolved in 100 .mu.l of methylene chloride. This solution was
added to 36 mg of liquid vitamin E and mixed manually by stirrer.
The solution was allowed to stand at room temperature for 1 hour to
enable the methylene chloride to evaporate from the solution. The
resulting cerivastatin/vitamin E mixture was used to coat three
Protg model stents by simple surface application. Approximately
10-12 mg of vitamin E and drug was deposited on each stent. A
release profile was obtained for the coated stent as shown in FIG.
8.
[0062] In preferred embodiments, the controlled release studies
were done to determine the integrity and activity of cerivastatin
released from stents coated with polymer and cerivastatin. Stents
coated according to the process of Example 2 were immersed in an
Eppendorf tube containing 1 ml phosphate buffered saline (PBS) and
incubated on a rotator in a 37.degree. C. oven. Buffer exchanges
were performed at 1, 2, and 4 days following immersion in PBS.
Collected samples were assayed for the spectral characteristics of
cerivastatin using a UV-VIS spectrophotometer. Cerivastatin
released from an EVA and cerivastatin coated stent such as the
stent of Example 2 and pure cerivastatin in deionized water had
almost identical Uv-VIS spectra, as shown in FIG. 4, suggesting
that the cerivastatin released from the stent was unaltered and
thus remained biologically active.
[0063] The release of cerivastatin from stents coated according to
the process of Example 2 was monitored over 7 days, as shown in
FIG. 5. An EVA and cerivastatin coated stent such as the stent of
Example 2 released >20 .mu.g/ml cerivastatin per day, which is
significantly higher than the 0.5 .mu.g/ml concentration needed to
inhibit proliferation of smooth muscle cells. Thus, stents produced
according to this invention release a sufficient amount of
cerivastatin to inhibit the proliferation of smooth muscle cells
which occurs during restenosis.
[0064] The release of cerivastatin from stents coated with
polycaprolactone film according to the process of Example 1 was
monitored over 80 days, as shown in FIG. 6. A polycaprolactone and
cerivastatin coated stent such as the stent of Example 1 released
>20 .mu.g/ml cerivastatin per day. The release of cerivastatin
from stents according to the process of Example 4 was monitored
over 20 days, as shown in FIG. 7. A cerivastatin and silicone
coated stent such as the stent of Example 4 released >20
.mu.g/ml cerivastatin per day.
[0065] The release of cerivastatin from stents according to the
process of Example 5 was monitored over 11 days, as shown in FIG.
8. A liquid vitamin E and cerivastatin coated stent such as the
stents of Example 5 released >20 .mu.g/ml cerivastatin per
day.
[0066] While the foregoing is directed to embodiments of the
present invention, other and further embodiments of the invention
may be devised without departing from the basic scope thereof, and
the scope thereof is determined by the claims that follow,
including equivalents.
* * * * *