U.S. patent application number 14/320077 was filed with the patent office on 2014-10-23 for gradient coated stent and method of fabrication.
The applicant listed for this patent is Medtronic Vascular, Inc.. Invention is credited to Patrice Brint, Wenda Carlyle, Peiwen Cheng, Diane Judd, Kishore Udipi.
Application Number | 20140314945 14/320077 |
Document ID | / |
Family ID | 35057075 |
Filed Date | 2014-10-23 |
United States Patent
Application |
20140314945 |
Kind Code |
A1 |
Cheng; Peiwen ; et
al. |
October 23, 2014 |
GRADIENT COATED STENT AND METHOD OF FABRICATION
Abstract
The gradient coated stent 150 of the present invention provides
a coated stent having a continuous coating 130 disposed on the
stent elements. The continuous coating 130 includes a first coating
component and a second coating component. The concentration of the
first coating component varies continuously over at least part of
the thickness of the continuous coating 130. The concentration of
the second coating component can also vary over at least part of
the thickness of the continuous coating 130. In one embodiment, the
concentration of the first coating component decreases in the
direction from the stent element towards the outer edge of the
continuous coating 130 and the concentration of the second coating
component increases in the direction from the stent element towards
the outer edge of the continuous coating 130.
Inventors: |
Cheng; Peiwen; (Santa Rosa,
CA) ; Brint; Patrice; (Santa Rosa, CA) ;
Carlyle; Wenda; (Silverado, CA) ; Judd; Diane;
(Minneapolis, MN) ; Udipi; Kishore; (Santa Rosa,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Medtronic Vascular, Inc. |
Santa Rosa |
CA |
US |
|
|
Family ID: |
35057075 |
Appl. No.: |
14/320077 |
Filed: |
June 30, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10921735 |
Aug 18, 2004 |
8801692 |
|
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14320077 |
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60505675 |
Sep 24, 2003 |
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Current U.S.
Class: |
427/2.25 ;
118/612 |
Current CPC
Class: |
A61L 2300/41 20130101;
A61L 2300/416 20130101; A61F 2/86 20130101; A61L 2300/606 20130101;
A61F 2002/072 20130101; A61F 2230/0054 20130101; A61L 2300/45
20130101; A61F 2/958 20130101; A61F 2/91 20130101; A61F 2250/0067
20130101; A61F 2002/91541 20130101; A61F 2/0077 20130101; A61F
2210/0004 20130101; A61L 31/10 20130101; A61L 31/16 20130101; A61F
2/915 20130101 |
Class at
Publication: |
427/2.25 ;
118/612 |
International
Class: |
A61F 2/86 20060101
A61F002/86 |
Claims
1-18. (canceled)
19: A method for coating a stent comprising: providing a first
coating solution 270; providing a second coating solution 272;
applying the first coating solution to the stent through an
applicator 274; and applying the second coating solution to the
stent through the applicator 276.
20: The method of claim 19 wherein applying the first coating
solution to the stent through an applicator; and applying the
second coating solution to the stent through the applicator
comprises: mixing the first coating solution and the second coating
solution to form a gradient mixture; and applying the gradient
mixture to the stent through the applicator.
21: The method of claim 20 wherein the first coating solution
includes a first coating component, and mixing the first coating
solution and the second coating solution to form a gradient mixture
comprises mixing the first coating solution and the second coating
solution to vary concentration of the first coating component in
the gradient mixture with time.
22: The method of claim 21 wherein the concentration of the first
coating component in the gradient mixture varies linearly with
time.
23: The method of claim 21 wherein the concentration of the first
coating component in the gradient mixture decreases with time.
24: The method of claim 21 wherein the second coating solution
includes a second coating component, and mixing the first coating
solution and the second coating solution to form a gradient mixture
further comprises mixing the first coating solution and the second
coating solution to vary concentration of the second coating
component in the gradient mixture with time.
25: The method of claim 24 wherein the concentration of the first
coating component in the gradient mixture decreases with time and
the concentration of the second coating component in the gradient
mixture increases with time.
26: The method of claim 21 wherein the first coating component is
selected from the group consisting of drugs, therapeutic agents,
polymers, bi-polymers, co-polymers, and combinations thereof.
27: The method of claim 19 wherein the first coating solution and
the second coating solution are incompatible.
28: The method of claim 19 wherein applying the first coating
solution to the stent through an applicator comprises applying the
first coating solution to the stent through an applicator using an
application method selected from a group consisting of spraying,
ultrasonic spraying, pressure spraying, painting, wiping, rolling,
printing, ink jet printing, and combinations thereof.
29: A system for producing a coated stent comprising: means for
mixing a first coating component with a first solvent to form a
first coating solution; means for mixing a second coating component
with a second solvent to form a second coating solution; means for
mixing the first coating solution and the second coating solution
to form a gradient mixture so that the ratio of the first coating
solution to the second coating solution in the gradient mixture
varies with time; means for applying the gradient mixture to a
stent.
30: The system of claim 29 wherein the means for mixing the first
coating solution and the second coating solution to form a gradient
mixture so that the ratio of the first coating solution to the
second coating solution in the gradient mixture varies with time
comprises means for mixing the first coating solution and the
second coating solution so that concentration of the first coating
component in the gradient mixture varies with time.
31: The system of claim 30 wherein the means for mixing the first
coating solution and the second coating solution to form a gradient
mixture so that the ratio of the first coating solution to the
second coating solution in the gradient mixture varies with time
comprises means for mixing the first coating solution and the
second coating solution so that concentration of the second coating
component in the gradient mixture varies with time.
32: A method for coating a stent comprising: mixing a first coating
component with a first solvent to form a first coating solution
280; mixing a second coating component with a second solvent to
form a second coating solution 282; mixing the first coating
solution and the second coating solution to form a gradient mixture
so that the ratio of the first coating solution to the second
coating solution in the gradient mixture varies with time 284;
applying the gradient mixture to the stent 286.
33: The method of claim 32 wherein mixing the first coating
solution and the second coating solution to form a gradient mixture
so that the ratio of the first coating solution to the second
coating solution in the gradient mixture varies with time comprises
mixing the first coating solution and the second coating solution
so that concentration of the first coating component in the
gradient mixture varies with time.
34: The method of claim 33 wherein the concentration of the first
coating component in the gradient mixture varies linearly with
time.
35: The method of claim 33 wherein the concentration of the first
coating component in the gradient mixture decreases with time.
36: The method of claim 33 wherein mixing the first coating
solution and the second coating solution to form a gradient mixture
so that the ratio of the first coating solution to the second
coating solution in the gradient mixture varies with time comprises
mixing the first coating solution and the second coating solution
so that concentration of the second coating component in the
gradient mixture varies with time.
37: The method of claim 36 wherein the concentration of the first
coating component in the gradient mixture decreases with time and
the concentration of the second coating component in the gradient
mixture increases with time.
38: The method of claim 32 wherein the first coating component is
selected from the group consisting of drugs, therapeutic agents,
polymers, bi-polymers, co-polymers, and combinations thereof.
39: The method of claim 32 wherein at least one pair of materials
selected from the group consisting of the first coating component,
the first solvent, the second coating component, and the second
solvent are incompatible.
40: The method of claim 32 applying the gradient mixture to the
stent comprises applying the gradient mixture to the stent using an
application method selected from the group consisting of spraying,
ultrasonic spraying, pressure spraying, painting, wiping, rolling,
printing, ink jet printing, and combinations thereof.
41: A system for producing a coated stent comprising: means for
mixing a first coating component with a first solvent to form a
first coating solution; means for mixing a second coating component
with a second solvent to form a second coating solution; means for
mixing the first coating solution and the second coating solution
to form a gradient mixture so that the ratio of the first coating
solution to the second coating solution in the gradient mixture
varies with time; means for applying the gradient mixture to a
stent.
42: The system of claim 41 wherein the means for mixing the first
coating solution and the second coating solution to form a gradient
mixture so that the ratio of the first coating solution to the
second coating solution in the gradient mixture varies with time
comprises means for mixing the first coating solution and the
second coating solution so that concentration of the first coating
component in the gradient mixture varies with time.
43: The system of claim 42 wherein the means for mixing the first
coating solution and the second coating solution to form a gradient
mixture so that the ratio of the first coating solution to the
second coating solution in the gradient mixture varies with time
comprises means for mixing the first coating solution and the
second coating solution so that concentration of the second coating
component in the gradient mixture varies with time.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application 60/505,675 filed Sep. 24, 2003.
TECHNICAL FIELD
[0002] The technical field of this disclosure is medical implant
devices, particularly, a gradient coated stent and methods of
making the same.
BACKGROUND OF THE INVENTION
[0003] Stents are generally cylindrical shaped devices that are
radially expandable to hold open a segment of a blood vessel or
other anatomical lumen after implantation into the body lumen.
Stents have been developed with coatings to deliver drugs or other
therapeutic agents.
[0004] Stents are used in conjunction with balloon catheters in a
variety of medical therapeutic applications including intravascular
angioplasty. For example, a balloon catheter device is inflated
during PTCA (percutaneous transluminal coronary angioplasty) to
dilate a stenotic blood vessel. The stenosis may be the result of a
lesion such as a plaque or thrombus. After inflation, the
pressurized balloon exerts a compressive force on the lesion
thereby increasing the inner diameter of the affected vessel. The
increased interior vessel diameter facilitates improved blood flow.
Soon after the procedure, however, a significant proportion of
treated vessels re-narrow.
[0005] To prevent restenosis, short flexible cylinders, or stents,
constructed of metal or various polymers are implanted within the
vessel to maintain lumen size. The stents acts as a scaffold to
support the lumen in an open position. Various configurations of
stents include a cylindrical tube defined by a mesh, interconnected
stents or like segments. Some exemplary stents are disclosed in
U.S. Pat. No. 5,292,331 to Boneau, U.S. Pat. No. 6,090,127 to
Globerman, U.S. Pat. No. 5,133,732 to Wiktor, U.S. Pat. No.
4,739,762 to Palmaz and U.S. Pat. No. 5,421,955 to Lau.
Balloon-expandable stents are mounted on a collapsed balloon at a
diameter smaller than when the stents are deployed. Stents can also
be self-expanding, growing to a final diameter when deployed
without mechanical assistance from a balloon or like device.
[0006] Stents have been used with coatings to deliver drug or other
therapy to the patient at the site of the stent, such as the
interior wall of an artery or vessel. Typically, the coating forms
a uniform radial layer over the stent elements with a fixed ratio
of drug to polymer. Although many factors (such as the
hydrophilicity, hydrophobilicity, and molecular size of the drug,
and the hydrophilicity, hydrophobilicity, amorphous, crystallinity,
morphology, glass transition temperature of the polymer matrix)
affect the diffusion rate of the drug from the coating, the
diffusion rate is generally proportional to the difference in drug
concentration across the coating (AC). This causes problems with
the dose of drug delivered with time. Initially, the drug
concentration is high, so a large quantity of drug is released.
This is called burst releasing and results in local tissue damage
for certain drugs that are toxic in high doses. Later after
implantation, the drug concentration is depleted and the AC become
smaller and smaller, so little drug is released. This results in
delivery of a less-than-effective dose. With a uniform radial drug
coating, stent designer must choose between a stent which risks
initial tissue damage and a stent which has a limited effective
drug lifetime.
[0007] A uniform drug coating may not provide the most effective
therapy over time. Immediately after stent implantation,
inflammation and thrombosis occur due to the tissue trauma from the
angioplasty and the presence of the stent. While the inflammation
normally subsides after a few days, tissue growth may result in
restenosis three to six months after stent implantation. A uniform,
single drug coating is unable to treat both conditions.
Anti-inflammatory drugs are desirable initially, but
anti-proliferative drugs are required later.
[0008] There are also difficulties associated with manufacturing
stents having multiple components or multiple layers. The coating
is typically applied to the stent by dipping or spraying the stent
with a liquid containing the drug or therapeutic agent dispersed in
a polymer/solvent mixture. The liquid coating then dries to a solid
uniform coating. Combinations of dipping and spraying can also be
used.
[0009] Problems also arise during manufacture when the drugs,
polymers, or solvents are incompatible. For example, one solvent
may be suitable for a particular drug, but unsuitable for a
particular polymer. The combination of a particular drug and a
particular polymer may be incompatible and one or the other degrade
when held in solution too long. Incompatibility results in
ineffective drugs or defective coatings.
[0010] Manufacturing techniques producing multiple coating layers
with varying characteristics have been developed, but such methods
increase the time and expense of manufacturing. Separate steps are
required to apply each coating layer, which must dry and have its
surface prepared before the next layer is applied. In dip coating,
several pots holding solutions with different drug/polymer ratios
can be prepared. The stent is then dipped in each pot, starting
with the solution of highest drug/polymer ratio and ending with the
lowest to form a profile coating. In such a stepwise approach,
however, each drug/polymer coat can be dissolved by subsequent dip
process if similar solvent is used. Poor surface preparation and
layer incompatibilities can cause voids and defects at the
boundaries between coating layers.
[0011] It would be desirable to have a gradient coated stent and
methods of making the same that would overcome the above
disadvantages.
SUMMARY OF THE INVENTION
[0012] One aspect of the present invention provides a stent with a
gradient coating in which at least one coating component varies
continuously with coating thickness.
[0013] Another aspect of the present invention provides a stent
with a gradient coating to avoid burst release and to deliver an
appropriate long-term drug release.
[0014] Another aspect of the present invention provides a stent
with a gradient coating with a high concentration of a therapeutic
agent at the inner edge of the stent coating and a low
concentration at the outer edge of the stent coating.
[0015] Another aspect of the present invention provides a stent
with a gradient coating having a linear drug gradient or
step-gradient to generate desired elution profiles.
[0016] Another aspect of the present invention provides a stent
with a gradient coating able to deliver different drug therapies as
a function of time.
[0017] Another aspect of the present invention provides a method of
manufacture for a gradient coated stent with coatings formed from
generally incompatible materials.
[0018] Another aspect of the present invention provides a method of
manufacture for a gradient coated stent avoiding dissolving
subsequent layers.
[0019] Another aspect of the present invention provides a method of
manufacture for a gradient coated stent generating a cap coat in a
single step after spraying a drug/polymer solution.
[0020] Another aspect of the present invention provides a method of
manufacture for a gradient coated stent providing a uninterrupted
process of stent coating.
[0021] Another aspect of the present invention provides a method of
manufacture for a gradient coated stent reducing labor and allowing
process automation.
[0022] The foregoing and other features and advantages of the
invention will become further apparent from the following detailed
description of the presently preferred embodiments, read in
conjunction with the accompanying drawings.
[0023] The detailed description and drawings are merely
illustrative of the invention, rather than limiting the scope of
the invention being defined by the appended claims and equivalents
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 shows a stent delivery system made in accordance with
the present invention.
[0025] FIGS. 2 & 3 show a stent and a cross section,
respectively, of a coated stent made in accordance with the present
invention.
[0026] FIGS. 4A-4C show exemplary graphs of coating component
concentration versus coating thickness for a coated stent made in
accordance with the present invention.
[0027] FIG. 5 shows a system for coating a stent in accordance with
the present invention.
[0028] FIGS. 6A-6C show exemplary graphs of coating component
concentration in the gradient mixture versus time for the coating
system of FIG. 5.
[0029] FIG. 7 shows another system for coating a stent in
accordance with the present invention.
[0030] FIG. 8 shows exemplary graphs of coating component
concentration in the gradient mixture versus time for the coating
system of FIG. 7.
[0031] FIGS. 9 & 10 show methods of manufacturing a coated
stent made in accordance with the present invention.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENT
[0032] FIG. 1 shows a stent delivery system made in accordance with
the present invention. The stent delivery system 100 includes a
catheter 105, a balloon 110 operably attached to the catheter 105,
and a stent 120 disposed on the balloon 110. The balloon 110, shown
in a collapsed state, may be any variety of balloons capable of
expanding the stent 120. The balloon 110 may be manufactured from a
material such as polyethylene, polyethylene terephthalate (PET),
nylon, Pebax.RTM. polyether-block co-polyamide polymers, or the
like. In one embodiment, the balloon 110 may include retention
means 111, such as mechanical or adhesive structures, for retaining
the stent 120 on the balloon 110 until it is deployed. The catheter
105 may be any variety of balloon catheters, such as a PTCA
(percutaneous transluminal coronary angioplasty) balloon catheter,
capable of supporting a balloon during angioplasty.
[0033] The stent 120 may be any variety of implantable prosthetic
devices known in the art and capable of carrying a coating. In one
embodiment, the stent 120 may have a plurality of identical
cylindrical stent segments placed end to end. Four stent segments
121, 122, 123, and 124 are shown, and it will be recognized by
those skilled in the art that an alternate number of stent segments
may be used.
[0034] The stent 120 includes at least one continuous coating 130.
The continuous coating 130 is typically a polymer coating carrying
one or more therapeutic agents, such as anti-inflammatory agents or
anti-proliferative agents. The continuous coating 130 is merely
exemplary: other coating configurations, such as multiple coating
layers on top of the continuous coating 130, are possible. Although
the continuous coating 130 are shown schematically on the outer
circumference of the stent 120, the continuous coating 130 can coat
the whole stent 120, both inside and outside, and around the cross
section of individual stent elements. The continuous coating 130
can be any coating that can elute a therapeutic agent and maintain
coverage of the stent elements. The coating components, such as the
therapeutic agent or the polymer, vary continuously over the
thickness of the continuous coating 130.
[0035] FIG. 2 shows a coated stent made in accordance with the
present invention. The stent 150 comprises a number of segments
160. The pattern of the segments 160 can be W-shaped or can be a
more complex shape with the elements of one segment continuing into
the adjacent segment. The stent 150 can be installed in the stent
delivery system of FIG. 1 for implantation in a body lumen.
[0036] Referring to FIG. 2, the stent 150 is conventional to stents
generally and can be made of a wide variety of medical implantable
materials, such as stainless steel (particularly 316-L or 316LS
stainless steel), MP35 alloy, nitinol, tantalum, ceramic, nickel,
titanium, aluminum, polymeric materials, tantalum, MP35N, titanium
ASTM F63-83 Grade 1, niobium, high carat gold K 19-22, and
combinations thereof. The stent 150 can be formed through various
methods as well. The stent 150 can be welded, laser cut, molded, or
consist of filaments or fibers which are wound or braided together
in order to form a continuous structure. Depending on the material,
the stent can be self-expanding, or be expanded by a balloon or
some other device. The continuous coating can be disposed on the
surface of the segments 160.
[0037] FIG. 3 shows a cross section of a coated stent made in
accordance with the present invention. A plurality of stent
elements 170 are provided with a continuous coating 130. The stent
elements form the segments which form the stent. Although the cross
section of the stent elements 170 is shown as generally rectangular
with rounded corners, the cross section can be any number of shapes
depending on fabrication methods, materials, and desired effect.
The cross section of the stent elements 170 can be circular,
ellipsoidal, rectangular, hexagonal, square, polygonal, or of other
cross-sectional shapes as desired.
[0038] The continuous coating 130 comprises coating components,
such as polymers and therapeutic agents. One or more polymers
typically form the bulk of the continuous coating 130. The
therapeutic agents, such as anti-inflammatory or anti-proliferative
agents, are dispersed in the polymer. The therapeutic agent can be
dissolved throughout the polymer, or can be dispersed throughout
the polymer in discrete units like nano-particles. One or more
therapeutic agents can be used to accomplish the desired
result.
[0039] Nano-particles can be used when a common solvent for drug
and polymer cannot be found or when further control of the
therapeutic agent is needed. In one embodiment, nano-particles are
small particles of crystalline therapeutic agents ground to a small
size, such as nanometer-sized particles. Such nano-particles
increase the speed of delivery of the anti-proliferative agent
because of the large surface area to volume ratio. In another
embodiment, the nano-particles can include a therapeutic agent as a
core and a polymer as a shell. The polymer acts as barrier to
further control the release profile. Nano-particles can be formed
by many methods suitable for the particular therapeutic agent and
known to those in the art, including oil in water, water in oil,
oil in water in oil.
[0040] The concentration of the therapeutic agent in the polymer
varies continuously over the thickness of the continuous coating
130. Different profiles of the therapeutic agent can accomplish
different therapeutic results. For example, a high concentration of
therapeutic agent in the continuous coating 130 near the stent
element 170 with a low concentration in the continuous coating 130
at the outer edge will suppress any burst release and provide a
steady long-term dose. Additional coating layers can be applied on
top of the continuous coating 130 to provide particular release
effects or to act as a cap coat to establish desirable mechanical
properties for the exposed surface of the stent.
[0041] In one embodiment, the continuous coating 130 can be made of
a biodegradable or erodible material. Biodegradable polymer
coatings release the therapeutic agent with degradation of the
polymer. The products of degradation are weak organic acids, water,
and carbon dioxide. Erodible materials include natural polymers,
such as a carbohydrate or gelatin, or a synthetic polymer, such as
polyglycolide. Erodible materials that can be used for the
continuous coating 130, include, but are not limited to,
poly(D-lactic acid), poly(L-lactic acid), poly(caprolactone), and
copolymers or terpolymers of any two or all three of these
monomers; polyhydroxyalkanoates, such as poly(hydroxybutyrate),
poly(hydroxyvalerate), or copolymers thereof (e.g.
poly(hydroxybutyrate-co-valerate)); polydioxanone; polyorthoester;
polyanhydride; poly(propylene fumarate); poly(glycolic
acid-co-trimethylene carbonate); polyphosphoester; polyphosphoester
urethane; poly(amino acids); poly(alkyl cyanoacrylates);
poly(trimethylene carbonate); poly(iminocarbonate);
copoly(ether-esters) (e.g. PEO/PLA); poly(ester amides);
poly(ester-urethane); polyalkylene oxalates; polyphosphazenes;
copolymers, terpolymers, blends, and copolymer blends of the above;
combinations of the above; and the like.
[0042] Biomacromolecules and their variants that can be used for
the continuous coating 130, include, but are not limited to,
fibrin; fibrinogen; cellulose; starch; collagen and hyaluronic
acid; hydrogels; polyhydroxyacids; polysaccharides; polyamines;
polyaminoacids; polyamides; polycarbonates; silk; keratin;
collagen; gelatin; fibrinogen; elastin; actin; myosin; cellulose;
amylose; dextran; chitin; glycosaminoglycans; proteins; protein
based polymers (e.g. polypeptides); copolymers, terpolymers,
blends, and copolymer blends of the above; combinations of the
above; and the like.
[0043] In one embodiment, the continuous coating 130 can be made of
a non-biodegradable material, such as phosphorylcholine polymer
from Biocompatibles International plc as set forth in U.S. Pat. No.
5,648,442. Non-biodegradable polymers can be divided into two
classes. The first class is hydrophobic polymers and the second
class is hydrophilic polymers. Hydrophobic polymers that can be
used for the continuous coating 130, include, but are not limited
to, polyolefins; acrylate polymers; vinyl polymers; styrene
polymers; polyurethanes; polyesters; epoxy; polysiloxane; natural
polymers; variants, copolymers, terpolymers, blends, and copolymer
blends of the above; combinations of the above; and the like.
Hydrophilic polymers or hydrogels that can be used for the
continuous coating 130, include, but are not limited to,
polyacrylic acid; polyvinyl alcohol; poly(N-vinylpyrrolidone);
poly(hydroxyl, al kymethacrylate); polyethylene oxide; hyaluronon;
variants, copolymers, terpolymers, blends, and copolymer blends of
the above; combinations of the above; and the like.
[0044] In one embodiment, the therapeutic agent in the continuous
coating 130 can be an anti-inflammatory agent, such as a steroid.
Anti-inflammatory agents that can be used in the continuous coating
130, include, but are not limited to, steroidal anti-inflammatory
agents, non-steroidal anti- inflammatory agents, hydrocortisone,
hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,
fluocinolone, medrysone, prednisolone acetate, fluoromethalone,
betamethasone, triaminolone, ibuprofen, ketoprofen, piroxicam,
naproxen, sulindac, choline subsalicylate, diflunisal, fenoprofen,
indomethacin, meclofenamate, salsalate, tolmetin, magnesium
salicylate, diclofenac, enoxaprin, angiopeptin, monoclonal
antibodies, hirudin, acetylsalicylic acid, amlodipine, doxazosin
and combinations thereof. Additional anti-inflammatory agents to
achieve a desired result, such as those included in the Merck
Index: An Encyclopedia of Chemicals, Drugs, & Biologicals
published by the Merck Publishing Group and incorporated herein by
reference, are well known to those skilled in the art.
[0045] In one embodiment, the therapeutic agent in the continuous
coating 130 can be an anti-proliferative agent, such as the drug
42-Epi-(tetrazolyl)-rapamycin, set forth in U.S. Pat. No. 6,329,386
assigned to Abbott Laboratories, Abbott Park, Ill. Other
anti-proliferative agents that can be used in the continuous
coating 130, include, but are not limited to, rapamycin and
rapamycin anglogs such as ABT-578 tetrazole-containing macrocyclic
immunosuppressant from Abbott Laboratories; statins; actinomycin;
paclitaxel; 5-fluorouracil; cisplatin; vinblastine; vincristine;
epothilones; methotrexate; azathioprine; adriamycin; mutamycin;
endostatin; angiostatin; thymidine kinase inhibitors; and
combinations thereof. Additional anti-neoplastic agents to achieve
a desired result, such as those included in the Merck Index: An
Encyclopedia of Chemicals, Drugs, & Biologicals published by
the Merck Publishing Group and incorporated herein by reference,
are well known to those skilled in the art.
[0046] Those skilled in the art will appreciate that a number of
therapeutic agents can be used in the continuous coating 130 to
beneficial effect. Protein and gene therapy agents can be included.
Therapeutic agents may limit or prevent the restenosis. For
example, antithrombogenic agents such as heparin or clotting
cascade IIb/IIIa inhibitors (e.g., abciximab and eptifibatide) can
be included to diminish thrombus formation. Such agents may
effectively limit clot formation at or near the implanted device.
Additional therapeutic agents can be used in the continuous coating
130 include antinflammatory agents; antioxidants;
immunosuppressants; antisense agents; antiangiogenesis agents;
antiendothelin agents; antimitogenic factors; antiplatelet agents;
antiproliferative agents; antithrombogenic agents; antibiotics;
antiinfective agents; antidiabetic agents; antiarteriosclerotics;
antiarythmics; calcium channel blockers; clot dissolving enzymes;
growth factors; growth factor inhibitors; nitrates; nitric oxide
releasing agents; vasodilators; virus-mediated gene transfer
agents; agents having a desirable therapeutic application;
combinations of the above; and the like. A variety of other drugs
may also be included to modulate localized immune response, limit
hyperplasia, or provide other benefits.
[0047] FIGS. 4A-4C show exemplary graphs of coating component
concentration versus coating thickness for a coated stent made in
accordance with the present invention. The coating component can be
any component for which it is desired to vary the concentration
with coating thickness, including, but not limited to, drugs,
therapeutic agents, and polymers.
[0048] FIG. 4A shows a graph of coating component concentration
versus coating thickness for coated stents formed by discrete steps
and continuous coating. Profile A shows a linear gradient coating
having decreasing coating component concentration with increasing
thickness. Profile B shows coating concentration formed in a series
of large steps, such as formed by dip coating a stent in a series
of solutions where each solution has a smaller coating component
concentration. Profile C shows coating concentration formed in a
series of small steps, such as formed by dip coating a stent in a
series of solutions where each solution has a smaller coating
component concentration and a greater number of dip coating steps
are performed. Profile C more closely approaches the linear
gradient of Profile A than does Profile B. As the number of dip
coating steps becomes large and the change in coating component
concentration between steps becomes small, the step coating result
will approach the linear gradient of Profile A.
[0049] FIG. 4B shows a graph of coating component concentration
versus coating thickness for a coated stent having decreasing
coating component concentration with increasing thickness. In these
three embodiments, the coating component concentration is a maximum
at the zero coating thickness at the stent element and declines to
a minimum at the coating thickness TO at the exterior of the stent.
Profile B is has a linear gradient, while profile A is concave down
and profile C is concave up. The three profiles illustrate how a
continuously varying coating component can be tailored for a
desired result.
[0050] If the coating component is a drug or other therapeutic
agent, these profiles avoid burst release and provide effective
long-term drug dosage. The drug near the exterior, which is
delivered shortly after implantation, is limited. The major portion
of the drug is located toward the stent element, where it can be
delivered long-term as the exterior drug depletes. The gradients
and the endpoints of the profiles can be tailored for particular
drug release characteristics.
[0051] If the coating component is a constituent polymer, the
coating near the exterior can be designed to erode quickly and the
coating toward the stent element designed to erode slowly or not at
all. For a coating including a durable polymer and an erodible
polymer, providing a lower concentration of the durable polymer
near the exterior allows the exterior to erode rapidly. Providing a
higher concentration of the durable polymer toward the stent
element keeps the stent element covered and maintains a long-term
drug reservoir. The gradients and the endpoints of the profiles can
be tailored for particular coating behaviors.
[0052] FIG. 4C shows a graph of coating component concentration
versus coating thickness for a coated stent having at least two
coating components of varying concentration. Profile A shows the
concentration of a first coating component and profile B shows the
concentration of a second coating component. The first and second
coating components can be any components for which it is desired to
vary the concentration with coating thickness, including, but not
limited to, drugs, therapeutic agents, and polymers.
[0053] The first coating component concentration of profile A is
highest at the zero coating thickness at the stent element and
declines to a minimum at the coating thickness T2 within the stent
coating. The second coating component concentration of profile B is
a minimum at coating thickness T1 within the stent coating and
increases to a maximum at the coating thickness TO at the exterior
of the stent. Although the profiles A and B are shown as linear in
this example, those skilled in the art will appreciate that the
profiles can be simple or compound curves, and can include
intermediate peaks or valleys above or below the concentrations
illustrated at thicknesses zero, T1, T2, and TO. Likewise, the
profiles A and B can overlap as shown or can be
non-overlapping.
[0054] In one embodiment, the coated stent of FIG. 4C can be a
binary drug coated stent. Profile A can be for a drug providing
long-term therapy, such as an anti-proliferative drug. Profile B
can be for a drug providing short-term therapy, such as an
anti-inflammatory drug. Immediately after implantation, the coated
stent delivers the anti-inflammatory drug to treat the tissue
trauma from angioplasty and stent implantation. At a desired time,
such as a few days to a few weeks, most of the anti-inflammatory
drug will be gone and the coated stent delivers the
anti-proliferative drug to prevent restenosis and tissue growth on
the stent. The anti-proliferative drug delivery continues long
term, such as a number of months or years. The continuously varying
coating component concentration provides control over the timing
and dosage of the two drugs. Multiple drug combinations, polymer
combinations, and polymer/drug combinations can be used to achieve
particular results.
[0055] Those skilled in the art will appreciate that coating
component concentration versus coating thickness for a coated stent
made in accordance with the present invention can be varied in a
number of ways. The coating component concentration can be a
compound curve with positive, negative and zero gradient, rather
than simply increasing or decreasing. The coating component
concentration can make step changes from changes of coating
components or coating component concentration when applying the
coating solution of solvent and coating component to the stent.
[0056] FIG. 5 shows a system for coating a stent in accordance with
the present invention. At least two reservoirs containing coating
solutions provide the coating solutions to a mixing volume, where
they are mixed to form a gradient mixture. The gradient mixture is
then provided to an applicator, which applies the gradient mixture
to a stent. Such systems are used to provide gradient solutions to
separation columns in high pressure or high performance liquid
chromatography (HPLC). Examples of typical HPLC pumps and systems
include the Rabbit-HP from Rainin Instrument, L.L.C.; Waters
Alliance Systems from Waters Corporation; the 1100 Series from
Agilent Technologies Inc.; the ProStar System from Varian, Inc.;
and the LC 2010 system from Shimadzu Corporation.
[0057] The coating system 200 includes a first reservoir 202, a
second reservoir 204, a mixing volume 206, and an applicator 208.
Tube 210 connects the first reservoir 202 to the mixing volume 206
through first flow controller 212. Tube 214 connects the second
reservoir 204 to the mixing volume 206 through second flow
controller 216. Master controller 218 provides a first flow control
signal 220 to the first flow controller 212 and a second flow
control signal 222 to the second flow controller 216. Tube 224
connects the mixing volume 206 to the applicator 208, which applies
the gradient mixture to a stent 226. The stent 226 can move
relative to the applicator 208 by moving the stent 226, the
applicator 208, or both, as desired.
[0058] In operation, the reservoirs 202, 204 are filled with
coating solutions containing the desired concentrations of coating
components. The master controller 218 adjusts the flow controllers
212, 216 as a function of time to regulate flow from the reservoirs
202, 204 to the mixing volume 206. The flow controllers 212, 216
set each flow from 0 to 100 percent, so flow from a single
reservoir to the mixing volume is possible. The coating solutions
from the reservoirs 202, 204 are mixed in the mixing volume 206 to
form a gradient mixture, which is provided to the applicator 208
and applied to the stent 226.
[0059] The first reservoir 202 and second reservoir 204 can be any
reservoirs suitable for containing first and second coating
solutions to be applied to a stent. The coating solutions comprise
one or more coating components dissolved or dispersed in a solvent,
or solvent alone. The coating components include drugs, therapeutic
agents, and polymers. Those skilled in the art will appreciate that
almost a limitless number of continuous stent coatings can be
achieved by selecting the coating solutions in the first reservoir
202 and second reservoir 204. In one embodiment, the first
reservoir 202 contains a solvent/polymer/drug solution containing a
first drug concentration and the second reservoir 204 contains a
solvent/polymer/drug solution containing a second drug
concentration. In another embodiment, the first reservoir 202
contains a solvent/polymer/drug solution containing a first drug
and the second reservoir 204 contains a solvent/polymer/drug
solution containing a second drug. In another embodiment, the first
reservoir 202 contains a solvent/polymer/drug solution containing a
first polymer and the second reservoir 204 contains a
solvent/polymer/drug solution containing a second polymer. In yet
another embodiment, the first reservoir 202 contains a solvent/drug
solution and the second reservoir 204 contains a solvent/polymer
solution, allowing a drug/polymer combination where the drug and
polymer are incompatible or require incompatible solvents.
Additional reservoirs can be used if more than two coating
solutions are to be applied to the stent, with associated flow
controllers and tubing to connect to the mixing volume.
[0060] The first flow controller 212 and second flow controller 216
can be any means for controlling flow from the reservoirs to the
mixing volume, such as pumps, valves, and combinations thereof. In
one embodiment, the flow controller is a metering pump. In another
embodiment, the flow controller is a pump with a flow control
valve. In another embodiment, the reservoir is pressurized and the
flow controller is a flow control valve. In yet another embodiment,
the flow controller is a syringe pump, which also acts as the
reservoir.
[0061] The master controller 218 provides flow control signals 220,
222 to the flow controllers 212, 216 to control the flow of the
first and second coating solutions from the reservoirs 202, 204 to
the mixing volume 206. The master controller 218 can be a
programmed general purpose computer, a microprocessor, or other
control device. The relative flow rate of the first and second
coating solutions determines the fraction of each coating solution
applied to the stent. The master controller 218 can adjust the
relative flow rate with time to provide a continuous gradient
coating on the stent 226.
[0062] The mixing volume 206 can be any means for mixing flow from
the first flow controller 212 and second flow controller 216 to
form a gradient mixture. In one embodiment, the mixing volume 206
is a separate volume. In another embodiment, the mixing volume 206
is a portion of the tubing, such as a Y junction between the flow
controllers and the applicator. In yet another embodiment as shown
in FIG. 6, the mixing volume 206 is one of the reservoirs.
[0063] Referring to FIG. 5, the applicator 208 receives the
gradient mixture from the mixing volume 206 and applies the
gradient mixture to a stent 226. The concentrations of the coating
components in the gradient mixture vary with time, so the
application rate can be adjusted to provide the desired gradient
profile in the stent coating. The applicator 208 can apply the
gradient mixture by spraying, painting, wiping, rolling, printing,
ink jet printing, or combinations thereof. Spraying can be
ultrasonic or pressure spraying. Drying of the gradient mixture can
be enhanced by nitrogen flow in the applicator 208. In one
embodiment, a pump can be provided in the tube 224 after the mixing
volume 206 and before the applicator 208 to provide pressure at the
applicator 208.
[0064] FIG. 6A-6C show exemplary graphs of coating component
concentration in the gradient mixture versus time for the coating
system of FIG. 5. The coating component concentration in the
gradient mixture being applied to the stent varies with time to
vary the coating component concentration with coating thickness on
the stent.
[0065] FIG. 6A shows an example of coating component concentration
decreasing with time. In this example, the coating component
concentration decreases linearly, although the decrease can follow
a simple or compound curve. The higher concentration of the coating
component is applied near the stent element and the lower
concentration of the coating component is applied at the outer edge
of the coating. When the coating component is a drug or other
therapeutic agent, such a coating profile will suppress burst
release and provide a steady long-term dose. In another embodiment,
the coating component concentration could increase with time. Two
reservoirs, each containing a coating solution, but with different
coating component concentrations, can produce a decreasing or
increasing coating component concentration. Each coating solution
typically contains at least a solvent with a drug and/or
polymer.
[0066] FIG. 6B shows an example of coating component concentration
varying with time for a first and a second coating component.
Profile A shows the coating component concentration for the first
coating component decreasing from time 0 to time t2 and profile B
shows the coating component concentration for the second coating
component increasing from time t1 to time t3. In this example, the
coating component concentrations change linearly, although the
changes can follow an increasing or decreasing simple or compound
curve. The higher concentration of the first coating component is
applied near the stent element. The higher concentration of the
second coating component is applied at the outer edge of the
coating. In one embodiment, the first coating component is an
anti-proliferative agent to provide long-term therapy and the
second coating component is an anti-inflammatory agent to provide
therapy immediately after stent implantation. Four reservoirs are
required to produce this example: two reservoirs containing coating
solutions with the first coating component, but different
concentrations of the first coating component, and two reservoirs
containing coating solutions with the second coating component, but
different concentrations of the second coating component. Each
coating solution typically contains at least a solvent with a drug
and/or polymer.
[0067] FIG. 6C shows another example of coating component
concentration varying with time for a first and a second coating
component. Profile A shows the coating component concentration for
the first coating component decreasing from time 0 to time t1, then
going to zero. Profile B shows the coating component concentration
for the second coating component going from zero to a constant
value at time t1, then holding at the constant value from time t1
to time t2. The higher concentration of the first coating component
is applied near the stent element. The concentration of the second
coating component is constant throughout its thickness. In one
embodiment, the first coating component is a drug or other
therapeutic agent and the second coating component is polymer to
provide a cap coat at the outer edge of the coating. Three
reservoirs are required to produce this example: two reservoirs
containing coating solutions with the first coating component, but
different concentrations of the first coating component, and one
reservoir containing a coating solution with the second coating
component. Each coating solution typically contains at least a
solvent with a drug and/or polymer.
[0068] FIG. 7 shows another system for coating a stent in
accordance with the present invention. At least two reservoirs
contain coating solutions. One reservoir acts as both a reservoir
and a mixing volume. The coating solution from one reservoir is
transferred into the other reservoir, where they are mixed to form
a gradient mixture. The gradient mixture is then provided to an
applicator, which applies the gradient mixture to a stent. Such
systems are used to provide pH and linear concentration gradients
for chromatography and electrophoresis applications. One example of
a typical system is the Gradient Mixer GM-1, Code Number
19-0495-01, available from Amersham Biosciences of Piscataway,
N.J.
[0069] The coating system 230 includes a first reservoir 232, a
second reservoir 234, and an applicator 236. Tube 238 connects the
first reservoir 232 to the second reservoir 234 through first flow
controller 240. Tube 242 connects the second reservoir 234 to the
applicator 236 through second flow controller 244. Master
controller 246 provides a first flow control signal 248 to the
first flow controller 240 and a second flow control signal 250 to
the second flow controller 244. The applicator 236 applies the
gradient mixture to a stent 252. The stent 252 can move relative to
the applicator 236 by moving the stent 246, the applicator 236, or
both, as desired.
[0070] In operation, the reservoirs 232, 234 are filled with
coating solutions containing the desired concentrations of coating
components. The coating solution from the first reservoir 232
passes through the tube 238 and mixes with the coating solution in
second reservoir 234 to form a gradient mixture. In this
embodiment, the second reservoir 234 serves as both a reservoir and
a mixing volume. An impeller 254 or other mixing device in the
second reservoir 234 can be used to provide rapid, thorough mixing.
The gradient mixture passes through the tube 242 to the applicator
236 and is applied to the stent 226.
[0071] The first flow controller 240 and second flow controller 244
can be any means for controlling flow from the first reservoir to
the second reservoir and from the second reservoir to the
applicator, such as pumps, valves, and combinations thereof. In one
embodiment, the first flow controller 240 is omitted with gravity
providing the driving force between the first reservoir 232 and the
second reservoir 234. The second flow controller 244 is a
peristaltic pump, which provides the gradient mixture to the
applicator 236. The applicator 236 can be an ultrasonic spray head.
In another embodiment, the flow controller is a metering pump. In
another embodiment, the flow controller is a pump with a flow
control valve. In yet another embodiment, the reservoir is
pressurized and the flow controller is a flow control valve.
[0072] The applicator 236 can apply the gradient mixture by
spraying, painting, wiping, rolling, printing, ink jet printing, or
combinations thereof. Spraying can be ultrasonic or pressure
spraying. Drying of the gradient mixture can be enhanced by
nitrogen flow in the applicator 236.
[0073] The master controller 246 provides flow control signals 248,
250 to the flow controllers 240, 244 to control flow from the first
reservoir 232 to the second reservoir 234 and from the second
reservoir 234 to the applicator 236. The master controller 246 can
be a programmed general purpose computer, a microprocessor, or
other control device. In one embodiment, the master controller 246
adjusts the flow controllers 240, 244 as a function of time to
regulate flow from the first reservoir 232 to the second reservoir
234 and/or from the second reservoir 234 to the applicator 236. In
another embodiment, the master controller 246 is omitted and the
flow controllers 240, 244 are set at a selected setting providing
the desired flow rate, the same flow controller setting being used
throughout the application process.
[0074] FIG. 8 shows exemplary graphs of coating component
concentration in the gradient mixture versus time for the coating
system of FIG. 7. The example of FIG. 8 assumes an initial
concentration of a coating component in the first reservoir 232 and
a lower concentration of the same coating component in the second
reservoir 234. Profile B shows the case where the flow rate from
the first reservoir 232 to the second reservoir 234 equals the flow
rate from the second reservoir 234 to the applicator 208. The
coating component concentration in the gradient mixture increases
linearly from the concentration of coating component in the second
reservoir 234 to the concentration of coating component in the
first reservoir 232. Profile A shows the case where the flow rate
from the first reservoir 232 to the second reservoir 234 is greater
than the flow rate from the second reservoir 234 to the applicator
236, so that the coating component concentration in the gradient
mixture increases more quickly than the linear case of Profile B.
Profile C shows the case where the flow rate from the first
reservoir 232 to the second reservoir 234 is less than the flow
rate from the second reservoir 234 to the applicator 236, so that
the coating component concentration in the gradient mixture
increases more slowly than the linear case of Profile B. Those
skilled in the art will appreciate that the cases presented in FIG.
8 are exemplary only and that many useful combinations are
possible. For example, the reservoirs can contain coating solutions
with different coating components and/or different coating
component concentrations. The initial concentration of a coating
component in the first reservoir 232 can be higher than
concentration of the coating component in the second reservoir 234,
so that the component concentration decreases with time, rather
than increasing.
[0075] FIG. 9 shows a method of manufacturing a coated stent made
in accordance with the present invention. A first coating solution
is provided at 270 and a second coating solution is provided at
272. At 274, the first coating solution is applied to the stent
through an applicator. At 276, the second coating solution is
applied to the stent through the applicator.
[0076] In one embodiment, applying the first and second coating
solutions to the stent through the applicator comprises mixing the
first coating solution and the second coating solution to form a
gradient mixture and applying the gradient mixture to the stent
through the applicator. The first coating solution can include a
first coating component and the concentration of the first coating
component in the gradient mixture can be varied with time. The
second coating solution can include a second coating component and
the concentration of the second coating component in the gradient
mixture can be varied with time. The coating components can be
selected from drugs, therapeutic agents, polymers, bi-polymers,
co-polymers, and combinations thereof. The mixing of the coating
solutions shortly before application to the stent allows use of the
method even if the first coating solution and the second coating
solution are incompatible.
[0077] The variation of the concentration of one or both of the
coating components with time can be selected as desired for a
particular application. The concentration can vary linearly with
time, increase with time, or decrease with time. The concentration
of the first coating component can decrease with time, while the
concentration of the second coating component increases with time.
Those skilled in the art will appreciate that many combinations are
possible to achieve a desired result.
[0078] FIG. 10 shows another embodiment of a method of
manufacturing a coated stent made in accordance with the present
invention. A first coating component is mixed with a first solvent
to form a first coating solution at 280 and a second coating
component is mixed with a second solvent to form a second coating
solution at 282. At 284, the first coating solution and the second
coating solution are mixed to form a gradient mixture, so that the
ratio of the first coating solution to the second coating solution
in the gradient mixture varies with time. The gradient mixture is
applied to the stent at 286.
[0079] In one embodiment, mixing the first and second coating
solutions to form a gradient mixture comprises mixing the first
coating solution and the second coating solution so that
concentration of the first coating component in the gradient
mixture varies with time. The coating components can be selected
from drugs, therapeutic agents, polymers, bi-polymers, co-polymers,
and combinations thereof. The mixing of the coating solutions
shortly before application to the stent allows use of the method
even if any pair of the first coating component, the first solvent,
the second coating component, and the second solvent are
incompatible with each other.
[0080] The variation of the concentration of one or both of the
coating components with time can be selected as desired for a
particular application. The concentration can vary linearly with
time, increase with time, or decrease with time. The concentration
of the first coating component can decrease with time, while the
concentration of the second coating component increases with time.
Those skilled in the art will appreciate that many combinations are
possible to achieve a desired result.
[0081] It is important to note that FIGS. 1-10 illustrate specific
applications and embodiments of the present invention, and is not
intended to limit the scope of the present disclosure or claims to
that which is presented therein. Upon reading the specification and
reviewing the drawings hereof, it will become immediately obvious
to those skilled in the art that myriad other embodiments of the
present invention are possible, and that such embodiments are
contemplated and fall within the scope of the presently claimed
invention.
[0082] While the embodiments of the invention disclosed herein are
presently considered to be preferred, various changes and
modifications can be made without departing from the spirit and
scope of the invention. The scope of the invention is indicated in
the appended claims, and all changes that come within the meaning
and range of equivalents are intended to be embraced therein.
* * * * *