U.S. patent application number 13/170065 was filed with the patent office on 2011-12-22 for coating designs for the tailored release of dual drugs from polymeric coatings.
This patent application is currently assigned to Abbott Cardiovascular Systems Inc.. Invention is credited to Stephen D. Pacetti.
Application Number | 20110311605 13/170065 |
Document ID | / |
Family ID | 40193746 |
Filed Date | 2011-12-22 |
United States Patent
Application |
20110311605 |
Kind Code |
A1 |
Pacetti; Stephen D. |
December 22, 2011 |
Coating Designs For The Tailored Release Of Dual Drugs From
Polymeric Coatings
Abstract
Provided herein are coating designs for the tailored release of
two therapeutic agents from polymer coatings and methods of making
and using the same.
Inventors: |
Pacetti; Stephen D.; (San
Jose, CA) |
Assignee: |
Abbott Cardiovascular Systems
Inc.
Santa Clara
CA
|
Family ID: |
40193746 |
Appl. No.: |
13/170065 |
Filed: |
June 27, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11877538 |
Oct 23, 2007 |
|
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13170065 |
|
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Current U.S.
Class: |
424/423 ;
427/2.1; 427/2.25; 514/171; 514/291 |
Current CPC
Class: |
A61P 9/10 20180101; A61L
2300/61 20130101; Y10T 428/3154 20150401; A61L 31/10 20130101; A61L
2420/08 20130101; A61P 9/00 20180101; Y10T 428/31855 20150401; A61L
31/16 20130101; A61L 27/44 20130101 |
Class at
Publication: |
424/423 ;
514/171; 514/291; 427/2.1; 427/2.25 |
International
Class: |
A61F 2/00 20060101
A61F002/00; B05D 1/36 20060101 B05D001/36; B05D 5/00 20060101
B05D005/00; A61K 31/56 20060101 A61K031/56; A61K 31/439 20060101
A61K031/439 |
Claims
1. A coating for an implantable medical device, the coating
comprising a first layer having a hydrophobic polymer and an olimus
therapeutic agent; a second layer having a hydrophobic polymer and
a crystallized non-olimus therapeutic agent; and a third optional
primer layer, wherein the first layer is deposited over the second
layer, wherein the second layer is deposited over the third layer
if present, or if not present, over a surface of the implantable
medical device, and wherein the crystallized non-olimus therapeutic
agent in the coating provides control of the release of the olimus
and non-olimus therapeutic agents.
2. The coating of claim 1, wherein the implantable medical device
is a stent.
3. The coating of claim 1, further comprising an optional finishing
coating layer for enhancing biocompatibility.
4. The coating of claim 1, wherein the hydrophobic polymer in the
first or second layer is selected from the group consisting of
poly(vinylidene fluoride), poly(vinylidene
fluoride-co-chlorotrifluoroethylene), poly(vinylidene
fluoride-co-hexafluoropropylene), poly(vinylidene chloride),
poly(vinyl fluoride), poly(vinyl chloride), polyvinyl acetate,
polystyrene, polyisobutylene, copolymers of styrene and
isobutylene, poly(styrene-b-isobutylene-b-styrene), poly(n-butyl
methacrylate), poly(butyl methacrylates), polycaprolactone,
poly(trimethylene carbonate), poly(L-lactide), poly(L-lactic acid),
poly(lactide-co-glycolide), poly(hydroxyvalerate),
poly(3-hydroxyvalerate), poly(hydroxybutyrate),
poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),
poly(hydroxybutyrate-co-valerate),
poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(glycolide),
poly(glycolic acid), poly(D,L-lactide-co-L-lactide),
poly(D,L-lactide-co-glycolide), poly(D,L-lactide), poly(D,L-lactic
acid), poly(glycolic acid-co-trimethylene carbonate),
polyanhydride, polyorthoester, SOLEF.TM. 21508 (formulation
available from Solvay Solexis), acrylic polymers and acrylic
copolymers, copolymers of vinyl monomers with each other and
olefins, ethylene-methyl methacrylate copolymers, ethylene-vinyl
acetate copolymers; ethylene-.alpha.-olefin copolymers,
poly(silicone-urethanes), poly(tyrosine arylates),
poly(tyrosine-derived carbonates); polyacrylates, polycarbonates,
poly-hydroxycarboxylic acids, polyisobutylene and
ethylene-.alpha.-olefin copolymers, polymethacrylates, polyolefins,
polyorthoesters, polyvinyl aromatics; polyvinyl esters, silicones,
vinyl copolymers, vinyl-olefin copolymers, vinyl halide polymers
and copolymers.
5. The coating of claim 1, wherein the olimus therapeutic agent in
the first layer is selected from the group consisting of sirolimus
(rapamycin), everolimus, zotarolimus, Biolimus A9, AP23572,
tacrolimus, pimecrolimus and derivates, analogs, and combinations
thereof.
6. The coating of claim 1, wherein the non-olimus therapeutic agent
in the second layer is selected from the group consisting of
dexamethasone, dexamethasone acetate, dexamethasone phosphate,
dexamethasone valerate, dexamethasone derivatives, momentasone,
clobetasol, cortisone, cortisone acetate, hydrocortisone,
corticosterone, deoxycorticosterone, hydrocortisone acetate,
deoxycorticosterone acetate, hydroxyprogesterone, prednisolone,
prednisolone acetate, triamicinolone, triamicinolone acetonide,
triamcinolone diacetate, betamethasone, betamethasone valerate,
steroids, glucocorticoids, estradiol, methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride,
mitomycin, antiplatelet compounds, anticoagulants, antifibrin,
antithrombins including sodium heparin, low molecular weight
heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,
prostacyclin, prostacyclin analogues,
D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist antibody, recombinant hirudin, thrombin inhibitors
including Angiomax a, calcium channel blockers including
nifedipine, colchicine, fibroblast growth factor (FGF) antagonists,
histamine antagonists, lovastatin, monoclonal antibodies,
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitors, suramin, serotonin blockers, thioprotease inhibitors,
triazolopyrimidine, nitric oxide or nitric oxide donors, super
oxide dismutases, super oxide dismutase mimetic, cytostatic
substances including angiopeptin, angiotensin converting enzyme
inhibitors including captopril, cilazapril or lisinopril,
antiallergic agents as in permirolast potassium, alpha-interferon,
bioactive RGD and derivates, analogs, and combinations thereof.
7. A method, comprising implanting in a patient in need of
treatment of a disorder an implantable medical device comprising
the coating of claim 1, wherein the disorder is selected from the
group consisting of atherosclerosis, thrombosis, restenosis,
hemorrhage, vascular dissection or perforation, vascular aneurysm,
vulnerable plaque, chronic total occlusion, patent foramen ovale,
claudication, anastomotic proliferation for vein and artificial
grafts, bile duct obstruction, ureter obstruction, tumor
obstruction, and combinations thereof.
8. A method of forming a coating including two drugs on a medical
device, the method comprising: optionally forming a primer layer on
a surface of the medical device; forming a first coating layer on a
surface of the medical device or on the primer layer if present,
the first coating layer comprising a hydrophobic polymer and a
non-olimus therapeutic agent; wherein at least some of the
non-olimus drugs forms crystals in the first coating layer; and
forming a second coating layer on the first coating layer, the
second coating layer comprising an olimus therapeutic agent and a
hydrophobic polymer, which may be the same as or different from the
hydrophobic polymer of the first coating layer; wherein the
formation of the second coating layer uses a solvent, the solvent
being acetone, 2-butanone, or a combination thereof; wherein the
coating provides a control of release of the olimus and the
non-olimus therapeutic agents.
9. The method of claim 8, wherein the medical device is a
stent.
10. The method of claim 8, the method further comprising forming an
optional finishing coating layer for enhancing biocompatibility
over the second coating layer.
11. The method of claim 8, wherein the hydrophobic polymer in the
first and/or second layer is selected from the group consisting of
poly(vinylidene fluoride), poly(vinylidene
fluoride-co-chlorotrifluoroethylene), poly(vinylidene
fluoride-co-hexafluoropropylene), poly(vinylidene chloride),
poly(vinyl fluoride), poly(vinyl chloride), polyvinyl acetate,
polystyrene, polyisobutylene, copolymers of styrene and
isobutylene, poly(styrene-b-isobutylene-b-styrene), poly(n-butyl
methacrylate), poly(butyl methacrylates), polycaprolactone,
poly(trimethylene carbonate), poly(L-lactide), poly(L-lactic acid),
poly(lactide-co-glycolide), poly(hydroxyvalerate),
poly(3-hydroxyvalerate), poly(hydroxybutyrate),
poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),
poly(hydroxybutyrate-co-valerate),
poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(glycolide),
poly(glycolic acid), poly(D,L-lactide-co-L-lactide),
poly(D,L-lactide-co-glycolide), poly(D,L-lactide), poly(D,L-lactic
acid), poly(glycolic acid-co-trimethylene carbonate),
polyanhydride, polyorthoester, SOLEF.TM. 21508 (formulation
available from Solvay Solexis), acrylic polymers and acrylic
copolymers, copolymers of vinyl monomers with each other and
olefins, ethylene-methyl methacrylate copolymers, ethylene-vinyl
acetate copolymers; ethylene-.alpha.-olefin copolymers,
poly(silicone-urethanes), poly(tyrosine arylates),
poly(tyrosine-derived carbonates); polyacrylates, polycarbonates,
poly-hydroxycarboxylic acids, polyisobutylene and
ethylene-.alpha.-olefin copolymers, polymethacrylates, polyolefins,
polyorthoesters, polyvinyl aromatics; polyvinyl esters, silicones,
vinyl copolymers, vinyl-olefin copolymers, vinyl halide polymers
and copolymers, and combinations thereof.
12. The method of claim 8, wherein the olimus therapeutic agent in
the first layer is selected from the group consisting of sirolimus
(rapamycin), everolimus, zotarolimus, Biolimus A9, AP23572,
tacrolimus, pimecrolimus, and derivates, analogs, and combinations
thereof.
13. The method of claim 8, wherein the non-olimus therapeutic agent
in the second layer is selected from the group consisting of
dexamethasone, dexamethasone acetate, dexamethasone phosphate,
dexamethasone valerate, dexamethasone derivatives, momentasone,
clobetasol, cortisone, cortisone acetate, hydrocortisone,
corticosterone, deoxycorticosterone, hydrocortisone acetate,
deoxycorticosterone acetate, hydroxyprogesterone, prednisolone,
prednisolone acetate, triamicinolone, triamicinolone acetonide,
triamcinolone diacetate, betamethasone, betamethasone valerate,
steroids, glucocorticoids, estradiol, methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride,
mitomycin, antiplatelet compounds, anticoagulants, antifibrin,
antithrombins including sodium heparin, low molecular weight
heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,
prostacyclin, prostacyclin analogues,
D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist antibody, recombinant hirudin, thrombin inhibitors
including Angiomax a, calcium channel blockers including
nifedipine, colchicine, fibroblast growth factor (FGF) antagonists,
histamine antagonists, lovastatin, monoclonal antibodies,
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitors, suramin, serotonin blockers, thioprotease inhibitors,
triazolopyrimidine, nitric oxide or nitric oxide donors, super
oxide dismutases, super oxide dismutase mimetic, cytostatic
substances including angiopeptin, angiotensin converting enzyme
inhibitors including captopril, cilazapril or lisinopril,
antiallergic agents, permirolast potassium, alpha-interferon,
bioactive RGD, and derivates, analogs, and combinations
thereof.
14. The method of claim 8, wherein the non-olimus therapeutic agent
is selected from the group consisting of dexamethasone,
dexamethasone acetate, dexamethasone phosphate, dexamethasone
valerate, dexamethasone derivatives, momentasone, clobetasol,
cortisone, cortisone acetate, hydrocortisone, corticosterone,
deoxycorticosterone, hydrocortisone acetate, deoxycorticosterone
acetate, hydroxyprogesterone, prednisolone, prednisolone acetate,
triamicinolone, triamicinolone acetonide, triamcinolone diacetate,
betamethasone, betamethasone valerate, steroids, glucocorticoids,
and combinations thereof.
15. The method of claim 8, wherein the olimus therapeutic agent in
the first layer is everolimus, zotarolimus, or a combination
thereof.
16. The method of claim 8, wherein the hydrophobic polymer in the
first and the second layer is poly(vinylidene
fluoride-co-hexafluoropropylene); wherein the non-olimus
therapeutic agent in the second layer is dexamethasone; and wherein
the olimus therapeutic agent in the first layer is everolimus,
zotarolimus, or a combination thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of co-pending U.S.
application Ser. No. 11/877,538, filed on Oct. 23, 2007 and
published as U.S. Patent Application Publication No. 2009-0104247
A1 on Apr. 23, 2009, which is incorporated by reference herein in
its entirety, including any drawings.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention is generally related to coatings for
implantable medical devices, such as drug delivery vascular stents
for controlling the release rate of bioactive agents from the
coating. This invention more particularly relates to coating
designs for independently controlling the release of two bioactive
agents from polymer coatings.
[0004] 2. Description of the Related Art
[0005] Biomaterials research is continuously striving to improve
the compositions from which medical articles, such as medical
devices and coatings for medical devices, are produced. An example
of a medical article is an implantable medical device.
[0006] A stent is an example of an implantable medical device that
can benefit from improvements, such as a coating that can be used
as a vehicle for delivering pharmaceutically active agents in a
predictable manner. Stents can act as a mechanical intervention to
physically hold open and, if desired, expand a passageway within a
subject. Typically, a stent may be compressed, inserted into a
small vessel through a catheter, and then expanded to a larger
diameter once placed in a proper location. Examples of patents
disclosing stents include U.S. Pat. Nos. 4,733,665, 4,800,882 and
4,886,062.
[0007] Stents play an important role in a variety of medical
procedures such as, for example, percutaneous transluminal coronary
angioplasty (PTCA), which is a procedure used to treat heart
disease. In PTCA, a balloon catheter is inserted through a brachial
or femoral artery, positioned across a coronary artery occlusion,
inflated to compress atherosclerotic plaque and open the lumen of
the coronary artery, deflated and withdrawn. Problems with PTCA
include formation of intimal flaps or torn arterial linings, both
of which can create another occlusion in the lumen of the coronary
artery. Moreover, thrombosis and restenosis may occur several
months after the procedure and create a need for additional
angioplasty or a surgical by-pass operation. Stents are generally
implanted to reduce occlusions, inhibit thrombosis and restenosis,
and maintain patency within vascular lumens, such as the lumen of a
coronary artery.
[0008] Stents are also being developed to provide local delivery of
agents. Local delivery of agents is often preferred over systemic
delivery of agents, particularly where high systemic doses are
necessary to achieve an effect at a particular site within a
subject-high systemic doses of agents can often create adverse
effects within the subject. One method of local delivery includes
coating the surface of a medical article with a polymeric carrier
and attaching an agent to, or blending it with, the polymeric
carrier.
[0009] Agent-coated stents have demonstrated dramatic reductions in
the rates of stent restenosis by inhibiting the tissue growth
associated with the restenosis. The process of restenosis in
coronary artery disease is derived from an interplay of several
implant-centered biological parameters. These are thought to be the
combination of elastic recoil, vascular remodeling, and neointimal
hyperplasia.
[0010] It has been found that the physiopathology of restenosis
involves early injury to smooth muscle cells (SMCs),
de-endothelialization and thrombus deposition. Inflammatory cells
such as monocytes, neutrophils, and lymphocytes are recruited to
the implant site in response to injury. Over time, this leads to
SMC proliferation and migration and extra-cellular matrix
deposition. There is an increasing body of evidence suggesting that
inflammation plays a pivotal role in linking this early vascular
injury with neointimal growth and eventual lumen compromise, i.e.,
restenosis. Further, it has been observed that, when stenting is
used, the inflammatory state is often more intense and prolonged
thus exacerbating the preceding effects.
[0011] Therefore, there is a need for developing a coating design
for an implantable medical device that inhibits the growth of
smooth muscle cells and endothelial cells, lowers the inflammation
on healing, controls the release rates of bioactive agents and
improves the mechanical properties.
[0012] The embodiments of the present invention address these
concerns as well as others that are apparent to one having ordinary
skill in the art.
SUMMARY OF THE INVENTION
[0013] Provided herein is a coating for an implantable medical
device and the method of making and using the same. The coating
comprises a first layer having a hydrophobic polymer and a olimus
therapeutic agent; a second layer having a polar polymer and a
non-olimus therapeutic agent; and a third optional primer layer,
wherein the first layer is deposited over the second layer, wherein
the second layer is deposited over the third layer, and wherein the
coating provides independent control of the release of olimus and
non-olimus therapeutic agents.
[0014] In certain embodiments, the coating further comprises an
optional finishing coating layer for enhancing
biocompatibility.
[0015] In some embodiments, the hydrophobic polymer in the coating
is selected from a group consisting of poly(vinylidene fluoride),
poly(vinylidene fluoride-co-chlorotrifluoroethylene),
poly(vinylidene fluoride-co-hexafluoropropylene), poly(vinylidene
chloride), poly(vinyl fluoride), poly(vinyl chloride), polyvinyl
acetate, polystyrene, polyisobutylene, copolymers of styrene and
isobutylene, poly(styrene-b-isobutylene-b-styrene), poly(n-butyl
methacrylate), poly(butyl methacrylates), polycaprolactone,
poly(trimethylene carbonate), poly(L-lactide), poly(L-lactic acid),
poly(lactide-co-glycolide), poly(hydroxyvalerate),
poly(3-hydroxyvalerate), poly(hydroxybutyrate),
poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),
poly(hydroxybutyrate-co-valerate),
poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(glycolide),
poly(glycolic acid), poly(D,L-lactide-co-L-lactide),
poly(D,L-lactide-co-glycolide), poly(D,L-lactide), poly(D,L-lactic
acid), poly(glycolic acid-co-trimethylene carbonate),
polyanhydride, polyorthoester, SOLEF.TM. 21508 (formulation
available from Solvay Solexis), acrylic polymers and acrylic
copolymers, copolymers of vinyl monomers with each other and
olefins, ethylene-methyl methacrylate copolymers, ethylene-vinyl
acetate copolymers; ethylene-.alpha.-olefin copolymers,
poly(silicone-urethanes), poly(tyrosine arylates),
poly(tyrosine-derived carbonates); polyacrylates, polycarbonates,
poly-hydroxycarboxylic acids, polyisobutylene and
ethylene-.alpha.-olefin copolymers, polymethacrylates, polyolefins,
polyorthoesters, polyvinyl aromatics; polyvinyl esters, silicones,
vinyl copolymers, vinyl-olefin copolymers, vinyl halide polymers
and copolymers.
[0016] In other embodiments, the polar polymer in the coating is
selected from a group consisting of poly(ethylene-co-vinyl
alcohol), poly(vinyl alcohol), ethylene vinyl alcohol copolymers,
poly(2-hydroxyethyl methacrylate), poly(2-hydroxyethyl
methacrylate-co-n-butyl methacrylate), poly(2-hydroxyethyl
methacrylate) copolymers, poly(2-methoxyethyl methacrylate),
poly(2-ethoxyethyl methacrylate), poly(2-methoxy-1-methylethyl
methacrylate), poly(carbamoylmethyl methacrylate),
poly(2-carbamoylethyl methacrylate),
poly(1-carbamoyl-1-methylmethyl methacrylate),
poly(N-(carbamoylmethyl) methacrylamide),
poly(N-(1-carbamoyl-1-methylmethyl) methacrylamide),
poly(phosphorylcholine methacrylate), poly(phosphoryl choline
methacrylate) copolymers, PC1036, PC2126, poly(cellulose ethers),
poly(amino acids), poly(ester amides), poly(ester-urethanes),
poly(ether-urethanes), poly(imino carbonates), poly(acrylic acids),
poly(alkylene oxalates), polyamides, poly(carboxylic acids),
polycyanoacrylates, polyethers, poly(mides), poly(ketones),
poly(oxymethylenes), poly(phosphazenes), poly(phosphoesters),
poly(phosphoester urethanes), poly(phosphoesters), polyurethanes,
poly(vinyl esters), poly(vinyl ethers), poly(vinyl ketones),
starch, sodium alginate, poly(vinyl pyrrolidone), poly(vinyl methyl
ether), poly(isocyanate), poly(ethylene glycol), poly(dioxanone),
poly(caprolactam), Nylon 66, hyaluronic acid, fibrinogen, fibrin,
elastin-collagen, collagen, cellulose propionate, cellulose
nitrate, cellulose butyrate, cellulose acetate butyrate, cellulose
acetate, cellulose, carboxymethyl cellulose, chitin, chitosan,
poly(N-acetylglucosamine), polyurethane, and PEO/PLA.
[0017] In some embodiments, the olimus therapeutic agent in the
coating is selected from a group consisting of sirolimus
(rapamycin), everolimus, zotarolimus, Biolimus A9, AP23572,
tacrolimus, pimecrolimus and derivates or analogs or combinations
thereof.
[0018] In certain embodiments, the non-olimus therapeutic agent in
the coating is selected from a group consisting of dexamethasone,
dexamethasone acetate, dexamethasone phosphate, dexamethasone
valerate, dexamethasone derivatives, momentasone, clobetasol,
cortisone, cortisone acetate, hydrocortisone, corticosterone,
deoxycorticosterone, hydrocortisone acetate, deoxycorticosterone
acetate, hydroxyprogesterone, prednisolone, prednisolone acetate,
triamicinolone, triamicinolone acetonide, triamcinolone diacetate,
betamethasone, betamethasone valerate, steroids, glucocorticoids,
estradiol, methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, doxorubicin hydrochloride, mitomycin, antiplatelet
compounds, anticoagulants, antifibrin, antithrombins including
sodium heparin, low molecular weight heparins, heparinoids,
hirudin, argatroban, forskolin, vapiprost, prostacyclin,
prostacyclin analogues, D-phe-pro-arg-chloromethylketone (synthetic
antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet
membrane receptor antagonist antibody, recombinant hirudin,
thrombin inhibitors including Angiomax a, calcium channel blockers
including nifedipine, colchicine, fibroblast growth factor (FGF)
antagonists, histamine antagonists, lovastatin, monoclonal
antibodies, nitroprusside, phosphodiesterase inhibitors,
prostaglandin inhibitors, suramin, serotonin blockers, thioprotease
inhibitors, triazolopyrimidine, nitric oxide or nitric oxide
donors, super oxide dismutases, super oxide dismutase mimetic,
cytostatic substances including angiopeptin, angiotensin converting
enzyme inhibitors including captopril, cilazapril or lisinopril,
antiallergic agents as in permirolast potassium, alpha-interferon,
bioactive RGD and derivates or analogs or combinations thereof.
[0019] In other embodiments, the coating comprises a differentially
permeable topcoat layer having a non-polar polymer; a drug
reservoir layer having a polar polymer, a olimus therapeutic agent,
a non-olimus therapeutic agent; and an optional primer layer,
wherein the topcoat layer is deposited over the drug reservoir
layer, wherein the drug reservoir layer is deposited over the
primer layer, and wherein the permeable topcoat layer controls the
release of olimus and non-olimus therapeutic agents.
[0020] In one embodiment, the polymer forming the differentially
permeable topcoat layer in the coating is selected from a group
consisting of poly(vinyl fluoride), poly(vinyl chloride),
polystyrene, polyisobutylene, copolymers of styrene and
isobutylene, poly(styrene-b-isobutylene-b-styrene), poly(n-butyl
methacrylate), poly(butyl methacrylates), acrylic polymers, acrylic
copolymers, copolymers of vinyl monomers with each other and
olefins, ethylene-methyl methacrylate copolymers, ethylene-vinyl
acetate copolymers; ethylene-.alpha.-olefin copolymers,
poly(silicone-urethanes), poly(tyrosine arylates),
poly(tyrosine-derived carbonates), polyacrylates, polycarbonates,
polyisobutylene and ethylene-.alpha.-olefin copolymers,
polymethacrylates, polyolefins, polyorthoesters, polyvinyl
aromatics, polyvinyl esters, silicones, vinyl copolymers,
vinyl-olefin copolymers, and vinyl halide polymers and
copolymers.
[0021] In further embodiments, the coating comprises a first layer
having a hydrophobic polymer and an olimus therapeutic agent; a
second layer having a hydrophobic polymer and a crystallized
non-olimus therapeutic agent; and a third, optional primer layer,
wherein the first layer is deposited over the second layer, wherein
the second layer is deposited over the third layer, and wherein the
crystallized of non-olimus therapeutic agent has a slow rate of
release from the coating so as to provide a control of release of
the olimus and non-olimus therapeutic agents.
[0022] In another embodiment, the present invention describes a
method, comprising implanting in a patient an implantable medical
device comprising a coating as described herein, wherein the
disorder is selected from the group consisting of atherosclerosis,
thrombosis, restenosis, hemorrhage, vascular dissection or
perforation, vascular aneurysm, vulnerable plaque, chronic total
occlusion, patent foramen ovale, claudication, anastomotic
proliferation for vein and artificial grafts, bile duct
obstruction, ureter obstruction, tumor obstruction, and
combinations thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 illustrates a coating design for an implantable
medical device according to some embodiments of the present
invention.
[0024] FIG. 2 illustrates a coating design for an implantable
medical device according to some embodiments of the present
invention.
[0025] FIG. 3 illustrates a coating design for an implantable
medical device according to some embodiments of the present
invention.
[0026] FIG. 4 illustrates an optical micrograph showing
crystallization of a non-olimus therapeutic agent in the coating
design for an implantable medical device according to some
embodiments of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0027] As discussed in more detail below, the embodiments of the
present invention generally encompass controlling release of two
agents from an implantable medical device. More particularly, the
present invention provides a coating on an implantable medical
device which provides independent control of release of an olimus
therapeutic agent and a non-olimus therapeutic agent from the
coating.
[0028] Coating Designs
[0029] Provided herein is a method of independently modulating rate
of release of at least two therapeutic agents from a coating by
incorporating specific coating design and the method of making and
using the coating.
[0030] As used herein, "hydrophobic" refers to a polymer that lacks
an affinity for water. That is, it tends to repel water, to not
dissolve in, mix with or be wetted by water or to do so only to a
very limited degree and to not absorb water or, again, to do so
only to a very limited degree. With regard to polymers, generally
hydrophobicity increase with increasing alkyl content in the
polymer backbone, that is, the greater the alkyl content in one or
more of the constitutional units of the polymer. The hydrophobicity
of a polymer may be characterized by determining the static contact
angle of droplets of distilled water on a surface of the polymer.
The greater the contact angle, the more hydrophobic the polymer.
Generally speaking, a contact angle of greater than 90.degree.
indicates a hydrophobic polymer. The specifics or such measurements
will not be presented here since they are well-known to those
skilled in the art.
[0031] As used herein, "contact angle" is defined as an angle at
the tangent of a droplet in a fluid phase that has taken an
equilibrium shape on a solid surface under ambient condition.
[0032] As used herein, "hydrophobicity" can be gauged using the
Hildebrand solubility parameter .delta.. The term "Hildebrand
solubility parameter" refers to a parameter indicating the cohesive
energy density of a substance. The .delta. parameter is determined
as follows:
.delta.=(.DELTA.E/V).sup.1/2
[0033] where .delta. is the solubility parameter,
(cal/cm.sup.3).sup.1/2;
[0034] .DELTA.E is the energy of vaporization, cal/mole; and
[0035] V is the molar volume, cm.sup.3/mole.
[0036] Accordingly, for the practice of the present invention,
whether a material is hydrophobic or hydrophilic is relative.
Between different materials, whichever has a lower Hildebrand value
(.delta.) value compared to the .delta. value of the other is
designated as a hydrophobic, and the material with a higher
Hildebrand value (.delta.) value is designated as a hydrophilic. In
one embodiment, the .delta. value defining the boundary between
hydrophobic and hydrophilic can be between about 9.9 and 10.1
(cal/cm.sup.3).sup.1/2. According to this embodiment, hydrophobic
is defined as having a .delta. value equal to or below about 9.9
(cal/cm.sup.3).sup.1/2, and hydrophilic is defined as having a
.delta. value of about 10.1 (cal/cm.sup.3) .sup.1/2 or higher.
Materials having a .delta. value between about 9.9 and 10.1
(cal/cm.sup.3).sup.1/2 can exhibit behavior characterized by both
hydrophilic and hydrophobic materials. Such materials are defined
as "amphiphilic." Measurements other than Hildebrand value for the
determination of hydrophobicity are known to those skilled in the
art and may be employed in the same manner as the Hildebrand value
to achieve the same end.
[0037] Representative examples of hydrophobic polymers include, but
are not limited to, poly(vinylidene fluoride), poly(vinylidene
fluoride-co-chlorotrifluoroethylene), poly(vinylidene
fluoride-co-hexafluoropropylene), poly(vinylidene chloride),
poly(vinyl fluoride), poly(vinyl chloride), polyvinyl acetate,
polystyrene, polyisobutylene, copolymers of styrene and
isobutylene, poly(styrene-b-isobutylene-b-styrene), poly(n-butyl
methacrylate), poly(butyl methacrylates), polycaprolactone,
poly(trimethylene carbonate), poly(L-lactide), poly(L-lactic acid),
poly(lactide-co-glycolide), poly(hydroxyvalerate),
poly(3-hydroxyvalerate), poly(hydroxybutyrate),
poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),
poly(hydroxybutyrate-co-valerate),
poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(glycolide),
poly(glycolic acid), poly(D,L-lactide-co-L-lactide),
poly(D,L-lactide-co-glycolide), poly(D,L-lactide), poly(D,L-lactic
acid), poly(glycolic acid-co-trimethylene carbonate),
polyanhydride, polyorthoester, SOLEF.TM. 21508 (formulation
available from Solvay Solexis), acrylic polymers and acrylic
copolymers, copolymers of vinyl monomers with each other and
olefins, ethylene-methyl methacrylate copolymers, ethylene-vinyl
acetate copolymers; ethylene-.alpha.-olefin copolymers,
poly(silicone-urethanes), poly(tyrosine arylates),
poly(tyrosine-derived carbonates); polyacrylates, polycarbonates,
poly-hydroxycarboxylic acids, polyisobutylene and
ethylene-.alpha.-olefin copolymers, polymethacrylates, polyolefins,
polyorthoesters, polyvinyl aromatics; polyvinyl esters, silicones,
vinyl copolymers, vinyl-olefin copolymers, vinyl halide polymers
and copolymers.
[0038] Representative examples of polar polymers include, but are
not limited to, poly(ethylene-co-vinyl alcohol), EVAL.RTM.,
poly(vinyl alcohol), ethylene vinyl alcohol copolymers,
poly(2-hydroxyethyl methacrylate), poly(-hydroxyethyl
methacrylate-co-n-butyl methacrylate), poly(2-hydroxyethyl
methacrylate) copolymers, poly(-methoxyethyl methacrylate),
poly(-ethoxyethyl methacrylate), poly(-methoxy-1-methylethyl
methacrylate), poly(carbamoylmethyl methacrylate),
poly(-carbamoylethyl methacrylate), poly(1-carbamoyl-1-methylmethyl
methacrylate), poly(N-(carbamoylmethyl) methacrylamide),
poly(N-(1-carbamoyl-1-methylmethyl) methacrylamide),
poly(phosphorylcholine methacrylate), poly(phosphoryl choline
methacrylate) copolymers, PC1036, PC2126, poly(cellulose ethers),
poly(amino acids), poly(ester amides), poly(ester-urethanes),
poly(ether-urethanes), poly(imino carbonates), poly(acrylic acids),
poly(alkylene oxalates), polyamides, poly(carboxylic acids),
polycyanoacrylates, polyethers, poly(imides), poly(ketones),
poly(oxymethylenes), poly(phosphazenes), poly(phosphoesters),
poly(phosphoester urethanes), poly(phosphoesters), polyurethanes,
poly(vinyl esters), poly(vinyl ethers), poly(vinyl ketones),
starch, sodium alginate, poly(vinyl pyrrolidone), poly(vinyl methyl
ether), poly(isocyanate), poly(ethylene glycol), poly(dioxanone),
poly(caprolactam), Nylon 66, hyaluronic acid, fibrinogen, fibrin,
elastin-collagen, collagen, cellulose propionate, cellulose
nitrate, cellulose butyrate, cellulose acetate butyrate, cellulose
acetate, cellulose, carboxymethyl cellulose, chitin, chitosan,
poly(N-acetylglucosamine), polyurethane, and PEO/PLA.
[0039] As used herein, "drug reservoir layer" refers either to a
layer of one or more therapeutic agents applied neat or to a layer
of polymer or blend of polymers that has dispersed within its
three-dimensional structure one or more therapeutic agents. A
polymeric drug reservoir layer is designed such that, by one
mechanism or another, e.g., without limitation, by elution or as
the result of biodegradation of the polymer, the therapeutic
substance is released from the layer into the surrounding
environment. For the purpose of this invention, the drug reservoir
layer also acts as rate-controlling layer.
[0040] As used herein, a "primer layer" refers to a coating
consisting of a polymer or blend of polymers that exhibit good
adhesion characteristics with regard to the material of which the
device body is manufactured and good adhesion characteristic with
regard to whatever material is to be coated on the device body.
Thus, a primer layer serves as an intermediary layer between a
device body and materials to be affixed to the device body and is,
therefore, applied directly to the device body. The presently
preferred polymers for the primer layer include, but are not
limited to, acrylate and methacrylate polymers, poly(n-butyl
methacrylate), and copolymers thereof. Some additional examples of
primers include, but are not limited to, poly(ethylene-co-vinyl
alcohol), poly(vinyl acetate-co-vinyl alcohol),
poly(methacrylates), poly(acrylates), polyethyleneamine,
polyallylamine, chitosan, poly(ethylene-co-vinyl acetate), and
parylene-C.
[0041] FIG. 1 illustrates a coating design for an implantable
medical device according to some embodiments of the present
invention. The coating comprises a first layer having a hydrophobic
polymer and a olimus therapeutic agent. The presently preferred
hydrophobic polymer is poly(vinylidene
fluoride-co-hexafluoropropylene) (PVDF-HFP). The coating comprises
a second layer having a polar polymer and a non-olimus therapeutic
agent. The presently preferred polar polymer is
poly(n-butylmethacrylate-co-2-hydroxyethylmethacrylate)
(PBMA-co-HEMA) (90:10). The non-olimus therapeutic agent is
dissolved in a polar polymer which prevents crystallization of
non-olimus therapeutic agent. The coating comprises a third
optional primer layer. The first layer is deposited over the second
layer. The second layer is deposited over the third layer. The
coating further comprises an optional finishing coating layer for
enhancing biocompatibility. The specific coating design
independently controls the release of olimus and non-olimus
therapeutic agents.
[0042] As used herein, a "topcoat layer" refers to an outermost
layer, that is, a layer that is in contact with the external
environment and that is coated over all other layers. The topcoat
layer may be a separate layer distinct from drug reservoir layer or
the drug reservoir layer may itself be the outermost layer and
therefore constitute the topcoat layer of a coating, if the drug
reservoir layer contains hemocompatible and/or prohealing moieties.
A separate topcoat layer may be applied to provide better
hydrophilicity to the device, to better lubricate the device or
merely as a physical protectant of the underlying layers.
[0043] Representative examples of the polymers of the
differentially permeable topcoat layer include, but are not limited
to, poly(vinyl fluoride), poly(vinyl chloride), polystyrene,
polyisobutylene, copolymers of styrene and isobutylene,
poly(styrene-b-isobutylene-b-styrene), poly(n-butyl methacrylate),
poly(butyl methacrylates), acrylic polymers, acrylic copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, ethylene-vinyl acetate
copolymers; ethylene-.alpha.-olefin copolymers,
poly(silicone-urethanes), poly(tyrosine arylates),
poly(tyrosine-derived carbonates), polyacrylates, polycarbonates,
polyisobutylene and ethylene-.alpha.-olefin copolymers,
polymethacrylates, polyolefins, polyorthoesters, polyvinyl
aromatics, polyvinyl esters, silicones, vinyl copolymers,
vinyl-olefin copolymers, and vinyl halide polymers and copolymers.
In a presently preferred embodiment, the topcoat layer comprises
styrene-isobutylene-styrene triblock polymer.
[0044] FIG. 2 illustrates a coating design for an implantable
medical device according to some embodiments of the present
invention. The coating comprises a differentially permeable topcoat
layer having a non-polar polymer; a drug reservoir layer having a
polar polymer, an olimus therapeutic agent, a non-olimus
therapeutic agent; and an optional primer layer. The topcoat layer
is deposited over the drug reservoir layer. The drug reservoir
layer is deposited over the primer layer. The coating further
comprises an optional finishing coating layer for enhancing
biocompatibility. Both the therapeutic agents are placed in a
single drug reservoir layer. A different release rate for each
therapeutic agent can be achieved by the use of a topcoat layer
with differential permeability for each of the olimus therapeutic
agent and the non-olimus therapeutic agent. The differentially
permeable topcoat layer becomes functional for differentially
controlling the rate of release of the agents when the permeability
of the olimus and that of the non-olimus therapeutic agent differ
at least by a factor of two. The drug permeability (P) is defined
to be the product of the drug diffusivity (D) and the drug
solubility (S) in the topcoat layer. The drug permeability (P), the
drug diffusivity (D) and the drug solubility (S) are represented by
the following equation:
P=D.times.S
Generally, the non-olimus therapeutic agents are smaller molecules
than the olimus therapeutic agent. Consequently, the diffusivity of
the non-olimus therapeutic agent in the topcoat layer is higher
than an olimus therapeutic agent. Normally, this higher diffusivity
would mean that the non-olimus agent would always release more
rapidly than the olimus agent. However, the solubility of the
non-olimus therapeutic agent in the differentially permeable
topcoat layer is lower than the olimus agent. This is because many
of the non-olimus agents of interest are more polar than the olimus
drugs. This leads to enhanced permeation of the olimus agent
through the topcoat layer relative to the non-olimus agent.
Therefore, the permeable topcoat layer controls the release of
olimus and non-olimus therapeutic agents. The selective permeation
of olimus therapeutic agent over non-olimus therapeutic agent can
be achieved by using polymers such as silicone,
poly(bl-styrene-bl-ethylene/butene-bl-styrene), silicone-urethanes
and fluoro-silicones in the topcoat layer. The presently preferred
differentially permeable polymer in the topcoat layer is
styrene-isobutylene-styrene triblock polymer and the polymer in the
drug reservoir layer is
poly(n-butylmethacrylate-co-2-hydroxyethylmethacrylate)
(PBMA-co-HEMA) (90:10). Polymers such as PVDF-HFP are not desired
for this type of topcoat layer as they have enough polarity for the
non-olimus therapeutic agent to have sufficient solubility to still
be released much more rapidly than the olimus agent.
[0045] FIG. 3 illustrates a coating design for an implantable
medical device according to some embodiments of the present
invention. The coating comprises a first layer having a hydrophobic
polymer and an olimus therapeutic agent, which controls the release
of an olimus therapeutic agent. The coating comprises a second
layer having a hydrophobic polymer and a crystallized non-olimus
therapeutic agent. The coating comprises a third optional primer
layer. The first layer is deposited over the second layer. The
second layer is deposited over the third layer. The coating further
comprises an optional finishing coating layer for enhancing
biocompatibility. The non-olimus therapeutic agent is crystallized
in the hydrophobic polymer, poly(vinylidene
fluoride-co-hexafluoropropylene) (PVDF-HFP), in the second layer.
The second layer is saturated with crystallized non-olimus
therapeutic agent dissolved in the layer. The dissolved non-olimus
therapeutic agent can diffuse into the first layer only to the
degree necessary to saturate the first layer which can be in very
small amounts. The use of crystallization of the non-olimus
therapeutic agent in a coating provides for control of the release
rate of the non-olimus therapeutic agent. The presently preferred
hydrophobic polymer for forming the first and second layer is
poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP).
Overall, the coating shown in FIG. 3 provides control of release of
both the olimus and non-olimus therapeutic agents.
[0046] FIG. 4 illustrates an optical micrograph showing
crystallized non-olimus therapeutic agent in the coating for an
implantable medical device according to some embodiments of the
present invention shown in FIG. 3. The non-olimus therapeutic agent
can be forced to crystallize out using hydrophobic polymer such as
PVDF-HFP in the second layer. The process of crystallization of the
non-olimus therapeutic agent in the second layer assures that the
non-olimus therapeutic agent remains in the second layer. The
crystal embolic hazard of the non-olimus therapeutic agent which
can accompany the release of a crystal agent can be reduced as the
crystals are buried in PVDF-HFP polymer in the second layer. As the
second layer is saturated with crystallized non-olimus therapeutic
agent, the variation in therapeutic agents release rate due to
different degrees of crystallinity can be less when PVDF-HFP
polymer in the second layer is saturated with dissolved non-olimus
therapeutic agent and thus, the varying amount of crystals on the
surface will not affect the release rate. Further, crystallization
during aging is unlikely as the non-olimus therapeutic agent is
insoluble in the PVDF-HFP that crystallization is likely to be
complete after ETO sterilization. The non-olimus therapeutic agent
in the second layer can be prevented from mixing into olimus
therapeutic agent in the first layer by using a spray of volatile
solvents such as acetone or 2-butanone.
[0047] Biocompatible Polymers
[0048] The coating described herein can include one or more
biocompatible polymer. The biocompatible polymer can be
biodegradable (either bioerodable or bioabsorbable) or
nondegradable and can be hydrophilic or hydrophobic. The
biocompatible polymer can be polar or non-polar in nature.
[0049] Representative biocompatible polymers include, but are not
limited to, poly(ester amide), polyhydroxyalkanoates (PHA),
poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),
poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),
poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) and
poly(3-hydroxyoctanoate), poly(4-hydroxyalkanoate) such as
poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),
poly(4-hydroxyhexanoate), poly(4-hydroxyheptanoate),
poly(4-hydroxyoctanoate) and copolymers including any of the
3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein
or blends thereof, poly(D,L-lactide), poly(L-lactide),
polyglycolide, poly(D,L-lactide-co-glycolide),
poly(L-lactide-co-glycolide), polycaprolactone,
poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),
poly(dioxanone), poly(ortho esters), poly(anhydrides),
poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine
ester) and derivatives thereof, poly(imino carbonates),
poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,
polyphosphoester urethane, poly(amino acids), polycyanoacrylates,
poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes,
polyphosphazenes, silicones, polyesters, polyolefins,
polyisobutylene and ethylene-alphaolefin copolymers, acrylic
polymers and copolymers, vinyl halide polymers and copolymers, such
as polyvinyl chloride, polyvinyl ethers, such as polyvinyl methyl
ether, polyvinylidene halides, such as polyvinylidene chloride,
polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, such as
polystyrene, polyvinyl esters, such as polyvinyl acetate,
copolymers of vinyl monomers with each other and olefins, such as
ethylene-methyl methacrylate copolymers, acrylonitrile-styrene
copolymers, ABS resins, and ethylene-vinyl acetate copolymers,
polyamides, such as Nylon 66 and polycaprolactam, alkyd resins,
polycarbonates, polyoxymethylenes, polyimides, polyethers,
poly(glyceryl sebacate), poly(propylene fumarate), poly(n-butyl
methacrylate), poly(sec-butyl methacrylate), poly(isobutyl
methacrylate), poly(tert-butyl methacrylate), poly(n-propyl
methacrylate), poly(isopropyl methacrylate), poly(ethyl
methacrylate), poly(methyl methacrylate), epoxy resins,
polyurethanes, rayon, rayon-triacetate, cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellophane,
cellulose nitrate, cellulose propionate, cellulose ethers,
carboxymethyl cellulose, polyethers such as poly(ethylene glycol)
(PEG), copoly(ether-esters) (e.g. poly(ethylene oxide/poly(lactic
acid) (PEO/PLA)), polyalkylene oxides such as poly(ethylene oxide),
poly(propylene oxide), poly(ether ester), polyalkylene oxalates,
polyphosphazenes, phosphoryl choline, choline, poly(aspirin),
polymers and co-polymers of hydroxyl bearing monomers such as
2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate
(HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG
methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and
n-vinyl pyrrolidone (VP), carboxylic acid bearing monomers such as
methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate,
alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate (TMSPMA),
poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,
polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,
poly(methyl methacrylate)-PEG (PMMA-PEG),
polydimethylsiloxane-co-PEG (PDMS-PEG), PLURONIC.TM. surfactants
(polypropylene oxide-co-polyethylene glycol), poly(tetramethylene
glycol), hydroxy functional poly(vinyl pyrrolidone), biomolecules
such as chitosan, alginate, fibrin, fibrinogen, cellulose, starch,
dextran, dextrin, fragments and derivatives of hyaluronic acid,
heparin, fragments and derivatives of heparin, glycosamino glycan
(GAG), GAG derivatives, polysaccharide, chitosan, alginate, or
combinations thereof. In some embodiments, the copolymer described
herein can exclude any one or more of the aforementioned
polymers.
[0050] As used herein, the terms poly(D,L-lactide),
poly(L-lactide), poly(D,L-lactide-co-glycolide), and
poly(L-lactide-co-glycolide) can be used interchangeably with the
terms poly(D,L-lactic acid), poly(L-lactic acid), poly(D,L-lactic
acid-co-glycolic acid), or poly(L-lactic acid-co-glycolic acid),
respectively.
[0051] Bioactive Agents
[0052] In embodiments, a coating described herein can optionally
include one or more bioactive agents. These bioactive agents can be
any agent which is a therapeutic, prophylactic, or diagnostic
agent. These agents can have anti-proliferative or
anti-inflammatory properties or can have other properties such as
antineoplastic, antiplatelet, anti-coagulant, anti-fibrin,
antithrombonic, antimitotic, antibiotic, antiallergic, or
antioxidant properties.
[0053] Presently preferred therapeutic agents of this invention are
the olimus therapeutic agent and non-olimus therapeutic agent.
[0054] As used herein, "olimus" therapeutic agent refers to the
family of therapeutic agents that include, but are not limited to,
sirolimus (rapamycin), everolimus, zotarolimus, Biolimus A9
(Biosensors International, Singapore), AP23572 (Ariad
Pharmaceuticals), tacrolimus, pimecrolimus and derivates or analogs
or combinations thereof.
[0055] As used herein, a "non-olimus" therapeutic agent refers to a
naturally occurring steroid hormone (corticosteroid) that is
produced in the adrenal cortex and to synthetic therapeutic agents
that exhibit corticosteroid-like pharmacological effects. Of
particular importance to the methods of this invention is the
ability of non-olimus therapeutic agent and their synthetic
counterparts to mediate physiological systems related to the immune
response and to regulation of inflammation.
[0056] Some examples of non-olimus therapeutic agents include, but
are not limited to, dexamethasone, dexamethasone acetate,
dexamethasone phosphate, dexamethasone valerate, dexamethasone
derivatives, momentasone, clobetasol, cortisone, cortisone acetate,
hydrocortisone, corticosterone, deoxycorticosterone, hydrocortisone
acetate, deoxycorticosterone acetate, hydroxyprogesterone,
prednisolone, prednisolone acetate, triamicinolone, triamicinolone
acetonide, triamcinolone diacetate, betamethasone, betamethasone
valerate, steroids, glucocorticoids, estradiol, methotrexate,
azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin
hydrochloride, mitomycin, antiplatelet compounds, anticoagulants,
antifibrin, antithrombins including sodium heparin, low molecular
weight heparins, heparinoids, hirudin, argatroban, forskolin,
vapiprost, prostacyclin, prostacyclin analogues,
D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist antibody, recombinant hirudin, thrombin inhibitors
including Angiomax, calcium channel blockers including nifedipine,
colchicine, fibroblast growth factor (FGF) antagonists, histamine
antagonists, lovastatin, monoclonal antibodies, nitroprusside,
phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,
serotonin blockers, thioprotease inhibitors, triazolopyrimidine,
nitric oxide or nitric oxide donors, super oxide dismutases, super
oxide dismutase mimetic, cytostatic substances including
angiopeptin, angiotensin converting enzyme inhibitors including
captopril, cilazapril or lisinopril, antiallergic agents as in
permirolast potassium, alpha-interferon, bioactive RGD and
derivates or analogs or combinations thereof.
[0057] In addition to an olimus and a non-olimus therapeutic agent,
an implantable medical device of this invention and the method
herein may comprise additional therapeutic agents that are known or
become known as being effective in treating the various
physiological events comprising vascular diseases.
[0058] For example, other therapeutic agents that may be useful
with the implantable medical device and method of this invention
include, without limitation, antiproliferative agents,
anti-inflammatory agents, antineoplastics and/or antimitotics,
antiplatelet, anticoagulant, antifibrin, and antithrombin drugs,
cytostatic or antiproliferative agents, antibiotics, antiallergic
agents and antioxidants.
[0059] Antiproliferative agents include, without limitation,
actinomycin D, taxol, docetaxel, paclitaxel and perfenidone.
[0060] Anti-inflammatory agents include, without limitation,
alclofenac, alpha amylase, amcinafal, amcinafide, amfenac sodium,
amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone,
balsalazide disodium, bendazac, benoxaprofen, benzydamine
hydrochloride, bromelains, broperamole, budesonide, carprofen,
cicloprofen, cintazone, cliprofen, clopirac, cortodoxone,
deflazacort, diclofenac potassium, diclofenac sodium, diflumidone
sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide,
drocinonide, endrysone, enlimomab, enolicam sodium, epirizole,
etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac,
fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort,
flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin
meglumine, fluocortin butyl, fluorometholone acetate, fluquazone,
flurbiprofen, fluretofen, fluticasone propionate, furaprofen,
furobufen, halopredone acetate, ibufenac, ibuprofen, ibuprofen
aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin
sodium, indoprofen, indoxole, intrazole, isoflupredone acetate,
isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride,
lomoxicam, loteprednol etabonate, meclofenamate sodium,
meclofenamic acid, meclorisone dibutyrate, mefenamic acid,
mesalamine, meseclazone, methylprednisolone suleptanate,
momiflumate, nabumetone, naproxen, naproxen sodium, naproxol,
nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin,
oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate
sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam,
piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate,
prifelone, prodolic acid, proquazone, proxazole, proxazole citrate,
rimexolone, romazarit, salcolex, salnacedin, salsalate,
sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,
suprofen, talmetacin, talniflumate, talosalate, tebufelone,
tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine,
tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,
triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin
(acetylsalicylic acid) and salicylic acid.
[0061] Anti-neoplastic and/or anti-mitotic agents include, without
limitation, paclitaxel, docetaxel, methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride,
and mitomycin.
[0062] Antiplatelet, anticoagulant, antifibrin, and antithrombin
agents include, without limitation, sodium heparin, low molecular
weight heparins, heparinoids, hirudin, argatroban, forskolin,
vapiprost, prostacyclin, prostacyclin dextran,
D-phe-pro-arg-chloromethylketone, dipyridamole, glycoprotein
IIb/IIIa platelet membrane receptor antagonist antibody,
recombinant hirudin and thrombin, thrombin inhibitors such as
Angiomax a, calcium channel blockers such as nifedipine,
colchicine, fish oil (omega 3-fatty acid), histamine antagonists,
lovastatin, monoclonal antibodies (such as those specific for
Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,
phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,
serotonin blockers, steroids, thioprotease inhibitors,
triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric
oxide donors, super oxide dismutases, super oxide dismutase
mimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO) and estradiol.
[0063] Cytostatic or anti-proliferative agents include, without
limitation, angiopeptin, angiotensin converting enzyme inhibitors
such as captopril, cilazapril or lisinopril, calcium channel
blockers such as nifedipine; colchicine, fibroblast growth factor
(FGF) antagonists; fish oil (.omega.-3-fatty acid); histamine
antagonists; lovastatin, monoclonal antibodies such as, without
limitation, those specific for Platelet-Derived Growth Factor
(PDGF) receptors; nitroprusside, phosphodiesterase inhibitors,
prostaglandin inhibitors, suramin, serotonin blockers, steroids,
thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist) and
nitric oxide. Anti-allergenic agents include, without limitation,
permirolast potassium.
[0064] Other potentially useful therapeutic agents include, without
limitation, alpha-interferon, genetically engineered epithelial
cells, DNA and RNA nucleic acid sequences, antisense molecules, and
ribozymes, antibodies, receptor ligands, enzymes, adhesion
peptides, blood clotting factors, inhibitors or clot dissolving
agents such as streptokinase and tissue plasminogen activator,
antigens for immunization, hormones and growth factors,
oligonucleotides, retroviral vectors; antiviral agents; analgesics;
anorexics; antihelmintics; antiarthritics, antiasthmatic agents;
anticonvulsants; antidepressants; antidiuretic agents;
antidiarrheals; antihistamines; antimigrain preparations;
antinauseants; antiparkinsonism drugs; antipruritics;
antipsychotics; antipyretics; antispasmodics; anticholinergics;
sympathomimetics; xanthine derivatives; cardiovascular preparations
including calcium channel blockers, beta-blockers such as pindolol,
antiarrhythmics; antihypertensives; diuretics; vasodilators
including general coronary; peripheral and cerebral; central
nervous system stimulants; cough and cold preparations, including
decongestants; hypnotics; immunosuppressives; muscle relaxants;
parasympatholytics; psychostimulants; sedatives; tranquilizers;
natural or genetically engineered lipoproteins; and restenosis
reducing agents.
[0065] The dosage or concentration of the bioactive agent required
to produce a favorable therapeutic effect should be less than the
level at which the bioactive agent produces toxic effects and
greater than the level at which non-therapeutic results are
obtained. The dosage or concentration of the bioactive agent can
depend upon factors such as the particular circumstances of the
patient, the nature of the trauma, the nature of the therapy
desired, the time over which the ingredient administered resides at
the vascular site, and if other active agents are employed, the
nature and type of the substance or combination of substances.
Therapeutically effective dosages can be determined empirically,
for example by infusing vessels from suitable animal model systems
and using immunohistochemical, fluorescent or electron microscopy
methods to detect the agent and its effects, or by conducting
suitable in vitro studies. Standard pharmacological test procedures
to determine dosages are understood by those of ordinary skill in
the art.
[0066] Examples of Implantable Devices
[0067] As used herein, an implantable device can be any suitable
medical substrate that can be implanted in a human or veterinary
patient. Examples of such implantable devices include
self-expandable stents, balloon-expandable stents, stent-grafts,
grafts (e.g., aortic grafts), heart valve prosthesis (e.g.,
artificial heart valves) or vascular graft, cerebrospinal fluid
shunts, pacemaker electrodes, catheters, endocardial leads (e.g.,
FINELINE and ENDOTAK, available from Guidant Corporation, Santa
Clara, Calif.), and devices facilitating anastomosis such as
anastomotic connectors. The underlying structure of the device can
be of virtually any design. The device can be made of a metallic
material or an alloy such as, but not limited to, cobalt chromium
alloy (ELGILOY), stainless steel (316L), high nitrogen stainless
steel, e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N,"
"MP2ON," ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,
platinum-iridium alloy, gold, magnesium, or combinations thereof
"MP35N" and "MP20N" are trade names for alloys of cobalt, nickel,
chromium and molybdenum available from Standard Press Steel Co.,
Jenkintown, PA. "MP35N" consists of 35% cobalt, 35% nickel, 20%
chromium, and 10% molybdenum. "MP20N" consists of 50% cobalt, 20%
nickel, 20% chromium, and 10% molybdenum. Devices made from
bioabsorbable or biostable polymers could also be used with the
embodiments of the present invention. The device can be, for
example, a bioabsorbable stent.
[0068] Method of Use
[0069] In accordance with embodiments of the invention, a coating
of the various described embodiments can be formed on an
implantable device or prosthesis, e.g., a stent. For coatings
including one or more active agents, the agent will be retained on
the medical device such as a stent during delivery and expansion of
the device, and released at a desired rate and for a predetermined
duration of time at the site of implantation. Preferably, the
medical device is a stent. A stent having the above-described
coating is useful for a variety of medical procedures, including,
by way of example, treatment of obstructions caused by tumors in
bile ducts, esophagus, trachea/bronchi and other biological
passageways. A stent having the above-described coating is
particularly useful for treating occluded regions of blood vessels
caused by atherosclerosis, abnormal or inappropriate migration and
proliferation of smooth muscle cells, thrombosis, restenosis and
the treatment of vulnerable plaque. Stents may be placed in a wide
array of blood vessels, both arteries and veins. Representative
examples of sites include the iliac, renal, and coronary
arteries.
[0070] For implantation of a stent, an angiogram is first performed
to determine the appropriate positioning for stent therapy. An
angiogram is typically accomplished by injecting a radiopaque
contrasting agent through a catheter inserted into an artery or
vein as an x-ray is taken. A guidewire is then advanced through the
lesion or proposed site of treatment. Over the guidewire is passed
a delivery catheter which allows a stent in its collapsed
configuration to be inserted into the passageway. The delivery
catheter is inserted either percutaneously or by surgery into the
femoral artery, brachial artery, femoral vein, or brachial vein,
and advanced into the appropriate blood vessel by steering the
catheter through the vascular system under fluoroscopic guidance. A
stent having the above-described coating may then be expanded at
the desired area of treatment. A post-insertion angiogram may also
be utilized to confirm appropriate positioning.
[0071] The implantable device comprising a coating described herein
can be used to treat an animal having a condition or disorder that
requires a treatment. Such an animal can be treated by, for
example, implanting a device described herein in the animal.
Preferably, the animal is a human being. Exemplary disorders or
conditions that can be treated by the method disclosed herein
include, but not limited to, atherosclerosis, thrombosis,
restenosis, hemorrhage, vascular dissection or perforation,
vascular aneurysm, vulnerable plaque, chronic total occlusion,
claudication, anastomotic proliferation for vein and artificial
grafts, bile duct obstruction, ureter obstruction, and tumor
obstruction.
EXAMPLES
[0072] The embodiments of the present invention will be illustrated
by the following set forth examples. All parameters and data are
not to be construed to limit the scope of the embodiments of the
invention.
Example 1
[0073] Primer Layer: A solution (2%) of poly(n-butyl methacrylate)
(PBMA) was formed by dissolving PBMA in acetone:cyclohexanone
(70:30 by weight). An external air-assisted atomizing spray nozzle,
such as an EFD.TM. 780S spray nozzle with a VALVEMATE.TM. 7040
control system (manufactured by EFD, Inc., East Providence, R.I.)
was used for spraying the polymer solution onto the stent. The
polymer solution was applied to stent while rotating in
longitudinal axis at a speed of 150 rpm. The stent was moved
linearly along the same axis at a speed of 6 mm/sec during the
application. The PBMA polymer solution (2%) was applied to a 12-mm
VISION.TM. stent (Abbott Vascular Inc.) in a series of 5-second
passes to deposit 8 .mu.g of coating per spray pass. The stent was
dried for 10 seconds using a flow of air at ambient temperature
between the spray passes. Eight spray passes were applied, followed
by baking the primer layer at 80.degree. C. for 30 minutes to form
60 .mu.g a primer layer.
[0074] Second layer: A mixture of poly(n-butyl
methacrylate-co-2-hydroxyethyl methacrylate) (PBMA-co-HEMA) (90:10)
(2% by weight), dexamethasone (0.67%) and ethanol:n-butanol (50:50
by weight) (97.33%) was prepared. The mixture was applied to the
stent by using the same apparatus as used for primer layer. Forty
two spray passes were performed at 12 .mu.g/pass to form a second
layer, followed by drying at 50.degree. C. for 1 hour to yield 480
.mu.g of a second layer.
[0075] First layer: A mixture of poly(vinylidene
fluoride-co-hexafluoropropylene) (PVDF-HFP) (85:15) (2%),
everolimus (0.5%) and 2-butanone (97.5%). The mixture was applied
to the stent by using the same apparatus as used for primer layer.
Twenty five spray passes were performed at 12 .mu.g/pass to form a
first layer, followed by drying at 50.degree. C. for 1 hour to
yield 285 .mu.g of a first layer.
[0076] Example 2
[0077] Primer Layer: A solution (2%) of poly(n-butyl methacrylate)
(PBMA) was formed by dissolving PBMA in acetone:cyclohexanone
(70:30 by weight). An external air-assisted atomizing spray nozzle,
such as an EFD.TM. 780S spray nozzle with a VALVEMATE.TM. 7040
control system (manufactured by EFD, Inc., East Providence, R.I.)
was used for spraying the polymer solution onto the stent. The
polymer solution was applied to stent while rotating in
longitudinal axis at a speed of 150 rpm. The stent was moved
linearly along the same axis at a speed of 6 mm/sec during the
application. The PBMA polymer solution (2%) was applied to a 12-mm
VISION.TM. stent (Abbott Vascular Inc.) in a series of 5-second
passes to deposit 8 .mu.g of coating per spray pass. The stent was
dried for 10 seconds using a flow of air at ambient temperature
between the spray passes. Eight spray passes were applied, followed
by baking the primer layer at 80.degree. C. for 30 minutes to form
60 .mu.g of a primer layer.
[0078] Drug reservoir layer: A mixture of poly(n-butyl
methacrylate-co-2-hydroxyethyl methacrylate) (PBMA-co-HEMA) (90:10)
(2% by weight), dexamethasone (0.67%), zotarolimus (0.5%) and
ethanol:n-butanol (50:50 by weight) (96.83%) was prepared. The
mixture was applied to the stent by using the same apparatus as
used for primer layer. Eighteen spray passes were performed at 12
.mu.g/pass to form a drug reservoir layer, followed by drying at
50.degree. C. for 1 hour to yield 185 .mu.g of a drug reservoir
layer.
[0079] Topcoat layer: A mixture of
poly(styrene-b-isobutylene-b-styrene) (25/50/25) (2% by weight),
everolimus (0.5%) and tetrahydrofuran:toluene (50:50 by weight)
(98%) was prepared. The mixture was applied to the stent by using
the same apparatus as used for primer layer.
[0080] Eighteen spray passes were performed at 12 .mu.g/pass to
form a topcoat layer, followed by drying at 50.degree. C. for 1
hour to yield 200 .mu.g of a topcoat layer.
[0081] Example 3
[0082] Primer Layer: A solution (2%) of poly(n-butyl methacrylate)
(PBMA) was formed by dissolving PBMA in acetone:cyclohexanone
(70:30 by weight). An external air-assisted atomizing spray nozzle,
such as an EFD.TM. 780S spray nozzle with a VALVEMATE.TM. 7040
control system (manufactured by EFD, Inc., East Providence, R.I.)
was used for spraying the polymer solution onto the stent. The
polymer solution was applied to stent while rotating in
longitudinal axis at a speed of 150 rpm. The stent was moved
linearly along the same axis at a speed of 6 mm/sec during the
application. The PBMA polymer solution (2%) was applied to a 12-mm
VISION.TM. stent (Abbott Vascular Inc.) in a series of 5-second
passes to deposit 8 .mu.g of coating per spray pass. The stent was
dried for 10 seconds using a flow of air at ambient temperature
between the spray passes. Eight spray passes were applied, followed
by baking the primer layer at 80.degree. C. for 30 minutes to form
60 .mu.g of a primer layer.
[0083] Second layer: A mixture of poly(vinylidene
fluoride-co-hexafluoropropylene) (PVDF-HFP) (85:15) (2%),
dexamethasone (2%) and acetone:cyclohexanone (70:30 by weight)
(96%) was prepared. The mixture was applied to the stent by using
the same apparatus as used for primer layer. Twenty one spray
passes were performed at 12 .mu.g/pass to form a second layer,
followed by drying the second layer at 50.degree. C. for 1 hour to
yield 235 .mu.g of a second layer.
[0084] First layer: A mixture of poly(vinylidene
fluoride-co-hexafluoropropylene) (PVDF-HFP) (85:15) (2%),
everolimus (0.5%) and 2-butanone (97.5%). The mixture was applied
to the stent by using the same apparatus as used for primer layer.
Twenty five spray passes were performed at 12 .mu.g/pass to form a
first layer, followed by drying at 50.degree. C. for 1 hour to
yield 285 .mu.g of a first layer.
[0085] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *