U.S. patent application number 15/832450 was filed with the patent office on 2018-04-05 for absorbable coating for implantable device.
The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Syed F.A. Hossainy, Lothar W. Kleiner, Stephen D. Pacetti, Mikael Trollsas.
Application Number | 20180093020 15/832450 |
Document ID | / |
Family ID | 43970902 |
Filed Date | 2018-04-05 |
United States Patent
Application |
20180093020 |
Kind Code |
A1 |
Kleiner; Lothar W. ; et
al. |
April 5, 2018 |
ABSORBABLE COATING FOR IMPLANTABLE DEVICE
Abstract
The present invention provides an absorbable coating for an
implantable device and the methods of making and using the
same.
Inventors: |
Kleiner; Lothar W.; (Los
Altos, CA) ; Hossainy; Syed F.A.; (Hayward, CA)
; Trollsas; Mikael; (San Jose, CA) ; Pacetti;
Stephen D.; (San Jose, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
43970902 |
Appl. No.: |
15/832450 |
Filed: |
December 5, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15192973 |
Jun 24, 2016 |
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15832450 |
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14182211 |
Feb 17, 2014 |
9387282 |
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15192973 |
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12751989 |
Mar 31, 2010 |
8685433 |
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14182211 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61L 2300/416 20130101; A61L 31/148 20130101; A61L 2420/02
20130101; A61P 7/02 20180101; A61L 2300/41 20130101; A61L 2420/08
20130101; A61L 31/16 20130101; A61P 9/10 20180101; A61P 13/02
20180101; A61L 31/10 20130101; A61P 1/16 20180101; A61L 2300/42
20130101; A61P 9/14 20180101; A61P 7/04 20180101; A61P 9/00
20180101; A61L 31/10 20130101; C08L 67/04 20130101 |
International
Class: |
A61L 31/14 20060101
A61L031/14; A61L 31/10 20060101 A61L031/10; A61L 31/16 20060101
A61L031/16; C08L 67/04 20060101 C08L067/04 |
Claims
1. A medical device, comprising: (a) a bio-absorbable stent body;
and (b) a coating layer, the coating layer consists of D,L-PLA,
novolimus, and BHT, wherein (i) the D,L-PLA has a number average
molecular weight below 60,000 Daltons, and (ii) the coating layer
has a thickness of less than 5 microns and has an absorption period
from about 3 months to about 6 months, and wherein the stent body
comprises poly(L-lactic acid-co-caprolactone) (PLLA-CL),
poly(D-lactic acid-co-caprolactone) (PDLA-CL), poly(DL-lactic
acid-co-caprolactone) (PDLLA-CL), poly(lactide-co-glycolide)
(PLA-GA), poly(D-lactic acid-glycolic acid (PDLA-GA), poly(L-lactic
acid-glycolic acid (PLLA-GA), poly(DL-lactic acid-glycolic acid
(PDLLA-GA), or poly(glycolide-co-caprolactone) (PGA-CL).
2. A medical device of claim 1, wherein the coating layer is
annealed at a temperature between about 40 deg. C and about 150
deg. C.
Description
CROSS-REFERENCE
[0001] This application is a continuation application of U.S.
application Ser. No. 15/192,973, filed Jun. 24, 2016, which is a
continuation of U.S. application Ser. No. 14/182,211, filed Feb.
17, 2014 (U.S. Pat. No. 9,387,282 issued on Jul. 12, 2016), which
is a continuation of U.S. application Ser. No. 12/751,989, filed
Mar. 31, 2010 (U.S. Pat. No. 8,685,433 issued on Apr. 1, 2014), the
teachings of which are incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates to an absorbable coating an
implantable device and methods of making and using the same.
BACKGROUND OF THE INVENTION
[0003] Percutaneous coronary intervention (PCI) is a procedure for
treating heart disease. A catheter assembly having a balloon
portion is introduced percutaneously into the cardiovascular system
of a patient via the brachial or femoral artery. The catheter
assembly is advanced through the coronary vasculature until the
balloon portion is positioned across the occlusive lesion. Once in
position across the lesion, the balloon is inflated to a
predetermined size to radially compress the atherosclerotic plaque
of the lesion to remodel the lumen wall. The balloon is then
deflated to a smaller profile to allow the catheter to be withdrawn
from the patient's vasculature.
[0004] Problems associated with the above procedure include
formation of intimal flaps or torn arterial linings which can
collapse and occlude the blood conduit after the balloon is
deflated. Moreover, thrombosis and restenosis of the artery may
develop over several months after the procedure, which may require
another angioplasty procedure or a surgical by-pass operation. To
reduce the partial or total occlusion of the artery by the collapse
of the arterial lining and to reduce the chance of thrombosis or
restenosis, a stent is implanted in the artery to keep the artery
open.
[0005] Drug eluting stents have reduced the incidence of in-stent
restenosis (ISR) after PCI (see, e.g., Serruys, P. W., et al., J.
Am. Coll. Cardiol. 39:393-399 (2002)), which has plagued
interventional cardiology for more than a decade. However, a few
challenges remain in the art of drug eluting stents. For example,
compromised coating integrity when an amorphous bioabsorbable
polymer is used for coating a stent, which can result from the
conditions of ethylene oxide (ETO) sterilization or from the
conditions of crimping a stent onto the delivery balloon.
Conditions such as elevated temperature, high relative humidity,
and high concentration of ETO in the ETO sterilization process can
result in plasticization and adhesion of the coating to the balloon
via polymer deformation and flow. In a similar way, a completely
amorphous bioabsorbable polymer may flow when crimped at
temperatures above the polymer glass transition temperature
(T.sub.g) on to the delivery balloon.
[0006] Aliphatic polyesters are used in pharmaceutical and
biomedical applications, including for example surgical sutures and
drug delivery systems. Poly(L-lactide) (PLLA) is one of the most
widely studied polymer biomaterials, attractive for its
biodegradable and biocompatible properties. However, PLLA is not
ideally suited for many aspects of drug delivery systems, including
those involving drug-eluting stents. Issues of L-lactide based drug
delivery stent systems include compromised mechanical properties
after the fabrication process and deployment of such systems, and a
sometimes relatively long absorption period.
[0007] The embodiments of the present invention address the
above-identified needs and issues.
SUMMARY OF THE INVENTION
[0008] In one aspect, the present invention provides a
bioabsorbable coating on an implantable medical device. The coating
comprises a primer layer comprising a bioabsorbable polymer having
a first molecular weight and a second layer comprising a
bioabsorbable polymer of a second molecular weight. The first
molecular weight is higher than the second molecular weight, and
the coating is completely or substantially completely absorbed upon
implantation in a human body within a period from about 3 months to
about 6 months.
[0009] In some embodiments, the primer layer comprises a high or
very high molecular weight (HMW or VHMW) absorbable polymer.
Examples of such HMW or VHMW absorbable polymer are PLLA, 85/15
PLGA, 75/25 PLGA, poly(ester amide), PLA-PCL-GA terpolymer, PCL-GA,
and copolymers thereof.
[0010] In some embodiments, optionally in combination with the
various embodiments above, the second layer comprises a low
molecular weight (LMW) absorbable polymer. An example of the LMW
absorbable polymer is LMW D,L-PLA.
[0011] In some embodiments, optionally in combination with the
various embodiments above, the second layer comprises a drug or a
drug embedded in an absorbable polymer.
[0012] In some embodiments, optionally in combination with the
various embodiments above, the second layer does not comprise a
drug and is formed on top of a layer of a drug on top of the primer
layer.
[0013] In some embodiments, optionally in combination with the
various embodiments above, the coating disclosed herein is
micro-porous and is formed by a process of controlled phase
inversion kinetics, wherein the second layer and/or the primer
layer can include D,L-PLA.
[0014] In some embodiments, optionally in combination with the
various embodiments above, the implantable device is a stent.
[0015] In some embodiments, optionally in combination with the
various embodiments above, the second layer comprises a drug
selected from the group consisting of are paclitaxel, docetaxel,
estradiol, 17-beta-estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), zotarolimus, novolimus, myolimus, temsirolimus,
deforolimus, .gamma.-hiridun, clobetasol, pimecrolimus, imatinib
mesylate, midostaurin, feno fibrate, prodrugs thereof, co-drugs
thereof, and combinations thereof.
[0016] In another aspect, the present invention provides a method
of fabricating an implantable device. The method comprises: [0017]
forming a primer layer on surface of an implantable device
comprising a high molecular weight (HMW) or very high molecular
weight (VHMW) absorbable polymer; and [0018] forming a second layer
comprising a low molecular weight (LMW) absorbable polymer, thereby
forming the coating, wherein the first molecular weight is higher
than the second molecular weight, [0019] wherein the coating is
completely or substantially completely absorbed upon implantation
in a human body within a period from about 3 months to about 6
months.
[0020] In some embodiments, the primer layer comprises a high or
very high molecular weight (HMW or VHMW) absorbable polymer.
Examples of such
[0021] HMW or VHMW absorbable polymer are PLLA, 85/15 PLGA, 75/25
PLGA, poly(ester amide), PLA-PCL-GA terpolymer, PCL-GA, and
copolymers thereof.
[0022] In some embodiments, optionally in combination with the
various embodiments above, the second layer comprises a low
molecular weight (LMW) absorbable polymer. An example of the LMW
absorbable polymer is LMW D,L-PLA.
[0023] In some embodiments, optionally in combination with the
various embodiments above, the second layer comprises a drug.
[0024] In some embodiments, optionally in combination with the
various embodiments above, the second layer does not comprise a
drug and is formed on top of a layer of a drug on top of the primer
layer.
[0025] In some embodiments, optionally in combination with the
various embodiments above, the coating disclosed herein is
micro-porous and is formed by a process of controlled phase
inversion kinetics, wherein the second layer and/or the primer
layer can include D,L-PLA.
[0026] In some embodiments, optionally in combination with the
various embodiments above, the implantable device is a stent.
[0027] In some embodiments, optionally in combination with the
various embodiments above, the second layer comprises a drug
selected from the group consisting of are paclitaxel, docetaxel,
estradiol, 17-beta-estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), zotarolimus, novolimus, myolimus, temsirolimus,
deforolimus, .gamma.-hiridun, clobetasol, pimecrolimus, imatinib
mesylate, midostaurin, feno fibrate, prodrugs thereof, co-drugs
thereof, and combinations thereof.
[0028] In some embodiments, optionally in combination with the
various embodiments above, the method further comprises enhancing
the degradation rate of the coating, which enhancing degradation
rate can be, for example, decreasing the molecular weight of the
bioabsorbable polymer in the first and/or second post coating prior
to deployment of the implantable device, or enhancing the rate of
hydrolysis of the bioabsorbable polymer in the first and/or second
layer.
[0029] In some embodiments, optionally in combination with the
various embodiments above, enhancing the degradation rate of the
coating comprises a step selected from: [0030] i) prolonged
e-beaming, multiple e-beaming post coating, e-beaming at a lower
dose rate for a total longer time under the beam, or e-beaming at
room temperature; [0031] ii) higher temperature treatment of a
coated implantable device for longer time drying in a high humidity
environment prior to vacuum/conventional drying; [0032] iii)
decreasing the BHT content in the coating if the coating comprises
BHT; [0033] iv) adding lactide monomers and/or oligomers in the
coating; [0034] v) adding-COOH terminated oligomers of D,L-PLA in
the coating; [0035] vi) sterilization by gamma radiation at the
same dose (i.e. 31 kGy) as would be used for e-beam; [0036] vii)
adding in the coating a plasticizer selected from ethyl lactate,
DMSO, NMP, and benzyl benzoate so as to lower the glass transition
temperature (T.sub.g) of the coating to accelerate degradation;
[0037] viii) adding a hygroscopic additive in a coating; [0038] ix)
adding micronized NaO.sub.2 or KO.sub.2, or superoxide salts in the
coating; [0039] x) adding more stannous octoate to bring its level
up to the maximum level allowed by the material specification;
[0040] xi) adding LMW D,L-PLA with a MW tuned to degrade within 3
to 6 months; [0041] xii) forming micro-porous D,L-PLA coating by a
process of controlled phase inversion kinetics; and [0042] xiii)
any combination of step i)-xii).
[0043] In a still further aspect of the present invention, it is
provided a method of treating, preventing, or ameliorating a
vascular medical condition, comprising implanting in a patient an
implantable medical comprising any of the implantable article
described above. The vascular medical condition can be restenosis,
atherosclerosis, thrombosis, 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,
tumor obstruction, or combinations of these.
DETAILED DESCRIPTION
[0044] In one aspect, the present invention provides a
bioabsorbable coating on an implantable medical device. The coating
has an absorption period from about three months to about six
months during which the coating is completely or substantially
completely absorbed upon implantation in a human body. The coating
comprises a primer layer on surface of the implantable device
comprising a bioabsorbable polymer having a first molecular weight
and a second layer comprising a bioabsorbable polymer of a second
molecular weight, where the first molecular weight is higher than
the second molecular weight. In some embodiments, the coating
comprises a primer layer comprising a high or very high molecular
weight (HMW or VHMW) absorbable polymer; and a second layer
comprising a low molecular weight (LMW) absorbable polymer. The
second layer can be a topcoat on top of a layer of a drug or a
matrix layer where the matrix layer may or may not include a drug.
In some embodiments, the matrix layer can include a drug.
[0045] In a second aspect, the present invention provides a method
of fabricating an implantable device. The method comprises
providing an implantable device and forming a coating on the
implantable device. The coating has an absorption period from about
three months to about six months during which the coating is
completely or substantially completely absorbed upon implantation
in a human body. The coating comprises a primer layer on surface of
the implantable device comprising a bioabsorbable polymer having a
first molecular weight and a second layer comprising a
bioabsorbable polymer of a second molecular weight, where the first
molecular weight is higher than the second molecular weight. In
some embodiments, forming a coating comprises: a) forming a primer
layer on surface of the implantable device comprising a HMW or VHMW
absorbable polymer; b) forming a second layer comprising a LMW
absorbable polymer, thereby forming the coating. The second layer
can be a topcoat on top of a layer of a drug or a matrix layer
where the matrix layer may or may not include a drug. In some
embodiments, the matrix layer can include a drug.
[0046] Suitable HMW absorbable polymer as primer generally has high
elongation.
[0047] Examples of such HMW absorbable polymers include, e.g., VHMW
PLLA, 85/15 PLGA, UMW or VHMW 75/25 PLGA, HMW or VHMW poly(ester
amide) (elastomeric), HMW or VHMW PLA-PCL-GA terpolymer, UMW or
VHMW PCL-GA, or copolymers thereof.
[0048] Additional examples include poly(.beta.-hydroxybutyrate)
(PHB), copolymers of 3-hydroxybutyrate (3HB) and 3-hyroxyvalerate
(3HV), random copolymers of 3HB and 4HV, polycarbonates,
polyanhydrides, poly(phosphate esters), polyphosphazenes, and
poly(orthoesters).
[0049] As used herein, the term HMW refers to a molecular weight
about 60,000 Daltons and below about 200,000 Daltons. The term VHMW
refers to a molecular weight about 200,000 Daltons or above.
Conversely, the term LMW refers to a number average molecular
weight below 60,000 Daltons, e.g., 57,000 Daltons.
[0050] In some embodiments, optionally in combination with any one
or combinations of the above embodiments, the method further
comprises increasing the rate of absorption of the coating
described above by decreasing the molecular weight of the polymer
in the coating. Decreasing the molecular weight of the polymer in
the coating can be achieved by various established methods. Such
methods, which are described in detail below, include, for example,
a prolonged e-beam process post coating to decrease the molecular
weight of the polymer in the coating. In some embodiments, such
method includes, e.g., selecting a commercial polymer of a desired
molecular weight or a commercial absorbable polymer having an acid
end group, and forming the second layer using commercial
polymer.
[0051] In some embodiments, optionally with one or any combination
of features of the various embodiments above, the stent or the
coating further comprises a bioactive agent. Examples of the
bioactive agent are paclitaxel, docetaxel, estradiol,
17-beta-estradiol, nitric oxide donors, super oxide dismutases,
super oxide dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), zotarolimus, myolimus, novolimus, temsirolimus,
deforolimus, .gamma.-hiridun, clobetasol, pimecrolimus, imatinib
mesylate, midostaurin, feno fibrate, prodrugs thereof, co-drugs
thereof, and combinations thereof.
[0052] The implantable article described herein is generally
degradable or bioabsorbable. In some embodiments, the coating can
degrade within about 1 month, 2 months, 3 months, 4 months, or 6
months after implantation of an implantable device comprising the
coating.
[0053] In some embodiments, the implantable article (e.g., an
implantable medical device or a coating on an implantable medical
device such as stent) can include one or more other biocompatible
polymers, which are described below.
[0054] The implantable device described herein, such as a stent,
can be implanted in a patient to treat, prevent, mitigate, or
reduce a vascular medical condition, or to provide a pro-healing
effect. In some embodiments, the vascular medical condition or
vascular condition is a coronary artery disease (CAD) and/or a
peripheral vascular disease (PVD). Some examples of such vascular
medical diseases are restenosis and/or atherosclerosis. Some other
examples of these conditions include thrombosis, 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, tumor obstruction, or combinations
of these.
Definitions
[0055] Wherever applicable, the definitions to some terms used
throughout the description of the present invention as provided
below shall apply.
[0056] The terms "biologically degradable" (or "biodegradable"),
"biologically erodable" (or "bioerodable"), "biologically
absorbable" (or "bioabsorbable"), and "biologically resorbable" (or
"bioresorbable"), in reference to polymers and coatings, are
sometimes used interchangeably and refer to polymers and coatings
that are capable of being completely or substantially completely
degraded, dissolved, and/or eroded over time when exposed to
physiological conditions and can be gradually resorbed, absorbed
and/or eliminated by the body, or that can be degraded into
fragments that can pass through the kidney membrane of an animal
(e.g., a human), e.g., fragments having a molecular weight of about
40,000 Daltons (40 kDa) or less. The process of breaking down and
eventual absorption and elimination of the polymer or coating can
be caused by, e.g., hydrolysis, metabolic processes, oxidation,
enzymatic processes, bulk or surface erosion, and the like. In some
embodiments, a distinction can be made between bioresorbable and
bioabsorbable where a bioresorbable polymer refers to one whose
degradants the body can use whereas a bioabsorbable polymer refers
to one whose degradants the body eliminates. Conversely, a
"biostable" polymer or coating refers to a polymer or coating that
is not biodegradable.
[0057] Whenever the reference is made to "biologically degradable,"
"biologically erodable," "biologically absorbable," and
"biologically resorbable" stent coatings or polymers forming such
stent coatings, it is understood that after the process of
degradation, erosion, absorption, and/or resorption has been
completed or substantially completed, no coating or substantially
little coating will remain on the stent. Whenever the terms
"degradable," "biodegradable," or "biologically degradable" are
used in this application, they are intended to broadly include
biologically degradable, biologically erodable, biologically
absorbable, and biologically resorbable polymers or coatings.
[0058] As used herein, the term "complete degradation" or
"completely degrade" shall be the state of full degradation or
absorption of the coating. The term "substantially complete
degradation" or "substantially completely degrade" shall mean a
state of degradation where at least 80% of the coating is degraded,
absorbed, or eroded. In some embodiments, "substantially complete
degradation" or "substantially completely degrade" shall mean about
80% to about 99%, about 85% to about 99%, about 90% to about 99%,
or about 95% to about 99% by weight of a coating is degraded,
absorbed, or eroded.
[0059] "Physiological conditions" refer to conditions to which an
implant is exposed within the body of an animal (e.g., a human).
Physiological conditions include, but are not limited to, "normal"
body temperature for that species of animal (approximately
37.degree. C. for a human) and an aqueous environment of
physiologic ionic strength, pH and enzymes. In some cases, the body
temperature of a particular animal may be above or below what would
be considered "normal" body temperature for that species of animal.
For example, the body temperature of a human may be above or below
approximately 37.degree. C. in certain cases. The scope of the
present invention encompasses such cases where the physiological
conditions (e.g., body temperature) of an animal are not considered
"normal."
[0060] As used herein, the term "micro-porous" refers to a coating
micro-scale pores, depots, channels, or cavity. The coating can
have a porosity from about 5% to about 50%, from about 5% to about
40%, from about 10% to about 50%, from about 10% to about 40%, from
about 10% to about 30%, from about 10% to about 20%, from about 20%
to about 50%, from about 20% to about 40%, from about 20% to about
30%, from about 30% to about 50%, from about 30% to about 40%, or
from about 40% to about 50% by volume. Specific examples of
porosity in such a coating can be about 10%, about 20%, about 30%,
about 40%, or about 50% by volume. The higher the porosity, the
higher the rate of water uptake and the higher the equilibrium
water content. This results in an enhanced rate of hydrolysis of
the coating.
[0061] In the context of a blood-contacting implantable device, a
"prohealing" drug or agent refers to a drug or agent that has the
property that it promotes or enhances re-endothelialization
kinetics of arterial lumen to promote healing of the vascular
tissue.
[0062] As used herein, a "co-drug" is a drug that is administered
concurrently or sequentially with another drug to achieve a
particular pharmacological effect. The effect may be general or
specific. The co-drug may exert an effect different from that of
the other drug, or it may promote, enhance or potentiate the effect
of the other drug.
[0063] As used herein, the term "prodrug" refers to an agent
rendered less active by a chemical or biological moiety, which
metabolizes into or undergoes in vivo hydrolysis to form a drug or
an active ingredient thereof. The term "prodrug" can be used
interchangeably with terms such as "proagent", "latentiated drugs",
"bioreversible derivatives", and "congeners". N. J. Harper, Drug
latentiation, Prog Drug Res., 4: 221-294 (1962); E. B. Roche,
Design of Biopharmaceutical Properties through Prodrugs and
Analogs, Washington, D.C.: American Pharmaceutical Association
(1977); A. A. Sinkula and S. H. Yalkowsky, Rationale for design of
biologically reversible drug derivatives: prodrugs, J. Pharm. Sci.,
64: 181-210 (1975). Use of the term "prodrug" usually implies a
covalent link between a drug and a chemical moiety, though some
authors also use it to characterize some forms of salts of the
active drug molecule. Although there is no strict universal
definition of a prodrug itself, and the definition may vary from
author to author, prodrugs can generally be defined as
pharmacologically less active chemical derivatives that can be
converted in vivo, enzymatically or nonenzymatically, to the
active, or more active, drug molecules that exert a therapeutic,
prophylactic or diagnostic effect. Sinkula and Yalkowsky, above; V.
J. Stella et al., Prodrugs: Do they have advantages in clinical
practice?, Drugs, 29: 455-473 (1985).
[0064] The terms "polymer" and "polymeric" refer to compounds that
are the product of a polymerization reaction. These terms are
inclusive of homopolymers (i.e., polymers obtained by polymerizing
one type of monomer), copolymers (i.e., polymers obtained by
polymerizing two or more different types of monomers), terpolymers,
etc., including random, alternating, block, graft, dendritic,
crosslinked and any other variations thereof.
[0065] As used herein, the term "implantable" refers to the
attribute of being implantable in a mammal (e.g., a human being or
patient) that meets the mechanical, physical, chemical, biological,
and pharmacological requirements of a device provided by laws and
regulations of a governmental agency (e.g., the U.S. FDA) such that
the device is safe and effective for use as indicated by the
device. As used herein, an "implantable device" may be any suitable
substrate that can be implanted in a human or non-human animal.
Examples of implantable devices include, but are not limited to,
self-expandable stents, balloon-expandable stents, coronary stents,
peripheral stents, stent-grafts, shunts, catheters, other
expandable tubular devices for various bodily lumen or orifices,
grafts, vascular grafts, arterio-venous grafts, by-pass grafts,
pacemakers and defibrillators, leads and electrodes for the
preceding, artificial heart valves, anastomotic clips, arterial
closure devices, patent foramen ovale closure devices,
cerebrospinal fluid shunts, and particles (e.g., drug-eluting
particles, microparticles and nanoparticles). The stents may be
intended for any vessel in the body, including neurological,
carotid, vein graft, coronary, aortic, renal, iliac, femoral,
popliteal vasculature, and urethral passages. An implantable device
can be designed for the localized delivery of a therapeutic agent.
A medicated implantable device may be constructed in part, e.g., by
coating the device with a coating material containing a therapeutic
agent. The body of the device may also contain a therapeutic
agent.
[0066] An implantable device can be fabricated with a coating
containing partially or completely a
biodegradable/bioabsorbable/bioerodable polymer, a biostable
polymer, or a combination thereof. An implantable device itself can
also be fabricated partially or completely from a
biodegradable/bioabsorbable/bioerodable polymer, a biostable
polymer, or a combination thereof.
[0067] As used herein, a material that is described as a layer or a
film (e.g., a coating) "disposed over" an indicated substrate
(e.g., an implantable device) refers to, e.g., a coating of the
material deposited directly or indirectly over at least a portion
of the surface of the substrate. Direct depositing means that the
coating is applied directly to the exposed surface of the
substrate. Indirect depositing means that the coating is applied to
an intervening layer that has been deposited directly or indirectly
over the substrate. In some embodiments, the term a "layer" or a
"film" excludes a film or a layer formed on a non-implantable
device.
[0068] In the context of a stent, "delivery" refers to introducing
and transporting the stent through a bodily lumen to a region, such
as a lesion, in a vessel that requires treatment. "Deployment"
corresponds to the expanding of the stent within the lumen at the
treatment region. Delivery and deployment of a stent are
accomplished by positioning the stent about one end of a catheter,
inserting the end of the catheter through the skin into a bodily
lumen, advancing the catheter in the bodily lumen to a desired
treatment location, expanding the stent at the treatment location,
and removing the catheter from the lumen.
Decreasing Molecular Weight
[0069] The molecular weight of polymer forming the coating
described herein can be reduced or decreased by various methods.
The molecular weight can be decreased post coating of an
implantable device prior to deployment of the implantable device
(t=0) or after implantation of implantable device, e.g., by
enhanced hydrolysis of the coating. Such methods include, e.g., one
or a combination of the following:
[0070] 1) prolonged e-beaming, multiple e-beaming post coating,
e-beaming at a lower dose rate for a total longer time under the
beam, or e-beaming at room temperature.
[0071] 2) higher temperature treatment (e.g., treatment at
50.degree. C. to 70.degree. C.) of coated device (e.g., stent) for
drying in a high humidity environment prior to vacuum/conventional
drying. As used herein, the term "high humidity environment" refers
to an environment having a degree of humidity higher than the
ambient. [0072] 3) decreasing the BHT content in the coating.
[0073] 4) addition of lactide monomers/oligomers in the coating.
[0074] 5) addition of -COOH terminated oligomers of d,1 PLA. 6)
sterilization by gamma radiation at the same dose (i.e. 31 kGy) as
would be used for e-beam. [0075] 6) addition of other plasticizers
to the coating, e.g., ethyl lactate, DMSO, NMP, benzyl benzoate,
which would lower the glass transition temperature (T.sub.g) of the
coating to accelerate degradation. [0076] 7) addition of a
hygroscopic additive to the coating to increase water adsorption of
D,L-PLA, if present, which hygroscopic additives can be, e.g., low
MW PVP, low MW PEG. A higher water concentration in the coating
increases hydrolysis rate, and the presence of water during
irradiation sterilization will accelerate MW decrease in this step.
Hygroscopic additive could be amphiphilic to allow better
homogenicity. [0077] 8) addition of micronized NaO.sub.2 or
KO.sub.2, or superoxide salts. These compounds are insoluble in
organics but will cleave ester bonds quite actively when hydrated
so as to decrease MW of the polymer in the coating. [0078] 9)
addition of more stannous octoate to bring its level up to the
maximum level allowed by the material specification. Stannous
octate will increase MW drop during extrusion, e-beam
sterilization, and in-vivo deployment. [0079] 10) addition of LMW
D,L-PLA with a MW tuned to degrade within 3 to 6 months. Generally,
such a LMW D,L-PLA would not form a coating of integrity. A primer
formed of a HMW or VHMW resorbable polymer would make such a
deficiency of the LMW D,L-PLA to allow forming a coating using such
a LMW D,L-PLA. LMW D,L-PLA that degrades within 3 to 6 months
generally have a molecular weight of below 60,000 Da. [0080] 11)
forming micro-porous D,L-PLA coating by a process of controlled
phase inversion kinetics. Such a micro-porous D,L-PLA coating
allows for enhanced water uptake so as to increase hydrolysis of
the coating. Phase inversion is within the general knowledge in the
art since it is a commercially available process (used to fabricate
membrane filters).
Biologically Active Agents
[0081] In some embodiments, the implantable device described herein
can optionally include at least one biologically active
("bioactive") agent. The at least one bioactive agent can include
any substance capable of exerting a therapeutic, prophylactic or
diagnostic effect for a patient.
[0082] Examples of suitable bioactive agents include, but are not
limited to, synthetic inorganic and organic compounds, proteins and
peptides, polysaccharides and other sugars, lipids, and DNA and RNA
nucleic acid sequences having therapeutic, prophylactic or
diagnostic activities. Nucleic acid sequences include genes,
antisense molecules that bind to complementary DNA to inhibit
transcription, and ribozymes. Some other examples of other
bioactive agents include 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 such as antisense oligonucleotides and ribozymes
and retroviral vectors for use in gene therapy. The bioactive
agents could be designed, e.g., to inhibit the activity of vascular
smooth muscle cells. They could be directed at inhibiting abnormal
or inappropriate migration and/or proliferation of smooth muscle
cells to inhibit restenosis.
[0083] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the implantable device
can include at least one biologically active agent selected from
antiproliferative, antineoplastic, antimitotic, anti-inflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic,
antiallergic and antioxidant substances.
[0084] An antiproliferative agent can be a natural proteineous
agent such as a cytotoxin or a synthetic molecule. Examples of
antiproliferative substances include, but are not limited to,
actinomycin D or derivatives and analogs thereof (manufactured by
Sigma-Aldrich, or COSMEGEN available from Merck) (synonyms of
actinomycin D include dactinomycin, actinomycin IV, actinomycin
I.sub.1, actinomycin X.sub.1, and actinomycin C.sub.1); all taxoids
such as taxols, docetaxel, and paclitaxel and derivatives thereof;
all olimus drugs such as macrolide antibiotics, rapamycin,
everolimus, structural derivatives and functional analogues of
rapamycin, structural derivatives and functional analogues of
everolimus, FKBP-12 mediated mTOR inhibitors, biolimus,
perfenidone, prodrugs thereof, co-drugs thereof, and combinations
thereof. Examples of rapamycin derivatives include, but are not
limited to, 40-O-(2-hydroxy)ethyl-rapamycin (trade name everolimus
from Novartis), 40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus, manufactured by Abbott Labs.), ABT-578, novolimus,
myolimus, deforolimus, temsirolimus, prodrugs thereof, co-drugs
thereof, and combinations thereof. An anti-inflammatory drug can be
a steroidal anti-inflammatory drug, a nonsteroidal
anti-inflammatory drug (NSAID), or a combination thereof. Examples
of anti-inflammatory drugs include, but are not limited to,
alclofenac, alclometasone dipropionate, algestone acetonide, 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, clobetasol, clobetasol
propionate, clobetasone butyrate, clopirac, cloticasone propionate,
cormethasone acetate, cortodoxone, deflazacort, desonide,
desoximetasone, dexamethasone, dexamethasone acetate, dexamethasone
dipropionate, diclofenac potassium, diclofenac sodium, diflorasone
diacetate, 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,
halcinonide, halobetasol propionate, 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), salicylic acid, corticosteroids,
glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof,
co-drugs thereof, and combinations thereof.
[0085] Alternatively, the anti-inflammatory agent can be a
biological inhibitor of pro-inflammatory signaling molecules.
Anti-inflammatory biological agents include antibodies to such
biological inflammatory signaling molecules.
[0086] In addition, the bioactive agents can be other than
antiproliferative or anti-inflammatory agents. The bioactive agents
can be any agent that is a therapeutic, prophylactic or diagnostic
agent. In some embodiments, such agents can be used in combination
with antiproliferative or anti-inflammatory agents. These bioactive
agents can also have antiproliferative and/or anti-inflammatory
properties or can have other properties such as antineoplastic,
antimitotic, cystostatic, antiplatelet, anticoagulant, antifibrin,
antithrombin, antibiotic, antiallergic, and/or antioxidant
properties.
[0087] Examples of antineoplastics and/or antimitotics include, but
are not limited to, paclitaxel (e.g., TAXOL.RTM. available from
Bristol-Myers Squibb), docetaxel (e.g., Taxotere.RTM. from
Aventis), methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin.RTM. from
Pfizer), and mitomycin (e.g., Mutamycin.RTM. from Bristol-Myers
Squibb).
[0088] Examples of antiplatelet, anticoagulant, antifibrin, and
antithrombin agents that can also have cytostatic or
antiproliferative properties include, but are not limited to,
sodium heparin, low molecular weight heparins, heparinoids,
hirudin, argatroban, forskolin, vapiprost, prostacyclin and
prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist antibody, recombinant
hirudin, thrombin inhibitors such as ANGIOMAX (from Biogen),
calcium channel blockers (e.g., nifedipine), colchicine, fibroblast
growth factor (FGF) antagonists, fish oil (e.g., omega 3-fatty
acid), histamine antagonists, lovastatin (a cholesterol-lowering
drug that inhibits HMG-CoA reductase, brand name Mevacor.RTM. from
Merck), monoclonal antibodies (e.g., 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
mimetics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), estradiol, anticancer agents, dietary supplements
such as various vitamins, and a combination thereof.
[0089] Examples of cytostatic substances include, but are not
limited to, angiopeptin, angiotensin converting enzyme inhibitors
such as captopril (e.g., Capoten.RTM. and Capozide.RTM. from
Bristol-Myers Squibb), cilazapril and lisinopril (e.g.,
Prinivil.RTM. and Prinzide.RTM. from Merck).
[0090] Examples of antiallergic agents include, but are not limited
to, permirolast potassium. Examples of antioxidant substances
include, but are not limited to,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO). Other
bioactive agents include anti-infectives such as antiviral agents;
analgesics and analgesic combinations; 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 and beta-blockers such as pindolol and
antiarrhythmics; antihypertensives; diuretics; vasodilators
including general coronary vasodilators; peripheral and cerebral
vasodilators; central nervous system stimulants; cough and cold
preparations, including decongestants; hypnotics;
immunosuppressives; muscle relaxants; parasympatholytics;
psychostimulants; sedatives; tranquilizers; naturally derived or
genetically engineered lipoproteins; and restenoic reducing
agents.
[0091] Other biologically active agents that can be used include
alpha-interferon, genetically engineered epithelial cells,
tacrolimus and dexamethasone.
[0092] A "prohealing" drug or agent, in the context of a
blood-contacting implantable device, refers to a drug or agent that
has the property that it promotes or enhances re-endothelialization
of arterial lumen to promote healing of the vascular tissue. The
portion(s) of an implantable device (e.g., a stent) containing a
prohealing drug or agent can attract, bind and eventually become
encapsulated by endothelial cells (e.g., endothelial progenitor
cells). The attraction, binding, and encapsulation of the cells
will reduce or prevent the formation of emboli or thrombi due to
the loss of the mechanical properties that could occur if the stent
was insufficiently encapsulated. The enhanced re-endothelialization
can promote the endothelialization at a rate faster than the loss
of mechanical properties of the stent.
[0093] The prohealing drug or agent can be dispersed in the body of
the bioabsorbable polymer substrate or scaffolding. The prohealing
drug or agent can also be dispersed within a bioabsorbable polymer
coating over a surface of an implantable device (e.g., a
stent).
[0094] "Endothelial progenitor cells" refer to primitive cells made
in the bone marrow that can enter the bloodstream and go to areas
of blood vessel injury to help repair the damage. Endothelial
progenitor cells circulate in adult human peripheral blood and are
mobilized from bone marrow by cytokines, growth factors, and
ischemic conditions. Vascular injury is repaired by both
angiogenesis and vasculogenesis mechanisms. Circulating endothelial
progenitor cells contribute to repair of injured blood vessels
mainly via a vasculogenesis mechanism.
[0095] In some embodiments, the prohealing drug or agent can be an
endothelial cell (EDC)-binding agent. In certain embodiments, the
EDC-binding agent can be a protein, peptide or antibody, which can
be, e.g., one of collagen type 1, a 23 peptide fragment known as
single chain Fv fragment (scFv A5), a junction membrane protein
vascular endothelial (VE)-cadherin, and combinations thereof.
Collagen type 1, when bound to osteopontin, has been shown to
promote adhesion of endothelial cells and modulate their viability
by the down regulation of apoptotic pathways. S. M. Martin, et al.,
J. Biomed. Mater. Res., 70A:10-19 (2004). Endothelial cells can be
selectively targeted (for the targeted delivery of immunoliposomes)
using scFv A5. T. Volkel, et al., Biochimica et Biophysica Acta,
1663:158-166 (2004). Junction membrane protein vascular endothelial
(VE)-cadherin has been shown to bind to endothelial cells and down
regulate apoptosis of the endothelial cells. R. Spagnuolo, et al.,
Blood, 103:3005-3012 (2004).
[0096] In a particular embodiment, the EDC-binding agent can be the
active fragment of osteopontin,
(Asp-Val-Asp-Val-Pro-Asp-Gly-Asp-Ser-Leu-Ala-Try-Gly). Other
EDC-binding agents include, but are not limited to, EPC (epithelial
cell) antibodies, RGD peptide sequences, RGD mimetics, and
combinations thereof.
[0097] In further embodiments, the prohealing drug or agent can be
a substance or agent that attracts and binds endothelial progenitor
cells. Representative substances or agents that attract and bind
endothelial progenitor cells include antibodies such as CD-34,
CD-133 and vegf type 2 receptor. An agent that attracts and binds
endothelial progenitor cells can include a polymer having nitric
oxide donor groups.
[0098] The foregoing biologically active agents are listed by way
of example and are not meant to be limiting. Other biologically
active agents that are currently available or that may be developed
in the future are equally applicable.
[0099] In a more specific embodiment, optionally in combination
with one or more other embodiments described herein, the
implantable device of the invention comprises at least one
biologically active agent selected from paclitaxel, docetaxel,
estradiol, nitric oxide donors, super oxide dismutases, super oxide
dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), ABT-578, novolimus, myolimus, temsirolimus,
deforolimus, pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, progenitor cell-capturing antibodies, prohealing drugs,
prodrugs thereof, co-drugs thereof, and a combination thereof. In a
particular embodiment, the bioactive agent is everolimus. In
another specific embodiment, the bioactive agent is dexamethasone
acetate.
[0100] An alternative class of drugs would be
p-para-.alpha.-agonists for increased lipid transportation,
examples include fenofibrate.
[0101] In some embodiments, optionally in combination with one or
more other embodiments described herein, the at least one
biologically active agent specifically cannot be one or more of any
of the bioactive drugs or agents described herein.
Coating Construct
[0102] According to some embodiments of the invention, optionally
in combination with one or more other embodiments described herein,
a coating disposed over an implantable device (e.g., a stent) can
have a construct of any design. The coating can be a multi-layer
structure that includes at least one primer layer described herein,
which is layer (1) described below, and at least one reservoir
layer, which is layer (2) described below, and can include any of
the following (3), (4) and (5) layers or combination thereof:
[0103] (1) a primer layer; [0104] (2) a reservoir layer (also
referred to "matrix layer" or "drug matrix"), which can be a
drug-polymer layer including at least one polymer (drug-polymer
layer) or, alternatively, a polymer-free drug layer; [0105] (3) a
release control layer (also referred to as a "rate-limiting
layer"); [0106] (4) a topcoat layer; and/or [0107] (5) a finishing
coat layer which is present to modulate the biological response the
coating
[0108] In some embodiments, a coating of the invention can include
two or more reservoir layers described above, each of which can
include a bioactive agent described herein.
[0109] Each layer of a coating can be disposed over the implantable
device (e.g., a stent) by dissolving the inventive polymer mixture
or block copolymer, optionally with one or more other polymers, in
a solvent, or a mixture of solvents, and disposing the resulting
coating solution over the stent by spraying or immersing the stent
in the solution. After the solution has been disposed over the
stent, the coating is dried by allowing the solvent to evaporate.
The process of drying can be accelerated if the drying is conducted
at an elevated temperature. The complete stent coating can be
optionally annealed at a temperature between about 40.degree. C.
and about 150.degree. C. for a period of time between about 5
minutes and about 60 minutes, if desired, to allow for
crystallization of the polymer coating, to finish physical aging of
the polymer, and/or to improve the thermodynamic stability of the
coating.
[0110] To incorporate a bioactive agent (e.g., a drug) into the
reservoir layer, the drug can be combined with the polymer solution
that is disposed over the implantable device as described above.
Alternatively, if it is desirable a polymer-free reservoir can be
made. To fabricate a polymer-free reservoir, the drug can be
dissolved in a suitable solvent or mixture of solvents, and the
resulting drug solution can be disposed over the implantable device
(e.g., stent) by spraying or immersing the stent in the
drug-containing solution.
[0111] Instead of introducing a drug via a solution, the drug can
be introduced as a colloid system, such as a suspension in an
appropriate solvent phase. To make the suspension, the drug can be
dispersed in the solvent phase using conventional techniques used
in colloid chemistry. Depending on a variety of factors, e.g., the
nature of the drug, those having ordinary skill in the art can
select the solvent to form the solvent phase of the suspension, as
well as the quantity of the drug to be dispersed in the solvent
phase. Optionally, a surfactant can be added to stabilize the
suspension. The suspension can be mixed with a polymer solution and
the mixture can be disposed over the stent as described above.
Alternatively, the drug suspension can be disposed over the stent
without being mixed with the polymer solution.
[0112] The drug-polymer layer can be applied indirectly over at
least a portion of the stent surface to serve as a reservoir for at
least one bioactive agent (e.g., drug) that is incorporated into
the reservoir layer over at least a portion of the primer layer.
The primer layer can be applied between the stent and the reservoir
to improve the adhesion of the drug-polymer layer to the stent. The
optional topcoat layer can be applied over at least a portion of
the reservoir layer and serves as a rate-limiting membrane that
helps to control the rate of release of the drug. In one
embodiment, the topcoat layer can be essentially free from any
bioactive agents or drugs. If the topcoat layer is used, the
optional finishing coat layer can be applied over at least a
portion of the topcoat layer for further control of the
drug-release rate and for improving the biocompatibility of the
coating. Without the topcoat layer, the finishing coat layer can be
deposited directly on the reservoir layer.
[0113] Sterilization of a coated medical device generally involves
a process for inactivation of micropathogens. Such processes are
well known in the art. A few examples are e-beam, ETO
sterilization, autoclaving, and gamma irradiation. Some of these
processes can involve an elevated temperature or can be performed
cold below room temperature. For example, ETO sterilization of a
coated stent generally involves heating above 50.degree. C. at
humidity levels reaching up to 100% for periods of a few hours up
to 24 hours. A typical ETO cycle would have the temperature in the
enclosed chamber to reach as high as above 50.degree. C. within the
first 3-4 hours then and fluctuate between 40.degree. C. to
50.degree. C. for 17-18 hours while the humidity would reach the
peak at 100% and maintain above 80% during the fluctuation time of
the cycle.
[0114] If neither a finishing coat layer nor a topcoat layer is
used, the stent coating could have only two layers--the primer and
the reservoir.
[0115] Any layer of a coating, except for the primer layer, can
contain any amount of bioresorbable, erodible or biodissolvable
polymers. Non-limiting examples of such polymers include
bioabsorbable polymers and biocompatible polymers include
poly(N-vinyl pyrrolidone); polydioxanone; polyorthoesters;
polyanhydrides; poly(glycolic acid); poly(glycolic
acid-co-trimethylene carbonate); polyphosphoesters;
polyphosphoester urethanes; poly(amino acids); poly(trimethylene
carbonate); poly(iminocarbonates); co-poly(ether-esters);
polyalkylene oxalates; polyphosphazenes; biomolecules, e.g.,
fibrin, fibrinogen, cellulose, cellophane, starch, collagen,
hyaluronic acid, and derivatives thereof (e.g., cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellulose nitrate,
cellulose propionate, cellulose ethers, and carboxymethyl
cellulose), polyurethane, polyesters, polycarbonates,
polyurethanes, poly(L-lactic acid-co-caprolactone) (PLLA-CL),
poly(D-lactic acid-co-caprolactone) (PDLA-CL), poly(DL-lactic
acid-co-caprolactone) (PDLLA-CL), poly(D-lactic acid-glycolic acid
(PDLA-GA), poly(L-lactic acid-glycolic acid (PLLA-GA),
poly(DL-lactic acid-glycolic acid (PDLLA-GA), poly(L-lactic
acid-co-caprolactone) (PLLA-CL), poly(D-lactic
acid-co-caprolactone) (PDLA-CL), poly(DL-lactic
acid-co-caprolactone) (PDLLA-CL), poly(glycolide-co-caprolactone)
(PGA-CL), or any copolymers thereof.
Method of Fabricating Implantable Device
[0116] Other embodiments of the invention, optionally in
combination with one or more other embodiments described herein,
are drawn to a method of fabricating an implantable device. In one
embodiment, the method comprises forming the implantable device of
a material containing a biodegradable polymer or copolymer.
[0117] Under the method, a portion of the implantable device or the
whole device itself can be formed of the material containing a
biodegradable polymer or copolymer. The method can deposit a
coating having a range of thickness over an implantable device. In
certain embodiments, the method deposits over at least a portion of
the implantable device a coating that has a thickness of
.ltoreq.about 30 microns, or .ltoreq.about 20 microns, or
.ltoreq.about 10 microns, or .ltoreq.about 5 microns.
[0118] In certain embodiments, the method is used to fabricate an
implantable device selected from stents, grafts, stent-grafts,
catheters, leads and electrodes, clips, shunts, closure devices,
valves, and particles. In a specific embodiment, the method is used
to fabricate a stent.
[0119] In some embodiments, to form an implantable device formed
from a polymer, a polymer or copolymer optionally including at
least one bioactive agent described herein can be formed into a
polymer construct, such as a tube or sheet that can be rolled or
bonded to form a construct such as a tube. An implantable device
can then be fabricated from the construct. For example, a stent can
be fabricated from a tube by laser machining a pattern into the
tube. In another embodiment, a polymer construct can be formed from
the polymeric material of the invention using an injection-molding
apparatus. In yet another embodiment, a bioabsorbable implant can
be fabricated by weaving fibers of bioabsorbable materials.
[0120] Non-limiting examples of polymers that can be used to
fabricate an implantable device include poly(N-acetylglucosamine)
(Chitin), Chitosan, poly(hydroxyvalerate),
poly(lactide-co-glycolide), poly(hydroxybutyrate),
poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,
poly(L-lactic acid-co-caprolactone) (PLLA-CL), poly(D-lactic
acid-co-caprolactone) (PDLA-CL), poly(DL-lactic
acid-co-caprolactone) (PDLLA-CL), poly(D-lactic acid-glycolic acid
(PDLA-GA), poly(L-lactic acid-glycolic acid) (PLLA-GA),
poly(DL-lactic acid-glycolic acid (PDLLA-GA), poly(L-lactic
acid-co-caprolactone) (PLLA-CL), poly(D-lactic
acid-co-caprolactone) (PDLA-CL), poly(DL-lactic
acid-co-caprolactone) (PDLLA-CL), poly(glycolide-co-caprolactone)
(PGA-CL), poly(thioesters), poly(trimethylene carbonate),
polyethylene amide, polyethylene acrylate, poly(glycolic
acid-co-trimethylene carbonate), co-poly(ether-esters) (e.g.,
PEO/PLA), polyphosphazenes, biomolecules (e.g., fibrin, fibrinogen,
cellulose, starch, collagen and hyaluronic acid), polyurethanes,
silicones, polyesters, polyolefins, polyisobutylene and
ethylene-alphaolefin copolymers, acrylic polymers and copolymers
other than polyacrylates, vinyl halide polymers and copolymers
(e.g., polyvinyl chloride), polyvinyl ethers (e.g., polyvinyl
methyl ether), polyvinylidene halides (e.g., polyvinylidene
chloride), poly(vinylidene fluoride), poly(vinylidene
fluoride-co-hexafluoropropylene), polyacrylonitrile, polyvinyl
ketones, polyvinyl aromatics (e.g., polystyrene), polyvinyl esters
(e.g., polyvinyl acetate), acrylonitrile-styrene copolymers, ABS
resins, polyamides (e.g., Nylon 66 and polycaprolactam),
polycarbonates, polyoxymethylenes, polyimides, polyethers,
polyurethanes, rayon, rayon-triacetate, cellulose and derivates
thereof (e.g., cellulose acetate, cellulose butyrate, cellulose
acetate butyrate, cellophane, cellulose nitrate, cellulose
propionate, cellulose ethers, and carboxymethyl cellulose), and
copolymers thereof.
Method of Treating or Preventing Disorders
[0121] An implantable device according to the present invention can
be used to treat, prevent or diagnose various conditions or
disorders. Examples of such conditions or disorders include, but
are not limited to, atherosclerosis, thrombosis, restenosis,
hemorrhage, vascular dissection, vascular perforation, vascular
aneurysm, vulnerable plaque, chronic total occlusion, patent
foramen ovale, claudication, anastomotic proliferation of vein and
artificial grafts, arteriovenous anastamoses, bile duct
obstruction, ureter obstruction and tumor obstruction. A portion of
the implantable device or the whole device itself can be formed of
the material, as described herein. For example, the material can be
a coating disposed over at least a portion of the device.
[0122] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the inventive method
treats, prevents or diagnoses a condition or disorder selected from
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection, vascular perforation, vascular aneurysm, vulnerable
plaque, chronic total occlusion, patent foramen ovale,
claudication, anastomotic proliferation of vein and artificial
grafts, arteriovenous anastamoses, bile duct obstruction, ureter
obstruction and tumor obstruction. In a particular embodiment, the
condition or disorder is atherosclerosis, thrombosis, restenosis or
vulnerable plaque.
[0123] In one embodiment of the method, optionally in combination
with one or more other embodiments described herein, the
implantable device is formed of a material or includes a coating
containing at least one biologically active agent selected from
paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), ABT-578, novolimus, myolimus, temsirolimus,
deforolimus, pimecrolimus, imatinib mesylate, midostaurin,
clobetasol, progenitor cell-capturing antibodies, prohealing drugs,
fenofibrate, prodrugs thereof, co-drugs thereof, and a combination
thereof.
[0124] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the implantable device
used in the method is selected from stents, grafts, stent-grafts,
catheters, leads and electrodes, clips, shunts, closure devices,
valves, and particles. In a specific embodiment, the implantable
device is a stent.
[0125] 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 claims are to encompass within their scope all such changes and
modifications as fall within the true sprit and scope of this
invention.
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