U.S. patent application number 14/580101 was filed with the patent office on 2015-06-25 for block copolymer comprising at least one polyester block and at least one poly(ethylene glycol) block.
The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Syed F. A. Hossainy, Michael H. Ngo, David J. Sherman, O. Mikael Trollsas.
Application Number | 20150174300 14/580101 |
Document ID | / |
Family ID | 40886622 |
Filed Date | 2015-06-25 |
United States Patent
Application |
20150174300 |
Kind Code |
A1 |
Trollsas; O. Mikael ; et
al. |
June 25, 2015 |
Block Copolymer Comprising at least one Polyester Block and at
least one Poly(ethylene glycol) Block
Abstract
The present invention provides a block copolymer for a coating
on an implantable device for controlling release of drug and
methods of making and using the same.
Inventors: |
Trollsas; O. Mikael; (San
Jose, CA) ; Ngo; Michael H.; (San Jose, CA) ;
Hossainy; Syed F. A.; (Hayward, CA) ; Sherman; David
J.; (Tarzana, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
40886622 |
Appl. No.: |
14/580101 |
Filed: |
December 22, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12106212 |
Apr 18, 2008 |
8916188 |
|
|
14580101 |
|
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Current U.S.
Class: |
424/423 ;
424/94.4; 514/180; 514/21.1; 514/252.18; 514/772.1; 523/113;
525/450 |
Current CPC
Class: |
A61L 31/16 20130101;
A61P 7/02 20180101; A61P 1/16 20180101; A61L 31/148 20130101; A61L
2300/416 20130101; A61L 31/10 20130101; A61P 9/00 20180101; A61P
35/00 20180101; A61L 31/06 20130101; A61L 31/10 20130101; A61P 9/10
20180101; C08L 71/02 20130101; C08L 67/04 20130101; C08L 71/02
20130101; C08L 67/04 20130101; A61L 31/06 20130101; A61L 31/06
20130101; A61L 31/047 20130101; A61L 2300/606 20130101; A61P 13/02
20180101; A61L 31/10 20130101 |
International
Class: |
A61L 31/10 20060101
A61L031/10; A61L 31/14 20060101 A61L031/14; A61L 31/06 20060101
A61L031/06; A61L 31/16 20060101 A61L031/16; A61L 31/04 20060101
A61L031/04 |
Claims
1. An implantable device, comprising a block copolymer, the block
copolymer comprising at least one polyester block and at least one
poly(ethylene glycol) (PEG) block, wherein: the PEG block has a
weight average molecular weight (M.sub.w) from about 1,000 Daltons
to about 30,000 Daltons, the block copolymer is biosoluble, and
upon exposure to a physiological environment, 80% mass of the block
copolymer will dissolve in a period of about 1 day to about 90
days.
2. The implantable device of claim 1, wherein the polyester block
comprises glycolide.
3. The implantable device of claim 1, wherein the polyester block
comprises lactide.
4. The implantable device of claim 1, wherein the lactide comprises
D,L-lactide, L-lactide, D-lactide, meso-lactide or combinations
thereof
5. The implantable device of claim 3, wherein the block copolymer
forms a coating on the implantable device, the coating comprising a
semi-crystalline morphology, and wherein the lactide in the
polyester block has a molar concentration of at least 60%.
6. The implantable device of claim 5, wherein the lactide in the
polyester block has a molar concentration of at least 80%.
7. The implantable device of claim 2, wherein the glycolide in the
polyester block has a molar concentration of between about 10% and
about 75%.
8. The implantable device of claim 1, wherein the block copolymer
comprises biodegradable side blocks.
9. The implantable device of claim 8, wherein the side blocks are
selected from the group consisting of polyanhydrides, poly(ester
amides), polythioesters, and combinations thereof
10. The implantable device of claim 1, wherein the polyester block
comprises units from caprolactone.
11. The implantable device of claim 1, wherein the block copolymer
is an alternating A-B block copolymer where A is a
poly(lactide-co-glycolide) (PLGA) block and B is the PEG block.
12. The implantable device of claim 1, wherein the block copolymer
is selected from the group consisting of
poly(lactide-co-glycolide-co-caprolactone)-block-PEG-poly(lactide-co-glyc-
olide-co-caprolactone), poly(trimethylene
carbonate-co-glycolide)-block-PEG-block-poly (trimethylene
carbonate-co-glycolide), polylactide-block-PEG-polyactide,
poly(trimethylene
carbonate-co-glycolide)-block-PEG-poly(trimethylene
carbonate-co-glycolide), and combinations thereof
13. The implantable device of claim 1, wherein the block copolymer
has a M.sub.w of about 60,000 Daltons or higher.
14. The implantable device of claim 1, wherein the block copolymer
has a M.sub.w of about 100,000 Daltons or higher.
15. The implantable device of claim 1, wherein the block copolymer
forms a coating on the implantable device.
16. The implantable device of claim 1, wherein the block copolymer
forms at least a portion of the body structure of the implantable
device.
17. The implantable device of claim 15, wherein the coating further
comprises a bioactive agent.
18. The implantable device of claim 17, wherein the bioactive agent
is selected from paclitaxel, docetaxel, estradiol,
17-beta-estradiol, nitric oxide donors, super oxide dismutases,
super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, dexamethasone acetate,
corticosteroids, 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, Biolimus A9 (Biosensors International,
Singapore), AP23572 (Ariad Pharmaceuticals), .gamma.-hiridun,
clobetasol, pimecrolimus, imatinib mesylate, midostaurin, cRGD,
feno fibrate, prodrugs thereof, co-drugs thereof, and combinations
thereof
19. The implantable device of claim 1, which is a stent.
20. The implantable device of claim 1, which is a bioabsorbable
stent.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application is a continuation of co-pending U.S.
patent application Ser. No. 12/106,212, filed on 18 Apr. 2008, and
published as United States pre-grant publication no. US
2009-0263457 A1 on 22 Oct. 2009, which is incorporated by reference
herein in its entirety, expressly including any drawings, and is
incorporated by reference herein for all purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to a block copolymer
comprising at least one polyester block(s) and a poly(ethylene
glycol) block for controlling the release of a drug from a coating
for an implantable device.
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 radial, 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 delivery 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 delivery stents. For example,
release of a drug from a coating formed of an amorphous may often
have a burst release of the drug, resulting in insufficient control
release of the drug.
[0006] Therefore, there is a need for a coating that provides for a
controlled release of a drug in the coating.
[0007] The embodiments of the present invention address the
above-identified needs and issues.
SUMMARY OF THE INVENTION
[0008] In according to one aspect of the present invention, it is
provided an implantable device. The implantable device comprises a
block copolymer that comprises at least one polyester block and at
least one poly(ethylene glycol) (PEG) block. The PEG block has a
weight average molecular weight (M.sub.w) from about 1,000 Daltons
to about 30,000 Daltons. The block copolymer is biosoluble, and
upon exposure to a physiological environment, 80% mass of the block
copolymer will dissolve in a period of about 1 day to about 90
days.
[0009] In some embodiments, the polyester block(s) in the block
copolymer comprises glycolide, lactide, trimethylene carbonate,
caprolactone, or combinations thereof. The lactide can be optically
active or racemic and can be D,L-lactide, L-lactide, D-lactide, or
combinations thereof. The polyester block(s) can have various molar
concentrations of any of these monomers. For example, the polyester
block(s) can have lactide with a molar concentration in the
polyester block(s) of at least 60% or at least 80%. In some
embodiments, the polyester block(s) can have glycolide with a molar
concentration in the polyester block(s) of between about 10% and
about 75%.
[0010] In some embodiments, the block copolymer can comprise
biodegradable side blocks. The side blocks can be any biodegradable
polymer, a few examples of which are polyanhydrides, poly(ester
amides), polythioesters, or combinations thereof.
[0011] In some embodiments, the block copolymer can be an
alternating A-B block copolymer where A is a
poly(lactide-co-glycolide) (PLGA) block and B is the PEG block.
[0012] A few non-limiting examples of the block copolymer are
poly(lactide-co-glycolide-co-caprolactone)-block-PEG-poly
(lactide-co-glycolide-co-caprolactone), poly(trimethylene
carbonate-co-glycolide)-block-PEG-block-poly(trimethylene
carbonate-co-glycolide), polylactide-block-PEG-polyactide,
poly(trimethylene
carbonate-co-glycolide)-block-PEG-poly(trimethylene
carbonate-co-glycolide), and combinations thereof
[0013] The block copolymer of embodiments described above can have
different molecular weights. In some embodiments, the block
copolymer has a weight-average molecular weight (M.sub.w) of about
60,000 Daltons or higher or a M.sub.w of about 100,000 Daltons or
higher.
[0014] The block copolymer of the various embodiments above can
form a coating on the implantable device or at least a portion of
the body structure of the implantable device. In some embodiments,
the coating or the body structure of the implantable device can
further comprise a bioactive agent. Some examples of the bioactive
agent can be paclitaxel, docetaxel, estradiol, 17-beta-estradiol,
nitric oxide donors, super oxide dismutases, super oxide dismutases
mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, dexamethasone
acetate, 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, Biolimus A9 (Biosensors International,
Singapore), AP23572 (Ariad Pharmaceuticals), .gamma.-hiridun,
clobetasol, pimecrolimus, imatinib mesylate, midostaurin, feno
fibrate, prodrugs thereof, co-drugs thereof, and combinations
thereof.
[0015] The implantable device can be any implantable device such as
a stent. The implantable device can be biodurable or bioabsorbable.
In some embodiments, the implantable device is a bioabsorbable
stent.
[0016] In according to a further aspect of the present invention,
it is provided a method of fabricating an implantable medical
device. The method comprises forming a coating on the implantable
device, the coating comprising a block copolymer of the various
embodiments described above. The coating can comprise crystalline,
amorphous, or semi-crystalline morphologies. In some embodiments,
the coating comprises a semi-crystalline morphology where the block
copolymer comprises polyester block(s) having lactide in a molar
concentration of at least 60% or at least 80%.
[0017] The implantable device described herein can be formed on an
implantable device such as a stent, which can be implanted in a
patient to treat, prevent, mitigate, or reduce a vascular medical
condition, or to provide a pro-healing effect.
[0018] 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.
[0019] 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, urethral obstruction, tumor obstruction, or
combinations of these.
DETAILED DESCRIPTION
[0020] The present invention provides a block copolymer comprising
a poly(ethylene glycol) (PEG) block and at least one polyester
block. The block copolymer can form a coating on an implantable
device for controlling the release of a drug from the coating. The
polyester block is hydrophobic, imparting hydrophobicity to the
block copolymer; and the PEG block is hydrophilic, imparting
hydrophilicity to the block copolymer. The block copolymer
generally has a weight-average molecular weight (M.sub.w) of about
60,000 Daltons or higher or, more preferably, about 100,000 Daltons
or higher.
[0021] The polyester block can include any monomers capable of
forming the polyester block. In some embodiments, the polyester
block(s) can include units such as lactide, glycolide,
caprolactone, trimethylene carbonate (TMC), or combinations
thereof. Selection of different monomers for the polyester block(s)
allows one to design the molecular structure of the blocks such
that the drug/polymer interaction parameter can be minimized to
provide for a better control of the drug release. A drug/polymer
interaction parameter is directly and positively related to the
difference between the solubility of drug and polymer. For the drug
to have a controlled release from the polymers, the drug and the
polymer should be miscible, which means their interaction parameter
is equal to zero. The miscibility of the drug and polymer can be
estimated by the Hildebrand solubility parameters, and therefore,
the Hildebrand solubility parameters of the drug and polymer
provide a measurement of the drug/polymer interaction parameter.
For example, to provide a controlled release of everolimus from a
coating formed of a polyester including PLLA and/or PLGA, the
polyester block(s) can be designed to include hydrophobic units
such as caprolactone units; PLLA or PLGA are more hydrophilic
compared to everolimus, and it's desirable to have a more
hydrophobic chain of caprolactone so that the polymer would be more
hydrophobic to be more miscible with drug.
[0022] In some embodiments, the block copolymer comprises at least
one polyester block comprising glycolide and a PEG block. The
glycolide provides an accelerated or enhanced degradation of the
block copolymer. For example, the block copolymer can comprises
polyester blocks derived from lactide and glycolide and a PEG block
where the glycolide monomer imparts enhanced degradation to the
polymer, and the lactide monomer imparts mechanical strength to the
block copolymer. For faster degradation, the polyester blocks
generally have a molar concentration of glycolide between about 10%
and about 75%.
[0023] The block copolymer disclosed herein can have various
absorption rate. For example, the block copolymer can have an
absorption rate that about 80% mass of the block copolymer can
dissolve in a period of about 1 day to about 90 days in a
physiological environment. A coating formed of such a block
copolymer is preferable to be biosoluble. Such biosoluble coatings
will absorb in the blood stream by dissolving mechanism thereby
mitigating side effects caused by smaller molecule by-products,
which can cause inflammation or other adverse reaction to the
vessel wall, produced in the absorption or degradation process of a
polymer in a coating.
[0024] In the block copolymer where the polyester block comprises
lactide monomer, the lactide can be DL-lactide, D-lactide,
L-lactide, or meso-lactide. Such a block copolymer can form a
coating with a semi-crystalline morphology where the L-lactide
molar concentration can be at least 60% of the polyester block(s),
e.g., more than 80% of the polyester block(s).
[0025] The PEG block also imparts biobeneficial properties to the
block copolymer. As used herein, the term "biobeneficial" shall
mean, among others, the attributes of being non-fouling and
inflammation reduction. Such attributes also include biosoluble. As
used herein, the term biosoluble refers to the attribute of being
absorbable in the blood stream by dissolving mechanism.
[0026] In the block copolymer, the M.sub.w of the PEG block
generally can range from about 1K Daltons to about 30K Daltons. In
some embodiments, the M.sub.w of the PEG block can be below 1K
Daltons or above 30K Daltons. However, the molecular weight of the
PEG block shall be small enough (e.g., below about 40,000 Daltons)
such that the block copolymer can degrades into fragments capable
of passing through the kidney membrane. Some exemplary M.sub.w of
the PEG block are 6,000 Daltons, 10,000 Daltons, 20,000 Daltons, or
25,000 Daltons. The block copolymer can have various levels of
PEG.
[0027] In some embodiments, the block copolymer described herein
can include side blocks. To avoid a build up of the polymers in the
kidneys, the side blocks can be designed to be biodegradable. Some
examples of the side blocks are polyanhydrides, poly(ester amide),
polyamino acids, peptides, and/or polythioesters.
[0028] Some examples of the block copolymers are PLGA-PEG-PLGA,
P(LA-GA-CL)-PEG-P(LA-GA-CL), P(TMC-GA)-PEG-P(TMC-GA), PLA-PEG-PLA,
P(TMC-GA)-PEG-P(TMC-GA). As used herein, "LA" is lactide, "GA" is
glycolide, "LGA" is lactide-co-glycolide, "CL" is caprolactone, and
TMC is trimethylene carbonate.
[0029] In some embodiments, the block copolymer can be an
alternating block copolymer. For example, the block copolymer is
A-B alternating block copolymer where the A block is PLGA and the B
block is PEG.
[0030] In some embodiments, the block copolymer can form a coating
that can include one or more bioactive agents, e.g., drug(s). Some
exemplary bioactive agents that can be included in a coating having
a hygroscopic layer described above are paclitaxel, docetaxel,
estradiol, 17-beta-estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-2-oxyl (4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, dexamethasone acetate,
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, Biolimus A9 (Biosensors International,
Singapore), AP23572 (Ariad Pharmaceuticals), .gamma.-hiridun,
clobetasol, pimecrolimus, imatinib mesylate, midostaurin, cRGD,
feno fibrate, prodrugs thereof, co-drugs thereof, and combinations
thereof. Some other examples of the bioactive agent include siRNA
and/or other oligoneucleotides that inhibit endothelial cell
migration. Some further examples of the bioactive agent can also be
lysophosphatidic acid (LPA) or sphingosine-1-phosphate (S1P). LPA
is a "bioactive" phospholipid able to generate growth factor-like
activities in a wide variety of normal and malignant cell types.
LPA plays an important role in normal physiological processes such
as wound healing, and in vascular tone, vascular integrity, or
reproduction. As used herein, in some embodiments, the term "drug"
and the term "bioactive agent" are used interchangeably.
[0031] A coating formed from a block copolymer described herein can
be formed on an implantable device such as a stent, which can be
implanted in a patient to treat, prevent, mitigate, or reduce a
vascular medical condition, or to provide a pro-healing effect.
[0032] 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, urethral obstruction, tumor obstruction, or
combinations of these.
Definitions
[0033] Wherever applicable, the definitions to some terms used
throughout the description of the present invention as provided
below shall apply. 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 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 K Daltons) 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. Conversely, a "biostable" polymer or coating refers
to a durable polymer or coating that is not biodegradable.
[0034] 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.
[0035] "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."
[0036] 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 of
arterial lumen to promote healing of the vascular tissue.
[0037] 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.
[0038] 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).
[0039] Unless otherwise specifically defined, 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 by
either chain or condensation polymers), copolymers (i.e., polymers
obtained by polymerizing two or more different types of monomers by
either chain or condensation polymers), condensation polymers
(polymers made from condensation polymerization, tri-block
copolymers, etc., including random (by either chain or condensation
polymers), alternating (by either chain or condensation polymers),
block (by either chain or condensation polymers), graft, dendritic,
crosslinked and any other variations thereof
[0040] 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, 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.
[0041] 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
[0042] 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.
[0043] 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.
[0044] As used herein, the term "crystalline" refers to having
crystallinity of more than 5% in a tri-block copolymer. In some
embodiments, the term "crystalline" can refer to having
crystallinity of more than about 10%, more than about 20%, more
than about 30%, more than about 40%, more than about 50%, or more
than about 60% in a tri-block copolymer.
[0045] The term "semi-crystalline morphology" refers to having
crystalline domain(s)/region(s) and amorphous domain(s)/region(s)
in a polymer.
[0046] Tri-block copolymers with different contents of these three
monomers have different properties with regard to, e.g., rate of
degradation, mechanical properties, drug permeability, water
permeability, and drug release rate, depending on a particular
composition of the monomers in the tri-block copolymer.
[0047] In some embodiments, the tri-block copolymer can have a
T.sub.g below about 60.degree. C. This tri-block copolymer can have
units derived from D-lactide, L-lactide, or D,L-lactide from about
10% to about 80% by weight. Monomers such as D-lactide, L-lactide,
glycolide, and dioxanone can crystallalize if present in high
concentration in a polymer. However, crystallization of units from
any of these monomers can be minimized or prevented if
concentration of each is below 80% by weight in the polymer.
Therefore, the composition of a tri-block copolymer described
herein shall include units of D-lactide or L-lactide at about
10-80% by weight, units of glycolide at about 5-80% by weight and
units from the third, low T.sub.g monomer at about 5-60% by weight.
The tri-block copolymer can have a weight-average molecular weight
(M.sub.w) of about 10K Daltons or above, preferably from about 20K
Daltons to about 600K Daltons.
[0048] Ratios of units from the lactide, glycolide and the low
T.sub.g monomers can vary, forming a tri-block copolymer having
different properties, e.g., different degradation rates, different
rates of release of a drug from a coating formed of the tri-block
copolymer, different drug permeability, different flexibility or
mechanical properties. As noted above, generally, the glycolide
provides an accelerated or enhanced degradation of the tri-block
copolymer, the lactide monomer provides mechanical strength to the
tri-block copolymer, and the third, low T.sub.g monomer can enhance
drug permeability, water permeability, and enhancing degradation
rate of the polymer, imparting greater flexibility and elongation,
and improving mechanical properties of a coating formed of the
tri-block copolymer.
[0049] In some embodiments, the ratio of the various monomers can
vary along the chain of the tri-block copolymer. In such a
tri-block copolymer, one point of the chain of polymer can be heavy
with one monomer while another point of the chain can be light with
the same monomer, for example. If a monofunctional initiator is
used, and if the selected monomers have highly different reactivity
ratios, then a gradient of composition is generated as the monomers
are consumed during the polymerization. In another methodology,
such a tri-block copolymer can be prepared by so-called gradient
polymerization wherein during the polymerization a first or second
monomer is progressively added to the reactor containing all, or a
portion of, the first monomer. (Matyjaszewski K. and Davis T. P.
eds. Handbook of Radical Polymerization, John Wiley & Sons,
2002, p. 789). Yet a third method is by introducing blocks of
various ratios of the monomers into the chain of the tri-block
copolymer.
[0050] In some embodiments, the block copolymer described herein
can be used to build one or more blocks in combination with other
blocks of biodegradable or biodurable polymers described below.
[0051] Preparation of the block copolymer described herein can be
readily accomplished by established methods of polymer synthesis.
For example, PLGA-PEG-PLGA can be synthesized by using PEG as an
initiator for the ring-opening polymerization of D,L-lactide and
glycolide in the presence of stannous octoate as a catalyst.
Biologically Active Agents
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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.), Biolimus A9
(Biosensors International, Singapore), AP23572 (Ariad
Pharmaceuticals), prodrugs thereof, co-drugs thereof, and
combinations thereof.
[0056] 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
[0057] 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.
[0058] 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-inflammmatory
properties or can have other properties such as antineoplastic,
antimitotic, cystostatic, antiplatelet, anticoagulant, antifibrin,
antithrombin, antibiotic, antiallergic, and/or antioxidant
properties.
[0059] 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).
[0060] 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.
[0061] 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).
[0062] 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.
[0063] Other biologically active agents that can be used include
alpha-interferon, genetically engineered epithelial cells,
tacrolimus and dexamethasone.
[0064] 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.
[0065] 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).
[0066] "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.
[0067] 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).
[0068] 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
[0069] 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.
[0070] 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.
[0071] 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, dexamethasone acetate,
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), Biolimus A9 (Biosensors International, Singapore),
AP23572 (Ariad Pharmaceuticals), 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 clobetasol.
[0072] An alternative class of drugs would be
p-para-.quadrature.-agonists for increased lipid transportation,
examples include feno fibrate.
[0073] 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
[0074] 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
include a block copolymer described herein in a layer according to
any design of a coating. The coating can be a multi-layer structure
that includes at least one reservoir layer, which is layer (2)
described below, and can include any of the following (1), (3), (4)
and (5) layers or combination thereof: [0075] (1) a primer layer;
(optional) [0076] (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; [0077] (3) a release
control layer (also referred to as a "rate-limiting layer")
(optional); [0078] (4) a topcoat layer; and/or (optional); [0079]
(5) a finishing coat layer. (optional).
[0080] 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.
[0081] Each layer of a stent coating can be disposed over the
implantable device (e.g., a stent) by dissolving the amorphous
polymer, 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., e.g., 80.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, and/or to improve the
thermodynamic stability of the coating.
[0082] 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.
[0083] 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.
[0084] The drug-polymer layer can be applied directly or 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. The optional 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.
[0085] 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, and irradiation. Most, if not all, of these
processes can involve an elevated 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.
[0086] The process of the release of a drug from a coating having
both topcoat and finishing coat layers includes at least three
steps. First, the drug is absorbed by the polymer of the topcoat
layer at the drug-polymer layer/topcoat layer interface. Next, the
drug diffuses through the topcoat layer using the void volume
between the macromolecules of the topcoat layer polymer as pathways
for migration. Next, the drug arrives at the topcoat
layer/finishing layer interface. Finally, the drug diffuses through
the finishing coat layer in a similar fashion, arrives at the outer
surface of the finishing coat layer, and desorbs from the outer
surface. At this point, the drug is released into the blood vessel
or surrounding tissue. Consequently, a combination of the topcoat
and finishing coat layers, if used, can serve as a rate-limiting
barrier. The drug can be released by virtue of the degradation,
dissolution, and/or erosion of the layer(s) forming the coating, or
via migration of the drug through the amorphous polymeric layer(s)
into a blood vessel or tissue.
[0087] In one embodiment, any or all of the layers of the stent
coating can be made of a block copolymer described herein. In
another embodiment, the outermost layer of the coating can be
limited to a block copolymer as defined above.
[0088] To illustrate in more detail, in a stent coating having all
four layers described above (i.e., the primer, the reservoir layer,
the topcoat layer and the finishing coat layer), the outermost
layer is the finishing coat layer, which can be made of a block
copolymer described. The remaining layers (i.e., the primer, the
reservoir layer and the topcoat layer) optionally having the
properties of being biodegradable or, biostable, or being mixed
with a block copolymer as described herein. The polymer(s) in a
particular layer may be the same as or different than those in any
of the other layers, as long as the layer on the outside of another
bioabsorbable should preferably also be bioabsorbable and degrade
at a similar or faster relative to the inner layer. As another
illustration, the coating can include a single matrix layer
comprising a polymer described herein and a drug.
[0089] If a finishing coat layer is not used, the topcoat layer can
be the outermost layer and should be made of a block copolymer as
described. In this case, the remaining layers (i.e., the primer and
the reservoir layer) optionally can also be fabricated of a block
copolymer described herein. The polymer(s) in a particular layer
may be the same as or different than those in any of the other
layers, as long as the outside of another bioabsorbable should
preferably also be bioabsorbable and degrade at a similar or faster
relative to the inner layer.
[0090] 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. In such a case, the reservoir is the outermost layer
of the stent coating and should be made of a block copolymer
described. The primer optionally can also be fabricated of a block
copolymer described herein and optionally one or more biodegradable
polymer(s), biostable polymer(s), or a combination thereof. The two
layers may be made from the same or different polymers, as long as
the layer on the outside of another bioabsorbable should preferably
also be bioabsorbable and degrade at a similar or faster relative
to the inner layer.
[0091] Any layer of a coating can contain any amount of a block
copolymer described herein and optionally being mixed with another
bioabsorbable and/or biocompatible polymer. Non-limiting examples
of 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(D-lactic
acid-co-glycolide-co-caprolactone) (PDLA-GA-CL), poly(L-lactic
acid-co-glycolide-co-caprolactone) (PLLA-GA-CL), poly(DL-lactic
acid-co-glycolide-co-caprolactone) (PDLLA-GA-CL), 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.
[0092] Any layer of a coating can also contain any amount of a
non-degradable polymer, or a blend of more than one such. When a
non-degradable polymer is used, the non-degradable polymer shall
have a molecular weight (M.sub.w) of about 40K Daltons or below. In
general since not many polymers are very elastic enough. If they
are not, the higher Mw will provide the toughness for the coating,
ideally in drug eluting stents, polymers of higher than 100 kD are
preferable. Also, since they are not degradable or soluble,
clearing the kidney should not be a concern. Non-limiting examples
of non-degradable polymers include poly(methyl methacrylate),
poly(ethyl methacrylate), poly(butyl methacrylate),
poly(-ethylhexyl methacrylate), poly(lauryl methacrylate),
poly(-hydroxylethyl methacrylate), poly(ethylene glycol (PEG)
acrylate), poly(PEG methacrylate), methacrylate polymers containing
2-methacryloyloxyethylphosphorylcholine (MPC), PC 1036, and
poly(n-vinyl pyrrolidone, poly(methacrylic acid), poly(acrylic
acid), poly(hydroxypropyl methacrylate), poly(hydroxypropyl
methacrylamide), methacrylate polymers containing
3-trimethylsilylpropyl methacrylate, and copolymers thereof.
Method of Fabricating Implantable Device
[0093] 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 block copolymer described herein,
optionally with one or more other biodegradable or biostable
polymer or copolymers.
[0094] Under the method, a portion of the implantable device or the
whole device itself can be formed of the material containing a
biodegradable or biostable 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 micron, or .ltoreq.about 20 micron, or
.ltoreq.about 10 micron, or .ltoreq.about 5 micron.
[0095] 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.
[0096] 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.
[0097] Non-limiting examples of polymers, which may or may not be
the block copolymers defined above, 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(D-lactic acid-co-glycolide-co-caprolactone) (PDLA-GA-CL),
poly(L-lactic acid-co-glycolide-co-caprolactone) (PLLA-GA-CL),
poly(DL-lactic acid-co-glycolide-co-caprolactone) (PDLLA-GA-CL),
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), 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.
[0098] Additional representative examples of polymers that may be
suited for fabricating an implantable device include ethylene vinyl
alcohol copolymer (commonly known by the generic name EVOH or by
the trade name EVAL), poly(butyl methacrylate), poly(vinylidene
fluoride-co-hexafluoropropylene) (e.g., SOLEF 21508, available from
Solvay Solexis PVDF of Thorofare, N.J.), polyvinylidene fluoride
(otherwise known as KYNAR, available from ATOFINA Chemicals of
Philadelphia, Pa.),
poly(tetrafluoroethylene-co-hexafluoropropylene-co-vinylidene
fluoride), ethylene-vinyl acetate copolymers, and polyethylene
glycol.
Method of Treating or Preventing Disorders
[0099] 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, urethral 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.
[0100] 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, urethral
obstruction and tumor obstruction. In a particular embodiment, the
condition or disorder is atherosclerosis, thrombosis, restenosis or
vulnerable plaque.
[0101] 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, dexamethasone acetate, 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), Biolimus A9 (Biosensors International, Singapore),
AP23572 (Ariad Pharmaceuticals), pimecrolimus, imatinib mesylate,
midostaurin, clobetasol, progenitor cell-capturing antibodies,
prohealing drugs, fenofibrate, prodrugs thereof, co-drugs thereof,
and a combination thereof.
[0102] 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.
[0103] 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.
* * * * *