U.S. patent application number 10/812780 was filed with the patent office on 2005-09-29 for biologically degradable compositions for medical applications.
Invention is credited to Hossainy, Syed F.A., Pacetti, Stephen Dirk, Tang, Yiwen, Tung, Andrew Chinfeng.
Application Number | 20050214339 10/812780 |
Document ID | / |
Family ID | 34964338 |
Filed Date | 2005-09-29 |
United States Patent
Application |
20050214339 |
Kind Code |
A1 |
Tang, Yiwen ; et
al. |
September 29, 2005 |
Biologically degradable compositions for medical applications
Abstract
A medical article is disclosed, comprising a biologically
degradable AB block copolymer and a biologically degradable polymer
that is capable, at equilibrium and at room temperature, of
absorbing less than about 5 mass % water.
Inventors: |
Tang, Yiwen; (San Jose,
CA) ; Hossainy, Syed F.A.; (Fremont, CA) ;
Tung, Andrew Chinfeng; (Castro Valley, CA) ; Pacetti,
Stephen Dirk; (San Jose, CA) |
Correspondence
Address: |
Cameron Kerrigan
Squire, Sanders & Dempsey L.L.P.
Suite 300
One Maritime Plaza
San Francisco
CA
94111
US
|
Family ID: |
34964338 |
Appl. No.: |
10/812780 |
Filed: |
March 29, 2004 |
Current U.S.
Class: |
424/423 |
Current CPC
Class: |
A61L 31/10 20130101;
A61L 27/34 20130101; A61L 31/148 20130101; C08L 67/04 20130101;
A61L 31/10 20130101; A61L 2420/06 20130101; A61L 27/34 20130101;
C08L 67/04 20130101 |
Class at
Publication: |
424/423 |
International
Class: |
A61K 009/00 |
Claims
What is claimed is:
1. A medical article, comprising: (a) a medical substrate; and (b)
a coating deposited on the substrate, the coating comprising a
first polymer and a second polymer, wherein the first polymer
includes a biologically degradable AB block copolymer, and the
second polymer includes a biologically degradable polymer that is
capable, at equilibrium and at room temperature, of absorbing less
than about 5 mass % water.
2. The medical article of claim 1, wherein the medical article is a
stent, graft, or a stent-graft.
3. The medical article of claim 1, wherein the AB block-copolymer
is capable of absorbing, at equilibrium and at room temperature,
about 5 mass % or more water.
4. The medical article of claim 1, wherein the second polymer does
not include or is substantially free from AB polymeric blocks.
5. The medical article of claim 1, wherein the AB block-copolymer
comprises a biocompatible polymeric moiety and a structural
polymeric moiety.
6. The medical article of claim 5, wherein the biocompatible
polymeric moiety is selected from a group consisting of a
poly(alkylene glycol), poly(2-hydroxyethyl methacrylate),
poly(3-hydroxypropyl methacrylamide), hydroxylated poly(vinyl
pyrrolidone), sulfonated dextran, sulfonated polystyrene, fibrin,
fibrinogen, cellulose, starch, collagen, hyaluronic acid, heparin,
a graft copolymer of poly(L-lysine)-graft-co-poly(ethylene glycol),
and copolymers thereof.
7. The medical article of claim 6, wherein the poly(alkylene
glycol) is selected from a group consisting of poly(ethylene
glycol), poly(propylene glycol), poly(tetramethylene glycol), and
poly(ethylene oxide-co-propylene oxide).
8. The medical article of claim 5, wherein the structural polymeric
moiety is selected from a group consisting of poly(D,L-lactide),
poly(caprolactone), poly(caprolactone-co-D,L-lactide),
poly(butylene terephthalate), poly(ester amide), poly(aspirin),
poly(L-lactide), poly(glycolide), poly(L-lactide-co-glycolide),
poly(D,L-lactide-co-glycol- ide), poly(3-hydroxybutyrate),
poly(4-hydroxybutyrate), poly(hydroxyvalerate),
poly(3-hydroxybutyrate-co-valerate),
poly(4-hydroxybutyrate-co-valerate), and polydioxanone.
9. The medical article of claim 1, wherein the AB block-copolymer
is selected from poly(ethylene-glycol)-block-co-poly(caprolactone)
and poly(ethylene-glycol)-block-co-poly(butyleneterephthalate).
10. The medical article of claim 1, wherein the AB block-copolymer
is: 5wherein m, n, I, K, and r are positive integers.
11. The medical article of claim 1, wherein the second polymer is
selected from a group consisting of poly(L-lactide),
poly(D,L-lactide), poly(glycolide), poly(L-lactide-co-glycolide),
poly(D,L-lactide-co-glycol- ide), poly(caprolactone),
poly(L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone),
polyhydroxyalkanoates, poly(3-hydroxybutyrate),
poly(4-hydroxybutyrate), poly(hydroxyvalerate),
poly(3-hydroxybutyrate-co-valerate),
poly(4-hydroxybutyrate-co-valerate), poly(ester amides),
poly(anhydrides), poly(carbonates), poly(trimethylene
carbonate-co-glycolide), poly(trimethylene carbonate-co-L-lactide),
poly(trimethylene carbonate-co-D,L-lactide), poly(dioxanone),
poly(phosphazenes), poly(orthoesters),
poly(tyrosine-co-carbonates), polyalkylene oxalates,
poly(glycerol-co-sebacic acid esters), cyanoacrylates, poly(amino
acids), poly(lysine), poly(glutamic acid) and combinations
thereof.
12. The medical article of claim 1, wherein the second polymer has
the formula: 6wherein n is a positive integer.
13. The medical article of claim 1, additionally including a
therapeutic substance.
14. A medical article, comprising a biologically degradable AB
block copolymer and a biologically degradable polymer that is
capable, at equilibrium and at room temperature, of absorbing less
than about 5 mass % water.
15. The article of claim 14, wherein the medical article is a
stent, a graft or a stent graft.
16. The article of claim 14, wherein the AB block-copolymer is
capable of absorbing, at equilibrium at room temperature, about 5
mass % or more water.
17. The article of claim 14, wherein the second polymer does not
include or is substantially free from AB polymeric blocks.
18. The article of claim 14, wherein the AB block-copolymer
comprises a biocompatible polymeric moiety and a structural
polymeric moiety.
19. The article of claim 18, wherein the biocompatible polymeric
moiety is selected from a group consisting of a poly(alkylene
glycol), poly(2-hydroxyethyl methacrylate), poly(3-hydroxypropyl
methacrylamide), hydroxylated poly(vinyl pyrrolidone), sulfonated
dextran, sulfonated polystyrene, fibrin, fibrinogen, cellulose,
starch, collagen, hyaluronic acid, heparin, a graft copolymer of
poly(L-lysine)-graft-co-poly(ethylene glycol), and copolymers
thereof.
20. The article of claim 19, wherein the poly(alkylene glycol) is
selected from a group consisting of poly(ethylene glycol),
poly(propylene glycol), poly(tetramethylene glycol), and
poly(ethylene oxide-co-propylene oxide).
21. The article of claim 18, wherein the structural polymeric
moiety is selected from a group consisting of poly(D,L-lactide),
poly(caprolactone), poly(caprolactone-co-D,L-lactide),
poly(butylene terephthalate), poly(ester amide), poly(aspirin),
poly(L-lactide), poly(glycolide), poly(L-lactide-co-glycolide),
poly(D,L-lactide-co-glycol- ide), poly(3-hydroxybutyrate),
poly(4-hydroxybutyrate), poly(hydroxyvalerate),
poly(3-hydroxybutyrate-co-valerate),
poly(4-hydroxybutyrate-co-valerate), and polydioxanone.
22. The article of claim 14, wherein the AB block-copolymer is
selected from poly(ethylene-glycol)-block-co-poly(caprolactone) and
poly(ethylene-glycol)-block-co-poly(butyleneterephthalate).
23. The article of claim 14, wherein the AB block-copolymer is
7wherein m, n, I, K, and r are positive integers.
24. The article of claim 14, wherein the biologically degradable
polymer that is capable, at equilibrium and at room temperature, of
absorbing less than about 5 mass % water is selected from a group
consisting of poly(L-lactide), poly(D,L-lactide), poly(glycolide),
poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),
poly(caprolactone), poly(L-lactide-co-caprolactone),
poly(D,L-lactide-co-caprolactone), polyhydroxyalkanoates,
poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),
poly(hydroxyvalerate), poly(3-hydroxybutyrate-co-valerate),
poly(4-hydroxybutyrate-co-valerate), poly(ester amides),
poly(anhydrides), poly(carbonates), poly(trimethylene
carbonate-co-glycolide), poly(trimethylene carbonate-co-L-lactide),
poly(trimethylene carbonate-co-D,L-lactide), poly(dioxanone),
poly(phosphazenes), poly(orthoesters),
poly(tyrosine-co-carbonates), polyalkylene oxalates,
poly(glycerol-co-sebacic acid esters), cyanoacrylates, poly(amino
acids), poly(lysine), poly(glutamic acid) and combinations
thereof.
25. The article of claim 14, wherein the biologically degradable
polymer that is capable, at equilibrium and at room temperature, of
absorbing less than about 5 mass % water is: 8wherein n is a
positive integer.
26. The article of claim 14, additionally including a therapeutic
agent mixed, bonded, conjugated, linked or blended with the block
copolymer and/or the polymer.
27. A method of treating a disorder in a human being, comprising:
implanting in the human being a medical article as defined in claim
14, wherein the disorder is selected from the group consisting of
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection or perforation, vascular aneurysm, vulnerable plaque,
chronic total occlusion, claudication, anastomotic proliferation
for vein and artificial grafts, bile duct obstruction, ureter
obstruction, tumor obstruction, and combinations thereof.
Description
BACKGROUND
[0001] 1. Field of the Invention
[0002] This invention is relates to biologically degradable
compositions for medical applications such as for coatings for
implantable medical devices.
[0003] 2. Description of the State of the Art
[0004] A wide spectrum of devices, from vascular devices such as
catheters, stents, and guidewires, to ocular devices such as
intra-ocular lenses is incorporating polymeric material. Polymeric
materials are being used for a variety of reasons, including making
a surface of a device more biocompatible or as a vehicle for
delivering a drug. Since polymeric materials are treated as a
foreign object by the body's immune system, the challenge has been
to make the polymers highly biocompatible as well as to reduce any
fouling effects that the polymer may produce or harbor. As a better
option, it may be better to make the polymer not only highly
biocompatible and non-fouling, but also biodegradable such that the
polymer is eliminated by the body after it has served its function.
The degradation of the polymer should not create any residues that
can provide adverse effects for the patient, such as excess
inflammation. To the contrary, the products of degradation should
enhance the treatment that is being provided to the patient or
should provide medicinal effects. Should the polymeric material
include a drug for local application, the composition should be
capable of carrying the drug so as to release the drug at an
efficacious rate for a therapeutically effective duration of time.
Finally, if the material is used as a coating, the properties of
the composition should be suitable so as to allow a film layer to
be formed on the medical device. For devices that include body
geometry that expand or fold, such as a stent or a balloon, the
polymer must be flexible enough so as to expand or fold with the
device without significant detachment or delamination of the
coating. Tradeoffs do exist between biocompatibility, structural
integrity and drug delivery capabilities of the polymer. Enhancing
one characteristic may determinately affect the other. Accordingly,
a proper balance must be drawn to provide for a polymeric
composition that meets the specific need of the application for
which it is being used.
[0005] The embodiments of the present invention provide for
biocompatible polymeric compositions that can be used medical
applications.
SUMMARY
[0006] A medical article is provided comprising a biologically
degradable AB block copolymer and a biologically degradable polymer
that is capable, at equilibrium and at room temperature, of
absorbing less than about 5 mass % water. The medical article can
be a stent, a graft or a stent graft. The AB block-copolymer can be
capable of absorbing, at equilibrium and at room temperature, about
5 mass % or more water. The AB block-copolymer can include a
biocompatible polymeric moiety and a structural polymeric moiety.
The biocompatible polymeric moiety can be, for example,
poly(alkylene glycol), poly(2-hydroxyethyl methacrylate),
poly(3-hydroxypropyl methacrylamide), hydroxylated poly(vinyl
pyrrolidone), sulfonated dextran, sulfonated polystyrene, fibrin,
fibrinogen, cellulose, starch, collagen, hyaluronic acid, heparin,
a graft copolymer of poly(L-lysine)-graft-co-poly(ethylene glycol),
and copolymers thereof. The structural polymeric moiety can be
poly(D,L-lactide), poly(caprolactone),
poly(caprolactone-co-D,L-lactide), poly(butylene terephthalate),
poly(ester amide), poly(aspirin), poly(L-lactide), poly(glycolide),
poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),
poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),
poly(hydroxyvalerate), poly(3-hydroxybutyrate-co- -valerate),
poly(4-hydroxybutyrate-co-valerate), and polydioxanone. The second
polymer can be poly(L-lactide), poly(D,L-lactide), poly(glycolide),
poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycol- ide),
poly(caprolactone), poly(L-lactide-co-caprolactone),
poly(D,L-lactide-co-caprolactone), poly(3-hydroxybutyrate),
poly(4-hydroxybutyrate), poly(hydroxyvalerate),
poly(3-hydroxybutyrate-co- -valerate),
poly(4-hydroxybutyrate-co-valerate), poly(ester amides),
poly(anhydrides), poly(carbonates), poly(trimethylene
carbonate-co-glycolide), poly(trimethylene carbonate-co-L-lactide),
poly(trimethylene carbonate-co-D,L-lactide), poly(dioxanone),
poly(phosphazenes), poly(orthoesters),
poly(tyrosine-co-carbonates), polyalkylene oxalates,
poly(glycerol-co-sebacic acid esters), cyanoacrylates, poly(amino
acids), poly(lysine), poly(glutamic acid) and combinations
thereof.
DETAILED DESCRIPTION
Terms and Definitions
[0007] For the purposes of the present invention, the following
terms and definitions apply:
[0008] The terms "biologically degradable" and "biodegradable" are
used interchangeably and refer to polymers that are capable of
being completely degraded and/or eroded when exposed to bodily
fluids such as blood and can be gradually resorbed, absorbed and/or
eliminated by the body. The processes of breaking down and eventual
absorption and elimination of the polymer can be caused by, for
example, hydrolysis, metabolic processes, bulk or surface erosion,
and the like. For coating applications, it is understood that after
the process of degradation, erosion, absorption, and/or resorption
has been completed, no polymer will remain on the device. In some
embodiments, very negligible traces or residue may be left behind.
Whenever the terms "degradable," "biodegradable," or "biologically
degradable" are used in this application, they are intended to
broadly include biologically erodable, bioabsorbable, and
bioresorbable polymers as well as other types of polymers that are
broken down and/or eliminated by the body.
[0009] "Biodegradable polymer composition" or "biodegradable
composition" is defined as a composition having a combination of at
least two biologically degradable polymers. In some embodiments,
the composition can also include a non-biologically degradable
component or polymer. The polymers can be blended, combined, mixed,
bonded, linked by linking agent, or conjugated.
[0010] The term "block-copolymer" is defined in accordance with the
terminology used by the International Union for Pure and Applied
Chemistry (IUPAC). "Block-copolymer" refers to a copolymer
containing a linear arrangement of blocks. The block is defined as
a portion of a polymer molecule in which the monomeric units have
at least one constitutional or configurational feature absent from
the adjacent portions. The term "AB block-copolymer" is defined as
a block-copolymer having moieties A and B arranged according to the
general formula 1
[0011] where each of "m," "n," and "x" is a positive integer, and m
can be .gtoreq.2 and n can be .gtoreq.2. The blocks of the AB
block-copolymers, could be, but need not be linked on the ends,
since the values of the integers "m" and "n" determining the number
of blocks are such as to ensure that the individual blocks are
usually long enough to be considered polymers in their own right.
An AB block copolymer can be, accordingly, named poly
A-block-co-poly B block polymer. In some embodiments, the AB
block-copolymer can be part of a chain of another polymer such as
in the backbone or as a pendant or side group.
[0012] The term "moiety" is defined as a portion of a complete
structure of a copolymer, the portion to include at least 2 atoms
joined together in a particular way. The term "moiety" includes
functional groups and/or discreet bonded residues that are present
in the macromolecule of a copolymer. The term "moiety" as used in
the present application is inclusive of individual units in the
copolymers. The term "moiety" as used in the present application is
also inclusive of entire polymeric blocks in the copolymers.
Embodiments of the Invention
[0013] The biodegradable polymer composition includes at least one
biodegradable AB block-copolymer or a polymer that includes
biodegradable AB blocks ("the first component") and at least one
other biodegradable polymer ("the second component"). The first
component can be capable of absorbing, at equilibrium and at room
temperature, about 2 mass % or more water, preferably 5 mass % or
more water. The second component can be capable of absorbing, at
equilibrium and at room temperature, less than about 2 mass %
water, preferably less than about 5 mass % water. The second
component is not or does not include an AB polymeric block or can
include a polymer that is substantially free of AB polymeric
blocks. In other words, the second component can include a polymer
the molecular structure of which is substantially free of fragments
shown by formula (I) above. The ratio between the first component
and the second component in the biodegradable polymer composition
can be between about 1:1 and about 1:99, more narrowly, between
about 1:2 and about 1:49, for example, about 1:19.
The First Component (AB Block-Copolymer)
[0014] The AB block copolymer can be capable of absorbing, at
equilibrium and at room temperature, about 2 mass %, preferably
about 5 mass % or more water. AB block copolymers that can be used
comprise two polymeric moieties A and B. The first polymeric moiety
is a biocompatible moiety that can be capable of providing the
block-copolymer with blood compatibility. The second polymeric
moiety is a structural moiety that can be capable of providing the
block-copolymer with mechanical and/or adhesive properties. The
structural moiety allows the copolymer to form a film layer on
substrates, such as metallic stents. Moiety A can be the
biocompatible moiety and moiety B can be the structural moiety. In
some embodiments, Moiety B can be the biocompatible moiety and
moiety A can be the structural moiety. The mass ratio between be
the biocompatible moiety and the structural moiety can be between
about 1:9 and about 1:0.7, for example, about 1:0.81. The mass
ratio 1:0.81 corresponds to an AB block-copolymer comprising about
55 mass % the biocompatible moiety and the balance, the structural
moiety.
[0015] The biocompatible and the structural moieties can be
selected to make the AB block-copolymers biologically degradable.
Molecular weight of a biocompatible moiety that can be used can be
below 40,000 Daltons, for example, between about 300 and 20,000
Daltons. To illustrate, one example of a biocompatible moiety A
that can be used is poly(ethylene glycol) (PEG) having the
molecular weight between about 300 and 20,000 Daltons. In this
example (when the A moiety is PEG), the value of "m" in formula (I)
can be between about 5 and about 1,000.
[0016] In addition to PEG, other poly(alkylene glycols) can be used
to form the biocompatible moiety, for example, poly(propylene
glycol) (PPG), poly(tetramethylene glycol), or poly(ethylene
oxide-co-propylene oxide). Examples of other biocompatible moieties
that can be used include poly(2-hydroxyethyl methacrylate),
poly(3-hydroxypropyl methacrylamide), hydroxylated poly(vinyl
pyrrolidone), sulfonated dextran, sulfonated polystyrene, fibrin,
fibrinogen, cellulose, starch, collagen, hyaluronic acid, heparin,
poly(L-lysine)-graft-co-poly(ethylene glycol), which is a graft
copolymer of poly(L-lysine) and PEG, or copolymers thereof.
[0017] Molecular weight of a structural moiety that can be used can
be between about 20,000 and about 200,000 Daltons, more narrowly,
between about 40,000 and about 100,000 Daltons, for example, about
60,000 Daltons. To illustrate, one example of a structural moiety B
that can be used is poly(D,L-lactide) having the molecular weight
between about 20,000 and about 200,000 Daltons. In this example,
the value of "n" in formula (I) can be between about 250 and about
3,000.
[0018] In addition to poly(D,L-lactide), other structural moieties
can be used. Some examples of such moieties include
poly(caprolactone) (PCL), poly(caprolactone-co-D,L-lactide),
poly(butylene terephthalate) (PBT), poly(ester amide),
poly(aspirin), poly(L-lactide), poly(glycolide),
poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),
poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),
poly(hydroxyvalerate), poly(3-hydroxybutyrate-co-valerate),
poly(4-hydroxybutyrate-co-valerate), and polydioxanone.
[0019] One example of the biodegradable AB block copolymer is
poly(ethylene-glycol)-block-co-poly(caprolactone) (PEG-PCL). One
possible structure of the PEG-PCL block copolymer can be
illustrated by formula (II): 2
[0020] wherein m are n are positive integers.
[0021] In PEG-PCL block copolymer shown by formula (II), the PEG
blocks constitute the biocompatible moiety A, while the PCL block
constitutes the structural moiety B. Block copolymer shown by
formula (II) can be synthesized by standard methods known to those
having ordinary skill in the art, for example, copolycondensation
of PEG with PCL. The process of copolycondensation can be catalyzed
by a catalyst which can be selected by those having ordinary skill
in the art, for example, by an acid catalyst or a base
catalyst.
[0022] Another example of the PEG-containing polyester includes a
block-copolymer of PEG with PBT, such as
poly(ethylene-glycol)-block-poly- (butyleneterephthalate)(PEG-PBT),
shown by formula (III): 3
[0023] wherein m, n, I and K are positive integers.
[0024] The PEG-PBT block-copolymer can be obtained by a synthetic
process that can be selected by those having ordinary skill in the
art. One example of the synthetic process that can be used includes
trans-esterification of dibutyleneterephthalate with PEG. One brand
of PEG-PBT block copolymer is known under a trade name
PolyActive.TM. and is available from IsoTis Corp. of Holland. In
PEG-PBT, the ratio between the PEG units and the PBT units can be
between about 0.67:1 and about 9:1. The molecular weight of the PEG
units can be between about 300 and about 4,000 Daltons.
[0025] PEG-PCL and PEG-PBT block copolymers all contain fragments
with ester bonds. Ester bonds are known to be water-labile bonds.
When in contact with slightly alkaline blood, ester bonds are
subject to catalyzed hydrolysis, thus ensuring biological
degradability of the block-copolymer. One product of degradation of
every block polymer, belonging to the group PEG-PCL and PEG-PBT, is
expected to be PEG, which is highly biologically compatible. PEG
also has an additional advantage of being biologically active,
reducing smooth muscle cells proliferation at the lesion site and
thus capable of treating, delaying, preventing or inhibiting
restenosis.
The Second Component
[0026] The second component of the composition can comprise at
least one biodegradable polymer capable of absorbing, at
equilibrium and at room temperature, less than about 2 mass %,
preferably less than 5 mass % water.
[0027] Examples of suitable biodegradable polymers that can be used
as a second component of the biodegradable polymer composition
include poly(L-lactide), poly(D,L-lactide), poly(glycolide),
poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),
poly(caprolactone), poly(L-lactide-co-caprolactone),
poly(D,L-lactide-co-caprolactone), polyhydroxyalkanoates,
poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),
poly(hydroxyvalerate), poly(3-hydroxybutyrate-co-valerate),
poly(4-hydroxybutyrate-co-valerate), poly(ester amides),
poly(anhydrides), poly(carbonates), poly(trimethylene
carbonate-co-glycolide), poly(trimethylene carbonate-co-L-lactide),
poly(trimethylene carbonate-co-D,L-lactide), poly(dioxanone),
poly(phosphazenes), poly(orthoesters),
poly(tyrosine-co-carbonates), polyalkylene oxalates,
poly(glycerol-co-sebacic acid esters), cyanoacrylates, poly(amino
acids), poly(lysine), poly(glutamic acid) and mixtures thereof.
Optional Third Components
[0028] In some embodiments, a third component can be included,
mixed, blended, bonded, conjugated or linked with the composition.
This can be a drug, an active agent, or a therapeutic substance. In
some embodiments, another polymer can be included, mixed, blended,
bonded, conjugated or linked with the composition. These polymers
need not be biodegradable. Examples include polyacrylates, such as
poly(butyl methacrylate), poly(ethyl methacrylate), and poly(ethyl
methacrylate-co-butyl methacrylate), and fluorinated polymers
and/or copolymers, such as poly(vinylidene fluoride) and
poly(vinylidene fluoride-co-hexafluoro propene), poly(vinyl
pyrrolidone), polyurethanes, silicones, polyesters, polyolefins,
polyisobutylene and ethylene-alphaolefin copolymers, vinyl halide
polymers and copolymers (such as polyvinyl chloride), polyvinyl
ethers (such as polyvinyl methyl ether), polyvinylidene chloride,
polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as
polystyrene), polyvinyl esters (such as polyvinyl acetate),
copolymers of vinyl monomers with each other and olefins, e.g.,
poly(ethylene-co-vinyl alcohol) (EVAL), ethylene-methyl
methacrylate copolymers, acrylonitrile-styrene copolymers, ABS
resins, and ethylene-vinyl acetate copolymers, polyamides (such as
Nylon 66 and polycaprolactam), alkyd resins, polyoxymethylenes,
polyimides, polyethers, epoxy resins, rayon, rayon-triacetate,
cellulose, cellulose acetate, cellulose butyrate, cellulose acetate
butyrate, cellophane, cellulose nitrate, cellulose propionate,
cellulose ethers, and carboxymethyl cellulose.
[0029] The therapeutic substance can include any substance capable
of exerting a therapeutic, diagnostic or prophylactic effect for a
patient. The therapeutic substance may include small molecule
substances, peptides, proteins, oligonucleotides, and the like. The
therapeutic substance could be designed, for example, to inhibit
the activity of vascular smooth muscle cells. It can be directed at
inhibiting abnormal or inappropriate migration and/or proliferation
of smooth muscle cells to inhibit restenosis.
[0030] Examples of therapeutic substances include antiproliferative
substances such as actinomycin D, or derivatives and analogs
thereof (manufactured by Sigma-Aldrich of Milwaukee, Wis., or
COSMEGEN available from Merck). Synonyms of actinomycin D include
dactinomycin, actinomycin IV, actinomycin II, actinomycin X.sub.1,
and actinomycin C.sub.1. The active agent can also fall under the
genus of antineoplastic, anti-inflammatory, antiplatelet,
anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,
antiallergic and antioxidant substances. Examples of such
antineoplastics and/or antimitotics include paclitaxel (e.g.
TAXOL.RTM. by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel
(e.g. Taxotere.RTM., from Aventis S. A., Frankfurt, Germany)
methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,
doxorubicin hydrochloride (e.g. Adriamycin.RTM. from Pharmacia
& Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin.RTM.
from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such
antiplatelets, anticoagulants, antifibrin, and antithrombins
include 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, and thrombin inhibitors such as ANGIOMAX (Biogen, Inc.,
Cambridge, Mass.). Examples of such cytostatic or antiproliferative
agents include angiopeptin, angiotensin converting enzyme
inhibitors such as captopril (e.g. Capoten.RTM. and Capozide.RTM.
from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or
lisinopril (e.g. Prinivil.RTM. and Prinzide.RTM. from Merck &
Co., Inc., Whitehouse Station, N.J.); calcium channel blockers
(such as nifedipine), colchicine, fibroblast growth factor (FGF)
antagonists, fish oil (omega 3-fatty acid), histamine antagonists,
lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol
lowering drug, brand name Mevacor.RTM. from Merck & Co., Inc.,
Whitehouse Station, N.J.), monoclonal antibodies (such as those
specific for Platelet-Derived Growth Factor (PDGF) receptors),
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitors, suramin, serotonin blockers, steroids, thioprotease
inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric
oxide. An example of an antiallergic agent is permirolast
potassium. Other therapeutic substances or agents which may be
appropriate include alpha-interferon, genetically engineered
epithelial cells, tacrolimus, dexamethasone, and rapamycin and
structural derivatives or functional analogs thereof, such as
40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of
EVEROLIMUS available from Novartis),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, prodrugs thereof, co-drugs thereof, and
combinations thereof.
Application of the Composition
[0031] The composition can have a variety of medical applications,
such as coatings for medical devices, coatings for implantable
prostheses, capsules for drugs, drug delivery particles as well as
devices made at least in part from the composition. Examples of
medical devices, that can be used in conjunction with the
embodiments of this invention include stents (e.g., self expandable
or balloon expandable), biodegradable stents, stent-grafts, grafts
(e.g., aortic grafts), catheters, balloons, coating on balloons,
guidewires, artificial hearts and valves, blood oxygenerators,
ventricular assist devices, cardiopulmonary bypass systems,
cerebrospinal fluid shunts, pacemaker electrodes, axius coronary
shunts and leads as well as other devices such as intraocular
lenses. The devices, e.g., the stent, can be made from a metallic
material or an alloy such as, but not limited to, cobalt-chromium
alloys (e.g., ELGILOY), stainless steel (316L), "MP35N," "MP20N,"
ELASTINITE (Nitinol), tantalum, tantalum-based alloys,
nickel-titanium alloy, platinum, platinum-based alloys such as,
e.g., platinum-iridium alloy, iridium, gold, magnesium, titanium,
titanium-based alloys, zirconium-based alloys, or combinations
thereof. Devices made from bioabsorbable or biostable polymers can
also be used or coated with the embodiments of the present
invention. "MP35N" and "MP20N" are trade names for alloys of
cobalt, nickel, chromium and molybdenum available from Standard
Press Steel Co. of Jenkintown, Pa. "MP35N" consists of 35% cobalt,
35% nickel, 20% chromium, and 10% molybdenum. "MP20N" consists of
50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
Drug Delivery Stent
[0032] A coating for a stent made from the composition of the
present invention can be a multi-layer structure and can include a
primer layer; a drug-polymer layer (also referred to as "reservoir"
or "reservoir layer") or alternatively a polymer free drug layer;
and/or a topcoat layer. Intermediary layers can also be provided.
Each layer of the stent coating can be formed on the stent by
dissolving the biodegradable polymer composition in a solvent, or a
mixture of solvents, and applying the resulting solution on the
stent by spraying or immersing the stent in the solution. At least
one of the layers should include the bidegradable polymeric
composition of the present invention. The remaining portion of a
layer or the other layers can be made from other polymeric
material, such as poly(butyl methacrylate), poly(ethyl
methacrylate), and poly(ethyl methacrylate-co-butyl methacrylate),
or the others disclosed above.
[0033] Preferably, the outer most layer (e.g., the reservoir layer
or the topcoat layer) is made from the biodegradable composition.
If a topcoat layer is used, the topcoat layer can be made from the
biodegradable polymer. The reservoir layer or the optional primer
layer can be made from the same composition, the same composition
but with different ratios of the first to second component, the
same composition but with different ratios of the first to second
to third component or from a different polymeric material.
[0034] In some embodiments at least two of the layers can be made
from the embodiments of the biodegradable polymeric composition
such that for each layer the ratio of the first to second component
is different. In some embodiments, if a third component is used,
the ratio of the first to second to third component can be
different for each layer.
[0035] After the solution has been applied onto 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.
[0036] Representative examples of some solvents suitable for making
the coating solution include N,N-dimethylacetamide (DMAC),
N,N-dimethylformamide (DMF), tethrahydrofurane (THF),
cyclohexanone, xylene, toluene, acetone, i-propanol, methyl ethyl
ketone, propylene glycol monomethyl ether, methyl butyl ketone,
ethyl acetate, n-butyl acetate, and dioxane. Some solvent mixtures
can be used as well. Representative examples of the mixtures
include DMAC and methanol (e.g., a 50:50 by mass mixture); water,
i-propanol, and DMAC (e.g., a 10:3:87 by mass mixture); i-propanol
and DMAC (e.g., 80:20, 50:50, or 20:80 by mass mixtures); acetone
and cyclohexanone (e.g., 80:20, 50:50, or 20:80 by mass mixtures);
acetone and xylene (e.g. a 50:50 by mass mixture); acetone, FLUX
REMOVER AMS, and xylene (e.g., a 10:50:40 by mass mixture); and
1,1,2-trichloroethane and chloroform (e.g., a 80:20 by mass
mixture). FLUX REMOVER AMS is trade name of a solvent manufactured
by Tech Spray, Inc. of Amarillo, Tex. comprising about 93.7% of a
mixture of 3,3-dichloro-1,1,1,2,2-pentafluoropropane and
1,3-dichloro-1,1,2,2,3-pent- afluoropropane, and the balance of
methanol, with trace amounts of nitromethane. Those having ordinary
skill in the art will select the solvent or a mixture of solvents
suitable for a particular polymer being dissolved.
[0037] To incorporate a drug into the reservoir layer, the drug in
a form of a solution can be combined with the polymer solution that
is applied onto the stent as described above. Alternatively, to
fabricate a polymer free drug layer, the drug can be dissolved in a
suitable solvent or mixture of solvents, and the resulting drug
solution can be applied on the stent by spraying or immersing the
stent in the drug solution. Instead of introducing the drug in 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 or emulsion chemistry. Depending on a
variety of factors, e.g., the nature of the drug, those having
ordinary skill in the art can select the suitable solvent to form
the solvent phase of the suspension, as well as the quantity of the
drug to be dispersed in the solvent phase. The suspension can be
mixed with a polymer solution and the mixture can be applied on the
stent as described above. Alternatively, the drug suspension can be
applied on the stent without being mixed with the polymer
solution.
[0038] The biological degradation of the biodegradable polymer
composition is expected to cause an increase of the rate of release
of the drug due to the gradual disappearance of the polymer that
forms the reservoir and/or the topcoat layer. By choosing an
appropriate biodegradable polymer composition or by varying the
ratio of the components of the composition, or by including a third
polymeric component to the matrix, a stent coating having a
costumed release rate can be engineered.
Method of Use
[0039] In accordance with embodiments of the invention, a coating
of the various described embodiments can be formed on an
implantable device or prosthesis, e.g., a stent. For coatings
including one or more active agents, the agent will be retain on
the medical device such as a stent during delivery and expansion of
the device, and released at a desired rate and for a predetermined
duration of time at the site of implantation. Preferably, the
medical device is a stent. A stent having the above-described
coating is useful for a variety of medical procedures, including,
by way of example, treatment of obstructions caused by tumors in
bile ducts, esophagus, trachea/bronchi and other biological
passageways. A stent having the above-described coating is
particularly useful for treating occluded regions of blood vessels
caused by abnormal or inappropriate migration and proliferation of
smooth muscle cells, thrombosis, and restenosis. Stents may be
placed in a wide array of blood vessels, both arteries and veins.
Representative examples of sites include the iliac, renal, and
coronary arteries.
[0040] The compositions of the invention can be used for the
treatment of a variety of disorder in mammals including
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection or perforation, vascular aneurysm, vulnerable plaque,
chronic total occlusion, claudication, anastomotic proliferation
for vein and artificial grafts, bile duct obstruction, ureter
obstruction, tumor obstruction, cancer as well as other
disorders.
[0041] For implantation of a stent, an angiogram is first performed
to determine the appropriate positioning for stent therapy. An
angiogram is typically accomplished by injecting a radiopaque
contrasting agent through a catheter inserted into an artery or
vein as an x-ray is taken. A guidewire is then advanced through the
lesion or proposed site of treatment. Over the guidewire is passed
a delivery catheter which allows a stent in its collapsed
configuration to be inserted into the passageway. The delivery
catheter is inserted either percutaneously or by surgery into the
femoral artery, brachial artery, femoral vein, or brachial vein,
and advanced into the appropriate blood vessel by steering the
catheter through the vascular system under fluoroscopic guidance. A
stent having the above-described coating may then be expanded at
the desired area of treatment. A post-insertion angiogram may also
be utilized to confirm appropriate positioning.
EXAMPLES
[0042] The following examples are provided to further illustrate
embodiments of the present invention.
Example 1
[0043] A first composition can be prepared by mixing about 1.0 mass
% to about 15 mass %, for example, about 2.0 mass %
poly(caprolactone) (PCL); and the balance, mixture of
tetrahydrofuran (THF) and xylene solvents, where a mass ratio
between THF and xylene was about 3:1. The first composition can be
applied onto the surface of a bare 12 mm VISION stent (available
from Guidant Corporation) by spraying and dried to form a primer
layer. A spray coater was used, having a 0.014 fan nozzle
maintained at about 60.degree. C. with a feed pressure of about 0.2
atm (about 3 psi) and an atomization pressure of about 1.3 atm
(about 20 psi). About 75 .mu.g of the wet coating can be applied.
The primer was baked at about 60.degree. C. for about 2 hours,
yielding a dry primer layer.
[0044] A second composition can be prepared by mixing about 1.0
mass % to about 15 mass %, for example, about 2.0 mass % PCL; about
0.05 mass % to about 2.0 mass %, for example, about 1.0 mass %
EVEROLIMUS; and the balance, THF/xylene solvent mixture described
above. The second composition can contain about 300 .mu.g PCL and
about 150 .mu.g EVEROLIMUS. The second composition can be applied
onto the dried primer layer to form the reservoir layer, using the
same spraying technique and equipment used for applying the primer
layer, followed by drying, e.g., by baking at about 50.degree. C.
for about 1 hour. A third composition can prepared by mixing about
1.0 mass % to about 15 mass %, for example, about 2.0 mass % PCL;
about 1.0 mass % to about 15 mass %, for example, about 2.0 mass %
PEG-PBT (4000PEGT80PBT20); and the balance, THF/xylene solvent
mixture described above.
[0045] The brand of PEG-PBT that can be used can have about 20
molar % PBT units and about 80 molar % PEG units. The molecular
weight of the PEG units was about 4,000 Daltons. The third
composition can contain about 50 .mu.g PCL and about 50 .mu.g
PEG-PBT. The third composition can be applied onto the dried
reservoir layer to form a topcoat layer, using the same spraying
technique and equipment used for applying the primer layer and the
reservoir layer, followed by drying at about 50.degree. C. for
about 1 hour.
Example 2
[0046] A primer and reservoir layers can be formed on a stent as
described in Example 1. A composition can be prepared by mixing
about 1.0 mass % to about 15 mass %, for example, about 2.0 mass %
poly(L-lactide); about 1.0 mass % to about 15 mass %, for example,
about 2.0 mass % PEG-PBT; and the balance, the mixture of
chloroform and tricholoethane solvents, wherein the mass ratio
between chloroform and trichlorethane can be about 1:1. The same
brand of PEG-PBT as described in Example 1 can be used. The
composition can contain about 60 .mu.g poly(L-lactide), about 40
.mu.g PEG-PBT, and if desired, about 200 .mu.g paclitaxel. The
composition can be applied onto the dried reservoir layer to form a
topcoat layer.
Example 3
[0047] A primer and reservoir layers can be formed on a stent as
described in Example 1, except rapamycin can be used instead of
EVEROLIMUS. A composition can be prepared by mixing about 1.0 mass
% to about 15 mass %, for example, about 1.5 mass % poly(ester
amide); about 1.0 mass % to about 15 mass %, for example, about 0.5
mass % PEG-PBT; and the balance, a mixture of ethanol and DMAC
solvents, wherein mass ratio between ethanol and DMAC can be about
1:1.
[0048] The same brand of PEG-PBT as described in Example 1 can be
used. Poly(ester amide)-8,4 having the formula (IV) can be used:
4
[0049] wherein n is a positive integer.
[0050] The composition can contain about 75 .mu.g poly(ester
amide), and about 25 .mu.g PEG-PBT. The composition can be applied
onto the dried reservoir layer to form a topcoat layer, using the
same spraying technique and equipment as described above, followed
by drying, e.g., by baking. The poly(ester amide) shown by formula
(IV) is expected to degrade when exposed to bodily fluids such as
blood to yield sebacic and glycolic acids and 1,4-butanediamine
(putrescine), all of which are biocompatible.
[0051] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *