U.S. patent application number 12/115347 was filed with the patent office on 2008-08-28 for biologically absorbable coatings for implantable devices and methods for fabricating the same.
Invention is credited to Syed F.A. Hossainy, Eugene T. Michal, Yiwen Tang.
Application Number | 20080206307 12/115347 |
Document ID | / |
Family ID | 34103802 |
Filed Date | 2008-08-28 |
United States Patent
Application |
20080206307 |
Kind Code |
A1 |
Hossainy; Syed F.A. ; et
al. |
August 28, 2008 |
BIOLOGICALLY ABSORBABLE COATINGS FOR IMPLANTABLE DEVICES AND
METHODS FOR FABRICATING THE SAME
Abstract
Coatings for an implantable medical device and a method of
fabricating thereof are disclosed, the coatings comprising a
biologically degradable, biologically erodable, and/or biologically
resorbable ABA or AB block copolymer. A biologically active agent
can be conjugated to the block copolymer.
Inventors: |
Hossainy; Syed F.A.;
(Fremont, CA) ; Michal; Eugene T.; (San Francisco,
CA) ; Tang; Yiwen; (San Jose, CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA, SUITE 300
SAN FRANCISCO
CA
94111
US
|
Family ID: |
34103802 |
Appl. No.: |
12/115347 |
Filed: |
May 5, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11641250 |
Dec 18, 2006 |
7378106 |
|
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12115347 |
|
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Current U.S.
Class: |
424/423 ;
514/291; 623/1.46 |
Current CPC
Class: |
A61L 2300/606 20130101;
A61L 31/16 20130101; A61L 2300/114 20130101; A61L 31/10 20130101;
A61L 31/10 20130101; A61L 31/10 20130101; C08L 71/02 20130101; C08L
67/04 20130101 |
Class at
Publication: |
424/423 ;
623/1.46; 514/291 |
International
Class: |
A61F 2/06 20060101
A61F002/06; A61F 2/00 20060101 A61F002/00; A61K 31/436 20060101
A61K031/436 |
Claims
1. A medical article comprising an implantable substrate having a
coating, the coating including an ABA or an AB block copolymer and
a biologically active agent conjugated to the copolymer, the block
copolymer having A and B blocks, wherein one of the blocks
comprises a biological moiety that produces a biological response
and the other block comprises a structural moiety that provides the
block copolymer with structural functionality, wherein the
structural moiety comprises polycaprolactone or copolymers thereof,
and wherein the biologically active agent is selected from
paclitaxel, polyarginine, rapamycin, or derivatives or analogs of
rapamycin.
2. The medical article of claim 1, wherein the medical article is a
stent.
3. The medical article of claim 1, wherein block A comprises the
biological moiety, and block B comprises the structural moiety.
4. The medical article of claim 1, wherein block B comprises the
biological moiety, and block A comprises the structural moiety.
5. The medical article of claim 1, wherein the biological moiety is
selected from a group consisting of poly(alkylene glycols),
poly(ethylene oxide), poly(ethylene oxide-co-propylene oxide),
poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic
acid) and salts thereof, sulfonated dextran, polyphosphazenes,
poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid,
hyaluronic acid having a stearoyl or palmitoyl substitutent group,
poly(ethylene glycol)-hyaluronic acid, poly(ethylene
glycol)-hyaluronic acid-stearoyl, poly(ethylene glycol)-hyaluronic
acid-palmitoyl, heparin, poly(ethylene glycol)-heparin, and
copolymers thereof.
6. The medical article of claim 5, wherein the poly(alkylene
glycol) is selected from a group consisting of poly(ethylene
glycol), poly(propylene glycol), poly(tetramethylene glycol), a
graft copolymer of poly(L-lysine) and poly(ethylene glycol), and
copolymers thereof.
7. The medical article of claim 1, additionally comprising a first
biologically active agent incorporated into the coating.
8. The medical article of claim 1, wherein the derivative or analog
of rapamycin is selected from everolimus,
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or
40-O-tetrazole-rapamycin.
9. The medical article of claim 1, wherein the block copolymer
comprises blocks of poly(ethylene glycol) (PEG) and
polycaprolactone (PCL) having a formula I or II: ##STR00006##
wherein m, n, and p are independent integers greater than 0,
wherein the PEG block has a molecular weight between 300 and about
40,000 Daltons, and wherein the PCL block has a molecular weight
between about 20,000 and about 250,000 Daltons.
10. A medical article comprising an implantable substrate having a
coating, the coating including an ABA or an AB block copolymer and
diazenium diolate conjugated to the block copolymer, the block
copolymer having A and B blocks, wherein one of the blocks
comprises a biological moiety that produces a biological response
and the other block comprises a structural moiety that provides the
block copolymer with structural functionality, and wherein the
structural moiety comprises polycaprolactone or copolymers
thereof.
11. The medical article of claim 10, wherein the block copolymer
comprises blocks of poly(ethylene glycol) (PEG) and
polycaprolactone (PCL) having a formula I or II: ##STR00007##
wherein m, n, and p are independent integers greater than 0,
wherein the PEG block has a molecular weight between 300 and about
40,000 Daltons, and wherein the PCL block has a molecular weight
between about 20,000 and about 250,000 Daltons.
12. A method for fabricating a medical article, the method
including applying a coating on at least a portion of an
implantable substrate, the coating including an ABA or an AB block
copolymer and a biologically active agent conjugated to the
copolymer, wherein the block copolymer having A and B blocks,
wherein one of the blocks comprises a biological moiety that
produces a biological response and the other block comprises a
structural moiety that provides the block copolymer with structural
functionality, wherein the structural moiety comprises
polycaprolactone or copolymers thereof, and wherein the
biologically active agent is selected from paclitaxel,
polyarginine, rapamycin, or derivatives or analogs of
rapamycin.
13. The method of claim 12, wherein the medical article is a
stent.
14. The method of claim 12, wherein block A comprises the
biological moiety, and block B comprises the structural moiety.
15. The method of claim 12, wherein block B comprises the
biological moiety, and block A comprises the structural moiety.
16. The method of claim 12, wherein the biological moiety is
selected from a group consisting of poly(alkylene glycols),
poly(ethylene oxide), poly(ethylene oxide-co-propylene oxide),
poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic
acid) and salts thereof, sulfonated dextran, polyphosphazenes,
poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid,
hyaluronic acid having a stearoyl or palmitoyl substitutent group,
poly(ethylene glycol)-hyaluronic acid, poly(ethylene
glycol)-hyaluronic acid-stearoyl, poly(ethylene glycol)-hyaluronic
acid-palmitoyl, heparin, poly(ethylene glycol)-heparin, and
copolymers thereof.
17. The method of claim 16, wherein the poly(alkylene glycol) is
selected from a group consisting of poly(ethylene glycol),
poly(propylene glycol), poly(tetramethylene glycol), a graft
copolymer of poly(L-lysine) and poly(ethylene glycol), and
copolymers thereof.
18. The method of claim 12, additionally comprising a first
biologically active agent incorporated into the coating.
19. The method of claim 12, wherein the derivative or analog of
rapamycin is selected from everolimus,
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or
40-O-tetrazole-rapamycin.
20. The method of claim 12, wherein the block copolymer comprises
blocks of poly(ethylene glycol) (PEG) and polycaprolactone (PCL)
having a formula I or II: ##STR00008## wherein m, n, and p are
independent integers greater than 0, wherein the PEG block has a
molecular weight between 300 and about 40,000 Daltons, and wherein
the PCL block has a molecular weight between about 20,000 and about
250,000 Daltons.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation application of U.S.
application Ser. No. 11/641,250, filed on Dec. 18, 2006, the
teaching of which is incorporated herein in its entirety by
reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention is directed to coatings for drug delivery
devices, such as drug eluting vascular stents, and methods for
producing the same.
[0004] 2. Description of the State of the Art
[0005] Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease. A catheter assembly having a
balloon portion is introduced percutaneously into the
cardiovascular system of a patient via the brachial or femoral
artery. The catheter assembly is advanced through the coronary
vasculature until the balloon portion is positioned across the
occlusive lesion. Once in position across the lesion, the balloon
is inflated to a predetermined size to radially compress against
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.
[0006] A problem associated with the above procedure includes
formation of intimal flaps or torn arterial linings which can
collapse and occlude the 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 bypass operation. To reduce the
partial or total occlusion of the artery by the collapse of
arterial lining and to reduce the chance of the development of
thrombosis and restenosis, a stent is implanted in the lumen to
maintain the vascular patency.
[0007] Stents are used not only as a mechanical intervention but
also as a vehicle for providing biological therapy. As a mechanical
intervention, stents act as scaffoldings, functioning to physically
hold open and, if desired, to expand the wall of the passageway.
Typically, stents are capable of being compressed, so that they can
be inserted through small vessels via catheters, and then expanded
to a larger diameter once they are at the desired location.
Examples in patent literature disclosing stents which have been
applied in PTCA procedures include stents illustrated in U.S. Pat.
No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to
Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor.
[0008] Biological therapy can be achieved by medicating the stents.
Medicated stents provide for the local administration of a
therapeutic substance at the diseased site. In order to provide an
efficacious concentration to the treated site, systemic
administration of such medication often produces adverse or toxic
side effects for the patient. Local delivery is a preferred method
of treatment in that smaller total levels of medication are
administered in comparison to systemic dosages, but are
concentrated at a specific site. Local delivery thus produces fewer
side effects and achieves more favorable results. One proposed
method for medicating stents involves the use of a polymeric
carrier coated onto the surface of a stent. A solution which
includes a solvent, a polymer dissolved in the solvent, and a
therapeutic substance dispersed in the blend is applied to the
stent. The solvent is allowed to evaporate, leaving on the stent
surface a coating of the polymer and the therapeutic substance
impregnated in the polymer.
[0009] Local administration of therapeutic agents via stents has
shown favorable results in reducing restenosis. However, there is a
great need for better and more effective coatings for local drug
delivery.
SUMMARY
[0010] A medical article comprising an implantable substrate having
a coating is provided the coating includes an ABA or an AB block
copolymer, the block copolymer having moieties A and B, wherein one
of the moieties produces a biological response and the other moiety
provides the block copolymer with structural functionality.
Examples of the biological moiety include poly(alkylene glycols),
poly(ethylene oxide), poly(ethylene oxide-co-propylene oxide),
poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic
acid) and salts thereof, sulfonated dextran, hyaluronic acid,
heparin, or copolymers thereof. Examples of the structural moiety
include poly(caprolactone), poly(butylene terephthalate),
poly(ester amide), or copolymers thereof. The coating can include a
biologically active agent incorporated into the coating, and can
include a biologically active agent conjugated to the block
copolymer. Examples of the biologically active agents that can be
conjugated to the ABA block copolymer include paclitaxel, antisense
agents, polyarginine, rapamycin and structural derivatives or
functional analogs thereof, such as EVEROLIMUS,
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, and sources of nitrogen oxide, such as
diazenium diolates.
[0011] A medical article comprising an implantable substrate having
a coating is provided, the coating includes phosphoryl choline or
polyaspirin.
[0012] A method for fabricating a medical article is provided. The
method includes applying a coating to at least a portion of an
implantable substrate, the coating including an ABA or an AB block
copolymer, wherein one of the moieties in the block copolymer
produces a biological response and the other moiety provides the
block copolymer with structural functionality.
DETAILED DESCRIPTION
1. Terms and Definitions
[0013] The following definitions apply:
[0014] The terms "biologically degradable," "biologically
erodable," "bioabsorbable," and "bioresorbable" coatings and/or
polymers are defined as coatings and/or polymers that are capable
of being completely degraded and/or eroded when exposed to bodily
fluids such as blood and are gradually resorbed, absorbed and/or
eliminated by the body. The processes of breaking down and eventual
absorption and elimination of the coating and/or polymer can be
caused, for example, by hydrolysis, metabolic processes, bulk or
surface erosion, and the like.
[0015] Whenever the reference is made to "biologically degradable,"
"biologically erodable," "bioabsorbable," and "bioresorbable" stent
coatings and/or polymers forming such stent coatings, it is
understood that after the process of degradation, erosion,
absorption, and/or resorption has been completed, no 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, bioabsorbable, and bioresorbable
coatings and/or polymers.
[0016] "Biodegradability," "bioerodability," "bioabsorbability,"
and "bioresorbability" are defined as inherent properties of the
coating and/or polymer making the coating and/or polymer
biologically degradable, biologically erodable, or biologically
absorbable, and biologically resorbable.
[0017] The term "biologically beneficial" refers to a biodegradable
product that brings about biological benefits to the patient as a
result of the degradation and absorption of the product by the
patient's body.
[0018] "Fast release" is defined as in vivo release of
substantially the entire amount of the drug from the stent coating
in less than 15 days, for example, within 7 to 14 days. "Slow
release" is defined as in vivo release of substantially the entire
amount of the drug from the stent coating in 15 days or longer, for
example, within 15 to 56 days.
[0019] The terms "block copolymer" and "graft copolymer" are
defined in accordance with the terminology used by the
International Union of 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. "Graft
copolymer" refers to a polymer composed of macromolecules with one
or more species of block connected to the main chain as side
chains, these side chains having constitutional or configurational
features that differ from those in the main chain.
2. Embodiments of the Invention
[0020] A coating for an implantable medical device, such as a
stent, according to embodiments of the present invention, can be a
multi-layer structure that can include the following four
layers:
[0021] (a) a drug-polymer layer (also referred to as "reservoir" or
"reservoir layer") or a polymer free drug layer;
[0022] (b) an optional primer layer;
[0023] (c) an optional topcoat layer; and/or
[0024] (d) an optional finishing coat layer.
[0025] Each layer of the stent coating can be formed on the stent
by dissolving the polymer or a blend of polymers in a solvent, or a
mixture of solvents, and applying the resulting polymer solution on
the stent by spraying or immersing the stent in the solution. 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.
[0026] To incorporate a drug into the reservoir layer, the drug 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. In one embodiment, the reservoir can optionally
incorporate an additional active agent or drug, for example, by
having the additional drug or active agent conjugated to the
polymer forming the reservoir layer.
[0027] Instead of introducing the drug as 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. 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.
[0028] The drug-polymer layer can be applied directly onto at least
a part of the stent surface to serve as a reservoir for at least
one active agent or a drug which 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 which helps to control the rate of release of the
drug. In one embodiment, the topcoat layer can be essentially free
from any active agents or drugs. In another embodiment, besides the
active agent or drug contained in the reservoir layer, the topcoat
can incorporate an additional active agent or drug, for example, by
having the additional drug or active agent conjugated to the
polymer forming the topcoat layer. If a topcoat layer is used, the
optional finishing coat layer can be applied over at least a
portion of the topcoat layer for improving the biocompatibility of
the coating.
[0029] The process of the release of the 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 on the drug-polymer layer/topcoat layer interface. Next, the
drug diffuses through the topcoat layer using empty spaces between
the macromolecules of the topcoat layer polymer as pathways for
migration. Next, the drug arrives to the topcoat layer/finishing
layer interface. Finally, the drug diffuses through the finishing
coat layer in a similar fashion, arrives to the outer surface of
the finishing coat layer, and desorbs from the outer surface. At
this point, the drug is released into the blood stream.
Consequently, a combination of the topcoat and finishing coat
layers, if used, can serve as a rate limiting barrier.
[0030] In one embodiment, any or all of the layers of the stent
coating can be made of a polymer that is biologically beneficial
and biologically degradable, erodable, absorbable, and/or
resorbable. In another embodiment, the outermost layer of the
coating can be limited to such a polymer.
[0031] To illustrate in more detail, in the 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 is made of a
polymer that is biologically beneficial and biologically
degradable, erodable, absorbable, and/or resorbable. In this case,
optionally, the remaining layers (i.e., the primer, the reservoir
layer, the topcoat layer) can also be fabricated from a polymer
that is both biologically beneficial and biologically degradable;
the polymer can be the same or different in each layer.
[0032] If the finishing coat layer is not used, the topcoat layer
can become the outermost layer and is made of a polymer that is
both biologically beneficial and biologically degradable. In this
case, optionally, the remaining layers (i.e., the primer and the
reservoir layer) can be also fabricated of a polymer that is both
biologically beneficial and biologically degradable; and the
polymer can be the same or different in each of the four
layers.
[0033] If neither the finishing coat layer nor the topcoat layer is
used, the stent coating can have only two layers, the optional
primer and the reservoir. The reservoir in this case is the
outermost layer of the stent coating and is made of a polymer that
is both biologically beneficial and biologically degradable.
Optionally, the primer can be also fabricated of a biologically
degradable and biologically beneficial polymer, which can be the
same or different in the reservoir and in the primer.
[0034] The biological degradation, erosion, absorption and/or
resorption of a biologically degradable, erodable, absorbable
and/or resorbable and biologically beneficial polymer are expected
to cause at least three results. First, the rate of release of the
drug will increase due to the gradual disappearance of the polymer
that forms the reservoir or the topcoat layer, or both. By choosing
an appropriate degradable polymer, the stent coating can be
engineered to provide either fast or slow release of the drug, as
desired. Those having ordinary skill in the art can determine
whether a stent coating having slow or fast release is advisable
for a particular drug. For example, fast release may be recommended
for stent coatings loaded with antimigratory drugs, which often
need to be released within 1 to 2 weeks. For antiproliferative
drugs, slow release may be needed (up to 30 days release time).
[0035] Second, if an additional active agent or drug is conjugated
to the polymer of the topcoat layer, that active agent or drug is
expected to be released as the polymer of the topcoat layer
disappears as a result of degradation, erosion, absorption and/or
resorption, thus providing additional therapeutic benefit. This
embodiment is described in more detailed later in this
application.
[0036] Third, upon degradation of a biologically degradable,
erodable, absorbable and/or resorbable polymer, which is at the
same time biologically beneficial, the products of degradation of
the polymer can serve as other additional active agents which can
be absorbed by the body of the patient bringing about additional
medical and biological benefits.
[0037] Biologically degradable, erodable, absorbable and/or
resorbable polymers that are also biologically beneficial and that
can be used for making any of the stent coating layers, include
block copolymers. Examples of block copolymers include ABA block
copolymers, AB block copolymers or polymers that are not
necessarily block copolymers, as defined below, but still comprise
ABA or AB blocks. Both ABA and AB block copolymers contain a
polymeric moiety A and a polymeric moiety B.
[0038] One way of describing the ABA block copolymers is by using
the formula -[A-A-A].sub.m-[B-B-B].sub.n-[A-A-A].sub.p-, where each
of "m," "n," and "p" is an integer greater than 0. The AB block
copolymers can be described by the formula
-[A-A-A].sub.m-[B-B-B].sub.n-, where each of "m" and "n" is an
integer greater than 0. The blocks of the ABA and AB block
copolymers need not be linked on the ends, since the values of the
integers determining the number of A and B blocks ensure that the
individual blocks are usually long enough to be considered polymers
in their own right. Accordingly, the ABA block copolymer can be
named poly-A-block-co-poly-B-block-co-poly-A-block copolymer, and
the AB block copolymer can be named poly-A-block-co-poly-B-block
copolymer. Blocks "A" and "B," typically larger than three-block
size, can be alternating or random. The values of "m" and "p" can
be selected to have the block copolymer with the molecular weight
of blocks A between about 300 and about 40,000 Daltons, such as
between about 8,000 and about 30,000 Daltons, for example, about
15,000 Daltons. The values of "n" are selected to have the block
copolymer with the molecular weight of blocks B between about
50,000 and about 250,000 Daltons, such as between about 80,000 and
about 200,000 Daltons, for example, about 100,000 Daltons.
[0039] In the ABA and AB block copolymers, one polymeric moiety can
provide the block copolymer with blood compatibility ("a
biocompatible moiety") and the other polymeric moiety ("a
structural moiety") can provide the block copolymer with mechanical
and adhesive properties that the block copolymer needs for making
the stent coatings. In one embodiment, moiety A is the
biocompatible moiety and moiety B is the structural moiety.
[0040] In another embodiment, moiety A is the structural moiety and
moiety B is the biocompatible moiety. The biocompatible and the
structural moieties are selected to make the ABA and AB block
copolymers biologically degradable. Examples of suitable
biocompatible moieties include poly(alkylene glycols), for example,
poly(ethylene glycol) (PEG), poly(ethylene oxide), poly(propylene
glycol) (PPG), poly(tetramethylene glycol), poly(ethylene
oxide-co-propylene oxide), poly(N-vinyl pyrrolidone),
poly(acrylamide methyl propane sulfonic acid) and salts thereof
(AMPS and salts thereof), poly(styrene sulfonate), sulfonated
dextran, polyphosphazenes, poly(orthoesters), poly(tyrosine
carbonate), hyaluronic acid, hyaluronic acid having a stearoyl or
palmitoyl substitutent group, copolymers of PEG with hyaluronic
acid or with hyaluronic acid-stearoyl, or with hyaluronic
acid-palmitoyl, heparin, copolymers of PEG with heparin, a graft
copolymer of poly(L-lysine) and PEG, or copolymers thereof. A
molecular weight of a suitable biocompatible polymeric moiety can
be below 40,000 Daltons to ensure the renal clearance of the
compound, for example, between about 300 and about 40,000 Daltons,
more narrowly, between about 8,000 and about 30,000 Daltons, for
example, about 15,000 Daltons.
[0041] Examples of suitable structural moieties include
poly(caprolactone) (PCL), poly(butylene terephthalate) (PBT),
poly(ester amide), moieties containing butyl methacrylate
fragments, moieties containing a lauryl group, poly(lactic acid)
(PLA), poly(aspirin), and copolymers thereof. Molecular weight of
the blocks comprising the structural moiety can be between about
20,000 and about 250,000 Daltons, more narrowly, between about
80,000 and about 200,000 Daltons, such as about 100,000
Daltons.
[0042] One example of the biodegradable ABA block copolymer is
poly(ethylene glycol)-block-poly(caprolactone)-block-poly(ethylene
glycol)(PEG-PCL-PEG). One possible structure of the PEG-PCL-PEG
block copolymer is shown by formula (I):
##STR00001##
[0043] In the PEG-PCL-PEG block copolymers shown by formula (I),
the PEG blocks constitute the biodegradable moiety, while the PCL
block constitutes the structural moiety. If desired, the positions
of the moieties can be switched to obtain a BAB block copolymer,
poly(caprolactone)-block-poly(ethylene
glycol)-block-poly(caprolactone)(PCL-PEG-PCL). One possible
structure of the PCL-PEG-PCL block copolymer is shown by formula
(II):
##STR00002##
[0044] Block copolymers shown by formulae (I) and (II) can be
synthesized by standard methods known to those having ordinary
skill in the art, for example, by acid- or based-catalyzed
copolycondensation of PEG with PCL. Another example of a
PEG-containing polyester, suitable for making a stent and/or a
stent coating in accordance with the present invention includes a
block copolymer of PEG with PBT, such as poly(ethylene
glycol)-block-poly(butyleneterephthalate) (PEG-PBT), poly(ethylene
glycol)-block-poly(butylene terephthalate)-block-poly(ethylene
glycol) (PEG-PBT-PEG). PEG-PBT-PEG block copolymer can be obtained,
for example, by trans-esterification of dibutyleneterephthalate
with PEG. Another example of the PEG-containing polyester, suitable
for making a stent and/or a stent coating in accordance with the
present invention includes a block copolymer of PEG with PLA, such
as poly(ethylene glycol)-block-poly(lactic
acid)-block-poly(ethylene glycol) (PEG-PLA-PEG). In PEG-PLA-PEG,
the molecular weight of the units derived from ethylene glycol can
be between about 550 and about 30,000 Daltons, and the molecular
weight of the units derived from lactic acid can be between about
20,000 and about 150,000 Daltons.
[0045] PEG-PBT and PEG-PBT-PEG block copolymers are known under a
trade name POLYACTIVE and are available from IsoTis Corp. of
Holland. In POLYACTIVE, the ratio between the units derived from
ethylene glycol and the units derived from butylene terephthalate
can be between about 0.67:1 and about 9:1. The molecular weight of
the units derived from ethylene glycol can be between about 300 and
about 4,000 Daltons, and the molecular weight of the units derived
from butylene terephthalate can be between about 50,000 and about
250,000, for example, about 100,000 Daltons.
[0046] Alternatively, if desired, the positions of the moieties in
the PEG-PBT-PEG and PEG-PLA-PEG block copolymers can be switched to
obtain a BAB block copolymers,
poly(butyleneterephthalate)-block-poly(ethylene
glycol)-block-poly(butyleneterephthalate) (PBT-PEG-PBT) and
poly(lactic acid)-block-poly(ethylene glycol)-block-poly(lactic
acid) (PLA-PEG-PLA).
[0047] PEG-PCL-PEG, PCL-PEG-PCL, PEG-PBT, PEG-PBT-PEG, PBT-PEG-PBT,
PEG-PLA-PEG and PLA-PEG-PLA 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-PEG,
PCL-PEG-PCL, PEG-PBT, PEG-PBT-PEG, PBT-PEG-PBT, PEG-PLA-PEG and
PLA-PEG-PLA is expected to be PEG, which is highly biologically
compatible. PEG also has an additional advantage of being
biologically beneficial, reducing smooth muscle cells proliferation
at the lesion site and thus capable of inhibiting restenosis.
[0048] In one embodiment, instead of, or in addition to, the ABA
block copolymers and/or AB block copolymers described above,
compounds other than ABA block copolymers and/or AB block
copolymers can be used for making any layer of the stent coating,
so long as these compounds are both biologically degradable and
biologically beneficial. Examples of such compounds include
polyaspirin and phosphoryl choline.
[0049] Any layer of the stent coating can contain any amount of the
biodegradable ABA or AB block copolymers described above, or a
blend of more than one such copolymers. If less than 100% of the
layer is made of the biodegradable ABA or AB block copolymer(s),
other polymers can comprise the balance. Examples of the
alternative polymers that can be used 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(N-vinyl
pyrrolidone), poly(hydroxyvalerate), poly(L-lactic acid),
polycaprolactone, poly(lactide-co-glycolide),
poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),
polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid),
poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene
carbonate), polyphosphoester, polyphosphoester urethane, poly(amino
acids), cyanoacrylates, poly(trimethylene carbonate),
poly(iminocarbonate), co-poly(ether-esters), polyalkylene oxalates,
polyphosphazenes, biomolecules (such as fibrin, fibrinogen,
cellulose, starch, collagen and hyaluronic acid), 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, polycarbonates,
polyoxymethylenes, polyimides, polyethers, epoxy resins,
polyurethanes, rayon, rayon-triacetate, cellulose, cellulose
acetate, cellulose butyrate, cellulose acetate butyrate,
cellophane, cellulose nitrate, cellulose propionate, cellulose
ethers, and carboxymethyl cellulose.
[0050] Representative examples of some solvents suitable for making
the stent coatings include N,N-dimethylacetamide (DMAC),
N,N-dimethylformamide (DMF), tethrahydrofuran (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:
[0051] (1) DMAC and methanol (e.g., a 50:50 by mass mixture);
[0052] (2) water, i-propanol, and DMAC (e.g., a 10:3:87 by mass
mixture);
[0053] (3) i-propanol, and DMAC (e.g., 80:20, 50:50, or 20:80 by
mass mixtures);
[0054] (4) acetone and cyclohexanone (e.g., 80:20, 50:50, or 20:80
by mass mixtures);
[0055] (5) acetone and xylene (e.g. a 50:50 by mass mixture);
[0056] (6) acetone, FLUX REMOVER AMS, and xylene (e.g., a 10:50:40
by mass mixture); and
[0057] (7) 1,1,2-trichloroethane and chloroform (e.g., an 80:20 by
mass mixture).
[0058] 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-pentafluoropropane, and the balance
methanol, with trace amounts of nitromethane. Those having ordinary
skill in the art will select a solvent or a mixture of solvents
suitable for the particular polymer being dissolved.
[0059] The therapeutic substance that can be used in the reservoir
layer can include any substance capable of exerting a therapeutic
or prophylactic effect for a patient. The therapeutic substance may
include small molecule substances, peptides, proteins,
oligonucleotides, and the like. The therapeutic substance can 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.
[0060] Examples of therapeutic substances that can be used 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 I.sub.1,
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. Taxoteree.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.
[0061] As mentioned above, the drug(s) can be conjugated to the
polymer, to form a drug-polymer adduct. The drug-polymer adduct can
be then used for making the reservoir and/or topcoat layer. In
addition to the conjugated drug, the coating can be also
impregnated with the drug. For example, the drug-polymer adduct can
be dissolved in a suitable solvent, or a mixture of solvents, and
the resulting solution of the drug-polymer adduct can be applied on
the stent as described above.
[0062] The conjugated drug can include any substance capable of
exerting a therapeutic or prophylactic effect in the practice of
the present invention. Some examples of drugs that can be used for
conjugation with the ABA block copolymer include paclitaxel,
antisense agents (e.g., Rensten-NG), polyarginine (e.g., R7),
rapamycin and structural derivatives or functional analogs thereof,
such as EVEROLIMUS, 40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, and molecules that are sources of
nitrogen oxide (NO) such as diazenium diolates.
[0063] One method of conjugating an additional drug to the ABA
block copolymer is by utilizing the reactive functional groups of
the copolymer. For instance, when the ABA block copolymer is
PEG-PCL-PEG, the terminal hydroxyls of the PEG blocks can be used
for carrying out the process of conjugating. Conjugating an
additional drug to the ABA block copolymer can be illustrated by
the process of binding diazenium diolate type nitric oxide donors
to PEG-PCL-PEG.
[0064] Diazenium-diolate-type nitric oxide donors are adducts of
nitric oxide with nucleophilic amines. Diazenium diolates, also
known as "NONOates," are highly biologically compatible, and in
slightly acidicmedia, they spontaneously release NO. One example of
diazenium diolate that can be used is spermine diazenium diolate
(SDD).
[0065] SDD, also known by its chemical name as 1,3-propanediamine,
N-{4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]butyl}-diazen-1-ium--
1,2-diolate, is an aliphatic NONOate having the formula
NH.sub.2--(CH.sub.2).sub.3--N[N.sup.+(O)N.sup.---OH)]--(CH.sub.2).sub.4---
NH--(CH.sub.2).sub.3--NH.sub.2 and is available from Molecular
Probes, Inc. of Eugene, Oreg. Alternatively, other
diazenium-diolate-type NO donors can be used. Some examples of the
alternative diazenium-diolate-type NO donors that can be conjugated
to the PEG blocks of PEG-PCL-PEG include
1-{N-methyl-N-[6-(N-methylammonio)hexyl]amino}diazen-1-ium-1,2-diolate
having the formula
CH.sub.3--N.sup.+H.sub.2--CH.sub.2).sub.6--N(CH.sub.3--N.sup.+(O.sup.-).d-
bd.N--O.sup.- (MAHMA-NO), and
Z-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate
having the formula
O--N.sup.+[N(CH.sub.2CH.sub.2NH.sub.2)CH.sub.2CH.sub.2N.sup.+H.sub.3].dbd-
.N--O.sup.- (DETA-NO). MAHMA-NO and DETA-NO can be obtained from
Cayman Chemical Co. of Ann Arbor, Mich.
[0066] In order to carry out conjugation of SDD to a PEG-PCL-PEG
block copolymer, the PEG block of the copolymer can be
preliminarily derivatized by tosylation (treatment with tosyl
chloride), or alternatively by tresylation (by reacting with tresyl
chloride). Tosyl chloride is a derivative of toluene,
para-toluenesulfonyl chloride, having the formula
CH.sub.3--C.sub.6H.sub.4--SO.sub.2Cl (TsCl). The process of
PEG-PCL-PEG derivatization can be conducted outside the stent or
directly on the stent. The processes of tosylation or tresylation
include an attack on the terminal hydroxyl of the PEG block and can
be illustrated by reactions (III) and (IV), respectively:
##STR00003##
[0067] Alternatively, tresyl chloride
(2,2,2-trifluoroethanesulphonyl chloride) can be used to
derivatrize PEG-PCL-PEG, according to reaction scheme (IV) and
tresyl group is attached to the PEG-PCL-PEG backbone via hydroxy
group:
##STR00004##
[0068] Next, tosylated or tresylated PEG-PCL-PEG can be modified by
conjugating SDD. Due to the presence of two primary and one
secondary amino groups, SDD is readily conjugated to the tosylated
or tresylated PEG-PCL-PEG via alkylation of the amino groups. One
possible process of conjugating can be shown for tosylated
PEG-PCL-PEG as reaction (V):
##STR00005##
[0069] One or both PEG blocks of PEG-PCL-PEG can be modified with
SDD according to the process described by reactions (III-V). Those
having ordinary skill in the art can determine under which
conditions the two-step process of conjugating SDD to PEG-PCL-PEG
described by reactions (III-V) can be carried out. The resulting
polymeric adduct can be described schematically as Dz-PEG-PCL-PEG
(one PEG block is modified) or Dz-PEG-PCL-PEG-Dz (two PEG blocks
are modified), where Dz is a fragment derived from SDD.
[0070] The coatings and methods of the present invention have been
described with reference to a stent, such as a balloon expandable
or self-expandable stent. The use of the coating is not limited to
stents, however, and the coating can be used with a variety of
other medical devices. Examples of the implantable medical device
that can be used in conjunction with the embodiments of this
invention include stent-grafts, grafts (e.g., aortic grafts),
artificial heart valves, cerebrospinal fluid shunts, pacemaker
electrodes, axius coronary shunts and endocardial leads (e.g.,
FINELINE and ENDOTAK, available from Guidant Corporation). The
underlying structure of the device can be of virtually any design.
The device can be made of a metallic material or an alloy such as,
but not limited to, cobalt-chromium 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 with the
embodiments of the present invention.
[0071] "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.
3. Examples
[0072] The following examples are provided to further illustrate
embodiments of the present invention.
Example 1
[0073] A first composition can be prepared by mixing the following
components:
[0074] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % poly(caprolactone) (PCL); and
[0075] (b) the balance DMAC solvent.
[0076] The first composition can be applied onto the surface of a
bare 18 mm PENTA stent (available from Guidant Corporation) by
spraying and dried to form a primer layer. A spray coater can be
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 70
.mu.g of the wet coating can be applied. The primer can be baked at
about 60.degree. C. for about 2 hours, yielding a dry primer
layer.
[0077] A second composition can be prepared by mixing the following
components:
[0078] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PCL-PEG, where the molecular weight
of each PEG block can be about 10,000 Daltons, and the molecular
weight of the PCL block can be about 70,000 Daltons;
[0079] (b) between about 0.05 mass % and about 2.0 mass %, for
example, about 1.0 mass % paclitaxel; and
[0080] (c) the balance DMAC solvent.
[0081] The second composition can contain about 300 .mu.g
PEG-PCL-PEG and about 200 .mu.g paclitaxel. 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 as
described above.
[0082] A third composition can be prepared by mixing the following
components:
[0083] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PCL-PEG;
[0084] (b) the balance the DMAC solvent.
[0085] 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. About 200 .mu.g of the wet coating can be applied,
followed by drying, e.g., by baking as described above.
Example 2
[0086] The primer layer can be applied on a stent as described in
Example 1.
[0087] A composition can be prepared by mixing the following
components:
[0088] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PCL-PEG;
[0089] (b) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PCL;
[0090] (c) between about 0.05 mass % and about 2.0 mass %, for
example, about 1.0 mass % paclitaxel; and
[0091] (c) the balance DMAC solvent.
[0092] The composition can contain about 200 .mu.g PEG-PCL-PEG,
about 100 .mu.g PCL, and about 200 .mu.g paclitaxel. The
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 as described above.
Example 3
[0093] The stent can be coated as described in Example 1, but
instead of the topcoat layer that comprises PEG-PCL-PEG, the
topcoat layer can be made of a Dz-PEG-PCL-PEG-Dz adduct.
Example 4
[0094] The stent can be coated as described in Example 1. A
composition can be prepared by mixing the following components:
[0095] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % polyaspirin;
[0096] (b) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % EVEROLIMUS; and
[0097] (c) the balance DMAC solvent.
[0098] The composition can contain about 150 .mu.g polyaspirin, and
about 100 .mu.g EVEROLIMUS. The composition can be applied onto the
dried topcoat layer to form the finishing coat layer, using the
same spraying technique and equipment used for applying the primer
layer, followed by drying, e.g., by baking as described above.
Example 5
[0099] The stent can be coated as described in Example 1, but
instead of a reservoir layer that comprises paclitaxel, the
reservoir layer can include EVEROLIMUS.
Example 6
[0100] A first composition can be prepared by mixing the following
components:
[0101] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PBT; and
[0102] (b) the balance a solvent blend comprising
1,1,2-trichloroethane and chloroform in a mass ratio between about
4:1.
[0103] The brand of PEG-PBT that can be used can have about 45
molar % PBT units and about 55 molar % PEG units. The molecular
weight of the PEG units can be about 300 Daltons, and the molecular
weight of the PBT blocks can be about 100,000 Daltons. The first
composition can be applied onto the surface of a bare 18 mm PENTA
stent to form a primer layer as described in Example 1. The primer
can contain about 70 .mu.g PEG-PBT.
[0104] After the primer layer has been formed, a reservoir layer
comprising three sub-layers can be formed according to the
following procedure. A second composition can be prepared by mixing
the following components:
[0105] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % poly(L-arginine) R7; and
[0106] (b) the balance a solvent blend containing methanol and
water in a mass ratio of about 3:1.
[0107] The second composition can be applied over the primer layer
using techniques described above, and dried, e.g., by baking, to
form a first reservoir sub-layer.
[0108] A third composition can be prepared by mixing the following
components:
[0109] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % hyaluronic acid; and
[0110] (b) the balance a solvent blend containing ethanol and water
in a mass ratio of about 3:1.
[0111] The third composition can be applied over the first
reservoir sub-layer using techniques described above, and dried,
e.g., by baking, to form a second reservoir sub-layer.
[0112] A fourth composition can be prepared by mixing the following
components:
[0113] (a) between about 1.0 mass % and about 15 mass %, for
example, about 3.0 mass % PEG-PBT; and
[0114] (b) the balance a solvent blend of 1,1,2-trichloroethane and
chloroform described above.
[0115] The brand of PEG-PBT that can be used can have about 30
molar % PBT units and about 70 molar % PEG units. The molecular
weight of the PEG blocks can be about 1,000 Daltons, and the
molecular weight of the PBT blocks can be about 100,000 Daltons.
The fourth composition can be applied over the second reservoir
sub-layer using techniques described above, and dried, e.g., by
baking to complete formation of the reservoir layer by forming a
third reservoir sub-layer. The overall reservoir layer can contain
about 300 .mu.g R7, about 200 .mu.g hyaluronic acid, and about 300
.mu.g PEG-PBT.
[0116] A fifth composition can be prepared by mixing the following
components:
[0117] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PBT having about 20 molar % PBT units
and about 80 molar % PEG units (The molecular weight of the PEG
units can be about 4,000 Daltons);
[0118] (b) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % an adduct of the same brand of PEG-PBT
with hyaluronic acid; and
[0119] (c) the balance the blend of 1,1,2-trichloroethane and
chloroform described above.
[0120] The PEG-PBT-hyaluronic acid adduct can be synthesized by
esterification of PEG-PBT with hyaluronic acid with a mass ratio
between PEG-PBT and hyaluronic acid of about 2:1. Those having
ordinary skill in the art can determine the conditions under which
the esterification can be carried out.
[0121] The fifth composition can be applied onto the dried
reservoir layer to form a topcoat layer using the same spraying and
drying techniques, as described above. The topcoat layer can
contain about 200 .mu.g PEG-PBT and about 100 .mu.g hyaluronic
acid.
Example 7
[0122] A first composition can be prepared by mixing the following
components:
[0123] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % a silk-elastin protein block copolymer;
and
[0124] (b) the balance DMAC solvent.
[0125] Silk-elastin protein block copolymers combine repeating
blocks of amino acids providing the copolymer with the mechanical
strength characterizing silk and the flexibility characterizing
elastin. Silk-elastin block copolymer can be obtained from Protein
Polymer Technologies, Inc. of San Diego, Calif. The first
composition can be applied onto the surface of a bare 18 mm PENTA
stent to form a primer layer as described in Example 1. The primer
can contain about 70 .mu.g silk-elastin.
[0126] After the primer layer has been formed, a reservoir layer
comprising two sub-layers can be formed according to the following
procedure. A second composition can be prepared by mixing the
following components:
[0127] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % poly(L-arginine) R7; and
[0128] (b) the balance a solvent blend containing methanol and
water in a mass ratio of about 3:1.
[0129] The second composition can be applied over the primer layer
using techniques described above, and dried, e.g., by baking, to
form a first reservoir sub-layer.
[0130] A third composition can be prepared by mixing the following
components:
[0131] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % hyaluronic acid;
[0132] (b) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % silk-elastin; and
[0133] (c) the balance a solvent blend containing methanol and
water in a mass ratio of about 3:1.
[0134] The third composition can be applied over the first
reservoir sub-layer using techniques described above, and dried,
e.g., by baking, to complete formation of the reservoir layer by
forming a second reservoir sub-layer. The overall reservoir layer
can contain about 100 .mu.g R7, about 100 .mu.g hyaluronic acid,
and about 100 .mu.g silk-elastin.
[0135] A fourth composition can be prepared by mixing the following
components:
[0136] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % silk-elastin; and
[0137] (b) the balance a solvent blend containing methanol and
water in a mass ratio of about 3:1.
[0138] The fourth composition can be applied over the reservoir
layer using techniques described above, and dried, e.g., by baking
to form an intermediate layer. The intermediate layer can contain
about 50 .mu.g silk-elastin.
[0139] A fifth composition can be prepared by mixing the following
components:
[0140] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PBT having about 20 molar % PBT units
and about 80 molar % PEG units. The molecular weight of the PEG
units can be about 4,000 Daltons;
[0141] (b) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PBT having about 45 molar % PBT units
and about 55 molar % PEG units. The molecular weight of the PEG
units can be about 300 Daltons; and
[0142] (c) the balance the blend of 1,1,2-trichloroethane and
chloroform described above.
[0143] The fifth composition can be applied onto the dried
reservoir layer to form the topcoat layer using the same spraying
and drying techniques, as described above. The topcoat layer can
then be annealed by heating to about 80.degree. C. for about 30
minutes and then to about 50.degree. C. for about 1 hour. The
topcoat layer can contain about 100 .mu.g of each kind of
PEG-PBT.
Example 8
[0144] A stent can be coated with a primer layer as described in
Example 6. A first composition can be prepared, comprising:
[0145] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PBT having about 45 molar % PBT units
and about 55 molar % PEG units. The molecular weight of the PEG
units can be about 300 Daltons;
[0146] (b) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % EVEROLIMUS;
[0147] (c) the balance the blend of 1,1,2-trichloroethane and
chloroform described above.
[0148] The composition can contain about 100 .mu.g PEG-PBT, and
about 100 .mu.g EVEROLIMUS. The 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 as described above.
[0149] A second composition can be prepared by mixing the following
components:
[0150] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PBT; and
[0151] (b) the balance the blend of 1,1,2-trichloroethane and
chloroform described above.
[0152] The same kind of PEG-PBT as the one used for making the
reservoir layer can be used. The second composition can be applied
over the reservoir layer using techniques described above, and
dried, e.g., by baking, to form an intermediate layer. The
intermediate layer can contain about 70 .mu.g PEG-PBT. The
reservoir layer/the intermediate layer sequence can be repeated 4
times to achieve a total EVEROLIMUS load of about 400 .mu.g.
[0153] Following formation of the reservoir layer/intermediate
layer system, the topcoat layer can be formed as described in
Example 7.
Example 9
[0154] A stent can be coated with a primer layer as described in
Example 6. A first composition can be prepared, comprising:
[0155] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PBT having about 45 molar % PBT units
and about 55 molar % PEG units (The molecular weight of the PEG
units can be about 300 Daltons);
[0156] (b) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % EVEROLIMUS;
[0157] (c) the balance the blend of 1,1,2-trichloroethane and
chloroform described above.
[0158] The composition can contain about 100 .mu.g PEG-PBT and
about 100 .mu.g EVEROLIMUS. The composition can be applied onto the
dried primer layer to form a reservoir layer using the same
spraying technique and equipment used for applying the primer
layer, followed by drying, e.g., by-baking, as described above.
[0159] A second composition can be prepared, comprising:
[0160] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PBT having about 45 molar % PBT units
and about 55 molar % PEG units (The molecular weight of the PEG
units can be about 300 Daltons);
[0161] (b) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % polyaspirin; and
[0162] (c) the balance the blend of 1,1,2-trichloroethane and
chloroform described above.
[0163] The second composition can be applied over the reservoir
layer using techniques described above, and dried, e.g., by baking,
to form an intermediate layer. The intermediate layer can contain
about 50 .mu.g PEG-PBT and about 50 .mu.g polyaspirin. The
reservoir layer/intermediate layer sequence can be repeated 4 times
to achieve a total EVEROLIMUS load of about 400 .mu.g and a total
polyaspirin load of about 200 .mu.g.
[0164] A third composition can be prepared by mixing the following
components:
[0165] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % PEG-PBT having about 45 molar % PBT units
and about 55 molar % PEG units (The molecular weight of the PEG
units can be about 300 Daltons);
[0166] (b) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % polyaspirin; and
[0167] (c) the balance the blend of 1,1,2-trichloroethane and
chloroform described above.
[0168] The third composition can be applied onto the dried
reservoir layer/intermediate layer system to form a topcoat layer
using the same spraying and drying techniques as described above.
The topcoat layer can then be annealed by being heated to about
80.degree. C. for about 30 minutes and then to about 50.degree. C.
for about 1 hour. The topcoat layer can contain about 100 .mu.g
PEG-PBT and about 200 .mu.g polyaspirin.
[0169] 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.
* * * * *