U.S. patent application number 14/082922 was filed with the patent office on 2014-04-10 for coatings for implantable devices comprising poly(hydroxy-alkanoates) and diacid linkages.
This patent application is currently assigned to ABBOTT CARDIOVASCULAR SYSTEMS INC.. The applicant listed for this patent is ABBOTT CARDIOVASCULAR SYSTEMS INC.. Invention is credited to Thierry Glauser, Stephen Dirk Pacetti.
Application Number | 20140100302 14/082922 |
Document ID | / |
Family ID | 35800231 |
Filed Date | 2014-04-10 |
United States Patent
Application |
20140100302 |
Kind Code |
A1 |
Pacetti; Stephen Dirk ; et
al. |
April 10, 2014 |
COATINGS FOR IMPLANTABLE DEVICES COMPRISING
POLY(HYDROXY-ALKANOATES) AND DIACID LINKAGES
Abstract
Coatings for an implantable medical device and a method of
fabricating thereof are disclosed, the coatings including
block-polymers comprising at least one poly(hydroxyacid) or
poly(hydroxy-alkanoate) block, at least one block of a biologically
compatible polymer and at least one type of linking moiety.
Inventors: |
Pacetti; Stephen Dirk; (San
Jose, CA) ; Glauser; Thierry; (Redwood City,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ABBOTT CARDIOVASCULAR SYSTEMS INC. |
Santa Clara |
CA |
US |
|
|
Assignee: |
ABBOTT CARDIOVASCULAR SYSTEMS
INC.
Santa Clara
CA
|
Family ID: |
35800231 |
Appl. No.: |
14/082922 |
Filed: |
November 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13686380 |
Nov 27, 2012 |
8586075 |
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14082922 |
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10902982 |
Jul 30, 2004 |
8357391 |
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13686380 |
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Current U.S.
Class: |
523/105 |
Current CPC
Class: |
C08G 63/66 20130101;
C09D 167/00 20130101; A61L 27/34 20130101; A61L 31/10 20130101 |
Class at
Publication: |
523/105 |
International
Class: |
A61L 31/10 20060101
A61L031/10 |
Claims
1. A polymer of formula: ##STR00009## wherein: A are
poly(hydroxyacid) or poly(hydroxy-alkanoate) blocks selected from
the group consisting of poly(lactide-co-glycolide);
poly(L-lactide); poly(D-lactide); poly(D,L-lactide);
poly(L-lactide-co-glycolide); poly(D,L-lactide-co-glycolide);
poly(L-lactide-co-caprolactone); poly(D,L-lactide-co-caprolactone);
poly(L-lactide-co-D,L-lactide); poly(L-lactide-co-trimethylene
carbonate); poly(D,L-lactide-co-trimethylene carbonate);
poly(L-lactic acid); poly(D-lactic acid); poly(D,L-lactic acid);
and a combination thereof; B are blocks of a polymeric
biocompatible moiety selected from the group consisting of
poly(alkylene glycols), PEG, poly(L-lysine)-graft-co-poly(ethylene
glycol), poly(ethylene oxide), poly(propylene glycol) (PPG),
poly(tetramethylene glycol), or poly(ethylene oxide-co-propylene
oxide); poly(N-vinyl pyrrolidone); poly(acrylamide methyl propane
sulfonic acid) and salts thereof; poly(styrene sulfonate);
sulfonated dextran; polyphosphazenes; poly(orthoesters);
poly(tyrosine carbonate); hyaluronic acid and derivatives thereof,
hyaluronic acid having a stearoyl or palmitoyl substituent group,
copolymers of PEG with hyaluronic acid or with hyaluronic
acid-stearoyl, or with hyaluronic acid-palmitoyl; heparin and
derivatives thereof; copolymers of PEG with heparin; or copolymers
thereof; poly(2-hydroxyethyl methacrylate); .epsilon.-caprolactone;
.beta.-butyrolactone; .delta.-valerolactone; a graft copolymer of
poly(L-lysine) and poly(ethylene glycol) and mixtures thereof;
glycolide; poly(2-hydroxyethyl methacrylate); poly(3-hydroxypropyl
methacrylate); poly(3-hydroxypropyl methacrylamide); and a
combination thereof; X is a linking moiety derived from oxalic
acid, malonic acid, succinic acid, glutaric acid, adipic acid,
pimelic acid, brassylic acid, dodecane-1,12-dicarboxylic acid,
tridecane-1,13-dicarboxylic acid, thapsic acid, fumaric acid,
maleic acid, 1,3-acetonedicarboxylic acid, or combination thereof;
Y is a linking moiety selected from the group consisting of
ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol,
1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol,
1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol,
1,12-dodecanediol, 1,4-cyclohexanedimethanol,
1,4-hydroxymethylbenzene, serinol, dihydroxyacetone, any linear or
branched C2 to C12 hydrocarbon with two primary hydroxyl groups,
and any linear or branched C2 to C12 with unsaturation and two
primary hydroxyl groups, and a combination thereof; and n is an
integer between about 2 and about 700.
2-3. (canceled)
4. The polymer of claim 1 wherein B is one of poly(alkylene
glycols), PEG, poly(L-lysine)-graft-co-poly(ethylene glycol),
poly(ethylene oxide), polypropylene glycol) (PPG),
poly(tetramethylene glycol), or poly(ethylene oxide-co-propylene
oxide).
5-7. (canceled)
8. The polymer of claim 1 wherein n is about 10.
9. The polymer of claim 1 having the formula: ##STR00010## wherein
m is between about 2 and about 700; n is between about 2 and about
700; x is between about 5 and about 100; y is between about 2 and
about 700; z is between about 2 and about 700; a is between about 5
and about 100; and b is between about 2 and about 700.
10. The polymer of claim 9 wherein m is about 10; n is about 10; x
is about 14; y is about 10; z is about 10; a is about 14; and b is
about 10.
11-24. (canceled)
25. A coating made with the polymer of claim 1.
26-28. (canceled)
29. A coating made with the polymer of claim 9.
30. A medical device comprising the coating of claim 25.
31-33. (canceled)
34. A medical device comprising the coating of claim 29.
35-38. (canceled)
39. The polymer of claim 1, wherein the biologically compatible
polymer is: hyaluronic acid or derivatives thereof; hyaluronic acid
having a stearoyl or palmitoyl substituent group; copolymers of PEG
with hyaluronic acid or with hyaluronic acid-stearoyl, or with
hyaluronic acid-palmitoyl; or a combination thereof.
40. The polymer of claim 1, wherein the biologically compatible
polymer is poly(N-vinyl pyrrolidone); poly(acrylamide methyl
propane sulfonic acid) or salts thereof; poly(styrene sulfonate);
sulfonated dextran; polyphosphazenes; poly(orthoesters);
poly(tyrosine carbonate); or a combination thereof.
41. The polymer of claim 1, wherein the biologically compatible
polymer is heparin or derivatives thereof; copolymers of PEG with
heparin, or copolymers thereof; or a combination thereof.
42. The polymer of claim 1, wherein the biologically compatible
polymer is poly(2-hydroxyethyl methacrylate);
.epsilon.-caprolactone; .beta.-butyrolactone;
.delta.-valerolactone; a graft copolymer of poly(L-lysine) and
poly(ethylene glycol); glycolide; poly(2-hydroxyethyl
methacrylate); poly(3-hydroxypropyl methacrylate);
poly(3-hydroxypropyl methacrylamide); or a combination thereof.
Description
FIELD
[0001] This invention is directed to coatings for drug delivery
devices, such as drug eluting vascular stents, and methods for
producing the same.
DESCRIPTION OF THE STATE OF THE ART
[0002] Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease, which often manifests itself
as stenoses in coronary arteries due to atherosclerosis. A surgeon
inserts a catheter assembly having a balloon portion through the
skin into a patient's cardiovascular system by way of the brachial
or femoral artery. The surgeon positions the catheter assembly
across the occlusive lesion. The surgeon inflates the balloon, once
positioned, to a predetermined size to radially compress the
atherosclerotic plaque of the lesion and to remodel the artery
wall. After deflating the balloon, the surgeon withdraws the
catheter from the patient's vasculature.
[0003] But sometimes this procedure forms intimal flaps or tears
arterial linings. These injuries can collapse or occlude the
vessel. Moreover, the artery may develop thrombosis and restenosis
up to several months after the procedure and may require further
angioplasty or a surgical by-pass operation. Implanting a stent
into the artery can rectify the injuries and help preserve vascular
patency.
[0004] In a related manner, local administration of therapeutic
agents with stents or stent coatings has reduced restenosis. But
even with the progress in stent technology in recent years, stents
still can cause undesirable effects. For example, the continued
exposure of a stent to blood can lead to thrombus formation itself,
and the presence of a stent in a blood vessel can weaken the blood
vessel wall over time, which may allow arterial rupture or the
formation of an aneurism. A stent can also become so tissue
overgrown that it becomes less useful and that its continued
presence may cause a variety of problems or complications.
Therefore, biodegradable or bioabsorbable stents are desirable to
diminish risks that would otherwise associate with the continued
presence of a no-longer-needed device at the treatment site.
[0005] Polymeric stent coatings can cause adverse and inflammatory
reactions in vivo. And there is much less history of using
polymerically coated stents, while bare metal stents have an
extensive history. Use of absorbable or resorbable coatings also
allows for drug release profiles that are difficult to achieve with
non-absorbable polymers. Hence, there is great interest in using
erodable, absorbable, or resorbable coatings on stents. Next,
device coatings with non-fouling properties are desirable.
Non-fouling compounds such as poly(ethylene glycol) (PEG) provide
these properties. But in order for a copolymer containing PEG to
possess non-fouling properties, it is believed that the copolymer
must present a high concentration of PEG at the polymer-water
interface--to repel protein because repelling proteins requires
this. High PEG concentration in the copolymer can deleteriously
affect other coating performance aspects. For example, high PEG
levels can significantly increase water swelling. This, in turn,
can lead to too rapid drug release. It can also reduce the
coating's mechanical properties, compromising its durability.
Accordingly, there is a need for non-fouling coatings based on
biologically absorbable or biologically degradable polymers that
are simultaneously non-fouling and that have the drug release and
mechanical properties suitable for a coating.
SUMMARY
[0006] Embodiments of the current invention relate to block
copolymers comprising a poly(hydroxyacid) or
poly(hydroxy-alkanoate) block, a block comprising a biocompatible
polymer, and a linking moiety.
[0007] In some embodiments, the poly(hydroxyacid) or
poly(hydroxy-alkanoate) are chosen from specific compounds that are
described below. Some embodiments select the biologically
compatible polymer to be poly(ethylene glycol) or other polymers
that are described below.
[0008] Some embodiments select the linking moiety from dicarboxylic
acids, diacid chlorides, anhydrides, or from a diisocyanate. In
some cases the dicarboxylic acid is selected from specific
compounds that are discussed below.
[0009] Invention block polymers can have the following formula
##STR00001## [0010] wherein A are poly(hydroxyacid) or
poly(hydroxy-alkanoate) blocks, B are blocks of polymeric
biocompatible moiety, X is a linking moiety, and n is an integer
between about 2 and about 700.
[0011] In addition to polymer embodiments, embodiments of the
current invention are directed towards methods of making the
polymers, coatings made from the polymers, and medical devices
comprising those coatings.
DETAILED DESCRIPTION
[0012] The following definitions apply:
[0013] "Biologically degradable," "biologically erodable,"
"bioabsorbable," and "bioresorbable" coatings or polymers mean
those coatings or polymers that can completely degrade or erode
when exposed to bodily fluids such as blood and that the body
gradually resorbs, absorbs, or eliminates. The processes of
breaking down, absorbing and eliminating the coating or polymer
occurs by hydrolysis, metabolic processes, enzymatic processes,
bulk or surface degradation, etc.
[0014] For purposes of this disclosure "biologically degradable,"
"biologically erodable," "bioabsorbable," and "bioresorbable" are
used interchangeably.
[0015] "Biologically degradable," "biologically erodable,"
"bioabsorbable," or "bioresorbable" stent coatings or polymers mean
those coating that, after the degradation, erosion, absorption, or
resorption process finishes, no coating remains on the stent.
"Degradable," "biodegradable," or "biologically degradable" broadly
include biologically degradable, biologically erodable,
bioabsorbable, or bioresorbable coatings or polymers.
[0016] "Biodegradability," "bioerodability," "bioabsorbability,"
and "bioresorbability" are those properties of the coating or
polymer that make the coating or polymer biologically degradable,
biologically erodable, or biologically absorbable, or biologically
resorbable.
[0017] "Bulk degradation" and "bulk-degrading" refer to degradation
processes with several hallmarks. First, the water penetration rate
into the polymeric body of the stent or coating is much faster than
the polymer hydrolysis or mass loss rate. Next, hydrolysis-induced
reduction of the polymer molecular weight occurs throughout the
polymeric stent body or stent coating. Certain spatial variations
in hydrolysis rate due to a buildup of acidic degradation products
within the polymeric body can occur and are termed the
autocatalytic effect. The acidic degradation products themselves
catalyze further polymer hydrolysis. The mass-loss phase typically
occurs later in a bulk degradation process, after the molecular
weight of the polymeric body has fallen. As a result, in an
idealized bulk-degrading case, the stent or coating mass loss,
occurs throughout the entire stent or the coating rather than just
at the surface.
[0018] 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.
[0019] The term "AB block-copolymer" is defined as a
block-copolymer having moieties A and B arranged according to the
general formula -{[A-].sub.m-[B].sub.n}-.sub.x, where each of "m,"
"n," and "x" is a positive integer, and m.gtoreq.2, and
n.gtoreq.2.
[0020] The term "ABA block-copolymer" is defined as a
block-copolymer having moieties A and B arranged according to the
general formula -{[A-].sub.m-[B-].sub.n-[A].sub.p}-.sub.x, where
each of "m," "n," "p," and "x" is a positive integer, and
m.gtoreq.2, and n.gtoreq.2, and p.gtoreq.2.
[0021] 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 are such as to 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.
[0022] The term "poly(hydroxyacid)" refers to polymeric
hydroxyacids. Hydroxyacids are substances having at least one
hydroxyl group ands at least one carboxyl group.
[0023] The term "poly(hydroxy-alkanoate)" refers to polymeric
hydroxy-alkanoates. Hydroxy-alkanoates are esters of
hydroxyacids.
[0024] 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 any of the following four
layers or layer combinations: [0025] a primer layer; [0026] a
drug-polymer layer (also referred to as "reservoir" or "reservoir
layer") or alternatively a polymer-free drug layer; [0027] a
topcoat layer; or [0028] a finishing coat layer.
[0029] Each coating layer can be formed by dissolving the polymer
or polymer blend in a solvent, or a solvent mixture, and applying
that solution by spraying it onto the device or immersing the
device into the solution. After this application, the coating dries
by evaporation. Drying at an elevated temperature accelerates the
process. The coating can be annealed between about 40.degree. C.
and about 150.degree. C. for between about 5 minutes and about 60
minutes. In some embodiments, annealing the coating improves its
thermodynamic stability. Some embodiments require annealing; some
embodiments specifically exclude annealing.
[0030] To incorporate a drug into the reservoir layer, the drug can
be combined with the polymer solution that is applied onto the
device, as described above. Alternatively, a polymer-free reservoir
can be made. Some embodiments desiring rapid drug release use
polymer-free drug reservoirs. To fabricate a polymer free
reservoir, the drug can be dissolved in a suitable solvent or
mixture of solvents, and the resulting drug solution can be applied
on the stent by spraying or immersing the stent in the drug
solution.
[0031] Alternatively, the drug can be introduced as a colloid
system, such as a suspension in an appropriate solvent phase.
Depending on a variety of factors, e.g., the nature of the drug,
those having ordinary skill in the art can select the suspension
solvent the solvent phase of the suspension, as well as the
quantity of the drug to be dispersed in it. The suspension can be
mixed with a polymer solution and the mixture can be applied on the
device as described above. The drug's suspension is applied on the
device without being mixed with the polymer solution.
[0032] The drug-polymer layer can be applied directly onto at least
part of the device surface to store at least one active agent or a
drug that is incorporated into the reservoir layer. The optional
primer layer can be applied between the device and the reservoir.
In some embodiments, this improves the adhesion of the drug-polymer
layer to the device. The optional topcoat layer can be applied over
at least a portion of the reservoir layer and can serve as a rate
limiting membrane, which helps to control the drug release rate. In
one embodiment, the topcoat layer can be essentially free from
active agents or drugs. If a topcoat layer is used, the optional
finishing coat layer can be applied over at least a portion of the
topcoat layer for further control of the drug release rate and for
improving coating biocompatibility. Without a topcoat layer, the
finishing coat layer can be deposited directly on the reservoir
layer.
[0033] Release of a drug from a coating having both topcoat and
finishing coat layers includes at least three steps. First, the
polymer of the topcoat layer absorbs a drug at the
drug-polymer-topcoat-layer interface. Next, the drug diffuses
through the free volume between the topcoat layer macromolecules.
Next, the drug arrives at the topcoat-finishing layer interface.
Finally, the drug similarly diffuses through the finishing coat
layer, arrives at the finish coat layer's outer surface, and these
desorb from it into the surrounding tissue or bloodstream.
Consequently, topcoat and finishing coat layer combinations, if
used, can serve as a rate limiting barrier. The drug can be
released through the degradation, dissolution, or erosion of the
layer.
[0034] In one embodiment, any or all of the layers of the device
coating, can be made of a biologically degradable, erodable,
absorbable, or resorbable polymer. In another embodiment, the
outermost layer of the coating can be limited to such a
polymer.
[0035] To illustrate in more detail, in a 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 degradable, erodable, absorbable, or resorbable. In
this case, the remaining layers (i.e., the primer, the reservoir
layer, the topcoat layer) can also comprise a biologically
degradable polymer, which can be the same or different in each
layer.
[0036] If a finishing coat layer is not used, the topcoat layer can
be the outermost layer and can be made of a biologically degradable
polymer. In these or other embodiments, the remaining layers (i.e.,
the primer and the reservoir layer) can also comprise a
biologically degradable polymer, which can be the same or different
in each of the three layers.
[0037] If neither a finishing coat layer nor a topcoat layer is
used, the device coating may have only two layers, the primer, and
the reservoir. The reservoir in this case is the outermost layer of
the device coating and can comprise biologically degradable
polymer. Optionally, the primer can also comprise a biologically
degradable polymer. The two layers can comprise the same or
different materials.
[0038] The biological degradation, erosion, absorption or
resorption of a biologically degradable, erodable, absorbable or
resorbable polymer can increase the drug release rate due to the
gradual disappearance of the reservoir polymer, the topcoat layer,
or both. Whether the release rate increases depends on the drug
release rate versus the polymer degradation, erosion, and
adsorption or resorption rate. By choosing an appropriate polymer,
drug-to-polymer ratio, or concentration, and coating design, the
coating can provide either fast or slow drug release, as desired.
By choice of the PEG or hydrophilic component content, the hydroxy
acid ester bond lability, the polymer molecular weight, in coating
design, the polymer can be engineered to show fast or slow
degradation. Those having ordinary skill in the art can determine
whether a coating having slow or fast release rate is advisable for
a particular drug. For example, fast release may be recommended for
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).
[0039] Biologically degradable, erodable, absorbable, or resorbable
polymers that can be used for making any of the stent coating
layers include at least one of poly(hydroxyacids), or derivatives
thereof, such as poly(hydroxy-alkanoates), or any combination
thereof. Examples of poly(hydroxyacids) include any of poly(lactic
acids), i.e., poly(D,L-lactic acid) (DLPLA), poly(D-lactic acid),
poly(L-lactic acid), poly(L-lactide), poly(D-lactide),
poly(D,L-lactide), poly(caprolactone), poly(.beta.-butyrolactone),
poly(valerolactone), poly(glycolide), poly(3-hydroxyvaleric acid
(.beta.-lactone), and poly(dioxanone). Some embodiments
specifically exclude any one of or any combination of these
poly(hydroxyacids).
[0040] Poly(lactic acid), H--[O--CH(CH.sub.3)--C(O)].sub.n--OH, can
be obtained by ring-opening polymerization of lactide (a cyclic
dimer of lactic acid), as demonstrated schematically by Reaction I,
where lactide is compound (A) and poly(lactic acid) is compound
(B):
##STR00002##
[0041] The number average molecular weight of poly(lactides) can be
between about 5,000 and about 300,000 Daltons, corresponding to the
value of the integer n in the compound (B) between about 69 and
about 4,166. Those having ordinary skill in the art can determine
the conditions under which the transformation of lactide to
poly(lactide) illustrated by Reaction I can be carried out.
[0042] Polymers including poly(hydroxyacid) or
poly(hydroxy-alkanoate) moieties that can be used include
block-copolymers illustrated by Formula I:
##STR00003##
[0043] wherein A are blocks of a poly(hydroxyacids) or a
poly(hydroxy-alkanoate), B are blocks of a polymeric biocompatible
moiety, X is a linking moiety, and n is an integer having a value
between about 1 and about 880, such as, about 2 and about 350, or
about 4 and about 175.
[0044] A-Blocks
[0045] The number average molecular weight of a poly(hydroxyacid)
or poly(hydroxy-alkanoate) A-blocks can be between about 72 and
about 100,000 Daltons, more narrowly, between about 360 and about
30,000 Daltons, or about 1000 Daltons.
[0046] Instead of poly(lactides), other poly(hydroxyacid) or
poly(hydroxy-alkanoate) A-blocks can compose the block-copolymer of
Formula I. Examples of some of the poly(hydroxy-alkanoates) that
can be used for making the alternative A-blocks include: [0047]
poly(3- or 4-hydroxybutyrate) (3-PHB or 4-PHB); [0048]
poly(3-hydroxyvalerate) (3-PHV); [0049]
poly(3-hydroxybutyrate-co-valerate) (3-PHB-3-HV); [0050]
poly(caprolactone) (PCL); [0051] poly(lactide-co-glycolide) (PLGA);
[0052] poly(L-lactide); [0053] poly(D-lactide); [0054]
poly(D,L-lactide); [0055] poly(L-lactide-co-glycolide); [0056]
poly(D,L-lactide-co-glycolide); [0057]
poly(L-lactide-co-caprolactone); [0058]
poly(D,L-lactide-co-caprolactone); [0059]
poly(glycolide-co-caprolactone); [0060]
poly(L-lactide-co-D,L-lactide); [0061]
poly(L-lactide-co-trimethylene carbonate); [0062]
poly(D,L-lactide-co-trimethylene carbonate); [0063]
poly(glycolide-co-trimethylene carbonate); [0064] poly(L-lactic
acid); [0065] poly(D-lactic acid); or [0066] poly(D,L-lactic
acid)
[0067] Any mixture of compounds of the groups described above can
be also used. In some embodiments, these compounds are selected
such that they exclude any one or any combination of the groups
described above.
[0068] B. B-Blocks
[0069] B-blocks are biologically compatible polymers. Examples of
suitable biocompatible moieties include: [0070] poly(alkylene
glycols), for example, PEG, poly(L-lysine)-graft-co-poly(ethylene
glycol), poly(ethylene oxide), polypropylene glycol) (PPG),
poly(tetramethylene glycol), or poly(ethylene oxide-co-propylene
oxide); [0071] poly(N-vinyl pyrrolidone); poly(acrylamide methyl
propane sulfonic acid) (AMPS) and salts thereof; [0072]
poly(styrene sulfonate); sulfonated dextran; [0073]
polyphosphazenes; [0074] poly(orthoesters); [0075] poly(tyrosine
carbonate); [0076] hyaluronic acid and derivatives thereof, for
example, 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; [0077]
heparin and derivatives thereof, for example, copolymers of PEG
with heparin; or copolymers thereof; [0078] poly(2-hydroxyethyl
methacrylate); [0079] a graft copolymer of poly(L-lysine) and
poly(ethylene glycol) and mixtures thereof; [0080]
poly(2-hydroxyethyl methacrylate); [0081] poly(3-hydroxypropyl
methacrylate); or [0082] poly(3-hydroxypropyl methacrylamide).
[0083] Any mixture of the compounds of these groups can be also
used. Some embodiments select these compounds such that any one or
any combination of these groups or compounds is specifically
excluded.
[0084] In some embodiments, the molecular weight of a suitable
biocompatible polymeric moiety is chosen such that the patient's
kidneys can clear the material from the patient's bloodstream. A
molecular weight of a suitable biocompatible polymeric moiety can
be below 40,000 Daltons to ensure the renal clearance of the
compound, or between about 100 and about 40,000 Daltons, between
about 300 and about 20,000 Daltons, or about 1000 Daltons.
[0085] C. Linking Moiety X
[0086] The linking moiety X in block-copolymer (II) serves to
connect two adjacent interior poly(hydroxyacid) or
poly(hydroxy-alkanoate) blocks. Moiety X can be derived from a
dicarboxylic acid, (HOOC--(CH.sub.2).sub.y--COOH), from its
anhydride, from an acid chloride, from a diisocyanate, such as
hexamethylene diisocyanate, 1,4-diisocyanatocyclohexane, or lysine
diisocyanate, in which the carboxyl has been converted to an ester
or other non-reactive group. One example of a dicarboxylic acid
that can be used is succinic acid. Examples of some other
dicarboxylic acids that can be used are summarized in Table 1.
TABLE-US-00001 TABLE I Dicarboxylic Acid
(HOOC--(CH.sub.2).sub.y--COOH) y Formula Name 0 HOOC--COOH oxalic
(ethanedioic) acid 1 HOOC--CH.sub.2--COOH malonic (propanedioic) 3
HOOC--(CH.sub.2).sub.3--COOH glutaric (pentanedioic) acid 4
HOOC--(CH.sub.2).sub.4--COOH adipic (hexanedioic) acid 5
HOOC--(CH.sub.2).sub.5--COOH pimelic (heptanedioic) acid 6
HOOC--(CH.sub.2).sub.6--COOH suberic (octanedioic) acid 7
HOOC--(CH.sub.2).sub.7--COOH azelaic (nonanedioic acid) 8
HOOC--(CH.sub.2).sub.8--COOH sebacic (decanedioic) acid 9
HOOC--(CH.sub.2).sub.9--COOH nonane-1,9-dicarboxylic
(undecanedioic) acid 10 HOOC--(CH.sub.2).sub.10--COOH
decane-1,10-dicarboxylic (dodecanedioic) acid 11
HOOC--(CH.sub.2).sub.11--COOH brassylic (tridecanedioic) acid 12
HOOC--(CH.sub.2).sub.12--COOH dodecane-1,12-dicarboxylic
(tetradecanedioic) acid 13 HOOC--(CH.sub.2).sub.13--COOH
tridecane-1,13-dicarboxylic (pentadecanedioic) acid 14
HOOC--(CH.sub.2).sub.14--COOH thapsic (hexadecanedioic) acid NA
HOOC--(C.sub.6H.sub.4)--COOH terephthalic acid NA
HOOC--(C.sub.2H.sub.2)--COOH fumaric acid NA
HOOC--(C.sub.2H.sub.2)--COOH maleic acid NA
HOOC--(CH.sub.2COCH.sub.2)--COOH 1,3-acetonedicarboxylic acid
[0087] Any mixture of dicarboxylic acids shown in
[0088] Table I, or their anhydrides, can be also used. In some
embodiments, the dicarboxylic acid is specifically selected to
exclude any one or any combination of the acids listed in
[0089] Table I.
[0090] Block-copolymer shown by Formula I can be synthesized by
standard methods known to those having ordinary skill in the art,
for example, polycondensation of PEG with PLA, followed by reaction
with a dicarboxylic acid or anhydride, or acid chloride, or
chloroanhydride.
[0091] One way of synthesizing a Formula I block-copolymer is a
two-step process, comprising, first, ring opening polymerization
and, second, a coupling step. Ring opening polymerization comprises
reacting lactide with PEG, where PEG is used as a macroinitiator.
Condensation can occur at an elevated reaction temperature (about
140.degree. C.), neat or in a solvent, such as toluene, in the
presence of stannous octanoate. to this yields a
hydroxyl-terminated, triblock-copolymer PLA-PEG-PLA. Coupling
comprises further reacting the PLA-PEG-PLA triblock-copolymer with
a dicarboxylic acid or anhydride to connect the chains. For
example, succinic or adipic, acid or anhydride can be used as the
dicarboxylic acid. Coupling can be carried out in the presence of a
coupling agent, such as 1,3-dicyclohexylcarbodiimide (DCC). Instead
of DCC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) can be
used. With carbodiimides, a catalyst such as
N-dimethylaminopyridine (DMAP), diazabicycloundecane (DBU),
N-(methylpolystyrene)-4-(methylamino)pyridine, or
4-pyrrolidinopyridine is used in coupling. Instead of the
dicarboxylic acid or anhydride, a diisocyanate or diacid chloride
can be used.
[0092] In some embodiments, using succinic anhydride as an
anhydride, the obtained block copolymer, as in Formula I, can
obtained, in which poly(D,L-lactide) serves as A-blocks,
poly(ethylene-glycol) as B-blocks, and the succinic-acid-derived
group, --CO--(CH.sub.2).sub.12--COOH--, serves as the linking
moiety X. One possible structure of such a block-copolymer is shown
by Formula II:
##STR00004##
[0093] The block-copolymer shown by Formula II can have a total
number-average molecular weight between about 2000 and about
200,000 Daltons, or about 45,000 Daltons. The value of the integer
m can be between about 2 and about 700, or about 10. The value of
the integer n can be between about 2 and about 700, or about 10.
The value of the integer x can be between about 5 and about 100, or
about 14. The value of the integer y can be between about 2 and
about 700, or about 10. The value of the integer z can be between
about 2 and about 700, or about 10. The value of the integer a can
be between about 5 and about 100, or about 14. The value of the
integer b can be between about 2 and about 700, or about 10.
[0094] In these or other embodiments, instead of dicarboxylic acid
or anhydride, a chloroanhydride of a dicarboxylic acid can be used
in chain extending. For example, adipoyl, sebacyl, or terephthaloyl
chloride can be used. In this reaction, HCl, which is released as a
by-product, can be neutralized to avoid hydrolyzing the PLA blocks.
Common neutralizing agents are triethylamine and pyridine. Those
having ordinary skill in the art can determine how to neutralize
HCl. In some embodiments, a bromoanhydride of a dicarboxylic acid
can be used in chain extending.
[0095] According to another embodiment of the present invention,
the step sequence can be reversed. Condensation can comprise
reacting an alpha-hydroxy acid, such as lactic acid, with a
dicarboxylic acid or anhydride, to obtain a poly(lactic
acid)-dicarboxylic acid adduct with carboxyl end groups. Coupling
comprises further reacting the PLA-dicarboxylic acid adduct with a
hydroxy-terminated, biocompatible molecules such as PEG. Coupling
can be carried out in the presence of a coupling agent, such as DCC
or, alternatively, EDC, and a catalyst such as DMAP. This scheme
gives rise to a very similar multi-block copolymer with the
formula:
##STR00005##
[0096] where the A and B blocks are defined as before.
[0097] According to yet another embodiment of the invention, a
block copolymer is made wherein the poly(hydroxy acid) and
polymeric, biocompatible moieties are reacted separately, and then
coupled. Specifically, a first block is made by reacting a
hydroxy-terminated polymeric, biocompatible moiety, such as PEG
with a diacid or anhydride as shown below in Reaction II.
##STR00006##
[0098] A second block is made by ring opening polymerization with a
cyclic hydroxy-alkanoate, such as lactide, using a dihydric
initiator, such as 1,3-propanediol, as shown in Reaction III.
##STR00007##
[0099] These two blocks are then coupled together using a coupling
agent, such as DCC or EDC, facilitated by a catalyst such as
N-dimethylaminopyridine (DMAP), diazabicycloundecane (DBU),
N-(methylpolystyrene)-4-(methylamino)pyridine, or
4-pyrrolidinopyridine. This embodiment may be described by Formula
III, below:
##STR00008##
[0100] wherein, A-blocks and B-blocks, and linking moiety X are as
described before. Linking moiety Y is a dihydric moiety that can be
ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol,
1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol,
1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol,
1,12-dodecanediol, 1,4-cyclohexanedimethanol,
1,4-hydroxymethylbenzene, serinol, dihydroxyacetone, any linear or
branched C.sub.2 to C.sub.12 hydrocarbon with two primary hydroxyl
groups, and any linear or branched C.sub.2 to C.sub.12 with
unsaturation and two primary hydroxyl groups. In some embodiments,
the Y-moiety is selected to specifically exclude any one or any
combination of those listed above.
[0101] Any layer of the coating can contain any amount of the
bioabsorbable polymer(s) described above, or a blend of more than
one such polymer. If less than 100% of the layer comprises a
bioabsorbable polymer(s) described above, other, alternative,
polymers can comprise the balance. Examples of the alternative
polymers that can be used include polyacrylates, such as poly(butyl
methacrylate), poly(ethyl methacrylate), poly(ethyl
methacrylate-co-butyl methacrylate), poly(acrylonitrile),
poly(ethylene-co-methyl methacrylate),
poly(acrylonitrile-co-styrene), and poly(cyanoacrylates);
fluorinated polymers or copolymers, such as poly(vinylidene
fluoride) and poly(vinylidene fluoride-co-hexafluoro propene);
poly(N-vinyl pyrrolidone); polydioxanone; polyorthoester;
polyanhydride; poly(L-lactide); poly(D,L-lactide); poly(D-lactide);
poly(glycolide); poly(lactide-co-glycolide); poly(caprolactone);
poly(3-hydroxybutyrate); poly(4-hydroxybutyrate);
poly(3-hydroxybutyrate-co-3-hydroxyvalerate); poly(glycolic acid);
poly(glycolic acid-co-trimethylene carbonate); polyphosphoester;
polyphosphoester urethane; poly(amino acids); 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;
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); ABS resins; and poly(ethylene-co-vinyl acetate);
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. Some embodiments select the
alternate polymers to specifically exclude any one or any
combination of the alternate polymers listed above.
[0102] Representative examples of some solvents suitable for making
the stent coatings include N,N-dimethylacetamide (DMAC),
N,N-dimethylformamide (DMF), tetrahydrofuran (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:
[0103] DMAC and methanol (e.g., a 50:50 by mass mixture); [0104]
water, i-propanol, and DMAC (e.g., a 10:3:87 by mass mixture);
[0105] i-propanol, and DMAC (e.g., 80:20, 50:50, or 20:80 by mass
mixtures); [0106] acetone and cyclohexanone (e.g., 80:20, 50:50, or
20:80 by mass mixtures); [0107] acetone and xylene (e.g. a 50:50 by
mass mixture); [0108] acetone, FLUX REMOVER AMS, and xylene (e.g.,
a 10:50:40 by mass mixture); and [0109] 1,1,2-trichloroethane and
chloroform (e.g., an 80:20 by mass mixture).
[0110] 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 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.
[0111] Some embodiments comprise invention polymers coated onto a
medical device containing or constructed from a polymer, a medical
device containing or constructed from a metal, or a bare medical
device, or invention polymers coated on top of drug coatings
already present on a medical device. Alternatively, some
embodiments comprise invention polymers disposed between a medical
device and a drug coating. Also, some embodiments comprise
invention polymers composing polymer-based medical devices or
invention polymers composing medical device substrates (implantable
or not). Some invention embodiments comprise medical devices not
made from polymer-containing or -constructed stents. Some invention
embodiments comprise stents not made from metal-containing or
constructed stents.
[0112] In some embodiments, invention polymers serve as the base
material for coatings on medical devices. In some embodiments,
coatings may contain a primer layer. Some embodiments exclude a
primer layer. In some embodiments, invention polymers serve as a
topcoat on drug reservoir layers either that contain or do not
contain polymers. Some embodiments employ an additional polymer
layer on top of the invention polymer. This top layer can be
another layer of inventive polymer, a typical plasma polymerized
layer, a layer polymerized without a plasma source, or any
combination of these. Of these embodiments, some specifically
exclude layers of additional inventive polymers, typical plasma
polymerized layers, layers polymerized without a plasma source, or
any combination of these.
[0113] Some embodiments add conventional drugs, such as small,
hydrophobic drugs, to invention polymers (as discussed in any of
the embodiments, above), making them biostable, drug systems. Some
embodiments graft-on conventional drugs or mix conventional drugs
with invention polymers. Invention polymers can serve as base or
topcoat layers for biobeneficial polymer layers. In some
embodiments, a drug is any substance capable of exerting a
therapeutic, diagnostic, or prophylactic effect in a patient.
[0114] The selected drugs can inhibit vascular, smooth muscle cell
activity. More specifically, the drug activity can aim at
inhibiting abnormal or inappropriate migration or proliferation of
smooth muscle cells to prevent, inhibit, reduce, or treat
restenosis. The drug can also include any substance capable of
exerting a therapeutic or prophylactic effect in the practice of
the present invention. Examples of such active agents include
antiproliferative, antineoplastic, antiinflammatory, antiplatelet,
anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,
and antioxidant substances, as well as their combinations, and any
prodrugs, metabolites, analogs, congeners, derivatives, salts and
their combinations.
[0115] An example of an antiproliferative substance is actinomycin
D, or derivatives and analogs thereof (manufactured by
Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233;
or COSMEGEN available from Merck). Synonyms of actinomycin D
include dactinomycin, actinomycin IV, actinomycin I1, actinomycin
X1, and actinomycin C1. Examples of antineoplastics include
paclitaxel and docetaxel. Examples of antiplatelets,
anticoagulants, antifibrins, and antithrombins include aspirin,
sodium heparin, low molecular weight heparin, hirudin, argatroban,
forskolin, vapiprost, prostacyclin and prostacyclin analogs,
dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist, recombinant hirudin, thrombin inhibitor (available from
Biogen), and 7E-3B.RTM. (an antiplatelet drug from Centocor).
Examples of antimitotic agents include methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, adriamycin, and mutamycin.
Examples of cytostatic or antiproliferative agents include
angiopeptin (a somatostatin analog from Ibsen), angiotensin
converting enzyme inhibitors such as CAPTOPRIL (available from
Squibb), CILAZAPRIL (available from Hoffman-LaRoche), or LISINOPRIL
(available from Merck & Co., Whitehouse Station, N.J.), calcium
channel blockers (such as Nifedipine), colchicine, fibroblast
growth factor (FGF) antagonists, histamine antagonist, LOVASTATIN
(an inhibitor of HMG-CoA reductase, a cholesterol lowering drug
from Merck & Co.), monoclonal antibodies (such as PDGF
receptors), nitroprusside, phosphodiesterase inhibitors,
prostaglandin inhibitor (available from Glazo), Seramin (a PDGF
antagonist), serotonin blockers, thioprotease inhibitors,
triazolopyrimidine (a PDGF antagonist), and nitric oxide. Other
useful drugs may include alpha-interferon, genetically engineered
epithelial cells, dexamethasone, estradiol, clobetasol propionate,
cisplatin, insulin sensitizers, receptor tyrosine kinase
inhibitors, and carboplatin. Exposure of the composition to the
drug should not adversely alter the drug's composition or
characteristic. Accordingly, drug containing embodiments choose
drugs that are compatible with the composition. Rapamycin is a
suitable drug. Additionally, 40-O-(2-hydroxy)ethyl-rapamycin, or a
functional analog or structural derivative thereof, is suitable, as
well. Examples of analogs or derivatives of
40-O-(2-hydroxy)ethyl-rapamycin include, among others,
40-O-(3-hydroxy)propyl-rapamycin and
40-O-2-(2-hydroxy)ethoxyethyl-rapamycin. Those of ordinary skill in
the art know of various methods and coatings for advantageously
controlling the release rate of drugs, such as
40-O-(2-hydroxy)ethyl-rapamycin.
[0116] Some embodiments choose the drug such that it does not
contain at least one of or any combination of antiproliferative,
antineoplastic, antiinflammatory, antiplatelet, anticoagulant,
antifibrin, antithrombin, antimitotic, antibiotic, or antioxidant
substances, or any prodrugs, metabolites, analogs, congeners,
derivatives, salts or their combinations.
[0117] Some invention embodiments choose the drug such that it does
not contain at least one of or any combination of actinomycin D,
derivatives and analogs of Actinomycin D, dactinomycin, actinomycin
IV, actinomycin I1, actinomycin X1, actinomycin C1, paclitaxel,
docetaxel, aspirin, sodium heparin, low molecular weight heparin,
hirudin, argatroban, forskolin, vapiprost, prostacyclin,
prostacyclin analogs, dextran, D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist, recombinant hirudin,
thrombin inhibitor and 7E-3B, methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, adriamycin, mutamycin,
angiopeptin, angiotensin converting enzyme inhibitors, CAPTOPRIL,
CILAZAPRIL, or LISINOPRIL, calcium channel blockers, Nifedipine,
colchicine, fibroblast growth factor (FGF) antagonists, histamine
antagonist, LOVASTATIN, monoclonal antibodies, PDGF receptors,
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitor, Seramin, PDGF antagonists, serotonin blockers,
thioprotease inhibitors, triazolopyrimidine, nitric oxide,
alpha-interferon, genetically engineered epithelial cells,
dexamethasone, estradiol, clobetasol propionate, cisplatin, insulin
sensitizers, receptor tyrosine kinase inhibitors, carboplatin,
Rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, or a functional analogs
of 40-O-(2-hydroxy)ethyl-rapamycin, structural derivative of
40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin,
and 40-O-2-(2-hydroxy)ethoxyethyl-rapamycin, or any prodrugs,
metabolites, analogs, congeners, derivatives, salts or their
combinations.
[0118] Some invention embodiments comprise a drug or drug
combination, and some require a drug or combination of drugs. Of
the drugs specifically listed above, some invention embodiments
exclude a single or any combination of these drugs.
[0119] Some embodiments comprise invention polymers combined with
other polymers in multilayer arrangements. For example, an
invention polymer could under- or over-lay another polymer such as
a polymer coated on a device, a medical device, an implantable
medical device, or a stent. In some embodiments, invention polymers
do not underlay another polymer; in other embodiments, invention
polymers must overlay another polymer.
[0120] Some invention embodiments define the genera of medical
devices to exclude at least one of self-expandable stents,
balloon-expandable stents, stent-grafts, grafts (e.g., aortic
grafts), vascular grafts, artificial heart valves, cerebrospinal
fluid shunts, pacemaker electrodes, guidewires, ventricular assist
devices, artificial hearts, cardiopulmonary by-pass circuits, blood
oxygenators, or endocardial leads.
[0121] Some invention embodiments comprise multilayered structures
in which an invention polymer is present in one or more of the
layers of the multilayered structure.
[0122] The drug-polymer layer can be applied directly onto at least
a part of the medical device surface to serve as a reservoir for at
least one active agent or a drug. An optional primer layer can be
applied between the device and the reservoir to improve polymer
adhesion to the medical device. Some embodiments apply the topcoat
layer over at least a portion of the reservoir layer, and the
topcoat layer serves as a rate limiting membrane, which helps to
control the rate of release of the drug.
[0123] Implantable medical devices are also within the scope of the
invention. Examples of such implantable devices include stents,
stent-grafts, grafts (e.g., aortic grafts), artificial heart
valves, abdominal aortic aneurysm devices, cerebrospinal fluid
shunts, pacemaker electrodes, 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 alloy (ELGILOY), stainless steel
(316L), "MP35N," "MP20N," ELASTINITE (Nitinol), tantalum,
nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or
combinations thereof "MP35N" and "MP20N" are trade names for alloys
of cobalt, nickel, chromium and molybdenum available from Standard
Press Steel Co. 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.
EXAMPLES
[0124] The following examples are provided to further illustrate
embodiments of the present invention.
Example 1
Synthesis of Multi-Block PEG300-Poly(D,L-Lactide), 30/70 Weight
Ratio, Coupled by Succinic Acid
[0125] To a 250 ml, three necked flask, equipped with magnetic
stirring, vacuum, and argon purge is added PEG300 (37.5 gm (0.125
mole). Using an oil bath, the PEG is heated to 105.degree. C., and
stirred under vacuum for two hours to remove water. The flask is
purged with argon, and D,L-lactide (76.94 g, 0.534 mole) is added,
and vacuum applied with stirring for another 30 minutes. After
purging with argon, the flask is heated to 140.degree. C., and
polymerization is initiated by adding 10.8 ml of a 5% (w/w)
stannous-octanoate-dry-toluene solution. After stirring for 24
hours, the reaction solution is cooled and poured into 500 ml of
cold methanol to precipitate the polymer. The polymer is washed
with methanol/petroleum ether and dried under vacuum. The triblock
copolymer from above (25 g, 4.17.times.10.sup.-4 mole) and succinic
anhydride (0.0417 g, 4.17.times.10.sup.-4 mole) is dissolved in 200
ml of anhydrous dichloromethane. To this is added
1,3-dicyclohexylcarbodiimide (0.103 g, 5.times.10.sup.-4 mole) and
4-dimethylaminopyridine (0.0012 g, 1.times.10.sup.-5 mole). After
stirring at room temperature for 24 hours, the reaction solution is
centrifuged to precipitate dicyclohexylurea and the supernatant
solution poured into 150 ml of cold methanol to precipitate the
polymer. After filtration, the polymer is washed with
methanol/petroleum ether and dried under vacuum.
Example 2
Synthesis of Multi-Block PEG600-Poly(D,L-Lactide), 10/90 Weight
Ratio, Coupled by Hexamethylene Diisocyanate
[0126] To a 250 ml, three necked flask, equipped with magnetic
stirring, vacuum, and argon purge is added PEG600 (12.5 gm (0.0208
mole). Using an oil bath, the PEG is heated to 105.degree. C., and
stirred under vacuum for two hours to remove water. The flask is
purged with argon and D,L-lactide (109.4 g, 0.76 mole) is added,
and the vacuum applied with stirring for another 30 minutes. After
purging with argon, the flask is heated to 140.degree. C., and
polymerization initiated by addition of 15.4 ml of a 5% (w/w)
solution of stannous octanoate in dry toluene. After stirring for
24 hours, 1,6-diisocyanatohexane (10.13 g, 0.0602 mole) as a 10%
solution in dry dimethylformamide is added and the solution stirred
at 140.degree. C. for another hour. The reaction solution is cooled
and poured into 500 ml of cold methanol to precipitate the polymer.
The polymer is washed with methanol/petroleum ether and dried under
vacuum. The triblock copolymer from above (25 g,
4.17.times.10.sup.-4 mole) and succinic anhydride (0.0417 g,
4.17.times.10.sup.-4 mole) is dissolved in 200 ml of anhydrous
dichloromethane. To this is added 1,3-dicyclohexylcarbodiimide
(0.103 g, 5.times.10.sup.-4 mole) and 4-dimethylaminopyridine
(0.0012 g, 1.times.10.sup.-5 mole). After stirring at room
temperature for 24 hours, the reaction solution is centrifuged to
precipitate dicyclohexylurea and the supernatant solution poured
into 150 ml of cold methanol to precipitate the polymer. After
filtration, the polymer is washed with methanol/petroleum ether and
dried under vacuum.
Example 3
Use of the Polymer from Example 1 as a Biocompatible Topcoat
[0127] A first composition can be prepared by mixing the following
components: [0128] about 2.0 mass % poly(D,L-lactide); and [0129]
the balance, acetone.
[0130] The first composition can be applied onto the surface of
bare 12 mm small VISION stent (available from Guidant Corporation).
The coating can be sprayed and dried to form a primer layer. A
spray coater can be used having a 0.014 round nozzle maintained at
ambient temperature with a feed pressure 2.5 psi (0.17 atm) and an
atomization pressure of about 15 psi (1.02 atm). About 20 .mu.g of
the coating can be applied at per one spray pass. Between the spray
passes, the stent can be dried for about 10 seconds in a flowing
air stream at about 50.degree. C. About 110 .mu.g of wet coating
can be applied. The stents can be baked at about 80.degree. C. for
about one hour, yielding a primer layer composed of approximately
100 .mu.g of poly(D,L-lactide)
[0131] A second composition can be prepared by mixing the following
components: [0132] about 2.0 mass % poly(D,L-lactide); [0133] about
1.0 mass % everolimus; and [0134] the balance, a 50/50 blend (w/w)
of acetone and 2-butanone.
[0135] The second composition can be applied onto the dried primer
layer, using the same spraying technique and equipment used for
applying the primer layer, to form the drug-polymer layer. About
180 .mu.g of wet coating can be applied followed by drying and
baking at about 50.degree. C. for about 1 hour, yielding a dry
drug-polymer layer having solids content of about 170 .mu.g.
[0136] A third composition can be prepared by mixing the following
components: [0137] about 2.0 mass % the polymer of example 1; and
[0138] the balance, a 50/50 blend (w/w) of acetone and
chloroform.
[0139] The third composition can be applied onto the dried
drug-polymer layers, using the same spraying technique and
equipment used for applying the primer and drug-polymer layers, to
form a topcoat layer. About 110 .mu.g of wet coating can be applied
followed by drying and baking at about 50.degree. C. for about 1
hour, yielding a dry topcoat layer having solids content of about
100 .mu.g.
Example 4
Use of the Polymer from Example 1 as a Drug/Polymer Reservoir
Coating
[0140] A first composition can be prepared by mixing the following
components: [0141] about 2.0 mass % poly(D,L-lactide); and [0142]
the balance, acetone.
[0143] The first composition can be applied onto the surface of
bare 12 mm small VISION stent (available from Guidant Corporation).
The coating can be sprayed and dried to form a primer layer. A
spray coater can be used having a 0.014 round nozzle maintained at
ambient temperature with a feed pressure 2.5 psi (0.17 atm) and an
atomization pressure of about 15 psi (1.02 atm). About 20 .mu.g of
the coating can be applied at per one spray pass. Between the spray
passes, the stent can be dried for about 10 seconds in a flowing
air stream at about 50.degree. C. About 110 .mu.g of wet coating
can be applied. The stents can be baked at about 80.degree. C. for
about one hour, yielding a primer layer composed of approximately
100 .mu.g of poly(D,L-lactide)
[0144] A second composition can be prepared by mixing the following
components: [0145] about 2.0 mass % the polymer of example 2;
[0146] about 0.5%; paclitaxel [0147] the balance, a 50/50 blend
(w/w) of acetone and chloroform.
[0148] The second composition can be applied onto the dried primer
layer, using the same spraying technique and equipment used for
applying the primer layer, to form the drug-polymer layer. About
150 .mu.g of wet coating can be applied followed by drying and
baking at about 50.degree. C. for about 1 hour, yielding a dry
drug-polymer layer having solids content of about 140 .mu.g.
[0149] 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 the embodiments of this invention in its broader
aspects and, therefore, the appended claims are to encompass within
their scope all such changes and modifications as fall within the
true spirit and scope of the embodiments of this invention.
[0150] Additionally, various embodiments have been described above.
For convenience's sake, combinations of aspects (such as monomer or
initiator type) composing invention embodiments have been listed in
such a way that one of ordinary skill in the art may read them
exclusive of each other when they are not necessarily intended to
be exclusive. But a recitation of an aspect for one embodiment is
meant to disclose its use in all embodiments in which that aspect
can be incorporated without undue experimentation. In like manner,
a recitation of an aspect as composing part of an embodiment is a
tacit recognition that a supplementary embodiment exists in which
that aspect specifically excludes that aspect.
[0151] Moreover, some embodiments recite ranges. When this is done,
it is meant to disclose the ranges as a range, and to disclose each
and every point within the range, including end points. For those
embodiments that disclose a specific value or condition for an
aspect, supplementary embodiments exist that are otherwise
identical, but that specifically include the value or the
conditions for the aspect.
* * * * *