U.S. patent application number 14/996555 was filed with the patent office on 2016-05-12 for medical devices having bioerodable layers for the release of therapeutic agents.
The applicant listed for this patent is BOSTON SCIENTIFIC SCIMED, INC.. Invention is credited to Peter G. Edelman, Jeffrey S. Lindquist.
Application Number | 20160129165 14/996555 |
Document ID | / |
Family ID | 40329282 |
Filed Date | 2016-05-12 |
United States Patent
Application |
20160129165 |
Kind Code |
A1 |
Lindquist; Jeffrey S. ; et
al. |
May 12, 2016 |
MEDICAL DEVICES HAVING BIOERODABLE LAYERS FOR THE RELEASE OF
THERAPEUTIC AGENTS
Abstract
According to an aspect of the present invention, medical devices
are provided which comprise: (a) a substrate and (b) bioerodable
polymeric layer over the substrate that contains (i) one or more
biodegradable polymers (ii) one or more therapeutic agents, and
(iii) one or more plasticizers.
Inventors: |
Lindquist; Jeffrey S.;
(Maple Grove, MN) ; Edelman; Peter G.; (Maple
Grove, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BOSTON SCIENTIFIC SCIMED, INC. |
Maple Grove |
MN |
US |
|
|
Family ID: |
40329282 |
Appl. No.: |
14/996555 |
Filed: |
January 15, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11900980 |
Sep 14, 2007 |
9248219 |
|
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14996555 |
|
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Current U.S.
Class: |
424/426 ;
514/449 |
Current CPC
Class: |
A61L 33/0052 20130101;
A61L 31/148 20130101; A61L 31/141 20130101; A61L 29/141 20130101;
A61L 27/502 20130101; A61L 31/10 20130101; A61L 2300/604 20130101;
A61L 31/16 20130101; A61F 2002/30062 20130101; A61L 2300/204
20130101; A61L 31/10 20130101; C08L 67/04 20130101; A61L 2420/08
20130101 |
International
Class: |
A61L 31/14 20060101
A61L031/14; A61L 31/10 20060101 A61L031/10; A61L 31/16 20060101
A61L031/16 |
Claims
1. A medical device comprising: a substrate; and a bioerodable
polymeric layer disposed over the substrate, the bioerodable
polymeric layer including poly(lactic acid) or poly(lactic
acid-co-glycolic acid) and a plasticizer selected from glycolic
acid, an oligomer comprising glycolic acid, and combinations
thereof.
2. The medical device of claim 1, wherein the substrate comprises a
stent.
3. The medical device of claim 1, wherein the bioerodable polymeric
layer further comprises a therapeutic agent.
4. The medical device of claim 3, wherein the therapeutic agent is
selected from antiproliferative agents, anti-thrombotic agents,
anti-angiogenic agents, anti-restenotic agents, anti-inflammatory
agents, anti-migratory agents, agents affecting extracellular
matrix production and organization, antineoplastic agents,
anti-mitotic agents, anesthetic agents, anti-coagulants, vascular
cell growth promoters, vascular cell growth inhibitors,
cholesterol-lowering agents, vasodilating agents, agents that
interfere with endogenous vasoactive mechanisms, and combinations
thereof.
5. The medical device of claim 1, wherein the plasticizer comprises
glycolic acid.
6. The medical device of claim 1, wherein the plasticizer comprises
an oligomer comprising glycolic acid.
7. The medical device of claim 1, wherein the plasticizer comprises
a combination of glycolic acid and an oligomer comprising glycolic
acid.
8. The medical device of claim 1, wherein the bioerodable polymeric
layer is disposed over a portion of the substrate.
9. The medical device of claim 1, wherein the bioerodable polymeric
layer is disposed over all of the substrate.
10. A stent comprising: a substrate; and a bioerodable polymeric
layer disposed over the substrate, the bioerodable polymeric layer
including poly(lactic acid) or poly(lactic acid-co-glycolic acid)
and a plasticizer selected from glycolic acid, an oligomer
comprising glycolic acid, and combinations thereof.
11. The stent of claim 10, wherein the stent has an abluminal
surface and a luminal surface, and the biodegradable polymeric
layer is disposed over the abluminal surface, but not the luminal
surface.
12. The stent of claim 10, wherein the substrate comprises a
metallic substrate.
13. The stent of claim 10, wherein the stent comprises a polymeric
substrate.
14. The stent of claim 10, wherein the biodegradable polymeric
layer comprises poly(lactic acid-co-glycolic acid), and the
poly(lactic acid-co-glycolic acid) comprises 30 to 100 wt % lactic
acid and 0 to 70 wt % glycolic acid.
15. The stent of claim 10, wherein the biodegradable polymeric
layer has a number average molecular weight of 10,000 or more.
16. The stent of claim 10, wherein the biodegradable polymeric
layer has a number average molecular weight of 25,000 or more.
17. A stent comprising: a substrate; and a bioerodable polymeric
layer disposed over the substrate, the bioerodable polymeric layer
including 50 to 99 wt. % of poly(lactic acid) or poly(lactic
acid-co-glycolic acid) and 1 to 50 wt. % of glycolic acid and/or an
oligomer comprising glycolic acid.
18. The stent of claim 17, wherein the substrate comprises a
metallic substrate.
19. The stent of claim 17, wherein the stent comprises a polymeric
substrate.
20. The stent of claim 17, wherein the stent has an abluminal
surface and a luminal surface, and the biodegradable polymeric
layer is disposed over the abluminal surface, but not the luminal
surface.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/900,980, filed on Sep. 14, 2007, the entire contents of
which being incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to medical devices which are a
least partially bioerodable and which release therapeutic
agents.
BACKGROUND
[0003] Numerous polymer-based medical devices have been developed
for implantation or insertion into the body. For example, in recent
years, drug eluting coronary stents, which are commercially
available from Boston Scientific Corp. (TAXUS and PROMUS), Johnson
& Johnson (CYPHER) and others, have become the standard of care
for maintaining vessel patency. These existing products are based
on metallic balloon expandable stents with biostable polymer
coatings, which release antiproliferative drugs at a controlled
rate and total dose.
[0004] Specific examples of biostable polymers for biostable drug
eluting polymer coatings include homopolymers and copolymers, such
as poly(ethylene-co-vinyl acetate), poly(vinylidene
fluoride-co-hexafluoropropylene) and poly(isobutylene-co-styrene),
for example, poly(styrene-b-isobutylene-b-styrene triblock
copolymers (SIBS), which are described in U.S. Pat. No. 6,545,097
to Pinchuk et al. FIG. 1, which is taken from Pub. No. US
2006/0171981 to Richard et al., illustrates a release profile of a
stent coating that contains 25 wt % paclitaxel and 75 wt %
SIBS.
[0005] Biodegradable polymers may have certain advantages over
biostable polymers. For example, because they erode over time,
biodegradable polymers may reduce or eliminate long term effects
that may be associated with non-biodegradable polymers (e.g.,
foreign body effects, late stent thrombosis, etc.).
SUMMARY OF THE INVENTION
[0006] According to an aspect of the present invention, medical
devices are provided which comprise: (a) a substrate and (b)
bioerodable polymeric layer over all or a portion of the substrate
that contains (i) one or more biodegradable polymers, (ii) one or
more therapeutic agents, and (iii) one or more plasticizers.
[0007] Advantages of the present invention, in addition to those
advantages associated with biodegradable polymers that are
described above, include enhanced ability to modulate/influence one
or more of the following: a) therapeutic agent release behavior of
the bioerodable layer, b) rate of bioerosion of the bioerodable
layer, and/or c) mechanical properties of the bioerodable
layer.
[0008] Other aspects and embodiments of the invention, as well as
various additional advantages of the same, will become readily
apparent to those of ordinary skill in the art upon reading the
disclosure to follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a plot of percent paclicaxel release as a function
of time from a stent coating that contains 25 wt % paclitaxel and
75 wt % SIBS, in accordance with Pub. No. US 2006/0171981 to
Richard et al.
[0010] FIG. 2A is a schematic perspective view of a coronary stent,
in accordance with an embodiment of the invention. FIG. 2B is a
schematic cross-sectional view taken along line b-b of FIG. 2A.
[0011] FIGS. 3 and 4A-4B are further schematic cross-sectional
views of stent struts, in accordance with various embodiments of
the invention.
[0012] FIG. 5 illustrates various hypothetical release
profiles.
DETAILED DESCRIPTION OF THE INVENTION
[0013] According to an aspect of the present invention, medical
devices are provided which comprise: (a) a substrate and (b)
bioerodable polymeric layer over all or a portion of the substrate
that contains (i) one or more (i.e., blends of) biodegradable
polymers, (ii) one or more therapeutic agents, and (iii) one or
more plasticizers.
[0014] As discussed further below, in certain embodiments of the
invention, a further bioerodable polymeric layer is provided, which
contains one or more biodegradable polymers and one or more
therapeutic agents, and which may or may not contain one or more
plasticizers. The bioerodable polymeric layers may be provided, for
example, over, under, or lateral to one another.
[0015] In certain embodiments of the invention, polymeric layers
for use in the medical devices of the invention may contain, for
example, (a) from 50 wt % or less to 60 wt % to 70 wt % to 80 wt %
to 90 wt % to 95 wt % to 97.5 wt % to 99 wt % or more of one or
more types of biodegradable polymers, (b) from 1 wt % or less to
2.5 wt % to 5 wt % to 10 wt % to 20 wt % to 30 wt % or more of one
or more types of therapeutic agent and (c) from 0 wt % to 1 wt % to
2.5 wt % to 5 wt % to 10 wt % to 20 wt % to 30 wt % to 40 wt % to
50 wt % or more of one or more types of plasticizers.
[0016] "Therapeutic agents," "drugs," "pharmaceutically active
agents," "biologically active materials," and other related terms
may be used interchangeably in the present disclosure.
[0017] As used herein a "layer" of a given material is a region of
that material whose thickness is small compared to both its length
and width. A layer need not be planar, for example, taking on the
contours of an underlying substrate. Layers in accordance with the
present invention may be disposed over all or a portion on an
underlying substrate and can be discontinuous (e.g., patterned).
Terms such as "film," "layer" and "coating" may be used
interchangeably herein.
[0018] As used herein, a "polymeric layer" is one that contains one
or more types of polymers (i.e., a single type of polymer of a
mixture of polymers). As is well known, "polymers" are molecules
that contain multiple copies (e.g., 2 to 5 to 10 to 25 to 50 to 100
to 250 to 500 to 1000 to 10,000 or more copies) of one or more
constitutional units, commonly referred to as monomers. As used
herein, the term "monomers" may refer to the free monomers and
those that are incorporated into polymers, with the distinction
being clear from the context in which the term is used. Polymers
may take on a number of configurations, which may be selected, for
example, from cyclic, linear, branched and networked (e.g.,
crosslinked) configurations. Branched configurations include
star-shaped configurations (e.g., configurations in which three or
more chains emanate from a single branch point, such as a seed
molecule), comb configurations (e.g., configurations having a main
chain and a plurality of side chains), and dendritic configurations
(e.g., arborescent and hyperbranched polymers), among others.
Depending on the polymer structure, the polymer may contain
amorphous regions or a mixture of amorphous and crystalline regions
(known as semicrystalline). As used herein, "homopolymers" are
polymers that contain multiple copies of a single type of monomer.
"Copolymers" are polymers that contain multiple copies of at least
two different monomers, examples of which include random,
statistical, gradient, periodic (e.g., alternating), and block
copolymers.
[0019] As used herein, a polymer is "biodegradable" if it undergoes
bond cleavage along the polymer backbone in vivo, regardless of the
mechanism of bond cleavage (e.g., enzymatic breakdown, hydrolysis,
oxidation, etc.).
[0020] As used herein, a polymer is "biostable" if it does not
undergo substantial bond cleavage along the polymer backbone in
vivo.
[0021] "Bioerosion" or "bioabsorption" of a polymeric component
(e.g., a polymeric layer) of a medical device is defined herein to
be a result of polymer biodegradation (as well as other in vivo
disintegration processes such as dissolution, etc.) and is
characterized by a substantial loss in vivo over time (e.g., the
period that the device is designed to reside in a patient) of the
original polymer mass of the polymeric component. "Biostablity" of
a polymeric component, on the other hand, is characterized herein
by the substantial maintenance in vivo over time of the original
polymer mass of the polymeric component. The polymer layers of the
invention are adapted to be substantially completely bioeroded
(i.e., 95 wt % to 97.5 wt % to 99 wt % to 100 wt % of the polymer
mass of each layer bioerodes) in vivo over the period that the
device is designed to reside in a patient.
[0022] As used herein a "plasticizer" is a substance that, when
added to a polymeric component, changes the polymer one or more
ways relative to the same polymeric component without the
plasticizer. The most commonly measured effect of a plasticizer is
a lowering in the glass transition (Tg) of a polymer as measured by
Differential Scanning calorimetry (DSC) or a change mechanical
properties such as the tan delta. For a device coated with a
polymeric coating layer containing a therapeutic agent, other
beneficial effects that may be imparted to the coating include
modulation of the drug release rate and improved coating mechanical
properties.
[0023] Examples of medical devices benefiting from the present
invention vary widely and include implantable or insertable medical
devices from which one or more therapeutic agents may be delivered,
for example, stents (including coronary vascular stents, peripheral
vascular stents, cerebral, urethral, ureteral, biliary, tracheal,
gastrointestinal and esophageal stents), stent coverings, stent
grafts, vascular grafts, abdominal aortic aneurysm (AAA) devices
(e.g., AAA stents, AAA grafts), vascular access ports, dialysis
ports, catheters (e.g., urological catheters or vascular catheters
such as balloon catheters and various central venous catheters),
guide wires, balloons, filters (e.g., vena cava filters and mesh
filters for distil protection devices), embolization devices
including cerebral aneurysm filler coils (including Guglielmi
detachable coils and metal coils), septal defect closure devices,
drug depots that are adapted for placement in an artery for
treatment of the portion of the artery distal to the device,
myocardial plugs, patches, pacemakers, leads including pacemaker
leads, defibrillation leads, and coils, ventricular assist devices
including left ventricular assist hearts and pumps, total
artificial hearts, shunts, valves including heart valves and
vascular valves, anastomosis clips and rings, cochlear implants,
tissue bulking devices, and tissue engineering scaffolds for
cartilage, bone, skin and other in vivo tissue regeneration,
sutures, suture anchors, tissue staples and ligating clips at
surgical sites, cannulae, metal wire ligatures, urethral slings,
hernia "meshes", artificial ligaments, tacks for ligament
attachment and meniscal repair, joint prostheses, orthopedic
prosthesis such as bone grafts, bone plates, fins and fusion
devices, orthopedic fixation devices such as interference screws in
the ankle, knee, and hand areas, rods and pins for fracture
fixation, screws and plates for craniomaxillofacial repair, dental
implants, or other devices that are implanted or inserted into the
body and from which therapeutic agent is released.
[0024] The medical devices of the present invention thus include,
for example, implantable and insertable medical devices that are
used for systemic diagnosis and treatment, as well as those that
are used for the localized diagnosis and treatment of any mammalian
tissue or organ. Non-limiting examples are tumors; organs including
the heart, coronary and peripheral vascular system (referred to
overall as "the vasculature"), the urogenital system, including
kidneys, bladder, urethra, ureters, prostate, vagina, uterus and
ovaries, eyes, ears, spine, nervous system, lungs, trachea,
esophagus, intestines, stomach, brain, liver and pancreas, skeletal
muscle, smooth muscle, breast, dermal tissue, cartilage, tooth and
bone.
[0025] As used herein, "treatment" refers to the prevention of a
disease or condition, the reduction or elimination of symptoms
associated with a disease or condition, or the substantial or
complete elimination of a disease or condition. Preferred subjects
are vertebrate subjects, more preferably mammalian subjects and
more preferably human subjects.
[0026] Examples of biodegradable polymers for use in the polymeric
layers of present invention may be selected from one or more (i.e.,
mixtures) suitable members of the following, among many others: (a)
polyester homopolymers and copolymers such as polyglycolic acid
(PGA), polylactic acid (PLA) including poly-L-lactic acid,
poly-D-lactic acid and poly-D,L-lactic acid,
poly(beta-hydroxybutyrate), polygluconate including
poly-D-gluconate, poly-L-gluconate, poly-D,L-gluconate,
poly(epsilon-caprolactone), poly(delta-valerolactone),
poly(p-dioxanone), poly(lactic acid-co-glycolic acid) (PLGA) which
can have a range of ratios of lactic acid to glycolic acid,
additionally with either the racemic or meso DL lactide or the pure
L-lactide, poly(lactic acid-co-delta-valerolactone), poly(lactic
acid-co-epsilon-caprolactone), poly(lactic acid-co-beta-malic
acid), poly(beta-hydroxybutyrate-co-beta-hydroxyvalerate),
poly[1,3-bis(p-carboxyphenoxy)propane-co-sebacic acid], and
poly(sebacic acid-co-fumaric acid), among others, (b) poly(ortho
ester) homopolymers and copolymers such as those synthesized by
copolymerization of various diketene acetals and diols, among
others, (c) polyanhydride homopolymers and copolymers such as
poly(adipic anhydride), poly(suberic anhydride), poly(sebacic
anhydride], poly(dodecanedioic anhydride), poly(maleic anhydride),
poly[1,3-bis(p-carboxyphenoxy)methane anhydride], and
polyalpha,omega-bis(p-carboxyphenoxy)alkane anhydrides such as
poly[1,3-bis(p-carboxyphenoxy)propane anhydride and
poly[1,3-bis(p-carboxyphenoxy)hexane anhydride], among others; (d)
polycarbonate homopolymers and copolymers such as poly(trimethylene
carbonate), poly(lactic acid-co-trimethylene carbonate) and
poly(glycolic acid-co-trimethylene carbonate), among others, and
(e) amino-acid-based polymers including tyrosine-based polyarylates
(e.g., copolymers of a diphenol and a diacid linked by ester bonds,
with diphenols selected, for instance, from ethyl, butyl, hexyl,
octyl and bezyl esters of desaminotyrosyl-tyrosine and diacids
selected, for instance, from succinic, glutaric, adipic, suberic
and sebacic acid), tyrosine-based polycarbonates (e.g., copolymers
formed by the condensation polymerization of phosgene and a
diphenol selected, for instance, from ethyl, butyl, hexyl, octyl
and bezyl esters of desaminotyrosyl-tyrosine), and tyrosine-,
leucine- and lysine-based polyester-amides; specific examples of
tyrosine-based polymers include includes polymers that are
comprised of a combination of desaminotyrosyl tyrosine hexyl ester,
desaminotyrosyl tyrosine, and various di-acids, for example,
succinic acid and adipic acid, among others.
[0027] Where one or more types of poly(lactic acid-co-glycolic
acid) (PLGA) are employed in the layers of the invention, whether
the lactic acid is D-lactic acid, L-lactic acid or a mixture of D-
and L-lactic acid, the mol % of lactic acid in PLGA for either the
inner or the outer layer may range from 1 to 99 mol %, for example,
ranging from 30 mol % or less to 40 mol % to 50 mol % to 75 mol %
to 85 mol % to 90 mol % or more.
[0028] In many embodiments, the one or more types of biodegradable
polymers will have a number average molecular weight of 10,000 or
more, for example, ranging from 10,000 to 25,000 to 50,000 to
75,000 to 100,000 to 125,000 to 150,000 or more.
[0029] As noted above, in addition to one or more biodegradable
polymers and one or more therapeutic agents, bioerodable layers
within the medical devices of the invention may also contain one or
more plasticizers in some embodiments. Without wishing to be bound
by theory, it is believed plasticizers act to increase polymer
chain mobility and free volume, improving the mechanical properties
of the polymeric layers such as flexibility. Moreover, as discussed
elsewhere herein, the addition of plasticizers can also modulate
the therapeutic agent release properties of the polymeric layers
and the biodegradation rate of the polymeric layers, among other
possible effects.
[0030] Examples of plasticizers for bioerodable layers in
accordance with the present invention include those that contain or
consist of the monomers making up the biodegradable polymer(s)
within the bioerodable layer, and they include the monomers
themselves as well as oligomers of the same (i.e., defined herein
as polymers ranging from 2 to 3 to 5 to 10 units in length), and
short polymers of the same (i.e., defined herein as polymers of 11
or more monomer units in length up to a molecular weight of 10,000)
For example, in some embodiments, the plasticizers will have a
number average molecular weight ranging from 500 to 1,000 to 2,500
to 5,000 to 7,500 to 10,000. Plasticizers therefore include
monomers, oligomers, and short polymers of the following: glycolic
acid, lactic acid (D-, L- or combinations), gluconic acid (D-, L-
or combinations), beta-hydroxybutyric acid, beta-hydroxyvaleric
acid, malic acid, epsilon-caprolactone, delta-valerolactone, as
well as various other C2-C15 hydroxy acids and C3-C15 cyclic
esters; adipic acid, adipic anhydride, suberic acid, suberic
anhydride, sebacic acid, sebacic anhydride, dodecanedioic acid,
dodecanedioic anhydride, and other C2-C15 diacids and C3-C15 cyclic
anhydrides; 1,3-Dioxan-2-one and other C3-C15 cyclic carbonates,
among many others.
[0031] For instance, where PLGA is selected as a polymer for use in
a bioerodable layer in accordance with the invention, the
plasticizer may be based on lactic acid, glycolic acid or both.
Lactic acid and glycolic acid are the natural degradation products
of PLGA and are biocompatible since they are found in the body as
metabolites and are part of the Krebs cycle. Examples of such
plasticizers include one or more of the following: glycolic acid,
glycolic acid dimer, glycolic acid trimer, further glycolic acid
oligomers and short polymers, lactic acid, lactic acid dimer,
lactic acid trimer, further lactic acid oligomers and short
polymer, glycolic acid-lactic acid dimer and other glycolic
acid-lactic acid oligomers and short polymers, wherein the forgoing
oligomers and short polymers may be linear or cyclic in
configuration. As elsewhere herein the lactic acid may be L-lactic
acid, D-lactic acid or a mixture of the same, where the relative
amounts of the L- and D-isomers can be measured using specific
rotation. Various species, including inherent short polymers,
oligomers or unreacted monomers may be distinguished using several
techniques such as gel permeation chromatography (e.g., with
columns that resolve the low molecular weight of the distribution),
end group analysis using NMR, and titration, among others.
[0032] In some embodiments, the weight ratio of the one or more
biodegradable polymers to the one or more plasticizers in the
polymeric layers ranges from 10:1 to 100:1 to 1000:1 to
10000:1.
[0033] In some embodiments, an analysis of the molecular weight of
the polymeric species within a polymeric layer in accordance with
the invention may be multimodal, for example, having one mode
corresponding to a small polymer plasticizer and another mode
corresponding to a biodegradable polymer.
[0034] As noted above, in some embodiments, plasticizers for
bioerodable layers in accordance with the present invention include
those that contain or consist of the monomers making up the
biodegradable polymer(s) within the bioerodable layer. In some
embodiments, the plasticizers may correspond to monomers, oligomers
and small polymers that comprise or consist of monomers that do not
correspond to those making up the one or more types of
biodegradable polymers within the bioerodable layers. Such
plasticizers may be water soluble or insoluble. If the plasticizing
molecule is not water soluble, it may biodegrade to water soluble
fragments. Such plasticizers may or may not be miscible with one or
more biodegradable polymers within the bioerodable layer or
immiscible.
[0035] For example, where PLGA is selected as a polymer, examples
of suitable miscible plasticizing polymers include
methoxypolyethylene glycol (MePEG) and polylactic acid-MePEG
diblock copolymer (PLA-MePEG), both of which are water soluble.
These polymers are known to plasticize PLGA polymers (50:50 and
85:15), increasing their elasticity. These polymers have also been
observed to reduce the glass transition temperature (Tg) of PLGA
polymers, thereby making otherwise brittle PLGA flexible at room
temperature. Single Tg values intermediate between the Tg values of
the pure components have been observed for blends containing PLGA
and the above plasticizing polymers, which is indicative of the
miscibility of the components. MePEG was observed to partition out
of the PLGA films in aqueous media over a period of 72 hours, with
an accompanying increase in Tg. A benefit of this behavior is that
a polymeric material (e.g., a stent coating) is plasticized during
implantation or insertion (e.g., during stent expansion in a lesion
to create intimate contact between the abluminal surface of the
stent and the artery wall). After placement, when flexibility and
durability are no longer needed, the plasticizer elutes from the
polymeric material. This may improve mechanical properties and,
where a therapeutic agent is present, shift the release profile of
the therapeutic agent to a desired range. The PLA-MePEG on the
other hand showed controlled release over a period of about 1
month, which was attributed to affinity of the polylactic acid
blocks of the PLA-MePEG with the PLGA. Addition of paclitaxel was
observed to offset somewhat the increase in elasticity arising from
the plasticizing polymers (paclitaxel has also been observed to
increase the Tg of PLA). Paclitaxel was observed to be in the form
of a particulate dispersion. Paclitaxel release from PLGA-MePEG
films was found to be very slow (less than 5% after 16 days), but
was reported to be dramatically increased for PLGA films containing
30 wt % PLA-MePEG diblock copolymer (approx. 15% after 10 days). It
was speculated that this could represent a critical loading level,
causing a significantly increase in matrix hydrophilicity and
leading to increased water uptake, the formation of water-filled
channels in the matrix, and greatly increased paclitaxel release
rates. For further information, see, e.g., J. K. Jackson et al.,
Int. J. Pharm. 283 (2004) 97-109.
[0036] Adding one or more plasticizers to polymeric layers in
accordance with the invention will, of course, provide a
plasticizing action as discussed above. This can improve the
mechanical properties of the polymeric layer, for instance,
resulting in one or more of the following, among others: increased
resistance to cracking/crazing propagation, improved
bending/modulus properties, increased fatigue resistance, and
resistance to particulate formation in vivo, both acute and
chronic, among other properties.
[0037] Adding one or more of the plasticizers can also affect the
bioerosion rate of the polymeric layer, for example, increasing the
same. For example, a plasticizer may partition out of the polymeric
layer in vivo, increasing void volume, creating a porous structure
(particularly in the case of partially phase-separated immiscible
plasticizers), and promoting the transport of water into the layer.
As another example, certain plasticizers may act as catalysts for
the biodedgradation process. For example, glycolic acid and lactic
are known to increase the degradation rate of PLGA due to a local
lowering of the pH. Where a therapeutic agent is present, adding
one or more of plasticizers can affect the rate of therapeutic
agent release from the polymeric layer. In addition to affecting
release by affecting the degradation rate of the polymer,
plasticizer addition may also have one or more of the following
effects, each of which may influence therapeutic agent release: the
plasticizer may act to lower the Tg of the polymer, the plasticizer
may create a phase-separated matrix for the therapeutic agent which
can, for example, lead to void formation (e.g., where the
plasticizer is immiscible), the plasticizer may solubilize the
therapeutic agent of interest which may, for example, lead to more
rapid diffusion from the polymer matrix, and/or the plasticizer may
drive drug to the surface based compatibility with certain species
in the polymeric layer. With respect to solubilization of the
therapeutic agent, more hydrophilic plasticizers may be selected to
dissolve more hydrophilic therapeutic agents, more hydrophobic
plasticizers may be selected to dissolve more hydrophobic
therapeutic agents, and so forth. As a specific example, where PLGA
is selected for use as the biodegradable polymer, one may wish to
select a lactic-acid-based plasticizer for more a more hydrophobic
therapeutic agent (e.g., paclitaxel) and a glycolic-acid-based
plasticizer for a more hydrophilic therapeutic agent (e.g.,
everolimus).
[0038] A stent in accordance with the present invention will now be
described with reference to the drawings. In this regard, FIG. 2A
is a schematic perspective view of a stent 100 which contains a
number of interconnected struts 100s. FIG. 2B is a schematic
cross-section taken along line b-b of the strut 100s of FIG. 2. The
stent strut 100s shown includes a stent substrate 110 and a
bioerodable polymeric layer 120 in accordance with the present
invention. An alternative embodiment is illustrated in FIG. 3,
which, like FIG. 2B, is a schematic cross-sectional view of a stent
strut. In FIG. 3, however, the polymeric layer 120 covers the
abluminal surface 10a of the stent substrate 110, but not the
opposing luminal surface 1001 or the intervening side surfaces. In
the embodiments of FIGS. 2B and 3, the bioerodable polymeric layer
120 contains one or more biodegradable polymers (i.e., a single
type of biodegradable polymer or a mixture of two or more types of
biodegradable polymers), one or more therapeutic agents (i.e., a
single type of therapeutic agent or a mixture of two or more types
of therapeutic agents), and one or more plasticizers (i.e., a
single type of plasticizer or a mixture of two or more types of
plasticizer) as described above.
[0039] In accordance with a further embodiment of the invention,
FIG. 4A, like FIGS. 2B and 3, is a schematic cross-sectional view
of a stent strut 100s. However, the stent strut 100s shown in FIG.
4A includes a stent substrate 110 an inner bioerodable polymeric
layer 120a and an outer bioerodable polymeric layer 120b, in
accordance with an embodiment of the invention. An alternative
embodiment is illustrated in FIG. 4B, which, like FIG. 4A, is a
schematic cross-sectional view of a stent strut 100s and includes a
stent substrate 110 and inner and outer bioerodable polymeric
layers 120a, 120b. In FIG. 4B, however, the inner and outer
bioerodable polymeric layers 120a, 120b are disposed over the
abluminal surface 110a of the stent substrate 110, but not the
opposing luminal surface 1001 or the intervening side surfaces.
Each of the inner and outer bioerodable polymeric layers 120a, 120b
in FIGS. 4A and 4B contains one or more biodegradable polymers
(i.e., a single type of biodegradable polymer or a mixture of two
or more types of biodegradable polymers) and one or more
therapeutic agents (i.e., a single type of therapeutic agent or a
mixture of two or more types of therapeutic agents). Moreover, one
or both of the inner and outer bioerodable polymeric layers 120a,
120b contains one or more plasticizers (i.e., a single type of
plasticizer or a mixture of two or more types of plasticizer) as
described above.
[0040] By "inner" is merely meant that the bioerodable polymeric
layer is inner relative to the outer bioerodable polymeric
layer--not that it is necessarily the innermost layer of the
device, although it can be. Similarly, by "outer" is meant that the
bioerodable polymeric layer is outer relative to the inner
bioerodable polymeric layer--not that it is necessarily the
outermost layer of the device, although it can be.
[0041] As discussed above, FIG. 1 is a release profile for a
hydrophobic drug (paclitaxel) from a biostable polymeric layer.
Biodegradable polymer layers, on the other hand, typically do not
yield release profiles like those shown in FIG. 1. By way of
background and without wishing to be bound by theory, the release
of a drug from a thin biodegradable polymeric film typically
consists of three phases. The first phase is an initial burst phase
(e.g., at days 0-10), which is due to dissolution of drug residing
on the surface of the coating. The rate of release during this
first phase may be dictated, for example, by the solubility and
rate of dissolution of the drug (e.g., drug particles) into the
surrounding media. The second phase is characterized by a slower
sustained release phase. The sustained release phase is governed by
diffusion processes, including the rate of diffusion of the drug
through the polymer matrix (which is a function of drug solubility
in the polymer, among other factors). Because the layer is
bioerodable, however, a third phase commonly ensues in which an
increase in drug release is observed, which is influenced by the
hydrolysis behavior of the polymer as it bioerodes. Eventually,
drug release ceases due to the complete degradation of the
polymeric film. For a more complete discussion of the factors that
affect the polymer degradation rate, see, e.g., S. Prabhu et al.,
"Modeling of degradation and drug release from a biodegradable
stent coating", Journal of Biomedical Materials Research, Part A,
80 (2007) 732-741.
[0042] For example, FIG. 5 is a graphical representation of a few
hypothetical cumulative release curves for release of a hydrophobic
drug (e.g., paclitaxel, among many others) from single- and
double-layer release systems that further contain a biodegradable
polyester (e.g., PLGA). FIG. 5 contains lower (dark triangles) and
upper (light triangles) hypothetical cumulative release target
curves between which it is desired to maintain cumulative drug
release.
[0043] FIG. 5 further includes a curve (diamonds) representing
hypothetical cumulative release from a slower degrading formulation
(e.g., one containing PLGA with an 85:15 wt/wt lactic acid:glycolic
acid ratio). For example, the coating may correspond to an
abluminal stent coating (e.g., 100 microgram weight) which contains
85-90 wt % 85:15 PLGA having a molecular weight of .about. 50-60
kDa and about 10-15 wt % paclitaxel. Consistent with the
description in the prior paragraph, this curve shows an initial
burst, followed by a slower sustained release phase, followed by an
increase in release, which eventually tapers off. As seen from FIG.
5, the initial burst for this curve is insufficient to surpass the
lower cumulative release target, and a sub-therapeutic dose is
released in the early stages.
[0044] The curve designated by circles in FIG. 5 represents
cumulative release from a faster degrading formula (e.g., one
containing PLGA with a 50:50 wt/wt lactic acid:glycolic acid ratio
or one containing PLGA with an 85:15 wt/wt lactic acid:glycolic
acid ratio and an added plasticizer, such as a monomer, which in
this particular hypothetical instance is provided at a level such
that the release that is observed during polymer degradation
exceeds the desired upper limit). For example, the coating may
correspond to an abluminal stent coating (e.g., 200 microgram
weight) which contains 85-90 wt % 50:50 PLGA having a molecular
weight of .about. 50-60 kDa and about 10-15 wt % paclitaxel. Like
the prior formulation (designated by diamonds), this curve shows an
initial burst, followed by a slower sustained release phase,
followed by an increase in release that eventually tapers off,
although these events happen at an earlier time. Because the
formula contains twice the amount of drug as the prior formulation,
the initial burst is sufficient surpass the lower limit. However,
the subsequent increase in release that is observed during polymer
degradation exceeds the desired upper limit, leading to a
hyper-therapeutic cumulative dose.
[0045] The hypothetical curve represented by squares in FIG. 5 is
for a two layer composition, representing a blend of two single
layer schemes. The first (underlying) layer is like that described
above for a slower degrading formula (e.g., one containing
paclitaxel and PLGA with an 85:15 wt/wt lactic acid:glycolic acid
ratio). Disposed over this layer is layer that contains plasticizer
in addition to paclitaxel and PLGA with a 85:15 lactic
acid:glycolic acid wt/wt ratio. As a specific example, the
abluminal surface of a stent may be first coated with 100
micrograms of a first layer based on 85:15 PLGA having a molecular
weight of .about. 60 kDa, which contains about 10 wt % paclitaxel
(PTx). This layer is then overcoated with 30 micrograms of a second
layer based on 85:15 PLGA having a molecular weight of .about. 60
kDa, which contains about 10 wt % PTx and about 10% lactic acid as
a monomeric plasticizer.
[0046] Thus, the present invention provides an approach whereby
plasticizers are used to modulate drug release rate and bioerosion
behavior for coatings that utilize existing 50/50, 75/25, or 85/15
composition ratio PLGA materials and mixtures thereof, among many
others, while at the same time providing improved acute and chronic
mechanical behavior (including resistance to cracking/crazing,
bending modulus properties, fatigue resistance, and resistance to
particulate formation). As a specific example, by adding one or
more types of plasticizer to 85/15 PLGA material, it may be
possible to increase the amount of drug released in the initial
release phase (e.g., increasing drug release from sub-therapeutic
to therapeutic levels) and to modulate the bioerosion rate (e.g.,
decreasing the time required for bioerosion and thus the time
period where one is vulnerable to foreign body effects). Moreover,
85/15 PLGA is normally a brittle material, which may lead to
problems under certain circumstances (e.g., coating cracking upon
stent expansion); however, the addition of one or more types of
plasticizer will improve the flexibility of the polymer. Thus, the
present invention may provide those of ordinary skill in the art
with the ability to tailor the mechanical properties, drug release
rate and the degradation rate in a synergistic way by adding
controlled amounts of one or more types of plasticizer (e.g.,
monomers, oligomers and small polymers based on lactic acid,
glycolic acid or both) to PLGA polymers of different LA/GA ratios
and mixtures thereof.
[0047] As suggested from the above discussion, the present
invention provides various ways of affecting the mechanical,
release and bioerosion characteristics of a given drug-containing
layer. These include, for example, the nature of the coating (e.g.,
single layer or multilayer structure) selected, the coating weight
selected, and the relative amounts of the various coating
constituents selected, including the one or more types of
biodegradable polymer, one or more types of plasticizer and one or
more types of therapeutic agent within the layer.
[0048] With respect to the one or more types of plasticizer,
monomeric, oligomeric and/or short polymeric plasticizers of
varying hydrophilicity/hydrophobicity may be employed.
[0049] The specific biodegradable polymer(s) employed is also
important. For example, the monomer content will have a significant
effect upon the mechanical biodegradation and release
characteristics. For instance, polymers having relatively high
rates of hydrolysis, such as polyanhydrides and polyorthoesters,
may be used to promote more rapid release, whereas polymers having
relatively lower rates of hydrolysis, such as polyesters, may be
used to promote more prolonged release. Moreover, different
monomers within a given class of monomers may be employed to alter
release. For example, PLA erodes slower than PGA. Similarly, for
copolymers of lactic acid and glycolic acid (PLGA), higher amounts
of lactic acid lead to slower rates of erosion. These effects are
thought to be due to the fact that lactic acid is more hydrophobic
than glycolic acid.
[0050] Polymer molecular weight is also known to affect release.
For instance, polymers having higher molecular weight may be
selected for extended release applications as these tend to
biodegrade at a lower rate than polymers having lower molecular
weight, and vice versa.
[0051] Moreover, layers may be formed in which the plasticizer is
preferentially located at the surface of the layer (which may or
may not be covered by another layer), either during layer formation
or post-layer-formation processing, which will result in desirable
self-stratification (i.e., concentration gradient that is a
function of depth). An advantage of having a plasticizer-rich
surface is that a layer may be formed which contributes to a
desired burst characteristic, for example, in a layer containing
PLGA of high molecular weight (e.g., number average mol. wt. of
50,000 to 70,000 or more) and high lactide content (e.g., 85/15).
As used herein a surface is "plasticizer-rich" where the
plasticizer concentration at the surface of the layer is at least
50% higher than the overall plasticizer concentration in the layer,
and may be measured, for example, by one or more of the following:
atomic force microscopy, confocal Raman spectroscopy or
time-of-flight secondary ion mass spectrometry.
[0052] For example, a plasticizer-rich surface may be created by
solvent vapor exposure or by providing a solvent which has a
greater affinity for the base polymer than the plasticizer, thereby
urging the plasticizer to the polymer surface (rather than the
bulk). One way of selecting a solvent composition that has greater
affinity for the base polymer relative to the plasticizer is to
select a solvent whose polarity more closely matches that of the
base polymer. One measure of the polarity of solvents is known as
the Snyder Polarity Index (PI). See Snyder, L. J., "Classification
of the Solvent Properties of Common Liquids," Chromatography, 92,
1974, 223-230. In general, the affinity of the solvent for each of
the components (base polymer, therapeutic agent and plasticizer) is
such that the solvent is able to dissolve the components to create
a solution suitable for forming a polymeric coating layer. However,
as noted above, the solvent selected should nonetheless have a
higher affinity for the base polymer than the plasticizer, where
one wishes to urge the plasticizer to the polymer surface.
[0053] A plasticizer-rich surface may also be created by
application of one or more plasticizers (as well as other agents,
if desired, such as one or more therapeutic agents, etc.) to the
surface of a bioerodable polymeric layer that contains one or more
biodegradable polymers (as well as other agents, if desired, such
as one or more therapeutic agents, one or more plasticizers,
etc.).
[0054] As noted above, "therapeutic agents," "drugs,"
"pharmaceutically active agents," "pharmaceutically active
materials," and other related terms may be used interchangeably
herein. These terms include genetic therapeutic agents, non-genetic
therapeutic agents and cells.
[0055] Exemplary non-genetic therapeutic agents for use in
conjunction with the present invention include: (a) anti-thrombotic
agents such as heparin, heparin derivatives, urokinase, and PPack
(dextrophenylalanine proline arginine chloromethylketone); (b)
anti-inflammatory agents such as dexamethasone, prednisolone,
corticosterone, budesonide, estrogen, sulfasalazine and mesalamine;
(c) antineoplastic/antiproliferative/anti-miotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, angiopeptin, monoclonal
antibodies capable of blocking smooth muscle cell proliferation,
and thymidine kinase inhibitors; (d) anesthetic agents such as
lidocaine, bupivacaine and ropivacaine; (e) anti-coagulants such as
D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing
compound, heparin, hirudin, antithrombin compounds, platelet
receptor antagonists, anti-thrombin antibodies, anti-platelet
receptor antibodies, aspirin, prostaglandin inhibitors, platelet
inhibitors and tick antiplatelet peptides; (f) vascular cell growth
promoters such as growth factors, transcriptional activators, and
translational promotors; (g) vascular cell growth inhibitors such
as growth factor inhibitors, growth factor receptor antagonists,
transcriptional repressors, translational repressors, replication
inhibitors, inhibitory antibodies, antibodies directed against
growth factors, bifunctional molecules consisting of a growth
factor and a cytotoxin, bifunctional molecules consisting of an
antibody and a cytotoxin; (h) protein kinase and tyrosine kinase
inhibitors (e.g., tyrphostins, genistein, quinoxalines); (i)
prostacyclin analogs; (j) cholesterol-lowering agents; (k)
angiopoietins; (l) antimicrobial agents such as triclosan,
cephalosporins, aminoglycosides and nitrofurantoin; (m) cytotoxic
agents, cytostatic agents and cell proliferation affectors; (n)
vasodilating agents; (o) agents that interfere with endogenous
vasoactive mechanisms; (p) inhibitors of leukocyte recruitment,
such as monoclonal antibodies; (q) cytokines; (r) hormones; (s)
inhibitors of HSP 90 protein (i.e., Heat Shock Protein, which is a
molecular chaperone or housekeeping protein and is needed for the
stability and function of other client proteins/signal transduction
proteins responsible for growth and survival of cells) including
geldanamycin, (t) alpha receptor antagonist (such as doxazosin,
Tamsulosin) and beta receptor agonists (such as dobutamine,
salmeterol), beta receptor antagonist (such as atenolol,
metaprolol, butoxamine), angiotensin-II receptor antagonists (such
as losartan, valsartan, irbesartan, candesartan and telmisartan),
and antispasmodic drugs (such as oxybutynin chloride, flavoxate,
tolterodine, hyoscyamine sulfate, diclomine), (u) bARKct
inhibitors, (v) phospholamban inhibitors, (w) Serca 2 gene/protein,
(x) immune response modifiers including aminoquizolines, for
instance, imidazoquinolines such as resiquimod and imiquimod, (y)
human apolioproteins (e.g., AI, AII, AIII, AIV, AV, etc.), (z)
selective estrogen receptor modulators (SERMs) such as raloxifene,
lasofoxifene, arzoxifene, miproxifene, ospemifene, PKS 3741, MF 101
and SR 16234, (aa) PPAR agonists such as rosiglitazone,
pioglitazone, netoglitazone, fenofibrate, bexaotene, metaglidasen,
rivoglitazone and tesaglitazar, (bb) prostaglandin E agonists such
as alprostadil or ONO 8815Ly, (cc) thrombin receptor activating
peptide (TRAP), (dd) vasopeptidase inhibitors including benazepril,
fosinopril, lisinopril, quinapril, ramipril, imidapril, delapril,
moexipril and spirapril, and (ee) thymosin beta 4 (ff)
phospholipids including phosphorylcholine, phosphatidylinositol and
phosphatidylcholine, (gg) VLA-4 antagonists and VCAM-1
antagonists.
[0056] Specific examples of non-genetic therapeutic agents include
taxanes such as paclitaxel, (including particulate forms thereof,
for instance, protein-bound paclitaxel particles such as
albumin-bound paclitaxel nanoparticles, e.g., ABRAXANE), sirolimus,
everolimus, tacrolimus, zotarolimus, Epo D, dexamethasone,
estradiol, halofuginone, cilostazole, geldanamycin, alagebrium
chloride (ALT-711), ABT-578 (Abbott Laboratories), trapidil,
liprostin, Actinomcin D, Resten-NG, Ap-17, abciximab, clopidogrel,
Ridogrel, beta-blockers, bARKct inhibitors, phospholamban
inhibitors, Serca 2 gene/protein, imiquimod, human apolioproteins
(e.g., AI-AV), growth factors (e.g., VEGF-2), as well derivatives
of the forgoing, among others.
[0057] Numerous therapeutic agents, not necessarily exclusive of
those listed above, have been identified as candidates for vascular
treatment regimens, for example, as agents targeting restenosis.
Such agents are useful for the practice of the present invention
and include one or more of the following: (a) Ca-channel blockers
including benzothiazapines such as diltiazem and clentiazem,
dihydropyridines such as nifedipine, amlodipine and nicardapine,
and phenylalkylamines such as verapamil, (b) serotonin pathway
modulators including: 5-HT antagonists such as ketanserin and
naftidrofuryl, as well as 5-HT uptake inhibitors such as
fluoxetine, (c) cyclic nucleotide pathway agents including
phosphodiesterase inhibitors such as cilostazole and dipyridamole,
adenylate/Guanylate cyclase stimulants such as forskolin, as well
as adenosine analogs, (d) catecholamine modulators including
.alpha.-antagonists such as prazosin and bunazosine,
.beta.-antagonists such as propranolol and
.alpha./.beta.-antagonists such as labetalol and carvedilol, (e)
endothelin receptor antagonists, such as bosentan, sitaxsentan
sodium, atrasentan, endonentan, (f) nitric oxide donors/releasing
molecules including organic nitrates/nitrites such as
nitroglycerin, isosorbide dinitrate and amyl nitrite, inorganic
nitroso compounds such as sodium nitroprusside, sydnonimines such
as molsidomine and linsidomine, nonoates such as diazenium diolates
and NO adducts of alkanediamines, S-nitroso compounds including low
molecular weight compounds (e.g., S-nitroso derivatives of
captopril, glutathione and N-acetyl penicillamine) and high
molecular weight compounds (e.g., S-nitroso derivatives of
proteins, peptides, oligosaccharides, polysaccharides, synthetic
polymers/oligomers and natural polymers/oligomers), as well as
C-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds and
L-arginine, (g) Angiotensin Converting Enzyme (ACE) inhibitors such
as cilazapril, fosinopril and enalapril, (h) ATII-receptor
antagonists such as saralasin and losartin, (i) platelet adhesion
inhibitors such as albumin and polyethylene oxide, (j) platelet
aggregation inhibitors including cilostazole, aspirin and
thienopyridine (ticlopidine, clopidogrel) and GP IIb/IIIa
inhibitors such as abciximab, epitifibatide and tirofiban, (k)
coagulation pathway modulators including heparinoids such as
heparin, low molecular weight heparin, dextran sulfate and
.beta.-cyclodextrin tetradecasulfate, thrombin inhibitors such as
hirudin, hirulog, PPACK (D-phe-L-propyl-L-arg-chloromethylketone)
and argatroban, FXa inhibitors such as antistatin and TAP (tick
anticoagulant peptide), Vitamin K inhibitors such as warfarin, as
well as activated protein C, (l) cyclooxygenase pathway inhibitors
such as aspirin, ibuprofen, flurbiprofen, indomethacin and
sulfinpyrazone, (m) natural and synthetic corticosteroids such as
dexamethasone, prednisolone, methprednisolone and hydrocortisone,
(n) lipoxygenase pathway inhibitors such as nordihydroguairetic
acid and caffeic acid, (o) leukotriene receptor antagonists, (p)
antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 and
ICAM-1 interactions, (r) prostaglandins and analogs thereof
including prostaglandins such as PGE1 and PGI2 and prostacyclin
analogs such as ciprostene, epoprostenol, carbacyclin, iloprost and
beraprost, (s) macrophage activation preventers including
bisphosphonates, (t) HMG-CoA reductase inhibitors such as
lovastatin, pravastatin, atorvastatin, fluvastatin, simvastatin and
cerivastatin, (u) fish oils and omega-3-fatty acids, (v)
free-radical scavengers/antioxidants such as probucol, vitamins C
and E, ebselen, trans-retinoic acid, SOD (orgotein) and SOD mimics,
verteporfin, rostaporfin, AGI 1067, and M 40419, (w) agents
affecting various growth factors including FGF pathway agents such
as bFGF antibodies and chimeric fusion proteins, PDGF receptor
antagonists such as trapidil, IGF pathway agents including
somatostatin analogs such as angiopeptin and ocreotide, TGF-.beta.
pathway agents such as polyanionic agents (heparin, fucoidin),
decorin, and TGF-.beta. antibodies, EGF pathway agents such as EGF
antibodies, receptor antagonists and chimeric fusion proteins,
TNF-.alpha. pathway agents such as thalidomide and analogs thereof,
Thromboxane A2 (TXA2) pathway modulators such as sulotroban,
vapiprost, dazoxiben and ridogrel, as well as protein tyrosine
kinase inhibitors such as tyrphostin, genistein and quinoxaline
derivatives, (x) matrix metalloprotease (MMP) pathway inhibitors
such as marimastat, ilomastat, metastat, batimastat, pentosan
polysulfate, rebimastat, incyclinide, apratastat, PG 116800, RO
1130830 or ABT 518, (y) cell motility inhibitors such as
cytochalasin B, (z) antiproliferative/antineoplastic agents
including antimetabolites such as purine analogs (e.g.,
6-mercaptopurine or cladribine, which is a chlorinated purine
nucleoside analog), pyrimidine analogs (e.g., cytarabine and
5-fluorouracil) and methotrexate, nitrogen mustards, alkyl
sulfonates, ethylenimines, antibiotics (e.g., daunorubicin,
doxorubicin), nitrosoureas, cisplatin, agents affecting microtubule
dynamics (e.g., vinblastine, vincristine, colchicine, Epo D,
paclitaxel and epothilone), caspase activators, proteasome
inhibitors, angiogenesis inhibitors (e.g., endostatin, angiostatin
and squalamine), olimus family drugs (e.g., sirolimus, everolimus,
tacrolimus, zotarolimus, etc.), cerivastatin, flavopiridol and
suramin, (aa) matrix deposition/organization pathway inhibitors
such as halofuginone or other quinazolinone derivatives,
pirfenidone and tranilast, (bb) endothelialization facilitators
such as VEGF and RGD peptide, (cc) blood rheology modulators such
as pentoxifylline and (dd) glucose cross-link breakers such as
alagebrium chloride (ALT-711).
[0058] Further additional therapeutic agents useful for the
practice of the present invention are also disclosed in U.S. Pat.
No. 5,733,925 to Kunz.
[0059] A variety of materials may be used as substrate materials
for the medical devices of the present invention. Examples of such
materials include non-metallic materials such as ceramics,
homopolymers, copolymers, and polymer blends. Examples of such
materials also include metallic materials, which may be selected,
for example, from metals such as gold, iron, niobium, platinum,
palladium, iridium, osmium, rhodium, titanium, tantalum, tungsten,
ruthenium, magnesium, iron and zinc, among others, and metal alloys
such as those comprising iron and chromium (e.g., stainless steels,
including platinum-enriched radiopaque stainless steel), niobium
alloys, titanium alloys, alloys comprising nickel and titanium
(e.g., Nitinol), alloys comprising cobalt and chromium, including
alloys that comprise cobalt, chromium and iron (e.g., elgiloy
alloys), alloys comprising nickel, cobalt and chromium (e.g., MP
35N), alloys comprising cobalt, chromium, tungsten and nickel
(e.g., L605), alloys comprising nickel and chromium (e.g., inconel
alloys), and biodisintegrable alloys including alloys of magnesium,
zinc and/or iron (and their alloys with combinations of Ce, Ca, Zn,
Zr and Li), among others. Composites of two or more of the forgoing
(e.g., polymer-ceramic composites, polymer-metal composites,
metal-ceramic composites, etc.) may also be employed. Materials
having both super elastic and shape-memory characteristics, for
example, alloys comprising nickel and titanium (e.g., Nitinol), may
be beneficial in certain embodiments.
[0060] Numerous techniques are available for forming the medical
devices (or portions thereof) of the invention.
[0061] For example, in some embodiments, solvent-based techniques
are used to form one or more of the polymeric layers in accordance
with the present invention. Using these techniques, layers can be
formed by first providing a solution that contains the chemical
species that make up the layer (e.g., polymer, plasticizer,
therapeutic agent, and/or other chemical species), dissolved or
dispersed in a solvent system, and subsequently removing the
solvent system. The solvent system that is ultimately selected will
contain one or more solvent species, which may be selected based on
their ability to dissolve or disperse the various chemical species,
as well as other factors, including drying rate, surface tension,
etc. Examples of solvent-based techniques include spin coating
techniques, web coating techniques, coating via an applicator
(e.g., roller, brush, ink jet techniques, etc.), solvent spraying
techniques, dipping techniques, techniques involving coating via
mechanical suspension including air suspension, electrostatic
techniques, and combinations of these processes, among others.
[0062] In other embodiments, thermoplastic processing techniques
are used to form one or more polymeric layers in accordance with
the present invention. Using these techniques, layers can be formed
by first providing a melt that contains the chemical species that
make up the polymeric layer, and subsequently cooling the melt.
Examples of thermoplastic techniques include dipping, spraying,
spin coating, web coating, extrusion, coating via an applicator
(e.g., roller, brush, ink jet, etc.), and combinations of these
processes, among others.
[0063] Other ways of forming medical devices in accordance with the
present invention will become readily apparent to those of ordinary
skill upon review of the above description of the invention.
EXAMPLES
Example 1
[0064] A 16 mm Liberte WH stent (Boston Scientific, Natick, Mass.,
USA) is provided with two abluminal layers. The inner layer is a
100 .mu.g layer that consists of about 90 wt % 85:15 PLGA having a
molecular weight of .about.60 kDa and about 10 wt % PTx. The outer
layer is a 30 .mu.g layer that consists of about 80 wt % 85:15 PLGA
having a molecular weight of .about.60 kDa, about 10 wt %
paclitaxel, and about 10% lactic acid as a monomeric
plasticizer.
Example 2
[0065] A 20 mm Liberte stent (Boston Scientific, Natick, Mass.,
USA) is provided with a single layer that consists of a blend of
7525 DLG 1A from Lakeshore Biomaterials, Birmingham, Ala., USA
(75:25 PLGA having acid end groups and an inherent viscosity of
0.05-0.15 dL/g, which is a short polymer having a molecular weight
on the order of 10,000 Daltons) and 7525 DLG 4A from Lakeshore
Biomaterials (75:25 PLGA having acid end groups, an inherent
viscosity of 0.35-0.55 dL/g and a molecular weight on the order of
50,000 to 70,000 Daltons) at a ratio of 25:75 w:w 7525 DLG 1A:7525
DLG 4A, at 5% paclitaxel and 125 microgram coat weight.
Example 3
[0066] A 20 mm Liberte stent (Boston Scientific, Natick, Mass.,
USA) is provided with 2 abluminal layers that consists of the
following (a) 8515 DLG 1A from Lakeshore Biomaterials (85:15 PLGA
having acid end groups and an inherent viscosity of 0.05-0.15 dL/g,
which is a short polymer having a molecular weight on the order of
10,000 Daltons) at 2.75% paclitaxel and 100 microgram coat weight
over (b) 8515 DLG 4A from Lakeshore Biomaterials (85:15 PLGA having
acid end groups, an inherent viscosity of 0.35-0.55 dL/g and a
molecular weight on the order of 50,000 to 70,000 Daltons) at 2.75%
paclitaxel and 150 microgram coat weight.
[0067] Although various embodiments are specifically illustrated
and described herein, it will be appreciated that modifications and
variations of the present invention are covered by the above
teachings and are within the purview of the appended claims without
departing from the spirit and intended scope of the invention
* * * * *