Note: Descriptions are shown in the official language in which they were submitted.
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MEDICAL DEVICE COATINGS AND COATED STENTS
(Applicant Docket No. ZAM-001PC)
BACKGROUND OF THE INVENTION
Related A212lications
This application claims the benefit of U.S. Provisional Application Serial No.
60/862,640, filed on October 24, 2006. The entire teachings of the above-
referenced
Application are incorporated herein by reference.
Field of the invention
The invention relates to a medical device, e.g., a stent having drugs, agents
or
compounds affixed thereto to minimize a biological organism's reaction to the
introduction of the medical device into the organism.
Summary of the related art
One of the many implantable medical devices used in the treatment of vascular
disease is a stent. The stent is designed to prevent collapse of a vessel that
has been
weakened or damaged by angioplasty. Insertion of stents has been shown to
prevent
harmful remodeling of the vessel while healing of the vessel proceeds over
several
months after angioplasty.
Known stent designs include monofilament wire coil stents, welded metal
cages and thin-walled metal cylinders with axial slots formed around the
circumference. Known construction materials for use in stents include
polymers,
organic fabrics and biocompatible metals, such as stainless steel, silver,
gold,
tantalum, titanium, and shape memory alloys such as Nitinol.
Vascular stents are typically introduced percutaneously and transported
intraluminally to a desired location within the vessel. The stent is then
expanded
within the vessel either mechanically, such as by the expansion of a balloon
within the
stent, or self-expanding by releasing stored energy upon actuation within the
vessel.
Upon expansion of the stent during angioplasty, smooth muscle cells within
the vessel wall become injured, initiating a thrombotic and inflammatory
response.
Contributing factors in this response include cell derived growth factors such
as
platelet derived growth factors, thrombin and other factors released by
platelets. The
resulting restenosis of the vessel is reduced through the permanent
implantation of the
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stent, as apposed to balloon angioplasty alone. Nevertheless, blockage or even
collapse of the stent may occur.
To reduce restenosis of the vessel in which the stent has been deployed,
numerous drugs or agents have been utilized to coat the stent or to otherwise
be
diffusably released by the stent. For example, heparin coating of the stent
has been
shown to reduce restenosis. Other agents having anti-proliferative activity
have been
used, such as paclitataxel and rapamycin. These and other agents have been
incorporated into bioabsorbable or biodegradable polymers as a coating on the
stent,
or have been applied to the surface of the stent through dip, spray, or spin
coating
processes, or by electrostatic abluminal coating. Unfortunately, many of the
drugs or
agents used for this purpose have their own associated toxicities and may
therefore be
less than optimally suitable.
More recently, doctors have found that a small number of patients develop
blood clots within some drug coated stents long after they are implanted.
Optimally a
compound used to render a deployed stent less subject to restenosis should be
sufficiently active to produce a therapeutic dose for an extended period of
time,
should not be toxic to the regrowth of endothelial cells within the vessel
lumen, and
should function to prevent blood clot formation within the stent.
The compound diadenosine 5', 5"', Pi, P4 tetraphosphate (Ap4A) was first
discovered by Moffatt, Can. J. Chem. 42: 599 (1964) as a minor by-product of
the
chemical synthesis of adenosine triphosphate (ATP). It was subsequently shown
by
Zamecnik et al., Biochem. Biophys. Res. Comm. 24: 91-97 (1966) to be present
as the
back reaction product in amino acid activation, the first step in protein
synthesis, and
to be a ubiquitous component of eukaryotic and prokaryotic cells. Flodgaard
and
Klenow, Biochem. J. 208: 737 (1982) discovered that platelets have a high
content of
Ap4A in their dense granules.
Subsequent studies showed some promise for clinical applications for Ap4A.
Louie et al., Thromb. Res. 49: 557-565 (1988) showed that Ap4A acts as a
competitive inhibitor of ADP-induced platelet aggregation and inhibited clot
formation in a rabbit model. However, Ap4A was found to have a short in vivo
half
life due to phosphodiesterase activity. Consequently, analogs of Ap4A were
developed and studied. Zamecnik et al., Proc. Natl. Acad. Sci. USA 89: 2370-
2373
(1992) teaches that Ap4A analogs having a halogenated methylene bridge in
place of
an oxygen atom are superior to Ap4A in inhibiting ADP-induced aggregation of
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human platelets and are resistant to hydrolytic enzymes. Chan et al., Proc.
Natl. Acad.
Sci. USA 94: 4034-4039 (1997) discloses additional Ap4A analogs that are
effective
at preventing platelet aggregation induced by ADP and other agonists.
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BRIEF SUMMARY OF THE INVENTION
The invention provides medical devices coated with Ap4A and/or Ap4A
analogs, either alone or in combination with other medicaments. The medical
devices
according to the invention are expected to prevent restenosis and thrombus
formation
associated with some drug coated stents.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention provides medical devices coated with Ap4A and/or Ap4A
analogs, either alone or in combination with other medicaments. The medical
devices
according to the invention are expected to prevent restenosis and thrombus
formation
associated with some drug coated stents.
The patents and publications cited herein reflect the level of knowledge in
the
field and are hereby incorporated by reference in their entirety. Any conflict
between
the teachings of these references and this specification shall be resolved in
favor of
the latter.
In a first aspect, the invention provides a vascular stent that is coated with
Ap4A and/or Ap4A analogs.
For purposes of the invention, the term "stent" is given its conventional
meaning within the medical devices art and includes both mechanically
expandable
and self-expandable stents.
For purposes of the invention, the term "coated with" means that the stent is
associated with Ap4A or a Ap4A analog in a manner that allows the Ap4A or an
Ap4A
analog to locally contact platelets and other cell types that are in contact
with, or in
the immediate vicinity of the stent. Such associations include covalent
attachment of
the molecule to the stent. Such covalent attachment may be reversible or
irreversible.
In preferred embodiments, reversible attachment to the stent may be via a
chemical
linkage that is labile in vivo. Such labile linkages include ester linkages,
including
phosphoester linkages, as well as amide or peptide linkages.
Many means of coating the stent are known in the art, including dip, spray or
spin coating processes. For example, US2006/0217801A1 discloses a stent having
an
engineered abluminal surface that is engineered to have a material comprising
a
mixture of a polymer and a drug extending from the abluminal surface by
depositing
microdrops of the mixture onto the abluminal surface of the stent.
US2006/0229706A1 discloses a stent having a drug-release coating of a
thickness of
3-30 microns and composed of 20-80 weight percent polymer substrate and 20-80
weight percent active compound, where the coating is effective to release an
amount
of the active compound to prevent restenosis at the site of the stent. In a
preferred
embodiment, the stent body is metallic and the polymer is selected from
polymethylacrylate, ethylene vinyl alcohol, poly-lactide polymers (especially
poly-dl-
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lactide), E-caprolactone, ethyl vinyl acetate, polyvinyl alcohol and
polyethylene oxide.
US2006/0222756A1 discloses a method for coating a stent with a therapeutic
agent
comprising the steps of creating a polymer utilizing vinylidene fluoride and
hexafluoropropylene in a batch emulsion polymerization process, priming the
stent
with the polymer utilizing a dip coating process, creating a polymer and
therapeutic
agent mixture, applying the polymer and therapeutic agent mixture on the
primer
layer utilizing a spin coating process, and drying the coated stent in a
vacuum oven
for approximately sixteen hours at a temperature in the range of fifty to
sixty degrees
centigrade. US2006/0216431A1 discloses a method for electrostatically coating
the
abluminal surfaces of a stent that is crimp-mounted on a balloon catheter
comprising
threading a wire through a lumen of the stent-balloon assembly and applying a
charge
to the wire, while the stent is grounded, and applying an electrostatic spray
coating to
the stent-balloon assembly. Alternatively, a charge can be applied to the
stent that is
opposite to the charge applied to the wire. In a preferred embodiment, the
wire is the
guidewire for the catheter which is threaded through the guidewire lumen.
Generally,
the delivery of an active agent from the coating to the vascular wall is
through
diffusion of the active agent through either a bulk polymer or through pores
that are
created in the polymer structure, or by erosion of a biodegradable coating.
For purposes of the invention, Ap4A refers to diadenosine 5', 5"1, Pi, P4
tetraphosphate, which has the structural formula (I):
NH2
N
N
0 0 0 0 OH OH
pppp
N N O I- I- I- I
O O O-
O
N N
OH OH
N N
NH2
For purposes of the invention, an "Ap4A analog" is a compound having anti-
platelet activity similar to or greater than Ap4A , and a structural formula
derived
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from (I), wherein one or more atom is replaced by another atom or atoms or one
or
more chemical bond. For example, one or more bridging oxygen atoms in formula
(I)
may be replaced by a methylene, halomethylene, or dihalomethylene group. One
or
more non-bridging oxygen atom may be replaced by a sulfur atom, by a lower
alkyl
group (including a methyl group), by an 0-lower alkyl group (including an 0-
methyl
group), by an amino or amido group, or by a boronate group. One or more
phosphate
group may be replaced by a peptide linkage. One or both hydroxyl moieties on
either
or both ribosyl groups may be replaced by hydrogen, or by halo or alkoxy
groups, or
may be in a locked 2',4' ring configuration. One adenine moiety may be missing
or
replaced by purine or another purine analog, or by pyrimidine or another
pyrimidine
analog. One adenosyl moiety may be missing. These modifications, or any
combination of these modifications are within the intended scope of an "Ap4A
analog", as long as the resultant compound exhibits an anti-platelet activity
similar to
or greater than Ap4A. "Similar to" means at least about one tenth the anti-
platelet
activity of Ap4A in a conventional anti-platelet assay, e.g., as taught in
Chan et al.,
Proc. Natl. Acad. Sci. USA 94: 4034-4039 (1997).
Ap4A or an Ap4A analog should be present on the stent or in the stent coating
in an amount effective to prevent platelet aggregation on a surface of the
stent or
within the stent.
Those skilled in the art will recognize that the present invention can be used
alone or in conjunction with other medicaments to coat the stent.
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