(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0193257 A1
`(43) Pub. Date:
`Sep. 30, 2004
`Wu et al.
`
`US 20040193257A1
`
`(54) MEDICAL DEVICES HAVING DRUG
`ELUTING PROPERTIES AND METHODS OF
`MANUFACTURE THEREOF
`
`(76) Inventors: Ming H. Wu, Bethel, CT (US);
`Philippe Poncet, Sandy Hook, CT (US)
`
`Correspondence Address:
`CANTOR COLBURN LLP
`55 Grif?n Road South
`Bloom?eld, CT 06002 (US)
`
`(21) Appl. No.:
`
`10/811,466
`
`(22) Filed:
`
`Mar. 26, 2004
`
`Related US. Application Data
`
`(60) Provisional application No. 60/459,392, ?led on Mar.
`31, 2003.
`
`Publication Classi?cation
`
`(51) rm.c1.7 ...................................................... ..A61F 2/06
`(52) Us. 01. .......................................................... .. 623/1.46
`
`(57)
`
`ABSTRACT
`
`Arnedical device comprises a shape memory alloy having a
`reverse martensitic transformation start temperature of
`greater than or equal to about 0° C.; and a drug coating
`comprising a polymeric resin and a biologically active
`agent. A method of manufacturing a stent comprises cold
`forming a shape memory alloy from a Wire; heat treating the
`cold formed shape memory alloy at a temperatures greater
`than that at Which a martensitic transformation can occur;
`and coating the stent With a drug coating comprising a
`biologically active agent.
`
`28
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`'2
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`18
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`22 1O
`Z . /
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`26
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`20
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`14
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`Medtronic Exhibit 2009
`Edwards v. Medtronic
`IPR2014-00362
`
`

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`Patent Application Publication Sep. 30, 2004 Sheet 1 0f 2
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`US 2004/0193257 A1
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`22 10
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`Patent Application Publication Sep. 30, 2004 Sheet 2 0f 2
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`US 2004/0193257 A1
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`r.
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`I
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`US 2004/0193257 A1
`
`Sep. 30, 2004
`
`MEDICAL DEVICES HAVING DRUG ELUTING
`PROPERTIES AND METHODS OF
`MANUFACTURE THEREOF
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims the bene?t of US. Provi
`sional Application Serial No. 60/459,392 ?led 31 Mar. 2003.
`
`BACKGROUND
`
`[0002] The present disclosure relates to medical devices
`having drug eluting properties and methods of manufacture
`thereof.
`[0003] Vascular diseases caused by the progressive block
`age of the blood vessels often leads to hypertension,
`ischemic injury, stroke, or myocardial infarction. Athero
`sclerotic lesions, Which limit or obstruct blood ?oW, are the
`major cause of vascular disease. Balloon angioplasty is a
`medical procedure Whose purpose is to increase blood ?oW
`through an artery and it is used as a predominant treatment
`for vessel stenosis. The increasing use of this procedure is
`attributable to its relatively high success rate and its minimal
`invasiveness compared With coronary bypass or vascular
`surgery. A limitation associated With balloon angioplasty is
`the abrupt or progressive post-procedural re-closure of the
`vessel or restenosis.
`
`[0004] The dif?culties associated With balloon angioplasty
`have facilitated the use of medical devices such as stents and
`stent technology in most coronary or vascular interventions.
`The use of such medical devices has signi?cantly reduced
`the restenosis rate from about 40% after balloon angioplasty
`alone, to about less than 15% When balloon angioplasty is
`folloWed by a subsequent placement of a medical device
`such as a stent. While contractive remodeling of the vessel
`is the primary mechanism that leads to restenosis after
`balloon angioplasty, the restenosis after stent placement is
`associated With neointimal hyperplasia, Which assumed to
`be caused by vessel injury during stent placement. The
`in-stent restenosis process occurs ?rst With platelet accumu
`lation on the stent surface. Smooth muscle begins to migrate
`to the site of the platelet accumulation and proliferate in
`response to the in?ammation. Extracellular matrix ?nally
`deposits on the site during the later stages of the healing
`process. The platelet accumulation and development of
`extracellular matrix is detrimental to the functioning of the
`artery.
`[0005] To battle restenosis, medical devices such as stents
`often encapsulate drugs or are coated With drugs in order to
`inhibit or minimiZe various stages of undesirable cell activ
`ity. The pharmacological characteristics of the drugs pro
`posed as coatings for the attenuation of such undesirable cell
`activity include but are not limited to anti-in?ammation,
`anti-proliferation, immuno-suppressive and anti-migration
`properties. Examples of such drugs include SIROLIMUS,
`EVEROLIMUS, ABT 578, PACLITAXEL, DEXAM
`ETHASONE and MYCOPHENOLIC ACID.
`[0006] Drug coatings generally comprise biologically
`active agents and polymers. The biologically active agent
`may be physically blended or encapsulated into a bio
`resorbable polymer, to form a drug coating, Which is then
`used to coat the medical device and alloWing drug release(s)
`
`at various rates post procedurally. Since the polymers uti
`liZed in drug coatings generally have glass transition tem
`peratures around room temperature (i.e., about 23° C.) they
`can be designed and fabricated to have suf?cient ?exibility
`at temperatures higher than room temperature. HoWever,
`When cooled to temperatures beloW the glass transition
`temperature they are easily embrittled and suffer permanent
`damage thus rendering them unusable or ineffective.
`
`[0007] Some of the alloys used in the manufacture of
`self-expanding medical devices such as stents (upon Which
`are applied the drug coatings) can be shape memory alloys
`having a reverse martensitic transformation start tempera
`ture (AS) of about 0° C. With an austenite transformation
`?nish temperature
`of about 20° C. to 30° C. Because of
`the superelastic properties displayed by these alloys at
`temperatures greater than or equal to about Af, loading a
`self-expanding medical device into a delivery system at or
`near ambient temperature is highly challenging as the device
`often displays a tendency to recover its expanded shape just
`like a regular spring. To minimiZe this spring-like phenom
`ena and to achieve free or enhanced loading characteristics
`into a delivery system, a self-expanding device is generally
`?rst cooled to a temperature beloW its AS temperature, Which
`is also beloW the ambient temperature. As stated above, this
`loW temperature deformation of the device promotes
`embrittlement of the drug coating, Which often leads to
`undesirable ruptures or mechanical degradation in the coat
`mg.
`
`SUMMARY
`
`[0008] In one embodiment, a medical device comprises a
`shape memory alloy having a reverse martensitic transfor
`mation start temperature of greater than or equal to about 0°
`C.; and a drug coating comprising a polymeric resin and a
`biologically active agent.
`
`[0009] In another embodiment, the medical device is an
`implantable stent.
`
`[0010] In yet another embodiment, a nickel-titanium alloy
`composition comprises about 55.5 Wt % of nickel based on
`the total composition of the alloy.
`
`[0011] In yet another embodiment, a nickel-titanium-nio
`bium alloy composition comprises about 48 Wt % nickel and
`about 14 Wt % niobium based on the total composition of the
`alloy.
`[0012] In yet another embodiment, a method of manufac
`turing a stent comprises cold forming a shape memory alloy
`from a Wire; heat treating the cold formed shape memory
`alloy at a temperatures greater than that at Which a marten
`sitic transformation can occur; and coating the stent With a
`drug coating comprising a biologically active agent.
`[0013] In yet another embodiment, a method of manufac
`turing a stent comprises laser cutting, Water jet cutting,
`electrode discharge machining (EDM), chemically, electro
`chemically or photo-chemically etching a nickel-titanium
`alloy having about 55.5 Wt % of nickel or a nickel-titanium
`niobium alloy having about 48 Wt % nickel and about 14 Wt
`% niobium from a tube, Wherein the Weight percents are
`based on the total Weight of the composition; heat treating
`the alloy at a temperatures greater than that at Which a
`martensitic transformation can occur; and coating the alloy
`With a drug coating comprising a biologically active agent.
`
`

`

`US 2004/0193257 A1
`
`Sep. 30, 2004
`
`BRIEF DESCRIPTION OF THE FIGURES
`[0014] FIG. 1 represents a cross-sectional vieW of the end
`of a catheter illustrating a stent to be implanted;
`
`[0015] FIG. 2 is a graphical representation of a tensile
`stress-strain curve of Ti-55.5 Wt % Ni tested at 10° C.; and
`
`[0016] FIG. 3 is a graphical representation of a tensile
`stress-strain curve of Ti-55.5 Wt % Ni tested at 37° C.
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`[0017] Disclosed herein is a medical device coated With a
`drug coating comprising a polymeric resin and a biologically
`active agent, Wherein the medical device is manufactured
`from an alloy having a reverse martensitic transformation
`start temperature A5 of greater than or equal to about 0° C.,
`preferably greater than or equal to about 10° C. and further
`Wherein the polymeric resin also has a glass transition
`temperature (Tg) of less than or equal to about AS. The use
`of an alloy having an AS of greater than or equal to about 0°
`C. in conjunction With a drug coating Wherein the polymer
`has a Tg is less than or equal to about AS, advantageously
`alloWs the medical device to be used at temperatures that are
`generally loWer than sub-ambient temperatures Without any
`permanent deformation and embrittlement of the polymeric
`resin. Additionally, since the alloy used in the medical
`device has an AS greater than or equal to about 0° C., the
`need to cool the medical device to temperatures beloW 0° C.
`to minimize the “spring-like behavior” is reduced, thereby
`easing the loading of the device onto the delivery system
`improving the performance of the medical device post
`procedurally.
`[0018] The medical device may be a stent, a covered stent
`or stent graft, a needle, a curved needle, bone staples, a vena
`cava ?lter, a suture or anchor-like mechanism, or the like. In
`one exemplary embodiment, the medical device is an
`implantable stent. A stent as de?ned herein may be either a
`solid, holloW, or porous implantable device, Which is coated
`With or encapsulate the drug coating(s). Since the stent may
`be holloW, solid or porous, the drug coating(s) may be
`applied to the outer surface, the inner surface, both surfaces
`of the stent, on selective locations on the stent, for example
`a different coating could be applied to the ends of a stent
`compared to its middle portion
`
`[0019] The ?gure illustrates one embodiment of a catheter
`having an implantable stent. In the ?gure, the distal end of
`a catheter 11 having a stent 16 carried Within it for implan
`tation into the body of a patient. The proximal end of the
`catheter 11 is connected to a suitable delivery mechanisms
`and the catheter 11 is of suf?cient length to reach the point
`of implantation of the stent 16 from the introduction point
`into the body. The catheter 11 includes an outer sheath 10,
`a middle tube 12 Which may be formed of a compressed
`spring, and a ?exible (e.g., polyamide) inner tube 14. Astent
`16 for implantation into a patient is carried Within the outer
`sheath 10. The stent 16 is generally manufactured from a
`shape memory alloy frame 18, Which is formed in a criss
`cross pattern, Which may be laser cut. One or both ends of
`the stent 16 may be left uncovered as illustrated at 22 and 24
`to provide anchoring Within the vessel Where the stent 16 is
`to be implanted.
`[0020] Aradiopaque atraumatic tip 26 is generally secured
`to the end of the inner tube 14 of the catheter. The atraumatic
`
`tip 26 has a rounded end and is gradually sloped to aid in the
`movement of the catheter through the body vessel. The
`atraumatic tip 26 is radiopaque so that its location may be
`monitored by appropriate equipment during the surgical
`procedure. The inner tube 14 is holloW so as to accommo
`date a guide Wire, Which is commonly placed in the vessel
`prior to insertion of the catheter, although a solid inner
`section and be used Without a guide Wire. Inner tube 14 has
`suf?cient kink resistance to engage the vascular anatomy
`Without binding during placement and WithdraWal of the
`delivery system. In addition, inner tube 14 is of suf?cient
`siZe and strength to alloW saline injections Without rupture.
`[0021] A generally cup-shaped element 28 is provided
`Within the catheter 11 adjacent the rear end of the stent 16
`and is attached to the end of the spring 12 by appropriate
`means, e.g., the cup element 28 may be plastic Wherein the
`spring 12 is molded into its base, or the cup element 28 may
`be stainless steel Wherein the spring 12 is secured by
`Welding or the like. The open end of the cup element 28
`serves to compress the end 24 of the stent 16 in order to
`provide a secure interface betWeen the stent 16 and the
`spring 12. Alternatively, instead of a cup shape, the element
`28 could be formed of a simple disk having either a ?at or
`slightly concave surface for contacting the end 24 of the
`stent 16.
`
`[0022] The alloys used in the medical devices are prefer
`ably shape memory alloys having an AS greater than or equal
`to about 0° C. The medical devices may be self expanding
`or thermally expanding. It is desirable for a self expanding
`medical device to have the AS of the shape memory alloy be
`greater than or equal to about 10° C., preferably greater than
`or equal to about 15° C., preferably greater than or equal to
`about 20° C., and more preferably greater than or equal to
`about 23° C. In another embodiment, the shape memory
`alloys used in the self-expanding medical devices have anAf
`temperature of about 25° C. to about 37° C. Within this
`range it is generally desirable to have an Af temperature of
`greater than or equal to about 28° C., preferably greater than
`or equal to about 30° C. Also desirable Within this range is
`an Af temperature of less than or equal to about 36° C.,
`preferably less than or equal to about 35° C.
`[0023] If the medical device is thermally expanding, then
`it is preferable for the shape memory alloys to have an AS
`greater than or equal to about 35° C. When a medical device
`is thermally expanding such as is achieved by the use of a
`hot saline solution, it may be desirable to have an Af
`temperature of less than or equal to about 50° C.
`
`[0024] It is generally desirable to use shape memory alloys
`having pseudo-elastic properties, and Which are formable
`into complex shapes and geometries Without the creation of
`cracks or fractures. It is also generally desirable to use shape
`memory alloys, Which permit large plastic deformations
`during fabrication of the medical device before the desired
`pseudoelastic properties are established and Wherein the
`pseudoelastic properties are developed after fabrication.
`
`[0025] Shape memory alloys that may be used in the
`medical devices are generally nickel titanium alloys. Suit
`able examples of nickel titanium alloys are nickel-titanium
`niobium,
`nickel-titanium-copper,
`nickel-titanium-iron,
`nickel-titanium-ha?iium, nickel-titanium-palladium, nickel
`titanium-gold, nickel-titanium-platinum alloys and the like,
`and combinations comprising at least one of the foregoing
`
`

`

`US 2004/0193257 A1
`
`Sep. 30, 2004
`
`nickel titanium alloys. Preferred alloys are nickel-titanium
`alloys and titanium-nickel-niobium alloys.
`[0026] Nickel-titanium alloys that may be used in the
`medical devices generally comprise nickel in an amount of
`about 54.5 Weight percent (Wt %) to about 57.0 Wt % based
`on the total composition of the alloy. Within this range it is
`generally desirable to use an amount of nickel greater than
`or equal to about 54.8, preferably greater than or equal to
`about 55, and more preferably greater than or equal to about
`55.1 Weight % based on the total composition of the alloy.
`Also desirable Within this range is an amount of nickel less
`than or equal to about 56.9, preferably less than or equal to
`about 56.5, and more preferably less than or equal to about
`56.0 Wt %, based on the total composition of the alloy.
`[0027] An exemplary composition of a nickel-titanium
`alloy having an AS greater than or equal to about 0° C. is one
`Which comprises about 55.5 Wt % nickel (hereinafter Ti-55 .5
`Wt %-Ni alloy) based on the total composition of the alloy.
`The Ti-55.5 Wt %-Ni alloy has an AS temperature in the fully
`annealed state of about 30° C. After cold fabrication and
`shape-setting heat treatment, the Ti-55.5 Wt %-Ni alloy has
`an A5 of about 10 to about 15° C. and an austenite transfor
`mation ?nish temperature
`of about 30 to about 35° C.
`[0028] Another exemplary composition of a nickel-tita
`nium alloy having an AS greater than or equal to about 0° C.
`is one Which comprises about 55.8 Wt % nickel (hereinafter
`Ti-55.8 Wt %-Ni alloy) based on the total composition of the
`alloy. The Ti-55.8 Wt %-Ni alloy generally has an A5 of 0°
`C. in its as-fabricated state, and an Af of about 15 to about
`20° C. HoWever, upon subjecting the Ti-55.8Wt %-Ni alloy
`to aging through annealing, the AS andAf are both increased.
`The Ti-55.8 Wt %-Ni alloy has an AS temperature in the fully
`annealed state of about —10° C. After cold fabrication and
`shape-setting heat treatment, the Ti-55.8 Wt %-Ni alloy has
`an A5 of about 0° C. and an austenite transformation ?nish
`temperature
`of about 20° C.
`[0029] Nickel-titanium-niobium (NiTiNb) alloys that may
`be used in the medical devices generally comprise nickel in
`an amount of about 30 Wt percent (Wt %) to about 56 Wt %
`and niobium in an amount of about 4 Wt % to about 43 Wt
`%, With the remainder being titanium. The Weight percents
`are based on the total composition of the alloy. Within the
`range for nickel, it is generally desirable to use an amount
`greater than or equal to about 35, preferably greater than or
`equal to about 40, and more preferably greater than or equal
`to about 47 Wt %, based on the total composition of the alloy.
`Also desirable Within this range is an amount of nickel less
`than or equal to about 55, preferably less than or equal to
`about 50, and more preferably less than or equal to about 49
`Wt %, based on the total composition of the alloy. Within the
`range for niobium, it is generally desirable to use an amount
`greater than or equal to about 11, preferably greater than or
`equal to about 12, and more preferably greater than or equal
`to about 13 Wt %, based on the total composition of the alloy.
`Also desirable Within this range is an amount of niobium less
`than or equal to about 25, preferably less than or equal to
`about 20, and more preferably less than or equal to about 16
`Wt %, based on the total composition of the alloy.
`
`[0030] An exemplary composition of a titanium-nickel
`niobium alloy is one having about 48 Wt % nickel and about
`14 Wt % niobium, based on the total composition of the
`alloy. The alloy in the fully annealed state has an AS
`
`temperature beloW the body temperature. HoWever, When
`subsequently deformed With a properly controlled amount of
`deformation at a cryogenic temperature, the AS temperature
`can be elevated above the ambient temperature. The cryo
`genic temperature as de?ned herein are temperatures from
`about —10° C. to about —90° C. ANiTiNb alloy can therefore
`be fabricated in its expanded geometry, annealed and then
`subsequently deformed to manipulate the AS temperature
`above the ambient.
`
`[0031] The medical devices may be manufactured from
`the shape memory alloys by a variety of different methods.
`For example, a medical device such as a stent can be
`fabricated from Wires via cold forming and shape-setting
`heat treatment process or via Warm forming at temperatures
`above the temperature Where martensitic transformation can
`no longer be mechanically induced. The stent can also be
`fabricated from nickel-titanium tubes by laser cutting,
`chemical etching or other cutting means folloWed by shape
`setting heat treatment or other forming and heat treating
`processes. Once the AS temperature of the stent is above the
`ambient temperature, the stent may be coated With the drug
`coating and then crimped into the delivery system at the
`ambient temperature. During stent deployment, if the Af
`temperature remains beloW the body temperature, the stent
`can be self-expanding and deployed by simply removing the
`sheath. HoWever, if the Af temperature is above the body
`temperature, the stent needs to be thermally deployed by, for
`example, ?ushing hot saline inside an expansion balloon.
`
`[0032] The drug coating used to coat the stent may com
`prise any polymeric resin having a glass transition tempera
`ture less than or equal to about the AS. It is generally
`desirable for the polymeric resin to have a glass transition
`temperature greater than or equal to about —100° C., pref
`erably greater than or equal to about —50° C., more prefer
`ably greater than or equal to about 0° C., and even more
`preferably around about 10° C., depending upon the A5 of
`the shape memory alloy utiliZed in the medical device. In
`general, the polymeric resin may be derived from a suitable
`oligomer, polymer, block copolymer, graft copolymer, star
`block copolymer, dendrimers, ionomers having a number
`average molecular Weight (Mn) of about 1000 grams per
`mole (g/mole) to about 1,000,000 g/mole. The polymeric
`resin may be either a thermoplastic resin, thermosetting
`resin or a blend of a thermoplastic resin With a thermosetting
`resin. Suitable examples of thermoplastic resins include
`polyacetal, polyacrylic, styrene acrylonitrile, acrylonitrile
`butadiene-styrene, polycarbonates, polystyrenes, polyethyl
`ene, polypropylenes, polyethylene terephthalate, polybuty
`lene terephthalate, polyamides such as nylon 6, nylon 6,6,
`nylon 6,10, nylon 6,12, nylon 11 or nylon 12, polyamide
`imides, polybenZimidaZoles, polybenZoxaZoles, polyben
`ZothiaZoles, polyoxadiaZoles, polythiaZoles, polyquinoxa
`lines, polyimidaZopyrrolones, polyarylates, polyurethanes,
`thermoplastic ole?ns such as ethylene propylene diene
`monomer, ethylene propylene rubber, polyarylsulfone, poly
`ethersulfone, polyphenylene sul?de, polyvinyl chloride,
`polysulfone, polyetherimide, polytetra?uoroethylene, ?u
`orinated ethylene propylene, per?uoroalkoxy polymer, poly
`chlorotri?uoroethylene, polyvinylidene ?uoride, polyvinyl
`?uoride, polyetherketone, polyether etherketone, polyether
`ketone ketone, or the like, or combinations comprising at
`least one of the foregoing thermoplastic resins.
`
`

`

`US 2004/0193257 A1
`
`Sep. 30, 2004
`
`[0033] Suitable examples of blends of thermoplastic resins
`include acrylonitrile-butadiene-styrene/nylon, polycarbon
`ate/acrylonitrile-butadiene-styrene, acrylonitrile butadiene
`styrene/polyvinyl chloride, polyphenylene ether/polysty
`rene, polyphenylene ether/nylon, polysulfone/acrylonitrile
`butadiene-styrene, polycarbonate/thermoplastic urethane,
`polycarbonate/polyethylene terephthalate, polycarbonate/
`polybutylene terephthalate, thermoplastic elastomer alloys,
`nylon/elastomers,
`polyester/elastomers,
`polyethylene
`terephthalate/polybutylene terephthalate, acetal/elastomer,
`styrene-maleicanhydride/acrylonitrile-butadiene-styrene,
`polyether etherketone/polyethersulfone, polyethylene/ny
`lon, polyethylene/polyacetal, or the like, or combinations
`comprising at least one of the foregoing thermoplastic
`blends. Suitable examples of polymeric thermosetting mate
`rials include polyurethanes, natural rubber, synthetic rubber,
`epoxy, phenolic, polyesters, polyamides, silicones, or the
`like, or combinations comprising at least one of the forego
`mg.
`[0034] The polymeric resin is generally blended With or
`encapsulates a biologically active agent to form the drug
`coating, Which is used to coat the medical device. The
`biologically active agent may also be disposed betWeen
`layers of polymer to form the drug coating. The biologically
`active agent is then gradually released from the drug coating,
`Which simply acts as a carrier. When the polymeric resin is
`physically blended (i.e., not covalently bonded) With the
`biologically active agent, the release of the biologically
`active agent from the drug coating is diffusion controlled. It
`is generally desirable for the drug coating to comprise an
`amount of about 5 Wt % to about 90 Wt % of the biologically
`active agent based on the total Weight of the drug coating.
`Within this range, it is generally desirable to have the
`biologically active agent present in an amount of greater
`than or equal to about 10, preferably greater than or equal to
`about 20, and more preferably greater than or equal to about
`30 Wt % based on the total Weight of the drug coating.
`Within this range it is generally desirable to have the
`biologically active agent present in an amount of less than or
`equal to about 75, preferably less than or equal to about 70,
`and more preferably less than or equal to about 65 Wt %
`based on the total Weight of the drug coating. The drug
`coating may be optionally coated With an additional surface
`coating if desired. When an additional surface coating is
`used, the release of the biologically active agent is interfa
`cially controlled.
`[0035] In another exemplary embodiment, the biologically
`active agent may be covalently bonded With a biodegradable
`polymer to form the drug coating. The rate of release is then
`controlled by the rate of degradation of the biodegradable
`polymer. Suitable examples of biodegradable polymers are
`as polylactic-glycolic acid (PLGA), poly-caprolactone
`(PCL), copolymers of polylactic-glycolic acid and poly
`caprolactone (PCL-PLGA copolymer), polyhydroxy-bu
`tyrate-valerate (PHBV), polyorthoester (POE), polyethylene
`oxide-butylene terephthalate (PEO-PBTP), poly-D,L-lactic
`acid-p-dioxanone-polyethylene glycol block copolymer
`(PLA-DX-PEG), or the like, or combinations comprising at
`least one of the foregoing biodegradable polymers.
`[0036] When the drug coating comprises a biodegradable
`polymer, it is generally desirable for the biologically active
`agent to be present in an amount of about 5 Wt % to about
`90 Wt % based on the total Weight of the drug coating.
`
`Within this range, it is generally desirable to have the
`biologically active agent present in an amount of greater
`than or equal to about 10, preferably greater than or equal to
`about 20, and more preferably greater than or equal to about
`30 Wt % based on the total Weight of the drug coating.
`Within this range, it is also generally desirable to have the
`biologically active agent present in an amount of less than or
`equal to about 75, preferably less than or equal to about 70,
`and more preferably less than or equal to about 65 Wt %
`based on the total Weight of the drug coating.
`
`[0037] The drug coating may be coated onto the medical
`device in a variety of Ways. In one embodiment, the drug
`coating may be dissolved in a solvent such as Water, acetone,
`alcohols such ethanol, isopropanol, methanol, toluene, dim
`ethylformamide, dimethylacetamide, hexane, and the like,
`and coated onto the medical device. In another embodiment,
`a monomer may be covalently bonded With the biologically
`active agent and then polymeriZed to form the drug coating,
`Which is then applied onto the medical device. In yet another
`embodiment, the polymeric resin may ?rst be applied as a
`coating onto the medical device, folloWing Which the coated
`device is immersed into the biologically active agent, thus
`permitting diffusion into the coating to form the drug coat
`mg.
`
`[0038] It may also be desirable to have tWo or more
`biologically active agents dispersed in a single drug coating
`layer. Alternatively, it may be desirable to have tWo or more
`layers of the drug coating coated upon the medical device.
`Various methods of coating may be employed to coat the
`medical device such as spin coating, electrostatic painting,
`dip-coating, plasma or vacuum deposition, painting With a
`brush, and the like, and combinations comprising at least
`one of the foregoing methods of coating.
`
`[0039] Various types of biologically active agents may be
`used in the drug coating, Which is used to coat the medical
`device. The coatings on the medical device may be used to
`deliver therapeutic and pharmaceutic biologically active
`agents including anti-proliferative/antimitotic agents includ
`ing natural products such as vinca alkaloids (e.g., vinblas
`tine, vincristine, and vinorelbine), paclitaxel, epidipodo
`phyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g.,
`dactinomycin, actinomycin D, daunorubicin, doxorubicin
`and idarubicin), anthracyclines, mitoxantrone, bleomycins,
`plicamycin, mithramycin and mitomycin, enZymes (L-as
`paraginase, Which systemically metaboliZes L-asparagine
`and deprives cells Which do not have the capacity to syn
`thesiZe their oWn asparagine), antiplatelet agents such as
`G(GP) IIb/IIIa inhibitors and vitronectin receptor antago
`nists, anti-proliferative/antimitotic alkylating agents such as
`nitrogen mustards (e.g., mechlorethamine, cyclophospha
`mide and analogs, melphalan, chlorambucil), ethylenimines
`and methylmelamines (e.g., hexamethylmelamine and
`thiotepa), alkyl sulfonates- busulfan, nitrosoureas (e.g., car
`mustine (BCNU) and analogs, streptoZocin), traZenes--dac
`arbaZinine (DTIC), anti-proliferative/antimitotic antime
`tabolites such as folic acid analogs (e.g., methotrexate),
`pyrimidine analogs (e.g., ?uorouracil, ?oxuridine, cytara
`bine), purine analogs and related inhibitors (e.g., mercap
`topurine, thioguanine, pentostatin and 2-chlorodeoxyad
`enosine {cladribine}), platinum coordination complexes
`(e.g., cisplatin, carboplatin), procarbaZine, hydroxyurea,
`mitotane, aminoglutethimide, hormones (e.g., estrogen),
`anti-coagulants (e.g., heparin, synthetic heparin salts and
`
`

`

`US 2004/0193257 A1
`
`Sep. 30, 2004
`
`other inhibitors of thrombin), ?brinolytic agents (e.g., tissue
`plasminogen activator, streptokinase and urokinase), aspirin,
`dipyridamole, ticlopidine, clopidogrel, abciximab, antimi
`gratory, antisecretory (e.g., breveldin), anti-in?ammatory:
`such as adrenocortical steroids (e.g., cortisol, cortisone,
`?udrocortisone, prednisone, prednisolone, 6ot-methylpred
`nisolone, triamcinolone, betamethasone, and dexametha
`sone), non-steroidal agents (e.g., salicylic acid derivatives
`such as aspirin, para-aminophenol derivatives such as
`acetominophen, indole and indene acetic acids (e.g.,
`indomethacin, sulindac, etodalac), heteroaryl acetic acids
`(e.g., tolmetin, diclofenac, ketorolac), arylpropionic acids
`(e.g., ibuprofen and derivatives), anthranilic acids (e.g.,
`mefenamic acid, meclofenamic acid), enolic acids (e.g.,
`piroxicam, tenoxicam, phenylbutaZone, oxyphenthatra
`Zone), nabumetone, gold compounds (e.g., aurano?n,
`aurothioglucose, gold sodium thiomalate), immunosuppres
`sives (e.g., cyclosporine, tacrolimus (PK-506), sirolimus
`(e.g., rapamycin, aZathioprine, mycophenolate mofetil),
`angiogenic agents such as vascular endothelial groWth factor
`(VEGF), ?broblast groWth factor (FGF), angiotensin recep
`tor blockers, nitric oxide donors, anti-sense oligionucle
`otides and combinations thereof, cell cycle inhibitors,
`mTOR inhibitors, and groWth factor receptor signal trans
`duction kinase inhibitors, retenoids, cyclin/CDK inhibitors,
`HMG co-enZyme reductase inhibitors (statins), protease
`inhibitors.
`[0040] In one embodiment, a preferred medical device
`manufactured from an alloy having a reverse martensitic
`transformation temperature AS greater than or equal to about
`10° C., and coated With the drug coating is a stent. Referring
`noW to the ?gure, in order to deploy the stent 16 inside a
`body vessel during a surgical procedure, the catheter 11 is
`introduced into the designated vessel via an introducer
`positioned at the skin of the patient. A guide Wire may have
`previously been introduced into the vessel, in Which case the
`catheter 11 is introduced by passing the tip 26 over the end
`of the guide Wire outside of the patient and moving the
`catheter 11 along the path Within the vessel, Which has been
`established by the guide Wire.
`[0041] The position of the catheter 11 is tracked by
`monitoring the tip 26 by means of a ?uoroscope. When the
`catheter 11 is at the desired location i.e., When the stent 16
`is positioned at the location Where it is be implanted, the
`movement of the catheter 11 is halted. The catheter 11 must
`then be removed, leaving the stent 16 in place at the desired
`location Within the vessel. This is accomplished by initially
`retracting the outer sheath 10, i.e., toWards the left in the
`?gure, until it no longer covers the stent 16. The spring 12