Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.


  1. Advanced Patent Search
Publication numberUS20050106210 A1
Publication typeApplication
Application numberUS 10/989,946
Publication dateMay 19, 2005
Filing dateNov 16, 2004
Priority dateApr 19, 1995
Also published asCA2231727A1, CA2231727C, DE69636351D1, DE69636351T2, DE69636351T3, DE69637302D1, DE69637302T2, EP1019107A1, EP1019107B1, EP1019107B2, EP1500406A2, EP1500406A3, EP1500407A2, EP1500407A3, EP1500407B1, EP1559439A1, EP1559439B1, EP1647287A2, EP1647287A3, EP2082753A2, EP2082753A3, US5837313, US6358556, US20020071902, WO1997010011A1
Publication number10989946, 989946, US 2005/0106210 A1, US 2005/106210 A1, US 20050106210 A1, US 20050106210A1, US 2005106210 A1, US 2005106210A1, US-A1-20050106210, US-A1-2005106210, US2005/0106210A1, US2005/106210A1, US20050106210 A1, US20050106210A1, US2005106210 A1, US2005106210A1
InventorsNi Ding, Michael Helmus
Original AssigneeBoston Scientific Scimed, Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Medical device with drug
US 20050106210 A1
A method of coating implantable open lattice metallic stent prosthesis is disclosed which includes sequentially applying a plurality of relatively thin outer layers of a coating composition comprising a solvent mixture of uncured polymeric silicone material and crosslinker and finely divided biologically active species, possibly of controlled average particle size, to form a coating on each stent surface. The coatings are cured in situ and the coated, cured prosthesis are sterilized in a step that includes preferred pretreatment with argon gas plasma and exposure to gamma radiation electron beam, ethylene oxide, steam.
Previous page
Next page
1-23. (canceled)
24. An implantable medical device having an outer surface, covered at least in part by a conformal coating comprising an undercoat of a hydrophobic biostable elastomeric material which does not degrade, and incorporates an amount of a biologically active material therein for timed delivery therefrom;
and a topcoat comprising a polymeric material, which at least partially covers the undercoat,
wherein the undercoat and the topcoat are of different formulations.
25. The medical device of claim 24, wherein the medical device is a stent for vascular implantation.
26. The medical device of claim 25, wherein the stent is expandable.
27. The medical device of claim 25, wherein the stent comprises a tubular body having open ends and an open lattice sidewall structure and wherein said coating conforms to said sidewall structure in a manner that preserves said open lattice.
28. The medical device of claim 25, wherein the stent comprises stainless steel.
29. The medical device of claim 24, wherein the undercoat comprises an ethylene vinyl acetate copolymer.
30. The medical device of claim 24, wherein most or all of the biologically active material is contained in the undercoat.
31. The medical device of claim 24, wherein the topcoat consists of the polymeric material.
32. The medical device of claim 24, wherein the biologically active material is an antibiotic.
33. A method of making the medical device of claim 24, wherein said method comprises the steps of:
(a) applying an undercoat of a formulation containing uncured hydrophobic elastomeric material in solvent mixture and an amount of the biologically active material that is finely divided;
(b) curing said hydrophobic elastomeric material; and
(c) applying a topcoat of a formulation comprising the polymeric material to form the topcoat.
34. A method of coating an implantable prosthesis with a first polymeric material incorporating an amount of biologically active material therein for timed delivery therefrom comprising the steps of:
(a) applying a first formulation comprising the first polymeric material and the biologically active material to a surface of the prosthesis to form an under layer when the biologically active material is particulate;
(b) applying a second formulation comprising a second polymeric material over the under layer to form a top layer; and
(c) curing the first and second polymeric materials, wherein the first polymeric material is a hydrophobic elastomeric material, the average particle size of the biologically active material in the first formulation is less than or equal to about 15 μm and at least some of the biologically active material is particulate after curing, whereby the first and second formulations are applied to the prosthesis in a manner to adheringly conform thereto.
35. The method of claim 34 wherein the elastomeric material is selected from the group consisting of silicones, polyurethanes, polyamide elastomers, ethylene vinyl acetate copolymers, polyolefin elastomers, EPDM rubbers and combinations thereof.
36. The method of claim 34, wherein the first formulation comprises about 25-45 weight percent of the biologically active material includes heparin.
37. The method of claim 34, wherein the biologically active material has an average particle size less than or equal to about 10 μm before curing.
38. The method of claim 34, wherein the biologically active material includes heparin.
39. The method of any one of claim 34, wherein the implantable prosthesis is an expandable stent having a tubular metal body with a surface of an open lattice nature having openings therein, and wherein the first and second formulations are applied with the stent expanded.
40. The method of claim 39 wherein the expandable stent is a self-expanding stent.
41. The method of claim 34 wherein the second formulation is substantially free of any biologically active material.
42. The method of claim 34 wherein the second formulation is substantially free of the biologically active material in the first formulation.
43. The method of claim 34 wherein the under layer and the top layer each have a thickness and the ratio of the thickness of the top layer to the thickness of the under layer is from about 1:10 to 1:2.

The present application is a Continuation-In-Part of copending application Ser. No. 08/526,273, filed Sep. 11, 1995, and a Continuation-In-Part of copending application Ser. No. 08/424,884, filed Apr. 19, 1995, all portions of the parent applications not contained in this application being deemed incorporated by reference for any purpose. Cross-reference is also made to application Ser. No. 08/______, entitled “DRUG RELEASE STENT COATING AND PROCESS”, filed of even date and of common inventorship and assignee, that is also a Continuation-In-Part of both above-referenced patent applications. Any portion of that application that is not contained herein is also deemed to be incorporated by reference for any purpose.


II. Field of the Invention

The present invention relates generally to therapeutic expandable stent prosthesis for implantation in body lumens, e.g., vascular implantation and, more particularly, to a process for providing biostable elastomeric coatings on such stents which incorporate biologically active species having controlled release characteristics directly in the coating structure.

II. Related Art

In surgical or other related invasive medicinal procedures, the insertion and expansion of stent devices in blood vessels, urinary tracts or other difficult to access places for the purpose of preventing restenosis, providing vessel or lumen wall support or reinforcement and for other therapeutic or restorative functions has become a common form of long-term treatment. Typically, such prosthesis are applied to a location of interest utilizing a vascular catheter, or similar transluminal device, to carry the stent to the location of interest where it is thereafter released to expand or be expanded in situ. These devices are generally designed as permanent implants which may become incorporated in the vascular or other tissue which they contact at implantation.

One type of self-expanding stent has a flexible tubular body formed of several individual flexible thread elements each of which extends in a helix configuration with the centerline of the body serving as a common axis. The elements are wound in a common direction, but are displaced axially relative to each other and meet, under crossing a like number of elements also so axially displaced, but having the opposite direction of winding. This configuration provides a resilient braided tubular structure which assumes stable dimensions upon relaxation. Axial tension produces elongation and corresponding diameter contraction that allows the stent to be mounted on a catheter device and conveyed through the vascular system as a narrow elongated device. Once tension is relaxed in situ, the device at least substantially reverts to its original shape. Prosthesis of the class including a braided flexible tubular body are illustrated and described in U.S. Pat. Nos. 4,655,771 and 4,954,126 to Wallsten and 5,061,275 to Wallsten et al.

Implanted stents have also been used to carry medicinal agents, such as thrombolytic agents. U.S. Pat. No. 5,163,952 to Froix discloses a thermal memoried expanding plastic stent device which can be formulated to carry a medicinal agent by utilizing the material of the stent itself as an inert polymeric drug carrier. Pinchuk, in U.S. Pat. No. 5,092,877, discloses a stent of a polymeric material which may be employed with a coating associated with the delivery of drugs. Other patents which are directed to devices of the class utilizing bio-degradable or bio-sorbable polymers include Tang et al, U.S. Pat. No. 4,916,193, and MacGregor, U.S. Pat. No. 4,994,071. Sahatjian in U.S. Pat. No. 5,304,121, discloses a coating applied to a stent consisting of a hydrogel polymer and a preselected drug; possible drugs include cell growth inhibitors and heparin. A further method of making a coated intravascular stent carrying a therapeutic material in which a polymer coating is dissolved in a solvent and the therapeutic material dispersed in the solvent and the solvent thereafter evaporated is described in Berg et al, U.S. Pat. No. 5,464,650, issued Nov. 5, 1995 and corresponding to European patent application 0 623 354 A1 published 09 Nov. 1994.

An article by Michael N. Helmus (a co-inventor of the present invention) entitled “Medical Device Design—A Systems Approach: Central Venous Catheters”, 22nd International Society for the Advancement of Material and Process Engineering Technical Conference (1990) relates to polymer/drug/membrane systems for releasing heparin. Those polymer/ drug/membrane systems require two distinct layers to function.

The above cross-referenced grandparent application supplies an approach that provides long-term drug release, i.e., over a period of days or even months, incorporated in a controlled-release system. The parent application and present invention provide a process for coating such stents including techniques that enable the initial burst effect of drug elation to be controlled and the drug release kinetic profile associated with long-term therapeutic effect to be modified.

Metal stents of like thickness and weave generally have better mechanical properties than polymeric stents. Metallic vascular stents braided of even relatively fine metal filament can provide a large amount of strength to resist inwardly directed circumferential pressure in blood vessels. In order for a polymer material to provide comparable strength characteristics, a much thicker-walled structure or heavier, denser filament weave is required. This, in turn, reduces the cross-sectional area available for flow through the stent and/or reduces the relative amount of open space available in the structure. In addition, when applicable, it is usually more difficult to load and deliver polymeric stents using vascular catheter delivery systems.

It will be noted, however, that while certain types of stents such as braided metal stents may be superior to others for some applications, the process of the present invention is not limited in that respect and may be used to coat a wide variety of devices. The present invention also applies, for example, to the class of stents that are not self-expanding including those which can be expanded, for instance, with a balloon. Polymeric stents, of all kinds can be coated using the process. Thus, regardless of particular detailed embodiments the use of the invention is not considered or intended to be limited with respect either to stent design or materials of construction. Further, the present invention may be utilized with other types of implant prostheses.

Accordingly, it is a primary object of the present invention to provide a coating process for coating a stent to be used as a deployed stent prosthesis, the coating being capable of long-term delivery of biologically active materials.

Another object of the invention is to provide a process for coating a stent prosthesis using a biostable hydrophobic elastomer in which biologically active species are incorporated within a cured coating.

Still another object of the present invention is to provide a multi-layer coating in which the percentage of active material can vary from layer to layer.

A further object of the present invention is to control or modify aspects of the timed or time variable drug delivery from a stent coating by controlling average particle size in the biologically active species.

Other objects and advantages of the present invention will become apparent to those skilled in the art upon familiarization with the specification and appended claims.


The present invention provides processes for producing a relatively thin layer of biostable elastomeric material in which an amount of biologically active material is dispersed as a coating on the surfaces of a deployable stent prosthesis. The preferred stent to be coated is a self-expanding, open-ended tubular stent prosthesis. Although other materials, including polymer materials, can be used, in the preferred embodiment, the tubular body is formed of an open braid of fine single or polyfilament metal wire which flexes without collapsing and readily axially deforms to an elongate shape for transluminal insertion via a vascular catheter. The stent resiliently attempts to resume predetermined stable dimensions upon relaxation in situ.

The coating is preferably applied as a mixture, solution or suspension of polymeric material and finely divided biologically active species dispersed in an organic vehicle or a solution or partial solution of such species in a solvent or vehicle for the polymer and/or biologically active species. For the purpose of this application, the term “finally divided” means any type or size of included material from dissolved molecules through suspensions, colloids and particulate mixtures. The active material is dispersed in a carrier material which may be the polymer, a solvent, or both. The coating is preferably applied as a plurality of relatively thin layers sequentially applied in relatively rapid sequence and is preferably applied with the stent in a radially expanded state. In some applications the coating may further be characterized as a composite initial tie coat or undercoat and a composite topcoat. The coating thickness ratio of the topcoat to the undercoat may vary with the desired effect and/or the elution system. Typically these are of different formulations.

The coating may be applied by dipping or spraying using evaporative solvent materials of relatively high vapor pressure to produce the desired viscosity and quickly establish coating layer thicknesses. The preferred process is predicated on reciprocally spray coating a rotating radially expanded stent employing an air brush device. The coating process enables the material to adherently conform to and cover the entire surface of the filaments of the open structure of the stent but in a manner such that the open lattice nature of the structure of the braid or other pattern is preserved in the coated device.

The coating is exposed to room temperature ventilation for a predetermined time (possibly one hour or more) for solvent vehicle evaporation. Thereafter the polymeric precuser material is cured at room temperature or elevated temperatures or the solvent evaporated away from the dissolved polymer as the case may be. Curing is defined as the process of converting the elastomeric or polymeric material into the finished or useful state by the application of heat and/or chemical agents which include physical-chemical charges. Where, for example, polyurethane thermoplastic elastomers are used, solvent evaporation can occur at room temperature rendering the polymeric material useful for controlled drug release without further curing. Non-limiting examples of curing according to this definition include the application of heat and/or chemical agents and the evaporation of solvent which may induce physical and/or chemical changes.

The ventilation time and temperature for cure are determined by the particular polymer involved and particular drugs used. For example, silicone or polysiloxane materials (such as polydimethylsiloxane) have been used successfully. These materials are applied as pre-polymer in the coating composition and must thereafter be cured. The preferred species have a relatively low cure temperatures and are known as a room temperature vulcanizable (RTV) materials. Some polydimethylsiloxane materials can be cured, for example, by exposure to air at about 90° C. for a period of time such as 16 hours. A curing step may be implemented both after application of a certain number of lower undercoat layers and the topcoat layers or a single curing step used after coating is completed.

The coated stents may thereafter be subjected to a postcure sterilization process which includes an inert gas plasma treatment, and then exposure to gamma radiation, electron beam, ethylene oxide (ETO) or steam sterilization may also be employed.

In the plasma treatment, unconstrained coated stents are placed in a reactor chamber and the system is purged with nitrogen and a vacuum applied to about 20-50 mTorr. Thereafter, inert gas (argon, helium or mixture of them) is admitted to the reaction chamber for the plasma treatment. A highly preferred method of operation consists of using argon gas, operating at a power range from 200 to 400 watts, a flow rate of 150-650 standard ml per minute, which is equivalent to about 100-450 mTorr, and an exposure time from 30 seconds to about 5 minutes. The stents can be removed immediately after the plasma treatment or remain in the argon atmosphere for an additional period of time, typically five minutes.

After the argon plasma pretreatment, the coated and cured stents are subjected to gamma radiation sterilization nominally at 2.5-3.5 Mrad. The stents enjoy full resiliency after radiation whether exposed in a constrained or non-constrained status. It has been found that constrained stents subjected to gamma sterilization without utilizing the argon plasma pretreatment lose resiliency and do not recover at a sufficient or appropriate rate.

The elastomeric material that forms a major constituent of the stent coating should possess certain properties. It is preferably a suitable hydrophobic biostable elastomeric material which does not degrade and which minimizes tissue rejection and tissue inflammation and one which will undergo encapsulation by tissue adjacent to the stent implantation site. Polymers suitable for such coatings include silicones (e.g., polysiloxanes and substituted polysiloxanes), polyurethanes (including polycarbonate urethanes), thermoplastic elastomers in general, ethylene vinyl acetate copolymers, polyolefin elastomers, EPDM rubbers and polyamide elastomers. The above-referenced materials are considered hydrophobic with respect to the contemplated environment of the invention.

Agents suitable for incorporation-include antithrobotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, antinflammatories, agents that inhibit hyperplasia and in particular restenosis, smooth muscle cell inhibitors, antibiotics growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters and drugs that may enhance the formation of healthy neointimal tissue, including endothelial cell regeneration. The positive action may come from inhibiting particular cells (e.g., smooth muscle cells) or tissue formation (e.g., fibromuscular tissue) while encouraging different cell migration (e.g., endothelium) and tissue formation (neointimal tissue).

The preferred materials for fabricating the braided stent include stainless steel, tantalum, titanium alloys including nitinol (a nickel titanium, thermomemoried alloy material), and certain cobalt alloys including cobalt-chromium-nickel alloys such as Elgiloy® and Phynox®. Further details concerning the fabrication and details of other aspects of the stents themselves, may be gleaned from the above referenced U.S. Pat. Nos. 4,655,771 and 4,954,126 to Wallsten and 5,061,275 to Wallsten et al. To the extent additional information contained in the above-referenced patents is necessary for an understanding of the present invention, they are deemed incorporated by reference herein.

Various combinations of polymer coating materials can be coordinated with biologically active species of interest to produce desired effects when coated on stents to be implanted in accordance with the invention. Loadings of therapeutic materials may vary. The mechanism of incorporation of the biologically active species into the surface coating, and egress mechanism depend both on the nature of the surface coating polymer and the material to be incorporated. The mechanism of release also depends on the mode of incorporation. The material may elute via interparticle paths or be administered via transport or diffusion through the encapsulating material itself.

For the purposes of this specification, “elution” is defined as any-process of release that involves extraction or release by direct contact of the material with bodily fluids through the interparticle paths connected with the exterior of the coating. “Transport” or “diffusion” are defined to include a mechanism of release in which a material released traverses through another material.

The desired release rate profile can be tailored by varying the coating thickness, the radial distribution (layer to layer) of bioactive materials, the mixing method, the amount of bioactive material, the combination of different matrix polymer materials at different layers, and the crosslink density of the polymeric material. The crosslink density is related to the amount of crosslinking which takes place and also the relative tightness of the matrix created by the particular crosslinking agent used. This, during the curing process, determines the amount of crosslinking and so the crosslink density of the polymer material. For bioactive materials released from the crosslinked matrix, such as heparin, a crosslink structure of greater density will increase release time and reduce burst effect.

Additionally, with eluting materials such as heparin, release kinetics, particularly initial drug release rate, can be affected by varying the average dispersed particle size. The observed initial release rate or burst effect may be substantially reduced by using smaller particles, particularly if the particle size is controlled to be less than about 15 microns and the effect is even more significant in the particle size range of ≦10 microns, especially when the coating thickness is not more than about 50 μm and drug loading is about 25-45 weight percent.

It will also be appreciated that an unmedicated silicone thin top layer provides an advantage over drug containing top coat. Its surface has a limited porosity and is generally smooth, which may be less thrombogeneous and may reduce the chance to develop calcification, which occurs most often on the porous surface.


In the drawings, wherein like numerals designate like parts throughout the same:

FIG. 1 is a schematic flow diagram illustrating the steps of the process of the invention;

FIG. 2 represents a release profile for a multi-layer system showing the percentage of heparin released over a two-week period;

FIG. 3 represents a release profile for a multi-layer system showing the relative release rate of heparin over a two-week period;

FIG. 4 illustrates a profile of release kinetics for different drug loadings at similar coating thicknesses illustrating the release of heparin over a two-week period;

FIG. 5 illustrates drug elution kinetics at a given loading of heparin over a two-week period at different coating thicknesses;

FIG. 6 illustrates the release kinetics in a coating having a given tie-layer thickness for different top coat thicknesses in which the percentage heparin in the tie coat and top coats are kept constant;

FIG. 7 illustrates the release kinetics of several coatings having an average coating thickness of 25 microns and a heparin loading of 37.5% but using four different average particle sizes;

FIGS. 8-11 are photomicrographs of coated stent fragments for the coatings of FIG. 7 having a corresponding average particle size of 4 microns, 17 microns, 22 microns and 30 microns, respectively.


According to the present invention, the stent coatings incorporating biologically active materials for timed delivery in situ in a body lumen of interest are preferably sprayed in many thin layers from prepared coating solutions or suspensions. The steps of the process are illustrated generally in FIG. 1. The coating solutions or suspensions are prepared at 10 as will be described later. The desired amount of crosslinking agent is added to the suspension/solution as at 12 and material is then agitated or stirred to produce a homogenous coating composition at 14 which is thereafter transferred to an application container or device which may be a container for spray painting at 16. Typical exemplary preparations of coating solutions that were used for heparin and dexamethasone appear next.

General Preparation of Heparin Coating Composition

Silicone was obtained as a polymer precursor in solvent (xylene) mixture. For example, a 35% solid silicone weight content in xylene was procured from Applied Silicone, Part #40,000. First, the silicone-xylene mixture was weighed. The solid silicone content was determined according to the vendor's analysis. Precalculated amounts of finely divided heparin (2-6 microns) were added into the silicone, then tetrahydrofuron (THF) HPCL grade (Aldrich or EM) was added. For a 37.5% heparin coating, for example: Wsilicone=5 g; solid percent=35%; Whep=5×0.35×0.375/(0.625)=1.05 g. The amount of THF needed (44 ml) in the coating solution was calculated by using the equation Wsilicone solid/VTHF=0.04 for a 37.5% heparin coating solution). Finally, the manufacturer crosslinker solution was added by using Pasteur P-pipet. The amount of crosslinker added was formed to effect the release rate profile. Typically, five drops of crosslinker solution were added for each five grams of silicone-xylene mixture. The crosslinker may be any suitable and compatible agent including platinum and peroxide based materials. The solution was stirred by using the stirring rod until the suspension was homogenous and milk-like. The coating solution was then transferred into a paint jar in condition for application by air brush.

General Preparation of Dexamethasone Coating Composition

Silicone (35% solution as above) was weighed into a beaker on a Metler balance. The weight of dexamethasone free alcohol or acetate form was calculated by silicone weight multiplied by 0.35 and the desired percentage of dexamethasone (1 to 40%) and the required amount was then weighed. Example: Wsilicone=5 g; for a 10% dexamethasone coating, Wdex=5×0.35×0.1/0.9=0.194 g and THF needed in the coating solution calculated. Wsilicone solid/VTHF=0.06 for a 10% dexamethasone coating solution. Example: Wsilicone=5 g; VTHF=5×0.35/0.06≈29 ml. The dexamethasone was weighed in a beaker on an analytical balance and half the total amount of THF was added. The solution was stirred well to ensure full dissolution of the dexamethasone. The stirred DEX-THF solution was then transferred to the silicone container. The beaker was washed with the remaining THF and this was transferred to the silicone container. The crosslinker was added by using a Pasteur pipet. Typically, five drops of crosslinker were used for five grams of silicone.

The application of the coating material to the stent was quite similar for all of the materials and the same for the heparin and dexamethasone suspensions prepared as in the above Examples. The suspension to be applied was transferred to an application device, typically a paint jar attached to an air brush, such as a Badger Model 150, supplied with a source of pressurized air through a regulator (Norgren, 0-160 psi). Once the brush hose was attached to the source of compressed air downstream of the regulator, the air was applied. The pressure was adjusted to approximately 15-25 psi and the nozzle condition checked by depressing the trigger.

Any appropriate method can be used to secure the stent for spraying and rotating fixtures were utilized successfully in the laboratory. Both ends of the relaxed stent were fastened to the fixture by two resilient retainers, commonly alligator clips, with the distance between the clips adjusted so that the stent remained in a relaxed, unstretched condition. The rotor was then energized and the spin speed adjusted to the desired coating speed, nominally about 40 rpm.

With the stent rotating in a substantially horizontal plane, the spray nozzle was adjusted so that the distance from the nozzle to the stent was about 2-4 inches and the composition was sprayed substantially horizontally with the brush being directed along the stent from the distal end of the stent to the proximal end and then from the proximal end to the distal end in a sweeping motion at a speed such that one spray cycle occurred in about three stent rotations. Typically a pause of less than one minute, normally about one-half minute, elapsed between layers. Of course, the number of coating layers did and will vary with the particular application. For example, for a coating level of 3-4 mg of heparin per cm2 of projected area, 20 cycles of coating application are required and about 30 ml of solution will be consumed for a 3.5 mm diameter by 14.5 cm long stent.

The rotation speed of the motor, of course, can be adjusted as can the viscosity of the composition and the flow rate of the spray nozzle as desired to modify the layered structure. Generally, with the above mixes, the best results have been obtained at rotational speeds in the range of 30-50 rpm and with a spray nozzle flow rate in the range of 4-10 ml of coating composition per minute, depending on the stent size. It is contemplated that a more sophisticated, computer-controlled coating apparatus will successfully automate the process demonstrated as feasible in the laboratory.

Several applied layers make up what is called the tie layer as at 18 and thereafter additional upper layers, which may be of a different composition with respect to bioactive material, the matrix polymeric materials and crosslinking agent, for example, are applied as the top layer as at 20. The application of the top layer follows the same coating procedure as the tie layer with the number and thickness of layers being optional. Of course, the thickness of any layer can be adjusted by modifying the speed of rotation of the stent and the spraying conditions. Generally, the total coating thickness is controlled by the number of spraying cycles or thin coats which make up the total coat.

As shown at 22 in FIG. 1, the coated stent is thereafter subjected to a curing step in which the pre-polymer and crosslinking agents cooperate to produce a cured polymer matrix containing the biologically active species. The curing process involves evaporation of the solvent xylene, THF, etc. and the curing and crosslinking of the polymer. Certain silicone materials can be cured at relatively low temperatures, (i.e. RT-50° C.) in what is known as a room temperature vulcanization (RTV) process. More typically, however, the curing process involves higher temperature curing materials and the coated stents are put into an oven at approximately 90° C. or higher for approximately 16 hours. The temperature may be raised to as high as 150° C. for dexamethasone containing coated stents. Of course, the time and temperature may vary with particular silicones, crosslinkers, and biologically active species.

Stents coated and cured in the manner described need to be sterilized prior to packaging for future implantation. For sterilization, gamma radiation is a preferred method particularly for heparin containing coatings; however, it has been found that stents coated and cured according to the process of the invention subjected to gamma sterilization may be too slow to recover their original posture when delivered to a vascular or other lumen site using a catheter unless a pretreatment step as at 24 is first applied to the coated, cured stent.

The pretreatment step involves an argon plasma treatment of the coated, cured stents in the unconstrained configuration. In accordance with this procedure, the stents are placed in a chamber of a plasma surface treatment system such as a Plasma Science 350 (Himont/Plasma Science, Foster City, Calif.). The system is equipped with a reactor chamber and RF solid-state generator operating at 13.56 mHz and from 0-500 watts power output and being equipped with a microprocessor controlled system and a complete vacuum pump package. The reaction chamber contains an unimpeded work volume of 16.75 inches (42.55 cm) by 13.5 inches (34.3 cm) by 17.5 inches (44.45 cm) in depth.

In the plasma process, unconstrained coated stents are placed in a reactor chamber and the system is purged with nitrogen and a vacuum applied to 20-50 mTorr. Thereafter, inert gas (argon, helium or mixture of them) is admitted to the reaction chamber for the plasma treatment. A highly preferred method of operation consists of using argon gas, operating at a power range from 200 to 400 watts, a flow rate of 150-650 standard ml per minute, which is equivalent to 100-450 mTorr, and an exposure time from 30 seconds to about 5 minutes. The stents can be removed immediately after the plasma treatment or remain in the argon atmosphere for an additional period of time, typically five minutes.

After this, as shown at 26, the stents are exposed to gamma sterilization at 2.5-3.5 Mrad. The radiation may be carried out with the stent in either the radially non-constrained status—or in the radially constrained status.

With respect to the anticoagulant material heparin, the percentage in the tie layer is nominally from about 20-50% and that of the top layer from about 0-30% active material. The coating thickness ratio of the top layer to the tie layer varies from about 1:10 to 1:2 and is preferably in the range of from about 1:6 to 1:3.

Suppressing the burst effect also enables a reduction in the drug loading or in other words, allows a reduction in the coating thickness, since the physician will give a bolus injection of antiplatelet/anticoagulation drugs to the patient during the stenting process. As a result, the drug imbedded in the stent can be fully used without waste. Tailoring the first day release, but maximizing second day and third day release at the thinnest possible coating configuration will reduce the acute or subcute thrombosis.

FIG. 4 depicts the general effect of drug loading for coatings of similar thickness. The initial elution rate increases with the drug loading as shown in FIG. 5. The release rate also increases with the thickness of the coating at the same loading but tends to be inversely proportional to the thickness of the top layer as shown by the same drug loading and similar tie-coat thickness in FIG. 6.

The effect of average particle size is depicted in the FIGS. 7-11 in which coating layers with an average coating thickness of about 25 microns (μm), prepared and sterilized as above, were provided with dispersed heparin particles (to 37.5% heparin) of several different average particle sizes. FIG. 7 shows plots of elution kinetics for four different sizes of embedded heparin particles. The release took place in phosphate buffer (pH 7.4) at 37° C. The release rate using smaller, particularly 4-6 μm average sized particles noticeably reduces the initial rate or burst effect and thereafter the elution rate decreases more slowly with time. Average particle sizes above about 15 μm result in initial release rates approaching bolus elution. This, of course, is less desirable, both from the standpoint of being an unnecessary initial excess and for prematurely depleting the coating of deserved drug material.

In addition, as shown in the photomicrographs of FIGS. 8-11, as the average particle size increases, the morphology of the coating surface also changes coatings containing larger particles (FIGS. 9-11) have very rough and irregular surface characteristics. These surface irregularities may be more thrombogenic or exhibit an increased tendency to cause embolization when the corresponding stent is implanted in a blood vessel.

Accordingly, it has been found that the average particle size should generally be controlled below about 15 μm to reduce the burst effect and preferably should be ≦ about 10 μm for best results. The 4-6 μm size worked quite successfully in the laboratory. However, it should be noted that larger particle size can also be advantageously used, for instance, when the drug load is low, such as below 25 weight percent. Elution kinetics can be adjusted by a combination of changing the particle size and changing the load or concentration of the dispersed drug material.

What is apparent from the data gathered to date, however, is that the process of the present invention enables the drug elution kinetics to be modified to meet the needs of the particular stent application. In a similar manner, stent coatings can be prepared using a combination of two or more drugs and the drug release sequence and rate controlled. For example, antiproliferation drugs may be combined in the undercoat and anti-thrombotic drugs in the topcoat layer. In this manner, the anti-thrombotic drugs, for example, heparin, will elute first followed by antiproliferation drugs, e.g. dexamethasone, to better enable safe encapsulation of the implanted stent.

The heparin concentration measurement were made utilizing a standard curve prepared by complexing azure A dye with dilute solutions of heparin. Sixteen standards were used to compile the standard curve in a well-known manner.

For the elution test, the stents were immersed in a phosphate buffer solution at pH 7.4 in an incubator at approximately 37° C. Periodic samplings of the solution were processed to determine the amount of heparin eluted. After each sampling, each stent was placed in heparin-free buffer solution.

As stated above, while the allowable loading of the elastomeric material with heparin may vary, in the case of silicone materials heparin may exceed 60% of the total weight of the layer. However, the loading generally most advantageously used is in the range from about 10% to 45% of the total weight of the layer. In the case of dexamethasone, the loading may be as high as 50% or more of the total weight of the layer but is preferably in the range of about 0.4% to 45%.

It will be appreciated that the mechanism of incorporation of the biologically active species into a thin surface coating structure applicable to a metal stent is an important aspect of the present invention. The need for relatively thick-walled polymer elution stents or any membrane overlayers associated with many prior drug elution devices is obviated, as is the need for utilizing biodegradable or reabsorbable vehicles for carrying the biologically active species. The technique clearly enables long-term delivery and minimizes interference with the independent mechanical or therapeutic benefits of the stent itself.

Coating materials are designed with a particular coating technique, coating/drug combination and drug infusion mechanism in mind. Consideration of the particular form and mechanism of release of the biologically active species in the coating allow the technique to produce superior results. In this manner, delivery of the biologically active species from the coating structure can be tailored to accommodate a variety of applications.

Whereas the above examples depict-coatings having two different drug loadings or percentages of biologically active material to be released, this is by no means limiting with respect to the invention and it is contemplated that any number of layers and combinations of loadings can be employed to achieve a desired release profile. For example, gradual grading and change in the loading of the layers can be utilized in which, for example, higher loadings are used in the inner layers. Also layers can be used which have no drug loadings at all. For example, a pulsatile heparin release system may be achieved by a coating in which alternate layers containing heparin are sandwiched between unloaded layers of silicone or other materials for a portion of the coating. In other words, the invention allows untold numbers of combinations which result in a great deal of flexibility with respect to controlling the release of biologically active materials with regard to an implanted stent. Each applied layer is typically from approximately 0.5 microns to 15 microns in thickness. The total number of sprayed layers, of course, can vary widely, from less than 10 to more than 50 layers; commonly, 20 to 40 layers are included. The total thickness of the coating can also vary widely, but can generally be from about 10 to 200 microns.

Whereas the polymer of the coating may be any compatible biostable elastomeric material capable of being adhered to the stent material as a thin layer, hydrophobic materials are preferred because it has been found that the release of the biologically active species can generally be more predictably controlled with such materials. Preferred materials include silicone rubber elastomers and biostable polyurethanes specifically.

This invention has been described herein in considerable detail in order to comply with the Patent Statutes and to provide those skilled in the art with the information needed to apply the novel principles and to construct and use embodiments of the example as required. However, it is to be understood that the invention can be carried out by specifically different devices and that various modifications can be accomplished without departing from the scope of the invention itself.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3168565 *Nov 20, 1959Feb 2, 1965Richardson Merrell IncTrifluoromethyl derivatives of amino triarylethanols, -ethanes, and -ethylenes
US3634517 *Aug 19, 1968Jan 11, 1972Richardson Merrell IncTriarylalkenones
US3932627 *Feb 4, 1974Jan 13, 1976Rescue Products, Inc.Siver-heparin-allantoin complex
US3940422 *Jan 17, 1974Feb 24, 1976Kissei Yakuhin Kogyo Kabushiki KaishaAromatic carboxylic amide derivatives
US4070484 *Dec 21, 1976Jan 24, 1978Kissei Pharmaceutical Co., Ltd.Antiallergic composition containing aromatic carboxylic amide derivatives and method of using the same
US4133814 *Sep 17, 1976Jan 9, 1979Eli Lilly And Company2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents
US4310523 *Oct 10, 1980Jan 12, 1982Schering AktiengesellschaftCombined antiestrogens and antigonadotropically effective antiandrogens for the prophylaxis and therapy of hyperplasia of the prostate
US4315028 *Sep 18, 1979Feb 9, 1982Scheinberg Israel HMethod of treatment of rheumatoid arthritis
US4317915 *Jan 14, 1980Mar 2, 1982Hoffmann-La Roche Inc.Novel thiophene derivatives
US4428963 *Mar 10, 1983Jan 31, 1984Hoffmann-La Roche Inc.Novel thiophene derivatives
US4491574 *Mar 2, 1983Jan 1, 1985Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva UniversityReduction of high dose aspirin toxicity by dietary vitamin A
US4577636 *Jan 27, 1984Mar 25, 1986The Beth Israel Hospital AssociationMethod for diagnosis of atherosclerosis
US4732763 *Sep 28, 1984Mar 22, 1988Stolle Research And Development CorporationActive/passive immunization of the internal female reproductive organs
US4733665 *Nov 7, 1985Mar 29, 1988Expandable Grafts PartnershipExpandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
US4894231 *Jul 28, 1987Jan 16, 1990Biomeasure, Inc.Therapeutic agent delivery system
US4897255 *Jun 19, 1987Jan 30, 1990Neorx CorporationMetal radionuclide labeled proteins for diagnosis and therapy
US4900561 *Jan 3, 1989Feb 13, 1990Zinpro CorporationCopper complexes of alpha-amino acids that contain terminal amino groups, and their use as nutritional supplements
US4906452 *Apr 28, 1988Mar 6, 1990Neorx CorporationTrichothecene conjugates and methods of use
US4984594 *Oct 27, 1989Jan 15, 1991Shell Oil CompanyVacuum method for removing soil contamination utilizing surface electrical heating
US4990158 *May 10, 1989Feb 5, 1991United States Surgical CorporationSynthetic semiabsorbable tubular prosthesis
US4990538 *Aug 23, 1989Feb 5, 1991Harris Adrian LUse of toremifene and its metabolites for the reversal of multidrug resistance of cancer cells against cytotoxic drugs
US4994033 *May 25, 1989Feb 19, 1991Schneider (Usa) Inc.Intravascular drug delivery dilatation catheter
US4994071 *May 22, 1989Feb 19, 1991Cordis CorporationBifurcating stent apparatus and method
US4994384 *Oct 27, 1987Feb 19, 1991W. R. Grace & Co.-Conn.Multiplying bovine embryos
US4996225 *Oct 12, 1989Feb 26, 1991Farmos Group Ltd.Tri-phenyl alkane derivatives and their oestrogenic, anti-oestrogenic and progestanic uses
US4997652 *May 31, 1989Mar 5, 1991VisionexBiodegradable ocular implants
US5082834 *Sep 18, 1990Jan 21, 1992Sorensen John R JAnti-inflammatory and anti-ulcer compounds and process
US5176617 *Oct 21, 1991Jan 5, 1993Medical Innovative Technologies R & D Limited PartnershipUse of a stent with the capability to inhibit malignant growth in a vessel such as a biliary duct
US5180366 *Oct 10, 1990Jan 19, 1993Woods W TApparatus and method for angioplasty and for preventing re-stenosis
US5180376 *May 1, 1990Jan 19, 1993Cathco, Inc.Non-buckling thin-walled sheath for the percutaneous insertion of intraluminal catheters
US5182317 *Jun 17, 1991Jan 26, 1993Cardiopulmonics, Inc.Multifunctional thrombo-resistant coatings and methods of manufacture
US5185260 *Aug 29, 1991Feb 9, 1993The United States Of America As Represented By The United States Department Of EnergyMethod for distinguishing normal and transformed cells using G1 kinase inhibitors
US5185408 *Nov 18, 1991Feb 9, 1993Allied-Signal Inc.Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides
US5188791 *Apr 1, 1991Feb 23, 1993Savoie RefractairesConcrete composition for the manufacture of moulds, mould and process for the manufacture of a mould
US5189046 *Jun 4, 1991Feb 23, 1993Nova Pharmaceutical CorporationProtein kinase C modulators
US5189212 *Sep 7, 1990Feb 23, 1993University Of Georgia Research Foundation, Inc.Triarylethylene carboxylic acids with estrogenic activity
US5280016 *Sep 3, 1991Jan 18, 1994Glycomed IncorporatedNon-anticoagulant heparin derivatives
US5280040 *Mar 11, 1993Jan 18, 1994Zymogenetics, Inc.Methods for reducing bone loss using centchroman derivatives
US5280109 *Jan 27, 1992Jan 18, 1994Ludwig Institute For Cancer ResearchIsolated, large latent complexes of TGF-β2 and TGF-β3, and new binding protein for latent form TGF-β1, TGF-β2 and TGF-β3 LTBP-2
US5282785 *Oct 5, 1992Feb 1, 1994Cortrak Medical, Inc.Drug delivery apparatus and method
US5282823 *Mar 19, 1992Feb 1, 1994Medtronic, Inc.Intravascular radially expandable stent
US5283257 *Jul 10, 1992Feb 1, 1994The Board Of Trustees Of The Leland Stanford Junior UniversityMethod of treating hyperproliferative vascular disease
US5284763 *Mar 4, 1992Feb 8, 1994Genentech, Inc.Nucleic acid encoding TGF-β and its uses
US5284869 *Dec 17, 1991Feb 8, 1994Emil BisacciaPhotophoresis methods for treating atherosclerosis and for preventing restenosis following angioplasty
US5288711 *Apr 28, 1992Feb 22, 1994American Home Products CorporationMethod of treating hyperproliferative vascular disease
US5288735 *Jun 15, 1992Feb 22, 1994Trager Seymour FTreatment of glaucoma
US5378475 *Feb 21, 1991Jan 3, 1995University Of Kentucky Research FoundationSustained release drug delivery devices
US5380299 *Aug 30, 1993Jan 10, 1995Med Institute, Inc.Thrombolytic treated intravascular medical device
US5380716 *Dec 28, 1992Jan 10, 1995Glycomed, Inc.Sulfated polysaccharides as inhibitors of smooth muscle cell proliferation
US5383928 *Aug 19, 1993Jan 24, 1995Emory UniversityStent sheath for local drug delivery
US5384332 *May 11, 1994Jan 24, 1995Eli Lilly And CompanyMethods for inhibiting aortal smooth muscle cell proliferation and restenosis with 1,1,2-triphenylbut-1-ene derivatives
US5385935 *Sep 7, 1993Jan 31, 1995Kissei Pharmaceutical Co., Ltd.Method for the inhibition of restenosis associated with coronary intervention
US5387680 *Aug 10, 1993Feb 7, 1995American Home Products CorporationC-22 ring stabilized rapamycin derivatives
US5389670 *Dec 21, 1993Feb 14, 1995Eli Lilly CompanyMethods of inhibiting the symptoms of premenstrual syndrome/late luteal phase dysphoric disorder
US5391378 *Feb 22, 1993Feb 21, 1995Elizabeth-Hata International, Inc.Two-part medicinal tablet and method of manufacture
US5391557 *Oct 15, 1993Feb 21, 1995Eli Lilly And CompanyMethods for the treatment of peri-menopausal syndrome
US5393763 *Jan 12, 1994Feb 28, 1995Eli Lilly And CompanyMethods for inhibiting bone loss
US5393772 *Nov 24, 1993Feb 28, 1995Boehringer Mannheim Pharmaceuticals CorporationUse of, and method of treatment using, hydroxycarbazole compounds for inhibition of smooth muscle migration and proliferation
US5393785 *Jul 14, 1992Feb 28, 1995Endorecherche, Inc.Therapeutic antiestrogens
US5480888 *Jan 14, 1993Jan 2, 1996Daiichi Pharmaceutical Co., Ltd.Inhibitor for restenosis after percutaneous coronary arterioplasty
US5480903 *Apr 17, 1994Jan 2, 1996Zymogenetics, Inc.3,4-diarylchromans for inhibiting calmodulin activity
US5480904 *Oct 28, 1993Jan 2, 1996Eli Lilly And CompanyMethods for inhibiting uterine fibrosis
US5482851 *Nov 5, 1993Jan 9, 1996Genentech, Inc.Nucleic acid encoding TGF-β and its uses
US5482949 *Mar 19, 1993Jan 9, 1996Eli Lilly And CompanySulfonate derivatives of 3-aroylbenzo[b]thiophenes
US5482950 *Oct 15, 1993Jan 9, 1996Eli Lilly And CompanyMethods for lowering serum cholesterol
US5484795 *Apr 21, 1995Jan 16, 1996Eli Lilly And CompanyNaphthyl compounds, intermediates, processes, compositions, and method of inhibiting restenosis
US5484796 *Apr 21, 1995Jan 16, 1996Eli Lilly And CompanyNaphthyl compounds, intermediates, processes, compositions, and method of inhibiting aortal smooth muscle cell proliferation
US5484797 *Apr 21, 1995Jan 16, 1996Eli Lilly And CompanyNaphthly compounds, intermediates, processes, compositions, and method for inhibiting endometrosis
US5484798 *Apr 19, 1995Jan 16, 1996Eli Lilly And CompanyBenzothiopene compounds, compositions, and method of inhibiting restenosis
US5484808 *Feb 9, 1995Jan 16, 1996Eli Lilly And CompanyMethods of inhibiting cell-cell adhesion
US5486357 *Oct 27, 1993Jan 23, 1996Cordis CorporationRadiofrequency plasma biocompatibility treatment of inside surfaces
US5489587 *Jan 20, 1995Feb 6, 1996Eli Lilly And CompanyBenzofurans used to inhibit bone loss
US5491159 *Aug 30, 1994Feb 13, 1996American Home Products Corporation2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-oxazoles as anti-atherosclerotic agents
US5491173 *Jan 24, 1994Feb 13, 1996Orion-Yhtyma OyTri-phenyl alkene derivatives and their preparation and use
US5492895 *Feb 14, 1994Feb 20, 1996Corvas International, Inc.Inhibitors of thrombosis
US5492921 *Apr 19, 1995Feb 20, 1996Eli Lilly And CompanyBenzothiophene compounds, compositions, and methods for inhibiting aortal smooth muscle proliferation
US5492922 *Jun 6, 1995Feb 20, 1996Eli Lilly And CompanyBenzothiophene compounds intermediate compositions and methods for inhibiting aortal smooth muscle proliferation
US5492926 *Apr 14, 1995Feb 20, 1996Eli Lilly And CompanyMethods for inhibiting vascular smooth muscle cell proliferation and restinosis
US5492927 *Dec 21, 1993Feb 20, 1996Eli Lilly And CompanyNon-peptide tachykinin receptor antagonists to treat allergy
US5493931 *Feb 14, 1994Feb 27, 1996Grand Haven Stamped Products Company, Div. Of Jsj Corp.Vehicle shifter
US5591224 *Sep 15, 1994Jan 7, 1997Medtronic, Inc.Bioelastomeric stent
US5591227 *Apr 27, 1995Jan 7, 1997Medtronic, Inc.Drug eluting stent
US5595722 *Jun 7, 1995Jan 21, 1997Neorx CorporationMethod for identifying an agent which increases TGF-beta levels
US5597578 *Apr 28, 1994Jan 28, 1997OncogenTGF-β protein compositions for inhibition of cell proliferation
US5599352 *Sep 15, 1994Feb 4, 1997Medtronic, Inc.Method of making a drug eluting stent
US5599844 *Sep 15, 1995Feb 4, 1997Neorx CorporationPrevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells
US5605696 *Mar 30, 1995Feb 25, 1997Advanced Cardiovascular Systems, Inc.Drug loaded polymeric material and method of manufacture
US5605700 *Mar 25, 1993Feb 25, 1997Orion-Yhtyma OyTopical administration of toremifene and its metabolites
US5705477 *Jul 5, 1994Jan 6, 1998The United States Of America As Represented By The Department Of Health And Human ServicesCompositions of transforming growth factor β(TGF-β) which promotes wound healing and methods for their use
US5705609 *May 16, 1995Jan 6, 1998La Jolla Cancer Research FoundationDecorin fragments inhibiting cell regulatory factors
US5716981 *Jun 7, 1995Feb 10, 1998Angiogenesis Technologies, Inc.Anti-angiogenic compositions and methods of use
US5863285 *Jan 30, 1997Jan 26, 1999Cordis CorporationBalloon catheter with radioactive means
US5873904 *Feb 24, 1997Feb 23, 1999Cook IncorporatedSilver implantable medical device
US6013099 *Apr 29, 1998Jan 11, 2000Medtronic, Inc.Medical device for delivering a water-insoluble therapeutic salt or substance
US6168619 *Oct 16, 1998Jan 2, 2001Quanam Medical CorporationIntravascular stent having a coaxial polymer member and end sleeves
US6171609 *Oct 23, 1995Jan 9, 2001Neorx CorporationTherapeutic inhibitor of vascular smooth muscle cells
US6187370 *Sep 16, 1999Feb 13, 2001Medtronic, Inc.Medical device for delivering a therapeutic substance and method therefor
US6689159 *May 1, 2003Feb 10, 2004Advanced Cardiovascular Systems, Inc.Expandable stents and method for making same
US20030039675 *Nov 27, 2001Feb 27, 2003Angiotech Pharmaceuticals, Inc.Therapeutic inhibitor of vascular smooth muscle cells
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US7648727Aug 26, 2004Jan 19, 2010Advanced Cardiovascular Systems, Inc.Methods for manufacturing a coated stent-balloon assembly
US7658758Mar 2, 2005Feb 9, 2010Innovational Holdings, LlcMethod and apparatus for loading a beneficial agent into an expandable medical device
US7691401May 17, 2005Apr 6, 2010Advanced Cardiovascular Systems, Inc.Poly(butylmethacrylate) and rapamycin coated stent
US7713637Mar 3, 2006May 11, 2010Advanced Cardiovascular Systems, Inc.Coating containing PEGylated hyaluronic acid and a PEGylated non-hyaluronic acid polymer
US7758636Mar 14, 2005Jul 20, 2010Innovational Holdings LlcExpandable medical device with openings for delivery of multiple beneficial agents
US7758881Mar 24, 2005Jul 20, 2010Advanced Cardiovascular Systems, Inc.Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US7775178May 26, 2006Aug 17, 2010Advanced Cardiovascular Systems, Inc.Stent coating apparatus and method
US7785647Jul 25, 2005Aug 31, 2010Advanced Cardiovascular Systems, Inc.Methods of providing antioxidants to a drug containing product
US7807211May 27, 2004Oct 5, 2010Advanced Cardiovascular Systems, Inc.Thermal treatment of an implantable medical device
US7854957Jan 30, 2007Dec 21, 2010Innovational Holdings, LlcSystems and methods for producing a medical device
US7862495May 31, 2001Jan 4, 2011Advanced Cardiovascular Systems, Inc.Radiation or drug delivery source with activity gradient to minimize edge effects
US7867547Dec 19, 2005Jan 11, 2011Advanced Cardiovascular Systems, Inc.Selectively coating luminal surfaces of stents
US7997226Jan 30, 2007Aug 16, 2011Innovational Holdings LlcSystems and methods for producing a medical device
US8011316Jan 30, 2007Sep 6, 2011Innovational Holdings, LlcSystems and methods for producing a medical device
US8029816May 10, 2007Oct 4, 2011Abbott Cardiovascular Systems Inc.Medical device coated with a coating containing elastin pentapeptide VGVPG
US8067025Mar 20, 2007Nov 29, 2011Advanced Cardiovascular Systems, Inc.Nitric oxide generating medical devices
US8147769 *May 16, 2007Apr 3, 2012Abbott Cardiovascular Systems Inc.Stent and delivery system with reduced chemical degradation
US8524166Mar 12, 2012Sep 3, 2013Abbott Cardiovascular Systems Inc.Stent and delivery system with reduced chemical degradation including a Chitooligosaccharide
US8709469Jul 16, 2010Apr 29, 2014Abbott Cardiovascular Systems Inc.Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US8932345Feb 4, 2008Jan 13, 2015Cook Medical Technologies LlcMedical device coatings for releasing a therapeutic agent at multiple rates
US9056155May 29, 2007Jun 16, 2015Abbott Cardiovascular Systems Inc.Coatings having an elastic primer layer
US20040098117 *Sep 22, 2003May 20, 2004Hossainy Syed F.A.Composite stent with regioselective material and a method of forming the same
US20040238978 *Jun 18, 2004Dec 2, 2004Diaz Stephen HunterMethod and apparatus for loading a benefical agent into an expandable medical device
US20050002986 *Apr 21, 2004Jan 6, 2005Robert FaloticoDrug/drug delivery systems for the prevention and treatment of vascular disease
US20050287287 *Jun 24, 2004Dec 29, 2005Parker Theodore LMethods and systems for loading an implantable medical device with beneficial agent
U.S. Classification424/423, 427/2.1, 623/1.42
International ClassificationA61L31/00, A61L33/00, A61F, A61K9/00, A61L, A61F2/90, A61F2/82, A61F2/86, A61L27/22, A61F2/00, A61L31/10, A61L31/14, A61L31/16
Cooperative ClassificationA61L33/0011, A61L2300/236, A61F2/90, A61L2300/602, A61F2250/0067, A61L31/10, A61L2420/02, A61L31/141, A61F2/86, A61L2300/406, A61F2/82, A61L31/16, A61F2210/0014, A61L2300/42, A61L2300/222, A61L2300/608, A61L2300/606, A61L2300/622, A61L27/227
European ClassificationA61L27/22R, A61L31/10, A61L31/16, A61L33/00H2, A61L31/14B, A61F2/86, A61F2/90, A61F2/82
Legal Events
Oct 30, 2006ASAssignment
Effective date: 20050101
Effective date: 19990427
Effective date: 20050101
Jun 17, 2010ASAssignment