United States Patent:  6,099,562

Assignee:  Schneider (USA) Inc. (Plymouth, MN)

Filed:  December 22, 1997

A coating and method for a coating an implantable device or prostheses are disclosed. The coating includes an undercoat of polymeric material containing an amount of biologically active material, particularly heparin, dispersed therein. The coating further includes a topcoat which covers less than the entire surface of the undercoat and wherein the topcoat comprises a polymeric material substantially free of pores and porosigens. The polymeric material of the topcoat can be a biostable, biocompatible material which provides long term non-thrombogenicity to the device portion during and after release of the biologically active material.

SUMMARY OF THE INVENTION

The present invention provides a relatively thin layered coating of biostable elastomeric material containing an amount of biologically active material dispersed therein in combination with a non-thrombogenic surface that is useful for coating the surfaces of prostheses such as deployable stents.

The preferred stent to be coated is a self-expanding, open-ended tubular stent prostheses. Although other materials, including polymer materials, can be used, in the preferred embodiment, the tubular body is formed of a self expanding open braid of fine single or polyfilament metal wire which flexes without collapsing, readily axially deforms to an elongate shape for transluminal insertion via a vascular catheter and resiliently expands toward predetermined stable dimensions upon removal in situ.

In the process, the initial 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 "finely divided" means any type or size of included material from dissolved molecules through suspensions colloids and particulate mixtures. The biologically 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 many applications the layered coating is referred to or characterized as including an undercoat and topcoat. The coating thickness ratio of the topcoat to undercoat may vary with the desired effect and/or the elution system. Typically these are of different formulations with most or all of the biologically active material being contained in the undercoat and a non-thrombogenic or biocompatible non-porous surface found in the topcoat.

It is desirable that the topcoat be substantially free of connected pores or porosigens (materials which can elute during implantation and form pores). The addition of a porous membrane as a top coat will increase the coating thickness and reduce the overall drug loading. Also, the release of porosigens into the body can be undesirable since it introduces additional foreign materials into the body, which can cause the patient to have adverse reactions.

Since in some embodiments the topcoat should be substantially free of pores, the topcoat should cover less than the entire surface of the undercoat. Preferably, the topcoat should cover only about 10% to about 95% of the surface of the undercoat.

By partially covering the surface during manufacture or inducing "breaks" in the topcoat during mounting/implanting of the coated device, the biologically active material or drug of the undercoat is permitted to be released from the undercoat through those parts of the undercoat which are not covered by the topcoat.

Additionally, it is preferred that the topcoats have an average thickness equivalent to the average particle size of the drug in the undercoat. Preferably the average thickness is about 1 to 7 microns and more preferable that the topcoat average thickness be about 1 to 5 microns. Also, the polymer of the topcoat may be the same as or different from the polymer of the undercoat.

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. In the case of certain undercoat materials, thereafter the polymer material is cured at room temperature or elevated temperatures. 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 induce physico-chemical changes. Where, for example, polyurethane thermoplastic elastomers are used as an undercoat material, solvent evaporation can occur at room temperature rendering the undercoat useful for controlled drug release without further curing.

The applicable 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. Urethane prepolymers can also be utilized. Unlike the polyurethane thermoplastic elastomers, some of these materials are applied as prepolymers in the coating composition and must thereafter be heat cured. The preferred silicone species have 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^oC. for a period of time such as 16 hours. A curing step may be implemented both after application of the undercoat or a certain number of lower layers and the top layers or a single curing step used after coating is completed.

The coated stents may thereafter be subjected to a postcure process which includes an inert gas plasma treatment, and sterilization which may include gamma radiation, ETO treatment, electron beam or steam treatment.

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 20-50 mTorr. Thereafter, inert gas (argon, helium or mixture of them) is admitted to the reaction chamber for the plasma treatment. One method uses argon (Ar) 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.

In accordance with the invention, the topcoat or surface coating may be applied in any of several ways to further control thrombolytic effects and optionally, control the release profile especially the initial very high release rate associated with the elution of heparin.

In one embodiment, an outer layer of fluorosilicone (FSi) is applied to the undercoat as a topcoat. The outer layer can also contain heparin. In another embodiment, polyethylene glycol (PEG) is immobilized on the surface of the coating. In this process, the underlayer is subjected to inert gas plasma treatment and immediately thereafter is treated by ammonia (NH3) plasma to aminate the surface. Amination, as used in this application, means creating mostly imino groups and other nitro containing species on the surface. This is followed by immediate immersion into electrophilically activated polyethylene glycol(PEG) solution with a reductive agent, i.e., sodium cyanoborohydride.

To form a topcoat which is substantially free of pores, porosigens or materials capable of eluting from the topcoat during implantation, should not be included in the composition used to form the topcoat. For example, a substantially non-porous topcoat can be produced from a topcoat composition which comprises a substantially pure polymeric material. The material preferably provides biocompatibility to the implanted device during and after release of the biologically active material.

To prepare a topcoat which covers less than the entire surface of the undercoat, a number of methods can be used. For instance, by controlling the thickness of the topcoat so that it has an average thickness less than that of the diameter of certain drug particles, the undercoat will be only partly covered by the topcoat since some of drug particles will not be covered by the topcoat.

Also, a partial topcoat can be formed by using a topcoat polymer which is incompatible with the undercoat polymer to generate a microphase separation in the topcoat. Furthermore, to make a topcoat which covers less than the entire surface of the undercoat or which only partially covers the undercoat, a poor solvent wash can be applied to the topcoat, to force the topcoat polymer to shrink so that the undercoat is not entirely covered.

In other embodiments the topcoat can partially or fully cover the undercoat prior to delivery or implantation of the device. The topcoat materials can be selected so they have certain water permeability. When water penetrates the topcoat and into the drug particles of the undercoat, the water will swell the particles or dissolve the particles. In either situation, it creates osmotic pressure in the surrounding coating material of the undercoat. The pressure then breaks the thinnest part of the topcoat, and leave the void space in the topcoat for the drug to elute out.

In another embodiment, the topcoat material has a different Young's modulus (either while it is wet or dry) than that of the undercoat material. More specifically, the Young's modulus can be higher for the topcoat material. During the mounting of the coated devices onto the delivery device or during deployment of the coated device, the coating undergoes compression or stretching. Topcoat materials with higher Young's modulus tend to crack and form void spaces for the drug to elute from undercoat.

Another way to form a topcoat is to cover the undercoat with a bioabsorbable material. In this embodiment, the topcoat can cover either the entire undercoat or only part of the undercoat before or after implantation. Upon contact with body fluids, the bioabsorbable material of the topcoat will degrade. The rate of degradation depends upon the bioabsorbable material used. When the topcoat is partially absorbed, the undercoat is exposed to the body fluid and the drug is released, however the burst effect will be reduced.

The coated and cured stents having the modified outer layer or surface optionally are subjected to a final gamma radiation sterilization nominally at 2.5-3.5 Mrad. Argon (Ar) plasma treated stents enjoy full resiliency after radiation whether exposed in a constrained or non-constrained status, while constrained stents subjected to gamma sterilization without Ar plasma pretreatment lose resiliency and do not recover at a sufficient or appropriate rate where the undercoat is silicone.

The elastomeric materials that form the stent coating underlayers should possess certain properties. Preferably the layers should be of suitable hydrophobic biostable elastomeric materials which do not degrade. Surface layer or topcoat materials should minimize tissue rejection and tissue inflammation and permit encapsulation by tissue adjacent the stent implantation site. Exposed material is designed to reduce clotting tendencies in blood contacted and the surface is preferably modified accordingly. Thus, underlayers of the above materials are preferably provided with a silicone or a fluorosilicone outer coating layer which should not contain imbedded bioactive material, such as heparin in order to avoid the formation of pores in the topcoat. Alternatively, the outer coating may consist essentially of polyethylene glycol (PEG), polysaccharides, phospholipids, or combinations of the foregoing.

Polymers generally suitable for the undercoats or underlayers include silicones (e.g., polysiloxanes and substituted polysiloxanes), polyurethanes, thermoplastic elastomers in general, ethylene vinyl acetate copolymers, polyolefin elastomers, polyamide elastomers, and EPDM rubbers. The above-referenced materials are considered hydrophobic with respect to the contemplated environment of the invention. Surface layer or topcoat materials can include the same polymer as that of the undercoat. Examples of suitable polymers include without limitation fluorosilicones and polyethylene glycol (PEG), polysaccharides, phospholipids, and combinations of the foregoing.

While heparin is preferred as the incorporated active material, agents possibly suitable for incorporation include antithrobotics, anticoagulants, antibiotics antiplatelet agents, thrombolytics, antiproliferatives, steroidal and nonsteroidal antiinflammatories, agents that inhibit hyperplasia and in particular restenosis, smooth muscle cell inhibitors, 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).

Suitable 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.RTM. and Phynox.RTM.. 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., which are 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 the 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 also the crosslink density of the polymer material. For bioactive materials released from the crosslinked matrix, such as heparin, a denser crosslink structure will result in a longer release time and reduced burst effect.

It will also be appreciated that an unmedicated silicone thin top layer provides some advantage and additional control over drug elution.

Claim 1 of 27 Claims

1. A medical device having at least a portion which is implantable into the body of a patient, wherein at least a part of the device portion is covered with a coating for release of at least one biologically active material, wherein said coating comprises an undercoat having an outer surface and comprising a polymeric material incorporating an amount of biologically active material therein for timed release therefrom, and wherein said coating further comprises a topcoat formed of a discontinuous coating being disposed over the entire outer surface of the undercoat, thereby forming covered and uncovered areas of the undercoat throughout the entire outer surface, said topcoat comprising a polymeric material substantially free of pores and porosigens.

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