MXPA97004436A - Coating and procedure to cover a farm release fixer - Google Patents

Abstract

A coating and a method for coating metal fixator prostheses of open and implantable network structure is described, the coating includes a relatively thin layer of a biostable elastomeric material containing an amount of biologically active material particularly heparin, dispersed in the coating in combination with a non-thrombogenic surface, in one embodiment, the surface is provided with high electronegativity species sites by means of the fluorosilicone coating that aids in elution control, particularly the initial release rate and reduced thrombogenic activity; other non-thrombogenic outer layers for heparin, such as covalently linked polyethylene glycol (PE)

Description

COATING AND PROCEDURE TO COVER A DRUG RELEASE FIXER CROSS REFERENCE f RELATED APPLICATIONS 5 The present application is a continuation in art of copending application No. 08 / 526,273 filed on September 1, 19 * 35 and a continuation in par e of the co-pending application Serial No. 08 / 424,884 submitted on April 19 of 1995, all portions of related applications not contained in this application are considered incorporated by reference for any purpose. c., e makes cross reference also to serial No. 08 /, entitled "PROCEDURE OF COATING DF FIJJRDOR OF LIBF.ROCION DF FARMRCO ", filed on the same day, of common inventors and assignee and also a continuation in part of both of the aforementioned applications. Because it is not contained in this, that request is also considered incorporated in 1 A present by reference for any purpose. 20 FIELD OF THE INVENTION The present invention relates to the provision of biostable elastomeric coatings on the OR H implant surfaces incorporating biologically active species that have controlled release characteristics in the coating, will par ticularly provide a non-tissue super fi ct during and after the controlled time release of biologically active species. The invention is particularly described in terms of coatings on expandable fixative therapeutic prostheses for implantation in body lumens, e.g., vascular implantation.

RELATED TECHNIQUE In surgical procedures or in other related invasive procedures, the insertion and expansion of fixative devices into blood vessels, urinary tracts or other locations difficult to access otherwise for the purpose of avoiding restenosis, providing support or reinforcement of the lumen or vessel wall and for other therapeutic or restorative functions, it has become a long-term facility for long-term treatment. Typically, such prostheses are applied to a location of interest using a vascular catheter or similar transilluminal device, to carry the fixative to the location of interest where it is subsequently released to expand or be expanded in situ. These devices are usually designed as permanent implants, which can be incorporated into the vascular tissue or other tissue with which they have contact in the implantation.

A type of self-expanding fixator has a flexible tubular body formed of several flexible and individual strand elements, each of which extends into a helix confi uration with the center line of the body serving as a common axis. The elements are wound in the same direction but are unfolded axially to one another and meet, crossing under a similar number of elements also axially deployed but having opposite winding direction. This configuration provides a braided and elastic tubular structure that assumes stable spreads after relaxation. The axial tension produces the elongation and contraction of the corresponding diameter that allows the fixator to be mounted on a catheter device and transported through the vascular system * as a narrow elongated device. Once the tension is relaxed in situ, the device is reversed at least substantially in its original form, prostheses of this kind including a braided flexible tubular body are illustrated and described in US Patent Nos. 4,655 771 and 4. 954 126 to Uallsten and 5 061 275 to CJallsten et al.The implanted fixators have been used to carry medicinal agents, such as troinbolite agents, US Pat. No. 5,163,952 to Froix, which describes an expandable plastic fixator with memory and thermal formulated to carry a medicinal agent in the material of the same fixative., in the patent of E.U.A. No. 5 092 877, describes a fixer made of a polymeric material which may have a coating associated with the assortment of drugs. Other patents that are directed to devices of the type which use iodegradable or bioabsorbent polymers include the F.U.f. 4 916 193 to Tang y o ros and the patent of E.U.fl. 4 994 071 to MacGregor. A patent to Sahatjian No. 5 304 121, discloses a coating applied to a fixative, which consists of a hydrogel polymer and a preselected drug such as cell or hepapine growth inhibitors. An additional method for manufacturing a coated invasive fixator carrying a therapeutic material is described in the U.S. Patent. No. 5,664,650 to Berg et al., Issued November 7, 1995 and corresponding to European patent application No. 0 623 354 Al published on November 9, 1994. In that description, a polymer coating material it dissolves in a solvent and the therapeutic material dispersed in the solvent; and the solvent evaporated after the application. An article by Michael N. Helrn? S (a co-inventor of the present invention) entitled "Medical Device De? Gn - A Systems Approach: Central Venous Catheters", 22nd International Society for the End of Material and Process Engineering Engineering Conference (1990), refers to polymer systems or / drug / membrane to release hepapna. These polymer / tree / membrane systems require two different types of layers to function. It has been recognized that contacting the blood with the surface of a foreign body m vivo has a tendency to induce thrombogenic responses and that by increasing the surface area of a foreign device in contact with host blood, the tendency to coagulation also increases. and clot formation on those surfaces. This has led! use of thrombolytic agents or immobilized systematic anticoagulants such as heparma on blood contact surfaces such as oxygen assimilation devices to reduce this phenomenon. Such an approach is described by Winters et al. In the patents of F.U.A. 5 182 317; 26? 451 and 5 338 770 in which the amine functional groups of the active material are covalently bound using polyethylene or (PEO) on a siloxane surface. Another approach is described in the patent of E.U.fl. No. 4,613,665 to Larrn, in which heparin is covalently and chemically bound to plastic surface materials containing primary amino groups to impart a non-bogem surface to the material. Other approaches to bind heparin are described in Barbucci et al., "Coa ing of commercially available material with a new heparinizable material," Journal of Bioethical Materials Research, Vol 25, 1259-1274 (1991); Hubbell, J.A., "Pharmacologic Modification of Materials," Cardiovascular Pathology, Vol 2, No. 3 (Suppl.), 121-127 (1993); Gravlee, G.P., "Hepapna-Coated Cardiopulmonary Bypasss Circuits", Journal of Cardiot horací c and Vascular Anesthesia, Vol 8, No?, Pp? 13. 222 (1994). In reference to fasteners, polyurethane fasteners, although effective, may have mechanical properties that are inferior to those of similar fasteners of thickness and tissue. Metallic vascular fasteners braided with a uniform and relatively thin metal can provide a large amount of resistance to withstand the inwardly directed circumferential pressure. A polymer material of comparable strength requires a thicker wall structure or a denser and heavier filament fabric, which in turn reduces the transverse area available for flow through the fixative and / or reduces the relative amount of open space in the tissue. Also, it is commonly more difficult to load and supply polymeric fixatives using catheter assortment systems. Although certain types of fasteners such as braided metal fasteners may be preferred for some applications, the coating and coating modification process of the present invention is not so limited and can be used in a wide variety of prosthetic devices. Thus, in the case of fasteners, the present invention also applies, for example, to the class of fasteners that are not self-expandable including those that can be expanded, for example, with a balloon; and eß applicable to fixedreß polirnépcos of all types. Other medical devices that may benefit from the present invention include blood exchange devices, vascular excess ports, central venous catheters, cardiovascular catheters, ex-coronary circuits, vascular grafts, pumps, heart valves, and cardiovascular sutures. to name just a few. Regardless of the detailed embodiments, the applicability of the invention should not be considered limited with respect to implant design and location or construction materials of the implant. In addition, the present invention can be used with other types of plantable prostheses. Accordingly, it is a principal object of the present invention to provide a coating and method for coating a fixative to be used as a deployed fixator prosthesis, the coating being capable of a controlled and effective long-term assortment of biologically active materials. Another object of the invention is to provide a coating and method for coating a fixative prosthesis using a biostable hydrophobic elastomer, in which the biologically active species are incorporated within a coating. Also the object of the present invention is to provide a multi-coat coating and a process for the southward of biologically active species in which the percentage of active material may vary from layer to layer.

A further object of the present invention is to provide a multi-layer coating and a process for the south leaving biologically active species from a coating with a non-ornhogenic surface. A further object of the invention is to provide a multispecific coating for the assortment of biologically active species such as heparin, which have an upper layer of fluorosis. Still a further object of the invention is to provide a multilayer coating for the release of biologically active species such as heparin having a surface containing immobilized polyethylene glycol (PEG). Other objects and advantages of the present invention will be apparent to those skilled in the art after becoming familiar with the description and the appended claims.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a relatively thin layer coating of bioelastizable elastomeric material containing an amount of biologically active material dispersed therein in combination with a non-trimeric surface which is useful for coating the surfaces of prostheses such as fasteners. drop-down The preferred fixative to be coated is a self-expanding open-ended tubular fixator prosthesis. Although other materials, including polymer materials, can be used, in the preferred embodiment the tubular body is formed by a self-expanding open braid of metal wire of one or fine polyfilaments, which is bent without collapse, easily axes up to an elongated shape for translucent insertion by means of a vascular catheter and elastically expanding to stable predetermined dimensions after its removal m if you. In the process, the initial coating is preferably applied as a mixture, solution or suspension of polymethic 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 material included in molecules dissolved through suspensions, colloids, and particle mixtures. The active material is dißperfected 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 relatively sequentially applied in a relatively rapid sequence and preferably applied with the fixer with a radially expanded state. lü In many applications, the coating of layers is called or characterized as including a sub-region and an overlay. The ratio of coating thickness of the overcoat to the subcoat may vary * with the desired effect and / or the elution system. Typically these are of different formulations with most or all of the active material being contained in the ßubrevest uniente and a non-thrombogenic surface found in the reverse envelope. The coating can be applied by unersion or spray using relatively high vapor pressure evaporative solvent materials to produce the desired viscosity and quickly establish coating layer thicknesses. The preferred process is carried out reciprocally by the spray coating of a rotating radially expanding fixator, using an air brush device. The coating process makes it possible for the material to conform to and cover the entire surface of the filaments of the open structure of the fixative, but in such a way that the nature of the open network structure of the braid structure is preserved. another pattern in the coated device. The coating is exposed to ventilation at room temperature for a predetermined time (possibly one hour or more) for the evaporation of the solvent vehicle. In the case of certain sub-convection materials, after the polymer material is cured at room temperature or at elevated temperatures. Curing is defined as the process of converting the elastomeric or polyrneric material into the finished or useful state of re-application of heat and / or chemical agents that induce physical-surgical changes. When, for example, polyurethane elastomer elastomers are used as a subcoat material, evaporation of the solvent can occur at room temperature making the subcoating useful for controlled drug release without further curing., Ventilation time and temperature Applicable for curing are determined by the particular polymer involved and the particular drugs used. For example, silicon or polylysiloxane materials (such as polydinet ilsiloxane) have been used successfully. Urethane prepolymers can also be used. Unlike polyurethane thermoplastic elastomers, some of the materials are applied as prepolymers in the coating composition and must be cured by heat * afterwards. Preferred silicone species have relatively low cure temperatures and are known as vulcamzableß at room temperature (RTV). Some polydimethylsiloxane materials can be cured, for example, by exposure to air at about 90 ° C for a period of 16 hours. A curing step can be implemented both after the application of the coating with a certain number of lower layers and the upper layers or a single curing step used after coating or has been completed. The coated fasteners can then be subjected to a post-curing process which includes a plasma treatment of inert gas and sterilization which can include gamma radiation, FTO treatment, electron beam or steam treatment. In the plasma treatment, the non-contracted coated fasteners are placed in a reactor chamber and the system is purged with nitrogen and a vacuum applied at 20-50 mTorr. Subsequently, inert gas (argon, helium or a mixture thereof) is admitted into the reaction chamber for plasma treatment. One method uses argon (Ar) gas, operating at a power scale of 200 to 400 watts, a flow rate of 150-650 rnl normal per minute, which is equivalent to approximately 100-450 mTorr, and an exposure time from 30 seconds to approximately 5 minutes, the fixatives can be removed immediately after the plasma treatment or remain in the argon atmosphere for an additional period, typically five minutes. In accordance with the invention, the overcoat or surface coating can be applied in any of several ways to control the other side effects and optionally, control the release profile, especially the very high initial release rate associated with the elution. of the hepap na.

In one embodiment, an outer layer of fluorosi licon (FSi) is applied to the undercoating as a reverse envelope. The outer layer may also contain he ina. In another embodiment, polyethylene glycol (PFG) is immobilized on the surface of the coating. In this procedure, the sublayer is subjected to treatment with inert gas plasma and immediately after it is treated with ammonia plasmas (NH3) to animate the surface. The animation, e ú used in this application, means (rear main e groups and other species that contain nitro on 1 A surface.) This is followed by immediate immersion in a solution of polyethylene glycol (PFG) electrically activated with A reducing agent, ie, sodium cyanoborohydride The coated and cured fasteners having the outer layer or modified surface are subjected to a final sterilization of nonnally range radiation at 2.5-3.5 Mrad. The fixatives treated with argon plasma (Ar ) enjoy full diffusion elasticity of the radiation whether exposed in a contracted or uncontracted state, while contracted fasteners subjected to gamma sterilization without Ar plasma pretreatment lose elasticity and are not recovered at a sufficient or adequate rate. The elastomeric materials that form the ßubcapaß of the fixative coating must have certain properties. The layers must be made of elastomer materials that are bioestable, hydrophobic, and not degradable. The material of the surface layer should minimize rejection of the tissue and inflammation of the tissue, and allow encapsulation by the tissue adjacent to the implantation site of the fixator *. The exposed material is designed to reduce the coagulation tendencies in the contacted blood and the surface is preferably modified accordingly. In this way, the sublayers of the above materials are preferably provided with an outer coating layer of fluorosilicon which may or may not contain an included bioactive material, such as heparin. Alternatively, the outer coating may consist essentially of polyethylene glycol (PEG), polysaccharide, phospholipid or combinations of the foregoing. Polymers generally suitable for sub-coatings or sub-layers include silicones (e.g., substituted polysiloxanes and polysiloxanes), pol urethanes, thermoplastic elastomers in general, ethylene vinyl acetate copolymers, polyolefin elastomers, polyester elastomers, and EPDM rubbers. The aforementioned materials are considered hydrophobic with respect to the contemplated environment of the invention. The aterialeß of the surface layer include fluorosilicones and polyethylene glycol (PEG), polysaccharides, phosphoiipids and combinations of the anteporeß. Although heparin is preferred as the active material incorporated, agents suitable for incorporation include antithrombotic agents, anticoagulants, antiplatelet agents, antibiotics, antituberculous agents, anti-proliferative agents, steroidal anti-inflammatory agents and non-steroidal agents that inhibit hyperplasia. and in particular restenosis, mh? b? dor * is smooth muscle cell, growth factor, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters and drugs that can improve tissue formation neointima healthy, including the regeneration of endothelial cells. Positive action may be amplified by inhibiting particular cells (eg, smooth muscle cells) or tissue formation (eg, fibrornußcular tissue) while promoting the migration of different cells (eg, endothelium) and tissue formation (neointimal tissue). Suitable materials for making the braided fastener include stainless steel, tantalum, titanium alloys including m ol (a nickel-titanium thermal memory alloy material), and certain cobalt alloys including cobalt-chromium-nickel alloys such as ElgiloyR and PhynoxR. Additional details concerning the manufacture and details of other aspects of the fasteners may be compiled from the patents of E.U.fl. previously mentioned Noß. 4 655 771 and 4 954 126 to Uallsten and 5 061 275 to Uallsten and others, which are incorporated by reference herein. Various combinations of polymer coating materials can be coordinated with biologically active peptide species to produce desired effects when coated on fasteners that will be implanted according to the invention, the loads of therapeutic materials can vary *. The mechanism of incorporation of the biologically active species into the surface coating and the exit mechanism depend "both on the nature of the surface reversal polymer and the material to be incorporated. The release mechanism also depends on the incorporation form. The material can be eluted through trajectories of terparticle or be administered through transport or diffusion through the encapsulation material ism. For the purposes of this description, "elution" is defined as any release procedure that includes extraction or release by direct contact of the material with body fluids through mrtepartic paths connected to the exterior of the liner. "Transportation" or "diffusion" are defined as including a release mechanism in which the released material travels through or through material. The profile of released release velocity can be dissoned by varying the thickness of the coating, the radial distribution (layer by layer) of bioactive materials, the mixing method, the amount of bioactive material, the combination of different matrix polymer materials in different layers and the interlacing density of the polyrneric material. The density of interlacing eßta related to the amount of entanglement that takes place and also to the relative eßtrechez of the rnat pz created by the entanglement agent used in particular *. This, during the curing process, determines the amount of entanglement and therefore the interlacing density of the pol poly material. For bioactive materials released from the interlaced matrix, such as the hepapin, a denser interlacing structure will result in a longer release time and a reduced bursting effect. It will also be appreciated that a thin top layer of non-medicated silicone provides some advantage and additional control over the elution of the drug.; however, in the case of hepanna for example, it has been found that a modified upper coating or ßupenfice to additionally control the initial release of initial hepar- ma or to render the surface non-thrombogenic presents a distinct advantage.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings, in which like numbers designate like parts throughout them: Figure 1 is a schematic flow chart illustrating the steps of the method of the invention; Figure 2 represents a release profile for a multi-layer system showing the percentage of hepapna IB released during a period of two weeks. Figure 3 depicts a release profile for a multilayer system showing the rate of relative release of hopapna over a period of two weeks; Figure 4 illustrates a profile of the release kinetics for different drug loading at similar thicknesses of thickness illustrating the release of hepapne over a period of two weeks without associated media to provide a non-thrombotic surface long or later; Figure 5 illustrates the drug eluting emetics in a given heparin loading over a period of two weeks at different coating thicknesses and associated media to provide a long term non-thrombogenic surface later; Figure 6 illustrates the emetic of releasing certain sub-surface material and coating material that varies according to the thickness, in which the percentage of heparma in the sub-coating and on coatings is constant; Figure 7 is a graph of the heparin release rate in a phosphate pH regulation system at pH 7.4 with and without a fluorosilicone (FSi) coating: and Figure 8 is another graph of the kinetics. of hepapna release in a phosphate pH regulation system in which an envelope containing Luorosilicon (FSi) is compared only with an envelope of FSi (containing 16.7% of hepapne included).

DETAILED DESCRIPTION According to the present invention, fixative coatings incorporating biologically active materials for a time controlled assortment in a lumen of the body of prents are preferably sprayed in many thin layers of prepared solutions or suspensions of reverse. . The steps of the process are generally illustrated in FIG. 1. Coating solutions or sußpensions are prepared as described below. The desired amount of entanglement agent (if present) is added to the suspension / solution as in 12 and the material is subsequently stirred or stirred to produce a homogenous coating co-position in 14, which is then transferred to a container or dispensing device which can be a container for an aßpersion coating in the 16th. Typical exemplary coating solutions that were used for the heparma and dexarnetaßone appear below.

General preparation of the composition of heparin sub-coating. Silicon was obtained as a polymer precursor in a solvent mixture (xylene). For example, a weight content of solid silica of 35% in xylene was obtained from npplied Silicone, Part # 40,000. First, the mixture of only? Full was heavy. The content of the solid icon was determined according to the vendor analysis. The precalcuminated quantities of hepap to finely divided (2-6 microns) were added in the silicon, then raphrofuran (THF) grade HPOL (flldpch or FM) was added. For a coating of 37.5% hepapine, for example: Psiiicdn - 5 g; the solid percentage = 35%; P hep = 5 x 0.35x .375 / (0.625) - 1.05 g. The amount of THF needed (44 rnl) for the coating solution ße was calculated using the equation P i cón cón out / VTHF = 0.04 for a heparin coating solution of 37.5%). Finally, the manufacturer's cross-linking solution was added using a P-Pasteur pipettor. The amount of interleaver added ß formed to effect the release rate profile. Typically, five drops of the crosslinker solution was added for every five grams of silicone-xylene mixture. The solution was stirred using the stir bar until the suspension became homogeneous and milky. The coating solution was subsequently transferred to a paint bottle under conditions for air brush application.

General preparation of the dexamethasone sub-coating composition. Silcone (35% solution as above) was weighed into a beaker on a Metier scale. The amount of alcohol or dexamethasone-free acetate was calculated by the siiicone pellet multiplied by 0.35 and the desired percentage of dexamethasone (1 to 40%) and the required amount was subsequently weighed. Example: Pßiiicon = 5 g; for a 10% dexamethasone coating, Pdex = 5 x 0.35 x 0.1 / 0.9 = 0.194 g and the THF needed in the calculated reversal solution. Pßiiicfin SÓH.O / VTHF = 0.06 for a 10% dexamethasone coating solution. Example: Pe? I icon 5 g; V? H F = 5 x 0.35 / 0.06 -z 29 ml. The dexamethasone was weighed in a batch of precipitate on an analytical balance and half of the total amount of THF was added. The solution was well shaken to ensure complete dissolution of the dexamethasone. The stirred DEX-THF solution was subsequently transferred to the silicone container. The beaker was washed with the remaining THF and transferred to the silicone container. The interleaver was added using a Pasteur pipette. Typically, five drops of interlacing were used for five silicon grenades. The application of the coating material to the fixative was quite similar for all the rnaterialeß and the same for the ßuepenßionee of hepapna and dexamethasone prepared as in the previous examples. The 00 The suspension to be applied was transferred to an application device, at 16 in Figure 1. Typically a paint bottle placed in an air brush, such as a Ba ger Model 150, supplied with an air source priced at - Birds of a regulator (Norgren, 0-11.25 lg / cm2) was used. Once the spray hose was placed at the compressed air source downstream of the regulator, I applied the air. The pressure was adjusted to approximately 1.05-1.76 l-g / crnS and the condition of the nozzle verified by depressing the trigger. Any suitable method can be used to secure the. fixative for the spray and in the laboratory rotary apparatuses were successfully used. Both ends of the relaxed fastener were fastened to the apparatus by two elastic tensioners, commonly alligator clips, with the distance between the fasteners adjusted so that the fastener remains in a relaxed and undrained condition. The rotor was subsequently activated and the spindle speed adjusted to the desired coating speed, normally around 40 rpm. With the fixator rotating in a substantially horizontal plane, the spray nozzle was adjusted such that the distance from the nozzle to the fixer was approximately 50.8-101.6 m and the composition was sprayed sub-substantially horizontally by directing the brush along the fixer. from the diefai end of the fixator towards the proxirnal end, and from the proximal end towards the distal end in a sweep form at a speed such that a spray cycle occurred in approximately three turns of fixative. Typically a pause of less than one minute, usually about half a minute, lapse between layers. Of course, the coating layer number varied and varied with the particular application. For example, the typical bond layer, such as that of 18 in Figure 1, for a level of reversal of 3-4 heparm per projected area, requires 20 coating application cycles and approximately 30 milliliters of solution. will be consumed ar-a fixer of 3.5 inm di meter by 14.5 crn long. Of course, the speed of rotation of the motor can be adjusted as well as the viscosity of the composition and the flow velocity of the spray nozzle as desired to modify the layer structure. Generally, with the above mixtures, the best results have been obtained at rotary speeds in the range of 30-50 rpm and with a spray nozzle flow rate in the range of 4-10 rnl of coating composition per minute., depending on the size of the fixative. It is contemplated that a more sophisticated computer controlled coating will automate successfully the procedure demonstrated as feasible in the laboratory. Several layers applied constitute what is called the ßubrevestimiento as in 18. Fn a procedure, additional upper sub-coating layers, which can be 2 k of the same or different composition with respect to the bioactive material, the matrix polymers materials and the interlacing agent, for example, can be applied as the top layer as in 20. The application of the top layer follows the same coating process than the lower layer, the number and thickness of the layers being optional. Of course, the thickness of any layer can be adjusted by adjusting the speed of rotation of the fixator and the spray conditions. Generally, the total thickness of the coating is controlled by the number of spray cycles or thin coatings that make up the total coating. As shown in 22 in FIG. 1, the coated fixative is subsequently subjected to a curing step in which the prepolymer and entangling agents cooperate to produce a cured polymer matrix containing the biologically active species. The curing process involves the evaporation of the solvent x full, THF, etc., as well as the curing and interlacing of the polymer. Certain silicon materials can be cured at relatively low temperatures (ie RT-50 ° C) in what is known as a vulcanization procedure at room temperature (RTV). More typically, however, the curing process involves higher temperature curing materials and the coated fasteners are placed from one oven at about 90 ° C or more during the first 16 hours. The temperature ß can rise as high as 150 ° C for the revetment fixatives containing dexernetasone. Of course, the time and temperature may vary * with the Lions, interlacing and biologically active species par iculares. Fixatives coated and cured in the manner described need to be sterilized before packing for future implantation. For sterilization, the gamma irradiation method is particularly preferred-to coatings containing hepapna; however, it has been discovered that the coated and cured fasteners according to the method of the invention and subjected to gamma sterilization can be very slow to recover their original position when they are supplied in a vascular or other lumen site using a catheter, unless a pre-treatment step as in 24 is first applied to the cured and coated fixative.The prettarning step involves a treatment with argon plasma of the fixatives cured and revetted in the uncontracted configuration. With this procedure, fixatives are placed in a chamber of a plasma surface treatment device, such as a Plasma Science 350 (Himont / Plasma Science, Foeter City, CA) .The system is equipped with a reactor chamber and a generator-solid-state RF that operates at 13.56 mHz and from 0 to 500 watts of output power, and that is equipped with a system controlled by Nicroprocessor and a package e full vacuum pump. The reaction chamber contains an unimpeded work volume of 42.55 c by 34.3 crn by 44.45 cm deep. The plasma procedure, the non-contracted coated fixatives are placed in a reactor chamber and the β-istenone is purged with nitrogen and a vacuum is applied at 20-50 rnTorr. Subsequently, the inert gas (argon, helium or a mixture thereof) is allowed to enter the reaction chamber for plasma treatment. A highly preferred method of operation consists of using argon gas, operating at a power scale of 200 to 400 watts, a flow rate of 150-650 milliliters normal per minute, which is equivalent to 100-450 mTorr, and a time of exposure from 30 seconds to approximately 5 minutes. The fixatives can be withdrawn immediately after plasma treatment or remain in the argon atmosphere for an additional period, typically five minutes. After this, as shown in 26, fasteners can be exposed to gamma sterilization at 2.5-3.5 Mrad. The radiation can be carried out with the fixative either in the non-contracted state radially or in the radially contracted state. Preferably, however. the surface is modified before plasma treatment or just before sterilization by one of several additional processing methods of which some are described in relation to the following examples.

EXAMPLE 1 Surface treatment with fluorosilicon coating eluent of heparin. The sub-frame i of a fixator was coated as multiple layers applied as described above, and cured as described in 22. The heparma content of the sub-coating was 37.5% and the coating thickness was approximately 30-40u. A fl uorosilicon spray solution (FSi) was prepared at 30 from a fluorosilicon suspension (Applied Silicone # 40032) by weng a quantity of fluorosilicon suspension and adding tetrahydrofuran (THF) according to the ratio equation of VtHF-l-2 x the we of the fluorosi 1 icon suspension. The solution was stirred very well and sprayed on the fixative to be coated on the 32 using the technique of applying the sub-diplex procedure on the 18 and the coated fixatives were cured at 90 ° C (for 16 hours). with argon plasma before gamification sterilization according to the procedures described above according to lags 22-26.Figure 7 is a graph of hepapna release kinetics in phosphate pH regulation system with overcoat Fluorosilicon and without any overcoating, the thickness of the coating is about 10-15u, although it does not appear in the graph of Figure 7, it should be noted that the release rate for the coating without FSI is approximately 25 times more that is with FSi, ie, during the first two hours. This is, of course, clearly strong on the scale of the graph. it is also important to note, that the coating with the upper layer of FSi or diffusion barrier, if it shows a depressed initial release rate combined with an improved elution rate after the first day and throughout the first week until apr-ox nailed the tenth day. In addition, the overlying fluorosilicon icon (FSi), by virtue of the hflow electronegativity, maintains non-thrombogenic surface qualities during and after the elution of the biologically active hepapna species. Furthermore, due to the negative charges on the hepapin itself, the electronegati on of the envelope of fl oorose liqueur-may be, at least in part, amenable to the modified profile of hepapin release kinetics. Figure 8 compares a graph of fluorosilicon overcoat (FSi) containing 16.7% of heparm included with one containing fluorosilicon (FSi) only. A srebreathing is identical to that used in FIG. 7, which contains approximately 37.5% of heparin at a thickness of approximately -30-40 microns. These elution kinetics are quite comparable with the upper layer of FSH free, reducing greatly the initial exposition of hepa ray release of another form to the top layer of FS II with a sl free liporation. rnayo r during the period of the test.

EXAMPLE 2 Immobilization of polyethylene glycol (PEG) on an eluant coating of drug. A subrevertem was coated on a fixative and cured on 22 as in Example 1. The fixative was subsequently treated by argon gas plasma or in 24 gaß ammonium plasma in 40. The equipment the treatment procedure with argon gas were as described above. The treatment with ammonium plasma was carried out immediately after the treatment with gaß argon plaster to bring the surface of the coating closer. The ammonium flow rate was at a scale of 100-700 cubic centimeters per minute (ccM), preferably on a scale of 500-600 ccM. The output power of the radio frequency plasma was on the scale of 50-500 watts, preferably at -200 watts. The processing time was on the scale of 30 sec- 10 in, preferably -5 minutes. Immediately after the animation, the fixators were immersed in a solution of polyethylene glycol (PFG) electrophilically activated in 42. It is known that PEG is an inhibitor of protein absorption. Examples of activated electrolytic PFG are nitrophenyl carbonates of PEG, carbonates of tpclorofem of PFG, PFG thresylate, glycidyl ether of PEG, PFG isocyanate, etc., optionally with a terminus terminated by a methoxyl group. The molecular weight of the PEG varied from about 1000 to 6000, and is preferably about 3000. It has been observed that simple ammonium arnination will not generate large amounts of primary and secondary amines over the supex of the polyester or elastomeric (by silicone example). Fn place of it, the mu na (>; c = N-H), and other groups containing nitro plus oxidants will dominate the surface. It is generally necessary to add a reducing agent such as aBH3C in the reaction medium so that the functional group β on PEG can react with imine and possibly other species containing nitro on the surface, and therefore immobilize the PEG on the surface . The typical concentration of aBH3CN is approximately 2rng / rnl. Since PFG and its derivatives are dissolved in water and in many polar and aromatic solvents, the solvent used in the coating must be a solvent for the PEG but not for the drug in the coating to avoid the possible loss of the drug through of leaching. In the case of the eluant coating of hepapna, a mixed solvent of forrnarnide and rnethyl ethyl ketone (MEK) or a mixed solvent of formanide and acetone-pson preferred solvents (preferably at ratios of 30 forrnamide: 70 of MFK or acetone by volume) , since eßtoß will dissolve the hepa i a. The concentration of PEG, the reaction time, the reaction temperature and the pH value depend on the type of PEG used. In the case of the heparin-eluting reversal, 5% PFG tresylate in formaldehyde / MFK (30-70) was used successfully. The reaction time was 3 hours at room temperature. The PEG was then bound covalently to the surface. The gamma radiation was poetenormente used r > for the sterilization of this modality as described above. With respect to the hepapine anticoagulant material, the percentage in the subcoat is nominally (J approximately 30-50% and that of overcoat of approximately 0-30% active material.) The thickness ratio of the revelant to the subvertex varies from approximately 1:10 to 1: 2 and preferably in the range of approximately 1: 6 to 1: 3. The suppression of the blast effect also makes possible a reduction in drug loading or in other words, allows a reduction in The thickness of the reversal, since the doctor will give a bolus injection of antiplaquet drugs to the patient during the application of the fixative, as a result, the drug included in the fixative can be used completely without waste. Designing the release of the first day, but maximizing the release of the second and third day to the configuration of aß thin coating possible to reduce acute or subacute thrombosis. Figure 4 illustrates the overall effect of the loading of drug par-a reverses of similar thickness. The initial elution rate increases with the drug loading as shown in Figure 5. The rate of release also increases with the thickness of the coating with the same charge, but it tends to be inversely proponal to the thickness of the envelope r-evest a slow , as illustrated by the same drug loading and the similar thickness of the subvestment in Figure 6. What is apparent from the data gathered to date, however, is that the method of the present invention makes possible that the kinetics of drug elution is controlled in a desired manner to meet the needs of the paular fixative application. In a similar manner, fixative coatings can be prepared using a combination of two or more drugs and the controlled drug release and rate sequence. For example, antiproliferative drugs can be combined in the subcoat and ani-platelet drugs in the bland coating. In this way, antiplatelet drugs, for example hepapine, will elute first followed by antiproliferation drugs to enable a more secure encapsulation of the implanted fixative. The measurement of hepapna concentration was made using a curve of eßtándareß prepared by complexing bluish dye A with diluted solutions of heparma. Sixteen standards were used to conform to the standards curve in a well-known manner. For the elution test, the fixatives were immersed in a phosphate pH buffer at a pH of 7.4 in an incubator at approximately 37 ° C. The periodic sampling of the solution was processed to determine the amount of heparma eluted. After each sampling, each fixative was placed in a buffer solution free of heparma pH. As mentioned above, while the perimatic load of the steric material with hepapna may vary, in the case of materials with a silica the hepapna may exceed 60% of the total weight of the layer. However, the generally and most advantageously used charge is on the scale of about 10% to 45% of the total weight of the layer. In the case of dexanetasone, the filler may be as high as 50% or more of the total weight of the layer, but is preferably on the scale of about 0.4% to 45%. It will be appreciated that the mechanism of incorporating biologically active laß eßpecies into a thin surface coating structure applicable to a metal fastener is an important aspect of the present invention. The need for relatively thick-walled polymer elution fixatives or any membrane opener associated with many prior drug eluting devices is obvious, as is the need to use biodegradable or readable vehicles to carry the biological species. The technique makes the long-term selection clearly possible and minimizes interference with the independent mechanical or mechanical benefits of the fixatives or the coating materials are designed as a technical particular coating, coating / drug combination, and the fusing mechanism in mind The consideration of the particular release form and mechanism of the biologically active species in the coating will allow the technique to produce superior results. Assortment of biologically active species from the coating structure can be designed to accommodate a variety of applications. While the above examples illustrate coatings having two different drug loads or percentages of biologically active material that will be released, this is not in any way limiting with respect to the invention and it is contemplated that any number of layer and combinations of charges they can be used to obtain a desired release profile. For example, the graduation and the gradual change in the load of the layers can be used, in which, for example, higher loads are used in the inner layers. Layers that do not have drug gas can also be used. By far, a pulsating hepapna release system can be obtained by a reversal in which alternative layers containing hepar a are sandwiched between non-loaded silicate layers or other materials for a portion of the coating. In other words, the invention allows for unnamed numbers of combinations that result in a large amount of flexibility with respect to controlling the release of biologically active materials with respect to an implanted fixator. Each applied layer typically has about 0.5 micron to 15 micron thick. The total number of layers sprayed, of course, can vary widely, from less than 10 to more than 50 layers; Commonly 20 to 40 capaß ßon included. The total thickness of the reverse may also vary widely, but may generally be from 10 to 200 microns. While the polymer of the coating can be any biostable, combattable elastomeric material capable of being adhered to the fixative material as a thin layer, hydrophobic materials are preferred because it has discovered that the release of biologically active species It can be generally more predictably controlled with such materials. Preferred materials include silicone rubber elastomers and speci? Cally biostable polyurethanes. The invention has been described herein in considerable detail to comply with the patent statutes and to provide those skilled in the art with the information necessary to apply the novel principles to construous and use modalities of the example as required. However, it should be understood that the invention can be carried out by means of specifically different devices and that various modifications can be made without going beyond the scope of the invention itself.

Claims (31)

NOVELTY OF THE INVENTION CLAIMS

1. An implantable medical device having an outer surface covered at least in part by a compliant revetment of a hydrosulphobic elastomer material incorporating a quantity of biologically active material therein for a controlled assortment of time therefrom and associated media with the conformal coating to provide a non-thrombogenic surface after said controlled time assortment of the biologically active material.

2. The device according to claim 1, wherein the conformal coating comprises an amount of finely divided biologically active material in the hydrophobic elastomer material.

3. The diepopositive according to claim 2, wherein the finely divided biologically active material has an average particle size of less than about 15 microns.

4. The device according to claim 2, wherein the finely divided biologically active material has an average particle size of less than about 10 microns and a drug loading of about 25-60% by weight of the conformal coating.

5. The device according to claim 1, wherein the conformal coating comprises an amount of biologically active material distributed molecularly in the elastomeric material.

6. The device according to claim 1, in which the biologically active material is selected from the group consisting of antitroin- bicos, anticoagulants, anti-iplaquetae agents, rhombus, antiproliferative, n-n-steroidal and non-steroidal nflamatopos, agents that inhibit hyperplasia and in particular restenosis, smooth muscle cell inhibitors, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, drugs that improve the formation of tissue or neointi and combinations thereof

7. The device according to claim 1, wherein the hydrophobic elastomer material is selected from the group consisting of silicones, polyurethanes, ethylene vinyl acetate copolymers, polyolefin elastomer, polyacide elatomers. and rubbers of EPDM and combi ations of them 8.- The device according to the reiv indication 1, wherein the conformal coating comprises multiple layers of elastomeric material incorporating a quantity of biologically active material in the fabrics. 9. The device according to claim 1, wherein the means associated with the conformal coating < they undertake an outer layer that at least partially covers the conformal coating, the outer layer comprising a non-thromboembolic polyuronic bully. 10. The device according to claim 9, wherein the non-thrombogenic polymer material is selected from the group consisting of f1-uorosilicone, polyethylene glycol, polysaccharide and fophfolipides and combinations thereof. 11. The device according to claim 10, wherein the non-thrombogenic polimepco material comprises a fluoropolymer coating adhopdo to the conformal coating. 12. The device according to claim 10, wherein the polirnepco non-trogenic material comprises a polyethylene glycol covalently bonded to an animated conformal coating. 13. The device according to claim 1, wherein the implanted medical dipstick is formed of metal. 14. An expandable fixator for implantation in a body comprising a tubular metal body having open ends and a sidewall structure of open network structure and a continuous conformal coating on the surface of said side wall structure, said covering It comprises a hydrophobic elastornic material that incorporates a quantity of biologically active material therein for a controlled assortment of time from the same, wherein said liner conforms to said side wall structure in a manner that retains the open network structure and wherein said liner has an outer surface having non-reboileric qualities. 15. The device according to claim 14, wherein said material biologically activates or eß hepari na. 16. The device according to claim 15, wherein the outer surface layer of said coating includes a material selected from fluorosilicone and polyethyleneglycol (PEG). 17. The device according to claim 16, wherein said outer coating * is fl uorosili with. 1

8. The device according to claim 17, wherein said outer layer optionally and additionally comprises a finely divided amount of hepapin. 1

9. The device according to claim 16, wherein said outer layer comprises polyethylene glycol (PEG). 20. A fixator for implantation in a vascular lumen comprising a tubular body (having open ends and a side wall and a continuous conformal coating on the surface of said lateral wall, said overlay also comprising a sub-layer of a material eiaßtornepco hydrophobic that incorporates a quantity of hepapna finely divided in the same for the assortment of time controlled from it, in which the reverse side also comprises a reversal envelope containing a quantity of fluorosilicon. device according to claim 20, wherein said coating envelope additionally and optionally comprises a quantity of finely divided hepapin. 22. A fixator for implantation in a vascular lumen comprising a tubular body having open ends and a wall. lateral and a continuous conformal coating on the surface of said side wall, said coating further comprises a Undercoating of a hydrophobic elastomeric material incorporating a finely divided amount of hepapin in the same or the controlled assortment of time therefrom, wherein said coating further comprises an overcoat containing an amount of polyethylene glycol (PEG). 2. 3 . - A method for coating implant fixative prostheses is with a layer that comprises a hydrophilic elastomeric material that incorporates a quantity of biologically active material in the same for the period of time controlled from the Other comprising the steps of: a) applying an overcoat of a formulation containing uncured polyneo material in solvent mixture and a number of finely divided biologically active species; and b) curing said polymeric material; c) applying an overcoat of a formulation having qualities that create both a non-thrombogenic surface and a modified assortment of said biologically active material. 24. The method according to claim 14, wherein the elastomeric material is a silicone and the biologically active material is hepapine. 25.- The method in accordance with the claim 24, wherein said overlay comprises fluo osilicon. 26.- The method according to the claim 25, wherein said overcoat eompr-ende an amount of heparin. 27. The method according to claim 24, wherein said coated coating comprises polyethylene glycol (PEG). 28. The method according to claim 27, further comprising the steps of: d) treating said overcoat after curing with inert gas plasma followed by treatment with ammonia plasma; e) applying an outer coating of polyethylene glycol (PEG) from a solution thereof. 29.- The method of compliance with the claim 28, in ex. that the polyethylene glycol (PEG) in said solution is selected from mofophenyl carbonates of PEG, trichlorofemlo earbonates of PFG, PFG tresylate, PEG glycidyl erythylene, PEG isocyanate and combinations thereof. method according to claim 28, wherein the (PEG) is electrophily active. 31. The method according to claim 28, wherein the (PFG) has one end terminated with a gr-upo rn t op lo.