MXPA98001941A - Procedure to cover a farm releasing fastening protesis - Google Patents

Abstract

Disclosed is an implantable open-network metal fixator prosthesis coating method that includes sequentially applying a plurality of relatively thin outer layers of a coating composition comprising a solvent mixture of uncured polymeric silicone material and interlacing as well as biologically divided species. active, possibly of controlled average particle size, to form a coating on each surface of the fixative, the coatings are cured in situ and the coated cured prostheses are sterilized in a step that includes a preferred pretreatment with argon gas plasma and exposure to a ace of gamma radiation electrons, ethylene oxide, vap

Description

PROCEDURE TO COVER A PROSTHESIS OF LIBERATING FIXATION E F? RMACO BACKGROUND OF THE INVENTION I.- REFERENCE TO RELATED REQUESTS The present application is a continuation in part of the pending application »Serial No. 08 / 526,273» filed on September 11, 1995 »and a continuation in part of the pending application Serial No. 08/424» 8B4 » filed on April 19, 1995; all the portions of the predecessor seats »not contained in this application, are considered as incorporated by that reference, for all purposes. Reference is also made to the application Serial No. 08 / 663,518, entitled "COATING OF PROSTHESIS OF FIXATION OF DRUGS AND PROCEDURE", filed on the same date as this and of the same inventors, on behalf of the same successor in title » which is a continuation in part of the patent applications referred to above. Any portion of that application that is not contained here is also considered as incorporated by reference "for all purposes.

II.- FIELD OF THE INVENTION The present invention relates generally to prostheses of expandable, therapeutic fixation elements for implanting in body lumens for example vascular implants and, more particularly, to a method for providing biostable elastomeric coatings in said fixation prostheses, which incorporate biologically active species, which have controlled release characteristics directly in the coating structure.

II.- THE RELATED TECHNIQUE In surgery and in other related invasive medicinal procedures, the insertion and expansion of devices for fixing prosthesis in blood vessels »urinary tracts and other places of difficult access, in order to prevent restenosis, provide support or reinforcement to the vessel or the wall of the lumen, or for other therapeutic or restorative functions, has become a common form of long-term treatment. Typically such prostheses are applied to a site of interest using a vascular catheter, or similar transluminal device, to bring the fixation prosthesis to the site of interest "where it is subsequently released to expand or expand in situ. These devices are usually designed as permanent implants, which can be incorporated into the vascular tissue or other tissue with which they are in contact in the plantation. One type of self-expanding fixation prosthesis has a flexible tubular body, formed of several »individual» flexible wire elements each of which extends in a helical configuration »the central axis of the body serving as a common axis. The elements are wound in a common direction, but they are axially offset relative to each other and are under the crossing of an equal number of elements also arranged axially like this, but having the opposite direction of winding. This configuration provides a braided »elastic» tubular structure that assumes stable dimensions when relaxed. The axial tension produces elongation and contraction of corresponding diameter "which allows the fixation prosthesis to be mounted on a catheter device and is delivered through the vascular system as an elongated and narrow device. Once tension in situ is relaxed, the device at least returns substantially to its original form. Prostheses of the kind that include a flexible braided tubular body are illustrated and described in US Patents 4,655,771 and 4,954,126, Wallsten and 5,061,275 Wallsten and coauthors. Fixation prostheses implanted as trorabolitic agents have also been used. US Pat. No. 5,163,952 to Froix discloses an expanding plastic fixation prosthesis device, with thermal memory »that can be formulated to carry a medicinal agent, using the material itself of the fixation prosthesis as an inert polymer carrier of the drug. Pinchuk »in the United States patent 5, 092,877, discloses a fixation prosthesis of a polymeric material that can be employed with a coating associated with the delivery of drugs. Other patents that are directed to devices of the kind using biodegradable or bioabsorbable polymers include Tang and co-authors, U.S. Patent 4,916,193 and MacGregor, U.S. Patent 4,994,071. Sahatjian »in U.S. Patent No. 5,304,121» describes a coating applied to a fixation prosthesis consisting of a hydrogel polymer and a preselected drug; Possible drugs include inhibitors of cell growth and heparin. Another method for forming a coated intravascular fixation prosthesis carrying a therapeutic material in which a polymeric coating is dissolved is a solvent and a therapeutic material dispersed in the solvent, and the solvent is subsequently evaporated such a corao is described in U.S. Pat. of Berg No. 5,464,650, issued November 5, 1995"and corresponding to the European patent application No. 623,354 Al /" published on November 9, 1994. An article by Michael N. He1 mus (a co-inventor of the present invention) »entitled" Medical Device Pesian -A Systems Approach: Central Venous Catheters "(Design of medical device- A system approach: Central Venous Catheters), 22nd International Society for the Advancement of Material and Process Engineering Technical Conference ( 1990) refers to polymer / drug / membrane systems to release heparin, which requires two different polymer / drug / membrane systems. s layers to function. The predecessor application referred to above provides an approach that provides long-term drug release "ie" over a period of days or even months "incorporated into a controlled release system. The prior application and the present invention provide a method for coating said fixation prostheses including techniques that allow the drug's delay effect during initial discharge to be controlled; and that the kinetic profile of the release of the drug with the long-term therapeutic effect "be modified. Metal fixation prostheses of similar thickness and tissue »generally have better mechanical properties than polymeric fixation prostheses. Metallic vascular fixation prostheses "of still relatively fine metallic filament" can provide a large amount of force to withstand the circumferential pressure directed inwardly into the blood vessels. In order for a polymeric material to provide comparable strength characteristics, a much thicker wall structure or a heavier, denser filament fabric is needed. This »in turn» reduces the cross-sectional area available for the flow through the fixation prosthesis and / or reduces the relative amount of open space available in the structure. Additionally »when applicable» it is usually more difficult to load and deliver polymeric fixation prostheses using vascular catheter delivery systems. However, it will be noted that indeed certain types of fixation prostheses, such as braided metal fixation prostheses may be superior to others for some applications, the method of the present invention is not limited in that sense and may be used. to coat a wide variety of devices. The present invention also applies, for example, to the class of fixation prostheses that are not self-expanding "including those that can be expanded" eg, with a balloon. Polymeric fixation prostheses of all kinds can be coated using the procedure. A) Yes. Depending on the particular detailed arrangements, the use of the invention is not considered nor is it intended to be limited with respect to the design of the fixation prosthesis or the construction materials. Additionally, the present invention can be used with other types of implant prostheses. Accordingly, it is a primary object of the present invention to provide a coating method for coating a fixation prosthesis to be used as an expanded fixation prosthesis prosthesis, the coating being capable of long-term delivery of biologically active materials. Another object of the present invention is to provide a method for coating a prosthesis of fixation prosthesis, using a hydrophobic, biostable elastomer, in which biologically active specare incorporated, within a cured coating. Yet another object of the present invention is to provide a multilayer coating, in which the percentage of active material can vary from one layer to another. A further objective of the present invention is to control or modify aspects of the drug supply in controlled time, or with a time variable »from a fixing prosthesis coating» by controlling the average particle size in the biologically active spec Other objects and advantages of the present invention will become apparent to those skilled in the art when they are familiar with the specification and with the claims that come at the end.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides methods for producing a relatively thin layer of biostable elastomeric material "wherein a quantity of biologically active material, such as a coating" is dispersed on the surfaces of a deployable fixation prosthesis prosthesis. The preferred fixation prosthesis to be coated is an open-ended, self-expanding prosthesis. While other materials, including polymeric materials, can be used, in the preferred embodiment, the tubular body of an open braid of fine, mono or polyester metallic wire is formed, which flexes without crushing and easily deforms in the direction axial to an elongated shape, for transluminal insertion, by means of a vascular catheter. The fixation prosthesis attempts elastically to resume its predetermined stable dimensions, when it relaxes in situ. The coating is preferably applied as a mixture, solution or suspension of polymeric material and biologically active species, finely divided, dispersed in an organic vehicle, or a solution or partial solution of said species in a solvent or vehicle for the polymer and / or for biologically active species. For the purposes of the present application, the term "finely divided" means any type or size of material included, from dissolved molecules to suspensions, colloids and mixtures of particles. The active material is dispersed in a carrier material which may be the polymer, a solvent or both. Preferably the coating is applied as a plurality of relatively thin layers, applied sequentially in relatively rapid sequence, and preferably applied with the fixation prosthesis in a radially expanded state. In some applications, the coating may additionally be characterized as an initial, mixed liner, or as an applied substrate and a mixed top coat. The coating thickness ratio of the top coating to the substrate coating can vary with the desired effect and / or with the elution system. Typically these are of different formulations. The coating can be applied by dipping or spraying using evaporating solvent materials of relatively high vapor pressure to produce the desired viscosity and quickly establishing coating layer thicknesses. The preferred method is predicated on reciprocally spraying a radially expanded fixation prosthesis, which is rotating, using an air brush device. The coating process allows the material to adhere to, and cover the entire surface of, the shapes of the open structure of the fixation prosthesis; but in such a way that the open network nature of the braid structure or other pattern is preserved 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. Subsequently, the polymeric precursor material is cured at room temperature or at elevated temperatures, or the evaporated solvent is removed from the dissolved polymer, as the case may be. Curing is defined as the process of converting the elatomeric or polymeric material to a finished or useful state "by the application of heat and / or chemical agents, including physicochemical loads. When "for example" polyurethane thermoplastic elastomers are used »evaporation of the solvent at room temperature can occur, which makes the polymeric material useful for the controlled release of drugs, without further healing. Non-limiting examples of cure, according to this definition, include the application of heat and / or chemical agents and the evaporation of the solvent, which can induce physical and / or chemical changes. Ventilation time and temperature for healing are determined by the particular polymer involved and the particular drugs used. For example, silicone or polysiloxane materials (such as pol dimethylsi loxane) have been used satisfactorily. These materials are applied as a prepolymer in the coating composition and subsequently must be cured. Preferred species have relatively low cure temperatures and are known as vulcanizable materials at room temperature (RTV). 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 cure step can be implemented both after the application of a number of lower underlying layers, and of topcoat layers, or a single cure step can be used after the coating is completed. Subsequently, the coated fixation prostheses can be subjected to a post-healing sterilization process, which includes a plasma treatment of inert gas, and then exposure to gamma radiation, electronic beam, ethylene oxide (EtO) or sterilization can also be used. with steam. In the plasma treatment, the coated fixation prostheses are placed unrestrained in a reactor chamber and the system is purged with nitrogen and a vacuum is applied to about 20-50 mTorr. Subsequently, inert gas (argon, helium or a mixture thereof) is admitted to the reaction chamber for treatment with the plasma. A highly preferred method of operation is to use argon gas, which operates at a power scale of 200 to 400 watts, at a flow rate of 150 to 650 ml per minute, which is equivalent to about 100-450 mTorr , and with an exposure time of 30 seconds to around 5 minutes. The fixation prostheses can be removed immediately after treatment with the plasma, or they can be left in the argon atmosphere for an additional period of time, typically five minutes. After pre-treatment with argon plasma, the coated and cured fixation prostheses are subjected to sterilization with gamma radiation, nominally at 2.5-3.5 Mrad. Fixation prostheses maintain full elasticity after radiation, whether they are exposed in a restricted or unrestricted state. It has been found that restricted fixation prostheses subjected to gamma sterilization without pre-treatment with argon plasma lose elasticity and are not recovered at a sufficient or appropriate rate. The elastomeric material that forms a major constituent of the fixation prosthesis must possess certain properties. Preferably it is a suitable biostable hydrophobic elastomeric material, which is not degraded and which minimizes tissue rejection and inflammation of the tissue, and one which will undergo encapsulation by the tissue adjacent to the implantation site of the prosthesis. fixation. Suitable polymers for such coatings include silicones (for example, polys loxanes and substituted polysiloxanes), polyurethanes (including polycarbonate urethanes), thermoplastic elastomers in general, ethylene / vinyl acetate copolymers, polyolefin elastomers, EPDM rubber and polyamine elastomers. The materials referred to above are considered hydrophobic with respect to the contemplated environment of the invention. Suitable agents for incorporation include: ant thrombotic agents, anticoagulants. antiplatelet agents. Ionic thrombolysis. antiproliferants, anti-inflammatory drugs, agents that inhibit hyperplasia and, in particular, restenosis; inhibitors of smooth muscle cells, antibiotics, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters and drugs that can increase the formation of healthy neointimal tissue, including the regeneration of endothelial cells. The positive action can come from the inhibition of particular cells (e.g., smooth muscle cells) or the formation of tissue (e.g., fibromuscular tissue) while promoting the migration of different cells (e.g., endothelium) and the formation of tissue (neointima tissue). Preferred materials for making the braided fixation prosthesis include stainless steel, tantalum, titanium alloys, including nitinol (a nickel-titanium thermal memory alloy material) and certain cobalt alloys, including cobalt-chrome alloys -nickel, such as Elgiloy * '»» and Phynox < ',,,. Further details regarding the fabrication and details of other aspects of the fixation prostheses themselves can be elucidated in U.S. Patents 4,655,771 and 4,954,126 to Wallsten and 5,061,275 to Wallsten and coauthors, to which reference was made above. To the extent that the additional information contained in the patents referred to above is necessary for the understanding of the present invention, they are considered incorporated herein by this reference. Various combinations of polymeric coating materials can be coordinated with biologically active species of interest to produce the desired effects when applied to fixation prostheses to be implanted according to the invention. The loads of therapeutic materials may vary. The mechanism of incorporation of the biologically active species into the surface coating, and the mechanism of egress, both depend on the nature of the surface coating polymer and the material to be incorporated. The release mechanism also depends on the mode of incorporation. The material can be eluted through the trajectories between particles or it can be administered by transport or diffusion through the encapsulating material itself. For the purposes of this specification, "elution" is defined as any release process involving the extraction or release by direct contact of the material with body fluids, through the trajectories between the particles, connected to the outside of the body. coating. "Transport" or "diffusion" is defined to include a release mechanism in which a released material passes through another material. The desired release rate profile can be adapted to the needs by varying the thickness of the coating, the radial distribution (from one layer to another) of bioactive materials, the mixing method, the amount of bioactive material, the combination of different polymer materials of matrix, in the different layers, and the interlacing density of the polymeric material. The interlacing density is related to the amount of interlacing that occurs and also to the relative grip of the matrix created by the particular interlacing agent used. This, during the curing process, determines the amount of entanglement and, thus, the interlacing density of the polymeric material. For bioactive materials released from the interlaced matrix, such as heparin, a higher density interlacing structure will increase the release time and reduce the discharge effect. Additionally, with elution materials, such as heparin, the kinetics of irradiation, particularly the rate of initial release of the drug, can be affected by varying the average size of the dispersed particle. The initial release rate, or discharge effect, observed, can be substantially reduced by using smaller particles, in particular if the particle size is controlled to be less than about 15 microns and the effect is still more significant on the particle size scale of less than or equal to 10. microns, especially when the thickness of the coating is no more than about 50 μm and the drug loading is about 25 to 45 weight percent. It will also be appreciated that a thin top layer of silicone, without medication, gives an advantage over a drug-containing topcoat. Its surface has a limited porosity and, in general, is smooth, which may be less thrombogenic and may reduce the probability of developing calcification that occurs very frequently on the porous surface.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings, where the same numbers designate the same parts in all of them: Figure 1 is a schematic flow chart illustrating the steps of the method of the present invention. Figure 2 depicts a release profile for a multilayer system, showing the percentage of heparin released over a period of two weeks. Figure 3 depicts a release profile for a multilayer system, showing the rate of relative release of heparin over a period of two weeks. Figure 4 illustrates a release kinetics profile for different drug loads, at similar coating thicknesses, illustrating the release of heparin over a period of two weeks. Figure 5 illustrates the kinetics of drug elution, at a given heparin loading, over a period of two weeks, at different coating thicknesses. Figure 6 illustrates the release kinetics in a coating having a given adhesion layer thickness, for different topcoat thicknesses, where the percentage of heparin in the adhesion coating and in the top coatings is kept constant. Figure 7 illustrates the release kinetics of various coatings having an average coating thickness of 25 microns, and a heparin load of 37.5%. but they use four different average particle sizes. Figures 8-11 are photomicrographs of coated fixation prosthesis fragments, for the coatings of Figure 7, which have a corresponding average particle size of 4 microns, 17 microns, 22 microns and 30 microns, respectively.

DETAILED DESCRIPTION According to the present invention, fixation prosthesis coatings incorporating biologically active materials during controlled delivery in time, in situ, in a body lumen, of interest, are preferably sprayed in many thin layers from solutions or suspensions Coating. The steps of the process are generally illustrated in Figure 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 in 12, and then the material is stirred or shaken to produce a homogenous coating composition at 14, which is subsequently transferred to a container or application device. which can be a container for spray painting »in 16. Typical exemplary coating solutions that were used for heparin and dexamethasone appear below.

GENERAL PREPARATION OF THE COATING COMPOSITION OF HEPART A S licon was obtained as a polymer precursor in solvent mixture (xylene). For example, a weight content of silicone solids of 35% in xylene was sought from Appl ed Sil cone, part number 40,000. First, the silcone-xi mixture was weighed. Then the silicone solids content was determined, according to the vendor's analysis. Pre-calculated amounts of finely divided heparin (2-6 microns) were added to the silicon, then tetrahydrofuran (THF), HPLC grade (Aldrich or EM) was added. For a coating of 37.5% heparin, for example: W (weight of silicone) = 5 g; % solids = 35%; W (hep) (heparin weight) = 5 x 0.35 x 0.375 / (0.625) = 1.05 g. The amount of THF needed (44 ml) in the coating solution was calculated using the equation: W (weight of silicone solids) / V (volume of THF) = 0.04 for a 37.5% heparin coating solution. Finally, the manufacturer's interlacing solution was added using a Pasteur P pipette. The added amount of interleaver was formed to effect the release rate profile. Typically, five drops of interlacing solution were added for every five grams of a 1-icon mixture. The interleaver may be any suitable and compatible agent, including platinum and peroxide-based materials. The solution was stirred using the shaker bar until the suspension was homogeneous and milky. Then the coating solution was transferred to a paint bottle, in condition for application by air brush.

GENERAL PREPARATION OF THE DEXAMETHASONE COATING COMPOSITION Silicone (a 35% solution, as before) was weighed into a beaker on a Metler scale. The weight of the dexamethasone-free alcohol or acetate form was calculated by the weight of the silicone multiplied by 0.35, and the desired percentage of dexamethasone (1 to 40%) and then the required amount was weighed. Example: W (weight of silicone) = 5 g; for a 10% dexamethasone coating, W (dexamethasone weight) = 5 x 0.35 x 0.1 / 0.9 = 0.194 g and the THF needed in the coating solution was calculated. W (silicone solid) / V (THF) = 0.06 for a 10% dexametasone coating solution. Example: W (weight of silicone) = 5 g; V (THF volume) = 5 x 0.35 / 0.06 = 29.17 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 complete 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 interlayer was added using a Pasteur pipette. Typically five drops of interleaver were used for five grams of silicone. The application of the coating material to the fixation prosthesis was quite similar for all materials and the same for the heparin and dexamethasone suspensions prepared as in the previous examples. The suspension to be applied was transferred to an application device, typically a paint bottle connected to an air brush, such as the Badger Model 150, fed with a source of pressurized air, by means of a regulator ( Norgren, 0-1124 KPa Once the brush hose was connected to the compressed air source »downstream of the regulator, the air was applied, the pressure was adjusted to approximately 1-1.7 atm, and the condition was checked of the nozzle by squeezing the trigger, any appropriate method can be used to secure the fixation prosthesis for spraying, and rotating attachments were used satisfactorily in the laboratory, both ends of the relaxed fixation prosthesis were attached to the abutment by means of two elastic retainers. , commonly alligator clips, adjusting the distance between the forceps so that the fixation prosthesis remained in a relaxed condition, not stretched. The rotor and the speed of rotation were adjusted to the desired coating speed »nominally around 40 rpm. With the prosthesis rotating in a substantially horizontal plane, the spray nozzle was adjusted so that the distance from the nozzle to the fixation prosthesis was about 5.08-10.16 cm, and the composition was sprayed substantially horizontally, directing the brush along the fixation prosthesis, from the distal end of the fixation prosthesis to the proximal end and then from the proximal end to the distal end, in a sweeping motion at such a speed that a spray cycle occurred in around three rotations of the fixation prosthesis. Typically, a pause of less than one minute elapses between the layers, usually around half a minute. Of course, the number of coating layers will be varied and will vary with the particular application. For example, for a coating level of 3-4 mg of heparin per cm * of projected area, it requires 20 cycles of coating application and about 30 ml of solution will be consumed for a diameter of 3.5 mm by a fixation prosthesis of 14.5 cm in length. The speed of rotation of the motor, of course, can be adjusted as well as the viscosity of the composition and the flow rate of the spray nozzle, as desired, to modify the layer structure. In general, with the above mixtures the best results have been obtained at rotation speeds in the range of 30-50 rpm and with a flow rate of the spray nozzle in the range of 4-10 ml of coating composition per minute. , depending on the size of the fixation prosthesis. It is contemplated that a more complicated, computer-controlled coating apparatus will successfully automate the procedure demonstrated as feasible in the laboratory.

Several applied layers constitute what is called the binding or bonding layer, as in 18, and subsequently and subsequently additional upper layers are applied, which may be of different composition with respect to the bioactive material, the polymeric matrix and the interlacing agent, for example, as the upper layer in 20. The application of the upper layer follows the same coating procedure as the bond layer, the number and thickness of the layers being optional. Of course, the thickness of any layer can be adjusted by modifying the rotational speed of the fixation prosthesis and the spray conditions. In general, the total coating thickness is controlled by the number of spray cycles or thin coatings, which constitute the total coating. As shown in 22 in Figure 1, the coated fixation prosthesis is subsequently subjected to a healing step. wherein the prepolymer and the crosslinking agents cooperate to produce a cured polymer matrix containing the biologically active species. The curing process comprises the evaporation of the solvent solvent, the THF, etc., and the curing and interlacing of the polymer. Certain silicone materials can be cured at relatively low temperatures (i.e., from room temperature to 50 ° C), and in a process known as vulcanization at room temperature (RTV). However, it is more typical that the curing process comprises materials that cure at higher temperature, and the coated fixation prostheses are brought to an oven at about 90 ° C or more, for about 16 hours. The temperature can be raised to 150 ° C for coated fixation prostheses containing dexamethasone. Of course, the time and temperature may vary with silicones, particular interlacing agents and biologically active species. Fixation prostheses coated and cured in the manner described need to be sterilized before packing for future implantation. To sterilize gamma radiation is a preferred method, in particular for coatings containing heparin; however, it has been found that the fixation prostheses coated and cured according to the method of the invention, subjected to sterilization with gamma rays, may be too slow to recover their original posture when they are delivered to a vascular site or other lumen. , using a catheter, unless a pre-treatment step is applied first, as in 24, to the coated and cured fixation prosthesis. The pretreatment step involves a treatment with argon plasma of the coated, cured fixation prostheses in the unrestricted configuration. According to this method, the fixation prostheses are placed in a chamber of a plasma surface treatment system, such as Plasma Science 50 (Himont / Plasma Science, Foster City, CA, E.U.A.). The system is equipped with a reactive camera and a solid-state radio frequency generator that operates at 13.56 MHz and 0 to 500 watts of power output, and is equipped with a microprocessor-controlled system, and a vacuum pump package full. The reaction chamber contains an unobstructed work volume of 42.55 cm by 34.3 cm by 44.45 cm depth. In the plasma procedure, the coated, non-stressed fixation prostheses are placed in a reactor chamber and the system is purged with nitrogen and a vacuum of 20 to 50 mTorr is applied. Subsequently, an inert gas (argon, helium or a mixture thereof) is admitted to the reaction chamber for treatment with the plasma. An extremely preferred method of operation is to use argon gas, operate at a power scale of 200 to 400 watts, a flow rate of 150 to 650 ml per minute, which is equivalent to 100-450 mTorr, and with a exposure time from 30 seconds to around 5 minutes. The fixation prosthesis can be eliminated immediately after treatment with the plasma, or they can remain in the argon atmosphere for an additional period of time »typically five minutes. After this, as shown in 26. the fixation prostheses are exposed to sterilization with gamma radiation, at 2.5-3.5 Mrad. The irradiation can be carried out with the fixation prosthesis in a radially unrestricted state or in a radially restricted state.

With respect to the heparin anticoagulant material, the percentage in the binding layer is nominally around 20 to 50%, and in the upper layer, about 0-30% of active material. The coating thickness ratio of the top layer to the link layer varies from 1:10 to 1: 2, and is preferably in the range of 1: 6 to 1: 3. Suppressing the discharge effect also allows a reduction in drug loading or, in other words, allows a reduction in coating thickness, since the physician will administer a bolus injection of antiplatelet / anticoagulation drugs to the patient, during the process of implantation of the fixation prosthesis. As a result »the drug embedded in the fixation prosthesis can be used completely, without waste. The restrictive adaptation of the release of the first day, but the maximization on the second and third days of the release in the thinnest possible lining configuration, will reduce acute or subacute thrombosis. Figure 4 illustrates the general effect of drug loading for coatings of similar thickness. The initial elution rate increases with the drug loading "as shown in Figure 5. The release rate also increases with the thickness of the coating at the same load" but tends to be inversely proportional to the thickness of the top layer, as shown by the same drug loading and the similar bond coating thickness, in Figure 6.

The effect of the average particle size is illustrated in Figures 7-11, where coating layers were provided with an average coating thickness of about 25 microns, prepared and sterilized as before, with dispersed particles of heparin (up to 37.5% of heparin) of several different average particle sizes. Figure 7 shows graphs of elution kinetics for four different sizes of embedded heparin particles. The release takes place in phosphate buffer (pH 7.4) at 37 ° C. The rate of release using smaller particles, particularly of an average size of 4-6 microns, markedly reduces the initial velocity or discharge effect "and subsequently the rate of elution decreases more slowly over time. Average particle sizes of more than about 15 microns result in initial release rates approaching bolus elution. Of course, this is less convenient both from the point of view that it is an initial unnecessary excess, and from the premature exhaustion of the coating of the drug material. Additionally »as shown in the photomicrographs of Figures 8-11, as the average particle size increases, the morphology of the coating surface also changes. Coatings containing larger particles (Figures 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 fixation prosthesis is implanted in a blood vessel. As a result, it has been found that the average particle size should be controlled generally at less than about 15 microns, to reduce the discharge effect and, preferably, should be less than or equal to about 10 microns for better results. The size of 4-6 micras worked quite satisfactorily in the laboratory. However, it should be noted that a larger particle size can also be advantageously used, for example, when the drug load is low, such as less than 25% by weight. The elution kinetics can be adjusted by combining the change in particle size and the change in charge or the concentration of the dispersed drug material. What is evident from the data gathered so far, however, is that the method of the present invention allows the elution kinetics of the drug to be modified to meet the needs of the particular application of the fixation prosthesis. In a similar way, fixation prosthesis coatings can be prepared using a combination of two or more drugs, and the sequence and rate of release of the drugs is controlled. For example, antiproliferation drugs can be combined in the underlying coating and anti thrombotic drugs in the topcoat layer. In this way »anti thrombotic drugs, for example heparin, will be eluted first, followed by anti-proliferation drugs, for example, dexamethasone» to better allow the secure encapsulation of the implanted implant prosthesis. The heparin concentration measurements were made using a standard curve prepared by the formation of blue dye A complexes with diluted heparin solutions. Sixteen standards were used to compile the norm curve in a known manner. For the elution test, the fixation prostheses were immersed in a phosphate buffer at pH 7.4 in an incubator at approximately 37 ° C. Periodic samples of the solution were processed to determine the amount of heparin eluted. After each sampling, each fixation prosthesis was placed in a heparin-free buffer solution. As noted above, although the allowable load of 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 load generally used as very advantageous is in the approximate range of 10% to 45% of the total weight of the layer. In the case of dexamethasone the charge may be up to 50% or more of the total weight of the layer, but preferably it is in the approximate range of 0.4% to 45%. It will be appreciated that the mechanism of incorporation of biologically active species into a thin surface coating structure "applicable to a metal fixation prosthesis" is an important aspect of the present invention. The need for a relatively thin wall fixation prosthesis, for polymer elution, or any membrane cover layers, associated with many prior drug eluting devices is obviated, as is the need to use biodegradable or resorbable vehicles to carry the species biologically active. The technique clearly allows for long-term delivery and minimizes interference with the mechanical or therapeutic benefits independent of the fixation prosthesis itself. The coating materials are designed with a particular coating technique, a coating / drug combination and a particular drug infusion mechanism, in mind. By taking into account the particular form and the particular mechanism of release of the biologically active species present in the coating, the technique allows to produce superior results. In this way, the supply of biologically active species from the coating structure can be tailored to accommodate a variety of applications. While the above examples illustrate coatings having two different drug loads, or two different percentages of the biologically active material to be released this in no way means a limitation with respect to the invention, and it is contemplated that any number may be employed. of layers and load combinations, to obtain a desired release profile. For example, a gradual gradation and gradual change in the loading of the layers may be used where, for example, larger loads are used in the inner layers. You can also use layers that have absolutely no drug load. For example, a pulsed heparin delivery system can be obtained by a coating in which alternating layers containing hepar na are sandwiched between layers without silicone filler or other materials, for a portion of the coating. In other words, the invention allows countless numbers of combinations that result in great flexibility with respect to the control of the release of biologically active materials, with respect to an implanted fixation prosthesis. Each applied layer has an approximate thickness, typically, from 0.5 microns to 15 microns. 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 in general it will be around 10 to 200 microns. While the coating polymer may be any biostable, compatible elastomeric material capable of being adhered to the fixation prosthesis material, such as a thin layer, hydrophobic materials are preferred because it has been found that the preservation of the species biologically active can be controlled in general in a more predictable manner with these materials. Preferred materials include silicone rubber elastomers and biostable polyurethanes, specifically. This invention has been described here in considerable detail in order to comply with the patent statutes, and to give those skilled in the art the information necessary to apply the novel principles and to construct and use the 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 obtained without departing from the scope of the invention itself.

Claims (25)

NOVELTY OF THE INVENTION CLAIMS

1. - A method for coating an implantable prosthesis with at least one layer comprising a hydrophobic elastomeric material that incorporates a quantity of biologically active material therein, for delivery for a period of time therefrom, characterized in that it comprises the steps of: (a) applying a formulation containing the elastomeric material in solvent mixture "and an amount of a biologically active material" to a surface of the prosthesis "wherein the average particle size of the biologically active material present in the formulation is less than or equal to 15 microns; and (b) curing the elastomeric material.

2. The method according to claim 1, further characterized in that 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. of them.

3. The method according to claim 2, further characterized in that the biologically active material includes heparin.

4. The method according to claim 3, further characterized in that the layer comprises from 25 to 45 weight percent of biologically active material.

5. The method according to claim 1 »further characterized in that the biologically active material has an average particle size less than or equal to about 10 microns.

6. The method according to claim 5 »further characterized in that the biologically active material includes heparin.

7. A method for controlling the delivery kinetics of a biologically active, eluted, particulate material incorporated in a polymeric coating having at least one layer on a surface of an implantable prosthesis; characterized in that it comprises incorporating a biologically active particulate material, having an average particle size less than or equal to about 15 microns, in at least one layer of the coating.

8. The method according to claim 7, further characterized in that the biologically active material is heparin.

9. The method according to claim 8, further characterized in that the layer comprises about 25 to 45 weight percent of biologically active material.

10. The method according to claim 7, further characterized in that the biologically active material is incorporated to produce a substantially smooth surface on the prosthesis.

11. - A coated implantable prosthesis, characterized in that it has an outer surface covered with at least one layer comprising a hydrophobic elastomeric material that incorporates a quantity of biologically active material in the form of particles, dispersed therein, for delivery during the time from the same; wherein the average particle size of the biologically active material is less than or equal to about 15 microns.

12. The device according to claim 11. further characterized in that the elastomeric material is selected from the group consisting of sil cones. polyurethanes »polyamide elastomers. ethylene / vinyl acetate copolymers. polyolefin elastomers. EPDM rubber and its combinations.

13. The device according to claim 11. further characterized in that the biologically active material includes heparin.

14. The device according to claim 11, further characterized in that the layer comprises about 25-45 weight percent of biologically active material.

15. The device according to claim 11. further characterized in that the biologically active material has an average particle size less than or equal to about 10 microns.

16. The device according to claim 15. further characterized in that the biologically active material includes heparin.

17. The device according to claim 11. further characterized in that the layer comprises about 25-45 weight percent of biologically active material; and wherein the biologically active material is heparin which has an average particle size less than or equal to about 10 microns.

18. An implantable »coated» prosthesis characterized in that it has an external surface »covered with a coating comprising an elastomeric material incorporating an amount of biologically active material having an average particle size less than or equal to about 15 microns» dispersed in the elastomeric material.

19.- The method according to the claim 1, further characterized in that the implantable prosthesis is an expandable member having a tubular metal body having open ends and a side wall structure having openings »and wherein the formulation forms at least one coating layer on a surface of the side wall structure »which continuously conforms to the side wall structure, in a manner that preserves the openings when the element is expanded.

20. The method according to the rei indication 19"further characterized in that the expandable element eß a self-expanding element.

21. - The method of compliance with the rei indication 19"further characterized in that the formulation is applied with the element fully expanded.

22. The method according to claim 19 »further characterized in that the biologically active material has an average particle size less than or equal to about 10 microns.

23. The method according to the rei indication 19, further characterized in that the coating layer comprises about 25-45 weight percent of biologically active material.

24. A method for coating at least a portion of an implantable prosthesis, having at least one opening, with a hydrophobic elastomeric material that incorporates therein an amount of biologically active material for delivery during the time therefrom, characterized because it comprises the steps of: (a) applying a coating comprising the elastomeric material, a solvent and a quantity of biologically active material, finely divided, in at least a portion of the prosthesis; wherein, when the biologically active material is in particles, the average particle size of the biologically active material is less than or equal to about 15 microns; and wherein the coating is applied to the prosthesis in a manner that adheres adherently thereto, to preserve the opening; and (b) curing the coating so that at least some of the biologically active material is particulate after curing. 25.- A method to control the supply of a biologically active material that is eluted. embedded in an elastomeric coating having at least one layer in at least a portion of an implantable prosthesis having at least one opening; characterized in said method because it comprises: incorporating a biologically active particulate material, having an average particle size less than or equal to about 15 microns, into at least one layer of the coating, "and applying the elastomeric coating in a manner that adheres adherently to the surface to preserve the opening, and cure the coating so that at least some of the biologically active material is particulate after curing.