JP2008508054A - Metallic drug release medical device and method for producing the same - Google Patents

Abstract

  Disclosed is an implantable drug release medical device (10) as shown in FIG. 4A made of a metal film or a pseudo metal film. Metallic or pseudo-metallic membranes made of biocompatible materials having a plurality of micropores (20) that pass through the membrane in a pattern that imparts a fabric-like quality to the device, resulting in geometric deformation of the medical device Is possible. The implantable medical device is preferably fabricated by vacuum-depositing a metal material and / or a pseudo-metal material into a single layer structure or a multi-layer structure, wherein the plurality of micropores comprises sections of the deposited film. By selective removal, it is formed during or after deposition. Implantable medical devices are suitable for use as endoluminal or surgical grafts, such as vascular grafts, stent grafts, skin grafts, shunts, bone grafts, surgical patches, It can be used as non-vascular conduits, valve leaflets, filters, occlusive membranes, artificial sphincters, tendons, and ligaments.

Description

  This application is a part of co-pending US patent application Ser. No. 10 / 258,087 filed Nov. 17, 2002, which is co-pending US patent application Ser. This is part of the 716146 specification. This application is also filed earlier in co-pending and co-assigned US patent application Ser. No. 10/135316, filed Apr. 29, 2002, and US Patent Application No. 10 / 135,626 filed Apr. 29, 2002. Both of which are both incorporated herein by reference, U.S. Provisional Patent Application No. 60 / 310,617, filed Aug. 7, 2001, and Aug. 8, 2002, each of which is incorporated herein by reference. Claims priority to co-pending and co-pending US patent application Ser. No. 10/258087, filed Oct. 17, 2002, corresponding to PCT International Application No. WO02060606A1 published in Japan.

  The present invention generally relates to implantable metallic medical devices capable of releasing pharmacologically active agents. More specifically, the present invention relates to implantable drug release medical devices, such as surgical grafts and intraluminal vascular grafts, stents, stent grafts, coated stents, skin grafts, shunts, bone grafts There are pieces, surgical patches, non-vascular conduits, valve leaflets, filters, occlusive membranes, sphincters, artificial tendons and ligaments, vascular obturators, orthopedic implants and dental implants. More specifically, the present invention is biocompatible having a plurality of micropores passing through the membrane and having a plurality of drug release pockets defined within the membrane and disposed between adjacent pairs of micropores. The present invention relates to an implantable medical implant made of a metal film or pseudo metal film of a material. The plurality of micropores impart both compliance and fabric-like quality to the metal or pseudo-metal membrane of biocompatible material and to allow, for example, circumferential or longitudinal expansion of the tubular membrane Allows the membrane to deform geometrically.

  For the purposes of this application, both metallic and pseudo-metallic films of biocompatible materials are collectively referred to as “metal films” or “metallic films”. The metal films of the present invention can be fabricated by conventional wrought metal processing techniques or can be created by nanofabrication techniques such as physical vapor deposition or chemical vapor deposition.

  For the purposes of this application, the term “micropore” or “microopening” when used in the singular or plural is intended to mean an opening having an open surface area in submillimeter to nanometer size openings. To do.

  The metal film can have a generally tubular geometric shape, can have a generally planar geometric shape, or can be formed into a complex geometric shape. However, those skilled in the art will understand that regardless of the specific geometry of the metal film, the metal film generally has two opposing surfaces, hereinafter referred to as the first metal film surface and the second metal film surface. Will.

  The drug release pocket is completely encapsulated inside the metal film, but is not bound or encapsulated by the polymer matrix, but releases the drug through the opening by diffusion, pumping, or other active or passive means. At least one opening in the pocket of sufficient size to allow is removed. The drug release pocket is bounded on all sides by the metal film and has a substantially pillow chamber or box chamber geometry, wherein the at least one opening is a first surface and a second surface of the metal film. Pass through the metal film in either or both.

  In addition to acting as a boundary for the drug release pockets, the multiple micropores can, for example, allow for geometric deformation of the membrane, impart fabric-like quality to the membrane, and provide flexibility to the membrane. It can serve multiple purposes, including granting. The term “fabric-like” is intended to mean a quality that is supple and / or bendable in a manner similar to that found for natural or synthetic woven fabrics.

  The implantable implants of the present invention are made entirely with self-supporting membranes made of biocompatible metals or biocompatible pseudometals. The metal film can be a single-layer metal film or a multi-layer film. The terms “metal film”, “thin metal film” and “metal film” are used in this application to be made of a biocompatible metal or biocompatible pseudometal having a thickness greater than 0 μm and less than about 125 μm. Is used as a synonym to refer to a single layer film or multiple layer film. To date, in the field of implantable medical devices, one of its elements is the fabrication of implantable medical devices comprising one implant of a completely self-supporting or pseudo-metallic material, such as a covered stent or stent-graft. It was unknown to do. As used herein, the term “implant” essentially comprises a material that is delimited by said surface, the distance between the two surfaces being the thickness of the implant, and integral. It is intended to indicate any type of device or part of a device that exhibits dimensional strength and has micropores that pass through the thickness of the implant. The implants of the present invention can be formed in flat sheets, toroids, and other shapes that a particular application field can guarantee. However, for purposes of illustration only, this application refers to tubular implants. For the purposes of this application, the terms “pseudometal” and “made of pseudometal” are intended to mean a biocompatible material that exhibits approximately the same biological response and material characteristics as a biocompatible metal. Examples of pseudo-metallic materials include, for example, polymers, composite materials, and ceramics. The composite material consists of a matrix material reinforced with any of a variety of fibers made from ceramic, metal, carbon, or polymer.

  When implanted in the body, metals are generally considered to have better biocompatibility than that exhibited by the polymers used to make commercially available polymer implants. It has been found that integrin receptors on the cell surface interact with the prosthetic surface when the prosthetic material is implanted. Integrin receptors are unique to ligands that are in vivo. When specific proteins are adsorbed on the surface of the prosthesis and the ligand is exposed, cell binding to the surface of the prosthesis may occur by integrin ligand docking. It has also been observed that proteins bind to metals in a more permanent manner than when bound to polymers, thereby providing a more stable adhesive surface. Protein conformation bound to the surface of most medical metals and alloys exposes more ligands and preferentially metal or alloyed endothelial cells with surface integrin clusters compared to leukocytes It seems to attract to the surface. Finally, metals and metal alloys exhibit superior resistance to metal degradation compared to polymers, thereby providing better long-term structural integrity and stable boundary conditions.

  Because of the relatively better adhesion surface profile, metals are also susceptible to short-term platelet activity and / or thrombogenicity. These detrimental properties can now be offset by the regular use and administration of pharmacologically active antithrombotic agents. Surface thrombogenicity usually disappears 1-3 weeks after initial exposure. Coverage in preventing thrombus formation is routinely provided during this time period of coronary stenting. In non-vascular applications such as musculoskeletal and dental, metals also have better tissue compatibility than polymers due to similar molecular considerations. The best literature to demonstrate that all polymers are inferior to metals is (eg, Non-Patent Document 1).

US Pat. No. 5,897,911 US Pat. No. 5,725,573 US Pat. No. 5,955,588 US Pat. No. 5,649,951 US Pat. No. 5,387,247 US Pat. No. 5,607,463 US Pat. No. 5,690,670 US Pat. No. 5,891,507 US Pat. No. 5,782,908 US Pat. No. 5,932,299 US Patent Application Publication No. 2003/0170287, filed on Sep. 11, 2003 U.S. Patent Application No. 60/414209, filed September 26, 2002 US patent application Ser. No. 10 / 672,695, filed Sep. 26, 2003 van der Giessen, WJ. et al. Marked inflammatory sequelae to implantation of biodegradable and non-biodegradable polymers in porcine coronary arteries, Circulation, 1996: 94 (7): 1690-7 Davies, PF, Robotewskyi A., Griem ML Endothelial cell adhesion in real time., J. Clin. Invest. 1993; 91: 2640-2652, Davies, PF, Robotewski, A., Griem, ML, Qualitiative studies of endothelical cell adhesion, J. Clin. Invest. 1994; 93: 2031-2038 H. Holleck, V. Schier: Multilayer PVD coatings for wear protection, Sufface and Coatings Technology, Vol. 76-77 (1995) pp. 328-336

Normally, endothelial cells (EC) migrate and grow to cover the bare area until confluence is achieved. Migration that is quantitatively more important than growth proceeds at a rate of approximately 25 μm / hr or under normal blood flow at 2.5 times the diameter of the EC, which is usually 10 μm. ECs migrate by a rotational movement of the cell membrane coordinated by a complex system of detailed membrane integrin receptor clusters, specifically intracellular filaments attached to the focal point of contact. Integrins within the focal site of contact are represented by a complex signaling mechanism and ultimately bind to a specific amino acid sequence of the substrate adhesion molecule. EC has approximately 16-22% of the cell surface represented by integrin clusters (see, for example, Non-Patent Document 2). This is a dynamic process that suggests over 50% remodeling in 30 minutes. Focal adhesion contacts vary in size and distribution, but 80% is measured to be less than 6 [mu] m ^2, most of which is approximately 1 [mu] m ^2, it tends to extend in the direction of flow, and concentrated at the leading edge of the cell is there. Although the understanding of the recognition and signaling processes that determine the response of a specific attached receptor to an attachment site is incomplete, the availability of attachment sites has an advantageous impact on attachment and migration. It is known that materials commonly used as medical implants, such as polymers, are not covered with EC and therefore do not heal after being placed in an artery. Accordingly, it is an object of the present invention to replace a polymer implant material with a metal film material that has a better healing response and is more comfortable with EC coverage and can be fully healed. Furthermore, the non-uniformity of the metallic film material of the present invention in contact with the blood flow is preferably controlled by exerting control over the processing parameters used during vacuum deposition of the device forming material.

  Covering the stent with a polymeric material (see, for example, Patent Document 1), applying a diamond-shaped carbon coating on the stent (see, for example, Patent Document 2), and covalently attaching a hydrophobic moiety to a heparin molecule ( For example, see Patent Document 3), coating the stent with a blue layer to blacken zirconium oxide or zirconium nitride (see, for example, Patent Document 4), coating the stent with a layer of turbostratic carbon ( For example, see Patent Document 5), coating the tissue contact surface of a stent with a thin layer of Group VB metal (see, for example, Patent Document 6), porous coating of titanium alloys such as titanium or Ti-Nb-Zr alloys. Application on the surface of the stent (see, for example, US Pat. Coating the stent with heparin, endothelial derived growth factor, vascular growth factor, silicone, polyurethane, or a synthetic or bioactive agent such as polytetrafluoroethylene or a synthetic inert or bioinactive agent (e.g., Patent Document 8), coating a stent with a silane compound having a vinyl function, and then polymerizing with a vinyl group of the silane compound (see, for example, Patent Document 9), a monomer, an oligomer, or Implanting monomers, oligomers, or polymers on the surface of the stent using infrared radiation, microwave radiation, or high voltage polymerization to impart polymer properties to the stent (see, for example, US Pat. Including medical devices such as stents Scan a number of attempts to promote endothelialization of have been made. However, all these approaches do not address the lack of endothelialization of polymer grafts.

  Accordingly, it is desirable to fabricate the metallic and / or pseudo-metallic materials of the present invention that are fabricated in a manner that controls the mechanical, physical, and chemical properties of the material. The metal device of the present invention can be made of existing conventional wrought metallic materials such as stainless steel or Nitinol hypotube, or it can be physical vapor deposition or chemical vapor deposition. It can be manufactured by a vacuum vapor deposition technique. According to the present invention, it is preferable to fabricate the embedded device of the present invention by vacuum deposition. Vacuum deposition allows better control over many material characteristics and properties of the resulting device. For example, vacuum deposition allows control over mechanical properties such as granule size, granule phase, granule material composition, bulk material composition, surface topography, transition temperature in the case of shape memory alloys . In addition, the vacuum deposition process can create devices with better material purity without introducing large amounts of contaminants that adversely affect the material, mechanical, or biological properties of the embedded device become. Vacuum deposition techniques also help to make more complex devices that are possible with manufacturing by conventional cold working techniques. For example, extremely fine control over material tolerances such as multilayer structure, complex geometry, thickness or surface uniformity are all advantages of the vacuum deposition process.

  In vacuum deposition techniques, the material is formed in exactly the desired geometric shape, for example planar or tubular. The common principle of the vacuum deposition process is to take materials as raw materials in a minimally processed form, such as known pellets or thick foils, and atomize them. Atomization can be performed, for example, using heat, as in physical vapor deposition, or using the effect of a collision process as in sputter deposition. In some forms of vapor deposition, processes such as laser ablation that create microparticles, usually composed of one or more atoms, can replace atomization. The number of atoms per particle can be several thousand or more. The raw material atoms or particles are then deposited on a substrate or mandrel to positively form the desired object. In other deposition methods, the chemical reaction between the ambient gas introduced into the vacuum chamber, i.e. the gas source and the attached atoms and / or particles, is part of the deposition process. Vapor deposition materials include compound species formed by reaction of a solid source with a gas source, such as in the case of chemical vapor deposition. In most cases, the vapor deposition material is then partially or completely removed from the substrate to form the desired product.

  The first advantage of the vacuum deposition process is that the vacuum deposition of the metal film and / or pseudo metal film enables tight process control and is regular and uniform atoms and molecules along the fluid contact surface It is possible to attach a film having a distribution pattern of Different process parameters used in the vacuum deposition process are used to achieve fabrication of metal and / or pseudo-metal films with controlled material properties, atomic and molecular composition, and controlled surface non-uniformity. It is possible to control. Process parameters that can be controlled in controlling the properties of the resulting deposited film include, for example, the composition, shape, and configuration of the object, the temperature of the object and / or the substrate, the deposition Rate, magnetron shape and configuration, magnetic field shape and strength, applied electric field strength, gas partial pressure during deposition, chamber pressure, substrate composition and / or topography, or vacuum chamber configuration. Vacuum deposition of device-forming films avoids significant changes in surface composition, creates predictable oxidation and organic adsorption patterns, and has predictable interactions with water, electrolytes, proteins, and cells. Specifically, EC migration is supported by a uniform distribution of binding domains that act as natural or embedded cell attachment sites to facilitate uninhibited migration and attachment.

  Second, in addition to materials and devices made from a single metal or metal alloy, hereinafter referred to as layers, the implant of the present invention is formed into a layer of biocompatible material or overlaid in a self-supporting multilayer structure. Can be composed of multiple layers of a biocompatible material because the multilayer structure generally increases the mechanical strength of the sheet material or is superelastic, shape memory, radiopaque This is because it is known to provide special qualities by including layers with special properties such as corrosion resistance. A special advantage of the vacuum deposition technique is that it is possible to deposit a layered material, thus making it possible to create a film with exceptional quality (see, for example, Non-Patent Document 3). Layered materials such as superstructures or multilayers are typically deposited to utilize certain chemical, electronic, or optical properties of the material as a coating. A common example is an anti-reflective coating on an optical lens. Multilayers are also used in the field of thin film fabrication in order to increase the mechanical properties of thin films, specifically hardness and toughness.

Thirdly, the possible configurations and application possibilities of the implants of the present invention are greatly improved by using nanofabrication methods. Vacuum deposition cannot be achieved cost-effectively by using conventional wrought fabrication techniques or in some cases a potentially complex three-dimensional geometric shape that cannot be achieved at all And an additional technique that is useful for the fabrication of nearly uniform thin materials with structure. In addition, subtraction processes such as photolithography, etching, including but not limited to chemical etching and laser etching or electrical discharge machining (EDM), selectively remove material from the existing film, from 10 ^{-8 in} the film. It can be used to create very small scale features such as 10 ^-10 .

  Conversely, traditional wrought metal fabrication techniques may require refining, hot working, cold working, heat treatment, high temperature annealing, precipitation annealing, grinding, ablation, wet etching, dry etching, cutting, and welding. There is. All of these processing steps have drawbacks, including contamination, reduced material properties, final achievable configurations, dimensions and tolerances, biocompatibility, and cost. For example, conventional forging processes are not suitable for making tubes with diameters greater than about 20 mm, and such processes have wall thicknesses up to a minimum of about 5 μm with a tolerance of less than μm. It is also not suitable for the production of materials with

  While the metal or pseudo-metal drug release implant of the present invention can be made of a wrought material conventionally produced according to the optimal mode contemplated for the present invention, the drug release implant of the present invention comprises: It is preferably made by vacuum deposition techniques. By vacuum-depositing a metal film and / or pseudo-metal film as the precursor material of the pharmaceutical release implant of the present invention, the result obtained is more strictly than is possible with conventional graft-forming materials. It is possible to control the membrane material and graft material, biocompatibility, and mechanical properties obtained. The self-supporting graft of the present invention can be used alone. That is, the entire implantable device can be made of a single implant, or the implant can be associated with other implants or other structures such as scaffolds, stents, and other devices. When used in conjunction with an element, it can be part of the structure. The term “related” refers to those created by welding, fusion, or other joining methods, as well as forming areas of parts in the implant and other areas of parts to other members or devices. It can mean an actual connection, such as one made from the same piece of material by forming in part.

  According to a preferred embodiment of the present invention, there is provided a self-supporting graft member having a wall thickness of between about 1 mμ and about 75 mμ, wherein a plurality of micropores pass through the thickness of the graft wall, Are placed between adjacent pairs of micropores, formed within the thickness of the graft wall, or formed on the surface of the graft, with an enclosure chamber within each enclosure pocket and an exterior of the enclosure pocket Having a plurality of drug release openings communicating between them. The graft member can assume virtually any geometric configuration, including a sheet, tube, or ring, but is preferably provided as a generally tubular configuration. The plurality of micropores impart geometric compliance to the graft, impart geometric distendability to the graft, and / or fluid flow through the graft wall under normal physiological conditions. Acts to limit or allow passage of bodily fluids or biological material through the graft, such as promoting transmural endothelialization while preventing flow. The plurality of micropores can also be fabric-like by imparting flexibility and / or elastic, plastic, superelastic compliance to the graft, such as those required for longitudinal flexibility in the case of vascular grafts. Add quality to the graft.

  According to a preferred embodiment of the invention, the drug release pocket is located in the middle of the adjacent pair of micropores and is completely present at the wall thickness of the graft material and is further completely bounded by the graft material. Defined and at least one opening communicates between the interior chamber in the drug release pocket and the exterior of the implant.

  According to an alternative embodiment of the invention, the drug release pocket is disposed on the first surface or the second surface of the graft, the drug release pocket being on at least one surface rather than completely by the graft material. A boundary is defined and at least one opening communicates between the chamber within the drug release pocket and the exterior of the implant.

  In the first embodiment, when the implant applies force, the micropore is a length for planar implants such as surgical patch implants, or a diameter for tubular implants such as vascular grafts, etc. It may be made of a plastically deformable material so as to deform geometrically so as to impart a permanent extension of one or more axes of the implant. In a second embodiment, the implant can be made of an elastic or superelastic material. Elastic and / or superelastic materials allow the micropores to deform geometrically when a force is applied in a manner that allows for recoverable changes in one or more axes of the implant. .

  The applied force can also be used to deform the implantable material opening in communication with the implantable material drug delivery chamber, thereby releasing the drug product from the implantable material. For example, a balloon mounted on a catheter can be used as a source of force applied to the implantable material.

  The location and structure of the drug release pocket can be controlled to allow forces applied by geometric deformation of the plurality of micropores to be transmitted to the drug release pocket, thereby A pumping-like force is applied to act to release a metered dose of drug in the drug release pocket. Alternatively, the pockets can be isolated from strains resulting from the geometric deformation of the plurality of micropores to prevent drug release during the geometric deformation of the drug release implant.

  According to a preferred embodiment of the present invention, the pharmaceutical is evenly distributed around the circumferential and longitudinal axes of the device so as to provide substantially uniform coverage and release around all axes of the device. It is desirable to place a discharge pocket. However, according to alternative embodiments of the present invention, the drug release pockets can be arranged such that different longitudinal or circumferential regions of the device have higher or lower drug release pocket density and distribution. is there. By changing the position, density, size, and distribution of the drug release pocket relative to the position along the axis of the device, the drug dosage can be controlled as a function of the position of the drug release pocket.

  In current polymer-coated drug release stents, the drug is released approximately uniformly around the polymer and along the length of the device. However, at the proximal and distal ends of the device where the polymer surface area from which the drug can be released is small, the concentration of released drug is significantly reduced. In contrast, in the present invention, the position of the drug release pocket is such that the drug is released directionally, i.e., on the lumen side, on the abluminally side, in the longitudinal or circumferential axis of the device. Can be selected during design and fabrication of the device to release the drug at selected locations along the device or from either or both of the proximal and distal ends of the device.

  In each of the first and second embodiments of the present invention, the implant has a fabric-like quality by controlling the membrane thickness, material properties, and the geometry of the plurality of micropores. It is possible to manufacture by the method which has. Furthermore, in cases where minimal invasive delivery is required, such as for intraluminal delivery of vascular grafts, the first and second embodiments may be used for balloon inflation and self-inflation, respectively, or both. Expect to deliver using the combination. Minimally invasive delivery can also be achieved by folding the implant for delivery, as well as wrinkling, grooving, or folding the angioplasty balloon. The implant may be delivered by spreading the device in vivo, with the aid of, for example, using balloons, or by the plastic, elastic, or superelastic properties of the graft material, or a combination thereof. Is possible. The plurality of micropores can be patterned in a manner that allows for further dimension expansion of the drug release implant member in vivo by elastic or plastic deformation, such as radial expansion positive pressure.

  For some applications, the size of each of the plurality of micropores may be such that cells can migrate through each opening without allowing fluid flow to pass through. preferable. In this way, for example, blood cannot flow through multiple micropores (in its deformed or undeformed state), but various cells or proteins promote healing of the implant in vivo. In order to do so, it is possible to freely pass through a plurality of fine holes. In other applications, a moderate amount of fluid flow through a plurality of deformed or undeformed micropores may be acceptable. For example, intraluminal saphenous vein grafts allow transmural endothelialization, while toxic substances circulate, excluding the passage of biological debris such as thrombus through the thickness of the graft wall It can be fabricated with micropores that perform a dual function that effectively eliminates entry. In this example, each of the deformed or undeformed micropores can exceed a few hundred microns.

  One skilled in the art will appreciate that there is a direct relationship between the size of the implantable implant pore and the overall rate of expansion or deformation. Thus, it is generally understood that the pore size must be increased to improve the effective achievable degree of graft expansion or deformation.

  In applications where both large deformations and small pore sizes are required, according to other aspects of the implant embodiments of the present invention, two or more such as an oppositely concentric implant for a tubular configuration It is contemplated that an implant member may be used. The two or more graft members have a pattern of a plurality of micropores passing therethrough, the plurality of patterned micropores of the first and second graft members concentrically engaged. They are offset from each other, such as tortuous cell migration paths through the walls, as well as to create smaller effective pore sizes. The two or more graft members can each be a drug release implant or a combination of drug release and non-drug release implants. For example, only a luminal graft can be drug-released so as to release the pharmacologically active agent into the bloodstream, while a non-release graft placed concentrically is on the abluminal side. It can be a graft. Alternatively, the relative position of the luminal graft and the antiluminal graft can be exchanged so that the luminal graft releases the drug and the luminal graft is non-releasing. .

  In order to facilitate cell migration through the first graft member and the second graft member and healing of the first graft member and the second graft member in vivo, the first graft member and the second graft member It may be preferable to provide an additional cytophoretic pathway that communicates between multiple micropores. These additional cytophoretic pathways are, if necessary, 1) a ring that acts as a spacer and allows cell migration and cell communication between multiple micropores in the first and second graft members Over the luminal surface of the second graft or the antiluminal surface of the first graft, or both surfaces, which acts to maintain an opening between the first and second graft members. 2) a plurality of fines that can be random, radial, helical, or longitudinal with respect to the longitudinal axis of the first and second graft members A plurality of grooves that are of sufficient size to allow cell migration and propagation along the grooves and that act as cytophoretic conduits between the plurality of micropores in the first and second graft members 3) or micro-holes are deformed To be designed to impart out-of-plane motion of the graft material, thereby, to maintain a well-defined space between the planes defining the beginning of the facing surfaces of the implant, it is possible to impart.

  Each of the drug release implant member or the non-release implant member can be formed as a single layer membrane or can be formed from multiple membrane layers formed on top of each other. . The specific materials used to form the biocompatible metal and / or pseudo metal layers are selected for biocompatibility, corrosion fatigue resistance, and mechanical properties, i.e., tensile strength, yield strength. The metals include the following titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt, palladium, manganese, molybdenum, and zirconium-titanium-tantalum alloys, Nitinol and its alloys such as, but not limited to, stainless steel. In addition, each material layer used to form the implant can be doped with tantalum, gold, or radioisotopes to improve material properties such as radiopacity or radioactivity. It is possible to dope with these materials. Alternatively, the pseudometallic material can include a polymer, carbon fiber, or ceramic.

  With the above background, the present invention will now be described with reference to the preferred embodiments and with reference to the accompanying figures. As indicated above, the microporous metallic implantable device of the present invention can assume many geometric configurations, including, for example, planar sheets, tubes, toroids, or other geometric configurations It is. However, for ease of reference, the accompanying figures and the following description of the invention refer to a tubular implantable graft member. However, those skilled in the art will appreciate that this is merely an exemplary geometric configuration and is not intended to limit the scope of the present invention to a tubular member or to application to an implant member. You will understand.

  With particular reference to FIGS. 1-2, the implantable medical device 10 of the present invention is shown as an implant. Device 10 is described herein only as a non-limiting example of an implantable medical device of the present invention, and the implantable medical device of the present invention can assume other geometric shapes. It will be appreciated that and can be used for other application areas or suggestions. The device 10 generally comprises a body member 12 comprising a coherent metallic material or pseudo-metallic material and having a first surface 14 and a second surface 16 and a thickness 18 between the first surface 14 and the second surface 16. Consists of. A plurality of micro holes 20 are provided and pass through at least one of the first surface 14, the second surface 16, or the thickness 18 of the body member 12, and the inter-hole region 22 of the body member 12 is adjacent to the micro holes 20. Exists between the pair. Each of the plurality of micropores 20 undergoes a change in geometric shape in a state where an externally applied load is applied or released, or during a phase change of a material such as a shape memory or a superelastic change. It is possible to have an easy geometric configuration. Alternatively, the plurality of micropores 20 can have a pattern and geometric configuration that imparts fabric-like quality and compliance to the material of the device 10. A plurality of drug release chambers 15 are provided in an inter-hole region 22 between adjacent pairs of micropores 20 and are released through at least one micropore 20 in a fluid flow communicating with the drug release chamber 15. 24 is held.

Each of the plurality of micropores 20 in an undeformed state preferably has an open surface area of less than about 2 mm ² and the total open surface area of the undeformed implant is between 0.001 and 99%. The open surface area of the plurality of micropores and the open surface area of the implant can change significantly as the plurality of micropores 20 deform. The size of the micropore 20 in the deformed state and the undeformed state, and the total open surface area of the body member 12 in the deformed state and the undeformed state are selected based on the graft application field in consideration of the following non-exclusive factors: It is possible. 1) the desired compliance of the device 10, 2) the desired strength of the device 10, 3) the desired stiffness of the device 10, 4) the desired degree of geometric expansion of the micropores 20 during deformation, 5) vessel graft In some cases, such as having strips, the desired and post-delivery profiles, and 6) the drug release profile for delivering the pharmacologically active agent from the drug release pocket.

  According to a preferred embodiment of the present invention, the plurality of micropores 20 are patterned in such a way as to define regions of the body member that allow deformation of the device 10 but do not require deformation of the device 10. . The thickness 18 is between 0.1 μm and 75 μm, preferably between 1 μm and 50 μm. When fabricated within these thicknesses, the device 10 has a thickness 18 that is less than the wall thickness of conventional non-metallic implantable implants and the wall thickness of conventional metal endoluminal stents. .

  The plurality of micro holes 20 are patterned in a regular array that forms a regular array of micro holes 20 in both the longitudinal and circumferential axes of the body member 12. For reference, the pattern of micropores 20 is hereinafter described with respect to a planar XY axis that corresponds to the longitudinal or circumferential axis of the tubular member for tubular members. One skilled in the art will refer to the X-axis or Y-axis when applied to a tubular member, where the term “X-axis” can correspond to the longitudinal or circumferential direction of the tubular member, referred to as “Y-axis”. It will be understood that the term may be used to refer to the corresponding circumferential or longitudinal axis of the tubular member.

  One skilled in the art will appreciate that each different geometric pattern can have an associated intended use, function, or mechanical requirement for a particular device. Thus, the specific intended use of the device 10 of the present invention is a consideration in selecting a specific geometric pattern of the plurality of micropores 20. For example, if the device 10 of the present invention is intended to be used as a stand-alone implantable intraluminal vascular graft, a large circumferential expansion rate and longitudinal flexibility may be desirable. Thus, a particular geometric shape of the plurality of micropores 20 that provides these characteristics is selected. The plurality of micropores 20 also affects the material properties of the device 10 of the present invention. For example, the geometric shape of each micropore 20 can be changed so that each micropore 20 exhibits a stress strain relaxation capability, or the micropore 20 can have a geometric deformation of the micropore 20. Even plastic, elastic, or superelastic deformations can be controlled. Thus, the geometry of the individual micropores 20, the orientation of the micropores 20 with respect to the XY axis of the device 10, and the pattern of the micropores 20 directly impart the mechanical and material properties of the device 10. It is possible to choose to influence them or control them.

  The plurality of drug release chambers 15 can be located completely within the thickness 18 of the main body member 12, are not completely located within the thickness 18 of the main body member 12, and the first surface of the main body member 12. 14 or the second surface or both, or at least one of the first surface 14 and the second surface 16 and between the first surface 14 and the second surface 16. It can be defined by an encapsulated recess. One of ordinary skill in the art could have the first surface 14 and the second surface 16 be opposing surfaces of a single member, or a plurality disposed adjacent to each other as indicated by the perspective line 37 in FIG. It will be understood that the surface of the member can be the same.

  Suitable pharmacologically active agents include paclitaxel, taxol, rapamycin, rapamycin derivatives (see, for example, Patent Document 11), sirolimus, rapamune, tacrolimus, dexamethasone, everolimus, ABT-578 (rapamycins that inhibit mTOR cell cycle regulatory protein) Things), and growth factors such as VEG-F, but are not limited thereto. The pharmacologically active agent can be loaded into a plurality of drug release chambers 15 by using a pharmacologically acceptable carrier. As used herein, the term “pharmacologically active agent” is used synonymously with “pharmaceutical agent”.

  The pharmacologically active agent can be incorporated into or attached to the device 10 in several ways and using any biocompatible material. The pharmacologically active agent can be incorporated into a polymer or polymer matrix and sprayed onto the device. A mixture of pharmacologically active agent and polymeric material can be prepared with a solvent or solvent mixture and added to the device 10 again by dip coating, brush coating, and / or dip / spin coating, where the components of the solvent are captured. It is possible to evaporate so as to leave a film with the formulated pharmaceutical product. In the case of stents where the drug is delivered from micropores, struts, or channels, a solution of the polymer can be additionally added as an outer layer to control the release of the drug. Alternatively, the active agent can be provided in the micropores, struts, channels, or internal chambers, and the active adjuvant can be incorporated into the external layer, and vice versa. Also, the active agent can be attached at the inner layer of the stent, and the active adjuvant can be attached at the outer layer, and vice versa. The medicament can also be attached to the surface of the stent by a covalent bond, such as an ester, amide, or anhydride, including chemical induction. The pharmaceutical agent can also be incorporated into a biocompatible porous ceramic coating, such as a nanoporous ceramic coating. The medical device of the present invention is configured to release the active adjuvant simultaneously with the release of the active agent or after the release of the active agent.

  Examples of polymeric materials include hydrophilic, hydrophobic, or biocompatible biodegradable materials such as polycarboxylic acids; cellulose polymers; starch, collagen; hyaluronic acid; gelatin; lactone-based polyesters such as polylactide. Or copolyester; polyglycolide; polylactide-glycolide; polycaprolactone; polycaprolactone-glycolide; poly (hydroxybutyrate); poly (hydroxyvalerate); polyhydroxy (butyrate-co-valerate); polyglycolide-co-trimethylene Carbonate; Poly (diaxanone); Polyorthoester; Polyanhydride; Polyamino acid; Polysaccharide; Polyphosphoether; Polyphosphoester-urethane; Polycyanoacrylate; Polyphosphazene; EO-PLLA, poly (ether-ester) copolymers such as fibrin; fibrinogen; or mixtures thereof; and biocompatible non-degrading materials such as polyurethane; polyolefins; polyesters; polyamides; polycaprolactans; polyimides; Methyl ether; polyvinyl alcohol or vinyl alcohol / olefin copolymer such as vinyl alcohol / ethylene copolymer; polyacrylonitrile; polystyrene copolymer of vinyl monomer having olefin such as styrene acrylonitrile copolymer, ethylene methyl methacrylate copolymer; polydimethylcyclohexane; poly (ethylene-vinyl Acetate); polybutyl methacrylate, poly (hydroxyethylmethyl methacrylate) It is or mixtures thereof; cellulose esters such as cellulose acetate, cellulose nitride or cellulose propionate; g) acrylate-based polymer or copolymer, such as; polyvinylpyrrolidinone; polytetrafluoride fluorinated polymers such as ethylene.

  When a polymer matrix is used, this means, for example, a base layer in which the drug is incorporated, such as ethylene-co-vinyl acetate and polybutyl methacrylate, and polybutyl methacrylate where no drug is present and which acts as a diffusion control for the drug It is possible to provide two layers of a top coat such as Alternatively, the active agent can be provided in the base layer, and the active adjuvant can be incorporated in the outer layer, and vice versa.

  The plurality of drug delivery chambers 15 and the associated plurality of micropores 20 are similarly dimensioned to achieve a substantially uniform drug delivery profile from the device 10 and the longitudinal and circumferential axes of the device 10. It is possible to arrange them almost uniformly along both. Alternatively, the drug delivery chamber 15 and the associated plurality of pores 20 are different about the circumferential axis and the longitudinal axis of the device 10 to provide different dose-position relationships or dose-time relationships. It is possible to size and arrange. In addition, at least some of the plurality of micropores 20 may be disposed on either or both of the luminal surface and the anti-luminal surface of the device to release the drug from the outer periphery of the device and / or from the inner periphery of the device 10. It is possible to arrange on top. The release of the concentration of the drug over time can be adjusted by providing the drug with differently sized micropores 20 that allow different release rates, so as to achieve the desired concentration plateau over an extended period of time. It is possible to control.

  Furthermore, conventional polymer-coated drug release stents have a release profile that releases the drug around the entire peripheral axis of the coating, with a significant drop in concentration from the proximal and distal ends of the device. This concentration drop is often associated with end restenosis known in the art as the “candy wrapper effect”. By allowing various variations in the positioning of the drug delivery chamber 15 and associated micropores 20, the directional orientation, position, and concentration of the drug release can be controlled in the device 10 of the present invention.

  An exemplary, non-limiting geometric pattern of the plurality of micropores 20 of FIGS. 1-2 is shown in FIG. 4A. 4A and 4B show an implantable drug delivery device 30 having a longitudinal axis L and a circumferential axis C indicated by directional arrows L and C, respectively, in FIG. 4A. 4B is a transverse cross-sectional view taken along the circumferential axis C of the device 30 shown in FIG. 4A. A plurality of first elongated micropores 32 having a common orientation parallel to the longitudinal axis L of the device 30 are provided and pass through the thickness of the device 30 and its first and / or second surface 31. The circumferentially adjacent pairs of the first elongate micropores 32 are longitudinally displaced so that the end of each elongate micropore 32 is circumferentially adjacent to the intermediate region of the adjacent first elongate micropores 32. Located.

  A plurality of second elongated micropores 34 are provided, have a common orientation parallel to the circumferential axis C of the device 30 and pass through the thickness of the device 30 and its first or second surface 31. A single second elongated microbore 34 is located in the middle of the adjacent pair of first elongated microbore 32, and each end of the second elongate microbore 32 is circumferentially adjacent to the first elongate microbore. Located in the vicinity of the intermediate region of the hole 32.

  Each of the first and second generally elongated micropores 32, 34 preferably has a terminal fillet 35 on each opposing end of each elongated micropore 32, 34. The end fillet 35 performs a strain relief function that assists in the distribution of strain through the intermediate region 22 between adjacent slots 32 and 34.

  Those skilled in the art will appreciate that each of the micropores 20 can have any of a wide range of geometric configurations, dimensions, and surface areas, and the exemplary slot configurations of FIGS. 4A and 4B are illustrative. You will understand that only. Alternative micropore 20 geometries are disclosed (eg, US Pat. Nos. 10,135,316 and 10 / 135,626, both filed on Sep. 26, 2002). (See the specification, Patent Document 13), both of which are named “Implantable Graft and Methods of Making Same”, both of which are from the same applicant as the present application, both of which are a wide range of suitable geometries of the micropores 20. Which is expressly incorporated herein by reference to show the specific shape.

  Providing multiple drug release chambers 36 is particularly important for the present invention. According to one embodiment of the present invention, as shown in FIGS. 4A and 5, the plurality of drug release chambers 36 are completely within the thickness of the device 30, the first surface 31 and the second surface of the device 30. It is possible to be in the middle of 33. Alternatively, as shown in FIGS. 3 and 6, the drug release chamber 36 is located adjacent to the first surface 21 or the second surface 22 of the device 10 and acts as an encapsulating cap for the drug release chamber 36. It can be delimited by a second layer of device material 46. The plurality of openings 20 are preferably in communication with the drug release chamber 36 through the second layer of device material 46 to allow the drug release from the drug release chamber 36. Finally, according to the third embodiment shown in FIG. 7, the drug release chamber can be formed as a recess 56 in the first layer of the device material 52, and then the recess 56 comprises at least one recess The opening 58 is covered by a second layer of device material 54 having a plurality of passing openings 58 patterned to positionally correspond to one of the recesses 56.

  Thus, one embodiment of the present invention is biocompatible and can be geometrically altered by folding and unfolding or by applying plastic, elastic, or superelastic deformation forces, and suitably small delivery New metal and / or pseudo metal implantable implants are provided that can be delivered intraluminally in profile. Suitable metal materials for fabricating the implants of the present invention are selected for biocompatibility, mechanical properties, i.e. tensile strength, yield strength, and ease of fabrication. The bendable nature of the graft material of the present invention can be used to form the graft into complex shapes by deforming the graft of the present invention over a suitably designed mandrel or fixture. It is. Plastic deformation and shape setting thermal treatments can be used to ensure that the implantable member 10 of the present invention retains the desired structure.

  According to a first preferred method of making the implant of the present invention, the drug release device is at least two vacuum deposited metal films and / or pseudo metal films in which a plurality of micropores are formed. Produced. The at least two membranes are combined in such a way as to form an internal chamber pattern in the boundary region between the two membranes. A plurality of discharge openings are then formed through one or both of the at least two membranes and in communication with the interior chamber pattern. Finally, the pharmacologically active agent is loaded through the release opening.

  According to a second preferred method of making a device of the invention, a first layer of device forming material is vacuum deposited, then a pattern of sacrificial material is applied on the surface of the first layer of device forming material, and then A second layer of device forming material is vacuum deposited over the first layer and the sacrificial material. A plurality of fine holes are formed through the first layer and the second layer of the device forming material between the regions where the sacrificial material exists. A plurality of emission openings are then formed through at least one of the first and second layers of device-forming material and in communication with the sacrificial material region. The sacrificial material is then removed through the release opening, such as by chemical etching characteristic of the sacrificial material. The pharmacologically active agent is then loaded through the release opening.

  A method 50 of making the inventive drug delivery device of the present invention is shown in FIG. A first material blank of a conventionally manufactured or vacuum deposited biocompatible or pseudo-metallic material is provided in step 52. If the sacrificial material is used to form the drug release pocket of the device, the sacrificial material is deposited in a pattern corresponding to the location of the drug release pocket on the first material blank in step 56 and then the second material. A blank is provided at step 56 and associated with the first material blank from step 52 at step 58. Methods of depositing material patterns on other material surfaces are well known in the field of semiconductor processing and can be achieved, for example, by photolithography. If the drug release pocket is not formed by using a sacrificial material in step 56, the first material blank from step 52 and the second material blank from step 56 are combined in step 58 without intervening sacrificial material. Is done. The association step 58 can be accomplished in at least one of two ways. First, the first material blank from step 52 juxtaposes the first material blank and the second material blank to create a weld pattern 37 in the bore region 22 that delimits the drug release chamber 36. Can be associated with the second material blank from the step (see, eg, FIGS. 4B and 5). The weld pattern 37 may be formed by spot welding, laser welding, ultrasonic welding, chemical bonding, or other such suitable method of joining two similar or different biocompatible metals or pseudo-metals. Is possible.

  A second method for associating the first material blank from step 52 with the second material blank from step 54 is to vacuum deposit the second material blank over the first material blank. In this second method, it is desirable to use the pattern of sacrificial material from step 56 because the second material blank follows the topography of the first material blank and later the first material blank and the second material blank. Creating a drug release chamber between the adhesion layers of the first material blank and the second material blank without removing a portion of the material blank is not technically feasible under currently known fabrication techniques. It is. In this way, a second material blank from step 54 is formed over the first material blank from step 52 and over the sacrificial material from step 56, following the topography of the first material blank and the sacrificial material. .

  Under a first method of joining an existing first material blank and a second material blank and demarcating the drug release chamber by a weld joint, a plurality of openings in communication with the drug release chamber are formed with the first material blank. After the second material blank has been associated, it can be formed in step 60, or before joining the materials as indicated by the double headed arrows between step 60 and steps 52 and 54, respectively. It can be formed in step 60. Under the second method of vacuum depositing the second material over the first material blank and the sacrificial material in step 54, step 60, i.e., forming the plurality of openings in communication with the drug release chamber, comprises the first material blank and The second material blank needs to be performed after being performed in step 58 so that the deposition of either or both of the first material blank and the second material blank, and the deposition of the sacrificial material is a plurality of openings. Can be done with or without occlusion.

  As a result of the combined step 58 where the plurality of internal chambers are welded together the first material blank and the second material blank, or as a result of removing the sacrificial material through the plurality of openings formed in step 60, Created in step 62. Finally, the pharmacologically active agent can be loaded into the drug release chamber at step 64 as a final step in creating the drug release chamber of the present invention.

  The plurality of micropores in either or both of the first material blank and the second material blank can be formed before or after the materials are combined. If a vacuum deposition process is used in the performance of the method, it is better for those skilled in the art to form a plurality of micropores after the first second material blank and the second material blank are combined in step 58. You will notice. If the first material blank and the second material blank are joined together by welding, those skilled in the art will realize that it is more desirable to form a plurality of micropores prior to joining the first material blank and the second material blank. I will.

  The plurality of micropores can be formed by masking the material blank so that only the regions defining the plurality of micropores are exposed. The exposed areas are then removed by etching, such as a wet or dry chemical etching process where an etchant is selected based on the precursor blank material, or by machining such as laser ablation or EDM. Alternatively, when using vacuum deposition techniques, a pattern mask corresponding to a plurality of micropores is inserted between the object and the source so that the metal or pseudometal forms the patterned micropores. It can be deposited via a pattern mask. Further, when using vacuum deposition, multiple film layers are deposited to form a multilayer structure of the film before or simultaneously with forming the multiple micropores. It is possible. Alternatively, multiple layers of material blanks can be used and combined by welding. However, those skilled in the art have the problem of device profiles because it is difficult to make ultra-thin material blanks of sizes between about 0.1 μm and about 15 μm using conventional frequent vacuum deposition production methods. It will be appreciated that this is likely to be associated with the use of methods in which non-vacuum deposited material blanks are employed.

  Thus, the present invention is biocompatible and compliant and can be geometrically varied by folding and unfolding or by applying plastic, elastic, or superelastic deformation forces, New metal and / or pseudo-metal implantable drug release materials that form a wide range of drug delivery devices that can be delivered intraluminally with a suitably small delivery profile and a suitably low post-delivery profile I will provide a. Metal materials suitable for making the implants of the present invention are selected for biocompatibility, mechanical properties, i.e. tensile strength, yield strength and ease of attachment when vacuum deposition is deployed, and the following titanium, Vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt, palladium, manganese, molybdenum, and zirconium-titanium-tantalum alloys, nitinol, chromium-cobalt alloys, and There are alloys such as, but not limited to, stainless steel. Examples of pseudo-metallic materials potentially useful for the present invention include, for example, composite materials and ceramics.

  The present invention also provides for vacuum deposition of metal or pseudo-metal material blanks and removal of sections of deposited material, such as etching, EDM, ablation, or other similar methods, or during the deposition process. Also provided is a method of making the pharmaceutical delivery material of the present invention by forming a micropore by inserting a pattern mask corresponding to the micropore between the source. Alternatively, existing metal material blanks and / or pseudo-metal material blanks manufactured by conventional non-vacuum deposition methods, such as wrought hypotubes or sheets, can be obtained, and micropores can be etched, EDM, ablated , Or other similar methods, etc., can be formed in existing metal films and / or pseudo-metal films by removing sections of the film. An advantage of using a multilayer structure to form the drug release material of the present invention is that it can provide different functions in discrete layers. For example, a radiopaque material such as tantalum can form one layer of the structure, while the other layer provides an implant having the desired mechanical and structural properties. Selected.

  According to a preferred embodiment of fabricating the microporous metallic implantable drug release device of the present invention in which the device is fabricated from a vacuum deposited Nitinol tube, a cylindrical deoxygenated copper substrate is provided. The substrate is machined and / or electropolished to provide a substantially uniform surface topography that accommodates metal deposition on the substrate. A cylindrical hollow cathode magnetron sputtering device was used, the cathode was on the outer surface, and the substrate was placed along the longitudinal axis of the cathode. A nickel titanium alloy cylindrical object comprising a nickel-titanium alloy having a nickel to titanium atomic ratio of about 50-50% and adjustable by spot welding a nickel or titanium wire to the object, or A nickel cylinder having a plurality of titanium strips spot welded to the inner surface of the nickel cylinder or a titanium cylinder having a plurality of nickel strips spot welded to the inner surface of the titanium cylinder is provided. In the field of sputter deposition, it is known to cool an object in a deposition chamber by maintaining thermal contact between the object and a cooling jacket in the cathode. In accordance with the present invention, it has been found useful to reduce thermal cooling by thermally isolating the object from the cooling jacket within the cathode while providing electrical contact to the object. By isolating the object from the cooling jacket, the object can become hot in the reaction chamber. Two methods were used to thermally isolate the cylindrical object from the cathode cooling jacket. First, a plurality of wires having a diameter of 0.0381 mm were spot welded to the outer periphery of the object to provide an equivalent spacing between the object and the cathode cooling jacket. Second, a tubular ceramic isolation sleeve was inserted between the outer periphery of the object and the cathode cooling jacket. Furthermore, since the Ni—Ti sputtering yield may depend on the temperature of the object, a method that allows the object to be uniformly hot is preferred.

The deposition chamber is evacuated to a pressure of about 2-5 × 10 ⁻⁷ Torr or less, and the substrate is pre-cleaned under vacuum. During deposition, the substrate temperature is preferably maintained within the range of 300 degrees Celsius and 700 degrees Celsius. It is preferred to apply a negative bias voltage to the substrate between 0 and 1000 volts, preferably between -50 and -150 volts, which is sufficient to allow the energy species to reach the surface of the substrate. . During vapor deposition, the gas pressure is maintained between 0.1 Torr and 40 mTorr, but is preferably between 1 mTorr and 20 mTorr. Sputtering is preferably performed in the presence of an argon atmosphere. The argon gas must be high purity and a special pump can be used to reduce the partial pressure of oxygen. The deposition time varies depending on the desired thickness of the deposited tubular film.

  After deposition of the first material, a copper sacrificial layer was vacuum deposited on the first material. A photolithographic mask corresponding to the desired pattern of sacrificial material was applied over the copper sacrificial layer and the entire assembly immersed in nitric acid. Nitric acid specifically etches the undesired layer of the copper sacrificial layer, leaving only the desired sacrificial region corresponding to the drug release chamber. Other modes of ablation techniques such as chemical etching, photoetching, laser etching, or machining techniques such as electrical discharge machining (EDM) can be used to remove unwanted regions of the sacrificial material. is there.

  A second layer of nickel-titanium was vacuum deposited on the first material blank and sacrificial copper following the above procedure. After deposition of the second nickel-titanium layer, a plurality of openings are laser cut through the second layer of nickel-titanium into the sacrificial layer, and the entire assembly then etches the copper sacrificial material through the plurality of openings. Soaked in nitric acid for a period of time sufficient to leave multiple drug release chambers between the first and second layers of nickel-titanium alloy.

  According to the present invention, when using a non-biocompatible sacrificial metal, such as copper or hexavalent chromium, for example, a material deposited between the first material and the sacrificial material, and thus on the patterned sacrificial material and sacrificial material. It has been found desirable to include a diffusion barrier between the second layer. It has been found that certain metals, such as copper, tend to diffuse into the surfaces of the first material blank and the second material blank under vacuum deposition conditions. Since the presence of non-biocompatible metals is undesirable, the insertion of a diffusion barrier that is removable with the sacrificial material acts to prevent metal diffusion and the presence of undesirable metals in the final device. Suitable diffusion barriers can include, for example, titanium nitride, silicon oxide, TiSiN, or tantalum that is itself biocompatible and does not require removal.

  After deposition, a plurality of micropores are formed in the tube by removing regions of the deposited film by etching such as chemical or photoetching, ablation by excimer laser or EDM, and the like. After the formation of multiple micropores, the formed microporous film is removed from the copper substrate by exposing the substrate and film to a nitric acid bath for a period of time sufficient to dissolve and remove the copper substrate. The

  Although the present invention has been described in terms of a preferred embodiment, those skilled in the art will recognize that changes in materials, dimensions, geometries, and fabrication methods are or may be known in the art, and It will be understood and appreciated that it remains within the scope of the invention which is limited only by the scope.

1 is a perspective view of a pharmaceutical release implant of the present invention. FIG. FIG. 2 is a fragmentary cross-sectional view taken along line 2-2 of FIG. FIG. 3 is a fragmentary plan view of an embodiment of a pharmaceutical release implant of the present invention showing the pattern of chambers and openings in the implant. FIG. 6 is a fragmentary plan view of an alternative embodiment of the pharmaceutical release implant of the present invention showing the pattern of chambers and openings in the implant. FIG. 4B is a cross-sectional view taken along line 4B-4B of FIG. 4A. FIG. 5 is a fragmentary cross-sectional view taken along line 5-5 of FIG. 4A. FIG. 6 is a fragmentary cross-sectional view taken along line 6-6 of FIG. FIG. 6 is a fragmentary cross-sectional view of an alternative embodiment of the present invention. 2 is a process flow diagram illustrating a method of making an implantable drug release medical device of the present invention.

Claims (33)

a. A body member comprising a material selected from the group consisting of a metallic material and a pseudo-metallic material and having a first surface, a second surface, and a thickness intermediate between the first surface and the second surface;
b. A plurality of enclosures disposed completely within the thickness of the body member;
c. At least one opening passing through at least one of the first surface and the second surface and communicating with one of the plurality of enclosure chambers;
d. A drug-releasing medical device, comprising: at least one pharmacologically active agent disposed inside the plurality of enclosure chambers and releasable through the at least one opening.   The medical device according to claim 1, wherein the main body member further includes a thin metallic film.   The material of the main body member is titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt, palladium, manganese, molybdenum, and alloys thereof, cobalt chromium 2. The drug release medical device according to claim 1, wherein the device is made of a metal material selected from the group consisting of an alloy, stainless steel, and nickel titanium alloy.   The drug release medical device according to claim 1, further comprising a biocompatible polymer covering the at least one opening of a plurality of openings.   The apparatus of claim 1, further comprising a plurality of openings patterned in the body member for directional release of the at least one pharmacologically active agent from a proximal end and a distal end of the body member. 2. A medical release medical device according to 2.   The plurality of openings around the at least one of the longitudinal axis and the circumferential axis of the device, such that the plurality of openings provide different drug releases along at least one of the longitudinal axis and the circumferential axis of the body member. The medical-release medical device according to claim 1, wherein the medical-release medical device is disposed on the medical device.   7. The drug release medical device of claim 6, wherein the plurality of openings have different opening sizes sufficient to provide different drug release rates.   The body member further comprises a tubular member, the first surface further comprises a luminal surface of the tubular member, and the second surface further comprises an anti-lumen surface of the tubular member. 2. The medical device for medical drug release according to 1.   The medical release medical device according to claim 8, wherein the at least one opening of a plurality of openings passes through at least one of the luminal surface and the anti-lumen side surface of the tubular member.   The medical device according to claim 1, wherein the plurality of enclosing chambers are distributed substantially uniformly around a circumferential axis and a longitudinal axis of the tubular member.   11. The drug release medical device according to claim 10, wherein the at least one opening communicates with at least one of the anti-luminal surface and the luminal surface of the tubular member.   The drug release medical device according to claim 1, further comprising a polymer carrier of the at least one pharmacologically active agent.   The pharmaceutical release medical device of claim 1, further comprising a polymeric material that at least partially occludes the at least one opening.   Stents, coated stents, vascular grafts, cardiovascular patches, soft tissue patches, surgical membranes, vascular plugs, embolic protection devices, heart valves, venous valves, angioplasty balloons, orthopedic implants, dental implants, plastic reconstruction The drug release medical device according to claim 1, wherein the device is selected from the group consisting of an implant, a penile implant, an intrauterine device, and a subcutaneous implant.   The body member further comprises at least two material layers, a first layer forming the first surface and a second layer forming the second surface, the at least two material layers being associated with each other at an interval. The medical device according to claim 1, wherein the plurality of enclosing chambers are formed between the associated regions of the at least two material layers.   The plurality of containment chambers have at least a lateral surface and a top or bottom surface of each containment chamber by a recess in the first layer of material and a second layer of material associated over the first material layer. 16. The pharmaceutical release medical device according to claim 15, defined on one side, thereby enclosing each of the plurality of enclosure chambers. a. A body member comprising at least two material layers, a first layer forming a first surface of the body member and a second layer forming a second surface, wherein the at least two material layers have a thickness of the body member. The body members associated with each other at an interval so as to form a plurality of containment chambers disposed completely within
b. At least one opening passing through at least one of the first surface and the second surface and communicating with at least one of the plurality of enclosure chambers;
c. A drug-releasing medical device, comprising: at least one pharmacologically active agent disposed inside the plurality of enclosure chambers and releasable through the at least one opening.   18. The pharmaceutical release medical device according to claim 17, wherein the at least two material layers consist essentially of a material selected from the group consisting of a biocompatible metal and a biocompatible pseudometal.   The biocompatible metal is titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt, palladium, manganese, molybdenum, and alloys thereof, cobalt chromium alloy 19. The pharmaceutical release medical device according to claim 18, further comprising a metallic material selected from the group consisting of stainless steel, and nickel titanium alloy.   The drug release medical device according to claim 17, further comprising a polymer material covering at least one of the first and second surfaces of the body member.   18. The pharmaceutical release medical device according to claim 17, further comprising a polymer material disposed in at least some of the plurality of enclosures together with the pharmacologically active agent. A method of making a drug release device comprising:
a. Providing a first layer and a second layer of biocompatible material;
b. Associating the first layer and the second layer to define a plurality of internal chambers intermediate the first layer and the second layer;
c. Providing at least one opening that passes through at least one of the first layer and the second layer and communicates with at least one of the plurality of internal chambers;
d. Loading at least one pharmacologically active agent into at least one of the plurality of internal chambers in sufficient form to be eluteable through the at least one opening.   23. The method of claim 22, wherein step (a) further comprises forming the first layer and the second layer of biocompatible material by a vacuum deposition process.   The first and second layers of biocompatible material are titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt, palladium, manganese, 24. A metal or pseudometal selected from the group consisting of molybdenum and its alloys, cobalt chromium alloys, stainless steel, and nickel titanium alloys, ceramics, biocompatible polymers, and carbon fiber matrices. The method described in 1.   The plurality of internal chambers are partially defined in the first layer of vacuum deposition material, and the second layer of vacuum deposition material is associated with the first layer of vacuum deposition material. The method of claim 22.   23. The method of claim 22, further comprising providing a sacrificial material between the first layer and the second layer of biocompatible material.   27. The method of claim 26, further comprising patterning a vacuum deposited sacrificial material prior to depositing the second layer of biocompatible material thereon.   The method further comprises adding a diffusion barrier between the first layer of biocompatible material and patterning the sacrificial material prior to depositing the second layer of biocompatible material thereon. 26. The method according to 26.   30. The method of claim 28, further comprising adding a diffusion barrier between the sacrificial material and the second layer of biocompatible material.   Removing the sacrificial material through the at least one opening passing through at least one of the first layer and the second layer and communicating with at least one of the plurality of internal chambers of biocompatible material. 27. A method according to claim 26.   The method further comprises removing the sacrificial material through the at least one opening that passes through at least one of the first layer and the second layer and communicates with at least one of the plurality of internal chambers. 30. The method of claim 29.   The method further comprises removing the diffusion barrier through the at least one opening that passes through at least one of the first layer and the second layer and communicates with at least one of the plurality of internal chambers. The method of claim 30.   32. The method of claim 31, wherein the step of removing the diffusion barrier further comprises etching the diffusion barrier.

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