WO2002026162A2 - A method of loading a substance onto an implantable device - Google Patents

A method of loading a substance onto an implantable device Download PDF

Info

Publication number
WO2002026162A2
WO2002026162A2 PCT/US2001/027627 US0127627W WO0226162A2 WO 2002026162 A2 WO2002026162 A2 WO 2002026162A2 US 0127627 W US0127627 W US 0127627W WO 0226162 A2 WO0226162 A2 WO 0226162A2
Authority
WO
WIPO (PCT)
Prior art keywords
particles
implantable device
method
outer surface
onto
Prior art date
Application number
PCT/US2001/027627
Other languages
French (fr)
Other versions
WO2002026162A3 (en
Inventor
Sameer Harish
Steven Z. Wu
Original Assignee
Advanced Cardiovascular Systems, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US67175900A priority Critical
Priority to US09/671,759 priority
Application filed by Advanced Cardiovascular Systems, Inc. filed Critical Advanced Cardiovascular Systems, Inc.
Publication of WO2002026162A2 publication Critical patent/WO2002026162A2/en
Publication of WO2002026162A3 publication Critical patent/WO2002026162A3/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08Materials for coatings
    • A61L31/10Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05DPROCESSES FOR APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D1/00Processes for applying liquids or other fluent materials
    • B05D1/02Processes for applying liquids or other fluent materials performed by spraying
    • B05D1/12Applying particulate materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A61F2002/91533Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other characterised by the phase between adjacent bands
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067Means for introducing or releasing pharmaceutical products into the body
    • A61F2250/0068Means for introducing or releasing pharmaceutical products into the body the pharmaceutical product being in a reservoir
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2420/00Materials or methods for coatings medical devices
    • A61L2420/02Methods for coating medical devices
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05DPROCESSES FOR APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D1/00Processes for applying liquids or other fluent materials
    • B05D1/002Processes for applying liquids or other fluent materials the substrate being rotated
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05DPROCESSES FOR APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D2401/00Form of the coating product, e.g. solution, water dispersion, powders or the like
    • B05D2401/30Form of the coating product, e.g. solution, water dispersion, powders or the like the coating being applied in other forms than involving eliminable solvent, diluent or dispersant
    • B05D2401/32Form of the coating product, e.g. solution, water dispersion, powders or the like the coating being applied in other forms than involving eliminable solvent, diluent or dispersant applied as powders
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05DPROCESSES FOR APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D2451/00Type of carrier, type of coating (Multilayers)
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05DPROCESSES FOR APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D7/00Processes, other than flocking, specially adapted for applying liquids or other fluent materials to particular surfaces or for applying particular liquids or other fluent materials
    • B05D7/50Multilayers
    • B05D7/52Two layers

Abstract

Methods of loading a substance onto an implantable device are disclosed. The implantable device may be a stent or a graft, with or without depots formed within an outer surface thereof. An exemplary method includes the act of projecting particles of the substance from a pressurized particle source onto a preselected region of the implantable device. An implantable device loaded with a substance in accordance with the method is also provided. The projected particles may be made of any substance or substances suitable for loading onto an implantable device in solid form including, but not limited to, therapeutic substances or agents, radioisotopes, radiopaque substances, polymers, proteins, and nucleic acids. Also provided is a method of loading a substance onto a stent having an outer surface with a plurality of depots formed therein. The method includes the act of projecting particles including the substance from a pressurized particle source onto the outer surface of the stent, wherein the particles are loaded into the plurality of depots. A stent loaded with a substance in accordance with the method is also provided.

Description

A METHOD OF LOADING A SUBSTANCE ONTO AN IMPLANTABLE DEVICE

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates generally to implantable devices, examples of which include stents and grafts. More particularly, the present invention is directed to a method of loading an implantable device with one or more substances.

Description of the Related Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress the atherosclerotic plaque of the lesion against the inner wall of the artery to dilate the lumen. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the vessel after the balloon is deflated. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, an implantable device, examples of which include stents and grafts, may be implanted.

Stents are scaffoldings, usually cylindrical or tubular in shape, which function to physically hold open and, if desired, to expand the wall of the vessel. Typically stents are capable of being compressed, so that they may be inserted through small cavities via catheters, and then expanded to a larger diameter once they are at the desired location. Examples in patent literature disclosing stents include U.S. Patent No. 4,733,665 issued to Palmaz, U.S. Patent No. 4,800,882 issued to Gianturco, and U.S. Patent No. 4,886,062 issued to Wiktor.

Synthetic vascular grafts are vessel-like configurations that may be positioned into the host blood vessel as a replacement for a diseased or occluded segment that has been removed. Alternatively, a graft may be sutured to the host vessel at each end so as to form a bypass conduit around a diseased or occluded segment of the host vessel.

Although stents and grafts are significant innovations in the treatment of occluded vessels, there remains a need for administering therapeutic substances to the treatment site. Systemic administration of the therapeutic substance often produces adverse or toxic side effects for the patient. Local delivery of therapeutic substances, by contrast, provides a smaller overall dosage that is concentrated at a specific site. Local delivery can produce fewer side effects and achieve more effective results in many cases.

One technique for the local delivery of therapeutic substances is through the use of medicated coatings on implantable devices. A common method for medicating an implantable device involves the use of a polymeric carrier coated onto the surface of the implantable device. A composition is formed by dissolving a therapeutic substance in a solution containing a polymer and a solvent. The composition is applied to the implantable device using conventional techniques, such as spray-coating or dip-coating. The solvent is then removed, leaving on the implantable device surface a coating of the polymer and the therapeutic substance impregnated in the polymer.

A shortcoming of the above-described method is the burst effect, in which an initial rapid release of therapeutic substance upon implantation of the implantable device is followed by a slower, sustained release of therapeutic substance. A higher concentration of therapeutic substance exists at the drying surface, or polymer-air interface, since the therapeutic substance concentrates where the solvent was at the end of the drying process.

Another shortcoming of the above-described method for medicating an implantable device results from the requirement that the therapeutic substance be dissolved in the solvent or solvent-polymer solution. The amount of therapeutic substance that may be loaded onto the implantable device is limited by the solubility of the therapeutic substance in the solvent or solvent-polymer solution.

Another shortcoming of the above-described method for medicating an implantable device is incompatibility with some therapeutic substances. For example, some therapeutic substances are delicate and cannot tolerate processing in the presence of a solvent and/or a polymer for extended periods of time. This is especially true for peptide-type therapeutic substances, which have tertiary structures susceptible to transmutation.

SUMMARY OF THE INVENTION

The present invention provides a method by which implantable devices, such as stents and grafts, may be loaded with therapeutic substances, among other possibilities, such that the burst effect and the transmutation of delicate therapeutic substances are minimized while loading of the substances is maximized.

An exemplary method within the present invention includes the act of projecting a dry stream of particles including a therapeutic substance from a pressurized particle source onto a preselected region of the implantable device.

In some embodiments, the therapeutic substance is selected from antineoplastic, antimitotic, antiinflammatory, antiplatelet, anticoagulant, antifϊbrin, antithrombin, antiproliferative, antibiotic, antioxidant, and antiallergic substances and combinations thereof. In other embodiments, the substance is a radioactive isotope or a radiopaque substance. In still other embodiments, the substance is a bioabsorbable polymer, abiomolecule, or a biostable polymer.

The preselected region upon which the particles are projected may include the entire outer surface or a portion of the implantable device, such as a portion in a middle section of the implantable device or a portion adjacent an end of the implantable device.

In some embodiments, the outer surface of the implantable device includes a plurality of depots formed therein. In such embodiments, particles may be projected onto a portion of the outer surface and within the depots. The method may additionally include the act of removing the particles from the outer surface such that the particles remain within the depots.

Another exemplary method within the present invention includes the act of applying a polymeric primer to the implantable device prior to the act of projecting particles. In addition, the method may include the act of applying a polymeric topcoat to the implantable device subsequent to the act of projecting particles.

These and other aspects of the present invention may be better appreciated in view of the detailed description and drawings of the exemplary embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 A is a perspective view of an implantable device with a central hollow bore.

Figure IB is a cross-sectional side view of the implantable device of Figure 1 A taken along line IB- IB of Figure 1A.

Figure 1C is a side view of the implantable device of Figure IB taken along line 1C-1C of Figure IB.

Figure 2A is a side view of an exemplary stent formed of thread elements engaged to one another by connecting elements.

Figure 2B is an enlarged view of section 2B of the stent of Figure 2A, wherein the thread elements and connecting elements have depots formed therein.

Figure 2C is a cross-sectional view of a depot of the stent of Figure 2B taken along line 2C-2C of Figure 2B.

Figure 3 illustrates a particle that includes a therapeutic substance.

Figure 4 illustrates a method of projecting particles like that of Figure 3 onto the implantable device of Figure 1 A in accordance with one embodiment of the present invention.

Figure 5 A illustrates the implantable device of Figure 1C onto which a primer layer has been applied prior to the loading of particles thereon by the method of Figure 4. Figure 5B illustrates the primered implantable device of Figure 5A, wherein the particles of Figure 3 have adhered to the primer layer.

Figure 5C illustrates the primered implantable device of Figure 5 A, wherein the particles of Figure 3 have been embedded in the primer layer.

Figures 6 A, 6B, and 6C illustrate various patterns in which the particles of Figure 3 may be loaded onto the outer surface of the implantable device of Figure 1A.

Figure 7A illustrates the stent of Figure 2C, wherein the particles of Figure 3 have been loaded onto the outer surface and within the depot.

Figure 7B illustrates the stent of Figure 7 A after surplus particles have been removed from areas other than within the depot.

Figure 8 illustrates the stent of Figure 2C, wherein the particles of Figure 3 have been loaded onto the primered outer surface and within the primered depot.

Figure 9 A illustrates the implantable device of Figure 5B after a topcoat has been applied over the particles.

Figure 9B illustrates the implantable device of Figure 7B after a topcoat has been applied over the particles within the depot.

Figure 9C illustrates the implantable device of Figure 7B after a topcoat has been applied along the outer surface and over the particles within the depot.

Figure 9D illustrates the implantable device of Figure 8 after a topcoat has been applied over the particles within the depot and over the particles along the outer surface.

DETAILED DESCRIPTION

The present invention provides methods of loading a substance onto an implantable device, i.e., a device that is designed to be implanted in a human or animal body. The substance so applied may include any therapeutic substance compatible with the loading methods described below, which involve the projection of a dry stream of particles from a pressurized source onto the surface of the implantable device.

The implantable device may have surface features or treatments that facilitate the loading of the substance onto the implantable device. The present invention provides both effective and economical means for preparing implantable devices that have the capability of delivering therapeutic substances, including substances that are incompatible with conventional methods of loading implantable devices.

Implantable Device

The implantable device used in conjunction with the present invention may be any implantable device, examples of which include self-expandable stents, balloon-expandable stents, and grafts, among other possibilities. The implantable device can be made of a metallic material or an alloy such as, but not limited to, stainless steel, "MP35N," "MP20N," ELASTLNITE (Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof. "MP35N" and "MP20N" are trade names for alloys of cobalt, nickel, chromium and molybdenum available from standard Press Steel Co., Jenkintown, PA. "MP35N" consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. "MP20N" consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. The implantable device may also be made from bioabsorbable or biostable polymers. A polymeric implantable device should be chemically compatible with any substance to be loaded onto the implantable device.

Figures 1A, IB, and 1C provide views of an exemplary implantable device 10, e.g., a stent or graft. Implantable device 10 is a generally tubular structure that includes a body 12 having a first end 14 and an opposing second end 16, A central hollow bore 18 extends longitudinally through body 12 from first end 14 to second end 16, giving body 12 a thickness t! between an outer surface 20 and an inner surface 22. Implantable device 10 can have any suitable length 1]. The values of length li and thickness ti depend, for example, on the procedure for which implantable device 10 is used. The surface properties of implantable device 10 may vary according to the desired use of implantable device 10. In some embodiments, inner surface 22 and/or outer surface 20 of implantable device 10 is polished via conventional electropolishing techniques, the use of abrasive slurries, or other polishing methods known to those of ordinary skill in the art. In other embodiments, portions of outer surface 20 are roughened via the creation of asperities while inner surface 22 remains smooth. Asperities can be created by projecting a stream of pressurized grit onto outer surface 20. Asperities can also be formed by removing material from outer surface 20, for example, by chemical etching with or without a patterned mask. Alternatively, asperities can be formed by adding material to outer surface 20, for example, by welding powder to outer surface 20 or by sputtering onto outer surface 20.

Figure 2 A is a side view of implantable device 10. In Figure 2 A, body 12 of implantable device 10 is formed from thread elements 24 engaged to one another by connecting elements 26. However, the underlying structure of implantable device 10 can be of virtually any design.

Figure 2B illustrates the portion of implantable device 10 shown in circle 2B of Figure 2A. Figure 2B shows that thread elements 24 and connecting elements 26 have a plurality of depots 28 formed in outer surface 20. Depots 28, which may also be referred to as pores or cavities, can be formed in virtually any implantable device 10 structure at any preselected location within implantable device 10. The location of depots 28 within implantable device 10 varies according to intended usage and application. Depots 28 may be formed on implantable device 10 by exposing outer surface 20 to an energy discharge from a laser, such as an excimer laser. Alternative methods of forming such depots 28 include, but are not limited to, physical and chemical etching techniques. Such techniques are well-known to one of ordinary skill in the art.

Figure 2C is a cross-sectional view of a single depot 28 of Figure 2B Depot 28 may have any preselected depth d, width w, and geometrical configuration. Depth d and width w of depot 28 typically depend on the material and dimensions of implantable device 10 and the type and amount of substances deposited within depot 28 as well as on the clinical purpose and usage of implantable device 10. Depth d and width w of the individual depots 28 formed on a single implantable device 10 can vary relative to one another. Depot 28 may be formed in a variety of selected geometrical shapes including, but not limited to, generally cylindrical shapes, generally conical shapes, generally round shapes, elongated trenches, and irregular shapes. As discussed further below, particles may be deposited into depots 28 and/or along outer surface 20 of implantable device 10.

Substances Applied to the Implantable Device

In accordance with the present invention, particles are projected onto an implantable device, e.g., implantable device 10 of Figures 1A-1C and 2A-2C. The particles may be made of any substance suitable for loading onto implantable device 10 in solid form. Such substances include, but are not limited to, therapeutic substances or agents, radioisotopes, radiopaque substances, polymers, proteins, and nucleic acids.

In addition, a single particle maybe made of more than one substance, e.g., a therapeutic substance and a carrier substance. For example, a single particle may include a mixture of at least two different substances. In another embodiment, a single particle includes a first substance and a second substance that covers at least a portion of the first substance so that there may be a timed release of the first substance. In such embodiments, the number, type, and ratio of substances within the particle are treatment-specific. However, the substances within a single particle should be mutually compatible, such that the characteristics, effectiveness, and physical structure of the substances are not adversely altered.

An exemplary particle 30 is illustrated in Figure 3. Typically, particle 30 is rounded or spherical in shape as depicted in Figure 3. .However, particle 30 may be of any shape as long as particle 30 is otherwise suitable for use with the present invention.

The size of particle 30 is dependent, in part, on the size of the particular region of implantable device 10 upon which loading of particles 30 is desired. In embodiments in which outer surface 20, in part or in entirety, is to be loaded with particles 30, the diameter dp of particles 30 can range from about 5 microns to about 20 microns, or more particularly from about 5 microns to about 10 microns. In embodiments in which depot 28 within outer surface 20 is to be loaded with particles 30, however, particles 30 should be no larger than depot 28 itself. More particularly, particles 30 should have a size that not more than about 25% of the size of depot 28.

Particles 30 of suitable size may be made using various conventional techniques known to those of ordinary skill in the art including, but not limited to, micronizing bulk materials. Alternatively, suitable particles 30 of a particular substance maybe obtained from a commercial supplier of that substance and used in the present invention with or without modification. Particles 30, particularly when obtained from a commercial supplier, may include extraneous materials, e.g., fillers such as cellulose, in addition to the substance desired to be loaded onto implantable device 10. Such materials should be biocompatible as well as compatible with the substance to be loaded onto implantable device 10, such that the characteristics, effectiveness, and physical structure of the substance is not adversely altered.

While particles 30 themselves are projected in dry, solid form onto implantable device 10, as will be described below, particles 30 may contain trace amounts of a liquid, such as a solvent used during manufacturing or processing of particles 30. In addition, particles 30 may contain some amount of .water, particularly if particle 30 is made of a hygroscopic substance, since such substances absorb moisture from the air.

Therapeutic substances that may be used with the present invention include, but are not limited to, antineoplastic, antimitotic, antiirm'ammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antiproliferative, antibiotic, antioxidant, antiallergic, antiangiogenic, and angiogenic substances as well as combinations thereof. Examples of such antineoplastics and/or antimitotics include paclitaxel (e.g., TAXOL by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g., TAXOTERE from Aventis S.A., Frankfurt, Germany) methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., ADRIAMYCIN from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g., MUTAMYCIN from Bristol-Myers Squibb Co., Stamford, Conn.) Examples of such suitable antiinflammatories include glucocorticoids such as dexamethasone, methylprednisolone, hydrocortisone and betamethasone, superpotent glucocorticoids such as clobustasol, halobetasol, and diflucortolone, and non-steroidal antiinflammatories such as aspirin, indomethacin and ibuprofen. Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein πb/lTla platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as ANGIOMAX (Biogen, Inc., Cambridge, Mass.) Examples of such cytostatic or antiproliferative agents include actinomycin D as well as derivatives and analogs thereof (manufactured by Sigma- Aldrich, Milwaukee, WI; or COSMEGEN available from Merck & Co., Inc., Whitehouse Station, NJ), angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g., CAPOTEN and CAPOZIDE from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g., PP NIVIL and PRINZIDE from Merck & Co., Inc., Whitehouse Station, NJ); calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name MENACOR from Merck & Co., Inc., Whitehouse Station, ΝJ), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Examples of antiangio genie agents include thalidomide and angiostatin. Examples of angiogenic agents include vascular endothelial cell growth factor (NEGF) and fibroblast growth factor (FGF). Examples of arteriogenic agents include histimine, MCP-1, lipo-polysaccharide, and β-FGF. Other therapeutic substances or agents that may be used include alpha-interferon, genetically engineered epithelial cells, and dexamethasone. While the preventative and treatment properties of the foregoing therapeutic substances or agents are well-known to those having ordinary skill in the art, the substances or agents are provided by way of example and are not meant to be limiting. Other therapeutic substances are equally applicable for use with the disclosed methods and compositions.

In other embodiments, the particles may be made of a radioactive isotope or a radiopaque substance. Such substances help to facilitate implantable device usage in radiotherapeutic procedures. Examples of radioactive isotopes include, but are not limited to, phosphoric acid (H3P32O ), palladium (Pd103), cesium (Cs131), and iodine (I125). An example of a radiopaque substance is gold.

In still other embodiments, the particles may be made of a polymeric material. Suitable polymeric materials include, but are not limited to, bioabsorbable polymers, biomolecules, and biostable polymers. Bioabsorbable polymers are gradually absorbed or eliminated by the body by hydrolysis, metabolic process, bulk, or surface erosion and thus are not present sufficiently long after delivery to cause an adverse local response. Examples of bioabsorbable materials include, but are not limited to, polycaprolactone (PCL), poly-D, L-lactic acid (DL-PLA), poly-L- lactic acid (L-PLA), poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate- co-valerate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycoiic acid- cotrimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly (amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters), polyalkylene oxalates, polyphosphazenes, polyiminocarbonates, and aliphatic polycarbonates. Biomolecules such as heparin, fibrin, fibrinogen, cellulose, starch, and collagen are typically also suitable. A biostable polymer does not break down in the body, and thus a biostable polymer is present in the body for a substantial amount of time after delivery unless some modification is made to allow the polymer to break down. Examples of biostable polymers include, but are not limited to, PARYLENE, PARYLAST, polyurethane (for example, segmented polyurethanes such as BIOSPAN), polyethylene, polyethlyene teraphthalate, ethylene vinyl acetate, silicone, and polyethylene oxide.

In other embodiments, particles 30 may include nucleic acids or proteins. Examples of such nucleic acids include phosphorodiamidate morpholino oligomers (PMO), cyclic-3'-5'- adenosine monophosphate (8-Cl-cAMP), Antisense oligonucleotides, and various nucleic acids encoding for growth factors such as vascular endothelial cell growth factor (VEGF). Examples of proteins include growth factors such as VEGF.

Loading Particles onto an Implantable Device

Prior to projecting particles 30 onto implantable device 10, implantable device 10 should be clean and free from contaminants that may be introduced during manufacturing. Implantable device 10 may optionally be subjected to physical treatments, such as, but not limited to, the creation of depots 28 within outer surface 20 or the polishing of inner surface 22 and/or outer surface 20, as described above.

In embodiments in which inner surface 22 of implantable device 10 has been polished smooth, particular care should be taken to protect inner surface 22 during projection of particles 30 onto outer surface 20. For example, a mandrel or a hypo tube may be inserted within hollow bore 18 of implantable device 10, such that inner surface 22 is shielded from projected particles 30. Alternatively, a balloon may be inserted into hollow bore 18 of implantable device 10 and inflated to prevent particles 30 from striking inner surface 22. Inner surface 22 can also be masked with a temporary protective coating that is removed after particles 30 have been projected onto outer surface 20 of implantable device 10. By example and not limitation, polyvinyl alcohol (PVA) can be dissolved in water having a temperature of 100°C to form an 80% PVA solution by weight. The PNA solution is applied to inner surface 22 and allowed to dry. After particles 30 have been projected onto outer surface 20, the temporary PVA coating can be removed from inner surface 22 by soaking the coated stent in water.

In Figure 4, implantable device 10 is shown mounted upon a rotatable mandrel 32. Mandrel 32 moves implantable device 10 in a rotational direction 34 while particles 30 are projected at outer surface 20 from a pressurized particle source 36 at an angle θ to a vertical axis y of implantable device 10 and from a distance dpS0s between particle source 36 and outer surface 20. Particle source 36 is passed along the y axis over outer surface 20 of implantable device 10 as particles 30 are projected at implantable device 10. By way of example-and not limitation, pressures from about 10 to about 60 PSI (from about 69 to about 410 kPa) can be used to project particles 30 at the angle θ of 30-90° to vertical axis y and from the distance dps0s of approximately 3-10 cm from outer surface 20 of implantable device 10 for approximately 1-3 seconds.

The pressure with which particles 30 are projected from particle source 36 depends, in part, on the size of particles 30 to be projected. Larger particles 30, e.g., 10-20 microns, are typically projected using lower pressures, e.g., 30-60 PSI (210-410 kPa), while smaller particles 30, e.g., 5-10 microns, are typically projected using higher pressures, e.g., 60-90 PSI (410-620 kPa). Regardless of the size of projected particles 30, the pressure at which particles 30 are projected should not be so high as to cause removal of polish or roughening of outer surface 20.

The angle θ to vertical axis y of implantable device 10 is dependent upon the distance pSos between particle source 36 and outer surface 20; the greater the distance dpSos, the smaller the angle θ employed. The angle θ is typically in the range from about 30° to about 90°, or more particularly in the range from about 35° to about 45°.

A stream of particles 30 is projected onto outer surface 20 of implantable device 10 in this embodiment. Individual particles 30 within the stream may or may not be of uniform size and shape. Further, individual particles 30 within the stream may or may not be of uniform composition, since individual particles 30 within a stream maybe made of the same substance(s) or of different substances. In some embodiments, mandrel 32 is capable of motion along the x, y, and z axes as well as in the rotational direction 34. Similarly, particle source 36 may be capable of motion along the x, y, and z axes as well as of rotation about implantable device 10, with or without a mandrel inserted therein, in the direction 34.

The method of projecting particles as depicted in Figure 4 and described above may be used to load particles onto a preselected region of implantable device 10 as discussed below.

a. Loading Particles on the Outer Surface of the Implantable Device

In some embodiments, it is desired to load particles 30 along outer surface 20 of implantable device 10. In such embodiments, a polymeric primer 38, maybe applied to outer surface 20 of implantable -device 10 prior to the projection of particles 30 onto outer surface 20, as depicted in Figure 5A. Primer 38 facilitates retention of particles 30 on outer surface 20. As shown in Figure 5B, particles 30 may adhere to the polymeric material of primer 38 upon impact. Alternatively, particles 30 may become completely or partially embedded in primer 38, as depicted in Figure 5C.

The primer 38 should be biocompatible, including polymers that are non-toxic, noninflammatory, chemically inert, and substantially non-immunogenic in the applied amounts. Examples of suitable polymers were listed above with reference to polymers of which particle 30 may be made, and such examples are equally applicable here.

Polymeric primer 38 may itself include a therapeutic substance, which may be delivered in combination with the therapeutic substance of particle 30.

Polymeric primer 38 can be applied onto outer surface 20 of implantable device 10 by any conventional method, such as by spraying the polymeric material onto implantable device 10 or immersing implantable device 10 in the polymeric material. Variations of spray and immersion techniques are also suitable methods of applying primer 38 to implantable device 10. In one such variation, primer 38 may be applied by spraying or immersing implantable device 10 as described above. The polymer-coated implantable device 10 is then centrifuged. The rotation of implantable device 10 creates a centrifugal force upon the polymeric material applied to implantable device 10. This centrifugal force causes excess accumulations of the polymer to be more evenly redistributed over implantable device 10 and thus provides a more even, uniform primer 38 on implantable device 10. The rotational speed during centrifugation can be varied. Higher RPM values may provide improved uniformity and a reduction in defects. However, lower RPM values improve the total loading of the polymeric material onto implantable device 10. Increasing the total centrifugation time may also improve the uniformity and reduce defects in the primer 38 on implantable device 10.

By way of example, and not limitation, the polymeric primer 38 can have a thickness t2 of about 0.5 microns to about 2.0 microns. The particular thickness t2 is dependent on the desired use of primer 38 and the type of procedure for which implantable device 10 is employed.

The primer 38 may be dried prior to the projection of particles 30 onto the primer 38. Such drying may be accomplished using conventional methods known to one of ordinary skill in the art using techniques such as, but not limited to, evaporation at ambient pressure and room temperature in an anhydrous atmosphere for up to 48 hours, or exposure to mild heat, e.g., 60- 65°C, with or without vacuum.

Once primer 38 has been applied, and optionally dried, particles 30 may be loaded onto the primer-coated outer surface 20. In some embodiments, outer surface 20 of implantable device 10 is completely loaded with particles 30, as depicted in Figure 6 A. In such embodiments, the above-described process of projecting particles 30 upon outer surface 20 from particle source 36, as depicted in Figure 4, may be performed in multiple cycles, with implantable device 10 being rotated in rotational direction 34 between cycles. By way of example and not limitation, a first cycle may be performed in which particle source 36 is passed along the y axis over outer surface 20 at a pressure of about 10 PSI (69 kPa) from distance dps0s of 10 cm for approximately 3 seconds. Implantable device 10 is then rotated 120° in rotational direction 34, and the process is repeated for two more cycles, in between which implantable device 10 is again rotated 120° in rotational direction 34, thereby loading the entire outer surface 20 with particles 30 as depicted in Figure 6A.

It is important to note that the entire outer surface 20 need not be loaded with particles 30. For example, particles 30 may be projected solely at a middle region 40 of the primered implantable device 10, such that particles 30 are loaded only in middle region 40 of outer surface 20 and are not loaded near to opposing ends 14 and 16 of outer surface 20 as shown in Figure 6B. Alternatively, as shown in Figure 6C, particles 30 may be projected at one or both ends 14 and 16 of outer surface 20 to load particles 30 at one or both ends 14 and 16 of the primered implantable device 10.

b. Loading Particles into Depots Formed in the Outer Surface of the Implantable Device

As mentioned above, some implantable devices may have depots formed in a surface thereof, e.g., Figures 2B and 2C. In such embodiments, it may be desired to load particles 30 solely within the depots 28 of outer surface 20 of implantable device 10. Other than cleaning, implantable device 10 typically requires ho particular surface treatment to retain particles 30 within depots 28.

The number of particles 30 loaded into depots 28 may be controlled by controlling parameters such as, but not limited to, the pressure with which particles 30 are projected from particle source 36, the angle θ of particle source 36 relative to depot 28, the distance dpsos between particle source 36 and depot 28, the ratio of therapeutic substance to filler within particles 30, and the actual size of particles 30. The number of particles 30 that will fit into any given depot 28 is primarily a function of the size of particles 30. Generally, larger particles 30 do not pack together within a defined space as easily as smaller particles 30 do. As the size of particles 30 increases, more empty spaces are created within depot 28 in between particles 30. By contrast, smaller particles 30 can pack together more readily, thereby allowing more particles 30 to be loaded into depot 28.

Figure 7 A depicts a portion of implantable device 10 that contains depot 28 within outer surface 20 and has been loaded with particles 30 as described above. During the process, some particles 30 enter depot 28 while other particles 30 may be deposited along surface 20. Particles 30 located on outer surface 20 but not within depot 28 may be removed to yield implantable device 10 having particles 30 loaded solely in depot 28 as depicted in Figure 7B.

Particles 30 may be removed from outer surface 20 using conventional techniques, such as, but not limited to, scraping, squeegeeing, or soaking. The scraping method involves the mechanical stripping of particles 30 from outer surface 20 using, for example, a brush. The squeegeeing method involves passing implantable device 10 through an opening in a sponge filled with cleaning solution containing liquids such as, but not limited to, water, ethanol, DMSO, or hexane. The soaking method involves soaking implantable device 10 in a cleaning solution containing liquids such as, but not limited to, water, ethanol, DMSO, or hexane. The soaking method may or may not include sonication. Particular care should be taken during the removal of particles 30 from outer surface 20 such that particles 30 are not also removed from within depot 28.

c. Loading Particles into Depots and onto the Outer Surface of the Implantable Device

In some embodiments, loading of particles 30 is desired along outer surface 20 as well as within depots 28 of implantable device 10. In such embodiments, polymeric primer 38, with or without a therapeutic substance, is applied to outer surface 20 and depot 28 prior to the projection of particles 30 onto implantable device 10 to facilitate retention of particles 30 on outer surface 20 and within depot 28, as described above. The application of polymeric primer 38 is controlled such that depot 28 is not more than 50% filled with polymeric primer 38. The primered implantable device 10 is then loaded with particles 30 as described above. During the process, some particles 30 enter primered depot 28 while other particles 30 are deposited along primered outer surface 20. The particles 30 entering depot 28 as well as the particles 30 loaded onto outer surface 20 will adhere to and/or become embedded in primer 38, as depicted in Figure 8.

d. Use of Topcoats

In some embodiments, a polymeric topcoat 42, with or without a therapeutic substance therein, is deposited atop particles 30 loaded onto implantable device 10. Polymeric topcoat 42 can be applied by any conventional method, such as the immersion or spray techniques described above with reference to the application of polymeric primer 40. Polymeric topcoat 42 may be used to secure particles 30 to implantable device 10. Polymeric topcoat 42 also will typically reduce the rate of release of the substance or substances of which particles 30 are made from implantable device 10. Examples of suitable polymers were listed above, and such examples are equally applicable here. By way of example and not limitation, the polymeric topcoat 42 can have a thickness of about 0.25 microns to about 1.5 microns. Typically, topcoat 42 can have a thickness of about 1 micron. It will be appreciated by one of ordinary skill in the art that the thickness of the polymeric topcoat 42 is based on factors such as the type of procedure for which implantable device 10 is employed and the rate of release that is desired. Figure 9A illustrates an embodiment in which polymeric topcoat 42 is applied and dried subsequent to the loading of particles 30 onto outer surface 20 of primered implantable device 10. Such an embodiment facilitates immobilization of particles 30 on outer surface 20 via primer 38 followed by the controlled release of the substance or substances of which particles 30 are made via topcoat 42.

Figures 9B, 9C, and 9D illustrate alternative embodiments in which topcoat 42 is applied to implantable device 10 having depots 28 formed therein. In Figure 9B, topcoat 42 is applied over particles 30 within depot 28. In Figure 9C, topcoat 42 is applied along outer surface 20, which has no particles 30 loaded thereon, as well as over particles 30 within depot 28. In Figure 9D, topcoat 42 is applied over particles 30 within depot 28 and over particles 30 along primered outer surface 20.

Methods of Use

As mentioned above, implantable devices that may be treated according to the methods of the present invention "include stents and grafts, among other possibilities. An implanted stent or graft, having one or more substances loaded thereon as described above, is useful for treating occluded regions of blood vessels caused by thrombosis and/or restenosis, among other possible uses.

Stents may be placed in a wide array of blood vessels, both arteries and veins. Briefly, an angiography is first performed to determine the appropriate positioning for stent therapy. Angiography is typically accomplished by using a catheter to inject a radiopaque contrasting agent into an artery or vein as an X-ray is taken. A guidewire is then advanced through the lesion or proposed site of treatment. Over the guidewire is passed a delivery catheter which allows a stent in its collapsed configuration to be inserted into the passageway. The delivery catheter is inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein and advanced into the appropriate blood vesserby steering the catheter through the vascular system under fiuoroscopic guidance. A stent having the above described covering may then be expanded at the desired area of treatment. A post-insertion angiogram may also be utilized to confirm appropriate positioning. Vascular grafts may be used to replace, bypass, or reinforce diseased or damaged sections of a vein or artery. The general procedure for implantation includes the step of pre-clotting, wherein the graft is immersed in the blood of the patient and allowed to stand for a period of time sufficient for clotting to ensue. After pre-clotting, hemorrhaging is less likely to occur when the graft is implanted, and thus the growth of tissue is not impeded. Grafts may be placed either through invasive surgery or non-invasively through percutaneous endoluminal transport. Percutaneous delivery of a graft avoids the complications and risks of surgery. The graft may be attached to the vessel at each end of the diseased region, thus bypassing the diseased region. Alternatively, the diseased region may be removed and replaced by the graft.

While particular embodiments and applications of the present invention have been shown and described, it will be apparent to those of ordinary skill in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.

Claims

CLAIMSWhat is claimed is:
1. A method of loading a therapeutic substance onto an implantable device, said method comprising: projecting a dry stream of particles from a pressurized particle source onto a preselected region of said implantable device, said particles including a therapeutic substance.
2. An implantable device loaded with a therapeutic substance in accordance with the method of Claim 1.
3. The method of Claim 1, wherein said implantable device 10 is selected from a group of stents and grafts.
4. The method of Claim 1, wherein said therapeutic substance is selected from a group consisting of antineoplastic, antimitotic, antiinflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antiproliferative, antibiotic, antioxidant, and antiallergic substances and combinations thereof.
5. The method of Claim 1, wherein said therapeutic substance is selected from a group consisting of radioactive isotopes and radiopaque substances.
6. The method of Claim 1, wherein said therapeutic substance is selected from a group consisting of bioabsorbable polymers, biomolecules, and biostable polymers.
7. The method of Claim 1 , wherein said preselected region of said implantable device comprises the entire outer surface.
8. The method of Claim 1 , wherein said preselected region of said implantable device comprises a middle section of said implantable device.
9. The method of Claim 1 , wherein said preselected region of said implantable device comprises a portion of said implantable device adjacent an end of said implantable device.
10. The method of Claim 1 , wherein an outer surface of said implantable device has a plurality of depots formed therein, wherein said preselected region of said implantable device comprises a portion of said outer surface having said plurality of depots formed therein, and wherein said particles are loaded onto said portion of said outer surface and within said plurality of depots.
11. The method of Claim 10, wherein said method additionally comprises the act of: removing said particles from said portion of said outer surface, wherein said particles remain within said plurality of depots.
12. The method of Claim 1 , wherein said pressurized source is operated at a pressure in the range between 10 PSI and 60 PSI.
13. The method of Claim 1 , wherein prior to said act of proj ecting particles, the method further comprises the act of: applying a polymeric primer to said preselected region of said implantable device.
14. The method of Claim 13, wherein said particles are projected so as to become embedded within said polymeric primer.
15. The method of Claim 1 , the method further comprising: applying a polymeric topcoat disposed on at least a portion of said particles on said preselected region of said implantable device.
16. A method of loading a therapeutic substance onto a stent having an outer surface having a plurality of depots formed therein, said method comprising: projecting a dry stream of particles from a pressurized source onto said outer surface of said stent, so that said particles are loaded into said plurality of depots, said particles including a therapeutic substance.
17. A stent loaded with a therapeutic substance in accordance with the method of Claim 16.
18. The method of Claim 17, wherein said particles are proj ected so as to be loaded onto said outer surface.
19. The method of Claim 18, additionally comprising the act of: removing said particles from said outer surface of said stent, wherein said particles remain within said plurality of depots.
20. The method of Claim 18, wherein prior to said act of proj ecting particles, the method further comprises the act of: applying a polymeric primer to said outer surface and within said depot, wherein said particles are retained on said primer following said act of projecting particles.
1. The method of Claim 16, the method further comprising: applying a polymeric topcoat disposed on at least a portion of said particles on said stent.
PCT/US2001/027627 2000-09-26 2001-09-05 A method of loading a substance onto an implantable device WO2002026162A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US67175900A true 2000-09-26 2000-09-26
US09/671,759 2000-09-26

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
AU8880901A AU8880901A (en) 2000-09-26 2001-09-05 A method of loading a substance onto an implantable device

Publications (2)

Publication Number Publication Date
WO2002026162A2 true WO2002026162A2 (en) 2002-04-04
WO2002026162A3 WO2002026162A3 (en) 2003-01-16

Family

ID=24695768

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/027627 WO2002026162A2 (en) 2000-09-26 2001-09-05 A method of loading a substance onto an implantable device

Country Status (2)

Country Link
AU (1) AU8880901A (en)
WO (1) WO2002026162A2 (en)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003011191A1 (en) * 2001-08-02 2003-02-13 Scimed Life Systems, Inc. Method for enhancing sheet or tubing metal stent radiopacity
WO2003039407A2 (en) * 2001-11-09 2003-05-15 Biocompatibles Limited Method for manufacturing a stent
WO2004026182A2 (en) 2002-09-20 2004-04-01 Conor Medsystems, Inc. Method and apparatus for loading a beneficial agent into an expandable medical device
EP1518517A2 (en) * 2002-04-24 2005-03-30 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
DE102004054084A1 (en) * 2004-11-09 2006-05-11 Admedes Schuessler Gmbh Stent, comprising marker visible under use of x-rays and designed as string accommodated in groove
WO2007058841A1 (en) * 2005-11-14 2007-05-24 Boston Scientific Limited Coated and imprinted medical devices and methods of making the same
WO2007081551A1 (en) * 2006-01-04 2007-07-19 Abbot Cardiovascular Systems Inc. Stents with radiopaque markers
WO2008039319A2 (en) * 2006-09-25 2008-04-03 Boston Scientific Scimed, Inc. Injection of therapeutic into porous regions of a medical device
WO2008100735A1 (en) * 2007-02-12 2008-08-21 Medtronic Vascular Inc. Stent ring surface formation
EP1997456A1 (en) * 2004-02-13 2008-12-03 Conor Medsystems, Inc. Drug coating device and method for wire filaments
WO2009018340A2 (en) * 2007-07-31 2009-02-05 Boston Scientific Scimed, Inc. Medical device coating by laser cladding
US7682387B2 (en) 2002-04-24 2010-03-23 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7785653B2 (en) 2003-09-22 2010-08-31 Innovational Holdings Llc Method and apparatus for loading a beneficial agent into an expandable medical device
US7854957B2 (en) 2006-10-18 2010-12-21 Innovational Holdings, Llc Systems and methods for producing a medical device
US7896912B2 (en) 1998-03-30 2011-03-01 Innovational Holdings, Llc Expandable medical device with S-shaped bridging elements
US7927650B2 (en) 2001-08-20 2011-04-19 Innovational Holdings, Llc System and method for loading a beneficial agent into a medical device
AU2006230204B2 (en) * 2005-03-31 2011-08-11 Conor Medsystems, Inc. System and method for loading a beneficial agent into a medical device
US20120121665A1 (en) * 2002-02-08 2012-05-17 Boston Scientific Scimed, Inc. Implantable or insertable medical device resistant to microbial growth and biofilm formation
US8206435B2 (en) 1998-03-30 2012-06-26 Conor Medsystems, Inc. Expandable medical device for delivery of beneficial agent
CN101467921B (en) 2001-11-05 2012-08-15 生物传感器国际集团有限公司 Method for producing bracket for eluting medicament
US8361537B2 (en) 1998-03-30 2013-01-29 Innovational Holdings, Llc Expandable medical device with beneficial agent concentration gradient
US8439968B2 (en) 1998-03-30 2013-05-14 Innovational Holdings, Llc Expandable medical device for delivery of beneficial agent
US8673336B2 (en) 2005-09-12 2014-03-18 Innovational Holdings Llc Composition, system, and method for modulating release kinetics in implantable drug delivery devices by modifying drug solubility
EP2198976A3 (en) * 2002-11-07 2014-08-20 Abbott Laboratories Method of loading beneficial agent to a prosthesis by fluid-jet application
US9028859B2 (en) 2006-07-07 2015-05-12 Advanced Cardiovascular Systems, Inc. Phase-separated block copolymer coatings for implantable medical devices
US9038260B2 (en) 2006-05-26 2015-05-26 Abbott Cardiovascular Systems Inc. Stent with radiopaque markers
US9056155B1 (en) 2007-05-29 2015-06-16 Abbott Cardiovascular Systems Inc. Coatings having an elastic primer layer
US9067000B2 (en) 2004-10-27 2015-06-30 Abbott Cardiovascular Systems Inc. End-capped poly(ester amide) copolymers
US9084671B2 (en) 2002-06-21 2015-07-21 Advanced Cardiovascular Systems, Inc. Methods of forming a micronized peptide coated stent
US9579424B2 (en) 2006-10-20 2017-02-28 Biosensors International Group, Ltd. Drug delivery endovascular stent and method of use
US9737368B2 (en) 2015-02-24 2017-08-22 Abbott Cardiovascular Systems Inc. System and method for attaching a radiopaque marker bead to an endoprosthesis
US9763818B2 (en) 2010-01-30 2017-09-19 Abbott Cardiovascular Systems Inc. Method of crimping stent on catheter delivery assembly
US9827119B2 (en) 2010-01-30 2017-11-28 Abbott Cardiovascular Systems Inc. Polymer scaffolds having a low crossing profile
US9999527B2 (en) 2015-02-11 2018-06-19 Abbott Cardiovascular Systems Inc. Scaffolds having radiopaque markers
US10076591B2 (en) 2010-03-31 2018-09-18 Abbott Cardiovascular Systems Inc. Absorbable coating for implantable device

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8741378B1 (en) 2001-06-27 2014-06-03 Advanced Cardiovascular Systems, Inc. Methods of coating an implantable device
US20070032853A1 (en) 2002-03-27 2007-02-08 Hossainy Syed F 40-O-(2-hydroxy)ethyl-rapamycin coated stent
US7758880B2 (en) 2002-12-11 2010-07-20 Advanced Cardiovascular Systems, Inc. Biocompatible polyacrylate compositions for medical applications
US7776926B1 (en) 2002-12-11 2010-08-17 Advanced Cardiovascular Systems, Inc. Biocompatible coating for implantable medical devices
US7279174B2 (en) 2003-05-08 2007-10-09 Advanced Cardiovascular Systems, Inc. Stent coatings comprising hydrophilic additives
US9114198B2 (en) 2003-11-19 2015-08-25 Advanced Cardiovascular Systems, Inc. Biologically beneficial coatings for implantable devices containing fluorinated polymers and methods for fabricating the same
USRE45744E1 (en) 2003-12-01 2015-10-13 Abbott Cardiovascular Systems Inc. Temperature controlled crimping
US8293890B2 (en) 2004-04-30 2012-10-23 Advanced Cardiovascular Systems, Inc. Hyaluronic acid based copolymers
US9561309B2 (en) 2004-05-27 2017-02-07 Advanced Cardiovascular Systems, Inc. Antifouling heparin coatings
US7563780B1 (en) 2004-06-18 2009-07-21 Advanced Cardiovascular Systems, Inc. Heparin prodrugs and drug delivery stents formed therefrom
US7494665B1 (en) 2004-07-30 2009-02-24 Advanced Cardiovascular Systems, Inc. Polymers containing siloxane monomers
US7901451B2 (en) 2004-09-24 2011-03-08 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7604818B2 (en) 2004-12-22 2009-10-20 Advanced Cardiovascular Systems, Inc. Polymers of fluorinated monomers and hydrocarbon monomers
US9561351B2 (en) 2006-05-31 2017-02-07 Advanced Cardiovascular Systems, Inc. Drug delivery spiral coil construct
US9284409B2 (en) 2007-07-19 2016-03-15 Boston Scientific Scimed, Inc. Endoprosthesis having a non-fouling surface
WO2009020520A1 (en) 2007-08-03 2009-02-12 Boston Scientific Scimed, Inc. Coating for medical device having increased surface area
US8920491B2 (en) 2008-04-22 2014-12-30 Boston Scientific Scimed, Inc. Medical devices having a coating of inorganic material
WO2009132176A2 (en) 2008-04-24 2009-10-29 Boston Scientific Scimed, Inc. Medical devices having inorganic particle layers

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4733665A (en) 1985-11-07 1988-03-29 Expandable Grafts Partnership Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
US4800882A (en) 1987-03-13 1989-01-31 Cook Incorporated Endovascular stent and delivery system
US4886062A (en) 1987-10-19 1989-12-12 Medtronic, Inc. Intravascular radially expandable stent and method of implant

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5609629A (en) * 1995-06-07 1997-03-11 Med Institute, Inc. Coated implantable medical device

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4733665A (en) 1985-11-07 1988-03-29 Expandable Grafts Partnership Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
US4733665B1 (en) 1985-11-07 1994-01-11 Expandable Grafts Partnership Expandable intraluminal graft,and method and apparatus for implanting an expandable intraluminal graft
US4733665C2 (en) 1985-11-07 2002-01-29 Expandable Grafts Partnership Expandable intraluminal graft and method and apparatus for implanting an expandable intraluminal graft
US4800882A (en) 1987-03-13 1989-01-31 Cook Incorporated Endovascular stent and delivery system
US4886062A (en) 1987-10-19 1989-12-12 Medtronic, Inc. Intravascular radially expandable stent and method of implant

Cited By (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8623068B2 (en) 1998-03-30 2014-01-07 Conor Medsystems, Inc. Expandable medical device with ductile hinges
US8361537B2 (en) 1998-03-30 2013-01-29 Innovational Holdings, Llc Expandable medical device with beneficial agent concentration gradient
US7896912B2 (en) 1998-03-30 2011-03-01 Innovational Holdings, Llc Expandable medical device with S-shaped bridging elements
US8439968B2 (en) 1998-03-30 2013-05-14 Innovational Holdings, Llc Expandable medical device for delivery of beneficial agent
US8206435B2 (en) 1998-03-30 2012-06-26 Conor Medsystems, Inc. Expandable medical device for delivery of beneficial agent
US6926733B2 (en) 2001-08-02 2005-08-09 Boston Scientific Scimed, Inc. Method for enhancing sheet or tubing metal stent radiopacity
WO2003011191A1 (en) * 2001-08-02 2003-02-13 Scimed Life Systems, Inc. Method for enhancing sheet or tubing metal stent radiopacity
US7927650B2 (en) 2001-08-20 2011-04-19 Innovational Holdings, Llc System and method for loading a beneficial agent into a medical device
CN101467921B (en) 2001-11-05 2012-08-15 生物传感器国际集团有限公司 Method for producing bracket for eluting medicament
US7727275B2 (en) 2001-11-05 2010-06-01 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method of forming the same
WO2003039407A2 (en) * 2001-11-09 2003-05-15 Biocompatibles Limited Method for manufacturing a stent
WO2003039407A3 (en) * 2001-11-09 2003-11-27 Biocompatibles Ltd Method for manufacturing a stent
US9034346B2 (en) * 2002-02-08 2015-05-19 Boston Scientific Scimed, Inc. Implantable or insertable medical device resistant to microbial growth and biofilm formation
US20120121665A1 (en) * 2002-02-08 2012-05-17 Boston Scientific Scimed, Inc. Implantable or insertable medical device resistant to microbial growth and biofilm formation
AU2003231757B2 (en) * 2002-04-24 2009-07-09 Biosensors International Group, Ltd. Polymer compositions containing a macrocyclic triene compound
EP1518517A3 (en) * 2002-04-24 2005-12-14 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7682387B2 (en) 2002-04-24 2010-03-23 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US8252046B2 (en) 2002-04-24 2012-08-28 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
EP1518517A2 (en) * 2002-04-24 2005-03-30 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
EP2316377A1 (en) * 2002-04-24 2011-05-04 Biosensors International Group, Ltd. Drug-Delivery Endovascular Stent And Method For Treating Restenosis
US9084671B2 (en) 2002-06-21 2015-07-21 Advanced Cardiovascular Systems, Inc. Methods of forming a micronized peptide coated stent
WO2004026182A3 (en) * 2002-09-20 2004-07-15 Conor Medsystems Inc Method and apparatus for loading a beneficial agent into an expandable medical device
AU2003272615B2 (en) * 2002-09-20 2010-01-21 Innovational Holdings, Llc Method and apparatus for loading a beneficial agent into an expandable medical device
US8349390B2 (en) 2002-09-20 2013-01-08 Conor Medsystems, Inc. Method and apparatus for loading a beneficial agent into an expandable medical device
JP2010088924A (en) * 2002-09-20 2010-04-22 Innovational Holdings Llc Method for loading beneficial agent into expandable medical device
AU2009202719B2 (en) * 2002-09-20 2012-04-12 Innovational Holdings, Llc Method and apparatus for loading a beneficial agent into an expandable medical device
US9254202B2 (en) 2002-09-20 2016-02-09 Innovational Holdings Llc Method and apparatus for loading a beneficial agent into an expandable medical device
WO2004026182A2 (en) 2002-09-20 2004-04-01 Conor Medsystems, Inc. Method and apparatus for loading a beneficial agent into an expandable medical device
EP2198976A3 (en) * 2002-11-07 2014-08-20 Abbott Laboratories Method of loading beneficial agent to a prosthesis by fluid-jet application
US7785653B2 (en) 2003-09-22 2010-08-31 Innovational Holdings Llc Method and apparatus for loading a beneficial agent into an expandable medical device
US8197881B2 (en) 2003-09-22 2012-06-12 Conor Medsystems, Inc. Method and apparatus for loading a beneficial agent into an expandable medical device
EP1997456A1 (en) * 2004-02-13 2008-12-03 Conor Medsystems, Inc. Drug coating device and method for wire filaments
US9067000B2 (en) 2004-10-27 2015-06-30 Abbott Cardiovascular Systems Inc. End-capped poly(ester amide) copolymers
DE102004054084A1 (en) * 2004-11-09 2006-05-11 Admedes Schuessler Gmbh Stent, comprising marker visible under use of x-rays and designed as string accommodated in groove
EP1656905A1 (en) * 2004-11-09 2006-05-17 Admedes Schuessler GmbH Method for attaching radiopaque markers to a stent
DE102004054084B4 (en) * 2004-11-09 2007-08-02 Admedes Schuessler Gmbh Stent with a marker to improve the X-ray visibility, the use of and a method of manufacturing such stents
AU2006230204B2 (en) * 2005-03-31 2011-08-11 Conor Medsystems, Inc. System and method for loading a beneficial agent into a medical device
US8673336B2 (en) 2005-09-12 2014-03-18 Innovational Holdings Llc Composition, system, and method for modulating release kinetics in implantable drug delivery devices by modifying drug solubility
WO2007058841A1 (en) * 2005-11-14 2007-05-24 Boston Scientific Limited Coated and imprinted medical devices and methods of making the same
US7935379B2 (en) 2005-11-14 2011-05-03 Boston Scientific Scimed, Inc. Coated and imprinted medical devices and methods of making the same
JP2009522050A (en) * 2006-01-04 2009-06-11 アボット カーディオヴァスキュラー システムズ インコーポレイテッド Radiopaque markers with stent
EP3146941A1 (en) * 2006-01-04 2017-03-29 Abbott Cardiovascular Systems Inc. Stents with radiopaque markers
EP2910220A1 (en) * 2006-01-04 2015-08-26 Abbott Cardiovascular Systems, Inc. Stents with radiopaque makers
US10070975B2 (en) 2006-01-04 2018-09-11 Abbott Cardiovascular Systems Inc. Stents with radiopaque markers
WO2007081551A1 (en) * 2006-01-04 2007-07-19 Abbot Cardiovascular Systems Inc. Stents with radiopaque markers
US9038260B2 (en) 2006-05-26 2015-05-26 Abbott Cardiovascular Systems Inc. Stent with radiopaque markers
US9694116B2 (en) 2006-05-26 2017-07-04 Abbott Cardiovascular Systems Inc. Stents with radiopaque markers
US9028859B2 (en) 2006-07-07 2015-05-12 Advanced Cardiovascular Systems, Inc. Phase-separated block copolymer coatings for implantable medical devices
WO2008039319A2 (en) * 2006-09-25 2008-04-03 Boston Scientific Scimed, Inc. Injection of therapeutic into porous regions of a medical device
WO2008039319A3 (en) * 2006-09-25 2008-05-15 Boston Scient Scimed Inc Injection of therapeutic into porous regions of a medical device
US7854957B2 (en) 2006-10-18 2010-12-21 Innovational Holdings, Llc Systems and methods for producing a medical device
US9579424B2 (en) 2006-10-20 2017-02-28 Biosensors International Group, Ltd. Drug delivery endovascular stent and method of use
WO2008100735A1 (en) * 2007-02-12 2008-08-21 Medtronic Vascular Inc. Stent ring surface formation
US9056155B1 (en) 2007-05-29 2015-06-16 Abbott Cardiovascular Systems Inc. Coatings having an elastic primer layer
WO2009018340A3 (en) * 2007-07-31 2009-06-25 Boston Scient Scimed Inc Medical device coating by laser cladding
WO2009018340A2 (en) * 2007-07-31 2009-02-05 Boston Scientific Scimed, Inc. Medical device coating by laser cladding
US9763818B2 (en) 2010-01-30 2017-09-19 Abbott Cardiovascular Systems Inc. Method of crimping stent on catheter delivery assembly
US9770351B2 (en) 2010-01-30 2017-09-26 Abbott Cardiovascular Systems Inc. Crush recoverable polymer scaffolds
US9827119B2 (en) 2010-01-30 2017-11-28 Abbott Cardiovascular Systems Inc. Polymer scaffolds having a low crossing profile
US9867728B2 (en) 2010-01-30 2018-01-16 Abbott Cardiovascular Systems Inc. Method of making a stent
US10123894B2 (en) 2010-01-30 2018-11-13 Abbott Cardiovascular Systems Inc. Method of crimping stent on catheter delivery assembly
US10076591B2 (en) 2010-03-31 2018-09-18 Abbott Cardiovascular Systems Inc. Absorbable coating for implantable device
US9999527B2 (en) 2015-02-11 2018-06-19 Abbott Cardiovascular Systems Inc. Scaffolds having radiopaque markers
US9737368B2 (en) 2015-02-24 2017-08-22 Abbott Cardiovascular Systems Inc. System and method for attaching a radiopaque marker bead to an endoprosthesis

Also Published As

Publication number Publication date
AU8880901A (en) 2002-04-08
WO2002026162A3 (en) 2003-01-16

Similar Documents

Publication Publication Date Title
US7169173B2 (en) Composite stent with regioselective material and a method of forming the same
US6926919B1 (en) Method for fabricating a coating for a medical device
AU2002211321B2 (en) Coated medical devices and sterilization thereof
AU716005B2 (en) Implantable medical device
EP1660148B1 (en) Biologically absorbable coatings for implantable devices
US7022334B1 (en) Therapeutic composition and a method of coating implantable medical devices
US6908624B2 (en) Coating for implantable devices and a method of forming the same
AU2002239436B2 (en) Coated implantable medical device
EP1723976B1 (en) Intraluminal medical devices in combination with therapeutic agents
EP1362603B1 (en) Coated stent for release of active agents
CA2538669C (en) Medicated stent having multi-layer polymer coating
US7261735B2 (en) Local drug delivery devices and methods for maintaining the drug coatings thereon
CN102283730B (en) Drug-delivery endovascular stent
US7220275B2 (en) Stent with protruding branch portion for bifurcated vessels
US7341598B2 (en) Stent with protruding branch portion for bifurcated vessels
AU2003203722B2 (en) Coated medical devices for the treatment of vascular disease
US6254632B1 (en) Implantable medical device having protruding surface structures for drug delivery and cover attachment
EP2324866B1 (en) Angioplasty balloons drug-coated in an expanded condition
US20020111590A1 (en) Medical devices, drug coatings and methods for maintaining the drug coatings thereon
US20040236415A1 (en) Medical devices having drug releasing polymer reservoirs
US9610386B2 (en) Method for electrostatic coating of a medical device
US8323333B2 (en) Fragile structure protective coating
US20070179596A1 (en) Medical Devices, Drug Coatings And Methods for Maintaining the Drug Coatings Thereon
EP1827308B1 (en) Abluminal, multilayer coating constructs for drug-delivery stents
EP1566187A2 (en) Polyacrylates coating for implantable medical devices

Legal Events

Date Code Title Description
AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP