WO2008090554A2 - Surfaces conductrices modifiées préparées par électrogreffage de sels diazonium - Google Patents

Surfaces conductrices modifiées préparées par électrogreffage de sels diazonium Download PDF

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Publication number
WO2008090554A2
WO2008090554A2 PCT/IL2008/000103 IL2008000103W WO2008090554A2 WO 2008090554 A2 WO2008090554 A2 WO 2008090554A2 IL 2008000103 W IL2008000103 W IL 2008000103W WO 2008090554 A2 WO2008090554 A2 WO 2008090554A2
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WO
WIPO (PCT)
Prior art keywords
aryl moiety
moiety
aryl
diazonium
group
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PCT/IL2008/000103
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English (en)
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WO2008090554A3 (fr
Inventor
Abraham Jackob Domb
Yulia Shaulov
Yair Levi
Daniel Mandler
Noam Tal
Original Assignee
Elutex Ltd.
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Publication of WO2008090554A2 publication Critical patent/WO2008090554A2/fr
Publication of WO2008090554A3 publication Critical patent/WO2008090554A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
    • C09D5/44—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes for electrophoretic applications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L31/00—Materials 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
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00—Processes of polymerisation
    • C08F2/58—Polymerisation initiated by direct application of electric current
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F285/00—Macromolecular compounds obtained by polymerising monomers on to preformed graft polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F291/00—Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/003—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D151/00—Coating compositions based on graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers
    • C09D151/003—Coating compositions based on graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
    • C09D5/44—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes for electrophoretic applications
    • C09D5/4476—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes for electrophoretic applications comprising polymerisation in situ

Definitions

  • the present invention in some embodiments thereof, relates to a modified conductive surface and to uses thereof, and more particularly, but not exclusively, to a modified conductive surface, such as stainless steel surfaces, which can be utilized for efficiently attaching thereto a coating and/or drug, and can therefore be beneficially used in a variety of medical and other applications.
  • metallic structures are often implanted in a living body for various purposes. Such metallic structures include, for example, pacemakers, grafts, stents, wires, orthopedic implants, implantable diffusion pumps and heart valves.
  • One problem associated with metals implanted in a living body is the biocompatibility thereof, and more particularly, the blood compatibility and the tissue compatibility of metallic implants.
  • An implant is typically considered blood biocompatible when activation of coagulation factors (e.g., proteins and platelets) is only mildly induced thereby and tissue compatible when cell proliferation and chronic inflammation are not excessively induced thereby.
  • coagulation factors e.g., proteins and platelets
  • One strategy for minimizing undesirable biological reactions associated with metallic implants is to coat the metallic surface with biomolecules that provide a substrate for the growth of a protective cell layer.
  • Biomolecules used include, for example, growth factors, cell attachment proteins, and cell attachment peptides.
  • a related strategy is to attach molecules or active pharmaceutical ingredients that reduce undesired biological reactions such as antithrombogenics, antiplatelet agents, anti- inflammatory agents, antimicrobials, and the like.
  • WO 01/39813, EP Patent No. 1233795 and U.S. Patent Application No. 10/148,665 teach the attachment of active pharmaceutical ingredients to a surface using electropolymerizable monomers by covalent bonding of active pharmaceutical ingredients, or entities carrying active pharmaceutical ingredients, to electropolymerizable monomers prior to polymerization and by providing electropolymerizable monomers having functional groups which, subsequent to film production through electropolymerization, are used to covalently attach the active pharmaceutical ingredients or the entities carrying active pharmaceutical ingredients.
  • U.S. Patent Application No. 11/183,850 teaches the coating of conductive surfaces using electropolymerizable polymers, to which the active agent is attached by covalent and non-covalent bonds.
  • WO 2006/008739 teaches conductive surfaces which have been modified by electrochemically attaching thereto functional substances to which an active agent can be bound or by electrochemically attaching thereto the active agent itself.
  • the modified conductive surfaces disclosed in this patent application are prepared by utilizing various electroattachable groups, such as, for example, a carboxylate, a sulfonate, a sulfate, a phosphonate and a phosphate.
  • WO 02/066092 teaches electrodepositing a hydrophobic molecule containing a diazonium moiety onto the surface of an endo vascular device (e.g. a stainless steel surface) to obtain a functionalized surface, followed by passively depositing a lipophilic drug onto the functionalized surface, providing slow elution of the drug into a tissue when the device is brought into contact with the tissue.
  • an endo vascular device e.g. a stainless steel surface
  • WO 07/099137 teaches electrografting of a polymer film onto a conductive or semiconductive surface by reduction of a solution comprising a diazonium salt and a chain polymerizable monomer by applying a cathodic potential to the surface, and that such a polymer film may serve as an adhesion primer for a thicker polymer layer.
  • WO 07/099137 further teaches that a macrostructure such as a polymer, protein, nucleic acid, polysaccharide, liposome or cell, which is functionalized by a chain polynierizable group, may also be electrografted according to the abovementioned procedure.
  • U.S. Patent No. 6,435,240 describes the modification of the surface of a carbon-containing material by using diazonium salts.
  • U.S. Patent No. 6,217,740 describes the modification of the surface of a carbon-containing material by reacting carboxylates via the Kolbe reaction.
  • an article-of-manufacturing comprising an object having a conductive surface and at least one aryl moiety being electrochemically attached to the conductive surface to form a layer of the at least one aryl moiety on the surface.
  • the at least one aryl moiety is selected such that the layer of the at least one aryl moiety remains intact upon being subjected to physiological and/or mechanical conditions associated with the medical device for at least 30 days.
  • the conductive surface has at least two aryl moieties being electrochemically attached thereto, the aryl moieties being different from one another;
  • the aryl moiety is substituted by at least one functional group at a meta or ortho position of the aryl moiety, with respect to the position of the aryl moiety that is being electrochemically attached to the surface;
  • the aryl moiety is electrochemically attached to the surface via at least two positions thereof; (iv) the aryl moiety comprises at least two aromatic groups fused to one another; and/or
  • the aryl moiety comprises at least two aromatic groups covalently linked to one another via a linker.
  • the article-of-manufacturing further comprises a coating which coats the layer of the at least one aryl moiety.
  • the aryl moiety is a polymer comprising a plurality of aromatic groups being covalently linked to one another via a linker.
  • the plurality of aromatic groups comprises phenyl.
  • the polymer is polystyrene.
  • the aryl moiety comprises at least two aromatic groups covalently linked to one another via a linker, and the linker comprises a plurality of alkoxy groups, each of the alkoxy groups being attached to one of the at least two aromatic groups.
  • the aryl moiety electrochemically attached to the surface comprises a phenyl attached to the surface via at least two positions thereof.
  • the two positions of the phenyl are at a meta position with respect to one another.
  • the article-of-manufacturing further comprises a plurality of microparticles and/or nanoparticles covalently bound to the aryl moiety.
  • the microparticles and/or nanoparticles comprises a pharmaceutically active agent.
  • the article-of-manufacturing further comprises a pharmaceutically active agent bound to the aryl moiety via an interaction selected from the group consisting of a covalent bond, an ionic bond, a hydrogen bond and a van der Waals interaction.
  • a process of preparing an object having a conductive surface, and at least one aryl moiety being electrochemically attached to the surface and forming a layer of the at least one aryl moiety comprising: providing at least one aryl moiety substituted by at least one diazonium moiety; and electrochemically attaching the at least one aryl moiety substituted by the at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of the at least one aryl moiety being electrochemicaUy attached to the surface.
  • the process further comprises interacting the at least one aryl moiety electroattached to the conductive surface with at least one pharmaceutically active agent, to thereby bind the at least one pharmaceutically active agent to the at least one aryl moiety.
  • the aryl moiety substituted by the at least one diazonium moiety comprises at least one of a first functional group
  • the pharmaceutically active agent comprises a second functional group, the first functional group and the second functional group being selected capable of interacting with each other to thereby bind the at least one pharmaceutically active agent to the at least one aryl moiety.
  • a process of preparing an object having a conductive surface, at least one aryl moiety being electrochemically attached to the surface and forming a layer of the at least one aryl moiety, and a coating which coats the layer of the at least one aryl moiety comprising: providing at least one aryl moiety substituted by at least one diazonium moiety; electrochemically attaching the at least one aryl moiety substituted by the at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of the at least one aryl moiety being electrochemically attached to the surface; and applying a coating onto the layer of the at least one aryl moiety.
  • a process of preparing an object having a conductive surface and at least one aryl moiety being electrochemically attached to the surface and forming a layer of the at least one aryl moiety, the aryl moiety being covalently bound to at least one microparticle and/or nanoparticle comprising: providing at least one aryl moiety substituted by at least one diazonium moiety; electrochemically attaching the at least one aryl moiety substituted by the at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of the at least one aryl moiety being electrochemically attached to the surface; and reacting the aryl moiety electroattached to the conductive surface with the at least one microparticle and/or nanoparticle, thereby obtaining the aryl moiety being covalently bound to at least one microparticle and/or nanoparticle.
  • a process of preparing an object having a conductive surface and at least one aryl moiety being electrochemically attached to the surface and forming a layer of the at least one aryl moiety, the aryl moiety being covalently bound to at least one microparticle and/or nanoparticle comprising: providing at least one aryl moiety substituted by at least one diazonium moiety and covalently linked to the at least one microparticle and/or nanoparticle; and electrochemically attaching the at least one aryl moiety substituted by at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of the at least one aryl moiety being electrochemically attached to the surface, the aryl moiety being covalently bound to at least one microparticle and/or nanoparticle.
  • a process of preparing an object having a conductive surface and at least one aryl moiety being electrochemically attached to the surface and forming a layer of the at least one aryl moiety, the aryl moiety being covalently bound to at least one pharmaceutically active moiety comprising: providing at least one aryl moiety substituted by at least one diazonium moiety and covalently linked to the at least one pharmaceutically active moiety; and electrochemically attaching the at least one aryl moiety substituted by at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of the at least one aryl moiety being electrochemically attached to the surface, the aryl moiety being covalently bound to at least one pharmaceutically active agent.
  • a process of preparing an object having a conductive surface and at least one aryl moiety being electrochemically attached to the surface and forming a layer of the at least one aryl moiety, the aryl moiety being covalently bound to at least one polymer comprising: providing at least one aryl moiety substituted by at least one diazonium moiety; electrochemically attaching the at least one aryl moiety substituted by at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of the at least one aryl moiety being electrochemically attached to the surface; and reacting the aryl moiety electroattached to the conductive surface with a plurality of monomers, such that the monomers undergo polymerization to form a polymer covalently bound to the aryl moiety.
  • the monomer is selected from the group consisting of acrylic acid, acrylic acid ester, methacrylic acid and methacrylic acid ester. According to some embodiments of the invention, the monomer is methyl methacrylate.
  • the aryl moiety comprises a functional group selected capable of reacting with the plurality of monomers, such that the monomers undergo polymerization to form a polymer covalently bound to the aryl moiety.
  • the coating is a matrix which comprises at least one pharmaceutically active agent.
  • the coating comprises a polymeric material.
  • the polymeric material has a pharmaceutically active agent embedded therein.
  • the polymeric material comprises a polymer selected from the group consisting of poly(ethylene-vinyl acetate), poly(butyl methacrylate), poly(styrene-isobutylene-styrene), poly-L-lactide and poly- ⁇ -caprolactone, and mixtures and copolymers thereof.
  • applying the coating comprises contacting the object having the layer of the at least one aryl moiety being electrochemically attached to the surface with a solution that comprises the coating.
  • the solution comprises a polymer.
  • the solution further comprises at least one pharmaceutically active agent.
  • the at least one aryl moiety substituted by the at least one diazonium moiety comprises at least two aryl moieties, each being substituted by the at least one diazonium moiety, and being different from one another;
  • the aryl moiety substituted by the at least one diazonium moiety is further substituted by at least one functional group at a meta or ortho position of the aryl moiety, with respect to the position of the aryl moiety that is substituted with a diazonium moiety
  • the aryl moiety substituted by at least one diazonium moiety comprises at least two aromatic groups fused to one another;
  • the aryl moiety substituted by at least one diazonium moiety comprises at least two aromatic groups covalently linked to one another via a linker.
  • the aryl moiety comprises at least one functional group selected from the group consisting of alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, carboxy, thiocarboxy, ether, thioether, epoxide (oxirane), sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, carbamyl and thiocarbamyl.
  • the aryl moiety substituted by at least two diazonium groups is selected from the group consisting of:
  • D is a diazonium moiety
  • B is aryl
  • n is an integer greater than 1 ;
  • A is at least one group substituting a position of the aryl, the at least one group being independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, carboxy, thiocarboxy, ether, thioether, epoxide (oxirane), sulfonyl, suliinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, carbamyl and thiocarbamyl; and (b) a compound having the formula:
  • E is a diazonium moiety
  • G is aryl
  • J is absent or is selected from the group consisting of O, S and NH; m is an integer greater than 1 ; and
  • K is selected from the group consisting of alkylene and a polymer.
  • the aryl moiety substituted by at least one diazonium moiety is a polymer comprising a plurality of aromatic groups being covalently linked to one another via a linker.
  • the aryl moiety comprises phenyl substituted by at least two diazonium moieties.
  • the two diazonium moieties substituting the phenyl are at a meta position with respect to one another.
  • the aryl moiety comprises anthracene.
  • the anthracene is attached to the surface via at least two positions thereof.
  • the conductive surface has at least two aryl moieties being electrochemically attached thereto, at least one of the aryl moieties comprising a hydrophilic functional group and at least one other of the aryl moieties comprising a hydrophobic functional group.
  • the coating adheres to the at least one aryl moiety electrochemically attached to the conductive surface more strongly than to the conductive surface without the at least one aryl moiety, such that peeling of the coating from the at least one aryl moiety electrochemically attached to the conductive surface is at least 10 % lower than peeling of the coating from the conductive surface without the at least one aryl moiety when performing a D-3359-02 ASTM test following incubation of each of the surfaces with the coating in an aqueous solution of a phosphate buffer comprising 0.3 % sodium dodecyl sulfate, at a pH of 7.4 and a temperature of 37 °C.
  • the coating adheres to the at least one aryl moiety electrochemically attached to the conductive surface more strongly than to the conductive surface without the at least one aryl moiety, such that the percentage of defective areas on the coating adhered to the at least one aryl moiety electrochemically attached to the conductive surface is at least 10 % lower than the percentage of defective areas on the coating adhered to the conductive surface without the at least one aryl moiety when examining each of the coatings by scanning electron microscopy at a magnification of x300 following incubation of the coatings in an aqueous solution of a phosphate buffer comprising 0.3 % sodium dodecyl sulfate, at a pH of 7.4 and a temperature of 60 °C, the areas being a field of about 0.9 mm by about 0.9 mm, and the defective areas being any of the areas in which a failure in the integrity of the coating is visible.
  • the coating remains physically intact for at least 30 days under physiological conditions.
  • the aryl moiety substituted by at least one diazonium moiety comprises at least one of a first functional group
  • the microparticle and/or nanoparticle comprises a second functional group, the first functional group and the second functional group being selected capable of reacting with each other to thereby covalently bind the aryl moiety electroattached to the conductive surface to the at least one microparticle and/or nanoparticle.
  • the microparticle and/or nanoparticle comprise at least one pharmaceutically active agent.
  • the object is a medical device.
  • the object is an implantable medical device.
  • the object is a stent.
  • a method of treating a subject having a medical condition in which implanting a medical device is beneficial comprising: implanting the abovementioned medical within the subject, thereby treating the medical condition.
  • the medical condition is selected from the group consisting of a cardiovascular disease, atherosclerosis, thrombosis, stenosis, restenosis, a cardiologic disease, a peripheral vascular disease, an orthopedic condition, a proliferative disease, an infectious disease, a transplantation- related disease, a degenerative disease, a cerebrovascular disease, a gastrointestinal disease, a hepatic disease, a neurological disease, an autoimmune disease, and an implant-related disease.
  • a cardiovascular disease atherosclerosis, thrombosis, stenosis, restenosis
  • a cardiologic disease a peripheral vascular disease
  • an orthopedic condition a proliferative disease
  • an infectious disease a transplantation- related disease
  • a degenerative disease a cerebrovascular disease
  • a gastrointestinal disease a hepatic disease
  • neurological disease an autoimmune disease
  • an implant-related disease an implant-related disease.
  • B is aryl; n is an integer greater than 1 ;
  • A is at least one group substituting a position of the aryl, the at least one group being independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, carboxy, thiocarboxy, ether, thioether, epoxide (oxirane), sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, carbamyl and thiocarbamyl.
  • B is phenyl
  • the compound comprises two diazonium moieties which are attached to the phenyl at meta positions with respect to one another.
  • A is selected from the group consisting of hydrogen and carboxyl.
  • B is a fused ring aryl.
  • the fused ring aryl is anthracene.
  • A is hydrogen. According to an aspect of some embodiments of the present invention there is provided a compound having the formula:
  • E is a diazonium moiety
  • G is aryl
  • J is absent or is selected from the group consisting of O, S and NH; m is an integer greater than 1; and
  • K is selected from the group consisting of alkylene and a polymer.
  • K is polyethylene and J is absent.
  • m is in the range of 10 to 40.
  • K is C(CH2)4 and m is 4.
  • J is O.
  • G is phenyl
  • the diazonium moiety is attached to the phenyl at a para position with respect to the position of the phenyl that is attached to J or K.
  • the salt is a tetrafluoroborate salt. According to an aspect of some embodiments of the present invention there is provided a use of any of the abovementioned compounds for forming a layer of at least one aryl moiety on a conductive surface.
  • FIGs. la-b are graphs presenting electrical current as a function of voltage during a cyclic voltammetric electrocoating of a stent with polydiazostyrene;
  • FIG. 2 is a graph presenting electrical current over time during a fixed potential electrocoating of a stent with polydiazostyrene
  • FIG. 3 is a graph presenting the imaginary component of the impedance (y- axis) as a function of the real component of the impedance (x-axis) for bare stents and stents electrocoated with polydiazostyrene;
  • FIG. 4 is a graph presenting electrical current as a function of voltage during cyclic voltammetry with bare stents (blue) and stents electrocoated with polydiazostyrene (red);
  • FIGs. 5a-b are graphs presenting electrical current as a function of voltage during electrocoating of a stent with tetrakis[(4-diazophenoxy)methyl]methane;
  • FIGs. 6a-b are graphs presenting the imaginary component of the impedance
  • FIGs. 7a-b are graphs presenting electrical current as a function of voltage during cyclic voltammetry with bare stents (red) and stents electrocoated with tetrakis[(4-diazophenoxy)methyl]methane (blue);
  • FIGs. 8a-b are graphs presenting electrical current as a function of voltage during a cyclic voltammetric electrocoating of a stent with 1,8-didiazoanthracene;
  • FIG. 9 is a graph presenting the imaginary component of the impedance (y- axis) as a function of the real component of the impedance (x-axis) for bare stents (red) and stents electrocoated with 1,8-didiazoanthracene (blue);
  • FIG. 10 is a graph presenting electrical current as a function of voltage during cyclic voltammetry with bare stents (blue) and stents electrocoated with 1,8- didiazoanthracene (red);
  • FIGs. l la-b are graphs presenting electrical current as a function of voltage during electrocoating of a stent with 3,5-didiazobenzoic acid;
  • FIGs. 12a-b are graphs presenting the imaginary component of the impedance (y-axis) as a function of the real component of the impedance (x-axis) for bare stents (red) and stents electrocoated with 3,5-didiazobenzoic acid (blue);
  • FIGs. 13a-b are graphs presenting electrical current as a function of voltage during cyclic voltammetry with bare stents (red in Figure 13a, blue in Figure 13b) and stents electrocoated with 3,5-didiazobenzoic acid (blue in Figure 13a, red in Figure 13b);
  • FIG. 14 is a graph presenting the imaginary component of the impedance (y- axis) as a function of the real component of the impedance (x-axis) for a bare metal stent (1), a stent electrocoated with 4-(2-bromoethyl)phenyl diazonium (2), a non- electrocoated stent subjected to PMMA grafting solution (3) and a stent electrocoated with 4-(2-bromoethyi)phenyl diazonium and then subjected to PMMA grafting solution;
  • FIG. 14 is a graph presenting the imaginary component of the impedance (y- axis) as a function of the real component of the impedance (x-axis) for a bare metal stent (1), a stent electrocoated with 4-(2-bromoethyl)phenyl diazonium (2), a non- electrocoated stent subjected to PMMA grafting solution (3) and a
  • FIG. 15 is a graph presenting the integration of electrical current over time for the cyclic voltammetric electrocoating of stents with various proportions of DS04 (4- (2-hydroxyethyl)phenyl diazonium) and DS06 (4-dodecyloxyphenyl diazonium);
  • FIG. 16 is a graph presenting the imaginary component of the impedance (y- axis) as a function of the real component of the impedance (x-axis) for bare stents and stents electrocoated with various proportions of DS04 (4-(2-hydroxyethyl)phenyl diazonium) and DS06 (4-dodecyloxyphenyl diazonium);
  • FIG. 16 is a graph presenting the imaginary component of the impedance (y- axis) as a function of the real component of the impedance (x-axis) for bare stents and stents electrocoated with various proportions of DS
  • 17 is a graph presenting electrical current as a function of voltage during cyclic voltammetry with bare stents and stents electrocoated with various proportions of DS04 (4-(2-hydroxyethyl)phenyl diazonium) and DS06 (4-dodecyloxyphenyl diazonium);
  • FIGs. 18a-b are photographs showing all of a non-electrocoated stent at low magnification ( Figure 18a) and a maximum stress area of the same stent at high magnification ( Figure 18b), following spray-coating of the stent with PEVA:PBMA:paclitaxel;
  • FIGs. 19a-c are photographs showing a non-electrocoated stent coated with PEVA:PBMA:paclitaxel, followed by incubation for 3 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 °C;
  • FIGs. 20a-c are photographs showing a stent electrocoated with 4- dodecyloxyphenyl diazonium and coated with PEVA:PBMA:paclitaxel, followed by incubation for 3 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 °C;
  • FIGs. 21a-d are scanning electron micrographs showing a non-electrocoated stent ( Figures 21a-b) and a stent electrocoated with 4-dodecyloxyphenyl diazonium ( Figures 21c-d) which have been coated with PEVA:PBMA:paclitaxel, followed by incubation for 3 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 0 C;
  • FIGs. 22a-b are scanning electron micrographs showing a non-electrocoated stent coated with PEVA:PBMA:paclitaxel, followed by incubation for 12 days in phosphate buffer with 0.3 % SDS, pH 7, at 60 °C;
  • FIGs. 23a-b are scanning electron micrographs showing a stent electrocoated with 4-(2-bromoethyl)phenyl diazonium, grafted with PMMA and coated with PEVA:PBMA:paclitaxel, followed by incubation for 12 days in phosphate buffer with 0.3 % SDS, pH 7, at 60 °C;
  • FIGs. 24a-b are scanning electron micrographs showing a non-electrocoated stent coated with 5 ⁇ m of SIBS:paclitaxel, followed by incubation for 3 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 0 C;
  • FIGs. 25a-b are scanning electron micrographs showing a stent electrocoated with 4-dodecyloxyphenyl diazonium and coated with 5 ⁇ m of SIBSrpaclitaxel, followed by incubation for 3 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 0 C;
  • FIGs. 26a-b are scanning electron micrographs showing a non-electrocoated stent coated with 0.5 ⁇ m of SIBS:paclitaxel, followed by incubation for 3 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 °C;
  • FIGs. 27a-b are scanning electron micrographs showing a stent electrocoated with 4-dodecyloxy ⁇ henyl diazonium and coated with 0.5 ⁇ m of SIBS:paclitaxel, followed by incubation for 3 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 0 C;
  • FIGs 28a-b are scanning electron micrographs showing a stent coated with PEVA:PBMA:paclitaxel and a PBMA top layer prior to incubation;
  • FIGs. 29a-b are scanning electron micrographs showing a non-electrocoated stent coated with PEVA:PBMA:paclitaxel and a PBMA top layer, followed by incubation for 3 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 0 C;
  • FIGs. 30a-b are scanning electron micrographs showing a non-electrocoated stent coated with PEVA:PBMA:paclitaxel and a PBMA top layer, followed by incubation for 30 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 °C;
  • FIGs. 31a-b are scanning electron micrographs showing a stent electrocoated with 4-dodecyloxyphenyl diazonium and coated with PEVA:PBMA:paclitaxel and a PBMA top layer, followed by incubation for 3 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 0 C;
  • FIGs. 32a-b are scanning electron micrographs showing a stent electrocoated with 4-dodecyloxyphenyl diazonium and coated with PEVA:PBMA:paclitaxel and a PBMA top layer, followed by incubation for 30 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 60 0 C;
  • FIGs. 33a-c are photographs showing a non-electrocoated stent coated with RESOMER® LC 703 S, followed by incubation for 30 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 37 0 C;
  • FIGs. 34a-c are photographs showing a stent electrocoated with 4- dodecyloxyphenyl diazonium and coated with RESOMER® LC 703 S, followed by incubation for 30 days in phosphate buffer with 0.3 % SDS, pH 7.4, at 37 °C; FIGs.
  • 35a-b are graphs presenting the amount in micrograms (Figure 35a) and percentage (Figure 35b) of paclitaxel released during incubation in phosphate buffer with 0.3 % SDS (pH 7.4, 37 °C) from stents electrocoated with dodecyloxyphenyl diazonium and coated with a thick (10 ⁇ m, 25 % paclitaxel) or thin (0.5 ⁇ m, 40 % paclitaxel) coating of SIBS:paclitaxel;
  • FIG. 36 is a graph presenting the percentage of paclitaxel released during incubation in phosphate buffer with 0.3 % SDS (pH 7.4, 37 °C) from stents coated with a 0.5 ⁇ m coating of SIBS ⁇ aclitaxel, both with and without pretreatment by electrocoating with dodecyloxyphenyl diazonium (each data point represents the average for 5 stents);
  • FIGs. 37a-b are graphs presenting the percentage of paclitaxel released during incubation in phosphate buffer with 0.3 % SDS (pH 7.4, 37 °C) from non-sterilized ( Figure 37a) and sterilized ( Figure 37b) stents coated with PEVA:PBMA:paclitaxel, both with and without pretreatment by electrocoating with dodecyloxyphenyl diazonium;
  • FIG. 38 is a graph presenting the percentage of paclitaxel released during incubation in phosphate buffer with 0.3 % SDS (pH 7.4, 37 0 C) from slow release (SR) and fast release (FR) model stents comprising a PEVA:PBMA:paclitaxel coating on bare metal stents, stents electrocoated with 4-(2-bromoethyl)phenyl diazonium and stents electrocoated with 4-(2-bromoethyl)phenyl diazonium with PMMA grafting;
  • FIGs. 39a-c are photographs showing a non-electrocoated stent ( Figure 39a), a stent electrocoated with 90 % 4-(2-hydroxyethyl)phenyl diazonium and 10 % 4- dodecyloxyphenyl diazonium ( Figure 39b) and a stent electrocoated with 90 % 4- dodecyloxyphenyl diazonium and 10 % 4-(2-hydroxyethyl)phenyl diazonium ( Figure 39c), which were coated with PEVA:PBMA:paclitaxel and incubated for 3 days in phosphate buffer with 0.3 % SDS at 60 °C;
  • FIGs. 40a-c are photographs showing a non-electrocoated stent ( Figure 40a), a stent electrocoated with 90 % 4-(2-hydroxyethyl)phenyl diazonium and 10 % 4- dodecyloxyphenyl diazonium ( Figure 40b) and a stent electrocoated with 90 % 4- dodecyloxyphenyl diazonium and 10 % 4-(2-hydroxyethyl)phenyl diazonium ( Figure 40c) which were coated with PEVA:PBMA:paclitaxel and incubated for 30 days in phosphate buffer with 0.3 % SDS at 60 0 C; FIGs.
  • FIGs. 42a-b are photographs showing stents electrocoated with 4- dodecyloxyphenyl diazoniuni, incubated for 30 days in phosphate buffer with 0.3 % SDS at 37 0 C, coated with PEVA:PBMA:paclitaxel and further incubated for 3 days ( Figure 41a) or 30 days ( Figure 41b) at 60 °C;
  • FIGs. 42a-b are photographs showing non-electrocoated stents incubated for 30 days in phosphate buffer with 0.3 % SDS at 37 °C, coated with PEVA:PBMA:paclitaxel and further incubated for 3 days ( Figure 42a) or 30 days ( Figure 42b) at 60 °C.
  • the present invention in some embodiments thereof, relates to a modified conductive surface and to uses thereof and, more particularly, but not exclusively, to a to a modified conductive surface, such as stainless steel surfaces, which can be utilized for efficiently attaching thereto a coating and/or drug, and can therefore be beneficially used in a variety of medical and other applications.
  • the present inventors have now designed a novel methodology for obtaining an organic coating on a conductive surface, which is highly beneficial for coating implantable medical devices.
  • This methodology is based on electrochemically attaching to a conductive surface optionally substituted aryl diazonium compounds, such as aryl diazonium salts, whereby these aryl diazonium compounds are designed so as to form aryl moieties that are electrochemically attached to the surface and are optionally further substituted by a functional moiety, as described herein.
  • the methodology presented herein is preferably effected by pretreatment of the substrate by application of cathodic potential, followed by reduction of the selected diazonium salts on its surface, resulting in a chemical bond between the metal and the aryl carbon formerly attached to the diazonium moiety.
  • the bond formed in this reaction is strong enough to withstand ultrasonication in acetonitrile for 15 minutes, and remains intact following incubation for 30 days and more under physiological conditions (e.g., pH 7.4, at 37 °C).
  • the aryl moieties were also found to be excellent adhesion primers for coatings applied onto the aryl moiety layer.
  • the inventors have developed novel aryl diazonium compounds which are particularly useful for attaching a coating thereto.
  • Figures 1 to 4 present electrochemical data indicating that poly(p-diazostyrene) was successfully electroattached to stainless steel stents.
  • electroattach and grammatical derivatives thereof, describes the electrochemical attachment of an aryl moiety (or aryl moieties) to a conductive surface.
  • the electroattached aryl moiety (or aryl moieties) may form a continuous layer on the surface. Formation of such a layer is also referred to herein as
  • Figures 5-7 present electrochemical data indicating that tetrakis[(4- diazophenoxy)methyl]methane was successfully electroattached to stents
  • Figures 9-10 demonstrate electrocoating with 1,8-didiazoanthracene
  • Figures 11-13 demonstrate electrocoating with 3,5-didiazobenzoic acid.
  • Figure 14 presents electrochemical data indicating both the successful electroattachment of 4-(2-bromoethyl)phenyl diazonium to a stent, as well as the successful grafting of PMMA onto the electrochemically attached 4-(2- bromoethyl)phenyl moieties.
  • Figures 15-17 present electrochemical data for stents electroattached to various proportions of 4-dodecyloxyphenyl diazonium and 4-(2-hydroxyethyl)phenyl diazonium. The results presented therein indicate successful electrocoating. The results further indicate that the electrochemical properties of the stent surface depend on the proportion of the two diazonium compounds used, and thus the properties of the stent may be modulated by changing the proportions of diazonium compounds used for electrocoating.
  • Figures 18-35 are photographs and scanning electron micrographs which demonstrate that polymer-based coatings on electrocoated stents are far more stable to incubation than are polymer-based coatings on non-electrocoated stents.
  • Figures 36-38 present data indicating that electrocoating stents alters the kinetics of the release of paclitaxel from polymer-based coatings on the stents.
  • Figures 39-40 are photographs showing that polymer-based coatings on stents electrocoated with mixtures of 4-dodecyloxyphenyl diazonium and 4-(2- hydroxyethyl)phenyl are more stable to incubation than polymer-based coatings on non-electrocoated stents. The results further indicate that the degree of stabilization depends on the proportion of the two diazonium salts used to electrocoat the stents.
  • Figures 41-42 are photographs showing that electrocoated stents which have been incubated under physiological conditions for 30 days before being coated with a polymer retain the ability to preserve the integrity of the polymer-based coating.
  • composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.
  • the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.
  • the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
  • an article-of-manufacturing comprising an object having a conductive surface and at least one aryl moiety being electrochemically attached to the conductive surface, such that a plurality of such aryl moieties attached to the conductive surface form a layer on the surface.
  • conductive surface encompasses the surface of electrically conductive and electrically semiconductive substances.
  • exemplary conductive surfaces comprise one or more metals or an alloy thereof.
  • the metal may be, for example, iron, stainless steel, titanium, nickel, tantalum, platinum, gold, silver, copper and any combination thereof.
  • the conductive surface comprises stainless steel.
  • the article-of-manufacturing is a medical device.
  • the medical device can be any medical device that comprises a metal surface and includes, for example, extra corporeal devices such as aphaeresis equipment, blood handling equipment, blood oxygenators, blood pumps, blood sensors, fluid transport tubing and the like.
  • the medical device can be an intra corporeal device such as, but not limited to, aortic grafts, arterial tubing, artificial joints, blood oxygenator membranes, blood oxygenator tubing, bodily implants, catheters, dialysis membranes, drug delivery systems, endoprostheses, endotracheal tubes, guide wires, heart valves, intra- aortic balloons, medical implants, pacemakers, pacemaker leads, stents, ultrafiltration membranes, vascular grafts, vascular tubing, venous tubing, wires, orthopedic implants, implantable diffusion pumps and injection ports.
  • intra corporeal device such as, but not limited to, aortic grafts, arterial tubing, artificial joints, blood oxygenator membranes, blood oxygenator tubing, bodily implants, catheters, dialysis membranes, drug delivery systems, endoprostheses, endotracheal tubes, guide wires, heart valves, intra- aortic balloons, medical implants, pacemakers, pacemaker leads, stents, ultra
  • the medical device is optionally an implantable medical device, i.e. a medical device suitable for implantation in a subject.
  • implantable device i.e. a medical device suitable for implantation in a subject.
  • implantable device is used herein to describe any medical device that is placed within a bodily cavity for a prolonged time period.
  • implantable medical devices include a pacemaker, a graft, a stent, a wire, an orthopedic implant, an implantable diffusion pump, an injection port and a heart valve.
  • the device is a stent, and more particularly an expandable stent.
  • stents can be of various types, shapes, applications and metal compositions and may include any known stents. Representative examples include the Z, Palmaz, Medivent, Strecker, Tantalum and Nitinol stents.
  • the article-of-rnanufacturing is a medical device
  • the aryl moiety is selected such that the layer of the aryl moiety on the surface remains intact upon being subjected to physiological and/or mechanical conditions associated with the medical device.
  • the aryl moiety may be selected, for example, such that the layer remains intact for at least 3 days under such conditions, for at least 6 days, for at least 10 days, for at least 20 days, for at least 30 days, for at least 3 months, and even for at least one year under such conditions.
  • the aryl moiety layer may be shown to remain intact by determining that a property of the aryl moiety layer (e.g. electrical insulation or the ability to strengthen adhesion of a coating) before exposing the layer to the abovementioned conditions remains present and substantially unchanged following exposure to those conditions.
  • a property of the aryl moiety layer e.g. electrical insulation or the ability to strengthen adhesion of a coating
  • physiological conditions include, for example, aqueous media, blood and serum, and all biological factors and entities present therein.
  • Mechanical conditions include, for example, expansion (e.g., in case of a stent) and mechanical abrasion.
  • the durability of the aryl moiety layer when subjected to mechanical conditions such as expansion is important.
  • the expansion procedure involved in stent implantation weakens the binding of a coating on the stent and thus adversely affects the stability of the coating and its efficacy in exerting its desired activity.
  • the aryl moiety is therefore selected such that the later formed thereof remains intact also during the expansion procedure.
  • Another important feature is the mechanical pressures involved in orthopedic implantable devices, which often adversely affect the binding of a coating to the device.
  • the aryl moiety described herein is therefore selected such that the layer formed thereof remains intact also upon being subjected to these pressures.
  • physiological and/or mechanical conditions associated with the device will depend on the type and/or use of the device, and will be apparent to one skilled in the art.
  • One skilled in the art will be familiar with methods for reproducing such conditions in order to test the aryl moiety layer on a device.
  • physiological conditions in the blood may be reproduced by exposing a device to serum and/or any buffer used in the art to provide physiological conditions (e.g. phosphate buffer, pH 7.4).
  • physiological conditions in the device may be reproduced by exposing a device to serum and/or any buffer used in the art to provide physiological conditions (e.g. phosphate buffer, pH 7.4).
  • Mechanical conditions may be reproduced by exposing the device to friction and/or stress equivalent to the maximal friction and/or stress for which the device is expected to be exposed during use.
  • the article-of- manufacturing further comprises a coating which coats the aryl moiety layer.
  • the coating comprises a polymeric material.
  • Exemplary polymers include poly(ethylene-vinyl acetate) (a copolymer of ethylene and vinyl acetate, also referred to herein as PEVA), poly(butyl methacrylate) (PBMA), poly(styrene-isobutylene-styrene) (SIBS), poly-L- lactide and poly- ⁇ -caprolactone, as well as mixtures and copolymers thereof.
  • the polymer may be, for example, a mixture of PEVA and PBMA, or SIBS, or a copolymer of po Iy-L- lactide and poly- ⁇ -caprolactone.
  • polymeric material and “polymer-based” describe a material that is made essentially from a polymer.
  • the coating polymer is biodegradable.
  • biodegradable polymers include poly-L-lactide and poly- ⁇ -caprolactone, as well as mixtures and copolymers thereof.
  • the coating adheres to the layer of the at least one aryl moiety electrochemically attached to the conductive surface more strongly than to the conductive surface without the aryl moiety layer.
  • the adhesion of the coating to the two abovementioned types of surface may be measured by various methods which will be known to one of ordinary skill in the art.
  • the adhesion is measured under conditions similar or equivalent to the physiological and/or mechanical conditions associated with the use of a particular device being coated according to an embodiment of the present invention.
  • the stronger adhesion of the coating to the surface is characterized in that peeling of the coating from the aryl moiety layer electrochemically attached to the conductive surface is at least 5 % lower, optionally at least 10 % lower, optionally at least 20 % lower, optionally at least 30 % lower, optionally at least 50 % lower, optionally at least 75 % lower, and optionally at least 90 % lower, than peeling of the same coating from the conductive surface without the aryl moiety, when performing a comparative D-3359-02 ASTM test following incubation of each of the surfaces with the coating in an aqueous solution of a phosphate buffer (e.g. about 0.1 M phosphate) comprising 0.3 % (by weight) sodium dodecyl sulfate (SDS), at a pH of 7.4 and a temperature of 37 °C.
  • a phosphate buffer e.g. about 0.1 M phosphate
  • SDS sodium dodecyl sulfate
  • the stronger adhesion of the coating to the surface is characterized in that the percentage of defective areas on the coating adhered to the aryl moiety layer electrochemically attached to the conductive surface is at least 10 % lower, optionally at least 20 % lower, optionally at least 30 %, optionally at least 50 % lower, optionally at least 75 %, optionally at least 90 % lower, optionally at least 95 % lower and optionally at least 98 % lower than the percentage of defective areas on a same coating adhered to the conductive surface without the aryl moiety layer when examining each of the coatings by scanning electron microscopy at a magnification of x300 following incubation of the coatings in an aqueous solution of a phosphate buffer comprising 0.3 % sodium dodecyl sulfate, at a pH of 7.4 and a temperature of 60 °C, each of the areas being a field of about 0.9 mm by about 0.9 mm, and the defective areas being any of
  • the phrase "failure in the integrity of the coating” refers to the presence of any gap or tear in the coating of the surface, such as a crack, or partial or complete detachment of a portion of the coating so as to reveal underlying coating material and/or the conductive surface.
  • a failure in the integrity of the coating is defined as any defect from the group consisting of cracking, flaking, delamination and peeling, as these terms are defined in the art.
  • the coating remains intact for at least 3, 6, 10, 20 or even 30 days under physiological conditions.
  • the abovementioned aqueous solution is used to reproduce physiological conditions.
  • the coating remains intact for at least 3, 6, 10, 20 or 30 days under any other conditions used in the art to reproduce physiological conditions.
  • the coating is a matrix that comprises at least one pharmaceutically active agent.
  • pharmaceutically active agent describes any agent that exhibits a beneficial activity when administered to a subject.
  • the agent may exhibit such an activity directly or may trigger biological processes that result is such an activity.
  • a beneficial activity includes, for example, reducing adverse side effects induced by the metal surface and/or any other therapeutic activity.
  • the active agent can further be a labeling agent, which may serve for detecting and/or locating the substance to which it is attached in the body and may be used, for example, for diagnosis and follow-up purposes.
  • labeling agent is therefore used herein to describe a detectable moiety or a probe and includes, for example, chromophores, fluorescent compounds, phosphorescent compounds, heavy metal clusters, and radioactive labeling compounds, as well as any other known detectable moieties.
  • the active agent may be labeled and thus further serves as a labeling agent.
  • some labeling agents, such as radioisotopes can also serve as pharmaceutically active agents.
  • Exemplary pharmaceutically active agents for use in the context of any of the embodiments described herein include, without limitation, an anti-thrombogenic agent, an anti-platelet agent, an anti-coagulant, a growth factor, a statin, a toxin, an antimicrobial agent, an analgesic, an anti-metabolic agent, a vasoactive agent, a vasodilator agent, a prostaglandin, a hormone, a thrombin inhibitor, an enzyme, an oligonucleotide, a nucleic acid, an antisense, a protein, an antibody, an antigen, a vitamin, an immunoglobulin, a cytokine, a cardiovascular agent, endothelial cells, an anti-inflammatory agent, an antibiotic, a chemotherapeutic agent, an antioxidant, a phospholipid, an anti-proliferative agent, a corticosteroid, a heparin, a heparinoid, albumin, a gamma glob
  • Pharmaceutically active agents such as anti-thrombogenic agents, anti-platelet agents, anti-coagulants, statins, vasoactive agents, vasodilator agents, prostaglandins, thrombin inhibitors, plasma proteins, cardiovascular agents, endothelial cells, anti- inflammatory agents, antibiotics, antioxidants, phospholipids, heparins and heparinoids are particularly useful when the medical device is a stent.
  • Pharmaceutically active agents such as analgesics, anti-metabolic agents, antibiotics, growth factors and the like, are particularly useful when the medical device is an orthopedic implant.
  • An anti-proliferative agent is particularly suitable for certain medical devices (e.g. stents).
  • Paclitaxel is an exemplary anti-proliferative agent.
  • the matrix may comprise a plurality of layers comprising different ingredients. Some of the layers may comprise at least one pharmaceutically active agent, as described herein, while some of the layers may lack a pharmaceutically active agent.
  • a matrix may consist of a layer comprising a pharmaceutically active agent beneath a layer (i.e. a "top coat") which does not comprise a pharmaceutically active agent.
  • top coat a layer comprising a pharmaceutically active agent beneath a layer which does not comprise a pharmaceutically active agent.
  • the term "matrix” describes a solid or semi-solid (e.g., gel- like) substance having an agent (e.g. a pharmaceutically active agent) bound thereto. The agent may be bound by a molecular interaction with the solid or semi-solid substance.
  • the agent can be bound to the solid or semi-solid substance via a covalent, electrostatic (ionic), hydrophobic, van der Waals and hydrogen bonding chemical interaction.
  • the agent may be physically bound to the matrix by, for example, being embedded in the solid or semi-solid substance of the matrix.
  • the article-of- manufacturing further comprises a plurality of microparticles and/or nanoparticles covalently bound to the aryl moiety layer.
  • each individual aryl moiety is bound to a single particle.
  • an aryl moiety may be bound to more than one particle.
  • the particles are bound to the aryl moiety via a chemical reaction with one or more functional groups of the aryl moiety. The number of these functional groups and their chemical nature can determine the number of particles bound to an aryl moiety.
  • microparticle describes a particle between 1 and 100 ⁇ m (microns) in size
  • nanoparticle describes a particle smaller than 1 ⁇ m (micron) in size
  • particle encompasses microparticles and nanoparticles.
  • An aryl moiety may be covalently bound to a particle by a linking group that is a substituent of any part of the aryl moiety and/or a linking group that is a substituent of the particle.
  • the linking group may be any linking group, as defined herein.
  • the linking group is a group which may be readily formed by reacting two end groups.
  • the particles comprise a pharmaceutically active agent.
  • the article-of- manufacturing further comprises a pharmaceutically active agent bound to the aryl moiety via an interaction selected from the group consisting of a covalent bond, an ionic bond, a hydrogen bond and a van der Waals interaction.
  • the pharmaceutically active agent may be covalently bound to the aryl moiety in the same manner as described hereinabove for microparticles and/or nanoparticles.
  • aryl moiety refers to a chemical moiety comprising at least one aromatic group.
  • the aryl moiety further comprises one or more substituents attached to the aromatic group.
  • the substituent may be an end group or a linking group, as defined herein.
  • aromatic group encompasses aryl and heteroaryl, as these terms are defined herein.
  • the aromatic group is phenyl.
  • end group describes a group (a substituent) that is attached to a single moiety in the compound via one atom thereof.
  • linking group describes a group (a substituent) that is attached to two or more moieties in the compound.
  • a linking group in an aryl moiety may be attached to two or more moieties comprised by the aryl moiety (e.g. two or more aromatic groups and/or two or more atoms of a single aromatic group).
  • a linking group may also link the aryl moiety to one or more other moieties.
  • a substituent attached to an aromatic group may comprise at least one functional group which is an end group or a linking group.
  • the substituent consists of the functional group.
  • the phrase "functional group” describes a chemical group which confers a functionality (e.g. a chemical and/or physical property) upon a compound comprising that group.
  • Exemplary functional groups include alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, carboxy, thiocarboxy, ether, thioether, epoxide (oxirane), sulfonyl, sulf ⁇ nyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, carbamyl and thiocarbamyl.
  • the functional group is selected from the group consisting of alkyl, hydroxyalkyl, haloalkyl, alkoxy, carboxy and nitro.
  • the conductive surface has at least two aryl moieties being electrochemically attached thereto, at least one of the aryl moieties comprising a hydrophilic functional group and at least one other of the aryl moieties comprising a hydrophobic functional group.
  • Dodecyloxy is an exemplary hydrophobic functional group.
  • 2-hydroxyethyl is an exemplary hydrophilic functional group.
  • 4-dodecyloxyphenyl is an exemplary aryl moiety comprising a hydrophobic functional group.
  • 4-(2-hydroxyethyl)phenyl is an exemplary aryl moiety comprising a hydrophilic functional group.
  • alkyl describes a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 20 carbon atoms. Whenever a numerical range; e.g., "1-20", is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted.
  • Substituted alkyl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, guanyl, guanidine and hydrazine.
  • substituent group can independently be, for example, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide,
  • the alkyl group can be an end group, as this phrase is defined hereinabove, wherein it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, which connects two or more moieties.
  • cycloalkyl describes an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system.
  • the cycloalkyl group may be substituted or unsubstituted.
  • Substituted cycloalkyl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyi, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, guanyl, guanidine and hydrazine.
  • the cycloalkyl group can be an end group, as this phrase is defined hereinabove, wherein it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, connecting two or more moie
  • aryl describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system.
  • the aryl group may be substituted or unsubstituted.
  • Substituted aryl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, guanyl, guanidine and hydrazine.
  • the aryl group can be an end group, as this term is defined hereinabove, wherein it is attached to a single adjacent atom, or a linking group, as this term is defined hereinabove, connecting two or more moieties.
  • heteroaryl describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
  • the heteroaryl group may be substituted or unsubstituted.
  • Substituted heteroaryl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxy, O- carboxyl, N-thiocarbamate, 0-thiocarbamate, urea, thiourea, 0-carbamate, N- carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.
  • substituent group can independently be, for example, hydroxyalkyl, haloalkyl, cycloalkyl, al
  • the heteroaryl group can be an end group, as this phrase is defined hereinabove, where it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, connecting two or more moieties.
  • Representative examples are pyridine, pyrrole, oxazole, indole, purine and the like.
  • amine describes both a -NRxRy group and a -NRx- group, wherein Rx and Ry are each independently hydrogen, alkyl, cycloalkyl, or aryl, as these terms are defined herein.
  • the amine group can therefore be a primary amine, where both Rx and Ry are hydrogen, a secondary amine, where Rx is hydrogen and Ry is alkyl, cycloalkyl or aryl, or a tertiary amine, where each of Rx and Ry is independently alkyl, cycloalkyl or aryl.
  • halide and "halo" describes fluorine, chlorine, bromine or iodine.
  • haloalkyl describes an alkyl group as defined above, further substituted by one or more halide(s).
  • hydroxyalkyl describes an alkyl group as defined above, further substituted by one or more hydroxy groups.
  • aminoalkyl describes an alkyl group as defined above, further substituted by one or more amines.
  • sulfonamide encompasses both S-sulfonamides and N-sulfonamides.
  • dithiosulfide refers to a -S-SRx end group or a -S-S- linking group, as these phrases are defined hereinabove, where Rx is as defined herein.
  • aldehyde as used herein, describes a carbonyl end group wherein Rx is hydrogen.
  • hydroxy and “hydroxyl” describe a -OH group.
  • alkoxy describes both an -O-alkyl and an -O-cycloalkyl group, as defined herein.
  • aryloxy describes both an -O-aryl and an -O-heteroaryl group, as defined herein.
  • thiohydroxy describes a -SH group.
  • thioalkoxy describes both a -S-alkyl group, and a -S-cycloalkyl group, as defined herein.
  • thioaryloxy describes both a -S-aryl and a -S-heteroaryl group, as defined herein.
  • ether describes groups in which a carbon atom in an alkyl, cycloalkyl, aryl or heteroaryl is attached to an alkoxy or aryloxy group.
  • thioether describes groups in which a carbon atom in an alkyl, cycloalkyl, aryl or heteroaryl is attached to a thioalkoxy or thioaryloxy group.
  • nitro describes an -NO 2 group.
  • peroxo describes an -O-ORx end group or an -0-0- linking group, as these phrases are defined hereinabove, with Rx as defined hereinabove.
  • thiocarboxy encompasses both C-thiocarboxy and 0-thiocarboxy groups.
  • amide as used herein, encompasses both C-amides and N-amides.
  • thiocarbamyl or "thiocarbamate”, as used herein, encompasses both O-thiocarbamates and N-thiocarbamates.
  • epoxide describes a group or a Rx R y linking group, as these phrases are defined hereinabove, where Rx, Ry Rw are as defined herein.
  • thiirane describes a group that is equivalent to an epoxide, wherein the oxygen atom of the epoxide is replaced with a sulfur atom.
  • aziridine describes a group that is equivalent to an epoxide, wherein the oxygen atom of the epoxide is replaced with a nitrogen atom, and the nitrogen atom binds, in addition to two adjacent carbon atoms, Rq, wherein Rq is defined according to the same definition as Rx.
  • hydrazine describes a -NRx-NRyRw end group or a -NRx-NRy- linking group, as these phrases are defined hereinabove, with Rx, Ry, and Rw as defined herein.
  • disulfide describes an end group -S-S-Rx, or a linking group -S-S-, wherein Rx is as defined hereinabove.
  • heteroalicyclic describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. The heteroalicyclic may be substituted or unsubstituted.
  • Substituted heteroalicyclic may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxy, O-carboxy, N-thiocarbamate, O-thiocarbamate, urea, thiourea, O-carbamate, N-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.
  • substituent group can independently be, for example, hydroxyalkyl, haloalkyl, cycloalkyl,
  • the heteroalicyclic group can be an end group, as this phrase is defined hereinabove, where it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, connecting two or more moieties.
  • Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino and the like.
  • the phrases "electrochemically attached” and “electrochemically attaching” describe a moiety attached to a substance (e.g. a conductive surface) by a chemical reaction that is induced by an application of an electric potential and/or current.
  • the chemical reaction is a redox reaction.
  • the application of the electric potential and/or current is by connecting the conductive surface to a voltage source and/or current source.
  • the moiety may be attached by one or more of any type of molecular interaction (e.g. a covalent bond, a hydrogen bond, a hydrophobic interaction, an ionic bond, a van der Waals interaction).
  • the aryl moiety is non-covalently attached to the conductive surface.
  • the aryl moiety is covalently attached to the conductive surface.
  • an aryl moiety is considered covalently attached to a surface when a bond between the aryl moiety and the surface represents at last one of the valence bonds of the aryl moiety.
  • the present inventors have devised a methodology that utilizes various aryl moieties, designed suitable to achieve the desired properties of the resulting article-of- manufacturing.
  • the layer of at least one aryl moiety being electrochemically attached to the conductive surface comprises at least two aryl moieties being electrochemically attached to the surface, the aryl moieties being different from one another.
  • the properties of the surface with the attached aryl moiety layer may be modulated by selecting appropriate proportions of the different aryl moieties.
  • the aryl moiety is substituted by at least one functional group at a meta or ortho position of the aryl moiety, with respect to the position of the aryl moiety that is being electrochemically attached to the surface.
  • the aryl moiety is electrochemically attached to the surface via at least two positions of the aryl moiety.
  • Such an aryl moiety provides a particularly strong attachment of the aryl moiety layer to the surface thereby increasing the durability of the layer.
  • the aryl moiety comprises at least two aromatic groups covalently linked to one another via a linker.
  • aromatic groups are particularly suitable for attachment to a conductive surface, such an aryl moiety allows attachment to the conductive surface at a plurality of positions, while minimizing the steric hindrance typically involved in attaching an aryl moiety to a surface via more than one position.
  • the aryl moiety comprises one or more functional groups which are alkyl and/or alkoxy.
  • exemplary alkyl and alkoxy groups suitable for use in the context of the present embodiments include alkyl and alkoxy groups comprising from 4 to 20 carbon atoms (e.g. hexyloxy, dodecyloxy and octadecyloxy groups).
  • the alkyl and/or alkoxy groups are unsubstituted.
  • the alkoxy group is dodecyloxy (e.g. -O-C12H25).
  • the aryl moiety comprises a hydroxyalkyl functional group.
  • 2-hydroxyethyl is an exemplary hydroxyalkyl group.
  • the aryl moiety comprises a haloalkyl functional group.
  • 2-haloethyl e.g. 2-bromoethyl
  • 2-haloalkyl is an exemplary haloalkyl group.
  • the aryl moiety comprises a mtro group as a functional group.
  • the aryl moiety comprises a phenyl group electrochemically attached to the conductive surface.
  • phenyl describes an aromatic group consisting of a 6-carbon aryl ring, the ring being either substituted or non-substituted.
  • the phenyl may be an end group (e.g. -C6H5) or a linking group (e.g. -C6H4-), as these terms are defined hereinabove.
  • the phenyl can be substituted by any of the abovementioned alkyl, hydroxyalkyl, haloalkyl, alkoxy, carboxy and/or nitro functional groups.
  • a functional group is attached to the phenyl at a para position with respect to a position of the phenyl that is electrochemically attached to the conductive surface.
  • the phenyl is substituted by a single functional group, such that the aryl moiety consists of alkylphenyl, hydroxyalkylphenyl, haloalkylphenyl, alkoxyphenyl, carboxyphenyl or nitrophenyl.
  • the phenyl is attached to the surface at a single position of the phenyl.
  • the aryl moiety is a polymer comprising a plurality of aromatic groups being covalently linked to one another via a linker.
  • the plurality of aromatic groups comprises a plurality of phenyl groups.
  • Polystyrene wherein one or more of the phenyl groups thereof is attached to the conductive surface, is an exemplary polymer comprising a plurality of phenyl groups.
  • a plurality of phenyl groups of the polystyrene are attached to the conductive surface (e.g. at the para position with respect to the linker).
  • all of the phenyl groups are attached to the surface.
  • the polystyrene is further substituted by a substituent (e.g. a substituent attached to a phenyl).
  • polymer describes a molecule comprising 3 or more repeating, covalently bound, structural units.
  • structural units are a substituted aromatic group (e.g. styrene).
  • the polymer (e.g., the polystyrene described herein) comprises 10 or more repeating structural units (e.g., aromatic groups). In one embodiment, the polymer comprises from about 10 to about 40 aromatic groups.
  • the polystyrene preferably comprises from about 15 to about 30 aromatic groups (i.e. phenyl), more preferably from about 20 to about 25 aromatic groups.
  • the number of aromatic groups in a polymer refers to the mean number of aromatic groups in the polymer, which may be calculated for example, from the number average molecular weight of the polymer, as determined by any suitable method (e.g. gel permeation chromotography).
  • the polydispersity of the polymer size is less than 1.3.
  • the polydispersity is less than 1.2.
  • the aryl moiety comprises at least two aromatic groups covalently linked to one another via a linker.
  • the aryl moiety may comprise more than one linker linking at least two aromatic groups.
  • Each linker may link two or more aromatic groups.
  • the linker may be any linking group, as this term is defined herein.
  • the linker is a bond linking two aromatic groups, such that the aryl moiety comprises at least two aromatic groups linked by one or more bonds (e.g. biphenyl, terphenyl, polyphenylene, fluorene and the like).
  • the linker comprises a plurality of alkoxy groups, wherein each of the alkoxy groups is attached to one of the at least two aromatic groups of the aryl moiety.
  • each aromatic group is attached to a single alkoxy group on the linker.
  • the aryl moiety is a polymer, as described hereinabove.
  • the aryl moiety is not a polymer, as defined hereinabove.
  • a linking group derived from pentaerythritol e.g. C(CH2O-)4 is an exemplary linker.
  • the aryl moiety comprises a phenyl attached to the surface via at least two positions of the phenyl.
  • the two attached positions of the phenyl are at a meta position with respect to one another.
  • the phenyl is further substituted by a carboxy group.
  • Exemplary aryl moieties include benzoic acid attached to the surface at the 3- and 5- positions thereof.
  • the aryl moiety comprises at least two aromatic groups fused to one another.
  • the aryl moiety comprises anthracene.
  • the anthracene is attached to the surface via at least two positions thereof.
  • Exemplary aryl moieties include anthracene attached to the surface via. the 1- and 8- positions thereof.
  • the abovementioned article-of-manufacturing optionally comprises the aryl moiety electrochemically attached to the conductive surface by electrochemically reacting a diazo-substituted derivative of the aryl moiety with the conductive surface, as described in detail hereinbelow.
  • a process of preparing an object having a conductive surface and at least one aryl moiety being electrochemically attached to the surface and forming a layer of the at least one aryl moiety comprising: providing at least one aryl moiety substituted by at least one diazonium moiety (also referred to herein as a "diazo-substituted aryl moiety"); and electrochemically attaching the aryl moiety substituted by the at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of the at least one aryl moiety being electrochemically attached to the surface.
  • diazo and diazonium moiety refer to a -N+ ⁇ N end group.
  • the aryl moiety substituted by at least one diazonium moiety will in many cases be electrically charged, and thus will be in the form of a salt comprising the substituted aryl moiety and at least one counter-ion.
  • Tetrafluoroborate i.e. BF4-
  • the at least one diazonium moiety is a substituent(s) of an aromatic group of the aryl moiety.
  • a compound which consists of the aryl moiety, as defined hereinabove, substituted by the at least one diazonium moiety, or a salt thereof.
  • the compound consists of the aryl moiety substituted by the at least one diazonium group, the aryl moiety being attached to one or more additional moieties.
  • the diazo-substituted aryl moiety is substituted by a diazonium moiety at each position of the aryl moiety that is electrochemically attached to the conductive surface.
  • the diazo-substituted aryl moiety is electrochemically attached to the conductive surface at only part of the positions substituted by a diazonium moiety.
  • Exemplary diazo-substituted aryl moieties are designed to be capable of reacting with a conductive surface so as to provide a high yield of bonds between the aryl moiety and the surface.
  • the aryl moiety is attached to a portion of the conductive surface.
  • the aryl moiety is attached to the whole area conductive surface.
  • the abovementioned process further comprises interacting at least one aryl moiety electroattached to the surface with at least one pharmaceutically active agent, to thereby bind the at least one pharmaceutically active agent.
  • the interacting may comprise contacting the at least one aryl moiety with the pharmaceutically active agent so as to form a covalent bond, an ionic bond, a hydrogen bond and/or a van der Waals interaction between the pharmaceutically active agent and the aryl moiety.
  • the provided diazo-substituted aryl moiety comprises a first functional group
  • the pharmaceutically active agent comprises a second functional group
  • the first functional group and the second functional group being selected capable of interacting with each other to thereby bind the at least one pharmaceutically active agent to the at least one aryl moiety.
  • a reagent is provided which induces a reaction between the first and second functional groups.
  • the pharmaceutically active agent is optionally modified so as to comprise the abovementioned second functional group.
  • a covalent bond in the pharmaceutically active agent linked to an aryl moiety is biodegradable such that a pharmaceutically active agent is released from the aryl moiety attached to the surface when exposed to a physiological environment.
  • a process of preparing an object having a conductive surface, at least one aryl moiety being electrochemically attached to the surface and forming a layer of said at least one aryl moiety, and a coating which coats the layer of said at least one aryl moiety comprising: providing at least one aryl moiety substituted by at least one diazonium moiety; electrochemically attaching the at least one aryl moiety substituted by the at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of at least one aryl moiety being electrochemically attached to the surface; and applying a coating onto the layer of the at least one aryl moiety.
  • the coating is applied subsequent to the electrochemical attachment of the at
  • the coating may be any coating described hereinabove, including, for example, a matrix which comprises at least one pharmaceutically active agent, as defined hereinabove.
  • applying the coating comprises contacting the object having a layer of at least one aryl moiety electrochemically attached to a surface of the object with a solution that comprises the coating.
  • the solution may consist essentially of the component(s) of the coating, wherein for example, the solution hardens to form the coating.
  • the solution may alternatively comprise the component(s) of the coating dissolved or dispersed in a solvent, wherein the coating is formed when the solvent evaporates.
  • the solution comprises a polymer, the polymer being a component of the coating.
  • the polymer may comprise a mixture of polymers and/or a copolymer.
  • the solution further comprises at least one pharmaceutically active agent, the active agent being a component of the coating. Exemplary polymers (including copolymers and polymer mixtures) and pharmaceutically active agents for inclusion in coatings are described hereinabove.
  • the abovementioned process comprises providing at least two aryl moieties, each being substituted by at least one diazonium moiety, and being different from one another; and/or providing a one diazo-substituted aryl moiety that is further substituted by at least one functional group at a meta or ortho position of the aryl moiety with respect to a position that is substituted with a diazonium moiety; and/or a diazo-substituted aryl moiety substituted by at least two diazonium moieties; and/or a diazo-substituted aryl moiety comprising at least two aromatic groups fused to one another; and/or a diazo- substituted aryl moiety comprising at least two aromatic groups linked to one another via a linker, as defined and discussed hereinabove.
  • Exemplary functional groups, linkers and aromatic groups are as described hereinabove with regard to aryl moieties attached to a conductive surface.
  • Exemplary aryl moieties substituted by at least two diazonium groups include: (a) a compound having the formula:
  • B is aryl; n is an integer greater than 1 ;
  • A is at least one group substituting a position of said aryl, said at least one group being independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, haioalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, carboxy, thiocarboxy, ether, thioether, epoxide (oxirane), sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, carbamyl and thiocarbamyl; and/or (b) a compound having the formula:
  • E is a diazonium moiety
  • G is aryl
  • J is absent or is selected from the group consisting of O, S and NH; m is an integer greater than 1; and K is selected from the group consisting of alkylene and a polymer.
  • the A moiety herein throughout includes all atoms and/or substituents of the aryl (i.e. the B moiety) which are not D (i.e. the diazonium moieties).
  • aryl which has 6 positions for substituents
  • A includes 6-n groups independently selected groups from among the abovementioned groups;
  • naphthalene which has 8 positions for substituents, A includes 8-n groups.
  • two or more such groups are linked so as to form a linking group which is attached to B at at least two positions thereof.
  • polydiazostyrene a compound wherein K is polyethylene, J is absent and G is phenyl
  • the polydiazostyrene comprises from about 10 to about 40 phenyl groups, optionally from about 15 to about 30 phenyl groups, and optionally from about 20 to about 25 phenyl groups.
  • the abovementioned process comprises electrochemically attaching at least two aryl moieties, each being substituted by at least one diazonium moiety, to the conductive surface, at least one of the aryl moieties comprising a hydrophilic functional group and at least one other of the aryl moieties comprising a hydrophilic functional group.
  • Dodecyloxy is an exemplary hydrophobic functional group.
  • 2-hydroxyethyl is an exemplary hydrophilic functional group.
  • 4-dodecyloxyphenyl diazonium is an exemplary diazo-substituted aryl moiety comprising a hydrophobic functional group.
  • 4-(2-hydroxyethyl)phenyl diazonium is an exemplary diazo-substituted aryl moiety comprising a hydrophilic functional group.
  • a process of preparing an object having a conductive surface and at least one aryl moiety being electrochemically attached to the surface and forming a layer of at least one aryl moiety, the aryl moiety being covalently bound to at least one microparticle and/or nanoparticle comprising: providing at least one aryl moiety substituted by at least one diazonium moiety; electrochemically attaching the at least one aryl moiety substituted by at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of at least one aryl moiety being electrochemically attached to said surface; and reacting the aryl moiety electroattached to the conductive surface with the at least one microparticle and/or nanoparticle, thereby obtaining the aryl
  • the aryl moiety comprises at least one of a first functional group and the microparticle and/or nanoparticle comprises a second functional group, the first functional group and second functional group being selected capable of reacting with each other, as described hereinabove, to covalently bind the aryl moiety to the microparticle and/or nanoparticle.
  • the microparticle and/or nanoparticle comprises at least one pharmaceutically active agent.
  • a process of preparing an object having a conductive surface and at least one aryl moiety being electrochemically attached to the surface and forming a layer of the at least one aryl moiety, the aryl moiety being covalently bound to at least one microparticle and/or nanoparticle comprising: providing at least one aryl moiety substituted by at least one diazonium moiety and covalently linked to the at least one microparticle and/or nanoparticle; and electrochemically attaching the at least one aryl moiety substituted by at least one diazonium moiety to the conductive surface, thereby obtaining the object having a layer of at least one aryl moiety being electrochemically attached to the surface, the aryl moiety being covalently bound to at least one microparticle and/or nanoparticle.
  • a process of preparing an object having a conductive surface and at least one aryl moiety being electrochemically attached to the surface and forming a layer of at least one aryl moiety, the aryl moiety being covalently bound to at least one pharmaceutically active moiety comprising: providing at least one aryl moiety substituted by at least one diazonium moiety and covalently linked to the at least one pharmaceutically active moiety; and electrochemically attaching the at least one aryl moiety substituted by at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of at least one aryl moiety being electrochemically attached to the surface, the aryl moiety being covalently bound to at least one pharmaceutically active agent.
  • pharmaceutically active moiety describes a moiety comprising a pharmaceutically active agent.
  • a process of preparing an object having a conductive surface and at least one aryl moiety being electrochemically attached to the surface and forming a layer of at least one aryl moiety, the aryl moiety being covalently bound to at least one polymer comprising: providing at least one aryl moiety substituted by at least one diazonium moiety; electrochemically attaching the at least one aryl moiety substituted by at least one diazonium moiety to the conductive surface, thereby obtaining the object having the layer of at least one aryl moiety being electrochemically attached to the surface; and reacting the aryl moiety electroattached to the conductive surface with a plurality of monomers, such that the monomers undergo polymerization to form a polymer covalently bound to the aryl moiety.
  • the plurality of monomers may comprise a single species of monomer or a plurality of species of monomer.
  • Exemplary monomers include acrylic acid, methacrylic acid, esters of acrylic acid and esters of methacrylic acid.
  • the monomer is methyl methacrylate.
  • the diazo-substituted aryl moiety comprises a functional group selected capable of reacting with the plurality of monomers, such that the monomers undergo polymerization to form a polymer covalently bound to the aryl moiety.
  • An exemplary functional group for use in the abovementioned process is haloalkyl (e.g. 2- bromoethyl).
  • a catalyst is provided to catalyze a reaction between the aryl moiety and the monomer.
  • a reagent capable of inducing such a reaction e.g. a sacrificial initiator
  • the object of any of the processes described hereinabove is a medical device.
  • the medical device is an implantable medical device (e.g. a stent).
  • a method of treating a subject having a medical condition in which implanting a medical device is beneficial comprising implanting a medical device described hereinabove within the subject, thereby treating the condition.
  • exemplary conditions include a cardiovascular disease, atherosclerosis, thrombosis, stenosis, restenosis, a cardiologic disease, a peripheral vascular disease, an orthopedic condition, a proliferative disease, an infectious disease, a transplantation-related disease, a degenerative disease, a cerebrovascular disease, a gastrointestinal disease, a hepatic disease, a neurological disease, an autoimmune disease, and an implant-related disease.
  • the inventors of the present invention have developed novel compounds, specifically compounds comprising at least 2 diazonium moieties attached to an aromatic group, which are suitable for use in the abovementioned process.
  • B is aryl; n is an integer greater than 1; and A is at least one group substituting a position of said aryl, said at least one group being independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, carboxy, thiocarboxy, ether, thioether, epoxide (oxirane), sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, carbamyl and thiocarbamyl.
  • A includes all atoms and/or substituents attached to B which are not diazonium moieties, as described hereinabove.
  • B is phenyl.
  • the compound further comprises two diazonium moieties which are attached to the phenyl at meta positions with respect to one another.
  • A is selected from the group consisting of hydrogen and carboxyl.
  • B is a fused ring aryl, optionally anthracene.
  • A consists solely of hydrogens.
  • n 2.
  • An aryl moiety having at least two diazonium moieties attached to an aromatic group may also comprise a plurality of aromatic groups, each aromatic group being substituted by a single diazonium moiety.
  • E is a diazonium moiety
  • G is aryl
  • J is absent or is selected from the group consisting of O, S and NH; m is an integer greater than 1; and
  • K is selected from the group consisting of alkylene and a polymer.
  • Phenyl is an exemplary aryl (i.e. G moiety).
  • the diazonium moiety is selected from the group consisting of alkylene and a polymer.
  • E moiety is attached to the phenyl at a para position with respect to the position of the phenyl that is attached to J, or to K when J is absent.
  • K is polyethylene and J is absent.
  • m is in the range of 10 to 40, optionally in the range of 15 to 30, and optionally in the range of 20 to 25.
  • K is C(CH2)4 and m is 4, such that each CH2 is attached to a (- J-G-E) moiety.
  • J is oxygen.
  • Tetrafluoroborate salts are exemplary salts of the abovementioned compounds. According to another aspect of the present invention there is provided a use of any of the abovementioned compounds for forming a layer of at least one aryl moiety on a conductive surface.
  • Stainless steel stents (STI 316L, 0.9 cm) were obtained from STI Laser
  • Acetonitrile was obtained from Biolab;
  • Acetonitrile (extra-dry, ⁇ 10 ppm water) was obtained from Sigma- Aldrich; 4-aminophenol was obtained from Sigma-Aldrich;
  • Chloroform was obtained from Biolab
  • CuCl and CuC12 were obtained from Sigma-Aldrich;
  • Dichloromethane was obtained from Biolab; 3,5-diaminobenzoic acid was obtained from Sigma-Aldrich;
  • 1,8-dinitroanthroquinone was obtained from Sigma-Aldrich;
  • Methyl methacrylate was obtained from Fluka
  • Nitrophenolate was obtained from Sigma-Aldrich; Paclitaxel was obtained from BioxelPharma;
  • Pentaerythritol was obtained from Sigma-Aldrich;
  • TSf,N,N',N",N"-pentamethyldiethylenetriamine was obtained from Sigma-Aldrich; 1 -phenyl ethyl bromide (1-PEBr) was obtained from Sigma-Aldrich;
  • Poly(butyl methacrylate) (molecular weight 340,000 Da) was obtained from Sigma-Aldrich;
  • Poly(ethylene-vinyl acetate) was obtained from Dupont;
  • Tetrabutyl ammonium tetrafluoroborate (TBATFB, or Bu4N+ BF4-) was obtained from Sigma-Aldrich; Tetrafluoroboric acid was obtained from Sigma-Aldrich;
  • Tosyl chloride was obtained from Sigma-Aldrich.
  • FTIR 3058, 3024 (aryl C-H stretching theoretic value 3010-3080); 1600 (aryl C-H stretching theoretic value 1600); 697, (mono-substituted benzene theoretic value 690-710).
  • FTIR 2931 (aliphatic C-H stretching theoretic value 2980-2900); 1517 and 1350 (nitro theoretic value 1517 and 1347).
  • FTIR 1460 (CH 2 theoretic value 1440-1480), 1251 (CH 2 -O-C 6 H 4 theoretic value 1230-1270), 1514-(aromatic nitro theoretic value 1510-1550) ; 1342 (aromatic nitro theoretic value 1365-1335); 851 (aromatic nitro theoretic value 840-860).
  • 0.96 gram of tetrakis[(4-nitrophenoxy)methyl]methane, 0.5 gram palladium on carbon (Pd/C) 10 % and 50 ml tetrahydrofuran (THF) were placed in a hydrogenation bottle and hydrogenated using a Parr instrument at 65 pounds per square inch for 72 hours. The THF solution was filtrated twice, and the solvent was then evaporated. The yield was 0.74 gram of tetrakis[(4-aminophenoxy)methyl]methane as a brown oil.
  • FTIR -2250 (diazonium theoretic value 2200-2300), 1038 (BF 4 " theoretic value 1030-1060); 1384 (OC 6 H 4 - theoretic value 1310-1410).
  • Mass spectrometry 239(10O)[MH] + , 238(64)[M] + 1.8 grams of 1,8-diaminoanthraquinone and 100 ml dry isopropanol (freshly distilled over barium oxide) were placed into a 250 ml round flask with a magnetic stirrer and a condenser with a calcium chloride tube. 4.00 grams sodium borohydride was added in portions over the course of 2 minutes and the condenser was then put in place. The reaction mixture was heated to reflux for 48 hours, cooled to room temperature and poured into 200 ml ice and water. The mixture was extracted with dichloromethane, filtrated to remove salts, and dried over magnesium sulfate.
  • the product was purified using chromatography with silica gel 60 and chloroform to elute the first fraction of red material, followed by chloroform with 5 % methanol to elute a yellow-green solution which was evaporated to obtain 350 mg of 1,8-diaminoanthracene as a green powder.
  • Mass spectrometry 209(4I)[MH] + ,208(10O)[M] + 0.25 gram of 1 ,8-diaminoanthracene, 10 ml of DDW, 2 ml of 48 %HBF 4 , and
  • 4-aminophenoI (7.5 grams, 69 mmol) and 50 ml dimethylformamide (DMF) were introduced into a 250 ml 3 -neck flask equipped with a condenser, dropping funnel and efficient magnetic stirrer. The reaction mixture was stirred until the solid was completely dissolved. KOH (4.0 grams, 71 mmol) was added in portions and the mixture was stirred until almost all the KOH disappeared and the color changed to black. Another 50 ml of DMF were then added and the mixture was heated to 80 °C for an hour, and cooled to room temperature. Bromooctane (51 mmol, 9.9 grams) was added to the reaction mixture and the reaction mixture was stirred for additional 30 minutes.
  • DMF dimethylformamide
  • the condenser was thereafter replaced with a vacuum distillation apparatus and the DMF was distilled out under reduced pressure at 45 °C.
  • the reaction mixture was cooled to room temperature and extracted with 200 ml of dichloromethane, washed with 10 % solution of ammonium chloride, dried over MgSO 4 , mixed with carbon powder, filtered and evaporated to yield a black oil, which was purified by distillation at 180-190 0 C under reduced pressure to give 4-octyloxyaniline.
  • 4-butoxyaniline was prepared using n-butyl bromide and 4-dodecyloxyaniline was prepared using n-dodecyl bromide
  • 4-dodecyloxyaniline (0.502 gram, 1.81 mmol) was dissolved in a mixture of 4 ml DDW, 3 ml HBF 4 48 % and 5 ml methyl cyanide, and the solution was cooled to 0 °C.
  • a solution of sodium nitrite (0.125 gram, 1.80 mmol) in 1 ml DDW was added at once. The mixture was diluted to 20 ml stirred for 5 minutes and kept at -4 0 C.
  • Stents were first cleaned in an ultrasonic cleaner in order to remove impurities from the surface of the metal.
  • the stents were then immersed in an etching solution consisting of 10 % (v/v) of nitric acid (70 %), 2 % (v/v) of hydrofluoric acid (50 %) and 88 % (v/v) double-distilled water (DDW), followed by rinsing with distilled water.
  • the etched stents were subjected to an electrical discharge of 0.35 Amperes for approximately 40 seconds in a solution consisting of 50 % (v/v) glycerol, 35 % of phosphoric acid (85 %) and 15 % DDW, then rinsed with distilled water and immersed again in the etching solution, and then rinsed with distilled water, dried with acetone and kept in a desiccator.
  • Stents were electrocoated with a solution of either 1, 4 or 8 mM of a diazonium salt in acetonitrile with 0.1 M tetrabutyl ammonium tetrafluoroborate (TBATFB), using either cyclic voltammetry (application of 10 or more repetitive potential cycles between OCP (open circuit potential) and 300 mV negative to the reduction peak of the diazonuim salt and reverse) or potentiostatic electrocoating (setting the potential at a value that was 300 mV negative to the voltammetric peak for 400 seconds). After electrolysis, the stents were thoroughly rinsed with acetonitrile in an ultrasonic cleaner for 15 minutes.
  • TBATFB tetrabutyl ammonium tetrafluoroborate
  • the counter- electrode was a circular platinum foil
  • the reference electrode was a platinum rod
  • the working electrode was a 316L stainless steel stent wrapped with a stainless steel wire and placed in the center of the cell.
  • Stainless steel stents and plates were electrocoated with 4-(2- bromoethyl)phenyl diazonium, according to the procedure described hereinabove. Bare metal stents and plates (which were sonicated in acetonitrile) were used as a control. Electrocoated and bare metal were both subjected to the grafting procedure. All stents were spray-coated following the grafting procedure, as described hereinabove.
  • Methyl methacrylate (MMA) was passed through an alumina column to remove deactivators. N,N,1 ⁇ T,N",N" ⁇ pentamethyldiethylenetriamine (PMDETA), CuCl, and CuCl 2 were used as catalysts. 1-PEBr (1 -phenyl ethyl bromide) was used as a sacrificial initiator.
  • the polymer was dissolved in excess chloroform, and taken to molar mass analysis by gel permeation chromatography.
  • Plates/stents were removed from the flasks and rinsed in chloroform (twice), dichloromethane, and acetonitrile, under sonication, in 4 periods of 15 minutes each, in order to remove any physisorbed polymer chains that have been synthesized in solution without any anchoring site on the metal surface.
  • the polymer was weighed in a new vial and the solution was then shaken until all polymer dissolved. The solution was then filtered through a syringe filter with 0.2 ⁇ m pores. Solutions with drug were vortexed until homogeneous. Solutions were stored in a refrigerator for up to one week.
  • the spray-coating was performed using a stent spray-coating device (Sono- Tek). Each stent was placed on a new Petri dish in a glove box. The stent was placed gently on the stent holder. Each half of the stent was then sprayed separately. Following spray-coating, the entire stent was examined in the X and Y axes. All movement of the stent was performed carefully with clean tweezers in order to avoid mechanical deformations. All procedures were performed while avoiding exposure to oxygen.
  • EIS was performed in an. electrochemical cell having a calomel electrode as a reference electrode, which was installed using a salt bridge with a Lugin capillary in the center of the stent.
  • a platinum wire with a 25 mm 2 surface area was used as a counter-electrode, and the immersed half of the stent in the electrolyte was used as the working electrode.
  • the solution was phosphate buffer adjusted to a pH of 7, with 5 mM Fe(CN) 6 3" , 5 mM Fe(CN) 6 4" and 0.1 M KCl.
  • OCP open circuit potential
  • Cyclic voltammetry was performed using the electrochemical cell described above for EIS. After setting up the electrochemical cell, scanning was performed from the OCP to -0.7 V vs. OCP and back to 0.7 V vs. OCP.
  • FTIR Fourier transform infrared
  • Spectra were recorded on a FTIR spectrometer (Nicolet Instrument Corp.) at a 4 cm "1 spectral resolution, in a KBr pellet, and using a standard DTGS detector. 16 scans were performed for each measurement.
  • XPS X-ray photoelectron spectroscopy
  • XPS measurements were performed on a Kratos Axis Ultra X-ray photoelectron spectrometer. Spectra were acquired with a monochromated Al K 1486.7 eV) X-ray source with a 0° takeoff angle. The pressure in the chamber was maintained at 1.5 x 10 "9 torr during acquisition. The survey spectra were collected from 1200 to -5 eV (binding energy) with pass energy 80 eV. High resolution XPS scans were collected for C Is, O Is, Fe 2p, Cr 2p and Br 3d peaks with pass energy 20 eV. Step size was 1 eV for survey scans and 0.1 eV for high-resolution spectra.
  • XPS binding energy was calibrated with respect to the peak position of Fe 0 2p 3/2 as 707.0 eV.
  • Data analysis and processing were performed with Vision processing data reduction software (Kratos Analytical Ltd.) and CasaXPS (Casa Software Ltd.).
  • Metal surfaces were incubated in 0.1 M phosphate buffer with 0.3 % SDS (sodium dodecyl sulfate) at a pH of 7.4, in order to assess the effect of incubation on the surfaces. Incubation at 37 °C was considered exposure to physiological conditions. Incubation at 60 °C was considered as "accelerated conditions”.
  • SDS sodium dodecyl sulfate
  • Stents were kept in 5 ml glass vials. Each vial was filled with 1 ml of phosphate buffer, contained one expanded stent, and was sealed tightly with a cork. Vials were then placed in a shaking incubator (100 rpm) either at 37 0 C (physiological conditions) or 60 °C (accelerated conditions).
  • Solution samples were taken at intervals of 0, 3, 7, 12, 21 and 30 days. Samples were drawn from the vials with a sterile 1 ml pipette and put into HPLC detection vials. All samples were vortexed before running.
  • the hydrophobic phase was left overnight (or incubated at 37 °C for 1 hour) to evaporate the chloroform.
  • the hydrophobic phase was then brought to the initial volume by addition of acetonitrile, and filtered through a polytetrafluoroethylene filter with 0.2 ⁇ m pores.
  • 20 ⁇ l of each phase was injected into the HPLC system (Hewlett Packard) with a diode array to obtain the paclitaxel spectrum. Paclitaxel was measured at a rate of 15 minutes per sample, a flow rate of 1 ml per minute and a wavelength of 220 ran.
  • Each stent was removed from solution and placed gently (without using tweezers) to dry on a KIMWIPES ® paper.
  • the dry stent was placed gently on a plastic tissue culture plate by putting the plate on the stent and turning the plate and stent upside-down.
  • the plate was covered with its cover and sealed with a paraffin strip at the edges.
  • Each stent was then placed on a clean and transparent surface (or on a white paper), and fixed in a special holding device.
  • the light intensity was then adjusted, and the entire stent was examined in the X and Y axes.
  • the light intensity was fixed for all images taken, in order to enable a more reliable comparison of the stents. Two images were taken for every frame.
  • the other side was also imaged. Pictures of the whole stent were taken first. If the stent exhibited a defect, such as visible detachment of a portion of the coating and/or changes in color, two representative areas of that defect were framed and images were taken of the area.
  • a defect such as visible detachment of a portion of the coating and/or changes in color
  • Each stent was removed from solution, placed gently (without using tweezers) to dry on a KIMWIPES ® paper, and placed gently in a plastic tissue culture plate, as described hereinabove. After drying further in the plastic plate for 24 hours, the stent was weighed, and then gently placed (without using tweezers) on conductive carbon paper in designated holders of the scanning electron microscope. The stents were then coated with gold at a thickness of 10 nm using a spray deposition machine.
  • the microscope parameters were then set as following: acceleration voltage, 30 V; and working distance, 10mm.
  • the stents were then scanned in order to assess damage. Scanning was conducted only on the three internal stent struts, and not on the two side struts, in order to avoid the possible damage which may have been caused to the side struts during handling.
  • Ethylene oxide sterilization Sterilization of coated stents in ethylene oxide was conducted by Mediplast
  • Sterilization parameters were as follows: exposure time, 360 minutes; number of cycles, 1; ventilation time, 24 hours.
  • Stents were electrocoated with a solution comprising 20 mg/ml polydiazostyrene tetrafluoroborate, according to the procedure described hereinabove.
  • the electrocoating was further characterized by impedance spectroscopy.
  • stents electrocoated with polydiazostyrene have a different capacitance from that of non-treated stents.
  • electrocoating stents with polydiazostyrene blocks the current through the stent surface.
  • Stents were electrocoated with a solution comprising 8 mM tetrakis[(4- diazophenoxy)methyl] methane tetrafluoroborate, according to the procedure described hereinabove.
  • stents electrocoated with the diazonium compound have a higher polarization resistance and capacitance than that of bare stents.
  • Stents were electrocoated with a solution comprising 8 mM 1,8- didiazoanthracene tetrafluoroborate, according to the procedure described hereinabove.
  • the electrocoating was further characterized by impedance spectroscopy. As shown in Figure 9, stents electrocoated with the didiazoanthracene have a higher polarization resistance and capacitance than that of bare stents.
  • electrocoating stents with didiazoanthracene blocks the current through the stent surface.
  • Stents were electrocoated with a solution comprising 8 mM 1,8- didiazoanthracene tetrafluoroborate, according to the procedure described hereinabove.
  • stents electrocoated with the didiazobenzoate have a higher polarization resistance and capacitance than that of bare stents.
  • the insulation resulting from the electrocoating was also observed by out-of- process cyclic voltammetry in a redox couple solution.
  • electrocoating stents with didiazobenzoate blocks the current through the stent surface.
  • Stents were electrocoated using 8 mM 4-(2-bromoethyl)phenyl diazonium, as described hereinabove.
  • PMMA was grafted onto some of the electrocoated stents as described hereinabove.
  • Control stents were prepared by omitting the electrocoating procedure and/or the grafting procedure.
  • the coating on the stent was analyzed by cyclic voltammetry, X-ray photoelectron spectroscopy (XPS) elemental analysis as well as impedance measurements.
  • XPS X-ray photoelectron spectroscopy
  • the metal (iron and chromium) content of the surface of the stent was decreased and the carbon content was increased by electrocoating, and even more so by electrocoating followed by PMMA grafting.
  • the oxygen composition is highest for bare stents due to the thick ( ⁇ 50 ⁇ m) oxide layer on stainless steel.
  • the combination of electrocoating and PMMA grafting shifted the oxygen Is peak to a higher energy (component III), suggesting the presence of an organic compound comprising oxygen (e.g. the carboxyl group of PMMA) as the main component instead of the inorganic oxides typical of stainless steel (e.g. component II).
  • Table 2 high-resolution XPS analysis of oxygen on stent surfaces following electrocoating with 4-(2-bromoethyl)phenyI diazonium and PMMA-grafting
  • the polarization resistance and impedance are increased by either electrocoating with 4-(2-bromoethyl) ⁇ henyl diazonium or exposure to the PMMA grafting solution, and increased the most by electrocoating with 4-(2-bromoethyl)phenyl diazonium followed by PMMA grafting.
  • Stainless steel stents were electrocoated as described hereinabove with 4- dodecyloxyphenyl diazonium tetrafluoroborate (DS06) and 4-(2-hydroxyethyl)phenyl diazonium tetrafluoroborate (DS04) in ratios of 0:100, 10:90, 50:50, 90:10 and 100:0 (weight percentage ratios), at a combined concentration of 8 mM.
  • the electrocoated stents were characterized by XPS, cyclic voltammetry and electrochemical impedance spectroscopy.
  • BMS Non-electrocoated bare metal stents
  • the integral of current over time during the electrocoating process indicates the amount of material reduced during the process. As shown in Figure 15, the amount of reduction depended on the proportion of 4-dodecyloxyphenyl diazonium and 4-(2- hydroxyethyl)phenyl diazonium used to electrocoat the stents.
  • the polarization resistance and capacitance of electrocoated stents were significantly higher than those of control stents, indicating that the stents were successfully electrocoated. Furthermore, the polarization resistance and capacitance were dependent on the proportion of 4-dodecyloxyphenyl diazonium and 4-(2-hydroxyethyl)phenyl diazonium used to electrocoat the stents.
  • electrocoating of stents blocked the current through the stent surface, as observed by out-of-process cyclic voltammetry, further indicating successful electrocoating of the stents. Furthermore, the degree to which current was blocked depended on the proportion of 4-dodecyloxyphenyl diazonium and 4-(2- hydroxyethyl)phenyl diazonium used to electrocoat the stents.
  • Table 4 XPS elemental analysis of stents surfaces following electrocoating with
  • the C-H component of the carbon peak is increased, and the C-O component is decreased, by electrocoating with the diazonium compounds, which comprise more C-H than C-O.
  • the metal oxide component of the oxygen peak is decreased, and the organic component is increased, by electrocoating with the organic diazonium compounds.
  • Stainless steel stents were electrocoated as described hereinabove, using 8 mM of 4-dodecyloxyphenyl diazonium tetrafluoroborate as the diazonium salt. Electrocoated stents were then spray-coated with spray-coating solution (a)
  • Non- electrocoated stents were spray-coated as a control.
  • Non-treated stents were observed to have defects in 47 ⁇ 14.8 % of all AOIs examined by SEM following incubation for 3 days at accelerated conditions. In contrast, no defects were observed in any AOIs of treated stents SEM following incubation for 3 days at accelerated conditions.
  • Stents were electrocoated with 4-(2-bromoethyl)phenyl diazonium tetrafluoroborate and grafted with PMMA as described hereinabove, and then spray- coated with spray-coating solution (a) (PEVA:PBMA:paclitaxel in ethyl acetate), as described hereinabove.
  • Non-treated (bare metal) stents were spray-coated as a control.
  • the stents were then incubated for 12 days at accelerated conditions.
  • the surfaces of non-treated stents exhibited considerable peeling of the polymer-based coating from the stainless steel of the stent.
  • the surfaces of treated stents exhibited full adhesion of the coating to the stent surface, with no peeling.
  • Stents were prepared as described in Example 7, except that solution (c) was used instead of solution (a) for spray-coating. Coatings with a thickness of either 5 ⁇ m or 0.5 ⁇ m were applied by spray-coating.
  • the SIBS polymer is more cohesive than the PBMA:PEVA polymer. Hence, only drug near the surface is released. Thin SIBS coatings may thus be desirable.
  • SIBS coatings e.g. 12 ⁇ m in the TAXUS® stent
  • relatively thick SIBS coatings are typically used in order to improve the adhesion of the SIBS coating to the metal surface of the stent.
  • the electrocoated diazonium compound is capable of causing even a 0.5 ⁇ m thick SIBS + paclitaxel coating to remain adhered to the surface of the stent.
  • Stents were treated as described in Example 7, except that a 0.5 ⁇ m thick top coat of PBMA (solution (b)) was added in order to slow the release of paclitaxel from the polymer + paclitaxel coating.
  • PBMA solution (b)
  • Treated and non-treated stents were incubated under accelerated conditions. Damage was assessed on days 0, 3 and 30 of the incubation by measuring weight loss and quantifying defects using scanning electron microscopy.
  • Table 7 weight loss and defects in electrocoated and control stents incubated under accelerated conditions
  • Figure 28 shows stents prepared as described above before incubation. As shown in Figure 29, some damage to the surface of non-treated stents was observable after 3 days of incubation under accelerated conditions. For example, some of the pores in the coating appear enlarged. As shown in Figure 30, severe delamination of the polymer-based coating was observed on the surface of non-coated stents following 30 days of incubation at 60 °C. Large patches on the surface were completely delaminated.
  • Stents were electrocoated with 4-dodecyloxyphenyl diazonium as described hereinabove, and then coated with a 5 ⁇ m thick coating of RESOMER® LC 703 S (spray-coating solution (d)), a biodegradable copolymer of L-lactide and ⁇ - caprolactone, which is absorbed completely in the human body within approximately
  • Stents were prepared as described in Example 8, and the controlled release of paclitaxel from stents incubated in physiological conditions was monitored over a period of 30 days.
  • Stents were prepared with either a thick or thin SIBS coating. Thick coatings were approximately 10 ⁇ m thick, weighed approximately 200 ⁇ g and comprised approximately 50 ⁇ g of paclitaxel. Thin coatings were approximately 0.5 ⁇ m thick, weighed approximately 10 ⁇ g and comprised approximately 4 ⁇ g of paclitaxel. As shown in Figure 35, the release pattern of paclitaxel from the treated stents was significantly related to the coating thickness. The thin coating had released 98 % of the drug following 30 days of incubation, with an initial burst release of 55 %, while the thick coating released less than 10 % of the drug following 30 days of incubation, with only a small burst. The absolute amount of drug that had been released was fairly similar in both systems (1.4 ⁇ g, and 1.6 ⁇ g respectively).
  • the pattern of release also differed between treated and untreated stents. As shown in Figure 36, initial burst of drug release from thin coatings was significantly lower in treated stents than in non-treated stents. The results shown were obtained from 5 samples for each group.
  • Stents were electrocoated and coated with PEVA:PBMA:paclitaxel as described in Example 7.
  • the polymer-based coatings were 5 ⁇ m thick and comprised approximately 90 ⁇ g paclitaxel. Some of the stents were sterilized with ethylene oxide after being spray-coated, as described hereinabove.
  • Stents electrocoated with 4-(2-bromoethyl)phenyl diazonium were prepared as described hereinabove. Some of the electrocoated stents were PMMA-grafted as described hereinabove.
  • Slow release (SR) and fast release (FR) model stents were prepared.
  • the slow release model comprised a 250 ⁇ g PBMA:PEVA:paclitaxel coating
  • the fast release model further comprised a 50 ⁇ g PBMA top coat above the PBMA:PEVA:paclitaxel coating.
  • Non-electrocoated plates were dip-coated as controls.
  • the coated plates were incubated in phosphate buffer with 0.3 % SDS at 37 0 C.
  • the adhesion test was then performed by applying and removing 3M 250 adhesion tape, according to the D-3359-02 ASTM standard test. All plates were photographed with a microscope camera following the adhesion test, and the percentage of the surface which peeled off was calculated.
  • Table 8 shows that almost all of the PEVA:PBMA coating peeled off during adhesion tests performed on non-treated plates following incubation for 3 or 15 days. In contrast, only a relatively fraction of the PEVA:PBMA coating peeled off of the surface of plates electrocoated with 4-dodecyloxyphenyl diazonium even after 15 days of incubation.
  • Stainless steel stents were electrocoated with various proportions of 4- dodecyloxyphenyl diazonium tetrafluoroborate (DS06) and 4-(2-hydroxyethyl)phenyl diazonium tetrafluoroborate (DS04), as described in Example 6.
  • the stents were then spray-coated with PEVArPBMA with paditaxel, as described in Example 7.
  • the integrity of the polymer-based coating was then determined following incubation of the stents in phosphate buffer with 0.3 % SDS, using light microscopy.
  • Stainless steel stents were electrocoated with 4-dodecyloxyphenyl diazonium tetrafluoroborate as described hereinabove, and incubated at 37 0 C in phosphate buffer with 0.3 % SDS for 3 days. Stents were analyzed by out-of-process cyclic voltammetry before and after incubation. Before incubation, the peak current through the surface of electrocoated stents was 0.04 ⁇ 0.02 niA, whereas the peak current for non-treated control stents was 0.1836 ⁇ 0.071 mA.
  • the peak current for electrocoated stents was 0.081 ⁇ 0.044 mA, whereas the peak current for non-treated stents was 0.146 ⁇ 0.012 mA.
  • the surface of electrocoated stents remained blocked relative to controls after incubation for 3 days.
  • Electrocoated stents were also incubated for 30 days at 37 °C in phosphate buffer with 0.3 % SDS and then spray-coated with PEVA:PBMA with paclitaxel. The polymer-coated stents were then incubated at 60 0 C, and the ability of the electrocoated layer to preserve the integrity of a coating of PEVA:PBMA with paclitaxel was observed following 3 and 30 days incubation at 60 0 C.
  • a conductive surface is electrocoated with a functionalized aryl moiety as described hereinabove in the Methods section.
  • Nanoparticles are prepared by adding about 200 mg of a polymer (e.g. polylactic acid) dissolved in about 18 ml of a volatile hydrophobic solvent (e.g. dichloromethane or acetone) to a solution comprising about 200 ml DDW and about
  • a polymer e.g. polylactic acid
  • a volatile hydrophobic solvent e.g. dichloromethane or acetone
  • a surfactant such as tocopherol and stirring with a homogenizer for at least 1 hour.
  • the mixture is then frozen and lyophilized, yielding nanoparticles.
  • 5 % (by weight) of a compound (preferably hydrophobic) having the desired functional group e.g. a long-chain alkyl thiol in order to introduce a thiohydroxy group
  • a covalent disulfide bond is formed by electrolyzing a solution of an alcohol (e.g.
  • methanol comprising about 0.5 M of a sodium alkoxide (e.g. NaOCH 3 ) and he nanoparticles, using a platinum foil as anode and the electrocoated conductive surface as a cathode.
  • a current in the range of 250 to 700 mA is used.
  • a solution of hydrogen peroxide is used to oxidize the thiohydroxy groups to a disulfide group.
  • a covalent amide bond is formed by placing the electrocoated conductive surface and the nanoparticles in a solvent such as dichloromethane and adding about 150 mM of hydroxybenzotriazole and about 150 mM of N,N'-diisopropylcarbodiimide, followed by stirring for about 2 hours.
  • a covalent ester bond is formed by placing the electrocoated conductive surface and the nanoparticles in an alcohol (e.g. methanol) and adding boric acid and stirring overnight.
  • an alcohol e.g. methanol

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Abstract

La présente invention concerne des articles manufacturés comprenant au moins un groupement aryle lié électrochimiquement à la surface de ceux-ci, ainsi que des procédés de préparation desdits articles manufacturés et leurs utilisations. L'invention concerne en outre de nouveaux composés comprenant un groupement aryle et substitués par au moins deux groupements diazonium, qui peuvent éventuellement être utilisés pour préparer lesdits articles manufacturés.
PCT/IL2008/000103 2007-01-22 2008-01-22 Surfaces conductrices modifiées préparées par électrogreffage de sels diazonium WO2008090554A2 (fr)

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CN102657900A (zh) * 2012-04-10 2012-09-12 微创医疗器械(上海)有限公司 一种基于氢键作用的药物球囊及其涂层方法
EP2674173A1 (fr) * 2012-06-15 2013-12-18 Commissariat A L'energie Atomique Et Aux Energies Alternatives Matériau implantable greffé avec une cellule antiprolifératives et/ou film antibactérien et son procédé de greffage
WO2013186388A1 (fr) * 2012-06-15 2013-12-19 Commissariat À L'Énergie Atomique Et Aux Énergies Alternatives (Cea) Matériau implantable sur lequel est greffé un film aux propriétés antiprolifération cellulaire et/ou antibactériennes et son procédé de greffe
JP2015519160A (ja) * 2012-06-15 2015-07-09 コミッサリア ア レネルジ アトミック エ オ ゼネルジ アルテルナティヴＣｏｍｍｉｓｓａｒｉａｔ Ａ Ｌ’Ｅｎｅｒｇｉｅ Ａｔｏｍｉｑｕｅ Ｅｔ Ａｕｘ Ｅｎｅｒｇｉｅｓ Ａｌｔｅｒｎａｔｉｖｅｓ 細胞抗増殖性および／または抗菌性皮膜でグラフトされる埋め込み可能材料ならびにそのグラフト化方法
US9855373B2 (en) 2013-06-14 2018-01-02 Biowintech Implantable material grafted with a cell antiproliferative and/or antibacterial film synthetized from a bifunctional molecule
US10125105B2 (en) 2014-06-11 2018-11-13 Arizona Board Of Regents On Behalf Of The University Of Arizona Triazabutadienes as cleavable cross-linkers
US9593080B1 (en) 2014-06-11 2017-03-14 The Arizona Board Of Regents On Behalf Of The University Of Arizona Triazabutadienes as cleavable cross-linkers
US10047061B2 (en) 2014-06-11 2018-08-14 Arizona Board Of Regents On Behalf Of The University Of Arizona Water-soluble triazabutadienes
US9458143B1 (en) 2014-06-11 2016-10-04 The Arizona Board Of Regents On Behalf Of The University Of Arizona Triazabutadienes as additives in adhesive systems
US10472330B2 (en) 2015-08-11 2019-11-12 Arizona Board Of Regents On Behalf Of The University Of Arizona Substituted triazenes protected from degradation by carboxylation of N1
US10954195B2 (en) 2015-08-11 2021-03-23 Arizona Board Of Regents On Behalf Of The University Of Arizona Substituted triazenes protected from degradation by carboxylation of N1
CN106146801A (zh) * 2016-07-04 2016-11-23 武汉工程大学 新型化合物四[(对氨基苯氧基)甲基]甲烷作为固化剂在环氧树脂体系的应用
US11339129B2 (en) 2016-07-29 2022-05-24 Arizona Board of Regents on behalf of the University of Arizon Triazabutadienes as cleavable cross-linkers
PL442508A1 (pl) * 2022-10-12 2024-04-15 Politechnika Śląska Biofunkcjonalizowana powłoka organiczna, sposób jej otrzymywania oraz zastosowanie

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