Field of the Invention
This invention generally relates to a coating having heparin attached thereto on an implantable device, such as a stent.
Description of the Background
Blood has a property of being coagulated by the action of various components in blood when it has come into contact with foreign matters. Hence, there is need for a high anticoagulant property in component materials for medical articles or instruments used on the part coming into contact with blood, as exemplified by artificial hearts, artificial cardiac valves, artificial blood vessel, blood vessel catheters cannulas, pump-oxygenators, blood vessel by-pass tubes, intraaortic balloon pumping, transfusion instruments and extracorporeal circulation circuits. Heparin has been commonly used to impart to the medical devices anticoagulant properties, but a systemic use of heparin may undesirably lead to the formation of a large number of bleeding nests.
Methods have been developed to minimize side effects associated with the use of heparin with limited success (see, for example, U.S. Pat. Nos. 5,270,064 and 6,630,580). The efficacy of using heparin not only depends on the nature and property of heparin, but also depends on the nature and property of the materials used in associated with heparin. For example, surfaces in-vivo are quickly covered by proteins, which may thus reduce the effectiveness of heparin attached thereto. Moreover, direct attachment of heparin to substrate surfaces may block the binding sites on the heparin molecule such that they become inaccessible to the binding proteins, further reducing the effectiveness of heparin.
The present invention addresses such problems by providing a coating composition for coating implantable devices.
Provided herein is heparin attached to a substrate surface via a spacer. The spacer is sufficiently long that allows the binding sites of the heparin molecule to be accessible to binding proteins. The substrate is optionally coated with an anti-fouling material. In one embodiment, the spacer is poly(ethylene glycol) (PEG) having a molecular weight of between, e.g., about 500 daltons to 5,000 daltons.
The substrate can be coated with any biocompatible polymeric material. The polymeric material can be hydrophilic or hydrophobic. Preferably, the polymeric material is a non-fouling material. In one embodiment, the anti-fouling material can be, for example, PEG, etc. The coating optionally includes an anti-fouling material. The coating may further include a bioactive agent.
Provided herein is a coating formed of a biocompatible polymer having heparin attached thereto via a spacer. Heparin can be used as is or used in a modified form. The spacer comprises a grouping that renders the heparin molecule attached to the polymer to be flexible such that the binding sites of the heparin molecule become accessible by binding proteins. Particularly, the attached heparin molecule with a spacer and a binding protein bond to each other, as described in Scheme 1 below, with a binding constant (Kd) (Equation 1) of about 0.01 to 1 micromolar, for example, about 0.01 to 0.28 micromolars.
The heparin binding expression can be given by Equation 1:
Kd=[AT-IIIf]X[Sf]/[AT-IIIb] (Equation 1)
where AT-IIIf is the concentration of free antithrombin, AT-IIIb is the concentration of bound antithrombin, and Sf is the concentration of free binding sites on the heparin (Soons H, Tans G. Hemker HC, Biochem. J. (1988): 256 (815-820).
The coating optionally includes an anti-fouling or non-fouling material. The coating may further include a bioactive agent. As used herein, the term anti-fouling and non-fouling are used interchangeably. Non-fouling or anti-fouling is defined as preventing, delaying or reducing the amount of formation of protein build-up caused by the body's reaction to foreign material.
Heparin is a highly charged glycosaminoglycan made of repeating disaccharide units (generally 2-9 units). Each glycosamine and iduronic acid residues (
The term “heparin” refers to a heparin molecule, a fragment of the heparin molecule, or a derivative of heparin. Heparin derivatives can be any functional or structural variation of heparin. Representative variations include alkali metal or alkaline—earth metal salts of heparin, such as sodium heparin (e.g., hepsal or pularin), potassium heparin (e.g., clarin), lithium heparin, calcium heparin (e.g., calciparine), magnesium heparin (e.g., cutheparine), and low molecular weight heparin (e.g., ardeparin sodium). Other examples include heparin sulfate, heparinoids, heparin based compounds and heparin having a hydrophobic counter-ion.
Heparin is a molecule which is very hydrophilic. It usually dissolves very well in water but not in organic solvent. This lack of solubility in organic solvents may limit the use of handling of heparin. Modification with a hydrophobic material may increase solubility of heparin in organic solvents and ease of handling heparin.
Useful hydrophobic materials for modifying heparin include hydrophobic polymers and hydrophobic counter ions. Heparin can be coupled or crosslinked to or grafted onto a hydrophobic polymer and complexed or conjugate to hydrophobic counter ions.
Any biocompatible polymers can be used to modify the hydrophilicity of heparin. Exemplary useful hydrophobic polymers include, but are not limited to, poly(ester amide), polystyrene-polyisobutylene-polystyrene block copolymer (SIS), polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylene, polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(4-hyroxyhexanoate), mid-chain polyhydroxyalkanoate, poly (trimethylene carbonate), poly (ortho ester), polyphosphazenes, poly (phosphoester), poly(tyrosine derived arylates), poly(tyrosine derived carbonates), polydimethyloxanone (PDMS), polyvinylidene fluoride (PVDF), polyhexafluoropropylene (HFP), polydimethylsiloxane, poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP), poly (vinylidene fluoride-co-chlorotrifluoroethylene) (PVDF-CTFE), poly(butyl methacrylate), poly(methyl methacrylate), poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes), poly(ether-urethanes), poly(carbonate-urethanes), poly(silicone-urethanes), poly(urea-urethanes) and a combination thereof. Methods of derivatizing heparin with hydrophobic materials or polymers are described in, for example, U.S. Pat. Nos. 4,331,697; 5,069,899; 5,236,570; 5,270,046; 5,453,171; 5,741,881; 5,770,563; 5,855,618; 6,589,943 and 6,630,580.
Any hydrophobic counter ions can be used to modify the hydrophilicity of heparin. For example, hydrophobic quaternary ammonium compounds have been commonly used to form complexes with heparin that are soluble in organic solvents. Some exemplary useful hydrophobic quaternary ammonium compounds and methods of forming complexes of these compounds with heparin are described in U.S. Pat. Nos. 4,654,327, 4,871,357 and 5,047,020.
Generally, the spacers useful for attaching heparin and a polymer in a coating described herein have two functional groups, one capable of attaching to heparin, the other capable of attaching to the coating material. The spacer must have a grouping of atoms of such a length that the spacer, once attached to the heparin and then to the polymer, renders the heparin molecule flexible so as to allows a binding site of the heparin molecule to be accessible by a binding protein.
A general formula of the spacers can be Y—R—X where X and Y represent the two functional groups and R represents a monomeric, oligomeric, or polymeric di-radical.
Exemplary X and Y groups include, but are not limited to, hydroxyl, epoxide, carboxyl, amino, imide, aziridine, thiol, phosphoryl, aldehyde, anhydride, acyl halide, silyl, isocyanate, diisocyanate, carbodiimide, a dihydrazide, a multiaziridine, a multifunctional carbodiimide, a diamine, a primary amine side group on a polymer, N-hydroxy-succinamide, acryloxy terminated polyethylene glycol, methacryloxy terminated polyethylene glycol, and isothiocyanate.
Exemplary R di-radicals include hydrocarbon di-radicals, polyolefin di-radicals, polyether di-radicals, poly(alkylene glycol) di-radicals, poly(ethylene glycol) di-radicals, poly(ester amide) di-radicals, poly(ether amine) di-radicals, polyamino acid di-radicals, poly(hydroxy acid) di-radicals, polyhydroxyalkanoate di-radicals, polystyrene di-radicals, 2-methacryloyloxyethylphosphorylcholine (MPC), hydrophilic spacers, polyvinyl alcohol di-radicals, polyphosphazene di-radicals, poly(hydroxyl ethyl methacrylate) di-radicals, poly(hydroxyl ethyl acrylate) di-radicals, poly(hydroxyl propyl methacrylamide) di-radicals, hydroxyl propyl cellulose di-radicals, polyacrylic acid di-radicals, polyvinyl sulfonic acid di-radicals, polyalginate di-radicals, dextrin di-radicals, dextrose di-radicals, dextran di-radicals, carboxymethyl cellulose di-radicals, or hydroxyl functional poly(vinyl pyrrolidone) di-radicals.
The spacer can be provided by a linking agent comprising one of the di-radicals defined above or by a chemical agent comprising one of the di-radicals defined above.
The heparin and modified heparin can be attached to any substrate surface. In one embodiment, the substrate surface can have a metallic surface modified with linking chemical agents such as silyl or siloxyl groups. The substrate surface can be made from a polymeric material. The substrate surface can be a polymeric coating with or without a bioactive agent.
In one embodiment of the present invention, the substrate surface is a polymeric coating surface formed of one or more polymeric material, in mixed blended or conjugated form. The coating may include one or more bioactive agent that can be a therapeutic agent. The polymeric material can be any biocompatible polymer such as a hydrophobic polymer, a hydrophilic polymer or a combination thereof.
The substrate can be made from or coated with a biostable or biodegradable polymer. “Biodegradable” refers to polymers that are capable of being completely degraded and/or eroded when exposed to bodily fluids such as blood and can be gradually resorbed, absorbed and/or eliminated by the body. The processes of breaking down and eventual absorption and elimination of the polymer can be caused by, for example, hydrolysis, metabolic processes, bulk or surface erosion, and the like. For coating applications, it is understood that after the process of degradation, erosion, absorption, and/or resorption has been completed, no polymer will remain on the device. In some embodiments, very negligible traces or residue may be left behind.
In one embodiment, the polymeric material is a hydrophobic polymer. Representative hydrophobic polymers include, but are not limited to, poly(ester amide), polystyrene-polyisobutylene-polystyrene block copolymer (SIS), polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylene, polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(4-hyroxyhexanoate), mid-chain polyhydroxyalkanoate, poly (trimethylene carbonate), poly (ortho ester), polyphosphazenes, poly (phosphoester), poly(tyrosine derived arylates), poly(tyrosine derived carbonates), polydimethyloxanone (PDMS), polyvinylidene fluoride (PVDF), polyhexafluoropropylene (HFP), polydimethylsiloxane, poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP), poly (vinylidene fluoride-co-chlorotrifluoroethylene) (PVDF-CTFE), poly(butyl methacrylate), poly(methyl methacrylate), poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes), poly(ether-urethanes), poly(carbonate-urethanes), poly(silicone-urethanes), poly(2-hydroxyethyl methacrylate), PVDF-Solef® (polyvinylidenefluoride), poly(urea-urethanes) and a combination thereof. In some embodiments, the polymer can exclude any one of the aforementioned polymers.
In one embodiment, the polymeric material is a hydrophilic polymer. Representative hydrophilic polymers include, but are not limited to, polymers and co-polymers of hydroxyl ethyl methacrylate (HEMA), PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone (VP), carboxylic acid bearing monomers such as methacrylic acid (MA), acrylic acid (AA), hydroxyl bearing monomers such as HEMA, hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, alkoxymethacrylate, alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate (TMSPMA), poly(ethylene glycol) (PEG), poly(propylene glycol), SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS-PEG, PVDF-PEG, PLURONIC™ surfactants (polypropylene oxide-co-polyethylene glycol), poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), polyalkylene oxide, dextran, dextrin, sodium hyaluronate, hyaluronic acid, heparin, elastin, chitosan, and combinations thereof. In some embodiments, the polymer can exclude any one of the aforementioned polymers.
The composition described herein can be used for coating an implantable device such as a stent or for controlled delivery of a bioactive agent.
The method of attaching heparin to a polymer or a polymeric coating can be achieved using a linking agent having at least two linking functionalities and a grouping that may serve as a spacer of the heparin. Optionally, heparin or a heparin/spacer species and a polymer can be functionalized to attach a reactive group to the carboxylic acid residue of heparin or to the spacer grouping of the heparin/spacer species and to the polymer. The heparin or heparin/spacer species are then coupled with each other via the linking agent (see, for example, Sorenson, W.; Sweeny, F.; Campbell, T., Preparative Methods of Polymer Chemistry, 3rd Edition, John Wiley & Sons, copyright 2001).
Useful functionalities that heparin or a heparin/spacer and a polymer can be functionalized to bear include, for example, hydroxyl, epoxide, carboxyl, amino, imide, aziridine, thiol, phosphoryl, aldehyde, anhydride, acyl halide, silyl, isocyanate, diisocyanate, carbodiimide, a dihydrazide, a multiaziridine, a multifunctional carbodiimide, a diamine, a primary amine side group on a polymer, N-hydroxy-succinamide, acryloxy terminated polyethylene glycol, methacryloxy terminated polyethylene glycol, and isothiocyanate.
Useful linking agents include, for example, agents bearing hydroxyl, epoxide, carboxyl, amino, imide, aziridine, thiol, phosphoryl, aldehyde, anhydride, acyl halide, silyl, isocyanate, diisocyanate, carbodiimide, a dihydrazide, a multiaziridine, a multifunctional carbodiimide, isothiocynate or a diamine functionalities, a polymer bearing a primary amine side group or side groups, N-hydroxy-succinamide, acryloxy terminated polyethylene glycol, and methacryloxy terminated polyethylene glycol. Other linking agents are listed in commercial catalogues such as Shearwater catalogue (Shearwater Polymers, Inc., Huntsville, Ala.) and Piercenet, found at www.Piercenet.com (Pierce Biotechnology, Inc., Rockford, Ill.).
The following describes a few embodiments of the present invention making a coating having heparin attached to a polymeric coating via a spacer.
In one aspect of the present invention, a spacer can be coupled to heparin by reacting heparin possessing a terminal aldehyde to an amine terminated polymer as spacer such as PEG, as described in Scheme 2. The other end of the polymer can be a protected moiety that can form a functional group for grafting to a surface or coupling to a polymer using a carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). The protected moiety can be, for example, a functionality capable of grafting to a surface or coupling to a polymer such as a carboxylic acid, amine, or hydroxyl group. An exemplary method of attaching PEG as a spacer to heparin is shown in Scheme 2 where an amine-terminated PEG is coupled to an aldehyde-terminated heparin, followed by removal of the t-BOC protective group on the second amine. The second amino can then be used to graft the heparin-spacer moiety to a polymer or a substrate surface.
Heparin with a spacer can be attached to a polymeric substrate surface by direct coupling of the heparin/spacer species to a polymeric surface on a medical device via a functional group on the spacer distant from the heparin. Alternately, the heparin/spacer species can be first coupled to a polymer to form a heparin/spacer functionalized polymer, which can then be applied to a medical device to provide a non-thrombogenic surface on the medical device.
In one embodiment, a polymer having a carboxylic acid functionalized polymer backbone can be made. A heparin/spacer species can then be coupled to the polymer to form a conjugate having a general formula heparin-spacer-polymer. The heparin-spacer-polymer conjugate can be coated on a medical device. Alternately, a polymer having a carboxylic acid functionalized polymer backbone can be coated on a medical device to form a polymeric coating. The heparin-spacer species can then be grafted or coupled to the polymeric coating via a carboxyl functionality on the surface of the coating. For example, a hydrophobic copolymer of acrylic monomers such as methyl methacrylate (MMA) and t-butyl methacrylate (t-BMA) can be used as a coating with carboxyl functionalities. The carboxyl functionalities are obtained upon removal of the t-butyl protecting group. Scheme 3 shows the de-protection of an acrylic copolymer of MMA and t-BMA to yield a carboxylic acid bearing polymer.
Alternately, a carboxyl containing monomer such as methacrylic acid or itaconic acid can be used to form a polymer bearing carboxyl functionalities. A functional group such as dihydrazide can be reacted to the carboxylic acid to give primary amine functionalities. Therefore, the polymer can be applied to a medical device to form a coating. A carboxy heparin/spacer species can be coupled to the carboxylic acid functionalities available at the surface, as depicted in Scheme 4 (upper path). This coupling can be mediated by, for example, a water soluble carbodiimide such as (1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC). An alternative is to functionalize the heparin/spacer species and then graft the species onto the surface coated with the carboxylic acid functional polymer, as depicted in Scheme 4 (lower path).
Amine terminated heparin/spacer species can be directly coupled to carboxylic acid moieties using an agent such as a carbodiimide such as EDC mediated by an agent such as N-hydroxybenzotriazole (HOBT), substituted HOBT, or N-hydroxysuccinamide. This can be done as grafting from the polymer coated surface, or as coupling to the copolymer that is subsequently applied to the surface to coat.
In another aspect of the present invention, a heparin, which has a carboxylic acid moiety in its iduronic acid residue, can be coupled to a hydrazide reactive group in an aqueous medium such as water. A linking agent with at least two hydrazide reactive groups would be capable of coupling heparin with a coating surface having carboxylic acid groups. In order to avoid crosslinking of molecules bearing multiple carboxylic acid groups by the linking agent, the reaction is done in an excess of the linking agent such as a dihydrazide, and the degree of functionalization can be controlled by the amount of a carbodiimide such as EDC (Luo, Y. et al., J. Contr. Release 69:169-184 (2000)) (Scheme 5).
For example, an acrylic copolymer can be functionalized with a dihydrazide as shown in Scheme 6. The functionalized copolymer, which has a remaining hydrazide group,
can react with the carboxylic acid residue on heparin or a carboxylic end of the spacer part of the heparin/spacer conjugate using the carbodiimide chemistry and then can be coated on a medical device. Alternately, the functionalized copolymer can be coated onto a medical device, and heparin or a heparin/spacer conjugate then can be grafted onto the coating using the carbodiimide chemistry.
In accordance with a further aspect of the present invention, a multifunctional aziridine agent can be used as a crosslinker to couple a heparin or heparin/spacer conjugate with a polymer having carboxylic acid moieties. For example, pentaerythritol tris(3-aziridinopropionate) from Sybron Chemicals (NJ) can be used as a crosslinker (see, for example, Gianolino, D. A., et al., Crosslinked sodium hyaluronate containing labile linkages, Abstract from Society for Biomaterials 2002) (Scheme 7).
The crosslinking of this polymer must be done on the surface to coat. By using an excess of the trifunctional crosslinker, some residual aziridine groups will still be available at the surface to graft heparin and optionally carboxy-PEG with or without spacer with a carboxylic acid functionality.
In another aspect of the present invention, a multifunctional carbodiimide can be used to attach heparin, with or without a spacer, to a polymer with carboxylic acid functionalities (see Scheme 8). Multifunctional carbodiimides are available from Nisshinbo (CARBODILITE™) and Bayer (BAYDERM™ Fix CD).
In accordance with a further aspect of the present invention, heparin, with or without a spacer, can be attached to a polymer formed of a monomer bearing primary amine functionalities via direct EDC mediated amide formation between the amine groups and the carboxyls on heparin and/or carboxy-PEG. Some examples of such a polymer is polyacrylic polymers formed of primary amine functional monomers such as N-(3-aminopropyl)methacrylamide HCl (available from Polysciences), ethyl 3-aminocrotonate (available from Aldrich), ethyl 3-amino-4,4,4-trifluorocrotonate (available from Aldrich), or combinations thereof. Succinimidyl derivatives of PEG can also react with these amino functional monomers in a facile manner. These monomers can polymerize with acrylates or methacrylates such as n-butyl methacrylate or methyl methacrylate. For example, as shown in Scheme 9, polymers substituted with mixed populations of PEG and heparin, with or without a spacer, can be produced via this scheme (Scheme 9).
Succinimidyl derivatives of mPEG can be obtained from Nektar Corp. As an alternative, the entire polymer can be synthesized first, including heparin or the heparin/spacer species, optionally with PEG, and then applied to the stent.
The polymeric coatings or the polymeric substrate described herein may optionally include one or more bioactive agents. The bioactive agent can be any agent which is biologically active, for example, a therapeutic, prophylactic, or diagnostic agent.
Examples of suitable therapeutic and prophylactic agents include synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities. Nucleic acid sequences include genes, antisense molecules which bind to complementary DNA to inhibit transcription, and ribozymes. Compounds with a wide range of molecular weight can be encapsulated, for example, between 100 and 500,000 grams or more per mole. Examples of suitable materials include proteins such as antibodies, receptor ligands, and enzymes, peptides such as adhesion peptides, saccharides and polysaccharides, synthetic organic or inorganic drugs, and nucleic acids. Examples of materials which can be encapsulated include enzymes, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator; antigens for immunization; hormones and growth factors; polysaccharides such as heparin; oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy. The polymer can also be used to encapsulate cells and tissues. Representative diagnostic agents are agents detectable by x-ray, fluorescence, magnetic resonance imaging, radioactivity, ultrasound, computer tomagraphy (CT) and positron emission tomagraphy (PET). Ultrasound diagnostic agents are typically a gas such as air, oxygen or perfluorocarbons.
In the case of controlled release, a wide range of different bioactive agents can be incorporated into a controlled release device. These include hydrophobic, hydrophilic, and high molecular weight macromolecules such as proteins. The bioactive compound can be incorporated into polymeric coating in a percent loading of between 0.01% and 70% by weight, more preferably between 5% and 50% by weight.
In one embodiment, the bioactive agent can be for inhibiting the activity of vascular smooth muscle cells. More specifically, the bioactive agent can be aimed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells for the inhibition of restenosis. The bioactive agent can also include any substance capable of exerting a therapeutic or prophylactic effect in the practice of the present invention. For example, the bioactive agent can be for enhancing wound healing in a vascular site or improving the structural and elastic properties of the vascular site. Examples of active agents include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1, actinomycin X1, and actinomycin C1. The bioactive agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel, (e.g. TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®, from Aventis S. A., Frankfurt, Germany) methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc., Whitehouse Station, N.J.); calcium channel blockers (such as nifedipine), colchicine, proteins, peptides, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate agents include alpha-interferon, genetically engineered epithelial cells, anti-inflammatory agents, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antivirals, anticancer drugs, anticoagulant agents, free radical scavengers, estradiol, antibiotics, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin, ABT-578, clobetasol, cytostatic agents, prodrugs thereof, co-drugs thereof, and a combination thereof.
The foregoing substances are listed by way of example and are not meant to be limiting. Other active agents which are currently available or that may be developed in the future are equally applicable.
The dosage or concentration of the bioactive agent required to produce a favorable therapeutic effect should be less than the level at which the bioactive agent produces toxic effects and greater than the level at which non-therapeutic results are obtained. The dosage or concentration of the bioactive agent required to inhibit the desired cellular activity of the vascular region can depend upon factors such as the particular circumstances of the patient; the nature of the trauma; the nature of the therapy desired; the time over which the ingredient administered resides at the vascular site; and if other active agents are employed, the nature and type of the substance or combination of substances. Therapeutic effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies. Standard pharmacological test procedures to determine dosages are understood by one of ordinary skill in the art.
As used herein, an implantable device may be any suitable medical substrate that can be implanted in a human or veterinary patient. Examples of such implantable devices include self-expandable stents, balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, available from Guidant Corporation, Santa Clara, Calif.). The underlying structure of the device can be of virtually any design. The device can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devices made from bioabsorbable or biostable polymers could also be used with the embodiments of the present invention.
In accordance with embodiments of the invention, a coating of the various described embodiments can be formed on an implantable device or prosthesis, e.g., a stent. For coatings including one or more active agents, the agent will retain on the medical device such as a stent during delivery and expansion of the device, and released at a desired rate and for a predetermined duration of time at the site of implantation. Preferably, the medical device is a stent. A stent having the above-described coating is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, esophagus, trachea/bronchi and other biological passageways. A stent having the above-described coating is particularly useful for treating occluded regions of blood vessels caused by abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis, and restenosis. Stents may be placed in a wide array of blood vessels, both arteries and veins. Representative examples of sites include the iliac, renal, and coronary arteries.
For implantation of a stent, an angiogram is first performed to determine the appropriate positioning for stent therapy. An angiogram is typically accomplished by injecting a radiopaque contrasting agent through a catheter inserted into an artery or vein as an x-ray is taken. A guidewire is then advanced through the lesion or proposed site of treatment. Over the guidewire is passed a delivery catheter which allows a stent in its collapsed configuration to be inserted into the passageway. The delivery catheter is inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering the catheter through the vascular system under fluoroscopic guidance. A stent having the above-described coating may then be expanded at the desired area of treatment. A post-insertion angiogram may also be utilized to confirm appropriate positioning.
The embodiments of the present invention will be illustrated by the following set forth examples. All parameters and data are not to be construed to unduly limit the scope of the embodiments of the invention.
2-Ethoxyethyl methacrylate (10 g) and 2-ethylamino methacrylate hydrochloride (1 g) can be copolymerized by free radical polymerization in a solution of hexadecane and water (0.7 g and 80 g respectively) using tert-butylhydroperoxide (0.1 g) as a catalyst. After the addition of sodium formaldehyde sulfoxylate, the emulsion can be let to react for 60 min. at 60° C. The resulting polymer can be precipitated in cold methanol.
The methacrylic copolymer (2 g) can be dissolved with heparin aldehyde (0.4 g) in dimethyl formamide (10 wt % solids). Sodium cyanoborohydride can be added to the solution, which can be stirred for 48 h at 40° C. The resulting polymer can be precipitated in water, filtered and dried under vacuum for 48 h.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.
Number | Name | Date | Kind |
---|---|---|---|
2072303 | Herrmann et al. | Mar 1937 | A |
2386454 | Frosch et al. | Oct 1945 | A |
3688317 | Kurtz | Sep 1972 | A |
3773737 | Goodman et al. | Nov 1973 | A |
3849514 | Gray, Jr. et al. | Nov 1974 | A |
3914802 | Reick | Oct 1975 | A |
4226243 | Shalaby et al. | Oct 1980 | A |
4314043 | Kojima et al. | Feb 1982 | A |
4329383 | Joh | May 1982 | A |
4331697 | Kudo et al. | May 1982 | A |
4343931 | Barrows | Aug 1982 | A |
4420395 | Tanihara et al. | Dec 1983 | A |
4478961 | Tanaka et al. | Oct 1984 | A |
4510135 | Teng | Apr 1985 | A |
4521564 | Solomon et al. | Jun 1985 | A |
4529792 | Barrows | Jul 1985 | A |
4611051 | Hayes et al. | Sep 1986 | A |
4654327 | Teng | Mar 1987 | A |
4656242 | Swan et al. | Apr 1987 | A |
4703042 | Bodor | Oct 1987 | A |
4733665 | Palmaz | Mar 1988 | A |
4745180 | Moreland et al. | May 1988 | A |
4800882 | Gianturco | Jan 1989 | A |
4834746 | Kira | May 1989 | A |
4871357 | Hsu et al. | Oct 1989 | A |
4882168 | Casey et al. | Nov 1989 | A |
4886062 | Wiktor | Dec 1989 | A |
4931287 | Bae et al. | Jun 1990 | A |
4941870 | Okada et al. | Jul 1990 | A |
4977901 | Ofstead | Dec 1990 | A |
5019096 | Fox, Jr. et al. | May 1991 | A |
5047020 | Hsu | Sep 1991 | A |
5069899 | Whitbourne et al. | Dec 1991 | A |
5081161 | Ostapchenko | Jan 1992 | A |
5084065 | Weldon et al. | Jan 1992 | A |
5092841 | Spears | Mar 1992 | A |
5100992 | Cohn et al. | Mar 1992 | A |
5112457 | Marchant | May 1992 | A |
5133742 | Pinchuk | Jul 1992 | A |
5141991 | Konno et al. | Aug 1992 | A |
5151192 | Matkovich et al. | Sep 1992 | A |
5163952 | Froix | Nov 1992 | A |
5165919 | Sasaki et al. | Nov 1992 | A |
5204323 | Findlay et al. | Apr 1993 | A |
5217492 | Guire | Jun 1993 | A |
5219980 | Swidler | Jun 1993 | A |
5232444 | Just et al. | Aug 1993 | A |
5236570 | Ma et al. | Aug 1993 | A |
5258020 | Froix | Nov 1993 | A |
5270046 | Sakamoto et al. | Dec 1993 | A |
5272012 | Opolski | Dec 1993 | A |
5276015 | Khouri et al. | Jan 1994 | A |
5292516 | Viegas et al. | Mar 1994 | A |
5296471 | Holme et al. | Mar 1994 | A |
5298260 | Viegas et al. | Mar 1994 | A |
5300295 | Viegas et al. | Apr 1994 | A |
5302385 | Khan et al. | Apr 1994 | A |
5304121 | Sahatjian | Apr 1994 | A |
5306501 | Viegas et al. | Apr 1994 | A |
5306786 | Moens et al. | Apr 1994 | A |
5328471 | Slepian | Jul 1994 | A |
5330768 | Park et al. | Jul 1994 | A |
5350800 | Verhoeven et al. | Sep 1994 | A |
5356433 | Rowland et al. | Oct 1994 | A |
5372719 | Afeyan et al. | Dec 1994 | A |
5380299 | Fearnot et al. | Jan 1995 | A |
5417981 | Endo et al. | May 1995 | A |
5447724 | Helmus et al. | Sep 1995 | A |
5453171 | Ma et al. | Sep 1995 | A |
5455040 | Marchant | Oct 1995 | A |
5457158 | Caporiccio et al. | Oct 1995 | A |
5462990 | Hubbell et al. | Oct 1995 | A |
5464650 | Berg et al. | Nov 1995 | A |
5475052 | Rhee et al. | Dec 1995 | A |
5476909 | Kim et al. | Dec 1995 | A |
5480436 | Bakker et al. | Jan 1996 | A |
5485496 | Lee et al. | Jan 1996 | A |
5496346 | Horzewski et al. | Mar 1996 | A |
5507768 | Lau et al. | Apr 1996 | A |
5516881 | Lee et al. | May 1996 | A |
5545213 | Keogh et al. | Aug 1996 | A |
5554689 | Langstein et al. | Sep 1996 | A |
5569463 | Helmus et al. | Oct 1996 | A |
5575818 | Pinchuk et al. | Nov 1996 | A |
5578073 | Haimovich et al. | Nov 1996 | A |
5584877 | Miyake et al. | Dec 1996 | A |
5605696 | Eury et al. | Feb 1997 | A |
5607467 | Froix | Mar 1997 | A |
5609629 | Fearnot et al. | Mar 1997 | A |
5610241 | Lee et al. | Mar 1997 | A |
5616338 | Fox, Jr. et al. | Apr 1997 | A |
5618298 | Simon | Apr 1997 | A |
5624411 | Tuch | Apr 1997 | A |
5628730 | Shapland et al. | May 1997 | A |
5644020 | Timmermann et al. | Jul 1997 | A |
5649977 | Campbell | Jul 1997 | A |
5658995 | Kohn et al. | Aug 1997 | A |
5667767 | Greff et al. | Sep 1997 | A |
5670558 | Onishi et al. | Sep 1997 | A |
5674242 | Phan et al. | Oct 1997 | A |
5679400 | Tuch | Oct 1997 | A |
5696100 | Holme et al. | Dec 1997 | A |
5700286 | Tartaglia et al. | Dec 1997 | A |
5702754 | Zhong | Dec 1997 | A |
5711958 | Cohn et al. | Jan 1998 | A |
5716981 | Hunter et al. | Feb 1998 | A |
5721131 | Rudolph et al. | Feb 1998 | A |
5723219 | Kolluri et al. | Mar 1998 | A |
5728751 | Patnaik | Mar 1998 | A |
5735897 | Buirge | Apr 1998 | A |
5741881 | Patnaik | Apr 1998 | A |
5746998 | Torchilin et al. | May 1998 | A |
5759205 | Valentini | Jun 1998 | A |
5770563 | Roberts et al. | Jun 1998 | A |
5776184 | Tuch | Jul 1998 | A |
5783657 | Pavlin et al. | Jul 1998 | A |
5788979 | Alt et al. | Aug 1998 | A |
5800392 | Racchini | Sep 1998 | A |
5808021 | Holme et al. | Sep 1998 | A |
5820917 | Tuch | Oct 1998 | A |
5824048 | Tuch | Oct 1998 | A |
5824049 | Ragheb et al. | Oct 1998 | A |
5830178 | Jones et al. | Nov 1998 | A |
5836962 | Gianotti | Nov 1998 | A |
5837008 | Berg et al. | Nov 1998 | A |
5837313 | Ding et al. | Nov 1998 | A |
5849859 | Acemoglu | Dec 1998 | A |
5851508 | Greff et al. | Dec 1998 | A |
5854376 | Higashi | Dec 1998 | A |
5855618 | Patnaik et al. | Jan 1999 | A |
5858746 | Hubbell et al. | Jan 1999 | A |
5858990 | Walsh | Jan 1999 | A |
5865723 | Love | Feb 1999 | A |
5865814 | Tuch | Feb 1999 | A |
5869127 | Zhong | Feb 1999 | A |
5873904 | Ragheb et al. | Feb 1999 | A |
5876433 | Lunn | Mar 1999 | A |
5876463 | Garcia | Mar 1999 | A |
5877224 | Brocchini et al. | Mar 1999 | A |
5879713 | Roth et al. | Mar 1999 | A |
5897955 | Drumheller | Apr 1999 | A |
5902875 | Roby et al. | May 1999 | A |
5905168 | Dos Santos et al. | May 1999 | A |
5910564 | Gruning et al. | Jun 1999 | A |
5914387 | Roby et al. | Jun 1999 | A |
5919893 | Roby et al. | Jul 1999 | A |
5925720 | Kataoka et al. | Jul 1999 | A |
5932299 | Katoot | Aug 1999 | A |
5955509 | Webber et al. | Sep 1999 | A |
5958385 | Tondeur et al. | Sep 1999 | A |
5962138 | Kolluri et al. | Oct 1999 | A |
5971954 | Conway et al. | Oct 1999 | A |
5980928 | Terry | Nov 1999 | A |
5980972 | Ding | Nov 1999 | A |
5997517 | Whitbourne | Dec 1999 | A |
6010530 | Goicoechea | Jan 2000 | A |
6011125 | Lohmeijer et al. | Jan 2000 | A |
6015541 | Greff et al. | Jan 2000 | A |
6033582 | Lee et al. | Mar 2000 | A |
6034204 | Mohr et al. | Mar 2000 | A |
6042875 | Ding et al. | Mar 2000 | A |
6051549 | Roberts et al. | Apr 2000 | A |
6051576 | Ashton et al. | Apr 2000 | A |
6051648 | Rhee et al. | Apr 2000 | A |
6054553 | Groth et al. | Apr 2000 | A |
6056993 | Leidner et al. | May 2000 | A |
6060451 | DiMaio et al. | May 2000 | A |
6060518 | Kabanov et al. | May 2000 | A |
6080488 | Hostettler et al. | Jun 2000 | A |
6096070 | Ragheb et al. | Aug 2000 | A |
6096525 | Patnaik | Aug 2000 | A |
6099562 | Ding et al. | Aug 2000 | A |
6107416 | Patnaik et al. | Aug 2000 | A |
6110188 | Narciso, Jr. | Aug 2000 | A |
6110483 | Whitbourne et al. | Aug 2000 | A |
6113629 | Ken | Sep 2000 | A |
6120491 | Kohn et al. | Sep 2000 | A |
6120536 | Ding et al. | Sep 2000 | A |
6120788 | Barrows | Sep 2000 | A |
6120904 | Hostettler et al. | Sep 2000 | A |
6121027 | Clapper et al. | Sep 2000 | A |
6129761 | Hubbell | Oct 2000 | A |
6132462 | Li | Oct 2000 | A |
6136333 | Cohn et al. | Oct 2000 | A |
6143354 | Koulik et al. | Nov 2000 | A |
6153252 | Hossainy et al. | Nov 2000 | A |
6159978 | Myers et al. | Dec 2000 | A |
6165212 | Dereume et al. | Dec 2000 | A |
6172167 | Stapert et al. | Jan 2001 | B1 |
6177523 | Reich et al. | Jan 2001 | B1 |
6180632 | Myers et al. | Jan 2001 | B1 |
6193746 | Strecker | Feb 2001 | B1 |
6203551 | Wu | Mar 2001 | B1 |
6211249 | Cohn et al. | Apr 2001 | B1 |
6214901 | Chudzik et al. | Apr 2001 | B1 |
6231600 | Zhong | May 2001 | B1 |
6240616 | Yan | Jun 2001 | B1 |
6245753 | Byun et al. | Jun 2001 | B1 |
6245760 | He et al. | Jun 2001 | B1 |
6248129 | Froix | Jun 2001 | B1 |
6251136 | Guruwaiya et al. | Jun 2001 | B1 |
6254632 | Wu et al. | Jul 2001 | B1 |
6258121 | Yang et al. | Jul 2001 | B1 |
6258371 | Koulik et al. | Jul 2001 | B1 |
6262034 | Mathiowitz et al. | Jul 2001 | B1 |
6270788 | Koulik et al. | Aug 2001 | B1 |
6273913 | Wright et al. | Aug 2001 | B1 |
6277449 | Kolluri et al. | Aug 2001 | B1 |
6283947 | Mirzaee | Sep 2001 | B1 |
6283949 | Roorda | Sep 2001 | B1 |
6284305 | Ding et al. | Sep 2001 | B1 |
6287285 | Michal et al. | Sep 2001 | B1 |
6287628 | Hossainy et al. | Sep 2001 | B1 |
6299604 | Ragheb et al. | Oct 2001 | B1 |
6306176 | Whitbourne | Oct 2001 | B1 |
6331313 | Wong et al. | Dec 2001 | B1 |
6335029 | Kamath et al. | Jan 2002 | B1 |
6338904 | Patnaik et al. | Jan 2002 | B1 |
6344035 | Chudzik et al. | Feb 2002 | B1 |
6346110 | Wu | Feb 2002 | B2 |
6358556 | Ding et al. | Mar 2002 | B1 |
6361819 | Tedeschi et al. | Mar 2002 | B1 |
6369168 | Al-Lamee et al. | Apr 2002 | B1 |
6379381 | Hossainy et al. | Apr 2002 | B1 |
6383215 | Sass | May 2002 | B1 |
6387379 | Goldberg et al. | May 2002 | B1 |
6395326 | Castro et al. | May 2002 | B1 |
6419692 | Yang et al. | Jul 2002 | B1 |
6451373 | Hossainy et al. | Sep 2002 | B1 |
6458383 | Chen et al. | Oct 2002 | B2 |
6465588 | Li | Oct 2002 | B1 |
6482834 | Spada et al. | Nov 2002 | B2 |
6494862 | Ray et al. | Dec 2002 | B1 |
6497729 | Moussy et al. | Dec 2002 | B1 |
6503538 | Chu et al. | Jan 2003 | B1 |
6503556 | Harish et al. | Jan 2003 | B2 |
6503954 | Bhat et al. | Jan 2003 | B1 |
6506437 | Harish et al. | Jan 2003 | B1 |
6524347 | Myers et al. | Feb 2003 | B1 |
6525145 | Gevaert et al. | Feb 2003 | B2 |
6527801 | Dutta | Mar 2003 | B1 |
6527863 | Pacetti et al. | Mar 2003 | B1 |
6528526 | Myers et al. | Mar 2003 | B1 |
6530950 | Alvarado et al. | Mar 2003 | B1 |
6530951 | Bates et al. | Mar 2003 | B1 |
6540776 | Sanders Millare et al. | Apr 2003 | B2 |
6544223 | Kokish | Apr 2003 | B1 |
6544543 | Mandrusov et al. | Apr 2003 | B1 |
6544582 | Yoe | Apr 2003 | B1 |
6555157 | Hossainy | Apr 2003 | B1 |
6558733 | Hossainy et al. | May 2003 | B1 |
6565659 | Pacetti et al. | May 2003 | B1 |
6572644 | Moein | Jun 2003 | B1 |
6585755 | Jackson et al. | Jul 2003 | B2 |
6585765 | Hossainy et al. | Jul 2003 | B1 |
6585926 | Mirzaee | Jul 2003 | B1 |
6589943 | Byun et al. | Jul 2003 | B2 |
6605154 | Villareal | Aug 2003 | B1 |
6616765 | Castro et al. | Sep 2003 | B1 |
6623448 | Slater | Sep 2003 | B2 |
6625486 | Lundkvist et al. | Sep 2003 | B2 |
6630580 | Tsang et al. | Oct 2003 | B2 |
6645135 | Bhat | Nov 2003 | B1 |
6645195 | Bhat et al. | Nov 2003 | B1 |
6656216 | Hossainy et al. | Dec 2003 | B1 |
6656506 | Wu et al. | Dec 2003 | B1 |
6660034 | Mandrusov et al. | Dec 2003 | B1 |
6663662 | Pacetti et al. | Dec 2003 | B2 |
6663880 | Roorda et al. | Dec 2003 | B1 |
6666880 | Chiu et al. | Dec 2003 | B1 |
6673154 | Pacetti et al. | Jan 2004 | B1 |
6673385 | Ding et al. | Jan 2004 | B1 |
6682886 | Gold | Jan 2004 | B1 |
6689099 | Mirzaee | Feb 2004 | B2 |
6695920 | Pacetti et al. | Feb 2004 | B1 |
6706013 | Bhat et al. | Mar 2004 | B1 |
6706289 | Lewis et al. | Mar 2004 | B2 |
6709514 | Hossainy | Mar 2004 | B1 |
6712845 | Hossainy | Mar 2004 | B2 |
6713119 | Hossainy et al. | Mar 2004 | B2 |
6716444 | Castro et al. | Apr 2004 | B1 |
6723120 | Yan | Apr 2004 | B2 |
6733768 | Hossainy et al. | May 2004 | B2 |
6740040 | Mandrusov et al. | May 2004 | B1 |
6743462 | Pacetti | Jun 2004 | B1 |
6749626 | Bhat et al. | Jun 2004 | B1 |
6753071 | Pacetti | Jun 2004 | B1 |
6758859 | Dang et al. | Jul 2004 | B1 |
6759054 | Chen et al. | Jul 2004 | B2 |
6764505 | Hossainy et al. | Jul 2004 | B1 |
6929955 | Bucha et al. | Aug 2005 | B2 |
6961610 | Yang et al. | Nov 2005 | B2 |
7077860 | Yan et al. | Jul 2006 | B2 |
7396541 | Hossainy et al. | Jul 2008 | B2 |
7494824 | Bucha et al. | Feb 2009 | B2 |
7722894 | Wang et al. | May 2010 | B2 |
20010007083 | Roorda | Jul 2001 | A1 |
20010014717 | Hossainy et al. | Aug 2001 | A1 |
20010018469 | Chen et al. | Aug 2001 | A1 |
20010020011 | Mathiowitz et al. | Sep 2001 | A1 |
20010027340 | Wright et al. | Oct 2001 | A1 |
20010029351 | Falotico et al. | Oct 2001 | A1 |
20010037145 | Guruwaiya et al. | Nov 2001 | A1 |
20010044651 | Steinke et al. | Nov 2001 | A1 |
20010044654 | Chen et al. | Nov 2001 | A1 |
20010051608 | Mathiowitz et al. | Dec 2001 | A1 |
20020004101 | Ding et al. | Jan 2002 | A1 |
20020005206 | Falotico et al. | Jan 2002 | A1 |
20020007213 | Falotico et al. | Jan 2002 | A1 |
20020007214 | Falotico | Jan 2002 | A1 |
20020007215 | Falotico et al. | Jan 2002 | A1 |
20020009604 | Zamora et al. | Jan 2002 | A1 |
20020013549 | Zhong et al. | Jan 2002 | A1 |
20020016625 | Falotico et al. | Feb 2002 | A1 |
20020032414 | Ragheb et al. | Mar 2002 | A1 |
20020032434 | Chudzik et al. | Mar 2002 | A1 |
20020051730 | Bodnar et al. | May 2002 | A1 |
20020062148 | Hart | May 2002 | A1 |
20020071822 | Uhrich | Jun 2002 | A1 |
20020077693 | Barclay et al. | Jun 2002 | A1 |
20020082679 | Sirhan et al. | Jun 2002 | A1 |
20020087123 | Hossainy et al. | Jul 2002 | A1 |
20020091433 | Ding et al. | Jul 2002 | A1 |
20020094440 | Llanos et al. | Jul 2002 | A1 |
20020111590 | Davila et al. | Aug 2002 | A1 |
20020120326 | Michal | Aug 2002 | A1 |
20020123505 | Mollison et al. | Sep 2002 | A1 |
20020123801 | Pacetti et al. | Sep 2002 | A1 |
20020133183 | Lentz et al. | Sep 2002 | A1 |
20020142039 | Claude | Oct 2002 | A1 |
20020155212 | Hossainy | Oct 2002 | A1 |
20020165608 | Llanos et al. | Nov 2002 | A1 |
20020176849 | Slepian | Nov 2002 | A1 |
20020183581 | Yoe et al. | Dec 2002 | A1 |
20020188037 | Chudzik et al. | Dec 2002 | A1 |
20020188277 | Roorda et al. | Dec 2002 | A1 |
20020192449 | Hobbs et al. | Dec 2002 | A1 |
20020197261 | Li et al. | Dec 2002 | A1 |
20030004141 | Brown | Jan 2003 | A1 |
20030021762 | Luthra et al. | Jan 2003 | A1 |
20030028243 | Bates et al. | Feb 2003 | A1 |
20030028244 | Bates et al. | Feb 2003 | A1 |
20030031780 | Chudzik et al. | Feb 2003 | A1 |
20030032767 | Tada et al. | Feb 2003 | A1 |
20030036794 | Ragheb et al. | Feb 2003 | A1 |
20030039689 | Chen et al. | Feb 2003 | A1 |
20030040712 | Ray et al. | Feb 2003 | A1 |
20030040790 | Furst | Feb 2003 | A1 |
20030059520 | Chen et al. | Mar 2003 | A1 |
20030060877 | Falotico et al. | Mar 2003 | A1 |
20030065377 | Davila et al. | Apr 2003 | A1 |
20030072868 | Harish et al. | Apr 2003 | A1 |
20030073961 | Happ | Apr 2003 | A1 |
20030083646 | Sirhan et al. | May 2003 | A1 |
20030083739 | Cafferata | May 2003 | A1 |
20030097088 | Pacetti | May 2003 | A1 |
20030097173 | Dutta | May 2003 | A1 |
20030099712 | Jayaraman | May 2003 | A1 |
20030105518 | Dutta | Jun 2003 | A1 |
20030113439 | Pacetti et al. | Jun 2003 | A1 |
20030138487 | Hogan et al. | Jul 2003 | A1 |
20030150380 | Yoe | Aug 2003 | A1 |
20030157241 | Hossainy et al. | Aug 2003 | A1 |
20030158517 | Kokish | Aug 2003 | A1 |
20030190406 | Hossainy et al. | Oct 2003 | A1 |
20030203991 | Schottman et al. | Oct 2003 | A1 |
20030207020 | Villareal | Nov 2003 | A1 |
20030211230 | Pacetti et al. | Nov 2003 | A1 |
20030236514 | Schwarz | Dec 2003 | A1 |
20040018296 | Castro et al. | Jan 2004 | A1 |
20040029952 | Chen et al. | Feb 2004 | A1 |
20040047978 | Hossainy et al. | Mar 2004 | A1 |
20040047980 | Pacetti et al. | Mar 2004 | A1 |
20040052858 | Wu et al. | Mar 2004 | A1 |
20040052859 | Wu et al. | Mar 2004 | A1 |
20040054104 | Pacetti | Mar 2004 | A1 |
20040060508 | Pacetti et al. | Apr 2004 | A1 |
20040062853 | Pacetti et al. | Apr 2004 | A1 |
20040063805 | Pacetti et al. | Apr 2004 | A1 |
20040071861 | Mandrusov et al. | Apr 2004 | A1 |
20040072922 | Hossainy et al. | Apr 2004 | A1 |
20040073298 | Hossainy | Apr 2004 | A1 |
20040086542 | Hossainy et al. | May 2004 | A1 |
20040086550 | Roorda et al. | May 2004 | A1 |
20040096476 | Uhrich et al. | May 2004 | A1 |
20040096504 | Michal | May 2004 | A1 |
20040098117 | Hossainy et al. | May 2004 | A1 |
20040180039 | Toner et al. | Sep 2004 | A1 |
20050239131 | Bucha et al. | Oct 2005 | A1 |
20060014720 | Hossainy et al. | Jan 2006 | A1 |
20060121085 | Warren | Jun 2006 | A1 |
20060178738 | Yan et al. | Aug 2006 | A1 |
Number | Date | Country |
---|---|---|
42 24 401 | Jan 1994 | DE |
0 301 856 | Feb 1989 | EP |
0 396 429 | Nov 1990 | EP |
0 514 406 | Nov 1992 | EP |
0 596 615 | May 1994 | EP |
0 604 022 | Jun 1994 | EP |
0 623 354 | Nov 1994 | EP |
0 665 023 | Aug 1995 | EP |
0 701 802 | Mar 1996 | EP |
0 716 836 | Jun 1996 | EP |
0 809 999 | Dec 1997 | EP |
0 832 655 | Apr 1998 | EP |
0 850 651 | Jul 1998 | EP |
0 879 595 | Nov 1998 | EP |
0 910 584 | Apr 1999 | EP |
0 923 953 | Jun 1999 | EP |
0 947 205 | Oct 1999 | EP |
0 953 320 | Nov 1999 | EP |
0 970 711 | Jan 2000 | EP |
0 982 041 | Mar 2000 | EP |
1 023 879 | Aug 2000 | EP |
1 192 957 | Apr 2002 | EP |
1 273 314 | Jan 2003 | EP |
06-218038 | Aug 1994 | JP |
08-191887 | Jul 1996 | JP |
2001-500407 | Jan 2001 | JP |
2001-500408 | Jan 2001 | JP |
2001-190687 | Jul 2001 | JP |
2001-519839 | Oct 2001 | JP |
2001-527539 | Dec 2001 | JP |
2002-501788 | Jan 2002 | JP |
872531 | Oct 1981 | SU |
876663 | Oct 1981 | SU |
905228 | Feb 1982 | SU |
790725 | Feb 1983 | SU |
1016314 | May 1983 | SU |
811750 | Sep 1983 | SU |
1293518 | Feb 1987 | SU |
WO 8905616 | Jun 1989 | WO |
WO 9112846 | Sep 1991 | WO |
WO 9409760 | May 1994 | WO |
WO 9510989 | Apr 1995 | WO |
WO 9524929 | Sep 1995 | WO |
WO 9640174 | Dec 1996 | WO |
WO 9710011 | Mar 1997 | WO |
WO 9745105 | Dec 1997 | WO |
WO 9746590 | Dec 1997 | WO |
WO 9808463 | Mar 1998 | WO |
WO 9810805 | Mar 1998 | WO |
WO 9810806 | Mar 1998 | WO |
WO 9817331 | Apr 1998 | WO |
WO 9832398 | Jul 1998 | WO |
WO 9836784 | Aug 1998 | WO |
WO 9846648 | Oct 1998 | WO |
WO 9849206 | Nov 1998 | WO |
WO 9901118 | Jan 1999 | WO |
WO 9938546 | Aug 1999 | WO |
WO 9963981 | Dec 1999 | WO |
WO 0002599 | Jan 2000 | WO |
WO 0012147 | Mar 2000 | WO |
WO 0018446 | Apr 2000 | WO |
WO 0021572 | Apr 2000 | WO |
WO 0064506 | Nov 2000 | WO |
WO 0101890 | Jan 2001 | WO |
WO 0115751 | Mar 2001 | WO |
WO 0117577 | Mar 2001 | WO |
WO 0145763 | Jun 2001 | WO |
WO 0149338 | Jul 2001 | WO |
WO 0151027 | Jul 2001 | WO |
WO 0174414 | Oct 2001 | WO |
WO 0203890 | Jan 2002 | WO |
WO 0226162 | Apr 2002 | WO |
WO 0234311 | May 2002 | WO |
WO 02056790 | Jul 2002 | WO |
WO 02058753 | Aug 2002 | WO |
WO 02067908 | Sep 2002 | WO |
WO 02085419 | Oct 2002 | WO |
WO 02102283 | Dec 2002 | WO |
WO 03000308 | Jan 2003 | WO |
WO 03022323 | Mar 2003 | WO |
WO 03028780 | Apr 2003 | WO |
WO 03037223 | May 2003 | WO |
WO 03039612 | May 2003 | WO |
WO 03080147 | Oct 2003 | WO |
WO 03082368 | Oct 2003 | WO |
WO 2004000383 | Dec 2003 | WO |
WO 2004009145 | Jan 2004 | WO |
WO 2004021976 | Mar 2004 | WO |
WO 2004026359 | Apr 2004 | WO |
Entry |
---|
Byun et al. Journal of Biomedical Materials Research 1996 30:423-427. |
Kang et al. Journal of Biomaterials Science, Polymer Edition 2001 12:1091-1108. |
Shoichet et al. Macromolecules 1991 24:982-986. |
Betz et al. Nuclear Instruments and Methods in Physics Research B 2003 208:434-441. |
Na et al. Biotechnology Letters 2003 25:381-385. |
Manta et al. Enzyme and Microbial Technology 2003 33:890-898. |
Search Report and the Written Opinion for PCT/US2005/017811, filed May 19, 2005, mailed Aug. 10, 2005, 14 pgs. |
Vulić et al., “Heparin-containing block copolymers. Part II In vitro and ex vivo blood compatibility”, J. of Mat. Science Materials in Medicine vol. 4, No. 5, pp. 448-459, 1993. |
Anonymous, Cardiologists Draw—Up the Dream Stent, Clinica 710:15 (Jun. 17, 1996), http://www.dialogweb.com/cgi/document?req=1061848202959, printed Aug. 25, 2003 (2 pages). |
Anonymous, Heparin-coated stents cut complications by 30%, Clinica 732:17 (Nov. 18, 1996), http://www.dialogweb.com/cgi/document?req=1061847871753, printed Aug. 25, 2003 (2 pages). |
Anonymous, Rolling Therapeutic Agent Loading Device for Therapeutic Agent Delivery or Coated Stent (Abstract 434009), Res. Disclos. pp. 974-975 (Jun. 2000). |
Anonymous, Stenting continues to dominate cardiology, Clinica 720:22 (Sep. 2, 1996), http://www.dialogweb.com/cgi/document?req=1061848017752, printed Aug. 25, 2003 (2 pages). |
Aoyagi et al., Preparation of cross-linked aliphatic polyester and application to thermo-responsive material, Journal of Controlled Release 32:87-96 (1994). |
Barath et al., Low Dose of Antitumor Agents Prevents Smooth Muscle Cell Proliferation After Endothelial Injury, JACC 13(2): 252A (Abstract) (Feb. 1989). |
Barbucci et al., Coating of commercially available materials with a new heparinizable material, J. Biomed. Mater. Res. 25:1259-1274 (Oct. 1991). |
Chung et al., Inner core segment design for drug delivery control of thermo-responsive polymeric micelles, Journal of Controlled Release 65:93-103 (2000). |
Dev et al., Kinetics of Drug Delivery to the Arterial Wall Via Polyurethane-Coated Removable Nitinol Stent: Comparative Study of Two Drugs, Catheterization and Cardiovascular Diagnosis 34:272-278 (1995). |
Dichek et al., Seeding of Intravascular Stents with Genetically Engineered Endothelial Cells, Circ. 80(5):1347-1353 (Nov. 1989). |
Eigler et al., Local Arterial Wall Drug Delivery from a Polymer Coated Removable Metallic Stent: Kinetics, Distribution, and Bioactivity of Forskolin, JACC, 4A (701-1), Abstract (Feb. 1994). |
Helmus, Overview of Biomedical Materials, MRS Bulletin, pp. 33-38 (Sep. 1991). |
Herdeg et al., Antiproliferative Stent Coatings: Taxol and Related Compounds, Semin. Intervent. Cardiol. 3:197-199 (1998). |
Huang et al., Biodegradable Polymers Derived from Aminoacids, Macromol. Symp. 144, 7-32 (1999). |
Inoue et al., An AB block copolymer of oligo(methyl methacrylate) and poly(acrylic acid) for micellar delivery of hydrophobic drugs, Journal of Controlled Release 51:221-229 (1998). |
Kataoka et al., Block copolymer micelles as vehicles for drug delivery, Journal of Controlled Release 24:119-132 (1993). |
Katsarava et al., Amino Acid-Based Bioanalogous Polymers. Synthesis and Study of Regular Poly(ester amide)s Based on Bis(α-amino acid)α,ω-Alkylene Diesters, and Aliphatic Dicarbolic Acids, Journal of Polymer Science, Part A: Polymer Chemistry, 37(4), 391-407 (1999). |
Levy et al., Strategies for Treating Arterial Restenosis Using Polymeric Controlled Release Implants, Biotechnol. Bioact. Polym. [Proc. Am. Chem. Soc. Symp.], pp. 259-268 (1994). |
Liu et al., Drug release characteristics of unimolecular polymeric micelles, Journal of Controlled Release 68:167-174 (2000). |
Marconi et al., Covalent bonding of heparin to a vinyl copolymer for biomedical applications, Biomaterials 18(12):885-890 (1997). |
Matsumaru et al., Embolic Materials for Endovascular Treatment of Cerebral Lesions, J. Biomater. Sci. Polymer Edn 8(7):555-569 (1997). |
Miyazaki et al., Antitumor Effect of Implanted Ethylene-Vinyl Alcohol Copolymer Matrices Containing Anticancer Agents on Ehrlich Ascites Carcinoma and P388 Leukemia in Mice, Chem. Pharm. Bull. 33(6) 2490-2498 (1985). |
Miyazawa et al., Effects of Pemirolast and Tranilast on Intimal Thickening After Arterial Injury in the Rat, J. Cardiovasc. Pharmacol., pp. 157-162 (1997). |
Nordrehaug et al., A novel biocompatible coating applied to coronary stents, European Heart Journal 14, p. 321 (P1694), Abstr. Suppl. (1993). |
Ohsawa et al., Preventive Effects of an Antiallergic Drug, Pemirolast Potassium, on Restenosis After Percutaneous Transluminal Coronary Angioplasty, American Heart Journal 136(6):1081-1087 (Dec. 1998). |
Ozaki et al., New Stent Technologies, Progress in Cardiovascular Diseases, vol. XXXIX(2):129-140 (Sep./Oct. 1996). |
Pechar et al., Poly(ethylene glycol) Multiblock Copolymer as a Carrier of Anti-Cancer Drug Doxorubicin, Bioconjucate Chemistry 11(2):131-139 (Mar./Apr. 2000). |
Peng et al., Role of polymers in improving the results of stenting in coronary arteries, Biomaterials 17:685-694 (1996). |
Saotome, et al., Novel Enzymatically Degradable Polymers Comprising α-Amino Acid, 1,2-Ethanediol, and Adipic Acid, Chemistry Letters, pp. 21-24, (1991). |
Shigeno, Prevention of Cerebrovascular Spasm by Bosentan, Novel Endothelin Receptor, Chemical Abstract 125:212307 (1996). |
van Beusekom et al., Coronary stent coatings, Coronary Artery Disease 5(7):590-596 (Jul. 1994). |
Wilensky et al., Methods and Devices for Local Drug Delivery in Coronary and Peripheral Arteries, Trends Cardiovasc. Med. 3(5):163-170 (1993). |
Yokoyama et al., Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor, Journal of Controlled Release 50:79-92 (1998). |
Soons et al., The heparin-catalysed inhibition of human Factor Xla by antithrombin III is dependent on the heparin type, Biochem.J. vol. 256, 815-820 (1988). |
Luo et al., Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery, Journal of Controlled Release 69 (2000) 169-184. |
Translation of Notification of Refusal received from JPO for Appl. No. 2007-515203, mailed Apr. 24, 2012, 7 pgs. |
PartialTranslation of Notification of Refusal received from JPO for Appl. No. 2007-515203, mailed Feb. 5, 2013, 2 pgs. |
CAS Registry file for Hyaluronic acid, accessed Oct. 9, 2008. |
Devaux “Static and Dynamic Lipid Asymmetry in Cell Membranes”, Biochemsitry 30(5), p. 1173-1179, (1991). |
Galli et al. “Acute and Mid-Term Results of Phosphorylcholine-Coated Stents in Primary Coronary Stenting for Acute Myocardial Infarction” Catheterization and Cardiovascular Interventions 53, p. 182-187 (2001). |
Luo et al., “Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery”, J. of Controlled Release 69, pp. 169-184 (2000). |
Medtronic, Trillium Affinity NT, Oxygenator, Product Information, 6 pages (2000). |
Palanzo et al. “Effect of Carmeda®”, Perfusion 16, pp. 279-283 (2001). |
Simon et al. “Species Variations in Phospholipid Class Distribution of Organs II. Heart and Skeletal Muscle” Lipids 4(6), pp. 607-614 (1969). |
Soons et al., “The heparin-catalysed inhibition of human Factor Xia by antithrombin III is dependent on the heparin type”, Biochem J. 256, pp. 815-820 (1988). |
Sun et al. “Synthesis and Terminal Functionalization of a Polymerizable Phosphatidylethanolamine”, Biconjugate Chemistry, 12(5), pp. 673-677 (2001). |
Trillium(R) Affinity(R) NT Oxygenator Product Monograph from Medtronic, 6 pgs. (2000). |
U.S. Appl. No. 11/171,111, filed Jun. 29, 2005, Glauser et al. |
Durrani et al. “Biomembranes as models for polymer surfaces,” Biomaterials, vol. 7, 1996, pp. 121-125. |
Francois et al. “Physical and biological effects of a surface coating procedure on polyurethane catheters,” Biomaterials, vol. 17, No. 7, 1996, pp. 667-678. |
Gautier et al. “Amphiphilic copolymers of ε-caprolactone and γ-substituted ε-caprolactone. Synthesis and functionalization of poly(D,L-lactide) nanoparticles.” J. Biomater. Sci. Polymer Edn, vol. 14, No. 1, 2003, pp. 63-85. |
Gisselfat et al. “Effect of Sort Segment Length and Chain Extender Structure on Phase Separation and Morphology in Poly (urethane urea)s” Macromol. Mater. Eng., vol. 288, 2003, pp. 265-271. |
Lamberg et al. “Glycosaminoglycans, A Biochemical and Clinical Review,” J. Invest. Dermatol., vol. 63, No. 6, 1974, pp. 433-449. |
Lee et al. “Synthesis and Degradation of End-Group-Functionalized Polylactide,” Journal of Polymer Science: Part A: Polymer Chemistry, vol. 39, 2001, pp. 973-985. |
Park et al. “Blood compatibility of SPUU-PEO-heparin graft copolymers,” Journal of Biomedical Materials Research, vol. 26, 1992, pp. 739-756. |
Number | Date | Country | |
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20050266038 A1 | Dec 2005 | US |