Hyaluronic acid based copolymers

Information

  • Patent Grant
  • 9101697
  • Patent Number
    9,101,697
  • Date Filed
    Friday, April 11, 2014
    10 years ago
  • Date Issued
    Tuesday, August 11, 2015
    9 years ago
Abstract
Hyaluronic acid (HA) conjugates or crosslinked HAs compositions for coating an implantable device are provided. The implantable device can be used for treating a disorder such as atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.
Description
BACKGROUND OF THE INVENTION

1. Field of the Invention


This invention generally relates to a hyaluronic acid copolymer and compositions formed therefrom for coating an implantable medical device.


2. Description of the Background


Blood vessel occlusions are commonly treated by mechanically enhancing blood flow in the affected vessels, such as by employing a stent. Stents act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of the passageway. Typically stents are capable of being compressed, so that they can be inserted through small lumens via catheters, and then expanded to a larger diameter once they are at the desired location.


Stents are used not only for mechanical intervention but also as vehicles for providing biological therapy. Biological therapy can be achieved by medicating the stents. Medicated stents provide for the local administration of a therapeutic substance at the diseased site. Local delivery of a therapeutic substance is a preferred method of treatment because the substance is concentrated at a specific site and thus smaller total levels of medication can be administered in comparison to systemic dosages that often produce adverse or even toxic side effects for the patient. One method of medicating a stent involves the use of a polymeric carrier coated onto the surface of the stent.


Despite their utility, stents have been plagued by two problems, namely, acute occlusion due to thrombosis and persistent occurrence of restenosis. Recent studies show that coronary stenting results in significant platelet, polymorphonuclear leukocyte, and macrophage activation, as well as activation of the coagulation pathway which induce clots despite passivation and/or anti-coagulation treatment of the stent surface. This limitation relates to the surface exposure of adhesion receptors on activated platelets to the foreign surface of the stent, producing the aforementioned thrombogenic activity that must be countered with intense anti-coagulation regimens. Subacute stent thrombosis occurs most frequently during the first few days after implantation and almost always in the first two weeks. Thereafter, neointimal cells including proliferating smooth muscle cells from the vessel wall and endothelial hyperplastic cells encompass the stent surface and ameliorate the risk of stent thrombosis.


Hyaluronic acid (HA) has been used as a material for imparting biobeneficial properties to stent coatings (see, for example, U.S. Pat. No. 5,849,368) that help reduce restenosis and thrombosis. However, HA is very hydrophilic and highly water soluble and organic solvent insoluble. Also, because of its high water solubility, HA lacks film-forming ability on an implantable device such as a stent. It is also to be note that HA molecule is delicate, that degradation of the molecule can lead to a dramatic decrease in molecular weight.


The compositions and the coatings formed thereof disclosed herein address the above described problems and other needs.


SUMMARY OF THE INVENTION

Provided herein are hyaluronic acid (HA) conjugates including HA copolymers and crosslinked HAs and compositions formed therefrom for coating implantable devices such as a stent that can be a metallic stent or a polymeric stent which can be durable, biodegradable or bioabsorbable. The HA conjugate can have molecular HA and at least a component that can be heparin, poly(ethylene glycol) (PEG), hydrophobic side chains, biocompatible hydrophobic polymers, and combinations thereof. Alternatively, the HA conjugate can have a moiety derived from HA or HA derivative and at least one moiety or derivative derived from heparin, poly(ethylene glycol) (PEG), hydrophobic side chains, biocompatible hydrophobic polymers, and combinations thereof.


The HA conjugates can be formed by functionalizing HA with a reactive agent that would provide the functionalized HA a reactive and accessible reactive group and reacting the functionalized HA with hydrophobic species, PEG, heparin, biocompatible polymers, and combinations thereof. Representative reactive agents include hydrazide, dihydrazide, aziridine, epoxides, and vinyl sulphones.


In one embodiment, crosslinked HAs can be formed by crosslinking functionalized HAs bearing crosslinking moieties in the presence of biocompatible initiator by applying a crosslinking means such as heating, UV, or combinations thereof. Crosslinking moieties such as acryloyl or methacryloyl moieties can be introduced into HA by their reaction with functionalized HA such as HA-hydrazide.


In another embodiment, crosslinked HA can be formed by reacting HA with a biocompatible crosslinker such as the aziridine crosslinker from Sybron Chemicals (New Jersey) and other crosslinkers having two or more linking moieties.


In still another embodiment, hydrophobic species, poly(ethylene glycol) (PEG), or heparin can be functionalized with two or more crosslinking moieties such as hydrazides, aziridines, epoxides, vinyl sulfphones, aldehydes and used as crosslinker to crosslink HA.


In a further embodiment, the cyclic dimmer 3-hydroxypropionatealdehyde (3-HPA) can be used as a crosslinker to crosslink HA.


The HA conjugate or crosslinked HA can be used to form a coating on an implantable device, which may include a bioactive agent. Representative bioactive agents include, but are not limited to, ABT-578™, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugs thereof, co-drugs thereof, and combinations thereof.


The composition provided herein can be coated onto an implantable device. The implantable device can be any implantable device. In one embodiment, the implantable device is a drug-delivery stent. The implantable device can be used for the treatment of a medical condition such as atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.





BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1A is a schematic structure of hyaluronic acid's building blocks; FIG. 1B shows the structure of adipic dihydrazide.





DETAILED DESCRIPTION

Provided herein are hyaluronic acid (HA) conjugates including HA copolymers and crosslinked HAs and compositions formed therefrom for coating implantable devices such as a stent that can be a metallic stent or a polymeric stent which can be durable, biodegradable or bioabsorbable. The HA conjugate can have molecular HA and at least a component that can be heparin, poly(ethylene glycol) (PEG), hydrophobic side chains, biocompatible hydrophobic polymers, and combinations thereof. Alternatively, the HA conjugate can have a moiety derived from HA or HA derivative and at least one moiety or derivative derived from heparin, poly(ethylene glycol) (PEG), hydrophobic side chains, biocompatible hydrophobic polymers, and combinations thereof. The HA containing conjugate can have organic solvent solubility and film forming property. The coating including the HA conjugate has acute and long term biobeneficial properties. In addition, the coating can provide for controlled release of a bioactive agent such as everolimus.


As used herein, biobeneficial properties of a material refers to the material capable of enhancing the biocompatibility of a device by being non-fouling, hemocompatible, actively non-thrombogenic, or anti-inflammatory, all without depending on the release of a pharmaceutically active agent. 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. Similarly, non-thrombogenic and anti-inflammatory means completely preventing, delaying or minimizing to a desirable degree the formation of thrombin and inflammation.


The term HA conjugate as used herein refers to a substance that includes a HA component that can be HA or a moiety derived from HA and at least one other component that can be a species or a polymer as defined herein. The components in the HA conjugate can have an interaction such as covalent bonding, ionic interaction, hydrogen bonding, van der Waals interaction, and interpenetrating network.


Modification of HA

The conjugate can be formed from a functionalized HA with a modifying species such as hydrophobic side chain species, a hydrophobic, biodegradable polymers, poly(ethylene glycol) (PEG), or heparin. The conjugate can also be formed from a HA with a functionalized modifying species.


A. Functionalization of HA


The HA backbone has two potential sites for functionalization, namely, a carboxylic acid and a primary hydroxyl (FIG. 1A). HA can reach molecular weights in the millions of Daltons, while its repeating unit has a molecular weight of 435 Daltons. This results in the HA molecule having a very large number of potential reactive sites, which allows one to functionalize HA via a linking agent for modification of HA.


In one embodiment, the linking agent can be a difunctional reactive species having two reactive groups. One of the two reactive groups links to Site 1 or Site 2 of HA (FIG. 1A), and the other reactive group links to another polymer or material to form a modified HA such as a block copolymer comprising the HA. For example, the difunctional reactive species can be a dihydrazide. The dihydrazide can be any dihydrazide. As an example, the dihydrazide can be adipic dihydrazide (FIG. 1B). Functionalization of HA can be achieved by coupling of adipic dihydrazide with HA in the presence of an agent such as carbodiimide (ethyl carbodiimide (EDCI), for example) (see, Luo, Y., et al., J. Contr. Release 69:169-184 (2000)) (Scheme 1).




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The reaction can be carried out in water. In order to avoid crosslinking of HA by the dihydrazide, the reaction can be carried out in an excess of dihydrazide, and the degree of functionalization can be controlled by the amount of carbodiimide used. For example, using a stoichiometric amount of carbodiimide would result in about 100% functionalization of HA, and using 50% of the stoichiometric amount of carbodiimide would result in about 50% functionalization of HA. The amount of carbodiimide used can range from about 0% to about 100% stoichiometric amount, from about 20% to about 80% stoichiometric amount, or from about 30% to about 50% stoichiometric amount.


In another embodiment, HA can be functionalized via an aziridine, which can be conducted in water (see, for example, Gianolino, D. A., et al., Crosslinked sodium hyaluronate containing labile linkages, Abstract from Society for Biomaterials 2002). For example, HA can be functionalized by coupling with pentaerythritol tris(3-aziridinopropionate), which is commercially available, in water (scheme 2).




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In a further embodiment, the functionalization of HA can be carried out by any other suitable agents. Exemplary other suitable agents include epoxides and/or vinyl sulphones. The functionalized HA then can be coupled with another polymer or material to form a derivatized HA under conditions known in the art suitable for coupling.


The functionalized HA can bear hydrazide group, terminal amine group, terminal anhydride group, terminal aldehyde group, and combinations thereof.


B. Conjugation with Hydrophobic Species


In accordance with one embodiment of the present invention, functionalized HA can be coupled with a hydrophobic species to form a conjugate with hydrophobic side chains. Exemplary useful hydrophobic species to provide for the hydrophobic side chains of the conjugate include, for example, saturated and unsaturated fatty acids, saturated and unsaturated fatty alcohols. Exemplary useful hydrophobic, saturated and unsaturated fatty acids include, for example, castor oil, laurate, stearate, palmitate and/or oleate. Exemplary saturated and unsaturated fatty alcohols include, for example, hexanol, dodecanol, stanol, sterol, cholesterol, and/or cetyl. In some embodiments, the hydrophobic species is a short chain hydrophobic species. As used herein, the term “short chain hydrophobic species” refers to a C2-C20 hydrophobic species.


In some embodiments, a hydrophobic compound can be conjugated to HA such that the compound has a Hildebrand solubility parameter (δ) less than 12 (cal/cm3)1/2, less than 11 (cal/cm3)1/2, less than 10.5 (cal/cm3)1/2, or alternatively less than 9 (cal/cm3)1/2.


In accordance with another embodiment of the present invention, the functionalized HA can be coupled with a biocompatible hydrophobic polymer, which can be non-absorbable, biodegradable or bioabsorbable. Useful biocompatible hydrophobic polymers include, for example, poly(ester amide), poly(ester amide) that may contain alkyl groups, amino acid groups, or poly(ethylene glycol) (PEG) groups, polyethylene glycol (PEG), polyhydroxyalkanoates (PHA), poly(2-hydroxyalkanoates), poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) and poly(3-hydroxyoctanoate), poly(4-hydroxyalknaote) such as poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymers comprising any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein or blends thereof, polyesters, poly(D,L-lactide), poly(L-lactide), polyglycolide, poly(D,L-lactide-co-glycolide), polycaprolactone, poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine ester) and derivatives thereof, poly(imino carbonates), poly(phosphoesters), polyphosphazenes, poly(amino acids), polysaccharides, collagen, chitosan, alginate, polyethers, polyamides, polyurethanes, polyalkylenes, polyalkylene oxides, polyethylene oxide, polypropylene oxide, polyethylene glycol (PEG), PHA-PEG, polyvinylpyrrolidone (PVP), alkylene vinyl acetate copolymers such as ethylene vinyl acetate (EVA), alkylene vinyl alcohol copolymers such as ethylene vinyl alcohol (EVOH or EVAL), poly(n-butyl methacrylate) (PBMA), SOLEF™ (poly (vinylidene fluoride-co-hexafluoropropene) and combinations thereof.


The hydrophobic side chain species and biodegradable polymers can be simply added in excess and coupled via a carbodiimide in an appropriate solvent that is a common solvent for the functionalized HA and the hydrophobic side chain species or biodegradable polymer. For example, HA-hydrizide can be coupled to high molecular weight polylactic acid with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) in an acetone solution with an adjusted pH for example pH=8.


While the conjugate can be formed from a functionalized HA and the hydrophobic side chain species or hydrophobic biodegradable polymers, as described above, the conjugate also can be formed from an unfunctionalized HA and a functionalized hydrophobic side chain species or hydrophobic biodegradable polymer. For example, HA can form a conjugate with commercially available octanoic hydrazide by direct coupling of the HA and octanoic hydrazide in a solvent that is a solvent for both materials.


C. Conjugation with Poly(Ethylene Glycol)


In accordance with a further aspect of the present invention, functionalized HA can form a conjugate with a high molecular weight PEG. The PEG useful for forming the HA-PEG conjugates described herein has a molecular weight in the range between 500 Daltons to 250,000 Daltons, specifically between 1,000 Daltons and 100,000 Dalton, and more specifically between 5,000 Daltons and 50,000 Daltons.


In one embodiment, PEG can be functionalized so as to form a PEG bearing a terminal aldehyde. The PEG with a terminal aldehyde can readily react at room temperature in water with a hydrazide functionalized HA to form a HA-PEG conjugate.


In another embodiment, PEG can be functionalized so as to form a PEG bearing a terminal amine group. The PEG bearing a terminal amine group can react directly with HA that was functionalized with a terminal anhydride, yielding a block copolymer, HA-co-PEG.


In a further embodiment, PEG can be functionalized so as to form a PEG succinamide. The PEG succinamide then can be coupled to HA to from a conjugate comprising HA and PEG.


PEG functionalized with amino, aldehyde, or succinyl, or combinations thereof are commercially available. For example, linear amino-PEG of average molecular weight of 6,000 Daltons can be purchased from Shearwater Polymers, Inc. (Huntsville, Ala.).


In still a further embodiment, PEG can be modified to bear an amine group, and HA can be oxidized by an oxidizing agent such as a peroxide or nitrous acid to have terminal aldehyde groups. The amine terminated PEG can then be coupled to the HA bearing terminal aldehyde groups via reductive amination to form a HA and PEG conjugate.


D. Conjugation with Heparin


In accordance with another aspect of the present invention, HA can form a conjugate with heparin. The conjugation can be achieved by coupling a functionalized HA with an unfunctionalized heparin, a functionalized heparin with an unfunctionalized HA, or a functionalized heparin with a functionalized heparin.


In one embodiment, an aldehyde terminated HA can be coupled to amino-functionalized heparin, which is commercially available, via reductive amination to form a HA/heparin conjugate.


In another embodiment, HA can be derivatized with sebacic dihydrazide as described above, PEG-dialdehyde, or a bis-succinimidyl moiety. An amine terminated heparin can then be allowed to react with the derivatized HA to form HA/heparin conjugates having sebacicdihydrazide, PEG, and bis-succinimidyl linkages, respectively.


As used herein, the term “heparin” includes molecular heparin and any of heparin derivatives. 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.


The HA conjugates described herein can take a variety of formulae. In one embodiment, the conjugate can be HA-co-PEG or HA-co-heparin, which is end-capped with hydrophobic species such as fatty acids such as stearate, laurate, palmitate, and oleate, fatty alcohols such as hexanol, dodecanol, stanol, sterol, cholesterol, and cetyl, or biodegradable hydrophobic polymers such as poly(ester amide) that may optionally contain alkyl, amino acid, PEG or alcohol groups, polycaprolactone, polylactide, polyglycolide, polyhydroxyalkanoate (PHA), polydioxanone (PDS), or PHA-PEG. The PHA may include poly(α-hydroxyacids), poly(β-hydroxyacid) such as poly(3-hydroxybutyrate) (PHB), poly(3-hydroxybutyrate-co-valerate) (PHBV), poly(3-hydroxyproprionate) (PHP), poly(3-hydroxyhexanoate) (PHH), or poly(4-hydroxyacid) such as poly (4-hydroxybutyrate), poly(4-hydroxyvalerate) or poly(4-hydroxyhexanoate). The hydrophobic species or biodegradable hydrophobic polymers can be side chains attached to HA-co-PEG or HA-co-heparin.


In one embodiment, the HA conjugate is a PEG-HA-(C12-C18 alkyl) conjugate.


E. Crosslinking of Functionalized HA


In accordance with a further embodiment of the present invention, a modified HA can be crosslinked using a crosslinker. Because of the high hydrophilicity of HA, modified HAs may become a weak hydrogel when immersed in water. Crosslinking of the modified HA would lead to the formation of a coating comprising the modified HA.


In one embodiment, acrylic moieties can be introduced into a modified HA by reacting a HA-hydrazide with acryloyl or methacryloyl chloride to form a HA bearing olefinic moieties such as acryloyl or methacryloyl groups. This material can be mixed with a biocompatible initiator, applied to an implantable device by, for example, dip coating, and then crosslinked upon exposure to a radiation, for example, UV radiation.


In another embodiment, an un-functionalized HA and a crosslinking agent with multiple aziridine groups can be separately applied to the surface of an implantable device to coat and left to react at a temperature such as an ambient temperature. The crosslinking agent can be, for example, pentaerythritol tris(3-aziridinopropionate) available from Sybron Chemicals (NJ). Any other agents having multiple aziridine groups can also be employed.


In a further embodiment of the present invention, a hydrophobic side chain species described herein or a polymer such as PEG can be functionalized with two or more hydrazides, aziridines, aldehydes, amines, diacrylate, bisacrylamide, and other functionalities for use as crosslinkers. A functionalized or un-functionalized HA can be subjected to crosslink with these crosslinkers with or without heating. An example of a hydrophobic side chain species is cyclic dimmer 3-hydroxypropionatealdehyde (3-HPA) found in reuterin.


In still a further embodiment, HA can be coupled to a polymeric surface on an implantable device via, for example, plasma treatment. The surface can be first treated with an argon (Ar) and NH3 plasma to attach amine functionalities that can then be reacted with an anhydride, for example, succinic anhydride, to the surface. These functionalities can then be coupled to one or more functionalized HA, e.g., HA-hydrazide in the presence of a carbodiimide to form a crosslinked HA surface. If desirable, the crosslinked HA surface can be further modified with a biobeneficial material such as heparin. The biobeneficial material can be functionalized with one or more crosslinking moieties such as hydrazide or aziridine groups, with or without a PEG spacer, and attached to the crosslinked HA surface after dip coating.


Bioactive Agent

The modified HA described herein can be used to form coating compositions that may 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, for example, between about 100 and about 500,000 grams or more per mole or between about 100 and about 500,000 grams or more per mole, can be encapsulated. Some other examples of suitable materials include proteins such as antibodies, receptor ligands, and enzymes, peptides such as adhesion peptides, and saccharides and polysaccharides. Some further examples of materials which can be included include 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. Representative diagnostic agents are agents detectable by x-ray, fluorescence, magnetic resonance imaging, radioactivity, ultrasound, computer tomagraphy (CT) and positron emission tomagraphy (PET).


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 for the patient. 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, 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), nitric oxide or nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), sirolimus and sirolimus derivatives, paclitaxel and paclitaxel derivatives, estradiol, steroidal anti-inflammatory agents, antibiotics, anticancer agents, dietary supplements such as various vitamins, and a combination thereof. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, ABT-578™, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugs thereof, co-drugs thereof, and combinations 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.


Coatings on Implantable Devices

Compositions having any of the HA conjugates and/or crosslinked HAs can be used to coat implantable devices, with or without a bioactive agent. The coating described herein can be formed as a single layer of coating on an implantable device or in conjunction with, such as on top of, another layer of coating including a polymer other than the HA conjugate or crosslinked HA described herein. In some embodiments, the HA coating could be the outmost layer of a coated device. In other embodiments, the HA layer could be a top coat layer for a polymer-drug reservoir layer or a polymer free drug layer.


The HA conjugate or crosslinked HA can also be blended with one or more polymers such as biocompatible and/or bioabsorbable polymers. Examples include, but not limited to, poly(ester amide), poly(ester amide) that may optionally contain alkyl groups, amino acid groups, or poly(ethylene glycol) (PEG) groups, polyethylene glycol (PEG), polyhydroxyalkanoates (PHA), poly(2-hydroxyalkanoates), poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) and poly(3-hydroxyoctanoate), poly(4-hydroxyalknaote) such as poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymers comprising any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein or blends thereof, polyesters, poly(D,L-lactide), poly(L-lactide), polyglycolide, poly(D,L-lactide-co-glycolide), polycaprolactone, poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine ester) and derivatives thereof, poly(imino carbonates), poly(phosphoesters), polyphosphazenes, poly(amino acids), polysaccharides, collagen, chitosan, alginate, polyethers, polyamides, polyurethanes, polyalkylenes, polyalkylene oxides, polyethylene oxide, polypropylene oxide, polyethylene glycol (PEG), PHA-PEG, polyvinylpyrrolidone (PVP), alkylene vinyl acetate copolymers such as ethylene vinyl acetate (EVA), alkylene vinyl alcohol copolymers such as ethylene vinyl alcohol (EVOH or EVAL), poly(n-butyl methacrylate) (PBMA) and combinations thereof. In one preferred embodiment, the blend is with SOLEF™ (poly (vinylidene fluoride-co-hexafluoropropene).


In another embodiment, the composition described herein can be used for coating an implantable device such as a drug-delivery stent for controlled release of a bioactive agent. The composition may comprise any of HA conjugates or crosslinked HAs alone or as a blend component with other biocompatible polymers.


In some further embodiments, with the chemistries mentioned previously different type of networks and architectures can be achieved. Exemplary such architectures can be, for example, physical crosslinking or interpenetrating networks. In one embodiment, an interpenetrating network (IPN) can be made by locking HA in a tightly crosslinked network of PEG diacrylate. In this IPN, the HA is not covalently bound to the crosslinked polymer, but trapped in the network. HA can also be physically locked in the coating by being applied simultaneously with an ultra high molecular weight polymer such as poly(D,L-lactide). In addition, HA can be covalently bound to a thermoreversible gel based on a N-isopropylacrylamide (NIPAM)-PEG diblock copolymer.


Method of Coating a Device

The composition described herein can be coated on an implantable device such as a stent by spray coating or any other coating process available in the art. Generally, the coating involves dissolving or suspending the composition, or one or more components thereof, in a solvent or solvent mixture to form a solution, suspension, or dispersion of the composition or one or more components thereof, applying the solution or suspension to an implantable device, and removing the solvent or solvent mixture to form a coating or a layer of coating. Suspensions or dispersions of the composition described herein can be in the form of latex or emulsion of microparticles having a size between 1 nanometer and 100 microns, preferably between 1 nanometer and 10 microns. Heat and/or pressure treatment can be applied to any of the steps involved herein. In addition, if desirable, the coating described here can be subjected to further heat and/or pressure treatment. Some additional exemplary processes of coating an implantable device that may be used to form a coating on an implantable using the composition described herein are described in, for example, Lambert T L, et al. Circulation, 1994; 90: 1003-1011; Hwang C W, et al. Circulation, 2001; 104: 600-605; Van der Giessen W J, et al. Circulation, 1996; 94: 1690-1697; Lincoff A M, et al. J Am Coll Cardiol 1997; 29: 808-816; Grube E. et al, J American College Cardiology Meeting, Mar. 6, 2002, ACCIS2002, poster 1174-15; Grube E, et al, Circulation, 2003, 107: 1, 38-42; Bullesfeld L, et al. Z Kardiol, 2003, 92: 10, 825-832; and Tanabe K, et al. Circulation 2003, 107: 4, 559-64.


The composition can be coated onto the implantable device in the form of a single layer of coating or components of the composition can be coated onto the device in the form of separate layers of coating.


The bioactive agent can be coated onto an implantable device as a separate layer or together with the composition having any of the HA conjugates or crosslinked HAs. In one embodiment, the bioactive agent is coated onto the device as a separate layer. In another embodiment, the bioactive agent is coated onto the device together with the composition described herein.


In a further embodiment, the bioactive agent or a second bioactive agent can be loaded onto a coating described here by swell-loading. The composition having one or more of HA conjugates and/or functionalized HAs can be formulated with a crosslinker such as hydrazides, aziridines, aldehydes, amines, diacrylate, bisacrylamide and applied on top of a medical device coating. Upon photoactivated or thermally initiated crosslinking, a thin surface gel comprising the one or more of the HA conjugates or crosslinked HAs described herein would form. The bioactive agent described herein and/or a second drug can then be swell-loaded in this surface gel. The swell loaded bioactive agent can have a fast release rate, e.g., about 50% to 100% release in vivo in a period of, for example, from about one, two, or three hours to about one day or two days. This would allow the forming of a medical device coating system that has a bimodal release rate that may be efficacious for more refractory lesions such as diabetes, long vessel, high cholesterol, or vulnerable plaques by forming a coating with a first agent that has a controlled release of the first agent and a surface gel described herein with a second agent swell loaded therein. The first agent and the second agent can be the same agent or different agents, which are described above.


As used herein, the term “solvent” refers to a liquid substance or composition that is compatible with the polymer and/or the drug is capable of dissolving or suspending the drug and/or polymeric composition or one or more components thereof at a desired concentration. Representative examples of solvents include chloroform, acetone, water (buffered saline), dimethylsulfoxide (DMSO), propylene glycol monomethyl ether (PM) iso-propylalcohol (IPA), n-propyl alcohol, methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide (DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane, nonane, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol, 2-butanone, cyclohexanone, dioxane, methylene chloride, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, formamide, hexafluoroisopropanol, 1,1,1-trifluoroethanol, and hexamethyl phosphoramide and a combination thereof.


Examples of medical devices that can be used with the chemicals of the present invention 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 (316E), 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 one embodiment, the implantable device is a metallic stent or a biodegradable or bioabsorbable stent.


The compositions described herein can be coated onto a bare metallic or polymeric implantable device or on top of a drug eluting or drug delivery systems.


Method of Use

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 be retained 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 implantable device comprising a coating described herein can be used to treat an animal having a condition or disorder that requires a treatment. Such an animal can be treated by, for example, implanting a device described herein in the animal. Preferably, the animal is a human being. Exemplary disorders or conditions that can be treated by the method disclosed herein include, but not limited to, atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.


EXAMPLES

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.


Example 1

A stent can be coated according to the procedure and in the configuration as specified below:


Primer layer: 100 μg of PLA;


Matrix drug layer: 500 μg of poly(lactic acid) (PLA) and everolimus (weight ratio of PLA to everolimus can be 1:1, for example); and


Topcoat layer: 300 μg of HA conjugate blended with PLA (weight ratio of HA conjugate to everolimus can be 1:1, for example).


Example 2

A stent can be coated according to the procedure and in the configuration as specified below:


Primer layer: 100 μg of PLA;


Matrix drug layer: 500 μg of PLA and everolimus (weight ratio of PLA to everolimus can be 1:1, for example); and


Topcoat layer: 300 μg HA conjugate blended with PEGlyated PLA (e.g. triblock PLA-PEG-PLA) (weight ratio of HA conjugate to PEGlyated PLA can be 1:1, for example)


Example 3

A stent can be coated according to the procedure and in the configuration as specified below:


Primer layer: 100 μg of PLA;


Matrix drug layer: 500 μg of PLA and everolimus (weight ratio of PLA to everolimus can be 1:1, for example); and


Topcoat layer: 300 μg pure HA conjugate.


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.


Additional Embodiments

1. A hyaluronic acid (HA) conjugate comprising HA and at least a component selected from the group consisting of


heparin,


poly(ethylene glycol) (PEG),


hydrophobic side chains,


biocompatible hydrophobic polymers, and


combinations thereof.


2. The HA conjugate of embodiment 1 wherein the short hydrophobic side chains are selected from the group consisting of saturated and unsaturated fatty acids and fatty alcohols.


3. The HA conjugate of embodiment 1 wherein the biocompatible hydrophobic polymers are selected from the group consisting of poly(ester amide), poly(ester amide) that may contain alkyl groups, amino acid groups, or poly(ethylene glycol) (PEG) groups, polyethylene glycol (PEG), polyhydroxyalkanoates (PHA), polyesters, poly(D,L-lactide), poly(L-lactide), polyglycolide, poly(D,L-lactide-co-glycolide), polycaprolactone, poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine ester) and derivatives thereof, poly(imino carbonates), poly(phosphoesters), polyphosphazenes, poly(amino acids), polysaccharides, collagen, chitosan, alginate, polyethers, polyamides, polyurethanes, polyalkylenes, polyalkylene oxides, polyethylene oxide, polypropylene oxide, polyethylene glycol (PEG), PHA-PEG, polyvinylpyrrolidone (PVP), alkylene vinyl acetate copolymers such as ethylene vinyl acetate (EVA), alkylene vinyl alcohol copolymers such as ethylene vinyl alcohol (EVOH or EVAL), poly(n-butyl methacrylate) (PBMA), SOLEF™ (poly (vinylidene fluoride-co-hexafluoropropene) and combinations thereof.


4. The HA conjugate of embodiment 3 wherein the PHA is selected from the group consisting of poly(2-hydroxyalkanoates), poly(3-hydroxyalkanoates), poly(3-hydroxypropanoate), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate), poly(3-hydroxyoctanoate), poly(4-hydroxyalkanoate), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymers comprising any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein or blends thereof, and combinations thereof.


5. The HA conjugate of embodiment 1 wherein the hydrophobic side chains are selected from the group consisting of castor oil, laurate, state, palmitate, oleate, hexanol, dodecanol, stanol, sterol, cholesterol, cetyl, and combination thereof.


6. The HA conjugate of embodiment 1 comprising a heparin and a crosslinker which comprises a moiety selected from the group consisting of difunctional carbodiimide, PEG-dialdehyde, and a bis-succinidyl moieties.


7. The HA conjugate of embodiment 1 comprising a poly(ester amide) which optionally comprises one or more groups selected from the group consisting of alkyl, amino acids, PEG, and combinations thereof.


8. The HA conjugate of embodiment 1 wherein the biocompatible polymer is biodegradable.


9. The HA conjugate of embodiment 1 which is a copolymer comprising a PEG-HA-(C12-C18 alkyl) conjugate.


10 A crosslinked HA composition produced by a process comprising


crosslinking a HA having crosslinking groups by a crosslinking means selected from the group consisting of photo radiation, heating, chemical reaction, physical crosslinking, and combinations thereof.


11. The crosslinked HA composition of embodiment 10 wherein the crosslinking groups are olefinic groups, and


wherein the crosslinking means is photo radiation.


12. The crosslinked HA composition of embodiment 11 wherein the olefinic groups are selected from the group consisting of acryloyl groups, methacryloyl groups, and combinations thereof.


13. A crosslinked HA composition produced by a process comprising


crosslinking HA with a crosslinker by chemical reaction.


14. The crosslinked HA composition of embodiment 13 wherein the crosslinker comprises a hydrophobic moiety or PEG and two or more crosslinking moieties.


15. The crosslinked HA composition of embodiment 14 wherein the hydrophobic moiety is selected from the group consisting of saturated and unsaturated fatty acids, fatty alcohols, hydrophobic polymers, and combinations thereof and


wherein the two or more crosslinking moieties are selected from the group consisting of hydazides, azeridines, aldehydes, amines, diacrylate, bisacrylamide, and combinations thereof.


16. The crosslinked HA composition of embodiment 14 wherein the hydrophobic moiety is selected from the group consisting of castor oil, laurate, state, palmitate, oleate, hexanol, dodecanol, stanol, sterol, cholesterol, cetyl, poly (ester amides), poly(caprolactone), polylactide, polyglycolide, poly(lactide-co-glycolide), poly(DL-lactide-co-glycolide), polyhydroxyalkanoate (PHA), poly(3-hydroxybutyrate) (PHB), poly(3-hydroxybutyrate-co-valerate) (PHBV), poly(3-hydroxyproprionate) (PHP), poly(3-hydroxyhexanoate) (PHH), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate); poly(4-hydroxyhexanoate), poly(dioxanone), and PHA-PEG, and a combination thereof.


17. The crosslinked HA composition of embodiment 15 wherein the crosslinker is cyclic dimmer of 3-hydroxypropionatealdehyde.


18. An implantable device comprising the HA conjugate of embodiment 1.


19. An implantable device comprising the HA conjugate of embodiment 2.


20. An implantable device comprising the HA conjugate of embodiment 3.


21. An implantable device comprising the HA conjugate of embodiment 4.


22. An implantable device comprising the HA conjugate of embodiment 5.


23. An implantable device comprising the HA conjugate of embodiment 6.


24. An implantable device comprising the HA conjugate of embodiment 7.


25. An implantable device comprising the HA conjugate of embodiment 8.


26. An implantable device comprising the HA conjugate of embodiment 9.


27. An implantable device comprising the crosslinked HA composition of embodiment 10.


28. An implantable device comprising the crosslinked HA composition of embodiment 11.


29. An implantable device comprising the crosslinked HA composition of embodiment 12.


30. An implantable device comprising the crosslinked HA composition of embodiment 13.


31. An implantable device comprising the crosslinked HA composition of embodiment 14.


32. An implantable device comprising the crosslinked HA composition of embodiment 15.


33. An implantable device comprising the crosslinked HA composition of embodiment 16.


34. An implantable device comprising the crosslinked HA composition of embodiment 17.


35. The implantable device of embodiment 18 further comprising a bioactive agent.


36. The implantable device of embodiment 18 further comprising a bioactive agent selected from the group consisting of ABT-578™, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugs thereof, co-drugs thereof, and combinations thereof.


37. The implantable device of embodiment 27 further comprising a bioactive agent.


38. The implantable device of embodiment 27 further comprising a bioactive agent selected from the group consisting of ABT-578™, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugs thereof, co-drugs thereof, and combinations thereof.


49. A method of treating a disorder selected from the group consisting of atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof, comprising:


implanting in the human being the implantable device of embodiment 18.


50. A method of treating a disorder selected from the group consisting of atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof, comprising:


implanting in the human being the implantable device of embodiment 27.


51. A hyaluronic acid (HA) conjugate comprising a moiety derived from HA and at least one moiety derived from a material selected from the group consisting of


heparin,


poly(ethylene glycol) (PEG),


hydrophobic side chains,


biocompatible hydrophobic polymers, and


combinations thereof.


52. An implantable device comprising the HA conjugate of embodiment 51.


53. The implantable device of embodiment 52 further comprising a bioactive agent.


54. A method of treating a disorder selected from the group consisting of atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof, comprising:


implanting in the human being the implantable device of embodiment 53.

Claims
  • 1. A hyaluronic acid (HA) conjugate comprising a moiety derived from HA and at least one component that is heparin or a moiety derived from heparin, wherein the moiety derived from HA is a HA derivatized with a reactive agent selected from the group consisting of hydrazide, aziridine, epoxide, vinyl sulphone, and bis-succinimidyl;wherein the HA conjugate is formed by coupling the moiety derived from HA and heparin or a moiety derived from heparin.
  • 2. The HA conjugate of claim 1, wherein the moiety derived from heparin is a heparin derivatized with two or more hydrazides, aziridines, epoxides, vinyl sulphones, and aldehydes.
  • 3. An implantable device comprising the HA conjugate of claim 1.
  • 4. The implantable device of claim 3, further comprising a bioactive agent.
  • 5. The implantable device of claim 4, wherein the bioactive agent is selected from the group consisting of ABT-578™, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxyl)ethyl-rapamycin (everolimus), 40-O-(3-hydroxyl)propyl-rapamycin, 40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugs thereof, co-drugs thereof, and combinations thereof.
  • 6. A method of treating a disorder selected from the group consisting of atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof, comprising: implanting in a human being an implantable device comprising the HA conjugate of claim 1.
  • 7. The HA conjugate of claim 1, wherein the heparin derivative is an alkali metal or alkaline-earth metal salts of heparin.
  • 8. The HA conjugate of claim 7, the alkali metal or alkaline-earth metal salts of heparin is selected from the group consisting of sodium heparin, potassium heparin, lithium heparin, calcium heparin, magnesium heparin, and low molecular weight heparin.
  • 9. The HA conjugate of claim 1, wherein the heparin derivative is selected from the group consisting of heparin sulfate, heparinoids, and heparin having a hydrophobic counter-ion.
  • 10. The HA conjugate of claim 1, wherein the HA conjugate is end-capped with hydrophobic species.
  • 11. The HA conjugate of claim 10, wherein the hydrophobic species is selected from the group consisting of stearate, laurate, palmitate, and oleate, fatty alcohols, and poly(ester amide) that optionally contains alkyl, amino acid, PEG or alcohol groups, polycaprolactone, polylactide, polyglycolide, polyhydroxyalkanoate (PHA), polydioxanone (PDS), or PHA-PEG.
  • 12. The HA conjugate of claim 11, wherein the fatty alcohol is selected from the group consisting of hexanol, dodecanol, stanol, sterol, cholesterol, and cetyl.
  • 13. The HA conjugate of claim 11, wherein the PHA is selected from the group consisting of poly(3-hydroxybutyrate) (PHB), poly(3-hydroxybutyrate-co-valerate) (PHBV), poly(3-hydroxyproprionate) (PHP), poly(3-hydroxyhexanoate) (PHH), poly(4-hydroxyacid), poly (4-hydroxybutyrate), poly(4-hydroxyvalerate), and poly(4-hydroxyhexanoate).
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser. No. 13/631,399 filed on Sep. 28, 2012 which is a divisional application of U.S. application Ser. No. 10/835,912 entitled “Hyaluronic Acid Based Copolymers” filed on Apr. 30, 2004 and issued as U.S. Pat. No. 8,293,890, the teachings of which are incorporated by reference herein in its entirety.

US Referenced Citations (347)
Number Name Date Kind
2072303 Herrmann et al. Mar 1937 A
2386454 Frosch et al. Oct 1945 A
3773737 Goodman et al. Nov 1973 A
3839309 Keyes et al. Oct 1974 A
3849514 Gray, Jr. et al. Nov 1974 A
4226243 Shalaby et al. Oct 1980 A
4329383 Joh May 1982 A
4343931 Barrows Aug 1982 A
4529792 Barrows Jul 1985 A
4611051 Hayes et al. Sep 1986 A
4656242 Swan et al. Apr 1987 A
4733665 Palmaz Mar 1988 A
4800882 Gianturco Jan 1989 A
4806621 Kohn et al. Feb 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
4956489 Auriol et al. Sep 1990 A
4957744 Della Valle et al. Sep 1990 A
4977901 Ofstead Dec 1990 A
5019096 Fox, Jr. et al. May 1991 A
5026821 Boustta et al. Jun 1991 A
5100992 Cohn et al. Mar 1992 A
5112457 Marchant May 1992 A
5133742 Pinchuk Jul 1992 A
5149691 Rutherford Sep 1992 A
5163952 Froix Nov 1992 A
5165919 Sasaki et al. Nov 1992 A
5214112 Shimizu et al. May 1993 A
5219980 Swidler Jun 1993 A
5258020 Froix Nov 1993 A
5272012 Opolski Dec 1993 A
5292516 Viegas et al. Mar 1994 A
5298260 Viegas et al. Mar 1994 A
5300295 Viegas et al. Apr 1994 A
5306501 Viegas et al. Apr 1994 A
5306786 Moens et al. Apr 1994 A
5316912 Heimgartner et al. May 1994 A
5324755 Rhee et al. Jun 1994 A
5328471 Slepian Jul 1994 A
5330768 Park et al. Jul 1994 A
5380299 Fearnot et al. Jan 1995 A
5417981 Endo et al. May 1995 A
5443907 Slaikeu et al. Aug 1995 A
5447724 Helmus et al. Sep 1995 A
5455040 Marchant Oct 1995 A
5462990 Hubbell et al. Oct 1995 A
5464650 Berg et al. Nov 1995 A
5470911 Rhee et al. Nov 1995 A
5476909 Kim et al. Dec 1995 A
5485496 Lee et al. Jan 1996 A
5510418 Rhee et al. Apr 1996 A
5516881 Lee et al. May 1996 A
5569463 Helmus et al. Oct 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
5624411 Tuch Apr 1997 A
5628730 Shapland et al. May 1997 A
5644020 Timmermann et al. Jul 1997 A
5649977 Campbell Jul 1997 A
5652347 Pouyani et al. 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
5690961 Nguyen Nov 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
5735897 Buirge Apr 1998 A
5746998 Torchilin et al. May 1998 A
5759205 Valentini Jun 1998 A
5770637 Vanderlaan 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
5820917 Tuch Oct 1998 A
5824048 Tuch Oct 1998 A
5824049 Ragheb et al. Oct 1998 A
5830178 Jones et al. Nov 1998 A
5837008 Berg et al. Nov 1998 A
5837313 Ding et al. Nov 1998 A
5849368 Hostettler et al. Dec 1998 A
5849859 Acemoglu Dec 1998 A
5851508 Greff et al. Dec 1998 A
5854376 Higashi Dec 1998 A
5858746 Hubbell et al. Jan 1999 A
5865814 Tuch Feb 1999 A
5869127 Zhong Feb 1999 A
5873904 Ragheb et al. Feb 1999 A
5876433 Lunn Mar 1999 A
5877224 Brocchini et al. Mar 1999 A
5879713 Roth et al. Mar 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
6031017 Waki et al. Feb 2000 A
6033582 Lee et al. Mar 2000 A
6034204 Mohr et al. Mar 2000 A
6042875 Ding et al. Mar 2000 A
6051576 Ashton et al. Apr 2000 A
6051648 Rhee 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
6099562 Ding et al. Aug 2000 A
6103255 Levene 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
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
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
6261544 Coury et al. Jul 2001 B1
6262034 Mathiowitz et al. Jul 2001 B1
6270788 Koulik 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
6287628 Hossainy et al. Sep 2001 B1
6288043 Spiro 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
6344035 Chudzik et al. Feb 2002 B1
6346110 Wu Feb 2002 B2
6358556 Ding et al. Mar 2002 B1
6379381 Hossainy et al. Apr 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
6482834 Spada et al. Nov 2002 B2
6494862 Ray 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
6534560 Loomis et al. Mar 2003 B2
6540776 Sanders 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
6585765 Hossainy et al. Jul 2003 B1
6585926 Mirzaee Jul 2003 B1
6605154 Villareal Aug 2003 B1
6616765 Hossaony et al. Sep 2003 B1
6623448 Slater Sep 2003 B2
6625486 Lundkvist et al. Sep 2003 B2
6630457 Aeschlimann et al. Oct 2003 B1
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
6666880 Chiu et al. Dec 2003 B1
6673154 Pacetti et al. Jan 2004 B1
6673385 Ding et al. Jan 2004 B1
6689099 Mirzaee Feb 2004 B2
6695920 Pacetti et al. Feb 2004 B1
6706013 Bhat et al. Mar 2004 B1
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 et al. Jun 2004 B1
6758859 Dang et al. Jul 2004 B1
6759054 Chen et al. Jul 2004 B2
6764505 Hossainy et al. Jul 2004 B1
6946499 Loomis et al. Sep 2005 B2
7091191 Laredo et al. Aug 2006 B2
7129224 Byun et al. Oct 2006 B1
7202064 Skraly et al. Apr 2007 B2
7368169 Kohn et al. May 2008 B2
7511083 Madsen et al. Mar 2009 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
20010029351 Falotico et al. Oct 2001 A1
20010037145 Guruwaiya et al. Nov 2001 A1
20010051608 Mathiowitz et al. Dec 2001 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
20020016625 Falotico et al. Feb 2002 A1
20020032414 Ragheb et al. Mar 2002 A1
20020032434 Chudzik et al. Mar 2002 A1
20020032477 Helmus et al. Mar 2002 A1
20020049281 Zhao et al. Apr 2002 A1
20020051730 Bodnar et al. 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
20020099438 Furst Jul 2002 A1
20020111590 Davila et al. Aug 2002 A1
20020120326 Michal Aug 2002 A1
20020123801 Pacetti et al. Sep 2002 A1
20020142039 Claude Oct 2002 A1
20020155212 Hossainy Oct 2002 A1
20020161376 Barry et al. Oct 2002 A1
20020165608 Llanos et al. Nov 2002 A1
20020176849 Slepian Nov 2002 A1
20020183581 Yoe et al. Dec 2002 A1
20020183858 Contiliano et al. Dec 2002 A1
20020188037 Chudzik et al. Dec 2002 A1
20020188277 Roorda et al. Dec 2002 A1
20030004141 Brown Jan 2003 A1
20030012765 Thompson 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
20030050422 Bezemer et al. Mar 2003 A1
20030059463 Lahtinen Mar 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
20030083732 Stinson May 2003 A1
20030083739 Cafferata May 2003 A1
20030097088 Pacetti May 2003 A1
20030097173 Dutta May 2003 A1
20030099712 Jayaraman May 2003 A1
20030100830 Zhong et al. May 2003 A1
20030100937 Tsuboi et al. May 2003 A1
20030104028 Hossainy et al. Jun 2003 A1
20030105518 Dutta Jun 2003 A1
20030113439 Pacetti et al. Jun 2003 A1
20030125800 Shulze et al. Jul 2003 A1
20030143315 Pui et al. Jul 2003 A1
20030150380 Yoe Aug 2003 A1
20030157241 Hossainy et al. Aug 2003 A1
20030158517 Kokish Aug 2003 A1
20030161938 Johnson Aug 2003 A1
20030170287 Prescott Sep 2003 A1
20030190406 Hossainy et al. Oct 2003 A1
20030195610 Herrmann et al. Oct 2003 A1
20030207020 Villareal Nov 2003 A1
20030208258 Reilly et al. Nov 2003 A1
20030211230 Pacetti et al. Nov 2003 A1
20030216758 Signore Nov 2003 A1
20040010048 Evans et al. Jan 2004 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
20040096504 Michal May 2004 A1
20040098117 Hossainy et al. May 2004 A1
20040106987 Palasis et al. Jun 2004 A1
20050089970 Bradburne et al. Apr 2005 A1
20050129731 Horres et al. Jun 2005 A1
20050147642 Laredo et al. Jul 2005 A1
20050152949 Hotchkiss et al. Jul 2005 A1
20050208093 Glauser et al. Sep 2005 A1
20070098675 Elisseeff et al. May 2007 A1
Foreign Referenced Citations (85)
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
0 604 022 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
0 953 320 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
1 270 018 Jan 2003 EP
1 273 314 Jan 2003 EP
1270018 Jan 2003 EP
63-105003 May 1988 JP
8-333402 Dec 1996 JP
08-333402 Dec 1996 JP
9-59303 Apr 1997 JP
10-506560 Jun 1998 JP
2001-190687 Jul 2001 JP
2002-85549 Mar 2002 JP
2003-524465 Aug 2003 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 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 9817331 Apr 1998 WO
WO 9832398 Jul 1998 WO
WO 9836784 Aug 1998 WO
WO 9901118 Jan 1999 WO
WO 9910385 Mar 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 0041739 Jul 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 0193846 Dec 2001 WO
WO 0203890 Jan 2002 WO
WO 0206373 Jan 2002 WO
WO 0206373 Jan 2002 WO
WO 0226162 Apr 2002 WO
WO 0234311 May 2002 WO
WO 0234312 May 2002 WO
WO 02056790 Jul 2002 WO
WO 02058753 Aug 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
Non-Patent Literature Citations (71)
Entry
Luo et al. “Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery,” Journal of Controlled Release, 2000, vol. 69, pp. 169-184.
Organics Synthesis II: Alcohol and Amine, Jikken Kagaku Kouza, 4th ed., The 4th series of Experimental Chemistry, The Chemical Society of Japan Ed., 1992, pp. 300-302.
Notification of Reasons for Refusal with partial translation dated Jul. 8, 2014 for Japanese Patent Application No. 2007-510975, 30 pp.
Translation of Notification of Reasons for Refusal dated Jul. 8, 2014 for Japanese Patent Application No. 2007-510975, 31 pp.
Decision of Refusal dated Dec. 11, 2012 for Japanese Patent Application No. 2007-510975, 2 pp.
Translation of the Decision of Refusal dated Dec. 11, 2012 for Japanese Patent Application No. 2007-510975, 5 pp.
Notification of Reasons for Refusal with partial translation dated Nov. 8, 2011 for Japanese Patent Application No. 2007-510975, 5 pp.
Translation of Notification of Reasons for Refusal with partial translation dated Nov. 8, 2011 for Japanese Patent Application No. 2007-510975, 5 pp.
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).
Bullesfeld et al., “Long term evaluation of paclitaxel-coated stents for treatment of native coronary lesions”, Z. Kardiol. 92, pp. 825-832 (2003).
Bulpitt et al., Journal of Biomedical Materials Research 1999, 47:152-169.
Chung et al., Inner core segment design for drug delivery control of thermo-responsive polymeric micelles, Journal of Controlled Release 65:93-103 (2000).
Clark, “Reduction of Carboxylic Acids,” www.chemguide.com.uk/organicprops/acids/reduction.html, 3 pgs (2004).
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).
Grinstaff et al. “Photocrosslinkable polysaccharides for in situ bydrogel formation,” J. of Biomed. Mat. Res. vol. 54, No. 1, pp. 115-121 (2001).
Grinstaff et al., “Photocrosslinkable polymers for biomedical applications”, Polymer Preprints 42(2), pp. 101-102 (2001).
Grube et al., “Safety and Performance of a Pacilitaxel-Eluting Stent for the Treatment of in-Stent Restenosis: Preliminary Results of the Taxus III Trial”, J. of Am. Coll. of Cardiology 39, Abstract 1 pg. (2002).
Grube et al., “Six-and Twelve-Month Results from a Randomized, Double-Blind Trial on a Slow-Release Paclitaxel-Eluting Stent for De Novo Coronary Lesions”, Circulation 107, pp. 38-42 (2003).
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).
Hwang et al., “Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery”, Circulation 104, pp. 600-605 (2001).
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).
International Search Report for PCT/US2005/014614 filed Apr. 27, 2005, mailed May 18, 2006, 17 pgs.
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).
Kim et al. Biomaterials 2003 24: 4671-4679.
Kirker et al. Biomaterials 2002 23:3661-3671.
Lambert et al., “Localized Arterial Wall Drug Delivery From a Polymer-Coated Removable Metallic Stent”, Circulation vol. 90, issue 2, pp. 1003-1011(1994).
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).
Lincoff et al., “Sustained Local Delivery of Dexamethasone by a Novel Intravascular Eluting Stent to Prevent Restenosis in the Porcine Coronary Injury Model”, JACC vol. 29, No. 4, pp. 808-816 (1997).
Liu et al., Drug release characteristics of unimolecular polymeric micelles, Journal of Controlled Release 68:167-174 (2000).
Liu et at., Advances in Polymer Technology 1992, 11:249-262.
Luo et al., “Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery”, J. of Controlled Release 69, pp. 169-184 (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).
Moriyama et al. Journal of Controlled Release 1999 59:77-86.
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 17:685694 (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).
Smeds et al., “Photocrosslinkable polysaccharides for in situ hydrogel formation”, J. of Biomed. Mat. Res. vol. 54, No. 1, pp. 115-121 (2001).
Sousa et al., New frontiers in cardiology Drug-eluting stents: part I. Circulation 2003, 107: 2274-2279.
Tanabe et al., “In-Stent Restenosis Treated With Stent-Based Delivery of Paclitaxel Incorporated in a Slow-Release Polymer Formulation”, Circulation 107, pp. 559-564 (2003).
Translation of Notification of Refusal from JPO for appl. No. 20078-510975, mailed Nov. 8, 2011, 5 pgs.
van Beusekom et al., Coronary stent coatings, Coronary Artery Disease 5(7):590-596 (Jul. 1994).
Van Der Giesen et al. “Marked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries”, Circulation vol. 94, issue 7, pp. 1690-1697 (1996).
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).
Yoshida et al. “Convenient synthesis of polymers containing terminal aldehyde and ketone moieties by selective oxidation of polymeric terminal diols with an oxoaminium salt,” Makromolecular Chemistry 194: pp. 2507-2515 (1993).
Jai et al. Macromolecules, 2004, 37:3239-3248.
Raddatz Necleic Acid Research 2002 30:4793-4802.
Leach et al. Biotechnology and Bioengineering, 2003 82:578-589.
Prestwich et al. Journal of Cotrolled Release 1998 53:93-103.
Chen et al. Journal of Biomedical Materials Research 2002 61:360-369.
Hamad et al. Molecules 20005:895-907.
Luo et al. Journal of Controlled Release 2000 69:169-184.
Gianolio et al. “Cross-Linked Hyaluronan Containing Labile Linkages,” Society for Biomaterials, 2002, 1 pp.
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Number Date Country
Parent 13631399 Sep 2012 US
Child 14251489 US
Parent 10835912 Apr 2004 US
Child 13631399 US