Claims for Patent: 8,784,862

Summary for Patent: 8,784,862

Title:	Compounds and method for coating surfaces in a hemocompatible manner
Abstract:	The invention concerns oligosaccharides and polysaccharides as well as the use of these oligosaccharides and/or polysaccharides, which contain the sugar unit N-acylglucosamine or N-acylgalactosamine for the production of hemocompatible surfaces as well as methods for the hemocompatible coating of surfaces with said oligosaccharides and/or polysaccharides, which imitate the common biosynthetic precursor substance of heparin, heparan sulphates and chitosan. The invention further describes methods for producing said oligosaccharides and/or polysaccharides and discloses various possibilities of using hemocompatibly coated surfaces. The invention relates particularly to the use of said oligosaccharides and/or polysaccharides on stents with at least one according to invention deposited hemocompatible coating, which contains an antiproliferative, antiinflammatory and/or antithrombotic active agent, methods for the preparation of said stents as well as the use of said stents for the prevention of restenosis.
Inventor(s):	Horres; Roland (Stolberg, DE), Linssen; Marita Katharina (G ttingen, DE), Hoffmann; Michael (Eschweiler, DE), Hoffmann; Erika (Eschweiler, DE), DiBiase; Donate (Aachen, DE), Faust; Volker (Aachen, DE)
Assignee:	Hemoteq AG (Wurselen, DE)
Application Number:	12/827,710
Patent Claims:	1. A metal stent, wherein the surface of the stent is coated directly and covalently with a hemocompatible layer, comprising at least one oligosaccharide and/or polysaccharide according to formulas (Ia) or (Ib): ##STR00005## wherein n is an integer between 4 and 1050, Y and Z, independently of each other, represent the groups --CHO, --COCH.sub.3, --COC.sub.2H.sub.5, --COC.sub.3H.sub.7, --COC.sub.4H.sub.9, --COC.sub.5H.sub.11, --COCH(CH.sub.3).sub.2, --COCH.sub.2CH(CH.sub.3).sub.2, --COCH(CH.sub.3)C.sub.2H.sub.5, --COC(CH.sub.3).sub.3, --CH.sub.2COO--, --C.sub.2H.sub.4COO--, --C.sub.3H.sub.6COO--, --C.sub.4H.sub.8COO--, and salts of said compounds. 2. The stent according to claim 1, further comprising at least one biostable and/or biodegradable layer on the hemocompatible layer, and at least one additional hemocompatible layer on the biostable and/or biodegradable layer. 3. The stent according to claim 1, wherein the hemocompatible layer is coated completely or incompletely with at least one, superjacent biostable and/or biodegradable layer. 4. The stent according to claim 2, wherein at least one active agent layer is present between the biostable and/or biodegradable layer and the hemocompatible layer covalently bonded to the stent, and wherein the active agent layer comprises at least one antiproliferative, antiinflammatory and/or antithrombotic active agent. 5. The stent according to claim 1, wherein at least one antiproliferative, antiinflammatory and/or antithrombotic active agent is bound covalently and/or adhesively in and/or on the hemocompatible layer. 6. The stent according to claim 5, wherein the at least one antiproliferative, antiinflammatory and/or antithrombotic active agent is selected from the group consisting of sirolimus (rapamycin), everolimus, pimecrolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxyoxycyclophosphamide, estramustine, melphalan, ifosfamide, tropfosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, thymosin .alpha.-1, tremozolomide, thiotepa, tialin (2-methylthiazolidine-2,4-dicarboxylic acid), tialin-Na (sodium salt of tialin), aunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine-5'-dihydrogenphosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegasparase, anastrozole, exemestane, letrozole, formestane, aminoglutethemide, adriamycin, azithromycin, spiramycin, cepharantin, smc proliferation inhibitor-2w, epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil, c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin, muparfostat, melanocyte stimulating hormon (.alpha.-MSH), activated protein C, IL1-.beta. inhibitor, fumaric acid and its esters, dermicidin, calcipotriol, tacalcitol, lapachol, .beta.-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon .alpha.-2b, lanograstim (r-HuG-CSF), filgrastim, dacarbazine, letrozol, goserelin, trastuzumab, exemestan, basiliximab, daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines, cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, (1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid), fluoroblastin, monoclonal antibodies, which inhibit the muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one, scopolectin, colchicine, NO donors, tamoxifen, staurosporine, .beta.-estradiol, .alpha.-estradiol, estriol, estrone, ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids, which are applied in the therapy of cancer, verapamil, tyrosine kinase inhibitors (tyrphostines), cyclosporine A, paclitaxel, baccatin, synthetically and from native sources obtained macrocyclic oligomers of carbon suboxide (MCS), mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, f3-sitosterin, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticine, N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]-glyoxyl Amide, ((S)-6,7-Dihydro-1,2,3,10-tetramethoxy-7-(methylamino)benzo[.alpha.]hepta- len-9(5H)-on), cytochalasin A-E, indanocine, nocadazole, S 100 protein, bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and -2, free nucleic acids, nucleic acids incorporated into virus transmitters, DNA and RNA fragments, plaminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, IGF-1, active agents from the group of antibiotics, cefazolin, cefaclor, cefotixin, tobramycin, gentamycin, penicillins, oxacillin, sulfonamides, metronidazol, antithrombotics, aspirin, abciximab, synthetic antithrombin, bivalirudin, warfarin sodium, enoxoparin, tissue plasminogen activator, GpIIb/IIIa platelet membrane receptor, factor Xa inhibitor antibody, heparin, hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase, urokinase, vasodilators, trapidil, nitroprussides, PDGF antagonists, ACE inhibitors, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon .alpha., .beta. and .gamma., histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, NF-kB or Bc1-xL antisense oligonucleotides, halofuginone, nifedipine, tocopherol, tranirast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, Boswellic acids, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone, procainimid, retinoic acid, quinidine, disopyrimide, flecamide, propafenone, sotolol, amidorone, natural and synthetically obtained steroids, inotodiol, maquiroside A, mansonine, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances (NSAIDS), ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral agents, ganciclovir and zidovudine, antimycotics, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents, mefloquine, quinine, natural terpenoids, barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7, tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-.alpha.-senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, cymarin, apocymarin, aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, cheliburin chloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-.beta.-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid, helenalin, indicine, indicine-N-oxide, lasiocarpine, glycoside 1a, podophyllotoxin, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, marchantin A, maytansine, lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine, aristolactam-AII, periplocoside A, ghalakinoside, deoxypsorospermin, psycorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, sphatheliachromen, stizophyllin, strebloside, akagerine, dihydrousambaraensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, (5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium)- , oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferon, afromoson, acetylvismione B, desacetylvismione A, vismione A, and vismione B. 7. The stent according to claim 6, wherein the at least one antiproliferative, antiinflammatory and/or antithrombotic active agent is selected from the group consisting of tacrolimus, pimecrolimus, muparfostat, thymosin .alpha.-1, PETN, baccatine, docetaxel, colchicin, paclitaxel, trapidil, .alpha.- and .beta.-estradiol, dermicidin, tialin-sodium, simvastatin, macrocyclic suboxide (MCS), sirolimus, tyrphostine, N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]-glyoxyl Amide, fumaric acid and its esters, activated protein C (aPC), interleukin 1.beta. inhibitors and melanocyte stimulating hormon (.alpha.-MSH) as well as mixtures of these active agents. 8. The stent according to claim 1, further comprising a polymer deposited in amounts between 0.01 mg to 3 mg/layer. 9. The stent according to claim 4, wherein the antiproliferative, antiinflammatory and/or antithrombotic active agent is comprised in a pharmaceutically active concentration of 0.001-10 mg per cm.sup.2 stent surface. 10. A metallic stent, wherein the surface of the stent is coated with a hemocompatible layer comprising at least one oligosaccharide and/or polysaccharide according to formulas (Ia) or (Ib) and at least one interjacent biostable layer, wherein the interjacent biostable layer is covalently bonded to the stent and wherein the hemocompatible layer is covalently bonded to the interjacent biostable layer ##STR00006## wherein n is an integer between 4 and 1050, Y and Z, independently of each other, represent the groups --CHO, --COCH.sub.3, --COC.sub.2H.sub.5, --COC.sub.3H.sub.7, --COC.sub.4H.sub.9, --COC.sub.5H.sub.11, --COCH(CH.sub.3).sub.2, --COCH.sub.2CH(CH.sub.3).sub.2, --COCH(CH.sub.3)C.sub.2H.sub.5, --COC(CH.sub.3).sub.3, --CH.sub.2COO.sup.-, --C.sub.2H.sub.4COO.sup.-, --C.sub.3H.sub.6COO.sup.-, --C.sub.4H.sub.8COO.sup.-, and salts of said compounds. 11. The stent according to claim 10, wherein at least one antiproliferative, antiinflammatory and/or antithrombotic active agent is bound covalently and/or adhesively in and/or on the hemocompatible layer. 12. The stent according to claim 11, wherein the at least one antiproliferative, antiinflammatory and/or antithrombotic active agent is chosen from the group consisting of tacrolimus, pimecrolimus, muparfostat, thymosin .alpha.-1, PETN, baccatine, docetaxel, colchicin, paclitaxel, trapidil, .alpha.- and .beta.-estradiol, dermicidin, tialin-sodium, simvastatin, macrocyclic suboxide (MCS), sirolimus, tyrphostine, N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]-glyoxyl Amide, fumaric acid and its esters, activated protein C (aPC), interleukin 1.beta. inhibitors and melanocyte stimulating hormone (.alpha.-MSH) as well as mixtures of these active agents. 13. The stent according to claim 5, wherein the antiproliferative, anti-inflammatory and/or antithrombotic active agent is comprised in a pharmaceutically active concentration of 0.001-10 mg per cm.sup.2 stent surface.

Details for Patent 8,784,862

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2022-05-10
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2022-05-10
Clinigen, Inc.	PROLEUKIN	aldesleukin	For Injection	103293	05/05/1992		2022-05-10
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Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	12/22/1994		2022-05-10