COMPOUNDS AND METHOD FOR COATING SURFACES IN A HEMOCOMPATIBLE MANNER

• US 20110009955A1
• Filed: 06/30/2010
• Published: 01/13/2011
• Est. Priority Date: 05/09/2002
• Status: Active Grant

• Current Assignee: Hemoteq AG (Freudenberg & Company KG)
• Original Assignee: Hemoteq GmbH
• Inventors: Hoffmann, Michael, DiBiase, Donate, Horres, Roland, Faust, Volker, Hoffmann, Erika, Linssen, Marita Katharina
• Granted Patent: US 8,784,862 B2
• Time in Patent Office: Days
• US Class Current: 623/1.42
• CPC Class Codes: A61K 31/045 Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• CPC Class Codes: A61K 31/075 Ethers or acetals
• CPC Class Codes: A61K 31/095 Sulfur, selenium, or tellurium compounds, e.g. thiols
• CPC Class Codes: A61K 31/11 Aldehydes
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/28 Compounds containing heavy metals
• CPC Class Codes: A61K 31/33 Heterocyclic compounds
• CPC Class Codes: A61K 31/722 Chitin, chitosan
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61L 33/08 Polysaccharides
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C08B 37/0075 : Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08L 5/10 : Heparin; Derivatives thereof
• CPC Class Codes: C09D 105/08 : Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

1-51. -51. (canceled)

52. Medical device, wherein the surface of the medical device is coated directly and/or via at least one interjacent biostable and/or biodegradable layer and/or active agent layer with a hemocompatible layer comprising at least one oligosaccharide and/or polysaccharide according to formulas Ia and Ib:

53. The medical device according to claim 52, wherein under the hemocompatible layer or between two hemocompatible layers at least one biostable and/or biodegradable layer is present.

54. The medical device according to claim 52, wherein the hemocompatible layer is coated completely and/or incompletely with at least another, suprajacent biostable and/or biodegradable layer.

55. The medical device according to claim 53, wherein at least one active agent layer is present between the biostable and/or biodegradable layer and the hemocompatible layer, which comprises at least one antiproliferative, antiinflammatory and/or antithrombotic active agent covalently and/or adhesively bound.

56. The medical device according to claim 52, wherein at least one antiproliferative, antiinflammatory and/or antithrombotic active agent is bound covalently and/or adhesively in and/or on the hemocompatible layer and/or the biostable and/or biodegradable layer.

57. The medical device according to claim 56, wherein the at least one antiproliferative, antiinflammatory and/or antithrombotic active agent is chosen from the group containing 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, etoboside, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxyoxycyclophosphamide, estramustine, melphalan, ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, thymosin α

-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, PI-88 (sulphated oligosaccharide), melanocyte stimulating hormon (α

-MSH), activated protein C, IL1-β

inhibitor, fumaric acid and its esters, dermicidin, calcipotriol, tacalcitol, lapachol, β

-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon α

-2b, lanograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, letrozol, goserelin, chephalomannin, trastuzumab, exemestan, basiliximab, daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines, cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin, camptothecin, 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 such as pentaerythritol tetranitrate and syndnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine, β

-estradiol, α

-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 and derivatives thereof such as 6-α

-hydroxy-paclitaxel, baccatin, taxotere and others, synthetically and from native sources obtained macrocyclic oligomers of carbon suboxide (MCS) and derivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, β

-sitosterin, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851 (Calbiochem), colcemid, 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 such as cefadroxil, cefazolin, cefaclor, cefotixin, tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazol, antithrombotics such as argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxoparin, desulphated and N-reacetylated heparin, tissue plasminogen activator, GpIIb/IIIa platelet membrane receptor, factor Xa inhibitor antibody, heparin, hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipyramidole, trapidil, nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α

, β and

γ

, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators such as p65, NF-kB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tocopherol, tranirast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, Boswellic acids and derivatives thereof, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone, mutamycin, procainimid, retinoic acid, quinidine, disopyrimide, flecamide, propafenone, sotolol, amidorone, natural and synthetically obtained steroids such as bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances (NSAIDS) such as fenoporfen, ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral agents such as acyclovir, ganciclovir and zidovudine, antimycotics such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents such as chloroquine, mefloquine, quinine, moreover natural terpenoids such as hippocaesculin, 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-α

-senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, moreover cymarin, apocymarin, aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburin chloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-β

-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, glycoside la, podophyllotoxin, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A, marchantin A, maytansine, lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII, bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid, deoxypsorospermin, psycorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, sphatheliachromen, stizophyllin, mansonine, strebloside, akagerine, dihydrousambaraensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferon, afromoson, acetylvismione B, desacetylvismione A, vismione A and B.

58. The medical device according to claim 57, wherein the at least one antiproliferative, antiinflammatory and/or antithrombotic active agent is chosen from the group containing tacrolimus, pimecrolimus, PI 88, thymosin α

-1, PETN, baccatine and its derivatives, docetaxel, colchicin, paclitaxel and its derivatives, trapidil, α

- and β

-estradiol, dermicidin, tialin-sodium, simvastatin, macrocyclic suboxide (MCS) and its derivatives, sirolimus, tyrphostine, D24851, colchicin, fumaric acid and its esters, activated protein C (aPC), interleukin 1β

inhibitors and melanocyte stimulating hormon (α

-MSH) as well as mixtures of these active agents.

59. The medical device according to claim 52, wherein the medical device concerns prostheses, organs, vessels, aortas, heart valves, tubes, organ spare parts, implants, fibers, hollow fibers, stents, hollow needles, syringes, membranes, tinned goods, blood containers, titrimetric plates, microtiter plates, pacemakers, adsorbing media, chromatography media, chromatography columns, dialyzers, connexion parts, sensors, valves, centrifugal chambers, recuperators, endoscopes, filters, pump chambers.

60. The medical device according to claim 59, wherein the medical device is a stent.

61. The stent according to claim 60, wherein the polymer is deposited in amounts between 0.01 mg to 3 mg/layer, preferred between 0.20 mg to 1 mg and especially preferred between 0.2 mg to 0.5 mg/layer.

62. The stent according to claim 60, wherein the antiproliferative, antiinflammatory and/or antithrombotic active agent is comprised in a pharmaceutically active concentration of 0.001-10 mg per cm² stent surface.