# US 8,784,862 B2 · Compounds and method for coating surfaces in a hemocompatible manner

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- Number: US 8,784,862 B2
- Document ID: US8784862B2
- Status: Granted
- Kind: B2
- Application number: 12/827,710
- Filed: 2010-06-30
- Published: 2011-01-13
- Granted: 2014-07-22
- Earliest claimed: 2002-05-09
- Assignees: Hemoteq AG
- Applicants: Roland Horres; Marita Katharina Linssen; Michael Hoffmann; Erika Hoffmann; Donate DiBiase; Volker Faust
- Inventors: Roland Horres; Marita Katharina Linssen; Michael Hoffmann; Erika Hoffmann; Donate DiBiase; Volker Faust
- Web page: https://patentgrep.com/patent/US8784862B2

## CPC

- A61L 31/10: Macromolecular materials
- A61K 31/045: Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K 31/075: Ethers or acetals
- A61K 31/095: Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K 31/11: Aldehydes
- A61K 31/12: Ketones
- A61K 31/13: Amines {(A61K31/04 takes precedence)}
- A61K 31/21: Esters, e.g. nitroglycerine, selenocyanates
- A61K 31/28: Compounds containing heavy metals
- A61K 31/33: Heterocyclic compounds
- A61K 31/722: Chitin, chitosan
- A61K 31/727: Heparin; Heparan
- A61L 31/16: Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)}
- A61L 33/08: Polysaccharides
- A61P 3/06: Antihyperlipidemics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C08B 37/0075: {Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof}
- C08L 5/10: Heparin; Derivatives thereof
- C09D 105/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- 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
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C08B: POLYSACCHARIDES; DERIVATIVES THEREOF (polysaccharides containing less than six saccharide radicals attached to each other by glycosidic linkages C07H; fermentation or enzyme-using processes C12P19/00; sugar industry C13; production of cellulose D21)
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- C09D: COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR (cosmetics A61K; processes for applying liquids or other fluent materials to surfaces, in general, B05D; staining wood B27K5/02; glazes or vitreous enamels C03C; natural resins, French polish, drying-oils, driers, turpentine, per se, C09F; polishing compositions other than French polish, ski waxes C09G; adhesives or use of materials as adhesives C09J; materials for sealing or packing joints or covers C09K3/10; materials for stopping leaks C09K3/12; processes for the electrolytic or electrophoretic production of coatings C25D)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO 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

### Claim 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):
wherein
n is an integer between 4 and 1050,
Y and Z, independently of each other, represent the groups —CHO, —COCH3, —COC2H5, —COC3H7, —COC4H9, —COC5H11, —COCH(CH3)2, —COCH2CH(CH3)2, —COCH(CH3)C2H5, —COC(CH3)3, —CH2COO—, —C2H4COO—, —C3H6COO—, —C4H8COO—, and salts of said compounds.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 2)

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.

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 5)

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 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, muparfostat, 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, 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, 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, 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[α]heptalen-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 α, β and γ, 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-α-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-β-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.

### Claim 7 (depends on 6)

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 α-1, PETN, baccatine, docetaxel, colchicin, paclitaxel, trapidil, α- and β-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 1β inhibitors and melanocyte stimulating hormon (α-MSH) as well as mixtures of these active agents.

### Claim 8 (depends on 1)

The stent according to claim 1, further comprising a polymer deposited in amounts between 0.01 mg to 3 mg/layer.

### Claim 9 (depends on 4)

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 cm2 stent surface.

### Claim 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
wherein
n is an integer between 4 and 1050,
Y and Z, independently of each other, represent the groups —CHO, —COCH3, —COC2H5, —COC3H7, —COC4H9, —COC5H11, —COCH(CH3)2, —COCH2CH(CH3)2, —COCH(CH3)C2H5, —COC(CH3)3, —CH2COO−, —C2H4COO−, —C3H6COO−, —C4H8COO−, and salts of said compounds.

### Claim 11 (depends on 10)

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.

### Claim 12 (depends on 11)

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 α-1, PETN, baccatine, docetaxel, colchicin, paclitaxel, trapidil, α- and β-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 1β inhibitors and melanocyte stimulating hormone (α-MSH) as well as mixtures of these active agents.

### Claim 13 (depends on 5)

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 cm2 stent surface.