DE102010022589A1 - Stent, whose surface at least partially exhibits a full surface or continuous coating with a felt, useful to prevent, reduce and treat e.g. stenosis, restenosis, in-stent-restenosis, arteriosclerosis, atherosclerosis and vascular occlusion - Google Patents

Abstract

Stent, whose surface at least partially exhibits a full surface or continuous coating with a felt, is claimed. An independent claim is included for a method for coating an expandable device for widening of a vessel lumen comprising providing an expandable device, dissolving a polymer in volatile solvents, and applying a felt made from the polymer by spraying or electrospinning. ACTIVITY : Vulnerary; Vasotropic; Antiarteriosclerotic; Dermatological. MECHANISM OF ACTION : None given.

Description

The present invention relates to lattice-like or reticulated vascular supports having a continuous or continuous coating with a felt, this continuous coating covering both the struts and the spaces between the individual struts of the vascular supports.

Pathological changes in and on all body passages can lead to narrowing and even complete closure.

In addition to acute thrombosis, arteriosclerosis is often the cause of a heart attack or stroke. Another and equally common danger that affects body passages is the growth of malignant and benign tumors. By rapid and uncontrolled cell division it comes to the spread of the tumor and in the hollow organs and so to the obstruction or closures in the body paths. Examples include esophageal cancer, colon cancer, lung cancer, kidney cancer, bile duct closures, pancreas and urethra.

For the treatment of narrowed body passages, the stent has proven to be a suitable locally acting therapy in the last two decades. It is placed after widening the affected area with a balloon catheter or after removal of the constriction at the affected site, where he expands the vessel wall in an expanded form so that the native vessel diameter of the affected vessel is restored and keep it open.

Especially in the case of coming into contact with blood stents cause these as foreign body material, the formation of restenosis. Efforts to further develop stents to improve biocompatibility of the stent material, increase flexibility with less material fatigue, and reduce the size of the foreign surface are designed to further minimize the risk of stent-induced restenosis.

As a promising further development, in addition to the stated basic conditions on the stent body, the coating of the stent surface with biocompatible biodegradable or biostable materials has proven to act as a carrier of an antirestenotically active substance. This is intended to stop the restenosis-promoting process by means of a time-adapted and concentration-adapted release. The requirements are equally high not only for the stent itself, but also for the coating material, the quality of the coating and the active ingredients.

The same basic body is used, for example, to prevent or hinder narrowing due to tumor growth in the esophagus or in the bronchial trachea. In contrast to the atherosclerosis-fighting vascular stent, these stents are provided with a polymeric sheath enveloping the stent body, which as a mechanical barrier is intended to prevent or at least slow down the retraction of the tumor through the interstices into the lumen.

Common to all foreign materials used in body cavities is the guarantee of as unlimited flexibility as possible, ie the physiologically necessary undisturbed mobility of the target organ, with simultaneous removal or retardation of occurred local disturbances of the conventionally normal transition state. This flexibility is determined by the material and design of the hollow body and has led to a hollow body with a low relative vessel wall cover and a wide-mesh or net-like structure.

Depending on the clinical picture and site of use, different requirements for the properties of the implant must be taken into account. Thus, for a vascular support, which is used in an artery, different conditions than, for example, for a vascular support, which is used in the esophagus. However, while the vascular coated as well as uncoated stent should have as little foreign surface as possible to prevent stent-induced restenosis, a stent in the tumor treatment can only be a barrier if it can completely cover the affected area. This is only possible if the stent-typical large interstices can not remain consistent and can restrain tumor growth. This is achieved with a surrounding the vessel support polymer shell.

Since the wrapped in polymer stent should fulfill its location adapted function safely and ideally ensure the undisturbed function of the target organ or support but not negatively influence or even disturbing, various concepts have been developed in the past, with the help of a stent with a Polymer shell to be provided.

So describes US5876448 ( WO 93/22986 ) a self-expanding esophageal stent, which is slipped over a silicone tube in the middle region and compresses this area in such a way that the stent has a smaller diameter than in the tube-free proximal and distal end regions. The proximal and distal ends are not wrapped to allow better fixation on the walls of the lumen with the help of these free stent struts. However, this stent has not proven to be successful because of the narrowing of the stent body problems arise, for. For example, during vomiting, the forces on the stent are increased such that the stent is moved and injures the oesophageal wall with the free stent ends.

In addition, under these circumstances, the silicone tube tear or peel, between the vessel wall and silicone coating can mucus or food particles settle, which in addition to the possible risk of inflammation represent different extremely negative for the patient scenarios.

WO 2005/030086 describes a method for the full-surface coating of self-expanding stent bodies, with a polyurethane sheath, in which after a first spray coating of the stent with the polymer, the polymer is applied by means of a balloon or other suitable hollow template as a foil from the inside of the struts. In this case, the coating covering the entire stent takes place from the lumen side, so that on the outside the stent struts can continue to give the stent a hold in the vessel wall. The subsequent heating of the system above the softening temperature is intended to bind the polyurethane to the stent. There are problems here because the polymer shell is not bound quantitatively to the coated stent and therefore does not remain permanently on the stent under the given conditions. Likewise, the heating can cause small holes which, in the case of implantation, may possibly enlarge and eventually lead to the separation of coating material and even to delocalization of the entire stent.

Furthermore, the heating above the softening point of the polymer can lead to the fact that on the one hand the spray coating on the outside of the stent struts and on the other hand, the adhesion of the polymer coating is not only to the stent, but also to the also made of a polymer balloon , Thus, when retracting the balloon, the inner coating has adhesion problems that at least partially peel off when the balloon is removed from the stent. This can settle between solvent coating and inner wall food or mucus, which gradually separates the coating from the stent, but especially obstructs the undisturbed passage. The dissolving material protrudes into the vessel and additionally leads to irritation, nausea or cough, which promotes the defixation of the entire stent.

An example of a partially full-surface coated stent is in US5951599 to find. The stent described herein is intended for the treatment of aneurysms in blood vessels. Aneurysms are the result of morbid sagging of the vessel wall, in which the blood accumulates and clots as it expands. In addition to the growing risk of thrombosis, this ultimately leads to vascular rupture. US5951599 This problem is solved by filling the free spaces of a vascular stent with a small meshed polymer network that lies in the blood vessel above the recess and covers the aneurysm in such a way that the blood flow in the outer stagnation stagnates. As a result of the lack of movement, it forms a solid thrombus, thus stopping the enlargement of the aneurysm. In addition, the polymeric cover should prevent the blood plug or parts of the clot from being flushed into the bloodstream and cause infarction elsewhere. Here, too, due to poor adhesion to corresponding problems that deprive the stent of its function and thus lead to an increased risk for the patient. Currently, aneurysms are still treated by filling with metal wire ("coils"), which should bring the flow of blood within the Aussackung to a standstill.

The object of the present invention is now to provide an implant which avoids the described disadvantages and to provide an optimal production method for such implants.

This object is solved by the technical teaching of the independent claims of the present invention. Further advantageous embodiments of the invention will become apparent from the dependent claims, the description and the examples.

It has been found that the problems of the prior art can be solved by expandable devices whose surface at least partially has a full-surface coating with a felt. This felt is preferably spray felt or, in the case of this felt coating, preferably a spray felt coating.

Used for coating are posts for body passageways, which are also commonly referred to as "vessels," such as veins, veins, esophagus, bile ducts, kidney ducts, trachea, canals in the bronchi, small intestine segments, large intestine, or other approximately tubular body passageways Vascular supports have a lattice-shaped or reticulate structure such as a stent. The term "body passages" includes not only natural body passages or body channels, but also artificial body openings and body channels such as bypasses and artificial bowel exits. Further applications for vascular supports coated according to the invention are therefore, for example, larynx implants, bypasses, catheters or artificial intestinal outlets and, in general, all areas in or on the living organism where the body passage must remain free as well as mobile, whereby the vascular walls should continue to be supplied optimally, but the Exposure of the implanted foreign body to the environment is to be minimized.

A vascular support such. B. a stent does not form a solid tube, but a mesh. Consider, for example, a stent, it will be made of a solid tube z. B. cut by laser, so that there are individual struts, which are interconnected. As used herein, the term "struts" is intended to mean the individual stent struts of the stent framework which are interconnected at junctions and form the expandable and flexible structure of the stent.

When cutting a stent, segments are cut out between the individual struts, which are referred to herein as "spaces". A vascular support therefore has a plurality of solid framework components (eg, struts, rings, spirals, wires, and nodes) that together form the vascular support and a plurality of spaces between these solid components, such as the vascular support. B. Nodes and struts. In the common embodiment of vascular supports, the struts converge at nodal points so that the spaces are defined by the surrounding struts and nodes. However, there are also embodiments of stents in which no or almost no nodes are present and the struts z. B. have the form of rings or spirals. In such vascular supports, for example, there is also no longer a large number of intermediate spaces, but only a few or only one intermediate space, which is determined by, for example, two spirals running into one another. Such gaps are then no longer completely bounded but may have one or two or more open ends or open sides. However, by "interstitial spaces" it is meant the open or circumscribed area between the solid components of the vascular support.

Continuous coating is understood as meaning a coating covering the entire surfaces over the full area. This coating is also referred to as continuous, i. H. a film is formed over a space that rests only on the struts surrounding this space. This coating spans the gap like a suspension bridge, which is only attached to the edges and rests in the space on any solid surface.

A felt consists of loosely and randomly arranged fibers, which are not yet connected to each other, but due to the confused structure can only be separated into individual fibers with difficulty. The strength of a felt is thus based on the fiber's own adhesion and the tangled structure, but can be influenced by work-up. In order to be able to process and use the felt, it must be solidified, for which various methods can be used. Only a solidified felt is to be called felt. The adhesion of the threads to each other and thus the solidification results here in the ideal case already during the drying process by the evaporation of the solvent. Even after the drying process, the felt coating is tear resistant, expandable, and compressible or crimpable (i.e., can be placed on a catheter balloon).

Felt, also referred to simply as felt below, is a textile fabric made of individual fibers that are not interwoven. In contrast, woven, knitted and knitted fabrics of yarns and membranes are made of films that are subject to certain ordering principles and weaving mechanisms.

Felt fabrics, on the other hand, consist of fibers whose position can only be described by statistical methods. The fibers are confused with each other in the felt. Felt fabrics are distinguished, inter alia, by the fiber material (eg the polymer in the case of chemical fibers), the bonding process, the type of fiber (staple or continuous fibers), the fiber fineness and the fiber orientation. The fibers can be deposited defined in a preferred direction or be completely stochastically oriented as in the random felt.

According to the invention, the expandable device may be coated from a felt consisting of a polymer or a mixture of polymers which may be biodegradable or biostable. The polymer (s) can be selected from the group comprising:
Polyurethane, polyethylene terephthalate; Polyvinyl chloride, polyvinyl esters, polyvinyl acetal polyamides, polyimides, polyacrylonitriles, polyethers, polyesters such as. Poly-3-hydroxybutylates, poly-3-hydroxyalkanoates, polyamino acids, polysaccharides, polylactides, polyglycolides, polylactide glycolides, chitosans, carboxymethyl chitosans, collagen, polyphosphazenes, Polystyrenes, polysulfones, polysaccharides and derivatives, block polymers, copolymers and mixtures of the aforementioned polymers. In principle, all biocompatible, uncrosslinked and soluble in a solvent polymers can be used.

The present invention therefore relates to methods for the continuous coating of grid-like or net-like biostable or biodegradable stents, in particular stents, which are felt-coated with a polymer dissolved in a suitable solvent which is as readily volatile as possible.

• a) Bereitstellung einer expandierbaren Vorrichtung,
• b) Lösen eines Polymers in einem leicht flüchtigen Lösungsmittel,
• c) Aufbringen von einem Filz aus dem Polymer durch Sprühtechnik oder Elektrospinning.

It is particularly preferred if the coating consists of a spray felt. The invention therefore also encompasses methods for coating a vascular support for dilating a vessel lumen, comprising the following steps:

• a) providing an expandable device,
• b) dissolving a polymer in a volatile solvent,
• c) applying a felt from the polymer by spraying or electrospinning.

In addition to the spray coating, a coating can also be effected by means of electrospinning.

The solvents used are preferably those solvents which dissolve the polymer well and are volatile. As the solvent, high vapor pressure solvents such as acetone, tetrahydrofuran, benzene, toluene, dimethylformamide, xylene, ethylene glycol, water, methanol, ethanol, chloroform, ethyl acetate, n-hexane, isopropanol, phenol or mixtures thereof are preferably used.

In this method according to the invention the bonding of the fibers of the fiber felt is carried out by the fibers, which are formed only by the spraying of the solution by these fibers are attached with still sticky wet surface to the felt and in this case the fibrous additives whose surfaces are not sticky or at least do not have to be sticky, incorporate into the fiber felt. Thus, no separate adhesive is needed that would significantly change the fiber surfaces, but the fibers of the felt are glued together by the still sticky, produced only by spraying the solution fibers to the fiber felt. Thus, it is not necessary to use any type of external adhesive which would cover the fiber surfaces, so that the fiber-specific effects could not be unfolded. Further, by bringing about the cohesion of the felt through only at points of intersection of the fibers bonded together, the structure of the felt also has better capillary properties favorable to the absorption of liquid and moisture. The spraying of the solution to form the fibers can preferably be effected by means of compressed air atomizing nozzles.

The felt coating of the inventive vascular support preferably has a porosity of from 1 to 150 ml, more preferably from 10 to 100 ml and more preferably from 20 to 50 ml of air per square centimeter per minute at a pressure difference of 1.2 KPa, defined as air permeability.

The felt coating of the stent according to the invention preferably has a porosity defined as water permeability in the range of 100 to 300 ml / cm ² · min, in particular 150 to 250 ml / cm ² · min. These water permeability values were measured according to Wesolowski's method of determination at 120 mmHg.

A vascular support according to the invention may be characterized in that the felt coating is porous.

In further preferred embodiments felts are used or applied according to the invention, which further contain at least one antiproliferative, antimigrative, antiangiogenic, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic and / or antithrombotic agent. This active ingredient may be contained in covalently bound form or in adhesive or ionic bonded form. As a result, coated medical devices or stents are obtained which contain at least one active substance in the felt coating, preferably in the form of a drug-releasing layer.

• 1. Der vollflächige Filz hüllt die entstandenen Unebenheiten der Körperdurchgänge im Verletzungsbereich ein und sorgt damit für eine wesentlichen und notwendigen Schutz für Thrombozytenanlagerungen im Bereich der Verletzung und bildet damit eine wesentliche Hemmung der durch die Anlagerung von aktivierten Thrombozyten eingeleiteten Gerinnungskaskade mit der daraus folgenden lebensbedrohlichen Hämostase.
• 2. Der verletzte Gefäßwandbereich ist durch die vollflächige Beschichtung von den im Hohlraum stattfindenden Vorgängen weitestgehend geschützt, so dass die Heilungsprozesse optimal ablaufen können.
• 3. Die vollflächige Beschichtung sorgt für zusätzliche Stabilität der Körperdurchgänge im Verletzungsbereich.
• 4. Die vollflächige Beschichtung dient als mechanische Barriere gegen Hyperproliferation.
• 5. Über die noch durchlässige Struktur des Filzes bleibt trotz vollflächiger Beschichtung mindestens der notwendige Minimalkontakt zur Hohlraumseite erhalten.
• 6. Die texturierte Oberfläche sorgt für zusätzlichen Halt der Gefäßstütze in der Gefäßwand
• 7. Die vollflächige Beschichtungsoberfläche sorgt für eine sinnvolle gleichmäßige Verteilung eines zugefügten Wirkstoffes über den gesamten betroffenen. Bereich.
• 8. Über die wesentlich größere Oberfläche der Beschichtung lässt sich die eingebrachte Wirkstoffmenge erhöhen.
• 9. Über die wesentlich größere Oberfläche der Beschichtung lassen sich auch Wirkstoffe sinnvoll einsetzen, die erst ab einer Dosierungsmenge zu erfolgreichen Behandlung führen können, die mit einer alleinigen Strebenbeschichtung nicht realisierbar ist. Somit kann die erfindungsgemäße vollflächige Beschichtung in einfachster Weise die Auswahl geeigneter Wirkstoffe erweitern.
• 10. Die vollflächige Beschichtung als auch die Textur bieten eine wesentlich größere Oberfläche für unterschiedlichste Ansätze zur Behandlung einer Verletzung an den Gefäßwänden eines Körperdurchganges als eine nicht vollflächig beschichtete Gefäßstütze.

It is advantageous here that the outer surface in contact with the vessel wall of the stent coated in this way is enlarged to such an extent by the full-area coating and the non-smooth felt texture that the delivery of the incorporated active substance is ensured over the entire diseased area. This leads in contrast to the currently commercial Drug eluting stents to a nationwide supply of the diseased site with the necessary remedies and not only for selective treatment of the affected areas or even the treatment of injury-related areas. Likewise, the rough felt texture compared to the smooth coating of the struts of conventional stents is helpful in colonizing the damaged areas with new cells since adhesion is facilitated. The following advantages can be named for the full-surface coating of vascular supports with a felt-like coating:

• 1. The full-surface felt wraps the resulting bumps in the body passages in the injury area and thus provides a substantial and necessary protection for platelet deposits in the area of injury, thus forming a significant inhibition of initiated by the deposition of activated platelets coagulation cascade with the consequent life-threatening hemostasis ,
• 2. The injured vessel wall area is largely protected by the full-surface coating of the processes taking place in the cavity, so that the healing processes can proceed optimally.
• 3. The full-surface coating provides additional stability of the body passages in the injury area.
• 4. The full-surface coating serves as a mechanical barrier to hyperproliferation.
• 5. Through the still permeable structure of the felt at least the necessary minimum contact with the cavity side remains despite full surface coating.
• 6. The textured surface provides additional support for the vascular support in the vessel wall
• 7. The full-surface coating surface ensures a meaningful uniform distribution of an added active ingredient over the entire affected. Area.
• 8. On the much larger surface of the coating, the amount of active ingredient introduced can be increased.
• 9. On the much larger surface of the coating can also be used effectively agents that can only lead to successful treatment from a dosage amount that is not feasible with a single strut coating. Thus, the full-surface coating of the invention in the simplest way can expand the selection of suitable active ingredients.
• 10. The full-surface coating as well as the texture provide a much larger surface area for a variety of approaches to treating an injury to the vessel walls of a body passage than a non-fully coated vascular support.

Ultimately, the full-surface coating with adequate temporally limited stability, even without vascular support adapted to the invention tasks temporarily and temporally appropriate adopted. This can be done either in the form of an expandable full-surface polymer unit on a balloon catheter or by the removal of the vascular support after some time or dissolution of the vascular support.

Of course, it must be ensured that the full-surface coating releases no fragments or particles that can lead to life-threatening conditions.

Of course, it is also possible to apply the active substance (s) in a further coating step to the first or preferably second layer so that a further active ingredient layer is present.

The concentration per active ingredient is preferably in the range of 0.001-500 mg per cm ^{2 of} fully coated surface of the vascular support, ie, the surface is calculated taking into account the total surface area of the coated struts and the surface area of the interstices between the struts.

Depending on the coating method, the active substance (s) may be below, in and / or on the felt coating. As antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiinflammatory, cytostatic, cytotoxic and / or antithrombotic agents may be preferably used: abciximab, acemetacin, acetylvismion B, aclarubicin, ademetionin, adriamycin, aescin, Afromoson, Akagerin, aldesleukin, amidorone, aminoglutethemide, amsacrine , Anakinra, anastrozole, anemonin, anopterin, antimycotics, antithrombotics, apocymarin, argatroban, aristolactam-all, aristolochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin , Betulinic acid, bilobol, bisparthenolidine, bleomycin, bombrestatin, boswellic acids and their derivatives, bruceanols A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, o-carbamoylphenoxyacetic acid, carboplatin, carmustine, celecoxib, cepharantin, Cerivastatin, CETP inhibitors, chlorambucil, chlorine oquinphosphate, cictoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, concanamycin, coumadin, C-type natriuretic peptides (CNP), cudraisoflavone A, curcumin, cyclophosphamide, cyclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac , 1,11-dimethoxycanthin-6-one, docetaxel, doxorubicin, dunaimycin, epirubicin, epothilones A and B, erythromycin, estramustine, etoboside, everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine, fludarabine 5'-dihydrogen phosphate, fluorouracil, folimycin , Fosfestrol, gemcitabine, ghalacinoside, ginkgol, ginkgolic acid, glycoside 1a, 4-hydroxyoxycyclophosphamide, idarubicin, ifosfamide, josamycin, lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, Thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegasparase, exemestane, letrozole, formestan, mitoxanthrone, mycopheno latmofetil, β-lapachone, Podophyllotoxin, podophyllic acid 2-ethyl hydrazide, molgramostim (rhuGM-CSF), peginterferon α-2b, lanograstim (r -HuG-CSF), macrogol, selectin (cytokine antagonist), cytokine inhibitors, COX-2 inhibitor, angiopeptin, monoclonal antibodies inhibiting muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1-hydroxy-11-methoxycanthin-6-one, scopolectin, NO donors, pentaerythrityl tetranitrate and syndnoeimines, S-nitrosated derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, Estriol, estrone, ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, camebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), paclitaxel and its derivatives, 6-a-hydroxy paclitaxel, Taxotere, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterol, myrtainaine, polidocanol, nonivamide , Levomenthol, ellipticin, D-24851 (Calbiochem), colcemid, cytochalasin A-E, indanocine, nocadazoles, bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator, metalloproteinase 1 and 2 tissue inhibitor, free nucleic acids, nucleic acids incorporated in virus carriers , DNA and RNA Fragments, Plaminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2, Antisense Oligonucleotides, VEGF Inhibitors, IGF-1, Drugs from the Antibiotic Group, Cefadroxil, Cefazolin, Cefaclor, Cefotixin Tobramycin, Gentamycin , Penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxoparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidol, trapidil, nitroprusside, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril , Cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ, histamine antagonists, Serot oninblockers, apoptosis inhibitors, apoptosis regulators, halofuginone, nifedipine, tocopherol tranilast, molsidomine, tea polyphenols, epicatechingallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, etoposide, dicloxacylline, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotolol , natural and synthetic steroids, inotodiol, maquiroside A, ghalacinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal substances (NSAIDS), fenoporfen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir, zidovudine, clotrimazole , Flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol-C21-angelst, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachine, ovatodiolides, 4,7 Oxycycloanisomic acid, Bacch arinoids B1, B2, B3 and B7, tubeimoside, bruceantinosides C, yadanziosides N, and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptate acid A, iso-iridogermanal. Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A and B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrine, Taxamairin A and B, Regenilol, Triptolide, Cymarin, Hydroxyanopterin, Protoanemonin, Cheliburine chloride, sinococulin A and B, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadiene 3,20-dione, helenaline, indicin, indicin-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatin, malloterine, mallotochromanol, isobutyrylmallotochromanol , Maquiroside A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidine, Oxoushinsunin, Periplocoside A, Ursolic Acid, Deoxypypsorospermine, Psycorubin, Ricin A, Sanguinarine, Manwuweizic Acid, Methylsorbifolin, Sphatheliachromes, Stizophyllin, Mansonin, Strebloside, Dihydrousambaraensin, Hydroxyusambarin , Strychnopentamine, Strychnophyllin, Usambarin, Usambarensin, Liriodenin, Oxoushinsunin, Daphnoretin, Lariciresinol, Methoxylariciresinol, Syringaresinol , Sirolimus (rapamycin) and its derivatives such as Biolimus A9, everolimus, myolimus, novolimus, pimecrolimus, ridaforolimus, tacrolimus FK 506, temsirolimus and zotarolimus., Somatostatin, tacrolimus, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide , Vinorelbine, Tropfosfamide, Treosulfan, Tremozolomide, Thiotepa, Tretinoin, Spiramycin, Umbelliferone, Desacetylvismion A, Vismion A and B and Zeorin.

It can also be made so thin that a passage of nutrients to supply a developing neointima is possible. During the formation of a neointima, such diffusion from the outside to the nutrient supply is advantageous.

The felt coating or pores of the felt coating may optionally be sealed with a resorbable impregnation.

Furthermore, in a step preceding the coating step with the felt, a haemocompatible layer can preferably be covalently bound to the uncoated surface of the vascular support or crosslinked by means of crosslinking, for example. B. immobilize with glutaric dialdehyde on the surface. A layer which does not activate blood clotting is useful if uncoated stent material can come into contact with blood. So it is preferable to equip a partially coated stent first with this inner hemocompatible layer. Alternatively, an outer, possibly additional haemocompatible layer can also be applied to the felt coating. As an "inner" layer or coating, the layer applied directly to the stent surface becomes Coating referred. The term "outer" layer or coating refers to the top or most distal layer or coating of the stent surface.

The preferably hemocompatible layer is prepared from the following preferred substances: heparin of native origin and regioselectively prepared derivatives of different degrees of sulfation and degrees of acetylation in the molecular weight range of the responsible for the antithrombotic effect pentasaccharide to the standard molecular weight of the commercially available heparin of about 13 kD, heparan sulfates and its derivatives, Erythrocyte glycol colony oligosaccharides and polysaccharides, oligosaccharides, polysaccharides, completely desulfated and N-reacetylated heparin, desulfated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated chitosan, polyacrylic acid, polyetheretherketones, polyvinylpyrrolidone, and / or polyethylene glycol and mixtures of these substances.

The methods of the invention are useful for coating, for example, vascular stents and, in particular, stents such as coronary stents, vascular stents, tracheal stents, bronchial stents, urethral stents, oesophageal stents, biliary stents, renal stents, small bowel stents, colon stents. In addition, guidewires, spirals, catheters, cannulas, tubes and generally tubular implants or parts of the aforementioned medical devices can be coated according to the invention if a structural element comparable to a stent is contained in such a medical device. If expandable medical devices or vascular supports are used, the coating is preferably carried out in the expanded state.

The vascular support, and in particular the stent, can be made of common materials such as medical grade stainless steel, titanium, chromium, vanadium, tungsten, molybdenum, gold, iron, cobalt-chromium, nitinol, magnesium, iron, alloys of the aforementioned metals, as well as bioresorbable metals and metal alloys such as As magnesium, zinc, calcium, iron, etc. as well as of polymeric material and preferably absorbable polymeric material such. As chitosan, heparans, polyhydroxybutyrates (PHB), polyglycerides, polylactides and copolymers of the aforementioned substances exist.

The coated medical devices are used in particular for keeping open all gait-like structures, such as urinary tract, esophagus, trachea, biliary tract, kidney, blood vessels throughout the body including the brain, duodenum, pilorus, small and large intestine but also to keep open artificial outputs as they for the intestine or used for the trachea.

Thus, the coated medical devices are useful for preventing, reducing or treating stenoses, restenosis, in-stent restenosis, arteriosclerosis, atherosclerosis, and all other forms of vascular occlusion or vascular constrictions of passageways or outlets.

Another embodiment of the present invention relates to a vascular support having a porous wall made of synthetic polymer, wherein in the wall of the prosthesis microparticles are incorporated, are immobilized on the surfaces of blood clotting inhibitors. The blood coagulation inhibitors are preferably immobilized on the surfaces of the microparticles via so-called linkers (spacer molecules). As a rule, the linkers are not covalently, preferably adsorptively bound to the microparticles. The blood clotting inhibitors are preferably covalently linked to the linkers. The covalent linkage is usually based on a chemical condensation reaction between functional groups, for example hydroxyl and / or amino groups, of the linker and suitable reactive groups of the inhibitors. By linking to the linkers, the blood clotting inhibitors are at a certain distance from the microparticles. As a result, activity impairments of the inhibitors can be largely avoided. The immobilization of the linker-inhibitor conjugates on the microparticle surfaces is preferably based on adsorptive, especially electrostatic, interactions between the linkers and the microparticle surfaces.

In another preferred embodiment, the linkers are polymer molecules, which are suitably linearly constructed. The linkers are preferably oligo- or polyalkylene glycols, in particular polyethylene glycol (PEG). The blood coagulation inhibitors are preferably serine protease inhibitors, in particular thrombin inhibitors. Thrombin is the central enzyme of plasmatic blood clotting, which cleaves fibrinogen to monomeric fibrin. This then polymerizes and cross-links adherent blood components to the thrombus wall to form a thrombus.

figure description

1 shows a PLGA felt of a partially pre-expanded stent that has been crimped and expanded after full-coverage sprayed felt coating. It is easy to see that the PLGA case has remained intact.

2 shows a full-surface spray-felt coated stent with micropores (d = 200 μm)

3 shows in comparison to 1 and 2 a non-pre-expanded vascular support with a PLGA coating after crimping and expansion experiments.

4 shows a vascular support with a smooth inner wall and a rough outer wall made of polyurethane

Examples

Example 1 Coating of a Vascular Support with PLGA

The struts of a vascular support are spray-coated with a 0.5% PLGA solution. For this purpose, the stent is hung horizontally on a thin metal rod, which is inserted on the axis of rotation of the rotary and feed system and rotated at a defined speed of rotation. At a defined feed amplitude and feed rate and a defined distance between stent and nozzle, the stent is sprayed with the spray solution. After drying at room temperature and storage in the fume hood overnight, weigh again. Pre-coating the stent struts or stent stays ensures better adhesion of the felt to the struts.

Example 2: Full-surface coating of the vascular support with a PLGA felt

After drying, the partially pre-expanded stents are sprayed on the same spray coater as in Example 1 with a 3% chloroform-containing PLGA solution to apply a dense felt.

Example 3 Production of a Fully Felt-Coated Vascular Support with a Smooth Inner Wall and PU Felt Coating on the Outer Surface

A vascular support is mounted firmly on a polished stainless steel rod and immersed in a viscous polyurethane solution (PU) in THF (about 16%). Onto this dried-on surface, a uniform felt layer with a 6% strength PU solution in THF is then applied with the spray system. After drying, the felt-coated stent is thus removed from the metal rod.

Example 4: Felt Spray Coating of a Vascular Support Placed on a Balloon Catheter

The stent is crimped onto the balloon catheter and then fully coated with a 5% PLGA spray solution in chloroform.

Example 5: Hemocompatible coating of the stent with desulfated reacetylated heparin

Unexpanded stents made of LVM 316 medical grade stainless steel are degreased with acetone and ethanol in an ultrasonic bath for 15 minutes and dried in an oven at 100 ° C. Then they are immersed for 5 minutes in a 2% solution of 3-aminopropyltriethoxysilane in a mixture of ethanol / water (50/50: (v / v)) and then dried for 5 minutes at 100 ° C. Subsequently, the stents are washed overnight with demineralized water.

3 mg desulfated and reacetylated heparin are dissolved at 4 ° C in 30 ml 0.1M MES buffer (2- (N-morpholino) ethanesulfonic acid) pH 4.75 and treated with 30 mg N-cyclohexyl-N '- (2 morpholinoethyl) carbodiimide methyl p-toluenesulfonate. In this solution, the stents are stirred for 15 hours at 4 ° C. The mixture is then rinsed with water, 4 M NaCl solution and water for 2 hours.

Example 6: Variation possibilities for the active substance-containing felt coating of a vascular support

• a) For this purpose, the spray solution from the corresponding examples above, a defined amount of a selected drug such. B Paclitaxel added and the spray felt applied.
• b) Likewise, a pure active substance layer can be applied to the felt coating by spraying the surface with a solution having a defined content of active ingredient and then drying it.
• c) The felt coating can also be loaded in a simple manner by immersion in a drug-containing solution with active ingredient.
• d) Likewise, different active ingredients can be applied separately, for example, the spray solution in Example 1 is provided with a different active ingredient than the following felt spray coating.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 5876448 [0011]
• WO 93/22986 [0011]
• WO 2005/030086 [0013]
• US 5951599 [0015, 0015]

Claims (12)

Vascular support whose surface at least partially has a full-surface or continuous coating with a felt. The stent of claim 1, wherein the felt is a spray felt. A stent according to claim 1 or 2, wherein the felt is made of a polymer selected from the group consisting of or consisting of: polyurethane, polyethylene terephthalate; Polyvinyl chloride, polyvinyl esters, polyvinyl acetal polyamides, polyimides, polyacrylonitriles, polyethers, polyesters such as. Poly-3-hydroxybutylates, poly-3-hydroxyalkanoates, polyamino acids, polysaccharides, polylactides, polyglycolides, polylactide glycolides, chitosans, carboxymethyl chitosans, collagen, polyphosphazenes, polystyrenes, polysulfones, polysaccharides, as well as derivatives, block polymers, copolymers and mixtures of the foregoing polymers. Vascular supports according to one of the preceding claims, wherein the felt coating is porous and optionally sealed with a resorbable impregnation. A vascular support according to any one of the preceding claims wherein the felt coating has a porosity defined as air permeability of from 1 to 150 ml of air per square centimeter per minute at a pressure differential of 1.2 KPa. A stent according to any one of the preceding claims, further comprising at least one antiproliferative, anti-inflammatory, anti-inflammatory, anti-inflammatory, antiangiogenic, cytostatic, cytotoxic, antineoplastic and / or antifungal agent. The vascular support of claim 6, wherein the at least one antiproliferative, anti-inflammatory, antimigrative, anti-inflammatory, antiangiogenic, cytostatic, cytotoxic, antineoplastic and / or antifungal agent is selected from the group consisting of: abciximab, acemetacin, acetylvismion B, aclarubicin, ademetionin, Adriamycin, Aescin, Afromosone, Akagerin, Aldesleukin, Amidorone, Aminoglutethemide, Amsacrine, Anakinra, Anastrozole, Anemonin, Anopterin, Antifungals, Antithrombotics, Apocymarin, Argatroban, Aristolactam-All, Aristolochic Acid, Ascomycin, Asparaginase, Aspirin, Atorvastatin, Auranofin, Azathioprine, Azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, bombrestatin, boswellic acids and their derivatives, bruceanols A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin , Capecitabine, o-carbamoylphenoxyacetic acid, carb oplatin, carmustine, celecoxib, cepharantin, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate, cictoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, concanamycin, coumadin, C-type natriuretic peptides (CNP), cudraisoflavone A, curcumin, cyclophosphamide, Cyclosporine A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1,11-dimethoxycanthin-6-one, docetaxel, doxorubicin, dunaimycin, epirubicin, epothilones A and B, erythromycin, estramustine, etoboside, everolimus, filgrastim, Fluroblastin, fluvastatin, fludarabine, fludarabine 5'-dihydrogen phosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghalacinoside, ginkgol, ginkgolic acid, glycoside 1a, 4-hydroxyoxycyclophosphamide, idarubicin, ifosfamide, josamycin, lapachol, lomustine, lovastatin, melphalan, midecamycin, Mitoxantrone, nimustin, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, Miltefosine, pentostatin, pegasparase, exemestane, letrozole, formestan, mitoxanthrone, mycophenolate mofetil, β-lapachone, podophyllotoxin, podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon α-2b, lanograstim (r-HuG-CSF), macrogol , Selectin (cytokine antagonist), cytokine inhibitors, COX-2 inhibitor, angiopeptin, monoclonal antibodies that inhibit muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1-hydroxy-11-methoxycanthin-6-one, scopolectin, NO donors, Pentaerythrityl tetranitrate and syndnoeimines, S-nitrosated derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinylestradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, camebakaurin, terpenoids, verapamil, tyrosine kinase inhibitors, tyrphostins, paclitaxel and its derivatives, 6-a-hydroxy-paclitaxel, taxotere, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothioma alat, oxaceprol, β-sitosterol, myrtecaine, polidocanol, nonivamide, levomenthol, ellipticin, colcemid, cytochalasin A-E, indanocine, nocadazole, bacitracin, vitronectin receptor antagonist, azelastine, guanidyl cyclase stimulator, tissue protector of metalloproteinase-1 and 2, free nucleic acids, nucleic acids incorporated in virus carriers, DNA and RNA fragments, Plaminogen Activator Inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, IGF-1, antibiotics, cefadroxil, cefazolin, cefaclor, cefotixine tobramycin , Gentamycin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxoparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidol, trapidil, nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors , Captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, Interferon α, β and γ, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, halofuginone, nifedipine, tocopherol tranilast, molsidomine, tea polyphenols, epicatechingallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, etoposide, dicloxacylline, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, Quinidine, disopyrimide, flecainide, propafenone, sotolol, natural and synthetic steroids, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal substances (NSAIDS), fenoporfen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral Agents, acyclovir, ganciclovir, zidovudine, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoic agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol-C21-angelate, 14-dehydroagrostistachine, agroskin, agrostistachin, 17-Hydroxyagrostista quinol, ovatodiolides, 4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and 67, tubeimoside, bruceantinosides C, yadanziosides N, and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptate acid A , Iso-Iridogermanal. Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A and B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrine, Taxamairin A and B, Regenilol, Triptolide, Cymarin, Hydroxyanopterin, Protoanemonin, Cheliburine chloride, sinococulin A and B, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadiene 3,20-dione, helenaline, indicin, indicin-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatin, malloterine, mallotochromanol, isobutyrylmallotochromanol , Maquiroside A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidine, Oxoushinsunin, Periplocoside A, Ursolic Acid, Deoxypypsorospermine, Psycorubin, Ricin A, Sanguinarine, Manwuweizic Acid, Methylsorbifolin, Sphatheliachromes, Stizophyllin, Mansonin, Strebloside, Dihydrousambaraensin, Hydroxyusambarin , Strychnopentamine, Strychnophyllin, Usambarin, Usambarensin, Liriodenin, Oxoushinsunin, Daphnoretin, Lariciresinol, Methoxylariciresinol, Syringaresinol , Sirolimus and its derivatives such as Biolimus A9, everolimus, myolimus, novolimus, pimecrolimus, ridaforolimus, tacrolimus FK 506, temsirolimus and zotarolimus., Somatostatin, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, tropfosfamide, Treosulfan, Tremozolomide, Thiotepa, Tretinoin, Spiramycin, Umbelliferone, Desacetylvismion A, Zeorin, Vismion A and Vismion B. A stent according to any one of the preceding claims, wherein the stent is provided with an outer hemocompatible layer. A vascular support according to any one of the preceding claims, wherein the vascular support is provided with an inner hemocompatible layer. A method of coating an expandable vascular lumen device comprising the steps of: a) providing an expandable device, b) dissolving a polymer in a volatile solvent, c) applying a felt from the polymer by spraying or electrospinning. The vascular support of any one of claims 1-9, wherein the expandable device is a vascular support or a stent. A vascular support according to claim 11 suitable for preventing, reducing or treating body vascular wall injuries, stenosis, restenosis, in-stent restenosis, atherosclerosis, atherosclerosis, vascular occlusions, vasoconstriction, constricted heart valves, aneurysms, artificial exits and accesses.