ES2374869T3 - MEDICAL DEVICES WITH HYDROPHILE COATING. - Google Patents

Abstract

Medical device with at least one coating containing at least one polyurethaneurea, characterized in that the polyurethaneurea is finished with a copolymer unit of poly (ethylene oxide) and poly (propylene oxide).

Description

Medical devices with hydrophilic coatings

The present invention relates to medical devices with hydrophilic coatings and compatible with polyurethaneurea blood. These medical devices with improved surface quality offer advantages in application due to less friction and their ability to reduce the risk of blood clots in contact with blood.

The use of medical devices, for example catheters, can be greatly improved by equipping them with hydrophilic surfaces. The use and displacement of urinary or blood vessel catheters is facilitated by the fact that hydrophilic surfaces adsorb a film of water in contact with blood or urine. This reduces the friction of the catheter surface with the vessel walls, so that the catheter can be placed and moved more easily. The devices can also be directly wetted before the intervention to reduce friction by forming a homogeneous water film. Affected patients have less pain and this reduces the risk of damaging the vessel walls. In addition, in the application of catheters in contact with blood there is always the risk of blood clots forming. In this context, hydrophilic coatings are generally considered useful for antithrombogenic coatings.

Catheters with hydrophilized surfaces are known from the prior art.

Thus, for example, WO 99/38545 A1 describes catheters which in a first embodiment consist of a base coating and a sliding hydrophilic coating. In addition, in this state of the art an embodiment is also described in which only a sliding coating is used, that is, a coating system without a base coating. In this case a sliding coating of a polyurethane is used. In this regard, isocyanate is used as a surface binding member for the attachment of hydrophilic groups. Therefore, toxic isocyanates are provided on the medical device, and catalysts containing very toxic tin must be used for acceleration of cure.

From WO 2006/037321 A1, medical devices with a moistened hydrophilic surface are known which will improve the sliding properties of the apparatus. The surface is formed by a coating composition with a hydrophilic polymer and a wetting agent comprising water and at least one lubricant. The coating composition known by this state of the art consists of several constituents, all of which must functionally cooperate to provide the resulting coating with the desired properties.

From US 2003/0203991 A1 hydrophilic coating materials are known which are based on mixtures of hydrophobic polymers with hydrophilic. Corresponding coating compositions for medical devices comprise (a) an aqueous polymer matrix; (b) a hydrophilic polymer; (c) a colloidal metal oxide and (d) a crosslinker. The necessary hydrophilicity of the coating according to US 2003/0203991 A1 is achieved by the polymer (b) which is incorporated in the corresponding polymer matrix. As a polymer matrix, but not as a hydrophilic polymer, polyurethane dispersions are also used, among others. The extensive ionic modification of these polyurethane dispersions can lead to an unwanted reduction of hydrophilicity.

Mixtures of polyurethane and polyvinylpyrrolidone as a hydrophilizing constituent are further described in US 5,061,424. In addition, US 5,041,100 and US 2005/054774 A1 respectively describe coating compositions containing polyurethane with poly (ethylene oxide) (US 5,041,100) or acrylates (US 2005/054774) as hydrophilizing constituents.

US 2006/040253 A1 describes the hydrophilic coating of medical devices to improve the sliding properties, the composition having at least one water soluble sliding polymer and an insoluble polymer. The water-soluble sliding polymer is selected, among others, from the group consisting of poly (ethylene oxide), poly (propylene oxide), poly (ethyl vinyl alcohol), poly (ethyl vinyl acetate) and polyvinyl pyrrolidone, while the insoluble polymer It is formed, among others, by polyurethanes, polyesterurethanes and polyetherurethanes.

Aliphatic polyether polyurethanes for hydrophilic coatings can also be obtained commercially, for example, Tecogel® (Thermedics Polymer Products) or Hydroslip® (CardioTech International Inc.).

Both the mixtures described in the literature as well as the polyether polyurethanes that can be obtained commercially have different disadvantages. Thus, in the case of these mixtures these are multi-component systems, that is, they comprise several separate coatings and, therefore, are of complex preparation, especially also those systems that are synthesized by covalent bonding of two polymers (see document US 2003/0203991 A1). Aliphatic polyetherurethanes are easier to apply, but often they can only be processed with proportions of organic solvents. But this is not desired in the application of medical devices, especially in human or animal bodies, due to the risk of release of traces of

coatings solvents. Therefore, in principle there is still a need for medical devices for use within the human or animal body that have hydrophilic surfaces, and preferably eliminate the disadvantages shown in the prior art.

In this context, US 5,589,563 recommends superficially modified terminal groups for biomedical polymers that can be used for coating medical devices. These polymers comprise different terminal groups that are selected from amines, fluorinated alkanols, polydimethylsiloxanes and poly (ethylene oxide) terminated with amine. However, these polymers do not have satisfactory properties as a coating for medical devices, especially as regards the hydrophilicity required.

Therefore, it is an object of the present invention to provide medical devices with hydrophilic surfaces. As these surfaces are frequently used in contact with blood, the surfaces of these materials will also have good blood compatibility and especially reduce the risk of blood clot formation.

The subject of this invention are medical devices with hydrophilic surfaces that can be generated by coating with special polyurethane dispersions.

The medical devices according to the invention comprise at least one coating containing at least one polyurethaneurea which is terminated with a copolymer unit of poly (ethylene oxide) and poly (propylene oxide).

According to the invention it was found that the compositions of these specific polyurethaneurea are excellently suitable as coatings of medical devices, provide them with an excellent sliding coating and at the same time reduce the risk of blood clot formation during treatment with the medical device.

Polyurethaneureas within the meaning of the present invention are polymeric compounds having

(a) at least two repeat units containing urethane groups of the following general structure

and at least one repeat unit containing urea groups

The coating compositions to be used according to the invention are based on polyurethaneurea that essentially do not exhibit ionic modification. In the context of the present invention, it is understood that the polyurethaneureas to be used according to the invention do not essentially have ionic groups, especially sulfonate, carboxylate, phosphate and phosphonate groups.

By the term "essentially no ionic modification" it is understood within the framework of the present invention that an ionic modification is present at most in a proportion of 2.50% by weight, preferably at most of 2.00% by weight, especially as maximum of 1.50% by weight, especially preferably a maximum of 1.00% by weight, especially a maximum of 0.50% by weight, being most preferred when absolutely no ionic modification of the polyurethaneure provided according to the invention.

The polyurethaneureas provided according to the invention for the coating of medical devices are preferably essentially linear molecules, but they can also be branched, which however is less preferred. By essentially linear molecules is meant lightly crosslinked systems having a polyol carbonate with an average hydroxyl functionality of preferably 1.7 to 2.3, especially 1.8 to 2.2, especially preferably 1.9 to 2.1. Systems of this type can still be dispersed satisfactorily.

The number average molecular weight of the polyurethaneureas preferably used according to the invention is preferably 1000 to 200000, especially preferably 5000 to 100000. In this regard, the number average molecular weight is measured against polystyrene as a standard in dimethylacetamide at 30 ° C. .

The average particle size of the dispersed polyurethaneureas according to the invention is preferably from 10 to 1000 nm, especially preferably from 20 to 800 nm, very especially preferably at 50 to 600 nm.

Polyurethaneureas

The polyurethaneure based coating systems to be used according to the invention are described in more detail below.

The polyurethaneureas used according to the invention in the coatings of medical devices are prepared by reaction of structural components comprising at least one polyol carbonate component, at least one polyisocyanate component, at least one polyoxyalkylene ether component, at least one diamine component and / or amino alcohol and, if necessary, a polyol component.

The individual structural components are now described in more detail below.

(a) Polycarbonate

The coating composition provided according to the invention of a polyurethaneurea comprises units having their origin in at least one polycarbonate containing hydroxyl groups (polyolcarbonate).

In principle, polyolcarbonates are suitable for the introduction of units based on a polycarbonate containing hydroxyl groups, that is, polyhydroxy compounds with an average hydroxyl functionality of 1.7 to 2.3, preferably 1.8 to 2.2, with Special preference from 1.9 to 2.1. Therefore, the polycarbonate is preferably formed essentially linear and only has an insignificant three-dimensional cross-linking.

As polycarbonates having hydroxyl groups are considered polycarbonates of the molecular weight (molecular weight determined by the OH index; DIN 53240) of preferably 400 to 6000 g / mol, especially preferably 500 to 5000 g / mol, especially 600 to 3000 g / mol, which can be obtained, for example, by reacting carbonic acid derivatives such as diphenyl carbonate, dimethyl carbonate or phosgene with polyols, preferably diols. Such diols include, for example, ethylene glycol, 1,2- and 1,3-propanediol, 1,3- and 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, neopentyl glycol, 1 , 4-bishydroxymethylcyclohexane, 2-methyl-1,3-propanediol, 2,2,4-trimethylpentane-1,3-diol, di-, tri-or tetraethylene glycol, dipropylene glycol, polypropylene glycols, dibutylene glycol, polybutylene glycols, bisphenol A, tetrabromobisphenol A also diols modified with lactone.

The diol component preferably contains from 40 to 100% by weight of hexanediol, preferably of 1,6-hexanediol and / or derivatives of hexanediol, preferably those which, in addition to terminal OH groups, have ether or ester groups, for example, products that are obtained by reacting 1 mol of hexanediol with at least 1 mol, preferably 1 to 2 moles, of caprolactone or by etherification of hexanediol with itself giving di- or trihexylene glycol. Polyether polycarbonates can also be used. The hydroxyl polycarbonates will be essentially linear. However, if necessary, they can be branched slightly by the incorporation of polyfunctional components, especially low molecular weight polyols. Suitable for this are, for example, glycerin, trimethylolpropane, 1,2,6-hexanotriol, 1,2,4-butanedriol, trimethylolpropane, pentaerythritol, quinitol, mannitol, sorbitol, methylglucoside or 1,3,4,6-dianhydrohexitols. Preferred are those polycarbonates based on 1,6-hexanediol, as well as co-diols of modifying action such as, for example, 1,4-butanediol or also εcaprolactone. Other preferred polydiolcarbonates are those based on mixtures of 1,6-hexanediol and 1,4-butanediol.

(b) Polyisocyanate

The coating composition provided according to the invention of a polyurethaneurea has units that have their origin in at least one polyisocyanate.

As polyisocyanates (b) all aromatic, araliphatic, aliphatic and cycloaliphatic isocyanates known to the expert of an average NCO functionality � 1, preferably � 2, can be used separately or in discretionary mixtures with each other, being irrelevant if they were prepared according to the phosgene or phosgene free procedure. These can also have structures of iminooxadiazindione, isocyanurate, uretdione, urethane, allophanate, biuret, urea, oxadiazintrione, oxazolidinone, acylurea and / or carbodiimide. The polyisocyanates can be used separately or in discretionary mixtures with each other.

Preferably isocyanates of the series of aliphatic or cycloaliphatic representatives are used, these having a basic carbon skeleton (without the NCO groups contained) of 3 to 30, preferably 4 to 20 carbon atoms.

Especially preferred compounds of component (b) correspond to the previously mentioned type

with aliphatic and / or cycloaliphatically linked NCO groups such as, for example, bis- (isocyanatoalkyl) ether, bis- and tris (isocyanatoalkyl) benzenes, bis- and tris- (isocyanatoalkyl) toluenes, as well as bis- and tris- (isocyanatoalkyl) xylenes, propanediisocyanates, butanediisocyanates, pentanediisocyanates, hexanediisocyanates (for example, hexamethylene diisocyanates, HDI), heptanediisocyanates, octanediisocyanates, nonanodiisocyanates (for example, trimethyl-HDI, 2,4, mixture of 2,4, and 2, 2, 4, 4, 4, and 2, 3, 4, 2, 4, 4, 4, and 4, 3, 2, 4, 4, 4, 3, 4, 3, 4, 3, 4, and 4, 3, 2, 4, 4, 4, 3, 4, 3, 4, 3, 4, 3, 4, and 4, 2, 4, 4, 3, 4, 2, 4, 4, and 4, 2, 4, 4, 4, 2, 4, 4, 2, 4, and 4, 2, 4, 4, 4, 4, 3, 4, 2, 4, 2, 4, 2, 4, 2, 4, 2, 4, 4, and 4-methyls. ), nonanotriisocyanates (for example, 4isocyanatomethyl-1,8-octanediisocyanate), dekanediisocyanates, decanotriisocyanates, undecanediisocyanates, undecanotriisocyanates, dodecanediisocyanates, dodecanotriisocyanates, 1,3-, isoxyl-methylenometry 3,5,5-trimethylcyclohexyl isocyanate (isophorondiisocyanate, IPDI), bis- (4-isocyanoccyclohexyl) methane (H12MDI) or bis- (isocyanatomethyl) norbornano (NBDI).

Very especially preferred compounds of component (b) are hexamethylene diisocyanate (HDI), trimethyl-HDI (TMDI), 2-methylpentane-1,5-diisocyanate (MPDI), isophorondiisocyanate (IPDI), 1,3-, as well as 1,4bis (isocyanatomethyl) cyclohexane (H6XDI), bis (isocyanatomethyl) norbornano (NBDI), 3 (4) -isocyanatomethyl-1-methylcyclohexyl isocyanate (IMCI) and / or 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) or mixtures of these isocyanates. Other examples are derivatives of the above diisocyanates with uretdione, isocyanurate, urethane, allophanate, biuret, iminooxadiazinedione and / or oxadiazintrione structure with more than two NCO groups.

The amount of constituent (b) in the coating composition to be used according to the invention preferably amounts to 1.0 to 4.0 moles, especially preferably 1.2 to 3.8 moles, especially 1.5 to 3.5 moles, respectively referred to the constituent (a) of the coating composition to be used according to the invention.

(c) Polyoxyalkylene Ether

The polyurethaneurea used in the present invention has units that have their origin in a copolymer of poly (ethylene oxide) and poly (propylene oxide). These copolymer units are present in the polyurethaneurea as terminal groups.

Non-ionically hydrophilic compounds (c) are, for example, polyhydric polyols of monohydric poly (alkylene oxide) having a statistical average of 5 to 70, preferably 7 to 55, units of ethylene oxide per molecule as they are accessible in a known manner. by alkoxylation of suitable initiator molecules (for example, in Ullmanns Enzyklopädie der technischen Chemie, 4th edition, volume 19, Verlag Chemie, Weinheim p. 31-38).

Suitable initiator molecules are, for example, saturated monoalcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, isomeric pentanoles, hexanols, octanoles and nonanols, ndecanol, n-dodecanol, n- tetradecanol, n-hexadecanol, n-octadecanol, cyclohexanol, isomeric methylcyclohexanols or hydroxymethylcyclohexane, 3-ethyl-3-hydroxymethylxetane or tetrahydrofurfuryl alcohol, monoalkyl ethers of diethylene glycol such as, for example, monobutyl ether of diethylene glycol alcohol 1,1-dimethylalkyl or oleic alcohol, aromatic alcohols such as phenol, isomeric cresols or methoxyphenols, araliphatic alcohols such as benzyl alcohol, anisic alcohol or cinnamyl alcohol, secondary monoamines such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, bis- (2-ethyl) -amine, N-methyl- and N-ethylcyclohexylamine or dicyclohexylamine, as well as secondary heter amines occyclics such as morpholine, pyrrolidine, piperidine or 1H-pyrazole. Preferred initiator molecules are saturated monoalcohols. As the initiator molecule, diethylene glycol monobutyl ether is used with particular preference.

The alkylene oxides ethylene oxide and propylene oxide can be used in discretionary order or also in admixture in the alkoxylation reaction.

In the case of poly (alkylene oxide) polyether alcohols, these are mixed poly (alkylene oxide) polyethers of ethylene oxide and propylene oxide whose alkylene oxide units are preferably constituted by at least 30 mol% , with particular preference for at least 40 mol%, of ethylene oxide units. Preferred non-ionic compounds are monofunctional mixed poly (alkylene oxide) polyethers having at least 40 mol% ethylene oxide units and a maximum 60 mol% propylene oxide units.

The average molar weight of the polyoxyalkylene ether is preferably 500 g / mol to 5000 g / mol, especially preferably 1000 g / mol to 4000 g / mol, especially 1000 to 3000 g / mol.

The amount of constituent (c) in the coating composition to be used according to the invention is preferably 0.01 to 0.5 moles, especially preferably 0.02 to 0.4 moles, especially 0.04 to 0.3 moles, respectively referred to the constituent (a) of the coating composition to be used according to the invention.

Furthermore, according to the invention it could be shown that polyurethaneureas with terminal groups based on mixed polyoxyalkylene ethers of poly (ethylene oxide) and poly (propylene oxide) are especially suitable for generating coatings with high hydrophilicity. As shown below in comparison with polyurethaneurea that are only finished with poly (ethylene oxide), the coatings according to the invention produce a clearly low contact angle and, therefore, are configured more hydrophilically.

(d) Diamine or amino alcohol

The composition of the coating provided according to the invention of a polyurethaneurea has units that have their origin in at least one diamine or an amino alcohol.

The so-called chain extenders (d) are used for the preparation of the polyurethane coatings according to the invention. Chain extenders of this type are di- or polyamines, as well as hydrazides, for example, hydrazine, 1,2-ethylenediamine, 1,2- and 1,3-diaminopropane, 1,4-diaminobutane, 1,6-diaminohexane, isophorondiamine, mixtures of 2,2,4- and 2,4,4-trimethylhexamethylenediamine, 2-methylpentamethylenediamine, diethylenetriamine, 1,3- and 1,4xilylenediamine, α, α, α ', α'-tetramethyl-1, 3- and -1,4-xylylenediamine and 4,4-diaminodicyclohexylmethane, dimethylethylenediamine, hydrazine, adipic acid dihydrazide, 1,4-bis (aminomethyl) cyclohexane, 4,4'-diamino-3,3'-dimethyldicyclohexylmethane and others di- and tetraalkyl (C1-C4) -dicyclohexylmethanes, for example, 4,4'-diamino-3,5-diethyl-3 ', 5'diisopropyldicyclohexylmethane.

Diamines or amino alcohols are generally considered diamines or aminoalcohols of low molecular weight containing active hydrogen with different reactivity towards NCO groups as compounds that, in addition to a primary amino group, also have secondary amino groups, or in addition to an amino group (primary or secondary) also OH groups. Examples of these are primary and secondary amines such as 3-amino-1-methylaminopropane, 3 amino-1-ethylaminopropane, 3-amino-1-cyclohexylaminopropane, 3-amino-1-methylaminobutane, in addition to amino alcohols such as N-aminoethylene ethanolamine, ethanolamine, 3 -aminopropanol, neopentanolamine and with special preference diethanolamine.

The constituent (d) of the coating composition to be used according to the invention can be used in its preparation as a chain extender and / or as a chain termination.

The amount of constituent (d) in the coating composition to be used according to the invention is preferably 0.05 to 3.0 moles, especially preferably 0.1 to 2.0 moles, especially 0.2 to 1.5 moles, respectively referring to the constituent (a) of the coating composition to be used according to the invention.

(e) Polyols

In another embodiment, the composition of the coating according to the invention of a polyurethaneurea comprises additional units having their origin in at least one other polyol.

The other low molecular weight polyols used for the synthesis of polyurethaneureas (e) generally produce a reinforcement and or a branching of the polymer chain. The molecular weight is preferably 62 to 500 g / mol, especially preferably 62 to 400 g / mol, especially 62 to 200 g / mol.

Suitable polyols may contain aliphatic, alicyclic or aromatic groups. Here it is worth mentioning, for example, low molecular weight polyols with up to about 20 carbon atoms per molecule such as, for example, ethylene glycol, diethylene glycol, triethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4- butanediol, 1,3-butylene glycol, cyclohexanediol, 1,4-cyclohexanedimethanol, 1,6-hexanediol, neopentyl glycol, hydroquinone dihydroxyethyl ether, bisphenol A (2,2-bis (4-hydroxyphenyl) propane), hydrogenated bisphenol A (2 , 2-bis (4-hydroxycyclohexyl) propane), as well as trimethylolpropane, glycerin or pentaerythritol and mixtures thereof, and if necessary also other low molecular weight polyols. Esterdiols can also be used, such as, for example, α-hydroxybutyl-ε-hydroxy-caproic acid ester, ω-hydroxyhexyl-γ-hydroxybutyric acid ester, (β-hydroxyethyl) ester of adipic acid or bis (β-hydroxyethyl) ester of terephthalic acid.

The amount of constituent (e) in the coating composition to be used according to the invention is preferably 0.1 to 1.0 mol, especially preferably 0.2 to 0.9 mol, especially 0.2 to 0.8 moles, respectively referred to the constituent (a) of the coating composition to be used according to the invention.

(f) Other structural units containing amine and / or hydroxy (structural component)

The reaction of the isocyanate-containing component (b) with the hydroxy or amine functional compounds (a), (c), (d) and if necessary (e) is usually carried out maintaining a slight excess of NCO compared to

hydroxylic or amine reactive compounds. By dispersion in water, isocyanate group residues are hydrolyzed into amine groups. But in the specific case it may be important to block the remaining isocyanate groups before the polyurethane dispersion.

Therefore, the polyurethaneurea coatings provided according to the invention may also contain structural components (f) that are respectively at the chain ends and terminate these. These structural units are derived, on the one hand, from monofunctional compounds reactive with NCO groups such as monoamines, especially mono-secondary amines, or monoalcohols.

Here are, for example, ethanol, n-butanol, ethylene glycol monobutyl ether, 2-ethylhexanol, 1-octanol, 1dodecanol, 1-hexadecanol, methylamine, ethylamine, propylamine, butylamine, octylamine, laurylamine, stearylamine, isononyloxypropylamine, dimethylamine , diethylamine, dipropylamine, dibutylamine, N-methylaminopropylamine, diethyl (methyl) aminopropylamine, morpholine, piperidine and suitable substituted derivatives thereof.

Since the structural units (f) are essentially used in the coatings according to the invention to destroy the excess of NCO, the amount required essentially depends on the amount of the excess NCO and cannot be specified in general.

(g) Other constituents

The polyurethaneurea coatings provided according to the invention may also contain other conventional constituents for the intended purpose as additives and fillers. An example of these are pharmacological active ingredients, drugs and additives that promote the release of pharmacological active ingredients (drug eluting additives, of "drug-eluting-additives").

The pharmacological active substances or drugs that can be used in the coatings according to the invention on medical devices are, in general, for example, thromboresistant agents, antibiotic agents, antitumor agents, growth hormones, antiviral agents, antiangiogenic agents, angiogenic agents, agents antimitotics, anti-inflammatory agents, cell cycle regulating agents, genetic agents, hormones, as well as their counterparts, derivatives, fragments, pharmaceutical salts and combinations thereof.

Thus, specific examples of drugs or pharmacological active ingredients of this type include thromboresistant (non-thrombogenic) agents or other agents to suppress acute thrombosis, stenosis or late restenosis of the arteries, for example, heparin, streptokinase, urokinase, plasminogen activator tissue, anti-thromboxane-B2 agent; anti-B-thromboglobulin agent, prostaglandin E, aspirin, dipyridimol, anti-thromboxane-A2 agent, murine monoclonal antibody 7E3, triazolopyrimidine, cyprorostene, hirudin, ticlopidine, nicorandil, etc. A growth factor can also be used as a drug to suppress fibromuscular hyperplasia at the site of arterial stenosis, or any other discretionary inhibitor of cell growth at the site of stenosis can be used.

The drug or pharmacological active ingredient may also be constituted by a vasodilator to counteract vasospasms, for example, an antispasmolytic agent such as papaverine. The drug may itself be a vasoactive agent such as calcium antagonists, or α- and �-adrenergic agonists or antagonists. Additionally, the therapeutic agent can be a biological adherent agent such as medical grade cyanoacrylate or fibrin that is used, for example, to glue a tissue valve to the wall of a coronary artery. The therapeutic agent may also be an antineoplastic agent such as 5-fluorouracil, preferably with a controlled release vehicle for the agent (for example, for the application of a continuous controlled release antineoplastic agent at a tumor site).

The therapeutic agent may be an antibiotic, preferably in combination with a controlled release vehicle for the continuous release of the coating of a medical device at an infection site located within the body. Similarly, the therapeutic agent may contain steroids in order to suppress inflammation in localized tissue or for other reasons.

Specific examples of suitable drugs include:

(to)

 Heparin, heparin sulfate, hirudin, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratane sulfate, lithic agents, including urokinase and streptokinase, their counterparts, analogues, fragments, derivatives and pharmaceutical salts thereof;

(b)

 antibiotic agents such as penicillins, cephalosporins, vacomycins, aminoglycosides, quinolones, polymyxins, erythromycins; tetracyclines, chloramphenicols, clindamycin, lincomycins, sulfonamides, their counterparts, analogs, derivatives, pharmaceutical salts and mixtures thereof;

(C)

 paclitaxel, docetaxel, immunosuppressants such as sirolimus or everolimus, alkylating agents included

mechlorethamine, chlorambucil, cyclophosphamide, melphalan and ifosfamide; antimetabolites including methotrexate, 6mercaptopurine, 5-fluorouracil and cytarabine; plant alkaloids including vinblastine; vincristine and etoposide; antibiotics including doxorubicin, daunomycin, bleomycin and mitomycin; nitrosourea including carmustine and lomustine; inorganic ions including cisplatin; biological reaction modifiers including interferon; angiostatinic agents and endostatinic agents; enzymes including asparaginase; and hormones including tamoxifen and flutamide, their counterparts, analogs, fragments, derivatives, pharmaceutical salts and mixtures thereof; Y

(d) antiviral agents such as amantadine, rimantadine, rabavirin, idoxuridine, vidarabine, trifluridine, acyclovir, ganciclocir, zidovudine, phosphonoformates, interferons, their counterparts, analogs, fragments, derivatives, pharmaceutical salts and mixtures thereof; Y

(e) anti-inflammatory agents such as ibuprofen, dexamethasone or methylprednisolone. In a preferred embodiment, the coating composition provided according to the invention comprises a

polyurethaneurea that is synthesized from a) at least one polyol carbonate; b) at least one polyisocyanate; c) at least one monofunctional mixed polyoxyalkylene ether of poly (ethylene oxide) and poly (oxide of

propylene), and d) at least one diamine or an amino alcohol. In another preferred embodiment, the coating composition according to the invention comprises a

polyurethaneurea that is synthesized from a) at least one polyol carbonate; b) at least one polyisocyanate; c) at least one monofunctional mixed polyoxyalkylene ether of poly (ethylene oxide) and poly (oxide of

propylene); d) at least one diamine or an amino alcohol; Y e) at least one polyol.

In another embodiment of the present invention, the coating composition provided according to the invention comprises a polyurethaneurea which is synthesized from a) at least one polyol carbonate;

b) at least one polyisocyanate; c) at least one monofunctional mixed polyoxyalkylene ether of poly (ethylene oxide) and poly (oxide of propylene);

d) at least one diamine or an amino alcohol; e) at least one polyol; Y f) at least one amine or hydroxyl-containing monomer found at the chain ends of the

polymer. According to the invention, polyurethaneurea which are synthesized from

a) at least one polyolcarbonate with an average molar weight between 400 g / mol and 6000 g / mol and a hydroxyl functionality of 1.7 to 2.3, or from mixtures of polyol carbonates of this type; b) at least one aliphatic, cycloaliphatic or aromatic polyisocyanate or mixtures of polyisocyanates of this type in

an amount per mole of the polyol carbonate of 1.0 to 4.0 moles; c) at least one monofunctional mixed polyoxyalkylene ether of poly (ethylene oxide) and poly (oxide of

propylene) or a mixture of polyethers of this type with an average molar weight between 500 g / mol and 5000 g / mol in an amount per mol of the polyol carbonate of 0.01 to 0.5 mol;

d) at least one aliphatic or cycloaliphatic diamine or at least one amino alcohol, such as so-called chain extenders, or mixtures of compounds of this type in an amount per mole of the polyol carbonate of 0.05 to 3.0 moles;

e) if necessary one or more aliphatic short chain polyols with a molar weight between 62 g / mol and 500 g / mol in an amount per mol of the polyol carbonate of 0.1 to 1.0 mol; Y

f) if necessary structural units containing amine or OH that are at the ends of polymer chains and terminate them.

According to the invention, polyurethaneurea which are synthesized from

a) at least one polyol carbonate with an average molar weight between 500 g / mol and 5000 g / mol and a hydroxyl functionality of 1.8 to 2.2, or from mixtures of polycarbonates of this type;

b) at least one aliphatic, cycloaliphatic or aromatic polyisocyanate or mixtures of polyisocyanates of this type in an amount per mole of the polyol carbonate of 1.2 to 3.8 moles;

c) at least one monofunctional mixed polyoxyalkylene ether of poly (ethylene oxide) and poly (propylene oxide) or a mixture of polyethers of this type with an average molar weight between 1000 g / mol and 4000 g / mol in an amount per mole of the polyol carbonate of 0.02 to 0.4 moles;

d) at least one aliphatic or cycloaliphatic diamine or at least one amino alcohol, such as so-called chain extenders, or mixtures of compounds of this type in an amount per mole of the polyolcarbonate of 0.1 to 2.0 moles;

e) where appropriate one or more aliphatic short chain polyols with a molar weight between 62 g / mol and 400 g / mol in an amount per mol of the polyol carbonate of 0.2 to 0.9 mol; Y

f) if necessary structural units containing amine or OH that are at the ends of polymer chains and terminate them.

According to the invention, polyurethaneurea are still more preferably used for coating catheter materials that are synthesized from

a) at least one polyol carbonate with an average molar weight between 600 g / mol and 3000 g / mol and a hydroxyl functionality of 1.9 to 2.1, or from mixtures of polycarbonates of this type;

b) at least one aliphatic, cycloaliphatic or aromatic polyisocyanate or mixtures of polyisocyanates of this type in an amount per mole of the polyol carbonate of 1.5 to 3.5 moles;

c) at least one monofunctional mixed polyoxyalkylene ether of poly (ethylene oxide) and poly (propylene oxide) or a mixture of polyethers of this type with an average molar weight between 1000 g / mol and 3000 g / mol in an amount per mole of the polyol carbonate of 0.04 to 0.3 moles;

d) at least one aliphatic or cycloaliphatic diamine or at least one amino alcohol, such as so-called chain extenders, or mixtures of compounds of this type in an amount per mole of the polyol carbonate of 0.2 to 1.5 moles;

e) if necessary, one or more aliphatic short chain polyols with a molar weight between 62 g / mol and 200 g / mol in an amount per mol of the polycarbonate of 0.2 to 0.8 mol; Y

f) if necessary structural units containing amine or OH that are at the ends of polymer chains and terminate them.

The coating composition is applied on a medical device.

Medical device

The term "medical device" should be broadly understood in the context of the present invention. Suitable non-limiting examples of medical devices (including instruments) are contact lenses; cannulas; catheters, for example, urological catheters such as urinary catheters or ureteral catheters; central venous catheters; catheters 9 10

venous or inlet or outlet catheters; dilatation balloons; catheters for angioplasty and biopsy; catheters used to insert an endovascular prosthesis, an embolism filter or a filter in the vena cava; balloon catheters or other expandable medical devices; endoscopes; laryngoscopes; tracheal devices such as endotracheal tubes, respirators and other tracheal aspiration apparatus; bronchoalveolar lavage catheters; catheters used in coronary angioplasty; guide rods, insertion guides and the like; vascular plugs; pacemaker components; cochlear implants; dental implant tubes for feeding, drainage tubes; and guide wires.

Furthermore, the coating solutions according to the invention can be used for the preparation of protective coatings, for example, for gloves, endovascular prostheses and other implants; tubes for extracorporeal blood (outside the body) (blood conduit tubes); membranes, for example, for dialysis; blood filters; apparatus to support circulation; bandage material for wound care; urine bags and stoma collection bags. Implants that contain a medically effective agent are also included as medically effective agents for endovascular prostheses or for balloon surfaces or for contraceptives.

Normally, the medical device consists of catheters, endoscopes, laryngoscopes, endotracheal tubes, feeding tubes, guide rods, endovascular prostheses and other implants.

As a substrate of the surface to be coated, many materials such as metals, textiles, ceramics or plastics are considered, with the use of plastics being preferred for the manufacture of medical devices.

According to the invention, it was found that medical devices with highly hydrophilic and compatible surfaces compatible with blood can be generated using aqueous non-ionic stabilized polyurethane dispersions of the type described above for the coating of the medical devices. The coating compositions described above are preferably obtained as aqueous dispersions and applied on the surface of medical devices.

Preparation of the coating solution

The constituents of the coatings described in more detail above are generally reacted so that initially a prepolymer with urea free isocyanate functionality is prepared by reacting the constituents (a), (b), (c) and, if necessary ( e), the ratio of the amount of the substance of isocyanate groups with respect to polyolcarbonate isocyanate reactive groups is preferably increased to 0.8 to 4.0, especially to 0.9 to 3.8, especially 1.0 to 3.5.

In an alternative embodiment, the constituent (a) can also be reacted separately with the isocyanate (b). Then, the addition of the constituents (c) and, if necessary, and their reaction can then be carried out. Then, in general, the remaining isocyanate groups are subjected to aminofunctional chain extension or termination before, during or after dispersion in water, the ratio of equivalents of isocyanate reactive groups of the compounds used for chain extension with with respect to the free isocyanate groups of the prepolymer preferably between 40 and 150%, especially preferably between 50 and 120%, especially between 60 and 120% (constituent (d)).

The polyurethane dispersions according to the invention are prepared in this regard preferably according to the so-called acetone process. For the preparation of the polyurethane dispersion according to this procedure with acetone, normally the constituents (a), (c) and (e), which must not have primary or secondary amino groups, and the polyisocyanate component (b) are provided completely or partially for the preparation of a polyurethane prepolymer with isocyanate functionality and if necessary diluted with a solvent miscible with water, but inert to isocyanate groups, and heated to temperatures in the range of 50 to 120 ° C. To accelerate the isocyanate addition reaction, catalysts known in polyurethane chemistry can be used, for example, dibutyltin dilaurate. Synthesis without catalyst is preferred.

Suitable solvents are the usual aliphatic ketofunctional solvents such as, for example, acetone, butanone which can be added not only at the beginning of the preparation, but also if necessary in parts later. Acetone and butanone are preferred. Other solvents, such as xylene, toluene, cyclohexane, butyl acrylate, methoxypropyl acetate, solvents with ether or ester units, can also be used and completely or partially distilled off or remain completely in the dispersion.

The constituents of (c) and (e) are dosed below, if not yet added at the beginning of the reaction.

In a preferred form, the prepolymer is prepared without the addition of solvent and only for chain extension is diluted with a suitable solvent, preferably acetone.

In the preparation of the polyurethane prepolymer, the ratio of the amount of substance of isocyanate groups with respect to isocyanate reactive groups is preferably 0.8 to 4.0, especially preferably 0.9 to 3.8, especially 1.0 to 3.5.

The reaction to give the prepolymer is carried out partially or completely, but preferably completely. Thus, polyurethane prepolymers containing free isocyanate groups in substance or in solution are obtained.

Then, in another process step, if it has not been produced or only partially, the prepolymer obtained is dissolved with the aid of aliphatic ketones such as acetone or butanone.

Next, possible components with NH2, NH and / or OH functionality are reacted with the remaining isocyanate groups. In this respect, this chain extension / termination can be carried out either in solvent before dispersion, during dispersion or in water after dispersion. Chain extension is preferably performed before dispersion in water.

If compounds corresponding to the definition of (d) with NH2 or NH groups are used for chain extension, the chain extension of the prepolymers is preferably performed before dispersion.

The degree of chain extension, that is, the ratio of equivalents of NCO reactive groups of the compounds used for chain extension with respect to free NCO groups of the prepolymer is preferably between 40 and 150%, especially preference between 50 and 120%, especially between 60 and 120%.

The amino components (d) can be used, if necessary, in a dilute form in water or solvent in the process according to the invention, separately or in mixtures, any order of addition being possible in principle.

If water or organic solvents are used together as diluents, then the diluent content preferably amounts to 70 to 95% by weight.

The preparation of the polyurethane dispersion from the prepolymers is carried out following the chain extension. For this, either the dissolved and extended chain polyurethane polymer is incorporated into the dispersion water, if necessary with strong shear, for example, strong agitation, or on the contrary the dispersion water is stirred in the solutions of prepolymer Preferably, water is added to the dissolved prepolymer.

Then, the solvent still contained in the dispersions after the dispersion step is normally removed by distillation. It is also possible to eliminate it during dispersion.

The solids content of the polyurethane dispersion after synthesis is between 20 and 70% by weight, preferably 20 to 65% by weight. For coating tests, these dispersions can be diluted discretionally with water so that the thickness of the coating can be adjusted variably. All concentrations of 1 to 60% by weight are possible, concentrations in the range of 1 to 40% by weight are preferred.

In this regard, discretionary layer thicknesses can be achieved, for example, from some 100 nm to some 100 µm, with greater and smaller thicknesses also being possible in the context of the present invention.

The polyurethane materials for coating medical devices can be diluted with water to any desired value by diluting the aqueous dispersions according to the invention. In addition, thickeners can be added if necessary to increase the viscosity of the polyurethane dispersions. Other additives are also possible, such as antioxidants, buffer materials to adjust the pH value or pigments. In addition, if necessary, other additives such as touch aids, colorants, matting agents, UV stabilizers, light stabilizers, other hydrophilizing agents, hydrophobicizing agents and / or leveling agents can still be used.

Coatings preparation

In the context of the present invention it is especially preferred that the coatings of the medical devices are prepared from dispersions of the coating composition described in more detail above. The dispersion is preferably obtained as described above.

According to the invention it has been found that the resulting coatings on medical devices differ depending on whether the coating is prepared from a dispersion or a solution.

In this regard, the coatings according to the invention on medical devices have advantages when

they are obtained from dispersions of the coating compositions described above since the dispersions of the coating systems according to the invention lead to coatings on medical devices that do not have organic solvent residues, that is, from the toxic point of view they are in generally harmless, and at the same time lead to more pronounced hydrophilicity, which can be identified, for example, at a low contact angle. For this, it refers to the tests and comparative tests explained below.

Therefore, in another configuration, the present invention relates to a medical device with at least one hydrophilic coating containing at least one polyurethaneurea, the coating being prepared from a polyurethaneurea dispersion. The polyurethaneurea is preferably the polyurethaneurea according to the invention described above.

In this regard, the medical devices according to the invention can be coated by different methods with the hydrophilic polyurethane dispersions. Coating techniques suitable for this are, for example, scraper application, printing, transfer coating, spraying, centrifugation or immersion coating.

Aqueous polyurethane dispersions that are used as the starting substance for the preparation of the coatings can be prepared according to discretionary procedures, however, the acetone process previously described is preferred.

In this regard, many substrates such as metals, textiles, ceramics and plastics can be coated. Coating of medical devices that are made of metals or plastic is preferred. As metals, for example: surgical stainless steel or nickel titanium alloys. Many polymeric materials are conceivable from which the medical device can be constructed, for example, polyamide; polystyrene; polycarbonate; polyether; polyester; poly (vinyl acetate); natural and synthetic rubbers; block copolymers of styrene and unsaturated compounds such as ethylene, butylene and isoprene; polyethylene or copolymers of polyethylene and polypropylene; silicone; poly (vinyl chloride) (PVC) and polyurethanes. For the best adhesion of the hydrophilic polyurethane on the medical device, other suitable coatings can be applied as a substrate before the application of these hydrophilic coating materials.

In addition to the hydrophilic properties of improved slip ability, the coating compositions provided according to the invention also stand out for their high blood compatibility. Because of this, work with these coatings is also especially advantageous in contact with blood. In comparison with polymers of the prior art, the materials show a reduced coagulation tendency in contact with blood.

The advantages of the catheters according to the invention with hydrophilic polyurethane coatings are set forth in the following examples by comparative tests.

Examples

The NCO content of the resins described in the examples and comparison examples was determined by titration according to DIN EN ISO 11909.

The solids content was determined according to DIN-EN ISO 3251. 1 g of polyurethane dispersion was dried at 115 ° C until proof of weight (15-20 min) by an infrared dryer.

The measurement of the average particle size of the polyurethane dispersions is carried out with the help of High Performance Particle Sizer (HPPS 3.3) from Malvern Instruments.

Unless otherwise noted, the data of specified amounts in% is understood as% by weight and refers to the aqueous dispersion obtained.

Substances and abbreviations used:

Desmophen C2200: polyol carbonate, OH 56 mg KOH / g, number average molecular weight 2000 g / mol (Bayer, MaterialScience AG, Leverkusen, DE)

Desmophen C1200: polyol carbonate, OH 56 mg KOH / g, number average molecular weight 2000 g / mol (Bayer Material Science AG, Leverkusen, DE)

Desmophen XP 2613: polyol carbonate, OH 56 mg KOH / g, number average molecular weight 2000 g / mol (Bayer Material Science AG, Leverkusen, DE)

PolyTHF® 2000: tetramethylene glycol polyol, OH 56 mg KOH / g, average molecular weight in

2000 g / mol number (BASF AG, Ludwigshafen, DE)

Polyether LB 25:

(monofunctional polyether based on ethylene oxide / propylene oxide, average molecular weight in number 2250 g / mol, OH 25 mg KOH / g index (Bayer Material Science AG, Leverkusen, DE)

Example 1:

This example describes the preparation of a polyurethaneurea dispersion according to the invention.

277.2 g of Desmophen C 2200, 33.1 g of the LB 25 polyether and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 110 ° C. After 3 h 40 min the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 15 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 41.5% and an average particle size of 164 nm.

Example 2:

This example describes the preparation of a polyurethaneurea dispersion according to the invention.

269.8 g of Desmophen C 2200, 49.7 g of the polyether LB 25 and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 100 ° C. After 21.5 h the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 5 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 41.3% and an average particle size of 109 nm.

Example 3:

This example describes the preparation of a polyurethaneurea dispersion according to the invention.

277.2 g of Desmophen C 1200, 33.1 g of the LB 25 polyether and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 110 ° C. After 2.5 h the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 5 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 40.4% and an average particle size of 146 nm.

Example 4:

This example describes the preparation of a polyurethaneurea dispersion according to the invention.

282.1 g of Desmophen C 2200, 22.0 g of the polyether LB 25 and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 110 ° C. After 21.5 h the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 5 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 41.7% and an average particle size of 207 nm.

Example 5:

This example describes the preparation of a polyurethaneurea dispersion according to the invention.

269.8 g of Desmophen XP 2613, 49.7 g of the LB 25 polyether and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 110 ° C. After 70 min the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 5 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 41.2% and an average particle size of 112 nm.

Example 6:

This example describes the preparation of a polyurethaneurea dispersion according to the invention.

249.4 g of Desmophen C 2200, 33.1 g of the polyether LB 25, 1.9 g of trimethylolpropane and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 110 ° C. After 4 h 20 min the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 720 g of acetone and then a solution of 3.3 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 15 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 38.9% and an average particle size of 144 nm.

Example 7:

282.1 g of Desmophen XP 2613, 22.0 g of the LB 25 polyether and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 110 ° C. After 70 min the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 5 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 38.3% and an average particle size of 215 nm.

Example 8:

This example describes the preparation of a polyurethaneurea dispersion as a comparison product with Example 1 according to the invention. Desmophen C2200 was changed to PolyTHF 2000.

277.2 g of PolyTHF 2000, 33.1 g of the LB 25 polyether and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 110 ° C. After 18 h the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 5 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 40.7% and an average particle size of 166 nm.

Example 9:

This example describes the preparation of a polyurethaneurea dispersion as a comparison product with Example 2 according to the invention. Desmophen C2200 was changed to PolyTHF 2000.

269.8 g of PolyTHF 2000, 49.7 g of the LB 25 polyether and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 100 ° C. After 17.5 h the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of

acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C within 10 min. The stirring time was 5 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 41.6% and an average particle size of 107 nm.

Example 10:

This example describes the preparation of a polyurethaneurea dispersion as a comparison product with Example 4 according to the invention. Desmophen C2200 was changed to PolyTHF 2000.

282.1 g of PolyTHF 2000, 22.0 g of the LB 25 polyether and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 110 ° C. After 21.5 h the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 5 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 37.5% and an average particle size of 195 nm.

Example 11: Preparation of coatings and measurement of static contact angle

The coatings for measuring the static contact angle were prepared on glass slides 25 x 75 mm in size with the aid of a centrifugal coating machine (RC5 Gyrset 5, Karl Süss, Garching, Germany). For this, a slide was clamped on the sample plate of the coater by centrifugation and covered homogeneously with approximately 2.5-3 g of aqueous undiluted polyurethane dispersion. By rotating the sample plate for 20 s at 1300 revolutions per minute, a homogeneous coating was obtained which dried 15 min at 100 ° C and then 24 h at 50 ° C. The coated slides obtained were directly subjected to a contact angle measurement.

A measurement of the static contact angle of the coatings obtained on the slides is made. Using the OCA20 video contact angle measuring device from Dataphysics with computer controlled injection, 10 drops of Millipore water are applied to the sample and its static wetting contact angle is measured. Previously the static charge (if present) on the surface of the sample is removed by an antistatic dryer.

Table 1: Static contact angle measurements

PU FILM

CONTACT ANGLE [º]

Example 1

<10

Example 2

eleven

Example 3

14

Example 4

twenty

Example 5

14

Example 6

26

Example 7

41

Comparison Example 8

66

Comparison Example 9

62

Comparison Example 10

77

As Table 1 shows, the polycarbonate-containing coatings of Examples 1 to 7 according to the invention give extraordinarily hydrophilic coatings with static contact angles � 45 °. The coatings of Examples 1 to 6 give extraordinarily hydrophilic coatings with static contact angles <30 °. In contrast, PolyTHF-containing coatings of Comparison Examples 7 to 10 are essentially

5 apolar, although the composition of these coatings is otherwise identical to that of Examples 1, 2 and 4.

In addition, the data disclosed in "Evaluation of a poly (vinylpyrrolidone) -coated biomaterial for urological use"; M.M. Tanney, S.P. Gorman, Biomaterials 23 (2002), 4601-4608, show that the contact angle of the polyurethane is approximately 97 ° and the PVP coated polyurethane is approximately 50 °.

10 Example 12: Measurement of coagulation parameters

From the polyurethane dispersion of Example 1, a film was prepared for blood contact studies by coating by centrifugation on glass. The sample surface was deposited in an autoclaved incubation chamber and incubated with 1.95 ml of blood. The exact construction of the experiment is described in U. Streller et al. J. Biomed. Mater. Res B, 2003, 66B, 379-390.

15 The venous blood needed for the experiment was extracted by a 19 G cannula from a male donor who had not taken any medication for at least 10 days. Coagulation was prevented by the addition of heparin (2 IU / ml). The blood thus prepared was then charged into the incubation chamber equipped with the previously thermally conditioned polyurethane surface at 37 ° C and incubated 2 h with permanent rotation of the chamber at 37 ° C. Glass and polytetrafluoroethylene (PTFE) were used as comparison materials. The glass is

20 a strongly activating surface for blood coagulation, while PTFE is a polymer that is an acceptable material for many applications (see U. Streller et al. J. Biomed. Mater. Res B, 2003, 66B, 379390) .

After incubation, three parameters were measured:

Thrombin-antithrombin complex (Enzygnost TAT micro, Dade Behring GmbH, Marburg, Germany)

25 Platelet factor 4 (complete PF 4 kit for ELISA from Haemochrom Diagnostica GmbH, Essen, Germany)

Thrombocyte reduction was measured in anticoagulated blood with EDTA by an automatic cell counting system (AcTdiff of Coulter, Krefeld, Germany).

Table 2: Thrombin-antithrombin complex

Surface

Thrombin-antithrombin complex (µg / ml)

Polyurethane of Example 1

27.7

PTFE

33.4

Table 3: Platelet Factor 4

Surface

Thrombin-antithrombin complex (IU / ml)

Polyurethane of Example 1

29.7

Glass

377.2

PTFE

59.2

Table 4: Reduction of blood thrombocytes

Surface

Number of thrombocytes (% reduction)

Polyurethane of Example 1

-0.3

Glass

17.9

PTFE

5.7

The three blood parameters measured show that the hydrophilic polyurethane of Example 1 activates coagulation only in a very moderate way. The thrombin-antithrombin complex as a measure for the activation of the intrinsic coagulation cascade shows that the polyurethane itself generates lower values compared to the PTFE considered as very compatible with blood and in this way an even lower activation is caused.

Platelet factor 4 is a marker of thrombocyte activation. This cellular part of the coagulation is also only activated to a small degree by hydrophilic polyurethane. PTFE very compatible with blood causes greater activation. Thrombocyte reduction is also evident for glass and also PTFE, which means that a part of the thrombocytes is fixed by addition to these surfaces. In contrast, no reduction can be seen in the hydrophilic polyurethane of Example 1.

Example 13:

This example describes the synthesis of an aqueous dispersion with terminal poly (ethylene oxide) structural units as a comparison material with the examples according to the invention in which a polyurethane is used which is terminated by a copolymer of poly (ethylene oxide) and poly (propylene oxide). The LB 25 polyether used in the sense of the present invention is exchanged in this example for the same molar amounts of a comparable pure poly (ethylene oxide) ether.

277.2 g of Desmophen C 2200, 29.4 g of polyethylene glycol 2000 monomethyl ether (source: Fluka, CAS No. 9004-744) and 6.7 g of neopentyl glycol were placed at 65 ° C and homogenized 5 min by stirring. To this mixture, 71.3 g of 4,4'-bis (isocyanathenocyclohexyl) methane (H12MDI) were added at 65 ° C over the course of 1 min and then 11.9 g of isophorondiisocyanate. It was heated to 110 ° C. After 35 min the theoretical NCO value was reached. The prepared prepolymer was dissolved at 50 ° C in 711 g of acetone and then a solution of 4.8 g of ethylenediamine in 16 g of water was dosed at 40 ° C over the course of 10 min. The stirring time was 5 min. It was then dispersed over the course of 15 min by adding 590 g of water. Solvent removal was followed by vacuum distillation. A stable polyurethane dispersion was obtained during storage with a solids content of 40.0% and an average particle size of 130 nm.

As described in Example 11, a glass coating was prepared by centrifugal coating and the static contact angle of this coating was determined. A static contact angle of 45 ° was obtained. Comparison of this value with the value for the coating of Example 1 (<10 °, see Table 1 in Example 11) shows that the use of the poly (ethylene oxide) -polis (propylene oxide) LB 25 mixed monol compared to pure poly (ethylene oxide) monol, it makes possible clearly lower contact angles and, therefore, more hydrophilic coatings.

Example 14:

This example describes the synthesis of the polyurethaneurea polymer of Example 1 according to the invention as an example of comparison in organic solution.

To a mixture of 277.2 g of Desmophen C 2200, 33.1 g of LB 25, 6.7 g of neopentyl glycol are added at 60 ° C 71.3 g of 4,4'-bis (isocyanatyclohexyl) methane (H12MDI) and 11.9 g of isophorondiisocyanate. The mixture was heated to 110 ° C and reacted to a constant NCO content of 2.4. It was allowed to cool and diluted with 475 g of toluene and 320 g of isopropanol. At room temperature, a solution of 4.8 g of ethylenediamine in 150 g of 1-methoxypropan-2-ol was added. After completion of the addition, it was stirred 2 h. 1350 g of a 30.2% polyurethane solution in toluene / isopropanol / 1-methoxypropan-2-ol with a viscosity of 607 mPas at 23 ° C were obtained.

As described in Example 11, a glass coating was prepared by centrifugal coating and the static contact angle of this coating was determined. A static contact angle of 27 ° was determined. Comparison of this value with the value for the coating of Example 1 (<10 °, see Table 1 in Example 11), a structurally equal coating, but dispersed in water, shows that

Aqueous dispersion coatings give more hydrophilic coatings compared to coatings that are obtained from corresponding solutions.

Claims (9)

1.- Medical device with at least one coating containing at least one polyurethaneurea, characterized in that the polyurethaneurea is finished with a copolymer unit of poly (ethylene oxide) and poly (propylene oxide). 2. Medical device according to claim 1, characterized in that the polyurethaneurea has units having their origin in at least one polycarbonate containing hydroxyl groups. 3. Medical device according to claim 1 or 2, characterized in that the polyurethaneurea has units that have their origin in at least one aliphatic, cycloaliphatic or aromatic isocyanate. 4. Medical device according to one of claims 1 to 3, characterized in that the polyurethaneurea has units that have their origin in at least one diamine or amino alcohol. Medical device according to one of claims 1 to 4, characterized in that the coating has a polyurethaneurea that is synthesized from a) at least one polyolcarbonate with an average molar weight between 400 g / mol and 6000 g / mol and a hydroxyl functionality of 1.7 to 2.3, or from mixtures of polyol carbonates of this type; b) at least one aliphatic, cycloaliphatic or aromatic polyisocyanate or mixtures of polyisocyanates of this type in an amount per mole of the polyol carbonate of 1.0 to 4.0 moles; c) at least one monofunctional mixed polyoxyalkylene ether of poly (ethylene oxide) and poly (propylene oxide) or a mixture of polyethers of this type with an average molar weight between 500 g / mol and 5000 g / mol in an amount per mol of the polyol carbonate of 0.01 to 0.5 mol; d) at least one aliphatic or cycloaliphatic diamine or at least one amino alcohol, such as so-called chain extenders, or mixtures of compounds of this type in an amount per mole of the polyol carbonate of 0.05 to 3.0 moles; e) if necessary one or more aliphatic short chain polyols with a molar weight between 62 g / mol and 500 g / mol in an amount per mol of the polyol carbonate of 0.1 to 1.0 mol; Y f) if necessary structural units containing amine or OH that are at the ends of 25 polymer chains and terminate these. 6. Process for the manufacture of a medical device with at least one coating, the coating can be obtained from a dispersion containing at least one polyurethaneurea according to the definition in one of claims 1 to 5. 7. Method according to claim 6, characterized in that the coating from a dispersion of polyurethaneurea is applied to the medical device by application with scraper, printing, transfer coating, spraying, centrifugation or immersion coating. 8. Medical device that can be obtained according to claim 6 or 7. 9. Medical device according to one of claims 1 to 5 or 8 in the form of contact lenses; cannulas; catheters, especially urological catheters such as urinary catheters or ureteral catheters; central venous catheters; venous catheters or input or output catheters; dilatation balloons; catheters for angioplasty and biopsy; catheters used to insert an endovascular prosthesis, an embolism filter or a filter in the vena cava; balloon catheters or other expandable medical devices; endoscopes; laryngoscopes; tracheal devices such as endotracheal tubes; tracheal aspiration respirators and apparatus; bronchoalveolar lavage catheters; catheters used in coronary angioplasty; guide rods and insertion guides; vascular caps 40; pacemaker components; cochlear implants; dental implant tubes for feeding; drainage pipes; guide wires; gloves; endovascular prostheses and other implants; tubes for extracorporeal blood; membranes, such as dialysis cells; blood filters; apparatus for strengthening circulation; bandage materials for wound care; urine bags; stoma collection bags; implants containing a medically effective agent such as medically effective agents for endovascular prostheses or for 45 balloon or contraceptive surfaces; endoscopes, laryngoscopes and feeding probes. 10. A medical device according to claim 9 in the form of a radioactive endovascular prosthesis, a drug-coated endovascular prosthesis, a bioresorbable endovascular prosthesis and an endovascular healing prosthesis ("healing").