Patent Application
20110021696
The present invention relates to a coating composition in the form of a polyurethane dispersion that can be used for producing hydrophilic coatings. Further subject matter of the present invention is a process for preparing such a coating composition, and the use of the coating composition, more particularly for the coating of medical devices.
The utilization of medical devices, such as of catheters, can be improved greatly through the equipping thereof with hydrophilic surfaces. The insertion and displacement of urinary or blood vessel catheters is made easier by the fact that hydrophilic surfaces in contact with blood or urine adsorb a water film. This reduces the friction between the catheter surface and the vessel walls, so making the catheter easier to insert and move. Direct watering of the devices prior to the intervention can also be carried out, in order to reduce the friction through the formation of a homogeneous water film. The patients concerned have less pain, and the risk of injury to the vessel walls is reduced as a result. Furthermore, when catheters are used in contact with blood, there is always a risk of blood clots forming. In this context, hydrophilic coatings are considered generally to be useful for antithrombogenic coatings.
Suitability for the production of such surfaces is possessed in principle by polyurethane coatings which are produced starting from solutions or dispersions of corresponding polyurethanes.
Thus U.S. Pat. No. 5,589,563 describes the use of coatings having surface-modified end groups for polymers which are used in the biomedical sector and which can also be used for the coating of medical devices. The resulting coatings are produced on the basis of solutions or dispersions, and the polymeric coatings comprise different end groups, selected from amines, fluorinated alkanols, polydimethylsiloxanes and amine-terminated polyethylene oxides. These polymers, however, do not have satisfactory properties as a coating for medical devices, more particularly in respect of the required hydrophilicity.
DE 199 14 882 A1 relates to polyurethanes, polyurethane-ureas and polyureas in dispersed or dissolved form that are synthesized from
DE 199 14 885 A1 relates to dispersions based on polyurethanes, polyurethane-polyureas or polyureas, which preferably represent reaction products of
These polyurethaneurea dispersions known from the prior art are not used for medical purposes, i.e. for coating medical devices.
Furthermore, the polyurethaneurea coatings known to date frequently have disadvantages in that they are not sufficiently hydrophilic for use as a coating on medical devices.
In this context, U.S. Pat. No. 5,589,563 recommends surface-modified end groups for biomedical polymers which can be used to coat medical devices. These polymers include different end groups, selected from amines, fluorinated alkanols, polydimethylsiloxanes and amine-terminated polyethylene oxides. As a coating for medical devices, however, these polymers likewise lack satisfactory properties, more particularly in respect of the required hydrophilicity.
It is an object of the present invention, therefore, to provide polyurethaneurea dispersions which can be used to equip medical devices with hydrophilic surfaces. Since these surfaces are frequently used in blood contact, the surfaces of these materials ought also to possess good blood compatibility and ought more particularly to reduce the risk of blood clots being formed.
This invention provides polyurethaneurea dispersions which can be used to equip medical devices with hydrophilic surfaces.
The polyurethaneurea dispersions of the invention are characterized in that they comprise
In accordance with the invention it has been found that compositions comprising these specific polyurethaneureas are outstandingly suitable as coatings on medical devices, to which they give an outstanding lubricous coating and at the same time reduce the risk of blood clots forming during treatment with the medical device.
Polyurethaneureas for the purposes of the present invention are polymeric compounds which have
and
at least one repeat unit containing urea groups
The coating compositions for use in accordance with the invention are based on polyurethaneureas which have substantially no ionic modification. By this is meant, in the context of the present invention, that the polyurethaneureas for use in accordance with the invention have essentially no ionic groups, such as, more particularly, no sulphonate, carboxylate, phosphate and phosphonate groups.
The term “essentially no ionic modification” means, in the context of the present invention, that any ionic modification is present at most in a fraction of 2.50% by weight, preferably at most 2.00% by weight, more particularly at most 1.50% by weight, more preferably at most 1.00% by weight, especially at most 0.50% by weight, the most preferred situation being for there to be no ionic modification at all of the inventive polyurethaneurea.
The polyurethaneureas of the invention are preferably substantially linear molecules, but may also be branched, although this is less preferred. By substantially linear molecules are meant systems with a low level of incipient crosslinking, comprising a polycarbonate polyol having an average hydroxyl functionality of preferably 1.7 to 2.3, more particularly 1.8 to 2.2, more preferably 1.9 to 2.1. Systems of this kind can still be dispersed to a sufficient extent.
The number-average molecular weight of the polyurethaneureas used with preference in accordance with the invention is preferably 1000 to 200 000, more preferably from 5000 to 100 000. The number-average molecular weight here is measured against polystyrene as standard in dimethylactamide at 30° C.
The polyurethaneureas of the invention are described in more detail below.
The polyurethaneureas of the invention are prepared by reaction of synthesis components which encompass at least one polycarbonate polyol component, a polyisocyanate component, a polyoxyalkylene ether component, a diamine and/or amino alcohol component and, if desired, a polyol component.
The individual synthesis components are now described in more detail below.
(a) Polycarbonate polyol
The polyurethaneurea of the invention comprises units which originate from at least one hydroxyl-containing polycarbonate (polycarbonate polyol).
Suitable in principle for the introduction of units based on a hydroxyl-containing polycarbonate are polycarbonate polyols, i.e. polyhydroxyl compounds, having an average hydroxyl functionality of 1.7 to 2.3, preferably of 1.8 to 2.2, more preferably of 1.9 to 2.1. The polycarbonate is therefore preferably of substantially linear construction and has only a slight three-dimensional crosslinking.
Suitable hydroxyl-containing polycarbonates are polycarbonates of a molecular weight (molecular weight determined via the OH number; DIN 53240) of preferably 400 to 6000 g/mol, more preferably 500 to 5000 g/mol, more particularly of 600 to 3000 g/mol, which are obtainable, for example, through reaction of carbonic acid derivatives, such as diphenyl carbonate, dimethyl carbonate or phosgene, with polyols, preferably diols. Examples of suitable such diols include 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, and also lactone-modified diols.
The diol component preferably contains 40% to 100% by weight of hexanediol, preferably 1,6-hexanediol and/or hexanediol derivatives, preferably those which as well as terminal OH groups contain ether or ester groups, examples being products obtained by reaction of 1 mol of hexanediol with at least 1 mol, preferably 1 to 2 mol, of caprolactone or through etherification of hexanediol with itself to give the di- or trihexylene glycol. Polyether-polycarbonate diols as well can be used. The hydroxyl polycarbonates ought to be substantially linear. If desired, however, they may be slightly branched as a result of the incorporation of polyfunctional components, more particularly low molecular weight polyols. Examples of those suitable for this purpose include glycerol, trimethylolpropane, hexane-1,2,6-triol, butane-1,2,4-triol, trimethylolpropane, pentaerythritol, quinitol, mannitol, sorbitol, methylglycoside or 1,3,4,6-dianhydrohexitols. Preferred polycarbonates are those based on hexane-1,6-diol, and also on co-diols with a modifying action such as butane-1,4-diol, for example, or else on ε-caprolactone. Further preferred polycarbonate diols are those based on mixtures of hexane-1,6-diol and butane-1,4-diol.
The polyurethaneurea of the invention additionally has units which originate from at least one polyisocyanate.
As polyisocyanates (b) it is possible to use all of the aromatic, araliphatic, aliphatic and cycloaliphatic isocyanates that are known to the skilled person and have an average NCO functionality ≧1, preferably ≧2, individually or in any desired mixtures with one another, irrespective of whether they have been prepared by phosgene or phosgene-free processes. They may also contain iminooxadiazinedione, isocyanurate, uretdione, urethane, allophanate, biuret, urea, oxadiazinetrione, oxazolidinone, acylurea and/or carbodiimide structures. The polyisocyanates may be used individually or in any desired mixtures with one another.
Preference is given to using isocyanates from the series of the aliphatic or cycloaliphatic representatives, which have a carbon backbone (without the NCO groups present) of 3 to 30, preferably 4 to 20, carbon atoms.
Particularly preferred compounds of component (b) conform to the type specified above having aliphatically and/or cycloaliphatically attached NCO groups, such as, for example, bis(isocyanatoalkyl)ethers, bis- and tris(isocyanatoalkyl)benzenes, -toluenes, and -xylenes, propane diisoscyanates, butane diisocyanates, pentane diisocyanates, hexane diisocyanates (e.g. hexamethylene diisocyanate, HDI), heptane diisocyanates, octane diisocyanates, nonane diisocyanates (e.g. trimethyl-HDI (TMDI), generally as a mixture of the 2,4,4 and 2,2,4 isomers), nonane triisocyanates (e.g. 4-isocyanatomethyl-1,8-octane diisocyanate), decane diisocyanates, decane triisocyanates, undecane diisocyanates, undecane triisocyanates, dodecane diisocyanates, dodecane triisocyanates, 1,3- and 1,4-bis(isocyanatomethyl)cyclohexanes (H6XDI), 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (isophorone diisocyanate, IPDI), bis(4-isocyanatocyclohexyl)methane (H12MDI) or bis(isocyanatomethyl)norbornane (NBDI).
Very particularly preferred compounds of component (b) are hexamethylene diisocyanate (HDI), trimethyl-HDI (TMDI), 2-methylpentane 1,5-diisocyanate (MPDI), isophorone diisocyanate (IPDI), 1,3- and 1,4-bis(isocyanatomethyl)cyclohexane (H6XDI), bis(isocyanato-methyl)norbornane (NBDI), 3(4)-isocyanatomethyl-1-methylcyclohexyl isocyanate (IMCI) and/or 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) or mixtures of these isocyanates. Further examples are derivatives of the above diisocyanates with a uretdione, isocyanurate, urethane, allophanate, biuret, iminooxadiazinedione and/or oxadiazinetrione structure and with more than two NCO groups.
The amount of constituent (b) in the coating composition for use in accordance with the invention is preferably 1.0 to 4.0 mol, more preferably 1.2 to 3.8 mol, more particularly 1.5 to 3.5 mol, based in each case on the constituent (a) of the coating composition for use in accordance with the invention.
(c) Polyoxyalkylene ethers
The polyurethaneurea of the invention has units which originate from a copolymer comprising polyethylene oxide and polypropylene oxide. These copolymer units are present in the form of end groups in the poyurethaneurea.
Nonionically hydrophilicizing compounds (c) are, for example, monofunctional polyalkylene oxide polyether alcohols containing an average 5 to 70, preferably 7 to 55, ethylene oxide units per molecule, of the kind available in conventional manner through alkoxylation of suitable starter molecules (e.g. in Ullmanns Enzyklopädie der technischen Chemie, 4th Edition, Volume 19, Verlag Chemie, Weinheim pp. 31-38).
Examples of suitable starter molecules are saturated monoalcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, the isomeric pentanols, hexanols, octanols and nonanols, n-decanol, n-dodecanol, n-tetradecanol, n-hexadecanol, n-octadecanol, cyclohexanol, the isomeric methylcyclohexanols or hydroxymethylcyclohexane, 3-ethyl-3-hydroxymethyloxetane or tetrahydrofurfuryl alcohol, diethylene glycol monoalkyl ethers, such as diethylene glycol monobutyl ether, for example, unsaturated alcohols such as allyl alcohol, 1,1-dimethylallyl alcohol or oleyl alcohol, aromatic alcohols such as phenol, the isomeric cresols or methoxyphenols, araliphatic alcohols such as benzyl alcohol, anisyl alcohol or cinnamyl alcohol, secondary monoamines such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, bis(2-ethylhexyl)amine, N-methyl- and N-ethylcyclohexylamine or dicyclohexylamine, and also heterocyclic secondary amines such as morpholine, pyrrolidine, piperidine or 1H-pyrazole. Preferred starter molecules are saturated monoalcohols. Particular preference is given to using diethylene glycol monobutyl ether as a starter molecule.
The alkylene oxides, ethylene oxide and propylene oxide, can be used in any order or else in a mixture in the alkoxylation reaction.
Polyalkylene oxide polyether alcohols are mixed polyalkylene oxide polyethers of ethylene oxide and propylene oxide, whose alkylene oxide units are composed preferably to an extent of at least 30 mol %, more preferably at least 40 mol %, of ethylene oxide units. Preferred non-ionic compounds are monofunctional mixed polyalkylene oxide polyethers which contain at least 40 mol % of ethylene oxide units and not more than 60 mol % of propylene oxide units.
The average molar weight of the polyoxyalkylene ether is preferably 500 g/mol to 5000 g/mol, more preferably 1000 g/mol to 4000 g/mol, more preferably 1000 to 3000 g/mol.
The amount of constituent (c) in the coating composition for use in accordance with the invention is preferably 0.01 to 0.5 mol, more preferably 0.02 to 0.4 mol, more particularly 0.04 to 0.3 mol, based in each case on constituent (a) of the coating composition for use in accordance with the invention.
In accordance with the invention it has been possible to show that the polyurethaneureas with end groups based on mixed polyoxyalkylene ethers comprising polyethylene oxide and polypropylene oxide are especially suitable for producing coatings having a high hydrophilicity. As will be shown later on below, in comparison to polyurethaneureas terminated only by polyethylene oxide, the coatings of the invention effect a significantly low contact angle and are therefore more hydrophilic in form.
(d) Diamine or amino Alcohol
The polyurethaneurea of the invention includes units which originate from at least one diamine or amino alcohol.
The polyurethane coatings of the invention are produced using what are called chain extenders (d). Such chain extenders are diamines or polyamines and also hydrazides, e.g. hydrazine, 1,2-ethylenediamine, 1,2- and 1,3-diaminopropane, 1,4-diaminobutane, 1,6-diaminohexane, isophoronediamine, isomer mixture of 2,2,4- and 2,4,4-trimethylhexame-thylenediamine, 2-methylpentamethylenediamine, diethylenetriamine, 1,3- and 1,4-xylylene-diamine, α,α,α′,α′-tetramethyl-1,3- and -1,4-xylylenediamine and 4,4-diamino-dicyclohexylmethane, dimethylethylenediamine, hydrazine, adipic dihydrazide, 1,4-bis(aminomethyl)cyclohexane, 4,4′-diamino-3,3′-dimethyldicyclohexylmethane and other (C1-C4) di- and tetraalkyldicyclohexylmethanes, e.g. 4,4′-diamino-3,5-diethyl-3′,5′-diisopropyldicy-clohexylmethane.
Suitable diamines or amino alcohols are generally low molecular weight diamines or amino alcohols which contain active hydrogen with differing reactivity towards NCO groups, such as compounds which as well as a primary amino group also contain secondary amino groups or which as well as amino group (primary or secondary) also contain OH groups. Examples of such compounds are primary and secondary amines, such as 3-amino-1-methylaminopropane, 3-amino-1-ethylaminopropane, 3-amino-1-cyclohexylaminopropane, 3-amino-1-methylaminobutane, and also amino alcohols, such as N-aminoethylethanolamine, ethanolamine, 3-aminopropanol, neopentanolamine and, with particular preference, diethanolamine.
The constituent (d) of the coating composition for use in accordance with the invention can be used, in the context of the preparation of the composition, as a chain extender and/or as a form of chain termination.
The amount of constituent (d) in the coating composition for use in accordance with the invention is preferably 0.05 to 3.0 mol, more preferably 0.1 to 2.0 mol, more particularly 0.2 to 1.5 mol, based in each case on constituent (a) of the coating composition for use in accordance with the invention.
In a further embodiment the polyurethaneurea of the invention further comprises units which originate from at least one further polyol.
The further low molecular weight polyols (e) used to synthesize the polyurethaneureas have the effect, generally, of stiffening and/or branching the polymer chain. The molecular weight is preferably 62 to 500 g/mol, more preferably 62 to 400 g/mol, more particularly 62 to 200 g/mol.
Suitable polyols may contain aliphatic, alicyclic or aromatic groups. Mention may be made here, for example, of the low molecular weight polyols having 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-cyclo-hexanedimethanol, 1,6-hexanediol, neopentyl glycol, hydroquinone dihydroxyethyl ether, bisphenol A (2,2-bis(4-hydroxyphenyl)propane), hydrated bisphenol A (2,2-bis(4-hydroxy-cyclohexyl)propane), and also trimethylolpropane, glycerol or pentaerythritol, and mixtures of these and, if desired, other low molecular weight polyols as well. Use may also be made of ester diols such as, for example, α-hydroxybutyl-ε-hydroxycaproic acid ester, ω-hydroxyhexyl-γ-hydroxybutyric acid ester, adipic acid (β-hydroxyethyl) ester or terephthalic acid bis(β-hydroxyethyl)ester.
The amount of constituent (e) in the coating composition for use in accordance with the invention is preferably 0.1 to 1.0 mol, more preferably 0.2 to 0.9 mol, more particularly 0.2 to 0.8 mol, based in each case on constituent (a) of the coating composition for use in accordance with the invention.
(f) Further amine- and/or hydroxy-Containing Units (Synthesis Component)
The reaction of the isocyanate-containing component (b) with the hydroxy- or amine-functional compounds (a), (c), (d) and, if used, (e) takes place typically with a slight NCO excess being observed over the reactive hydroxy or amine compounds. As a result of dispersion in water, residues of isocyanate groups are hydrolysed to amine groups. In the specific case, however, it may be important to block the remaining residue of isocyanate groups before the polyurethane is dispersed.
The polyurethaneurea coatings provided in accordance with the invention may therefore also comprise synthesis components (f), which are located in each case at the chain ends and cap them. These units derive on the one hand from monofunctional compounds that are reactive with NCO groups, such as monoamines, more particularly mono-secondary amines, or monoalcohols.
Mention may be made here, for example, of ethanol, n-butanol, ethylene glycol monobutyl ether, 2-ethylhexanol, 1-octanol, 1-dodecanol, 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 units (f) are used essentially in the coatings of the invention to destroy the NCO excess, the amount required is dependant essentially on the amount of the NCO excess, and cannot be specified generally.
In one preferred embodiment of the present invention no component (f) is used, and so the polyurethaneurea of the invention comprises only the constituents (a) to (d) and, if desired, component (e). It is further preferred if the polyurethaneurea of the invention is composed of constituents (a) to (d) and, if desired, of component (e), in other words not comprising any further synthesis components.
Furthermore, the polyurethaneurea of the invention may comprise further constituents typical for the intended purpose, such as additives and fillers. An example of such are active pharmacological substances, and additives which promote the release of active pharmacological substances (drug-eluting additives), and also medicaments.
Medicaments which may be used in the coatings of the invention on the medical devices are in general, for example, thromboresistant agents, antibiotic agents, antitumour agents, growth hormones, antiviral agents, antiangiogenic agents, angiogenic agents, antimitotic agents, anti-inflammatory agents, cell cycle regulators, genetic agents, hormones, and also their homologues, derivatives, fragments, pharmaceutical salts, and combinations thereof.
Specific examples of such medicaments hence include thromboresistant (non-thrombogenic) agents and other agents for suppressing acute thrombosis, stenosis or late restenosis of the arteries, examples being heparin, streptokinase, urokinase, tissue plasminogen activator, anti-thromboxan-B2 agent; anti-B-thromboglobulin, prostaglandin-E, aspirin, dipyridimol, anti-thromboxan-A2 agent, murine monoclonal antibody 7E3, triazolopyrimidine, ciprostene, hirudin, ticlopidine, nicorandil, etc. A growth factor can likewise be utilized as a medicament in order to suppress subintimal fibromuscular hyperplasia at the arterial stenosis site, or any other cell growth inhibitor can be utilized at the stenosis site.
The medicament may also be composed of a vasodilatator, in order to counteract vasospasm—for example, an antispasm agent such as papaverine. The medicament may be a vasoactive agent per se, such as calcium antagonists, or α- and β-adrenergic agonists or antagonists. In addition the therapeutic agent may be a biological adhesive such as cyanoacrylate in medical grade, or fibrin, which is used, for example, for bonding a tissue valve to the wall of a coronary artery.
The therapeutic agent may further be an antineoplastic agent such as 5-fluorouracil, preferably with a controlling releasing vehicle for the agent (for example, for the use of an ongoing controlled releasing antineoplastic agent at a tumour site).
The therapeutic agent may be an antibiotic, preferably in combination with a controlling releasing vehicle for the ongoing release from the coating of a medical device at a localized focus of infection within the body. Similarly, the therapeutic agent may comprise steroids for the purpose of suppressing inflammation in localized tissue, or for other reasons.
Specific examples of suitable medicaments include:
In one preferred embodiment the coating composition provided in accordance with the invention comprises a polyurethaneurea which is synthesized from
In a further embodiment of the present invention the coating composition provided in accordance with the invention comprises a polyurethaneurea which is synthesized from
In a further embodiment of the present invention the coating composition provided in accordance with the invention comprises a polyurethaneurea which is synthesized from
As already mentioned, in one especially preferred embodiment of the present invention, the polyurethaneurea of the invention is composed only of constituents (a) to (d) and, if desired, (e).
Preference is also given in accordance with the invention to polyurethaneureas which are synthesized from
Preference is further given in accordance with the invention to polyurethaneureas which are synthesized from
Preference is also further given in accordance with the invention to polyurethaneureas which are synthesized from
The coating composition is applied to a medical device.
The coating composition of the invention in the form of a dispersion can be used to form a coating on a medical device.
The term “medical device” is to be understood broadly in the context of the present invention. Suitable, non-limiting examples of medical devices (including instruments) are contact lenses; cannulas; catheters, for example urology catheters such as urinary catheters or ureteral catheters; central venous catheters; venous catheters or inlet or outlet catheters; dilation balloons; catheters for angioplasty and biopsy; catheters used for introducing a stent, an embolism filter or a vena caval filter; balloon catheters or other expandable medical devices; endoscopes; laryngoscopes; tracheal devices such as endotracheal tubes, respirators and other tracheal aspiration devices; 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.
The coating solutions of the invention may be used, furthermore, for producing protective coatings, for example for gloves, stents and other implants; external (extracorporeal) blood lines (blood-carrying pipes); membranes, for example for dialysis; blood filters; devices for circulatory support; dressing material for wound management; urine bags and stoma bags. Also included are implants which comprise a medically active agent, such as medically active agents for stents or for balloon surfaces or for contraceptives.
Typically the medical device is formed from catheters, endoscopes, laryngoscopes, endotracheal tubes, feeding tubes, guide rods, stents, and other implants.
There are many materials suitable as a substrate of the surface to be coated, such as metals, textiles, ceramics or plastics, the use of plastics being preferred for the production of medical devices.
In accordance with the invention it has been found that it is possible to produce medical devices having very hydrophilic and hence lubricous, blood-compatible surfaces by using aqueous, nonionically stabilized polyurethane dispersions of the type described above to coat the medical devices. The coating compositions described above are obtained preferably as aqueous dispersions and are applied to the surface of the medical devices.
The constituents of the coatings, described in more detail above, are generally reacted such that first of all an isocyanate-functional prepolymer free of urea groups is prepared by reaction of the constituents (a), (b), (c) and, if desired, (e), the amount-of-substance ratio of isocyanate groups to isocyanate-reactive groups of the polycarbonate polyol being preferably 0.8 to 4.0, more preferably 0.9 to 3.8, more particularly 1.0 to 3.5.
In an alternative embodiment it is also possible first to react the constituent (a) separately with the isocyanate (b). Then, after that, constituents (c) and (e) can be added and reacted. Subsequently, in general, the remaining isocyanate groups are given an amino-functional 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 to free isocyanate groups of the prepolymer being preferably between 40% to 150%, more preferably between 50% to 120%, more particularly between 60% to 120% (constituent d)).
The polyurethane dispersions of the invention are prepared preferably by the process known as the acetone process. For the preparation of the polyurethane dispersion by this acetone process, some or all of the constituents (a), (c) and (e), which must not contain any primary or secondary amino groups, and the polyisocyanate component (b) are typically introduced, for the preparation of an isocyanate-functional polyurethane prepolymer, and where appropriate are diluted with a water-miscible solvent which is nevertheless inert towards isocyanate groups, and the batch is heated to temperatures in the range from 50 to 120° C. To accelerate the isocyanate addition reaction it is possible to use the catalysts known in polyurethane chemistry, an example being dibutyltin dilaurate. Preference is given to synthesis without catalyst.
Suitable solvents are the typical aliphatic, keto-functional solvents such as, for example, acetone, butanone, which can be added not only at the beginning of the preparation but also, if desired, in portions later on as well. Acetone and butanone are preferred. Other solvents such as xylene, toluene, cyclohexane, butyl acetate, methoxypropyl acetate and solvents with ether units or ester units, for example, may likewise be used and may be removed in whole or in part by distillation or may remain entirely in the dispersion.
Subsequently any constituents of (c) and (e) not added at the beginning of the reaction are metered in.
In a preferred way, the prepolymer is prepared without addition of solvent and only for its chain extension is diluted with a suitable solvent, preferably acetone.
In the preparation of the polyurethane prepolymer, the amount-of-substance ratio of isocyanate groups to isocyanate-reactive groups is preferably 0.8 to 4.0, more preferably 0.9 to 3.8, more particularly 1.0 to 3.5.
The reaction to give the prepolymer takes place partially or completely, but preferably completely. In this way, polyurethane prepolymers which contain free isocyanate groups are obtained, in bulk or in solution.
Subsequently, in a further process step, if it has not yet taken place or has taken place only partly, the resulting prepolymer is dissolved by means of aliphatic ketones such as acetone or butanone.
Subsequently, possible NH2—, NH-functional and/or OH-functional components are reacted with the remaining isocyanate groups. This chain extension/termination may be carried out alternatively in solvent prior to dispersing, during dispersing, or in water after dispersion has taken place. Preference is given to carrying out the chain extension prior to dispersing in water.
Where compounds conforming to the definition of (d) with NH2 or NH groups are used for chain extension, the chain extension of the prepolymers takes place preferably prior to the dispersing.
The degree of chain extension, in other words the ratio of equivalents of NCO-reactive groups of the compounds used for chain extension to free NCO groups of the prepolymer, is preferably between 40% to 150%, more preferably between 50% to 120%, more particularly between 60% to 120%.
The aminic components (d) may if desired be used in water-diluted or solvent-diluted form in the process of the invention, individually or in mixtures, in which case any sequence of addition is possible in principle.
If water or organic solvents are used as diluents, the diluent content is preferably 70% to 95% by weight.
The preparation of the polyurethane dispersion from the prepolymers takes place following the chain extension. For this purpose, either the dissolved and chain-extended polyurethane polymer is introduced into the dispersing water, where appropriate with strong shearing, such as vigorous stirring, for example, or, conversely, the dispersing water is stirred into the prepolymer solutions. Preferably the water is added to the dissolved prepolymer.
The solvent still present in the dispersions after the dispersing step is typically then removed by distillation. Its removal during the actual dispersing is likewise a possibility.
The solids content of the polyurethane dispersion after the synthesis is between 20% to 70% by weight, preferably 20% to 65% by weight. For coating experiments these dispersions can be diluted arbitrarily with water, in order to allow the thickness of the coating to be varied. All concentrations from 1% to 60% by weight are possible; preference is given to concentrations in the 1% to 40% by weight range.
In this context it is possible to attain any desired coat thicknesses, such as, for example, from a few 100 nm up to several 100 μm, although higher and lower thicknesses are possible in the context of the present invention.
The polyurethane materials for the coating of the medical devices can be diluted to any desired value by dilution of the aqueous dispersions of the invention with water. Furthermore, it is possible to add thickeners, in order, where appropriate, to allow the viscosity of the polyurethane dispersions to be increased. Further additions, such as antioxidants, buffer materials for adjusting the pH, or pigments, for example, are likewise possible. It is also possible if desired, furthermore, to use further additions such as hand assistants, dyes, matting agents, UV stabilizers, light stabilizers, hydrophobicizing agents, hydrophilicizing agents and/or flow control assistants.
Starting from these dispersions, then, medical coatings are produced by the processes described above.
In accordance with the invention it has emerged that the resulting coatings on medical devices differ according to whether the coating is produced starting from a dispersion or from a solution.
The coatings of the invention on medical devices have advantages when they are obtained starting from dispersions of the above-described coating compositions, since dispersions of the coating systems of the invention lead to coatings on the medical devices that do not contain organic solvent residues, and therefore are generally unobjectionable from a toxicity standpoint, and at the same time lead to a more pronounced hydrophilicity, which is evident, for example, from a small contact angle. Reference is made on this point to the experiments, and comparative experiments, that are elucidated later on below.
The medical devices can be coated with the hydrophilic polyurethane dispersions of the invention by means of a variety of methods. Examples of suitable coating techniques for this purpose include knifecoating, printing, transfer coating, spraying, spin coating or dipping.
The aqueous polyurethane dispersions which are used as starting material for producing the coatings can be prepared by any desired processes, although the above-described acetone process is preferred.
A wide variety of substrates can be coated in this context, such as metals, textiles, ceramics and plastics. Preference is given to coating medical devices manufactured from metals or from plastic. Examples of metals include the following: medical stainless steel or nickel titanium alloys. Many polymer materials are conceivable from which the medical device may be constructed, examples being polyamide; polystyrene; polycarbonate; polyethers; polyesters; polyvinyl 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; polyvinyl chloride (PVC) and polyurethanes. For better adhesion of the hydrophilic polyurethanes to the medical device, further suitable coatings may be applied as a base before these hydrophilic coating materials are applied.
In addition to the hydrophilic properties of the improvement of slip, the coating compositions provided in accordance with the invention are also distinguished by a high level of blood compatibility. As a result, working with these coatings is also advantageous, particularly in blood contact. In comparison to polymers of the prior art, the materials exhibit reduced coagulation tendency in blood contact.
The advantages of the catheters of the invention with the hydrophilic polyurethane coatings are set out by means of comparative experiments in the following examples.
The NCO content of the resins described in the inventive and comparative examples was determined by titration in accordance with DIN EN ISO 11909.
The solids contents were determined in accordance with DIN-EN ISO 3251.1 g of polyurethane dispersion was dried at 115° C. to constant weight (15-20 min) using an infrared dryer.
The average particle sizes of the polyurethane dispersions are measured using the High Performance Particle Sizer (HPPS 3.3) from Malvern Instruments.
Unless noted otherwise, amounts indicated in % are % by weight and relate to the aqueous dispersion obtained.
This example describes the preparation of an inventive polyurethaneurea dispersion 277.2 g of Desmophen C 2200, 33.1 g of Polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 110° C. After 3 h 40 min the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 15 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 41.5% and an average particle size of 164 nm.
This example describes the preparation of an inventive polyurethaneurea dispersion 269.8 g of Desmophen C 2200, 49.7 g of Polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 100° C. After 21.5 h the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 5 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 41.3% and an average particle size of 109 nm.
This example describes the preparation of an inventive polyurethaneurea dispersion 277.2 g of Desmophen C1200, 33.1 g of Polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 110° C. After 2.5 h the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 5 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 40.4% and an average particle size of 146 nm.
This example describes the preparation of an inventive polyurethaneurea dispersion 282.1 g of Desmophen C 2200, 22.0 g of Polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 110° C. After 21.5 h the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 5 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 41.7% and an average particle size of 207 nm.
This example describes the preparation of an inventive polyurethaneurea dispersion 269.8 g of Desmophen XP 2613, 49.7 g of Polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 110° C. After 70 min the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 5 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 41.2% and an average particle size of 112 nm.
This example describes the preparation of an inventive polyurethaneurea dispersion 249.4 g of Desmophen C 2200, 33.1 g of Polyether LB 25, 1.9 g of trimethylolpropane and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 110° C. After 4 h 20 min the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 720 g of acetone and then at 40° C. a solution of 3.3 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 15 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 38.9% and an average particle size of 144 nm.
282.1 g of Desmophen XP 2613, 22.0 g of Polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 110° C. After 70 min the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 5 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 38.3% and an average particle size of 215 nm.
This example describes the preparation of a polyurethaneurea dispersion as a comparison product to the inventive Example 1. The Desmophen C2200 is replaced by PolyTHF 2000.
277.2 g of PolyTHF 2000, 33.1 g of Polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 110° C. After 18 h the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 5 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 40.7% and an average particle size of 166 nm.
This example describes the preparation of a polyurethaneurea dispersion as a comparison product to the inventive Example 2. The Desmophen C2200 is replaced by the PolyTHF 2000.
269.8 g of PolyTHF 2000, 49.7 g of Polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 100° C. After 17.5 h the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 5 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 41.6% and an average particle size of 107 nm.
This example describes the preparation of a polyurethaneurea dispersion as a comparison product to the inventive Example 4. The Desmophen C2200 is replaced by the PolyTHF 2000.
282.1 g of PolyTHF 2000, 22.0 g of Polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 110° C. After 21.5 h the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 5 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 37.5% and an average particle size of 195 nm.
The coatings for the measurement of the static contact angle were produced on glass slides measuring 25×75 mm using a spin coater (RC5 Gyrset 5, Karl Süss, Garching, Germany). For this purpose a slide was clamped onto the sample plate of the spincoater and covered homogeneously with about 2.5-3 g of aqueous undiluted polyurethane dispersion. Rotation of the sample plate at 1300 revolutions per minute for 20 sec gave a homogeneous coating, which was dried at 100° C. for 15 min and then at 50° C. for 24 h. The coated slides obtained were subjected directly to a contact angle measurement.
A static contact angle measurement is performed on the resulting coatings on the slides. Using the video contact angle measuring instrument OCA20 from Dataphysics, with computer-controlled injection, 10 drops of Millipore water are placed on the specimen, and their static wetting angle is measured. Beforehand, using an antistatic dryer, the static charge (if present) on the sample surface is removed.
As Table 1 shows, the polycarbonate-containing coatings of Inventive Examples 1 to 7 give extremely hydrophilic coatings with static contact angles s 45°. The coatings of Examples 1 to 6 produce extraordinarily hydrophilic coatings with static contact angles <30°. In contrast, the PoIyTHF-containing coatings from Comparative Examples 7 to 10 are substantially less polar, despite the fact that the composition of these coatings is otherwise identical with those of Examples 1, 2 and 4.
Furthermore, data disclosed in “Evaluation of a poly(vinylpyrollidone)-coated biomaterial for urological use”; M. M. Tanney, S. P. Gorman, Biomaterials 23 (2002), 4601-4608, show that the contact angle of polyurethane is about 97° and that of PVP-coated polyurethane is about 50°.
A film for blood contact studies was produced by spin-coating the polyurethane dispersion of Example 1 onto glass. The sample surface was inserted into an autoclaved incubation chamber and incubated with 1.95 ml of blood. The exact experimental set-up is described in U. Streller et al. J. Biomed. Mater. Res B, 2003, 66B, 379-390.
The venous blood required for the test was withdrawn via a 19 G cannula from a male donor who had not taken any medicaments for at least 10 days. Coagulation was prevented by the addition of heparin (2 IU/ml). The thus-prepared blood was then inserted into the incubation chamber equipped with the polyurethane surface and preheated to 37° C., and was incubated for 2 h with permanent rotation of the chamber at 37° C. Comparison materials used were glass and polytetrafluoroethylene (PTFE). Glass is a strongly activating surface for blood coagulation, while PTFE is a polymer which for many applications is an acceptable material (see U. Streller et al. J. Biomed. Mater. Res B, 2003, 66B, 379-390).
After incubation had taken place, three parameters were measured:
Thrombin-antithrombin complex (Enzygnost TAT micro, Dade Behring GmbH, Marburg, Germany)
Platelet factor 4 (ELISA PF 4 complete kit from Haemochrom Diagnostica GmbH, Essen, Germany)
The thrombocyte reduction was measured in blood containing EDTA anticoagulant by means of an automatic cell counting system (AcTdiff from Coulter, Krefeld, Germany).
All three blood parameters measured show that the hydrophilic polyurethane of Example 1 activates coagulation only to a very moderate extent. The thrombin-antithrombin complex, as a measure of the activation of the intrinsic coagulation cascade, shows that the polyurethane, even in comparison to PTFE, which is regarded as being very highly blood-compatible, produces lower values and, as a result, induces an even lower activation.
Platelet factor 4 is a marker for the activation of the thrombocytes. This cellular part of the coagulation as well is activated only to a small extent by the hydrophilic polyurethane. The highly blood-compatible PTFE induces a higher activation. The reduction in thrombocytes as well is significant for glass and PTFE as well, which means that some of the thrombocytes attach to these surfaces. In the case of the hydrophilic polyurethane of Example 1, in contrast, there is virtually no reduction apparent.
This example describes the synthesis of an aqueous dispersion with terminal polyethylene oxide units as a comparison material to the inventive examples using a polyurethane terminated by a copolymer comprising polyethylene oxide and polypropylene oxide. The Polyether LB 25 used for the purposes of the present invention is replaced in this example by equal molar amounts of a comparable pure polyethylene oxide ether.
277.2 g of Desmophen C 2200, 29.4 g of Polyethylene Glycol 2000 monomethyl ether (source: Fluka, CAS No. 9004-74-4) and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. At 65° C., this mixture was admixed over the course of 1 minute first with 71.3 g of 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) and then with 11.9 g of isophorone diisocyanate. This mixture was heated to 110° C. After 35 min the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylene diamine in 16 g of water was metered in over the course of 10 min. The subsequent stirring time was 5 min. Subsequently, over the course of 15 min, a dispersion was carried out by addition of 590 g of water. After that the solvent was removed by distillation under reduced pressure. This gave a storage-stable polyurethane dispersion having a solids content of 40.0% and an average particle size of 130 nm.
As described under Example 11, a coating on glass was produced by spincoating, and the static contact angle of this coating was ascertained. The result obtained was a static contact angle of 45°. Comparing this figure with the figure for the coating of Example 1 (<10°, see Table 1 in Example 11) shows that the use of the mixed polyethylene oxide polypropylene oxide Monol LB 25 in comparison to the pure polyethylene oxide monool allows significantly lower contact angles and hence more hydrophilic coatings.
This example describes the synthesis of the polyurethaneurea polymer of Inventive Example 1 as a comparative example in organic solution.
A mixture of 277.2 g of Desmophen C 2200, 33.1 g of LB 25, 6.7 g of neopentyl glycol is admixed at 60° C. with 71.3 g of 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) and 11.9 g of isophorone diisocyanate. The mixture was heated to 110° C. and reacted until a constant NCO content of 2.4 was obtained. The mixture 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 over the course. Following complete addition, stirring was continued for 2 h. This gave 1350 g of a 30.2% strength polyurethaneurea solution in toluene/isopropanol/1-methoxypropan-2-ol, having a viscosity of 607 mPas at 23° C.
As described under Example 11, a coating on glass was produced by spincoating, and the static contact angle of this coating was ascertained. The result obtained was a static contact angle of 27°. Comparing this figure with the figure for the coating of Example 1 (<10°, see Table 1 in Example 11), a structurally identical coating but in dispersion in water, shows that the coatings from aqueous dispersion, in comparison to coatings obtained starting from corresponding solutions, produce more hydrophilic coatings.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08153053.7 | Mar 2008 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2009/001898 | 3/16/2009 | WO | 00 | 9/17/2010 |
