Patent Application
20110022005
The present invention relates to medical devices having hydrophilic and blood-compatible coatings comprising polyurethaneureas. These medical devices with enhanced surface qualities offer advantages in application by virtue of reduced friction and of their capacity, on contact with blood, to reduce the risk of blood clots.
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 adsorption of a film of water by hydrophilic surfaces in contact with blood or urine. This reduces the friction between the catheter surface and the vessel walls, 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, there is always a risk of blood clots forming.
Catheters with hydrophilically treated surfaces are known per se from the prior art.
WO 99/38545 A1, for example, describes catheters which in a first embodiment are composed of a basecoating and a lubricious hydrophilic coating. Said prior art also describes, furthermore, an embodiment in which only a lubricious coating, i.e. a coating system without basecoating, is used. In that case a lubricious coating of a polyurethane is used.
Known from WO 2006/037321 A1 are medical devices having a moistened hydrophilic surface which is intended to enhance the slip properties of the device. The surface is formed by a coating composition with a hydrophilic polymer and a moistening agent, comprising water and at least one lubricant.
US 2003/0203991 A1 discloses hydrophilic coating materials which are based on mixtures of hydrophobic with hydrophilic polymers. Corresponding coating compositions for medical devices comprise (a) an aqueous polymeric matrix; (b) a hydrophilic polymer; (c) a colloidal metal oxide; and (d) a crosslinker. The requisite hydrophilicity of the coating according to US 2003/0203991 A1 is achieved by the polymer (b), which is incorporated into the corresponding polymeric matrix. Among the polymeric matrices used, but not used as a hydrophilic polymer, are polyurethane dispersions.
Mixtures of polyurethanes and polyvinylpyrrolidone as the hydrophilicizing constituent are described, furthermore, in U.S. Pat. No. 5,061,424. Moreover, U.S. Pat. No. 5,041,100 and US 2005/054774 A1 each describe polyurethane-containing coating compositions with polyethylene oxide (U.S. Pat. No. 5,041,100) or acrylates (US 2005/054774) as the hydrophilicizing constituents.
US 2006/040253 A1 describes hydrophilic coating of medical devices for the purpose of improving the slip properties, the composition comprising at least one water-soluble lubricious polymer and an insoluble polymer. The water-soluble lubricious polymer is selected inter alia from the group consisting of polyethylene oxide, polypropylene oxide, polyethyl vinyl alcohol, polyethyl vinyl acetate and polyvinylpyrrolidone, while the insoluble polymer is formed inter alia by polyurethanes, polyesterurethanes and polyetherurethanes.
Aliphatic polyetherpolyurethanes for hydrophilic coatings are likewise available commercially, an example being Tecogel® (Thermedics Polymer Products) or Hydroslip® (CardioTech International Inc.).
Not only the mixtures described in the literature but also the polyetherpolyurethanes available commercially have a variety of disadvantages. The mixtures are multi-component systems and are therefore complicated to prepare, including more particularly those systems which are synthesized by covalent linking of two polymers (cf. US 2003/0203991 A1).
A conceivable alternative to coating systems from organic solution are also polyurethanes in dispersion in an aqueous medium. A disadvantage of such aqueous dispersions is that, owing to the size of the dispersed particles, the coatings are relatively rough. In addition, films of dispersion polymers usually lack sufficient stability. Accordingly there continues to be a need for hydrophilic coating systems which can be prepared starting from polyurethanes.
In this context, U.S. Pat. No. 5,589,563 recommends the use of coatings with surface-modified end groups for polymers used in the field of biomedicine which can also be used to coat medical devices. The resulting coatings are produced from solutions or dispersions and the polymer coatings include different end groups, selected from amines, fluorinated alkanols, polydimethylsiloxanes and amine-terminated polyethylene oxides. As a coating for medical devices, however, these polymers lack satisfactory properties, particularly in respect of the required hydrophilicity.
It is an object of the present invention, therefore, firstly to provide 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 medical devices with hydrophilic surfaces which are produced by coating with specific polyurethane solutions.
The medical devices of the invention comprise at least one coating comprising at least one polyurethaneurea which is terminated with a copolymer unit comprising polyethylene oxide and polypropylene oxide.
In accordance with the invention it has been found that compositions comprising these special polyurethaneureas in solutions are outstandingly suitable for producing 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
(a) repeat units containing at least two urethane groups, of the following general structure
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 “substantially no ionic groups” means for the purposes of the present invention that the resulting coating of the polyurethaneurea contains ionic groups with a fraction of in general not more than 2.50% by weight, more particularly not more than 2.00% by weight, preferably not more than 1.50% by weight, more preferably not more than 1.00% by weight, and especially not more than 0.50% by weight, and even more especially contains no ionic groups. Hence it is particularly preferred that the polyurethaneurea contain no ionic groups, since high concentration of ions in organic solution result in the polymer no longer being sufficiently soluble and hence in it not being possible to obtain stable solutions. If the polyurethane used in accordance with the invention contains ionic groups, then the species in question are preferably carboxylates.
The polyurethaneureas provided in accordance with the invention for the coating of the medical devices 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.
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 dimethylacetamide at 30° C.
The polyurethaneurea-based coating systems for use in accordance with the invention are described in more detail below.
The polyurethaneureas used in accordance with the invention in the coatings of medical devices are formed by reaction of at least one polycarbonate polyol component, one polyisocyanate component, one polyoxyalkylene ether, one diamine and/or amino alcohol and, if desired, one polyol component.
The composition of the polyurethaneurea coating provided in accordance with the invention comprises units which originate from at least one polycarbonate polyol.
The polycarbonate polyol component that is used in one embodiment is a polycarbonate containing hydroxyl groups.
Suitable in principle for the introduction of units based on a hydroxyl-containing polycarbonate are polyhydroxy 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.
Suitable hydroxyl-containing polycarbonates are polycarbonates of a molecular weight determined via OH number 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 one 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 c-caprolactone. Further preferred polycarbonate diols are those based on mixtures of hexane-1,6-diol and butane-1,4-diol.
The polycarbonate is therefore preferably of substantially linear construction and has only a slight three-dimensional crosslinking so that polyurethananes are formed which comprise the abovementioned specification.
The composition of the polyurethaneurea coating provided in accordance with the invention 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, 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(isocyanatomethyl)norbornane (NBDI), 3(4)-isocyanatomethyl-1-methyl-cyclohexyl isocyanate (H6XDI) 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 in accordance with the invention is preferably 1.0 to 3.5 mol, more preferably 1.0 to 3.3 mol, more particularly 1.0 to 3.0 mol, based in each case on the constituent (a) of the coating for use in accordance with the invention.
The composition of the polyurethaneurea coating provided in accordance with the invention includes units which originate from at least one diamine or amino alcohol and serve as what are called chain extenders (c).
Such chain extenders are, for example, diamines or polyamines and also hydrazides, e.g. hydrazine, ethylenediamine, 1,2- and 1,3-diaminopropane, 1,4-diaminobutane, 1,6-diaminohexane, isophoronediamine, isomer mixture of 2,2,4- and 2,4,4-trimethylhexamethylenediamine, 2-methylpentamethylenediamine, diethylenetriamine, 1,3- and 1,4-xylylenediamine, α,α,α′,α′-tetramethyl-1,3- and -1,4-xylylenediamine and 4,4′-diaminodicyclohexylmethane, 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′-diisopropyldicyclohexylmethane.
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 an 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 (c) 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 (c) in the coating composition for use in accordance with the invention is preferably 0.1 to 1.5 mol, more preferably 2 to 1.3 mol, more particularly 0.3 to 1.2 mol, based in each case on constituent (a) of the coating composition for use in accordance with the invention.
The polyurethaneurea used in the present 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 polyurethaneurea and effect a hydrophilicization of the coating composition of the invention.
Nonionically hydrophilicizing compounds (d) 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 Enzyklopadie 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.
The 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 (d) 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 polyalkylene 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 have the effect of a significantly low contact angle and are therefore more hydrophilic in form.
In a further embodiment the composition of the polyurethaneurea coating provided by the invention comprises further units which originate from at least one further polyol.
The low molecular weight polyols (e) used to synthesis 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 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 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), 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-hydroxy-caproic 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 0.05 to 1.0 mol, more preferably 0.05 to 0.5 mol, more particularly 0.1 to 0.5 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 observed over the reactive hydroxy or amine compounds. In this case, at the end point of the reaction through achievement of a target viscosity, there always still remain residues of active isocyanate. These residues must be blocked, so that there is no reaction with large polymer chains. Such a reaction leads to the three-dimensional crosslinking and gelling of the batch. The processing of such a coating solution is possible only with restrictions, or is no longer possible at all. Customarily the batches include high quantities of alcohols. Within a number of hours on standing, or with stirring of the batch, at room temperature, these alcohols block the isocyanate groups that still remain.
If, however, it is desired to carry out rapid blocking of the residual isocyanate content that still remains, the polyurethaneurea coatings provided in accordance with the invention may therefore also comprise monomers (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 dependent essentially on the amount of the NCO excess, and cannot be specified generally.
Preferably these units are not used during the synthesis. Unreacted isocyanate is preferably converted into terminal urethanes as a result of the solvent alcohols that are present at very high concentrations.
Furthermore, the polyurethaneurea coatings provided in accordance with the invention may comprise further constituents typical for the intended purpose, such as additives and fillers. An example of such are active pharmacological substances, medicaments and additives which promote the release of active pharmacological substances (drug-eluting additives).
Active pharmacological substances and 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 active pharmacological substances and 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 active pharmacological substance or 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 vaso active 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 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 by 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
Particular preference is given in accordance with the invention to coating the medical devices using polyurethaneureas which are synthesized from
Preference is further given in accordance with the invention to coating medical devices using polyurethaneureas which are synthesized from
Preference is also further given in accordance with the invention to coating catheter materials using polyurethaneureas which are synthesized from
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 urological 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 lubricious, blood-compatible surfaces by using aqueous, nonionically stabilized polyurethane solutions of the type described above to coat the medical devices. The coating compositions described above are obtained preferably as organic solution and are applied to the surface of the medical devices.
Preference is given, in this context, to coatings synthesized from a mixture of polycarbonate polyols and a monofunctional polypropylene oxide-polyethylene oxide alcohol.
In the context of the present invention it is more particularly preferred for the coatings of the medical devices to be produced starting from solutions of the coating composition described in more detail above.
In accordance with the invention it has emerged that the resulting coatings on medical devices differ according to whether the coating composition described above 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 solutions of the above-described coating compositions.
Without wishing to be tied to any one theory, it is nevertheless assumed in accordance with the invention that by virtue of the particulate structure of the polyurethanes in aqueous dispersion the filming of the polymers is incomplete. In the films, the particle structures can generally still be seen, as for example by atomic force microscopy (AFM). Polyurethanes from solution yield smoother coatings. As a result of the internal interlocking and interlooping of the polyurethane molecules in organic solution, the dried films as well have greater tensile strength and are more resistant to storage in water.
In a further embodiment the present invention therefore provides a medical device having at least one hydrophilic coating comprising at least one polyurethaneurea which comprises essentially no ionic modification, the coating being produced starting from a solution of the polyurethaneurea.
The medical devices of the invention can be coated with the hydrophilic polyurethane solutions 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 organic polyurethane solutions can be prepared by any desired processes. A procedure which has been found to be preferred, however, is as follows:
For the preparation of the polyurethaneurea solutions for use in accordance with the invention for coating, preferably the polycarbonate polyol, the polyisocyanate, the monofunctional polyether alcohol and, if desired, the polyol are reacted with one another in the melt or in solution, until all of the hydroxyl groups have been consumed.
The stoichiometry used in this case between the individual components involved in the reaction is a product of the aforementioned proportions for the coating of the invention.
The reaction takes place at a temperature of preferably between 60 and 110° C., more preferably 75 to 110° C., more particularly 90 to 110° C., with temperatures around 110° C. being preferred on account of the rate of the reaction. Higher temperatures may likewise be employed, although in that case there is a risk, in certain cases and as a function of the individual constituents used, that decomposition processes and instances of discoloration will appear in the resultant polymer.
In the case of the prepolymer of isocyanate and all hydroxyl-containing components, reaction in the melt is preferred, although there is a risk of high viscosities in the fully reacted mixtures. In these cases it is also advisable to add solvents. However, as far as possible there should not be more than about 50% by weight of solvent present, since otherwise the dilution makes the reaction rate significantly slower.
In the case of the reaction of isocyanate and the hydroxyl-containing components, the reaction may take place in the melt in a period of 1 hour to 24 hours. Low levels of addition of quantities of solvent lead to a slowing down, but the reaction times are within the same periods.
The sequence of the addition or reaction of the individual constituents may differ from the sequence indicated above. This may be of advantage more particularly when the intention is that the mechanical properties of the resultant coatings should be changed. If, for example, all of the hydroxyl-containing components are reacted at the same time, the product is a mixture of hard and soft segments. If, for example, the low molecular mass polyol is added after the polycarbonate polyol component, defined blocks are obtained, and this may be accompanied by different properties in the resultant coatings. The present invention is hence not restricted to an arbitrary sequence of the addition or reaction of the individual constituents of the polyurethane coating.
Then further solvent is added and the chain extender diamine, in solution if desired, or the dissolved chain extender amino alcohol (compound (c)) is added.
The further addition of the solvent takes place preferably in steps, so as not to slow down the reaction unnecessarily, which would occur in the case of complete addition of the quantity of solvent at the beginning of the reaction, for example. Furthermore, in the case of a high level of solvent at the beginning of reaction, one is tied to a relatively low temperature, which is at least co-determined by the nature of solvent. This too leads to a slowing of the reaction.
When the target viscosity has been reached, the residues of NCO that still remain can be blocked by means of a monofunctional aliphatic amine. The remaining isocyanate groups are preferably blocked by reaction with the alcohols that are present in the solvent mixture.
Suitable solvents for the preparation and the application of the polyurethaneurea solutions of the invention include all conceivable solvents and solvent mixtures such as dimethylformamide, N-methylacetamide, tetramethylurea, N-methylpyrrolidone, aromatic solvents such as toluene, linear and cyclic esters, ethers, ketones and alcohols. Examples of esters and ketones are, for example, ethyl acetate, butyl acetate, acetone, γ-butyrolactone, methyl ethyl ketone and methyl isobutyl ketone.
Preference is given to mixtures of alcohols with toluene. Examples of the alcohols which are used together with the toluene are ethanol, n-propanol, isopropanol and 1-methoxy-2-propanol.
Generally speaking, in the reaction, the amount of solvent used is such as to give approximately 10% to 50% strength by weight solutions, more preferably approximately 15% to 45% strength by weight solutions, with particular preference approximately 20% to 40% strength by weight solutions.
The solids content of the polyurethane solutions is generally between 5% to 60% by weight, preferably 10% to 40% by weight. For coating experiments the polyurethane solutions can be diluted as desired with toluene/alcohol mixtures in order to allow the thickness of the coating to be varied. All concentrations from 1% to 60% by weight are possible, with preferred concentrations being in the 1% to 40% by weight range.
In this context it is possible to achieve any desired coat thicknesses, such as, for example, a few 100 nm up to a few 100 μm, although higher and lower thicknesses are possible in the context of the present invention.
Further additions such as antioxidants or pigments, for example, may likewise be used. Furthermore it is additionally possible if desired to use further additions such as tactility modifiers, dyes, matting agents, UV stabilizers, light stabilizers, hydrophobicizing agents, hydrophilicizing agents and/or flow control assistants.
Starting from these solutions, the coatings provided in accordance with the invention are then produced by the methods described above.
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 plastic. The following may be mentioned as examples of metals: medical stainless steel and 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.
The medical devices of the invention can be coated with the hydrophilic polyurethane dispersions by a variety of methods. Examples of suitable coating techniques are knifecoating, printing, transfer coating, spraying, spin coating or dipping.
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 drier.
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.
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 drier.
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.
Viscosity measurements were carried out using the Physics MCR 51 rheometer from Anton Paar GmbH, Ostfildern, Germany.
This example describes the preparation of an inventive polyurethaneurea solution.
198.6 g of Desmophen C 2200, 23.0 g of LB 25 and 47.8 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) were reacted at 110° C. in the melt to a constant NCO content of 2.4%. The product was cooled and diluted with 350.0 g of toluene and 200 g of isopropanol. At room temperature a solution of 12.5 g of isophoronediamine in 95.0 g of 1-methoxypropan-2-ol was added. After the end of the increase in molar weight and the attainment of the desired viscosity range (testing by measurement of the viscosity of a sample taken, using the rheometer cited above), the batch was stirred for a further 4 hours in order to block the remaining isocyanate content with isopropanol. This gave 927 g of a 30.4% strength solution of polyurethaneurea in toluene/isopropanol/1-methoxypropan-2-ol with a viscosity of 19 600 mPas at 23° C.
This example describes the preparation of an inventive polyurethaneurea solution.
195.4 g of Desmophen C 2200, 30.0 g of LB 25 and 47.8 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) were reacted at 110° C. to a constant NCO content of 2.3%. The product was cooled and diluted with 350.0 g of toluene and 200 g of isopropanol. At room temperature a solution of 12.7 g of isophoronediamine in 94.0 g of 1-methoxypropan-2-ol was added. After the end of the increase in molar weight and the attainment of the desired viscosity range, the batch was stirred for a further 4 hours in order to block the remaining isocyanate content with isopropanol. This gave 930 g of a 30.7% strength solution of polyurethaneurea in toluene/isopropanl/1-methoxypropan-2-ol with a viscosity of 38 600 mPas at 23° C.
This example describes the preparation of an inventive polyurethaneurea solution.
195.4 g of Desmophen XP 2613, 30.0 g of LB 25 and 47.8 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) were reacted at 110° C. to a constant NCO content of 2.4%. The product was cooled and diluted with 350.0 g of toluene and 200 g of isopropanol. At room temperature a solution of 12.7 g of isophoronediamine in 95.0 g of 1-methoxypropan-2-ol was added. After the end of the increase in molar weight and the attainment of the desired viscosity range, the batch was stirred for a further 4 hours in order to block the remaining isocyanate content with isopropanol. This gave 931 g of a 30.7% strength solution of polyurethaneurea in toluene/isopropanol/1-methoxypropan-2-ol with a viscosity of 26 500 mPas at 23° C.
This example describes the preparation of an inventive polyurethaneurea solution.
198.6 g of Desmophen C 1200, 23.0 g of LB 25 and 47.8 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) were reacted at 110° C. to a constant NCO content of 2.4%. The product was cooled and diluted with 350.0 g of toluene and 200 g of isopropanol. At room temperature a solution of 13.2 g of isophoronediamine in 100.0 g of 1-methoxypropan-2-ol was added. After the end of the increase in molar weight and the attainment of the desired viscosity range, the batch was stirred for a further 4 hours in order to block the remaining isocyanate content with isopropanol. This gave 933 g of a 30.3% strength solution of polyurethaneurea in toluene/isopropanol/1-methoxypropan-2-ol with a viscosity of 17 800 mPas at 23° C.
This example describes the preparation of an inventive polyurethaneurea solution.
195.4 g of Desmophen C 1200, 30.0 g of LB 25 and 47.8 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) were reacted at 110° C. to a constant NCO content of 2.4%. The product was cooled and diluted with 350.0 g of toluene and 200 g of isopropanol. At room temperature a solution of 11.8 g of isophoronediamine in 94.0 g of 1-methoxypropan-2-ol was added. After the end of the increase in molar weight and the attainment of the desired viscosity range, the batch was stirred for a further 4 hours in order to block the remaining isocyanate content with isopropanol. This gave 931 g of a 30.7% strength solution of polyurethaneurea in toluene/isopropanol/1-methoxypropan-2-ol with a viscosity of 23 700 mPas at 23° C.
This example describes the preparation of a polyurethaneurea solution as a comparison product to the inventive Example 1. The Desmophen C2200 is replaced by the PolyTHF 2000.
194.0 g of PolyTHF 2000, 22.6 g of LB 25 and 47.8 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) were reacted at 110° C. to a constant NCO content of 2.3%. The product was cooled and diluted with 350.0 g of toluene and 200 g of isopropanol. At room temperature a solution of 12.1 g of isophoronediamine in 89.0 g of 1-methoxypropan-2-ol was added. After the end of the increase in molar weight and the attainment of the desired viscosity range, the batch was stirred for a further 4 hours in order to block the remaining isocyanate content with isopropanol: This gave 916 g of a 30.2% strength solution of polyurethaneurea in toluene/isopropanol/1-methoxypropan-2-ol with a viscosity of 15 200 mPas at 23° C.
This example describes the preparation of a polyurethaneurea solution as a comparison product to the inventive Example 2. The Desmophen C2200 is replaced by the PolyTHF 2000.
190.6 g of PolyTHF 2000, 30.0 g of LB 25 and 47.8 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) were reacted at 110° C. to a constant NCO content of 2.3%. The product was cooled and diluted with 350.0 g of toluene and 200 g of isopropanol. At room temperature a solution of 12.1 g of isophoronediamine in 89.0 g of 1-methoxypropan-2-ol was added. After the end of the increase in molar weight and the attainment of the desired viscosity range, the batch was stirred for a further 4 hours in order to block the remaining isocyanate content with isopropanol. This gave 919 g of a 30.5% strength solution of polyurethaneurea in toluene/isopropanol/1-methoxypropan-2-ol with a viscosity of 21 000 mPas at 23° C.
The coatings for the measurement of the static contact angle were produced on glass slides measuring 25×75 mm using a spincoater (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 organic 15% strength polyurethane solution. All of the organic polyurethane solutions were diluted to a polymer content of 15% by weight with a solvent mixture composed of 65% by weight of toluene and 35% by weight of isopropanol. Rotation of the sample plate at 1300 revolutions per minute for 20 sec gave a homogeneous coating, which was dried at 100° C. for 1 h 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 was 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 were placed on the specimen, and their static wetting angle is measured. Beforehand, using an antistatic drier, the static charge (if present) on the sample surface was removed.
As Table 1 shows, the polycarbonate-containing coatings of Examples 1 to 5 give extremely hydrophilic coatings with static contact angles ≦40°. In contrast, the PolyTHF-containing coatings 7 to 9 are substantially less polar, despite the fact that the composition of these coatings is otherwise identical with those of Examples 1 and 2.
This comparative example describes the synthesis of a polyurethaneurea polymer which in place of the mixed monofunctional polyethylene-polypropylene oxide alcohol LB 25 contains the same molar fraction of a pure monofunctional polyethylene oxide alcohol. The polymer is identical with that of Example 1 except that it contains a different terminal group. The synthesis in toluene and alcohols as described in Examples 1 to 7 does not function when this alcohol is used. Consequently the synthesis is carried out in pure dimethylformamide (DMF).
198.6 g of Desmophen C 2200, 20.4 g of polyethylene glycol 2000 monomethyl ether (source: Fluka, Article No. 81321) and 47.8 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) were reacted at 110° C. in the melt to a constant NCO content of 2.4%. The product was cooled and diluted with 550.0 g of DMF. At room temperature a solution of 10.5 g of isophoronediamine in 100 g of DMF was added. After the end of the increase in molar weight and the attainment of the desired viscosity range (testing by measurement of the viscosity of a sample taken, using the rheometer cited above) 1.0 g of n-butylamine was added in order to block the small isocyanate content that remained. This gave 927 g of a 29.8% strength solution of polyurethaneurea in dimethylformamide with a viscosity of 22 700 mPas at 23° C.
This example describes the synthesis of an inventive polyurethaneurea polymer in DMF as solvent. The polymer is identical with that of Example 1, but was prepared in DMF in order to be able to compare its physical properties with the polymer of Example 9.
198.6 g of Desmophen C 2200, 23.0 g of LB 25 and 47.8 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) were reacted at 110° C. in the melt to a constant NCO content of 2.4%. The product was cooled and diluted with 550.0 g of DMF. At room temperature a solution of 10.5 g of isophoronediamine in 100 g of 1-methoxypropan-2-ol was added. After the end of the increase in molar weight and the attainment of the desired viscosity range (testing by measurement of the viscosity of a sample taken, using the rheometer cited above) 0.5 g of n-butylamine was added in order to block the small isocyanate content that remained. This gave 930 g of a 30.6% strength solution of polyurethaneurea in DMF with a viscosity of 16 800 mPas at 23° C.
As described in Example 8, films on glass were produced with the polyurethane solutions of Examples 9 and 10, and their static contact angles were measured.
The film of Example 10, produced with the mixed (polyethylene oxide/poly-propylene oxide) monofunctional polyether alcohol, exhibits, with 36°, a significantly lower static contact angle than the film of Example 9 (55° that contains pure polyethylene oxide units.
This example describes the synthesis of an inventive polyurethane in organic solution. This product was compared with the polyurethane, prepared correspondingly in aqueous dispersion, of Example 13 (see Example 14).
277.2 g of Desmophen C 2200, 33.1 g of LB 25, 6.7 g of neopentyl glycol, 71.3 g of 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) and 11.9 g of isophorone diisocyanate were reacted at 110° C. to a constant NCO content of 2.4%. The product was cooled and diluted with 500.0 g of toluene and 350.0 g of isopropanol. At room temperature a solution of 6.2 g of isophoronediamine in 186.0 g of 1-methoxypropan-2-ol was added. After the end of the increase in molar weight and the attainment of the desired viscosity range, the batch was stirred for a further 4 hours in order to block the remaining isocyanate content with isopropanol. This gave 1442 g of a 28.6% strength solution of polyurethaneurea in toluene/isopropanol/1-methoxypropan-2-ol with a viscosity of 17 500 mPas at 23° C.
This example describes the synthesis of the polyurethane of Example 12 in aqueous dispersion. It consists of the same polymer as described in Example 12. The two polymers are compared with one another in Example 14.
277.2 g of Desmophen C 2200, 33.1 g of LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and homogenized by stirring for 5 minutes. Added to this mixture at 65° C. and over the course of 1 minute were, first, 71.3 g of 4,4′-bis(isocyanato-cyclohexyl)methane (H12MDI) and thereafter 11.9 g of isophorone diisocyanate. The mixture was heated at 110° C. until a constant NCO value of 2.4% 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 ethylenediamine in 16 g of water was metered in over the course of 10 minutes. The subsequent stirring time was 5 minutes. Subsequently the product was dispersed over the course of 15 minutes by addition of 590 g of water. This was followed by the removal of the solvent by vacuum distillation. This gave a storage-stable polyurethane dispersion having a solids content of 40.7% and an average particle size of 136 nm. The pH of this dispersion was 6.7.
The two coatings of Examples 12 and 13 were applied to release paper using a 200 μm doctor blade. The coating of Example 12 was applied in undiluted form; the aqueous dispersion, before the production of a film, was admixed with 2% by weight of a thickener (Borchi Gel A LA, Borchers, Langenfeld, Germany) and homogenized by stirring at RT for 30 minutes. The wet films were dried at 100° C. for 15 minutes.
The parameters measured are tensile strength and breaking extension in the dry state and after 24 h of water exposure of the films. The investigations were carried out in accordance with DIN 53504.
The results of the table show that the breaking stress of the dried films corresponds to both polyurethanes, independently of their preparation as a solution or as an aqueous dispersion, within the bounds of experimental accuracy. The film of Example 12 produced from organic solution, however, possesses a higher elasticity (700% breaking extension as compared with 550% for the polymer from aqueous dispersion). Furthermore, breaking stress and breaking extension do not alter, within the bounds of measurement accuracy, for the film produced from organic solution, whereas breaking stress and breaking extension of the film produced from aqueous dispersion decrease significantly.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08153059.4 | Mar 2008 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2009/001900 | 3/16/2009 | WO | 00 | 9/20/2010 |
