CA1267576A

CA1267576A - Permanently bonded antithrombogenic polyurethane surface

Info

Publication number: CA1267576A
Application number: CA000501628A
Authority: CA
Inventors: Donald D. Solomon; Charles W. Mcgary; Vincent J. Pascarella
Original assignee: Deseret Medical Inc
Current assignee: Deseret Medical Inc
Priority date: 1985-04-01
Filing date: 1986-02-12
Publication date: 1990-04-10
Anticipated expiration: 2007-04-10
Also published as: JPS61236814A; JPH0441694B2; EP0200295A3; DE3670952D1; EP0200295B1; AU584389B2; US4600652A; AU5298986A; EP0200295A2

Abstract

ABSTRACT OF THE DISCLOSURE

An antithrombogenic polyurethane polymer being bound to a support substrate wherein the antithromb-genic agent is reacted through an aldehyde group with an amine functionality of a polyurethane-urea to form the covalently bonded antithrombogenic material.

Description

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The pre~ent invention relates to a novel anti-thrombogenic polyurethane polymer and proce6s for making the ~ame. More particularly the invention relates to a polyurethane polymer having an anti-thrombogenic material covalently bonded thereto 80 thatthe material is permanently affixed to the polymer and remains virtually nonleachable when the products made from the reaction product are in use.
Extensive investigations have been undertaken over many years to find materials that will be biologically and chemically stable toward~ body fluids. This area of researeh has become increasingly important with the development of various objects and articles which can be in contact with blood, such as artificial organs, vascular graftq, probes, cannulas, catheter~ and the like.
Artificial materials are being increasingly uqed as blood contact devices and may be subject to potential generation of thrombus. When blood contact~ a foreign material, a complex series of events occur. These involve protein deposition, cellular adhesion and aggre-gation, and activation of blood coagulation schemes.
Considerable research effort has been focused on this blood-material-interaction in the last twenty years.
~he overall objective of these investigations has been to minimize the potential for thrombus formation on the foreign materials, such as the device when introduced into the body upon contact with blood.
Early work by R. I. Leininger and R. D. Falb, ! 30 U.S. Patent No. 3,167,344, was based on binding quater-nary amines to a polymer surface and sub~equently ionically binding heparin thereto. In contrast, H. M.
Grotta established a method in U.S. Patent No. 3,846,353 in which heparin was complexed with a quaternary amine on a polymer surface. Both the Leininger et al. and Grotta methods have the disadvantage of being non-permanent or leachable 6ystems. In general, ~ ;~;6'~i7~i ionically bound ~ystems have limited viability due to their inherent leachability. J. Love and G. W. Holmes patented a method for the preparation of antithrombo-genic ~urfaces in u.S~ Patent No. 3,616,935 wherein polyalkylenimines are used to irreversibly absorb the antithrombogenic compound to cellulose, cellulose esters, silicone rubber, polypropylene, polycarbonate and glass through the formation of ionic bonds. The Love et al. technique, however, was not able to over-come the deficiencies of the prior techniques, notablyleaching of the antithrombogenic material rendering the system non-permanent and ineffective for long term internal use in the body.
U.S. Patent No. 3,826,678 of A.S. Hoffman and G. Schmer relates to a covalent bonding method involving the use of "~oft~ hydrogel surfaces wherein radiation grafting is employed with a reactable compound selected from polymers and copolymers on an inert polymeric substrate and thereafter a biologically active compound is chemically bound to the reactable compound. ~Soft~
gel-like surfaces are not appropriate for devices such as catheters or other medical devices which require a n hard" polymer surface. The "soft" hydrogel or hydro-philic surface of the Hoffman et al. patent would be subject to being stripped off catheters and in case of other blood contact devices, be devoid of the mechanical properties required. "Hard" polymers would provide the mechanical strength required in such applications.
U.S. Patent No. 4,326,532 to Hammar discloses a layered medical article having an antithrombogenic surface wherein a natural or synthetic polymeric sub-strate is reacted with chitosan and the antithrombogen is then bonded to the chitosan. Hammer discloses on column 3, lines 10 to 49 that the antithrombogenic material may be ionically bonded to the chitosan or covalently bonded using boron hydrides.

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In contrast to the aforementioned techniques, Larm et al. disclo~ed in "A ~ew No~Thrombogenic Surface Prepared by Selective Covalent Bonding of Heparin via A Modified Reducing Terminal Re~idue," Biomat., Med.
Dev., Art. Org.," (283) page~ 161-173 (1983) a new method for binding heparin to artificial surfaces. The procedure de~cribed involved partially degrading heparin and coupling the fragments through their reducing termi-nal units. Heparin wa~ then ionically and covalently coupled to different surfaces with best re~ults achieved using polyethylenimine containing primary, secondary and tertiary amino groups.
It would be desirable to provide a material which has excellent biological and chemical stability towards body fluids, namely blood, and which retains it~ anti-thrombogenic agent in a permanent and non-leachable fa~hion when in contact with blood. It would also be desirable to provide materials which, while being bio-compatible, are also biofunctional, that is, materials which have biological activity in a variety of functions.
The pre~ent invention accompli~hee all of these needs by use of a speciic covalently bonded anti-thrombogenic agent to a solid support. More particu-larly the invention involves an antithrombogenicpolyurethane polymer having a) a support substrate: b) a protonated amine rich polyurethane-urea bonded to said support substrate and c) an aldehyde containing antithrombogenic agent reacted with the amine function-ality of said polyurethane-urea to form a covalently bonded antithrombogenic material.
In another embodiment, the present invention involves a process for imparting antithrombogenic activity to polyurethane polymer materials which comprises a) treating the surface of a solid support .
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with a sol~tion of a protonated amine rich polyurethan~
urea 80 that the polyurethane-urea is bonded to the support sub~trate, b) removing solvent from the treated substrate to form a layer of the polyurethane-urea upon the support substrate, c) activating the amine function-ality on the polyurethan~urea by use of an alkaline buffer to form free amine groups, and d) reacting the free amine groups with an aldehyde containing antithro~
bogenic agent to covalently bond the antithrombogenic agent to the polyurethane-urea in the presence of a reducing agent.
The term antithrombogenic agent or material as used herein refers to any material which inhibits thrombus formation on its surface, such as by reducing platelet aggregation, dissolving fibrin, enhancing passivating protein deposition, or inhibiting one or more steps within the coagulation cascade. Illustra-tive antithrombogenic material may be selected from the group consisting of heparin, prostaglandins, urokinase, streptokinase, sulfated polysaccharide, albumin and mixtures thereof. The antithrombogenic material may be used in varying amounts depending on the particular material employed and ultimate desired effect. Prefer-red amounts have generally been found to be less than about 5% by weight of the final products and may range from about 0.2% to about 5~ by weight.
The support structure used in the invention is not critical and may be selected from a wide variety of materials that are compatible with a polyurethane-urea formulation. Exemplary support surfaces may be prepared from thermoplastic polyurethanes, thermosetting polyurethanes, vinyl polymers, polyethylene, polypropy-lene, polycarbonates, polystyrenes, polytetrafluoro-ethylene, polyesters, polyvinyl chlorides and the like.
The particular structures do not constitute a critical aspect of this invention other than to serve as a 5~7~

~upport substrate for the antithrombogenic agent. The supports are preferably performed into the desired shape or structure for the particular application prior to treatment according to the invention. Of significant importance i 8 the ability of the ~upport to bind the modified polyurethan~urea compound with the antithro~
bogenic agent in order to effect irreversible coupling.
It ha~ been found that any support may be used which has an average molecular weight different from the poly-urethane-urea compound u~ed to form the coupling complex and which does not dissolve in the organic ~olvent for the complex. This distinction i8 critical to enable bonding of performed supports without deformation while permitting a layer of polyurethane coupler to be bonded to the support structure. In this manner, an integral unit is formed which will not easily ~eparate upon use.
The first step in the process of the invention involves treating the surface of the solid support with a solution of a protonated amine rich polyurethane-urea 80 that the polyurethane-urea material is bonded to ; the support substrate. The polyurethane-urea materials of the invention may be selected from a wide variety of compounds prepared by reacting a polyurethane pre-polymer with a diamine.
Polyurethane-urea~ are known in the art. They are generally made by chain extending the reaction product of a dii~ocyanate and a high molecular weight glycol ~urethane prepolymer) with a diamine. Without being limited there to, one particularly preferred procedure of the present invention involves adding diamine in excess, that is from about 0.6 to 1 mole of diamine and preferably 0.75 to 1 mole for each free isocyanate group in the prepolymer to produce a polyurethane-urea with primary amine end groups. Use of ratio's below 0.6 have been found unsuitable to prepare an amine rich polyurethane-urea compound to enable sufficient reaction ~;'7~i w ith the antithrombogenic agent. Ra tio~ above about 1.0 result in the pre6ence of nonreactive excess d iamine which must be removed from the solution for a dequate processing.
The urethane prepolymer can be based on a variety of dii~ocyanates. Suitable diisocyanates include, 1,4-cyclohexane diisocyante, dicyclohexylmethane 4,4'-diisocyanate; xylene diisocyanate, l-isocyanat~3-i socyanatomethyl- 3,5,5-trimethylcyclohexane; hexamethyl-ene diisocyanate; 1,4-dimethylcyclohexyl diisocyanate;

2,4,4-trimethylhexamethylene diisocyanate; isocyanates such as m-phenylene diisocyanate; mixtures of 2,4-and 2,6 hexamethylene-1,5-d iisocyanate; hexahydrotolylene diisocyanate (and isomers), napthylene-1,5-dii~ocyanate;
1 5 l-m ethoxyphenyl -2, 4-d iisocyanate; diphenylmethane 4,4'-d ii~ocyanate; 4,4'-biphenylene diisocyanate;

3,3'-dimethoxy - 4,4-biphenyl diisocyanate, 3,3'-d imethyl - 4,4'-biphenyl diisocyanate, and 3,3' dimethyl d iphenylmethane - 4,4' diisocyanate and mixtures there-of. The aliphatic and alicyclic diisocyanates employed i n the process of this invention and the products made therefrom generally exhibit good resistance to the d egradative effects of ultraviolet light.
The high molecular weight glycols useful in the 2 5 present invention may be a polyether diol or polyester diol and range in number average molecular weight from about 400 to about 3,000 and preferably about 500 to about 2,000. The low molecular weight glycols may also be used to prepare the prepolymer which materials may have from about 2 to 10 carbon atoms. Exemplary of the low molecular weight glycols which may be employed to prepare polyester polypols are 1,6-hexanediol, neopentyl g lycol, trimethylolpropane, ethylene glycol, diethylene g lycol, triethylene glycol, 1,4-butanediol, 1,4-cyclohexanediol, 1,2-propanediol, 1,3-propanediol, 1,3-butylene glycol, 1,4-cyclohexane dimethanol, 1,6,-hexanediol, and the like, and mixtures thereof.

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The polyethers containing at least 2 hydroxyl groups u~ed in accordance with the invention are also known per 8e and are obtained, for example, by polymer-izing epoxides, such as ethylene oxide, propylene oxide, butylene oxide, tetrahydrofuran, styrene oxide or epichlorohydrin on their own, for example, in the presence of BF3, or by adding these epoxides, option-ally in admixture or in succession, to starter compo-nents containing reactive hydrogen atoms, such as water, alcohols, or amines, for example, ethylene glycol, 1,3- or 1,2-propylene glycol, 4,4'-dihydroxy diphenyl propane, aniline, ammonia, ethanolamine or ethylene diamine. The most preferred polyether diols are poly (tetramethylene ether) glycols.
The use of trihydric alcohols can be employed when branched polymers are desired to improve coating properties. Examples are glycerin, trimethyolpropane, adducts of trimethylolpropane or glycerin with ethylene oxide, or epsilo~ caprolactone, trimethylolethane, hexanetriol -tl,2,6), butanetriol (1,2,4) and pentaerythritol.
Illustrative polyesters may contain hydroxyl groups, for example, reaction products of polyhydric alcohols reacted with divalent carboxylic acids. It is also possible to use the corresponding polycarboxy-lic ac$d anhydrides or corresponding polycarboxylic acid esters of lower alcohol~ or mixtures thereof, for producing the polyester~. The polycarboxylic acids may be aliphatic, cycloaliphatic, aromatic and/or hetero-cyclic and may optionally be substituted, for example,by halogen atoms and/or unsaturated. Examples of poly-carboxylic acids of this kind include succinic acid, adipic acid, ouberic acid, azelaic acid, 6ebacic acid, phthalic acid, phthalic acid anhydride, tetrachloro-phthalic acid anhydride, endomethylene tetrahydro-phthalic acid anhydride, glutaric acid anhydride, maleic acid, maleic ac$d anhydride, fumaric acid, .

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dimeric and trimeric fatty acids such as oleic acid, optionally in admixture with monomeric fatty acids, terephthalic acid dimethyl ester and terephthalic acid bis-glycol ester. Examples of suitable polyhydric alcohols are ethylene glycol, 1,2-and 1,3-propylene glycol, 1,4- and 2,3-butylene glycol, 1,6-hexanediol, octanediol, neopentyl glycol, cyclohexane dimethanol (1,4-bis-hydroxy methyl cyclohexane), 2-methyl-1, 3-propanediol, also diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycols, dipropylene glycol, polypropylene glycol8, dibutylene glycol and polybutylene glycols. Polyesters of lactones, for example, -caprolactone or hydroxy carboxylic acids, for example,~ -hydroxycaproic acid, may also be used.
The prepolymer iB prepared by heating polyols and diisocyanate with agitation in solvent under an inert atmosphere to 60-100C. The ratio of NCO to hydroxyl (OH) groups in the prepolymer is from 1.5 to 2:1 with a ratio of 2:1 preferred. The higher NCO to OH ratio limits the molecular weight of the prepolymer and results in higher levels of amine functionality from the diamine reaction later.
The diol molecular weight can vary from 400-3000 molecular weight. Molecular weights of about 800 to about 1500 give a combination of good film formation with adequate levels of amine functionality at the end of the reaction sequence. A catalyst may be employed but is not required. The reactants are heated for a period sufficient to react all the hydroxyl groups.
The reaction time is generally 2-6 hours, however catalysts may shorten the reaction time to as little as 5 minutes. Suitable cataly~ts include tin salts such as dibutyltin dilaurate, stannous octoate or tertiary amines.

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The prepolymer reaction is preferably carried out in solvent and in a solvent which is unreactive to NCO.
Al ternatively, the prepolymer may be formed neat and solvent added after the prepolymer is formed. Con-S venient solvent~ u~ed in preparation of the prepolymer are aromatic hydrocarbons, ketones, ester~, methylene chloride or tetrahydrofuran. Certain ~olvents have potential reactivity with amines and therefore must be evaporated prior to the addition of amines, examples of such solvents include ketones and methylene chloride.
A diamine solution i~ made by dissolving the amine in an appropriate solvent. Isopropanol was selected because the diamine dissolves (or disperses) readily in it and it is a secondary alcohol with a low probability of competing for available NCO groups w ith the amine group~s. One particularly preferred f inal solvent mixture of toluene-isopropanol (2:1 by w t.) has the ability to solvate the highly polar p olyurethane-urea.
2 0 In addition to isopropanol, methanol, ethanol, propanol, butanol, isobutanol, tert-butanol and diacetone alcohol or mixtures of alcohols may also be used.
Am inea u~eful for thi~ invention are: ethylene diamlne, 1,3-propylene diamine, 1-4 butanediamine, 1-6 hexanediamine, 1,7-heptanediamine, 1,8-octane-diamine, l,9-nonanediamine, l,10-decanediamine, 1,12-dodecanediamine, piperazine, phenylene d iamine, tolylene diamine, hydrazine, methylene bis 3 0 aniline, methylene bis 4 aminocyclohexane, isophorone diamine, 2,2,4 trimethyl-1,6-hexanediamine, menthane diamine, polyoxypropylene diamines and polyoxyethylene-diamines known as "Jeffamines" from Jefferson Chemical Company, U.S.A.

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The prepolymer solution may be prepared at a con-centration of 10-60~, w-th 30-40% being preferred (wt/wt). A solution of diamine and solvent such as isopropanol is made with a concentration of 1-30%, with S-15~ being preferred (net weight). The prepolymer is slowly added to the diamine solution with good ~tirring, maintaining the temperature at 30C, in a nitrogen e~
vironment. After the reaction solution has been mixed well and the reaction is complete, a preferred optional procedure involves adding an acid 810wly to the amine rich polyurethane-urea solution. A ~ufficient amount of acid is added to protonate the amine functionality of the amine-rich polyurethane-urea. The solution concentration i8 adjusted to an appropriate concentration of 5-50 weight percent, where 10-30~ is preferred and 15-25% is most preferred.
The preferred acid addition technique used accord-ing to the invention prevents premature reaction of the free amine groups with carbon dioxide and other oxidiz-ing agents present in the reaction. This i8 achievedby converting the amine groups into ~alt radicals by reaction with a protonating acid. Suitable acids in-clude acetic acid, hydrochloric acid, phosphoric acid, formic acid, citric acid, butyric acid, toluene sulfonic acid, methane sulfonic acid and B0 forth. The reaction permits the amine-rich polyurethane-urea compound to be stored for long periods. It has been unexpectedly found that when this protective step was not employed, a sharp variation in results was evidenced due to variable and often relatively low amounts of anti-thrombogenic material bond to the polyurethane.
The choice of polyurethane-urea solvent for coating the substrate is an important factor. Many combinations of the previously listed solvents could be found useable by a coatings chemists skilled in the use of solubility .

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parameter theory. Al though the ~olvent mixture of toluene and i~opropanol has the proper characteri~;tics, many other combinations are useable.
Other solvents can be substituted by volatilizing the original reaction solvent and recon~tituting to 5-40% by weight where 15-25% is preferred. Exemplary ~olvents include toluene, methanol, ethanol, propanol, i sopropanol, acetonitrite, and the like. The solvent system i~ important to the invention but not critical or limiting.
On ce prepared, the protonated polyurethane-urea i 8 dispersed or dissolved in a solvent at the appropri-a te concentration of about 5% to about 40% and is c ontacted to form a layer upon the substrate by 1 5 conventional flow or dip coating processes. On ce contacting is complete, the structure is placed in a gaseous environment, preferably nitrogen, to remove t he solvent. The ~tructure is then ready for reaction w ith the antithrombogenic agent. Pr ior to reacting the protonated amine group with the antithrombogenic agent i t will be necessary to activate the amine function-a lity on the polyurethane-urea. Activation may be conveniently performed with an alkaline buffer. The particular buffer is not critical even though it is preferred that the pH of the buffer be above about 8Ø
Suitable buffers include, but are not limited to, sodium borate, sodium 5:5-diethylbarbiturate-HCl, Clarks and Lubs solution (NaOH, KCl and H3B03), and 8 odium bicarbonate.
It i~ essential according to the invention that t he antithrombogenic agent be modified to contain a reactive aldehyde moiety which does not inhibit the bioactivity of the antithrombogenic agent when coupling i 8 complete.
3S The formation of aldehyde containing agentA may be a chieved by conventional methods. For example when .~

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using heparin as the antithro~bogenic agent, heparin may be partially depolyrnerized by deaminative cleavage with aldehyde inducing compounds such as sodium perio-date and nitrous acid. Thi6 cleavage converts an amine 5 bearing carbohydrate residue to a 2,5-anhydro-D-mannose residue. One preferred method to produce an aldehyde m odified heparin involves the reaction of sodium heparinate with sodium periodate at a pH of between 3-7 w ith a preferred range of 4-5. The pH of the reaction 10 mixture is maintained by an appropriate buffer. The reaction is carried out with the reaction vessel pro-tected from light with constant stirring. upon compl~
t ion of the reaction, an excess of glycerin is added to neutrali~e the remaining unreacted periodate. The 15 aldehyde modified heparin is then optionally dried in a n itrogen environment. The dried aldehyde modified heparin may then be simply reconstituted in an appropriate acidic buffer of pH 3.0-8.0 where 4-7 is preferred and a reducing agent such as ~odium 20 cyanoborohydride i~3 added at weight percent of 1-40%, w here 5-3096 is preferred, and 5-1596 most preferred.
This solution is then exposed to the amine rich polyurethane-urea coated substrate. The aldehyde f unctional groups on the heparin are then reacted with 25 the free amine groups to give a Schiff base formation that may be reduced to provide stable secondary amines.
Exemplary reducing agents include sodium borohydride, 8 odium cyanoborohydride, and tetrahydrofuran- borane.
This reaction results in covalently bonding of the 30 antithrombogenic agent to the polyurethane-urea.
Upon completion of the antithrombogenic coupling reaction, the surface may be washed with water to remove loosely bound or unreacted antithrombogenic agent. Washing may be optionally performed with an 3 5 isotonic solution. The resulting covalently bonded heparin demonstrates high antithrombogenic activity as well as permanency and nonleachability.

The invention will be further illustrated by the following nonlimiting examples. All parts and percentages given throughout the Specification are by weight unless otherwise indicated.

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EXAMPLE
This example illustrates the synthesis of a prefer-red amine rich polyurethane-urea.
29.61g of trimethylolpropane and 215.149 of a low 5 molecular weight polyether polyol such as Teracol~ 650 (poly(oxytetramethylene) glycol) were added together in a mixing vessel (1.0 equivalent of each) and heated at 70C. After equilibrating, 346.909 (4.0 equivalents) of hydrogenated diphenyl methylene diisocyanate was 10 added and mixing continued. 0.09g of dibutyl tin dilaurate (0.01596) was added to the mixing solution.
After at least 5 minutes of mixing the reactants were transferred to a 90C oven for 60 minutes. After one hour the prepolymer was removed and the percent free 15 NCO groups was titrated and calculated. Typical values ranged from 8.0-9.5%. The prepolymer was then purged w ith nitrogen gas and stored.
60g of the previously prepared prepolymer (with NCO content of 8.46~) was added to 120g of toluene to 20 make a 3396 wt/wt solution. A diamine solution was prepared by adding 14.72g of 1,6-hexanediamine to 80g of isopropanol and 40g of toluene. The diamine solution was stirred vigorously with a magnetic stir bar. The prepolymer solution was then added dropwise 25 to the diamine solution over a ~wo hour period. The reaction was stirred for an additional two hours.
Glacial acetic acid (109) was then added dropwise to the reaction mixture. The resulting amine rich poly-urethane-urea polymer was then dried with nitrogen 30 gas and finally with vacuum. The amine rich poly-urethane-urea polymer was then dissolved in methanol to a 2096 wt/wt solution for coating.

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This example demonstrates the preparation of an aldehyde modified heparin.
Heparin (1.09) was added to a sodium acetate buffer which was prepared by dissolving 0.59 of sodium acetate in 300 ml distilled water. The pH of this solution was then adjus~ed to 4.5 with glacial acetic acid.
0.19 of sodium periodate ~NaI04) was added and the solution was reacted for 20 minutes in a light protected reaction vessel with constant stirring.
Thereafter, 3.09 of glycerol was added to neutralize any remaining periodate. The solution was concentrated by drying under nitrogen gas. The final solution was reconstituted to 1% wt/wt.

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d This example is illustrative of the preparation of an antithrombogenic surface according to the present invention.
An amine rich polyurethane-urea polymer of Example 1 was dissolved in methanol to a 20% wt/wt solution. A polyurethane substrate was coated with the amine-rich polyurethane-urea. After coating, the substrate was placed in nitrogen atmosphere for 60 minutes at ambient temperature. The samples were then placed in sodium borate buffer of pH 9.2, which was prepared by dissolving 57.219 of sodium borate in 15 liters of distilled water, and stored until reaction with heparin.
The samples were then placed in a mixing vessel and aldehyde-modified heparin of Example 2 was added to a concentration of 1~. The reaction was performed in a pH 4.5 sodium acetate buffer at 50C. Sodium cyano-borohydride (0.05g) was added as a reducing agent.
After 2 hours the samples were removed and placed in a 3M saline solution to remove any loosely bound or adsorbed heparin. Initial radiolabel assays showed that 117.2ug + 3 . 4ug of heparin was bound per cm2 of surface area. After 384 hours washing in a dynamic 3M
saline solution, essentially no heparin was leached or lost. Ths radiolabel assay showed 112.5ug + 6ug of heparin was still bound per cm2. This demonstrates the permanency of the covalent bonded heparin of this invention.

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various length diamines can be used in the synthesis of the amine rich polyurethane-urea. This example demonstrates the use of an eight carbon diamine.
29.619 of trimethylolpropane and 215.149 of a low molecular weight polyether polyol such as Teracol~ 650 (poly (oxytetramethylene) glycol~ were added together in a mixing vessel (1.0 equivalent of each) and heated at 70C. Thereafter, 346.gOg ~4.0 equivalents) of hydrogenated diphenyl methylene diisocyanate was added.
0.099 of dibutyl tin dilaurate, a catalyst, ~0.015%) was added to the mixing solution. After at least 5 minutes of mixing the reactants were transferred to a 90C oven for 60 minutes. After one hour the prepoly-mer was removed and the percent free -NCO groups were titrated and calculated. Typical values ranged from 8.0 - 9~5%. The prepolymer was then purged with nitrogen gas and stored.
159 of the previously prepared prepolymer ~with NCO content of 8.16%) was added to 30g of toluene to make a 33% wt/wt solution. A diamine solution was prepared by adding 5.099 of 1.8-octanediamine to 45g of 2:1 isopropanol/toluene ~by wt.) solvent mixture. The diamine solution was stirred vigorously with a magnetic stir bar. The prepolymer solution was then added drop-wise to the diamine solution over a two hour period.
The reaction was stirred for an additional two hours.
2.23g of glacial acetic acid was then added dropwise.
The resulting amine rich polyurethane-urea was then dried with nitrogen gas and finally with vacuum.
The amine rich polyurethane-urea polymer was then dissolved in propanol to a 15~ wt/wt solution for coating.

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This example demonstrates the effectiveness of the present invention in using longer chain diamines in the amine rich polyurethane-urea and the subsequent bonding of antithrombogenic agents.
An amine rich polyurethane-urea polymer of Example 4 was dissolved in propanol to a 15% wt/wt solution. A polyurethane substrate was coated with the amine rich polyurethane-urea. After coating, the sub-strate was placed in a nitrogen atmosphere for 60minutes at ambient temperature. The samples were then placed in sodium borate buffer of pH 9.2 and stored until reaction with heparin.
The samples were then placed in a mixing vessel and aldehyde-modified -heparin, similar to that of Example 2, was added to a concentration of 1%. The reaction was performed in a pH 4.5 sodium acetate buffer at 50C. Sodium cyanoborohydride (0.059) was added as a reducing agent. After 2 hours the samples were removed and placed in a 3M saline solution to remove any loosely bound or adsorbed heparin. Initial radiolabel assays showed that 113.6ug + 8.2ug of heparin was bound per cm2 of surface area. After 24 hours in a dynamic water wash, the radiolabel assay showed 90.7ug + 4.9ug of heparin was still bound per cm2. This demonstrates the permanency of the covalent bounded heparin of this invention.
The invention being thus described, it will be obvious that the same may be varied in many ways.
Such variations are not to be regarded as a departure from the spirit of scope of the invention and all such modifications are intended to be included within the scope of the claims.

Claims

What is claimed is:

1. An antithrombogenic polyurethane polymer, which comprises:
a. a support substrate;
b. a protonated amine rich polyurethane-urea bonded to said support substrate;
c. an aldehyde containing antithrombogenic agent reacted through the aldehyde group with the amine functionality of said polyurethane-urea to form a covalently bonded antithrombogenic material.

2. The antithrombogenic polyurethane polymer of claim 1 wherein the antithrombogenic agent is selected from the group consisting of aldehyde modified heparin, prostaglandins, urokinase, streptokinase, sulfated polysaccharide, albumin and mixtures thereof.

3. The antithrombogenic polyurethane polymer of claim 1 wherein the polyurethane polymer is selected from thermosetting polyurethane polymers and thermoplastic polyurethane polymers.

4. The antithrombogenic polyurethane polymer of claim 1 wherein the protonated amine rich polyurethane-urea is prepared from a polyurethane prepolymer and a diamine.

5. The antithrombogenic polyurethane polymer of claim 4 wherein the mole ratio of diamine to free isocyanate groups in the prepolymer is from about 0.6:1 to 1:1.

6. The antithrombogenic polyurethane polymer of claim 1 wherein the aldehyde containing antithrombo-genic agent is covalently bonded to the support substrate through the activation of amine groups on the protonated amine rich polyurethane-urea surface.

7. The antithrombogenic polyurethane polymer of claim 1 wherein the protonated amine is activated with an alkaline buffer to enable covalent coupling to the antithrombogenic agent in the presence of a reducing agent.

8. A process for imparting antithrombogenic activity to polyurethane polymer materials, which comprises:
a. treating the surface of a solid support with a solution of a protonated amine rich polyurethane-urea so that the polyurethane-urea is bonded to the support substrate;
b. removing solvent from the treated substrate to form a layer of the polyurethane-urea upon the support substrate;
c. activating the amine functionality on the polyurethane-urea with an alkaline buffer to form free amine groups; and d. reacting the free amine groups with an aldehyde containing antithrombogenic agent to covalently bond the antithrombo-genic agent to the polyurethane-urea in the presence of a reducing agent.

9. The process of claim 8 wherein the protonated amine rich polyurethane-urea is prepared from a poly-urethane prepolymer and a diamine.

10. The process of claim 9 wherein the mole ratio of diamine to free isocyanate groups in the prepolymer is from about 0.6:1 to 1:1.

11. The process of claim 8 wherein the antithrombogenic agent is heparin which is reacted with an aldehyde inducing compound to form aldehyde modified heparin.

12. The process of claim 11 wherein the aldehyde inducing compound is selected from the group consisting of sodium periodate and nitrous acid.

13. The process of claim 8 wherein the alkaline buffer has a pH greater than about 8Ø

14. The process of claim 8 wherein the polyurethane polymer is selected from thermosetting polyurethane polymers and thermoplastic polyurethane polymers.