CA1221631A - Covalent bonded antithrombogenic polyurethane material - Google Patents
Covalent bonded antithrombogenic polyurethane materialInfo
- Publication number
- CA1221631A CA1221631A CA000469313A CA469313A CA1221631A CA 1221631 A CA1221631 A CA 1221631A CA 000469313 A CA000469313 A CA 000469313A CA 469313 A CA469313 A CA 469313A CA 1221631 A CA1221631 A CA 1221631A
- Authority
- CA
- Canada
- Prior art keywords
- polyurethane
- antithrombogenic
- amine
- polymeric amine
- polyurethane polymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
- A61L33/0029—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate using an intermediate layer of polymer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0047—Enzymes, e.g. urokinase, streptokinase
Abstract
ABSTRACT OF THE DISCLOSURE
Antithrombogenic polyurethane polymers having the antithrombogenic material covalently bound to the polyurethane.
Antithrombogenic polyurethane polymers having the antithrombogenic material covalently bound to the polyurethane.
Description
3~
The present invention relates to a novel ~nti-thrombogenic polyurethane polymer and process for making the same. ~:ore particularly the invention relates to a polyurethane polymer having an antithrombogenic material covalently bound thereto so that the material is perma-nently affixed to the polymer and remains virtually nonleachable when the products ~ade form the reaction product are in use.
EX tensive investigations have been undertaken over many years to find materials that will be biologically and chemically stable towards body fluids. This area of research has become increasingly i~portant with the development of various objects and articles which can be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters and the like.
Artificial materials are being increasingly used as blood contact devices and may be subject to potential generation of thrombus. When blood contacts 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.
The overall objective of these investigations ha6 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, U.S.
Patent No. 3,617,344, was based on binains quaternary amines to a polymer surface and subsequently 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. ~oth the Leininger and Grotta methods have the disadvantage of being non-permanent or leachable systems. In general, ionically bound systems . q~
. , .
:,~ -, .
~- -12;~1~31 have limited viability due to their inherent leac~
ability. J. Love and G. W. Holres patented a method for the preparation of antithrombogenic surfaces in U.S.
Patent No. 3,616,935 wherein polyalkylenimines are used to irreversibly adsorb the antithrombogenic com-pound 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 overcome the deficiencies of the prior techniques,-notably leaching of the anti-thrombogenic material rendering the system non-perma-nent 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 "soft" 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 : 20 is chemically bound to the reactable compound. "Soft"
gel-like ~urfaces are not appropriate for devices such as catheters or other medical devices which require a - "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.
In contrast to the aforementioned technigues, U.S.
Patent 4,326,532 to Hammar discloses a layered medical article having an antithrombogenic surface wherein a natural or synthetic polymeric substrate is reacted with chitosan and the antithrombogenic is then bonded to the chitosan. Hammar disclosed on column 3, lines 10 to 49 that the antithrombogenic material may be ionically bonded to the chitosan or covalently bonded using boron hydrides.
~ ' , ' , ~:
:, , , , , :
. .
., : . . ' : .
. " ' ' ~ ' :
~2~1~i31 It would be desirable to provide a material which has excellent biological and chemical stability towards L O~- fiui~ , namely blood, which retains its antithrombogenic agent in a permanent and non-leachable fashion when in contact with blood. It would also be desirable to provide materials which, while being biocompatible, are also biofunctional, that is materials which have biological activity in a variety ; of functions.
The present invention accomplishes all of these needs by use of a covalently bonded antithrombogenic agent to a solid support. More particularly the invention involves an antithrombogenic polyurethane polymer having: a polyurethane substrate, a polymeric amine selected from the group consisting of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof covalently bonded to said polyurethane substrate and an antithrombogenic agent covalently bonded to said polymeric amine.
In another embodiment, the present invention in-volves a process for imparting antithrombogenic activity to polyurethane polymer materials which comprises:
treating the Yurface of the polyurethane poly~er material with a solution of a polymeric amine selected from the group con~istinq of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof 80 that the polymeric amine becomes covalently bonded to said polyurethane sub-strate and wherein the pH of the polymeric amine solution is at least 5.0, washing said surface essentially free of any non-covalently bonded polymeric amine, and treat the surface with an activated antithrombogenic agent to covalently bond the antithrombosenic agent to the polymeric amine.
The term antithrombogenic agent or material as used herein refer~ to any material which inhibits throm-bus formation on its surface, such as by reducing 1~1631 platelet agsregation, dissolving fibrin, enhancing passivating protein deposition, or inhibiting on~ or more steps within the coagulation cascade. Illustrative antithrombogenic material may be selected from the group consi~ting of heparin, prostaglandins, urokinase, ~treptokinase, ~ulfated poly~accharide, albumin and mixtures thereof. The antithrombogenic material may be used in varying amounts depending on the particular material employed and ultimate desired effect.
Preferred amounts have-generally been found to be less than about S~ by weight of the final products and may range from about 0.2~ to about 5% by weight.
The polyurethane polymerq used in the invention as the support structure may be selected from a wide range of thermosetting polyurethane polymers and thermo-plastic polyurethane polymers. The particular form~
tion~ do not constitute a critical aspect of this invention other than to serve as a support substrate for the antithrombogenic agent. The polyurethanes are preferably preformed into the desired shape or structure for the particular application prior to treatment according to the invention. Of significant importance is the ability of the polyurethane polymer to bind the polymeric amine with the antithrombogenic agent in order to effect irreversible coupling. This may be achieved by direct alteration of the polyurethane surface to enable activation of amine and hydroxyl groups from the urethane component. Alternately, various compositions may be chemically bound to the polyurethane surface which contain reactive amine and/or hydroxyl group~.
. ~ The chemical modification of the polyurethane surface may be achieved by convent$onal procedures, such as "etching" the surface with concentrated hydrochloric acid. Concentrated hydrochloric acid 1~ ~ results in partial hydroly~is of the polyurethane ~ component rendering free amino and hydroxyl groups (~
~ " ~
'' , - - . : ' '- ':
,, ,: ;
:: . -: .
':'~ ': ~' `, ': . ' ' which may be subsequently reacted with the polymeric a~ine directly by exchange condensation. When hydrochloric acid is employed, concentrations of 0.5 normal to S.0 normal at about 1~C to 50c temperatures ; 5 for about 5 to 20 hour times have be~n found quite suitable. It should be recognized that the concentra-tion, time and temperature may vary greatly depending on such factors as type of polyurethane polymer and degree of free amino group desired.
Alternatively, the polyurethane polymer surface may be coupled with a polyurethane prepolymer containing an excess of unreacted NC0 units present in the poly-isocyanate component. While the number of free ~C0 units may vary widely, it has been found to preferably employ a polyisocyanate prepolymer containing about 2%
to about 30% free NC0 units based upon total NC0 content.
Amounts below about 2% have been found to be ineffective in bonding sufficient amounts of polymeric amine whereas amounts greater than 30% result in the forma- -tion of polyurethane prepolymers that are difficult to handle.
When a prepolymer is used, the polyurethane surface is contacted with the preblended polyurethane prepolymer having a concentration in solution of about 5% to about ; 25 40% (weight to weight). The prepolymers contain conventional polyisocyanates and polyhydric alcohols.
The polyisocyanates useful in the invention in introducing the urethane linkage into the polymer chain may be selected from a wide range of aliphatic, cyclo-aliphatic and aromatic polyisocyanates. Useable diiso-cyanates may contain noninterfering groups, e.g., aliphatic hydrocarbon radicals such a~ lower alkyl or other groups, having substantially nonreactive hydrogens as determined by the Zerewitinoff test, J. Am. Chem.
Soc. 49,3181 (1927). The diisocyanate often has at least 6 carbon atoms and usual~y does not have more than about 40 c~rbon atomc. Diioocyanate~ of about b to 20 .' . . :
': . . , 1;Z~1~31 atoms in the hydrocarbon group are preferred. Suitable diisocyanates include 2,4-toluene diisocyanate, 2,6-tol~ene diisocyanate 1,4-cyclohexane diisocyante dicyclohexylmethane 4,4'-diisocyanate, xylene diisocyanate 1-isocyanat~3-iRocyanatomethyl-3,5,5-tri-methylcyclohexane hexamethylene diisocyanate, methyl-cyclohexyl diisocyanate 2,4,4-trimethylhexylmethylene diisocyanate, isocyanates such a~ mrphenylene diiso-cyanate mixtures of 2,4- and 2,6 hexamethylen~l,5-diisocyanate, hexahydrotolylene diisocyanate (andisomers), naphtylene-1,5-diisocyanate l-methoxyphenyl -
The present invention relates to a novel ~nti-thrombogenic polyurethane polymer and process for making the same. ~:ore particularly the invention relates to a polyurethane polymer having an antithrombogenic material covalently bound thereto so that the material is perma-nently affixed to the polymer and remains virtually nonleachable when the products ~ade form the reaction product are in use.
EX tensive investigations have been undertaken over many years to find materials that will be biologically and chemically stable towards body fluids. This area of research has become increasingly i~portant with the development of various objects and articles which can be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters and the like.
Artificial materials are being increasingly used as blood contact devices and may be subject to potential generation of thrombus. When blood contacts 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.
The overall objective of these investigations ha6 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, U.S.
Patent No. 3,617,344, was based on binains quaternary amines to a polymer surface and subsequently 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. ~oth the Leininger and Grotta methods have the disadvantage of being non-permanent or leachable systems. In general, ionically bound systems . q~
. , .
:,~ -, .
~- -12;~1~31 have limited viability due to their inherent leac~
ability. J. Love and G. W. Holres patented a method for the preparation of antithrombogenic surfaces in U.S.
Patent No. 3,616,935 wherein polyalkylenimines are used to irreversibly adsorb the antithrombogenic com-pound 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 overcome the deficiencies of the prior techniques,-notably leaching of the anti-thrombogenic material rendering the system non-perma-nent 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 "soft" 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 : 20 is chemically bound to the reactable compound. "Soft"
gel-like ~urfaces are not appropriate for devices such as catheters or other medical devices which require a - "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.
In contrast to the aforementioned technigues, U.S.
Patent 4,326,532 to Hammar discloses a layered medical article having an antithrombogenic surface wherein a natural or synthetic polymeric substrate is reacted with chitosan and the antithrombogenic is then bonded to the chitosan. Hammar disclosed on column 3, lines 10 to 49 that the antithrombogenic material may be ionically bonded to the chitosan or covalently bonded using boron hydrides.
~ ' , ' , ~:
:, , , , , :
. .
., : . . ' : .
. " ' ' ~ ' :
~2~1~i31 It would be desirable to provide a material which has excellent biological and chemical stability towards L O~- fiui~ , namely blood, which retains its antithrombogenic agent in a permanent and non-leachable fashion when in contact with blood. It would also be desirable to provide materials which, while being biocompatible, are also biofunctional, that is materials which have biological activity in a variety ; of functions.
The present invention accomplishes all of these needs by use of a covalently bonded antithrombogenic agent to a solid support. More particularly the invention involves an antithrombogenic polyurethane polymer having: a polyurethane substrate, a polymeric amine selected from the group consisting of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof covalently bonded to said polyurethane substrate and an antithrombogenic agent covalently bonded to said polymeric amine.
In another embodiment, the present invention in-volves a process for imparting antithrombogenic activity to polyurethane polymer materials which comprises:
treating the Yurface of the polyurethane poly~er material with a solution of a polymeric amine selected from the group con~istinq of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof 80 that the polymeric amine becomes covalently bonded to said polyurethane sub-strate and wherein the pH of the polymeric amine solution is at least 5.0, washing said surface essentially free of any non-covalently bonded polymeric amine, and treat the surface with an activated antithrombogenic agent to covalently bond the antithrombosenic agent to the polymeric amine.
The term antithrombogenic agent or material as used herein refer~ to any material which inhibits throm-bus formation on its surface, such as by reducing 1~1631 platelet agsregation, dissolving fibrin, enhancing passivating protein deposition, or inhibiting on~ or more steps within the coagulation cascade. Illustrative antithrombogenic material may be selected from the group consi~ting of heparin, prostaglandins, urokinase, ~treptokinase, ~ulfated poly~accharide, albumin and mixtures thereof. The antithrombogenic material may be used in varying amounts depending on the particular material employed and ultimate desired effect.
Preferred amounts have-generally been found to be less than about S~ by weight of the final products and may range from about 0.2~ to about 5% by weight.
The polyurethane polymerq used in the invention as the support structure may be selected from a wide range of thermosetting polyurethane polymers and thermo-plastic polyurethane polymers. The particular form~
tion~ do not constitute a critical aspect of this invention other than to serve as a support substrate for the antithrombogenic agent. The polyurethanes are preferably preformed into the desired shape or structure for the particular application prior to treatment according to the invention. Of significant importance is the ability of the polyurethane polymer to bind the polymeric amine with the antithrombogenic agent in order to effect irreversible coupling. This may be achieved by direct alteration of the polyurethane surface to enable activation of amine and hydroxyl groups from the urethane component. Alternately, various compositions may be chemically bound to the polyurethane surface which contain reactive amine and/or hydroxyl group~.
. ~ The chemical modification of the polyurethane surface may be achieved by convent$onal procedures, such as "etching" the surface with concentrated hydrochloric acid. Concentrated hydrochloric acid 1~ ~ results in partial hydroly~is of the polyurethane ~ component rendering free amino and hydroxyl groups (~
~ " ~
'' , - - . : ' '- ':
,, ,: ;
:: . -: .
':'~ ': ~' `, ': . ' ' which may be subsequently reacted with the polymeric a~ine directly by exchange condensation. When hydrochloric acid is employed, concentrations of 0.5 normal to S.0 normal at about 1~C to 50c temperatures ; 5 for about 5 to 20 hour times have be~n found quite suitable. It should be recognized that the concentra-tion, time and temperature may vary greatly depending on such factors as type of polyurethane polymer and degree of free amino group desired.
Alternatively, the polyurethane polymer surface may be coupled with a polyurethane prepolymer containing an excess of unreacted NC0 units present in the poly-isocyanate component. While the number of free ~C0 units may vary widely, it has been found to preferably employ a polyisocyanate prepolymer containing about 2%
to about 30% free NC0 units based upon total NC0 content.
Amounts below about 2% have been found to be ineffective in bonding sufficient amounts of polymeric amine whereas amounts greater than 30% result in the forma- -tion of polyurethane prepolymers that are difficult to handle.
When a prepolymer is used, the polyurethane surface is contacted with the preblended polyurethane prepolymer having a concentration in solution of about 5% to about ; 25 40% (weight to weight). The prepolymers contain conventional polyisocyanates and polyhydric alcohols.
The polyisocyanates useful in the invention in introducing the urethane linkage into the polymer chain may be selected from a wide range of aliphatic, cyclo-aliphatic and aromatic polyisocyanates. Useable diiso-cyanates may contain noninterfering groups, e.g., aliphatic hydrocarbon radicals such a~ lower alkyl or other groups, having substantially nonreactive hydrogens as determined by the Zerewitinoff test, J. Am. Chem.
Soc. 49,3181 (1927). The diisocyanate often has at least 6 carbon atoms and usual~y does not have more than about 40 c~rbon atomc. Diioocyanate~ of about b to 20 .' . . :
': . . , 1;Z~1~31 atoms in the hydrocarbon group are preferred. Suitable diisocyanates include 2,4-toluene diisocyanate, 2,6-tol~ene diisocyanate 1,4-cyclohexane diisocyante dicyclohexylmethane 4,4'-diisocyanate, xylene diisocyanate 1-isocyanat~3-iRocyanatomethyl-3,5,5-tri-methylcyclohexane hexamethylene diisocyanate, methyl-cyclohexyl diisocyanate 2,4,4-trimethylhexylmethylene diisocyanate, isocyanates such a~ mrphenylene diiso-cyanate mixtures of 2,4- and 2,6 hexamethylen~l,5-diisocyanate, hexahydrotolylene diisocyanate (andisomers), naphtylene-1,5-diisocyanate l-methoxyphenyl -
2,4-diisocyanate, diphenylmethane 4,4'-diisocyanate, 4,4'-biphenylene diisocyanate, 3,3'-dimethoxy - 4.4-biphenyl diisocyanate, 3,3' - dimethyl - 4,4'-biphenyl diisocyanate, and 3,3'dimethyl-diphenylmethane - 4,4'-diisocyanate and mixtures thereof. The aliphatic and alicyclic diicocyanates employed in the process of this invention and the products made therefrom generally exhibit good resistance to the degradative effects of ultraviolet light.
The polyisocyanate component used to form the prepolymers may contain a portion of polyisocyanates having more than two isocyanate (NC0) groups per molecule providing the urethane polymer compositions are not unduly deleteriously affected. The preferred polyisocyanate i~ selected from the group consisting of 4,4'-diphenylmethane diisocyanate, toluene diisocyanate, isophorone diisocyanate and methylene bis (4-cyclohexyl) diisocyanate.
The high molecular weight glycols useful in the present invention may be a polyether diol or polyester diol and range in number average molecular veight 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 polyols which may be employed to prepare polyester .~ ,...
: ~ ' . . . ~ :.
,; .
1~,41~31 polyols are 1,6-hexanediol, neopentyl glycol, tri-methylol propane, ethylene glycol, diethylene glycol, triethylene glycol, 1,4-butanediol, 1,4-cyclohexane, 1,2-propanediol, 1,3-propanediol, 1,3-butylene glycol, 1,4-cyclohexane dimethanol, 1,6-hexanediol, and the like, and mixtures thereof. The preferred low molecu-lar weight glycol is 1,4-butanediol. Illustrative polyesters may contain hydroxyl groups, for example, reaction products of polyhydric alcohols reacted with divalent carboxylic acids. It i8 also possible to use the corresponding polycarboxylic acid anhydrides or corresponding polycarboxylic acid esters of lower alcohols or mixtures thereof, for producing the polyesters. The polycarboxylic acids may be aliphatic, cycloaliphatic, aromatic and/or heterocyclic and may optionally be substituted, for example, by halogen atoms and/or unsaturated. Examples of polycarboxylic acids of this kind include succinic acid, adipic acid, suberic acid, azelaic acid, sebacic acid, phtalic acid, phtalic acid anhydride, tetrachlorophtalic acid anhydride, endomethylene tetrahydrophthalic acid anhydride, glutaric acid anhydride, maleic acid, maleic acid anhydride, fumaric acid, dimeric and trimeric fatty acids such as oleic acid, optionally in admixture with monomeric fatty acids, terephthalic acid dimethyl ester and terephtalic 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-hexane diol, 1,8-octane diol, neopentyl glycol, cyclohexane dimethanol ll,4-bix-hydroxy methyl cyclohexane), 2-methyl-1,3-propane diol, also diethylene glycol, triethylene glycol, tetra~ethylene glycol, poly-ethylene glycols, dipropylene glycol, polypropylene glycols, dibutylene glycol and polybutylene glycols.
Polyesters of lactones, for example, epsolon-caprolactone or hydroxy carboxylic acid6, for example,w-hydroxycaproic acid, may also be used.
The polyethers containing at least 2, generally 2 , ': ............................. . .
~' '~ , -, ` ' , ~, ' . , to 8, but preferably 2 to 3 hydroxyl groups used in accordance with the invention are also known per se ar,d are obtained, for example, by polymerizing epoxides, such as ethylene oxide, propylene oxide, butylene oxide, tetrahydrofuran, styrene oxide or epichlorohy-drin on their own, for example, in the presence of BF3, or by adding these epoxides, optionally in admixture or in succession, to starter components 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 diol are poly(tetramethylene ether) glycols.
The use of trihydric and tetrahydric alcohols should be employed when cross-linking i8 desired for rendering the polyurethane thermosetting.
The polyurethane prepolymers are prepared by con-ventional means well known to the skilled artisan. The NCO/OH ratio is generally greater than 1 to give free ~CO groups in the prepolymer. Generally this procedure involves heating while mixing the glycols to their melting point and then adding the polyisocyanate during mixing to enable formation of the prepolymer and stop-ping the reaction before the polymerization reaction is complete. Once prepared, the prepolymer is dispersed ; or dissolved in a solvent at the appropriate concentra-tion of about 5% to about 40~ and the polyurethane substrate is contacted to form a layer of prepolymer upon the polymer substrate. Once contacting is com-plete, the structure is placed in a nitrogen environ-ment to remove the solvent and is then ready for reaction with the polymeric amine. The solvents may be selected from a wide variety of materials that are capable of dispersing the prepolymer which are volatilizable at temperatures below the melting point ~ of the polymer substrate and prepolymer. Exemplary '~
. -; -. .
: . .
1~1tj31 solvents include ethyl acetate, acetonitrite, methylene chloride, tetrahydrofuran, and the like.
The polymeric amine used in the invention may be selected from the group consisting of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof. Although the polyalkylenimine polymers are branched, the amine unit may be shown by the formula.
¦ CH-CH-NH
I Rl I_ _I x wherein Rl is hydrogen, a methyl or ethyl group or larger with an attached amine and R2 is hydrogen or another amino alkylene unit according to the formula.
Exemplary materials include polyethylenimine and poly-propylenimine. Polymers with a mixture of amine units are also able to be used such as polymers prepared by the polymerization of mixtures of ethylenimine and propylenimine. Polybutylenimine is also useable but not preferred. The average molecular weight of the polyalkylenimine is normally preferably 11,000 to 100,000 and represents multiples of x as ~hown.
The polymeric amine used in this invention must be covalently bound to the polymeric ~upport. This may be conveniently done by coupling the polymeric amine directly to the polymer support or by coupling to a chemical arm or bonding layer previou~ly coupled to ~ the support. A preferred embodiment of the invention i 35 involves chemical reaction of the polymeric amine with activated amine groups via conden~ation interchange on the substrate or chemical reaction with free NC0 units , '~ .
.,' .
,. ~ . .
~: . ~ .- . ' - -: , , . , ,. . .: ,' . : ~
, . ~ . --lZ~1~31 present on a prepolymer layered onto the support surface.
Reaction of the polymeric amine with the polymer substrate, either through condensation interchange or through a che~ical arm or prepolymer layer i8 performed by dissolving the polymeric amine in water and contact-ing the activated sites to be bound for about 1 minute to 2 hours at 20C to about 50C. The length of time needed to perform the bonding step as well as tempera-ture of the solution may vary depending on such factorsa 8 the particular polymeric amine being used and con-centration of the amine solution. It has been found acceptable to employ polymeric amine solutions con-taining from about 1~ to abut 50~ and preferably about 10~ to about 20% by weight polymeric amine in the solution. Evaporating the water and post-curing the ~ system for periods up to several days at 20C to about ; 50C may increase the covalent bonding.
In order to maximize the covalent bonding of the polymeric amine to the activated amino groups, the pH
~X~ of the solution is maintained above 5.0, preferably from about 5.0 to about 12.0 and most preferably from about 7.0 to about 9Ø
Once the polymeric amine has been covalently coupled to the polymer support, the polymeric amine i8 washed essentially free of unbound polymeric amine. Washing may be performed with water or aupplemented with a d$1ute and/or base waJh.
Once washing is complete, the polymeric amine is
The polyisocyanate component used to form the prepolymers may contain a portion of polyisocyanates having more than two isocyanate (NC0) groups per molecule providing the urethane polymer compositions are not unduly deleteriously affected. The preferred polyisocyanate i~ selected from the group consisting of 4,4'-diphenylmethane diisocyanate, toluene diisocyanate, isophorone diisocyanate and methylene bis (4-cyclohexyl) diisocyanate.
The high molecular weight glycols useful in the present invention may be a polyether diol or polyester diol and range in number average molecular veight 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 polyols which may be employed to prepare polyester .~ ,...
: ~ ' . . . ~ :.
,; .
1~,41~31 polyols are 1,6-hexanediol, neopentyl glycol, tri-methylol propane, ethylene glycol, diethylene glycol, triethylene glycol, 1,4-butanediol, 1,4-cyclohexane, 1,2-propanediol, 1,3-propanediol, 1,3-butylene glycol, 1,4-cyclohexane dimethanol, 1,6-hexanediol, and the like, and mixtures thereof. The preferred low molecu-lar weight glycol is 1,4-butanediol. Illustrative polyesters may contain hydroxyl groups, for example, reaction products of polyhydric alcohols reacted with divalent carboxylic acids. It i8 also possible to use the corresponding polycarboxylic acid anhydrides or corresponding polycarboxylic acid esters of lower alcohols or mixtures thereof, for producing the polyesters. The polycarboxylic acids may be aliphatic, cycloaliphatic, aromatic and/or heterocyclic and may optionally be substituted, for example, by halogen atoms and/or unsaturated. Examples of polycarboxylic acids of this kind include succinic acid, adipic acid, suberic acid, azelaic acid, sebacic acid, phtalic acid, phtalic acid anhydride, tetrachlorophtalic acid anhydride, endomethylene tetrahydrophthalic acid anhydride, glutaric acid anhydride, maleic acid, maleic acid anhydride, fumaric acid, dimeric and trimeric fatty acids such as oleic acid, optionally in admixture with monomeric fatty acids, terephthalic acid dimethyl ester and terephtalic 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-hexane diol, 1,8-octane diol, neopentyl glycol, cyclohexane dimethanol ll,4-bix-hydroxy methyl cyclohexane), 2-methyl-1,3-propane diol, also diethylene glycol, triethylene glycol, tetra~ethylene glycol, poly-ethylene glycols, dipropylene glycol, polypropylene glycols, dibutylene glycol and polybutylene glycols.
Polyesters of lactones, for example, epsolon-caprolactone or hydroxy carboxylic acid6, for example,w-hydroxycaproic acid, may also be used.
The polyethers containing at least 2, generally 2 , ': ............................. . .
~' '~ , -, ` ' , ~, ' . , to 8, but preferably 2 to 3 hydroxyl groups used in accordance with the invention are also known per se ar,d are obtained, for example, by polymerizing epoxides, such as ethylene oxide, propylene oxide, butylene oxide, tetrahydrofuran, styrene oxide or epichlorohy-drin on their own, for example, in the presence of BF3, or by adding these epoxides, optionally in admixture or in succession, to starter components 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 diol are poly(tetramethylene ether) glycols.
The use of trihydric and tetrahydric alcohols should be employed when cross-linking i8 desired for rendering the polyurethane thermosetting.
The polyurethane prepolymers are prepared by con-ventional means well known to the skilled artisan. The NCO/OH ratio is generally greater than 1 to give free ~CO groups in the prepolymer. Generally this procedure involves heating while mixing the glycols to their melting point and then adding the polyisocyanate during mixing to enable formation of the prepolymer and stop-ping the reaction before the polymerization reaction is complete. Once prepared, the prepolymer is dispersed ; or dissolved in a solvent at the appropriate concentra-tion of about 5% to about 40~ and the polyurethane substrate is contacted to form a layer of prepolymer upon the polymer substrate. Once contacting is com-plete, the structure is placed in a nitrogen environ-ment to remove the solvent and is then ready for reaction with the polymeric amine. The solvents may be selected from a wide variety of materials that are capable of dispersing the prepolymer which are volatilizable at temperatures below the melting point ~ of the polymer substrate and prepolymer. Exemplary '~
. -; -. .
: . .
1~1tj31 solvents include ethyl acetate, acetonitrite, methylene chloride, tetrahydrofuran, and the like.
The polymeric amine used in the invention may be selected from the group consisting of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof. Although the polyalkylenimine polymers are branched, the amine unit may be shown by the formula.
¦ CH-CH-NH
I Rl I_ _I x wherein Rl is hydrogen, a methyl or ethyl group or larger with an attached amine and R2 is hydrogen or another amino alkylene unit according to the formula.
Exemplary materials include polyethylenimine and poly-propylenimine. Polymers with a mixture of amine units are also able to be used such as polymers prepared by the polymerization of mixtures of ethylenimine and propylenimine. Polybutylenimine is also useable but not preferred. The average molecular weight of the polyalkylenimine is normally preferably 11,000 to 100,000 and represents multiples of x as ~hown.
The polymeric amine used in this invention must be covalently bound to the polymeric ~upport. This may be conveniently done by coupling the polymeric amine directly to the polymer support or by coupling to a chemical arm or bonding layer previou~ly coupled to ~ the support. A preferred embodiment of the invention i 35 involves chemical reaction of the polymeric amine with activated amine groups via conden~ation interchange on the substrate or chemical reaction with free NC0 units , '~ .
.,' .
,. ~ . .
~: . ~ .- . ' - -: , , . , ,. . .: ,' . : ~
, . ~ . --lZ~1~31 present on a prepolymer layered onto the support surface.
Reaction of the polymeric amine with the polymer substrate, either through condensation interchange or through a che~ical arm or prepolymer layer i8 performed by dissolving the polymeric amine in water and contact-ing the activated sites to be bound for about 1 minute to 2 hours at 20C to about 50C. The length of time needed to perform the bonding step as well as tempera-ture of the solution may vary depending on such factorsa 8 the particular polymeric amine being used and con-centration of the amine solution. It has been found acceptable to employ polymeric amine solutions con-taining from about 1~ to abut 50~ and preferably about 10~ to about 20% by weight polymeric amine in the solution. Evaporating the water and post-curing the ~ system for periods up to several days at 20C to about ; 50C may increase the covalent bonding.
In order to maximize the covalent bonding of the polymeric amine to the activated amino groups, the pH
~X~ of the solution is maintained above 5.0, preferably from about 5.0 to about 12.0 and most preferably from about 7.0 to about 9Ø
Once the polymeric amine has been covalently coupled to the polymer support, the polymeric amine i8 washed essentially free of unbound polymeric amine. Washing may be performed with water or aupplemented with a d$1ute and/or base waJh.
Once washing is complete, the polymeric amine is
3~0 ~reacted with an activated antithrombogenic agent to covalently bond the antithrombogenic agent to~the poly eric amine. ictivation of the antlthrombogenic aqent may be performed in varioua waya, Jucb aa cb ical modification of the antithrombogenic agent with oxidizing or reducing agents. A particularly preferred way of activating the antithrombogenic agent to couple the agent with a reactive chemical moiety .' , ' ' - :, ' ' ' ' ' " . ''' -~, ~, , - .- :
,,~ . -~ . . .
: .. : , ~ ~ . . , :
lZ~1~i31 that will enable covalent bonding of the agent to the polymeric amine. Exemplary agents that can be used as the activating agent may be selected from the group consisting of N-ethyl-5-phenylisoxazolium-3~-sulfonate 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydro-chloride and l-cyclohexyl-3-(2-morpholinoethyl) carbodiimide. The mere use of ionic salts of the antithrombogenic agent i6 not effective and merely results in the formation of leachable ionic bonds.
The antithrombogenic covalent bonding reaction, when using the preferred activating agents may vary from about 5 to 35 hours or more depending on such factors as the particular agent used, concentration of agent employed and degree of coupling achieved.
Generally, the antithrombogenic agent solution concen-tration is from about 0.1 to about 30% by weight but may vary up to the solubility limit of the particular agent. The reaction is preferably performed at temperatures between 4C and 23C but may be performed at higher temperatures up to the deactivation tempera-ture of the antithrombogenic agent.
The amount of activating agent employed will vary with the particular antithrombogenic agent and must be - employed in the ratio of at least 1 molecule of activating agent to each molecule of antithrombogenic agent. When employing antithrombogenic agents that are polymeric in character, such as heparin which have repeating tetrasaccharide units, the equivalent ratio of the heparin to the activating agent may be 6-24 to one wherein the heparin equivalent weight i8 calculated on the basis of a tetrasaccharide moiety, namely 4 repeating saccharide molecules representing one unit.
Upon completion of the antithrombogenic coupling reaction, the surface may be washed with water to remove loosely bound or unreacted antithrombogenic :
.
. . .
., : . . - . . . -- .:: - , -- - . , ~. , , . ' ', -~' ', ,' .. ' ' ~ ' -"' ~' ' : '- '' .- ' - ~ ' ' 1Z~1631 agent. Washing may be optionally performed with an isotonic solution.
A procedure for preparing a preferred material according to the invention may be depicted from the following equation:
(1) /I NCO ~ NCO
/ I NCO / I ¦--NCO
- 1o /I ' /I
/1 .
(a) (b) (c) /1 1 o /1 I N~l2 (2) H2N (CH2-CH2-NH)XH ~ -N-C-N
(d) /¦ ¦ O
/¦ I N-C-N
~ /1 I H NH2 ~ (e) O O
(3) HEPARIN _C_O-C /1 1 O
0 C-c-NH-c2Hs /¦ ¦-N-C-N
. o /1 1 ~ - - /1 I N-C-HEPARIN
: ~ (f ) /l I O
/ ¦ ¦--N-C--N
, , ! N--C--HEPARIN
, ; ., ..-,,.
:
., ~, , .
,. .
,~,~`.
,; ' . . , . -,. ;.,, . . ~ . . . ~ . ~ . . ` -~ -. .. ... ~ - ~
..
. .
. . . .
. .
1~1631 In the reaction equation Acheme depicted, the polymeri~ support (a) is contacted with a polyurethane prepolymer (b) to prepare a solid support having free NC0 units (c). The free NC0 units are then reacted with a polyalkylenimine (d) to form a backbone support - structure for coupling with the antithrombogenic agent (e). In the final step, heparin coupled to N-ethyl-5-phenylisoKazolium-3'-sulfonate (f) is reacted with the support to form a structure wherein heparin is covalent-ly coupled to the polymeric support (g). The resulting covalently bonded heparin would demonstrate high antithrombogenic efficacy as well as permanency and nonleachability.
While the present invention has been des~ribed in terms of using polyurethane polymers as the qupport surface, it should be recognized that other solid support materials having active hydrogen groups or groups that can be aminolyzed by the polymeric amine are con-templated for use herein. Exemplary materials include polyamides, polyesters, and polyvinyl chlorides.
The invention will be further illustrated by the following 'non-limiting examples. All parts and per-centages given throughout the Specification are by ,,A weight unless otherwiee indicated.
~ampie l - Inventive-Run l This example demonstrates the preparation and etability of etructures of the invention ueing heparin as the antithrombogenic agent.
Samples of polyurethane tubing were dipped into a 40% solution of an NC0 terminated prepolymer in ethyl-acetate having a 9.5~ free NC0 concentration. 'The NC0 terminated prepolymer had the following formu-lation:
.
, ': ', ~:., ' ' ' ,' ,' : .' , - ' ~. : , .
: , , .
.
- . ' - .
.
Reactants Eg~ivalents ~ Free NC0 Trimethylolpro~âle 1 9.5 Long chain polytetramethylene ether (650 average M.W.) 5 Hydrogenated 4,4'-diphenyl 4.0 methane diisocyanate Dibutyl tin dilaurate (0.015~) The NC0 coated tubing was placed in a 25c enclosed environment for 30 minutes to flash the ; 10 solvent. During the flash-off period, the atmosphere was continuously flushed with nitrogen. After 30 minutes, the tubing was transferred to a 20% solution of polyethyleni~ine at 50C. After five minutes the tubing was removed and placed in a continuous flow water rinse for up to 48 hours to remove any non-covalently bound polyethylenimine. After the rinse period, the samples were then placed in a 0.25% solution of radio labeled heparin complexed with N-ethyl-5-phenylisoxazolium-3'-sulfonate for 16 hours at ambient conditions. Following the heparin reaction, the samples were exposed to a dynamic water rinse for varied times. The rinse i3 designed to remove any un-reacted reagents. A known area of tubing was then dis-solved in a solvent, placed in a scintillation counter and scintillation counting performed. It was shown that about 31 ug/cm2 was bound to the polymer surface. The results are summarized in Table I and demonstrate that the heparin was covalently bonded to the support and was essentially non-leachable after successive washes.
TABLE I
~' `` Heparin Bound ¦ Rlnse time ~hr) ' -- -' -- -~- 4 - -~ 24 48 1 37.1*2.0 33.3~8.8 33.7*~.7 31.1~4.3 l .. .. , . . ..... , . .... . .... .... .. ...... .. ~ .. ~ l 1.
: ', '~ ''. , , : ~.. , -, - , , , , ,. .
~ ' , ' ' ' ~ , J;~1 Example II
Inventive Run 2 and Comparative Runs A and B
This example compares the partial thromboplastin time of structures made according to the invention com-pared to ~everal non-inventive systems.
Round bottom shaped thimbles were made from the polyurethane of Example I by casting the polyurethane on the outside of a glass test tube. After the thimbles were stripped off and cut to ~ize, they were treated as in ~xample I with a prepolymer having the formulation:
Rea ents Equivalents ~ Free NC0 g Long chain polytetramethylene 1 6.6 ether (650 average M.W.) - Hydrogenated 4,4'-diphenyl 1.9 15 methane diisocyanate Dibutyl tin dilaurate(0.015%) The samples were then subjected to exhaustive washing procedures to insure removal of any unreacted reagents.
The samples were exposed to 144 hours of dynamic water rinse, followed by 144 hours in 0.855 sodium chloride, and finally to 72 hours in 3M sodium chloride. After a sample was removed from the 3M NaCl solution, it was rinsed with distilled water and dried in a desiccator before testing. Partial thromboplastin times (PTT) were determined for each thimble by the following procedure:
(a) The thimble was placed in a heating bloc~ well in a water bath at 37C.
(b) 0.1 ml. fresh, citrated, platelet-poor pla~ma and 0.1 ml. partial thromboplactin reagent were pipetted into a thimble and incubated for fiYe minutes.
(c) 0.1 ml. of 0.02 M CaC12 was added and a stop watch was started simultaneou-~ly.
- - .
12~1~31 (d) A nichrome loop was passed through the plasma mixture at a rate of two sweeps per second until the first strands of fibrin are detected.
Samples which were prepared in a similar manner were also tested by a modified PTT method, wherein step (b) of the previous procedure, "5 minutes" was changed to 30 minutes. The test demonstrates the need for truly covalent bonded systems to be incubated to allow the surface bound heparin to interact to produce an anti-coagulant effect. The results are aet forth in Table II.
TABLE II
.. . . . . . .
I 1 130 ~in. Incubation¦
I ¦ PTT ¦ PTT
15 ¦ Sample ¦ (8econd8) t ~9econds~ t ¦Glass (untreated) ¦ 60 1 59 ¦Polyurethane (untreated)¦ 171 1 266 - ¦Antithrombotic ¦ 178 ¦ 498 IPolyurethane ~olymer- ~ 1 ' ' '' ' ' ' ' ' " ' 1 ' ' ' ' ' ' ' ' ' ' ' ' I
There i9 a clear improvement in the PTT time for the - inventive structure over the glass and untreated poly-urethane structures. This demonstrates antithrombogenic - efficacy. The observed effect was not due to leached anticoagulant, but to a permanently bonded system. This is evidenced in three ways. First upon completion of the PTT testing, the plasma wa~ removed from the thimble and analyzed by scintillation counting techniques showed no detectable radio labeled heparin for the inventive structure. This data shows that leached heparin was not responsible for the anticoagulant effect. Secondly, the PTT column of data in Table II shows the results of a normal (5 minute incubation) PTT test. There is ~ ~' "' ,., ~ ' ' . " ' . .
~ ~ ' '- . -1ti31 no detectable anticoagulant effect. This demonstrates the system is not leachable but rather covalently bound.
As such, the system requires incubation to show anti-coagulant effect. Finally, the PTT test showed an extension of clotting time over the controlled materials as seen in the 30 minute incubation results of Table II
showing an anticoagulant effect.
A slight extension of PTT was observed in the untreated polyurethane after a 30 minute incubation.
Although not wanting to be held to a particular theory, this result may be due to passivation via adsorption of such pla~ma proteins as albumin.
Example III
Inventiv~ Run 3-and Comparative-Run C
This example compares the use of various amines to couple the antithrombogenic agent to the support.
Tubes identical to those used in Example I were coated with the NC0 terminated prepolymer of Example I.
A portion of the samples were treated exactly as in Example I. A second portion of the tubes were treated in the same manner except a 20~ aqueous solution of 1,6-hexanediamine was used in place of 20% polyalkylenimine.
The results are shown in Table III.
TABLE III
., , . . . . . . . . ., . . . . . . . . . ., ~ . . . . . . . . .. . . . . . .. . . . .
25 ¦ Amount 8eparin I Treatment Bound ( ug/cm2) ¦
~ .. ... . . . . ,. . . . .. . . .. .. . . . , .. . .. . .. . . .. . . . . . . . . . . l - 1 .
¦Polyurethane Polyalkylenimine 25-30 ¦Polyurethane 1,6-hexanediamine -- -- - l The amount of heparin permanently bound to the inventive tube was significantly greater than that ; achieved in the comparative technique.
.~
- : , - ., :
. ' ~
., : - : : :
. . ~ :: . -. :
' ' ', ' ~ ' ~ ' ', ' ' ' ' `' BX ample ~V
~nventive Run 4 This example demonstrates the preparation of structures according to the invention using an acid etch of the polymeric surface to provide reactive amine and hydroxyl groups.
Samples of polyurethane tubing were exposed to 3N
hydrochloric acid for a period of 18 hours. This treat-; ment was then followed by 3 hours in boiling water.
The tubing samples were subsequently dried and reacted ; for 24 hours with hydrogenated 4-4'-diphenyl methane diisocyanate or the hydrogenated form of the latter to which 0.15~ dibutyl tin dilaurate has been added.
The re~ulting NCO group is then converted to amine by reaction with a 25% solution of polyethylenimine for a period of 4 hours. The resulting structure was washed extensively in distilled water. Finally, the structure was exposed to a solution of activated ; heparin, where the heparin concentration of 0.25~ in water having 20~ of the -COOH groups of the heparin activated via N-ethyl-5-phenylisoxazolium-3'-sulfonate.
The modified polyurethane surface was then washed in 3M
NaCl for a period of 24 hours to remove any loosely or non-covalently bound heparin. The resulting heparin products were nonleachable when washed.
The invention being thus de~cribed, 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.
.i "
~`
~, .: .: .', - . -~,., ~ j . .
. ,~ - ~, . .. ....
--:., ,, : ,- , , ~ , , , . ~ . . .
,~ , .
,
,,~ . -~ . . .
: .. : , ~ ~ . . , :
lZ~1~i31 that will enable covalent bonding of the agent to the polymeric amine. Exemplary agents that can be used as the activating agent may be selected from the group consisting of N-ethyl-5-phenylisoxazolium-3~-sulfonate 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydro-chloride and l-cyclohexyl-3-(2-morpholinoethyl) carbodiimide. The mere use of ionic salts of the antithrombogenic agent i6 not effective and merely results in the formation of leachable ionic bonds.
The antithrombogenic covalent bonding reaction, when using the preferred activating agents may vary from about 5 to 35 hours or more depending on such factors as the particular agent used, concentration of agent employed and degree of coupling achieved.
Generally, the antithrombogenic agent solution concen-tration is from about 0.1 to about 30% by weight but may vary up to the solubility limit of the particular agent. The reaction is preferably performed at temperatures between 4C and 23C but may be performed at higher temperatures up to the deactivation tempera-ture of the antithrombogenic agent.
The amount of activating agent employed will vary with the particular antithrombogenic agent and must be - employed in the ratio of at least 1 molecule of activating agent to each molecule of antithrombogenic agent. When employing antithrombogenic agents that are polymeric in character, such as heparin which have repeating tetrasaccharide units, the equivalent ratio of the heparin to the activating agent may be 6-24 to one wherein the heparin equivalent weight i8 calculated on the basis of a tetrasaccharide moiety, namely 4 repeating saccharide molecules representing one unit.
Upon completion of the antithrombogenic coupling reaction, the surface may be washed with water to remove loosely bound or unreacted antithrombogenic :
.
. . .
., : . . - . . . -- .:: - , -- - . , ~. , , . ' ', -~' ', ,' .. ' ' ~ ' -"' ~' ' : '- '' .- ' - ~ ' ' 1Z~1631 agent. Washing may be optionally performed with an isotonic solution.
A procedure for preparing a preferred material according to the invention may be depicted from the following equation:
(1) /I NCO ~ NCO
/ I NCO / I ¦--NCO
- 1o /I ' /I
/1 .
(a) (b) (c) /1 1 o /1 I N~l2 (2) H2N (CH2-CH2-NH)XH ~ -N-C-N
(d) /¦ ¦ O
/¦ I N-C-N
~ /1 I H NH2 ~ (e) O O
(3) HEPARIN _C_O-C /1 1 O
0 C-c-NH-c2Hs /¦ ¦-N-C-N
. o /1 1 ~ - - /1 I N-C-HEPARIN
: ~ (f ) /l I O
/ ¦ ¦--N-C--N
, , ! N--C--HEPARIN
, ; ., ..-,,.
:
., ~, , .
,. .
,~,~`.
,; ' . . , . -,. ;.,, . . ~ . . . ~ . ~ . . ` -~ -. .. ... ~ - ~
..
. .
. . . .
. .
1~1631 In the reaction equation Acheme depicted, the polymeri~ support (a) is contacted with a polyurethane prepolymer (b) to prepare a solid support having free NC0 units (c). The free NC0 units are then reacted with a polyalkylenimine (d) to form a backbone support - structure for coupling with the antithrombogenic agent (e). In the final step, heparin coupled to N-ethyl-5-phenylisoKazolium-3'-sulfonate (f) is reacted with the support to form a structure wherein heparin is covalent-ly coupled to the polymeric support (g). The resulting covalently bonded heparin would demonstrate high antithrombogenic efficacy as well as permanency and nonleachability.
While the present invention has been des~ribed in terms of using polyurethane polymers as the qupport surface, it should be recognized that other solid support materials having active hydrogen groups or groups that can be aminolyzed by the polymeric amine are con-templated for use herein. Exemplary materials include polyamides, polyesters, and polyvinyl chlorides.
The invention will be further illustrated by the following 'non-limiting examples. All parts and per-centages given throughout the Specification are by ,,A weight unless otherwiee indicated.
~ampie l - Inventive-Run l This example demonstrates the preparation and etability of etructures of the invention ueing heparin as the antithrombogenic agent.
Samples of polyurethane tubing were dipped into a 40% solution of an NC0 terminated prepolymer in ethyl-acetate having a 9.5~ free NC0 concentration. 'The NC0 terminated prepolymer had the following formu-lation:
.
, ': ', ~:., ' ' ' ,' ,' : .' , - ' ~. : , .
: , , .
.
- . ' - .
.
Reactants Eg~ivalents ~ Free NC0 Trimethylolpro~âle 1 9.5 Long chain polytetramethylene ether (650 average M.W.) 5 Hydrogenated 4,4'-diphenyl 4.0 methane diisocyanate Dibutyl tin dilaurate (0.015~) The NC0 coated tubing was placed in a 25c enclosed environment for 30 minutes to flash the ; 10 solvent. During the flash-off period, the atmosphere was continuously flushed with nitrogen. After 30 minutes, the tubing was transferred to a 20% solution of polyethyleni~ine at 50C. After five minutes the tubing was removed and placed in a continuous flow water rinse for up to 48 hours to remove any non-covalently bound polyethylenimine. After the rinse period, the samples were then placed in a 0.25% solution of radio labeled heparin complexed with N-ethyl-5-phenylisoxazolium-3'-sulfonate for 16 hours at ambient conditions. Following the heparin reaction, the samples were exposed to a dynamic water rinse for varied times. The rinse i3 designed to remove any un-reacted reagents. A known area of tubing was then dis-solved in a solvent, placed in a scintillation counter and scintillation counting performed. It was shown that about 31 ug/cm2 was bound to the polymer surface. The results are summarized in Table I and demonstrate that the heparin was covalently bonded to the support and was essentially non-leachable after successive washes.
TABLE I
~' `` Heparin Bound ¦ Rlnse time ~hr) ' -- -' -- -~- 4 - -~ 24 48 1 37.1*2.0 33.3~8.8 33.7*~.7 31.1~4.3 l .. .. , . . ..... , . .... . .... .... .. ...... .. ~ .. ~ l 1.
: ', '~ ''. , , : ~.. , -, - , , , , ,. .
~ ' , ' ' ' ~ , J;~1 Example II
Inventive Run 2 and Comparative Runs A and B
This example compares the partial thromboplastin time of structures made according to the invention com-pared to ~everal non-inventive systems.
Round bottom shaped thimbles were made from the polyurethane of Example I by casting the polyurethane on the outside of a glass test tube. After the thimbles were stripped off and cut to ~ize, they were treated as in ~xample I with a prepolymer having the formulation:
Rea ents Equivalents ~ Free NC0 g Long chain polytetramethylene 1 6.6 ether (650 average M.W.) - Hydrogenated 4,4'-diphenyl 1.9 15 methane diisocyanate Dibutyl tin dilaurate(0.015%) The samples were then subjected to exhaustive washing procedures to insure removal of any unreacted reagents.
The samples were exposed to 144 hours of dynamic water rinse, followed by 144 hours in 0.855 sodium chloride, and finally to 72 hours in 3M sodium chloride. After a sample was removed from the 3M NaCl solution, it was rinsed with distilled water and dried in a desiccator before testing. Partial thromboplastin times (PTT) were determined for each thimble by the following procedure:
(a) The thimble was placed in a heating bloc~ well in a water bath at 37C.
(b) 0.1 ml. fresh, citrated, platelet-poor pla~ma and 0.1 ml. partial thromboplactin reagent were pipetted into a thimble and incubated for fiYe minutes.
(c) 0.1 ml. of 0.02 M CaC12 was added and a stop watch was started simultaneou-~ly.
- - .
12~1~31 (d) A nichrome loop was passed through the plasma mixture at a rate of two sweeps per second until the first strands of fibrin are detected.
Samples which were prepared in a similar manner were also tested by a modified PTT method, wherein step (b) of the previous procedure, "5 minutes" was changed to 30 minutes. The test demonstrates the need for truly covalent bonded systems to be incubated to allow the surface bound heparin to interact to produce an anti-coagulant effect. The results are aet forth in Table II.
TABLE II
.. . . . . . .
I 1 130 ~in. Incubation¦
I ¦ PTT ¦ PTT
15 ¦ Sample ¦ (8econd8) t ~9econds~ t ¦Glass (untreated) ¦ 60 1 59 ¦Polyurethane (untreated)¦ 171 1 266 - ¦Antithrombotic ¦ 178 ¦ 498 IPolyurethane ~olymer- ~ 1 ' ' '' ' ' ' ' ' " ' 1 ' ' ' ' ' ' ' ' ' ' ' ' I
There i9 a clear improvement in the PTT time for the - inventive structure over the glass and untreated poly-urethane structures. This demonstrates antithrombogenic - efficacy. The observed effect was not due to leached anticoagulant, but to a permanently bonded system. This is evidenced in three ways. First upon completion of the PTT testing, the plasma wa~ removed from the thimble and analyzed by scintillation counting techniques showed no detectable radio labeled heparin for the inventive structure. This data shows that leached heparin was not responsible for the anticoagulant effect. Secondly, the PTT column of data in Table II shows the results of a normal (5 minute incubation) PTT test. There is ~ ~' "' ,., ~ ' ' . " ' . .
~ ~ ' '- . -1ti31 no detectable anticoagulant effect. This demonstrates the system is not leachable but rather covalently bound.
As such, the system requires incubation to show anti-coagulant effect. Finally, the PTT test showed an extension of clotting time over the controlled materials as seen in the 30 minute incubation results of Table II
showing an anticoagulant effect.
A slight extension of PTT was observed in the untreated polyurethane after a 30 minute incubation.
Although not wanting to be held to a particular theory, this result may be due to passivation via adsorption of such pla~ma proteins as albumin.
Example III
Inventiv~ Run 3-and Comparative-Run C
This example compares the use of various amines to couple the antithrombogenic agent to the support.
Tubes identical to those used in Example I were coated with the NC0 terminated prepolymer of Example I.
A portion of the samples were treated exactly as in Example I. A second portion of the tubes were treated in the same manner except a 20~ aqueous solution of 1,6-hexanediamine was used in place of 20% polyalkylenimine.
The results are shown in Table III.
TABLE III
., , . . . . . . . . ., . . . . . . . . . ., ~ . . . . . . . . .. . . . . . .. . . . .
25 ¦ Amount 8eparin I Treatment Bound ( ug/cm2) ¦
~ .. ... . . . . ,. . . . .. . . .. .. . . . , .. . .. . .. . . .. . . . . . . . . . . l - 1 .
¦Polyurethane Polyalkylenimine 25-30 ¦Polyurethane 1,6-hexanediamine -- -- - l The amount of heparin permanently bound to the inventive tube was significantly greater than that ; achieved in the comparative technique.
.~
- : , - ., :
. ' ~
., : - : : :
. . ~ :: . -. :
' ' ', ' ~ ' ~ ' ', ' ' ' ' `' BX ample ~V
~nventive Run 4 This example demonstrates the preparation of structures according to the invention using an acid etch of the polymeric surface to provide reactive amine and hydroxyl groups.
Samples of polyurethane tubing were exposed to 3N
hydrochloric acid for a period of 18 hours. This treat-; ment was then followed by 3 hours in boiling water.
The tubing samples were subsequently dried and reacted ; for 24 hours with hydrogenated 4-4'-diphenyl methane diisocyanate or the hydrogenated form of the latter to which 0.15~ dibutyl tin dilaurate has been added.
The re~ulting NCO group is then converted to amine by reaction with a 25% solution of polyethylenimine for a period of 4 hours. The resulting structure was washed extensively in distilled water. Finally, the structure was exposed to a solution of activated ; heparin, where the heparin concentration of 0.25~ in water having 20~ of the -COOH groups of the heparin activated via N-ethyl-5-phenylisoxazolium-3'-sulfonate.
The modified polyurethane surface was then washed in 3M
NaCl for a period of 24 hours to remove any loosely or non-covalently bound heparin. The resulting heparin products were nonleachable when washed.
The invention being thus de~cribed, 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.
.i "
~`
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. ,~ - ~, . .. ....
--:., ,, : ,- , , ~ , , , . ~ . . .
,~ , .
,
Claims (23)
1. An antithrombogenic polyurethane polymer which comprises:
a) a polyurethane substrate, b) a polymeric amine selected from the group of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof covalently bonded to said polyurethane substrate and c) an antithrombogenic agent covalently bonded to said polymeric amine.
a) a polyurethane substrate, b) a polymeric amine selected from the group of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof covalently bonded to said polyurethane substrate and c) an antithrombogenic agent covalently bonded to said polymeric amine.
2. The antithrombogenic polyurethane polymer of claim 1 wherein the antithrombogenic material is selec-ted from the group consisting of 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 thermo-plastic polyurethane polymers.
4. The antithrombogenic polyurethane polymer of claim 1 wherein the polyalkylenimine is selected from the group consisting of polyethylenimine, polypropyl-enimine, polybutylenimine and mixtures thereof.
5. The antithrombogenic polyurethane polymer of claim 1 wherein the polymeric amine has an average molecular weight of at least about 11,000.
6. The antithrombogenic polyurethane polymer of claim 1 wherein the polymeric amine is covalently bonded to the polyurethane substrate through a polyisocyanate prepolymer.
7. The antithrombogenic polyurethane polymer of claim 6 wherein the polyisocyanate prepolymer contains 2 to 30% free NCO units based upon total NCO content.
8. The antithrombogenic polyurethane polymer of claim 1 wherein the polymeric amine is covalently bonded to the polyurethane substrate through the acti-vation of polyurethane surface functional amine groups.
9. The antithrombogenic polyurethane polymer of claim 1 wherein the antithrombogenic agent is activated with an activating agent to enable covalent coupling to the polymeric amine.
10. The antithrombogenic polyurethane polymer of claim 9 wherein the activating agent is selected from the group consisting of N-ethyl-5-phenylisoxazolium-3'-sulfonate, 1-ethyl-3-(3-dimethylaminopropyl) carbo-diimide hydrochloride) and 1-cyclohexyl-3-(2-morpholino-ethyl) carbodiimide.
11. A process for imparting antithrombogenic activity to polyurethane polymer materials, which comprises:
(a) treating the surface of the polyurethane polymer material with a solution of a polymeric amine selected from the group consisting of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof so that the polymeric amine becomes covalently bonded to said polyurethane substrate, wherein the pH of the polymeric amine solution is at least about 5Ø
(b) washing said surface essentially free of any non-covalently bonded polymeric amine; and (c) treat the surface with an activated anti-thrombogenic agent to covalently bond the antithrombogenic agent to the polymeric amine.
(a) treating the surface of the polyurethane polymer material with a solution of a polymeric amine selected from the group consisting of a polyvinyl amine, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof so that the polymeric amine becomes covalently bonded to said polyurethane substrate, wherein the pH of the polymeric amine solution is at least about 5Ø
(b) washing said surface essentially free of any non-covalently bonded polymeric amine; and (c) treat the surface with an activated anti-thrombogenic agent to covalently bond the antithrombogenic agent to the polymeric amine.
12. The process of claim 11 wherein the antithrom-bogenic material is selected from the group consisting of heparin, prostaglandins, urokinase, streptokinase, sulfated polysaccharide, albumin and mixtures thereof.
13. The process of claim 11 wherein the poly-urethane polymer is selected from thermosetting polyurethane polymers and thermoplastic polyurethane polymers.
14. The process of claim 11 wherein the poly-alkylenimine is selected from the group consisting of polyethylenimine, polypropylenimine, polybutyl-enimine and mixtures thereof.
15. The process of claim 11 wherein the polymeric amine has an average molecular weight of at least about 11,000.
16. The process of claim 11 wherein the polymeric amine is covalently bonded to the polyurethane substrate through a polyisocyanate prepolymer.
17. The process of claim 16 wherein the poly-isocyanate prepolymer contains 2 to 30% free NCO
units based upon total NCO content.
units based upon total NCO content.
18. The process of claim 11 wherein the polymeric amine is covalently bonded to the polyurethane substrate through the activation of polyurethane surface functional amine groups.
19. The process of claim 18 wherein activation of the polyurethane substrate is achieved by testing the polyurethane surface with concentrated hydrochloric acid.
20. The process of claim 11 wherein the pH of the polymeric amine solution is from about 5.0 to about 12Ø
21. The process of claim 20 wherein the pH of the polymeric amine solution is from about 7.0 to about 9Ø
22. The process of claim 11 wherein the anti-thrombogenic agent is activated with an activating agent to enable covalent coupling to the polyamine.
23. The process of claim 22 wherein the activating agent is selected from the group consisting of N-ethyl-5-phenylisoxazolium-3'-sulfonate, 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride) and 1-cyclo-hexyl-3-(2-morpholinoethyl) carbodiimide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US578,909 | 1984-02-10 | ||
| US06/578,909 US4521564A (en) | 1984-02-10 | 1984-02-10 | Covalent bonded antithrombogenic polyurethane material |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1221631A true CA1221631A (en) | 1987-05-12 |
Family
ID=24314825
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000469313A Expired CA1221631A (en) | 1984-02-10 | 1984-12-04 | Covalent bonded antithrombogenic polyurethane material |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4521564A (en) |
| EP (1) | EP0152699B1 (en) |
| JP (1) | JPH06836B2 (en) |
| AU (1) | AU581831B2 (en) |
| CA (1) | CA1221631A (en) |
| DE (1) | DE3482408D1 (en) |
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| JPS6037735B2 (en) * | 1978-10-18 | 1985-08-28 | 住友電気工業株式会社 | Artificial blood vessel |
| US4415490A (en) * | 1979-07-24 | 1983-11-15 | Nippon Zeon Co., Ltd. | Non-thrombogenic material |
| US4326532A (en) * | 1980-10-06 | 1982-04-27 | Minnesota Mining And Manufacturing Company | Antithrombogenic articles |
| DE3109141A1 (en) * | 1981-03-11 | 1982-09-23 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V., 8000 München | Antithrombogenic treatment of matrix surfaces |
| NL188622C (en) * | 1981-12-15 | 1992-08-17 | Cordis Europ | METHOD TO IMPROVE THE BLOOD COMPATIBILITY OF A MATERIAL SURFACE BY COATING MATERIALS WITH HEPARIN OR HEPARIN-ANALOGUES AND PROTEIN FILM AND OBJECT, INCLUDING A SURFACE WITH IMPROVED BLOOD COMPATIBILITY OBTAINED BY APPLYING TO THE SURFACE MADE HEPARIN OR HEPARIN-ANALOGUES AND PROTEIN FILM. |
| SE8200751L (en) * | 1982-02-09 | 1983-08-10 | Olle Larm | PROCEDURE FOR COVALENT COUPLING FOR MANUFACTURE OF CONJUGATE AND REQUIRED PRODUCTS |
| SE456347B (en) * | 1982-02-09 | 1988-09-26 | Ird Biomaterial Ab | SURFACE MODIFIED SOLID SUBSTRATE AND PROCEDURES FOR PRODUCING THEREOF |
-
1984
- 1984-02-10 US US06/578,909 patent/US4521564A/en not_active Expired - Lifetime
- 1984-12-04 CA CA000469313A patent/CA1221631A/en not_active Expired
- 1984-12-17 AU AU36825/84A patent/AU581831B2/en not_active Ceased
- 1984-12-20 JP JP59267590A patent/JPH06836B2/en not_active Expired - Lifetime
- 1984-12-21 EP EP84308999A patent/EP0152699B1/en not_active Expired
- 1984-12-21 DE DE8484308999T patent/DE3482408D1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| AU581831B2 (en) | 1989-03-02 |
| AU3682584A (en) | 1985-08-15 |
| EP0152699A2 (en) | 1985-08-28 |
| EP0152699B1 (en) | 1990-06-06 |
| DE3482408D1 (en) | 1990-07-12 |
| US4521564A (en) | 1985-06-04 |
| EP0152699A3 (en) | 1987-01-28 |
| JPS60170617A (en) | 1985-09-04 |
| JPH06836B2 (en) | 1994-01-05 |
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| MKEX | Expiry |