WO2002058758A2 - Antithrombogenic polymer coating - Google Patents
Antithrombogenic polymer coating Download PDFInfo
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- WO2002058758A2 WO2002058758A2 PCT/US2001/044597 US0144597W WO02058758A2 WO 2002058758 A2 WO2002058758 A2 WO 2002058758A2 US 0144597 W US0144597 W US 0144597W WO 02058758 A2 WO02058758 A2 WO 02058758A2
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L79/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing nitrogen with or without oxygen or carbon only, not provided for in groups C08L61/00 - C08L77/00
- C08L79/02—Polyamines
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S128/00—Surgery
- Y10S128/22—Blood coagulation
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
- Y10T428/31551—Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]
- Y10T428/31562—Next to polyamide [nylon, etc.]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
- Y10T428/31725—Of polyamide
Definitions
- This invention relates to an article having a non-thrombogenic surface and a process for making the article. More particularly, this invention relates to an article formed by (i) coating a polymeric substrate with a crosslinked chemical combination of a polymer having at least two amino substituted side chains, a crosslinking agent containing at least two crosslinking functional groups which react with amino groups on the polymer, and a linking agent containing a first functional group which reacts with a third functional group of the crosslinking agent, and (ii) contacting the coating on the substrate with an antithrombogenic agent, such as heparin, which covalently bonds to a second functional group of the linking agent.
- an antithrombogenic agent such as heparin
- Non-thrombogenic and “antithrombogenic” refer to any material which inhibits thrombus formation on a surface.
- antithrombogenic agents or anticoagulants such as heparin.
- Heparin is a highly sulfated dextrorotatory mucopolysaccharide composed of D-glucosamine and
- D-glucuronic acid residues and is known to prolong the clotting time of blood.
- heparin is ionically bound to a surface.
- Heparin is an anionic compound which easily forms ion complexes with cationic compounds.
- it has been proposed to attach a cationic substance to a surface and thereafter ionically bind heparin to the cationic substance.
- 3,617,344 discloses a method in which a polymeric surface is chemically modified to include a chloromethyl group, the chloromethyl group is aminated to provide a quaternary ammonium halide, and the halide is reacted with sodium heparin to ionically bond heparin to the surface.
- a polymeric surface is chemically modified to include a chloromethyl group
- the chloromethyl group is aminated to provide a quaternary ammonium halide
- the halide is reacted with sodium heparin to ionically bond heparin to the surface.
- One disadvantage with ionically bound systems is that the heparin can leach off the surface when contacted with blood or other fluids.
- hydrazide supports are presently commercially available for use as adsorbents in affinity chromatography.
- These hydrazide supports may be prepared by: (1) diimide coupling of polymeric amines with p-hydrazinobenzoic acid; (2) direct condensation of an epoxy-containing polymer with a dihydrazide like adipic dihydrazide; and (3) coupling of polymeric active esters with hydrazine.
- the preparation of hydrazide supports and their application in affinity chromatography of oligosaccharides, polysaccharides, glycoproteins, and enzymes carrying sugar units is described in a number of patents (See, for example, U.S.
- Immobilization is carried out by reaction of the hydrazide reagent with the reducing terminus of the target molecule.
- the hydrazide coupling is preceded by a periodate-oxidation (to split the vicinal diols of sugar unit and provide newly generated -CHO groups) and finally completed by NaBH 3 CN reduction.
- An article having a non-thrombogenic surface according to the present invention and by a process for rendering the surface of a substrate non-thrombogenic according to the present invention.
- An article according to the invention comprises a substrate, a coating disposed on at least a portion of the substrate, and an antithrombogenic agent covalently bonded to the coating.
- the coating comprises a crosslinked chemical combination of (i) a polymer having side chains along a backbone forming the polymer, at least two of the side chains containing an amino group, (ii) a crosslinking agent containing at least two functional groups capable of reacting with the amino groups, and (iii) a linking agent containing a first functional group and a second functional group, the first functional group capable of reacting with the crosslinking agent's functional groups.
- the antithrombogenic agent is covalently bonded to the second functional group of the linking agent.
- the substrate of an article according to the invention may comprise any polymeric material conventionally used to fabricate articles commonly used in contact with blood.
- the substrate serves as a support for the coating and the antithrombogenic agent.
- the polymer used in the coating comprises a polymer having side chains along a backbone forming the polymer wherein at least two of the side chains contain an amino group ( -NRH, -NH 2 , -NRH 2 + , -NH 3 + ).
- the polymer is a polyamide having amino substituted alkyl chains on one side of the polymer backbone.
- the crosslinking agent used in the coating contains at least two functional groups capable of reacting with the amino groups of the polymer used in the coating.
- the crosslinking agent is selected from the group consisting of phosphines having the general formula (A) 3 P, wherein A is hydroxyalkyl.
- One more specific example of the crosslinking agent used in the coating is tris(hydroxymethyl)phosphine.
- the linking agent used in the coating contains a first functional group and a second functional group wherein the first functional group is capable of reacting with a third functional group of the crosslinking agent.
- the linking agent is a polyhydrazide, that is, the linking agent includes at least two functional groups having the formula -CONHNH 2 .
- One specific example of the linking agent used in the coating is adipic dihydrazide.
- the antithrombogenic agent used in an article according to the invention may be 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.
- the antithrombogenic agent is selected from heparin, prostaglandins, urokinase, streptokinase, sulfated polysaccharide, albumin and mixtures thereof.
- heparin is selected from heparin.
- the article having a non-thrombogenic surface may be produced by a process according to the invention in which a polymer having at least two amino substituted side chains is mixed with a crosslinking agent and a linking agent to produce a polymer solution.
- the crosslinking agent contains at least two crosslinking functional groups which react and combine with amino groups on the polymer, and a third functional group.
- the linking agent contains a first functional group which reacts and combines with the third functional group of the crosslinking agent, and a second functional group.
- the polymer solution is coated on at least a portion of a substrate to produce a crosslinked polymer coating on the substrate.
- the versatile chemical methodology of the invention allows the attachment of heparin through covalent linkage to a two-dimensional polymer carrier that is deposited on a polymeric substrate (e.g., polydimethylsiloxane, polyurethane, and polypropylene).
- a polymeric substrate e.g., polydimethylsiloxane, polyurethane, and polypropylene.
- the two-dimensional polymers have a backbone of repeating ⁇ -amino acid units with long aliphatic side-chain and free NH- and NH 2 - substituents and are synthesized by condensation of 2(5H)-furanone, or maleic acid derivatives (such as anhydride, esters, and so on) with a long-chain amine (e.g., tetradecylamine) and a polyamine (e.g., pentaethylenehexamine).
- a long-chain amine e.g., tetradecylamine
- polyamine e.g., pentaethylenehexamine
- Coupling of the two-dimensional polymer with tris(hydroxymethyl)phosphine (the crosslinking agent) and adipic dihydrazide (or other di-, tri-, and polyhydrazide linking agents having at least two -CONHNH 2 groups) results in the formation of a triblock polymer with pendant hydrazide groups.
- the coupling solution is used (without isolation) directly for the preparation of an intermediary reactive coating.
- the latter is then allowed to react with heparin or heparin/sodium cyanoborohydride in aqueous medium to produce a covalently bonded antithrombogenic surface with remarkably enhanced heparin content (greater than or equal to 10 micrograms / cm 2 ) and improved operational stability.
- Direct heparinization with sodium heparin forms a hydrazone
- heparinization by reductive amination forms a reduced hydrazone.
- a linking agent i.e., spacer-arm
- Figure 1 A shows a process for synthesizing a polyamide that is suitable for forming an antithrombogenic polymer coating in accordance with the present invention
- Figure 1 B shows example polyamides having amino groups that are suitable for forming the antithrombogenic polymer coating in accordance with the present invention.
- Figures 2A and 2B show a process for synthesizing another example polyamide having amino groups that are suitable for forming the antithrombogenic polymer coating in accordance with the present invention.
- An article having a non-thrombogenic surface comprises a substrate, a coating disposed on at least a portion of the substrate, and an antithrombogenic agent covalently bonded to the coating.
- the coating comprises a crosslinked chemical combination of (i) a polymer having side chains along a backbone forming the polymer, at least two of the side chains containing an amino group, (ii) a crosslinking agent containing at least two functional groups capable of reacting with the amino groups, and (iii) a linking agent containing a first functional group and a second functional group, the first functional group capable of reacting with a third functional group of the crosslinking agent.
- the antithrombogenic agent is covalently bonded to the second functional group of the linking agent.
- an antithrombogenic agent such as heparin
- heparin may be readily attached to a two-dimensional polymer bearing side chains having hydrazide groups.
- Two-dimensional polymers bearing different hydrazide side chains are readily obtainable through crosslinking between the two-dimensional polymer with a crosslinking agent and a hydrazide linking agent (spacer arm) carrying at least two hydrazide groups.
- a tri-block composite solution containing a two-dimensional polymer, a polyhydrazide and a crosslinking agent is used directly, without isolation of the product, for the coating of a substrate. The best performance for the invention may be attained by the selection of proper reagents and optimum reaction conditions.
- the polymer used in the coating comprises a polymer having side chains along a backbone forming the polymer wherein at least two of the side chains contain an amino group ( -NRH, -NH 2 , -NRH 2 + , -NH 3 + ).
- the polymer is a polyamide synthesized using the polymerization reactions disclosed in PCT International Publication Number WO 00/17254, which are shown in Figure 1A. Looking at Figure 1A, it can be seen that the polyamide can be synthesized using an ⁇ , ⁇ -unsatu rated gamma- lactone, such as 2(5H)-furanone, as an agent to effect the regular, sequential alignment of side chains along a polyamide backbone.
- the furanone undergoes facile reaction with a primary amine by Michael-type addition to yield ⁇ , ⁇ -amino gamma-lactone which then polymerizes to form a polyamide chain with the pendant side chain.
- the method can produce many different types of polyamides.
- the R group is a polyamine (such as pentaethylene-hexamine)
- a polymer having alkyl chains on one side and amino substituted alkyl chains on the other side of the polymer backbone and hydroxymethyl groups on the other side of the backbone is formed. See Figure 1 B.
- This example two-dimensional polymer has a backbone of repeating ⁇ -amino acid units with fatty alkyl (tetradecyl) and polyamine (derived from pentaethylenehexamine) side chains randomly distributed along the chain.
- fatty alkyl tetradecyl
- polyamine derived from pentaethylenehexamine
- the two-dimensional polymers are easily soluble in both water and most organic solvents (e.g., alcohols, tetrahydrofuran, chloroform, toluene, N,N-dimethylformamide, and the like).
- One polyamide disclosed in PCT International Publication Number WO 00/17254 and useful in the present invention is formed by reacting an ⁇ , ⁇ - unsaturated lactone and a first amine to form an intermediate reaction product, wherein the first amine is selected from RR ⁇ H, RNH 2 , RR 1 NH 2 + , RNH 3 + and mixtures thereof, wherein R and R 1 can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof; and (ii) reacting the intermediate reaction product and a polyamine to form the polyamide, wherein the second polyamine is selected from R 2 R 3 NH, R 2 NH 2 , R 2 R 3 NH 2 + , R 2 NH 3 + and mixtures thereof, wherein R 2 and R 3 can be the same or different and each contain an amino group ( -NRH, -NH 2 , -NRH 2 + , -NH 3 + ) and between about 1
- R, R ⁇ R 2 , and R 3 may be selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, hydroxyl, nitrile, carboxyl, sulfate, phosphate, sulfonyl, trialkylammonium and combinations thereof and optionally can be substituted with a halogen selected from the group consisting of chlorine, iodine, bromine, fluorine and combinations thereof.
- the R, R 1 ( R 2 , and R 3 groups may be the same or different depending on the desired structure for the final polyamide. In other words, the first amine and the second amine used in the polymerization process may be the same or different.
- the polymer is a polyamide synthesized using the polymerization reaction disclosed in the U.S. Patent Application entitled “Two Dimensional Polyamides Prepared from Unsaturated Carboxylic Acids and Amines” filed on October 27, 2000 by William F. McDonald et al., which is owned by the assignee of the present invention and is incorporated herein by reference.
- U.S. Patent Application entitled “Two Dimensional Polyamides Prepared from Unsaturated Carboxylic Acids and Amines” filed on October 27, 2000 by William F. McDonald et al. which is owned by the assignee of the present invention and is incorporated herein by reference.
- U.S. Patent Application entitled “Two Dimensional Polyamides Prepared from Unsaturated Carboxylic Acids and Amines” filed on October 27, 2000 by William F. McDonald et al.
- Patent Application there is described a polymerization process in which a monomer selected from unsaturated carboxylic acids, esters of unsaturated carboxylic acids, anhydrides of unsaturated carboxylic acids, and mixtures thereof is reacted with a first amine to form an intermediate reaction product, and then the intermediate reaction product is reacted with a polyamine to form a polyamide wherein at least a portion of the side chains along a backbone forming the polyamide are amino substituted alkyl chains. See Figures 2A and 2B (wherein R 1 includes an amino group).
- the process for producing this polyamide involves reacting a monomer selected from unsaturated carboxylic acids, esters of unsaturated carboxylic acids, anhydrides of unsaturated carboxylic acids and mixtures thereof with a first amine to form an intermediate reaction product in the reaction mixture, wherein the first amine is selected from RR ⁇ H, RNH 2> RR 1 NH 2 + , RNH 3 + and mixtures thereof, wherein R and R-, can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof.
- the reaction of the monomer and the first amine forms an intermediate reaction product in the reaction mixture.
- the intermediate reaction product is then reacted with a second amine selected from R 2 R 3 NH, R 2 NH 2 , R 2 R 3 NH 2 + , R 2 NH 3 + and mixtures thereof, wherein R 2 and R 3 can be the same or different and each contain an amino group ( -NRH, -NH 2 , -NRH 2 + , -NH 3 + ) and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof.
- the reaction of the intermediate reaction product with the second amine forms the polyamide in the reaction mixture.
- the polyamide may then be separated from the reaction mixture.
- a polyamide produced in accordance with the method of the invention includes multiples of the R, RNase R 2 , and R 3 groups in vertically aligned spaced relationships along a backbone formed by the polyamide.
- Suitable unsaturated carboxylic acids, esters of unsaturated carboxylic acids, and anhydrides of unsaturated carboxylic acids for use as the monomer in this polymerization process have for example from 3 to 18 carbon atoms in the molecule.
- the monocarboxylic acid, acrylic acid, and the dicarboxylic acid, maleic acid are preferred.
- maleic acid monoesters are preferred.
- a non-limiting example of anhydrides of the unsaturated carboxylic acids is maleic anhydride.
- R, R 17 R 2 , and R 3 may be selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, hydroxyl, nitrile, carboxyl, sulfate, phosphate, sulfonyl, trialkylammonium and combinations thereof and optionally can be substituted with a halogen selected from the group consisting of chlorine, iodine, bromine, fluorine and combinations thereof.
- the R, R,, R 2 , and R 3 groups may be the same or different depending on the desired structure for the final polyamide. In other words, the first amine and the second amine used in the polymerization process may be the same or different.
- the crosslinking agent used in the coating contains at least two functional groups capable of reacting with the amino groups of the polymer used in the coating. It has been discovered that the polymer can be crosslinked using a phosphine crosslinking agent having the general formula (A) 3 P and mixtures thereof, wherein A is hydroxyalkyl.
- the A groups of the phosphine crosslinking agent undergo a spontaneous Mannich-type reaction with amino groups on the polymer under mild conditions (pH ⁇ 7, aqueous or organic media, room temperature, 2-24 hours). This results in the formation of an aminomethyl- phosphine linkage (N-CH 2 -P-CH 2 -N) which is much less susceptible to enzyme deactivation and hydrolysis at a low pH than other known crosslinkages.
- the phosphine crosslinking agent offers the benefits of operational simplicity, good biocompatibility, and low cost.
- the phosphine crosslinking agent can also react with the substrate to create tightly bound anchors between the polyamide coating and the substrate.
- Non-limiting examples of phosphine crosslinking agents include tris(hydroxymethyl)phosphine, tris(1 -hydroxyethyl)phosphine, and tris(1 -hydroxypropyl)phosphine.
- the amount of phosphine crosslinking agent and the amount of polymer used in the crosslinking process can be varied depending upon the particular crosslinking agent utilized, the reaction conditions and the particular product application contemplated.
- the ratio of A groups in the phosphine crosslinking agent to the total of amount of amino groups in the polyamide can be varied to achieve a predetermined level of crosslinking.
- the A groups in the phosphine crosslinking agent to the total of amount of amino groups in the polymer is about 30% to provide acceptable crosslinking.
- enough phosphine crosslinking agent is added to the polyamide such that at least 30% of the available amino groups in the polymer are crosslinked by the A groups in the phosphine crosslinking agent. This percentage or amount of phosphine crosslinker can be varied to obtain coatings with the desired crosslink density.
- the linking agent used in the coating contains a first functional group capable of reacting with a third functional group in the crosslinking agent and a second functional group capable of reacting to form a covalent bond with the antithrombogenic agent, such as heparin. It was determined that the stability of immobilized heparin and other biomolecules is greatly dependent on the length and the lipophilicity of the linking agent and the number of active groups it contains. As a result, it has been discovered that a linking agent having at least two hydrazide groups (-CONHNH 2 ) is capable of reacting with a functional group in the crosslinking agent and the antithrombogenic agent, and is beneficial when used in the present invention.
- a first hydrazide group of the linking agent can react and covalently combine with an A (i.e., hydroxyalkyl) group in the phosphine crosslinking agent described above, and a second hydrazide group of the linking agent can react and combine covalently with the antithrombogenic agent (e.g., heparin).
- the second hydrazide group covalently bonds with the antithrombogenic agent (e.g., heparin) at its reducing end.
- the linking agent may be a polyhydrazide, and may be selected from the following non-limiting examples of polyhydrazides: carbohydrazide, thiocarbohydrazide, adipic dihydrazide, azelaic dihydrazide, sebacic dihydrazide, isophthaloyl dihydrazide, terephthaloyl hydrazide, 2,6-naphthalenedicarboxylic dihydrazide, 4,4'-O-bis(benzoyl hydrazide), 4,4'-O-bis(benzenesulfonyl hydrazide), citric trihydrazide, 1 ,3,5-benzenetricarbonyl hydrazide, poly(methacrylyl hydrazide), poly(methacrylyl ADP), poly(methyl vinyl ether-a/f-maleic hydrazide), poly(methyl vinyl ether-a/.-maleic ADP), poly(iso
- the antithrombogenic agent may be 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) and which is capable of forming a covalent bond with a functional group (e.g., hydrazide) on the linking agent.
- Illustrative antithrombogenic agents may be selected from the group consisting of heparin, prostaglandins, urokinase, streptokinase, sulfated polysaccharide, albumin and mixtures thereof.
- the antithrombogenic agent is heparin.
- the antithrombogenic agent may be used in varying amounts depending on the particular material employed and ultimate desired effect. For instance, the preferred heparin level is about 0.5% by weight and may range from about 0.1 % by weight to about 1.0% by weight.
- the substrate of an article according to the invention may comprise any polymeric material conventionally used to fabricate articles commonly used in contact with blood.
- a suitable polymeric material may be selected from polyolefins, polyacrylics, polyvinyl chloride, polyamides, polyurethanes, polyurethaneureas, silicone urethane copolymers, polyvinylpyrrolidone, polyvinyl alcohols, cellulosic materials, polystyrene, polyesters, fluorinated polymers, silicone polymers, natural rubber, polycarbonates, and mixtures thereof.
- the particular substrate selected does not constitute a critical aspect of the invention other than to serve as a support substrate for the coating and the antithrombogenic agent. In other words, the substrate must be able to bond to the polymer coating.
- An article having a non-thrombogenic surface according to the invention may be prepared generally as follows. First, the substrate is precleaned, if necessary, and the surface of the substrate is modified, if necessary. A solution of the polymer having side chains along a backbone forming the polymer wherein at least two of the side chains contain an amino group ( -NRH, -NH 2 , -NRH 2 + , -NH 3 + ), the crosslinking agent, and the linking agent is then prepared. Typically, the polymer may be dissolved using polar solvents, followed by addition of the crosslinking agent and the linking agent to form a coating solution. Care is taken not to heat this solution as premature crosslinking is undesirable.
- the polymer / crosslinking agent / linking agent solution is applied to a substrate and the substrate may be heated or baked in an oven at 125°C for four hours to complete the crosslinking process and create a crosslinked polymer coating having pendant reactive groups on the substrate. Thereafter, the coating on the substrate is heparinized or treated with another antithrombogenic agent which is capable of forming a covalent bond with a functional group on the linking agent.
- One example process for producing an article having a non-thrombogenic surface proceeds as follows.
- a polydimethylsiloxane substrate is precleaned using a one time isopropanol rinse.
- the substrate surface is modified by dipping the substrate in 1 to 2% [2-(2-aminoethylamino) ethylaminojpropyltrimethoxysilane and 0.2% acetic acid in isopropanol and thereafter drying the substrate with hot air. This step may be repeated if necessary.
- a solution of a polyamide (which may be synthesized using the polymerization reactions disclosed in PCT International Publication Number WO 00/17254 to have amino substituted alkyl chains on the polymer backbone), a crosslinking agent (such as tris(hydroxymethyl)phosphine), and a linking agent (such as adipic dihydrazide) is then prepared to react the polyamide, the crosslinking agent, and the linking agent.
- a crosslinking agent such as tris(hydroxymethyl)phosphine
- a linking agent such as adipic dihydrazide
- isopropanol is one preferred solvent for the crosslinking and subsequent coating procedure.
- 1 -methoxy-2-propanol and tetrahydrofuran are sometimes used as co-solvents for improved solubility.
- the polymer solution is applied to the substrate by dipping the substrate in the solution and thereafter drying the substrate with hot air. This step may be repeated if necessary.
- the coated substrate is then successively washed with phosphate buffer (pH 7.4), and distilled water.
- phosphate buffer pH 7.4
- Surface functionalization resulting in either imbedded or surface-coated hydrazides can be verified by a 2,4,6- trinitrobenzenesulfonic acid test (described by T. Miron and M. Wilchek, in J.
- FT-IR Fourier Transform Infrared Spectroscopy
- the coated substrate having hydrazide groups may then be heparinized by immersing in a heparin sodium salt solution 0.5% in 50 mM citrate phosphate buffer, pH 5 for 1 hour, or immersing in a heparin sodium salt (0.5%) and NaBH 3 CN (0.17%) solution in 50 mM citrate phosphate buffer, pH 5) for 1 hour.
- the heparinized substrate is then successively washed with a phosphate buffer, pH 7.4, and water.
- a toluidine blue (in borate, pH 9) assay test may then be performed for quantifying the surface heparin content of the heparinized substrate.
- the heparinized substrate may then be subjected to an accelerated 5 day coating stability study.
- Another group of heparinized coated substrates were immersed in pH 7.4 phosphate buffered saline for 15 days with no detectable changes.
- Example 1 details the preparation of polyhydrazides suitable for use as the linking agent in the present invention.
- Example 2 details the preparation of hydroxyalkyl substituted phosphines suitable for use as the crosslinking agent in the present invention.
- Example 3 illustrates the preparation of a triblock crosslinked polyamide surface having pendant reactive hydrazide groups in accordance with the invention.
- Example 4 illustrates the preparation of another triblock crosslinked polyamide surface having pendant reactive hydrazide groups in accordance with the invention.
- Example 5 illustrates the heparinization of a triblock crosslinked polyamide surface having pendant reactive hydrazide groups in accordance with the invention. The examples are not intended to limit the invention in any way.
- Example 1 - Preparation of hydrazides Example 1a Citric trihydrazide was prepared as follows. A 4.5 milliliter sample (4.5 grams, 91.7 mmol) of hydrazine hydrate was added to a solution of 5.70 grams (5 milliliters, 20.5 mmol) of triethyl citrate in 50 milliliters absolute ethanol. After stirring at room temperature for 8 hours, the solution was poured into a mortar while allowing the solvent to evaporate for overnight under a hood. The resulting white crystalline product was ground in mortar, washed with about 50 milliliters of ethanol, filtered, and air-dried. The yield was 4.60 grams (95.5% of theoretical). MALDI-MS showed [M+H] + at m/z 249 (matrix: 4-hydroxy- ⁇ -cyanocinnamic acid).
- 1 ,3,5-benzenetricarbonyl trihydrazide was prepared as follows. To 5.0 grams of 1 ,3,5-benzenetricarbonyl chloride (18.86 mmol) suspended in 50 milliliters isopropanol was added dropwise 3.5 milliliters (70 mmol) hydrazine hydrate for 15 minutes under stirring. The mixture was then allowed to stand for overnight to leave a white product, which was finally ground in a mortar to provide a fine powder. The product was filtered and air-dried. The yield was 4.61 grams (96.5% of theoretical).
- Example 1c Poly(1-octadecene-a//,-maleic acid hydrazide) (POMAH) was prepared as follows. To 8.2 grams (23.4 milli-equivalent units) of poly(1-octadecene-a/f- maleic anhydride) (POMA) (available from Aldrich Chemical, M n 30-50k) in 100 milliliters 1 :1 (v/v) toluene-isopropanol was added 4.1 milliliters (84.5 mmol) hydrazine hydrate. The solution was stirred at room temperature for 24 hours (a white precipitate was formed after several hours).
- POMA poly(1-octadecene-a//,-maleic acid hydrazide)
- 80% THPC was mixed with 100 milliliters isopropanol and 50 milliliters toluene. The mixture was evaporated to dryness on a Rotavap (bath temperature 80-90°C), and the azeotropic distillation was repeated for 2 more times to provide a semi-solid mass of anhydrous THPC. The dried residue was dissolved in 60 milliliters of isopropanol, to which was added 40 milliliters dry triethylamine (TEA) under ice- cooling.
- TSA dry triethylamine
- EIMS electron ionization mass spectroscopy, direct inlet
- m/z 124 fragments at m/z 106, 94, 76, 64, 61 , 46, and 31 , formed due to successive loss of H 2 O, and CH 2 O from the molecular ion.
- Infrared absorptions occur at 3224 (broad), 2815, 1589, 1420, 1125 (strong), and 1030 (strong) cm “1 .
- the THP thus prepared is pure enough for use in crosslinking. It is relatively stable and can be stored in freezer for up to 8 weeks without noticeable decomposition. Further purification of THP by distillation is not recommended due to thermal decomposition above 130°C releasing PH 3 gas in the process.
- Example 3 Preparation of a Triblock Polymer Surface
- Example 3a Preparation of a Polymer with Side Chains
- Example 16 of WO 00/17254 The procedure described in Example 16 of WO 00/17254 was used to produce a polyamide with mixed side chains.
- This polymer was produced by adding 1 molar equivalent of furanone (2(5H)-furanone) to 50 milliliters isopropanol, followed by adding 0.5 molar equivalents of tetradecylamine to the furanone solution dropwise. Once the tetradecylamine addition is complete, 0.25 molar equivalents of pentaethylenehexamine is added.
- the polymer produced had the mixed side chains and is suitable for making coatings. This polymer had a structure analogous to those shown in Figure 1B.
- Example 3b Preparation of a polymer surface from a polymer having side chains A triblock polymer surface was prepared from the polymer prepared in
- Example 3a by crosslinking with tris(hydroxymethyl)phosphine prepared in Example 2 - THP as follows. Four hundred twenty milligrams (2.41 mmol) of a fine powder of adipic dihydrazide (ADH) was mixed (under stirring) with a solution of 50 milliliters of 2% polymer of Example 3a ( ⁇ 4 milliequivalent units) in isopropanol. After 10 minutes, 300 milligrams (2.41 mmol) of THP was added in one portion. Stirring was continued for 0.5 hours to enable maximum dissolution. Any insoluble material (e.g., 50-120 milligrams unreacted ADH recovered) is filtered off to leave a clear yellow solution. This solution remains clear for 4-8 hours.
- ADH a fine powder of adipic dihydrazide
- This triblock composite solution was applied to a polydimethylsiloxane and a polypropylene substrate material. In doing so, the substrate was dipped into the solution and removed after 0.5 to 2 minutes. The wet substrate was dried and cured by hot air at 120°C-150°C for 1 minute. The dip-and-dry operation can be repeated one or more times when a greater thickness is required. Finally, the coated article was incubated in 50 mM phosphate buffer at pH 7.4 (15 minutes) and rinsed with running distilled water to remove any loosely bonded material yielding a glassy coated surface.
- hydrazide was detected by dipping a sample into a 1% aqueous solution of 2,4,6- trinitrobenzenesulfonic acid to develop a faint yellow to deep orange coloration, depending on the abundance of the hydrazide function.
- the ratio of absorbance A2922/A1258 or A1645/A1258 was used as a measure for the surface thickness and homogeneity in quality control.
- Example 3c Preparation of a polymer surface from a polymer having side chains Another triblock polymer surface was prepared from the polymer prepared in Example 3a by crosslinking with tetrakis(hydroxymethyl)phosphonium chloride (THPC) as follows. Four hundred twenty milligrams (2.41 mmol) of a fine powder of adipic dihydrazide (ADH) was mixed (under stirring) with a solution of 50 milliliters of 2% polymer of Example 3a ( ⁇ 4 milliequivalent units) in isopropanol. After 10 minutes, 0.45 milliliters of 80% THPC (2.5 mmol) and 0.35 milliliters (2.5 mmol) of triethylamine were added in one portion.
- THPC tetrakis(hydroxymethyl)phosphonium chloride
- Example 4a Preparation of Another Polymer with Side Chains
- Another polymer with side chains was prepared as follows. First, 1.0 moles (144.1 grams) of maleic acid mono-ethyl ester (MAEE) was dissolved in 100 grams of isopropanol in a break away resin kettle. The kettle containing the MAEE / isopropanol solution was then cooled in an ice bath with agitation. Second, 0.5 moles (160.7 grams) of commercially available tetradecylamine was dissolved in 250 grams of isopropanol and added slowly to the cooled MAEE solution with stirring. A Michael-type addition reaction product began to precipitate within 5 minutes. The tetradecylamine addition required about two hours with ice bath conditions being maintained throughout.
- MAEE maleic acid mono-ethyl ester
- PEHA pentaethylenehexamine
- Example 4b Preparation of triblock polymer surface from Example 4a polymer
- POMAH finely ground poly(1-octadecene-a#-maleic acid hydrazide)
- Triton X-100 brand surfactant were added 10 milliliters each of tetrahydrofuran and 1-methoxy-2-propanol. After stirring for 10 minutes at room temperature, the suspension was mixed with 25 milliliter
- the coated article was incubated in 50 mM phosphate buffer at pH 7.4 (15 minutes) and rinsed with running distilled water to remove any loosely bonded material yielding a glassy coated surface.
- Surface hydrazide was detected by dipping a sample into a 1% aqueous solution of 2,4,6- trinitrobenzenesulfonic acid to develop a faint yellow to deep orange coloration, depending on the abundance of the hydrazide function.
- Infrared analysis of the resulting coated polydimethylsiloxane articles showed characteristic absorbances at 3300 (NH), 2922 (CH 2 /CH), 2850, 1650 (amide 1 ), and 1258 (Si-CH 3 of siloxane substrate) cm '1 .
- Example 5a Direct heparinization with sodium heparin (Hydrazone formation)
- the polymer coated articles prepared in Examples 3b, 3c and 4b were allowed to incubate in a solution of 0.5% sodium heparin in 50 mM phosphate buffer at pH 5 at room temperature for 1 hour.
- the products were rinsed with (i) distilled water, (ii) 50 mM phosphate buffer at pH 7.4 (15 minutes), and (iii) distilled water, and finally air-dried overnight.
- the products were rinsed with (i) distilled water, (ii) 0.5 mM phosphate buffer at pH 7.4 (15 minutes), (iii) distilled water, and finally air-dried overnight.
- This washing step removed the last trace of CN '1 ions as indicated by the absence of bands at 2328 (CN '1 -metal coordinated) and 2168 (CN '1 ) in an FT-IR infrared spectrum.
- the surface bonded heparin of the articles produced in Examples 5a and 5b was analyzed by the toluidine blue (basic) test described by B. Dick et al. in Ophthalmologica 211 , 75-78, 1997 and by L.B. Jaques in Methods of Biochem. Anal. v. 24 (D. Glick, ed.), pp. 241-243, Wiley & Sons, New York, 1977, by which the analyte was allowed to react with an excess of toluidine blue to form an insoluble heparin-cationic dye complex and the depleted dye was analyzed by measuring the UV-absorption at 631 nanometers.
- a mixture of 20 milligrams of toluidine blue, 50 milliliters of 0.025 M sodium borate, and 4.6 milliliters of 0.1 N HCl was diluted to 100 milliliters with water to form 0.02% (or 200 mg/L) toluidine blue in 0.0125 M sodium borate (pH 9.0). Then 16.6 milligrams of sodium heparin was dissolved in 100 milliliters of 0.2% NaCI to form a heparin solution (6.0 micrograms heparin / microliter solution).
- a sample of 1.0 milliliters of the toluidine blue reagent was added to each labeled centrifuge tube (15 milliliters) for standards and unknowns. Then 0, 25, 50, 75, and 100 micrograms of sodium heparin were added to each standard tube. Then 0.2% NaCI was added to each heparin and unknown tube to 5.0 milliliters.
- Heparinized samples from Examples 5a and 5b were added in small pieces to the tubes designated unknowns.
- One milliliter of hexane was added to each tube to promote the separation of unbound heparin-dye complex at the interface.
- the tubes were vortexed 3 times for 2 minutes each time and allowed to stand at room temperature for 2 hours.
- the lower layer was transferred from each tube to a 0.5-milliliter disposable cuvette and the absorption at 631 nanometers was recorded.
- a plot was then made of the average absorbance vs. concentration of the triplicate standard heparin solutions.
- the heparin concentration of the unknowns was determined by comparing the A 631 values against the standard curve.
- This protocol offers advantages over other procedures using acidic toluidine blue (such as that described by P.K. Smith, A.K. Mallia, and G.T. Hermanson in Anal. Biochem. 109, 466-473, 1980) because it is insensitive to the charge present on the polydimethylsiloxane substrate surface and does not give false positive responses in the presence of polymers of Examples 3a and 4a as analyzed in acidic media.
- the assay showed that heparin was present on the surface of the articles produced in Examples 5a and 5b at a concentration of about 5 to about 10 micrograms per square centimeter.
- this work has provided an improved antithrombogenic polymer coating that may be easily applied to a substrate to provide a material which has excellent biological and chemical stability towards blood and which retains its antithrombogenic properties in a permanent and non-leachable fashion when in contact with blood for prolonged periods.
- the process provides for the preparation of a two-dimensional-polymer surface containing pendant reactive hydrazide groups that may be further attached to an antithrombogenic agent such as heparin.
- the process also provides for the preparation of a two-dimensional-polymer surface containing pendant reactive hydrazide groups that is easily realized by coupling the polymer with a crosslinking agent in the presence of a linking agent (i.e., spacer-arm) containing at least two hydrazide groups wherein the intermediary layer from the copolymer thus obtained demonstrates excellent ability to form a stable linkage with the substrate while leaving its pendant hydrazide groups for further attachment to an antithrombogenic agent such as heparin.
- a linking agent i.e., spacer-arm
Abstract
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