SEGMENTED POLYURETHANE COMPOSITION

Abstract: Nonthrombogenic surfaces are formed from a polyurethane by end-capping an alpha , omega dihydroxy polyalkylene oxide with 1,4-transcyclohexane diisocyanate, which is then extended with a diamine or a short diol. Surfaces of body implants, coated with solutions of the above, are extremely bland toward blood platelets.

Description: SEGMENTED POLYURETHANE COMPOSITION Background of the Invention This invention relates to new segmented polyurethane composition useful in biomedical surface applications. Segmented polyurethanes have been widely studied and used in intravascular applications requiring contact with blood such as angiographic catheters.. Their thrombogenic potential, especially their ability to activate platelets, has usually been regarded as favorably low, but substantial variations have been reported. Unlike homopolymers such as polyacrylates, in which surface and bulk compositions are identical, the segmented polyurethanes depend upon separa¬ tion of two mutually incompatible molecular sequences for their mechanical integrity. One sequence known as the "soft" segment can be a polyether. This constitutes the continuous plase and is rubbery at temperatures of use. The other sequence known as the "hard" segment consists of strongly hydrogen-bonding structural units derived from diisocyanates and dia ines, which cluster in the discontinuous phase as glassy or crystalline micelles, thereby serving as effective junctions to connect the soft segment sequences. In such a two phase material, the composition of the material at the surface is not usually identical to that in the interior when surface free energy is allowed to act. It is known that the chemical analogs of the hard segment, for example, the copolymer of a diisocyanate and diamine, strongly cause platelet activation. The average fraction of platelets retained on such materials when whole blood is passed over them is about 0.8. For an "ideally bland" surface, the average fraction of platelets retained on such materials should be 0. To the extent that this phase SUBSTITUTE SHEET _ O PI_ appears in blood contacting surfaces of the polyurethanes, thrombogenicity is to be expected. Prior to the present invention, polyether polyurethanes have been prepared by reacting an α,ω-polyether diol such as polytetramethylene oxide, polypropylene oxide or polyethylene oxide with 2,4-tolylene diisocyanate or 4,4'-diphenylmethane diisocyanate followed by chain extension with a diamine. When cast as films from an appropriate polar solvent such as dimethyl fomamide, the best achievement of segmentation of the hard segment of the resultant polymer to below the sur¬ face of the film is about 60% as measured by x-ray photo- electron spectroscopy. It would be highly desirable to pro¬ vide such polymers wherein the soft segment of the polymer occupies as much of the surface as possible, in any event greater than about 60% of the surface. Summary of the Invention The present invention is based upon the discovery that by forming a segmented polyurethane by end-capping an α,ω dihydroxy polyalkylene oxide with 1,4-transcyclohexane diisocyanate which is then extended by a diamine or a short diol, has a very low or zero nitrogen content on the surface thereof. Thus, the compositions of this invention are ex¬ tremely bland toward blood platelets and are useful as coat- ings for devices implanted or inserted into the human body such as intravenous catheters, heart valves or the like. Description of Specific Embodiments In accordance with this invention, an α,ω dihydroxy polyalkylene oxide is end capped with 1,4-transcyclohexane diisocyanate which is then extended with a diamine or a short diol in either a two-step or a three-step procedure. Repre¬ sentative suitable polyalkylene oxides include polytetra¬ methylene oxide, polypropylene oxide, polyethylene oxide or -^tJE.E > ' the like. The polyalkylene oxide is dissolved in a suitable solvent such as a mixture of dimethyl sulfoxide and 4-methyl- 2-pentanone. To this solution is added the 1,4-transcyclo- hexane diisocyanate. Given the amount of polyether known, the amount of diisocyanate is calculated as to have a 1:2 mole ratio in a two-step synthesis, or 1:0.5 mole ratio in the first addition and 1:1 mole ratio in the second addition in a three-step synthesis. This addition is conducted in the absence of oxygen in order to avoid undesirable side reactions. Any inert atmosphere can be utilized such as argon, nitrogen or the like. The addition of the diisocyan¬ ate reactant can be performed in one step (as in a two-step synthesis) or in multiple steps, usually two steps (as in a three-step synthesis) . The resultant mixture is then heated to a temperature below 100°C, preferably between about 80 and about 90°C for a period of time usually between about 7 hours and about 10 hours. The resultant mixture then is allowed to cool, usually to about room temperature and the diamine or short diol can be added to the mixture in order to effect the desired polymeric extension. Representative suitable diamines and diols include ethylene diamine, hydra- zine, ethylene glycol, butane-l,4-diol. All that is neces¬ sary is that the diamine or diol be capable of reacting with residual isocyanate groups. The preferred extender is ethyl- ene diamine. Given the amount of diisocyanate known, the amount of extender is calculated as to have a 2:1 mole ratio in a two-step synthesis, or a 3:1 ratio in a three-step synthesis. The extension reaction can be conducted at room temperature wherein the extender is usually added dropwise in solution of a suitable solvent such as 3% solution in di¬ methyl sulfoxide. The resultant product then is recovered by removing the solvent. The resultant product is rubbery and soluble in hexafluoroisopropanol, formic acid and m- cresol, but insoluble in N,N-dimethylformamide (DMF) . Thus, SUBSiITϋis.. ** r— - T REA7J OMH these physical characteristics distinguish the products of this invention from other segmented polyurethanes which dis¬ solve in DMF and do not dissolve in hexafluoroisopropanol. The materials of this invention are extremely bland toward blood platelets and are therefore useful as coating on articles which are used in the body such as intravenous catheters, heart valves or the like. The compositions of this invention when cast as films from solutions, as examined by x-ray photoelectron spectroscopy, are nearly pure poiy- ether, generally about 80% or more which provides a strong basis that phase separation of the "hard segment" is much more complete and that the hard segment (diisocyanate-diamine) is below the surface. This contrasts with the prior art segmented polyurethanes which show no more than about 60% polyether at the surface. Figures 1 and 2 are plotted as the number of elec¬ trons divided by their kinetic energy LN(E) as a function of their binding energy in electron volts when segmented polyurethanes are examined by x-ray photoelectron spectos- copy. Figure 1 shows the proportion of oxygen, nitrogen and carbon on the surface of a segmented polyurethane pre¬ pared from polyethylene oxide, molecular weight 15000, 2,4- tolylene diisocyanate, 4,4*-diphenylmethane diisocyanate and ethylene diamine by the three-step procedure generally set forth in Example I, but utilizing dimethylformamide as the solvent. This segmented polyurethane represents one of the best nonthrombogenic segmented polyurethanes made by the prior art process. It shows strong oxygen and carbon peaks and some nitrogen peaks. In contrast, the curve of Figure 2 which utilized the segmented polyurethane produced by the three-step procedure of Example I shows no nitrogen. A comparison of the carbon to oxygen ether bonds on each of these surfaces shows the prior art fraction of carbon bonded to ether to be only about 0.6 while that of the surface pro- BSTITUTE SHEET O PI duced by the three-step procedure of Example I to be 0.82. If the surface were pure ethylene oxide, it would be 1.0. The composition of this invention can be dissolved in a suitable solvent and the resultant composition can be coated on any device inserted or implanted in the body in order to reduce thrombogenicity of the device such as a heart valve, intravenous catheter or the like. The following example illustrates the present inven¬ tion and is not intended to limit the same. EXAMPLE I Two-Steps Procedure: 30 grams of poly(ethylene glycol) of molecular weight 1500 are added to 100 ml of a 1:1 mixture of dimethyl sul- foxide (DMSO) and 4-methyl-2-pentanone. 6.65 gr-ams of trans- 1,4-cyclohexane-diisocyanate are added into the mixture. The mixture is stirred under argon for 8 hours at 85 C. At this stage, the mixture becomes lemonly-yellow in colour and somewhat turbid. The reactor is allowed to cool to room temperature. 400 ml of DMSO are added to the cooled mixture. 1.22 grams of ethylenediamine is then added drop by drop to the reactor as a 3% solution in DMSO in continuous stirring. After an hour, the reaction is quenched with 100 ml of meth- anol. DMSO, methanol and 4-methyl-2-pentanone are evaporated to leave behind a lemonly-yellow gel-like polyurethane. The polyurethane is precipitated and extensively washed in dis¬ tilled water and dried in an oven at 60 C for a week, in vacuo. The product is rubbery and soluble in hexafluoroiso- propanol (HFIP) , formic acid, and m-cresol, but insoluble in N,N-dimethylformamide (DMF) . Three-Steps Procedure: 30 grams of poly(ethylene glycol) of molecular weight 1500 are added to 100 ml of a 1:1 mixture of dimethyl sul- OMPI . foxide (DMSO) and 4-methyl-2-pentanone. 1.66 grams of trans- 1,4-cyclohexane-diisocy.anate (CHDI) are then added into the mixture. The mixture is stirred under argon for 8 hours at 85°C. 3.32 grams of CHDI are added into the reactor and the mixture is stirred under argon for another 8 hours at 85 C. The mixture becomes lemonly-yellow and somewhat turbid. The reactor is allowed to cool to room temperature. 400 ml of DMSO are added to the cooled mixture. 0.61 grams of ethyl- enediamine is then added drop by drop to the reactor as a 3% solutionn DMSO in continuous stirring. After an hour, the reaction is quenched with 100 ml of methanol, DMSO, methanol and 4-methyl-2-pentanone are evaporated to leave behind a lemonly-yellow gel-like polyurethane. The poly¬ urethane is precipitated and extensively washed in distilled water and dried in an oven at 60 C for a week, in vacuo. The product is rubbery and soluble in hexafluoroisopropanol (HFIP) , formic acid and m-cresol, but insoluble in N,N-di- methyl ormamide (DMF) . O-IEA^

Claims: CLAIMS 1. A segmented polyurethane comprising the reaction product of an α,ω diol polyalkylene oxide, 1,4-transcyclo- hexane diisocyanate and a polymer extender selected from the group consisting of a diamine, a short diol and mixtures thereof. 2. The composition of claim 1 wherein said poly¬ alkylene oxide is polyethylene oxide. 3. The composition of any one of claims 1 or 2 wherein said extender is a diamine. 4. The composition of any one of claims 1 or 2 wherein said extender is an ethylene diamine. 5. The composition of any one of claims 1 or 2 suspended in a solvent selected from the group consisting of hexafluoroisopropanol, formic acid and m-cresol. 6. The composition of claim 3 suspended in a solvent selected from the group consisting of hexafluoroisopropanol, formic acid and m-cresol. 7. The composition of claim 4 suspended in a solvent selected form the group consisting of hexafluoroisopropanol, formic acid and m-cresol. 8. An article suitable for implantation or insertion into the human body coated with the composition of claim 1. 9. An article suitable for implantation or insertion into the human body coated with the composition of claim 2. 10. An article suitable for implantation or insertion into the human body coated with the composition of claim 3. 11. An article suitable for implantation or insertion into the human body coated with the composition of claim 4.

Inventors: MERRILL EDWARD W, WAN STEPHEN S, MERRILL, EDWARD, W., WAN, STEPHEN, S
Applicants: MERRILL EDWARD WILSON, WAN STEPHEN S, MERRILL, EDWARD, W., WAN, STEPHEN, S
Application year: 1981
Main classification: C08G18
IPC codes: A61L26, A61L29, A61L33, C08G18, C09D175