Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
  • C08G18/72—Polyisocyanates or polyisothiocyanates
  • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
  • C08G18/75—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic
  • C08G18/751—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring
• • 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
  • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
  • A61L29/08—Materials for coatings
  • A61L29/085—Macromolecular materials
• • 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
  • A61L33/06—Use of macromolecular materials
  • A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/08—Processes
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/08—Processes
  • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
  • C08G18/40—High-molecular-weight compounds
  • C08G18/48—Polyethers
  • C08G18/4825—Polyethers containing two hydroxy groups

Definitions

• 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.
• 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.
• 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.
• polyether polyurethanes Prior to the present invention, polyether polyurethanes have been prepared by reacting an ⁇ , ⁇ -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.
• an ⁇ , ⁇ -polyether diol such as polytetramethylene oxide, polypropylene oxide or polyethylene oxide
• 2,4-tolylene diisocyanate or 4,4'-diphenylmethane diisocyanate 2,4-tolylene diisocyanate or 4,4'-diphenylmethane diisocyanate
• the present invention is based upon the discovery that by forming a segmented polyurethane by end-capping an ⁇ , ⁇ 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.
• 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.
• an ⁇ , ⁇ 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
• 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.
• suitable diamines and diols include ethylene diamine, hydra- zine, ethylene glycol, butane-l,4-diol.
• 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) .
• DMF N,N-dimethylformamide
• 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-
• 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 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) .
• HFIP hexafluoroiso- propanol
• DMF N,N-dimethylformamide
• OMPI . foxide DMSO
• 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.
• CHDI trans- 1,4-cyclohexane-diisocy.anate
• 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) .
• HFIP hexafluoroisopropanol
• DMF N,N-di- methyl ormamide

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• 1981
  • 1981-08-26 JP JP50289581A patent/JPS58502211A/ja active Pending
  • 1981-08-26 WO PCT/US1981/001156 patent/WO1983000695A1/fr not_active Application Discontinuation
  • 1981-08-26 EP EP19810902427 patent/EP0086192A4/fr not_active Withdrawn

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