JPH0585190B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a new antithrombotic material made of polyurethane or polyurethane urea that has both excellent mechanical properties and excellent antithrombotic properties, and a method for producing the same. [Prior art and problems to be solved by the invention] Conventional antithrombotic elastomers include polyether-based segmented polyurethanes (e.g. Biomer manufactured by Ethicon, Inc., USA), silicone resins, or block copolymers of polysiloxane and polyurethane (e.g. Cardiosan manufactured by Kontron, USA), heparinized polyurethane
13729) are known. These known elastomers still have insufficient antithrombotic properties from a practical standpoint. For example, known segmented polyurethane is desired to be further improved in its antithrombotic properties, and heparinized polyurethane allows heparin to flow out in a short period of time, resulting in an extremely short duration of antithrombotic action, and uses bioactive heparin. For this reason, molding and sterilization are complicated, resulting in high costs. In addition, a block copolymer (US Pat. No. 3,562,352) in which polysiloxane and polyurethane are directly bonded with nitrogen and silicon is a reactive material with a cross-linking reactive group, which has poor stability over time and has poor antithrombotic properties. storage conditions,
This varies widely depending on the molding conditions, and it is extremely difficult to create a blood-contacting surface that provides a certain level of excellent antithrombotic properties, even with strict process control. Hydrophilic segmented polyurethane has excellent antithrombotic properties, but due to its hydrophilic nature, when it comes into contact with blood, it absorbs water in the blood and swells, causing a change in volume. Parts of the material may melt out, and the mechanical properties deteriorate rapidly due to water absorption, making it impossible to put it to practical use. As described above, although an elastomer having both favorable mechanical properties and excellent antithrombotic properties is essential for the development of blood-contacting medical devices, it does not exist, and its development is strongly desired. [Means for Solving the Problems] The present inventor focused on the extremely excellent mechanical properties of polyether-based segmented polyurethanes having polytetramethylene oxide in the molecular chain, and After various studies on how to make this polyurethane hydrophilic without damaging it, we found that we can use hydrophobic polyurethane in which the polyether part is polytetramethylene oxide, and polyurethane in which the polyether part is polyalkylene oxide (alkylene has 2 and/or 33 carbon atoms). ), it was found that no matter how much the mixing ratio and mixing method were changed, the mechanical properties did not improve. The present invention combines the polytetramethylene oxide (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -O-) _o and polyalkylene oxide (-CHR-CH ₂ -) in the same main chain using a very special method. The present invention was achieved by discovering that hydrophilic segmented polyurethane containing O- _{) o} (where R=H or CH ₃ ) has both mechanical properties and excellent antithrombotic properties. The polyether of the soft segment part of the segmented polyurethane is polyalkylene oxide (however, the number of carbon atoms in alkylene is 2 and/or 3), specifically polyethylene oxide, polypropylene oxide, ethylene oxide-propylene oxide random copolymer, polyethylene oxide - polypropylene oxide block copolymer, (A-B
type, A-B-A type, B-A-B type, etc.), these polyurethanes are highly hydrophilic and will extremely absorb water and swell upon contact with water, and some of them are soluble in water. Although the mechanical properties are extremely poor, those containing polyalkylene oxide and polytetramethylene oxide in the same main chain have improved mechanical properties and are suitable for practical use, and also have antithrombotic properties. It has also been found that this product is dramatically improved compared to conventional products. The method for producing the antithrombotic material of the present invention includes polyalkylene glycol having hydroxyl groups at both ends (however, alkylene has 2 and/or 3 carbon atoms), specifically polyethylene glycol, polypropylene glycol, and ethylene glycol having hydroxyl groups at both ends. - A prepolymer () obtained by reacting a diisocyanate with at least one selected from the group consisting of a propylene glycol copolymer and a polypropylene glycol-polyethylene glycol block copolymer, a polytetramethylene glycol having hydroxyl groups at both terminals, and a diisocyanate. It is obtained by chain-extending a composition prepared by mixing a prepolymer () obtained by reacting with a diol, a diamine, and water. In this case, when chain-extending the prepolymer () and/or (), the above-mentioned () and/or () are reacted with a part of the chain extender independently in advance, and these partially reacted products are reacted with the prepolymer () and/or (). The present invention also includes a method of using it as a polymer and further extending the chain. When a diamine or water is used as a chain extender, the polyurethane used in the present invention forms a urea bond and becomes a polyurethane urea. Therefore, in this specification, the term polyurethane also includes polyurethane urea, unless otherwise specified. The weight composition ratio of the hydrophilic polyether (the polyalkylene oxide) and the hydrophobic polyether (the polytetramethylene oxide) of the antithrombotic material of the present invention exhibits the mechanical properties and antithrombotic properties of the present invention. It is important for this purpose that the content of the hydrophilic polyether in the total polyether is 1.0 to 60% by weight, preferably 2 to 30% by weight. If the content of hydrophilic polyether exceeds 60% by weight, swelling due to water absorption will be large, it will become partially soluble in water, and the mechanical properties will not be suitable for practical use. If the amount is less than 1.0% by weight, antithrombotic properties will be insufficient. The molecular weight of the hydrophilic polyether is 100 or more, preferably 200-3000, more preferably 300-2000. The molecular weight of the hydrophobic polyether (polytetramethylene oxide) used in the present invention is 200~
Used between 3000 and more preferably 300 to 2000
It is. A feature of the method for producing an antithrombotic material of the present invention is that a hydrophilic polyether and a hydrophobic polyether are mixed at the prepolymer stage, and this is chain-extended. After reacting with a portion of the polyether to chain the same type of polyether moieties, the chain may be further extended by mixing. To explain this in a little more detail, the synthesized hydrophilic polyether prepolymer () and the hydrophobic polyether prepolymer () are mixed in a solution state at a predetermined ratio depending on the purpose. The polyurethane or polyurethane area is produced by diluting it with a solvent depending on the conditions, adding a chain extender thereto, and reacting it. The resulting elastomer has a structure in which soft segments of the same type are unevenly distributed in the same molecular chain. It is also possible to mix a hydrophilic polyether containing isocyanate groups at both terminals synthesized in advance as described above and a hydrophobic polyether also containing isocyanate at both terminals, add a chain extender to this, and react in one step. However, when reacting with a chain extender, add a portion of the chain extender to the hydrophilic polyether and/or hydrophobic polyether having isocyanates at both terminals in advance to extend the chain to some extent. The two extended components may be mixed and these blocks may be further connected with a chain extender to form a polymer. At this time, the chain length of the hydrophilic polyether block and hydrophobic polyether block may be adjusted by changing the proportion of the chain extender reacted with the hydrophilic polyether part or the hydrophobic polyether part in advance. In the polyurethane or polyurethane urea synthesized in this way, the total length of the same type of segments in the same molecule can be varied to make them unevenly distributed. Although the production of each prepolymer can be carried out in the absence of a solvent, it is preferably carried out in the presence of a solvent. Preferred solvents include dimethylformamide,
dimethylacetamide, dimethyl sulfoxide,
Examples include tetrahydrofuran, dioxane, N-methylpyrrolidone, and mixed solvents mainly composed of these. The reaction with the isocyanate compound may be carried out without a catalyst by heating, or may be carried out using a catalyst. As the catalyst, those used in known urethane synthesis can be used, but triethylenediamine, diazabicycloundecene, etc. are particularly preferred from the viewpoint of medical use because they are easy to remove during the purification process. As the isocyanate compound used, all diisocyanates conventionally used for producing polyurethane can be used. Examples of preferred diisocyanates include 4,4'-diphenylmethane diisocyanate, 1,4-phenylene diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, tetramethylene diisocyanate, hexamethylene diisocyanate, 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate, cyclohexane-1,4-diisocyanate, 2,4-tolylene diisocyanate and 2,
Examples include a mixture of 6-tolylene diisocyanate, xylylene diisocyanate, 1,3-phenylene diisocyanate, and naphthalene-1,5-diisocyanate, which may be used alone or as a mixture. Examples of chain extenders include chain extenders having active hydrogen groups that react with difunctional isocyanate groups, such as aliphatic diamines such as ethylene diamine, propylene diamine, butylene diamine, and hexamethylene diamine; cyclohexane diamine, pepyrazine, and xylene diamine. Alicyclic and aliphatic acid diamines such as; aromatic diamines such as tolylene diamine, phenylene diamine, 4,4'-diphenylmethane diamine, hydrazines, ethylene glycol, 1,4-butanediol, etc. glycols,
and water are used. The polyurethane synthesized in this way can be produced in the form of a synthetic solution, or by precipitating the polyurethane in a precipitant such as water or alcohol, thoroughly washing it with water or ethanol, and, if desired, precipitating it again. After repeatedly removing impurities, it is dried and used. Furthermore, the antithrombotic material of the present invention can be molded as a solution by a coating method, dipping method, or casting method, or it can be made into pellets and then molded using conventional thermoplastic synthetic resin molding methods such as extrusion molding, injection molding, press molding, etc. It can be molded using In addition, this antithrombotic material is extremely stable not only in dry pellet form but also when stored in solution form, and does not undergo any molecular breakdown due to the influence of moisture, making it easy to handle and has good antithrombotic properties. It has an excellent property of being able to express. It is generally said that the mechanical properties of an antithrombotic material are good if the tensile strength is 100 Kg/cm ² or more and the elongation is 300 to 500% or more, but the polyurethane of the present invention has a tensile strength of 100 to 500 Kg/cm ² It has an elongation of over 300% and has excellent mechanical properties. [Function] The antithrombotic material of the present invention contains a hydrophilic polyether segment and a hydrophobic polyether segment in the same main chain, and the polyurethane bond and polyurethane urea bond are common. The segment structure is undisturbed and strong, there are soft segment domains, the hydrophobic polyether takes care of the mechanical properties, and the hydrophilic polyether swells with water, resulting in antithrombotic properties at the blood contact area. This contributes to Based on these results, the antithrombotic material of the present invention can be suitably used for blood contact surfaces of medical devices that come into direct contact with blood. Specific applications include artificial hearts, pumping chambers for auxiliary circulation devices, balloon pumps, extracorporeal circulation circuits for auxiliary circulation devices such as artificial livers and heart-lung machines, blood bags, and catheters. The present invention will be explained below with reference to Examples. [Example] Example 1 Polyethylene glycol (molecular weight 800) was placed in a sufficiently dried reaction vessel, and heated at 90°C and 0.1 mmHg.
Dehydration was carried out for 5 hours under the following reduced pressure. The temperature was lowered to 45°C, and 4 times the amount of dimethylacetamide which had been dehydrated to a water content of 5 ppm or less was added thereto, and then 4,4'-diphenylmethane diisocyanate was added in a conventional manner and reacted with stirring. Diazabicycloundecene was used as a catalyst, and
0.03% was added and reacted for 2 hours to produce a prepolymer. This was designated as prepolymer (). Separately, in the same manner as above, polytetramethylene glycol (molecular weight 1850) having a hydroxyl group at the end was reacted with 4,4'-diphenylmethane diisocyanate in dehydrated dimethylacetamide in a separate reaction vessel. I made a polymer (). The above prepolymer () and prepolymer () were mixed so that the weight ratio ()/() was 3/7, and 1,4-butanediol was added to this and reacted at 50℃ for 3 hours with stirring. Synthesized polyurethane. Purification of polyurethane involves adding methanol to the above reaction product to precipitate polyurethane, dissolving it again in a mixed solvent of dioxane-dimethylacetamide (7:3 weight ratio), and adding methanol to precipitate three times. The polyurethane was purified repeatedly and dried under reduced pressure. Example 2 A polyethylene glycol prepolymer (using polyethylene glycol with a molecular weight of 900) with a terminal isocyanate prepared under the same conditions as in Example 1 and a polytetramethylene glycol prepolymer with a terminal isocyanate prepared under the same conditions as in Example 1. When chain-extending the polymer (), 20% of the required amount of butanediol was separately reacted with the above prepolymer at 50°C for 2 hours, then both were mixed, and the remaining butanediol was added to this mixture. The reaction was then continued at 50°C for an additional 3 hours with stirring.
The rest of the processing method is the same as in the first embodiment. Example 3 In the same manner as in Example 1, polytetramethylene ether glycol with a terminal hydroxyl group (molecular weight 1600), polypropylene glycol with a terminal hydroxyl group (molecular weight
550) were separately reacted with 4,4'-diphenylmethane diisocyanate to prepare prepolymers in a conventional manner. Polyurethane was synthesized by mixing these prepolymers at a ratio of 8:2 and using ethylene glycol as a chain extender. Polyurethane purified in the same manner as in Example 1 was obtained. Example 4 Block copolyether diol of ethylene oxide (EO) and propylene oxide (PO) HO-(EO)a-(PO)b-(EO)a-OH a:b=1:2, molecular weight 1200, Using dimethyl sulfoxide as a solvent, it was reacted with 4,4'-diphenylmethane diisocyanate to produce a terminal diisocyanate prepolymer (). Separately, polytetramethylene glycol (molecular weight 1500) having hydroxyl groups at both terminals was reacted with 4,4'-diphenylmethane diisocyanate to prepare a terminal isocyanate prepolymer (2). Diazabicycloundecene was used as a catalyst in an amount of 0.04% based on the isocyanate used. Polyurethane urea was synthesized by mixing prepolymers () and () and using ethylenediamine as a chain extender. Methanol was added to this to precipitate polyurethane, reprecipitation was repeated three times using a dimethylacetamide-methanol system, and further ethanol extraction was performed using a Soxhlet and dried. This polyurethane was dissolved in dimethylacetamide to form a solution, and the solution was cast onto a glass plate to create a form. This film was transparent with no coloration and was extremely smooth when observed under a scanning electron microscope or an optical microscope. When this film was subjected to a tensile test to determine the tensile strength and elongation at break, the tensile strength was 0.69 Kg/mm and the elongation at break was 650%, indicating that it has sufficient mechanical properties. It was done. When the Lee-white test was conducted as a measure of antithrombotic properties, it was found to be 90 minutes, which is a dramatic improvement compared to the commercially available Biomer, which takes 55 minutes. Comparative example 1 Polytetramethylene glycol (molecular weight 1600)
and polypropylene glycol (molecular weight 550) (mixing ratio 8:2) was dissolved in dimethylacetamide, 4,4'-diphenylmethane diisocyanate and diazabicycloundecene were added as a catalyst in a conventional manner, and the mixture was heated at 50°C. The mixture was reacted for 1 hour with stirring to synthesize a prepolymer. Ethylene glycol was added as a chain extender to this, and a chain extension reaction was performed for 1 hour to obtain polyurethane. Purified polyurethane was obtained in the same manner as in Example 1. Comparative Example 2 Polyethylene glycol (molecular weight 800) having hydroxyl groups at both ends and polytetramethylene glycol (molecular weight 1850) having hydroxyl groups at both ends were dissolved in dimethylacetamide at a mixing ratio of 3:7, and 4,4'-
17 parts of diphenylmethane diisocyanate and 0.008 parts of diazabicycloundecene were added and reacted with stirring at 50°C. Subsequently, polyurethane was synthesized by a conventional method using 1,4-butanediol as a chain extender. Purified polyurethane was obtained in the same manner as in Example 1. Example 5 The polyurethanes synthesized in Examples 1, 2, and 3 and Comparative Examples 1 and 2 were dissolved in a solvent and cast onto a glass plate to prepare a film. This film was colorless and transparent, and was extremely smooth when observed under an optical microscope and a scanning electron microscope. This film was also subjected to a tensile test to determine its tensile strength and elongation at break. Antithrombotic properties were measured using a test tube (inner diameter 10 mm,
length 100 mm), and the Lee-White method (Izumi Kanai,
Blood coagulation time was measured according to Masamitsu Kanai (ed.: Clinical Testing Methods Summary, -81, Kanehara Publishing Co., Ltd., 1972). The results are summarized in the table below, including the results of tests on commercially available polyurethane (Biomer: Biomer: Cardiosan 51, manufactured by Ethicon; Cardiosan 51, manufactured by Kontron).

〔Effect of the invention〕

The present invention is an antithrombotic material made of a completely new polyurethane or polyurethane urea that maintains sufficient mechanical properties and is hydrophilic, and is excellent as a novel and practical antithrombotic material. This will contribute to the development of contact medical devices.

Claims (1)

[Claims] 1. A prepolymer () consisting of a polyalkylene glycol having hydroxyl groups at both ends (alkylene has 2 and/or 3 carbon atoms) and a diisocyanate.
An antithrombotic material made of polyurethane or polyurethane urea, characterized in that it is synthesized from a prepolymer () made of polytetramethylene glycol and diisocyanate having hydroxyl groups at both ends, and a chain extender. 2 Prepolymer () made from polyalkylene glycol having hydroxyl groups at both ends (alkylene has 2 and/or 3 carbon atoms) and diisocyanate, and prepolymer made from polytetramethylene glycol having hydroxyl groups at both ends and diisocyanate 1. A method for producing an antithrombotic material made of polyurethane or polyurethane urea, characterized in that the antithrombotic material is synthesized by mixing () with () and then acting with a chain extender. 3. By reacting a prepolymer () made from polyalkylene glycol (alkylene has 2 and/or 3 carbon atoms) having hydroxyl groups at both ends and diisocyanate, and polytetramethylene glycol having hydroxyl groups at both ends and diisocyanate. Using the prepared prepolymer (), at least one of the prepolymers () and () is reacted in advance with a chain extender to extend the chain, and then mixed, and further the chain extender is allowed to act on this mixture. A method for producing an antithrombotic material made of polyurethane or polyurethaneurea, characterized by: