JPH032549B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel medical material with excellent compatibility with living tissues and antithrombotic properties. In recent years, many polymer materials have come to be used in artificial organs such as artificial kidneys, artificial hearts, and artificial blood vessels, as well as medical devices such as various catheters, bags, blood circuits, and various tubes. .
Most of the polymeric materials used in these medical materials are repurposed from existing materials that have traditionally been used in other fields, and lack biocompatibility, especially when used for applications that come into direct contact with living organisms. This has become a serious problem as various undesirable foreign body reactions may occur due to removal. Medical materials should have:
Biocompatibility differs depending on the application, but the most problematic ones currently are that when it comes in contact with blood, it may cause blood coagulation, and when it comes in contact with living tissue, it may stimulate cells and cause inflammation. This is a phenomenon that occurs. By the way, polyether polyurethane urea and block copolymers of polyether polyurethane and polydimethylsiloxane are known as antithrombotic materials, and when used as elastic bodies such as pump materials for artificial hearts and balloon catheters, etc. shows satisfactory compatibility. However, it is not suitable for applications that require particular compatibility with living tissues, such as artificial blood vessels, shunts used during dialysis, wound dressings, and sutures, and is not suitable for use in various blood purification systems such as artificial kidneys. It could not be used as a membrane material, which is an important part of the industry. Under these circumstances, the present inventors conducted intensive research in order to develop a composite polymer material with excellent tissue compatibility and antithrombotic properties. The present invention was completed based on the discovery that polyamide-modified segmented polyurethane consisting of the following components is extremely superior. That is, the present invention utilizes segmented polyurethane.
The purpose is to provide medical materials comprising polyamide copolymers, and more specifically, from polyamides synthesized from polyester and/or polyether chains and raw materials selected from diamines, dicarboxylic acids, or lactams. A new polyamide-modified polyurethane resin, in which polyamide chains are copolymerized in a block form through urethane bonds and urea bonds, has excellent tissue compatibility and antithrombotic properties, and is also excellent in processability and mechanical properties. This was based on extensive knowledge. The constitution of the present invention will be clarified below by clarifying typical raw materials and manufacturing methods of the segmented polyurethane polyamide copolymer, which is a constituent material of the medical material according to the present invention. First, typical raw material components include (1) polyester and/or polyether with a molecular weight of 500 to 5000 having groups at both ends that have active hydrogen that can react with isocyanate groups, (ii) diisocyanates, and (iii) isocyanates. A low molecular weight compound with a molecular weight of 400 or less that has a group that has an active hydrogen that can react with a group, and (iv) a diamine, dicarboxylic acid, or lactam with a molecular weight of 500 to 8000 that has an amino group at both ends. There are four components of polyamide synthesized in this way. Among the above components (i), polyesters include ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, neopentyl glycol, hexamethylene glycol, decamethylene glycol,
1,4-dihydroxycyclohexane, 1,4-
Diols such as cyclohexanedimethanol, oxalic acid, succinic acid, glutaric acid, adipic acid,
Aliphatic dicarboxylic acids such as azelaic acid, sebacic acid, dodecanedicarboxylic acid, and dimer acid; aromatic dicarboxylic acids such as terephthalic acid and isophthalic acid; alicyclic dicarboxylic acids such as 1,4-cyclohexanedicarboxylic acid; or esters thereof Examples include polyester diols obtained from ester-forming derivatives, polylactone diols obtained by ring-opening polymerization of ε-caprolactone, etc.
Furthermore, it may be a polyester having at its terminal an active hydrogen group other than a hydroxyl group, for example, an amino group or an active hydrogen that can react with an acid and an isocyanate group such as a hydrazide group. Examples of the polyether include polyethers having active hydrogen at both ends, such as polyethylene glycol, polypropylene glycol, polytetramethylene glycol alone or block copolymers, and polyethers having amino groups at the ends. These polyesters and polyethers form the basic skeleton of segmented polyurethane chains, but since they have almost the same physical properties, they can be used alone or in combination of two or more. Finally, copolymerization can also be carried out. The molecular weight of these components (i) is
As mentioned earlier, the range of 500 to 5000 is preferable, and the reason for this is that when the molecular weight is less than 500, the physical properties become hard.
Molded products such as films and tubes become brittle, and at the same time blood compatibility decreases, probably because the expression of the microphase separation structure in the solid phase becomes unclear. On the other hand, if it exceeds 5000, it becomes too soft and the surface of the molded product becomes sticky. Next, component (ii), diisocyanates, is an essential component for forming urethane bonds between component (i) above and component (iii), which will be described later. tolylene diisocyanate,
2,6-tolylene diisocyanate or a mixture of both, xylylene diisocyanate, 4,
4'-diphenylmethane diisocyanate, 4,
Examples include 4'-diphenylpropane diisocyanate, phenylene diisocyanate, and naphthalene diisocyanate. In addition, the low molecular weight compound of component (iii) is blended as a chain extender, and is
Like component (i), it must have a group having an active hydrogen that can react with isocyanate groups, and specific examples include ethylene glycol, 1,
3-propylene glycol, 1,2-propylene glycol, 1,4-butanediol, 1,5-
pentanediol, 1,6-hexanediol,
Diols such as 1,6-cyclohexanedimethanol, diethylene glycol, triethylene glycol; ethylene diamine, 1,2-propylene diamine, 1,4-butylene diamine, 2,3
-butylene diamine, hexamethylene diamine,
Microhexanediamine, piperazine, 1,4-
Diamines such as diaminopiperazine, xylylene diamine, and tolylene diamine; Hydrazines such as hydrazine and monoalkylhydrazine; Acid dihydrazides such as adipic acid dihydrazide; Ethanolamine, aminopropyl alcohol, 3
Examples include alkanolamines such as -aminocyclohexyl alcohol. If the molecular weight of component (iii) exceeds 400 yen, the strength of the final product (eg, film, tube, etc.) will be weakened. Finally, component (iv) is an extremely important component as a modifier for polyurethane chains, and representative examples include polypyrrolidone, polycaprolactam, polyundecanolactam, and polydodecanol obtained by ring-opening polymerization of lactam. For example, polyhexamethylene adipamide (6,6-nylon) obtained by polycondensing diamines having about 4 to 12 carbon atoms such as nolactam, hexamethylene diamine, and octamethylene diamine with aliphatic dicarboxylic acids; polyhexamethylene azelamide (6,9-nylon),
Polyhexamethylene sebamide (6,10-nylon) Polyhexamethylene dodecanoamide (6,12
- nylon); ε-caprolactam or 6,6
- nylon salt and aliphatic diamine having 2-14 carbon atoms,
isophthalic acid, terephthalic acid, orthophthalic acid,
Examples include copolyamides obtained by copolymerizing xylylene diamine, phenylene diamine, methylenebis(4-aminocyclohexane), and the like. The molecular weight of these polyamides is 500~
8000 is preferred. The reason is that the molecular weight is 500
If it is less than 8,000, the blood compatibility will decrease, while if it exceeds 8,000, the physical properties of the final product will be hard, the tear strength will decrease,
This is because it brings about such things. Therefore, in its production, it is necessary to appropriately adjust the molar ratio of the amine component and the acid component so that amino groups are present at both ends and the average molecular weight is within the above-mentioned preferred range. The molar ratio of amino component/acid component is 1.05~
This purpose can be achieved by setting it in the range of 2.00. In the case of polyamides obtained from lactams, it is necessary to convert the terminal end into an amino group, and the most preferred diamines for this purpose include hexamethylene diamine, tetramethylene diamine, xylylene diamine, and the like. The segmented polyurethane/polyamide copolymer of the present invention is produced by reacting the above components (i) to (iv) simultaneously or sequentially, and the most preferred production method is as follows. It is. [] Polyester and/or polyether (i)
and diisocyanate (ii) are mixed and reacted, and then a solution obtained by mixing and dissolving a low molecular weight chain extender (iii) in a polyamide (iv) solution is added to the mixed reaction solution and reacted. [] Polyester and/or polyether (i)
and diisocyanate (ii) and small chain extender (iii)
A method of mixing and reacting, and then adding and reacting a polyamide (iv) solution. [] Polyester and/or polyether
After mixing and dissolving (i), low molecular weight chain extender (iii) and polyamide (iv) solution, diisocyanate (ii)
A method of adding and reacting. [] A method in which each component (i) to (iv) is divided into appropriate amounts and reacted. In this case, the polyamide solution is preferably prepared by dissolving the polyamide in an N,N-disubstituted amide solution in which inorganic salts are dissolved.
As the N,N-disubstituted amide compound, dimethylformamide, dimethylacetamide, dimethylpropionamide, methoxydimethylacetamide, N-methylpyrrolidone, hexamethylphosphoamide, etc. may be used alone or in combination of two or more. Further, as inorganic salts, lithium chloride, calcium chloride, magnesium chloride, calcium bromide, etc. are generally used, but of course, the salts are not limited to these. The blending ratio of the raw material components (i) to (iv) should be determined appropriately taking into consideration the molecular weight of each component and the degree of polymerization (molecular weight, i.e., physical properties) of the final product. It is desirable to adjust the blending ratio so that the content in the final copolymer is more than 10% by weight and less than 90% by weight. However, if polyamide(iv) is less than 10% by weight, it will not be able to satisfy the same biological tissue compatibility as conventional synthetic polymer materials, while if it exceeds 90% by weight, the content of polyurethane components will be relatively reduced. This results in poor mechanical performance. The reason why bio-tissue compatibility is greatly improved by modifying polyurethane with polyamide is not necessarily clear, but it is probably because the polyester chains and/or
Alternatively, a block copolymer produced by urethane bonding and/or urea bonding between a polyether chain and a polyamide chain forms a microphase-separated structure that does not give a foreign body feeling to living tissues or living cells when molded. It is thought that this is because of this. In any case, the polyamide-modified polyurethane resin obtained in this manner has excellent tissue compatibility and antithrombotic properties, as well as excellent mechanical properties, and is also resistant to toxicity and elution of harmful substances during use. There are also none. Therefore, artificial blood vessels, shunts, blood purification membranes, artificial skin, artificial hearts,
It can be widely used as a variety of medical materials, including artificial valves, artificial tracheas, artificial bladders, and artificial ureters, as well as patches and suture systems. Next, examples of the present invention will be shown. Note that parts in the examples refer to parts by weight, and antithrombotic properties were evaluated using the column method developed by Sakurai et al. [MaKyomol.
Chem. 179, 1121 (1978)], and the histocompatibility was evaluated using the method of Noichiki et al. [Artificial Organs Vol. 9, No. 3, 678
(1980)]. Example 1 130 parts of polytetramethylene glycol with an average molecular weight of 1300 and 9.3 parts of ethylene glycol were charged into a polymerization container and dimethylformamide (hereinafter referred to as DMF) was charged.
) and dissolve in a nitrogen stream.
Add and dissolve 100 parts of methylene bis(4-phenyl isocyanate) (hereinafter abbreviated as MDI) to this solution,
After carrying out the reaction at 70℃ for 60 minutes with stirring, the temperature was increased to 10℃.
Cool and add 370 parts of DMF to make a homogeneous solution. On the other hand, ε-caprolactam and hexamethylene diamine (molar ratio 10/1) were reacted to produce a polyamide with an average molecular weight of 1387 having amino groups at both ends, and this was mixed into DMF containing 8% lithium chloride.
Prepare 800 parts of a polyamide solution dissolved in the solution to a concentration of 25%. This polyamide solution was gradually added to the homogeneous solution obtained above, and the final temperature was 20°C.
A modified polyurethane resin solution with a poise of 1900, a polymer concentration of 28.2%, and a polyamide portion of 45.5% was obtained. Methanol was added to a portion of this polymer solution to precipitate a resin, which was thoroughly washed with water and methanol and dried. 0.4 part of the obtained resin
Dissolve in 100 parts of DMF and use this solution to make a diameter 20μ
glass beads were coated with resin. 0.5 g of resin-coated beads were packed close-packed into a 100 cm PVC tube with an inner diameter of 3 mm, which had holes at both ends, and was filled with physiological saline. Collect 2 ml of fresh blood from the cervical vein of an adult dog using a medical disposable syringe with a capacity of 10 ml, immediately set it in a syringe pump that can extrude at a constant flow rate, and add the beads to the tip of the syringe from which the needle has been removed. A packed column was connected, blood was allowed to flow for 1 minute at a flow rate of 1.2 ml/min, and the blood that had passed through the column was collected into a commercially available polydonor bottle 0110 treated with EDTA. The number of platelets in the blood that passed through the column was calculated using the BrecherCronKite method. Here, the platelet adhesion number was determined by subtracting the number of platelets after passing through the column from the number of platelets before passing through the column. Relative comparison of platelet adhesion between materials was determined by the following formula, and the smaller this value, the lower the platelet adhesion, that is, the better the antithrombotic property. Table 1 shows the evaluation results of relative adhesion = number of adhesion for beads coated with polymeric material/number of adhesion for glass beads alone. Example 2 In Example 1, ε-caprolactam, adipic acid and hexamethylene diamine (molar ratio 3.20:
0.40:1.00) with an average molecular weight of 987 and having amino groups at both ends was dissolved in an 8% lithium chloride DMF solution and polymerized in the same manner as in Example 1 to a 25% concentration. A modified polyurethane resin solution with a polymer concentration of 28.7% and a polyamide portion of 36.9% was obtained. Next, in the same manner as in Example 1, glass beads were coated with a resin, and antithrombotic properties were evaluated using a column method. Evaluation results first
Shown in the table. Example 3 In Example 1, instead of the polyamide obtained from ε-caprolactam and hexamethylene diamine (molar ratio 10:1), ε-caprolactam, isophthalic acid and hexamethylene diamine (molar ratio 10:1) were used.
Polymerization was carried out in the same manner except that 140 parts of polyamide with an average molecular weight of 1000 and having amino groups at both ends obtained from 3.20:0.40:1.00) was used, and at 20 ° C., 1950 poise, polymer concentration 28.7%, and polyamide portion 36.9%.
A modified polyurethane resin solution was obtained. Thereafter, antithrombotic properties were evaluated using the column method in the same manner as in Example 1. The evaluation results are shown in Table 1. Comparative Example 1 A commercially available polyether polyurethane for medical use (trade name: Mobay 85A) containing no polyamide was evaluated for antithrombotic properties by the column method in the same manner as in Example 1. . The evaluation results are shown in Table 1.

[Table] Example 4 979 parts of polytetramethylene glycol with an average molecular weight of 1290, 999 parts of DMF, 94.2 parts of ethylene glycol
and 797 parts of MDI were placed in a polymerization container and heated at 70℃.
After reacting for 45 minutes, cool to below 10℃,
Add 1756 parts of DMF to make a homogeneous solution. On the other hand, ε−
A polyamide with an average molecular weight of 900 having amino groups at both ends prepared from caprolactam, adipic acid and hexamethylene diamine (molar ratio 3.20:0.40:1.00) containing 4% calcium chloride.
Prepare 3.219 parts of a polyamide solution adjusted to 20% in DMF solution, and gradually add this to the homogeneous solution.Finally, at 20°C, at 2100 poise, polymer concentration 25%, and polyamide part 25.5%. A modified polyurethane resin solution was obtained. Methanol was added to a portion of this polymer solution to precipitate a resin, which was thoroughly washed with water and methanol and then dried. One part of the obtained resin was dissolved in 99 parts of DMF, and a 1×3 cm polyester fiber mesh was thinly coated to a thickness of 20 to 40 μm, thoroughly washed with pure water, and then air-dried. A commercially available polyester mesh was immersed in ethyl alcohol for a day and night, washed with pure water and ethyl alcohol, and then dried. 70% resin coated mesh
It was sterilized by soaking in alcohol for one week. Before implantation in vivo, the sample was immersed in physiological saline and implanted into the back muscle of an adult mongrel dog. After 4 weeks, the sample was excised along with the surrounding tissue, fixed in 10% formalin, and embedded in paraffin. . The thin section was stained with hematoxin-eosin and the tissue reaction to the material was observed using an optical microscope.
, and no foreign body reaction was observed. For comparison, a similar test was conducted using a polyester mesh sample without coating with the resin of the present invention, and the results corresponded to the standard (±) or (+). From these results, it was found that the resin of the present invention was better than polyester, which is said to have a low degree of foreign matter reactivity. The degree of foreign body reactivity was observed at the cellular level, and the criteria were classified as follows. (−): Cells do not particularly recognize the implanted material as a foreign object. (±): Between (-) and (+) (+): Cells recognize it as a foreign object, and foreign giant cells and epithelioid cells gather around it, but there are 10 layers of cells surrounding the foreign object. The degree of foreign body reactivity is slight at the following levels:: Between (+): There is a marked foreign body reaction, and the cells gather in many layers to form a lump. +++++: Acts more strongly as a cytotoxic agent, causing surrounding cells to become necrotic.

Claims (1)

[Scope of Claims] 1. A medical material comprising a segmented polyurethane/polyamide copolymer, wherein the polyamide is a polyamide synthesized from raw materials selected from diamines, dicarboxylic acids, or lactams. 2. The medical material according to claim 1, wherein the polyamide component in the segmented polyurethane-polyamide copolymer is 10 to 90% by weight. 3 In claim 1 or 2, the segmented polyurethane polyamide copolymer is
(i) Polyester and/or polyether with a molecular weight of 500 to 5,000 having groups at both ends that have active hydrogen that can react with isocyanate groups, (ii) Polyisocyanates, (iii) Active hydrogen that can react with isocyanate groups. and (iv) a low molecular weight compound with a molecular weight of 400 or less that has a group with a molecular weight of 500 or less that has an amino group at both ends.
A medical material that is a polymer made by reacting ~8000 polyamide.