JPH0454967A - Medical material - Google Patents

Abstract

PURPOSE:To obtain a biological fitness excellent stably for a long time by getting higher alcohol and/or a higher alcohol macromer bonded to a base material directly or through a polymer. CONSTITUTION:This medical material has higher alcohol and/or a higher alcohol macromer bonded to a base material directly or through a polymer to obtain a biological fitness excellent by the higher alcohol. Moreover, as a hydroxyl group of the higher alcohol are those reactive with a functional group of the base material or the polymer to put them together by ether bonding, the biological fitness can be obtained stably for a long time without the isolation of the higher alcohol. When the higher alcohol macromer is made, the use of the hydroxide group of the higher alcohol enables the bonding easily in such a conditions wherein side reactions are hard to occur due to the addition polymerization of a molecular chain (spacer).

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to medical materials. Specifically, the present invention relates to medical materials that exhibit stable and high biocompatibility. [Prior Art] Medical devices such as artificial organs that have parts that come into contact with blood or living tissue have been manufactured and used in the past, but when selecting the materials that make up these medical devices, Biocompatibility becomes an important issue. The surface quality of the medical device used is an important factor in this biocompatibility. on the other hand,
It goes without saying that physical properties as a medical device are also important. Therefore, it is considered effective to select a material with appropriate physical properties for a medical device and modify its surface properties when applied as a medical material. From this point of view, various surface modification methods have been proposed. One of them is a fat-soluble vitamin or fatty acid macromer having a reactive end, in which the reactive end is bonded to a base material. (Unexamined Japanese Patent Publication No. 63-130069) [Problem to be solved by the invention 1] This is because the physical properties of the base material as a medical material are fully exhibited, while the surface is made biocompatible. Although it was a revolutionary product, it could not be said that sufficient biocompatibility was achieved, and there was room for improvement in stabilizing and improving biocompatibility. Therefore, an object of the present invention is to provide a novel medical material that solves the above-mentioned problems. Another object of the present invention is to provide a medical material that is stable and exhibits excellent biocompatibility over a long period of time. [Means for Solving the Problems] In order to solve the above problems, the present invention provides a medical material in which a higher alcohol and/or a higher alcohol macromer is bonded to a base material directly or via a polymer. I will provide a. Furthermore, it is preferable that the higher alcohol is oleyl alcohol. The present invention will be explained in detail below. Since the medical material of the present invention has the higher alcohol and/or higher alcohol macromer bonded to the base material directly or via a polymer, excellent biocompatibility due to the higher alcohol can be obtained. Furthermore, the reaction between the hydroxyl group of the higher alcohol and the functional group of the base material or polymer results in an ether bond, resulting in a bond between the carpoquine group, which is the reactive end of the fatty acid, and the functional group of the base material or polymer. The bond is stronger than that formed by ester bonding through reaction, so there is no release of higher alcohols, and it exhibits stable biocompatibility over a long period of time. Furthermore, when producing a higher alcohol macromer, since the hydroxyl group of the higher alcohol is used, molecular chains (spacers) can be easily bonded by addition polymerization under conditions where side reactions are difficult to occur. In addition, if a higher alcohol macromer is used, the molecular chain between the higher alcohol and the base material or polymer (
The presence of a spacer is expected to suppress platelet adhesion, thereby imparting higher biocompatibility, and the length of the molecular chain can be easily controlled, leading to the expectation of stable molecular chain mobility. As the higher alcohol in the present invention, -hydric alcohol is preferable for adjusting the molecular chain length and producing medical materials. Furthermore, unsaturated alcohols are preferred from the viewpoint of antithrombotic properties. That is, higher alcohols include oleyl alcohol, lauryl alcohol, myristyl alcohol,
Examples include cetyl alcohol and stearyl alcohol. In particular, oleyl alcohol is preferred from the viewpoint of compatibility with blood. In the present invention, higher alcohols may be combined as the higher alcohol macromer via a spacer, preferably a hydrophilic spacer, in order to improve biocompatibility, particularly blood compatibility. Note that the term "macromer" generally refers to a polymer having a polymerizable functional group at the end, but in this specification, it means a polymer having a reactive functional group at the end in a broader sense. shall be taken as a thing. Specific examples of the spacer include alkylene glycols having highly reactive functional groups at both ends, with polyethylene glycol diamine, polypropylene glycol diamine, and polytetramethylene glycol diamine being preferred. For example, when the spacer has an alkylene glycol skeleton, the degree of polymerization thereof is preferably about 1-100, although it depends on the type of alkylene. In addition, particularly as the alkylene glycol, polyethylene glycol and polypropylene glycol are preferable, and polyethylene glycol with a degree of polymerization of 20 to 90,
Particularly preferred is polypropylene glycol having a degree of polymerization of 10 to 50. The polymer of the present invention has a molecular weight of 500 to 500,000, preferably 5.000 to 300,000, more preferably 10,000 to 100.000, and is bonded to higher alcohol and/or higher alcohol macromer. It is a polymer having a functional group that can be bonded to the substrate described below. When the molecular weight of the polymer is within this range, even if there are few bonding parts with the base material, the treated area on the surface of the base material is large, so that the effects of the polymer can be sufficiently exhibited. Specifically, when the molecular weight is low, such as less than 500, it is difficult to efficiently cover the entire surface of the substrate.
If the molecular weight is too high, the solubility of the polymer decreases and the reactivity with the substrate surface also decreases, making it difficult to use. Further, the polymer is preferably a copolymer. Since two or more types of monomers are used, the characteristics of each monomer can be utilized. For example, it is possible to set the amount of higher alcohol and/or higher alcohol macromer bonded to the copolymer, the amount of bond between the copolymer and the base material, and the like. Examples of the functional groups contained in the copolymer include epoxy groups, carboxyl groups, aldehyde groups, and amino groups. The raw material monomer for the copolymer having an epoxy group is preferably a (meth)acrylic acid-based glycidyl ester or a vinyl-based glycidyl ester, and the raw material having a carboxyl group is preferably (meth)acrylic acid or vinyl acetate. preferable. Typical base materials used in the present invention include cellulose and its derivatives, as well as polyvinyl alcohol, partially saponified polyvinyl acetate, ethylene vinyl alcohol copolymers, and ethylene vinyl acetate copolymers. Saponified products, polyacrylic acid or polymethacrylic acid and copolymers thereof, polyhydroxyethyl methacrylate, chitin, chitosan, collagen, polyacrylamide, etc. can be used. The base material can be a variety of molded objects, such as sheet-like or tube-like (
(including hollow fibers), fibers, etc. Although the method for producing the medical material of the present invention is not particularly limited, it is preferable to use the following method. That is, a step of covalently bonding a functional group of a higher alcohol and/or a higher alcohol macromer with a part of a functional group of a polymer, and a step of covalently bonding a part of a functional group of the polymer with a functional group of a base material. It has a process. These steps may be performed simultaneously or in any order. For example, higher alcohols having an amine group at the end and/or
Or, if a higher alcohol macromer is used, a polymer having an epoxy group and a higher alcohol macromer are
A graft copolymer is formed through the epoxy group of the polymer, or a copolymer having an epoxy group and a carboxyl group and a higher alcohol and/or a higher alcohol macromer are formed through the carboxyl group of the polymer. A polymer derivative is obtained as a graft copolymer. For the reaction, a known general synthesis reaction may be used.

【Example】

The present invention will be specifically explained below based on Examples. (Synthesis of oleyl alcohol macromer) Oleyl alcohol can be obtained by adding ethylene oxide to oleyl alcohol under an alkali catalyst. Polyethylene glycol monooleyl ether (average molecular weight: 4268) 20.00 g, triethylamine 1
．． 90g was dissolved in dioxane 50rnQ. To this, a solution of 1.85 g of p-toluenesulfonyl chloride in dioxane (1Qm) was slowly added dropwise, and the reaction was carried out at 60°C for 2 hours.
After addition and dissolution, purification was performed by cooling to 0°C and precipitating the desired product. Next, 0.55 g of potassium phthalimide was added to a DMF 30 m (+) solution of 6.50 g of the above product, and the mixture was reacted at 90°C for 2 hours.
After addition and dissolution, purification was performed by cooling to 0°C and precipitating the desired product. Next, 6.00 g of the product ethanol 3 (JrnQ
Add 1.00 g of hydrazine hydrate to the solution, and add 2.0 g of hydrazine hydrate under reflux.
Allowed time to react. The reaction product was purified by adding 60 mQ of acetone to dissolve it, cooling it to 0°C, and precipitating the target product to obtain 5.20 g of oleyl alcohol macromer having an amino group at the end. (Synthesis of copolymer) 0.15 parts by weight of azobisisobutyronitrile and 7.5 parts by weight of methyl methacrylate were added as a polymerization initiator to a glass polymerization tube.
parts by weight, 15 parts by weight of glycidyl methacrylate,
3-methacryloxypropyltris(methoxystoxy)silane (6 parts by weight of Chisso Co., Ltd., 1.5 parts by weight of methacrylic acid)
The polymerization tube was cooled and solidified in liquid nitrogen, and after repeating deaeration, nitrogen substitution, and deaeration using a vacuum pump, the tube was sealed. This was heated in a constant temperature bath at a predetermined temperature for a predetermined time. Thereafter, the container was cooled and opened, and the contents were dissolved in tetrahydro 7 run and reprecipitated in methanol to obtain a white polymer. Similarly, a copolymer containing no methacrylic acid was also synthesized. Epoxy equivalents were determined by dissolving these copolymers in methyl ethyl ketone and titrating with 0.01N perchloric acid/acetic acid solution using ethyltrimethylammonium bromide as a catalyst and crystal violet as an indicator, and then determining the glycidyl methacrylate composition. was calculated (Table 1). Table 1 Preparation Copolymerization Temperature Polymerization Time Kringle Monomer No. (℃)
(min) Late composition (vt%) A
1 60 50 52.
9B 2 60 5
0 52.7A: MMA/GMA/MPTMS/
MA=7.5/15/6/1.5 (weight ratio) B: MMA
/GMA/MPTMS=7.5/15/7.5 (weight ratio) MMA: Methyl methacrylate GMA Nigericidyl methacrylate MPTMS: 3-methacryloxypropyltris(methoxyethoxy)ranine MA: Methacrylic acid (along with oleyl alcohol macromer) Polymer Reaction) 4.00 g of the copolymer No. 1, 0.718 g of dicyclohexylcarbodiimide, and 100 ml of a mixed solvent of carbon tetrachloride/acetonitrile (1:1 volume ratio) were placed in a flask, and the mixture was heated at room temperature with a nitrogen stream. After stirring for 60 minutes, a solution of 9.92 g of the oleyl alcohol macromer in carbon tetrachloride/acetonitrile (1:1 volume ratio) 20+++ff was gradually added dropwise, and after stirring at room temperature for 60 minutes,
The mixture was further stirred at 60°C for 60 minutes. After cooling the reaction contents to room temperature, the contents were filtered through a glass filter, and the solvent of the filtrate was lightly distilled off to obtain a yellow, highly viscous crude product. Add methanol 200+n (2) to the obtained crude product,
After stirring at room temperature for about 30 minutes until there are no lumps,
Centrifugation was performed, and the supernatant was removed by decantation. After performing the same operation twice more, vacuum drying was performed to obtain 8.75 g of a polymer derivative. (Binding of polymer derivative to regenerated cellulose membrane) The above-mentioned polymer derivative was bonded to the surface of regenerated cellulose in the following manner. First, 0.5 (W/V)% aqueous solution of sodium hydroxide
In ooma, regenerated cellulose membrane (film thickness 0゜2mm) 0
．． 3g was soaked for 30 minutes. Next, the cellulose membrane was immersed in a 0.5 (W/V)% acetone solution of the polymer derivative and reacted at room temperature for 24 hours. After the reaction was completed, the regenerated cellulose membrane was taken out and thoroughly washed in the order of acetone, ethanol, and distilled water to obtain Sample 1 as an example of the medical material of the present invention. (Comparative Examples 1 and 2) 0.04 g of pyridine was added to 30 m of dry dioxane (2), and then 0.90 g of linoleic acid was put into a flask using this mixture, and the mixture was stirred at 80°C for 30 minutes. Furthermore, the above-mentioned copolymer No. 2-3 was added to this flask.
．． After adding a solution of OOg dissolved in 70 m of dry dioxane (2), the mixture was stirred at 80°C for 6 hours. After the reaction contents were cooled to room temperature, the solvent was lightly distilled off, and a pale brown highly viscous crude product was obtained. was obtained. 100 m+2 of methanol was added to this crude composition, and after stirring at room temperature for about 30 minutes (until there were no lumps), centrifugation was performed, and the supernatant was removed by decantation. The same operation was repeated two more times. After that, vacuum drying was performed, and 3.05 g of a polymer derivative was obtained.This polymer derivative was bonded to a regenerated cellulose membrane in the same manner as in Example, and this was used in Comparative Example 1.
(Sample 2). In addition, an untreated regenerated cellulose membrane was used as Comparative Example 2 (Sample 3).
And so. (Evaluation Test 1) Using Examples and Comparative Examples 1 and 2, the following M
Changes in complement values were measured by the ayeri method. The results are shown in Table 2. Each sample is pre-soaked in physiological saline to bring it into a state of sorption equilibrium. Gently remove moisture from the surface of each sample, cut into a 20 cm2 piece, place it in a plastic blood collection tube, and add 1 mff of adult dog serum. After activation by holding at 37°C for 3 hours, the complement value CH2
The change in O (complement value determined by 50% hemolysis method) was measured and the consumption rate was calculated. Sample Consumption rate (%) of CH30 Example (Sample 1) 13.5 Comparative example 1 (Sample 2) 1
4.2 Comparative Example 2 (Sample 3) 317 Table 2 From Table 2, it can be seen that the medical material of the present invention causes a very small decrease in serum complement value CH30, even when compared to untreated material. it is obvious. (Evaluation test 2) 3.8% sodium citrate (1/9 of the amount of blood collected)
Venous blood from a healthy individual was collected using a voriglopylene syringe containing 100% of the sample, gently transferred along the tube wall into a polypropylene test tube, and centrifuged at 800 rpm for 5 minutes. The supernatant platelet-rich plasma (PPP) was collected and diluted with 3.8% sodium citrate diluent (1/10 volume relative to Ringer's lactate) to prepare a platelet suspension. The number of platelets in this platelet suspension was 66,000/mm2. 0.2 mQ of this platelet suspension was added to Example and Comparative Example 1.
2 samples (1 cm") to a thickness of 2 mm, and were brought into contact with each other for 30 minutes at room temperature. After a predetermined period of time,
Each sample was lightly washed with a 3.8% diluted sodium citrate solution, and then fixed in 2.5% geltaraldehyde/lactated Ringer's solution by storing the sample in a cool place overnight. Furthermore, after washing lightly with 3.8% sodium citrate diluted solution,
Ethanol series with stepwise dehydration of 50%, 60%, 70%
. The samples were treated sequentially in 80%, 90%, 95%, 100%, and 100% ethanol solutions for 10 minutes. ), air-dried, and observed with a scanning electronic H microscope (J 5M-840, manufactured by JEOL Ltd.). The evaluation method was to look at the number of platelets attached to 0-07 mm' and changes in their morphology. The morphological changes are as follows:
classified into species. Type I: Platelets change from the normal disk shape to a spherical shape, 3 to 3.
It has four pseudopods and is thought to have relatively weak adhesion to the material surface. ■Type: A type with several or more pseudopods extended and the cell body expanded to half of the pseudopod, which seems to have strongly adhered to the material surface. ■Type: One with a thin cell expanded to more than half the length of the pseudopod, and one with a completely expanded cell that appears to be homogeneous and completely adhered to the material surface. The test results are shown in Table 3. Table 3 Sample Platelet morphology (%) Platelet adhesion number type I
■Type ■Type Number 10.07mm” Example 66.7
25.6 7.7, 78 Comparative Example 1 62.
3 31.2 6.5 93 Comparative Example 2 5],,
9 37, 2 10.9 478 From Table 3, it is clear that the medical materials of the present invention have better antithrombotic properties than untreated materials and materials with fixed fatty acids. [Effects of the Invention] As detailed above, since the medical material of the present invention uses higher alcohol, side reactions and decomposition during reaction are less likely to occur, so it can be stably produced as a medical material. Since the higher alcohol and/or higher alcohol macromer are bound to the base material directly or via a polymer, activation of the complement system is suppressed and stable biocompatibility is imparted to the base material over a long period of time. be done.

Claims (2)

[Claims] (1) A medical material characterized in that a higher alcohol and/or a higher alcohol macromer is bonded to a base material directly or via a polymer. (2) The medical material according to claim (1), wherein the higher alcohol is oleyl alcohol.