JPS60119955A - Synthetic polymer body for living body material - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a synthetic polymer suitable as a biomaterial such as an artificial device, a medical device material, a culture bed material, and the like.

The recent diversification of the polymer industry has extended to the field of so-called biological polymers, and applications of many materials have been attempted to date. Such polymers include polystyrene, polyethylene, silicone rubber, polypropylene, Teflon, natural rubber, epoxy resin, polyvinylidene fluoride, nylon, ionomer, polyurethane,
Examples include polyvinyl chloride and polyester.

An example of its application is artificial blood vessels. When used temporarily during surgery, etc., it can be used by applying a so-called anticoagulant such as heparin to the structural example of the polymer. However, when using this for a long period of time, or even when implanting it into the body, there are problems with adhesion with the living body and anti-blood coagulation, and so far it has not been possible to obtain a fully satisfactory product. is the current situation. In addition, an artificial kidney is an artificial organ that is relatively widely used, and it uses a dialysis membrane to perform the arbor function of protein metabolites and electrolytes such as urea, creatinine, and uric acid. be. In addition, research into the application of polymers as various artificial organs and medical materials has progressed, and some have even been put into practical use. however,
These materials have not yet been satisfactory in terms of so-called biocompatibility, as typically shown by blood coagulation time and degree of tissue culture inhibition.

Furthermore, some materials have problems such as leached materials from the materials, such as those tested in acute toxicity tests and pyrogen tests, and even worse, the materials themselves deteriorate in the body. .

From this point of view, the present inventors have made intensive studies and have found that a polymer having a specific composition can be used as an extremely good biomaterial, and have completed the present invention.

That is, the present invention has a basic nitrogen-containing functional group with a pKa of 4.0 or more, and the nitrogen content in the functional group is 0.05 to 0.05.
It is a synthetic polymer for biomaterials with a concentration of 5.5% by weight. The nitrogen content is the weight percent of the nitrogen atoms in the functional group in the total polymer. Even better performance is exhibited when the nitrogen content is between 0.5 and 1.5 inches.

The polymer of the present invention may be in any polymer form such as a linear polymer, a graft polymer, or a crosslinked polymer, and may be a homopolymer or a copolymer of two or more. .

The basic nitrogen-containing functional group of the present invention is represented by the following formula (a).

There is no particular restriction on the substituent RI +”! +R1,
Any substituent can be provided, provided that some substituent is connected to the main chain of the polymerization.

For example, it may be a hydrocarbon substituent such as hydrogen, a methyl group, an ethyl group, a propyl group, a phenyl group, a benzyl group, or a substituent containing a heteronuclear atom such as methylol or ethylol. However, unless the pKa of the basic functional group reaches 4.0 or more, the effects of the present invention will not be exhibited.

Two or more R1+ R,l RII may be cyclic, and examples thereof include pyridine, imidazole, piperidine, pyrrole, and pyrimidine.

The functional groups do not necessarily have to be present in the side chains of the polymer;
It may also be one that forms a main chain, such as polyethyleneimine.

Specific examples of such amines (usually expressed as monomer units) include allylamine, diallylamine, N,N-dimethylallylamine, N,N-diethylallylamine, N,N'-diallylpiperazine, N
, N'-diallylaniline, N,N'-diallylmelamine, aminostyrene, N,N'-dimethylaminostyrene, N,N-diethylaminostyrene, vinylbenzylamine, vinylphenethylamine, N,N-dimethylvinylphenethylamine, N , N-diethylvinylphenethylamine, N-propylvinylphenethylamine, vinylpyridi7.2-)thyl-5-vinylpyridine, 2-
Ethyl-5-vinylpyridine, 2-vinylpyridine, 2-
Vinylimidazole, 4-vinylimidazole, vinylpyrazoline, vinylpyrazine, 4-vinylpyrimidine/,
vinylamine, vinylcarbazole, ethyleneimine,
N-phenylethyleneimine, N,N'-diethyl-N
-vinylphenethylamine ester oligomers, polyamine macromers, etc.

Among these, diethylamine ethylstyrene-? N
, N'-diethyl-N-vinylphenethylamine and its oligomers, polyamine macromers, etc. are preferred examples.

It may be preferable that the polymer of the present invention contains a hydroxyl group. There is no particular restriction on the bonding method of hydroxyl groups in the polymer, and examples thereof include alkanol groups and phenol groups. Examples of monomers for polymerized units include hydroxystyrene, hydroxymethylstyrene, vinyl alcohol, 2-hydroxyethyl acrylate, and 2-hydroxyethyl methacrylate.

There are no particular restrictions on producing the polymer of the present invention, and addition polymerization including radical polymerization and anionic polymerization using monomers, ring-opening polymerization, polymerization by dehydrohalogenation, condensation reaction, etc. may be used. I can do it. Furthermore, a method using a polymer reaction can also be adopted. For example, a predetermined raw material polymer may be subjected to an amino ratio using a known method, or a hydroxyl group may be introduced as necessary. When producing a graft polymer, it can be obtained by copolymerizing a macromer with another monomer, or it can be obtained by performing a graft reaction on a polymer raw material.

In the present invention, biomaterials refer to so-called biomaterials, including artificial blood vessels, artificial valves, heart-lung machines, artificial kidneys, artificial hearts, etc. that are used in contact with blood. Artificial organs embedded in tissues such as organs, artificial bones, artificial joints, and pacemakers, as well as adsorbents for biological substances, oxygen transport materials,
These include microcapsule materials, bioadhesive materials, medical device materials such as syringes and catheters, and culture bed materials.

First, the polymer of the present invention was stable and exhibited extremely excellent blood compatibility. That is, the adsorption of albumin, fibrinogen, and globulin to the polymer was extremely small, and the adsorption amount decreased in the order of albumin, fibrinogen, and globulin. It was also observed that platelet adhesion was extremely low and no activation of coagulation factors occurred. These results showed that this polymer had excellent antithrombotic properties.

Furthermore, secondly, the polymer showed stable and excellent tissue compatibility. That is, when culturing the Senblast cells, very good results were obtained, and no hemolytic activity against red blood cells was observed. Furthermore, as a result of subcutaneous implantation of the polymer into dogs, it was found to have extremely good affinity for tissues.

A method of using the polymer of the present invention as a biomaterial will be described below.

Artificial blood vessels, artificial valves, heart-lung machines, artificial kidneys, artificial ICs? When used on land as organs, artificial bones, artificial joints, pacemakers, adsorbents for biological substances, oxygen transport materials, microcapsules, etc., the functions can be expressed by molding the polymer into a desired shape. I can do it. for example,
If it is desired to cast the film in the form of a film, it can be cast to a desired thickness by a known method such as using a solvent. Furthermore, it is possible to mold into shapes other than membranes using methods such as thermal plasticization. Materials for medical devices such as syringes and catheters, and culture beds can also exhibit their functions by shaping them into desired shapes. Furthermore, it is also possible to use a method such as coating on a known polymer.

The polymer of the present invention is a so-called synthetic polymer, and has manufacturing advantages over naturally occurring polymers.

Examples are shown below, but these are not intended to limit the scope of the present invention.

Reference Example N A polyamine macromer having a number average molecular weight of 2000 was synthesized by reacting N'-diethyl-N-(p-vinylphenethyl)ethylenediamine in tetrahydrofuran using lithium diisopropylamide as a catalyst. This macromer and 2-hydroxyethyl methacrylate were mixed in ethanol with 2,2'-azobis-
Copolymers were obtained by polymerization using (2,4-dimethylvaleronitrile) as an initiator (#01 to #02).

Using p-(2-diethylaminoethyl)styrene,
Similarly, a copolymer with 2-hydroxyethyl methacrylate was obtained (803). Copolymerization of styrene and the above polyamine macromer 〇 was also obtained by the same method (-#04
). The nitrogen content of polymers #01 to #04 was 0.80.1.50.2.90.0.10, respectively.

Example 2Of 48 to 60 mesh glass beads washed with sulfuric acid and water were mixed with 2Of glass beads in which 40 da of #01 polymer was dissolved.
It was impregnated with 0- ethanol solution.

This was stirred at room temperature for 1 hour, then filtered and dried under nitrogen atmosphere. The following experiments were conducted using the polymer-coated glass beads thus prepared.

That is, the above-mentioned glass beads were filled into a vinyl chloride tube having a diameter of 4 mm and a length of 10 fields, and fresh rat blood containing heparin was allowed to flow through the tube. Poly(2
-Hydroxyethyl acrylate) was coated and a similar experiment was conducted, but the tube became clogged and stopped flowing after 30 minutes, whereas with #01 polymer, no clogging was observed even after 3 hours of flowing down. There wasn't. Similarly, no clogging was observed in polymers #02 to #04.

Claims (4)

[Claims] (1) It has a basic nitrogen-containing functional group with a pKa of 4.0 or more, and the nitrogen content in the functional group is 0.05 to 3.5% by weight.
A synthetic polymer for biomaterials. (2) Claim 1 having a hydroxyl group
Synthetic polymer for biomaterials described in Section 1. (3) The synthetic polymer according to claim 1, which contains polymerized units of hydroxyethyl acrylate and hydroxyethyl methacrylate. (4) Diethylamine ethylstyrene or N, N'
The synthetic polymer for biomaterials according to claim 1, which contains an oligomer or a polyamine macromer of -diethyl-N-vinylphenethylethylenediamine diamine ore as polymerized units.