JPS5952170B2 - Anticoagulant hydrogel substrate - Google Patents

Description

[Detailed description of the invention] The present invention relates to anticoagulant hydrogel substrates.

More specifically, the present invention relates to an anti-blood coagulation hydrogel base material comprising a block copolymer in which a vinyl pyrrolidone polymer block and a methacrylic acid or acrylic acid (hereinafter collectively referred to as (meth)acrylic acid) ester polymer block are bonded. In recent years, with the advancement of medical technology, the opportunities for blood to come into contact with synthetic materials have increased, but in this case, blood coagulation due to contact between blood and foreign substances is always a problem, and the development of materials that do not cause blood to coagulate even when it comes into contact with blood. is urgently needed.

Vinylpyrrolidone polymers such as polyvinylpyrrolidone have the advantage of being less harmful to blood, so much so that they have been used as plasma substitutes, but because of their water solubility, they have not been able to be used as medical materials that come into contact with blood.

Furthermore, attempts to improve water resistance by crosslinking or copolymerization with hydrophobic monopolymers have yielded insufficient results. Focusing on the excellent biocompatibility of vinylpyrrolidone, the present invention aims to use a vinylpyrrolidone polymer as a medical material that comes into contact with living organisms, and has developed a hydrogel that has significantly improved water resistance and excellent anticoagulant properties. It provides a base material.

That is, the hydrogel base material of the present invention comprises vinylpyrrolidone, vinylpyrrolidone,
It consists of a block copolymer in which a polymer block and a (meth)acrylic acid ester polymer block are bonded together. The block copolymer is composed of a vinylpyrrolidone polymer having a hydroxyl group at the terminal obtained by polymerization using a polymerization initiator having a hydroxyl group such as hydrogen peroxide, and a ceric salt such as ceric ammonium nitrate. It is obtained by polymerizing (meth)acrylic acid ester underneath.
The block copolymer has excellent biocompatibility, especially when swollen by water absorption, and particularly excellent anticoagulability, and also has high mechanical strength even when water is absorbed. Here, the reason why the block copolymer has high anti-blood coagulability is
Although it is not always clear, this is partly due to the affinity of vinylpyrrolidone polymer itself to blood, and also due to the affinity of vinylpyrrolidone polymer itself with hydrophilic segments consisting of vinylpyrrolidone polymers and hydrophobic segments consisting of (meth)acrylic acid ester polymers. This is thought to be due to an appropriate combination of the following. Also, the corresponding (
The relatively good biocompatibility of the meth)acrylic acid ester polymer alone may also be a contributing factor. Here, the term "hydrogel" refers to a material whose water absorption rate expressed by the following formula is 10% or more, preferably 20% or more.

The block copolymer obtained by the present invention has a segment made of vinylpyrrolidone polymer and a segment made of (meth)acrylic acid ester that are chemically bonded, so it does not undergo phase separation and is transparent and uniform even in a water-containing state. Moreover, the vinyl pyrrolidone polymer does not elute.

As mentioned above, the vinyl pyrrolidone polymer used in the present invention is obtained by polymerization using a polymerization initiator such as hydrogen peroxide that has a hydroxyl group that can be incorporated into the polymer chain end as an initiator fragment, and vinyl pyrrolidone alone In addition to the polymer, it can be obtained by copolymerizing with other appropriate monomers.

A copolymer containing vinylpyrrolidone as a main component may also be used. However, the other monomers used here do not inhibit the desired biocompatibility of polyvinylpyrrolidone, and in order to facilitate the block copolymer synthesis reaction, they may cause the vinylpyrrolidone polymer to lose its water solubility. It's better if it's not. For example, hydroxyalkyl (meth)acrylate, (meth)acrylamide, etc. can be used. The molecular weight of the vinylpyrrolidone polymer is not particularly limited and can be appropriately selected in order to optimize the properties of the obtained block copolymer. The (meth)acrylic acid ester polymerized in the presence of the vinyl pyrrolidone polymer and the ceric salt includes methyl methacrylate, ethyl methacrylate, etc., and the block copolymer maintains flexibility even when dried. Ethyl acrylate, butyl acrylate, lauryl methacrylate, etc. are suitable for this purpose.

Acidic water is preferred as the reaction solvent, and ceric ammonium nitrate, ceric ammonium sulfate, ceric chlorate, etc. are used as the ceric salt.

The amount of ceric salt to be used is 1 to 1 to 1 per terminal hydroxyl group (assuming it has hydroxyl groups at both ends) of the vinylpyrrolidone polymer.
50 times (molar ratio) is desirable, and a large amount of ceric salt is not desirable because it inhibits polymerization. The ratio of (meth)acrylic acid ester to vinylpyrrolidone polymer can be varied over a wide range in order to change the composition and properties of the resulting block copolymer.
In order to improve the anticoagulability, it is desirable to increase the proportion of vinylpyrrolidone polymer added. However, if the content of the vinyl pyrrolidone polymer is high, the mechanical properties will deteriorate, so the ratio of (meth)acrylic acid ester to be charged is preferably within the range of 50 to 95 parts by weight based on 100 parts by weight of the vinyl pyrrolidone polymer. . The reaction is carried out by adding a (meth)acrylic acid ester to an aqueous solution of a vinylpyrrolidone polymer, purging the solution with nitrogen, adding an acidic aqueous solution of a ceric salt, and stirring the solution at room temperature to 100° C. for 1 to several hours. The reaction solution becomes an emulsion, but it can be treated with an ion exchange resin to remove acids and salts and then directly poured into a suitable mold to evaporate the solvent and unreacted materials to form a film. It can also be taken out as a precipitate by adding it to a suitable non-solvent such as , methanol or ethyl ether. In the present invention, a hydrogel (the base material absorbs water and becomes a hydrogel) made of a block copolymer of a vinylpyrrolidone polymer and a (meth)acrylic acid ester is formed into a film or a sheet depending on the purpose. shaped, tubular, rod-shaped, fibrous,
It can be given any suitable shape, such as granules, and can be applied as a coating layer to the surface of various molded materials.

In particular, the hydrogel exhibits excellent biocompatibility, especially anticoagulability and mechanical strength, and is suitable for various medical materials used in contact with blood, such as intravascular catheters, cannulae, shunts, blood circulation circuits, and blood transfusion sets. Suitable for use in blood transfusion packs, hemodialysis membranes, oxygen-added membranes, adsorbent coating materials for adsorption-type artificial kidneys, microcapsule materials, and materials for contact lenses, artificial corneas, and the like. Examples (including comparative examples) will be given below for specific explanation.

Examples Polymers or polymer compositions were produced by the following methods (of which (self) and (F) are comparative examples), and the anti-blood coagulability of these films was evaluated.

(4) Vinylpyrrolidone polymer 69 with a molecular weight of 360,000 and having hydroxyl groups at both ends of the molecular chain is dissolved in 300 d of water, 12 d of methyl methacrylate is added after nitrogen blowing, and 0.659 ceric ammonium nitrate is added to 12 d of 1N nitric acid. It was dissolved in and added.

When this was stirred at room temperature, it became cloudy in ten minutes. 5
After a time reaction, a white emulsion-like reaction solution was obtained.

After removing acids and salts from this emulsion using an ion exchange resin and discharging the ion exchange resin, the same amount of methanol was added to the furnace liquid and 1.5 times the amount of ethyl ether was added to obtain a reaction product. A small amount of unreacted vinylpyrrolidone polymer was removed by methanol extraction. The film obtained from the acetic acid solution of this block copolymer was transparent in the dry and water-absorbed state. The glass transition temperature of the film when dried was 120°C. 8 Vinylpyrrolidone polymer 59 with a molecular weight of 10,000 and having hydroxyl groups at both ends was mixed with 250 m of water.
11 and 10 ml of methyl methacrylate after nitrogen blowing.
and 10 d of butyl acrylate were added thereto, and 0.29 ceric ammonium nitrate dissolved in 10 ml of 1N nitric acid was added.

When this was stirred at room temperature, it became cloudy in ten minutes. 5
After the reaction for a period of time, the acid and salts were removed from the white emulsion-like reaction solution using an ion exchange resin, and after the ion exchange resin was removed, the resulting solution was cast onto a film forming plate to obtain a film.

The water absorption rate of the film was 17 (F6), and the glass transition temperature when dried was 22°C.
After dissolving in 50d and blowing nitrogen, methyl methacrylate 10
Add WLI and add 0 ceric ammonium nitrate.
．． 29 was dissolved in 10 ml of 1N nitric acid and added.

When this was stirred at room temperature, it became cloudy in ten minutes. 5
After a period of reaction, the acid and salts were removed from the white emulsion-like reaction solution using an ion exchange resin, and after the ion exchange resin was removed, the resulting solution was poured into a large amount of acetone to obtain a copolymer.

This copolymer was dissolved in dimethylformamide and a film was obtained by a casting method. The film was transparent in dry and water-absorbed states, and had a water absorption rate of 25%. 9 A vinylpyrrolidone polymer 69 having a molecular weight of 40,000 and having hydroxyl groups at both ends was dissolved in 300 TfL of water, and after nitrogen was blown in, 12 ml of lauryl methacrylate was added, and further 0.839 ceric ammonium nitrate was dissolved in 12 wL of 1N nitric acid. added.

When this was stirred at room temperature, it became cloudy in ten minutes. 4
After the reaction for several hours, the acid and salts were removed from the white emulsion-like reaction solution using an ion exchange resin, and after the ion exchange resin was removed, the finished solution was cast on a film forming plate to obtain a film.

The glass transition temperature of the film when dried was 25°C. 8 (Comparative example) Polyvinylpyrrolidone obtained by polymerizing vinylpyrrolidone using azobisisobutyronitrile as an initiator and methanol as a solvent was used to react in the same manner as in 4, but the resulting product was methanol-soluble. The methanol-soluble part is a homopolymer of vinylpyrrolidone, the methanol-insoluble part is a homopolymer of methyl methacrylate, and the proton copolymer of the two is separated into a monopolymer of vinylpyrrolidone and an insoluble part, and identified by infrared absorption spectroscopy. It was confirmed that it was not generated.

(F) (Comparative example) Polyvinylpyrrolidone 109 with a molecular weight of 40,000 and a molecular weight of 1
40,000 polymethyl methacrylate 59 was dissolved in 100 d of dimethylformamide, and the dimethylformamide was evaporated to obtain a film.

This film was heterogeneous and became noticeably cloudy when it contained water, and polyvinylpyrrolidone was observed to be eluted. Next, a film made of the polymers obtained in (1) to 9 above and the polymer compositions (g) and (g), as well as methyl methacrylate homopolymer and commercially available medical silicone was prepared by the following method. Coagulability was evaluated.

The anticoagulant property was evaluated according to the kinetic method of Imai et al. (Journal of Biomedical Materials Research, Vol. 6, p. 165 (1972)).

Claims (1)

[Claims] 1. An anti-blood coagulation hydrogel base material consisting of a block copolymer in which a vinyl pyrrolidone polymer block and a methacrylic acid or acrylic acid ester polymer block are bonded.