JPS5844699B2 - Sugreta Seinou Oyuusuru Hydrogel Youkizai - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a hydrogel made of a polymeric material that absorbs water and swells.

For details, refer to cross-linked polyvinyl alcohol (hereinafter referred to as PV
A-type) has a structure in which polyvinylpyrrolidone (hereinafter abbreviated as PVP) is trapped in a hydrophilic polymer network, and has a high equilibrium water content, solute, gas or water permeability, mechanical strength, and biocompatibility. The present invention relates to an excellent transparent hydrogel.

Conventionally, materials used for medical equipment include, for example, polyethylene.
Hydrophilic polymer materials such as hydroxyalkyl (meth)acrylate copolymers typified by 2-hydroxyethyl (meth)acrylate, cellulose, collagen or gelatin, and polyvinyl alcohol are known, and their purpose, site, application, etc. They are selected and used as appropriate.

When these hydrophilic polymers are used as materials for medical equipment, they have excellent compatibility with living organisms due to the material's wettability and water content, and they cause relatively little irritation even when they come into contact with living tissue, causing discomfort and foreign substances. It has the advantage of causing less sensation or pain.

However, the degree of biocompatibility varies depending on the material, and the mechanical strength when hydrated also varies depending on the material, and the two are generally in a contradictory relationship, making it difficult to use as a medical device. As the scope of application expands and more severe usage conditions are required, there are increasing expectations for the emergence of materials that simultaneously satisfy both biocompatibility and mechanical properties when hydrated.

To meet such requirements, it is conceivable to use, for example, a combination of a material with excellent biocompatibility and a material with excellent mechanical strength.

In this case, the latter also needs to have a certain level of biocompatibility.

Based on this idea, attempts have been made to copolymerize or polymer blend, but none of these methods have reached the desired performance.

In view of this situation, the inventors of the present invention conducted intensive research to obtain materials with even better performance, and as a result, they devised a new combination of materials that confine other types of materials within the gel network of one material. As a result of experiments, it was discovered that this combination method provides materials that meet the purpose, and the present invention was achieved.

The act of entrapping other polymers within the gel network of a polymer is itself known as a method of insolubilizing enzymes (inclusion method).

However, in this case, one (the confined one) is a functional polymer and the other is simply an insolubilizer, and as in the present invention, two types of materials are combined to form a new composite. The new knowledge that a material combines the advantages of each original material is something that cannot be imagined at all from the example of enzymes.

As can be seen from the above considerations, the material used for the entrapment is a polymer that has excellent biocompatibility, but by itself has poor mechanical performance when hydrated.

Such polymers include polyvinylpyrrolidone (P
There are mucopolysaccharides such as VP), agarose or agar, and heparin. Among them, PVP is a synthetic polymer useful in the fields of medicine and cosmetics. It was once used as artificial blood, and recently it has been used in soft contacts. Although it has excellent performance, such as its application to lenses and its performance as a dialysis membrane material, it is water-soluble alone and cannot be used as a hydrogel. It is one of the most extreme.

On the other hand, the material for making the gel lattice is not just ash that can be gelled through appropriate treatment to create a huge network with excellent mechanical strength; it is also hydrophilic enough to be compatible with the material to be trapped. It is necessary to be of a certain gender.

In order to obtain a hydrophilic gel, ie, a hydrogel, with excellent mechanical strength, it is necessary to cause crosslinking between molecules to make them insoluble.

However, it is not true that any hydrophilic polymer can produce a gel with the desired mechanical strength just by cross-linking, and even more so if other polymers that do not contribute to mechanical strength are included in the network. The range of combinations that can be selected becomes even narrower.

According to experiments conducted by the present inventors, only PVA-based polymers have so far met these requirements, and none of the others have provided satisfactory performance.

Furthermore, when a PVA-based polymer is used as a gel lattice material, agarose or agar has little compatibility with the PVA-based polymer, making it difficult to apply the present invention successfully.

Entrapment of the above hydrophilic polymer by PVA polymer is as follows:
This is carried out by applying a known method for crosslinking and insolubilizing a PVA polymer to a mixture or mixed solution of a PVA polymer and a hydrophilic polymer.

Such crosslinking and insolubilization methods include (a) intermolecular acetalization reaction using dialdehyde, (I)) high temperature heating in the presence of an acidic substance, (c) method using boric acid, titanate ester, or vanadium ion, ( Methods such as d) radiation irradiation and (e) diisocyanate crosslinking are known, and any of these methods may be used.

Among these, polyvalent aldehydes in the case of method (a) include polyvalent aldehydes such as PVA dialdehyde obtained by decomposing PVA by periodic acid treatment, oxidized starch, acrolein polymers and copolymers, etc. , or dialdehydes such as glyoxal glutaraldehyde and terephucraldehyde.

Among these, when using PVA dialdehyde, it is also possible to create a PVA-based hydrogel network by itself.

PVA-based polymers used as hydrogel network materials include completely saponified products, partially saponified products, and acetalized products of vinyl ester homopolymers, as well as vinyl alcohol-based copolymers containing a small proportion of other vinyl monomer units. It also includes saponified products or acetal products.

When using PVP as a confining material, it is preferable to have a molecular weight of 10,000 or more, and a material with a molecular weight lower than that has the disadvantage of large elution during use.

The mixing ratio of the two types of polymers is such that PVA accounts for at least 40% of the total weight, preferably 70-90%; if it is less than that, the strength of the gel will be poor, and if it is more than that, the biocompatibility of the entrapment polymer will not improve. It is hard to see the effect.

In the composite hydrogel obtained as described above,
At least at temperatures below 40° C., the trapped PVP is fixed in the PVA polymer gel network without being eluted.

The composite hydrogel according to the present invention is transparent and has a water content of 40 or more at room temperature at the time of equilibrium swelling as defined by the following formula: Water-containing polymer weight - absolute dry polymer weight, □.

. (To) Water content = Water-containing polymer weight Despite the high water content, it has greater strength than conventional hydrogels, has excellent biocompatibility, and has high anticoagulant properties.

Furthermore, when PVP is used, it has excellent permeability to solutes, particularly to so-called medium-molecular weight substances, which have relatively large molecular weights and are currently required for artificial kidney membranes.

The composite hydrogel of PVP and PVA-based polymer obtained according to the present invention can be used in molded products that are buried in or in contact with living organisms and used in contact with living tissue or body fluids, such as artificial lungs.
Planar or hollow fiber dialysis membranes in the field of artificial kidneys, coating materials for activated carbon adsorbents in adsorption-type artificial kidneys, tube wall coatings for artificial blood vessels, vascular catheters or urinary catheters, contact lenses, artificial skin, and even for medical treatment. It is used as a capsule material when encapsulating drugs or enzymes and implanting them into the body.

It is also expected to be applied to industrial or analytical enzyme carriers or separation membranes for applications that do not come into direct contact with the human body.

The present invention will be specifically explained below with reference to Examples, but these Examples do not limit the present invention to thin tubes.

Examples 1 to 4 PVA (polymerization degree 1700, saponification degree 99.9 or more, 7
A predetermined amount of an aqueous solution of PVP (molecular weight 700,000, concentration 5) and an aqueous solution of PVA dialdehyde (degree of polymerization 150, concentration 5) obtained by decomposing the above PVA with periodic acid and sodium chloride. After mixing and adjusting the pH to 1 with an aqueous IN-hydrochloric acid solution, the mixture was cast onto a glass plate and air-dried at room temperature for 2 days.

The obtained membrane was immersed in pure water at room temperature and peeled off from the glass plate to obtain a transparent hydrogel membrane.

The results of measuring the water content, mechanical properties in a water-containing state, and solute permeability of the obtained hydrogel membrane were compared to cuprophan, which is currently used in artificial kidney membranes, and which is used in contact lenses and many other medical fields. Polly
2-hydroxyethyl methacrylate (hereinafter referred to as P-HEM)
A comparison is shown in the following table.

It can be seen that the hydrogel membrane of the present invention has a high water content, good strength when hydrated, and excellent permeability to medium molecular weight substances (vitamins B and 2).

Examples 5 and 6 A PVA dialdehyde (polymerization degree: 150.5 weight ratio concentration) aqueous solution and PVP (molecular weight: 700,000, 5% by weight concentration) aqueous solution were mixed, and a hydrogel film was prepared in the same manner as in Examples 1 to 4. I got it.

This product was immersed in water, the extraction temperature was gradually increased, and the amount of polymer eluted by extraction at each temperature was measured.

The results are shown in the table below. The results show that after a small amount of polymer elutes in the early stage of extraction, almost no elution is observed at room temperature or body temperature, and only a small amount of polymer elutes even in hot water.

Example 7 An anticoagulant test was conducted on the samples of Examples 5 and 6 using dog blood.

That is, wash these films thoroughly with physiological saline,
Place 0.25 ml of dog AOD blood in a thermostat at 7°C, and add 0.025 ml of 0.1 MC5a C12 aqueous solution.
1 was added to initiate clotting.

Glass plate, medical silicone film, and PVA 75% were obtained in the same way by weighing the amount of blood clot taken out after 10 minutes.
When comparing the amount of blood clotting of a hydrogel made of a cross-linked product obtained with 25% of PVA dialdehyde and 25% of PVA dialdehyde, the results shown in the following table were obtained.

It can be seen that all the samples exhibited excellent anticoagulant properties on the same level as silicone, and that the anticoagulant properties were significantly increased by trapping PVA.

Claims (1)

[Claims] 1. Mixing a polyvinyl alcohol-based hydrophilic polymer and polyvinylpyrrolidone, and then crosslinking and insolubilizing the polyvinyl alcohol-based hydrophilic polymer, the polyvinyl pyrrolidone is present in the network of the crosslinked polyvinyl alcohol-based hydrophilic polymer. A hydrogel containing water of 40% or more by weight in a closed structure.