JPS6257562A - Production of antithrombotic organic polymer - 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 [Field of sedentary use] The present invention relates to a method for producing an anticoagulant organic polymer by immobilizing a polyallylamine sulfonate onto an organic polymer.

[Conventional technology]

In recent years, various organic polymer materials have come to be used as medical materials. When these polymeric materials are used as medical materials, these materials have the property of coagulating blood when they come into contact with blood. It was not suitable as a material, and its use as a medical material was limited. These M-machine polymer materials can be used as medical materials by mixing henophosphorus or its derivatives, which are known as anticoagulants, with these organic polymers and then forming them into medical materials. A method for coating and fixing henocrine or its derivatives on the surface of polymer molded medical materials was published in 1974.
This is disclosed in Japanese Patent Publication No. 17797, Japanese Patent Publication No. 58-541, etc.

[Problem that the invention seeks to solve]

However, the method of mixing heparin with an organic polymer and then molding it into a medical material is not only severely limited in its molding method because heparin does not have high thermal stability; Expansion of its use has been hindered due to reasons such as the extremely high price of the product.

Also, Special Publication No. 54-17797, Special Publication No. 58-3
The method disclosed in Publication No. 41 introduces a quaternized amine nitrogen base onto the surface of a molded article of a polymeric organic material, and then treats it with heparin to produce a medical material that has heparin internally. The anticoagulant properties of the medical materials obtained by these methods are extremely high, but since heparin is a natural product and the extraction procedure is complicated, the medical materials produced by these methods are also extremely expensive. This is the current situation.

[Means for solving problems]

Therefore, the present inventors are currently investigating to find an anticoagulant organic polymer that can replace heparin, and the sulfonated product of polyallylamine, which is a hydrophilic organic polymer, and its salts,
The present invention was completed based on the findings that the present invention exhibits anticoagulant properties comparable to heparin, and further studies on methods for immobilizing sulfonated polyallylamines onto organic polymer materials.

The gist of the present invention is to quaternize the amine groups of the graft polymer obtained by graft polymerizing dialkylaminoalkyl (meth)acrylate to an organic polymer, and then add a sulfonated polyallylamine to the polymer. To be combined by ionic bond'! ! -Process for producing a characteristic anticoagulant organic polymer.

The organic polymer used in carrying out the present invention is not particularly limited, but specific examples include polychlorotrifluoroethylene, polytetrafluoroethylene, polyvinyl fluoride, polyvinylidene fluoride, and perfluoroalkyl vinyl ether polymers. fluorine-containing polymers such as polyethylene, polyglobylene, ethylene-vinyl acetate copolymer, polyolefins such as poly-4-methylpentene-1, polystyrene, acrylonitrile polymer, methyl methacrylate polymer, polyvinyl chloride, polycarbonate, Examples include polyester, silicone rubber, and acrylic rubber.

These organic polymers can be used as membranes, hollow fiber membranes, and tubular membranes, and these membranes may be dense or porous. !
These organic polymers can be used as fabrics such as non-woven fabrics and felts, or as blood test instruments such as hematocrit tubes.
Alternatively, it can also be used in the form of molded articles such as artificial blood vessels, artificial sweat, and other medical materials.

Examples of the dialkylaminoalkyl acrylate or methacrylate to be grafted onto these organic polymers include diethylaminomethyl acrylate or methacrylate, dimethylaminoethyl acrylate or methacrylate, diethylaminopropyl acrylate or methacrylate, and the like.

Graft polymerization of these alkylaminoalkylacrylic l/-) or methacrylates onto an organic polymer is carried out by subjecting the organic polymer to X-rays, α-rays, β-rays, γ-rays, neutron beams, and electron beams in the presence of these vinyl compounds. ionizing radiation or ultraviolet metal irradiation method, or activating the organic polymer by the above-mentioned ionizing radiation treatment, plasma treatment, ozone oxidation treatment, etc. to completely adhere the vinyl compound,
Then, a method of heating and polymerizing can be used. It is preferable that at least L5 parts of these tertiary amine group-containing monomers are graft-polymerized to 100 parts by weight of the organic polymer. Furthermore, vinylpyrrolidone, hydroxyethyl acrylate or methacrylate may be used in combination.

The organic polymer that has been grafted with an amino group-containing vinyl compound may contain impurities such as by-product homopolymers and unreacted vinyl monomers generated in the grafting reaction system, or may contain impurities such as unreacted vinyl monomers. It can be easily removed by cleaning.

The tertiary amino group grafted onto the organic polymer is
Next, it is subjected to a quaternization reaction. The quaternization reaction is carried out by converting the graft polymer into alkyl halides such as ethyl chloride, allyl chloride, butyl chloride, benzyl chloride, ethyl bromide, probyl bromide, butyl bromide, iodine in the presence of an organic solvent such as methanol or ethanol. It is produced by reacting with methyl chloride, ethyl iodide, etc.

The other component of the present invention, the sulfonated polyallylamine, is obtained by sulfonating polyallylamine with sulfuric acid or chlorosulfonic acid. Polyallylamine is obtained by polymerizing allylamine, and is usually obtained by radical polymerizing allylamine inorganic salt in a water bath to obtain civolylylamine inorganic acid salt, and then removing the inorganic acid. Methods for removing inorganic acids include methods using basic ion exchange resins, dialysis methods, or salts such as sodium chloride produced by a neutralization reaction with a strong base such as caustic soda.
There is a method of separating P by precipitating it in methanol, which is a bath medium for polyallylamine.

As the method for sulfonating polyallylamine, it is preferable to use a method of sulfonating a secondary amino group using chlorosulfonic acid or concentrated sulfuric acid. To perform the sulfonation method of polyallylamine with chlorosulfonic acid, polyallylamine is dissolved in a solvent such as methanol, a lower alcohol such as ethanol, or formamide so that the CL concentration is 5% to 50% by weight, and then chlorosulfonic acid is added. to 100 parts by weight of polyallylamine,
A method of obtaining the entire desired polyallylamine sulfonated product by adding 50 parts by weight to 500 parts by weight and reacting with heating if necessary. Alternatively, the polyallylamine inorganic salt is reacted with chlorosulfonic acid in a solvent-free system. There are methods. In addition, to perform di-sulfonation in concentrated sulfuric acid, gradually add 100 parts by weight of polyallylamine to 50 to 300 parts by weight of concentrated sulfuric acid with a purity of 96% by weight or more,
The method is to heat it to a temperature of 200°C to make it react.
≦Good.

The sulfonated polyallylamine produced as described above is purified by removing chlorosulfonic acid and sulfuric acid remaining in the reaction system from the reaction system. This purification is carried out by a method in which the reaction product is dissolved in water and then dialyzed, or a sulfonated product of polyallylamine is precipitated by dropping it into a solvent such as methanol or acetone.

The sulfone group of the polyallylamine sulfonate, which is one of the constituent elements of the present invention, can be selected from a wide range, but in particular, the number of primary amine groups contained in the polyallylamine is 1 or more, preferably 5 or more. It is preferable to make it sulfonated.

The polyallylamine sulfonated product can be used as it is in the sulfonic acid form, but if necessary, some or all of the sulfonic acid groups can be converted into the salt form, such as sodium salt, potassium salt, etc.
It can be utilized as magnesium salt, barium salt, ammonium salt or amine salt.

When the sulfonated polyallylamine is brought into contact with the organic polymer to which the quaternary ammonium salt is fixed, it is immobilized on the organic polymer by ionic bonding and exhibits the anticoagulant properties aimed at by the present invention.

It is preferable to further strengthen the immobilization of the sulfonated polyallylamine on the organic polymer and to insolubilize the sulfonated polyallylamine. A typical example of this insolubilization reaction is an insolubilization reaction using aldehydes such as formaldehyde and glyoxal. When this insolubilization reaction occurs as an intramolecular reaction of polyallylamine, the chain molecule becomes a cyclic molecule, when it occurs as an intermolecular reaction, it becomes a star-shaped molecule or a macrocyclic molecule, and as the reaction progresses further, it changes between multiple molecules. A three-dimensional crosslinked structure is formed, and the sulfonated polyallylamine is firmly bonded to the surface of the organic polymer.

The organic polymer of the present invention produced as described above has anticoagulant properties comparable to heparin-treated polymeric organic materials, and is used in catheters, artificial blood vessels, artificial valves, artificial lungs, and artificial blood vessels. It can be usefully used as a material for kidneys.

〔Example〕

The present invention will be explained in more detail with reference to Examples below.

Example 1 Polyallylamine hydrochloride having a molecular weight of about 10,000 (manufactured by Nitto Boseki Co., Ltd., FAA-HC!L-L) 5 f'i Aliquoted into three flasks, and separately added 3 ml of chlorosulfonic acid, 6 a ! , 15-After addition, reaction was carried out at 100°C for 1 hour while degassing in vacuum, and the reaction product was washed with methanol, dried, and then dissolved in 500 g of water.
Desalination was performed by dialysis using water as a dialysate. Further, after neutralization with an aqueous sodium hydroxide solution and concentration under reduced pressure, this solution was dropped into 200 methanol to precipitate, followed by filtration and drying to obtain polyallylamine with a sulfonation rate of 8120% and 52%, respectively. The sodium salt of the sulfonate was obtained.

On the other hand, a polyethylene film with a nine porosity of 50% was impregnated with dimethylaminoethyl methacrylate by irradiation with gamma rays at a total dose of 4L OMrad in air, and graft polymerization was performed by heating at 85°C for 5 hours. A polymer film was obtained. This was boiled for 6 hours in an ethanol solution of ethyl 50-thibromide to form a quaternary chloride, and then washed with water and dried. Three sheets of the thus obtained grafted polyethylene films were all quaternary chlorinated, and 10% of the 10% polyethylene film prepared by adding inglobanol to a 30% water solution of the sodium salt of the above-mentioned three types of polyallylamine sulfonates was prepared. After being immersed in a water-itubrobanol solution for 10 minutes, it was taken out, dried, and then immersed in a 5% glyoxal aqueous solution for 2 minutes, washed with water, and dried.

Place fresh goat blood on the film of 5m Lfc obtained,
When the film was covered with the same type of film and left at room temperature for 2 hours, no blood clots were observed on the film surface.

Claims (1)

[Claims] An anticoagulant organic polymer in which the amino groups of the graft polymer obtained by graft polymerizing dialkylaminoalkyl (meth)acrylate to an organic polymer are quaternized, and then a sulfonated polyallylamine is ionically bonded to the polymer. manufacturing method.