CZ344499A3 - Process and material for cleaning physiological liquids of organisms and process for preparing such material - Google Patents

Abstract

The purification of the physiological fluids of the organisms is done by varnish that cleaning the fluid with the fluid that is removed from the patient passes the material having the size, shape and structure selected so that to remove toxic compounds from the physiological fluid having a molecular weight range of 300 to 3000 Daltons, wherein said material is formed of a porous hydrophobic material copolymer of divinylbenzene which is primarily exposed vinyl groups chemically converted most functional groups that are more hydrophilic and biocompatible than vinyl group, and returning fluid to the patient groups that are more hydrophilic and biocompatible than vinyl groups are grafted by hydrophilic polymer chain selected from the group consisting of 2- hydroxyethyl methacrylate, N-vinyl pyrrolidone, N-vinyl caprolactam and N-acrylamide. Method of manufacturing material consists in the oxidation of vinyl groups to epoxide groups and subsequent addition of small primary or secondary amines.

Description

A method and material for the purification of physiological fluids of an organism and a method for producing the material

Technical field

The present invention relates to a method and material for the purification of physiological fluids of organisms and to a method for producing the material.

BACKGROUND OF THE INVENTION

As is known, physiological fluids of organisms such as blood, plasma, peritoneal fluid, etc., in the case of poisoning or disease of the organism, such as liver or kidney disease, capture and then distribute various toxic substances to the organism.

It is therefore advisable to remove these toxic substances from physiological fluids, thereby significantly improving the patient's condition. Many methods of removing toxic substances from blood, plasma and other physiological fluids have already been invented and used. One of the most effective methods is hemodialysis. Unfortunately, in this way, small toxic molecules cannot be removed and so-called medium-sized toxins (molecular weights from 500 to 30000 Daltons) are removed too slowly, even with modern fast-flow dialysis membranes. It is believed appropriate to further improve existing methods to ensure effective purification of the physiological fluids of the organism, especially taking into account the larger molecules mentioned above, to prevent the spread of diseases or to treat diseases.

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components, if the conventional hemodialysis procedure is supplemented by an adsorption procedure. This is used to remove larger toxic particles whose diffusion through the dialyser's membrane is too slow.

The adsorbent should exhibit both a high adsorption capacity for medium molecular weight toxic substances as well as sufficient compatibility with blood or other appropriate physiological fluid. Describing a useful polymeric adsorbent material is one of the objects of the present invention.

Macroporous copolymers of styrendivinylbenzene are the most widespread type of polymeric adsorbent materials. Adsorbents of this category are produced by many companies. Probably the best is the Amberlite XAD-4 (manufactured by Rohm & Haas). Equally interesting, though less available, are the macroporous adsorbents obtained by copolymerizing divinylbenzene (DVB) with other monomers, for example butyl methacrylate, acrylonitrile and others.

In order to ensure a porous structure and a constant volume of polymer particles under different conditions of use, the three-dimensional network of these polymers must be sufficiently strong, i.e., contain a large proportion of the cross-linked divinylbenzene. However, such a pure product is relatively expensive. A more affordable technical product contains up to 30-40% ethylvinylstyrene, so commercially possible macroporous adsorbents should preferably be mentioned as copolymers of DVB, ethyl vinylstyrene and styrene. To produce this monomer mixture, organic solvents are commonly used as diluents which cause the microphase to separate during the polymerization process, and as a result, the macroporous structure of the resulting material is achieved.

It has been repeatedly proven that radical polymerization never consumes all of the DVB vinyl groups that enter the copolymerization. On average, about 30% of the DVB component fails in its function of cross-linking bridges and remains connected to the network by only one of its two vinyl groups. Thus, the presence of a relatively large amount of attached vinyl groups is a characteristic of macroporous adsorbents. It is to be expected that these free vinyl groups are likely to be exposed to the surface of the polymer beads and their macropores and will always be readily usable for chemical modification.

The chemical modification of the surface of the DVB macroporous copolymers relies on the chemical reactions of the attached vinyl groups exposed on the surface, and is intended to convert these groups into more hydrophilic functional groups. This conversion provides the originally hydrophobic adsorbent material with a blood compatibility property since the hydrophilic surface adsorbs less blood cells and plasma proteins and does not cause blood to clot as rapidly as the original hydrophobic surface.

Some solutions have been described in our earlier patent No. 08/756 455.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, it is an object of the present invention to provide a method and material for purifying the physiological fluids of an organism and a method for producing the material, which will be further improvements in the field described above.

The method of purifying physiological fluids of the organisms of the invention comprises removing physiological fluid containing toxic substances from the patient's body, allowing the physiological fluid to pass through a porous hydrophobic copolymer of divinylbenzene having first exposed vinyl groups on the surface which later chemically transformed to form other functional groups , exposed on the surface, groups more hydrophilic and biocompatible than vinyl groups.

In accordance with another aspect of the present invention, a porous hydrophobic copolymer of divinylbenzene has been proposed as a material for purifying physiological fluids of organisms which first had exposed vinyl groups on the surface, which were later chemically transformed to form other functional groups exposed on the surface. more hydrophilic and biocompatible than vinyl groups.

Finally, it is proposed to produce a material for the purification of physiological fluids of organisms, namely that the porous hydrophobic copolymer of divinylbenzene first has surface exposed vinyl groups, which are later chemically converted to form other functional groups exposed on the surface, more hydrophilic and biocompatible than vinyl groups.

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When the method and material for purifying the physiological fluids of the organism and the method for producing the material are provided in accordance with the applicant's invention, very favorable results will be obtained.

A preferred embodiment of the invention

In accordance with the present invention, it is proposed to purify the physiological fluids of an organism by removing toxic substances. The patient's blood is aspirated from the arterial bloodstream, released through the material described in this invention to remove toxic substances, and returned to the patient's bloodstream, into a vein. The material should be sized, shaped, and structured to remove toxic components from physiological fluid in the molecular weight range of 300 to 30,000 Daltons.

In accordance with the present invention, the material used in the inventive method of purifying physiological fluids of organisms and produced in accordance with the inventive method of manufacture is a porous hydrophobic copolymer of divinylbenzene having first exposed vinyl groups on the surface, which were later chemically converted to form other functional groups exposed on the surface, namely more hydrophilic and biocompatible groups than vinyl groups.

In accordance with the present invention, modification of the surface vinyl groups has been performed in an aqueous or aqueous organic medium according to the following three general procedures:

Attachment of hydrophilic polymer chains by radical polymerization of 2-hydroxyethyl methyl acrylate, N-vinylpyrrolidone, < - &gt; &quot; &quot; &quot; &quot; • ♦ ♦ · »»

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N-vinylcaprolactam or other water-soluble monomers, • oxidation of vinyl groups to epoxide groups and subsequent reactions of epoxide groups with water, ethylene glycol, amines or 2-aminoethanol molecules, and the surface of the polymer beads.

In any case, the hydrophilic nature of the surface so modified can simply be demonstrated by wetting the material in a dry modification with water, while the dry original adsorbent cannot be wetted by direct contact with water.

Examples of embodiments of the invention

In the following examples, a mesoporous divinylbenzenethylstyrenstyrene copolymer, a typical polystyrene type adsorbent material, and a DVB / butyl methyl acrylate double bonded surface-exposed copolymer were used for modification.

Modified surface materials showed good haemocompatibility, i.e., did not alter blood clotting rate particularly, did not cause haemolysis at all, and also showed no cytototoxic effects. Upon contact with blood plasma or complete blood, these materials effectively removed medium-sized molecules, as can be readily demonstrated by conventional spectrometric measurements.

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Preparation of mesoporous divinylbenzene copolymers

Example 1

A solution of 130 g of p-ethylstyrene, 132 g of divinylbenzene (about 1: 1 mixture of para and meta-isomers) and 2.62 g of benzoyl peroxide mixed with 150 ml of toluene and 100 ml of isoamyl alcohol was mixed in 4 liters of pure water containing 1% cellulose. as a stabilizer. After stirring at room temperature for 39 minutes, the mixture was heated at 40 ° C for 1 hour, 60 ° C for 2 hours, 80 ° C for 5 hours, and 90 ° C for 2 hours. After cooling the mixture to room temperature, the obtained beads of material were filtered and washed with hot water, methanol and water. The polymer was then dried in an oven at 80 ° C for one day.

Example 2

A solution of 75 g of butyl acrylate, 51 g of divinylbenzene (approximately 1: 1 mixture of para and meta-isomers) and 1 g of benzoyl peroxide in 250 ml of toluene was stirred in 2.4 liters of pure water containing 15 g of cellulose as stabilizer at room temperature. . After stirring for 30 minutes, the mixture was heated successively at 60, 80 and 95 ° C for 3 hours at each temperature. After cooling the mixture to room temperature, the obtained beads of material were filtered and washed with hot water, methanol and again with water. Then, the beads were dried in an oven for 7 hours at 80 ° C.

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Attaching hydrophilic polymer chains to surface-exposed vinyl groups

Example 3

The polymer prepared in Example 1 was washed with ethanol and then rinsed with water. Thus, a material fully moistened with water and with all pores filled with water was obtained. This material contained 40% polymer and 60% water. To 1 g of the polymer soaked with water was added 1 ml of a 3% aqueous solution of 2-hydroxyethyl methyl acrylate (HEMA) and 0.1 ml of a 10% aqueous ammonium persulfate and, with magnetic stirring, an aqueous sodium sulfite solution (2 moles per mole persulfate). The mixture was slowly stirred at 40 ° C for 2 hours or at 10 ° C for 10 hours. The polymer was then filtered, washed with water and dried at a temperature not higher than 80 ° C.

Example 4

To 1 g of the dry polymer prepared in Example 1 was added 3.5 ml of ethanol, then 1.6 ml of a 6% aqueous HEMA solution, 0.3 ml of a 10% aqueous ammonia persulfate solution, and finally 0.3 ml of 1M aqueous sodium sulfite solution (or 0.3 mL of a 0.5 M ascorbic acid solution). The mixture was stirred for 10 hours at 10 ° C. The polymer was then filtered, washed with water and dried at 70 ° C.

HEMA was coupled to the divinylbenzene-butyl methacrylate copolymer prepared in Example 2 in exactly the same manner.

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Example 5

To 1 g of the water-moistened polymer prepared in Example 1 was added 1.0 ml of a 6% aqueous solution of Nvinylpyrrolidone 0.2 ml of a 10% aqueous solution of ammonium persulfate, followed by stirring at 40 ° C for 2 hours. The polymer was then filtered, washed with water and dried.

Example 6

To 1 g of the polymer prepared in Example 1 and moistened with water was added 2.0 ml of 3% N-vinylpyrrolidone, 0.3 ml of an aqueous 10% sodium persulfate solution and 0.3 ml of sodium sulfite, and the mixture was stirred at 25 ° C. After 2 hours, the polymer was filtered, washed with water and dried.

Reactions of analogous polymers on surface-exposed double bonds.

Example 7

To 1 g of the polymer prepared in Example 2 and moistened with water was added 2.0 ml of 3% N-acrylamide, 0.3 ml of an aqueous 10% sodium persulfate solution and 0.3 ml of a 1 M aqueous sodium sulfite solution. The mixture was then stirred at 25 ° C for 2 hours. Finally, the polymer was filtered, washed with water and dried

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Example 8

To 6 g of the dry polymer prepared in Example 1 was added 25 ml of acetic anhydride and the mixture was cooled to 0 ° C. Then, 2 ml of an aqueous 40% hydrogen peroxide solution was added slowly, and the mixture was stirred at 10-15 ° C for 8 hours. The polymer was filtered and washed with glacial acetic acid to give epoxy-containing material.

To 2 g of the above-described polymer containing epoxy groups impregnated with glacial acetic acid was added 10-15 ml of water and 2 drops of concentrated sulfuric acid. The mixture was then kept under stirring at 5070 ° C for 3-5 hours. Thus, the epoxy groups were converted to diol groups. The polymer was then filtered, carefully washed with water and dried.

Example 9

To 2 g of the epoxy group-containing polymer described above (in accordance with Example 7) impregnated with glacial acetic acid, 1 ml of ethylene glycol in 5 ml of glacial acetic acid (or 5 ml of dry ethyl acetate) was added 2 drops of concentrated sulfuric acid. Then the mixture was kept under stirring at 5070 ° C for 5-8 hours. This procedure resulted in the addition of ethylene glycol to the functional epoxy group. The polymer was then filtered, washed with water, ethanol and again with water, and dried.

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Example 1 0 g of the epoxy group-containing polymer described above (in accordance with Example 7) impregnated with glacial acetic acid was carefully washed with dry ethyl acetate. 1 ml of 2-hydroxyethylamine in 4 ml of ethyl acetate was then added. The mixture was stirred at 40 ° C for 5 hours, resulting in the addition of the hydroxyethylamine group to the epoxide group. The polymer was then filtered, washed with aqueous 1N HCl and again with water to obtain a neutral pH.

In another experiment, diethylamine was used instead of 2-hydroxyethylamine. The product was washed with aqueous 1N HCl and water as described above.

Binding of poly (trifluoroethoxy) phosphazene to the polymer surface (molecular weight 20.10 ⁶ Daltons)

Example 11

The product obtained in Example 9 was dried under vacuum. A solution of 0.3 mg of poly (trifluoroethoxy) phosphazene (molecular weight 20.10 ⁶ ) in 10 ml of ethyl acetate was quickly added to 3 g of the polymer thus dried, and the resulting mixture was shaken until the polymer beads adsorbed all the added solvent. The material was then dried under reduced pressure and washed with ethanol.

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Example 12

To 3 g of dry unmodified polymer prepared in Example 2 was quickly added a solution of 1 mg of poly (trifluoroethoxy) phosphazene in 10 ml of ethyl acetate and then dried as described in Example 10.

It will be understood that any of the above-described parts of the invention, or two or more at once, may also find suitable uses in other methods and products other than those described above.

Although the invention has been illustrated and described in a particular form as a method and material for the purification of physiological fluids of an organism and a method for producing such material, it is not expected to be limited to the above details since various modifications and structural changes can be made without departing in any way. core of the invention.

Thus, without further analysis, what has been said fully reveals the main benefit of the present invention, so that others can, using known knowledge, adapt it to various purposes as needed without omitting the features that distinguish the invention from the prior art and are essential distinguishing features. unprotected solutions from specific aspects of the invention.

What is claimed to be new and required to be protected by a patent is set forth in the appended claims.

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Claims (10)

PATENT CLAIMS (modified) A method of purifying a physiological fluid of an organism, comprising the step of removing physiological fluid containing toxic substances from a patient's body, the step of flowing the physiological fluid with toxic substances through material having a shape, size and structure selected to remove toxic components in the range of 300 up to 30,000 Daltons from physiological fluid and consists of a porous hydrophobic copolymer of divinylbenzene having primarily exposed vinyl groups chemically converted to other exposed functional groups that are more hydrophilic and biocompatible than vinyl groups and a degree of fluid recovery to the patient. 2. A material for the purification of physiological fluids of an organism which comprises flowing physiological fluid through said material having a shape, size and structure selected to remove toxic components ranging from 300 to 30000 Daltons from physiological fluid and consisting of a porous hydrophobic copolymer of divinylbenzene , which had primarily surface-exposed vinyl groups chemically converted to other surface-exposed functional groups, more hydrophilic and biocompatible than vinyl groups. The material of claim 1, wherein said porous hydrophobic divinylbenzene copolymer comprises a divinylbenzene copolymer with comonomers selected from the group consisting of styrene, ethylstyrene, acrylonitrile and butyl methyl acrylate. The material of claim 1, wherein said surface-exposed functional groups are more hydrophilic and 99 99 9 9 999 999 «11 99 99 • · 99 99 9 9 9 9 9 9 9 9 More biocompatible than vinyl groups are grafted hydrophilic polymer chains from the group consisting of polymers of 2-hydroxyethyl methacrylate, N-vinylpyrrolidone, N-vinylcaprolactam and N-acrylamide. The material of claim 1, wherein said surface-exposed functional groups that are more hydrophilic and biocompatible than vinyl groups are products of oxidation of said vinyl groups to epoxy groups and subsequent addition of polar components from the group comprising water, ethylene glycol, small primary or secondary amines; and 2-hydroxyethylamine. The material of claim 4, wherein said surface-exposed functional groups that are more hydrophilic and biocompatible than vinyl groups are products of oxidation of said vinyl groups to epoxy groups and subsequent addition of small primary or secondary amines or 2-hydroxyethylamine and location of poly (trifluoroethoxy) ) of a high molecular weight phosphazene. A method for producing a physiological fluid purification material of an organism comprising preparing a porous hydrophobic copolymer of divinylbenzene having a shape, size and structure selected to remove toxic components in the range of 300 to 30,000 Daltons from a physiological fluid and having primarily exposed The vinyl groups are chemically converted to other functional groups which are also exposed to the surface and which are more hydrophilic and biocompatible than the vinyl groups. 0 0 0 0 0 00 ·· • 0 · 0 0 0 0 • · 0 0 0 0 - ♦ ·· ♦ 0 0 0 0 0 0 0 0 0 0 0 0 0 »0 0 0 000 0 0 0 The method of producing a material according to claim 1, wherein the chemical conversion of the vinyl groups, which results in other functional groups that are also exposed on the surface, of groups more hydrophilic and biocompatible than the vinyl groups, without appreciable damage to the porous structure and hydrophobic. The core of the original divinylbenzene copolymer comprises graft polymerization of water-soluble monomers selected from the group consisting of 2-hydroxyethyl methacrylate, Nvinylpyrrolidone, N-vinylcaprolactam and N-acrylamide in an aqueous or aqueous organic medium. The method of making a material according to claim 1, wherein the chemical conversion of vinyl groups which results in other surface-exposed functional groups, more hydrophilic and biocompatible than vinyl groups, without appreciably damaging the porous structure of the original divinylbenzene copolymer, comprises oxidizing said materials. vinyl groups, e.g., epoxy groups, followed by the addition of vinyl groups with a polar reagent selected from water, ethylene glycol, small primary or secondary amines, and 2-hydroxyethylamine. The method of claim 7, wherein said oxidation of vinyl groups to epoxy groups is followed by the addition of small primary or secondary amines or 2-hydroxyethylamine to the epoxy groups and placing poly (trifluoroethoxy) phosphazene dissolved in an organic solvent by forming a complex of said polyphosphazene and amine groups exposed to the surface.