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WO2022147847A1 - Adsorbant pour éliminer des toxines urémiques liées aux protéines au moyen d'une perfusion sanguine et son procédé de préparation - Google Patents

Adsorbant pour éliminer des toxines urémiques liées aux protéines au moyen d'une perfusion sanguine et son procédé de préparation Download PDF

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WO2022147847A1
WO2022147847A1 PCT/CN2021/071244 CN2021071244W WO2022147847A1 WO 2022147847 A1 WO2022147847 A1 WO 2022147847A1 CN 2021071244 W CN2021071244 W CN 2021071244W WO 2022147847 A1 WO2022147847 A1 WO 2022147847A1
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resin
adsorbent
parts
mass
protein
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Chinese (zh)
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欧来良
于浩峰
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Nankai University
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Nankai University
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/268—Polymers created by use of a template, e.g. molecularly imprinted polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28004—Sorbent size or size distribution, e.g. particle size
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28011—Other properties, e.g. density, crush strength
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28057—Surface area, e.g. B.E.T specific surface area
    • B01J20/28064—Surface area, e.g. B.E.T specific surface area being in the range 500-1000 m2/g
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/305—Addition of material, later completely removed, e.g. as result of heat treatment, leaching or washing, e.g. for forming pores
    • B01J20/3057—Use of a templating or imprinting material ; filling pores of a substrate or matrix followed by the removal of the substrate or matrix
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/3085—Chemical treatments not covered by groups B01J20/3007 - B01J20/3078

Definitions

  • the present disclosure relates to the technical fields of chemical industry and biomedicine, in particular, to an adsorbent for removing protein-bound uremic toxins by blood perfusion and a preparation method thereof.
  • Uremia is a clinical syndrome shared by various advanced chronic kidney disease (CKD), which refers to a comprehensive combination of a series of clinical manifestations that appear when chronic renal failure caused by CKD enters the end stage. sign.
  • Uremic toxins refer to a large group of metabolic products that accumulate in the blood and tissues and are toxic when the renal function declines and the renal clearance rate of solutes decreases.
  • EUTox European Working Group on Uremic Toxins
  • the molecular weight is usually greater than 500, such as parathyroid hormone, ⁇ 2 -microglobulin, leptin, etc., the conventional hemodialysis removal effect of such substances is not ideal , some substances can be removed by large-pore (high-flux) dialysis membranes and peritoneal dialysis; 3. Protein-bound toxoids, such as indoxyl sulfate, p-cresol sulfate, 3-carboxy-4-methyl-5- Propyl-2-furanpropionic acid (3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, CMPF), etc., most of the dialysis methods have poor removal effect on such substances.
  • CMPF 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid
  • PBUTs Protein bound uremic toxins
  • PBUTs are mainly derived from protein degradation in food, and these degradation products are absorbed by intestinal epithelial cells and further metabolized by hepatocytes into the circulation.
  • the binding of PBUTs to proteins leads to changes in the molecular structure, charge and even function of the proteins themselves.
  • Relevant studies have shown that the free form of PBUTs, that is, not bound to proteins, is the main factor that causes tissue toxicity.
  • the more representative PBUTs are indoxyl sulfate (IS) and p-cresylsulphate (PCS), the relative molecular weights of which are 213.21 and 188.21 respectively, both of which belong to small molecular type organic compounds.
  • Anionic toxins They are all derived from the fermentative decomposition of dietary amino acids by intestinal bacteria, in which tryptophan is metabolized to indole, tyrosine and phenylalanine are metabolized to p-cresol, which is absorbed through the intestinal tract and then enters the liver through the portal vein. In the liver, IS and PCS are finally formed by sulfation, etc.
  • MHD is the main alternative to prolong the life of patients with uremia, but clinical studies have shown that conventional low-flux hemodialysis (LFHD) treatment can effectively remove small molecule toxins from the body, and high-flux hemodialysis (high-flux hemodialysis) , HFHD) and peritoneal dialysis (PD) also have a certain removal effect on most medium and large molecular toxins, but PBUTs represented by IS and PCS cannot be carried out due to their binding to proteins and multi-chamber distribution.
  • LFHD low-flux hemodialysis
  • HFHD high-flux hemodialysis
  • PD peritoneal dialysis
  • PBUTs such as IS and PCS
  • other blood purification methods have been clinically developed and adopted.
  • the common ones are: 1.
  • Super-flux hemodialysis (SFHD) that increases the dialysis membrane pore size and ultrafiltration coefficient , can improve the clearance rate of IS, etc., but the patient loses more albumin; 2.
  • Hemodiafiltration (HDF) formed by combining the diffusion mechanism of hemodialysis and the convection mechanism of hemofiltration can significantly improve the The clearance rate of medium and macromolecular toxins, but the relevant reports on the clearance effect of PBUTs are inconsistent, there is controversy, the clearance rate of IS and PCS is not more than 45% as a whole; HP), due to the low clearance rate of single HP to small molecule toxins such as urea and creatinine, and its own lack of ability to correct water, electrolyte and acid-base balance disorders, it is often combined with conventional HD to achieve complementary advantages. Clinical studies have shown that HP combined with HD can significantly improve the clearance of protein-bound toxoids.
  • the clearance rate of IS and PCS can reach 50% to 60%, which is better than other blood purification methods, especially for CMPF with stronger binding force.
  • the advantages of PBUTs are more obvious, and long-term HD+HP treatment can maintain a low level of protein-bound toxoids in MHD patients, and can improve the quality of life of MHD patients.
  • HP is a blood purification technology that introduces the patient's blood into a perfusion device equipped with solid adsorbents, and removes exogenous or endogenous toxins, drugs or metabolic wastes that cannot be removed by dialysis in the blood through adsorption. It is the earliest adsorption mode used for clinical removal of various uremic toxins. In addition to uremia, HP technology has been clinically applied to hyperbilirubinemia, acute poisoning, sepsis, hyperlipidemia, systemic Treatment of lupus erythematosus, myasthenia gravis, etc.
  • the solid adsorbent in HP may be in the form of spherical particles, fiber bundles or membranes, and its performance is affected by the specific surface area of the adsorbent, relative molecular weight of the solute, molecular structure, temperature, pH value, etc., and is most commonly used in the treatment of uremia patients.
  • the adsorbent materials are activated carbon and resin.
  • the hemoperfusion devices used such as Zhuhai Jianfan HA series and Foshan Boxin MG series, are domestic products, and the adsorption material is macroporous adsorption resin.
  • HP can effectively remove PBUTs such as IS, PCS, CMPF, hippuric acid (HA), homocysteine (Hcy), and advanced glycation end products (AGEs).
  • PBUTs such as IS, PCS, CMPF, hippuric acid (HA), homocysteine (Hcy), and advanced glycation end products (AGEs).
  • the overall clearance rate of HA130 hemoperfusion device combined with HD on IS and PCS is about 50%
  • MG150 combined with HD is about 55%, which is significantly better than HD and slightly better than HDF.
  • the clearance rate of small molecule toxins such as blood urea nitrogen (BUN) and serum creatinine (sCr) by HA130 combined with HD is about 60%, which is comparable to HD; (intact parathyroid hormone, iPTH), MG350 combined with HD have a clearance rate of about 40% for medium molecular toxins such as ⁇ 2-microglobulin ( ⁇ 2-MG), which is significantly better than HD, but slightly lower than HDF.
  • BUN blood urea nitrogen
  • sCr serum creatinine
  • the objectives of the present disclosure include, for example, to provide an adsorbent for removing protein-bound uremic toxins by blood perfusion, which has a significant removal effect on protein-bound toxoids such as indoxyl sulfate , p-cresol sulfate, etc.
  • protein-bound toxoids such as indoxyl sulfate , p-cresol sulfate, etc.
  • Microglobulin, vitamin B 12 , creatinine, pentobarbital sodium and other medium and large molecules and small molecules also have certain scavenging ability, and have excellent safety performance and mechanical strength.
  • the purpose of the present disclosure also includes, for example, to provide a preparation method of an adsorbent for removing protein-bound uremic toxins by blood perfusion, the method has simple steps, mild conditions, is conducive to environmental protection and cost reduction, and the obtained adsorbent is in While maintaining good adsorption performance, it has high mechanical strength and good adsorption kinetics.
  • An adsorbent for removing protein-bound uremic toxins by blood perfusion which is a porous resin with an amide group and taking polystyrene-acrylonitrile-divinylbenzene as a skeleton, and the porous resin has imprinting of imprinted molecules Cavity; the imprinted molecule includes protein-binding toxoids and/or analogs of protein-binding toxoids.
  • the content of amide groups in the adsorbent is 1.0-2.5 mmol/g dry resin
  • the particle size of the adsorbent is 0.4-1.2 mm;
  • the moisture content of the adsorbent is 50% to 70%
  • the specific surface area of the adsorbent is 700-900 m 2 /g;
  • the sphericity after grinding of the adsorbent is ⁇ 90%
  • the protein-bound toxoid comprises at least one of p-cresol sulfate and indoxyl sulfate;
  • the analog of the protein-bound toxoid includes at least one of p-toluenesulfonic acid and L-tryptophan.
  • the oil phase includes styrene, acrylonitrile, divinylbenzene, porogen and benzoyl peroxide;
  • the aqueous phase includes gelatin, sodium chloride and water;
  • the oil phase is mainly composed of the following components in parts by mass: 5-15 parts of styrene, 5-15 parts of acrylonitrile, 80% diethylene 70-90 parts of benzene, 100-150 parts of porogen and 0.5-1.5 parts of benzoyl peroxide;
  • the aqueous phase includes the following components in mass concentration: gelatin 0.5%-2% and sodium chloride 5%-10%;
  • the mass ratio of the water phase to the oil phase is (2.5-4):1;
  • the mass ratio of the imprinted molecules to the resin B is (1-4):20;
  • the mass ratio of the anhydrous ferric chloride to the resin B is (3-8):20;
  • the porogen includes component A and component B, the component A is selected from alkanes and/or aromatic hydrocarbons, and the component B is selected from alcohols and/or esters;
  • the component A is selected from at least one of toluene, ethylbenzene, xylene, n-heptane and 200# gasoline;
  • the component B is selected from at least one of cyclohexanol, isoamyl alcohol, n-octanol, dodecanol and butyl acetate;
  • the mass of the component A is 50% to 70% of the total mass of the porogen.
  • step (a) the initial mixing temperature of the oil phase and the water phase is 48-52°C;
  • the oil phase and the water phase are mixed and left to stand, followed by stirring, heating and heat preservation;
  • the standing time is 8-12 min
  • the heating is to raise the temperature to 78-90°C at a rate of 0.8-1.1°C/2min;
  • the incubation is performed at 78-90° C. for 4-12 h.
  • step (a) the separation comprises: performing solid-liquid separation on the reacted mixture, and performing water washing, alcohol washing and sieving on the obtained resin to obtain resin A;
  • the temperature of the water washing is 48-52°C.
  • step (b) the concentrated sulfuric acid is slowly added to the resin A at 20-25° C. and stirred, and after the solid-liquid separation of the reacted mixture, gradient concentrated sulfuric acid is used. The separated resin was washed with water until neutral, and dried to obtain resin B.
  • the concentration of the concentrated sulfuric acid is 90% to 95%
  • the drying temperature for obtaining resin B after drying is 70-78°C;
  • the resin B is dried to less than 2% moisture.
  • step (c) the mixture of the ethanol solution of the imprinted molecule, the resin B, and 1,2-dichloroethane is stirred and swollen, and then anhydrous trichloride is added.
  • the iron is heated, heated and kept warm, and the solid-liquid is separated to obtain an adsorbent for blood perfusion to remove protein-bound uremic toxins;
  • the temperature for stirring the mixture of the ethanol solution of the imprinted molecule, the resin B, and 1,2-dichloroethane is 28-32° C., and the time is 1.8-2.2 h ;
  • the amount of the resin B is 20 parts by mass
  • the alcoholic solution of the imprinted molecule is composed of: 1-4 parts by mass of the imprinted molecule and 10-20 parts by volume of anhydrous ethanol;
  • the amount of the 1,2-dichloroethane is 80-120 parts by mass
  • the heating is increased to 65-80° C., and the holding time is 8-16 h;
  • the amount of the anhydrous ferric chloride is 3-8 parts by mass.
  • the resin after the solid-liquid separation described in step (c) is washed with ethanol and washed with water, the resin is packed into a column, washed with an acetone-acid solution, washed with water until neutral, and dried;
  • the number of times of washing with ethanol is 2 to 3 times, and the number of times of washing with water is 2 to 3 times; the amount of each time is 180 to 220 parts by mass;
  • the acetone-acid solution is composed of acetone, water and hydrochloric acid in a volume ratio of (4.9-5.1):(3.9-4.1):1;
  • the amount of the acetone-acid solution is 8-12 bed volumes.
  • the hemoperfusion adsorbent of the present disclosure adopts ternary copolymerization to introduce polar groups, and combines with the imprinted template molecules introduced on the basis of the post-crosslinking reaction of dangling double bonds.
  • the matching molecularly imprinted pore structure such as p-cresol sulfate can selectively improve the removal of free PBUTs, and the effect is obvious.
  • the residual amide group on the resin enhances the hydrophilicity and biocompatibility of the adsorbent.
  • a mesoporous structure of 20-50 nm is introduced through the use of a mixed porogen in the suspension polymerization process, and a microporous structure of less than 20 nm is introduced into the cross-linking reaction after dangling double bonds, so that the adsorption While removing PBUTs, the agent also maintains a certain ability to remove medium-sized and small-molecule toxins.
  • the multi-component pore structure enables the adsorbent to maintain good adsorption performance while maintaining high mechanical strength and good adsorption kinetics.
  • capillary pores also improves the surface hydrophilicity and hydrophobicity and blood compatibility of the adsorbent.
  • the post-crosslinking reaction of pendant double bonds has simple steps, mild conditions, and reduces the use of a large amount of organic solvents, which is beneficial to environmental protection and cost reduction.
  • the present disclosure relates to an adsorbent for hemoperfusion to remove protein-bound uremic toxins, which is a porous resin with amide groups and with polystyrene-acrylonitrile-divinylbenzene as a skeleton , the porous resin has imprinted cavities of imprinted molecules; the imprinted molecules include protein-binding toxoids and/or analogs of protein-binding toxoids.
  • the adsorbent of the present disclosure has a significant scavenging effect on protein-bound toxoids such as indoxyl sulfate and p-cresol sulfate, and has a significant scavenging effect on medium and large molecules such as ⁇ 2 -microglobulin, vitamin B 12 , creatinine, sodium pentobarbital, and the like. Small molecular substances also have a certain scavenging ability, and have good safety performance and mechanical strength.
  • the content of amide groups in the adsorbent is 1.0-2.5 mmol/g dry resin.
  • the content of amide groups in the adsorbent is 1.0-2.5 mmol/g, and 1.0 mmol/g, 1.1 mmol/g, 1.2 mmol/g, 1.3 mmol/g, 1.4 mmol/g can also be selected. g, 1.5mmol/g, 1.6mmol/g, 1.7mmol/g, 1.8mmol/g, 1.9mmol/g, 2mmol/g, 2.1mmol/g, 2.2mmol/g, 2.3mmol/g, 2.4mmol/g or 2.5mmol/g.
  • the particle size of the adsorbent is 0.4-1.2 mm.
  • the particle size of the adsorbent is 0.4-1.2 mm, and can also be selected from 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm or 1.2 mm.
  • the moisture content of the adsorbent is 50% to 70%.
  • the moisture content of the adsorbent is 50% to 70%, and 50%, 52%, 55%, 57%, 60%, 62%, 65% or 70% can also be selected.
  • the specific surface area of the adsorbent is 700-900 m 2 /g.
  • the specific surface area of the adsorbent is 700-900 m 2 /g, and 700 m 2 /g, 710 m 2 /g, 720 m 2 /g, 730 m 2 /g, 740 m 2 /g, 750m 2 /g, 760m 2 /g, 770m 2 / g, 780m 2 /g, 790m 2 /g, 800m 2 /g, 810m 2 /g, 820m 2 /g, 830m 2 / g, 840m 2 /g, 850m 2 /g, 860m 2 /g, 870m 2 /g, 880m 2 /g, 890m 2 /g or 900m 2 /g.
  • the sphericity of the adsorbent after grinding is ⁇ 90%.
  • the sphericity after grinding of the adsorbent is ⁇ 90%, and 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% can also be selected .
  • the protein-bound toxoid comprises at least one of p-cresol sulfate and indoxyl sulfate.
  • the analog of the protein-bound toxoid includes at least one of p-toluenesulfonic acid and L-tryptophan.
  • the present disclosure also relates to the above-mentioned preparation method of the adsorbent for removing protein-bound uremic toxins by blood perfusion, comprising the following steps:
  • the oil phase includes styrene, acrylonitrile, divinylbenzene, porogen and benzoyl peroxide;
  • the aqueous phase includes gelatin, sodium chloride and water;
  • the preparation method of the present disclosure has simple steps, mild conditions, and reduces the use of a large amount of organic solvents, which is beneficial to environmental protection and cost reduction.
  • Step (a) of the preparation method of the present disclosure is normal-phase suspension polymerization to obtain porous white spheres with polystyrene-acrylonitrile-divinylbenzene skeleton; step (b) hydrolyzes the obtained porous white spheres at room temperature with concentrated sulfuric acid to obtain amide group-containing white spheres The adsorption resin; step (c) suspending the double bond after the cross-linking reaction, and adding protein-bound toxoid or a small molecular substance with similar structure as an imprinting template during the reaction, forming a molecularly imprinted cavity, micropores and intermediates at the same time. Pore-structured novel hemoperfusion sorbent for the removal of protein-bound uremic toxins.
  • the polymerization process makes the adsorbent have a mesoporous structure of 20-50nm through a single or mixed porogen, which is conducive to the removal of medium and large molecular toxins with a molecular weight of 5000-20000, and uses ternary copolymerization to introduce polar molecules that can interact with imprinted template molecules. sex group.
  • the post-crosslinking reaction of hanging double bonds can increase the microporous structure below 20nm and improve the removal of small molecule toxins with molecular weight below 500.
  • the imprinting template molecules introduced on this basis can selectively improve the ability of free protein-bound uremic toxins. adsorption.
  • the oil phase is mainly composed of the following components in parts by mass: 5-15 parts of styrene, 5-15 parts of acrylonitrile, 70-90 parts of 80% divinylbenzene, 100-150 parts of porogen and 0.5-1.5 parts of benzoyl peroxide.
  • the styrene is 5-15 parts, and 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts or 15 parts can also be selected. share.
  • the acrylonitrile is 5 to 15 parts, and 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts or 15 parts can also be selected. share.
  • the 80% divinylbenzene is 70 to 90 parts, and 70 parts, 75 parts, 80 parts, 85 parts or 90 parts can also be selected.
  • 100 to 150 parts of the porogen 100 parts, 110 parts, 120 parts, 130 parts, 140 parts or 150 parts can also be selected.
  • the porogen includes component A and component B, the component A is selected from alkanes and/or aromatic hydrocarbons, and the component B is selected from alcohols and/or esters.
  • the component A is selected from at least one of toluene, ethylbenzene, xylene, n-heptane and 200# gasoline.
  • the component B is selected from at least one of cyclohexanol, isoamyl alcohol, n-octanol, dodecanol and butyl acetate.
  • the mass of the component A is 50% to 70% of the total mass of the porogen.
  • the benzoyl peroxide is 0.5 to 1.5 parts, and 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1 part, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts can also be selected. servings or 1.5 servings.
  • the aqueous phase includes the following components in mass concentration: 0.5%-2% of gelatin and 5%-10% of sodium chloride.
  • the mass ratio of the water phase to the oil phase is (2.5-4):1.
  • the mass ratio of the water phase to the oil phase is (2.5-4):1, and 2.5:1, 3:1, 3.5:1 or 4:1 can also be selected.
  • the initial mixing temperature of the oil phase and the water phase is 48-52°C.
  • the initial mixing temperature of the oil phase and the water phase is 48-52°C, and 48°C, 49°C, 50°C, 51°C or 52°C can also be selected .
  • the oil phase and the water phase are mixed and left to stand, followed by stirring, heating and heat preservation.
  • the standing time is 8-12 min.
  • the standing time is 8-12 minutes, and 8 minutes, 9 minutes, 10 minutes, 11 minutes or 12 minutes can also be selected.
  • the heating is to raise the temperature to 78-90°C at a rate of 0.8-1.1°C/2min.
  • the heating is to raise the temperature to 78-90°C at a rate of 1°C/2min.
  • the temperature is kept at 78-90° C. for 4-12 hours.
  • the separation comprises: performing solid-liquid separation on the reacted mixture, and performing water washing, alcohol washing and sieving on the obtained resin to obtain resin A.
  • the temperature of the water washing is 48-52°C.
  • the temperature of the water washing is 48-52°C, and 48°C, 49°C, 50°C, 51°C or 52°C can also be selected.
  • step (b) the concentrated sulfuric acid is slowly added to the resin A at 20-25° C. and stirred, and after the solid-liquid separation of the reacted mixture, gradient concentrated sulfuric acid is used to wash the separated resin , washed with water until neutral, and dried to obtain resin B.
  • the time for adding the concentrated sulfuric acid at 20-25° C. and stirring is 8-12 h.
  • the concentration of the concentrated sulfuric acid is 90% to 95%.
  • the drying temperature for obtaining resin B after drying is 70-78°C.
  • the drying temperature of resin B obtained after drying is 70-78°C, and 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C can also be selected. or 78°C.
  • the resin B is dried to a moisture content of less than 2%.
  • step (c) the mixture of the ethanol alcohol solution of the imprinted molecule, the resin B, and 1,2-dichloroethane is stirred and swollen, and then anhydrous ferric chloride is added and heated and heated. Heat preservation and solid-liquid separation to obtain an adsorbent for blood perfusion to remove protein-bound uremic toxins.
  • the mass ratio of the 1,2-dichloroethane to the resin B is (80-120):20.
  • the mass ratio of the imprinted molecules to the resin B is (1-4):20.
  • the mass/volume ratio of the imprinted molecule to the absolute ethanol solvent is (1-4):(10-20).
  • the mass ratio of the anhydrous ferric chloride to the resin B is (3-8):20.
  • the temperature for stirring the mixture of the ethanol solution of the imprinted molecule, the resin B, and 1,2-dichloroethane is 28-32° C., and the time is 1.8-2.2 h.
  • the temperature at which the mixture of the ethanol solution of the imprinted molecule, the resin B, and 1,2-dichloroethane is stirred is 28-32° C., and 28° C., 29° C., 30°C, 31°C or 32°C.
  • the time is 1.8-2.2h, and 1.8h, 1.9h, 2h, 2.1h or 2.2h can also be selected.
  • the heating temperature is increased to 65-80° C.
  • the holding time is 8-16 h.
  • the amount of the resin B used is 20 parts by mass.
  • the alcohol solution of the imprinted molecules is composed of: 1-4 parts by mass of the imprinted molecules and 10-20 parts by volume of absolute ethanol.
  • the amount of the 1,2-dichloroethane is 80-120 parts by mass.
  • the resin after the solid-liquid separation in step (c) is washed with ethanol and water, then washed with acetone-acid solution, washed with water until neutral, and dried.
  • the ethanol washing times are 2-3 times, and the water washing times are 2-3 times; the dosage for each time is 180-220 parts by mass.
  • the acetone-acid solution is composed of acetone, water and hydrochloric acid in a volume ratio of (4.9-5.1):(3.9-4.1):1.
  • the dosage of the acetone-acid solution is 8-12 bed volumes.
  • the volume ratio of the acetone, water and hydrochloric acid is 5:4:1; the consumption of the acetone-acid solution is 10 bed volumes.
  • a preparation method of an adsorbent for removing protein-bound uremic toxins by blood perfusion comprising the following steps:
  • BPO Benzoyl oxide
  • the quality of the water phase and the oil phase is The ratio is 4:1; after mixing, let stand for 10 minutes, start stirring, adjust the particle size to an appropriate range, then heat up to 90 °C at a rate of 1 °C/2min, and keep it for 12 h; stop the reaction, drain the polymerization mother liquor, and wash with water at 50 °C
  • the resin is clarified to the effluent, the porogen is extracted with ethanol at room temperature, and then transferred to the water phase, and sieved in the wet state to obtain 0.4-1.2 mm resin, and the free water is drained for use;
  • step (b) hydrolysis reaction slowly add 95% concentrated sulfuric acid to the resin obtained in the above step (a), and under stirring at 25 ° C, react for 12 hours; stop the reaction, drain the hydrolysis mother liquor, and use a gradient of sulfuric acid with a concentration from high to low.
  • the resin is washed until the water is neutral; the free water is drained, the resin is air-dried, and then dried in an oven at 75°C until the moisture is less than 2%, for use;
  • a preparation method of an adsorbent for removing protein-bound uremic toxins by blood perfusion comprising the following steps:
  • step (b) hydrolysis reaction slowly add 90% concentrated sulfuric acid to the resin obtained in the above step (a), and under stirring at 25° C., react for 8 hours; stop the reaction, drain the hydrolysis mother liquor, and use a gradient of sulfuric acid with a concentration from high to low.
  • the resin is washed until the water is neutral; the free water is drained, the resin is air-dried, and then dried in an oven at 75°C until the moisture is less than 2%, for use;
  • a preparation method of an adsorbent for removing protein-bound uremic toxins by blood perfusion comprising the following steps:
  • step (b) hydrolysis reaction slowly add 95% concentrated sulfuric acid to the resin obtained in the above step (a), and under stirring at 20° C., react for 12 hours; stop the reaction, drain the hydrolysis mother liquor, and use a gradient of sulfuric acid with a concentration from high to low.
  • the resin is washed until the water is neutral; the free water is drained, the resin is air-dried, and then dried in an oven at 75°C until the moisture is less than 2%, for use;
  • a preparation method of an adsorbent for removing protein-bound uremic toxins by blood perfusion comprising the following steps:
  • step (b) hydrolysis reaction slowly add 90% concentrated sulfuric acid to the resin obtained in the above step (a), and under stirring at 25 ° C, react for 10 hours; stop the reaction, drain the hydrolysis mother liquor, and use a gradient of sulfuric acid with a concentration from high to low.
  • the resin is washed until the water is neutral; the free water is drained, the resin is air-dried, and then dried in an oven at 75°C until the moisture is less than 2%, for use;
  • the adsorbent prepared by the method of the present disclosure is brown-yellow to brown-black opaque beads in appearance, with a particle size of 0.4-1.2 mm, a water content of 50-70%, and an amide group content of 1.0-2.5 mmol/g dry resin.
  • the specific surface area is 700 ⁇ 900m 2 /g, and the spherical rate after grinding is ⁇ 90%.
  • the degree of crosslinking in the polymerization reaction the amount and proportion of the porogen, the amount of acrylonitrile, the amount of benzoyl peroxide, the temperature and time of the polymerization reaction, the temperature and time of the post-crosslinking reaction, anhydrous Factors such as the dosage of ferric chloride, the dosage of imprinted template molecules and the ratio have obvious effects on the structure and adsorption performance of the adsorbent.
  • the removal rate of indoxyl sulfate by the adsorbent is ⁇ 55%
  • the removal rate of p-cresol sulfate is ⁇ 60%
  • the removal rate of ⁇ 2 -microglobulin is ⁇ 82%
  • the removal of vitamin B 12 (simulated middle molecule) The removal rate is ⁇ 95%
  • the removal rate of creatinine is ⁇ 65%
  • the removal rate of sodium pentobarbital (simulated small molecule) is ⁇ 98%.
  • Red blood cells, white blood cells, platelets decreased rate of ⁇ 10%, total protein adsorption rate ⁇ 15%.
  • the adsorbent of the present disclosure has a significantly higher removal rate of indoxyl sulfate and p-cresol sulfate than the adsorbents used in the commercially available HA series and MG series hemoperfusion devices, and the removal rate of ⁇ 2 -microglobulin is slightly higher than that of the HA adsorbent , creatinine removal rate was significantly higher than that of MG adsorbent.
  • the scavenging ability of the adsorbent for indoxyl sulfate and p-cresol sulfate was greatly improved, which was significantly higher than that of the commercial products. Thereby, it is further adsorbed by the microporous part of the adsorbent.
  • the adsorbent By adding a suitable pore-forming agent and controlling the degree of post-crosslinking in the first polymerization, the adsorbent has a suitable mesoporous structure and a large number of microporous structures, which can simultaneously maintain the resistance to medium and large molecules and small molecule toxins. Good removal effect, better than some commercially available products.
  • the in vitro safety performance is comparable to that of commercial products.
  • the next step can be considered to optimize and enlarge the adsorbent for the investigation of animal experiments and clinical trials.
  • the hemoperfusion adsorbent of the present disclosure adopts ternary copolymerization to introduce polar groups, and combines with the imprinted template molecules introduced on the basis of the post-crosslinking reaction of dangling double bonds.
  • the matching molecularly imprinted pore structure such as p-cresol sulfate can selectively improve the removal of free PBUTs, and the effect is obvious.
  • the residual amide group on the resin enhances the hydrophilicity and biocompatibility of the adsorbent.
  • a mesoporous structure of 20-50 nm is introduced through the use of a mixed porogen in the suspension polymerization process, and a microporous structure of less than 20 nm is introduced into the cross-linking reaction after dangling double bonds, so that the adsorption While removing PBUTs, the agent also maintains a certain ability to remove medium-sized and small-molecule toxins.
  • the multi-component pore structure enables the adsorbent to maintain good adsorption performance while maintaining high mechanical strength and good adsorption kinetics.
  • capillary pores also improves the surface hydrophilicity and hydrophobicity and blood compatibility of the adsorbent.
  • the post-crosslinking reaction of pendant double bonds has simple steps, mild conditions, and reduces the use of a large amount of organic solvents, which is beneficial to environmental protection and cost reduction.

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Abstract

L'invention concerne un adsorbant pour éliminer des toxines urémiques liées aux protéines au moyen d'une perfusion sanguine et son procédé de préparation. L'adsorbant pour éliminer les toxines urémique liées aux protéines au moyen d'une perfusion sanguine est une résine poreuse ayant un groupe amide et prenant du polystyrène-acrylonitrile-divinylbenzène en tant que squelette, la résine poreuse comprenant des trous à empreinte de molécules à empreintes, et les molécules à empreinte comprenant des toxines liées aux protéines et/ou des analogues de celles-ci. L'adsorbant présente un effet d'élimination significatif sur des toxines liées aux protéines telles que le sulfate d'indoxyle et le sulfate de p-crésol, et présente également une certaine capacité d'élimination sur des substances à macromolécules moyennes et petites molécules telles que la β2-microglobuline, la vitamine B12, la créatinine et le pentobarbital sodique, et présente une excellente performance de sécurité et une excellente résistance mécanique.
PCT/CN2021/071244 2021-01-05 2021-01-12 Adsorbant pour éliminer des toxines urémiques liées aux protéines au moyen d'une perfusion sanguine et son procédé de préparation Ceased WO2022147847A1 (fr)

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CN114405488B (zh) * 2022-01-12 2023-08-25 江苏贝美医疗科技有限公司 一种蛋白结合类毒素血液灌流吸附剂及其制备方法与应用
CN114797800B (zh) * 2022-04-19 2023-02-07 江苏贝美医疗科技有限公司 一种用于清除尿毒症患者体内毒素的吸附剂及制备方法
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