WO2019174560A1 - 用于生物流体净化的组合物 - Google Patents

用于生物流体净化的组合物 Download PDF

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Publication number
WO2019174560A1
WO2019174560A1 PCT/CN2019/077749 CN2019077749W WO2019174560A1 WO 2019174560 A1 WO2019174560 A1 WO 2019174560A1 CN 2019077749 W CN2019077749 W CN 2019077749W WO 2019174560 A1 WO2019174560 A1 WO 2019174560A1
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Prior art keywords
toxin
biological fluid
composition
composition according
peritoneal dialysate
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PCT/CN2019/077749
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English (en)
French (fr)
Inventor
蒋晨
孙涛
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必康生技（香港）有限公司
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Priority to US16/980,435 priority Critical patent/US20210015844A1/en
Priority to EP19767462.5A priority patent/EP3766529A4/en
Publication of WO2019174560A1 publication Critical patent/WO2019174560A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/002—Forward osmosis or direct osmosis
    • B01D61/005—Osmotic agents; Draw solutions
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
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    • A—HUMAN NECESSITIES
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Definitions

  • the present invention relates to novel compositions, devices and biological fluid purification methods useful for biological fluid purification.
  • the application provides a composition comprising a penetrant and a toxin removal agent, wherein the penetrant is capable of providing an osmotic pressure substantially isotonic or higher than isotonic with a biological fluid, and the toxin removal reagent is capable of The toxins in the biological fluid are reduced under osmotic exchange conditions.
  • the toxin removal reagent is capable of reducing the free, non-free amount, and/or total amount of the toxin in the biological fluid. In certain embodiments, the toxin removal reagent is capable of reducing the total or non-free amount of toxins in the biological fluid by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60. %, at least 70%, at least 80%, at least 90% or at least 95%.
  • the toxin removal reagent is capable of adsorbing, non-covalently binding, covalently binding, and/or degrading the toxin in the biological fluid.
  • the toxin removal reagent has one or more characteristics selected from the group consisting of: 1) having a porous structure; 2) capable of forming a charged structure; 3) capable of passing a non-covalent bond with the toxin Or a covalent bond or an ionic bond; and 4) capable of degrading the toxin.
  • the toxin removal reagent has a porous structure, and the porous structure conforms to one or more of the following features: a) having a specific surface area of from 70 cm 2 /g to 1000 m 2 /g; b) having 0.1 nm a pore size in the range of -10 ⁇ m; c) having a pore size distribution of 0.1 nm to 100 ⁇ m; d) having a porosity of about 5 to 95%; and e) capable of adsorbing the toxin at an adsorption rate of at least 0.2 mg/g.
  • the toxin removal agent having a porous structure is selected from the group consisting of a silicon-based porous material, a carbon-based porous material, a metal oxide-based porous material, a polymer-based porous material, and a metal organic framework compound. Porous material.
  • the toxin removal reagent is capable of forming a charged structure, and the charged structure has a charge density of 0.2-50 ⁇ C ⁇ cm -2 .
  • the charged structure comprises a charged ion or a charged colloid.
  • the toxin removal agent is selected from the group consisting of povidone, crospovidone, silica colloid, micronized silica gel, diatomaceous earth, and polyvinylcaprolactam-polyvinyl acetate-poly Ethylene glycol graft copolymer, and nano alumina.
  • the toxin removal reagent has a group capable of forming a non-covalent bond with the toxin (eg, a hydrogen atom, a hydroxyl group, an amino group, an amine group, a carboxyl group, etc.), and is capable of forming with the toxin a group of a covalent bond (for example, a thiol group, an aldehyde group, a hydroxyl group, a carboxyl group, etc.) or a group capable of forming an ionic bond with the toxin (for example, chloride ion, sulfate ion, calcium ion, carbonate ion, etc.) ).
  • a group capable of forming a non-covalent bond with the toxin eg, a hydrogen atom, a hydroxyl group, an amino group, an amine group, a carboxyl group, etc.
  • a group of a covalent bond for example, a thiol group, an al
  • the toxin removal reagent is capable of degrading the toxin
  • the toxin removal reagent is a biocatalyst or a chemical catalyst
  • the toxin removal agent is selected from the group consisting of activated carbon, povidone, crospovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, micronized silica gel, diatomaceous earth , and any combination thereof.
  • the presence or excess of the toxin in the biological fluid increases the risk of disease, exacerbates the disease condition, or impairs normal physiological function.
  • the toxin comprises an in vivo metabolite, a foreign substance that causes poisoning, or a molecule that causes disease.
  • the toxin is freely present in the biological fluid, in combination with a substance in the biological fluid, or both. In certain embodiments, at least a portion of the toxin forms a reversible binding with a substance in the biological fluid. In certain embodiments, the toxin binds to a substance in the biological fluid with a Kd value of at least 10 2 ⁇ mol/L, 10 3 ⁇ mol/L, 10 4 ⁇ mol/L, 10 5 ⁇ mol/L, 10 6 ⁇ mol/L, or 10 7 ⁇ mol/L. In certain embodiments, the binding of the toxin to a substance in the biological fluid has a Kd value of at least 10 5 to 10 7 ⁇ mol/L.
  • the toxin comprises: indophenol sulfate, asymmetric arginine, homocysteine, phenylacetic acid, p-cresol, AGE product (3-deoxyglucosone, fructose Amino acid, glyoxal, pyruvic aldehyde, pentosidine, hippuric acid, uremic toxin, hydrogen sulfide, or bilirubin.
  • the substance that binds to the toxin comprises a component in blood tissue, a component in adipose tissue, a component in connective tissue, a component in bone tissue, and the like.
  • the effect of the toxin removal reagent on adsorption or binding of the toxin is different from the binding of the toxin to a substance within the biological fluid.
  • the toxin removal reagent is different from a substance that binds to the toxin in the biological fluid.
  • the penetrant is capable of providing an osmotic pressure substantially equal to or greater than 280 mOsm/L, 300 mOsm/L, or 330 mOsm/L.
  • the penetrant comprises a saccharide, an amino acid, a polypeptide, glycerol, a carbonate, a bicarbonate, or an analog thereof, and combinations thereof.
  • the saccharide penetrant may be selected from the group consisting of a monosaccharide, an oligosaccharide, and a polysaccharide
  • the amino acid penetrant may be selected from the group consisting of a natural amino acid, an unnatural amino acid, an analog thereof, a derivative, and any combination thereof.
  • the monosaccharide may be selected from the group consisting of glucose, fructose, sorbitol, xylitol, amino sugars, and derivatives thereof;
  • the oligosaccharide includes oligomerization of one or more of the monosaccharides And/or the polysaccharide comprises a polymer of one or more of the monosaccharides.
  • the saccharide penetrant comprises a glucose polymer.
  • the ratio of the toxin removal agent to the penetrant in the composition is 1:1750 to 1:4 (eg, 1:1750 to 1:5, 1:1500 to 1:4, 1:1500 to 1:5, 1:1000 to 1:5, 1:750 to 1:6; 1:300 to 1:6; 1:75 to 1:6; 1: 30 to 1:6; 1:10 to 1:6; 1:1500 to 1:5; 1:1500 to 1:10; 1:1500 to 1:30; 1:1500 to 1:75; 1:1500 to 1:150; 1:1500 to 1:300; 1:1500 to 1:750.
  • 1:1750 to 1:4 eg, 1:1750 to 1:5, 1:1500 to 1:4, 1:1500 to 1:5, 1:1000 to 1:5, 1:750 to 1:6; 1:300 to 1:6; 1:75 to 1:6; 1: 30 to 1:6; 1:10 to 1:6; 1:1500 to 1:5; 1:1500 to 1:10; 1:1500 to 1:30; 1:1500 to 1:75; 1:1500 to 1:150; 1:1500 to 1:300; 1:1500 to
  • the amount of permeate in the dialysate ranges (weight/volume) from 0.05% to 10%. , 0.5%-10%, 1%-10%, 1.5%-10%, 1.5%-9%, 1.5%-8%, 1.5%-7.5%, 1.5%-6%, 1.5%-5%, and the like.
  • the toxin removal reagent when the composition provided herein is configured to be used directly in an osmotic exchange dialysate, has a content range (weight/volume) of at least 0.0001%, At least 0.0005%, at least 0.001%, at least 0.005%, at least 0.01%, at least 0.025%, at least 0.05%, at least 0.075%, at least 0.1%, at least 0.125%, at least 0.15%, at least 0.175%, at least 0.2%, or at least 0.25%.
  • the toxin removal reagent in the dialysate has a content range (weight/volume) of not more than 4%, no more than 3.5%, no more than 3.3%, no more than 3.0%, no Above 2.8%, not higher than 2.5%, not higher than 2.3%, not higher than 2.0%, not higher than 1.8%, not higher than 1.6%, not higher than 1.4%, not higher than 1.2%, not higher than 1.0%, no more than 0.8%, no more than 0.6%, or no more than 0.4%.
  • the composition further comprises one or more of a buffer, an electrolyte, and other dialysis components. In certain embodiments, the composition is sterilized.
  • the composition is a solid formulation, a semi-solid formulation, or a liquid formulation.
  • the toxin removal reagent is capable of osmotic exchange with the biological fluid through a semi-permeable medium.
  • the semi-permeable medium is an artificial semipermeable membrane or a biological semipermeable membrane.
  • the biological semipermeable membrane is selected from the group consisting of a vascular wall membrane, a lymphatic wall membrane, a peritoneum, a pulmonary membrane, a glandular envelope, and a mucosa.
  • the biological fluid is selected from the group consisting of blood, tissue fluid, lymph, plasma, serum, blood products, biological products. In certain embodiments, the biological fluid is in an individual or outside the individual.
  • the present application also provides a dialysis solution containing a composition according to the present application.
  • the dialysis solution is capable of providing a physiologically acceptable level of pH and/or electrolyte.
  • the present application also provides a kit for biological fluid purification comprising the composition provided herein.
  • the composition is in the form of a single composition in the kit or in the form of two or more components.
  • the composition or at least one of the components is a solid formulation, a semi-solid formulation, or a liquid formulation.
  • the composition is in the form of two or more components and is separately contained in separate containers.
  • the two or more components are respectively contained in two or more containers that are operably in fluid communication.
  • the composition is sterilized.
  • the kit further comprises a semi-permeable medium useful for biological fluid purification.
  • the present application also provides a dialysis device comprising a composition provided herein, wherein the device is configured to allow the composition to undergo osmotic exchange with a biological fluid to be dialyzed.
  • the device further comprises a semi-permeable medium that allows the composition to undergo osmotic exchange with the biological fluid.
  • the dialysis device can be mounted to a dialysis machine.
  • the present application also provides a method of reducing toxins in a biological fluid, comprising: a) contacting the biological fluid with a permeate solution containing the composition provided herein under conditions permitting osmotic exchange, and b The composition is allowed to reduce the amount of the toxin in the biological fluid.
  • the toxin in the biological fluid is transferred to the permeate solution by osmotic exchange under conditions that permit permeation exchange.
  • step a) comprises placing the biological fluid and the composition on either side of a semi-permeable medium.
  • the osmotic solution is substantially isotonic or higher than isotonic with the biological fluid.
  • the semi-permeable medium is an artificial semi-permeable membrane or a biological semi-permeable membrane (eg, vascular wall membrane, lymphatic wall membrane, peritoneum, pulmonary membrane, glandular capsule, and mucosa).
  • the biological fluid is in the body of an individual.
  • the step a) comprises administering the osmotic solution to the individual by intraperitoneal perfusion.
  • the biological fluid is in vitro.
  • step a) comprises administering the osmotic solution to the individual by hemodialysis.
  • the present application also provides a method of treating or preventing a disease or condition associated with a toxin comprising using the composition provided herein to contact the biological fluid of the individual under conditions that permit osmotic exchange to reduce The toxin in the biological fluid.
  • the present application also provides the use of a composition provided herein in the manufacture of a medicament for treating or preventing a disease or condition associated with a toxin, the composition being capable of reducing biological fluids in an individual The toxin.
  • Figure 1 shows the experimental group of rats with peritoneal dialysis treated with icodextrin peritoneal dialysate containing different amounts of toxin removal reagents, and the corresponding positive control group (ICO+DA), blank control group (ICO) and negative control.
  • ICO+DA positive control group
  • ICO blank control group
  • Figure 1 (a) shows the removal results of icodextrin peritoneal dialysate supplemented with different amounts of nano-carbon powder
  • Figure 1 (b) shows the addition The removal results of different amounts of Kollidon CL-SF icodextrin peritoneal dialysate
  • Figure 1 (c) shows the removal results of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M
  • Figure 1 (d) shows the removal results of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus
  • Figure 1(e) shows the removal results of icodextrin peritoneal dialysate with different amounts of microsilica gel added.
  • 1 (f) shows the removal results of icodextrin peritoneal dialysate supplemented with different amounts of diatomaceous earth.
  • Figure 2 shows the experimental group of rats with peritoneal dialysis treated with icodextrin peritoneal dialysate containing different amounts of toxin removal reagents, and the corresponding positive control group (ICO+DA), blank control group (ICO) and negative control.
  • ICO+DA positive control group
  • ICO blank control group
  • Figure 2(b) shows the addition.
  • Figure 3 shows the experimental group of rats with peritoneal dialysis treated with icodextrin peritoneal dialysate containing different amounts of toxin removal reagents, and the corresponding positive control group (ICO+DA), blank control group (ICO) and negative control.
  • ICO+DA positive control group
  • ICO blank control group
  • Fig. 3(a) shows the removal results of the icodextrin peritoneal dialysate to which different amounts of nanocarbon powder were added
  • Fig. 3(a) shows the removal results of the icodextrin peritoneal dialysate to which different amounts of nanocarbon powder were added
  • FIG. 3(b) shows The removal results of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-SF
  • Figure 3(c) shows the removal results of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M
  • Figure 3(d) shows the removal results of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus
  • Figure 3(e) shows the removal results of icodextrin peritoneal dialysate supplemented with different amounts of micronized silica gel
  • Figure 3(f) shows the removal results of icodextrin peritoneal dialysate supplemented with different amounts of diatomaceous earth.
  • Figure 4 shows the experimental group of rats with peritoneal dialysis treated with icodextrin peritoneal dialysate containing different amounts of toxin removal reagents, and the corresponding positive control group (ICO+DA), blank control group (ICO) and negative control.
  • ICO+DA positive control group
  • ICO blank control group
  • Fig. 4(a) shows the results of icodextrin peritoneal dialysate supplemented with different amounts of nano carbon powder
  • Fig. 4(b) shows the addition.
  • Figure 5 shows the experimental group of rats with peritoneal dialysis treated with icodextrin peritoneal dialysate containing different amounts of toxin removal reagents, and the corresponding positive control group (ICO+DA), blank control group (ICO) and negative control.
  • ICO+DA positive control group
  • ICO blank control group
  • Figure 5(b) shows the addition.
  • Figure 5(c) shows the results of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M
  • Figure 5(d) The results of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus are shown.
  • Figure 5(e) shows the results of icodextrin peritoneal dialysate supplemented with different amounts of micronized silica gel
  • Figure 5(f) shows The results of icodextrin peritoneal dialysate supplemented with different amounts of diatomaceous earth.
  • Figure 6 shows the experimental group of rats with peritoneal dialysis treated with icodextrin peritoneal dialysate containing different amounts of toxin removal reagents, and the corresponding positive control group (ICO+DA), blank control group (ICO) and negative control.
  • ICO+DA positive control group
  • ICO blank control group
  • Fig. 6(a) shows the results of the icodextrin peritoneal dialysate to which different amounts of nano carbon powder were added
  • FIG. 6(b) shows The results of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-SF
  • Figure 6(c) shows the results of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M
  • Figure 6 (d) shows the results of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus
  • Fig. 6(e) shows the results of icodextrin peritoneal dialysate supplemented with different amounts of micronized silica gel
  • Figure 6 ( f) shows the results of icodextrin peritoneal dialysate supplemented with different amounts of diatomaceous earth.
  • Figure 7 shows the removal of urea nitrogen in the blood of rats subjected to peritoneal dialysis treatment using glucose peritoneal dialysis solution containing different amounts of toxin removal reagent and the corresponding blank control group (GLU) and negative control group.
  • Fig. 7(a) shows the removal results of glucose peritoneal dialysate supplemented with different amounts of nanocarbon powder
  • Fig. 7(b) shows the removal of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-SF.
  • Fig. 7(c) shows the removal results of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M
  • 7(d) shows the removal results of glucose peritoneal dialysate supplemented with different amounts of Soluplus.
  • 7(e) shows the removal results of the glucose peritoneal dialysate to which different amounts of micronized silica gel were added, and
  • Fig. 7(f) shows the removal results of the glucose peritoneal dialysate to which different amounts of diatomaceous earth were added.
  • Figure 8 shows the results of removal of creatinine in the blood of rats subjected to peritoneal dialysis treatment using glucose peritoneal dialysis solution containing different amounts of toxin removal reagent and corresponding blank control group (GLU) and negative control group.
  • Figure 8(a) shows the removal results of glucose peritoneal dialysate with different amounts of nano-carbon powder added
  • Figure 8(b) shows the removal results of glucose peritoneal dialysate with different amounts of Kollidon CL-SF added.
  • Figure 8(c) shows the removal results of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M
  • Figure 8(d) shows the removal results of glucose peritoneal dialysate supplemented with different amounts of Soluplus
  • Figure 8 (e) shows the removal results of glucose peritoneal dialysate to which different amounts of micronized silica gel were added
  • Fig. 8(f) shows the removal results of glucose peritoneal dialysate to which different amounts of diatomaceous earth were added.
  • Figure 9 shows the experimental group of rats subjected to peritoneal dialysis treatment using glucose peritoneal dialysis solution containing different amounts of toxin removal reagents, and the indole sulfate in the blood of the corresponding blank control group (GLU) and the negative control group.
  • Figure 9 (a) shows the removal of glucose peritoneal dialysate with different amounts of nano-carbon powder added
  • Figure 9 (b) shows the glucose peritoneal dialysate with different amounts of Kollidon CL-SF added
  • Figure 9 (c) shows the removal of glucose peritoneal dialysate with different amounts of Kollidon CL-M
  • Figure 9 (d) shows the removal of glucose peritoneal dialysate with different amounts of Soluplus added.
  • Figure 9(e) shows the removal results of glucose peritoneal dialysate supplemented with different amounts of micronized silica gel
  • Figure 9(f) shows the removal results of glucose peritoneal dialysate supplemented with different amounts of diatomaceous earth.
  • Figure 10 shows the content of urea nitrogen in the peritoneal fluid of the experimental group of rat peritoneal dialysis treated with glucose peritoneal dialysate containing different amounts of toxin removal reagent and the corresponding blank control group (GLU) and the negative control group. Changes, wherein Figure 10(a) shows the results of glucose peritoneal dialysate with different amounts of nano-carbon powder added, and Figure 10(b) shows the results of glucose peritoneal dialysate with different amounts of Kollidon CL-SF added.
  • Figure 10 (c) shows the results of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M
  • Figure 10 (d) shows the results of glucose peritoneal dialysate supplemented with different amounts of Soluplus
  • Figure 10 (e) The results of glucose peritoneal dialysate supplemented with different amounts of micronized silica gel are shown
  • Fig. 10(f) shows the results of glucose peritoneal dialysate supplemented with different amounts of diatomaceous earth.
  • Figure 11 shows the changes in creatinine content in the peritoneal fluid of the experimental group of rats subjected to peritoneal dialysis treatment using glucose peritoneal dialysate containing different amounts of toxin removal reagent and the corresponding blank control group (GLU) and the negative control group.
  • Figure 11 (a) shows the results of glucose peritoneal dialysate with different amounts of nano-carbon powder added
  • Figure 11 (b) shows the results of glucose peritoneal dialysate with different amounts of Kollidon CL-SF added.
  • FIG. 11(c) shows the results of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M
  • Figure 11(d) shows the results of glucose peritoneal dialysate supplemented with different amounts of Soluplus
  • Figure 11(e) shows The results of glucose peritoneal dialysate supplemented with different amounts of micronized silica gel
  • Fig. 11(f) show the results of glucose peritoneal dialysate supplemented with different amounts of diatomaceous earth.
  • Figure 12 shows the experimental group of rat peritoneal dialysis treated with glucose peritoneal dialysate containing different amounts of toxin removal reagent and the corresponding blank control group (GLU) and the negative control group of rats in the peritoneal fluid of indole sulfate
  • GLU blank control group
  • Figure 12(a) shows the results of glucose peritoneal dialysate supplemented with different amounts of nano-carbon powder
  • Figure 12(b) shows the glucose peritoneal dialysate with different amounts of Kollidon CL-SF added.
  • Fig. 12(c) shows the results of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M
  • Fig. 12(d) shows the results of glucose peritoneal dialysate supplemented with different amounts of Soluplus
  • Fig. 12 ( e) shows the results of glucose peritoneal dialysate supplemented with different amounts of micronized silica gel
  • Fig. 12(f) shows the results of glucose peritoneal dialysate supplemented with different amounts of diatomaceous earth.
  • Porture refers to an agent that is capable of providing a certain osmotic pressure in a solution.
  • “Osmotic pressure” as used in this application refers to the additional pressure applied to the liquid level of the solution that just prevents the occurrence of infiltration.
  • osmotic pressure the minimum additional pressure applied on the high concentration side in order to prevent water from permeating from the low concentration side to the high concentration side.
  • the osmotic pressure of the solution is proportional to the number of particles (number of molecules or ions) of the solute that cannot pass through the semipermeable membrane contained in the monomer volume solution. The more the number of solute particles, the higher the concentration of the solution, the attraction to water. The larger the solution, the higher the osmotic pressure of the solution. Conversely, the smaller the number of solute particles, that is, the lower the concentration of the solution, the weaker the attraction to water, and the lower the osmotic pressure of the solution.
  • “Semi-permeable medium” as used in this application refers to a medium that selectively allows only a portion of the solute to permeate through without allowing another portion of the solute to pass.
  • the semi-permeable medium can be a material having a certain porosity, wherein the pores can allow passage of molecules small enough such as water, electrolytes, sugars, and the like.
  • a common example of a semi-permeable medium is a semi-permeable membrane.
  • the semi-permeable medium is not limited to the semi-permeable membrane, but may be other forms such as hollow fibers having semi-permeable properties, or tubular permeable membranes (for example, see, Yu Xuemin, etc., preparation and modification of hemodialysis membranes). And component design, Membrane Science and Technology, Vol. 35, No. 4, pp. 110-122).
  • Isotonic as used in this application means that the osmotic pressures of the two solutions or liquids or fluids are equal.
  • the solution containing the composition of the present application is substantially isotonic or higher than isotonic with the biological fluid such that when the solution and the biological fluid are on either side of the semi-permeable medium, the biological fluid.
  • the electrolyte, inorganic salts, sugars, etc. in the medium do not penetrate outward or do not excessively penetrate outward to affect or destroy the normal biological function of the biological fluid.
  • Basic isotonicity means that it is close to the osmotic pressure of the biological fluid, for example, no more than plus or minus 10%, plus or minus 8%, plus or minus 5%, plus or minus 3% or plus or minus 1% of the osmotic pressure of the biological fluid.
  • the osmotic pressure of normal human plasma is about 290-310 mmol/L
  • the osmotic pressures of plasma, gastric juice, pancreatic juice, intestinal fluid, bile, spinal fluid, and tear fluid are substantially equal in human body.
  • the osmotic pressure which is substantially isotonic with the above-mentioned biological fluid such as human blood or plasma is 290-310 mmol/L, or within a range of plus or minus 10% (i.e., in the range of 260-340 mmol/L).
  • concentration gradient is meant herein a concentration profile gradient resulting from the difference in free concentration of a substance in a fluid on either side of a semi-permeable medium.
  • Concentration gradient is the driving force of a substance transported from a high concentration side to a low concentration side through a semi-permeable medium. When the concentration of the substance in the fluid on both sides of the semi-permeable medium is equal, the concentration gradient disappears and the transport of the substance through the semi-permeable medium stops.
  • osmotic exchange it is meant in the present application that a substance moves from a high free concentration side to a low free concentration side through a semi-permeable medium.
  • Toxin refers to a substance that adversely affects physiological function when it is present in an organism (eg, a human) or when it is present at a level above a threshold concentration in an organism. Toxins may increase the risk of disease, aggravate disease conditions or impair normal physiological function. Toxins may include metabolites in the body, foreign substances that cause poisoning, or molecules that cause disease.
  • Bio fluid may include any fluid from or derived from an organism that may contain toxins in the present application.
  • the biological fluid can be treated or untreated.
  • examples of biological fluids include, but are not limited to, tissue fluids, lymph fluids, blood, plasma, serum, blood products, biological products, and the like.
  • free amount is meant herein the amount of toxin present in a biological fluid that is in a free state.
  • non-free amount is meant herein the amount of toxin present in a biological fluid that is in a non-free state, such as in a state of binding (eg, binding to a protein, complexation or chelation).
  • total amount of toxin refers to the total amount of toxin present in a biological fluid which is the sum of the amount of toxin in the free state and the amount of toxin in the non-free state.
  • dialysis solution or "dialysis solution” is meant herein a solution formulation that can be used in dialysis treatment.
  • the dialysis solution may be a liquid preparation suitable for administration as it is, or a liquid preparation suitable for use in a pre-use configuration.
  • the application provides a composition comprising a penetrant and a toxin removal agent.
  • the compositions provided herein can be used to remove or reduce toxins present in biological fluids by osmotic exchange with biological fluids.
  • the biological fluid and the penetrant are placed on either side of the semi-permeable medium, respectively.
  • concentration gradients on the sides of the semi-permeable medium for toxins such as the presence of toxins in biological fluids, and the absence of toxins in the penetrant. Therefore, the concentration difference of the toxins on both sides of the semi-permeable medium leads to a concentration gradient, which promotes the toxins from the biological fluids.
  • the side penetrant is permeated on one side.
  • the penetration of the toxin into the penetrant side results in an increase in the concentration of the toxin on the side of the penetrant, a decrease in the concentration on the side of the biological fluid, and a decrease in the concentration difference.
  • the concentration gradient is reduced until the concentrations on both sides are equal and the concentration gradient is zero.
  • the concentration gradient is zero, the toxin in the biological fluid is no longer reduced, but a dynamic equilibrium is reached, at which time the concentration of free toxin in the biological fluid is the final concentration, and the amount of toxin in the biological fluid is no longer reduced.
  • the penetrant can remove up to 50% of the free toxin present in the biological fluid by the concentration gradient itself, but considering that the volume on the side of the penetrant is often much smaller than the organism.
  • the volume of fluid eg, blood
  • which is actually capable of being removed by osmotic exchange, is often well below 50%, even 20% (eg, in the case of human hemodialysis).
  • toxins such as protein-bound toxins
  • strength of the toxin binding ie, whether it is readily dissociated to release free toxins
  • amount of toxin present in bound form ie, non-free form Ratio of toxin to free form toxin.
  • toxins that are predominantly present in bound form and/or that are relatively strong it is difficult to achieve satisfactory toxin removal by relying solely on the concentration gradient provided by the penetrant.
  • the compositions provided herein contain a penetrant and toxin removal agent.
  • the biological fluid and the compositions provided herein are placed on either side of the semi-permeable medium, respectively.
  • the toxin removal reagents in the compositions provided herein are capable of effectively adsorbing, binding and/or degrading toxins that penetrate one side of the composition, thereby continuously reducing the free amount of toxins on one side of the composition, thereby promoting the biological fluids.
  • the toxin continues to permeate the composition, thereby continuously reducing the total amount of toxins in the biological fluid (eg, the amount of free toxin, the amount of protein bound toxin, and/or the total amount of toxin) until the toxin removal reagent can no longer be removed.
  • Many toxins for example, a state in which adsorption is saturated.
  • the toxin removal reagent in the compositions of the present application is capable of removing more free toxins from the biological fluid than is the case where only the penetrant is present, and is capable of removing toxins present in the biological fluid in a bound form.
  • the compositions provided herein are capable of reducing the free, non-free amount, and/or total amount of the toxin in the biological fluid. In certain embodiments, the compositions provided herein are capable of reducing the free amount of toxins in a biological fluid to at most 50%, at most 40%, at most 30%, at most 20%, at most 10%, or at most 5%.
  • the initial free amount refers to the free amount of toxin measured by the biological fluid prior to treatment with the compositions of the present application.
  • the compositions provided herein are capable of reducing the total (or non-free amount) of toxins in a biological fluid by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%. At least 60%, at least 70%, at least 80%, at least 90% or at least 95%.
  • the total amount (or non-free amount) of toxins in the treated biological fluid is up to 90%, up to 80%, up to 70% prior to treatment compared to the biological fluid prior to treatment with the compositions provided herein. Up to 60%, up to 50%, up to 40%, up to 30%, up to 20%, up to 10%, or up to 5%.
  • compositions provided herein are capable of reducing the total amount (or free amount, or non-free amount) of toxins in a biological fluid to a physiological benefit level.
  • physiological benefit level refers to a level capable of reducing the risk of disease or alleviating symptoms caused by a toxin in an organism
  • disease level refers to a level of an organism in a disease state.
  • the level of physiological benefit may be any level between greater than or equal to the normal physiological level to below the disease level, such as, but not limited to, at least 10%, at least 20%, at least 30%, at least 40%, at least 50% lower than the disease level. Wait.
  • the normal physiological level of indole sulfate in normal human plasma is 0.59 ⁇ 0.26 mg / L, but the level in the uremic state is 53 ⁇ 4.5 mg / L or higher, therefore, the physiological characteristics of indole sulfate
  • the level of benefit may be any level ranging from greater than or equal to 0.59 to less than 53 mg/L, such as 0.59-48 mg/L, 0.59-42 mg/L, 0.59-36 mg/L, 0.59-32 mg/L, 0.59-26 mg/L. , 0.59-20 mg / L, 0.59-15 mg / L, 0.59-10 mg / L, or 0.59-5 mg / L.
  • the plasma physiological benefit level of creatinine may be any level ranging from 0.5 mg/dL or more to less than 136 mg/dL, such as 0.5-120 mg/dL, 0.5-100 mg/dL, 0.5-80 mg/dL, 0.5-60 mg/dL, 0.5-40 mg/dL, or 0.5-20 mg/dL.
  • the normal physiological level of urea nitrogen (BUN) in normal human plasma is 44-133 ⁇ mol/L
  • the level of renal failure compensation is 133-177 ⁇ mol/L
  • the level of decompensated renal failure is 177-442 ⁇ mol/ L
  • the level in the renal failure phase is 442 to 707 ⁇ mol/L
  • the level in the uremia phase is greater than 707 ⁇ mol/L
  • the physiological benefit level may be any level lower than the level of different developmental stages of renal function loss.
  • the level of renal failure compensation is lower than 133 ⁇ mol/L
  • the level of decompensation in renal failure is lower than 177 ⁇ mol/L
  • the level in renal failure is lower than 442 ⁇ mol/L, at the level of uremia. Below 707 ⁇ mol/L.
  • the free, non-free amount and/or total amount of toxin (i.e., free amount plus non-free amount) of the toxin in the biological fluid can be determined by detection and/or analytical methods known in the art. Methods that can be used, for example, equilibrium dialysis, ultrafiltration, ultracentrifugation, gel filtration, spectroscopy (including UV-visible spectroscopy, fluorescence spectroscopy, infrared spectroscopy, circular dichroism, Raman spectroscopy, optical rotation), nuclear magnetic Resonance method, optical biosensor method, biochemical analysis method, mass spectrometry, high-efficiency affinity chromatography, microcalorimetry, etc. (For details, please refer to the fifth edition of Biopharmaceutics and Pharmacokinetics, editor-in-chief Liu Jianping, p. 96; "Analytical Chemistry” Wuhan University Edition Fifth Edition).
  • the biological fluid and the isotonic solution can be respectively placed on both sides of the semipermeable membrane allowing only the toxin to permeate and not allowing the biomacromolecule to permeate, so that the toxin in the biological fluid can be driven without external force.
  • Diffusion through the semi-permeable membrane when the equilibrium is reached, the concentration of the toxin in the solution on both sides of the membrane is determined, and the data of the binding of the biomacromolecule to the toxin can be analyzed by calculation.
  • Ultrafiltration is a membrane separation technique based on pressure. For the purpose of separating macromolecules from small molecules, the pore size of the membrane is between.
  • the hollow fiber ultrafilter membrane
  • the hollow fiber ultrafilter has the advantages of high packing density per unit container and small floor space.
  • the aqueous solution flows under the pressure and flows through the surface of the membrane, which is smaller than the solvent (water) of the membrane pores and the small molecular solute permeable membrane, which becomes the purification liquid (filter solution), and the solute and solute base larger than the membrane pore.
  • the mass is trapped and discharged with water to become a concentrate.
  • Ultracentrifugation refers to the method of separating, preparing, and analyzing substances using a powerful centrifugal force in an ultracentrifuge.
  • the ultracentrifuge has a centrifugal speed of 60,000 rpm or more, and the centrifugal force is about 500,000 times the gravity acceleration. It can be divided into two types: a preparative ultracentrifuge and an analytical ultracentrifuge.
  • This method uses a solvent system in which a density can form a gradient (in a centrifuge tube whose density continuously increases from top to bottom) without agglomerating or deactivating the separated biologically active substance, and the particles of each substance can be pressed after centrifugation. Their respective specific gravity balances form zones in the corresponding solvent densities.
  • Gel filtration also known as molecular exclusion, uses a certain type of gel, with a certain size of mesh, allowing only the corresponding size of molecules into the gel particles, the macromolecules are excluded.
  • UV-visible spectra which are all due to the transition of valence electrons.
  • the ultraviolet visible spectrum and the degree of absorption generated by the absorption of ultraviolet and visible light by molecules or ions of a substance can be analyzed, determined, and inferred for the composition, content, and structure of the substance.
  • Fluorescence spectroscopy refers to the method of qualitative and quantitative analysis of substances by utilizing the properties and intensity of fluorescence generated by certain substances under ultraviolet light.
  • Infrared spectroscopy is a technique in which a molecule can selectively absorb infrared rays of certain wavelengths, causing a transition of a vibrational level and a rotational energy level in a molecule, and detecting an infrared absorption of a substance can obtain an infrared absorption spectrum of a substance, which is also called a molecular vibrational spectrum or vibration. Spectroscopy, qualitative analysis of the material by analysis of these spectra.
  • Circular dichroism uses a phenomenon in which the degree of absorption of two kinds of circularly polarized light of R and L is different.
  • the relationship between the difference in the degree of absorption and the wavelength is called circular dichroism, which is a spectroscopic method for determining the asymmetric structure of a molecule. It is mainly used in the field of molecular biology to determine the stereostructure of proteins, and can also be used to determine the stereostructure of nucleic acids and polysaccharides.
  • Raman spectroscopy is a kind of spectroscopy method for analyzing the scattering spectrum of different incident light frequencies to obtain molecular vibration and rotation information, and applied to molecular structure research.
  • optical activity also known as optical activity
  • organic compounds containing chiral carbon atoms When plane-polarized light passes through these substances (liquid or solution), the plane of vibration of the polarized light rotates to the left or to the right. This phenomenon is called optical rotation.
  • the optical rotation method is a method for determining the optical activity of a compound by utilizing the optical rotation property of the substance.
  • Nuclear magnetic resonance spectroscopy is to study the absorption of radio frequency radiation by nuclear nuclei in a strong magnetic field, so as to obtain an analytical method for molecular structure information of compounds.
  • a biosensor is an instrument that is sensitive to biological substances and converts its concentration into electrical signals for detection. It is made up of immobilized bio-sensitive materials as identification elements (including enzymes, antibodies, antigens, microorganisms, cells, tissues, nucleic acids and other biologically active substances), appropriate physical and chemical transducers (such as oxygen electrodes, photosensitive tubes, FETs, An analytical tool or system consisting of a piezoelectric crystal or the like and a signal amplifying device. Biosensors have the function of a receiver and a converter.
  • Biochemical analyzer is one of the most important analytical instruments used in clinical tests. It measures various biochemical indicators such as transaminase, hemoglobin, albumin, total protein, cholesterol, muscle liver, glucose, and inorganic by analyzing blood or other body fluids. Phosphorus, amylase, calcium, etc. Combined with other clinical data, comprehensive analysis can help diagnose diseases, evaluate organ function, identify concurrent factors, and determine the basis for future treatment.
  • Mass spectrometry is the use of electric and magnetic fields to move ions (charged atoms, molecules or molecular fragments, molecular ions, isotope ions, fragment ions, rearranged ions, multi-charged ions, metastable ions, negative ions and ion-molecules)
  • ions charged atoms, molecules or molecular fragments, molecular ions, isotope ions, fragment ions, rearranged ions, multi-charged ions, metastable ions, negative ions and ion-molecules
  • the exact mass of the ion is measured to determine the compound composition of the ion. This is because the exact mass of the nuclide is a multiple number of decimals.
  • the quality of the two nuclides will never be the same, and there will never be one nuclide whose mass is exactly an integer multiple of the mass of the other nuclide.
  • Analysis of these ions yields information on the molecular weight, chemical structure, cleavage pattern of
  • Affinity chromatography is a chromatography method in which one of two substances having a highly specific affinity with each other is used as a stationary phase, and the components are separated from impurities by affinity with a different degree from the stationary phase.
  • High-performance liquid chromatography refers to a high-pressure infusion pump that pumps a mobile phase with a single solvent of different polarity or a mixed solvent of different proportions, a buffer, etc. into a column containing a stationary phase, and injects a sample to be tested through an injection valve.
  • the mobile phase is brought into the column, and after the components in the column are separated, the detector is sequentially introduced for detection, thereby realizing the analysis of the composition of the sample.
  • Microcalorimetry (including isothermal titration calorimetry and differential scanning calorimetry) is an important structural biological method developed in recent years to study biothermodynamics and biodynamics. It adopts high sensitivity and high automation microcalorimeter. Continuously and accurately monitor and record the calorimetric curve of a changing process, providing thermodynamic and kinetic information simultaneously in situ, online, and without damage.
  • the biological fluid Prior to performing a specific test or analysis, the biological fluid may be pretreated, if desired, for example by adding an appropriate reagent (eg, an anticoagulant) to avoid undesired changes (eg, coagulation), separation, or extraction of the biological fluid.
  • an appropriate reagent eg, an anticoagulant
  • the toxin removal reagents in the compositions provided herein are capable of reducing toxins in biological fluids under conditions of osmotic exchange.
  • the toxin removal reagents of the present application can adsorb, non-covalently bind, covalently bind, and/or degrade toxins.
  • the toxin removal reagent may pass through, for example, a porous structure, a charged structure, a group capable of forming a non-covalent bond or a covalent bond or an ionic bond, etc., Adsorption and binding of toxins permeated in biological fluids.
  • the toxin removal reagent can also degrade toxins that permeate from the biological fluid.
  • the toxin removal reagent has a porous structure. Without being bound by any theory, it is believed that the porous structure can increase the surface area of the toxin removal reagent to better adsorb or bind the toxin.
  • the porous structure having a 70cm 2 / g ⁇ 2 / g of specific surface area of 1000m (e.g., 70cm 2 / g ⁇ 900m 2 / g, 70cm 2 / g ⁇ 850m 2 / g, 70cm 2 / g ⁇ 800m 2 / g, 70cm 2 / g ⁇ 750m 2 / g, 70cm 2 / g ⁇ 700m 2 / g, 70cm 2 / g ⁇ 650m 2 / g, 70cm 2 / g ⁇ 600m 2 / g, 70cm 2 / g ⁇ 550m 2 / g, 70cm 2 / g ⁇ 500m 2 / g, 70cm 2 / g ⁇ 450m 2 / g, 70cm 2 / g ⁇ 400m 2 / g, 70cm 2 / g ⁇ 350
  • a specific surface area of diatomaceous earth is 40 ⁇ 65m 2 / g
  • a specific surface area of porous silica may be 70 ⁇ 600m 2 / g (e.g. 70 ⁇ 500m 2 / g, 70 ⁇ 400m 2 / g, 70 ⁇ 300m 2 / g, 70 ⁇ 200m 2 / g, 70 ⁇ 100m 2 / g, 70 ⁇ 90m 2 / g, 70 ⁇ 85m 2 / g , etc.).
  • the specific surface area of the porous structural material can be measured by a known method (for example, gas adsorption method, fluid permeation method, mercury intrusion method, etc.), see, for example, Lowell, S. et al., Characterization of porous solids and powders: surface area, Pore size and density, published by Springer, 2004.
  • the toxin removal reagent having the porous structure may have a pore size of from 0.1 nm to 10 ⁇ m.
  • materials having a porous structure can also be classified into macroporous materials (e.g., pore size ranges greater than 50 nm), mesoporous materials (e.g., pore size ranges from about 2 to 50 nm), and microporous materials (e.g., pore size ranges less than 2 nm).
  • macroporous materials e.g., pore size ranges greater than 50 nm
  • mesoporous materials e.g., pore size ranges from about 2 to 50 nm
  • microporous materials e.g., pore size ranges less than 2 nm.
  • Microporous materials suitable for use in the present invention are, for example, but not limited to, amorphous silica, inorganic sol to crystalline molecular sieves, activated carbon, and the like.
  • Suitable for use in the present invention are mesoporous materials such as, but not limited to, silica mesoporous materials.
  • Macroporous materials suitable for use in the present invention are, for example, but not limited to, macroporous molecular sieve materials (see, for example, Science (2011), 333: 1131), macroporous silica gels (e.g., having a pore size of about 50 nm and a pore volume of about 2.5 to 3.0 ml/ g, the bulk specific gravity is about 180-220 g/L, the specific surface area is about 150-200 m 2 /g, and the particle size is about 80 mesh).
  • macroporous molecular sieve materials see, for example, Science (2011), 333: 1131
  • macroporous silica gels e.g., having a pore size of about 50 nm and a pore volume of about 2.5 to 3.0 ml/ g, the bulk specific gravity is about 180-220 g/
  • the pore size can be characterized by known methods (for example, direct observation of cross section (TEM), bubble emission, permeation method, mercury intrusion method, gas adsorption method, centrifugal force method, suspension filtration method, X-ray small angle scattering method, etc. ) Perform the measurement.
  • TEM direct observation of cross section
  • bubble emission permeation method
  • mercury intrusion method mercury intrusion method
  • gas adsorption method centrifugal force method
  • suspension filtration method X-ray small angle scattering method, etc.
  • the toxin removal reagent having the porous structure has a suitable pore size distribution.
  • at least 80% or more of the pores have a thickness of 0.1 nm to 100 ⁇ m (for example, 0.1 nm to 80 ⁇ m, 0.1 nm to 60 ⁇ m, 0.1 nm to 40 ⁇ m, 0.1 nm to 20 ⁇ m, 0.1 nm to 10 ⁇ m, 0.1 nm to 1 ⁇ m, 0.1 nm to 100 nm, A pore size distribution of 0.1 nm to 10 nm, 0.1 nm to 1 nm, 1 ⁇ m to 80 ⁇ m, 10 ⁇ m to 80 ⁇ m, 20 ⁇ m to 80 ⁇ m, 40 ⁇ m to 80 ⁇ m, 60 ⁇ m to 80 ⁇ m).
  • the toxin removal reagent having the porous structure has a porosity of from 5 to 95% (eg, from 5 to 90%, from 5 to 80%, from 5 to 70%, from 5 to 60%, from 5 to 5). 50%, 5 to 40%, 10 to 90%, 20 to 90%, 30 to 90%, 40 to 90%, 50 to 90%, 60 to 90%).
  • the toxin removal reagent having the porous structure can be at least 0.2 mg/g (eg, at least 0.3 mg/g, at least 0.5 mg/g, at least 0.7 mg/g, at least 0.9 mg/g, Adsorption rate adsorption of at least 1.0 mg/g, at least 2 mg/g, at least 3 mg/g, at least 4 mg/g, at least 5 mg/g, at least 6 mg/g, at least 7 mg/g, at least 8 mg/g, at least 9 mg/g)
  • the toxin refers to the weight of the toxin adsorbed per unit weight of the toxin adsorption reagent.
  • an adsorption rate of 0.2 mg/g means that 0.2 g of toxin can be adsorbed per gram of the toxin adsorption reagent.
  • the toxin removal reagent having a porous structure may include, for example but not limited to, a silicon-based porous material, a carbon-based porous material, a metal oxide-based porous material (eg, porous alumina, hydrotalcite-like). , a polymer-based porous material, and a metal organic framework compound porous material.
  • a silicon-based porous material refers to a multi-phase material composed of a solid phase and a large number of pores based on silicon.
  • a carbon-based porous material in the present application refers to a multi-phase material composed of a solid phase and a large number of pores based on a carbon element.
  • the silicon-based porous material and the carbon-based porous material generally have a stable skeleton structure, have a specific surface area and a pore size distribution, and preferably have a regular pore structure.
  • silicon-based porous materials include, but are not limited to, diatomaceous earth, porous silica (for example SLC 500), zeolite, quartz sand, clay, microporous glass, porous ceramics, mesoporous silica, clay, and molecular sieves.
  • carbon-based porous materials include, but are not limited to, activated carbon, expanded graphite, and mesoporous carbon.
  • metal oxide-based porous material examples include, but are not limited to, porous alumina, hydrotalcite-like, and the like.
  • polymeric porous materials include, but are not limited to, polystyrene porous beads, inulin, polyethylene, polypropylene, polytetrafluoroethylene, polyvinylidene fluoride, polyethyl vinyl acetate, polycarbonate , polyetheretherketone, and polyethersulfone.
  • metal organic framework compound porous materials include, but are not limited to, MOF-5, MOF-177, MOF-180, MOF-205, MOF-210, [COII(BPB)] ⁇ 3DMF, ED-MIL-101, SZ /MIL-101.
  • an exemplary toxin removal reagent having a porous structure is activated carbon.
  • the activated carbon may have a pore effective radius of 1 to 1000 nm, a pore radius of 2 nm or less, a mesoporous radius of 2 to 100 nm, and a macropore radius of 100 to 10,000 nm.
  • the pore volume may be from 0.15 to 0.90 mL/g
  • the mesopore volume may be from 0.02 to 0.10 mL/g
  • the macropore volume may be from 0.2 to 0.5 mL/g.
  • the amount of activated carbon adsorbed to the small molecule sulfadiazine is 0.54 mg/g.
  • diatomaceous earth Another exemplary toxin removal reagent having a porous structure is diatomaceous earth.
  • the diatomaceous earth has a density of 1.9-2.3 g/cm 3 , a bulk density of 0.3-0.65 g/cm 3 , a specific surface area of 40-65 m 2 /g, a pore volume of 0.45-0.98 m 3 /g, and water absorption.
  • the rate is 2-4 times its own volume and the fineness is between 100 and 2000 mesh.
  • porous silica Another exemplary toxin removal reagent having a porous structure is porous silica.
  • the porous silica has a specific surface area of from 10 to 1000 m 2 /g (eg, from 70 to 600 m 2 /g) (eg, The SLC 500 is 500 m 2 /g), the density is 100 to 1000 kg/m 3 , and the pore size distribution is 1 to 1000 nm.
  • the toxin removal reagent is capable of forming a charged structure.
  • the toxin removal reagent of the charged structure can adsorb oppositely charged toxins by acting, for example, by electrostatic adsorption.
  • positively charged toxin removal reagents eg, spermidine, spermine, nano-alumina
  • negatively charged toxins eg, sulphuric acid phenol
  • negatively charged toxin removal reagents eg, porous silica gel, microsilica gel
  • porous silica gel, microsilica gel can remove positively charged toxins (eg, spermidine, spermine) by adsorption.
  • the charged structure comprises charged ions or charged colloids.
  • Some submicron or nanoscale particles or polymers can form a colloidal solution when dispersed in a medium such as water or an aqueous solution.
  • the colloidal particles in the colloidal solution may carry a certain charge due to adsorption of some charged ions or ionization of groups on the surface.
  • the charged structure has a charge density of at least 0.2 ⁇ C ⁇ cm -2 or 0.2-50 ⁇ C ⁇ cm -2 (eg, 0.2-40 ⁇ C ⁇ cm -2 , 0.2-30 ⁇ C ⁇ cm -2 , 0.2-20 ⁇ C ⁇ cm -2 , 0.2-10 ⁇ C ⁇ cm -2 , 2-50 ⁇ C ⁇ cm -2 , 10-50 ⁇ C ⁇ cm -2 , 20-50 ⁇ C ⁇ cm -2 , 30-50 ⁇ C ⁇ cm -2 , or 40 -50 ⁇ C ⁇ cm -2 ).
  • the charged nature of the charged structure can be detected by known methods, for example, by measuring the conductivity of the colloidal solution (for example, see: Zhou Hongwei et al, Acta Phys.-Chim. Sin. 2013, 29(6), 1260 -1265).
  • the toxin removal reagent capable of forming a charged structure comprises povidone (eg, a polymer of 1-vinyl-2-pyrrolidone), crospovidone (for example, crosslinked polymer of 1-vinyl-2-pyrrolidone), silica colloid, micronized silica gel (also called colloidal silica), diatomaceous earth, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol Graft copolymers (for example, see U.S. Patent No. 8,636,929, U.S. Patent No. 9,011,912, PCT International Patent Application No. WO/2013/090, 842 A )Wait.
  • povidone eg, a polymer of 1-vinyl-2-pyrrolidone
  • crospovidone for example, crosslinked polymer of 1-vinyl-2-pyrrolidone
  • silica colloid silica colloid
  • micronized silica gel also called colloidal
  • the toxin removal reagent is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
  • suitable molecular weight ranges may range from 90,000 to 140 000 g/mol.
  • the weight ratio of polyethylene glycol:polyvinylcaprolactam:polyvinyl acetate is 13:57:30 in the copolymer.
  • the toxin removal reagent is capable of binding the toxin with a non-covalent bond or a covalent bond, or an ionic bond.
  • Non-covalent bonding can be based on any possible non-covalent bond, such as hydrogen bonding, hydrophobic interactions, electrostatic interactions, chelation, van der Waals forces, ⁇ - ⁇ stacking, and the like.
  • colloidal silica acts as a toxin removal reagent, it can form a hydrogen bond with the toxin creatinine, thereby removing creatinine from the biological fluid.
  • a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer for example, Soloplus
  • a toxin removal reagent when used as a toxin removal reagent, it can be combined with a toxin sulfated phenol by electrostatic interaction and hydrogen bonding. The sulphate is removed from the biological fluid.
  • a metal chelating agent can be used as a toxin removal reagent to form copper ions from the biological fluid by chelation with the toxin copper ions.
  • the toxin removal reagent has a group capable of forming a non-covalent bond with a toxin, such as a hydrogen atom, a hydroxyl group, an amino group, an amine group, a carboxyl group, and the like.
  • the toxin removal reagent is capable of binding the toxin in a covalent manner.
  • the covalent bonding may be based on any covalent bond that may be formed in the case of osmotic exchange, such as a disulfide bond, an ester bond, a hydrazone bond, a hydrazide bond, a hydrazide bond, and the like.
  • a disulfide bond can be formed with a toxin having glutathione or cysteine to remove such a toxin from the biological fluid.
  • a Schiff base an oxime bond
  • an amino group-containing compound such as an amino acid or a polypeptide toxoid
  • the toxin removal reagent has a group capable of forming a covalent bond with a toxin, such as a hydrogen atom, a hydroxyl group, a carboxyl group, a thiol group, an aldehyde group, an amino group, a hydrazide bond, a hydrazide bond.
  • the toxin removal reagent is a silica having a hydroxyl, carboxyl, sulfhydryl, aldehyde, amino, hydrazide linkage, or hydrazide linkage modification.
  • the toxin removal reagent is capable of binding the toxin by ionic bonding.
  • the ionic bond can be based on any combination of ion exchange that may be formed in the case of osmotic exchange.
  • the toxin removal reagent has a group capable of forming an ionic bond with the toxin, for example, chloride, sulfate, calcium, carbonate, and the like.
  • chloride ions in the ion exchange resin can form ionic bonds with the toxin silver ions, thereby removing toxin silver ions from the biological fluid.
  • Toxins suitable for removal in this manner may be toxic metal ions such as copper ions, aluminum ions, mercury ions, strontium ions, lead ions, chromium ions, cadmium ions, silver ions, and the like.
  • the toxin removal reagent is capable of degrading the toxin.
  • the toxin removal reagent is a biocatalyst or a chemical catalyst.
  • the biocatalyst may be a biological macromolecule having a catalytic reaction function, such as an enzyme.
  • the toxin removal reagent can be an enzyme and the toxin can be a substrate, and the enzyme as a toxin removal reagent can decompose or digest the substrate by interaction between the enzyme and the substrate.
  • a hydrolase as a toxin removal reagent can hydrolyze an ester toxin and remove an ester toxin in a biological fluid; a trypsin as a toxin removal reagent can digest and hydrolyze a protein toxin; and a nuclease as a toxin removal reagent can a nucleic acid Toxoid digestion and hydrolysis.
  • the chemical catalyst may be a chemical molecule having a catalytic reaction function.
  • An exemplary chemical catalyst may be manganese dioxide, which acts as a toxin removal reagent to decompose and remove reactive oxygen species (ROS) in biological fluids.
  • ROS reactive oxygen species
  • the toxin removal reagent has a group or domain capable of degrading or destroying the toxin molecule, such as a catalytic domain of an enzyme, or a catalytic group of a chemical molecule, and the like.
  • the toxin removal agent is selected from the group consisting of activated carbon, povidone, crospovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (see, for example, US patents) US 8,636,929, US 9,011,912, PCT International Patent Application WO/2013/090842 A3, CAS No. 402932-23-4, trade name ), micronized silica gel, diatomaceous earth, and any combination thereof.
  • the toxin removal reagent does not necessarily need to be a physiologically acceptable material.
  • the toxin removal reagent under conditions of osmotic exchange, the toxin removal reagent is in a physically separated state from the biological fluid, but the toxin in the biological fluid can penetrate to one side of the toxin removal reagent.
  • the toxin removal reagent preferably does not penetrate into the biological fluid under osmotic exchange conditions and thus does not necessarily have to be physiologically acceptable by itself.
  • the toxin removal reagents in the compositions provided herein are capable of removing toxins from biological fluids.
  • the toxin comprises one or more in vivo metabolites, a foreign substance that causes poisoning (eg, a drug, a pesticide, a chemical poison, a food-borne toxicant, or a biological exogenous toxin, etc.), or The molecule that causes disease.
  • a foreign substance that causes poisoning eg, a drug, a pesticide, a chemical poison, a food-borne toxicant, or a biological exogenous toxin, etc.
  • the molecule that causes disease eg, a drug, a pesticide, a chemical poison, a food-borne toxicant, or a biological exogenous toxin, etc.
  • In vivo metabolites are products derived from the metabolism of cells in a living body, or the digestion or metabolism of food by the body, or the production of a living state in a disease state. For example, urea (produced by protein metabolism), creatinine (produced by muscle metabolism), indole sulfate (at least partially produced by metabolism of terpenoids in food), and the like. Metabolites in the body can usually be excreted through the urine, but when renal function declines and kidney clearance decreases, metabolites accumulate in the blood and tissues and participate in the development of uremic syndrome. Toxins that participate in or cause uremia due to accumulation in the body are also known as uremic toxins. In certain embodiments, the compositions of the present application can remove uremic toxins.
  • the in vivo metabolic products may include urea, creatinine, uric acid, guanidine -ADMA, ⁇ 2 - microglobulin, cytokines, parathyroid hormone, indoxyl sulfate, homocysteine , p-cresol, hippuric acid, reactive oxygen species (referred to as ROS, such as peroxides, superoxides, hydroxyl radicals, single oxygen atoms, etc.), uremic toxins (such as AGE products (3-deoxyglucosone, Fructose lysine, glyoxal, pyruvaldehyde, pentosidine), 1-methyladenosine, 1-methylguanosine, 1-methylinosine, asymmetric dimethylarginine, ⁇ - Keto- ⁇ -valeric acid, ⁇ -N-acetylarginine, arabitol, arginine, benzyl alcohol, ⁇ -mercaptoprop
  • the toxins described herein can also be foreign substances that cause poisoning.
  • the exogenous substance may be a substance that is not naturally occurring in the living body (for example, a chemical poison, etc.), or is mainly taken into the living body by an external source (for example, a hormonal natural medicine to be taken, etc.).
  • the foreign substance causing the poisoning may include a drug, a pesticide, a chemical poison, a foodborne poison, or a biological exogenous toxin.
  • the drug causing poisoning may include sedative hypnotic drugs, antipsychotics, cardiovascular and cerebrovascular drugs, antipyretic and analgesic drugs, antiparasitic drugs, antimicrobial drugs, anesthesia and Anesthesia supplements, respiratory medicines, circulatory drugs, digestive system drugs, urinary system drugs, blood system drugs, metabolic and endocrine drugs, anti-allergic drugs, tumor therapeutic drugs, immunomodulatory drugs, obstetrics and gynecology drugs, male drugs, Anti-inflammatory drugs, Chinese medicine, etc.
  • Sedative hypnotic drugs such as barbiturates, anxiolytics, antihistamines, antipsychotics, analgesics, and other sedative and hypnotic drugs.
  • Barbiturate is a derivative of barbituric acid, such as barbital, phenobarbital, isobarbital, sedative, thiopental and the like.
  • Anxiolytics include benzodiazepines (eg, diazepam, nitrazepam, estazolam, alprazolam, zopiclone, etc.), tranquillity (eg, methamphetamine, myalin, clonazepam) Etc.), diphenylmethanes (eg, Antalone, butyl thiodiphenylamine, piperonyl ethanol, etc.) and other classes (eg, fenac, isobutyrazine tartrate, trimethoxyphylline, oryzanol, tasperidine).
  • benzodiazepines eg, diazepam, nitrazepam, estazolam, alprazolam, zopiclone, etc.
  • tranquillity eg, methamphetamine, myalin, clonazepam
  • diphenylmethanes eg, Antalone, butyl
  • sedative hypnotics may include, for example, chloral hydrate, hypnosis, glumet, methyl ethyl piperidone, adalin, acetylenic amine, gastrodin, bromide, and the like.
  • Antipsychotics also known as strong tranquilizers or nerve blockers, are drugs used to treat schizophrenia and other psychotic disorders.
  • Common antipsychotic drugs include phenothiazines (chlorpromazine, thiodarizine, perphenazine, trifluoperazine, fluphenazine, fluphenazine), butyrylbenzene (fluphenymate) Pyridinol, haloperidol acid, penfluridol, benzamide (sulpiride), dibenzodiazepines (clozapine, olanzapine), benzoisoxazoles (risperidone), Phenylisoxazoles (ziprasidone), diphenylthiazolidines (quetiapine) and quinolones (aripiprazole).
  • phenothiazines chlorpromazine, thiodarizine, perphenazine, trifluoperazine, fluphenazine, fluphenazine), butyrylbenzene (
  • Cardio-cerebral vascular drugs are drugs that act on the cardiovascular system.
  • Common cardiovascular and cerebrovascular drugs include anti-angina drugs (such as nitroglycerin, beta-adrenergic receptor antagonists, calcium antagonists, etc.), antiarrhythmic drugs (such as lidocaine, amiodarone, verapamil, etc.) ), antihypertensive drugs (such as valsartan, benazepril, metoprolol, nifedipine), anticardiac dysfunction (such as spironolactone, furosemide, irbesartan, etc.), peripheral blood vessels Dilatation drugs (pyridazine, sodium nitroprusside, nitrates, alpha-adrenergic receptor blockers, calcium antagonists, angiotensin converting enzyme inhibitors, etc.) and the like.
  • anti-angina drugs such as nitroglycerin, beta-adrenergic receptor antagonists, calcium antagonists, etc.
  • Antipyretic and analgesic drugs are drugs that can restore the body temperature of a fever patient to normal, but have no effect on the body temperature of a normal person. These drugs also have moderate tonic analgesic effects, but are less powerful than morphine and its synthetic substitutes. Commonly used antipyretic and analgesic drugs can be classified into salicylic acid (such as aspirin, lysine aspirin), aniline (such as acetaminophen), pyrazolone (such as analgin), and guanidine according to chemical structure.
  • salicylic acid such as aspirin, lysine aspirin
  • aniline such as acetaminophen
  • pyrazolone such as analgin
  • guanidine guanidine according to chemical structure.
  • Classes eg indomethacin
  • aryl acetic acids eg diclofenac sodium
  • aryl propionic acids eg ibuprofen
  • selective cyclooxygenase-2 inhibitors eg, celebrex, nimesulide, Meloxicam.
  • Common pesticides that cause poisoning include organic phosphorus, herbicides, pyrethroids, avermectin, and rodenticides.
  • Other common pesticide varieties include paraquat, dichlorvos, dimethoate, glyphosate, glufosinate, chlorpyrifos, omethoate, bromide, bromide, phoxim, imidacloprid, insecticidal, parathion, Phosphate, endogenous phosphorus, trichlorfon, malathion, hexachlorocyclohexane, DDT, dieldrin, endrin, aldrin, aluminum phosphide pesticide, nitrile chloropermethrin, fluoride Acetamide, tetramine, pentachlorophenol, dinitrocresol, diuron, dichlorvos, nematotoxin, rotenone, nicotine, methylated naphthalene, formazan, Bacill
  • Examples of chemical poisons may include, but are not limited to, toxins derived from toxic plants (eg, chicken mother beads, oleander, mandala, colchicum, rock sand anemone, lupin, wild lily), cyanide (eg cyanide) Sodium, potassium cyanide, calcium cyanide, lanthanum cyanide, cobalt cyanide, cobalt cyanide, potassium cobalt cyanide, nickel cyanide, nickel potassium cyanide, copper cyanide, silver cyanide, silver potassium cyanide, Zinc cyanide, cadmium cyanide, mercury cyanide, potassium cyanide, lead cyanide, cesium cyanide, cuprous cyanide, gold potassium cyanide, bromine cyanide, hydrogen cyanide, hydrocyanic acid, xylene , automotive antifreeze, arsenic trioxide, sodium arsenite, potassium arsenite, arsenic pentoxide, arsenic trichloride
  • Examples of foodborne toxins may include, but are not limited to, puffer toxin, ginkgo toxin, dolphin toxin, paralytic shellfish toxin, diarrhetic shellfish toxin, neurogenic shellfish toxin, amnestic shellfish toxin, cadmium toxin, Salmon carp, conotoxin, polyether toxoid, cadmium toxin, saxitoxin, scorpion toxin, botulinum toxin, cyanogenic steroid, linsein, amygdalin, hydrocyanic acid, benzaldehyde, Gossypol, solanine, poisonous scorpion venom, toxic peptide, chlorpyrifos, nitrite, histamine, lead, cadmium, mercury, arsenic, fluorine, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, methanol, rice Yeast acid, toxanthin, Fusarium enem
  • biological exogenous toxins may include, but are not limited to, snake venom, scorpion venom, jellyfish toxic, and the like.
  • the disease-causing molecule is selected from the group consisting of free DNA, free RNA, inflammatory factors, antibodies (eg, antibodies against autoantigens), antigens (eg, allergenic antigens), protein fragments , pathogenic microorganisms (such as viruses, bacteria) and so on.
  • the toxin is freely present in the biological fluid, in combination with a substance in the biological fluid, or both.
  • proteins such as plasma proteins
  • carbohydrates such as lipids, nucleic acids, etc.
  • proteins such as plasma proteins
  • carbohydrates such as lipids, nucleic acids, etc.
  • albumin is abundantly present in the blood and can bind to various in vivo metabolites, such as sulphate, making it difficult to remove.
  • the substance that binds to the toxin comprises components in blood tissue (eg, plasma proteins, albumin, red blood cells), components in adipose tissue (eg, fat, mono-vesicular fat cells, multivesicular fat) Cells), components in connective tissue (eg, cellulite, collagen fibers, elastic fibers, and reticular fibers), components in bone tissue (eg, calcium phosphate), and the like.
  • blood tissue eg, plasma proteins, albumin, red blood cells
  • adipose tissue eg, fat, mono-vesicular fat cells, multivesicular fat
  • connective tissue eg, cellulite, collagen fibers, elastic fibers, and reticular fibers
  • bone tissue eg, calcium phosphate
  • the toxin forms a reversible binding with a substance in the biological fluid.
  • Reversible binding means that the substance to which the toxin binds can spontaneously bind and dissociate, and this binding and dissociation can achieve a dynamic balance.
  • the concentration or amount of free toxin and bound toxin remains essentially unchanged. If the concentration of free toxin is lower than the concentration at the time of dynamic equilibrium, the bound toxin is released by dissociation. Conversely, if the concentration of free toxin is higher than the concentration at the time of dynamic equilibrium, free toxin binding will be promoted.
  • the reversible binding comprises by non-covalent bonds (eg, ion-dipole interactions, dipole-dipole interactions, hydrogen bonds, cation- ⁇ system interactions, ⁇ - ⁇ stacking, Reversible binding formed by hydrophobic effects, and/or van der Waals forces, etc.).
  • non-covalent bonds eg, ion-dipole interactions, dipole-dipole interactions, hydrogen bonds, cation- ⁇ system interactions, ⁇ - ⁇ stacking, Reversible binding formed by hydrophobic effects, and/or van der Waals forces, etc.
  • the force of non-covalent bond usually has an intensity of action, ion-dipole interaction force (50-200 kJ/mol); dipole-dipole interaction (5-50 kJ/mol), which belongs to intermolecular interaction; hydrogen Bond (4 ⁇ 120kJ/mol); cation- ⁇ system interaction (5 ⁇ 80kJ/mol); ⁇ - ⁇ stacking (0 ⁇ 50kJ/mol); hydrophobic effect (0 ⁇ 50kJ/mol); van der Waals force Less than 5kJ/mol).
  • ion-dipole interaction force 50-200 kJ/mol
  • dipole-dipole interaction 5-50 kJ/mol
  • hydrogen Bond (4 ⁇ 120kJ/mol)
  • cation- ⁇ system interaction 5 ⁇ 80kJ/mol
  • ⁇ - ⁇ stacking (0 ⁇ 50kJ/mol
  • hydrophobic effect (0 ⁇ 50kJ/mol
  • van der Waals force Less than 5kJ/mol van der Waals force Less than 5kJ/mol.
  • the strength of binding of a toxin to a substance (eg, a protein) in a biological fluid can be expressed as a Kd value.
  • the toxin binds to a substance in the biological fluid with a Kd value of at least 10 2 ⁇ mol/L, 10 3 ⁇ mol/L, 10 4 ⁇ mol/L, 10 5 ⁇ mol/L, 10 6 ⁇ mol /L, or 10 7 ⁇ mol/L.
  • the larger the Kd value the stronger the binding.
  • the high protein binding toxin has a Kd value of 10 5 to 10 7 ⁇ mol/L, and a low binding or medium binding strength Kd value of 10 2 to 10 4 ⁇ mol/L.
  • the binding of the toxin to a substance (eg, a protein) in the biological fluid has a Kd value of at least 10 5 to 10 7 ⁇ mol/L, 10 5.5 to 10 7 ⁇ mol/L, or 10 6 ⁇ 10 7 ⁇ mol/L.
  • the toxins in the biological fluid are primarily present in a combined form. Under such circumstances, the amount of free toxin in the biological fluid is relatively low, and only a part of the free toxin can be removed by the simple osmotic balance in the prior art, but most of the bound toxins still remain in the biological fluid. To effective clearance.
  • At least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% of the biological fluid The toxin is present in a combined form. In certain embodiments, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% of the biological fluid
  • the toxin is present in a form that binds to plasma proteins.
  • the binding of the toxin to a substance in the biological fluid can be detected by a variety of methods known in the art such as, but not limited to, equilibrium dialysis, ultrafiltration, ultracentrifugation, gel filtration , spectroscopy (including UV-Vis, fluorescence, infrared, circular dichroism, Raman spectroscopy), optical biosensor method.
  • the toxin is capable of reversibly binding to a protein in a biological fluid, such as, but not limited to, indophenol sulfate, asymmetric arginine, homocysteine, phenylacetic acid, para Phenol, AGE product (3-deoxyglucosone, fructose lysine, glyoxal, pyruvaldehyde, pentosidine), hippuric acid, uremic toxin, hydrogen sulfide, bilirubin and the like.
  • a biological fluid such as, but not limited to, indophenol sulfate, asymmetric arginine, homocysteine, phenylacetic acid, para Phenol, AGE product (3-deoxyglucosone, fructose lysine, glyoxal, pyruvaldehyde, pentosidine), hippuric acid, uremic toxin, hydrogen sulfide, bilirubin
  • the toxin is predominantly present in a combined form (eg, at least 50%, 60%, 70%, 80%, more than 90% is present in bound form) and has a substance (eg, a protein) within the biological fluid Strong binding (for example, a Kd value of at least 10 4 ⁇ mol/L, 10 5 ⁇ mol/L or higher).
  • tenoxicam an anti-inflammatory drug
  • digoxigenin a drug used to treat congestive heart failure
  • the toxin removal reagents in the compositions provided herein are different from the substances bound to the toxins in the biological fluid.
  • the toxin removal reagent in the composition of the present application may not use plasma proteins (e.g., albumin).
  • the toxin removal reagents in the compositions provided herein are not materials present in the biological fluid (eg, may be synthetic polymers, inorganics, etc.).
  • the toxin removal reagents in the compositions provided herein are not immunogenic. Such compositions have advantages when used in direct contact with an organism, such as when used for peritoneal dialysis.
  • the toxin removal reagents in the compositions provided herein are man-made materials.
  • Artificial material refers to a material that is not present in a biological fluid, or a material that has been artificially synthesized or prepared. For example, diatomaceous earth, silica, activated carbon, etc. are all man-made materials.
  • the binding of the toxin removal reagent to the toxin in the composition provided herein is different from the binding of the substance in the biological fluid to the toxin.
  • the toxin removal reagent is a porous material that binds to the toxin by porous adsorption, while the toxin in the biological fluid binds to albumin mainly by, for example, hydrogen bonding.
  • toxin removal reagents that provide different binding functions helps to break the dynamic balance of the original toxin binding in the biological fluid, thereby promoting the dissociation of the bound toxin from the biological fluid and removal.
  • the toxin removal reagent in the compositions provided herein has a greater effect on the adsorption or binding of the toxin than the substance within the biological fluid.
  • the toxin removal reagent binds to the toxin with a higher Kd value than the binding between the toxin and the substance in the biological fluid (eg, plasma protein) (eg, the binding of the toxin to the toxin removal reagent has a Kd value of 10 5 ⁇ mol/L.
  • the binding ratio of the toxin to the biological fluid substance is 10 4 ⁇ mol/L, and the ratio of binding is larger (for example, the binding ratio of the toxin to the toxin removal reagent is more than 80%, and the binding ratio of the toxin to the biological fluid substance is 50. %), and/or the binding species are more stable (eg, the toxin is covalently bonded to the toxin removal reagent and the toxin is bound to the biological fluid species by a non-covalent bond).
  • a penetrant is included in the compositions of the invention.
  • the penetrant can provide an osmotic pressure that is substantially isotonic or higher than isotonic with the biological fluid.
  • the penetrant can provide about 290-310 mmol/L, 260-340 mmol/L, or 260-350 mmol/L (eg, about 280 mOsm/L, 283 mOsm/L, 284 mOsm/L, 285 mOsm/L).
  • the penetrant provides an osmotic pressure that is substantially isotonic with the biological fluid, it is possible to avoid as much as possible the leakage of electrolytes, sugars, moisture or the like in the biological fluid, or to have an excessive adverse effect on the biological properties of the biological fluid.
  • the osmotic pressure provided by the osmotic agent is higher than the osmotic pressure of the biological fluid, the water in the biological fluid can be allowed to ooze out, which is advantageous for some patients with impaired kidney functions to excrete excess water in the body.
  • Suitable penetrants can be non-toxic, biologically inert, and/or metabolizable when used to treat biological fluids.
  • the penetrant can include a saccharide, an amino acid, a polypeptide, glycerin, a carbonate, or an analog thereof, or any combination thereof.
  • the penetrant can be of small molecular weight (e.g., having a molecular weight of no greater than 500 g/mol) or of a large molecular weight (e.g., having a molecular weight greater than 500 g/mol).
  • a variety of sugars suitable as penetrants can be used as penetrants, and may be monosaccharides, oligosaccharides (e.g., disaccharides, trisaccharides, etc.) and polysaccharides.
  • monosaccharides include, but are not limited to, glucose, fructose, sorbitol, xylitol, amino sugars, and derivatives thereof.
  • the oligosaccharide or polysaccharide includes an oligomer or a polymer of one or more monosaccharides, and each monosaccharide may be linked by, for example, an ⁇ -1,4 glycosidic bond, an ⁇ -1,6 glycosidic bond, or the like.
  • the oligosaccharide or polysaccharide is metabolized by, for example, the human or animal body.
  • suitable saccharide penetrants can include, for example, glucose, non-glucose monosaccharides (eg, sorbitol, fructose, xylitol, etc.), or monosaccharide polymers (eg, glucose polymers, maltose) Dextrin, icodextrin, chitooligosaccharide (see, for example, Chinese patent application CN107375318A)).
  • the glucose polymer comprises icodextrin.
  • the amino acid penetrant may be selected from the group consisting of natural amino acids, unnatural amino acids, analogs, derivatives thereof, and combinations thereof.
  • amino acid penetrants include, but are not limited to, leucine, valine, threonine, isoleucine, lysine, histidine, methionine, phenylalanine, tryptophan, alanine Acid, valine, arginine, glycine, serine, tyrosine, aspartic acid, glutamic acid, and derivatives thereof, and any combination thereof.
  • Exemplary amino acid penetrants can be found in U.S. Patent 5,629,025.
  • a peptide penetrant can also be used as a possible penetrant (see, for example, U.S. Patent No. 4,906,616, U.S. Patent No. 6,380,163, U.S. Patent No. 5,039,609).
  • the ratio of the toxin removal reagent to the penetrant (weight/weight) in the composition provided herein is from 1:1750 to 1:4 (eg, 1:1750 to 1:5, 1 : 1500 to 1:4, 1:1500 to 1:5, 1:1000 to 1:5, 1:750 to 1:6; 1:300 to 1:6; 1:75 to 1:6; 1:30 To 1:6; 1:10 to 1:6; 1:1500 to 1:5; 1:1500 to 1:10; 1:1500 to 1:30; 1:1500 to 1:75; 1:1500 to 1 :150; 1:1500 to 1:300; 1:1500 to 1:750.
  • 1:1750 to 1:4 eg, 1:1750 to 1:5, 1 : 1500 to 1:4, 1:1500 to 1:5, 1:1000 to 1:5, 1:750 to 1:6; 1:300 to 1:6; 1:75 to 1:6; 1:30 To 1:6; 1:10 to 1:6; 1:1500 to 1:5; 1:1500 to 1:10; 1:1500 to 1:30; 1:1500 to 1:75; 1:1
  • the amount of permeate in the dialysate ranges (weight/volume) from 0.05% to 10%. , 0.5%-10%, 1%-10%, 1.5%-10%, 1.5%-9%, 1.5%-8%, 1.5%-7.5%, 1.5%-6%, 1.5%-5%, and the like.
  • its content (weight/volume) in the dialysate for osmotic exchange may range from 3% to 8%, from 5 to 7.5%, or from about 7.5%.
  • the penetrant when the penetrant is glucose, its content in the dialysate for permeation exchange (weight/volume) may be 0.05%-2%, 0.05%-1.5%, 0.05%-1.0%, 0.05%- 0.75%, 0.5%-1.5%, or about 1.5%.
  • the toxin removal reagent when the composition provided herein is configured to be used directly in an osmotic exchange dialysate, has a content range (weight/volume) of at least 0.0001%, At least 0.0005%, at least 0.001%, at least 0.005%, at least 0.01%, at least 0.025%, at least 0.05%, at least 0.075%, at least 0.1%, at least 0.125%, at least 0.15%, at least 0.175%, at least 0.2%, or at least 0.25%.
  • the toxin removal reagent in the dialysate has a content range (weight/volume) of not more than 4%, no more than 3.5%, no more than 3.3%, no more than 3.0%, no Above 2.8%, not higher than 2.5%, not higher than 2.3%, not higher than 2.0%, not higher than 1.8%, not higher than 1.6%, not higher than 1.4%, not higher than 1.2%, not higher than 1.0%, no more than 0.8%, no more than 0.6%, or no more than 0.4%.
  • the content range (weight/volume) of the toxin removal reagent in the dialysate is a range of values obtained from any combination of the two end values respectively selected above, such as but not limited to at least 0.0001.
  • the toxin removal reagent is activated carbon, povidone, diatomaceous earth, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (eg, Soloplus), or micronized silica gel or Any combination, and when the composition is configured for direct use in osmotic exchange of dialysate, the range of the toxin removal reagent (weight/volume) in the dialysate meets the various ranges listed above.
  • compositions of the present invention may further comprise one or more components suitable for use under osmotic exchange conditions, such as buffers, electrolytes, other suitable osmotic exchange components.
  • compositions provided herein may further comprise a suitable buffer to provide the desired pH.
  • buffering agents include lactate, bicarbonate, citrate, isocitrate, dihydrogen phosphate, hydrogen phosphate, phosphate, pyruvate, succinate, fumarate, B
  • the acid salt, malate salt, oxaloacetate, chloride, pK 1 is one or more of the amino acids 7-13 (histidine, glycine, alanine) and the like.
  • the solution when the composition of the present application is configured as a solution for osmotic exchange with a biological fluid, the solution can be at a pH close to, or at least a physiologically acceptable level as, the biological fluid.
  • the pH of the solution measured at room temperature (20-25 ° C) may be 4.0 to 8.0, 5.0 to 8.0, 6.0 to 8.0, 4.0 to 7.8, 4.0 to 7.0, 5.0 to 7.5, or 6.5 to 7.5.
  • the concentration of the buffer in the solution can be, for example, but not limited to, 1.0 to 200 mM, 2.5 to 150 mM, 5 to 100 mM, 5 to 75 mM, 10 to 50 mM, 20 to 30 mM.
  • the electrolyte means a substance containing free ions and having electrical conductivity.
  • the electrolyte can be completely dissociated into cations and anions, preferably without significantly changing the pH of the composition.
  • Non-limiting examples of cations of the electrolyte include alkali metal cations (e.g., Na + and K + ), alkaline earth metal cations (Ca 2+ and Mg 2+ ).
  • Non-limiting examples of anions of the electrolyte include Cl - .
  • the electrolyte may be selected from one or more of the group consisting of a sodium salt, a calcium salt, a magnesium salt, and a potassium salt.
  • the composition wherein the composition is sterilized.
  • Sterilization can be carried out using a variety of methods well known in the art such as, but not limited to, autoclaving, steam sterilization, ultraviolet sterilization, filter sterilization, or any combination thereof.
  • the composition is a solid formulation, a semi-solid formulation, or a liquid formulation.
  • Compositions in solid or semi-solid form can be conveniently formulated into the desired liquid formulation with a suitable vehicle such as sterile water.
  • the liquid preparations may also be liquid concentrates of varying degrees of concentration, which may be combined with the vehicle in a suitable manner to provide the desired liquid preparation.
  • a dialysis solution comprising a composition of the present application is provided herein.
  • the dialysis solution may be a small molecule solution, and may also include a solution or a colloidal solution containing a macromolecule such as a polymer or the like.
  • the dialysis solution can be used as a peritoneal dialysis solution, or a hemodialysis solution.
  • the pH and/or electrolyte concentration of the dialysis solution provided herein is physiologically acceptable.
  • the dialysis solution is in the form of a concentrate or may be in a ready-to-use form.
  • the dialysis solution may be a single solution (eg, contained in a single container), or may be part of two or more dialysis solutions (eg, separately contained in two or more containers) ).
  • it is advantageous to separate the dialysis solution into different components to avoid unwanted interactions between the components of the composition eg neutral or alkaline pH may cause degradation of the glucose polymer during high temperature sterilization
  • the dialysis solution is divided into two or more components that are kept separate from each other until needed for use, for example, until a ready-to-use dialysis solution needs to be configured.
  • the constituents may have different forms, for example, may be in the form of a fluid, or at least one component may be in the form of a dry powder (eg, a buffer component), or at least one component may be in the form of a fluid concentrate (eg, an electrolyte concentrate). ).
  • the components in dry powder form are dissolved with a diluent prior to mixing with the other components, or the concentrate may be treated with a diluent in a ratio such as, but not limited to, 1:35, 1:45 or 1:200. dilution. Any suitable diluent can be used, such as sterile water, optionally without an electrolyte.
  • the first component of the dialysis solution contains a glucose polymer and has a pH in the range of 3.5 to 5.5.
  • the pH can be adjusted using one or more physiologically acceptable acids (e.g., lactic acid, pyruvic acid, acetic acid, citric acid, hydrochloric acid, and the like).
  • physiologically acceptable acids e.g., lactic acid, pyruvic acid, acetic acid, citric acid, hydrochloric acid, and the like.
  • carbon dioxide can be used instead of acid for pH adjustment.
  • the second component of the dialysis solution can contain a buffer solution, wherein the buffer solution is capable of providing a pH ranging from about 7 to about 9.
  • Suitable buffer solutions may contain, for example, sodium bicarbonate, sodium chloride, sodium lactate, one or more amino acids having a pK 1 value between 7 and 13 (eg, histidine, glycine, alanine, etc.) Or a combination thereof.
  • amino acids having a pK 1 value between 7 and 13 eg, histidine, glycine, alanine, etc.
  • the toxin removal reagent provided herein can be present in the first component described above, or in the second component, or in another third component.
  • two or more components of the dialysis solution can be contained in the container in any suitable manner, for example, a plurality of fluidly connectable containers can be used to separately accommodate different compositions of the dialysis solution.
  • the container fluid is operatively communicated (eg, by opening a fluidly connected valve or breaking the seal between the multiple compartment pockets) to obtain a ready-to-use dialysis solution.
  • the dialysis solution may further comprise an anticoagulant agent, such as heparin, citrate, and the like.
  • an anticoagulant agent such as heparin, citrate, and the like.
  • the present application also provides a kit for biological fluid purification comprising a composition as described herein.
  • the composition is sterilized.
  • the composition may be present as a single composition in the kit or may be in the form of two or more components. In certain embodiments, the composition or components thereof are sterilized. In certain embodiments, the composition or at least one of the components is a solid formulation, a semi-solid formulation, or a liquid formulation.
  • the components may have different forms, for example, may be in the form of a fluid, or at least one component may be in the form of a dry powder (e.g., a buffer component), or may be in the form of a fluid concentrate (e.g., an electrolyte concentrate).
  • the components in dry powder form are dissolved with a diluent prior to mixing with the other components, or the concentrate may be treated with a diluent in a ratio such as, but not limited to, 1:35, 1:45 or 1:200. dilution.
  • the two or more components are housed in different containers. In certain embodiments, the two or more components are kept separate from each other. In certain embodiments, the two or more components are respectively contained in two or more containers that are operably in fluid communication. When needed, these components can be mixed to configure the product to be used, such as a ready-to-use dialysis solution. Any suitable diluent can be used, such as sterile water, optionally without an electrolyte.
  • the kit further comprises a semi-permeable medium useful for biological fluid purification.
  • the application provides a dialysis device comprising a composition provided herein, and the device is configured to allow the composition to undergo osmotic exchange with a biological fluid to be dialyzed.
  • the dialysis device can be adapted for hemodialysis or peritoneal dialysis.
  • the dialysis device provided herein comprises: a first passageway for receiving biological fluid to be dialyzed, and a second passageway for containing the composition provided herein, and the first passageway A semi-permeable medium separated by a second passage.
  • the semi-permeable medium can allow the toxins in the biological fluid to be dialyzed to undergo osmotic exchange with the composition.
  • the dialysis device is disposable.
  • the dialysis device can be mounted to a dialysis machine and can be disassembled and discarded after completion of the dialysis process.
  • the dialysis machine can include various devices and components necessary for dialysis treatment, such as dialysis pumps, ultrafiltration pumps, proportional dosing devices, liquid thermostats, transmembrane pressure monitoring, conductivity monitoring, blood pumps, heparin pumps, arteriovenous One or more of pressure monitoring, bubble monitoring, blood leakage monitoring, displacement liquid balance scale, and double tube pump.
  • the dialysis device When the dialysis device is mounted to the dialysis machine, it can be configured to be operatively coupled to the dialysis host such that the biological fluid to be dialyzed enters the dialysis device into the first passage of the dialysis device for receiving biological fluid,
  • the osmotic exchange with the composition of the present application in the dialysis device is carried out by a semi-permeable medium in the dialysis device.
  • the biological fluid can be returned to the living body through the dialysis host after the osmotic exchange is completed.
  • the dialysis host can further have dedicated software that can control the course of dialysis (eg, temperature, pressure, addition of anticoagulant agents, etc.).
  • the dialysis device can be used in an artificial kidney (for example, see, for example, U.S. Patent No. 8,834,400, U.S. Patent No. 8,277,407, U.S. Patent No. 8,012,118, U.S. Patent No. 5,545,131, U.S. Patent No. 4,623,450). See, for example, U.S. Patent No. 9,650,609, U.S. Patent No. 9,775,863, the disclosure of which is incorporated herein by reference to U.S. Pat. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. Clear.
  • Artificial kidneys are a device that replaces kidney function and are used to help patients such as uremia. Mainly used to treat kidney failure and uremia. It extracts blood from the body by using dialysis, filtration, adsorption, membrane separation and other principles to eliminate excess nitrogen compounds, metabolic products or overdose drugs, regulate electrolyte balance and then lead the purified blood back to the body.
  • Artificial liver refers to the removal of various harmful substances produced or increased by liver failure by means of an in vitro mechanical, physicochemical or bioreactor device, supplementing essential substances such as proteins synthesized or metabolized by the liver, and improving the water, electrolytes and acid and alkali of patients. Balance and other internal environment, temporarily assist or replace the corresponding main functions of the liver, until autologous hepatocyte regeneration, liver function recovery, or improve the symptoms of patients with advanced liver disease, become a "bridge" for liver transplantation, improve patient survival.
  • Artificial lung also known as oxygenator or gas exchanger, is an artificial organ that replaces human lungs to emit carbon dioxide, ingest oxygen, and exchange gases.
  • the present application also provides a method of reducing toxins in a biological fluid.
  • the method of the present application may comprise: a) contacting the biological fluid with an osmotic solution containing the composition of the present application under conditions permitting osmotic exchange, and b) allowing the composition to reduce the toxin in the biological fluid The amount.
  • the methods provided herein are capable of reducing the free amount of toxins in a biological fluid to at most 50%, at most 40%, at most 30%, at most 20%, at most 10%, or at most 5 of the initial free amount. %. In certain embodiments, the methods provided herein are capable of reducing the total amount (or non-free amount) of toxins in a biological fluid by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, At least 60%, at least 70%, at least 80%, at least 90% or at least 95%. The total amount (or non-free amount) of toxins in the treated biological fluid is up to 90%, up to 80%, up to 70% prior to treatment compared to the biological fluid prior to treatment with the compositions provided herein. Up to 60%, up to 50%, up to 40%, up to 30%, up to 20%, up to 10%, or up to 5%.
  • the methods provided herein are capable of reducing the total amount (or free concentration, or non-free amount) of toxins in a biological fluid to a physiological benefit level.
  • physiological benefit level refers to a level that can reduce the risk of disease or reduce the symptoms of the organism due to toxins.
  • the toxin is freely present in the biological fluid, in combination with a substance in the biological fluid, or both. In certain embodiments, at least a portion of the toxin forms a reversible binding with a substance in the biological fluid. In certain embodiments, the binding of the toxin to a substance (eg, a protein) in the biological fluid has a Kd value of at least 10 5 to 10 7 ⁇ mol/L, 10 5.5 to 10 7 ⁇ mol/L, or 10 6 ⁇ 10 7 ⁇ mol/L. In certain embodiments, the toxins in the biological fluid are primarily present in a combined form.
  • At least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% of the biological fluid The toxin is present in a combined form. In certain embodiments, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% of the biological fluid
  • the toxin is present in a form that binds to plasma proteins.
  • the toxin is capable of reversibly binding to a protein in a biological fluid, such as, but not limited to, indophenol sulfate, asymmetric arginine, homocysteine, phenylacetic acid, para Phenol, AGE product (3-deoxyglucosone, fructose lysine, glyoxal, pyruvaldehyde, pentosidine), hippuric acid, uremic toxin, hydrogen sulfide, bilirubin and the like.
  • a biological fluid such as, but not limited to, indophenol sulfate, asymmetric arginine, homocysteine, phenylacetic acid, para Phenol, AGE product (3-deoxyglucosone, fructose lysine, glyoxal, pyruvaldehyde, pentosidine), hippuric acid, uremic toxin, hydrogen sulfide, bilirubin
  • the toxin in the biological fluid is transferred to the osmotic solution by osmotic exchange under conditions that permit osmotic exchange.
  • Permeation exchange is permitted herein to mean a difference in concentration of toxin between the biological fluid to be purified and the permeate solution comprising the composition of the present application, i.e., the concentration of the toxin in the biological fluid is higher than the concentration in the permeate solution.
  • an osmotic solution containing a composition of the present application can be used to purify a biological fluid, and toxins (and/or metabolic wastes) in the biological fluid by osmotic exchange of the substance between the osmotic solution and the biological fluid.
  • excess liquid is discharged to the osmotic solution.
  • the desired material in the biological fluid can also be transported from the osmotic solution to the biological fluid.
  • One common method of purifying biological fluids is dialysis, in which the toxin is diffused from the biological fluid through a semi-permeable medium into the osmotic solution by a concentration gradient of toxins between the biological fluid and the osmotic solution.
  • the osmotic solution is at least isotonic with the biological fluid.
  • the osmotic pressure of the osmotic solution is higher than the osmotic pressure of the biological fluid, which may allow moisture in the biological fluid to also be expelled from the biological fluid by osmotic diffusion.
  • step a) comprises placing the biological fluid and the composition on either side of a semi-permeable medium.
  • the semi-permeable medium is an artificial semipermeable membrane.
  • the artificial semipermeable membrane can be made of any suitable material such as, but not limited to, ceramics, graphite, metals, metal oxides, and polymers.
  • the artificial semipermeable membrane can be made from a polymer selected from the group consisting of polysulfones, polyamides, polycarbonates, polyesters, acrylonitrile polymers, vinyl alcohol polymers, acrylate polymers, A methacrylate polymer, a cellulose acetate polymer, and the like.
  • the semi-permeable medium is a bio-permeable membrane.
  • the biological semipermeable membrane may be a vascular wall membrane, a lymphatic wall membrane, a peritoneum, a lung membrane, a glandular capsule, and a mucosa (for example, an oral mucosa, a nasal mucosa, a gastric mucosa, an intestinal mucosa, a vaginal mucosa).
  • the biological fluid is in the body of an individual.
  • the biological fluid in the body can be blood in the blood circulation system of the body (for example, in the case of peritoneal dialysis), lymph in the lymphatic system, etc., or can be transported to the body in circulation with the circulation system of the body and then returned to the body.
  • Biological fluids in the body can include, for example, blood, lymph, and the like in the living body.
  • the biological fluid within the subject can be directly osmotically exchanged (eg, peritoneal dialysis) with the osmotic solution in vivo.
  • the biological fluid in the individual can be exported to the body, in vitro exchanged with the osmotic solution, and after the toxin is removed, and then introduced into the body (eg, hemodialysis).
  • blood in hemodialysis, blood can be withdrawn from a living body and purified in an extracorporeal blood circuit, and then the purified blood can be returned to the living body.
  • the blood flows on one side of the semipermeable membrane, and the permeate solution flows on the other side of the semipermeable membrane.
  • toxins in the blood and optionally various harmful and redundant metabolic wastes and excess electrolyte
  • excess fluid in the blood creates a transmembrane pressure differential across the semipermeable membrane that can be transported through the semipermeable membrane to the permeate solution by ultrafiltration.
  • a peritoneum of a living body such as a human body or an animal can be utilized as a semipermeable membrane, thereby purifying blood in a living body.
  • a sterile osmotic solution in the method of the present application can be introduced into the abdominal cavity by a catheter, and solute exchange between the osmotic solution and the blood is allowed for a sufficient time to remove toxins from the blood in the living body.
  • the flow of liquid is achieved to allow water to flow out of the blood by providing a suitable osmotic gradient from the permeate solution to the blood. This enables a suitable acid-base, electrolyte and fluid balance in the blood.
  • peritoneal dialysis After a period of time, the permeate solution is drained from the body cavity through the catheter.
  • peritoneal dialysis examples include continuous ambulatory peritoneal dialysis, automated peritoneal dialysis, and continuous flow peritoneal dialysis.
  • the step a) comprises administering the osmotic solution to the individual by intraperitoneal perfusion.
  • the peritoneum in the body acts as a semi-permeable medium.
  • the step a) comprises administering the osmotic solution to the individual by hemodialysis.
  • the biological fluid is in vitro.
  • the biological fluid in vitro comprises a fluid that does not form a fluid pathway with the biological fluid in the body.
  • the in vitro biological fluid can be a blood sample taken from an organism, or a treated blood product or biological product. By removing toxins (eg, blood products, biological products, etc.) from biological fluids outside the body of the individual, the biological fluid can be purified for subsequent application purposes.
  • biological fluids in vitro include, but are not limited to, whole blood, warm blood or cold blood, cord blood, and stored or fresh blood, treated blood, such as with at least one physiological solution (including but not limited to saline, nutrients) , additives and / or anticoagulant solutions) diluted blood, blood components (such as platelet concentrate (PC), platelet rich plasma (PRP), platelet poor plasma (PPP), platelet-free plasma, plasma, fresh Frozen plasma (FFP), plasma-derived components, hematocrit (PRC), transition zone material or buffy coat (BC), blood or blood components or bone marrow-derived blood products, stem cells, cell culture a physiological solution containing a bone marrow aspirate or the like.
  • PC platelet concentrate
  • PRP platelet rich plasma
  • PPP platelet poor plasma
  • FFP fresh Frozen plasma
  • PRC hematocrit
  • PC transition zone material or buffy coat
  • blood or blood components or bone marrow-derived blood products stem cells, cell culture a physiological solution
  • the present application is also a method of treating or preventing a disease or condition associated with a toxin comprising contacting a composition of the present application with a biological fluid of the individual under conditions permitting osmotic exchange to reduce The toxin in the biological fluid.
  • the present application also provides the use of a composition provided herein in the manufacture of a medicament for the treatment or prevention of a disease or condition associated with a toxin.
  • the composition reduces the toxin in a biological fluid in an individual.
  • a biological fluid e.g., blood
  • the presence or excess of the presence of such toxins can adversely affect the physiological function of the individual, such as causing metabolic dysfunction, and/ Or affect a variety of organs and organ systems, such as the cardiovascular system (hypertension, pericarditis and heart failure), peripheral nervous system (polyneuropathy), bone and joint system, central nervous system (memory, loss of concentration and slower Heart intelligence), blood system (anemia, bleeding tendency, blood coagulation, immune status (immunosuppression)), etc.
  • kidney disease eg, uremia, renal insufficiency, etc.
  • cardiovascular and cerebrovascular disease e.g., blood disease (eg, anemia, bleeding tendency, coagulation, etc.), autologous Immune diseases (autoimmune, immunosuppression, etc.), metabolic diseases (hyperlipidemia, diabetes, etc.), orthopedic diseases, digestive diseases (such as hepatobiliary diseases), overdose or poisoning.
  • blood disease eg, anemia, bleeding tendency, coagulation, etc.
  • autologous Immune diseases autoimmune, immunosuppression, etc.
  • metabolic diseases hyperlipidemia, diabetes, etc.
  • orthopedic diseases such as hepatobiliary diseases
  • Toxins associated with the above diseases include, but are not limited to, urea, creatinine, uric acid, strontium-ADMA, ⁇ 2-microglobulin, cytokines, parathyroid hormone, sulphate, homocysteine, para Phenol, hippuric acid, reactive oxygen species (ROS), uremic toxins (eg AGE products (3-deoxyglucosone, fructose lysine, glyoxal, pyruvaldehyde, pentosidine), 1-methyl gland Glycosides, 1-methylguanosine, 1-methylinosine, asymmetric dimethylarginine, ⁇ -keto- ⁇ -valeric acid, ⁇ -N-acetylarginine, arabitol, Arginine, benzyl alcohol, ⁇ -mercaptopropionic acid, ⁇ -lipotropin, creatine, cytidine, sodium N,N-dimethylglycine, erythritol,
  • Treatment includes any improvement in the disease or state of health, such as curing, alleviating symptoms, reducing the severity of the disease, delaying the progression of the disease, and improving the quality of life of the patient.
  • prevention includes reducing the risk of developing a disease and delaying the onset of the disease.
  • kidney disease can be treated or prevented by reducing one or more of the toxins described above in the biological fluid.
  • nephropathy that can be treated or prevented may be selected from the group consisting of uremia, chronic kidney disease, acute renal insufficiency, chronic pyelonephritis, acute pyelonephritis, chronic glomerulonephritis, acute progressive nephritic syndrome, nephrotic syndrome, Renal sclerosis, interstitial nephritis, diabetic nephropathy, focal glomerulosclerosis, membranous nephropathy, multiple purulent renal syndrome, renal vascular hypertension and hypertension syndrome, secondary nephropathy, Hyperphosphatemia, hyperkalemia, hyperuricemia or hypernatremia.
  • Icomodextrin peritoneal dialysate Baxter Baxter Idonau peritoneal dialysate, icodextrin content of 7.5%, indicating osmotic pressure of 284osmmol / Kg.
  • Glucose peritoneal dialysate Baxter Baxter low calcium peritoneal dialysate, lactate-G 1.5%, containing 1.5% glucose, indicating osmotic pressure of 343osmmol / Kg.
  • Nano-carbon powder Nano-carbon suspension injection produced by Chongqing Laimei Pharmaceutical Co., Ltd. under the trade name of Carnaline
  • Micronized silica gel Coated silica produced by Merck & Co., Ltd., product number 120091
  • Diatomaceous earth diatomaceous earth for biological use of Heilongjiang Fenghao Mining Investment Co., Ltd. (wherein silica content is 92.8%, specific surface area is 78-84 m 2 /g, pore volume cumulative volume is 0.25 cm 3 /g, average pore diameter It is 12nm.)
  • Freezing point reduction method The osmolality is determined by measuring the drop in the freezing point of the solution.
  • High performance liquid chromatography using an Agilent C18 reverse phase column with a column temperature of 25 ° C, a mobile phase of 25% by volume of acetonitrile and 75% by volume of an aqueous solution containing 0.1% trifluoroacetic acid at a flow rate of 1 ml. /min, the injection volume was 10 ⁇ l, and the ruthenium sulfate was detected using a fluorescence detector having an excitation wavelength of 295 nm and an emission wavelength of 360 nm. The analysis time was 10 minutes, and the peak time was 3.8-4.0 minutes.
  • Biochemical analyzer test The biochemical analyzer is used to measure the creatinine and urea nitrogen content of body fluids (blood or other body fluids).
  • Example 2 Effect of the amount of toxin removal reagent on the osmotic pressure of different peritoneal dialysate
  • Example 2-1 icodextrin peritoneal dialysate (wt% by weight to volume) added with different amounts of toxin removal reagent
  • the osmotic pressure of the peritoneal dialysate obtained by adding different amounts of the toxin removal reagent was measured by the freezing point reduction method.
  • the osmotic pressure slightly increased as the amount of addition increased.
  • the permeation pressure of the peritoneal dialysate obtained by adding different amounts of the toxin removal reagent as above was in accordance with the requirements of the peritoneal dialysate.
  • the amount of toxin removal reagent can be controlled to less than 0.25%.
  • Example 2-2 Glucose peritoneal dialysate with different amounts of toxin removal reagent added
  • the osmotic pressure of the peritoneal dialysate obtained by adding different amounts of the toxin removal reagent was measured by the freezing point reduction method.
  • the osmotic pressure slightly increased with the addition amount.
  • the permeation pressure of the peritoneal dialysate obtained by adding different amounts of the toxin removal reagent as above was in accordance with the requirements of the peritoneal dialysate.
  • the amount of toxin removal reagent can be controlled to less than 0.25%.
  • peritoneal dialysate with different amounts of toxin removal reagent still meets the requirements of peritoneal dialysate and can be used for peritoneal dialysis.
  • Example 3-1 Construction of a rat model of renal failure by cisplatin method
  • Rats were divided into groups. The positive control group was treated with basal peritoneal dialysate supplemented with 2.5 mg/L dopamine (DA). The negative control group was rats without peritoneal dialysis treatment, and the blank control group was only used. Rats treated with peritoneal dialysate, the experimental group were rats treated with basal peritoneal dialysate supplemented with different amounts of toxin removal reagent. During peritoneal dialysis, the peritoneal dialysate was infused into the peritoneal cavity of the rats at a dose of 80 ml/kg body weight, and blood was taken from the tail vein at 1 , 2, 4, and 8 hours, and the peritoneal effusion was taken. analysis.
  • DA dopamine
  • the blood was taken from the tail vein by taking 0.5 ml of blood from each tail vein into a 1.5 ml volume EP tube containing 20 ⁇ l of 1% heparin physiological saline solution.
  • the blood sample taken was centrifuged at 3000 rpm for 10 minutes, 100 ⁇ l of the supernatant was taken and 300 ⁇ l of methanol was added, vortexed for 10 seconds, then centrifuged at 10,000 rpm for 10 minutes, 100 ⁇ l of the supernatant was taken and 300 ⁇ l of methanol was added, and the vortex was added.
  • Example 3-3 icodextrin peritoneal dialysate supplemented with different amounts of toxin removal reagent
  • Peritoneal dialysis was performed on rats in the experimental group, the positive control group, the blank control group, and the negative control group according to the method described in Example 3-2, and the toxin in the tail vein blood and peritoneal effusion (Urea nitrogen (BUN) was tested. ), creatinine (CREA2) and indophenol (IS) content.
  • BUN peritoneal effusion
  • CREA2 creatinine
  • IS indophenol
  • Figures 1(a)-(f) show the blood urea nitrogen in the experimental group listed in Table 3 and the corresponding positive control group (ICO+DA), blank control group (ICO) and negative control group. Removal results.
  • Figure 1 (a) shows the removal of urea nitrogen in the blood of icodextrin peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that the experimental group 1 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight and 0.25% by weight of nanocarbon powder was used compared to the blank control group treated only with icodextrin peritoneal dialysate. 3 and 1-4 showed a significant decrease in urea nitrogen content, while experimental groups 1-1 and 1-2 treated with icodextrin peritoneal dialysate supplemented with 0.005 wt% and 0.01 wt% of nanocarbon powder were not shown. Significant reduction in urea nitrogen content.
  • Figure 1 (b) shows the results of removal of urea nitrogen in the blood of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight and 0.25% by weight of Kollidon CL-SF was used compared to the blank control group treated only with icodextrin peritoneal dialysate. -1 and 2-2 showed a significant decrease in urea nitrogen content, and the higher the Kollidon CL-SF content, the more the urea nitrogen content decreased.
  • Figure 1 (c) shows the results of removal of urea nitrogen in the blood of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight and 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with icodextrin peritoneal dialysate. -1 and 3-2 showed a significant decrease in urea nitrogen content, and the higher the Kollidon CL-M content, the more the urea nitrogen content decreased.
  • Figure 1 (d) shows the results of removal of urea nitrogen in the blood of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental group treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Soluplus was used compared to the blank control group treated only with icodextrin peritoneal dialysate.
  • 4-1, 4-2 and 4-3 show a significant reduction in urea nitrogen content, and only a 0.01% by weight of Soluplus can be added to achieve a significant reduction in urea nitrogen, but continue to increase the Souplus content to 0.25 wt%, urea The effect of reducing nitrogen content was not significantly improved.
  • Figure 1 (e) shows the results of removal of urea nitrogen in the blood of icodextrin peritoneal dialysate supplemented with different amounts of micronized silica gel. It can be seen that the experiment using icodextrin peritoneal dialysate added with 0.01% by weight, 0.05% by weight, and 0.1% by weight of micronized silica gel was used compared to the blank control group treated only with icodextrin peritoneal dialysate.
  • Groups 5-1, 5-2 and 5-3 showed a significant decrease in urea nitrogen content, and only a 0.01% by weight of micronized silica gel was added to achieve a significant reduction in urea nitrogen, but continued to increase the content of micronized silica to 0.1 weight. %, the effect of reducing the urea nitrogen content was not significantly improved.
  • Figure 1 (f) shows the results of removal of urea nitrogen in the blood of icodextrin peritoneal dialysate supplemented with different amounts of diatomaceous earth. It can be seen that compared with the blank control group treated only with icodextrin peritoneal dialysate, icodextrin peritoneal dialysate treated with 0.01% by weight, 0.05% by weight, and 0.1% by weight of diatomaceous earth was used. Experimental groups 6-1, 6-2, and 6-3 showed significant reductions in urea nitrogen content, and only 0.01% by weight of diatomaceous earth was added to achieve significant urea nitrogen reduction, but continued to increase diatomaceous earth content. Up to 0.1% by weight, the urea nitrogen content reduction effect was not significantly improved.
  • Figures 2(a)-(f) show creatinine in the blood of the experimental group listed in Table 3 and the corresponding positive control group (ICO+DA), blank control group (ICO) and negative control group. Remove the result.
  • Figure 2 (a) shows the removal of creatinine in the blood of icodextrin peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that the experimental groups 1-1 to 1-4 treated with the icodextrin peritoneal dialysate to which the test content of the nanocarbon powder was added were compared to the blank control group treated only with the icodextrin peritoneal dialysate. None of them showed a significant reduction in creatinine content.
  • Figure 2(b) shows the removal of creatinine in the blood of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2-1 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight of Kollidon CL-SF was not shown compared to the blank control group treated only with icodextrin peritoneal dialysate. A significant creatinine reduction effect was observed, whereas the experimental group 2-2 treated with icodextrin peritoneal dialysate supplemented with 0.25 wt% of Kollidon CL-SF showed a significant decrease in creatinine content during the first 4 hours.
  • Figure 2(c) shows the removal of creatinine in the blood of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3-1 treated with the icodextrin peritoneal dialysate supplemented with 0.025% by weight of Kollidon CL-M was not shown compared to the blank control group treated only with icodextrin peritoneal dialysate. A significant creatinine reduction effect was observed, whereas the experimental group 3-2 treated with icodextrin peritoneal dialysate supplemented with 0.25% by weight of Kollidon CL-SF showed a significant decrease in creatinine content during the first 4 hours.
  • Figure 2 (d) shows the results of removal of creatinine in the blood of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental group treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Soluplus was used compared to the blank control group treated only with icodextrin peritoneal dialysate. 4-1, 4-2, and 4-3 showed a significant decrease in creatinine content, and only a 0.01% by weight of Soluplus was added to achieve significant creatinine reduction, but continued to increase Soluplus content to 0.25 wt%, creatinine content The reduction effect has not been significantly improved.
  • Fig. 2(e) shows the results of removal of creatinine in blood of icodextrin peritoneal dialysate supplemented with different amounts of micronized silica gel. It can be seen that the experiment using icodextrin peritoneal dialysate added with 0.01% by weight, 0.05% by weight, and 0.1% by weight of micronized silica gel was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Groups 5-1, 5-2, and 5-3 showed a significant decrease in creatinine content, and only a 0.01% by weight of micronized silica gel was added to achieve significant creatinine reduction, but continued to increase the content of microsilica gel to 0.1% by weight. The effect of reducing creatinine content was not significantly improved.
  • Fig. 2(f) shows the results of removal of creatinine in blood of icodextrin peritoneal dialysate supplemented with different amounts of diatomaceous earth. It can be seen that compared with the blank control group treated only with icodextrin peritoneal dialysate, icodextrin peritoneal dialysate treated with 0.01% by weight, 0.05% by weight, and 0.1% by weight of diatomaceous earth was used. Experimental groups 6-1, 6-2, and 6-3 showed significant reduction in creatinine content, and only 0.01% by weight of diatomaceous earth was added to achieve significant creatinine reduction, but continued to increase diatomaceous earth content to 0.1. The weight % and urea nitrogen content reduction effect were not significantly improved.
  • Figures 3(a)-(f) show barium sulphate in the blood of the experimental group listed in Table 3 and the corresponding positive control group (ICO+DA), blank control group (ICO) and negative control group. The result of the removal of indophenol.
  • Figure 3 (a) shows the removal of indole sulfate in the blood of icodextrin peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that the icodextrin peritoneum added with 0.005 wt%, 0.1 wt%, 0.02 wt% or 0.25% by weight of nanocarbon powder was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Experimental groups 1-1 to 1-4 of dialysate treatment showed a significant decrease in the content of indole sulfate, especially after 2 hours of treatment; and the content of indole sulfate continued to remain low. The addition of different amounts (0.005 wt%, 0.1 wt%, 0.02 wt% or 0.25% by weight) of the nanocarbon powder showed a similar reduction effect of indole sulfate.
  • Figure 3 (b) shows the removal of indole sulfate in the blood of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight or 0.25% by weight of Kollidon CL-SF was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Both -1 and 2-2 showed a significant decrease in the content of indole sulfate and the indole sulfate content remained low. The addition of different amounts (0.025% by weight or 0.25% by weight) of Kollidon CL-SF showed a similar reduction effect of indole sulfate.
  • Figure 3(c) shows the removal of indole sulfate in the blood of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight or 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Both -1 and 3-2 showed a significant decrease in the content of indole sulfate and the indole sulfate content remained low. The addition of different amounts (0.025% by weight or 0.25% by weight) of Kollidon CL-M showed a similar reduction effect of indole sulfate.
  • Figure 3 (d) shows the results of removal of indole sulfate in blood of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental group treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Soluplus was used compared to the blank control group treated only with icodextrin peritoneal dialysate.
  • Fig. 3(e) shows the results of removal of indole sulfate in the blood of icodextrin peritoneal dialysate to which different amounts of micronized silica gel were added. It can be seen that the experiment using icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.1% by weight of micronized silica gel was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Groups 5-1, 5-2, and 5-3 all showed significant reduction in the content of indole sulfate and the indole sulfate content continued to remain low. The addition of different amounts (0.01% by weight, 0.05% by weight or 0.1% by weight) of the micronized silica gel showed a similar effect of reducing the indophenol sulfate.
  • Fig. 3(f) shows the results of removal of indole sulfate in blood of icodextrin peritoneal dialysate to which different amounts of diatomaceous earth were added. It can be seen that compared with the blank control group treated only with icodextrin peritoneal dialysate, treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.1% by weight of diatomaceous earth Experimental groups 5-1, 5-2, and 5-3 all showed significant reduction in the content of indole sulfate, and the content of indole sulfate continued to remain low. The addition of different amounts (0.01% by weight, 0.05% by weight or 0.1% by weight) of diatomaceous earth showed a similar effect of reducing the indophenol sulfate.
  • Figures 4(a)-(f) show the urea in the peritoneal fluid for the experimental groups listed in Table 3 and the corresponding positive control (ICO+DA), blank control (ICO), and negative control rats. The nitrogen content changes.
  • Figure 4 (a) shows the change in urea nitrogen content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that compared with the blank control group treated only with icodextrin peritoneal dialysate, icodextrin peritoneal dialysate treated with 0.005 wt%, 0.1 wt% or 0.02 wt% of nanocarbon powder was used. Experimental groups 1-1 to 1-3 all showed an increase in urea nitrogen content, but experimental groups 1-4 treated with icodextrin peritoneal dialysate supplemented with 0.25 wt% of nanocarbon powder showed urea nitrogen content. reduce.
  • Figure 4 (b) shows the change in urea nitrogen content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2-1 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight of Kollidon CL-SF was used before the blank control group treated only with icodextrin peritoneal dialysate. Within 2 hours, the urea nitrogen content was significantly increased, while the experimental group 2-2 treated with the icodextrin peritoneal dialysate supplemented with 0.25% by weight of Kollidon CL-SF showed a significant decrease in the urea nitrogen content.
  • Figure 4(c) shows the change in urea nitrogen content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3-1 treated with the icodextrin peritoneal dialysate supplemented with 0.025% by weight of Kollidon CL-M was shown compared to the blank control group treated only with icodextrin peritoneal dialysate. The similar urea nitrogen content changed, while the experimental group 3-2 treated with the icodextrin peritoneal dialysate supplemented with 0.25 wt% of Kollidon CL-M showed a significant decrease in the urea nitrogen content.
  • Figure 4 (d) shows the change in urea nitrogen content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental group treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Soluplus was used compared to the blank control group treated only with icodextrin peritoneal dialysate. 4-1 to 4-3 all showed significant reductions in urea nitrogen content, but there was no significant difference between the three experimental groups.
  • Figure 4 (e) shows the change in urea nitrogen content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of micronized silica gel. It can be seen that the experimental group 5-1 treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight or 0.1% by weight of micronized silica gel was used compared to the blank control group treated only with icodextrin peritoneal dialysate.
  • Both 5 and 5-3 showed a decrease in the urea nitrogen content, while the experimental group 5-2 treated with the icodextrin peritoneal dialysate to which 0.05% by weight of the micronized silica gel was added showed a significant increase in the urea nitrogen content.
  • Figure 4 (f) shows the change in urea nitrogen content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with varying amounts of diatomaceous earth. It can be seen that compared with the blank control group treated only with icodextrin peritoneal dialysate, treatment with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.1% by weight of diatomaceous earth was used. Experimental groups 6-1 to 6-3 all showed significant reductions in urea nitrogen content, but there was no significant difference between the three experimental groups.
  • Figures 5(a)-(f) show creatinine in peritoneal fluid for the experimental groups listed in Table 3 and the corresponding positive control (ICO+DA), blank control (ICO), and negative control rats. The content changes.
  • Figure 5 (a) shows the change in creatinine content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that icodextrin peritoneum was added using 0.005 wt%, 0.1 wt%, 0.02 wt%, and 0.25 wt% of nanocarbon powder compared to the blank control group treated only with icodextrin peritoneal dialysate. Experimental groups 1-1 to 1-4 of dialysate treatment showed an increase in creatinine content.
  • Figure 5 (b) shows the change in creatinine content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight or 0.25% by weight of Kollidon CL-SF was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Both -1 and 2-2 showed a significant increase in creatinine content.
  • Figure 5 (c) shows the change in creatinine content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight or 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Both -1 and 3-2 showed a significant increase in creatinine content.
  • Figure 5 (d) shows the change in creatinine content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental group treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Soluplus was used compared to the blank control group treated only with icodextrin peritoneal dialysate. 4-1 to 4-3 did not show significant differences.
  • Figure 5 (e) shows the change in creatinine content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of micronized silica gel. It can be seen that the experimental group 5-1 treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight or 0.1% by weight of micronized silica gel was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Both 5 and 5-3 showed a significant decrease in creatinine content, whereas the experimental group 5-2 treated with icodextrin peritoneal dialysate supplemented with 0.05% by weight of micronized silica gel showed no significant difference.
  • Figure 5 (f) shows the change in creatinine content in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with varying amounts of diatomaceous earth. It can be seen that compared with the blank control group treated only with icodextrin peritoneal dialysate, treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.1% by weight of diatomaceous earth Experimental groups 6-1 to 6-3 all showed a decrease in creatinine content, but there was no significant difference between the three experimental groups.
  • Figures 6(a)-(f) show the sulfuric acid in the peritoneal fluid for the experimental groups listed in Table 3 and the corresponding positive control (ICO+DA), blank control (ICO), and negative control rats. The content of indophenol is changed.
  • Figure 6 (a) shows the change in the content of indole sulfate in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that icodextrin peritoneum was added using 0.005 wt%, 0.1 wt%, 0.02 wt%, and 0.25 wt% of nanocarbon powder compared to the blank control group treated only with icodextrin peritoneal dialysate. Experimental groups 1-1 to 1-4 of dialysate treatment showed a decrease in the content of indole sulfate.
  • Figure 6 (b) shows the change in the content of indole sulfate in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight or 0.25% by weight of Kollidon CL-SF was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Both -1 and 2-2 showed a significant decrease in the content of indole sulfate, but there was no significant difference between the two experimental groups.
  • Figure 6(c) shows the change in the content of indole sulfate in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3 treated with icodextrin peritoneal dialysate supplemented with 0.025% by weight or 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Both -1 and 3-2 showed significant reduction in the content of indole sulfate, but there was no significant difference between the two experimental groups.
  • Figure 6 (d) shows the change in the content of indole sulfate in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental group treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Soluplus was used compared to the blank control group treated only with icodextrin peritoneal dialysate.
  • Figure 6 (e) shows the change in the content of indole sulfate in the peritoneal fluid of icodextrin peritoneal dialysate supplemented with different amounts of micronized silica gel. It can be seen that the experiment using icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.1% by weight of micronized silica gel was used compared to the blank control group treated only with icodextrin peritoneal dialysate. Groups 5-1 to 5-3 all showed significant reduction in the content of indole sulfate, but there was no significant difference between the three experimental groups.
  • Fig. 6(f) shows the change in the content of indole sulfate in the peritoneal fluid of icodextrin peritoneal dialysate to which different amounts of diatomaceous earth were added. It can be seen that compared with the blank control group treated only with icodextrin peritoneal dialysate, treated with icodextrin peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.1% by weight of diatomaceous earth Experimental groups 6-1 to 6-3 showed a decrease in the content of indole sulfate within 8 hours, of which there was no significant difference between the three experimental groups in the first 4 hours, and from the fourth From the hour on, the experimental group 6-3 showed a significant increase in the content of indole sulfate.
  • Example 3-3 Glucose peritoneal dialysate with different amounts of toxin removal reagent added
  • Peritoneal dialysis was performed on rats in the experimental group, the blank control group, and the negative control group according to the method described in Example 3-2, and the toxins (urea nitrogen (BUN), creatinine (in the tail vein blood and peritoneal effusion) were tested. CREA2) and indophenol (IS) content.
  • Figures 7(a)-(f) show the results of removal of urea nitrogen in the blood for the experimental groups listed in Table 4 and the corresponding blank control group (GLU) and the negative control group.
  • Figure 7 (a) shows the results of removal of urea nitrogen in the blood of glucose peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that the experimental groups 1-1 and 1-2 treated with the glucose peritoneal dialysate supplemented with 0.01% by weight and 0.05% by weight of the nanocarbon powder were displayed as compared with the blank control group treated only with the glucose peritoneal dialysate. Significant reduction in urea nitrogen content was observed, whereas experimental groups 1-3 treated with glucose peritoneal dialysate supplemented with 0.25 wt% of nanocarbon powder showed no significant reduction in urea nitrogen content during the first 2 hours, while at 2 After a few hours, it began to show a certain reduction in urea nitrogen content.
  • Figure 7 (b) shows the results of removal of urea nitrogen in the blood of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Kollidon CL-SF was used compared to the blank control group treated only with glucose peritoneal dialysate. 2-3 showed a significant decrease in urea nitrogen content, while the experimental group 2-3 treated with glucose peritoneal dialysate supplemented with 0.25 wt% of Kollidon CL-SF began to show urea nitrogen content after 4 hours. The rise.
  • Figure 7(c) shows the results of removal of urea nitrogen in the blood of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with glucose peritoneal dialysate. All of the 3-3 showed a significant decrease in urea nitrogen content, but there was no significant difference between the three experimental groups.
  • Figure 7 (d) shows the results of removal of urea nitrogen in the blood of glucose peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental groups 4-1 to 4- treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Soluplus were used as compared to the blank control group treated only with the glucose peritoneal dialysate. 3 showed a significant decrease in urea nitrogen content, but there was no significant difference between the three experimental groups.
  • Fig. 7(e) shows the results of removal of urea nitrogen in the blood of glucose peritoneal dialysate to which different amounts of micronized silica gel were added. It can be seen that the experimental groups 5-1 to 5 treated with the glucose peritoneal dialysate added with 0.01% by weight, 0.05% by weight, and 0.25% by weight of the micronized silica gel were compared to the blank control group treated only with the glucose peritoneal dialysate. -3 showed a significant decrease in urea nitrogen content, and experimental group 5-1 to which 0.01% by weight of micronized silica gel was added showed the best urea nitrogen lowering effect.
  • Fig. 7(f) shows the results of removal of urea nitrogen in the blood of glucose peritoneal dialysate to which different amounts of diatomaceous earth were added. It can be seen that the experimental group 6-1 treated with the glucose peritoneal dialysate added with 0.01% by weight, 0.05% by weight, and 0.25% by weight of diatomaceous earth was used as compared to the blank control group treated only with the glucose peritoneal dialysate. Both 6-3 showed a significant decrease in the urea nitrogen content, and the experimental group 6-3 to which 0.25 wt% of the fine powder silica gel was added showed the best urea nitrogen lowering effect.
  • Figures 8(a)-(f) show the results of removal of creatinine in the blood for the experimental groups listed in Table 4 and the corresponding blank control group (GLU) and the negative control group.
  • Fig. 8(a) shows the results of removal of creatinine in blood of glucose peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that the experimental groups 1-2 and 1-3 treated with the glucose peritoneal dialysate supplemented with 0.05% by weight and 0.25% by weight of the nanocarbon powder were compared to the blank control group treated only with the glucose peritoneal dialysate. Significant differences were shown, while experimental group 1-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight of nanocarbon powder showed a significant decrease in creatinine content.
  • Figure 8(b) shows the results of removal of creatinine in the blood of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Kollidon CL-SF was used compared to the blank control group treated only with glucose peritoneal dialysate. All of the 2-3 showed a significant decrease in creatinine content, but there was no significant difference between the three experimental groups.
  • Figure 8(c) shows the results of removal of creatinine in the blood of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with glucose peritoneal dialysate. All of the 3-3 showed a significant decrease in creatinine content, but there was no significant difference between the three experimental groups.
  • Figure 8 (d) shows the results of removal of creatinine in the blood of glucose peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental groups 4-1 to 4- treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Soluplus were used as compared to the blank control group treated only with the glucose peritoneal dialysate. 3 showed a significant decrease in creatinine content, and the creatinine removal effects of the experimental groups 4-1 and 4-3 to which 0.01% by weight and 0.25% by weight of Soluplus were added were similar, and the experimental group 4-added with 0.05% by weight of Soluplus 2 is better than creatinine removal.
  • Fig. 8(e) shows the results of removal of creatinine in the blood of glucose peritoneal dialysate to which different amounts of micronized silica gel were added. It can be seen that the experimental groups 5-1 to 5 treated with the glucose peritoneal dialysate added with 0.01% by weight, 0.05% by weight, and 0.25% by weight of the micronized silica gel were compared to the blank control group treated only with the glucose peritoneal dialysate. -3 showed a significant decrease in creatinine content, and experimental group 5-1 in which 0.01% by weight of micronized silica gel was added showed the best creatinine removal effect.
  • Fig. 8(f) shows the results of removal of creatinine in the blood of glucose peritoneal dialysate to which different amounts of diatomaceous earth were added. It can be seen that the experimental group 6-1 treated with the glucose peritoneal dialysate added with 0.01% by weight, 0.05% by weight, and 0.25% by weight of diatomaceous earth was used as compared to the blank control group treated only with the glucose peritoneal dialysate. Both 6-3 showed a significant decrease in creatinine content, but there was no significant difference between the three experimental groups.
  • Figures 9(a)-(f) show the results of removal of indole sulfate in the blood of the experimental group listed in Table 4 and the corresponding blank control group (GLU) and the negative control group.
  • Fig. 9(a) shows the results of removal of indole sulfate in blood of glucose peritoneal dialysate supplemented with different amounts of nanocarbon powder. It can be seen that the experimental group 1-1 treated with the glucose peritoneal dialysate added with 0.01% by weight, 0.05% by weight, and 0.25% by weight of the nanocarbon powder was compared to the blank control group treated only with the glucose peritoneal dialysate. Both 1-3 showed a significant decrease in the content of indole sulfate, but there was no significant difference between the three experimental groups.
  • Figure 9(b) shows the results of removal of creatinine in the blood of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2-2 treated with the glucose peritoneal dialysate supplemented with 0.05% by weight of Kollidon CL-SF showed no significant difference compared to the blank control group treated only with the glucose peritoneal dialysate, but added Experimental groups 2-1 and 2-3 treated with 0.01% by weight and 0.25% by weight of Hollidon CL-SF glucose peritoneal dialysate showed significant reduction in indole sulfate content, and there was no difference between the two experimental groups. obvious difference.
  • Fig. 9(c) shows the results of removal of indole sulfate in blood of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with glucose peritoneal dialysate. All of the 3-3 showed a significant decrease in the content of indole sulfate, but there was no significant difference between the three experimental groups.
  • Fig. 9(d) shows the results of removal of indole sulfate in blood of glucose peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental groups 4-1 to 4- treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight, and 0.25% by weight of Soluplus were used as compared to the blank control group treated only with the glucose peritoneal dialysate.
  • Fig. 9(e) shows the results of removal of indole sulfate in blood of glucose peritoneal dialysate to which different amounts of micronized silica gel were added. It can be seen that the experimental groups 5-1 to 5 treated with the glucose peritoneal dialysate added with 0.01% by weight, 0.05% by weight, and 0.25% by weight of the micronized silica gel were compared to the blank control group treated only with the glucose peritoneal dialysate. -3 showed a significant decrease in the content of indole sulfate, and the removal of the indole sulfate of the experimental group 5-1 in which 0.01% by weight of the micronized silica gel was added was the best.
  • Fig. 9(f) shows the results of removal of creatinine in the blood of glucose peritoneal dialysate to which different amounts of diatomaceous earth were added. It can be seen that the experimental group 6-1 treated with the glucose peritoneal dialysate added with 0.01% by weight of diatomaceous earth showed no significant difference compared to the blank control group treated only with the glucose peritoneal dialysate, but added Experimental groups 6-2 and 6-3 treated with 0.05% by weight and 0.25% by weight of diatomaceous earth glucose peritoneal dialysate showed significant reduction in indole sulfate content, and there was no significant difference between the two experimental groups. difference.
  • Figures 10(a)-(f) show changes in the content of urea nitrogen in the peritoneal fluid for the experimental groups listed in Table 4 and the corresponding blank control group (GLU) and the negative control group.
  • Figure 10 (a) shows the change in urea nitrogen content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that the experimental group 1-1 treated with the glucose peritoneal dialysate added with 0.01% by weight, 0.05% by weight or 0.25% by weight of the nanocarbon powder was compared to the blank control group treated only with the glucose peritoneal dialysate. 1-3 showed an increase in the urea nitrogen content, and the experimental group 1-2 in which 0.05% by weight of the nano carbon powder was added showed the largest increase in the urea nitrogen content, and the experimental group 1 in which 0.25 wt% of the nano carbon powder was added was added. -3 times, the experimental group 1-1 in which 0.01% by weight of the nano carbon powder was added was again.
  • Figure 10 (b) shows the change in urea nitrogen content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Kollidon CL-SF was used compared to the blank control group treated only with glucose peritoneal dialysate. Up to 2-3 showed an increase in urea nitrogen content. The three experimental groups showed no significant difference in the first 4 hours, but after 4 hours, 0.01% and 0.05% by weight of Kollidon CL-SF was added. Groups 2-1 and 2-2 showed a significant decrease in the urea nitrogen content until it was close to the urea nitrogen level of the negative control group.
  • Figure 10 (c) shows the change in urea nitrogen content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with glucose peritoneal dialysate. Up to 3-3 showed an increase in the urea nitrogen content, but there was no significant difference between the three experimental groups.
  • Figure 10 (d) shows the change in urea nitrogen content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental groups 4-1 to 4- treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Soluplus were compared to the blank control group treated only with glucose peritoneal dialysate. 3 The increase of urea nitrogen content was observed in the first 2 hours, and there was no significant difference between the three experimental groups and the negative control group.
  • Figure 10 (e) shows the change in urea nitrogen content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of micronized silica gel. It can be seen that the experimental groups 5-2 and 5-3 treated with the glucose peritoneal dialysate supplemented with 0.05% by weight or 0.25% by weight of the micronized silica gel were compared to the blank control group treated only with the glucose peritoneal dialysate. Significantly increased urea nitrogen content, and there was no significant difference between the two experimental groups. The experimental group 5-1 supplemented with 0.01% by weight of micronized silica gel showed no significant difference with the negative control group within the first 2 hours. This then shows a significant reduction in the urea nitrogen content.
  • Figure 10 (f) shows the change in the content of urea nitrogen in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of diatomaceous earth. It can be seen that the experimental group 5-1 treated with glucose peritoneal dialysate supplemented with 0.05% by weight, 0.05% by weight or 0.25% by weight of diatomaceous earth was used as compared to the blank control group treated only with the glucose peritoneal dialysate. 5-3 did not show a significant difference.
  • Fig. 11 (a) - (f) show changes in the content of creatinine in the peritoneal fluid for the experimental group listed in Table 4 and the corresponding blank control group (GLU) and the negative control group.
  • Figure 11 (a) shows the change in creatinine content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that the experimental group 1-1 treated with the glucose peritoneal dialysate added with 0.01% by weight of the nano carbon powder showed no significant difference compared to the blank control group treated only with the glucose peritoneal dialysate, and was added. Experimental groups 1-2 and 1-3 treated with glucose peritoneal dialysate of 0.05% by weight or 0.25% by weight of nano-carbon powder showed significant increase in urea nitrogen content, and there was no significant difference between the two experimental groups. .
  • Figure 11 (b) shows the change in creatinine content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Kollidon CL-SF was used compared to the blank control group treated only with glucose peritoneal dialysate. Up to 2-3 showed an increase in creatinine content. There was no significant difference between the three experimental groups in the first 4 hours, but after 4 hours, 0.01% and 0.05% by weight of the experimental group of Kollidon CL-SF was added. 2-1 and 2-2 showed a significant decrease in creatinine levels until they were close to the creatinine level of the negative control group.
  • Figure 11 (c) shows the change in creatinine content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with glucose peritoneal dialysate. No significant difference was shown to 3-3, but after 4 hours, the experimental group 2-1 to which 0.01% by weight of Kollidon CL-SF was added showed an apparent increase in creatinine content.
  • Figure 11 (d) shows the change in urea nitrogen content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental groups 4-1 and 4-3 treated with the glucose peritoneal dialysate supplemented with 0.01% by weight and 0.25% by weight of Soluplus were not shown compared to the blank control group treated only with the glucose peritoneal dialysate. Significant differences, while experimental group 4-2 treated with 0.05% by weight of Soluplus's glucose peritoneal dialysate showed a significant increase in creatinine content.
  • Figure 11 (e) shows the change in creatinine content in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of micronized silica gel. It can be seen that the experimental group 5-1 treated with the glucose peritoneal dialysate supplemented with 0.01% by weight of the micronized silica gel showed no significant difference compared to the blank control group treated with only the glucose peritoneal dialysate, and 0.05 was added. Experimental groups 5-2 and 5-3 of the % by weight and 0.25% by weight of the micronized silica gel showed a significant increase in creatinine content, and there was no significant difference between the two experimental groups.
  • Figure 11 (f) shows the change in creatinine content in the peritoneal fluid of glucose peritoneal dialysate supplemented with varying amounts of diatomaceous earth. It can be seen that the experimental groups 5-2 and 5-3 treated with the glucose peritoneal dialysate supplemented with 0.05% by weight and 0.25% by weight of diatomaceous earth were compared to the blank control group treated only with the glucose peritoneal dialysate. Significant differences were shown, while experimental group 5-1 with 0.01% by weight of diatomaceous earth showed a significant increase in creatinine content.
  • Figures 12(a)-(f) show the changes in the content of indoleol in the peritoneal fluid for the experimental groups listed in Table 4 and the corresponding blank control group (GLU) and the negative control group.
  • Figure 12 (a) shows the change in the content of indole sulfate in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of nano-carbon powder. It can be seen that the experimental groups 1-1 and 1-3 treated with the glucose peritoneal dialysate supplemented with 0.01% by weight or 0.25% by weight of the nanocarbon powder were compared to the blank control group treated only with the glucose peritoneal dialysate. Significant differences were shown, while experimental group 1-2 treated with glucose peritoneal dialysate supplemented with 0.05% by weight of nanocarbon powder showed an increase in the content of indole sulfate.
  • Figure 12 (b) shows the change in the content of indole sulfate in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-SF. It can be seen that the experimental group 2-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Kollidon CL-SF was used compared to the blank control group treated only with glucose peritoneal dialysate. Both to 2-3 showed a significant increase in the content of indole sulfate.
  • Figure 12 (c) shows the change in the content of indole sulfate in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of Kollidon CL-M. It can be seen that the experimental group 3-1 treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Kollidon CL-M was used compared to the blank control group treated only with glucose peritoneal dialysate. To 3-3 all showed a significant increase in the content of indole sulfate.
  • Figure 12 (d) shows the change in the content of indole sulfate in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of Soluplus. It can be seen that the experimental groups 4-1 to 4- treated with glucose peritoneal dialysate supplemented with 0.01% by weight, 0.05% by weight or 0.25% by weight of Soluplus were compared to the blank control group treated only with glucose peritoneal dialysate. 3 did not show significant difference in the first 2 hours, but after 2 hours, the experimental group 4-2 added with 0.05% by weight of Soluplus showed a significant increase in the content of indole sulfate, while adding 0.01 weight. The experimental groups 4-1 and 4-3 of % or 0.25 wt% of Soluplus were still not significantly different from the negative control group.
  • Figure 12 (e) shows the change in the content of indole sulfate in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of micronized silica gel. It can be seen that the experimental group 5-1 treated with the glucose peritoneal dialysate supplemented with 0.01% by weight of the micronized silica gel showed no significant difference compared to the blank control group treated with only the glucose peritoneal dialysate, and 0.05 was added. The experimental groups 5-2 and 5-3 of the % by weight and 0.25% by weight of the micronized silica gel all showed a significant increase in the content of indole sulfate, and there was no significant difference between the two experimental groups.
  • Figure 12 (f) shows the change in the content of indole sulfate in the peritoneal fluid of glucose peritoneal dialysate supplemented with different amounts of diatomaceous earth. It can be seen that the experimental groups 6-1 and 6-2 treated with the glucose peritoneal dialysate supplemented with 0.01% by weight and 0.05% by weight of diatomaceous earth were compared to the negative control group treated only with the glucose peritoneal dialysate.

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Abstract

一种可用于生物流体净化，例如血液透析、腹膜透析的组合物，其包括渗透剂和毒素去除试剂，其中所述毒素去除试剂能够在渗透交换的条件下去除生物流体中的毒素。提供了含有前述组合物的透析溶液和试剂盒，以及使用前述组合物去除生物流体中的毒素的方法、以及治疗与毒素相关的疾病的方法。

Description

用于生物流体净化的组合物 发明领域
本发明涉及新型的可用于生物流体净化的组合物、装置和生物流体净化方法。
背景技术
正常生物体内通过新陈代谢和肾脏清除可以去除体内生成的各种毒素，例如代谢废物等。如果不能正常清除，这些代谢废物将在体内蓄积，产生毒性。虽然目前主要通过血液透析或腹膜透析的方式降低血液中的代谢废物的含量，但目前的效果仍然比较有限，特别是对于某些难以通过渗透压平衡渗透的方式去除的代谢废物和毒素。因此，本领域仍然需要更加有效地能够降低体内毒素的组合物和方法。
发明内容
在一方面，本申请提供了一种包含渗透剂和毒素去除试剂的组合物，其中所述渗透剂能够提供与生物流体基本等渗或高于等渗的渗透压，并且所述毒素去除试剂能够在渗透交换的条件下降低所述生物流体中的毒素。
在某些实施方式中，所述毒素去除试剂能够降低所述生物流体中的所述毒素的游离量、非游离的量、和/或总量。在某些实施方式中，所述毒素去除试剂能够将生物流体中的毒素的总量或非游离的量降低至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％或至少95％。
在某些实施方式中，所述毒素去除试剂能够吸附、非共价结合、共价结合、和/或降解所述生物流体中的所述毒素。在某些实施方式中，所述毒素去除试剂具有一种或多种选自下组的特征：1)具有多孔结构；2)能够形成带电结构；3)能够与所述毒素通过非共价键或共价键或离子键结合；和4)能够降解所述毒素。
在某些实施方式中，所述毒素去除试剂具有多孔结构，并且所述多孔结构符合一个或多个以下特征：a)具有70cm 2/g～1000m 2/g的比表面积；b)具有0.1nm-10μm范围的孔径；c)具有0.1nm至100μm的孔径分布；d)具有约5～95％的孔隙率；e)能够以至少0.2mg/g的吸附率吸附所述毒素。
在某些实施方式中，所述具有多孔结构的所述毒素去除试剂选自下组：硅基多孔材料、碳基多孔材料、金属氧化物类多孔材料、聚合物类多孔材料和金属有机框架化合物多孔材料。
在某些实施方式中，所述毒素去除试剂能够形成带电结构，并且所述带电结构具有0.2-50μC·cm -2的电荷密度。在某些实施方式中，所述带电结构包括带电离子或带电的胶体。在某些实施方式中，所述毒素去除试剂选自下组：聚维酮、交联聚维酮、二氧化硅胶体、微粉硅胶、硅藻土、和聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、和纳米氧化铝。
在某些实施方式中，所述毒素去除试剂具有能够与所述毒素形成非共价键的基团(例如，氢原子、羟基、氨基、胺基、羧基等)，具有能够与所述毒素形成共价键的基团(例如，巯基、醛基、羟基、羧基等)、或者具有能够与所述毒素形成离子键的基团(例如，氯离子、硫酸根离子、钙离子、碳酸根离子等)。
在某些实施方式中，其中所述毒素去除试剂能够降解所述毒素，并且所述毒素去除试剂是生物催化剂或化学催化剂。
在某些实施方式中，所述毒素去除试剂选自活性炭、聚维酮、交联聚维酮、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、微粉硅胶、硅藻土，及其任意组合。
在某些实施方式中，所述毒素在所述生物流体中的存在或者过量存在会提高患病风险、加重疾病状况、或损害正常生理功能。在某些实施方式中，所述毒素包含体内代谢产物、引起中毒的外源物质、或引起疾病的分子。
在某些实施方式中，所述毒素在所述生物流体中游离存在、与所述生物流体中的物质结合存在、或者两者皆有。在某些实施方式中，至少部分所述毒素与所述生物流体中的物质形成可逆结合。在某些实施方式中，所述毒素与所述生物流体中的物质结合的Kd值至少为10 2μmol/L、10 3μmol/L、10 4μmol/L、10 5μmol/L、10 6μmol/L、或10 7μmol/L。在某些实施方式中，所述毒素与所述生物流体中的物质的结合的Kd值至少为10 5～10 7μmol/L。
在某些实施方式中，在所述生物流体中至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％的所述毒素以结合形式存在。在某些实施方式中，所述毒素包括：硫酸吲哚酚、非对称性精氨酸、高半胱氨酸、苯乙酸、对甲酚、AGE产物(3-脱氧葡糖醛酮、果糖赖氨酸、乙二醛、丙酮醛、戊糖素)、马尿酸、 尿毒症毒素、硫化氢、或胆红素。在某些实施方式中，与所述毒素结合的所述物质包括血液组织中的成分、脂肪组织中的成分、结缔组织中的成分、骨组织中的成分等。
在某些实施方式中，所述毒素去除试剂对毒素的吸附或结合的作用不同于所述毒素与所述生物流体内的物质的结合作用。在某些实施方式中，所述毒素去除试剂不同于在所述生物流体中与所述毒素结合的物质。
在某些实施方式中，所述渗透剂能够提供基本等于或高于280mOsm/L、300mOsm/L、或330mOsm/L的渗透压。在某些实施方式中，所述渗透剂包括糖类、氨基酸、多肽、甘油、碳酸盐、碳酸氢盐或其类似物及其组合。在某些实施方式中，所述糖类渗透剂可以选自单糖、寡糖和多糖，所述氨基酸类渗透剂可以选自天然氨基酸、非天然氨基酸、其类似物、衍生物及其任意组合。在某些实施方式中，所述单糖可以选自葡萄糖、果糖、山梨糖醇、木糖醇、氨基糖及其衍生物；所述寡糖包括一种或多种所述单糖的寡聚物；和/或所述多糖包括一种或多种所述单糖的多聚物。在某些实施方式中，所述糖类渗透剂包含葡萄糖聚合物。
在某些实施方式中，所述毒素去除试剂与所述渗透剂在所述组合物中的含量比例(重量/重量)为1:1750到1:4(例如：1:1750到1:5，1:1500到1:4，1:1500到1:5，1:1000到1:5，1:750到1:6；1:300到1:6；1:75到1:6；1:30到1:6；1:10到1:6；1:1500到1:5；1:1500到1:10；1:1500到1:30；1:1500到1:75；1:1500到1:150；1:1500到1:300；1:1500到1:750。
在某些实施方式中，当本申请提供的组合物被配置成直接用于渗透交换的透析液时，所述透析液中所述渗透剂的含量范围(重量/体积)为0.05％-10％，0.5％-10％，1％-10％，1.5％-10％，1.5％-9％，1.5％-8％，1.5％-7.5％，1.5％-6％，1.5％-5％等。
在某些实施方式中，当本申请提供的组合物被配置成直接用于渗透交换的透析液时，所述透析液中所述毒素去除试剂的含量范围(重量/体积)为至少0.0001％、至少0.0005％、至少0.001％、至少0.005％、至少0.01％、至少0.025％、至少0.05％、至少0.075％、至少0.1％、至少0.125％、至少0.15％、至少0.175％、至少0.2％、或至少0.25％。在某些实施方式中，所述透析液中所述毒素去除试剂的含量范围(重量/体积)不高于4％、不高于3.5％、不高于3.3％、不高于3.0％、不高于2.8％、不高于2.5％、不高于2.3％、不高于2.0％、不高于1.8％、不高于1.6％、不高于1.4％、不高于1.2％、不高于1.0％、不高于0.8％、不高于0.6％、或不高于0.4％。
在某些实施方式中，所述组合物进一步含有缓冲剂、电解质和其他透析组分中的一种或多种。在某些实施方式中，所述组合物是经过灭菌的。
在某些实施方式中，所述组合物是固体制剂、半固体制剂或液体制剂。
在某些实施方式中，所述毒素去除试剂能够与所述生物流体通过半渗透介质进行渗透交换。在某些实施方式中，其中所述半渗透介质是人造半透膜或生物半透膜。在某些实施方式中，所述生物半透膜选自下组：血管壁膜、淋巴管壁膜、腹膜、肺膜、腺体包膜和黏膜。
在某些实施方式中，所述生物流体选自：血液、组织液、淋巴液、血浆、血清、血液制品、生物制品。在某些实施方式中，所述生物流体在个体体内，或者在个体体外。
在另一方面，本申请还提供了含有根据本申请所述组合物的透析溶液。在某些实施方式中，所述透析溶液能够提供生理可接受水平的pH和/或电解质。
在另一方面，本申请还提供了用于生物流体净化的试剂盒，其含有本申请提供的组合物。在某些实施方式中，所述组合物在所述试剂盒中以单一的组合物形式存在，或者以两个或两个以上组成部分的形式存在。在某些实施方式中，所述组合物或至少一种所述组成部分是固体制剂、半固体制剂或液体制剂。在某些实施方式中，所述组合物以两个或两个以上组成部分的形式存在，并且分别容纳在不同的容器中。在某些实施方式中，所述两个或两个以上组成部分分别容纳在两个或两个以上能够被可操作地流体连通的容器中。在某些实施方式中，所述组合物是经过灭菌的。在某些实施方式中，所述试剂盒进一步包含可用于生物流体净化的半渗透介质。
在另一方面，本申请还提供了透析装置，其包含本申请提供的组合物，其中所述装置被配置为允许所述组合物能够与待透析的生物流体进行渗透交换。在某些实施方式中，所述装置进一步包含允许所述组合物与所述生物流体进行渗透交换的半渗透介质。在某些实施方式中，所述透析装置可以被安装到透析主机上。
在另一方面，本申请还提供了降低生物流体中的毒素的方法，其包括：a)将所述生物流体在允许渗透交换的条件下接触含有本申请提供的组合物的渗透溶液，以及b)允许所述组合物降低所述生物流体中的所述毒素的量。在某些实施方式中，所述方法中，在所述允许渗透交换的条件下，所述生物流体中的所述毒素通过渗透交换转移到所述渗透溶液中。在某些实施方式中，步骤a)包括将所述生物流体与所述组合物置于半渗透介质的两侧。 在某些实施方式中，所述渗透溶液与所述生物流体基本等渗或高于等渗。在某些实施方式中，所述半渗透介质为人造半透膜或生物半透膜(例如血管壁膜、淋巴管壁膜、腹膜、肺膜、腺体包膜和黏膜)。在某些实施方式中，所述生物流体在个体的体内。在某些实施方式中，所述步骤a)包括将所述渗透溶液通过腹腔灌注施用于所述个体。在某些实施方式中，所述生物流体在体外。在某些实施方式中，步骤a)包括将所述渗透溶液通过血液透析施用于所述个体。
在另一方面，本申请还提供了一种治疗或预防与毒素相关的疾病或状态的方法，包括使用本申请提供的组合物在允许渗透交换的条件下接触所述个体的生物流体，以降低所述生物流体中的所述毒素。
在另一方面，本申请还提供了将本申请提供的组合物在用于制备治疗或预防与毒素相关的疾病或状态的药物中的用途，所述组合物可降低个体体内的生物流体中的所述毒素。
附图说明
图1显示了使用包含不同量的毒素去除试剂的艾考糊精腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠的血液中的尿素氮的去除结果，其中图1(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的去除结果，图1(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的去除结果，图1(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的去除结果，图1(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的去除结果，图1(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的去除结果，图1(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的去除结果。
图2显示了使用包含不同量的毒素去除试剂的艾考糊精腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠的血液中的肌酐的去除结果，其中图2(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的去除结果，图2(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的去除结果，图2(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的去除结果，图2(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的去除结果，图2(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的去除结果，图2(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的去除结果。
图3显示了使用包含不同量的毒素去除试剂的艾考糊精腹膜透析液进行大鼠腹膜透析 处理的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠的血液中的硫酸吲哚酚的去除结果，其中图3(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的去除结果，图3(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的去除结果，图3(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的去除结果，图3(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的去除结果，图3(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的去除结果，图3(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的去除结果。
图4显示了使用包含不同量的毒素去除试剂的艾考糊精腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠的腹腔液中的尿素氮的含量变化，其中图4(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的结果，图4(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的结果，图4(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的结果，图4(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的结果，图4(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的结果，图4(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的结果。
图5显示了使用包含不同量的毒素去除试剂的艾考糊精腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠的腹腔液中的肌酐的含量变化，其中图5(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的结果，图5(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的结果，图5(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的结果，图5(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的结果，图5(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的结果，图5(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的结果。
图6显示了使用包含不同量的毒素去除试剂的艾考糊精腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠的腹腔液中的硫酸吲哚酚的含量变化，其中图6(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的结果，图6(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的结果，图6(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的结果，图6(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的结果，图6(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的结果，图6(f)显示了添加了不同量的硅 藻土的艾考糊精腹膜透析液的结果。
图7显示了使用包含不同量的毒素去除试剂的葡萄糖腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠的血液中的尿素氮的去除结果，其中图7(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的去除结果，图7(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的去除结果，图7(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的去除结果，图7(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的去除结果，图7(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的去除结果，图7(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的去除结果。
图8显示了使用包含不同量的毒素去除试剂的葡萄糖腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠的血液中的肌酐的去除结果，其中图8(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的去除结果，图8(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的去除结果，图8(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的去除结果，图8(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的去除结果，图8(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的去除结果，图8(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的去除结果。
图9显示了使用包含不同量的毒素去除试剂的葡萄糖腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠的血液中的硫酸吲哚酚的去除结果，其中图9(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的去除结果，图9(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的去除结果，图9(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的去除结果，图9(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的去除结果，图9(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的去除结果，图9(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的去除结果。
图10显示了使用包含不同量的毒素去除试剂的葡萄糖腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠的腹腔液中尿素氮的含量变化，其中图10(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的结果，图10(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的结果，图10(c)显示了添加了 不同量的Kollidon CL-M的葡萄糖腹膜透析液的结果，图10(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的结果，图10(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的结果，图10(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的结果。
图11显示了使用包含不同量的毒素去除试剂的葡萄糖腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠的腹腔液中肌酐的含量变化，其中图11(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的结果，图11(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的结果，图11(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的结果，图11(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的结果，图11(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的结果，图11(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的结果。
图12显示了使用包含不同量的毒素去除试剂的葡萄糖腹膜透析液进行大鼠腹膜透析处理的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠的腹腔液中硫酸吲哚酚的含量变化，其中图12(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的结果，图12(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的结果，图12(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的结果，图12(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的结果，图12(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的结果，图12(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的结果。
具体实施方式
定义
“渗透剂”在本申请中是指在溶液中能够提供一定渗透压的试剂。
“渗透压”在本申请中是指恰好能阻止渗透发生的施加于溶液液面的额外压强。例如，对于两侧水溶液浓度不同的半渗透介质(例如半透膜)，为了阻止水从低浓度一侧渗透到高浓度一侧而在高浓度一侧施加的最小额外压强称为渗透压。溶液的渗透压与单体体积溶液中所含的不能通过半透膜的溶质的粒子数(分子数或离子数)成正比，溶质粒子数越多，即溶液浓度越高，对水的吸引力越大，溶液渗透压越高，反之，溶质粒子数越少，即溶液浓度越低，对水的吸引力越弱，溶液渗透压越低。
“半渗透介质”在本申请中是指选择性地只允许部分溶质渗透通过而不允许另一部分溶质通过的介质。半渗透介质可以是具有一定孔隙的材料，其中的孔隙可以允许通过足够小的分子，例如水、电解质、糖等。半渗透介质的一个常见的例子是半透膜。但应理解半渗透介质不仅限于半透膜，还可以是其他的形式，例如具有半渗透性质的中空纤维，或管式渗透膜等(例如，请参见，俞学敏等，血液透析膜的制备改性及组件设计，膜科学与技术，第35卷第4期，第110-122页)。
“等渗”在本申请中是指两种溶液或者液体或者流体的渗透压相等。在本申请的一些实施方案中，含有本申请组合物的溶液与生物流体基本等渗或高于等渗，从而使得当所述溶液与生物流体位于半渗透介质的两侧时，所述生物流体中的电解质、无机盐、糖类等不会向外渗透或者不会过度向外渗透而影响或破坏生物流体的正常生物功能。基本等渗是指，与生物流体的渗透压接近，例如在与生物流体的渗透压相差不超过正负10％，正负8％，正负5％，正负3％或正负1％的范围内。举例来说，人体正常血浆的渗透压约为290-310mmol/L，人体中的血浆、胃液、胰液、肠液、胆汁、脊髓液，以及泪液的渗透压都大致相等。因此，与人体血液、血浆等上述生物流体基本等渗的渗透压为290-310mmol/L，或者在与之相差正负10％的范围内(即260-340mmol/L的范围内)。
“浓度梯度”在本申请中是指由于物质在半渗透介质两侧流体中的游离浓度差而产生的浓度分布梯度。浓度梯度是物质透过半渗透介质从高浓度一侧向低浓度一侧输运的动力。当物质在半渗透介质两侧流体中的浓度相等时，浓度梯度消失，则物质透过半渗透介质的输运停止。
“渗透交换”在本申请中是指物质通过半渗透介质从高游离浓度侧向低游离浓度侧移动。
“毒素”在本申请中是指当其在生物体(例如人体)中存在时或者当其在生物体中以高于阈值浓度的水平存在时会对生理功能产生不利影响的物质。毒素可能会提高患病风险、加重疾病状况或损害正常生理功能。毒素可包括体内代谢产物、引起中毒的外源物质、或引起疾病的分子。
“生物流体”在本申请中可以包括任何来自或衍生自生物体的可能含有毒素的流体。生物流体可以是经处理的，或者是未处理的。例如，生物流体的例子包括但不限于，组织液、淋巴液、血液、血浆、血清、血液制品、生物制品等。
“游离的量”在本申请中是指在生物流体中存在的处于游离状态下的毒素的量。
“非游离的量”在本申请中是指在生物流体中存在的处于非游离状态下(例如处于结合(如与蛋白结合)、络合或螯合等状态下)的毒素的量。
“毒素总量”在本申请中是指在生物流体中存在的毒素的总量，其为游离状态下的毒素的量和非游离状态下的毒素的量的总和。
“透析溶液”或“透析液”在本申请中是指可用于透析治疗的溶液制剂。透析溶液可以是适用于原样施用的液体制剂，也可以是适用于临用前配置的液体制剂。
组合物
在一方面，本申请提供了包含渗透剂和毒素去除试剂的组合物。本发明提供的组合物可以用于通过与生物流体进行渗透交换的方式，去除或降低在生物流体中存在的毒素。
在渗透交换的情形下，生物流体与渗透剂分别置于半渗透介质的两侧。半渗透介质两侧对于毒素而言存在浓度梯度，比如生物流体中存在毒素，而渗透剂中不存在毒素，因此毒素在半渗透介质两侧的浓度差导致浓度梯度，促使毒素能够从生物流体一侧向渗透剂一侧渗透。在只有渗透剂存在(而没有毒素去除试剂存在)的情形下，毒素渗透进入渗透剂一侧后，会导致渗透剂一侧的毒素浓度升高，生物流体一侧的浓度降低，进而浓度差降低，浓度梯度减小，直到两侧的浓度相等，浓度梯度为零。当浓度梯度为零时，生物流体内的毒素不再降低，而是达到一种动态平衡，此时生物流体内的游离毒素浓度为最终浓度，生物流体内的毒素的量不再降低。理论上，假设半渗透介质两侧的流体体积相等，那么渗透剂通过浓度梯度本身最多能去除生物流体内游离存在的50％的游离毒素，但考虑到渗透剂一侧的体积往往远远小于生物流体(例如血液)体积，实际上能够通过渗透交换去除的游离毒素往往远远低于50％，甚至连20％都不到(例如在人体血液透析的情形下)。对于非游离存在的毒素，例如与蛋白结合的毒素，往往取决于毒素结合的强弱(即是否容易解离以释放出游离的毒素)，以及以结合形式存在的毒素的多少(即非游离形式的毒素与游离形式毒素的比例)。对于主要以结合形式存在和/或结合比较强(难以解离)的毒素而言，单纯依赖渗透剂提供的浓度梯度难以获得满意的毒素去除效果。
不希望受任何理论限制，在本申请提供的组合物中含有渗透剂和毒素去除试剂。在渗透交换的情形下，生物流体与本申请提供的组合物分别置于半渗透介质的两侧。本申请提供的组合物中的毒素去除试剂能够有效地吸附、结合和/或降解渗透到组合物一侧的毒素， 从而持续地降低组合物一侧的毒素的游离量，进而促使生物流体中的毒素持续地向组合物渗透，从而不断地降低生物流体中的毒素的总量(例如游离毒素的量、蛋白结合的毒素的量和/或毒素的总量)，直到毒素去除试剂不能再去除更多的毒素(例如达到吸附饱和的状态)。与只有渗透剂存在的情形相比，本申请的组合物中的毒素去除试剂能够去除生物流体内更多的游离毒素，而且能够去除生物流体内原本以结合形式存在的毒素。
在某些实施方式中，本申请提供的组合物能够降低所述生物流体中的所述毒素的游离量、非游离的量、和/或总量。在某些实施方式中，本申请提供的组合物能够将生物流体中的毒素的游离量降低到初始游离量的至多50％、至多40％、至多30％、至多20％、至多10％或至多5％。初始游离量是指生物流体在使用本申请组合物处理之前测得的毒素的游离量。
在某些实施方式中，本申请提供的组合物能够将生物流体中的毒素的总量(或者非游离的量)降低至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％或至少95％。与用本申请提供的组合物处理之前的生物流体相比，经处理后的生物流体中的毒素的总量(或者非游离的量)为处理之前的至多90％、至多80％、至多70％、至多60％、至多50％、至多40％、至多30％、至多20％、至多10％、或至多5％。
在某些实施方式中，本申请提供的组合物能够将生物流体中的毒素的总量(或者游离量、或者非游离的量)降低到生理受益水平。“生理受益水平”是指能够降低疾病风险、或者使生物体因毒素而导致的症状减轻的水平，“疾病水平”是指生物体在疾病状态下的水平。生理受益水平可以是大于或等于正常生理水平到低于疾病水平之间的任何水平，例如但不限于，比疾病水平低至少10％、至少20％、至少30％、至少40％、至少50％等。例如，硫酸吲哚酚在正常人体血浆内的正常生理水平为0.59±0.26mg/L，但在尿毒症状态下的水平为53±4.5mg/L或更高，因此，硫酸吲哚酚的生理受益水平可以是从大于等于0.59到低于53mg/L范围内的任何水平，例如0.59-48mg/L、0.59-42mg/L、0.59-36mg/L、0.59-32mg/L、0.59-26mg/L、0.59-20mg/L、0.59-15mg/L、0.59-10mg/L、或0.59-5mg/L。类似的，肌酸酐的血浆生理受益水平可以是从大于等于0.5mg/dL到低于136mg/dL范围内的任何水平，例如0.5-120mg/dL、0.5-100mg/dL、0.5-80mg/dL、0.5-60mg/dL、0.5-40mg/dL、或0.5-20mg/dL。尿素氮(BUN)在正常人体血浆内的正常生理水平为44～133μmol/L，在肾衰竭代偿期的水平为133～177μmol/L，在肾衰竭失代偿期的水平为177～442μmol/L，在 肾功能衰竭期的水平为442～707μmol/L，在尿毒症期的水平大于707μmol/L，因此其生理受益水平可以是比肾功能缺失不同发展阶段水平降低的任何水平。例如，在肾衰竭代偿期的水平低于133μmol/L，在肾衰竭失代偿期的水平低于177μmol/L，在肾功能衰竭期的水平低于442μmol/L，在尿毒症期的水平低于707μmol/L。
可以通过本领域已知的检测和/或分析方法来测定生物流体中的毒素的游离量、非游离的量和/或毒素总量(即游离量加上非游离的量)。可以使用的方法例如，平衡透析法、超滤法、超速离心法、凝胶过滤法、光谱法(包括紫外可见光谱、荧光光谱、红外光谱、圆二色谱、拉曼光谱、旋光法)、核磁共振法、光学生物传感器法、生化分析法、质谱法、高效亲和色谱法、微量热法等等(具体可参考《生物药剂学与药物动力学》第五版，主编刘建平，第96页；《分析化学》武汉大学版第五版)。
例如，可以通过平衡透析法，将生物流体与等渗溶液分别置于只允许毒素透过而不允许生物大分子透过的半透膜两侧，使得生物流体中的毒素在无外力驱动条件下扩散透过半透膜，当达到平衡时，测定膜两侧溶液中毒素的浓度，通过计算即可分析得生物大分子与毒素结合的数据。
超滤法是以压力为推动力的膜分离技术。以大分子与小分子分离为目的，膜孔径在
Figure PCTCN2019077749-appb-000001
之间。中空纤维超滤器(膜)具有单位容器内充填密度高，占地面积小等优点。在超滤过程中，水溶液在压力推动下，流经膜表面，小于膜孔的溶剂(水)及小分子溶质透水膜，成为净化液(滤清液)，比膜孔大的溶质及溶质基团被截留，随水流排出，成为浓缩液。
超速离心法指的是在超速离心机中，应用强大的离心力分离、制备、分析物质的方法。超速离心机的离心速度为每分钟60000转或更多，离心力约为重力加速度的500000倍，可分成制备性超速离心机和分析性超速离心机两大类。这种方法使用一种密度能形成梯度(在离心管中，其密度从上到下连续增高)又不会使所分离的生物活性物质凝聚或失活的溶剂系统，离心后各物质颗粒能按其各自的比重平衡在相应的溶剂密度中形成区带。
凝胶过滤法，又称分子排阻法，利用一定型号的凝胶，具有大小一定的网孔，只允许相应大小的分子进入凝胶颗粒内部，大分子则被排阻在外。
紫外可见光谱，它们都是由于价电子的跃迁而产生的。利用物质的分子或离子对紫外和可见光的吸收所产生的紫外可见光谱及吸收程度可以对物质的组成、含量和结构进行分析、测定、推断。
荧光光谱分析，是指利用某些物质在紫外光照射下产生荧光的特性及其强度进行物质的定性和定量的分析的方法。
红外光谱是分子能选择性吸收某些波长的红外线，而引起分子中振动能级和转动能级的跃迁，检测红外线被吸收的情况可得到物质的红外吸收光谱，又称分子振动光谱或振转光谱，通过分析这些光谱进行物质定性分析。
圆二色谱利用对R和L两种圆偏振光吸收程度不同的现象，这种吸收程度的不同与波长的关系称圆二色谱，是一种测定分子不对称结构的光谱法。在分子生物学领域中主要用于测定蛋白质的立体结构，也可用来测定核酸和多糖的立体结构。
拉曼光谱是一种散射光谱，对与入射光频率不同的散射光谱进行分析以得到分子振动、转动方面信息，并应用于分子结构研究的一种分析方法。
许多物质具有旋光性(又称光学活性)，如含有手性碳原子的有机化合物。当平面偏振光通过这些物质(液体或溶液)时，偏振光的振动平面向左或向右旋转，这种现象称为旋光。旋光法即是利用物质的旋光性质测定化合物光学活性的方法。
核磁共振波谱法是研究处于强磁场中的原子核对射频辐射的吸收，从而获得有关化合物分子结构信息的分析方法。
生物传感器(biosensor)，是一种对生物物质敏感并将其浓度转换为电信号进行检测的仪器。是由固定化的生物敏感材料作识别元件(包括酶、抗体、抗原、微生物、细胞、组织、核酸等生物活性物质)、适当的理化换能器(如氧电极、光敏管、场效应管、压电晶体等等)及信号放大装置构成的分析工具或系统。生物传感器具有接受器与转换器的功能。
生化分析仪是临床检验中经常使用的重要分析仪器之一它通过对血液或者其他体液的分析来测定各种生化指标，如转氨酶、血红蛋白、白蛋白、总蛋白、胆固醇、肌肝、葡萄糖、无机磷、淀粉酶、钙等。结合其他临床资料，进行综合分析，可以帮助诊断疾病，对器官功能做出评价，鉴别并发因子，以及决定今后治疗的基准等。
质谱法即用电场和磁场将运动的离子(带电荷的原子、分子或分子碎片，有分子离子、同位素离子、碎片离子、重排离子、多电荷离子、亚稳离子、负离子和离子－分子相互作用产生的离子)按它们的质荷比分离后进行检测的方法。测出离子准确质量即可确定离子的化合物组成。这是由于核素的准确质量是一多位小数，决不会有两个核素的质量是一样的，而且决不会有一种核素的质量恰好是另一核素质量的整数倍。分析这些离子可获得化合物的分子量、化学结构、裂解规律和由单分子分解形成的某些离子间存在的某种相互关系等信息。
亲和色谱法是将相互间具有高度特异亲和性的二种物质之一作为固定相，利用与固定相不同程度的亲和性，使成分与杂质分离的色谱法。
高效液相色谱指的是高压输液泵将具有不同极性的单一溶剂或不同比例的混合溶剂、缓冲液等流动相泵入装有固定相的色谱柱，经进样阀注入待测样品，由流动相带入柱内，在柱内各成分被分离后，依次进入检测器进行检测，从而实现对试样的组成进行分析。
微量热法(包括等温滴定量热和差示扫描量热)是近年来发展起来的一种研究生物热力学与生物动力学的重要结构生物学方法，它通过高灵敏度、高自动化的微量量热仪连续和准确地监测和记录一个变化过程的量热曲线，原位、在线和无损伤地同时提供热力学和动力学信息。
在进行具体的检测或分析前，如果需要的话，可以对生物流体进行预处理，例如加入适当的试剂(例如抗凝剂)以避免生物流体出现不希望的改变(例如凝固)等、分离或提取上清液、使结合状态存在的毒素游离释放、和/或去除可能影响检测的不相关的生物成分。
1. 毒素去除试剂
在某些实施方式中，本申请提供的组合物中的毒素去除试剂能够在渗透交换的条件下降低生物流体中的毒素。在某些实施方式中，本申请中的毒素去除试剂可以吸附、非共价结合、共价结合和/或降解毒素。例如，在与待处理的生物流体之间存在渗透交换的情形下，毒素去除试剂可以通过例如多孔结构、带电结构、能形成非共价键或共价键或离子键的基团等，将从生物流体中渗透出的毒素吸附和结合。再例如，毒素去除试剂还可以降解从生物流体中渗透出的毒素。
在某些实施方式中，所述毒素去除试剂具有多孔结构。不受任何理论限制，但认为多孔结构可以增加毒素去除试剂的表面积，从而更好地吸附或结合毒素。
在某些实施方式中，所述多孔结构具有70cm 2/g～1000m 2/g的比表面积(例如，70cm 2/g～900m 2/g，70cm 2/g～850m 2/g，70cm 2/g～800m 2/g，70cm 2/g～750m 2/g，70cm 2/g～700m 2/g，70cm 2/g～650m 2/g，70cm 2/g～600m 2/g，70cm 2/g～550m 2/g，70cm 2/g～500m 2/g，70cm 2/g～450m 2/g，70cm 2/g～400m 2/g，70cm 2/g～350m 2/g，70cm 2/g～300m 2/g，70cm 2/g～250m 2/g，70cm 2/g～200m 2/g，70cm 2/g～180m 2/g，70cm 2/g～160m 2/g，70cm 2/g～140m 2/g，70cm 2/g～120m 2/g，70cm 2/g～100m 2/g，70cm 2/g～80m 2/g，70cm 2/g～60m 2/g，70cm 2/g～40m 2/g，700cm 2/g～160m 2/g，7000cm 2/g～160m 2/g，7m 2/g～160m 2/g，20m 2/g～160m 2/g，40m 2/g～160m 2/g等)。例如，硅藻土的比表面积为40～65m 2/g，多孔二氧化硅的比表面积可以为70～600m 2/g(例如70～500m 2/g，70～400m 2/g，70～300m 2/g，70～200m 2/g，70～100m 2/g，70～90m 2/g，70～85m 2/g等)。多孔结构材料的比表面积可以通过已知方法(例如气体吸附法，流体透过法，压汞法等)测定，请参见，例如，Lowell,S.等,Characterization of porous solids and powders:surface area,pore size and density,published by Springer,2004。
在某些实施方式中，具有所述多孔结构的毒素去除试剂可以具有0.1nm-10μm的孔径。根据孔径大小，也可以将具有多孔结构的材料分为大孔材料(例如孔径范围大于50nm)、介孔材料(例如孔径范围约2-50nm)和微孔材料(例如孔径范围小于2nm)等。适用于本发明的微孔材料例如，但不限于，无定型二氧化硅、无机溶胶到结晶态的分子筛、活性炭等。适用于本发明的为介孔材料例如，但不限于，二氧化硅介孔材料。适用于本发明的大孔材料例如，但不限于，大孔分子筛材料(例如，请参见Science(2011),333:1131)、大孔硅胶(例如孔径约50nm，孔容积约2.5～3.0ml/g，堆积比重约180～220g/L，比表面积约150～200m 2/g，粒度约80目)。
孔径的表征可以通过已知的方法(例如断面直接观测法(透射电镜)、气泡发、透过法、压汞法、气体吸附法、离心力法、悬浮液过滤法、X射线小角度散射法等)进行测定。
在某些实施方式中，具有所述多孔结构的毒素去除试剂具有适当的孔径分布。例如，至少80％以上的孔具有0.1nm至100μm(例如0.1nm至80μm、0.1nm至60μm、0.1nm至40μm、0.1nm至20μm、0.1nm至10μm、0.1nm至1μm、0.1nm至100nm、0.1nm至10nm、0.1nm至1nm、1μm至80μm、10μm至80μm、20μm至80μm、40μm至80μm、60μm至80μm)的孔径分布。
在某些实施方式中，具有所述多孔结构的毒素去除试剂具有的孔隙率在5～95％(例如，5～90％、5～80％、5～70％、5～60％、5～50％、5～40％、10～90％、20～90％、30～90％、40～90％、50～90％、60～90％)之间。
在某些实施方式中，具有所述多孔结构的毒素去除试剂能够以至少0.2mg/g(例如，至少0.3mg/g、至少0.5mg/g、至少0.7mg/g、至少0.9mg/g、至少1.0mg/g、至少2mg/g、至少3mg/g、至少4mg/g、至少5mg/g、至少6mg/g、至少7mg/g、至少8mg/g、至少9mg/g)的吸附率吸附所述毒素。吸附率是指每单位重量的毒素吸附试剂吸附的毒素的重量。例如0.2mg/g的吸附率是指每克毒素吸附试剂能够吸附0.2mg的毒素。
在某些实施方式中，所述具有多孔结构的毒素去除试剂可以包括，例如但不限于，硅基多孔材料、碳基多孔材料、金属氧化物类多孔材料(例如多孔氧化铝、类水滑石)、聚合物类多孔材料、和金属有机框架化合物多孔材料。
硅基多孔材料在本申请中是指基于硅元素的由固相与大量孔隙共同构成的多相材料。类似地，碳基多孔材料在本申请中是指基于碳元素的由固相与大量孔隙共同构成的多相材料。硅基多孔材料和碳基多孔材料通常具有稳定的骨架结构，有一定的比表面积和孔径分布，优选地具有规则的孔道结构。
硅基多孔材料的例子包括，但不限于，硅藻土、多孔二氧化硅(例如
Figure PCTCN2019077749-appb-000002
SLC 500)、沸石、石英砂、白土、微孔玻璃、多孔陶瓷、介孔硅、黏土、和分子筛等。
碳基多孔材料的例子包括，但不限于，活性炭、膨胀石墨、和介孔碳等。
金属氧化物类多孔材料的的例子包括，但不限于，多孔氧化铝、类水滑石等。
聚合物类多孔材料的例子包括，但不限于，聚苯乙烯多孔小球、菊粉、聚乙烯、聚丙烯、聚四氟乙烯、聚偏二氟乙烯、聚乙基醋酸乙烯酯、聚碳酸酯、聚醚醚酮、和聚醚砜等。
金属有机框架化合物多孔材料的例子包括，但不限于，MOF-5、MOF-177、MOF-180、MOF-205、MOF-210、[COII(BPB)]·3DMF、ED-MIL-101、SZ/MIL-101。
一种示例性的具有多孔结构的毒素去除试剂是活性炭。在某些实施方式中，活性炭的孔有效半径可以为1-10000nm，小孔半径可以在2nm以下，介孔半径可以为2-100nm，大孔半径可以为100-10000nm。小孔容积可以为0.15-0.90mL/g，介孔容积可以为0.02-0.10mL/g；大孔容积可以为0.2-0.5mL/g。在某些实施方式中，活性炭对小分子磺胺嘧啶的吸附量为0.54mg/g。
另一种示例性的具有多孔结构的毒素去除试剂是硅藻土。在某些实施方式中，硅藻土的密度1.9-2.3g/cm 3，堆密度0.3-0.65g/cm 3，比表面积40-65m 2/g，孔体积0.45-0.98m 3/g，吸水率是自身体积的2-4倍，细度在100～2000目。
另一种示例性的具有多孔结构的毒素去除试剂是多孔二氧化硅。在某些实施方式中，多孔二氧化硅比表面积为10～1000m 2/g(例如，70～600m 2/g)(例如
Figure PCTCN2019077749-appb-000003
SLC 500为500m 2/g)，密度100～1000kg/m 3，孔径分布为1～1000nm。
在某些实施方式中，所述毒素去除试剂能够形成带电的结构。不受任何理论限制，但认为带电结构的毒素去除试剂可以通过例如静电吸附等作用吸附带有相反电荷的毒素。例如，带有正电的毒素去除试剂(例如：亚精胺、精胺、纳米氧化铝)可以通过吸附除去带有负电的毒素(例如：硫酸吲哚酚)，或者带有负电的毒素去除试剂(例如：多孔硅胶、微粉硅胶)可以通过吸附除去带有正电的毒素(例如：亚精胺、精胺)。
在某些实施方式中，所述带电的结构包含带电离子或带电的胶体。某些亚微米级或纳米级的粒子或者聚合物分散在介质(例如水或水溶液)中时，可以形成胶体溶液。胶体溶液中的胶粒由于吸附某些带电离子或者表面所带基团的电离等原因，可以带有一定的电荷。在某些实施方式中，所述带电结构具有的电荷密度为至少0.2μC·cm -2或0.2-50μC·cm -2(例如：0.2-40μC·cm -2、0.2-30μC·cm -2、0.2-20μC·cm -2、0.2-10μC·cm -2、2-50μC·cm -2、10-50μC·cm -2、20-50μC·cm -2、30-50μC·cm -2、或40-50μC·cm -2)。带电结构的带电性质可以通过已知的方法进行检测，例如可以通过测定胶体溶液的电导率来测定(例如，请参见：周宏伟等，Acta Phys.-Chim.Sin.2013,29(6),1260-1265)。
在某些实施方式中，所述能够形成带电结构(例如带电的胶体结构)的毒素去除试剂包括，聚维酮(例如1-乙烯-2-吡咯酮的聚合物)、交联聚维酮(例如1-乙烯-2-吡咯酮的交联聚合物)、二氧化硅胶体、微粉硅胶(也称胶态二氧化硅)、硅藻土、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(例如，请参见美国专利US8,636,929、US9,011,912、PCT国际专利申请WO/2013/090842A3、CAS No.402932-23-4、商品名
Figure PCTCN2019077749-appb-000004
)等。
在某些实施方式中，毒素去除试剂是聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物。在某些实施方式中，其适当的分子量范围可以是90,000-140 000g/mol。在某些实施方式中，在该共聚物中，聚乙二醇:聚乙烯己内酰胺:聚醋酸乙烯酯的重量比为13:57:30。
在某些实施方式中，所述毒素去除试剂能够以非共价键或共价键、或离子键结合所述毒素。非共价结合可以是基于任何可能的非共价键，例如氢键、疏水作用、静电作用、螯合作用、范德华力、π-π堆积等。例如，当胶体二氧化硅作为毒素去除试剂时，可以与毒素肌酐形成氢键，进而从生物流体中去除肌酐。再例如，当聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(例如Soloplus)作为毒素去除试剂时，可以与毒素硫酸吲哚酚通过静电作用和氢键等多种结合，进而从生物流体中去除硫酸吲哚酚。又例如，可以使用金属螯合剂作为毒素去除试剂，通过与毒素铜离子形成螯合，进而从生物流体去除铜离子。
在某些实施方式中，所述毒素去除试剂具有能够与毒素形成非共价键的基团，例如氢原子、羟基、氨基、胺基、羧基等。
在某些实施方式中，所述毒素去除试剂能够以共价的方式结合所述毒素。共价结合可以是基于任何在渗透交换的情形下可能形成的共价键，例如二硫键、酯键、腙键、酰腙键、酰肼键等。例如，当巯基修饰的二氧化硅作为毒素去除试剂时，可以与具有谷胱甘肽或半胱氨酸的毒素形成二硫键，进而从生物流体中去除这样的毒素。再例如，当醛基修饰的二氧化硅作为毒素去除试剂时，可以与带氨基的化合物(如氨基酸、多肽类毒素)形成席夫碱(腙键)，进而从生物流体中去除这样的毒素。
在某些实施方式中，所述毒素去除试剂具有能够与毒素形成共价键的基团，例如氢原子、羟基、羧基、巯基、醛基、氨基、酰腙键、酰肼键。在某些实施方式中，所述毒素去除试剂是具有羟基、羧基、巯基、醛基、氨基、酰腙键、或酰肼键修饰的二氧化硅。
在某些实施方式中，所述毒素去除试剂能够通过离子键结合所述毒素。离子键可以是基于任何在渗透交换的情形下可能形成的离子交换的结合。在某些实施方式中，所述毒素去除试剂具有能够与所述毒素形成离子键的基团，例如，氯离子、硫酸根离子、钙离子、碳酸根离子等。举例来说，离子交换树脂中的氯离子可以与毒素银离子形成离子键，进而除去生物流体中的毒素银离子。适合通过此种方式去除的毒素可以是有毒金属离子，例如，铜离子、铝离子、汞离子、钡离子、铅离子、铬离子、镉离子、银离子等。
在某些实施方式中，所述毒素去除试剂能够降解所述毒素。在某些实施方式中，所述毒素去除试剂为生物催化剂或化学催化剂。生物催化剂可以是具有催化反应功能的生物大分子，例如酶类。例如，所述毒素去除试剂可以是酶而毒素可以是底物，通过酶和底物之间的相互作用，作为毒素去除试剂的酶可以将底物分解或消化。例如，作为毒素去除试剂的水解酶可以将酯类毒素水解并去除生物流体中的酯类毒素；作为毒素去除试剂的胰酶可 以将蛋白类毒素消化水解；作为毒素去除试剂的核酸酶可以将核酸类毒素消化水解。化学催化剂可以是具有催化反应功能的化学分子。示例性的化学类催化剂可以是二氧化锰，其作为毒素去除试剂时可以分解并去除生物流体中的活性氧物种(ROS)。在某些实施方式中，所述毒素去除试剂具有能够降解或破坏毒素分子的基团或结构域，例如酶的催化结构域，或者化学分子的催化基团等。
在某些实施方式中，所述毒素去除试剂选自活性炭、聚维酮、交联聚维酮、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(例如，请参见美国专利US8,636,929、US9,011,912、PCT国际专利申请WO/2013/090842A3、CAS No.402932-23-4、商品名
Figure PCTCN2019077749-appb-000005
)、微粉硅胶、硅藻土，及其任意组合。
在某些实施方式中，毒素去除试剂不一定需要是生理可接受的材料。本领域技术人员可以理解，在渗透交换的条件下，毒素去除试剂与生物流体处于物理分离的状态，但生物流体中的毒素可以渗透到毒素去除试剂的一侧。毒素去除试剂在渗透交换的条件下优选地不会渗透到生物流体中，因此其本身不一定必须是生理可接受的。
2. 毒素
本申请提供的组合物中的毒素去除试剂能够去除生物流体中的毒素。
2.1毒素种类
在某些实施方式中，所述毒素包含一种或多种体内代谢产物、引起中毒的外源物质(例如药物、农药、化工毒物、食源性毒物、或者生物类外源毒素等)、或引起疾病的分子。
“体内代谢产物”是源于生物体内细胞新陈代谢、或者食物经体内消化代谢、或者生物体在疾病状态下产生的产物。例如，尿素(由蛋白质代谢产生)、肌酐(由肌肉代谢产生)、硫酸吲哚酚(至少部分由食物中的吲哚类物质代谢产生)等。体内代谢产物通常可以通过尿液排泄，但当肾功能减退、肾脏清除率下降时，会导致代谢产物在血液和组织中不断蓄积并参与尿毒症综合征的发展。因在体内蓄积而参与或导致尿毒症的毒素也被称为尿毒症毒素。在某些实施方式中，本申请的组合物可以去除尿毒症毒素。
在本申请的一些实施方案中，体内代谢产物可包括尿素、肌酸酐、尿酸、胍-ADMA、β 2-微球蛋白、细胞因子、甲状旁腺激素、硫酸吲哚酚、同型半胱氨酸、对甲酚、马尿酸、活性氧物种(简称ROS，例如过氧化物、超氧化物、羟基自由基、单个氧原子等)、尿毒 症毒素(例如AGE产物(3-脱氧葡糖醛酮、果糖赖氨酸、乙二醛、丙酮醛、戊糖素)、1-甲基腺苷、1-甲基鸟苷、1-甲基肌苷、非对称性二甲基精氨酸、α-酮基-δ-胍戊酸、α-N-乙酰精氨酸、阿拉伯糖醇、精氨酸、苯甲醇、β-胍基丙酸、β-促脂解激素、肌酸、胞啶、N,N-二甲基甘氨酸钠、赤藻糖醇、γ-胍丁酸、次黄嘌呤、丙二醛、甘露醇、甲基胍、肌醇、N,N-二甲基鸟苷、N-乙酰胞嘧啶核苷、N-苏氨酰氨甲酰磷酸腺苷、乳清酸、乳清酸核苷、草酸盐、苯乙酰谷氨酰胺、假尿苷、对称性二甲基精氨酸、山梨醇、脒基牛磺酸、苏糖醇、胸腺嘧啶、尿嘧啶、尿苷、黄苷、2-甲氧基间苯二酚、3-脱氧葡糖醛酮、3-羧基-4-甲基-5-丙基-2-呋喃丙酸(CMPF)、果糖酰赖氨酸、同型半胱氨酸、对苯二酚、吲哚-3-乙酸、犬尿氨酸、犬尿喹啉酸、瘦蛋白、褪黑素、甲基乙二醛、Nε-羧甲基赖氨酸、甲酚、戊糖苷、苯酚、对羟基马尿酸、丁二胺、喹啉酸、视黄醇结合蛋白、亚精胺、精胺、肾上腺髓质素、心房钠尿肽、β-内啡肽、胆囊收缩素、克拉拉细胞蛋白(CC16)、人补体因子D、胱抑素C、脱粒抑制蛋白Ic、δ-睡眠诱导肽、内皮缩血管肽、透明质酸、白细胞介素-1β、白细胞介素-6、κ-免疫球蛋白轻链、λ-免疫球蛋白轻链、甲硫氨酸-脑啡肽、神经肽Y、甲状旁腺激素、肿瘤坏死因子-α)、硫化氢、胆红素等。
除了体内代谢产物之外，本申请所述的毒素还可以是引起中毒的外源物质。外源物质可以是在生物体内并非天然存在的物质(例如化工毒物等)，或者是主要是通过外源途径摄入生物体内(例如服用的激素类天然药物等)。在某些实施方式中，引起中毒的外源物质可以包括药物、农药、化工毒物、食源性毒物、或者生物类外源毒素。
药物的误服、剂量过量或滥用可能会引起中毒。在本发明的一些实施方案中，引起中毒的药物可包括镇静催眠类药物、抗精神病类药物、心脑血管类药物、解热镇痛类药物、抗寄生虫病药、抗微生物药、麻醉及麻醉辅助药、呼吸系统药物、循环系统药物、消化系统药物、泌尿系统药物、血液系统药物、代谢及内分泌药物、抗变态反应药物、肿瘤治疗药物、免疫调节药物、妇产科用药、男性用药、抗炎药、中药等。
镇静催眠类药物例如巴比妥类药、抗焦虑药、抗组胺药、抗精神病药、镇痛药、以及其他镇静催眠类药物等。巴比妥类药为巴比妥酸的衍生物，例如巴比妥、苯巴比妥、异戊巴比妥、速可眠、硫喷妥钠等。抗焦虑药包括苯二氮卓类(例如地西泮、硝西泮、艾司唑仑、阿普唑仑、佐匹克隆等)、安宁类(例如甲丙氨酯、肌安宁、氯硝安定等)、二苯甲烷类(例如安泰乐、丁硫二苯胺、哌苯乙醇等)和其他类(例如芬那露、异丁嗪酒石酸盐、 三甲氧啉、谷维素、太息定)。其他镇静催眠药可包括例如水合氯醛、安眠静、格鲁米特、甲乙哌啶酮、阿达林、炔己蚁胺、天麻素、溴化物等。
抗精神病类药物又称强安定药或神经阻滞剂，是用于治疗精神分裂症及其它精神病性精神障碍的药物。常见的抗精神病类药物包括吩噻嗪类(氯丙嗪、硫达利嗪、奋乃静、三氟拉嗪、氟奋乃静、氟奋乃静葵酸)、丁酰苯类(氟哌啶醇、氟哌啶醇葵酸、五氟利多)、苯甲酰胺类(舒必利)、二苯二氮卓类(氯氮平、奥氮平)、苯异恶唑类(利培酮)、苯异硫唑类(齐拉西酮)、二苯硫氮卓类(喹硫平)和喹诺酮类(阿立哌唑)。
心脑血管类药物是作用于心血管系统的药物。常见的心脑血管类药物包括抗心绞痛药(例如硝酸甘油、β肾上腺素受体拮抗药、钙离子拮抗剂等)、抗心律失常药(例如利多卡因、胺碘酮、维拉帕米等)、抗高血压药(例如缬沙坦、贝那普利、美托洛尔、硝苯地平等)、抗心功能不全药(例如螺内酯、呋塞米、厄贝沙坦等)、周围血管扩张药(肼苯哒嗪、硝普钠、硝酸酯类、α-肾上腺素受体阻断药、钙拮抗剂、血管紧张素转化酶抑制剂等)等。
解热镇痛类药物是能使发热病人的体温恢复正常，但对正常人的体温没有影响的药物。这类药物也具有中等强度的镇痛作用，但其强度不及吗啡及其合成代用品。常用的解热镇痛药按化学结构可分为水杨酸类(例如阿司匹林、赖氨酸阿司匹林)、苯胺类(例如对乙酰氨基酚)、吡唑酮类(例如安乃近)、吲哚类(例如吲哚美辛)、芳基乙酸类(例如双氯芬酸钠)、芳基丙酸类(例如布洛芬)、选择性环氧酶-2抑制剂(例如西乐葆、尼美舒利、美洛昔康)。
常见的引起中毒的农药包括有机磷、除草剂、拟除虫菊酯、阿维菌素、杀鼠剂。其他常见的农药品种包括百草枯、敌敌畏、乐果、草甘膦、草铵膦、毒死蜱、氧化乐果、溴敌隆、溴鼠灵、辛硫磷、吡虫啉、杀虫双、对硫磷、甲拌磷、内吸磷、敌百虫、马拉硫磷、六六六、滴滴涕、狄氏剂、异狄氏剂、艾氏剂、磷化铝农药、腈氯苯苯醚菊酯、氟乙酰胺、毒鼠强、五氯酚、二硝甲酚、敌草隆、敌草腈、沙蚕毒素、鱼藤酮、烟碱、氯化甲撑萘、甲脒、苏云金杆菌制剂、敌鼠钠盐、杀鼠灵、抗鼠灵、代森铵、福美锌、甲基汞、和2,4D丁酯。
化工毒物的例子可以包括但不限于，来源于有毒植物(例如鸡母珠、夹竹桃、曼陀罗、秋水仙、岩沙海葵、羽扇豆、野百合)的毒素，氰化物(例如氰化钠、氰化钾、氰化钙、氰化钡、氰化钴、氰化亚钴、氰化钴钾、氰化镍、氰化镍钾、氰化铜、氰化银、氰化银钾、 氰化锌、氰化镉、氰化汞、氰化汞钾、氰化铅、氰化铈、氰化亚铜、氰化金钾、氰化溴、氰化氢、氢氰酸)、二甲苯、汽车防冻液、三氧化二砷、亚砷酸钠、亚砷酸钾、五氧化二砷、三氯化砷、亚硒酸钾、硒酸钠、硒酸钾、氧氯化硒、氯化汞、氰氧化汞、氧化镉、羰基镍、五羰基铁、叠氮化钠、叠氮化钡、叠氮酸、氟化氢、黄磷、磷化钠、磷化钾、磷化镁、磷化铝、氟、磷化氢、砷化氢、硒化氢、锑化氢、一氧化氮、四氧化二氮、二氧化硫、二氧化氯、二氟化氧、三氟化氯、三氟化磷、四氟化硫、四氟化硅、五氟化氯、五氟化磷、六氟化硒、六氟化碲、六氟化钨、氯化溴、氯化氰、溴化羰、氰、碘化氰、砷、亚砷酸钙、亚砷酸锶、亚砷酸钡、亚砷酸铁、亚砷酸铜、亚砷酸银、亚砷酸锌、亚砷酸铅、亚砷酸锑、乙酰亚砷酸铜、砷酸、偏砷酸、焦砷酸、砷酸铵、砷酸钠、偏砷酸钠、砷酸氢二钠、砷酸氢二钠、砷酸二氢钠、砷酸钾、砷酸二氢钾、砷酸镁、砷酸钙、砷酸钡、砷酸铁、砷酸亚铁、砷酸铜、砷酸银、砷酸锌、砷酸汞、砷酸铅、砷酸锑、三氟化砷、三溴化砷、三碘化砷、二氧化硒、亚硒酸、亚硒酸氢钠、亚硒酸镁、亚硒酸钙、亚硒酸钡、亚硒酸铝、亚硒酸铜、亚硒酸银、亚硒酸铈、硒酸钡、硒酸铜、硒化铁、硒化锌、硒化镉、硒化铅、氯化硒、四氯化硒、溴化硒、四溴化硒、氯化钡、铊、氧化亚铊、氧化铊、氢氧化铊、氯化亚铊、溴化亚铊、碘化亚铊、三碘化铊、硝酸铊、硫酸亚铊、碳酸(亚)铊、磷酸亚铊、铍、氧化铍、氢氧化铍、氯化铍、碳酸铍、硫酸铍、硫酸铍钾、铬酸铍、氟铍酸铵、氟铍酸钠、四氧化锇、氯锇酸铵、五氧化二钒、氯化钒、钒酸钾、偏钒酸钾、偏钒酸钠、偏钒酸铵、聚钒酸铵、钒酸铵钠、砷化汞、硝酸汞、氟化汞、碘化汞、氧化汞、亚碲酸钠、硝普钠、磷化锌、溴、溴化氢、锗烷、三氟化硼、三氯化硼、有毒金属离子(例如铜离子、铝离子、汞离子、钡离子、铅离子、铬离子、镉离子、银离子)等。
食源性毒素的例子可以包括但不限于，河豚鱼毒素、白果毒素、海豚毒素、麻痹性贝类毒素、腹泻性贝类毒素、神经性贝类毒素、遗忘性贝类毒素、西加毒素、鲭鱼毒、芋螺毒素、聚醚类毒素、西加毒素、石房蛤毒素、刺尾鱼毒素、肉毒毒素、氰甙类、亚麻苦甙、苦杏仁甙、氢氰酸、苯甲醛、棉酚类、龙葵素、毒蕈毒、毒肽、毒伞肽类、亚硝酸盐、组胺类、铅、镉、汞、砷、氟、多环芳烃、多氯联苯、甲醇、米酵菌酸、毒黄素、雪腐镰刀菌烯醇、镰刀菌烯酮-X、T2毒素、麦类赤霉病毒、黄曲霉毒素、赭曲霉毒素、佛波醇酯、海兔毒素、大田软海绵酸、端镰菌肽、3-硝基丙酸、鹿花蕈素、乙醇、盐酸克伦特罗(瘦肉精)、咖啡因、海洛因、和茶碱等。
生物类外源毒素的例子可以包括但不限于，蛇毒、蝎毒、水母毒等。
在本发明的一些实施方案中，所述引起疾病的分子选自下组：游离DNA、游离RNA、炎症因子、抗体(例如针对自身抗原的抗体)、抗原(例如致过敏的抗原)、蛋白质碎片、致病微生物(例如病毒、细菌)等。
2.2毒素的存在形式
在某些实施方式中，所述毒素在所述生物流体中游离存在、与所述生物流体中的物质结合存在、或者两者皆有。
生物流体中通常存在其他生物成分，例如蛋白质(例如血浆蛋白)、糖类、脂类、核酸等分子，这些分子可能会与毒素形成结合。例如，白蛋白在血液中大量存在，可以结合各种体内代谢产物，例如硫酸吲哚酚，导致其难以被清除。在某些实施方式中，与所述毒素结合的所述物质包括血液组织中的成分(例如血浆蛋白、白蛋白、红细胞)、脂肪组织中的成分(例如脂肪、单泡脂肪细胞、多泡脂肪细胞)、结缔组织中的成分(例如蜂窝组织、胶原纤维、弹性纤维和网状纤维)、骨组织中的成分(例如磷酸钙)等。
在某些实施方式中，至少部分所述毒素与所述生物流体中的物质形成可逆结合。可逆结合是指毒素与其结合的物质可以自发地结合和解离，并且这种结合和解离可以达到一种动态平衡。当达到动态平衡时，游离的毒素和结合的毒素的浓度或量基本保持不变。如果游离毒素的浓度低于动态平衡时的浓度，则结合的毒素就会通过解离释放出来。反之，如果游离的毒素浓度高于动态平衡时的浓度，则会促使游离的毒素结合。
在某些实施方式中，所述可逆结合包括通过非共价键(例如离子-偶极相互作用、偶极-偶极相互作用、氢键、阳离子-π体系相互作用、π-π堆积作用、疏水效应、和/或范德华力作用等)形成的可逆结合。非共价键的作用力通常的作用强度为，离子-偶极相互作用力(50～200kJ/mol)；偶极-偶极相互作用(5～50kJ/mol)，属于分子间相互作用；氢键(4～120kJ/mol)；阳离子-π体系相互作用(5～80kJ/mol)；π-π堆积作用(0～50kJ/mol)；疏水效应(0～50kJ/mol)；范德华力作用(小于5kJ/mol)。对于上述非共价键的作用力的描述和介绍可以参见，例如《生物药剂学与药物动力学》第五版，人民卫生出版社，主编刘建平，第94页；Supramolecular Chemistry:From Molecules to Nanomaterials,Online 2012John Wiley & Sons,Ltd.
毒素与生物流体中的物质(例如蛋白)结合的强度可以用Kd值表示。在一些实施方案中，所述毒素与所述生物流体中的物质结合的Kd值至少为10 2μmol/L、10 3μmol/L、 10 4μmol/L、10 5μmol/L、10 6μmol/L、或10 7μmol/L。Kd值越大，表明结合越强。一般而言，高蛋白结合毒素的Kd值为10 5～10 7μmol/L，低结合或中等结合强度Kd值为10 2～10 4μmol/L。
在某些实施方式中，所述毒素与所述生物流体中的物质(例如蛋白)的结合的Kd值至少为10 5～10 7μmol/L、10 5.5～10 7μmol/L、或10 6～10 7μmol/L。
本领域技术人员可以理解，结合越强的毒素越不容易清除。某些毒素比较容易与血浆蛋白等形成较强的结合，例如具有较高的Kd值，导致难以通过现有技术中的方法去除。
在某些实施方式中，在生物流体中的毒素主要以结合形式存在。在这样的情况下，生物流体中的游离毒素量相对不高，通过现有技术中的单纯的渗透平衡最多只能除去部分游离的毒素，但大多数结合状态的毒素仍然在生物流体内得不到有效的清除。
在某些实施方式中，在所述生物流体中至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％的所述毒素以结合形式存在。在某些实施方式中，在所述生物流体中至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％的所述毒素以与血浆蛋白结合的形式存在。毒素与生物流体中的物质(例如蛋白或血浆蛋白)的结合可以通过本领域已知的多种方法进行检测，例如但不限于，平衡透析法、超滤法、超速离心法、凝胶过滤法、光谱法(包括紫外可见光谱、荧光光谱、红外光谱、圆二色谱、拉曼光谱)、光学生物传感器法等。
在某些实施方式中，所述毒素能够可逆结合生物流体中的蛋白，这样的毒素包括但不限于：硫酸吲哚酚、非对称性精氨酸、高半胱氨酸、苯乙酸、对甲酚、AGE产物(3-脱氧葡糖醛酮、果糖赖氨酸、乙二醛、丙酮醛、戊糖素)、马尿酸、尿毒症毒素、硫化氢、胆红素等。
在某些实施方式中，所述毒素主要以结合形式存在(例如至少50％、60％、70％、80％、90％以上以结合形式存在)并且与生物流体内的物质(例如蛋白)具有较强的结合(例如，Kd值至少为10 4μmol/L，10 5μmol/L或更高)。例如，替诺昔康(一种抗炎药物)与血浆蛋白结合率为99％，洋地黄毒苷(一种用于治疗充血性心功能不全药物)与血浆蛋白结合率为91％。
在某些实施方式中，本申请提供的组合物中的毒素去除试剂不同于生物流体中与毒素结合的物质。例如，当待处理的生物流体中的毒素与血浆蛋白(例如白蛋白)结合时，本申请组合物中的毒素去除试剂可以不选用血浆蛋白(例如白蛋白)。在某些实施方式中， 本申请提供的组合物中的毒素去除试剂不是生物流体中的存在的物质(例如，可以是人工合成的聚合物、无机物等)。
在某些实施方式中，本申请提供的组合物中的毒素去除试剂不具有免疫原性。这样的组合物在用于直接接触生物体时(例如用于腹膜透析时)具有优势。
在某些实施方式中，本申请提供的组合物中的毒素去除试剂为人造材料。人造材料是指不存在于生物流体中的材料，或者通过人工合成或制备得到的材料。例如硅藻土、二氧化硅、活性炭等都属于人造材料。
在某些实施方式中，本申请提供的组合物中的毒素去除试剂与毒素的结合作用不同于生物流体中的物质与毒素的结合作用。例如，毒素去除试剂为多孔材料，通过多孔吸附作用与毒素结合，而在生物流体中的毒素主要通过例如氢键作用与白蛋白结合。不受理论限制，但认为使用提供不同结合作用的毒素去除试剂有助于打破生物流体中原有的毒素结合的动态平衡，从而促进结合的毒素从生物流体中解离，并被去除。
在某些实施方式中，本申请提供的组合物中的毒素去除试剂对毒素的吸附或结合的作用强于所述毒素与生物流体内的物质的结合。例如，跟毒素与生物流体内的物质(例如血浆蛋白)之间的结合相比，毒素去除试剂与毒素结合的Kd值更高(例如毒素与毒素去除试剂的结合Kd值为10 5μmol/L，而毒素与生物流体物质的结合Kd值为10 4μmol/L)，结合的比例更大(例如毒素与毒素去除试剂的结合比例为大于80％，而毒素与生物流体物质的结合比例为50％)，和/或结合种类更稳定(例如毒素与毒素去除试剂以共价键结合，而毒素与生物流体物质以非共价键结合)。
3. 渗透剂
在本发明的某些实施方式中，本发明的组合物中包括渗透剂。渗透剂能够提供与生物流体基本等渗或高于等渗的渗透压。在某些实施方式中，所述渗透剂能够提供约290-310mmol/L、260-340mmol/L、或260-350mmol/L(例如约280mOsm/L、283mOsm/L、284mOsm/L、285mOsm/L、287mOsm/L、290mOsm/L、295mOsm/L、300mOsm/L、310mOsm/L、315mOsm/L、320mOsm/L、325mOsm/L、330mOsm/L、340mOsm/L或350mOsm/L)的渗透压。当渗透剂提供与生物流体基本等渗的渗透压时，可以尽可能避免生物流体中的电解质、糖、水分之类的物质渗出，或者不对生物流体的生物性质产生过度的不利影响。当渗 透剂提供的渗透压高于生物流体的渗透压时，可以允许生物流体中的水分渗出，这有利于某些肾脏功能有损伤的患者排出体内多余的水分。
在用于处理生物流体时，合适的渗透剂可以是无毒的、生物学惰性的、和/或可代谢的。
在某些实施方式中，所述渗透剂可以包括糖类、氨基酸、多肽、甘油、碳酸盐或其类似物或任意组合。渗透剂可以是小分子量的(例如分子量不高于500g/mol)，或者大分子量的(例如分子量高于500g/mol)。
各种适合作为渗透剂的糖都可以作为渗透剂使用，可以是单糖、寡糖(例如，二糖、三糖等)和多糖。单糖的例子包括，但不限于，葡萄糖、果糖、山梨糖醇、木糖醇、氨基糖及其衍生物等。寡糖或多糖包括一种或多种单糖的寡聚物或多聚物，各个单糖之间可以通过例如α-1,4糖苷键连接、α-1,6糖苷键连接等。在某些实施方式中，所述寡糖或多糖是可以被例如人体或动物体代谢的。
在某些实施方式中，合适的糖类渗透剂可以包括，例如葡萄糖、非葡萄糖的单糖(例如山梨糖醇、果糖、木糖醇等)、或单糖聚合物(例如葡萄糖聚合物、麦芽糖糊精、艾考糊精、壳寡糖(例如请参见中国专利申请CN107375318A))。在某些实施方式中，所述葡萄糖聚合物包括艾考糊精。
氨基酸类渗透剂可以选自天然氨基酸、非天然氨基酸、其类似物、衍生物及其组合。氨基酸类渗透剂的实例包括，但不限于，亮氨酸、缬氨酸、苏氨酸、异亮氨酸、赖氨酸、组氨酸、蛋氨酸、苯丙氨酸、色氨酸、丙氨酸、脯氨酸、精氨酸、甘氨酸、丝氨酸、酪氨酸、天冬氨酸、谷氨酸、以及其衍生物和任意组合等。示例性的氨基酸类渗透剂可参见美国专利5,629,025。
肽类渗透剂也可以作为可能的渗透剂(例如，请参见，美国专利4,906,616，美国专利6,380,163，美国专利5,039,609)。
4. 含量和其他成分
在某些实施方式中，本申请提供的组合物中所述毒素去除试剂与渗透剂的含量比例(重量/重量)为1:1750到1:4(例如：1:1750到1:5，1:1500到1:4，1:1500到1:5，1:1000到1:5，1:750到1:6；1:300到1:6；1:75到1:6；1:30到1:6；1:10到1:6；1:1500到1:5；1:1500到1:10；1:1500到1:30；1:1500到1:75；1:1500到1:150；1:1500到1:300；1:1500到1:750。
在某些实施方式中，当本申请提供的组合物被配置成直接用于渗透交换的透析液时，所述透析液中所述渗透剂的含量范围(重量/体积)为0.05％-10％，0.5％-10％，1％-10％，1.5％-10％，1.5％-9％，1.5％-8％，1.5％-7.5％，1.5％-6％，1.5％-5％等。例如，当渗透剂是艾考糊精时，其在用于渗透交换的透析液中的含量范围(重量/体积)可以为3％-8％，5-7.5％，或者约7.5％。例如，当渗透剂是葡萄糖时，其在用于渗透交换的透析液中的含量范围(重量/体积)可以为0.05％-2％，0.05％-1.5％，0.05％-1.0％，0.05％-0.75％，0.5％-1.5％，或者约1.5％。
在某些实施方式中，当本申请提供的组合物被配置成直接用于渗透交换的透析液时，所述透析液中所述毒素去除试剂的含量范围(重量/体积)为至少0.0001％、至少0.0005％、至少0.001％、至少0.005％、至少0.01％、至少0.025％、至少0.05％、至少0.075％、至少0.1％、至少0.125％、至少0.15％、至少0.175％、至少0.2％、或至少0.25％。在某些实施方式中，所述透析液中所述毒素去除试剂的含量范围(重量/体积)不高于4％、不高于3.5％、不高于3.3％、不高于3.0％、不高于2.8％、不高于2.5％、不高于2.3％、不高于2.0％、不高于1.8％、不高于1.6％、不高于1.4％、不高于1.2％、不高于1.0％、不高于0.8％、不高于0.6％、或不高于0.4％。在某些实施方式中，所述透析液中所述毒素去除试剂的含量范围(重量/体积)为分别选自上面组合的两个端值的任意组合得到的数值范围，例如但不限于至少0.0001％到不高于4％、至少0.005％到不高于4％、至少0.01％到不高于4％，等等，限于篇幅在此不再一一列出。在某些实施方式中，所述毒素去除试剂为活性炭、聚维酮、硅藻土、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(例如Soloplus)、或微粉硅胶或其任意组合，并且当所述组合物被配置成直接用于渗透交换的透析液时，所述透析液中所述毒素去除试剂的含量范围(重量/体积)符合上述列出的各种范围。
在本申请的一些实施方案中，本发明的组合物还可包含一种或多种在渗透交换的条件下适用的组分，例如缓冲剂、电解质、其他适宜渗透交换的组分。
在一些实施方案中，本申请提供的组合物中可以进一步含有合适的缓冲剂以提供所需的pH值。缓冲剂的非限制性的例子包括乳酸盐、碳酸氢盐、柠檬酸盐、异柠檬酸盐、磷酸二氢盐、磷酸氢盐、磷酸盐、丙酮酸盐、琥珀酸盐、延胡索酸盐、乙酸盐、苹果酸盐、草酰乙酸盐、氯化物、pK 1为7-13的氨基酸(组氨酸、甘氨酸、丙氨酸)及其类似物中的一种或多种。
在一些实施方案中，当本申请的组合物被配置成与生物流体进行渗透交换的溶液时，所述溶液可以与所述生物流体的pH值接近，或者至少是生理可接受水平。例如，所述溶液在室温(20-25℃)下测量的pH可为4.0至8.0，5.0至8.0，6.0至8.0，4.0至7.8，4.0至7.0，5.0至7.5，或6.5至7.5。缓冲剂在所述溶液中的浓度可以为，例如但不限于，1.0至200mM，2.5至150mM，5至100mM，5至75mM，10至50mM，20至30mM。
电解质表示包含游离离子并且具有导电性的物质。电解质可完全解离成阳离子和阴离子，优选地不会使组合物的pH发生显著的变化。电解质的阳离子的非限制性的例子包括碱金属阳离子(例如Na +和K +)、碱土金属阳离子(Ca 2+和Mg 2+)。电解质的阴离子的非限制性的例子包括Cl -。在某些实施方式中，所述电解质可以选自钠盐、钙盐、镁盐和钾盐中的一种或多种。
在一些实施方案中，所述的组合物，其中所述组合物是经过灭菌的。可以使用本领域公知的多种方法进行灭菌，例如但不限于，高压灭菌、蒸汽灭菌、紫外线灭菌、过滤灭菌或其任意组合。
在一些实施方案中，所述组合物是固体制剂、半固体制剂或液体制剂。固体或半固体形式的组合物可以很方便地与合适的溶媒(例如无菌水)配置成所需的液体制剂。液体制剂也可以是不同浓缩程度的液体浓缩物，可以以适当的方式与溶媒混合后配置成所需的液体制剂。
透析溶液
在另一方面，在此提供含有本申请组合物的透析溶液。透析溶液可以是小分子溶液，也可以包括含有大分子(例如聚合物等)的溶液或胶体溶液。在某些实施方式中，所述透析溶液可以作为腹膜透析溶液，或者血液透析溶液。在某些实施方式中，本申请提供的透析溶液的pH值和/或电解质浓度是生理可接受的。
在某些实施方式中，所述透析溶液是浓缩物的形式，也可以是即用的形式。在某些实施方式中，所述透析溶液可以是单一的溶液(例如容纳在单一容器中)，或者可以是两种或两种以上透析溶液组成部分(例如分别容纳在两个或多个容器中)。不受理论的限制，但将透析溶液分成不同的组成部分有利于避免组合物中的成分产生不必要的相互影响(例如中性或碱性的pH可能导致葡萄糖聚合物在高温灭菌期间降解)。
在某些实施方式中，所述透析溶液分成两个或两个以上组成部分，其被保持彼此分离直到需要使用时，例如直到需要配置成即用型透析溶液。所述组成部分可以具有不同的形式，例如可以都是流体形式，或者至少有一个组成部分是干粉形式(例如缓冲剂成分)，或者至少有一个组成部分可以是流体浓缩物形式(例如电解质浓缩物)。任选地，干粉形式的组成部分在与其他组成部分混合前用稀释剂进行溶解，或者浓缩物可以使用稀释剂按照一定比例(例如但不限于1:35、1:45或1:200)进行稀释。任何适宜的稀释剂都可以使用，例如无菌水，任选地可以不含有电解质。
在某些实施方式中，所述透析溶液的第一个组成部分含有葡萄糖聚合物，并且其pH在3.5到5.5的范围内。pH的调节可以使用一种或多种生理上可接受的酸(例如乳酸、丙酮酸、乙酸、柠檬酸、盐酸等等)。或者也可以使用二氧化碳来替代酸，用于pH的调节。在某些实施方式中，所述透析溶液的第二个组成部分可以含有缓冲溶液，其中所述缓冲溶液能够提供约7到约9范围的pH。合适的缓冲溶液可以含有例如，碳酸氢钠、氯化钠、乳酸钠、一种或一种以上pK 1值介于7到13之间的氨基酸(例如，组氨酸、甘氨酸、丙氨酸等)或其组合。
本申请提供的毒素去除试剂可以存在于上述第一个组成部分中，或者第二个组成部分中，或者存在于另外的第三个组成部分中。
在某些实施方式中，所述透析溶液的两个或两个以上组成部分可以以任何适合的方式容纳在容器中，例如，可以使用多个可以流体连通的容器来分别容纳透析溶液的不同组成部分，在需要配置成直接使用的透析溶液时，将容器流体操作性连通(例如通过开启流体连通的阀门，或者将多隔室袋之间的密封打破)，从而获得即用型透析溶液。
在某些实施方式中，所述透析溶液还可以进一步含有抗凝血的试剂，例如肝素、柠檬酸盐等。
试剂盒
在另一方面，本申请还提供了一种用于生物流体净化的试剂盒，其含有本申请所述的组合物。在某些实施方式中，所述组合物是经过灭菌的。
在某些实施方式中，所述组合物在所述试剂盒中可以以单一的组合物形式存在，或者可以以两个或两个以上组成部分的形式存在。在某些实施方式中，所述组合物或者其组成 部分是经过灭菌的。在某些实施方式中，所述组合物或者至少一种所述组成部分是固体制剂、半固体制剂或液体制剂。所述组成部分可以具有不同的形式，例如可以都是流体形式，或者至少有一个组成部分是干粉形式(例如缓冲剂成分)，或者可以是流体浓缩物形式(例如电解质浓缩物)。任选地，干粉形式的组成部分在与其他组成部分混合前用稀释剂进行溶解，或者浓缩物可以使用稀释剂按照一定比例(例如但不限于1:35、1:45或1:200)进行稀释。
在某些实施方式中，所述两个或两个以上组成部分容纳在不同的容器中。在某些实施方式中，所述两个或两个以上组成部分被保持彼此分离。在某些实施方式中，所述两个或两个以上组成部分分别容纳在两个或两个以上能够被可操作地流体连通的容器中。在需要使用时，可以再将这些组成部分混合以配置成需要使用的产品，例如即用型透析溶液。任何适宜的稀释剂都可以使用，例如无菌水，任选地可以不含有电解质。
在某些实施方式中，所述试剂盒进一步包含可用于生物流体净化的半渗透介质。
透析装置
在另一方面，本申请提供了一种透析装置，其中包含本申请提供的组合物，并且所述装置被配置为允许所述组合物能够与待透析的生物流体进行渗透交换。在某些实施方式中，所述透析装置可以适用于血液透析或者腹膜透析。
在某些实施方式中，本申请提供的透析装置包含：接收待透析的生物流体的第一通路，和用于容纳本申请提供的组合物的第二通路，以及将所述第一通路与所述第二通路分离的半渗透的介质。所述半渗透的介质可以允许待透析的生物流体中的毒素与所述组合物进行渗透交换。
在某些实施方式中，所述透析装置是一次性的。例如所述透析装置可以被安装到透析主机上，并且在完成透析过程后可以被拆卸丢弃。透析主机可以包括进行透析处理必须的各种装置和零部件，例如透析泵、超滤泵、比例配液装置、液体恒温装置、跨膜压监控、电导率监控、血泵、肝素泵、动静脉压监测、气泡监测、漏血监测、置换液平衡秤、双管泵中的一种或多种。当所述透析装置被安装到透析主机时，可以被被配置为与透析主机可操作地连接，使得待透析的生物流体经过透析主机进入所述透析装置中用于接收生物流体的第一通路，通过透析装置中的半渗透介质，与透析装置中的本申请组合物进行渗透交换。 在某些实施方式中，所述生物流体在完成渗透交换后，可以通过透析主机再回输到生物体内。在某些实施方式中，所述透析主机还可以进一步具有专用软件，其可以控制透析的过程(例如温度、压力、抗凝血试剂的加入等)。
在某些实施方式中，所述透析装置可以用于人工肾脏(例如，具体可参见美国专利8,834,400，美国专利8,277,407，美国专利8,012,118，美国专利5,545,131，美国专利4,623,450)、人工肝脏(例如，具体可参见美国专利9,650,609，美国专利9,775,863)、或人工肺(例如，具体可参见美国专利9,717,835，美国专利9,827,534，美国专利9,814,821，美国专利9,795,730，美国专利9,717,839)等，以实现对生物流体中的毒素的清除。
人工肾脏是一种替代肾脏功能的装置，用于帮助尿毒症等患者。主要用于治疗肾功能衰竭和尿毒症。它将血液引出体外利用透析、过滤、吸附、膜分离等原理排除体内过剩的含氮化合物，新陈代谢产物或逾量药物等，调节电解质平衡然后再将净化的血液引回体内。
人工肝脏是指借助一个体外的机械、理化或者生物反应器装置，清除因肝衰竭产生或增加的各种有害物质，补充需肝脏合成或代谢的蛋白质等必须物质，改善患者水、电解质及酸碱平衡等内环境，暂时辅助或替代肝脏相应的主要功能，直至自体肝细胞再生、肝功能恢复，或改善晚期肝病患者的症状，成为肝移植的“桥梁”，提高患者生存率。
人工肺又名氧合器或气体交换器，是一种代替人体肺脏排出二氧化碳、摄取氧气，进行气体交换的人工器官。
生物流体净化方法
在另一方面，本申请还提供了降低生物流体中的毒素的方法。本申请的方法可以包括：a)将所述生物流体在允许渗透交换的条件下接触含有本申请的组合物的渗透溶液，以及b)允许所述组合物降低所述生物流体中的所述毒素的量。
在某些实施方式中，本申请提供的方法能够将生物流体中的毒素的游离量降低到初始游离量的至多50％、至多40％、至多30％、至多20％、至多10％或至多5％。在某些实施方式中，本申请提供的方法能够将生物流体中的毒素的总量(或者非游离的量)降低至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％或至少95％。与用本申请提供的组合物处理之前的生物流体相比，经处理后的生物 流体中的毒素的总量(或者非游离的量)为处理之前的至多90％、至多80％、至多70％、至多60％、至多50％、至多40％、至多30％、至多20％、至多10％、或至多5％。
在某些实施方式中，本申请提供的方法能够将生物流体中的毒素的总量(或者游离浓度、或者非游离的量)降低到生理受益水平。“生理受益水平”是指能够降低疾病风险、或者使生物体因毒素而导致的症状减轻的水平。
在某些实施方式中，所述毒素在所述生物流体中游离存在、与所述生物流体中的物质结合存在、或者两者皆有。在某些实施方式中，至少部分所述毒素与所述生物流体中的物质形成可逆结合。在某些实施方式中，所述毒素与所述生物流体中的物质(例如蛋白)的结合的Kd值至少为10 5～10 7μmol/L、10 5.5～10 7μmol/L、或10 6～10 7μmol/L。在某些实施方式中，在生物流体中的毒素主要以结合形式存在。在某些实施方式中，在所述生物流体中至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％的所述毒素以结合形式存在。在某些实施方式中，在所述生物流体中至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％的所述毒素以与血浆蛋白结合的形式存在。在某些实施方式中，所述毒素能够可逆结合生物流体中的蛋白，这样的毒素包括但不限于：硫酸吲哚酚、非对称性精氨酸、高半胱氨酸、苯乙酸、对甲酚、AGE产物(3-脱氧葡糖醛酮、果糖赖氨酸、乙二醛、丙酮醛、戊糖素)、马尿酸、尿毒症毒素、硫化氢、胆红素等。
在某些实施方式中，在所述允许渗透交换的条件下，所述生物流体中的所述毒素通过渗透交换转移到所述渗透溶液中。允许渗透交换在本申请中是指，在待净化的生物流体与包含本申请的组合物的渗透溶液之间具有毒素的浓度差，即毒素在生物流体中的浓度高于渗透溶液中的浓度。在本申请提供的方法中，含有本申请组合物的渗透溶液可以用于净化生物流体，通过使渗透溶液与生物流体之间进行物质的渗透交换，使得生物流体中的毒素(和/或代谢废物，以及任选地，过量液体)排出至渗透溶液。在某些实施方式中，生物流体中的所需的物质还可以从渗透溶液中转运至生物流体。一种常见的净化生物流体的方法是透析，其中通过生物流体与渗透溶液之间的毒素的浓度梯度，使毒素从生物流体中扩散传递通过半渗透介质到渗透溶液中。在某些实施方式中，所述渗透溶液与所述生物流体至少等渗。在某些实施方式中，所述渗透溶液的渗透压高于所述生物流体的渗透压，这样可以允许生物流体中的水分也通过渗透扩散而从生物流体中排出。
在某些实施方式中，步骤a)包括将所述生物流体与所述组合物置于半渗透介质的两侧。
在某些实施方式中，所述半渗透介质为人造半透膜。人造半透膜可以由任何适宜的材料制得，例如，但不限于，陶瓷、石墨、金属、金属氧化物和聚合物。在一些实施方案中，所述人造半透膜可由选自如下的聚合物制得：聚砜、聚酰胺、聚碳酸酯、聚酯、丙烯腈聚合物、乙烯醇聚合物、丙烯酸酯聚合物、甲基丙烯酸酯聚合物和醋酸纤维素聚合物等。
在某些实施方式中，所述半渗透介质为生物半透膜。生物半透膜可以为血管壁膜、淋巴管壁膜、腹膜、肺膜、腺体包膜和黏膜(例如口腔黏膜、鼻粘膜、胃黏膜、肠道黏膜、阴道黏膜)等。
在某些实施方式中，所述生物流体在个体的体内。通过去除个体体内的生物流体中的毒素，可以降低个体体内的毒素的量，从而改善个体的健康状况。个体体内的生物流体可以是体内的血液循环系统中的血液(例如在腹膜透析的情形下)、淋巴系统中的淋巴液等等，或者是与体内循环系统循环连通的输送到体外再回输到体内的生物流体。个体体内的生物流体可以包括，例如，生物体内的血液、淋巴液等。
在某些实施方式中，个体体内的生物流体可以在体内直接与渗透溶液进行渗透交换(例如腹膜透析)。或者，在其他的一些实施方式中，个体体内的生物流体可以被导出体外，在体外与渗透溶液进行渗透交换以及毒素去除后，再被导入体内(例如血液透析)。
例如，在血液透析中，可以从生物体内抽出血液并在体外血液回路中净化血液，随后将净化的血液送回到生物体内。血液在半透膜一侧流动，渗透溶液在半透膜另一侧流动。由于血液与渗透溶液之间对于毒素的跨膜浓度差，血液中的毒素(以及任选地，各种有害以及多余的代谢废物和过多的电解质)通过扩散穿过半透膜而运输至渗透溶液。同时，血液中过量流体在半透膜上产生跨膜压差，从而可通过超滤穿过半透膜而转运至渗透溶液。
例如，在腹膜透析中，可以利用生物体(例如人体或动物)自身的腹膜作为半透膜，由此净化在生物体内的血液。在腹膜透析中，可以用导管将无菌的本申请方法中的渗透溶液引入腹腔，并在足够的时间内允许所述渗透溶液与血液之间进行溶质交换，从而清除生物体内的血液中的毒素。通过提供从渗透溶液至血液的合适的渗透梯度，从而实现液体的流动以使水从血液中流出。这能够在血液中实现合适的酸-碱、电解质和流体平衡。在一段 时间后，通过导管将渗透溶液从体腔排出。不同类型的腹膜透析的例子包括持续不卧床腹膜透析、自动腹膜透析和连续流动腹膜透析。
在某些实施方式中，所述步骤a)包括将所述渗透溶液通过腹腔灌注施用于所述个体。在这样的实施方式中，个体体内的腹膜作为半渗透介质。在某些实施方式中，所述步骤a)包括将所述渗透溶液通过血液透析施用于所述个体。
在某些实施方式中，所述生物流体在体外。在某些实施方式中，在体外的生物流体包括与体内生物流体没有形成流体通路的流体。例如，体外生物流体可以是取自生物体的血液样品、或者经处理的血液制品或生物制品。通过去除个体体外的生物流体中的毒素(例如血液制品、生物制品等)，可以净化生物流体，从而达到后续应用的目的。体外的生物流体的例子包括，但不限于，全血、温血或冷血、脐带血和贮存或新鲜的血液、经处理的血液，例如用至少一种生理溶液(包括但不限于盐水、营养物、添加剂和/或抗凝剂溶液)稀释的血液、血液成分(例如血小板浓缩物(PC)、富含血小板的血浆(PRP)、贫血小板血浆(PPP)、不含血小板的血浆、血浆、鲜冻血浆(FFP)、获自血浆的成分、红细胞压积(PRC)、过渡区材料或血沉棕黄层(BC))、来源于血液或血液成分或来源于骨髓的血液产品、干细胞、细胞培养物、包含骨髓抽吸物的生理溶液等。
治疗疾病的方法
在另一方面，本申请还涉及一种治疗或预防与毒素相关的疾病或状态的方法，包括将本申请所述的组合物在允许渗透交换的条件下接触所述个体的生物流体，以降低所述生物流体中的所述毒素。在另一方面，本申请还提供了将本申请提供的组合物在用于制备治疗或预防与毒素相关的疾病或状态的药物中的用途。在某些实施方式中，所述组合物可降低个体体内的生物流体中的所述毒素。
本领域技术人员能够理解，当个体内的生物流体中(例如血液)存在某些毒素时，这些毒素的存在本身或者过量存在会对个体的生理功能产生不利影响，例如导致代谢功能紊乱，和/或影响多种器官和器官系统，例如心血管系统(高血压、心包炎和心力衰竭)、周围神经系统(多神经病)、骨和关节系统、中枢神经系统(记忆不良、集中力丧失和较迟缓的心智能力)、血液系统(贫血、出血倾向、凝血、免疫状态(免疫抑制))等。
在某些实施方式中，其中所述与毒素相关的疾病或状态包括：肾病(例如尿毒症、肾功能不全等)、心脑血管疾病、血液疾病(例如贫血、出血倾向、凝血等)、自体免疫疾 病(自身免疫、免疫抑制等)、代谢性疾病(高血脂、糖尿病等)、骨科疾病、消化系统疾病(例如肝胆疾病)、药物过量或中毒。
与上述疾病相关的毒素包括，但不限于，尿素、肌酸酐、尿酸、胍-ADMA、β2-微球蛋白、细胞因子、甲状旁腺激素、硫酸吲哚酚、高半胱氨酸、对甲酚、马尿酸、活性氧物种(ROS)、尿毒症毒素(例如AGE产物(3-脱氧葡糖醛酮、果糖赖氨酸、乙二醛、丙酮醛、戊糖素)、1-甲基腺苷、1-甲基鸟苷、1-甲基肌苷、非对称性二甲基精氨酸、α-酮基-δ-胍戊酸、α-N-乙酰精氨酸、阿拉伯糖醇、精氨酸、苯甲醇、β-胍基丙酸、β-促脂解激素、肌酸、胞啶、N,N-二甲基甘氨酸钠、赤藻糖醇、γ-胍丁酸、次黄嘌呤、丙二醛、甘露醇、甲基胍、肌醇、N,N-二甲基鸟苷、N-乙酰胞嘧啶核苷、N-苏氨酰氨甲酰磷酸腺苷、乳清酸、乳清酸核苷、草酸盐、苯乙酰谷氨酰胺、假尿苷、对称性二甲基精氨酸、山梨醇、脒基牛磺酸、苏糖醇、胸腺嘧啶、尿嘧啶、尿苷、黄苷、2-甲氧基间苯二酚、3-脱氧葡糖醛酮、3-羧基-4-甲基-5-丙基-2-呋喃丙酸(CMPF)、果糖酰赖氨酸、同型半胱氨酸、对苯二酚、吲哚-3-乙酸、犬尿氨酸、犬尿喹啉酸、瘦蛋白、褪黑素、甲基乙二醛、Nε-羧甲基赖氨酸、甲酚、戊糖苷、苯酚、对羟基马尿酸、丁二胺、喹啉酸、视黄醇结合蛋白、亚精胺、精胺、肾上腺髓质素、心房钠尿肽、β-内啡肽、胆囊收缩素、克拉拉细胞蛋白(CC16)、人补体因子D、胱抑素C、脱粒抑制蛋白Ic、δ-睡眠诱导肽、内皮缩血管肽、透明质酸、白细胞介素-1β、白细胞介素-6、κ-免疫球蛋白轻链、λ-免疫球蛋白轻链、甲硫氨酸-脑啡肽、神经肽Y、甲状旁腺激素、肿瘤坏死因子-α)、硫化氢、胆红素、引起中毒的外源药物(镇静催眠类药物、抗精神病类药物、心脑血管类药物、解热镇痛类药物、抗寄生虫病药、抗微生物药、麻醉及麻醉辅助药、呼吸系统药物、循环系统药物、消化系统药物、泌尿系统药物、血液系统药物、代谢及内分泌药物、抗变态反应药物、肿瘤治疗药物、免疫调节药物、妇产科用药、男性用药、抗炎药、中药)、农药(例如百草枯、敌敌畏、乐果、草甘膦、甲胺磷、毒死蜱、氧化乐果、溴敌隆、溴鼠灵、辛硫磷、吡虫啉、阿维菌素、毒鼠皇、杀虫双、对硫磷、甲拌磷、内吸磷、敌百虫、马拉硫磷、六六六、滴滴涕、狄氏剂、异狄氏剂、艾氏剂、腈氯苯苯醚菊酯、氟乙酰胺、毒鼠强、五氯酚、二硝甲酚、敌草隆、敌草腈、沙蚕毒素、鱼藤酮、烟碱、氯化甲撑萘、甲脒、苏云金杆菌制剂、敌鼠钠盐、杀鼠灵、抗鼠灵、代森铵、福美锌、甲基汞、和2,4D丁酯)、化工毒物(例如来源于有毒植物(例如鸡母珠、夹竹桃)的毒素，二甲苯、和汽车防冻液)、食源性毒物(例如河豚鱼毒素、白果毒素、海豚毒素、麻痹性贝类毒素、腹泻性贝类毒素、神经性贝类毒素、遗忘性贝类毒素、河豚毒素、西加毒素、鲭鱼毒、肉毒毒素、氰甙类、亚麻苦甙、苦杏仁甙、氢氰酸、 苯甲醛、棉酚类、龙葵素、毒蕈毒、毒肽、毒伞肽类、亚硝酸盐、组胺类、铅、镉、汞、砷、氟、多环芳烃、多氯联苯、甲醇、米酵菌酸、毒黄素、雪腐镰刀菌烯醇、镰刀菌烯酮-X、T2毒素、麦类赤霉病毒、3-硝基丙酸、鹿花蕈素、乙醇、盐酸克伦特罗(廋肉精)、咖啡因、和茶碱)、生物类外源毒素(例如蛇毒、蝎毒、水母毒)、或引起疾病的分子(例如游离DNA、炎症因子、抗体、抗原、蛋白质碎片、和致病微生物)。
通过使用本申请的组合物降低个体的生物流体中的一种或多种这些毒素的水平，可以治疗或预防上述一种或多种疾病。在本申请中，“治疗”包括治愈、减轻症状、减轻疾病严重程度、延缓发病进程、提高病人生活质量等任何对疾病或健康状态的改善。“预防”包括降低疾病的发病风险、延缓疾病发病等。
在某些实施方式中，可以通过降低生物流体中的上述一种或多种毒素而治疗或预防肾病。可以治疗或预防的肾病的例子可以选自下组：尿毒症、慢性肾病、急性肾功能不全、慢性肾盂肾炎、急性肾盂肾炎、慢性肾小球肾炎、急性进行型肾炎综合征、肾病综合征、肾硬化症、间质性肾炎、糖尿病性肾病、局灶性肾小球硬化症、膜性肾病、多发性脓胞性肾综合征、肾血管性高血压和高血压综合征、继发性肾病、高磷血症、高钾血症、高尿酸血症或高钠血症。
实施例
参照如下实施例可更好地理解本发明，然而，如下实施例旨在说明本发明，不应理解为限制本发明的范围。考虑到本文的教导可能进行多种修改和改变，因此这些修改和改变在本发明的范围内。
在实施例中所用的各种试剂、设备和测量方法如下：
试剂
1.基础腹膜透析液
艾考糊精腹膜透析液：百特Baxter爱多尼尔腹膜透析液，艾考糊精含量7.5％，标示渗透压为284osmmol/Kg。
葡萄糖腹膜透析液：百特Baxter低钙腹膜透析液，乳酸盐-G1.5％，含1.5％葡萄糖，标示渗透压为343osmmol/Kg。
2.毒素去除试剂
纳米碳粉：重庆莱美药业股份有限公司生产的商品名为卡纳琳的纳米炭混悬注射液
Kollidon CL-SF：巴斯夫公司生产的交聚维酮CL-SF(
Figure PCTCN2019077749-appb-000006
CL-SF)
Kollidon CL-M：巴斯夫公司生产的交聚维酮CL-M(
Figure PCTCN2019077749-appb-000007
CL-M)
Soluplus：巴斯夫公司生产的产品编号为30446233的
Figure PCTCN2019077749-appb-000008
微粉硅胶：默克股份两合公司生产的产品编号为120091的给药硅土
硅藻土：黑龙江锋滔矿业投资股份有限公司的生物用硅藻土(其中二氧化硅含量92.8％，比表面积在78～84m 2/g，孔径累计体积为0.25cm 3/g，平均孔径直径为12nm。)
测试
冰点降低法：通过测量溶液的冰点下降来测定其渗透压摩尔浓度。
高效液相色谱法(HPLC)：使用安捷伦C18反向色谱柱柱，柱温为25℃，流动相为25体积％的乙腈和75体积％的含0.1％三氟乙酸的水溶液，流速为1毫升/分钟，进样量为10微升，使用激发波长为295nm、发射波长为360nm的荧光检测器对硫酸吲哚酚进行检测，分析时间为10分钟，出峰时间为3.8-4.0分钟。
生化分析仪检测：使用生化分析仪测量体液(血液或其它体液)的肌酐和尿素氮含量。
实施例1 腹膜透析液的制备
在无菌条件下量取一定体积的市售基础腹膜透析液，置于高压蒸汽灭菌容器中，加入一定量的已灭菌的毒素去除试剂，震荡摇晃混合均匀并密封，25℃下水浴超声(50Hz，40KW，30分钟)后，置于37℃水浴摇床(100rpm，30分钟)中处理，再次利用合适方法如高温蒸汽法灭菌。使用前需再次震荡摇匀。
实施例2 毒素去除试剂的量对不同腹膜透析液的渗透压的影响
实施例2-1：添加不同量的毒素去除试剂的艾考糊精腹膜透析液(重量％为重量体积比)
利用冰点降低法测量通过添加不同量的毒素去除试剂而获得的腹膜透析液的渗透压。
表1.包含不同添加量的毒素去除试剂的市售艾考糊精腹膜透析液的渗透压
Figure PCTCN2019077749-appb-000009
由表1可以看出，对于Kollidon CL-SF、Soluplus和微粉硅胶组，渗透压随添加量的增加而略微上升。但对于所有组，添加如上不同量的毒素去除试剂所获得的腹膜透析液的渗透压均符合腹膜透析液要求。如为减少腹膜透析可能造成的脱水，可将毒素去除试剂的量控制在低于0.25％。
实施例2-2：添加不同量的毒素去除试剂的葡萄糖腹膜透析液
利用冰点降低法测量通过添加不同量的毒素去除试剂而获得的腹膜透析液的渗透压。
表2.包含不同添加料的毒素去除试剂的市售葡萄糖腹膜透析液的渗透压
Figure PCTCN2019077749-appb-000010
Figure PCTCN2019077749-appb-000011
由表2可以看出，对于纳米炭粉、Kollidon CL-SF和Kollidon CL-M组，渗透压随添加量的增加而略微上升。但对于所有组，添加如上不同量的毒素去除试剂所获得的腹膜透析液的渗透压均符合腹膜透析液要求。如为减少腹膜透析可能造成的脱水，可将毒素去除试剂的量控制在低于0.25％。
由以上可知，添加不同量的毒素去除试剂的腹膜透析液仍然满足腹膜透析液的要求，可用于进行腹膜透析。
实施例3 包含毒素去除试剂的不同腹膜透析液的毒素降低作用
实施例3-1：顺铂法构建肾衰竭大鼠模型
选取200±5g雄性SD大鼠，腹腔给予8mg/kg体重的顺铂生理盐水溶液，不禁食，给药后第4天进行透析实验。
实施例3-2：腹膜透析方法
将大鼠分组，阳性对照组为使用添加了2.5mg/L多巴胺(DA)的基础腹膜透析液处理的大鼠，阴性对照组为不进行腹膜透析处理的大鼠，空白对照组为仅使用基础腹膜透析液 处理的大鼠，实验组为使用添加了不同量的毒素去除试剂的基础腹膜透析液处理的大鼠。进行腹膜透析时，将腹膜透析液以80ml/kg体重的剂量输注至大鼠腹腔中滞留，并分别在1、2、4和8小时的时间点在尾静脉取血及取腹腔积液进行分析。
尾静脉取血方式为每次尾静脉取血0.5毫升至含20微升1％肝素生理盐水溶液的1.5毫升体积EP管中。将取出的血样以3000rpm离心10分钟，取上清100微升并加入300微升甲醇，涡旋混合10秒，随后以10000rpm离心10分钟，取上清100微升并加入300微升甲醇，涡旋混合10秒，取200微升至高效液相色谱进样小瓶待检测毒素含量。
实施例3-3：添加不同量的毒素去除试剂的艾考糊精腹膜透析液
下表列出了使用包含不同量的毒素去除试剂的艾考糊精腹膜透析液进行大鼠腹膜透析处理的实验组分组。
表3.使用包含不同量的毒素去除试剂的艾考糊精腹膜透析液进行处理的大鼠实验组
Figure PCTCN2019077749-appb-000012
根据实施例3-2所述的方法，对实验组、阳性对照组、空白对照组和阴性对照组的大鼠进行腹膜透析，并测试尾部静脉血和腹腔积液中的毒素(尿素氮(BUN)、肌酐(CREA2)和硫酸吲哚酚(IS))含量。
结果：
(1)血液中尿素氮的去除效果
图1(a)-(f)显示了对于表3所列的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠，血液中的尿素氮的去除结果。
图1(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％和0.25重量％的纳米碳粉的艾考糊精腹膜透析液处理的实验组1-3和1-4显示出明显的尿素氮含量降低，而使用添加了0.005重量％和0.01重量％的纳米碳粉的艾考糊精腹膜透析液处理的实验组1-1和1-2未显示出明显的尿素氮含量降低。
图1(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％和0.25重量％的Kollidon CL-SF的艾考糊精腹膜透析液处理的实验组2-1和2-2显示出明显的尿素氮含量降低，而且Kollidon CL-SF含量越高，尿素氮含量降低越多。
图1(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％和0.25重量％的Kollidon CL-M的艾考糊精腹膜透析液处理的实验组3-1和3-2显示出明显的尿素氮含量降低，而且Kollidon CL-M含量越高，尿素氮含量降低越多。
图1(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Soluplus的艾考糊精腹膜透析液处理的实验组4-1、4-2和4-3显示出明显的尿素氮含量降低，而且仅添加0.01重量％的Soluplus即可达到明显的尿素氮降低效果，但继续增加Soluplus的含量至0.25重量％，尿素氮含量降低效果未见明显提高。
图1(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.1重量％的微粉硅胶的艾考糊精腹膜透析液处理的实验组5-1、5-2和5-3显示出明显的尿素氮含量降低，而且仅添加0.01重量％的微粉硅胶即可达到明显的尿素氮降低效果，但继续增加微粉硅胶的含量至0.1重量％，尿素氮含量降低效果未见明显提高。
图1(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.1重量％的硅藻土的艾考糊精腹膜透析液处理的实验组6-1、6-2和6-3显示出明显的尿素氮含量降低，而且仅添加0.01重量％的硅藻土即可达到明显的尿素氮降低效果，但继续增加硅藻土的含量至0.1重量％，尿素氮含量降低效果未见明显提高。
(2)血液中肌酐的去除效果
图2(a)-(f)显示了对于表3所列的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠，血液中的肌酐的去除结果。
图2(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了测试含量的纳米碳粉的艾考糊精腹膜透析液处理的实验组1-1至1-4均未显示出明显的肌酐含量降低效果。
图2(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％的Kollidon CL-SF的艾考糊精腹膜透析液处理的实验组2-1未显示出明显的肌酐降低效果，而使用添加了0.25重量％的Kollidon CL-SF的艾考糊精腹膜透析液处理的实验组2-2在前4个小时内显示出明显的肌酐含量降低。
图2(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％的Kollidon CL-M的艾考糊精腹膜透析液处理的实验组3-1未显示出明显的肌酐降低效果，而使用添加了0.25重量％的Kollidon CL-SF的艾考糊精腹膜透析液处理的实验组3-2在前4个小时内显示出明显的肌酐含量降低。
图2(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Soluplus的艾考糊精腹膜透析液处理的实验组4-1、4-2和4-3显示出明显的肌酐含量持续降低，而且仅添加0.01重量％的Soluplus即可达到明显的肌酐降低效果，但继续增加Soluplus的含量至0.25重量％，肌酐含量降低效果未见明显提高。
图2(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.1重量％的微粉硅胶的艾考糊精腹膜透析液处理的实验组5-1、5-2和5-3显示出明显的肌酐含量降低，而且仅添加0.01重量％的微粉硅胶即可达到明显的肌酐降低效果，但继续增加微粉硅胶的含量至0.1重量％，肌酐含量降低效果未见明显提高。
图2(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.1重量％的硅藻土的艾考糊精腹膜透析液处理的实验组6-1、6-2和6-3显示出明显的肌酐含量降低，而且仅添加0.01重量％的硅藻土即可达到明显的肌酐降低效果，但继续增加硅藻土的含量至0.1重量％，尿素氮含量降低效果未见明显提高。
(3)血液中硫酸吲哚酚的去除效果
图3(a)-(f)显示了对于表3所列的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠，血液中的硫酸吲哚酚的去除结果。
图3(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.005重量％、0.1重量％、0.025重量％或0.25重量％的纳米碳粉的艾考糊精腹膜透析液处理的实验组1-1至1-4均显示出明显的硫酸吲哚酚含量降低，特别是在处理2小时之后；而且硫酸吲哚酚含量持续保持低水平。添加不同量(0.005重量％、0.1重量％、0.025重量％或0.25重量％)的纳米碳粉显示出相近的硫酸吲哚酚降低效果。
图3(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％或0.25重量％的Kollidon CL-SF的艾考糊精腹膜透析液处理的实验组 2-1和2-2均显示出明显的硫酸吲哚酚含量降低，并且硫酸吲哚酚含量持续保持低水平。添加不同量(0.025重量％或0.25重量％)的Kollidon CL-SF显示出相近的硫酸吲哚酚降低效果。
图3(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％或0.25重量％的Kollidon CL-M的艾考糊精腹膜透析液处理的实验组3-1和3-2均显示出明显的硫酸吲哚酚含量降低，并且硫酸吲哚酚含量持续保持低水平。添加不同量(0.025重量％或0.25重量％)的Kollidon CL-M显示出相近的硫酸吲哚酚降低效果。
图3(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Soluplus的艾考糊精腹膜透析液处理的实验组4-1、4-2和4-3均显示出明显的硫酸吲哚酚含量降低，并且硫酸吲哚酚含量持续保持低水平，且使用添加0.01重量％和0.05重量％的Soluplus的艾考糊精腹膜透析液的实验组4-1和4-2显示出硫酸吲哚酚含量持续下降的趋势。在前4个小时内，添加不同量(0.01重量％、0.05重量％或0.25重量％)的Soluplus显示出相近的硫酸吲哚酚降低效果。
图3(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.1重量％的微粉硅胶的艾考糊精腹膜透析液处理的实验组5-1、5-2和5-3均显示出明显的硫酸吲哚酚含量降低，并且硫酸吲哚酚含量持续保持低水平。添加不同量(0.01重量％、0.05重量％或0.1重量％)的微粉硅胶显示出相近的硫酸吲哚酚降低效果。
图3(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.1重量％的硅藻土的艾考糊精腹膜透析液处理的实验组5-1、5-2和5-3均显示出明显的硫酸吲哚酚含量降低，并且硫酸吲哚酚含量持续保持低水平。添加不同量(0.01重量％、0.05重量％或0.1重量％)的硅藻土显示出相近的硫酸吲哚酚降低效果。
(4)腹腔液中尿素氮的含量变化
图4(a)-(f)显示了对于表3所列的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠，腹腔液中的尿素氮的含量变化。
图4(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.005重量％、0.1重量％或0.025重量％的纳米碳粉的艾考糊精腹膜透析液处理的实验组1-1至1-3均显示出尿素氮含量的升高，但添加了0.25重量％的纳米碳粉的艾考糊精腹膜透析液处理的实验组1-4显示出尿素氮含量的降低。
图4(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％的Kollidon CL-SF的艾考糊精腹膜透析液处理的实验组2-1在前2小时内，尿素氮的含量明显升高，而使用添加了0.25重量％的Kollidon CL-SF的艾考糊精腹膜透析液处理的实验组2-2显示出明显的尿素氮含量的降低。
图4(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％的Kollidon CL-M的艾考糊精腹膜透析液处理的实验组3-1显示出相近的尿素氮含量变化，而使用添加了0.25重量％的Kollidon CL-M的艾考糊精腹膜透析液处理的实验组3-2显示出明显的尿素氮的含量降低。
图4(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Soluplus的艾考糊精腹膜透析液处理的实验组4-1至4-3均显示出明显的尿素氮含量降低，但这三个实验组之间没有明显的差异。
图4(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％或0.1重量％的微粉硅胶的艾考糊精腹膜透析液处理的实验组5-1和5-3均显示出尿素氮含量的降低，而使用添加了0.05重量％的微粉硅胶的艾考糊精腹膜透析液处理的实验组5-2显示出尿素氮含量的明显升高。
图4(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01 重量％、0.05重量％或0.1重量％的硅藻土的艾考糊精腹膜透析液处理的实验组6-1至6-3均显示出明显的尿素氮含量降低，但这三个实验组之间没有明显的差异。
(5)腹腔液中肌酐的含量变化
图5(a)-(f)显示了对于表3所列的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠，腹腔液中的肌酐的含量变化。
图5(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.005重量％、0.1重量％、0.025重量％和0.25重量％的纳米碳粉的艾考糊精腹膜透析液处理的实验组1-1至1-4均显示出肌酐含量的升高。
图5(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％或0.25重量％的Kollidon CL-SF的艾考糊精腹膜透析液处理的实验组2-1和2-2均显示出肌酐含量的明显升高。
图5(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％或0.25重量％的Kollidon CL-M的艾考糊精腹膜透析液处理的实验组3-1和3-2均显示出肌酐的含量明显升高。
图5(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Soluplus的艾考糊精腹膜透析液处理的实验组4-1至4-3未显示出明显差异。
图5(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％或0.1重量％的微粉硅胶的艾考糊精腹膜透析液处理的实验组5-1和5-3均显示出明显的肌酐含量降低，而使用添加了0.05重量％的微粉硅胶的艾考糊精腹膜透析液处理的实验组5-2未显示出明显差异。
图5(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重 量％、0.05重量％或0.1重量％的硅藻土的艾考糊精腹膜透析液处理的实验组6-1至6-3均显示出肌酐含量的降低，但这三个实验组之间没有明显的差异。
(6)腹腔液中硫酸吲哚酚的含量变化
图6(a)-(f)显示了对于表3所列的实验组以及相应的阳性对照组(ICO+DA)、空白对照组(ICO)和阴性对照组的大鼠，腹腔液中的硫酸吲哚酚的含量变化。
图6(a)显示了添加了不同量的纳米碳粉的艾考糊精腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.005重量％、0.1重量％、0.025重量％和0.25重量％的纳米碳粉的艾考糊精腹膜透析液处理的实验组1-1至1-4均显示出硫酸吲哚酚含量的降低。
图6(b)显示了添加了不同量的Kollidon CL-SF的艾考糊精腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％或0.25重量％的Kollidon CL-SF的艾考糊精腹膜透析液处理的实验组2-1和2-2均显示出明显的硫酸吲哚酚含量降低，但这两个实验组之间没有明显的差异。
图6(c)显示了添加了不同量的Kollidon CL-M的艾考糊精腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.025重量％或0.25重量％的Kollidon CL-M的艾考糊精腹膜透析液处理的实验组3-1和3-2均显示出明显的硫酸吲哚酚含量降低，但这两个实验组之间没有明显的差异。
图6(d)显示了添加了不同量的Soluplus的艾考糊精腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Soluplus的艾考糊精腹膜透析液处理的实验组4-1至4-3在前2个小时内未显示出明显差异，但之后实验组4-2和4-3显示出硫酸吲哚酚含量的明显升高，而实验组4-1显示出硫酸吲哚酚含量的降低。
图6(e)显示了添加了不同量的微粉硅胶的艾考糊精腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.1重量％的微粉硅胶的艾考糊精腹膜透析液处理的实验组5-1至5-3均显示出明显的硫酸吲哚酚含量降低，但这三个实验组之间没有明显的差异。
图6(f)显示了添加了不同量的硅藻土的艾考糊精腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用艾考糊精腹膜透析液处理的空白对照组，使用添加了 0.01重量％、0.05重量％或0.1重量％的硅藻土的艾考糊精腹膜透析液处理的实验组6-1至6-3在8个小时内均显示出硫酸吲哚酚含量的降低，其中在前4个小时内，这三个实验组之间没有明显的差异，而自第4个小时起，实验组6-3显示出硫酸吲哚酚含量的明显升高。
实施例3-3：添加不同量的毒素去除试剂的葡萄糖腹膜透析液
下表列出了使用包含不同量的毒素去除试剂的葡萄糖腹膜透析液进行大鼠腹膜透析处理的实验组分组。
表4.使用包含不同量的毒素去除试剂的葡萄糖腹膜透析液进行处理的大鼠实验组
Figure PCTCN2019077749-appb-000013
根据实施例3-2所述的方法，对实验组、空白对照组和阴性对照组的大鼠进行腹膜透析，并测试尾部静脉血和腹腔积液中的毒素(尿素氮(BUN)、肌酐(CREA2)和硫酸吲哚酚(IS))含量。
结果：
(1)血液中尿素氮的去除效果
图7(a)-(f)显示了对于表4所列的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠，血液中的尿素氮的去除结果。
图7(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％和0.05重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-1和1-2显示出明显的尿素氮含量降低，而使用添加了0.25重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-3在前2个小时内未显示出明显的尿素氮含量降低，而在2个小时之后，开始显示出一定的尿素氮含量降低。
图7(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Kollidon CL-SF的葡萄糖腹膜透析液处理的实验组2-1至2-3均显示出明显的尿素氮含量降低，而使用添加了0.25重量％的Kollidon CL-SF的葡萄糖腹膜透析液处理的实验组2-3在4个小时之后，开始显示出尿素氮含量的升高。
图7(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Kollidon CL-M的葡萄糖腹膜透析液处理的实验组3-1至3-3均显示出明显的尿素氮含量降低，但这三个实验组之间没有明显的差异。
图7(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Soluplus的葡萄糖腹膜透析液处理的实验组4-1至4-3均显示出明显的尿素氮含量降低，但这三个实验组之间没有明显的差异。
图7(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的微粉硅胶的葡萄糖腹膜透析液处理的实验组5-1至5-3均显示出明显的尿素氮含量降低，其中添加了0.01重量％的微粉硅胶的实验组5-1显示出最佳的尿素氮降低效果。
图7(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的血液中尿素氮的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、 0.05重量％和0.25重量％的硅藻土的葡萄糖腹膜透析液处理的实验组6-1至6-3均显示出明显的尿素氮含量降低，其中添加了0.25重量％的微粉硅胶的实验组6-3显示出最佳的尿素氮降低效果。
(2)血液中肌酐的去除结果
图8(a)-(f)显示了对于表4所列的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠，血液中的肌酐的去除结果。
图8(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.05重量％和0.25重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-2和1-3未显示出明显的差异，而使用添加了0.01重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-1显示出明显的肌酐含量降低。
图8(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Kollidon CL-SF的葡萄糖腹膜透析液处理的实验组2-1至2-3均显示出明显的肌酐含量降低，但这三个实验组之间没有明显的差异。
图8(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Kollidon CL-M的葡萄糖腹膜透析液处理的实验组3-1至3-3均显示出明显的肌酐含量降低，但这三个实验组之间没有明显的差异。
图8(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Soluplus的葡萄糖腹膜透析液处理的实验组4-1至4-3均显示出明显的肌酐含量降低，其中添加0.01重量％和0.25重量％的Soluplus的实验组4-1和4-3的肌酐去除效果相近，且与添加0.05重量％的Soluplus的实验组4-2相比肌酐去除效果更好。
图8(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的微粉硅胶的葡萄糖腹膜透析液处理的实验组5-1至5-3均显示 出明显的肌酐含量降低，其中添加0.01重量％的微粉硅胶的实验组5-1显示出最佳的肌酐去除效果。
图8(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的硅藻土的葡萄糖腹膜透析液处理的实验组6-1至6-3均显示出明显的肌酐含量降低，但这三个实验组之间没有明显的差异。
(3)血液中硫酸吲哚酚的去除效果
图9(a)-(f)显示了对于表4所列的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠，血液中的硫酸吲哚酚的去除结果。
图9(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-1至1-3均显示出明显的硫酸吲哚酚含量降低，但这三个实验组之间没有明显的差异。
图9(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.05重量％的Kollidon CL-SF的葡萄糖腹膜透析液处理的实验组2-2未显示出明显差异，而添加了0.01重量％和0.25重量％的Kollidon CL-SF的葡萄糖腹膜透析液处理的实验组2-1和2-3均显示出明显的硫酸吲哚酚含量降低，且这两个实验组之间没有明显的差异。
图9(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Kollidon CL-M的葡萄糖腹膜透析液处理的实验组3-1至3-3均显示出明显的硫酸吲哚酚含量降低，但这三个实验组之间没有明显的差异。
图9(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的Soluplus的葡萄糖腹膜透析液处理的实验组4-1至4-3均显示出明显的硫酸吲哚酚含量降低，其中添加0.01重量％的Soluplus的实验组4-1的硫 酸吲哚酚去除效果最佳，添加0.25重量％的Soluplus的实验组4-3的硫酸吲哚酚去除效果次之，添加0.05重量％的Soluplus的实验组4-2的硫酸吲哚酚去除效果再次。
图9(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的血液中硫酸吲哚酚的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％和0.25重量％的微粉硅胶的葡萄糖腹膜透析液处理的实验组5-1至5-3均显示出明显的硫酸吲哚酚含量降低，其中添加0.01重量％的微粉硅胶的实验组5-1的硫酸吲哚酚去除效果最佳。
图9(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的血液中肌酐的去除结果。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％的硅藻土的葡萄糖腹膜透析液处理的实验组6-1未显示出明显差异，而添加了0.05重量％和0.25重量％的硅藻土的葡萄糖腹膜透析液处理的实验组6-2和6-3均显示出明显的硫酸吲哚酚含量降低，且这两个实验组之间没有明显的差异。
(4)腹腔液中尿素氮的含量变化
图10(a)-(f)显示了对于表4所列的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠，腹腔液中的尿素氮的含量变化。
图10(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-1至1-3均显示出尿素氮含量的升高，其中添加0.05重量％的纳米碳粉的实验组1-2显示出最大的尿素氮含量升高，添加0.25重量％的纳米碳粉的实验组1-3次之，添加0.01重量％的纳米碳粉的实验组1-1再次。
图10(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Kollidon CL-SF的葡萄糖腹膜透析液处理的实验组2-1至2-3均显示出尿素氮含量的升高，这三个实验组在前4个小时内无明显差异，但自4小时之后，添加0.01重量％和0.05重量％的Kollidon CL-SF的实验组2-1和2-2显示出尿素氮含量的明显降低直至与阴性对照组的尿素氮含量水平接近。
图10(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Kollidon CL-M的葡萄糖腹膜透析液处理的实验组3-1至3-3均显示出尿素氮含量的升高，但这三个实验组之间没有明显的差异。
图10(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Soluplus的葡萄糖腹膜透析液处理的实验组4-1至4-3在前2个小时内均显示出尿素氮含量的升高，之后这三个实验组与阴性对照组之间没有明显的差异。
图10(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.05重量％或0.25重量％的微粉硅胶的葡萄糖腹膜透析液处理的实验组5-2和5-3均显示出明显的尿素氮含量升高，且这两个实验组之间没有明显的差异，添加0.01重量％的微粉硅胶的实验组5-1在前2个小时内与阴性对照组未见明显差异，之后显示出明显的尿素氮含量降低。
图10(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.05重量％、0.05重量％或0.25重量％的硅藻土的葡萄糖腹膜透析液处理的实验组5-1至5-3未显示出明显的差异。
(5)腹腔液中肌酐的含量变化
图11(a)-(f)显示了对于表4所列的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠，腹腔液中的肌酐的含量变化。
图11(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-1未显示出明显差异，而添加了0.05重量％或0.25重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-2和1-3均显示出明显的尿素氮含量升高，且这两个实验组之间没有明显的差异。
图11(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Kollidon CL-SF的葡萄糖腹膜透析液处理的实验组2-1至2-3均显示出肌酐含量的升高，这三个实验组在前4个小时内无明显差异，但自4小时之后，添加0.01重量％和0.05重量％的Kollidon CL-SF的实验组2-1和2-2显示出肌酐含量的明显降低直至与阴性对照组的肌酐含量水平接近。
图11(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Kollidon CL-M的葡萄糖腹膜透析液处理的实验组3-1至3-3未显示出明显差异，但自4小时之后，添加0.01重量％的Kollidon CL-SF的实验组2-1显示出明显的肌酐含量升高。
图11(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的腹腔液中尿素氮的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％和0.25重量％的Soluplus的葡萄糖腹膜透析液处理的实验组4-1和4-3未显示出明显差异，而添加了0.05重量％的Soluplus的葡萄糖腹膜透析液处理的实验组4-2显示出明显的肌酐含量升高。
图11(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％的微粉硅胶的葡萄糖腹膜透析液处理的实验组5-1未显示出明显差异，而添加了0.05重量％和0.25重量％的微粉硅胶的实验组5-2和5-3均显示出明显的肌酐含量升高，且这两个实验组之间没有明显的差异。
图11(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的腹腔液中肌酐的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.05重量％和0.25重量％的硅藻土的葡萄糖腹膜透析液处理的实验组5-2和5-3未显示出明显差异，而添加了0.01重量％的硅藻土的实验组5-1显示出明显的肌酐含量升高。
(6)腹腔液中硫酸吲哚酚的含量变化
图12(a)-(f)显示了对于表4所列的实验组以及相应的空白对照组(GLU)和阴性对照组的大鼠，腹腔液中的硫酸吲哚酚的含量变化。
图12(a)显示了添加了不同量的纳米碳粉的葡萄糖腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％或0.25重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-1和1-3未显示出明显差异，而添加了0.05重量％的纳米碳粉的葡萄糖腹膜透析液处理的实验组1-2显示出硫酸吲哚酚含量的升高。
图12(b)显示了添加了不同量的Kollidon CL-SF的葡萄糖腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Kollidon CL-SF的葡萄糖腹膜透析液处理的实验组2-1至2-3均显示出明显的硫酸吲哚酚含量的持续升高。
图12(c)显示了添加了不同量的Kollidon CL-M的葡萄糖腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Kollidon CL-M的葡萄糖腹膜透析液处理的实验组3-1至3-3均显示出明显的硫酸吲哚酚含量的持续升高。
图12(d)显示了添加了不同量的Soluplus的葡萄糖腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％、0.05重量％或0.25重量％的Soluplus的葡萄糖腹膜透析液处理的实验组4-1至4-3在前2个小时均未显示出明显差异，但自2小时之后，添加0.05重量％的Soluplus的实验组4-2显示出明显的硫酸吲哚酚含量的持续升高，而添加了0.01重量％或0.25重量％的Soluplus的实验组4-1和4-3与阴性对照组相比仍然无明显差异。
图12(e)显示了添加了不同量的微粉硅胶的葡萄糖腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的空白对照组，使用添加了0.01重量％的微粉硅胶的葡萄糖腹膜透析液处理的实验组5-1未显示出明显差异，而添加了0.05重量％和0.25重量％的微粉硅胶的实验组5-2和5-3均显示出明显的硫酸吲哚酚含量的持续升高，且这两个实验组之间没有明显的差异。
图12(f)显示了添加了不同量的硅藻土的葡萄糖腹膜透析液的腹腔液中硫酸吲哚酚的含量变化。可以看出，相比于仅使用葡萄糖腹膜透析液处理的阴性对照组，使用添加了0.01重量％和0.05重量％的硅藻土的葡萄糖腹膜透析液处理的实验组6-1和6-2显示出明显的硫酸吲哚酚含量升高，而添加了0.25重量％的硅藻土的实验组6-3在前4个小时内显示出 明显的硫酸吲哚酚含量升高，但自4小时之后显示出硫酸吲哚酚含量的明显降低直至与阴性对照组的硫酸吲哚酚含量水平接近。
本发明不限于本文所述的具体实施方案的范围。事实上，根据上述说明，本发明的各种修改和改变对本领域技术人员而言是容易想到的。这些修改和改变也落在所附权利要求的范围内。

Claims (75)

  1. 一种包含渗透剂和毒素去除试剂的组合物，其中所述渗透剂能够提供与生物流体基本等渗或高于等渗的渗透压，并且所述毒素去除试剂能够在渗透交换的条件下降低所述生物流体中的毒素。
  2. 根据权利要求1所述的组合物，其中所述毒素去除试剂能够降低所述生物流体中的所述毒素的游离量、非游离的量、和/或总量。
  3. 根据权利要求2所述的组合物，其中所述毒素去除试剂能够将生物流体中的毒素的总量或非游离的量降低至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％或至少95％。
  4. 根据前述任一权利要求所述的组合物，其中所述毒素去除试剂能够吸附、非共价结合、共价结合、和/或降解所述生物流体中的所述毒素。
  5. 根据前述任一权利要求所述的组合物，其中所述毒素去除试剂具有一种或多种选自下组的特征：1)具有多孔结构；2)能够形成带电结构；3)能够与所述毒素通过非共价键或共价键或离子键结合；和4)能够降解所述毒素。
  6. 根据权利要求5所述的组合物，其中所述毒素去除试剂具有多孔结构，并且所述多孔结构符合一个或多个以下特征：
    1)具有70cm 2/g～1000m 2/g的比表面积；
    2)具有0.1nm-10μm范围的孔径；
    3)具有0.1nm至100μm的孔径分布；
    4)具有约5～95％的孔隙率；
    5)能够以至少0.2mg/g的吸附率吸附所述毒素。
  7. 根据权利要求6所述的组合物，其中所述具有多孔结构的所述毒素去除试剂选自下组：硅基多孔材料、碳基多孔材料、金属氧化物类多孔材料、聚合物类多孔材料和金属有机框架化合物多孔材料。
  8. 根据权利要求5所述的组合物，其中所述毒素去除试剂能够形成带电结构，并且所述带电结构具有0.2-50μC·cm -2的电荷密度。
  9. 根据权利要求8所述的组合物，其中所述带电结构包括带电离子或带电的胶体。
  10. 根据权利要求8所述的组合物，其中所述毒素去除试剂选自下组：聚维酮、交联聚维酮、二氧化硅胶体、微粉硅胶、硅藻土、和聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、和纳米氧化铝。
  11. 根据权利要求5所述的组合物，其中所述毒素去除试剂具有能够与所述毒素形成非共价键的基团(例如，氢原子、羟基、氨基、胺基、羧基等)，具有能够与所述毒素形成共价键的基团(例如，巯基、醛基、羟基、羧基、氨基、酰腙键、酰肼键等)、或者具有能够与所述毒素形成离子键的基团(例如，氯离子、硫酸根离子、钙离子、碳酸根离子等)。
  12. 根据权利要求5所述的组合物，其中所述毒素去除试剂能够降解所述毒素，并且所述毒素去除试剂是生物催化剂或化学催化剂。
  13. 根据前述任一权利要求所述的组合物，其中所述毒素去除试剂选自活性炭、聚维酮、交联聚维酮、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、微粉硅胶、硅藻土，及其任意组合。
  14. 根据前述任一权利要求所述的组合物，其中所述毒素在所述生物流体中的存在或者过量存在会提高患病风险、加重疾病状况、或损害正常生理功能。
  15. 根据前述任一权利要求所述的组合物，其中所述毒素包含体内代谢产物、引起中毒的外源物质、或引起疾病的分子。
  16. 根据权利要求15所述的组合物，其中所述代谢产物选自下组：尿素、肌酸酐、尿酸、胍-ADMA、β 2-微球蛋白、细胞因子、甲状旁腺激素、硫酸吲哚酚、高半胱氨酸、对甲酚、马尿酸、活性氧物种(ROS)、尿毒症毒素(例如AGE产物(3-脱氧葡糖醛酮、果糖赖氨酸、乙二醛、丙酮醛、戊糖素)、1-甲基腺苷、1-甲基鸟苷、1-甲基肌苷、非对称性二甲基精氨酸、α-酮基-δ-胍戊酸、α-N-乙酰精氨酸、阿拉伯糖醇、精氨酸、苯甲醇、β-胍基丙酸、β-促脂解激素、肌酸、胞啶、N,N-二甲基甘氨酸钠、赤藻糖醇、γ-胍丁酸、次黄嘌呤、丙二醛、甘露醇、甲基胍、肌醇、N,N-二甲基鸟苷、N-乙酰胞嘧啶核苷、N-苏氨酰氨甲酰磷酸腺苷、乳清酸、乳清酸核苷、草酸盐、苯乙酰谷氨酰胺、假尿苷、对称性二甲基精氨酸、山梨醇、脒基牛磺酸、苏糖醇、胸腺嘧啶、尿嘧啶、尿苷、黄苷、2-甲氧基间苯二酚、3-脱氧葡糖醛酮、3-羧基-4-甲基 -5-丙基-2-呋喃丙酸(CMPF)、果糖酰赖氨酸、同型半胱氨酸、对苯二酚、吲哚-3-乙酸、犬尿氨酸、犬尿喹啉酸、瘦蛋白、褪黑素、甲基乙二醛、Nε-羧甲基赖氨酸、甲酚、戊糖苷、苯酚、对羟基马尿酸、丁二胺、喹啉酸、视黄醇结合蛋白、亚精胺、精胺、肾上腺髓质素、心房钠尿肽、β-内啡肽、胆囊收缩素、克拉拉细胞蛋白(CC16)、人补体因子D、胱抑素C、脱粒抑制蛋白Ic、δ-睡眠诱导肽、内皮缩血管肽、透明质酸、白细胞介素-1β、白细胞介素-6、κ-免疫球蛋白轻链、λ-免疫球蛋白轻链、甲硫氨酸-脑啡肽、神经肽Y、甲状旁腺激素、肿瘤坏死因子-α)、硫化氢、胆红素中的一种或多种。
  17. 根据权利要求15所述的组合物，其中所述引起中毒的外源物质包括药物、农药、化工毒物、食源性毒物、或者生物类外源毒素。
  18. 根据权利要求17所述的组合物，其中所述药物选自下组：镇静催眠类药物、抗精神病类药物、心脑血管类药物、解热镇痛类药物、抗寄生虫病药、抗微生物药、麻醉及麻醉辅助药、呼吸系统药物、循环系统药物、消化系统药物、泌尿系统药物、血液系统药物、代谢及内分泌药物、抗变态反应药物、肿瘤治疗药物、免疫调节药物、妇产科用药、男性用药、抗炎药、和中药。
  19. 根据权利要求17所述的组合物，其中所述农药选自下组：百草枯、敌敌畏、乐果、草甘膦、甲胺磷、毒死蜱、氧化乐果、溴敌隆、溴鼠灵、辛硫磷、吡虫啉、阿维菌素、毒鼠皇、杀虫双、对硫磷、甲拌磷、内吸磷、敌百虫、马拉硫磷、六六六、滴滴涕、狄氏剂、异狄氏剂、艾氏剂、磷化铝农药、腈氯苯苯醚菊酯、氟乙酰胺、毒鼠强、五氯酚、二硝甲酚、敌草隆、敌草腈、沙蚕毒素、鱼藤酮、烟碱、氯化甲撑萘、甲脒、苏云金杆菌制剂、敌鼠钠盐、杀鼠灵、抗鼠灵、代森铵、福美锌、甲基汞、和2,4D丁酯。
  20. 根据权利要求17所述的组合物，其中所述化工毒物选自下组：来源于有毒植物(例如鸡母珠、夹竹桃、曼陀罗、秋水仙、岩沙海葵、羽扇豆、野百合)的毒素，氰化物(例如氰化钠、氰化钾、氰化钙、氰化钡、氰化钴、氰化亚钴、氰化钴钾、氰化镍、氰化镍钾、氰化铜、氰化银、氰化银钾、氰化锌、氰化镉、氰化汞、氰化汞钾、氰化铅、氰化铈、氰化亚铜、氰化金钾、氰化溴、氰化氢、氢氰酸)、二甲苯、汽车防冻液、三氧化二砷、亚砷酸钠、亚砷酸钾、五氧化二砷、三氯化砷、亚硒酸钾、硒酸钠、硒酸钾、氧氯化硒、氯化汞、氰氧化汞、氧化镉、羰基镍、五羰基铁、叠 氮化钠、叠氮化钡、叠氮酸、氟化氢、黄磷、磷化钠、磷化钾、磷化镁、磷化铝、氟、磷化氢、砷化氢、硒化氢、锑化氢、一氧化氮、四氧化二氮、二氧化硫、二氧化氯、二氟化氧、三氟化氯、三氟化磷、四氟化硫、四氟化硅、五氟化氯、五氟化磷、六氟化硒、六氟化碲、六氟化钨、氯化溴、氯化氰、溴化羰、氰、碘化氰、砷、亚砷酸钙、亚砷酸锶、亚砷酸钡、亚砷酸铁、亚砷酸铜、亚砷酸银、亚砷酸锌、亚砷酸铅、亚砷酸锑、乙酰亚砷酸铜、砷酸、偏砷酸、焦砷酸、砷酸铵、砷酸钠、偏砷酸钠、砷酸氢二钠、砷酸氢二钠、砷酸二氢钠、砷酸钾、砷酸二氢钾、砷酸镁、砷酸钙、砷酸钡、砷酸铁、砷酸亚铁、砷酸铜、砷酸银、砷酸锌、砷酸汞、砷酸铅、砷酸锑、三氟化砷、三溴化砷、三碘化砷、二氧化硒、亚硒酸、亚硒酸氢钠、亚硒酸镁、亚硒酸钙、亚硒酸钡、亚硒酸铝、亚硒酸铜、亚硒酸银、亚硒酸铈、硒酸钡、硒酸铜、硒化铁、硒化锌、硒化镉、硒化铅、氯化硒、四氯化硒、溴化硒、四溴化硒、氯化钡、铊、氧化亚铊、氧化铊、氢氧化铊、氯化亚铊、溴化亚铊、碘化亚铊、三碘化铊、硝酸铊、硫酸亚铊、碳酸(亚)铊、磷酸亚铊、铍、氧化铍、氢氧化铍、氯化铍、碳酸铍、硫酸铍、硫酸铍钾、铬酸铍、氟铍酸铵、氟铍酸钠、四氧化锇、氯锇酸铵、五氧化二钒、氯化钒、钒酸钾、偏钒酸钾、偏钒酸钠、偏钒酸铵、聚钒酸铵、钒酸铵钠、砷化汞、硝酸汞、氟化汞、碘化汞、氧化汞、亚碲酸钠、硝普钠、磷化锌、溴、溴化氢、锗烷、三氟化硼、三氯化硼、和有毒金属离子(例如铜离子、铝离子、汞离子、钡离子、铅离子、铬离子、镉离子、银离子)。
  21. 根据权利要求17所述的组合物，其中所述食源性毒物选自下组：河豚鱼毒素、白果毒素、海豚毒素、麻痹性贝类毒素、腹泻性贝类毒素、神经性贝类毒素、遗忘性贝类毒素、西加毒素、鲭鱼毒、芋螺毒素、聚醚类毒素、西加毒素、石房蛤毒素、刺尾鱼毒素、肉毒毒素、氰甙类、亚麻苦甙、苦杏仁甙、氢氰酸、苯甲醛、棉酚类、龙葵素、毒蕈毒、毒肽、毒伞肽类、亚硝酸盐、组胺类、铅、镉、汞、砷、氟、多环芳烃、多氯联苯、甲醇、米酵菌酸、毒黄素、雪腐镰刀菌烯醇、镰刀菌烯酮-X、T2毒素、麦类赤霉病毒、黄曲霉毒素、赭曲霉毒素、佛波醇酯、海兔毒素、大田软海绵酸、端镰菌肽、3-硝基丙酸、鹿花蕈素、乙醇、盐酸克伦特罗(瘦肉精)、咖啡因、海洛因、和茶碱。
  22. 根据权利要求17所述的组合物，其中所述引起疾病的分子选自下组：游离DNA、炎症因子、抗体、抗原、蛋白质碎片、和致病微生物。
  23. 根据前述任一权利要求所述的组合物，其中所述毒素在所述生物流体中游离存在、与所述生物流体中的物质结合存在、或者两者皆有。
  24. 根据前述任一权利要求所述的组合物，其中至少部分所述毒素与所述生物流体中的物质形成可逆结合。
  25. 根据权利要求24所述的组合物，其中所述毒素与所述生物流体中的物质结合的Kd值至少为10 2μmol/L、10 3μmol/L、10 4μmol/L、10 5μmol/L、10 6μmol/L、或10 7μmol/L。
  26. 根据权利要求25所述的组合物，其中所述毒素与所述生物流体中的物质的结合的Kd值至少为10 5～10 7μmol/L。
  27. 根据权利要求23-26任一所述的组合物，其中在所述生物流体中至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％的所述毒素以结合形式存在。
  28. 根据权利要求27所述的组合物，其中所述毒素包括：硫酸吲哚酚、非对称性精氨酸、高半胱氨酸、苯乙酸、对甲酚、AGE产物(3-脱氧葡糖醛酮、果糖赖氨酸、乙二醛、丙酮醛、戊糖素)、马尿酸、尿毒症毒素、硫化氢、或胆红素。
  29. 根据权利要求23-28任一所述的组合物，其中与所述毒素结合的所述物质包括血液组织中的成分、脂肪组织中的成分、结缔组织中的成分、骨组织中的成分等。
  30. 根据权利要求29所述的组合物，其中所述毒素去除试剂对毒素的吸附或结合的作用不同于所述毒素与所述生物流体内的物质的结合作用。
  31. 根据权利要求29所述的组合物，其中所述毒素去除试剂不同于在所述生物流体中与所述毒素结合的物质。
  32. 根据前述任一权利要求所述的组合物，其中所述渗透剂能够提供基本等于或高于280mOsm/L、300mOsm/L、或330mOsm/L的渗透压。
  33. 根据前述任一权利要求所述的组合物，其中所述渗透剂包括糖类、氨基酸、多肽、甘油、碳酸盐或其类似物及其组合。
  34. 根据前述任一权利要求所述的组合物，其中所述糖类渗透剂可以选自单糖、寡糖和多糖，所述氨基酸类渗透剂可以选自天然氨基酸、非天然氨基酸、其类似物、衍生物及其任意组合。
  35. 根据权利要求34所述的组合物，其中所述单糖可以选自葡萄糖、果糖、山梨糖醇、木糖醇、氨基糖及其衍生物；所述寡糖包括一种或多种所述单糖的寡聚物；和/或所述多糖包括一种或多种所述单糖的多聚物。
  36. 根据权利要求35所述的组合物，其中所述糖类渗透剂包含葡萄糖聚合物。
  37. 根据前述任一权利要求所述的组合物，其中所述毒素去除试剂与所述渗透剂在所述组合物中的含量比例(重量/重量)为1:1750到1:4(例如：1:1750到1:5，1:1500到1:4，1:1500到1:5，1:1000到1:5，1:750到1:6；1:300到1:6；1:75到1:6；1:30到1:6；1:10到1:6；1:1500到1:5；1:1500到1:10；1:1500到1:30；1:1500到1:75；1:1500到1:150；1:1500到1:300；1:1500到1:750。
  38. 根据前述任一权利要求所述的组合物，其中所述组合物进一步含有缓冲剂、电解质和其他透析组分中的一种或多种。
  39. 根据权利要求38所述的组合物，其中所述缓冲剂选自乳酸盐、碳酸氢盐、柠檬酸盐、异柠檬酸盐、丙酮酸盐、琥珀酸盐、延胡索酸盐、苹果酸盐、草酰乙酸盐、氯化物、pK 1为7-13的氨基酸(组氨酸、甘氨酸、丙氨酸)及其类似物中的一种或多种。
  40. 根据权利要求38所述的组合物，其中所述电解质选自钠盐、钙盐、镁盐和钾盐中的一种或多种。
  41. 根据前述任一权利要求所述的组合物，其中所述组合物是经过灭菌的。
  42. 根据前述任一权利要求所述的组合物，其中所述组合物是固体制剂、半固体制剂或液体制剂。
  43. 根据权利要求1所述的组合物，其中所述毒素去除试剂能够与所述生物流体通过半渗透介质进行渗透交换。
  44. 根据权利要求43所述的组合物，其中所述半渗透介质是人造半透膜。
  45. 根据权利要求43所述的组合物，其中所述半渗透介质是生物半透膜。
  46. 根据权利要求45所述的组合物，其中所述生物半透膜选自下组：血管壁膜、淋巴管壁膜、腹膜、肺膜、腺体包膜和黏膜。
  47. 根据前述任一权利要求所述的组合物，其中所述生物流体选自：血液、组织液、淋巴液、血浆、血清、血液制品、生物制品。
  48. 根据前述任一权利要求所述的组合物，其中所述生物流体在个体体内，或者在个体体外。
  49. 含有根据前述任一权利要求所述组合物的透析溶液。
  50. 根据权利要求49所述的透析溶液，其中所述透析溶液能够提供生理可接受水平的pH和/或电解质。
  51. 一种用于生物流体净化的试剂盒，其含有如权利要求1-48任一所述的组合物。
  52. 根据权利要求51所述的试剂盒，其中所述组合物以单一的组合物形式存在，或者以两个或两个以上组成部分的形式存在。
  53. 根据权利要求52所述的试剂盒，其中所述组合物或至少一种所述组成部分是固体制剂、半固体制剂或液体制剂。
  54. 根据权利要求52所述的试剂盒，其中所述组合物以两个或两个以上组成部分的形式存在，并且分别容纳在不同的容器中。
  55. 根据权利要求54所述的试剂盒，其中所述两个或两个以上组成部分分别容纳在两个或两个以上能够被可操作地流体连通的容器中。
  56. 根据权利要求51-55任一所述的试剂盒，其中所述组合物是经过灭菌的。
  57. 根据权利要求51-56任一所述的试剂盒，其中所述试剂盒进一步包含可用于生物流体净化的半渗透介质。
  58. 一种透析装置，包含权利要求1-48任一所述的组合物，其中所述装置被配置为允许所述组合物能够与待透析的生物流体进行渗透交换。
  59. 根据权利要求54所述的透析装置，其中所述装置进一步包含允许所述组合物与所述生物流体进行渗透交换的半渗透介质。
  60. 根据权利要求54或55所述的透析装置，其中所述透析装置可以被安装到透析主机上。
  61. 一种降低生物流体中的毒素的方法，其包括：
    a)将所述生物流体在允许渗透交换的条件下接触含有如权利要求1-48任一所述的组合物的渗透溶液，以及
    b)允许所述组合物降低所述生物流体中的所述毒素的量。
  62. 根据权利要求61所述的方法，其中在所述允许渗透交换的条件下，所述生物流体中的所述毒素通过渗透交换转移到所述渗透溶液中。
  63. 根据权利要求61-62任一所述的方法，其中步骤a)包括将所述生物流体与所述组合物置于半渗透介质的两侧。
  64. 根据权利要求63所述的方法，其中所述渗透溶液与所述生物流体基本等渗或高于等渗。
  65. 根据权利要求63所述的方法，其中所述半渗透介质为人造半透膜。
  66. 根据权利要求63所述的方法，其中所述半渗透介质为生物半透膜。
  67. 根据权利要求66所述的方法，其中所述生物半透膜为血管壁膜、淋巴管壁膜、腹膜、肺膜、腺体包膜和黏膜。
  68. 根据权利要求61-62任一所述的方法，其中所述生物流体在个体的体内。
  69. 根据权利要求68所述的方法，其中所述步骤a)包括将所述渗透溶液通过腹腔灌注施用于所述个体。
  70. 根据权利要求61-62任一所述的方法，其中所述生物流体在体外。
  71. 根据权利要求70任一所述的方法，其中所述步骤a)包括将所述渗透溶液通过血液透析施用于所述个体。
  72. 一种治疗或预防与毒素相关的疾病或状态的方法，包括使用根据权利要求1-48任一所述的组合物在允许渗透交换的条件下接触所述个体的生物流体，以降低所述生物流体中的所述毒素。
  73. 根据权利要求1-48任一所述的组合物在用于制备治疗或预防与毒素相关的疾病或状态的药物中的用途，所述组合物可降低个体体内的生物流体中的所述毒素。
  74. 根据权利要求72或73所述的方法或用途，其中所述与毒素相关的疾病或状态包括：肾病、心脑血管疾病、血液疾病、自体免疫疾病、代谢性疾病、骨科疾病、消化系统疾病、药物过量或中毒。
  75. 根据权利要求72-74任一所述的方法或用途，其中所述肾病选自尿毒症、慢性肾病、急性肾功能不全、慢性肾盂肾炎、急性肾盂肾炎、慢性肾小球肾炎、急性进行型肾炎综合征、肾病综合征、肾硬化症、间质性肾炎、糖尿病性肾病、局灶性肾小球硬化症、膜性肾病、多发性脓胞性肾综合征、肾血管性高血压和高血压综合征、继发性肾病、高磷血症、高钾血症、高尿酸血症或高钠血症。
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