Hemodialysis adsorbent, preparation method, hemodialysis adsorption column and blood purification device

Abstract

The invention provides a hemodialysis adsorbent and a preparation method thereof, a hemodialysis adsorption column and a blood purification device.The hemodialysis adsorbent comprises carbonized resin and a bisphosphonate medicine fixed to the carbonized resin through a chemical method, and the carbonized resin serves as an adsorbent matrix; the hydrogel has good biocompatibility, chemical stability, high temperature resistance and corrosion resistance, and the pore structure of the hydrogel ensures the effective load of drugs and the smooth passage of blood. The bisphosphonate medicine can be tightly combined with hydroxyapatite in blood to form a stable compound, so that in-vitro discharge of hydroxyapatite is promoted, and compared with an existing adsorption material, the adsorbent provided by the invention is high in specificity and can efficiently adsorb hydroxyapatite and the like instead of adsorbing albumin, so that the loss of albumin is reduced. The invention further provides a hemodialysis adsorption column and a blood purification device which are provided with the hemodialysis adsorbent, and the hemodialysis adsorbent shows an excellent effect in hemodialysis and is suitable for various blood purification scenes.

Description

Technical Field

[0001] The present invention belongs to the technical field of hemodialysis, and particularly relates to a hemodialysis adsorbent and a preparation method thereof, a hemodialysis adsorption column, and a blood purification device. Background Art

[0002] Patients with chronic kidney disease (CKD) often suffer from vascular calcification problems, which increase the risk of cardiovascular events and mortality. As renal function declines, phosphate metabolism disorders further exacerbate vascular calcification problems. During blood calcification, the transformation of the bone-vascular axis involves the combined action of hormones, cytokines, and regulatory proteins. CKD-related vascular calcification is essentially the transformation of vascular smooth muscle cells into osteoblast-like cells, which is a bone formation phenomenon. The occurrence of this process depends on the concentration of inorganic phosphorus and calcium reaching or approaching saturation, as well as the matrix for crystal nucleation, which are the key conditions for initiating calcium phosphate precipitation and crystal formation. During this process, smooth muscle cells produce matrix vesicles containing calcium phosphate crystals, which trigger mineralization reactions in the extracellular matrix.

[0003] Inorganic phosphorus in the blood is regulated by calcification inhibitors to form colloidal hydroxyapatite, called calciprotein particles (CPPs). CPPs are divided into primary and secondary types, which differ in morphology, function, and size. In vitro experiments have shown that secondary CPPs can trigger signal pathways that promote calcification in smooth muscle cells, thereby causing vascular inflammation and the transformation into osteoblast-like cells. In clinical studies, the level of CPPs in patients with end-stage kidney disease, especially those undergoing hemodialysis treatment, is significantly elevated.

[0004] To reduce the risk of vascular calcification, a resin hemoperfusion column has been developed in the field of hemodialysis. This device is mainly used to treat kidney diseases, drug poisoning, and metabolic disorders, such as adsorbing medium and large molecular toxins, blood phosphorus, parathyroid hormone, β2-microglobulin, etc. in the body of hemodialysis patients. The resin hemoperfusion column is designed to selectively remove toxins, metabolites, and other harmful substances from the blood through specific resin materials. The column consists of a column body and an adsorbent. The structure of the column body includes an end cap, a cap, a tapered plug, a sealing ring, and a frustum-shaped column cylinder. The adsorbent is a neutral macroporous adsorption resin treated by a special process. Its adsorption ability comes from the molecular sieve effect of its three-dimensional network structure, the charge attraction of resin molecular groups, and its lipophilic and hydrophobic properties, and it has a relative adsorption performance for target substances containing lipophilic and hydrophobic groups (such as those with benzene rings or cyclic structures) in the molecular structure.

[0005] However, the existing resin hemoperfusion columns still have some problems:

[0006] 1. The selectivity of resin hemoperfusion cartridges for macromolecular toxins in blood is limited. Since inorganic phosphorus in blood often binds tightly to albumin, the resin hemoperfusion cartridge has low efficiency in removing phosphorus, and usually requires an extended dialysis time.

[0007] 2. During hemoperfusion, the resin may adsorb not only the target substances, but also normal plasma proteins such as albumin. This non-specific adsorption may lead to the loss of albumin. As blood passes through the perfusion cartridge, some fine particles and molecules (including albumin) may be filtered out. Especially when the blood concentration is high, albumin may be filtered out through tiny pores.

[0008] Therefore, there is an urgent need to develop a new type of adsorbent material that can effectively remove calcium and phosphorus substances such as hydroxyapatite in blood that cause calcification, and at the same time has excellent biocompatibility and stability to improve the treatment efficiency and ensure the long-term health and safety of patients. Summary of the Invention

[0009] Aiming at the problems of existing blood adsorbent materials such as limited adsorption capacity and poor adsorption specificity resulting in the loss of normal plasma proteins, the present invention provides a hemodialysis adsorbent, a preparation method thereof, a hemodialysis adsorption column, and a blood purification device. The hemodialysis adsorbent is composed of a carbonized resin as a substrate, and a bisphosphonate drug is fixed thereon by chemical bonding and other methods. This carbonized resin not only has good biocompatibility and chemical stability, but also can withstand high temperature and corrosion. Its unique pore structure ensures the efficient loading of the drug and the smooth flow of blood, while the bisphosphonate drug can efficiently adsorb calcium and phosphorus particles such as hydroxyapatite in blood. Compared with existing adsorbent materials, the adsorbent of the present invention has higher specificity, can effectively adsorb hydroxyapatite without affecting albumin, thus avoiding the loss of albumin. Moreover, the preparation method of this hemodialysis adsorbent is simple, adopting efficient and easy-to-operate technical steps, ensuring the uniformity of the product, and providing convenience for large-scale production and clinical application. In addition, the present invention also includes a hemodialysis adsorption column and a blood purification device equipped with this adsorbent, which show excellent performance in hemodialysis treatment and are applicable to a wide range of blood purification application scenarios.

[0010] To achieve the above object, the present invention adopts the following technical solutions:

[0011] A hemodialysis adsorbent, comprising: a carbonized resin, and a bisphosphonate drug fixed on the carbonized resin.

[0012] In some embodiments, the carbonized resin is polystyrene-divinylbenzene; and / or, the bisphosphonate drug is alendronate sodium.

[0013] The present invention also provides a method for preparing the hemodialysis adsorbent. By immobilizing a bisphosphonate drug on a carbonized resin, the above-mentioned hemodialysis adsorbent can be obtained.

[0014] In some embodiments, the method of immobilization includes covalent bonding or adsorption.

[0015] In some embodiments, before immobilizing the bisphosphonate drug on the carbonized resin, it further includes: mixing the carbonized resin, a curing agent, and a catalyst in a certain proportion, and preparing an adsorbent matrix through high-temperature curing; and / or, after immobilizing the bisphosphonate drug on the carbonized resin, it further includes: a washing step to remove the unimmobilized bisphosphonate drug; a drying step to dry the hemodialysis adsorbent that has completed the washing step.

[0016] The present invention also provides a hemodialysis adsorption column, including: the above-mentioned hemodialysis adsorbent, or a hemodialysis adsorbent prepared by the above-mentioned preparation method, and a housing; the housing is provided with a blood inlet and a blood outlet adapted to be connected to a hemodialysis machine; the interior of the housing is provided with a receiving space for loading the hemodialysis adsorbent.

[0017] In some embodiments, the housing is cylindrical.

[0018] The present invention also provides a blood purification device, including the above-mentioned hemodialysis adsorption column.

[0019] In some embodiments, the blood purification device further includes: a hemodialysis machine connected to the hemodialysis adsorption column.

[0020] In some embodiments, the blood purification device further includes: a vascular access that is respectively connected to the patient and the hemodialysis machine to introduce the patient's blood into the hemodialysis machine for hemodialysis and return the purified blood to the patient's body.

[0021] Compared with the prior art, the hemodialysis adsorbent, the preparation method, the hemodialysis adsorption column, and the blood purification device provided by the present invention have the following beneficial effects:

[0022] 1. The hemodialysis adsorbent provided by the present invention uses carbonized resin as the matrix, and bisphosphonate drugs are chemically fixed on it. The carbonized resin itself has excellent high-temperature resistance and corrosion resistance. Its pore structure not only ensures the efficient loading of drugs but also guarantees the smooth flow of blood during the adsorption process. Bisphosphonate drugs can specifically recognize and efficiently adsorb calcium phosphate particles such as hydroxyapatite in the blood. Compared with the existing adsorption materials, the adsorbent of the present invention avoids common problems of existing materials, such as the loss of albumin. The high specificity of this adsorbent ensures that it does not adsorb albumin, effectively preventing the loss of albumin, which is of great significance for improving and preventing vascular calcification symptoms in dialysis patients;

[0023] 2. The preparation process of the hemodialysis adsorbent provided by the present invention is simple, efficient, and easy to operate. Using fine chemical fixation technology, drug molecules are fixed on the adsorbent substrate, ensuring the lasting stability of the active ingredients, so that the adsorbent can stably maintain its high adsorption performance during hemodialysis. This preparation technology greatly improves the production efficiency and at the same time ensures the uniformity of the product, creating convenient conditions for the large-scale industrial production of the adsorbent;

[0024] 3. The blood adsorption column and hemodialysis device provided by the present invention are equipped with a blood adsorbent with excellent adsorption effect and high specificity, showing high adsorption performance for substances such as hydroxyapatite in hemodialysis treatment. Its excellent performance makes it an advanced medical product worthy of wide promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The present invention will be further described below with reference to the drawings and embodiments.

[0026] Figure 1 It is a schematic structural diagram of the blood purification device provided by the present invention.

[0027] The meanings of the reference symbols in the drawings are as follows:

[0028] 1 - Patient; 2 - Vascular access; 3 - Hemodialysis machine; 4 - Hemodialysis adsorption column; 5 - Collection tank. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0029] The present invention will be further explained in detail below with reference to the drawings and the description of specific embodiments. However, the following description including the embodiments is only used to enable those of ordinary skill in the technical field to which the present invention belongs to more clearly understand the principles and essence of the present invention, and does not mean any form of limitation to the present invention.

[0030] Example 1

[0031] The present invention provides a hemodialysis adsorbent, comprising: carbonized resin and bisphosphonate drugs, and the bisphosphonate drugs are fixed on the carbonized resin by chemical methods.

[0032] The above carbonized resin serves as the adsorbent matrix, which not only has good biocompatibility and chemical stability, but also can withstand high temperatures and corrosion. At the same time, it has an abundant pore structure, ensuring the effective loading of drugs and the smooth passage of blood. The bisphosphonate drugs, as a traditional antiresorptive drug mainly used for treating bone metabolic diseases, their main function is to inhibit the loss of calcium in bones, especially in osteoporosis, bone metastasis, hypercalcemia and some metabolic bone diseases. The inventor found during the research process that bisphosphonate drugs can tightly bind to hydroxyapatite in the blood to form a stable complex, thereby promoting the in vitro excretion of hydroxyapatite.

[0033] In some embodiments, due to the problem that traditional dialysis fiber columns are prone to cause a large loss of albumin, the present invention selects carbonized resin as polystyrene-divinylbenzene and bisphosphonate drugs as alendronate sodium from the perspectives of specific selectivity and biocompatibility to construct an alendronate sodium-functionalized polystyrene-divinylbenzene microsphere adsorbent to reduce the loss of albumin and enhance adsorption specificity.

[0034] The specific adsorption of alendronate sodium to hydroxyapatite comes from: its molecular structure contains a P-C-P group, and this structure enables it to specifically adsorb to hydroxyapatite. After being fixed on the carbonized resin through chemical bonding, it can efficiently adsorb hydroxyapatite rather than albumin, thereby reducing the loss of albumin.

[0035] Example 2

[0036] Based on Example 1, the present invention provides a preparation method of the hemodialysis adsorbent, and the steps include: fixing the bisphosphonate drugs on the carbonized resin to obtain the hemodialysis adsorbent.

[0037] Furthermore, the above fixing methods include various fixing strategies such as covalent bond connection or adsorption, such as amidation reaction, which realizes the intermolecular covalent binding process by forming stable amide bonds. In addition, adsorption is also a commonly used fixing means, which relies on weak intermolecular forces such as van der Waals forces, hydrogen bonds or ion exchange. These fixing techniques not only ensure the effective attachment of bisphosphonate drugs.

[0038] It should be noted that during the fixing process, the pH value needs to be adjusted and the temperature needs to be controlled.

[0039] Further, before fixing the bisphosphonate drug to the carbonized resin, it also includes the preparation step of the adsorbent matrix: mixing the carbonized resin, curing agent, and catalyst in a certain proportion, and preparing it into an adsorbent matrix after high-temperature curing.

[0040] Preferably, the adsorbent matrix is made into microspheres, that is, synthesizing polystyrene-divinylbenzene with a curing agent and a catalyst into microspheres. These microspheres have good chemical stability and biocompatibility. Then, the microspheres are soaked in alendronate sodium, and alendronate sodium is fixed on the surface of the microspheres by a chemical bonding method (such as amidation reaction).

[0041] Further, after fixing the bisphosphonate drug to the carbonized resin, it also includes: a washing step to remove the unfixed bisphosphonate drug. Then, in the drying step, the hemodialysis adsorbent that has completed the washing step is dried to obtain the final adsorbent product.

[0042] Example 3

[0043] The present invention also provides a hemodialysis adsorption column, which includes the hemodialysis adsorbent in Example 1, or the hemodialysis adsorbent prepared by the preparation method of Example 2, and a housing.

[0044] The housing is internally provided with a accommodating space for loading the hemodialysis adsorbent. The housing is provided with a blood inlet and a blood outlet to facilitate connection with a hemodialysis machine, so as to carry out hemodialysis treatment.

[0045] Further, the housing is cylindrical, and the material of the housing is medical-grade plastic or stainless steel, which has good blood compatibility and sufficient mechanical strength.

[0046] It should be noted that during the filling process of the hemodialysis adsorbent, it is necessary to ensure a reasonable flow channel design to optimize the blood flow path and avoid forming dead ends or excessive pressure drops.

[0047] In some embodiments, the operating temperature requirement of the hemodialysis adsorption column is 35°C. During the extracorporeal circulation process of hemodialysis, this temperature condition helps to maintain the stability of the adsorption process and optimize the performance of the adsorbent.

[0048] During the operation of the hemodialysis adsorption column, the pH of the mobile phase usually needs to be adjusted to 3.3. Given that hemodialysis patients are prone to metabolic acidosis, maintaining this acidic condition helps the adsorption process of alendronate sodium and ensures the best interaction between the adsorbent and the target substance.

[0049] Example 4

[0050] To verify the effect of the hemodialysis adsorption column provided by the present invention in actual applications, a series of tests including in vitro simulation experiments and animal experiments were carried out.

[0051] (1) In vitro simulation experiment

[0052] Prepare simulated blood: Prepare simulated blood containing typical concentrations of hydroxyapatite to simulate the blood environment of patients with chronic kidney disease.

[0053] Experimental process: Pass the simulated blood through a hemodialysis adsorption column to simulate the actual operating environment of hemodialysis.

[0054] Sample collection and analysis:

[0055] Collect simulated blood samples before and after treatment, and use chemical analysis methods (such as spectroscopy and chromatography) and electron microscopy observation to evaluate the removal efficiency of hydroxyapatite particles.

[0056] At the same time, detect the changes of other key components in the blood (such as albumin, blood cells, etc.) by the hemodialysis adsorbent to evaluate the impact of the adsorption column on other components of the blood.

[0057] (2) Animal experiment

[0058] Establish an animal model: Select multiple chronic renal failure model animals (such as rats or rabbits).

[0059] Experimental grouping: Randomly divide the animals into two groups:

[0060] Experimental group: Add a hemodialysis adsorption column to the conventional hemodialysis treatment.

[0061] Control group: Only perform conventional hemodialysis treatment without using a hemodialysis adsorption column.

[0062] Experimental process: Perform regular hemodialysis treatment on both groups of animals, and connect the hemodialysis adsorption column to the experimental group during the dialysis cycle.

[0063] Before and after dialysis, collect blood samples regularly for hematological tests and evaluation of vascular calcification.

[0064] Through the comprehensive verification of in vitro simulation experiments and animal experiments, the hemodialysis adsorption column demonstrates high-efficiency clearance ability for hydroxyapatite particles, and at the same time does not cause adverse effects on other components of the blood. The experimental results fully confirm the feasibility, high efficiency, and safety of the hemodialysis adsorption column of the present invention, which can be widely applied to hemodialysis treatment and other blood purification fields.

[0065] Example 5

[0066] On the basis of Examples 1-3, the present invention further provides a blood purification device, including the hemodialysis adsorption column 4 described in the above examples.

[0067] Furthermore, as Figure 1As shown, the blood purification device further includes: a hemodialysis machine 3. The hemodialysis adsorption column 4 is connected to the dialysis circulation system of the hemodialysis machine 3 through a connector. The blood first flows through the above-mentioned hemodialysis adsorption column 4, and calcium and phosphorus particles such as hydroxyapatite in the blood will be specifically adsorbed by the CPPs adsorbent, reducing their deposition in the blood vessels. Then, it undergoes conventional purification by the hemodialysis machine 2 to remove solutes and metabolites. Finally, the purified blood returns to the patient 1's body.

[0068] Furthermore, the blood purification device further includes a vascular access 2. The vascular access 2 is respectively connected to the patient 1 and the hemodialysis machine 3, introducing the patient 1's blood into the hemodialysis machine 3 for efficient blood purification treatment, and ensuring that the purified blood can be safely transfused back into the patient's body.

[0069] Preferably, the blood purification device further includes a collection tank 5, which is connected to the hemodialysis adsorption column 4. The function of the collection tank 5 is to collect harmful substances (such as hydroxyapatite) adsorbed by the hemodialysis adsorbent in the adsorption column.

[0070] Based on the ideal embodiments of the present invention, through the above description, relevant staff can make various changes and modifications completely within the scope not deviating from the technical idea of this invention.

[0071] The technical scope of this invention is not limited to the content in the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A hemodialysis adsorbent, characterized in that: include: Carbonized resin and bisphosphonate drugs fixed on the carbonized resin.

2. The hemodialysis adsorbent according to claim 1, characterized in that: The carbonized resin is polystyrene-divinylbenzene; and / or, The bisphosphonate drug is alendronate sodium.

3. A method for preparing a hemodialysis adsorbent, characterized in that: The hemodialysis adsorbent according to any one of claims 1 to 2 can be obtained by fixing the bisphosphonate drugs on the carbonized resin.

4. The preparation method according to claim 3, characterized in that: The immobilization method includes covalent bonding or adsorption.

5. The preparation method according to claim 3 or 4, characterized in that: Before fixing the bisphosphonate drug on the carbonized resin, the method further includes: mixing the carbonized resin, a curing agent, and a catalyst in a certain proportion, and preparing an adsorbent matrix after high-temperature curing; and / or, After the bisphosphonate drugs are fixed on the carbonized resin, the method further comprises: a washing step to remove the unfixed bisphosphonate drugs; The drying step is to dry the hemodialysis adsorbent after the washing step.

6. Hemodialysis adsorption column, characterized in that: include: The hemodialysis adsorbent according to any one of claims 1-2, or the hemodialysis adsorbent prepared by the preparation method according to any one of claims 3-5, and a shell; The housing is provided with a blood inlet and a blood outlet suitable for connecting to a hemodialysis machine; The interior of the shell is provided with a containing space for filling the hemodialysis adsorbent.

7. The hemodialysis adsorption column according to claim 6, characterized in that: The shell is cylindrical.

8. A blood purification device, characterized in that: It comprises the hemodialysis adsorption column described in any one of claims 6-7.

9. The blood purification device according to claim 8, characterized in that: Also includes: A hemodialysis machine connected to the hemodialysis adsorption column.

10. The blood purification device according to claim 9, characterized in that: It also includes: a vascular access, which connects the patient and the hemodialysis machine respectively, so as to introduce the patient's blood into the hemodialysis machine for hemodialysis, and return the purified blood to the patient's body.

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