Rare-earth anticoagulant material for venous pipeline and preparation method and application of rare-earth anticoagulant material

Abstract

The invention provides a rare earth anticoagulant material for a venous pipeline and a preparation method and application thereof.The rare earth anticoagulant material is prepared from raw materials including ferulic acid and rare earth nitrate, the ferulic acid is a phenolic acid substance with the anti-oxidation, anti-inflammation and antibacterial effects, the chemical property of rare earth ions is quite similar to that of calcium ions, and the rare earth nitrate has the anti-oxidation, anti-inflammation and antibacterial effects. The rare earth ions are more than calcium ions by one positive charge, the ion charge density is higher than that of the calcium ions, and the rare earth ions have stronger combining capacity with oxygen-containing ligands and can competitively replace calcium to form a more stable complex, so that the protein structure is influenced, the normal blood coagulation process is destroyed, and the anticoagulation effect is achieved; the combination of the two can obtain a material with a better anticoagulant effect.

Description

Technical Field

[0001] This invention belongs to the field of anticoagulant materials, and in particular relates to a rare earth anticoagulant material for intravenous lines, its preparation method and application. Background Technology

[0002] Extracorporeal membrane oxygenation (ECMO) is a core technology for rescuing critically ill patients with cardiopulmonary failure. It can partially or completely replace cardiopulmonary function, buying time for the patient's organs to recover. It is widely used in the treatment of acute respiratory distress syndrome, cardiac arrest, and other conditions. The core components of the ECMO system include a membrane lung, a blood pump, and associated tubing. The fact that the tubing is in direct contact with blood makes it highly susceptible to coagulation, which can lead to thrombosis.

[0003] Meanwhile, frequent tubing replacements are necessary after thrombosis forms on the inner wall of the tubing. Currently available surface modification strategies for ECMO tubing have not effectively addressed the core issue of coagulation.

[0004] Blood clotting is closely related to calcium ions. Rare earth ions, due to their similar properties to calcium ions, can competitively inhibit the action of calcium ions, thus disrupting the clotting process. In recent years, combining pharmacologically active compounds with metal ions to enhance drug efficacy has become an important direction in the development of novel drugs, providing new ideas and methods for the development of anticoagulant medical devices. Summary of the Invention

[0005] In view of this, the present invention aims to provide a rare earth anticoagulant material for intravenous tubing, its preparation method and application. The method involves preparing an anticoagulant material with anticoagulant effect on blood by combining rare earth compounds with raw materials such as ferulic acid. This anticoagulant material is loaded onto the inner wall of the intravenous catheter by an ionic bonding impregnation method to form an anticoagulant coating. This intravenous tubing with an anticoagulant coating can effectively prevent blood from clotting during extracorporeal circulation.

[0006] To achieve the above objectives, the technical solution of the present invention is implemented as follows: A rare earth anticoagulant material for intravenous lines, the anticoagulant material being prepared from raw materials including ferulic acid, rare earth nitrates and other additives; wherein the mass ratio of ferulic acid to rare earth nitrates is 1:(1-1.5), the rare earth nitrates include two or three of cerium nitrate hexahydrate, samarium nitrate hexahydrate, and praseodymium nitrate hexahydrate, and the other additives include hexamethylenetetramine, tannic acid and tea polyphenols.

[0007] Rare earth elements can not only bind to biological macromolecules such as proteins, but also form complexes with nucleic acids and their structural units such as amino acids and nucleotides, thereby participating in or interfering with the metabolism and biosynthesis of cells in organisms.

[0008] Because rare earth ions and calcium ions share many similarities, such as their similar ionic radii, and the indispensable role of calcium ions in blood clotting, rare earth ions are commonly used in organisms as calcium antagonists or substitutes to interfere with the normal physiological function of calcium ions. Rare earth ions exhibit greater adaptability to coordination spatial structures with different coordination numbers. Furthermore, rare earth ions possess an additional positive charge compared to calcium ions, resulting in a higher ionic charge density and a stronger binding affinity for oxygen-containing ligands. This allows them to competitively replace calcium ions. Due to these unique properties, the high charge density of rare earth ions substitutes for calcium ions during blood clotting, forming more stable compounds that disrupt the normal conformation of proteins, thereby affecting their intact molecular structure and disrupting the normal clotting process, thus exerting an anticoagulant effect.

[0009] Furthermore, the rare earth nitrate includes a necessary component and an optional component. The necessary component is cerium nitrate hexahydrate, and the optional component is praseodymium nitrate hexahydrate and / or samarium nitrate hexahydrate. The mass ratio of the necessary component to the optional component is 1:(1-3).

[0010] Furthermore, the mass ratio of hexamethylenetetramine to rare earth nitrate is 1:(1-2).

[0011] Furthermore, the mass ratio of tannic acid to tea polyphenols is 1:(1-2), and the mass ratio of tannic acid to rare earth nitrates is 1:(10-12).

[0012] This invention also provides a method for preparing rare earth anticoagulant materials for intravenous lines. The method includes the following steps: ferulic acid, hexamethylenetetramine, and rare earth nitrates are dissolved in deionized water to obtain ferulic acid solution, hexamethylenetetramine solution, and rare earth nitrate solution, respectively; then, the hexamethylenetetramine solution is added to the ferulic acid solution to obtain a reaction solution, and the pH of the solution is maintained at 7. Subsequently, a gradient temperature control process is used to slowly add the rare earth nitrate solution dropwise to the reaction solution, and tannic acid and tea polyphenols are added as auxiliary ligands to enhance anticoagulant activity. The reaction is first carried out at 50-60℃ for 1-2 hours to promote the formation of coordination nuclei, and then the temperature is raised to 70-80℃ and the reaction is continued for 3-4 hours. After the reaction, the free small molecules are removed by dialysis membrane, purified by centrifugation with a mixed solvent of ethanol / acetone, and finally obtained by freeze-drying.

[0013] Furthermore, the final concentration of rare earth nitrates in the reaction solution is 100-120 g / L.

[0014] Furthermore, the dialysis membrane has a molecular weight cutoff of 2000 Da, and the volume ratio of ethanol / acetone in the mixed solvent is 1:1.

[0015] The present invention also provides an application of the above-mentioned rare earth anticoagulant material for venous tubing on the coating of venous tubing. The preparation method of the coating is as follows: ordinary PVC extracorporeal venous catheters are pretreated by sequentially using ethanol, deionized water and polyethyleneimine solution, then an 8-10 g / L rare earth anticoagulant material solution is prepared, the pretreated venous catheter is placed in it and immersed for 10-12 h to obtain a venous tubing with an anticoagulant coating.

[0016] Furthermore, the specific pretreatment method is as follows: cut a section of ordinary PVC extracorporeal venous catheter, infuse the catheter with 95% ethanol by volume, seal both ends with hemostatic forceps, shake in a constant temperature shaker at room temperature for 1-2 hours, then pour out the ethanol and rinse with deionized water, dry at 40-50℃, then infuse the catheter with 1%-2% polyethyleneimine solution, seal both ends with hemostatic forceps, place it in a constant temperature shaker and shake at room temperature for 10-12 hours, and then dry at 40-50℃ to complete the pretreatment of ordinary PVC extracorporeal venous catheter.

[0017] Compared with existing technologies, the rare earth anticoagulant material for intravenous lines, its preparation method, and its application described in this invention have the following advantages: (1) The rare earth anticoagulant material for intravenous lines described in this invention combines rare earth elements with ferulic acid. Ferulic acid is a phenolic acid substance widely found in natural plants, possessing antioxidant, anti-inflammatory, and antibacterial effects. Because the chemical properties of rare earth ions are very similar to those of calcium ions, and rare earth ions have an additional positive charge, resulting in a higher ion charge density, they have a stronger binding capacity for oxygen-containing ligands. This allows them to competitively replace calcium, forming a more stable complex, thereby affecting protein structure, disrupting the normal coagulation process, and exerting an anticoagulant effect. Compared to the control group, the blood clotting time was prolonged by nearly three times. Combining ferulic acid with rare earth elements results in superior anticoagulant performance.

[0018] (2) The rare earth anticoagulant material for intravenous catheters described in this invention is loaded onto the inner wall of the intravenous catheter using an ionic bonding impregnation method to form an anticoagulant coating. During the impregnation process, the anticoagulant material spreads and adsorbs along the inner wall of the catheter, forming a uniform coating with no pores and strong adhesion, completely covering the interface between the catheter and blood, avoiding "local coagulation points" caused by partial coating loss, and blocking direct contact between blood and PVC substrate from the source (PVC substrate itself is prone to platelet adhesion and aggregation). This material inhibits coagulation through a triple mechanism: rare earth ions competitively inhibit calcium ions, rare earth directly inhibits platelet production, and ferulic acid inhibits prothrombin synthesis. The triple action is synergistic and superimposed, resulting in a more lasting anticoagulant effect. Attached Figure Description

[0019] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 This is a SEM scan of the FLCSO prepared in Example 1 of the present invention. Detailed Implementation

[0020] It should be noted that, unless otherwise specified, the embodiments and features described in the present invention can be combined with each other.

[0021] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] Ferulic acid, hexamethylenetetramine, tannic acid, tea polyphenols, polyethyleneimine, ethanol, and acetone were purchased from Maclean Chemical Company.

[0023] Cerium nitrate hexahydrate, samarium nitrate hexahydrate, and praseodymium nitrate hexahydrate were purchased from Shandong Desheng New Materials Co., Ltd.

[0024] All chemicals were used without further processing, and the deionized water was prepared in the laboratory.

[0025] Unless otherwise specified, all reagents used are standard biochemical reagents; all experimental methods described are standard methods unless otherwise specified.

[0026] Example 1 1. Preparation of rare earth anticoagulant materials for intravenous tubing Weigh 38.8g of ferulic acid and add it to 100mL of deionized water. Weigh 22g of cerium nitrate hexahydrate and 22g of samarium nitrate hexahydrate and add them to 200mL of deionized water. Then weigh 28.9g of hexamethylenetetramine and add it to 100mL of deionized water. Then turn on the magnetic stirrer and stir for 10 minutes at room temperature to obtain ferulic acid solution, hexamethylenetetramine solution, and rare earth nitrate solution. Add the hexamethylenetetramine solution to the ferulic acid solution to obtain the reaction solution, maintaining the pH of the solution at 7. Then... A gradient temperature-controlled process was used, in which rare earth nitrate solution was slowly added dropwise to the reaction solution, along with 4.4 g of tannic acid and 4.4 g of tea polyphenols. The reaction was first carried out at 50 °C for 2 h to promote the formation of coordination nuclei, and then the temperature was raised to 70 °C and the reaction was continued for 4 h. After the reaction was completed, the free small molecules were removed by dialysis membrane (molecular weight cutoff 2000 Da), and purified by centrifugation at 10000 rpm / 10 min in a mixed solvent of ethanol / acetone (volume ratio 1:1). Finally, high-purity rare earth anticoagulant material FLCSO was obtained by freeze drying.

[0027] After grinding the dried FLCSO, SEM scanning was performed, and the results are as follows: Figure 1 As shown, the morphology of FLCSO material consists of micron-sized single particles aggregated into layers. The fine particles have irregular shapes and smooth surfaces, exhibiting unique characteristics.

[0028] 2. Preparation of rare earth anticoagulant venous tubing coating A 20cm section of a standard PVC extracorporeal venous catheter was cut, and 95% ethanol was infused into the catheter. Both ends were sealed with hemostats, and the catheter was shaken in a constant-temperature shaker at room temperature for 2 hours. The ethanol was then drained, the catheter was rinsed with deionized water, and dried at 45°C. Next, a 1% polyethyleneimine solution was infused into the catheter, and both ends were sealed with hemostats. The catheter was then placed in a constant-temperature shaker and shaken at room temperature for 12 hours, followed by drying at 45°C. This completed the pretreatment of the standard PVC extracorporeal venous catheter. A 10g / L FLCSO solution was prepared by dissolving FLCSO in deionized water. The pretreated venous catheter was immersed in this solution for 12 hours to obtain a venous tubing with an anticoagulant coating.

[0029] Example 2 The difference from Example 1 is that the rare earth nitrates used in the preparation of the rare earth anticoagulant material are 22g of cerium nitrate hexahydrate and 22g of praseodymium nitrate hexahydrate, resulting in the anticoagulant material FLCPO. Everything else is the same as in Example 1.

[0030] Example 3 The difference from Example 1 is that the rare earth nitrates used in the preparation of the rare earth anticoagulant material are 11g of cerium nitrate hexahydrate, 22g of praseodymium nitrate hexahydrate, and 11g of samarium nitrate hexahydrate, to obtain the anticoagulant material FLCPSO. Everything else is the same as in Example 1.

[0031] Example 4 The difference from Example 1 is that the amount of ferulic acid used in the preparation of the rare earth anticoagulant material was adjusted from 38.8g to 31.0g, resulting in the anticoagulant material FLCSO(a). Everything else is the same as in Example 1.

[0032] Example 5 The difference from Example 1 is that the amount of hexamethylenetetramine used in the preparation of the rare earth anticoagulant material was adjusted from 28.9g to 23.1g, resulting in the anticoagulant material FLCSO(b). All other aspects are the same as in Example 1.

[0033] Comparative Example 1 The difference from Example 1 is that the rare earth nitrate used in the preparation of the rare earth anticoagulant material is 44g of cerium nitrate hexahydrate, resulting in the anticoagulant material FLCO. Everything else is the same as in Example 1.

[0034] Comparative Example 2 The difference from Example 1 is that the rare earth nitrate used in the preparation of the rare earth anticoagulant material is 44g of samarium nitrate hexahydrate, resulting in the anticoagulant material FLSO. Everything else is the same as in Example 1.

[0035] Comparative Example 3 The difference from Example 1 is that the rare earth nitrate used in the preparation of the rare earth anticoagulant material is 44g of praseodymium nitrate hexahydrate, resulting in the anticoagulant material FLPO. Everything else is the same as in Example 1.

[0036] Comparative Example 4 The difference from Example 1 is that the amount of ferulic acid used in the preparation of the rare earth anticoagulant material was adjusted from 38.8g to 23.2g, resulting in the anticoagulant material FLCSO(c). Everything else is the same as in Example 1.

[0037] Comparative Example 5 The difference from Example 1 is that the amount of hexamethylenetetramine used in the preparation of the rare earth anticoagulant material was adjusted from 28.9g to 17.3g, resulting in the anticoagulant material FLCSO(d). Everything else is the same as in Example 1.

[0038] Comparative Example 6 The difference from Example 1 is that the rare earth anticoagulant material preparation process does not use a gradient temperature control process, but directly reacts at 70°C for 6 hours to obtain the anticoagulant material FLCSO(e). All other aspects are the same as in Example 1.

[0039] Comparative Example 7 The difference from Example 1 is that tannic acid and tea polyphenols are not added during the preparation of the rare earth anticoagulant material, resulting in the anticoagulant material FLCSO(f). Everything else is the same as in Example 1.

[0040] Comparative Example 8 The difference from Example 1 is that the rare earth anticoagulant material was not purified using a dialysis membrane during preparation. Instead, it was purified directly by centrifugation at 10,000 rpm for 10 min using a mixed solvent of ethanol / acetone (volume ratio 1:1), and then the product FLCSO(g) was obtained by freeze-drying. All other steps were the same as in Example 1.

[0041] Comparative Example 9 The difference from Example 1 is that the rare earth element compounds used in the preparation of the rare earth anticoagulant material are 22g of cerium chloride heptahydrate and 22g of samarium chloride heptahydrate, to obtain the anticoagulant material FLCSO(h). Everything else is the same as in Example 1.

[0042] Comparative Example 10 The difference from Example 1 is that the rare earth nitrates used in the preparation of the rare earth anticoagulant material are 22g of cerium nitrate hexahydrate and 22g of lanthanum nitrate hexahydrate, resulting in the anticoagulant material FLCLO. Everything else is the same as in Example 1.

[0043] Comparative Example 11 The difference from Example 3 is that the rare earth nitrates used in the preparation of the rare earth anticoagulant material are 22g of praseodymium nitrate hexahydrate and 11g of samarium nitrate hexahydrate, without the addition of cerium nitrate hexahydrate, to obtain the anticoagulant material FLPSO. Everything else is the same as in Example 1.

[0044] Test Example: Anticoagulation Duration Test Experiment Three clean intravenous tubings with anticoagulant coatings were prepared for each of the above-mentioned embodiments and comparative examples. Each tubing was cut to 10 cm in length. A blank tubing without rare earth anticoagulant coating (control group) was also prepared. One end of each tubing was sealed with hemostatic forceps, and the other end was left open. All tubing was placed in a 37°C water bath until it reached a constant temperature. Then, 3 mL of fresh blood from slaughtered cattle at a meat processing plant was gently dripped into the test tube. At the same time, a stopwatch was started, and the test tube was gently tilted at 30° continuously for careful observation. The blood and tubing walls were observed for any abnormalities. If thrombi and adhesion to the tubing walls were observed, it was confirmed that the blood had coagulated. The coagulation time was recorded at this moment.

[0045] Table 1. Clotting time of tubing with different rare earth anticoagulant coatings

[0046] Table 1 shows the statistical data on the anticoagulation time of the anticoagulation coated tubing prepared with various materials. Table 1 shows that the clotting time of the blank tubing was 8′48″. The clotting time of the tubing prepared in this embodiment of the invention is superior to that of the blank tubing. In particular, the clotting time of the FLCSO anticoagulation coated tubing can be extended to 36′06″, nearly three times longer. The FLCPO coated tubing is next, with a clotting time extended to 23′00″, and the FLCPO coated tubing also has a clotting time extended to 21′33″. This indicates that the anticoagulation material prepared in this invention is more conducive to improving the anticoagulation performance of the material. In the anticoagulation coating composed of ferulic acid and rare earth nitrate, due to the synergistic effect between the ferulic acid ligand and rare earth ions, the rare earth ions and ferulic acid in the complex act in the blood according to their respective anticoagulation mechanisms, mutually inhibiting each other's slow decomposition and release, antagonizing coagulation factors, thereby prolonging the clotting time and exhibiting a better anticoagulation effect.

[0047] Comparative Examples 1-3 used only one rare earth nitrate, which did not synergize well with ferulic acid, resulting in poor anticoagulant effects. In Comparative Examples 4 and 5, the ratio of ferulic acid to hexamethylenetetramine was not met, also affecting the anticoagulant effect. Comparative Example 6 did not employ a gradient temperature control process, leading to a surge in the probability of instantaneous collisions between rare earth ions and ligands, resulting in a large amount of disordered instantaneous nucleation and the formation of fine, fragmented precipitates rather than regular crystals. Auxiliary ligands such as tannins and tea polyphenols may have preempted the main ligand, disrupting the intended core structure and resulting in residual free rare earth ions. Comparative Example 7 did not add tannins and tea polyphenols, leading to reduced anticoagulant activity in the final product. Comparative Example 8 did not use a dialysis membrane for purification, failing to filter out small molecular fragments of free metal complexes. Some divalent ions in the blood exhibited a healing-promoting effect similar to calcium ions, affecting the anticoagulant effect. Comparative Example 9 did not use rare earth nitrates, Comparative Example 10 replaced rare earth nitrates, and Comparative Example 11 did not add cerium nitrate hexahydrate; all of these results in a decrease in anticoagulant effect.

[0048] This invention uses ferulic acid and rare earth nitrates to prepare an anticoagulant material. Through a chemical reaction, ferulic acid, a natural plant extract with anticoagulant effects, is combined with specific rare earth ions, which can antagonize clotting factors in the blood and affect the role of calcium ions in the clotting process, thus giving it strong antithrombotic and anticoagulant effects. Experimental tests show that it has good anticoagulant effects and can meet the requirements for external anticoagulant devices.

[0049] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A rare earth anticoagulant material for intravenous tubing, characterized in that: The anticoagulant material is prepared from raw materials including ferulic acid, rare earth nitrates and other adjuvants; wherein the mass ratio of ferulic acid to rare earth nitrates is 1:(1-1.5), the rare earth nitrates include two or three of cerium nitrate hexahydrate, samarium nitrate hexahydrate and praseodymium nitrate hexahydrate, and the other adjuvants include hexamethylenetetramine, tannic acid and tea polyphenols.

2. The rare earth anticoagulant material for intravenous tubing according to claim 1, characterized in that: Rare earth nitrates include essential components and optional components. The essential component is cerium nitrate hexahydrate, and the optional components are praseodymium nitrate hexahydrate and / or samarium nitrate hexahydrate. The mass ratio of the essential component to the optional components is 1:(1-3).

3. The rare earth anticoagulant material for intravenous tubing according to claim 1, characterized in that: The mass ratio of hexamethylenetetramine to rare earth nitrate is 1:(1-2).

4. The rare earth anticoagulant material for intravenous tubing according to claim 1, characterized in that: The mass ratio of tannic acid to tea polyphenols is 1:(1-2), and the mass ratio of tannic acid to rare earth nitrates is 1:(10-12).

5. A method for preparing a rare earth anticoagulant material for intravenous lines as described in any one of claims 1-4, characterized in that: The method includes the following steps: Ferulic acid, hexamethylenetetramine, and rare earth nitrates are dissolved in deionized water to obtain ferulic acid solution, hexamethylenetetramine solution, and rare earth nitrate solution, respectively; then, the hexamethylenetetramine solution is added to the ferulic acid solution to obtain a reaction solution, and the pH of the solution is maintained at 7. Subsequently, a gradient temperature control process is used to slowly add the rare earth nitrate solution dropwise to the reaction solution, and tannic acid and tea polyphenols are added as auxiliary ligands to enhance anticoagulant activity. The reaction is first carried out at 50-60℃ for 1-2 hours to promote the formation of coordination nuclei, and then the temperature is raised to 70-80℃ and the reaction is continued for 3-4 hours. After the reaction, the free small molecules are removed by dialysis membrane, purified by centrifugation with a mixed solvent of ethanol / acetone, and finally obtained by freeze-drying.

6. The method for preparing rare earth anticoagulant material for intravenous lines according to claim 5, characterized in that: The final concentration of rare earth nitrates in the reaction solution is 100-120 g / L.

7. The method for preparing rare earth anticoagulant material for intravenous lines according to claim 5, characterized in that: The dialysis membrane has a molecular weight cutoff of 2000 Da, and the volume ratio of ethanol and acetone in the mixed solvent is 1:

1.

8. The application of a rare earth anticoagulant material for intravenous lines as described in any one of claims 1-4 on the coating of intravenous lines, characterized in that: The preparation method of the coating is as follows: ordinary PVC extracorporeal venous catheters are pretreated with ethanol, deionized water and polyethyleneimine solution in sequence. Then, an 8-10 g / L rare earth anticoagulant material solution is prepared, and the pretreated venous catheter is placed in it and immersed for 10-12 h to obtain a venous tubing with an anticoagulant coating.

9. The application of the rare earth anticoagulant material for intravenous lines according to claim 8 in the coating of intravenous lines, characterized in that: The specific pretreatment method is as follows: cut a section of ordinary PVC extracorporeal venous catheter, infuse the catheter with 95% ethanol by volume, seal both ends with hemostatic forceps, shake in a constant temperature shaker at room temperature for 1-2 hours, then pour out the ethanol and rinse with deionized water, dry at 40-50℃, then infuse the catheter with 1%-2% polyethyleneimine solution by mass, seal both ends with hemostatic forceps, place in a constant temperature shaker and shake at room temperature for 10-12 hours, and then dry at 40-50℃ to complete the pretreatment of ordinary PVC extracorporeal venous catheter.

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