Membrane artificial organ material and method for producing the same

Abstract

The application discloses a kind of membrane artificial organ materials and preparation method thereof, by dipyridamole modification preparation;The membrane artificial organ material can improve the risk of membrane related thrombosis and inflammation by inhibiting platelet, and based on the antiviral effect of dipyridamole itself, the modified membrane has a positive effect on combating viruses and protecting coronary arteries.Dipyridamole modified artificial organ membrane uses PLGA copolymer, 4-(dimethylamino) pyridine, succinic anhydride and dichloromethane to prepare PLGA-COOH dipyridamole microspheres, and the film substrate is modified to obtain.

Description

Technical Field

[0001] This invention belongs to the field of medical device technology, and in particular relates to a membrane-type artificial organ material and its preparation method. Background Technology

[0002] Membrane-based artificial organs, such as artificial kidneys, extracorporeal membrane oxygenation (ECMO), and artificial livers, are widely used in critically ill patients with multiple organ dysfunction syndrome (MODS). As membrane-based artificial organs are extracorporeal materials, when the membrane material comes into contact with blood, platelets inevitably adhere to the membrane surface. The activated platelet factor 3 provides the necessary site for the activation of coagulation factors. After activation, a cascade reaction causes fibrin monomers to intertwine and network with platelets, ultimately forming a solid thrombus on the membrane surface under the contractile action of platelet troponin. Therefore, membrane materials with poor blood compatibility can lead to membrane-associated thrombosis (MATh), increasing the risk of blockage in artificial conduits and reducing the purification efficiency of the artificial organ. Platelets play a crucial role in this process.

[0003] On the other hand, MODS is often caused by severe infections, and blood purification membranes with poor blood compatibility are prone to inducing inflammatory responses, exacerbating systemic cytokine storms and organ damage. Platelet activation plays a crucial role in the development of MODS. Platelet activation can release various inflammatory mediators, activate leukocytes, increase the release of leukocyte contents, promote arachidonic acid metabolism and the production of oxygen free radicals, further aggravating the inflammatory response. Therefore, we need to modify conventional blood purification membranes and develop a novel membrane material that can simultaneously resist thrombosis and inflammation.

[0004] Current technologies, such as heparin and argatroban modified membranes that inhibit thrombin activity, and apixaban modified membranes that inhibit FX activity, achieve anticoagulation by inhibiting coagulation factor pathways. Other dialysis membranes that improve blood compatibility by increasing hydrophilicity, such as those used in artificial kidneys, extracorporeal membrane oxygenation (ECMO), and artificial livers, primarily enhance their anticoagulant properties without specifically inhibiting platelets. Furthermore, blood purification membranes with poor blood compatibility can exacerbate inflammatory responses in MODS patients. Moreover, existing technologies have limited research on the antiviral properties of membrane materials. Therefore, there is an urgent need for a membrane-based artificial organ material that can simultaneously target both antithrombotic and antiviral effects. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing a membrane-based artificial organ material based on dipyridamole; the preparation process is simple and easy to industrialize.

[0006] Another objective of this invention is to provide a dipyridamole-modified membrane artificial organ material, which can effectively prevent blood clotting, inhibit viral replication, and increase coronary blood flow. The base material of the material includes, but is not limited to, polylactic acid, polysulfone, polyester, and cellulose.

[0007] The technical solution adopted in this invention is to prepare a membrane-based artificial organ material based on dipyridamole modification, comprising the following steps:

[0008] S1, synthesized from PLGA-COOH;

[0009] S2. Preparation of PLGA-COOH supported dipyridamole microspheres;

[0010] S3. Synthesis of synthetic membrane artificial organ materials.

[0011] Furthermore, the specific synthesis steps for PLGA-COOH in S1 are as follows:

[0012] PLGA copolymer, 4-(dimethylamino)pyridine, succinic anhydride and dichloromethane were mixed, dissolved and stirred for 2-4 hours, and then transferred to a rotary evaporator to remove dichloromethane and concentrate the mixture. The mixture was precipitated three times in methanol and dried under vacuum to obtain carboxyl-terminated PLGA polymer, namely PLGA-COOH. The mass ratio of PLGA copolymer, 4-(dimethylamino)pyridine, succinic anhydride and dichloromethane was 2-6:1:1:60-70.

[0013] Furthermore, the specific preparation steps of the PLGA-COOH-loaded dipyridamole microspheres in S2 are as follows:

[0014] Weigh out 10–40 mg of dipyridamole and dissolve it in 1 ml of double-distilled water as the inner aqueous phase W1. Dissolve 200 mg of carboxyl-terminated PLGA polymer in 4–10 ml of dichloromethane and acetone as the oil phase O. The volume ratio of dichloromethane to acetone is [missing value]. The primary emulsion was obtained by slowly dripping W1 into the oil phase O under ultrasonic emulsification. 1% (w / v) PVA was dissolved in 30-50 mL of double-distilled water to obtain the external aqueous phase W2. The primary emulsion was slowly dripped into W2 and stirred for 5 min to obtain the W1 / O / W2 double emulsion. The double emulsion was poured into 400 mL of double-distilled water and stirred at 1000 r / min for 4-6 h until the residual organic solvent evaporated. Then, the microspheres were collected by high-speed centrifugation at 10000-12000 r / min, washed and dried to obtain PLGA-COOH supported dipyridamole microspheres.

[0015] Furthermore, the specific synthesis steps of the dipyridamole-modified membrane in S3 are as follows:

[0016] S31 dissolves PLGA-COOH-loaded dipyridamole microspheres and membrane substrate in DMF or DMAC to prepare a solution containing 16% to 20% of the substrate by mass.

[0017] S32 was allowed to stand and degas to obtain a casting solution; the 50℃ casting solution was placed in a 25℃ coagulation bath (pure water), solidified, and then soaked to obtain a film.

[0018] Furthermore, in S31, the mass ratio of PLGA-COOH-loaded dipyridamole microspheres to the membrane substrate is 2:(16-20).

[0019] Furthermore, the membrane substrate described in S32 includes any one of polyethersulfone, polyurethane, cellulose, and polylactic acid.

[0020] The beneficial effects of this invention are: the dipyridamole modified membrane material prepared by the method described in this invention can be used to treat membrane thrombosis caused by artificial kidneys, extracorporeal membrane oxygenation (ECMO), and artificial livers, while the modified membrane also provides coronary artery protection for critically ill patients. This method is simple, can be mass-produced industrially, and is suitable for widespread application. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0022] Figure 1 This is a flowchart of the preparation process of the present invention. Detailed Implementation

[0023] 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.

[0024] like Figure 1 The method for preparing dipyridamole-modified membrane-based artificial organ materials includes the following steps:

[0025] Synthesis of S1 and PLGA-COOH:

[0026] PLGA copolymer, 4-(dimethylamino)pyridine, succinic anhydride, and dichloromethane were mixed at a mass ratio of 2–5:1:1:50–70, thoroughly dissolved, and stirred for 2–4 hours. The mixture was then transferred to a rotary evaporator and vacuum-evaporated to remove most of the dichloromethane, concentrating the mixture. The mixture was precipitated three times in methanol and then vacuum-dried to obtain the carboxyl-terminated PLGA polymer, namely PLGA-COOH.

[0027] Preparation of S2, PLGA-COOH supported dipyridamole microspheres:

[0028] Weigh 10–40 mg of dipyridamole and dissolve it in 1 mL of double-distilled water to obtain the inner aqueous phase W1. Dissolve 200 mg of PLGA in 4–10 mL of dichloromethane / acetone solvent (volume ratio 3–4 / 1) to obtain the oil phase O. Slowly add W1 dropwise to the oil phase O under ultrasonic emulsification to obtain the primary emulsion. Dissolve 1% (w / v) PVA in 30–50 mL of double-distilled water to obtain the outer aqueous phase W2. Slowly add the primary emulsion dropwise to W2 and stir for 5 min to obtain the W1 / O / W2 double emulsion. Pour the double emulsion into 400 mL of double-distilled water and stir for 4–6 h (1000 r / min) to evaporate the residual organic solvent. Then, centrifuge at 10000–12000 r / min to collect the microspheres, wash and dry them to obtain PLGA-COOH-loaded dipyridamole microspheres.

[0029] Synthesis of S3, dipyridamole modified membrane

[0030] A membrane substrate (polysulfone / polyethersulfone / polyurethane / cellulose / polylactic acid, etc.) and dipyridamole microspheres are dissolved in DMF or DMAC to prepare a solution containing 16% to 20% of the substrate by mass. The solution is allowed to stand to remove bubbles, and a casting solution is obtained. The casting solution at 40 to 60°C is placed in a coagulation bath at 25°C, and after solidification, it is immersed to obtain a modified membrane. The mass ratio of dipyridamole microspheres to membrane substrate is 2:(16 to 20).

[0031] Example 1

[0032] Synthesis of S1 and PLGA-COOH:

[0033] PLGA copolymer, 4-(dimethylamino)pyridine, succinic anhydride, and dichloromethane were mixed in a mass ratio of 4:1:1:65, thoroughly dissolved, and stirred for 3 hours. Most of the dichloromethane was removed by vacuum distillation, and the concentrated mixture was then concentrated. The mixture was precipitated three times in methanol and dried under vacuum to obtain the carboxyl-terminated PLGA polymer, i.e., PLGA-COOH.

[0034] Preparation of S2, PLGA-COOH supported dipyridamole microspheres:

[0035] 25 mg of dipyridamole was dissolved in 1 mL of double-distilled water to form the inner aqueous phase W1. 200 mg of PLGA was dissolved in 7 mL of dichloromethane / acetone (volume ratio 4 / 1) to form the oil phase O. W1 was slowly added dropwise to the oil phase O under ultrasonic emulsification to obtain the primary emulsion. 1% PVA was dissolved in 40 mL of double-distilled water to obtain the outer aqueous phase W2. The primary emulsion was slowly added dropwise to W2 and stirred for 5 min to obtain the W1 / O / W2 double emulsion. The double emulsion was poured into 400 mL of double-distilled water and stirred for 5 h (1000 r / min) to evaporate the residual organic solvent. Then, the microspheres were collected by high-speed centrifugation at 11000 r / min, washed, and dried to obtain PLGA-COOH-loaded dipyridamole microspheres.

[0036] S3. Synthesis of dipyridamole modified membrane:

[0037] Polysulfone and dipyridamole microspheres were dissolved in DMF or DMAC to prepare a solution containing 16% to 20% of the substrate by mass. The solution was allowed to stand to remove bubbles, and a casting solution was obtained. The casting solution at 50°C was placed in a coagulation bath at 25°C, and after solidification, it was immersed to obtain a modified membrane. The mass ratio of the dipyridamole microspheres, membrane substrate and solvent was 2:18:80.

[0038] Example 2

[0039] Synthesis of S1 and PLGA-COOH:

[0040] PLGA copolymer, 4-(dimethylamino)pyridine, succinic anhydride, and dichloromethane were mixed in a mass ratio of 2:1:1:70, thoroughly dissolved, and stirred for 3 hours. Most of the dichloromethane was removed by vacuum distillation, and the concentrated mixture was then concentrated. The mixture was precipitated three times in methanol and dried under vacuum to obtain the carboxyl-terminated PLGA polymer, i.e., PLGA-COOH.

[0041] The method described in Example 1 was used to prepare S2PLGA-COOH supported dipyridamole microspheres and synthesize S3 dipyridamole modified membranes.

[0042] Example 3

[0043] PLGA copolymer, 4-(dimethylamino)pyridine, succinic anhydride, and dichloromethane were mixed in a mass ratio of 5:1:1:65, thoroughly dissolved, and stirred for 3 hours. Most of the dichloromethane was removed by vacuum distillation, and the concentrated mixture was then concentrated. The mixture was precipitated three times in methanol and dried under vacuum to obtain the carboxyl-terminated PLGA polymer, i.e., PLGA-COOH.

[0044] The method described in Example 1 was used to prepare S2PLGA-COOH supported dipyridamole microspheres and synthesize S3 dipyridamole modified membranes.

[0045] Example 4

[0046] The method of Example 1 was used to synthesize S1-terminated carboxylated poly(lactic acid / glycolic acid) copolymer (PLGA-COOH) and prepare S2PLGA-COOH-loaded dipyridamole microspheres.

[0047] Synthesis of S3, dipyridamole modified membrane

[0048] Polyethersulfone and dipyridamole microspheres were dissolved in DMF or DMAC to prepare a solution containing 16% to 20% of the substrate by mass. The solution was allowed to stand to remove bubbles, and a casting solution was obtained. The casting solution at 50°C was placed in a coagulation bath at 25°C, and after solidification, it was immersed to obtain a modified membrane. The mass ratio of the dipyridamole microspheres, membrane substrate and solvent was 2:18:80.

[0049] Example 5

[0050] The method of Example 1 was used to synthesize S1-terminated carboxylated poly(lactic acid / glycolic acid) copolymer (PLGA-COOH) and prepare S2PLGA-COOH-loaded dipyridamole microspheres.

[0051] Synthesis of S3, dipyridamole modified membrane

[0052] Polyurethane and dipyridamole microspheres were dissolved in DMF or DMAC to prepare a solution containing 16% to 20% of the substrate by mass. The solution was allowed to stand to remove bubbles, and a casting solution was obtained. The casting solution at 50°C was placed in a coagulation bath at 25°C, and after solidification, it was immersed to obtain a modified membrane. The mass ratio of dipyridamole microspheres, membrane substrate and solvent was 2:18:80.

[0053] Example 6

[0054] The method of Example 1 was used to synthesize S1-terminated carboxylated poly(lactic acid / glycolic acid) copolymer (PLGA-COOH) and prepare S2PLGA-COOH-loaded dipyridamole microspheres.

[0055] Synthesis of S3, dipyridamole modified membrane

[0056] Cellulose acetate and dipyridamole microspheres were dissolved in DMF or DMAC to prepare a solution containing 16% to 20% of the substrate by mass. The solution was allowed to stand to remove bubbles, and a casting solution was obtained. The casting solution at 50°C was placed in a coagulation bath at 25°C, and after solidification, it was immersed to obtain a modified membrane. The mass ratio of dipyridamole microspheres, membrane substrate and solvent was 2:18:80.

[0057] Example 7

[0058] The method of Example 1 was used to synthesize S1-terminated carboxylated poly(lactic acid / glycolic acid) copolymer (PLGA-COOH) and to prepare S2, PLGA-COOH-loaded dipyridamole microspheres.

[0059] Synthesis of S3, dipyridamole modified membrane

[0060] Polylactic acid and dipyridamole microspheres were dissolved in DMF or DMAC to prepare a solution containing 16% to 20% of the substrate by mass. The solution was allowed to stand to remove bubbles, and a casting solution was obtained. The casting solution at 50°C was placed in a coagulation bath at 25°C, and after solidification, it was immersed to obtain a modified membrane. The mass ratio of dipyridamole microspheres, membrane substrate and solvent was 2:18:80.

[0061] Verification example: Platelet aggregation test of dipyridamole modified membrane

[0062] The polysulfone membrane and the membrane-based artificial organ material of Example 1 were immersed in whole blood for 4 hours. The membranes were then removed and the aggregation rate was measured using a platelet aggregator. The results are shown in Table 1.

[0063] Table 1. Comparison of platelet aggregation rates between polysulfone membrane and dipyridamole modified membrane.

[0064] polysulfone membrane 87.34 255 Dipyridamole modified membrane 62.98 345

[0065] Platelet aggregation is an important function of platelets, referring to their ability to adhere to each other. Increased platelet aggregation makes it easier for platelets to adhere to each other and accumulate on the membrane surface, leading to thrombus formation upon further activation. Recalcification time is an indicator of the rate of thrombus formation; the longer the time, the less likely thrombus formation. Table 1 shows that the platelet aggregation rate of the dipyridamole-modified membrane is significantly lower than that of the ordinary polysulfone membrane, indicating that the dipyridamole-modified membrane can improve the risk of membrane-related thrombosis and inflammation by inhibiting platelets. The significantly longer recalcification time compared to the original membrane also demonstrates its good antithrombotic properties. Simultaneously, this modified membrane has positive effects on antiviral activity and coronary artery protection.

[0066] The various embodiments in this specification are described in a related manner. Similar or identical parts between embodiments can be referred to mutually. Each embodiment focuses on describing the differences from other embodiments. In particular, the system embodiments are basically similar to the method embodiments, so the description is relatively simple; relevant parts can be referred to the descriptions of the method embodiments.

[0067] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention are included within the scope of protection of the present invention.

Claims

1. A method for preparing a membrane-type artificial organ material, characterized in that, Includes the following steps: S1. Synthesis of PLGA-COOH; the specific synthesis steps are as follows: PLGA copolymer, 4-(dimethylamino)pyridine, succinic anhydride and dichloromethane were mixed, dissolved and stirred for 2-4 hours, and then transferred to a rotary evaporator to remove dichloromethane and concentrate the mixture. The mixture was precipitated three times in methanol and then dried under vacuum to obtain carboxyl-terminated PLGA polymer. S2. Preparation of PLGA-COOH supported dipyridamole microspheres; specific steps are as follows: Weigh 10-40 mg of dipyridamole and dissolve it in 1 ml of double-distilled water as the inner aqueous phase W1. Dissolve 200 mg of carboxyl-terminated PLGA polymer in 4-10 ml of dichloromethane and acetone as the oil phase O. Slowly add W1 to the oil phase O under ultrasonic emulsification to obtain the primary emulsion. Dissolve 1% w / v PVA in 30-50 mL of double-distilled water to obtain the outer aqueous phase W2. Slowly add the primary emulsion to W2 and stir for 5 min to obtain the W1 / O / W2 double emulsion. Pour the double emulsion into 400 mL of double-distilled water and stir at 1000 r / min for 4-6 h until the residual organic solvent evaporates. Then, collect the microspheres by high-speed centrifugation at 10000-12000 r / min, wash and dry to obtain PLGA-COOH-loaded dipyridamole microspheres. S3. Synthesizing membrane-based artificial organ materials; the synthesis steps are as follows: S31 dissolves PLGA-COOH-loaded dipyridamole microspheres and membrane substrate in DMF or DMAC to prepare a solution containing 16% to 20% of the substrate by mass. S32 was allowed to stand and degas to obtain a casting solution; the 50℃ casting solution was placed in pure water at 25℃, solidified, and then soaked to obtain a film.

2. The method for preparing membrane-type artificial organ materials according to claim 1, characterized in that... PLGA copolymer, 4-(dimethylamino)pyridine, succinic anhydride and dichloromethane are in a mass ratio of 2~6:1:1:60~70.

3. The method for preparing membrane-type artificial organ materials according to claim 1, characterized in that, In step S2, the volume ratio of dichloromethane to acetone is: .

4. The method for preparing membrane-type artificial organ materials according to claim 1, characterized in that... The mass ratio of PLGA-COOH-loaded dipyridamole microspheres to membrane substrate is 2:(16-20).

5. The method for preparing membrane-type artificial organ materials according to claim 1, characterized in that, The membrane substrate in S31 is any one of polyethersulfone, polyurethane, cellulose, or polylactic acid.

6. Artificial organ material prepared by the method for preparing membrane artificial organ material as described in any one of claims 1 to 5.

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