A method for preparing and applying an agarose-based liquid embolic agent

Abstract

This invention discloses a method for preparing and applying a liquid embolizing agent, relating to the field of biomedical embolizing materials technology. The steps are as follows: (1) Agarose modified with unsaturated hydrophobic groups, polyphenol monomers containing double bonds, and a photoinitiator are dissolved in an organic solvent at a certain mass ratio. After the reaction is completed, free radical polymerization is initiated under ultraviolet light. The embolizing copolymer is then obtained by washing with water, purifying, and freeze-drying. (2) The embolizing copolymer is dissolved in an organic solvent at a certain mass ratio to obtain the liquid embolizing agent. The mass ratio of agarose modified with unsaturated hydrophobic groups, polyphenol monomers containing double bonds, and the initiator is 50-150:50:3. This invention is liquid at room temperature and solidifies into a solid after contact with a liquid environment, including water, physiological saline, blood, body fluids, and urine. It has certain vascular compatibility, good biocompatibility, and the advantage of non-sticking to catheters, making it suitable for the application of medical vascular interventional embolization technology.

Description

Technical Field

[0001] This invention relates to the field of biomedical embolization materials technology, specifically a method for preparing and applying a liquid embolizing agent. Background Technology

[0002] Embolizing materials are preparations that can embolize aneurysms, isolate blood, or block diseased blood vessels. They are commonly used to treat patients with irregular aneurysms and arteriovenous malformations. With the increasing incidence of peripheral vascular disease, liver cancer, stroke, uterine fibroids, and other diseases, as well as the increasing penetration rate of minimally invasive surgery, the interventional embolization market is expected to enter a period of rapid growth in the future.

[0003] Based on their physical properties, embolic materials currently used in clinical practice can be divided into solid embolic materials and liquid embolic materials. Solid embolic materials mainly include gelatin sponge particles and polyvinyl alcohol microspheres. Liquid embolic materials mainly include N-butyl-cyanoacrylate (nBCA), Onyx (mainly composed of ethylene-vinyl alcohol copolymer and dimethyl sulfoxide), and iodized oil. Solid embolic materials have low vascular compatibility and are prone to causing vascular rupture, while some liquid embolic agents have poor diffusion and are prone to causing catheter adhesion. In addition, their high fluidity can easily lead to vascular recanalization, resulting in poor embolization effect. Summary of the Invention

[0004] The purpose of this invention is to provide a liquid embolizing agent, its preparation method, and its application. The liquid embolizing agent can rapidly transform into a solid in a body fluid or blood environment, and this phase transition process is usually formed through precipitation. The embolizing agent has a certain degree of flexibility, conforms to the environment of the vascular lumen, and has good diffusivity, making it easy to deliver to microvessels and target vessels with complex shapes. This gives it certain advantages of vascular compatibility, good biocompatibility, and non-sticking to the catheter.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A method for preparing a liquid embolic agent, comprising the following steps:

[0007] (1) Agarose modified with unsaturated hydrophobic groups, polyphenol monomers containing double bonds, and photoinitiator are dissolved in an organic solvent at a certain mass ratio. After the reaction is completed, free radical polymerization is initiated under ultraviolet light. The embolization copolymer is obtained by washing with water, purifying, and freeze-drying.

[0008] (2) The above-mentioned embolizing copolymer is dissolved in an organic solvent at a certain mass ratio to obtain the liquid embolizing agent.

[0009] Polyphenolic compounds containing double bonds can be grafted onto agarose modified with unsaturated hydrophobic groups via free radical polymerization. When the liquid embolic agent is injected into physiological fluids (such as blood, body fluids, and urine) or aqueous solutions, a rapid phase transition occurs to form a solid.

[0010] (3) The obtained liquid embolizing agent is a liquid at room temperature and solidifies into a solid after contact with a liquid environment, including water, physiological saline, blood, body fluids and urine.

[0011] The liquid embolizing agent comprises: 10 wt% unsaturated hydrophobic modified agarose, 5 wt% polyphenol monomers containing double bonds, and 0.3 wt% photoinitiator.

[0012] Further, the organic solvent is at least one of dimethyl sulfoxide (DMSO) and N,N-dimethylformamide, preferably dimethyl sulfoxide.

[0013] Furthermore, the unsaturated hydrophobic modified agarose is 2-octenyl succinic anhydride modified agarose or glycidyl methacrylate modified agarose.

[0014] Preferably, in step (1), the unsaturated hydrophobic modified agarose is 2-octenyl succinic anhydride modified agarose; the polyphenol monomer containing double bonds is caffeic acid; and the photoinitiator is I 2959.

[0015] Preferably, in step (1), the reaction time is 3 hours and the reaction temperature is 70°C.

[0016] Further, the mass ratio of 2-octenyl succinic anhydride modified agarose, caffeic acid, and I 2959 is 100:50:3; in step (2), the mass ratio of organic solvent to embolic copolymer is 20:3, and the mass concentration of embolic polymer is 17.5 wt%.

[0017] Preferably, in step (1), the mass ratio of 2-octenyl succinic anhydride-modified agarose to dimethyl sulfoxide solution is 1:10.

[0018] Preferably, in step (1), the mass ratio of caffeic acid to dimethyl sulfoxide solution is 1:20.

[0019] Preferably, in step (2), the dissolution temperature is 70°C and the dissolution time is 1 hour. The embolic agent prepared under the above conditions has the characteristics of low viscosity, good dispersibility and non-sticking to the tube.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] (1) The liquid embolizing agent prepared in this invention is a liquid embolizing agent prepared by using 2-octenyl succinic anhydride modified agarose and photoinitiator I2959 as the main raw materials. Both are FDA-approved compounds with high safety and good biocompatibility.

[0022] (2) The liquid embolizing agent of the present invention has good flexibility and diffusivity after solidification, and can be diffused into microvessels and target vessels with complex shapes, resulting in excellent embolization effect.

[0023] (3) The liquid embolizing agent prepared by the present invention has a suitable curing time and viscosity after being injected into physiological fluid (such as blood) or aqueous solution, has good operability and is not easy to stick to the tube.

[0024] (4) The liquid embolizing agent of the present invention can form a gel in situ through intrapolymer and interpolymer hydrogen bonding and electrostatic interaction caused by solvent exchange, and the gelation time and embolizing pressure of the solution can be adjusted. Attached Figure Description

[0025] Figure 1 include Figure 1 a, Figure 1 b is the product prepared according to the embodiments of the present invention. Figure 1 a is the embolic agent before solvent exchange, and it is a liquid; Figure 2 a is the embolic agent after solvent exchange, which is a solid. Figure 1 'a' refers to the intravascular embolization agent administered before injection. Figure 1 b represents the intravascular embolization agent administered after injection.

[0026] Figure 2 include Figure 2 a, Figure 2 b illustrates the process of achieving the non-stick properties of the liquid embolic agent prepared according to an embodiment of the present invention. As can be seen from the figure, the prepared liquid embolic agent can be injected from a syringe onto a stainless steel substrate underwater, and no adhesion occurs inside the syringe tube after removal.

[0027] Figure 3 include Figure 3 a, Figure 3 b is the injectability test of the liquid embolizing agent prepared in this embodiment. As can be seen from the figure, the prepared liquid embolizing agent can be injected underwater onto a stainless steel substrate.

[0028] Figure 4 include Figure 4 a, Figure 4 b、 Figure 4 c. Figure 4 d represents the rheological property test of the liquid embolic agent prepared according to the embodiments of the present invention. This is used to verify the phase transition properties of the liquid embolic agent. Figure 4 a and Figure 4b represents the amplitude scan. Before solvent exchange, the storage modulus is less than the loss modulus, indicating a liquid state. Figure 4 a) After solvent exchange, the storage modulus is greater than the loss modulus, and it is a solid ( Figure 4 b); Figure 4 c and Figure 4 d represents the frequency scan. Before solvent exchange, the storage modulus is less than the loss modulus, indicating a liquid state. Figure 4 c); After solvent exchange, the storage modulus is greater than the loss modulus, and it is a solid ( Figure 4 d).

[0029] Figure 5 include Figure 5 a Figure 5 b) demonstrates the phase transition properties from liquid to solid through time-modulus scanning. Time-modulus scanning also demonstrates the modulus change of the embolic agent before and after solvent exchange. Figure 5 'a' represents the state before solvent exchange. Figure 5 b represents the solvent exchange result.

[0030] Figure 6 This is a time-modulus scan of the liquid embolic agent prepared in this embodiment. The modulus reverses during the addition of water, demonstrating the phase transition property of the embolic agent in the presence of water, where it changes from liquid to solid. Detailed Implementation

[0031] The following is a detailed description with reference to the accompanying drawings and specific embodiments. The content of this invention is not limited to any specific embodiment, nor does it represent the best embodiment; common substitutions well known to those skilled in the art are also covered within the scope of protection of this invention.

[0032] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0033] Example 1

[0034] An embodiment of the agarose-based liquid embolizing agent of the present invention is provided, and the preparation method of the vascular liquid embolizing agent in this embodiment is as follows:

[0035] Step 1:

[0036] Weigh 0.2g of 2-octenyl succinic anhydride modified agarose, 0.1g of caffeic acid and 0.006g of I2959 powder and dissolve them in 2.0mL of dimethyl sulfoxide solution. Stir at 70℃ for 3h to obtain a mixed solution. Place the mixed solution under ultraviolet light for 30min, take it out, wash with water, purify and freeze dry to obtain the embolic copolymer.

[0037] Step 2:

[0038] The above-mentioned embolic copolymer was dissolved in a dimethyl sulfoxide solution at a mass ratio of 1:10 to obtain the liquid embolic agent.

[0039] Example 2

[0040] An embodiment of the agarose-based liquid embolizing agent of the present invention is provided, and the preparation method of the vascular liquid embolizing agent in this embodiment is as follows:

[0041] Step 1:

[0042] Weigh 0.1 g of glycidyl methacrylate-modified agarose, 0.1 g of methacrylamide and 0.006 g of azobisisobutyronitrile and dissolve them in 2.0 mL of dimethyl sulfoxide solution. Stir at 70 °C for 3 h to obtain a mixed solution. Place the mixed solution under ultraviolet light for 30 min, take it out, wash with water, purify, freeze dry and obtain the embolic copolymer.

[0043] Step 2:

[0044] The above-mentioned embolic copolymer was dissolved in an N,N-dimethylformamide solution at a mass ratio of 3:20 to obtain the liquid embolic agent.

[0045] Example 3

[0046] An embodiment of the agarose-based liquid embolizing agent of the present invention is provided, and the preparation method of the vascular liquid embolizing agent in this embodiment is as follows:

[0047] Step 1:

[0048] Weigh 0.3g of 2-octenyl succinic anhydride modified agarose, 0.1mL of urushiol and 0.006g of I2959 powder and dissolve them in 2.0mL of dimethyl sulfoxide solution. Stir at 70℃ for 3h to obtain a mixed solution. Place the mixed solution under ultraviolet light for 30min, take it out, wash with water, purify and freeze dry to obtain the embolic copolymer.

[0049] Step 2:

[0050] The above-mentioned embolic copolymer was dissolved in a dimethyl sulfoxide solution at a mass ratio of 1:5 to obtain the liquid embolic agent.

[0051] Example 4

[0052] An embodiment of the agarose-based liquid embolizing agent of the present invention is provided, and the preparation method of the vascular liquid embolizing agent in this embodiment is as follows:

[0053] (1) Weigh 0.2g of glycidyl methacrylate-modified agarose, 0.2g of caffeic acid and 0.006g of azobisisobutyronitrile and dissolve them in 2.0mL of dimethyl sulfoxide solution. Stir at 70℃ for 3h to obtain a mixed solution. Place the mixed solution under ultraviolet light for 30min, take it out, wash with water, purify and freeze dry to obtain the embolization copolymer.

[0054] Step 2:

[0055] The above-mentioned embolic copolymer was dissolved in an N,N-dimethylformamide solution at a mass ratio of 3:20 to obtain the liquid embolic agent.

[0056] Example 5

[0057] An embodiment of the agarose-based liquid embolizing agent of the present invention is provided, and the preparation method of the vascular liquid embolizing agent in this embodiment is as follows:

[0058] Step 1:

[0059] Weigh 0.3g of 2-octenyl succinic anhydride modified agarose, 0.2g of methacrylamide dopamine and 0.006g of I2959 powder and dissolve them in 2.0mL of dimethyl sulfoxide solution. Stir at 70℃ for 3h to obtain a mixed solution. Place the mixed solution under ultraviolet light for 30min, take it out, wash with water, purify, freeze dry and obtain the embolic copolymer.

[0060] Step 2:

[0061] The above-mentioned embolic copolymer was dissolved in an N,N-dimethylformamide solution at a mass ratio of 3:20 to obtain the liquid embolic agent.

[0062] Example 6

[0063] An embodiment of the agarose-based liquid embolizing agent of the present invention is provided, and the preparation method of the vascular liquid embolizing agent in this embodiment is as follows:

[0064] Step 1:

[0065] Weigh 0.1 g of glycidyl methacrylate-modified agarose, 0.05 g of caffeic acid and 0.006 g of azobisisobutyronitrile and dissolve them in 2.0 mL of dimethyl sulfoxide solution. Stir at 70 °C for 3 h to obtain a mixed solution. Place the mixed solution under ultraviolet light for 30 min, take it out, wash with water, purify and freeze dry to obtain the embolic copolymer.

[0066] Step 2:

[0067] The above-mentioned embolic copolymer was dissolved in a dimethyl sulfoxide solution at a mass ratio of 1:8 to obtain the liquid embolic agent.

[0068] Example 7

[0069] An embodiment of the agarose-based liquid embolizing agent of the present invention is provided, and the preparation method of the vascular liquid embolizing agent in this embodiment is as follows:

[0070] Step 1:

[0071] Weigh 0.3g of glycidyl methacrylate-modified agarose, 0.15mL of urushiol and 0.006g of I2959 powder and dissolve them in 2.0mL of dimethyl sulfoxide solution. Stir at 70℃ for 3h to obtain a mixed solution. Place the mixed solution under ultraviolet light for 30min, take it out, wash with water, purify, freeze dry and obtain the embolization copolymer.

[0072] Step 2:

[0073] The above-mentioned embolic copolymer was dissolved in a dimethyl sulfoxide solution at a mass ratio of 7:40 to obtain the liquid embolic agent.

[0074] This invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many modifications under the guidance of this invention without departing from the spirit and scope of the claims, and these modifications are all protected by this invention.

Claims

1. A method for preparing an agarose-based liquid embolic agent, i.e. a liquid embolic agent prepared by ultraviolet light initiation of an unsaturated hydrophobic group-modified agarose and a double bond-containing polyphenolic monomer in the presence of a photoinitiator; characterized in that, The preparation method comprises the following steps: (1) dissolving unsaturated hydrophobic group modified agarose and double bond containing polyphenol monomer in an organic solvent, and initiating free radical polymerization under a photoinitiator, and then preparing embolization copolymer after water washing, purification and freeze drying; The unsaturated hydrophobic group modified agarose is 2-octenyl succinic anhydride modified agarose or glycidyl methacrylate modified agarose; The double bond containing polyphenol monomer is caffeic acid, methacrylated dopamine, eugenol or urushiol; (2) dissolving the embolization copolymer in an organic solvent at a certain mass ratio to obtain liquid embolic agent; wherein the mass ratio of unsaturated hydrophobic group modified agarose, double bond containing polyphenol monomer and initiator is 50-150: 50: 3; (3) the liquid embolic agent is liquid at room temperature, and is solidified into solid after contacting with liquid environment, and the liquid environment includes water, physiological saline or body fluid.

2. The production method according to claim 1, characterized by, The liquid embolic agent comprises 10wt% of unsaturated hydrophobic group modified agarose, 5wt% of double bond containing polyphenol monomer and 0.3wt% of photoinitiator.

3. The preparation method according to claim 2, characterized in that, The photoinitiator is I 2959 or azobisisobutyronitrile.

4. The method of claim 1, wherein, The organic solvent is dimethyl sulfoxide or N,N-dimethylformamide, and the mass concentration of embolization copolymer is between 10wt% and 20wt%.

5. The production method according to claim 1 or 2, characterized by, The mass ratio of unsaturated hydrophobic group modified agarose and organic solvent is 1:20-3:

20.

6. The production method according to claim 1 or 2, characterized by, The mass ratio of double bond containing polyphenol monomer and organic solvent is 1:40-3:

40.

7. The liquid embolic agent prepared by the preparation method according to any one of claims 1-6.

8. The liquid embolic agent of claim 7, wherein, The liquid embolic agent is soluble in dimethyl sulfoxide and N,N-dimethylformamide solution, and is insoluble in water, physiological saline and body fluid.

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