A non-adhesive medical liquid embolic agent and its preparation method and application

Abstract

This invention provides a non-adhesive medical liquid embolic agent, its preparation method, and application, belonging to the field of medical device technology. It is prepared from a polyethylene glycol-cellulose acetate copolymer, an organic solvent, and a developer in a mass ratio of 12-15:30-50:15-20. This non-adhesive medical liquid embolic agent exhibits high strength, excellent stability, and good biocompatibility. It does not trigger cytotoxicity or immune responses, and does not metabolize to produce toxic substances. It can effectively load drugs and slowly release them after embolization surgery, specifically killing tumor cells and achieving long-lasting release, thereby enhancing the therapeutic effect and promising broad application prospects. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and in particular to a non-adhesive medical liquid embolic agent, a preparation method thereof, and an application thereof. Background Art

[0002] Malignant tumors are the second leading cause of death in the human population. The top five cancers in terms of mortality are: gastric cancer, liver cancer, lung cancer, esophageal cancer, and colorectal cancer. Currently, treatments for malignant tumors are limited, primarily through surgical resection, radiotherapy, chemotherapy, and interventional therapy. Transcatheter arterial embolization, a form of interventional therapy, has been proven to be one of the most effective non-surgical methods for treating solid tumors. Through an arterial catheter, embolic material is slowly injected into the blood vessels supplying the solid tumor or diseased organ, causing vascular embolization and thus interrupting the blood supply. This significantly restricts the growth of the corresponding tumor tissue due to a lack of nutrients and oxygen, thus achieving the therapeutic goal.

[0003] Embolic agents are primarily categorized as solid and liquid embolic agents. Among existing embolic materials, liquid embolic agents offer unique advantages. Liquid embolic agents flow through blood vessels as a fluid, enabling deep penetration of small-diameter target vessels. They can also adapt to any vessel shape before transitioning to a solid form. Liquid embolic agents are independent of the patient's coagulation system and are therefore effective even in patients with severe coagulopathy. When a catheter cannot reach the lesion, liquid embolic agents can also provide embolization from the catheter tip to the distal end. Existing clinical liquid embolic agent products include NBCA glue, Onyx, and PHIL. All three use dimethyl sulfoxide (DMSO) as a solvent, which can cause severe inflammation and even vasospasm in the tissue at the site of administration. Furthermore, DMSO is a highly polar solvent, requiring the use of specialized catheters, increasing manufacturing costs. Furthermore, NBCA embolic materials still suffer from the drawback of "tube sticking," meaning they are sticky and easily adhere to the vessel wall after injection, complicating surgical procedures.

[0004] Therefore, how to provide a non-adhesive medical liquid embolic agent that is easy to use and can be applied to tumor embolization is an urgent problem that needs to be solved by those skilled in the art. Summary of the Invention

[0005] The present invention aims to provide a non-adhesive medical liquid embolic agent, a preparation method thereof, and an application thereof, which solves the problem of insolubility of cellulose. At the same time, the prepared polyethylene glycol-cellulose acetate copolymer has high strength, good stability, and good biocompatibility, does not induce cytotoxicity and body immunity, and does not metabolize to produce toxic substances. After solidification, it has a porous structure, elasticity, no toxic side effects, and is non-adhesive. It can effectively load drugs and slowly release them after embolization surgery, specifically killing tumor cells, achieving long-term release, enhancing the quality of disease treatment, and has broad application prospects.

[0006] The technical solution of the present invention is achieved as follows:

[0007] The present invention provides a non-adhesive medical liquid embolic agent, which is prepared from a polyethylene glycol-cellulose acetate copolymer, an organic solvent, and a developer; the structural formula of the polyethylene glycol-cellulose acetate copolymer is shown in Formula I:

[0008]

[0009] Among them, m=1000-1500, n=200-400.

[0010] As a further improvement of the present invention, the mass ratio of the polyethylene glycol-cellulose acetate copolymer, the organic solvent, and the developer is 12-15:30-50:15-20.

[0011] As a further improvement of the present invention, the organic solvent is a mixture of dimethyl sulfoxide and ethanol in a volume ratio of 2-4:5.

[0012] As a further improvement of the present invention, the developer is selected from at least one of iodized oil, iodinated alcohol, iodinated ethane and iodinated acetic acid.

[0013] As a further improvement of the present invention, the preparation method of the polyethylene glycol-cellulose acetate copolymer is as follows:

[0014] S1. Dissolve cellulose in acid solution, add thionyl chloride, stir and react, and remove the solvent under reduced pressure to obtain chlorine-substituted cellulose with the following structural formula:

[0015] S2. The chlorine-substituted cellulose obtained in step S1 was dissolved in dichloromethane, polyethylene glycol and a base were added, the reaction was heated under reflux with stirring, the solvent was removed under reduced pressure, and acetone was added for precipitation to obtain a polyethylene glycol-cellulose copolymer having the following structural formula:

[0016] S3. The polyethylene glycol-cellulose copolymer obtained in step S2 is dissolved in dichloromethane, acetic anhydride and concentrated sulfuric acid are added, the mixture is heated under reflux with stirring, and water is added to precipitate to obtain the product.

[0017] As a further improvement of the present invention, the acid solution in step S1 is a 1-2 wt% acetic acid solution, the mass ratio of cellulose to thionyl chloride is 10-15:3-5, the stirring reaction temperature is room temperature, and the time is 0.5-1 h.

[0018] As a further improvement of the present invention, in step S2, the mass ratio of the chlorine-substituted cellulose, polyethylene glycol and base is 12-15:5-7:2-3, the base is selected from at least one of NaOH, KOH, triethylamine, diethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate, and the reaction time is 2-4 hours.

[0019] As a further improvement of the present invention, in step S3, the mass ratio of the polyethylene glycol-cellulose copolymer, acetic anhydride and concentrated sulfuric acid is 15-17:10-12:1-2, and the reaction time is 2-3 hours.

[0020] The present invention further protects a method for preparing the above-mentioned non-adhesive medical liquid embolic agent, which comprises dissolving a polyethylene glycol-cellulose acetate copolymer and a developer in an organic solvent in sequence, and stirring the mixture to obtain the non-adhesive medical liquid embolic agent.

[0021] The present invention further protects the use of the non-adhesive medical liquid embolic agent in the preparation of embolic therapy drugs.

[0022] The present invention has the following beneficial effects: the present invention prepares a polyethylene glycol-cellulose acetate copolymer, which not only solves the problem of cellulose being difficult to dissolve, but also has high strength, good stability, and good biocompatibility, does not induce cytotoxicity and body immunity, and does not metabolize to produce toxic substances. After solidification, the polyethylene glycol-cellulose acetate copolymer has a porous structure, is elastic, has no toxic side effects, and is non-adhesive. X-ray or CT angiography can be used during the delivery and solidification process of the liquid embolic agent, making it easier to observe and control the state of the embolic site during the embolization procedure, and guiding medical staff to make adjustments. At the same time, the polymer can effectively load drugs, and the embolic agent precipitates to form an embolus after contacting water or blood. After the embolization procedure, it is slowly released in a targeted manner to kill tumor cells in a targeted manner, achieving long-term release, enhancing the quality of the disease, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0024] Figure 1 The synthetic route of the polyethylene glycol-cellulose acetate copolymer of the present invention is shown in FIG. DETAILED DESCRIPTION

[0025] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0026] Preparation Example 1 Preparation of polyethylene glycol-cellulose acetate copolymer

[0027] like Figure 1 , the method is as follows:

[0028] S1. 10 parts by weight of cellulose were dissolved in 100 parts by weight of 1wt% acetic acid solution, 3 parts by weight of thionyl chloride were added, the reaction was stirred for 0.5h, and the solvent was removed under reduced pressure to obtain chlorine-substituted cellulose;

[0029] S2. 12 parts by weight of the chlorine-substituted cellulose obtained in step S1 were dissolved in 200 parts by weight of dichloromethane, 5 parts by weight of polyethylene glycol and 2 parts by weight of NaOH were added, and the reaction was stirred under reflux for 2h, the solvent was removed under reduced pressure, and acetone was added to precipitate to obtain a polyethylene glycol - cellulose copolymer;

[0030] S3. Dissolve 15 parts by weight of the polyethylene glycol-cellulose copolymer obtained in step S2 in 200 parts by weight of dichloromethane, add 10 parts by weight of acetic anhydride and 1 part by weight of 98 wt% concentrated sulfuric acid, heat under reflux and stir for 2 hours, and add water to precipitate to obtain the product. Infrared spectrum analysis shows the carbonyl group at 1720 cm -1 , 1040cm of cyclic ether bond -1 , 560cm -1 Typical characteristic peaks of polyethylene glycol and acetate appeared.

[0031] Preparation Example 2 Preparation of polyethylene glycol-cellulose acetate copolymer

[0032] like Figure 1 , the method is as follows:

[0033] S1. 15 parts by weight of cellulose were dissolved in 100 parts by weight of a 2wt% acetic acid solution, 5 parts by weight of thionyl chloride were added, the reaction was stirred for 1h, and the solvent was removed under reduced pressure to obtain chlorine-substituted cellulose;

[0034] S2 15 parts by weight of the chlorine-substituted cellulose obtained in step S1 was dissolved in 200 parts by weight of dichloromethane, 7 parts by weight of polyethylene glycol and 3 parts by weight of KOH were added, the reaction was heated under reflux with stirring for 4h, the solvent was removed under reduced pressure, acetone was added to precipitate, to obtain polyethylene glycol - cellulose copolymer;

[0035] S3. 17 parts by weight of the polyethylene glycol obtained in step S2 - cellulose copolymer was dissolved in 200 parts by weight of dichloromethane, 12 parts by weight of acetic anhydride and 2 parts by weight of 98wt% concentrated sulfuric acid were added, the reaction was stirred under reflux for 3h, and water was added to precipitate to obtain a product.

[0036] Preparation Example 3 Preparation of polyethylene glycol-cellulose acetate copolymer

[0037] like Figure 1 , the method is as follows:

[0038] S1. 12 parts by weight of cellulose were dissolved in 100 parts by weight of a 1.5wt% acetic acid solution, 4 parts by weight of thionyl chloride were added, the reaction was stirred for 1h, and the solvent was removed under reduced pressure to obtain chlorine-substituted cellulose;

[0039] S2 13.5 parts by weight of the chlorine-substituted cellulose obtained in step S1 was dissolved in 200 parts by weight of dichloromethane, 6 parts by weight of polyethylene glycol and 2.5 parts by weight of NaOH were added, and the reaction was stirred under reflux for 3h, the solvent was removed under reduced pressure, and acetone was added to precipitate to obtain a polyethylene glycol - cellulose copolymer;

[0040] S3. 16 parts by weight of the polyethylene glycol obtained in step S2 - cellulose copolymer was dissolved in 200 parts by weight of dichloromethane, 11 parts by weight of acetic anhydride and 1.5 parts by weight of 98wt% concentrated sulfuric acid were added, the reaction was stirred under reflux for 2.5h, and water was added to precipitate to obtain a product.

[0041] Example 1

[0042] This embodiment provides a non-adhesive medical liquid embolic agent, which is prepared from the polyethylene glycol-cellulose acetate copolymer prepared in Preparation Example 1, an organic solvent, and iodine alcohol in a mass ratio of 12:30:15. The organic solvent is a mixture of dimethyl sulfoxide and ethanol in a volume ratio of 2:5.

[0043] The preparation method comprises the following steps: dissolving polyethylene glycol-cellulose acetate copolymer and iodine ethanol in an organic solvent in sequence, and stirring the mixture evenly to obtain a non-adhesive medical liquid embolic agent.

[0044] Example 2

[0045] This example provides a non-adhesive medical liquid embolic agent, which is prepared from the polyethylene glycol-cellulose acetate copolymer prepared in Preparation Example 2, an organic solvent, and iodoacetic acid in a mass ratio of 15:50:20. The organic solvent is a mixture of dimethyl sulfoxide and ethanol in a volume ratio of 4:5.

[0046] The preparation method comprises the following steps: dissolving polyethylene glycol-cellulose acetate copolymer and iodoacetic acid in an organic solvent in sequence, and stirring the mixture evenly to obtain a non-adhesive medical liquid embolic agent.

[0047] Example 3

[0048] This example provides a non-adhesive medical liquid embolic agent, which is prepared from the polyethylene glycol-cellulose acetate copolymer prepared in Preparation Example 3, an organic solvent, and ethyl iodide in a mass ratio of 13.5:40:17. The organic solvent is a mixture of dimethyl sulfoxide and ethanol in a volume ratio of 3:5.

[0049] The preparation method comprises the following steps: dissolving polyethylene glycol-cellulose acetate copolymer and iodine ethane in an organic solvent in sequence, and stirring the mixture evenly to obtain a non-adhesive medical liquid embolic agent.

[0050] Comparative Example 1

[0051] Compared with Example 3, the difference is that the polyethylene glycol-cellulose acetate copolymer is replaced by cellulose acetate.

[0052] Comparative Example 2

[0053] Compared with Example 3, the difference is that the polyethylene glycol-cellulose acetate copolymer is replaced by polyethylene glycol.

[0054] Comparative Example 3

[0055] Compared with Example 3, the difference is that the polyethylene glycol-cellulose acetate copolymer is replaced by an ethylene-vinyl alcohol copolymer.

[0056] Test Example 1

[0057] The non-adhesive medical liquid embolic agents prepared in Examples 1-3 of the present invention and Comparative Examples 1-3 were tested for HU values. The results are shown in Table 1.

[0058] Table 1

[0059]

[0060] As can be seen from the above table, the non-adhesive medical liquid embolic agents prepared in Examples 1-3 of the present invention have higher HU values ​​and higher comprehensive performance.

[0061] Test Example 2

[0062] The non-adhesive medical liquid embolic agents prepared in Examples 1-3 of the present invention and Comparative Examples 1-3, as well as commercially available products, were subjected to performance tests. The results are shown in Table 2.

[0063] Density test:

[0064] The density of non-adhesive medical liquid embolic agents after solidification was tested using a density bottle.

[0065] Elastic modulus test:

[0066] The non-adhesive medical liquid embolic agent was placed in a nanoindenter, and the microspheres were compressed at a rate of 1% strain per second in compression mode. The elastic modulus of the microspheres was calculated based on the data, and the average value was repeated 5 times.

[0067] Table 2

[0068] Group <![CDATA[Density (g / cm 3 )]]> Elastic modulus (MPa) Example 1 1.11 3.2 Example 2 1.10 2.9 Example 3 1.09 2.8 Comparative Example 1 1.24 12.4 Comparative Example 2 1.21 13.1 Comparative Example 3 1.26 20.4 Commercially available 1.30 28.2

[0069] As can be seen from the table above, the non-adhesive medical liquid embolic agents prepared in Examples 1-3 of the present invention exhibit superior overall performance. After curing, the non-adhesive medical liquid embolic agents prepared in the present invention have a lower density, higher water content, and lower elastic modulus. Therefore, the embolic agents are more easily deformed and quickly recover their shape after deformation. Their catheter delivery performance and embolic performance are superior to those of commercially available and comparative examples.

[0070] 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 in the scope of protection of the present invention.

Claims

1. A non-adhesive medical liquid embolic agent, characterized in that: It is prepared from polyethylene glycol-cellulose acetate copolymer, organic solvent, and developer, wherein the mass ratio of the polyethylene glycol-cellulose acetate copolymer, organic solvent, and developer is 12-15:30-50:15-20; the structural formula of the polyethylene glycol-cellulose acetate copolymer is shown in Formula I: Formula I; Among them, m=1000-1500, n=200-400; The preparation method of the polyethylene glycol-cellulose acetate copolymer is as follows: S1. Dissolve cellulose in acid solution, add thionyl chloride, stir and react, and remove the solvent under reduced pressure to obtain chlorine-substituted cellulose with the following structural formula: The acid solution is 1-2wt% acetic acid solution, the mass ratio of the cellulose and thionyl chloride is 10-15:3-5, the stirring reaction temperature is room temperature, and the time is 0.5-1h; S2. The chlorine-substituted cellulose obtained in step S1 was dissolved in dichloromethane, polyethylene glycol and a base were added, the reaction was heated under reflux with stirring, the solvent was removed under reduced pressure, and acetone was added for precipitation to obtain a polyethylene glycol-cellulose copolymer having the following structural formula: The mass ratio of the chlorine-substituted cellulose, polyethylene glycol and base is 12-15: 5-7: 2-3, the base is selected from at least one of NaOH, KOH, triethylamine, diethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate, and the reaction time is 2-4h; S3. The polyethylene glycol obtained in step S2 is dissolved in dichloromethane, acetic anhydride and concentrated sulfuric acid are added, the reaction is heated under reflux with stirring, and water is added to precipitate to obtain a product; the mass ratio of the polyethylene glycol - cellulose copolymer, acetic anhydride and concentrated sulfuric acid is 15-17:10-12:1-2, and the reaction time is 2-3h.

2. The non-adhesive medical liquid embolic agent according to claim 1, characterized in that: The organic solvent is a mixture of dimethyl sulfoxide and ethanol in a volume ratio of 2-4:

5.

3. The non-adhesive medical liquid embolic agent according to claim 1, characterized in that: The developer is selected from at least one of iodized oil, iodinated alcohol, iodinated ethane and iodinated acetic acid.

4. A method for preparing the non-adhesive medical liquid embolic agent according to any one of claims 1 to 3, characterized in that: The polyethylene glycol-cellulose acetate copolymer and the developer are dissolved in an organic solvent in sequence and stirred evenly to obtain a non-adhesive medical liquid embolic agent.

5. Use of the non-adhesive medical liquid embolic agent according to any one of claims 1 to 3 in the preparation of embolic therapy drugs.

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