Self-developing medicine-loading liquid embolism agent as well as preparation method and application thereof

Abstract

The invention relates to a self-developing medicine-loadable liquid embolism agent and a preparation method and application thereof, and belongs to the technical field of liquid embolism agents. Acrylic ester compounds and vinyl ester compounds are copolymerized according to a certain proportion and subjected to base catalysis hydrolysis, then an iodine-containing compound developing agent is covalently coupled to a macromolecular chain, and the self-developing medicine-loadable liquid embolism agent is obtained. The prepared liquid embolism agent can be continuously and uniformly self-developed, no negative charge group needs to be additionally introduced, the copolymer subjected to base catalytic hydrolysis can serve as a negative charge carboxylate radical group on a macromolecular chain of the copolymer as a drug carrying group, multiple and a large number of chemotherapeutic drugs can be rapidly loaded, the curing time is short, and the curing time is short. The suppository can be used as a tumor treatment suppository and a chemotherapeutic drug carrying suppository for TACE treatment.

Description

Technical Field

[0001] The present application relates to the technical field of liquid embolic agents, and in particular to a self-imaging drug-carrying liquid embolic agent and a preparation method and application thereof. Background Art

[0002] Embolization is a technique proposed in 1904 to treat malignant tumors by deliberately occluding blood vessels. Compared with traditional surgery, embolization can be performed in a minimally invasive manner with the help of angiography. Today, with the improvement of imaging technology (such as high-quality digital subtraction angiography) and catheter technology, interventional embolization has become more feasible, versatile and widespread. Currently commonly used embolic materials include solid embolic agents such as coils, microspheres, liquid embolic agents and some hydrogel materials.

[0003] Compared with solid embolic agents with fixed shapes and sizes, liquid embolic agents can be delivered in liquid form, solidify quickly after being delivered to the target site, and can adapt to the size and caliber of blood vessels, which is more advantageous in clinical treatment. However, most liquid embolic agents currently do not have covalently linked X-ray-developable groups, and need to be mixed with additional contrast agents during use to achieve the development effect. They must be mixed for more than twenty minutes before surgery, which prolongs the surgical operation time. In addition, current liquid embolic agents cannot load drugs, which makes existing liquid embolic agents unusable as tumor embolic agents.

[0004] In Chinese patent CN117582535B, polyvinyl alcohol is modified by iodine-containing molecules and negatively charged groups to obtain a liquid embolic agent that can be developed and loaded with drugs. However, the liquid embolic agent introduces negatively charged drug-carrying groups by using inorganic strong acids such as concentrated sulfuric acid and concentrated nitric acid. Both concentrated sulfuric acid and concentrated nitric acid are highly corrosive acids and are not suitable for the preparation of interventional medical device products. In addition, the drug loading of the liquid embolic agent is low and the solidification time is long. Therefore, it still cannot achieve the ideal chemotherapy effect when used for transarterial catheter chemoembolization (TACE) treatment. Summary of the invention

[0005] In view of the deficiencies of the prior art, the purpose of the present application includes providing a self-imaging drug-loaded liquid embolic agent and a preparation method thereof, wherein the self-imaging drug-loaded liquid embolic agent can continuously and uniformly self-imaging, can rapidly solidify, and can rapidly load a variety of chemotherapy drugs in large quantities.

[0006] In a first aspect, the present invention provides a method for preparing a self-imaging drug-loaded liquid embolic agent, comprising the following steps:

[0007] S1: copolymerizing a first monomer, a second monomer, and an initiator in a certain proportion to obtain a copolymer (A); the first monomer is an acrylic acid ester compound, the second monomer is a vinyl ester compound, and the molar ratio of the first monomer to the second monomer is (1:2) to (1:10);

[0008] S2: subjecting the copolymer (A) to base-catalyzed hydrolysis to obtain a hydrolyzed copolymer (B);

[0009] S3: reacting the hydrolyzed copolymer (B) and the iodine-containing compound developer under the action of a catalyst.

[0010] The present application provides a method for preparing a self-developable drug-carrying liquid embolic agent, by selecting a specific first monomer and a second monomer for polymerization, and alkali-catalyzed hydrolysis to form a hydrolyzed copolymer (B), it can be coupled to an iodine-containing compound developer by covalent bonds on the polymer chain, so that it can be continuously and uniformly self-developed, without pre-mixing before surgery, and the operation is simple and fast. By controlling the molar ratio of the first monomer and the second monomer, the curing time and drug-carrying performance of the product can be effectively regulated. In addition, since the product after polymerization carries a large number of negatively charged carboxylate drug-carrying groups, a variety of and a large number of chemotherapeutic drugs can be quickly loaded, and drug loading is convenient and fast, without the need for long-term operation, greatly reducing the operation time. In addition, the present application does not need to use strong corrosive acids such as concentrated sulfuric acid and concentrated nitric acid to introduce negatively charged drug-carrying groups during the preparation process, and the preparation process is safer and the product is safer and more reliable.

[0011] In some embodiments of the present application, the first monomer includes at least one of methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, or butyl methacrylate. The second monomer includes at least one of vinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate, or vinyl valerate.

[0012] In some embodiments of the present application, the iodine-containing compound developer includes 1 to 4 iodine atoms covalently bonded to a benzene ring, and the molar ratio of the iodine-containing compound developer to the hydrolyzed copolymer (B) is (1:2) to (1:16).

[0013] In some embodiments of the present application, the catalyst includes at least one of methanesulfonic acid or p-toluenesulfonic acid.

[0014] In some embodiments of the present application, step S1 includes:

[0015] S11: mixing the first monomer and the second monomer in proportion and adding an initiator to prepare an oil phase;

[0016] S12: adding a dispersant into water to prepare an aqueous phase;

[0017] S13: slowly dropwise adding the oil phase into the water phase at 60-80° C. for reaction for 6-12 hours to obtain a copolymer (A);

[0018] The initiator is at least one of benzoyl peroxide, azobisisobutyronitrile, azobisisoheptylnitrile, tert-butyl perbenzoate or dimethyl azobisisobutyrate; the added amount of the initiator is 0.1% to 1.5% of the total mass of the first monomer and the second monomer; and the dispersant is at least one of polyvinyl alcohol, gelatin, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or ethyl cellulose.

[0019] In some embodiments of the present application, step S2 includes:

[0020] Adding the copolymer (A) and an inorganic base into a solvent in a certain ratio, and performing a hydrolysis reaction at 60 to 80° C. for 4 to 12 hours to obtain a hydrolyzed copolymer (B);

[0021] The molar ratio of the copolymer (A) to the hydroxide in the inorganic base is (1:3) to (1:5); the solvent is water, a mixed solvent with a methanol / water volume ratio of 1:1 to 1:5, or a mixed solvent with an ethanol / water volume ratio of (1:1) to (1:5).

[0022] In some embodiments of the present application, the reaction temperature of the grafting reaction in step S3 is 50 to 90° C., and the reaction time is 12 to 24 hours.

[0023] In a second aspect, the embodiments of the present application also provide a self-radiographic drug-loaded liquid embolic agent prepared by the above-mentioned preparation method.

[0024] In a third aspect, the present application also provides the use of the above-mentioned self-radiographic drug-loaded liquid embolic agent as an embolic agent carrying chemotherapy drugs for TACE treatment. The chemotherapy drugs may include at least one of doxorubicin hydrochloride, gemcitabine, camptothecin, pirarubicin, epirubicin, irinotecan, vincristine or bleomycin.

[0025] The self-developable drug-carrying liquid embolic agent provided in the present application can self-develop continuously and uniformly, and has a short curing time. Since it carries a large number of negatively charged carboxyl groups, it can quickly load a variety of chemotherapy drugs in large quantities, and can therefore be used as a chemotherapy drug-carrying embolic agent for TACE treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0027] Figure 1 This is a process flow chart of the method for preparing the self-imaging drug-loaded liquid embolic agent provided in an embodiment of the present application. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0029] The following is a detailed description of a self-imaging drug-loaded liquid embolic agent and a preparation method thereof according to an embodiment of the present application.

[0030] Figure 1 This is a process flow chart of the preparation method of the self-imaging drug-loaded liquid embolic agent provided in the embodiment of the present application. Figure 1 The method for preparing the self-imaging drug-loaded liquid embolic agent provided in the present application comprises the following steps:

[0031] S1: copolymerizing a first monomer, a second monomer, and an initiator in a certain proportion to obtain a copolymer (A); the first monomer is an acrylic acid ester compound, the second monomer is a vinyl ester compound, and the molar ratio of the first monomer to the second monomer is (1:2) to (1:10).

[0032] Preferably, the molar ratio of the first monomer to the second monomer is (1:5) to (1:10), specifically 1:3.6, 1:4.6, 1:5, 1:10, etc. The first monomer may include at least one of methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, or butyl methacrylate, and the second monomer may include at least one of vinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate, or vinyl valerate.

[0033] The initiator may be at least one of benzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, tert-butyl perbenzoate or dimethyl azobisisobutyrate, and the added amount of the initiator is 0.1% to 1.5% of the total mass of the first monomer and the second monomer.

[0034] As an example, step S1 may more specifically include the following steps:

[0035] The first monomer and the second monomer are mixed in proportion and an initiator is added to prepare an oil phase. The dispersant is added into water to prepare an aqueous phase. The oil phase is slowly added dropwise into the aqueous phase at 60-80° C. to react for 6-12 hours. After the reaction is completed, the solid product is collected, washed and dried to obtain a copolymer (A).

[0036] The dispersant may be at least one of polyvinyl alcohol, gelatin, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or ethyl cellulose.

[0037] S2: subjecting the copolymer (A) to base-catalyzed hydrolysis to obtain a hydrolyzed copolymer (B).

[0038] The temperature of the base-catalyzed hydrolysis reaction may be 60 to 80° C., and the reaction time may be 4 to 12 hours.

[0039] As an example, step S2 may more specifically include the following steps:

[0040] The copolymer (A) and the inorganic base are added to a solvent in a certain ratio to react. After the reaction, the solution is acidified to neutrality and dialyzed for desalination, followed by rotary evaporation and drying to obtain a hydrolyzed copolymer (B).

[0041] The inorganic base may be sodium hydroxide or potassium hydroxide, and the molar ratio of the hydroxide in the copolymer (A) and the inorganic base is (1:3) to (1:5).

[0042] The solvent may be water, a mixed solvent having a methanol / water volume ratio of (1:1) to (1:5), or a mixed solvent having an ethanol / water volume ratio of (1:1) to (1:5).

[0043] S3: reacting the hydrolyzed copolymer (B) and the iodine-containing compound developer under the action of a catalyst.

[0044] The iodine-containing compound developer includes 1, 2, 3 or 4 iodine atoms covalently bonded to a benzene ring, with an aldehyde group and its derivatives at one end and an aromatic iodine-containing group at the other end, connected in the middle by 1 to 6 carbon, oxygen and nitrogen atoms.

[0045] Preferably, the iodine-containing compound developer comprises 2 or 3 iodine atoms, specifically 4-iodobenzaldehyde, 3-hydroxy-4-iodobenzaldehyde, 2,3-difluoro-4-iodobenzaldehyde, 3-fluoro-4-iodobenzaldehyde, 2,3,5-triiodobenzaldehyde, 3,4,5-triiodobenzaldehyde, N-(2,2-dimethoxyethyl)-2,3,5-triiodobenzamide, 5-acrylamido-2,4,6-triiodobenzene-1,3-dicarboxylic acid or 5-amino-1,3-bis(2,2-dimethoxyethyl)-2,4,6-triiodoisophthalamide, N-(2,2-dimethoxyethyl)-2,3,5-triiodobenzamide -4-iodobenzamide, N-(2,2-dimethoxyethyl)-2,5-diiodobenzamide, N-formyl-2,3,5-triiodobenzamide, N-(2,2-dimethoxyethyl)-5-iodopicolinamide, N-(2,2-dimethoxyethyl)-2-(2,4,6-triiodophenoxy)acetamide, N-(2,2-diethoxyethyl)-2,3,5-triiodobenzamide, N-(2,2-dimethoxypropyl)-2,3,5-triiodobenzamide, N-(2,2-dimethoxyethyl)-2-(2,3,5-triiodophenyl)acetamide, etc.

[0046] The molar ratio of the iodine-containing compound developer to the hydrolyzed copolymer (B) is (1:2) to (1:16). By adjusting the molar ratio of the two, the grafting reaction can be optimized, the iodine content can be increased, and the development effect can be adjusted.

[0047] The catalyst includes at least one of methanesulfonic acid or p-toluenesulfonic acid.

[0048] The solvent for the grafting reaction may be dimethyl sulfoxide (DMSO), the reaction temperature may be 50 to 90° C., and the reaction time may be 12 to 24 hours.

[0049] After the grafting reaction is completed, the method may further include: precipitating the reaction solution in acetone, then washing with acetone, drying, and boiling in a sodium bicarbonate (NaHCO3) solution for 1 hour, and finally vacuum drying to obtain a grafted hydrolyzed copolymer (C) grafted with an iodine-containing compound, and dissolving the grafted hydrolyzed copolymer (C) in a biocompatible solvent in a certain proportion to obtain a self-radiographic drug-loaded liquid embolic agent.

[0050] The biocompatible solvent may include at least one of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, and the mass concentration of the grafted hydrolyzed copolymer (C) in the liquid embolic agent may be 5% to 45%.

[0051] In the present application, a specific first monomer and a second monomer are selected for copolymerization, and a hydrolyzed copolymer (B) is obtained after base-catalyzed hydrolysis, so that an iodine-containing compound developer can be chemically bonded to the polymer chain thereof. The preparation method is safe and reliable, and the prepared self-developable drug-carrying liquid embolic agent can continuously and uniformly self-develop, does not require pre-mixing before surgery, is simple and quick to operate, and reduces artifacts generated by physical mixing of contrast agents and embolic agents.

[0052] In the copolymer (A) obtained by copolymerization of the first monomer and the second monomer, the ester group in the polyacrylate can be hydrolyzed by alkalization to form a negatively charged carboxylate group, which can be used as a drug-carrying group to load positively charged chemotherapy drugs. There is no need to use strong corrosive acids such as concentrated sulfuric acid and concentrated nitric acid to introduce negatively charged drug-carrying groups, so that the prepared self-photographic drug-carrying liquid embolic agent can quickly load a variety of chemotherapy drugs in large quantities. The drug loading is convenient and fast, and no long-term operation is required, which greatly reduces the operation time. Among them, the higher the proportion of the first monomer, the more carboxylate groups in the product, thereby improving the water solubility and even failing to solidify; and the higher the proportion of the second monomer, the lower the content of carboxylate groups in the product, which will affect the drug loading performance of the product. Therefore, the curing speed and drug loading performance of the product can be controlled by simply adjusting the molar ratio of the first monomer and the second monomer.

[0053] The present application also provides a self-imaging drug-loaded liquid embolic agent prepared according to the above preparation method.

[0054] Correspondingly, the present application also provides an application of the above-mentioned self-radiographic drug-carrying liquid embolic agent, which can be used as an embolic agent for tumor treatment and as an embolic agent carrying chemotherapy drugs for TACE treatment.

[0055] Among them, the chemotherapy drugs that can be loaded include doxorubicin hydrochloride, gemcitabine, camptothecin, pirarubicin, epirubicin, irinotecan, vincristine or bleomycin, etc.

[0056] The self-photographic drug-loaded liquid embolic agent can be rapidly solidified with a solidification time of no longer than 70 seconds, and can rapidly load a variety of chemotherapy drugs in large quantities, such as a maximum drug loading capacity of more than 79 mg / mL for doxorubicin hydrochloride, more than 85 mg / mL for pirarubicin hydrochloride, and more than 250 mg / mL for irinotecan hydrochloride.

[0057] The features and performance of the present application are further described in detail below in conjunction with specific embodiments.

[0058] Example 1

[0059] This embodiment provides a self-imaging drug-loaded liquid embolic agent, and the preparation method thereof comprises the following steps:

[0060] S1: 16.1 mL of methyl methacrylate and 28 mL of vinyl acetate were mixed (molar ratio of 1:2) and 344.3 mg of initiator azobisisobutyronitrile (AIBN) was added to prepare an oil phase, and 6.88 g of dispersant polyvinyl alcohol was added to 172 mL of water and dissolved completely to prepare an aqueous phase. The oil phase was slowly added dropwise to the aqueous phase at 60°C to react for 12 hours. After the reaction was completed, the solid product was filtered, collected, washed, and dried to obtain a copolymer of methyl methacrylate and vinyl acetate (A);

[0061] S2: 8 g of copolymer (A) and 6 g of NaOH were added to a mixed solvent of 90 mL of methanol / deionized water (volume ratio of 1:3), and the mixture was hydrolyzed at 70° C. for 8 h. After the reaction, the solution was acidified to neutrality and dialyzed for desalination, followed by rotary evaporation and drying to obtain a hydrolyzed copolymer (B);

[0062] S3: 6g of the hydrolyzed copolymer (B) was dissolved in 100mL of DMSO and 3g of 2,3,5-triiodobenzaldehyde and 1.6mL of methanesulfonic acid were added, and the mixture was reacted at 65°C for 20h. After the reaction, the solution was precipitated in acetone, then washed with acetone, dried, and boiled in a NaHCO3 solution for 1h, and finally vacuum dried to obtain the grafted hydrolyzed copolymer (C). 3g of the grafted hydrolyzed copolymer (C) was dissolved in 10g of dimethyl sulfoxide to obtain a self-photographic drug-loaded liquid embolic agent with a concentration of 23%. The iodine content of the hydrolyzed copolymer (C) in the liquid embolic agent was tested, and the test result showed that the iodine content was 58.2%.

[0063] Example 2

[0064] This embodiment provides a self-imaging drug-loaded liquid embolic agent and a preparation method thereof. The preparation method is substantially the same as the preparation method in Example 1, except that:

[0065] 6.4 mL of methyl methacrylate and 28 mL of vinyl acetate were mixed (molar ratio of 1:5). 3 g of the grafted hydrolyzed copolymer was dissolved in 10 g of dimethyl sulfoxide to obtain a self-photographic drug-loaded liquid embolic agent with a concentration of 23%. The hydrolyzed copolymer in the liquid embolic agent was tested for iodine content, and the test result showed that the iodine content was 62.4%.

[0066] Example 3

[0067] This embodiment provides a self-imaging drug-loaded liquid embolic agent, the preparation method of which is substantially the same as the preparation method in Example 1, except that:

[0068] In step S1, 3.2 mL of methyl methacrylate and 28 mL of vinyl acetate were mixed (molar ratio of 1:10). 3 g of the grafted hydrolyzed copolymer was dissolved in 10 g of dimethyl sulfoxide to obtain a self-imageable drug-loaded liquid embolic agent with a concentration of 23%. The hydrolyzed copolymer in the liquid embolic agent was tested for iodine content, and the test result showed that the iodine content was 56.7%.

[0069] Example 4

[0070] This embodiment provides a self-imaging drug-loaded liquid embolic agent, and the preparation method thereof comprises the following steps:

[0071] S1: 9 mL of methyl acrylate and 28 mL of vinyl acetate were mixed (molar ratio of 1:3), and 229.5 mg of initiator benzoyl peroxide (BPO) was added to prepare an oil phase, 7.5 g of dispersant hydroxyethyl cellulose was added to 172 mL of water and dissolved completely to prepare an aqueous phase, the oil phase was slowly added dropwise to the aqueous phase at 65°C to react for 10 h, and after the reaction was completed, the solid product was filtered, collected, washed, and dried to obtain a copolymer of methyl acrylate and vinyl acetate;

[0072] S2: 12 g of a copolymer of methyl acrylate and vinyl acetate and 6 g of NaOH were added to 120 mL of deionized water, and the mixture was hydrolyzed at 80° C. for 8 h. After the reaction, the solution was acidified to neutrality and dialyzed for desalination, followed by rotary evaporation and drying to obtain a hydrolyzed copolymer;

[0073] S3: 8g of the hydrolyzed copolymer of methyl acrylate and vinyl acetate was dissolved in 100mL DMSO and 6g of N-(2,2-dimethoxyethyl)-2,3,5-triiodobenzamide and 4.25g of p-toluenesulfonic acid were added, and the mixture was reacted at 60°C for 24h. After the reaction, the solution was precipitated in acetone, then washed with acetone, dried, and boiled in a NaHCO3 solution for 1h, and finally vacuum dried to obtain a grafted hydrolyzed copolymer (C). 3g of the grafted hydrolyzed copolymer was dissolved in 10g of dimethyl sulfoxide to obtain a self-photographic drug-loaded liquid embolic agent with a concentration of 23%. The hydrolyzed copolymer in the liquid embolic agent was tested for iodine content, and the test result showed that the iodine content was 52.9%.

[0074] Example 5

[0075] This embodiment provides a self-imaging drug-loaded liquid embolic agent, and the preparation method thereof comprises the following steps:

[0076] S1: 9 mL of methyl acrylate and 36.4 mL of vinyl propionate were mixed (molar ratio of 1:3.4) and 172.1 mg of initiator azobisisoheptanenitrile was added to prepare an oil phase, 13.8 g of dispersant polyvinyl alcohol was added to 200 mL of water and dissolved completely to prepare an aqueous phase, the oil phase was slowly added dropwise to the aqueous phase at 60°C for reaction for 8 hours, and after the reaction was completed, the solid product was filtered, collected, washed, and dried to obtain a copolymer of methyl acrylate and vinyl propionate;

[0077] S2: 10 g of a copolymer of methyl acrylate and vinyl propionate and 8 g of NaOH were added to a mixed solvent of methanol / deionized water in a volume ratio of 25:100 mL, and the mixture was hydrolyzed at 70° C. for 8 h. After the reaction, the solution was acidified to neutrality and dialyzed for desalination, followed by rotary evaporation and drying to obtain a hydrolyzed copolymer;

[0078] S3: 8g of the hydrolyzed copolymer of methyl acrylate and vinyl propionate was dissolved in 100mL DMSO and 5g of 3,4,5-triiodobenzaldehyde and 2mL of methanesulfonic acid were added, and the reaction was carried out at 65°C for 18h. After the reaction, the solution was precipitated in acetone, then washed with acetone, dried, and boiled in a NaHCO3 solution for 1h, and finally vacuum dried to obtain a grafted hydrolyzed copolymer (C). 3g of the grafted hydrolyzed copolymer was dissolved in 10g of dimethyl sulfoxide to obtain a self-photographic drug-loaded liquid embolic agent with a concentration of 23%. The hydrolyzed copolymer in the liquid embolic agent was tested for iodine content, and the test result showed that the iodine content was 50.5%.

[0079] Comparative Example 1

[0080] This comparative example provides a liquid embolic agent, which is prepared according to the preparation method disclosed in Example 1 of Chinese patent CN117582535B.

[0081] Comparative Example 2

[0082] This comparative example provides a self-photographic drug-carrying liquid embolic agent, the preparation method of which is substantially the same as that in Example 1, except that:

[0083] In step S1, 31.8 mL of methyl methacrylate and 28 mL of vinyl acetate were mixed (1:1). 3 g of the grafted hydrolyzed copolymer was dissolved in 10 g of dimethyl sulfoxide to obtain a self-imageable drug-loaded liquid embolic agent with a concentration of 23%. The hydrolyzed copolymer in the liquid embolic agent was tested for iodine content, and the test result showed that the iodine content was 42.6%.

[0084] Comparative Example 3

[0085] This comparative example provides a self-photographic drug-carrying liquid embolic agent, the preparation method of which is substantially the same as that in Example 1, except that:

[0086] In step S1, 2.7 mL of methyl methacrylate and 28 mL of vinyl acetate were mixed (1:12). 3 g of the grafted hydrolyzed copolymer was dissolved in 10 g of dimethyl sulfoxide to obtain a self-imageable drug-loaded liquid embolic agent with a concentration of 23%. The hydrolyzed copolymer in the liquid embolic agent was tested for iodine content, and the test result showed that the iodine content was 33.1%.

[0087] Some of the preparation parameters in Examples 1-5 and Comparative Examples 1-3 are shown in Table 1.

[0088] Table 1 Partial preparation parameters in Examples 1-5 and Comparative Examples 1-3

[0089]

[0090] Performance testing and result analysis

[0091] (1) Curing time test.

[0092] Take the samples of liquid embolic agents prepared in Examples 1-5 and Comparative Examples 1-3, drop them into purified water respectively to form particle precipitation, and drop them at a uniform speed for 10 seconds. After the dropwise addition is completed, time is set, and some particles are scooped out at intervals of 10 seconds from 30 seconds to 200 seconds, respectively, to ensure that the particles scooped out at each time point are uniform in size and shape, without adhesion or deformity, and at least two are placed on two layers of clean cloth to dry the surface moisture. Take the precipitated particles at different time points respectively, cover the particles with two layers of clean cloth, press with a 1.5N weight for 10 seconds, and observe whether there is viscous liquid seeping out or adhering to the clean cloth. If there is no viscous liquid seeping out and no adhesion to the clean cloth, then the time point is recorded as the curing time. The test results are shown in Table 2.

[0093] Table 2 Solidification time of liquid embolic agents in Examples and Comparative Examples

[0094] Grouping Curing time(S) Example 1 72 Example 2 61 Example 3 54 Example 4 75 Example 5 63 Comparative Example 1 97 Comparative Example 2 Not solidified Comparative Example 3 <10

[0095] From the test results in Table 2, it can be seen that the self-photographic drug-loaded liquid embolic agents prepared in Examples 1-5 can be cured quickly, and the curing time is no longer than 70 seconds. However, the liquid embolic agent prepared by grafting modification of polyvinyl alcohol in the prior art, i.e., Comparative Example 1, has a curing time of up to 90 seconds, which is much higher than the curing time in the present application.

[0096] Comparing the test results of Comparative Examples 2 and 3 with those of Example 1, the content of the first monomer in Comparative Example 2 is too high, resulting in the prepared liquid embolic material being too water-soluble and unable to solidify; while the content of the second monomer in Comparative Example 3 is too high, and the solidification time is too fast, which is not conducive to the operation of technicians, easily causing panic, and is not suitable for practical application.

[0097] (2) Maximum drug loading test.

[0098] 80 mg of doxorubicin hydrochloride powder was dissolved in 1 mL of a liquid embolic solution with a mass concentration of 30%, and the liquid embolic solution in which the doxorubicin hydrochloride powder was dissolved was added dropwise to a phosphate buffered saline solution (PBS) to solidify it. 5.76 g of sodium dodecyl sulfate, 2000 mL of purified water, 2.72 mL of orthophosphoric acid, 2000 mL of acetonitrile and 240 mL of methanol were mixed evenly as an extract. The solidified embolic agent was added to the extract and leached for 24 hours to obtain a test solution. Another portion of the extract was taken, and 80 mg of doxorubicin hydrochloride powder was dissolved as a standard solution. The test solution and the standard solution were tested using a high performance liquid chromatograph, respectively, to obtain the amount of doxorubicin hydrochloride precipitated from the embolic agent, which was the maximum drug loading.

[0099] The experiment was repeated by replacing 80 mg of doxorubicin hydrochloride with 80 mg of pirarubicin hydrochloride or 200 mg of irinotecan hydrochloride. The test results are shown in Tables 3, 4 and 5.

[0100] Table 3 Maximum drug loading of doxorubicin hydrochloride in liquid embolic agents in Examples and Comparative Examples

[0101]

[0102] Table 4 Maximum drug loading of pirarubicin hydrochloride in liquid embolic agents in Examples and Comparative Examples

[0103]

[0104]

[0105] Table 5 Maximum drug loading of irinotecan hydrochloride in liquid embolic agents in Examples and Comparative Examples

[0106]

[0107] As shown in Tables 3 to 5, the maximum drug loading capacity of the self-photographic drug-loaded liquid embolic agents prepared in Examples 1-5 for doxorubicin hydrochloride is greater than 79 mg / mL, the maximum drug loading capacity for pirarubicin hydrochloride is greater than 85 mg / mL, and the maximum drug loading capacity for irinotecan hydrochloride is greater than 250 mg / mL. In Comparative Example 1, the drug-loading group is directly introduced by the sulfonated reagent concentrated sulfuric acid, the reaction efficiency is low, and the maximum drug loading capacity is also low. In Comparative Example 3, the proportion of the second monomer is too high, and the carboxyl content in the polymer is too low, which will reduce the drug loading performance of the embolic material.

[0108] The embodiments described above are part of the embodiments of the present application, rather than all of the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application for protection, but merely represents the selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present application.

Claims

1. A method for preparing a self-imaging drug-loaded liquid embolic agent, characterized in that: The following steps are involved: S1: copolymerizing a first monomer, a second monomer, and an initiator in a certain proportion to obtain a copolymer (A); the first monomer is an acrylic acid ester compound, the second monomer is a vinyl ester compound, and the molar ratio of the first monomer to the second monomer is (1:2) to (1:10); S2: subjecting the copolymer (A) to base-catalyzed hydrolysis to obtain a hydrolyzed copolymer (B); S3: reacting the hydrolyzed copolymer (B) and the iodine-containing compound developer under the action of a catalyst.

2. The preparation method according to claim 1, characterized in that: The first monomer includes at least one of methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate or butyl methacrylate; the second monomer includes at least one of vinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate or vinyl valerate.

3. The preparation method according to claim 1, characterized in that: The iodine-containing compound developer includes 1 to 4 iodine atoms covalently bonded to a benzene ring; and the molar ratio of the iodine-containing compound developer to the hydrolyzed copolymer (B) is (1:2) to (1:16).

4. The preparation method according to claim 1, characterized in that: The catalyst includes at least one of methanesulfonic acid or p-toluenesulfonic acid.

5. The preparation method according to any one of claims 1 to 2, characterized in that: Step S1 includes: S11: mixing the first monomer and the second monomer in proportion and adding the initiator to form an oil phase; S12: adding the dispersant into water to prepare an aqueous phase; S13: slowly dropwise adding the oil phase into the water phase at 60-80° C. for reaction for 6-12 hours to obtain the copolymer (A).

6. The preparation method according to claim 5, characterized in that: The initiator comprises at least one of benzoyl peroxide, azobisisobutyronitrile, azobisisoheptylnitrile, tert-butyl perbenzoate or dimethyl azobisisobutyrate; the added amount of the initiator is 0.1% to 1.5% of the total mass of the first monomer and the second monomer; The dispersant is at least one of polyvinyl alcohol, gelatin, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or ethyl cellulose.

7. The preparation method according to claim 1, characterized in that: Step S2 includes: The copolymer (A) and an inorganic base are added to a solvent in a certain ratio, and hydrolyzed at 60 to 80° C. for 4 to 12 hours to obtain the hydrolyzed copolymer (B); The molar ratio of the copolymer (A) to the hydroxide in the inorganic base is (1:3) to (1:5); the solvent is water, a mixed solvent with a methanol / water volume ratio of (1:1) to (1:5) or a mixed solvent with an ethanol / water volume ratio of (1:1) to (1:5).

8. The preparation method according to claim 1, characterized in that: The reaction temperature of the grafting reaction in step S3 is 50-90° C., and the reaction time is 12-24 hours.

9. A self-photographic drug-loaded liquid embolic agent prepared by the preparation method according to any one of claims 1 to 8.

10. A use of the self-radiographic drug-carrying liquid embolic agent as claimed in claim 9 as a chemotherapy drug-carrying embolic agent for TACE treatment, characterized in that: The chemotherapy drug includes at least one of doxorubicin hydrochloride, gemcitabine, camptothecin, pirarubicin, epirubicin, irinotecan, vincristine or bleomycin.

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