Embolic polymer, medical liquid embolic agent and its application

Abstract

The present invention relates to an embolic polymer and a medical liquid embolic agent capable of long-term self-development, and belongs to the technical field of medical devices. The embolic polymer is a hydrophobic and hydrophilic iodinated block copolymer, and its phase transition speed and strength are optimized by regulating the ratio of hydrophilic and hydrophobic segments and the iodine content. After the embolic polymer is prepared into an embolic agent with a polar solvent, an in-situ solid implant is spontaneously formed through solvent exchange, which can not only realize effective embolization of the target blood vessel site, but also achieve the dual purposes of real-time development and long-term development, which is helpful for postoperative review or further treatment, and has broad application prospects.

Description

Technical Field

[0001] The invention relates to an embolic polymer capable of long-term self-development and a medical liquid embolic agent, belonging to the technical field of medical devices. Background Art

[0002] Hepatocellular carcinoma (HCC) is the most common malignant tumor in the world. Among the various treatment methods for liver cancer, interventional therapy is considered to be the most commonly used technology for liver cancer treatment, of which TACE (transarterial chemoembolization) accounts for more than 90%, involving the treatment of almost all stages of liver cancer. TACE is assisted by the visual effect of imaging equipment (such as X-rays), using different types of catheters to inject embolic materials into the lesion through the artery or vein to block the blood supply, thereby achieving the purpose of controlling bleeding, treating vascular diseases, treating tumors and eliminating diseased organs. Among them, embolic materials are the key to the success of transcatheter embolization.

[0003] Commonly used embolic materials for liver cancer vessels include iodized oil, gelatin sponge, PVA particles, blank microspheres (c-TACE), drug-loaded microspheres (D-TACE), etc. The properties of embolic materials are different, and the applicable sites and diseases are also different. Solid embolic agents have a certain size, which limits the embolic blood vessel site. Compared with solid embolic materials, one of the unique characteristics of liquid embolic agents is that they can fill the target blood vessels and induce vascular occlusion by advancing with the blood flow and penetrating into the vascular bed to reach areas that solid embolic agents cannot reach. The degree of embolism is higher than that of solid embolic materials. Iodized oil is currently the most commonly used liquid embolic agent in liver cancer vascular embolization. It can be developed under X-rays, has good tissue compatibility, and can achieve terminal embolization. However, due to its low viscosity during use, it is easily washed away by blood, and the embolic effect is weak, which can easily cause vascular recanalization.

[0004] In addition, other commonly used liquid embolic agents such as Onyx and α-butyl cyanoacrylate (NBCA glue) are injected into the target site and solidify immediately, and are mainly used in local embolization scenarios. Therefore, the development of a phase-change liquid embolic agent that can achieve distal embolization and has certain mechanical properties without being washed away has good market application prospects. Currently, most of the embolic materials used in clinical practice use temporary contrast agents, so there are many disadvantages: for example, metal contrast agents such as tantalum powder have problems such as incomplete embedding, which will cause artifacts and affect the contrast effect; iodine-containing non-ionic contrast agents such as iohexol are easily metabolized in a short period of time after surgery, and during postoperative follow-up, the embolization site needs to be diagnosed by angiography again. Summary of the invention

[0005] The object of the present invention is to provide a medical liquid embolic agent that can be self-developed for a long time and can achieve distal embolization, which can be used to treat vascular diseases. The medical liquid embolic agent of the present invention is obtained by dissolving an embolic polymer in a non-protonic polar solvent. The embolic polymer is an iodine-containing compound and a block copolymer combined in the form of a covalent bond. By adjusting the block ratio and the iodine mass content, while ensuring that the embolic agent can be developed, by optimizing its phase change speed and strength, after entering the blood, through the solvent exchange effect, it spontaneously forms an in-situ solid implant, which can not only achieve effective embolization of the target blood vessel site, but also achieve the dual purposes of real-time development and long-term development.

[0006] According to the first aspect of the embodiment of the present application, the main body of the embolic polymer used in the present invention is a block copolymer obtained by copolymerization of hydrophobic monomers under the initiator PEG; wherein the hydrophobic monomers form hydrophobic segments, and PEG constitutes hydrophilic segments; by regulating the molecular weight of the initiator and the ratio of the block monomers, the hydrophilicity and hydrophobicity of the copolymer are regulated, thereby changing the phase transition speed and strength of the copolymer in the blood. In the present invention, the hydrophobic monomers that can be used are one or two of caprolactone, lactide, levorotatory lactide or glycolide, and the copolymer segments formed can be PDLLGA, PDLLA, PCL and PLLA segments. Further, the block copolymer is bonded to triiodobenzoic acid through a covalent bond to obtain an iodinated copolymer, i.e., an embolic polymer. The strength and phase transition speed of the embolic agent are further optimized by regulating the range of iodine content.

[0007] Among them, the iodine content is 17%~28%.

[0008] The specific preparation method is as follows: add initiator and monomer to a 250mL jacketed three-necked flask, heat up, vacuum remove water for 1h, and then add catalyst to react. After the reaction is completed, precipitate with n-hexane and dry in vacuum to obtain a block copolymer. Weigh the above block copolymer and add ultra-dry dichloromethane to stir and dissolve at room temperature, weigh triiodobenzoic acid and dissolve it with N, N dimethylformamide, weigh DCC (dicyclohexylcarbodiimide) and DMAP (4-dimethylaminopyridine) and dissolve it with ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix them for reaction. After the reaction is completed, the above product is further purified with n-hexane, the precipitate is collected, and then placed in a vacuum oven to dry for 24~72h to obtain the final product iodinated copolymer (embolic polymer).

[0009] Preferably, the comonomer is one or two of caprolactone, lactide, L-lactide or glycolide, and more preferably, the comonomer is caprolactone or L-lactide.

[0010] Preferably, the initiator is PEG600-PEG1500, more preferably, the initiator is PEG1000 or PEG1500.

[0011] Preferably, the molecular weight ratio of the hydrophilic segment PEG1000 to the hydrophobic segment PDLLGA is 1.3-1.8:1; the molecular weight ratio of the hydrophilic segment PEG1500 to the hydrophobic segment PDLLGA is 1.9-3.9:1.

[0012] Preferably, the molecular weight ratio of the hydrophilic segment PEG1000 to the hydrophobic segment PDLLA is 1.0-1.7:1; the molecular weight ratio of the hydrophilic segment PEG1500 to the hydrophobic segment PDLLA is 1.1-2.8:1.

[0013] Preferably, the molecular weight ratio of the hydrophilic segment PEG1000 to the hydrophobic segment PLLA is 0.8-1.2:1; the molecular weight ratio of the hydrophilic segment PEG1500 to the hydrophobic segment PLLA is 1.2-1.6:1.

[0014] Preferably, the molecular weight ratio of the hydrophilic segment PEG1000 and the hydrophobic segment PCL is 0.45-0.7:1; the molecular weight ratio of the hydrophilic segment PEG1500 and the hydrophobic segment PCL is 1.1-1.5:1.

[0015] Preferably, the molar ratio of block copolymer to triiodobenzoic acid is 1:2-4, more preferably, the molar ratio is 1:4.

[0016] According to a second aspect of the embodiment of the present application, a long-term self-developing medical liquid embolic agent is provided. The embolic polymer prepared above is solid and soluble in a non-protonic polar solvent at room temperature, wherein the mass concentration of the embolic polymer is 30-50%, and the non-protonic polar solvent is dimethyl sulfoxide or / dimethyl sulfoxide and ethanol.

[0017] The present invention relates to a method for preparing a phase-change controllable embolic agent, and the method comprises the following steps:

[0018] Under room temperature, a single iodinated copolymer is taken, a non-protonic polar solvent is added, and the mixture is stirred to dissolve; the completely dissolved liquid embolic agent is packaged in a vial and sterilized to obtain an in-situ phase-change liquid embolic agent capable of long-term self-development.

[0019] According to a third aspect of the embodiments of the present application, there is provided use of the medical liquid embolic agent of the second aspect in vascular embolization, especially terminal embolization of an auricular artery or a renal artery.

[0020] The technical solution provided by the embodiments of the present application may include the following beneficial effects: the embolic polymer based on the present invention is an in-situ phase-change liquid embolic material, which, after entering the human body, spontaneously forms an in-situ solid implant with excellent mechanical properties through solvent exchange, thereby achieving long-term embolization of the vascular extremities, and can also achieve the dual effects of real-time imaging and embolic imaging, which is helpful for postoperative review or further treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 (a) is a diagram showing the embolic effect of the embolic agent PDLLGA-1 in rabbit ears according to an embodiment of the present invention; Figure 1 (b) is a picture showing the embolic effect of the embolic agent PDLLA-1 in the embodiment of the present invention on rabbit ears;

[0022] Figure 2 (a) is a rabbit ear embolization effect diagram of the embolic agent PDLLGA-5 in an embodiment of the present invention; Figure 2 (b) is a picture showing the embolic effect of the embolic agent PDLLA-3 in rabbit ears according to an embodiment of the present invention; Figure 2 (c) is a picture showing the embolic effect of the PLLA-6 embolic agent in rabbit ears according to an embodiment of the present invention; Figure 2 (d) is a picture showing the embolic effect of the PCL-12 embolic agent in rabbit ears according to an embodiment of the present invention;

[0023] Figure 3 (a) is a diagram showing the effect of PDLLGA-5 embolic agent on rabbit kidney embolization in an embodiment of the present invention; Figure 3 (b) is the angiographic image of the PDLLGA-5 embolic agent 30 minutes after use in the embodiment of the present invention;

[0024] Figure 4 (a) is a diagram showing the embolization effect of the PDLLA-3 embolic agent on rabbit kidney in an embodiment of the present invention; Figure 4 (b) is an angiographic image of the PDLLA-3 embolic agent 30 minutes after use in an embodiment of the present invention;

[0025] Figure 5 (a) is a diagram showing the embolization effect of the PDLLA-3 embolic agent on rabbit kidney in an embodiment of the present invention; Figure 5 (b) is the angiographic image of the PLLA-6 embolic agent 30 minutes after use in the embodiment of the present invention;

[0026] Figure 6 (a) is a diagram showing the embolization effect of the PDLLA-3 embolic agent on rabbit kidney in an embodiment of the present invention; Figure 6 (b) is an angiographic image of the PCL-12 embolic agent 30 minutes after use in an embodiment of the present invention;

[0027] Figure 7 (a) is a follow-up angiogram 4 weeks after renal embolization with PCL-12 embolic agent in the embodiment of the present invention; Figure 7 (b) is a renal anatomical diagram 4 weeks after renal embolization with PCL-12 embolic agent in an example of the present invention. DETAILED DESCRIPTION

[0028] The following examples are used to further illustrate the present invention, and their purpose is to illustrate the present invention and should not be construed as limiting the scope of the present invention. Unless otherwise specified, all parts by weight and weight percentages are used below.

[0029] The raw materials used in the present invention, unless otherwise specified, are conventional commercially available products; the methods used in the present invention, unless otherwise specified, are conventional methods in the art.

[0030] PEG600, PEG1000, PEG1500: These are different molecular weight grades of polyethylene glycol (PEG). PEG is a linear polymer composed of repeating ethylene oxide units. The number represents the molecular weight, for example, PEG600 means that the average molecular weight of this PEG is about 600 Daltons.

[0031] In addition, PDLLGA refers to poly (rac-lactide-co-glycolide), also known as poly (lactic acid-co-glycolide), which is a random copolymer obtained by ring-opening polymerization of two monomers, racemic lactide (DL-LA) and glycolide (GA). PCL refers to polycaprolactone. PDLLA refers to racemic polylactide, also known as racemic polylactic acid, which is an amorphous polymer, while PLLA refers to left-handed polylactide, also known as left-handed polylactic acid, which has a certain degree of crystallinity; among them, PLLA is obtained by ring-opening polymerization of left-handed lactide, while PDLLA is obtained by ring-opening polymerization of racemic lactide.

[0032] Example 1: PDLLGA embolic agent system

[0033] (1) PDLLGA embolic agent 1 (PDLLGA-1)

[0034] In a 250mL jacketed three-necked flask, add 31.6g of DL-lactide (DL-LA), 8.4g of glycolide (GA), and 0.05g of 1, 4-butanediol, raise the temperature to 130℃, vacuum and remove water for 1h, then add 0.2g of stannous chloride and continue the reaction for 3h. After the reaction is completed, precipitate with n-hexane and vacuum dry to obtain poly(vinyl lactide) (PDLLGA) polymer. Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 10.0g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 4.1g of DCC (dicyclohexylcarbodiimide) and 0.61g of DMAP (4-dimethylaminopyridine) and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction is completed, the product is further purified with n-hexane, the precipitate is collected, and then placed in a vacuum oven for drying for 24 to 72 hours to obtain the final product, which is poly(lactide-glycolide)-iodine (I-PDLLGA-I, hereinafter referred to as PDLLGA-I).

[0035] The ratio of glycolide to lactide in the polymer was calculated to be 76 / 24 and the relative molecular weight was 2545 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer. The iodine mass content was 21% by iodine titration method.

[0036] (2) PDLLGA embolic agent 2 (PDLLGA-2)

[0037] In a 250mL jacketed three-necked flask, add 31.6g of DL-lactide (DL-LA), 8.4g of glycolide (GA), and 30.0g of PEG (1500), raise the temperature to 130℃, vacuum and remove water for 1h, then add 0.2g of stannous chloride and continue the reaction for 3h. After the reaction, precipitate with n-hexane and vacuum dry to obtain a block copolymer (PDLLGA-PEG1500-PDLLGA). Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 7.0g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 2.89g of DCC (dicyclohexylcarbodiimide) and 0.43g of DMAP (4-dimethylaminopyridine) and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and then dried in a vacuum oven for 24 to 72 hours to obtain the final product I-PDLLGA-PEG1500-PDLLGA-I (hereinafter referred to as PEG1500-PDLLGA-I).

[0038] The ratio of glycolide to lactide in the polymer was calculated to be 72 / 28 and the relative molecular weight was 3348 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer. The iodine mass content was 17% by iodine titration method.

[0039] (3) PDLLGA embolic agent 3 (PDLLGA-3)

[0040] In a 250mL jacketed three-necked flask, add 31.6g of DL-lactide (DL-LA), 8.4g of glycolide (GA), and 54.4g of PEG (1500), raise the temperature to 130℃, vacuum and remove water for 1h, then add 0.2g of stannous chloride and continue the reaction for 3h. After the reaction, precipitate with n-hexane and vacuum dry to obtain a block copolymer (PDLLGA-PEG1500-PDLLGA). Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 9.4g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 3.86g of DCC (dicyclohexylcarbodiimide) and 0.57g of DMAP (4-dimethylaminopyridine) and dissolve it in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and then dried in a vacuum oven for 24 to 72 hours to obtain the final product I-PDLLGA-PEG1500-PDLLGA-I (hereinafter referred to as PEG1500-PDLLGA-I).

[0041] The ratio of glycolide to lactide in the polymer was calculated to be 70 / 30 through hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the relative molecular weight was 2625. The iodine content by mass was 21% by iodine titration.

[0042] According to the basic operation steps of Example 1, other block copolymers were obtained by using PEG with different molecular weights as initiators and polymerizing with different monomers. Different amounts of triiodobenzoic acid were further added to participate in the reaction to obtain iodine-containing block copolymers with different mass contents. The specific parameters are as shown in the following table:

[0043]

[0044] Take 0.30 g of any of the above iodinated copolymers, add 0.70 g of DMSO, and stir to dissolve at room temperature. The completely dissolved liquid embolic agent is packaged in a vial and sterilized to obtain an in-situ phase-change liquid embolic agent capable of long-term self-development.

[0045] The mechanical properties of the embolic agent and whether it has distal embolic ability were initially determined through rabbit ear embolization experiments; the mechanical property evaluation criteria were: whether the embolic material was lost from the rabbit ear; the distal embolization evaluation criteria were: whether it reached the distal end of the auricular artery. The average gray value of the development degree was the gray value of the development of the embolic agent under DSA and the original photos were saved, and the gray value of the development was detected by Image Pro Plus image analysis software (the smaller the gray value, the better the development effect), and compared with iodized oil (the average gray value of iodized oil development was 16).

[0046] Rabbit ear embolization: Since the thickness of the rabbit ear central artery is suitable for puncture and can be clearly seen in vitro, New Zealand white rabbits were used to evaluate the embolic effect of the embolic agent. Before surgery, the animal was anesthetized by intramuscular injection of an appropriate amount of anesthetic, and the rabbit ear hair was shaved with an electric shaver, and then the animal was laid flat on the operating table. After disinfecting the proximal end of the ear root of the blood vessel with 75% ethanol, the embolic agent was slowly infused from the proximal end to the distal end through the rabbit ear central artery with a 1mL syringe (about 6s), with a dose of 0.1mL / ear. After the injection, the needle was pulled out and the puncture site was immediately pressed with a sterile cotton ball to prevent the drug solution from extravasating. After 1 hour, it was placed under the DSA imaging device to evaluate the embolic and imaging effects. The results of different formulations are shown in the following table: The results show that the iodinated PDLLGA liquid embolic agent has different embolic effects, and the mechanical properties of the embolic material can be further controlled by adjusting the hydrophilic and hydrophobic molecular weight of the block copolymer, so that the embolic material does not flow from the distal end.

[0047]

[0048] a The analysis of the grayscale values ​​of each sample was performed using the same range of intensity windows; b “+” represents greater than, and “-” represents less than.

[0049] From the above experimental cases, it can be seen that the iodine content and the segment ratio will comprehensively affect the performance of the embolic agent. The addition of iodine may involve changes in the molecular structure of the polymer, changes in phase transition behavior, or affect the mechanical properties of the polymer molecules. For example, the iodination process may cause changes in the molecular structure of PEG / polyester, especially the introduction of iodine atoms may increase the interaction forces between molecules, such as hydrogen bonds or van der Waals forces. The introduction of iodine may increase the distance between molecules, thereby affecting the physical properties of the polymer, such as melting point and glass transition temperature (Tg). As the iodine content increases, the material may become more rigid and reduce its flexibility. However, within a certain range, an appropriate amount of iodination may not significantly affect flexibility, but help maintain good mechanical properties. In summary, in the PDLLGA system, the iodine content is optimally controlled between 21-22%, the molecular weight ratio of the hydrophilic segment PEG1000 and the hydrophobic segment PDLLGA is 1.3~1.8:1; the molecular weight ratio of the hydrophilic segment PEG1500 and the hydrophobic segment PDLLGA is 1.9~3.9:1.

[0050] Example 2: PDLLA Embolic Agent System

[0051] (1) PDLLA embolic agent 1 (PDLLA-1)

[0052] Add 60g of DL-lactide (DL-LA) and 21.8g of PEG (1500) to a 250mL jacketed three-necked flask, raise the temperature to 130℃, vacuum and remove water for 1h, then add 0.3g of stannous chloride and continue the reaction for 3h. After the reaction is completed, precipitate with n-hexane and vacuum dry to obtain a block copolymer (PDLLA-PEG1500-PDLLA). Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 9.85g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 4.07g of DCC (dicyclohexylcarbodiimide) and 0.60g of DMAP (4-dimethylaminopyridine) and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and then placed in a vacuum oven for drying for 24 to 72 hours to obtain the final product I-PDLLA-PEG1500-PDLLA-I (hereinafter referred to as PEG1500-PDLLA-I).

[0053] The relative molecular weight of the polymer was calculated to be 4005 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the iodine mass content was 20% by iodine titration method.

[0054] (2) PDLLA embolic agent 2 (PDLLA-2)

[0055] Add 60g of DL-lactide (DL-LA) and 32.7g of PEG (1500) to a 250mL jacketed three-necked flask, raise the temperature to 130℃, vacuum and remove water for 1h, then add 0.3g of stannous chloride and continue the reaction for 3h. After the reaction is completed, precipitate with n-hexane and vacuum dry to obtain a block copolymer (PDLLA-PEG1500-PDLLA). Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 13.71g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 5.66g of DCC (dicyclohexylcarbodiimide) and 0.84g of DMAP (4-dimethylaminopyridine) and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and then placed in a vacuum oven for drying for 24 to 72 hours to obtain the final product I-PDLLA-PEG1500-PDLLA-I (hereinafter referred to as PEG1500-PDLLA-I).

[0056] The relative molecular weight of the polymer was calculated to be 3451 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the iodine mass content was 22% by iodine titration method.

[0057] (3) PDLLA embolic agent 3 (PDLLA-3)

[0058] Add 40g of DL-lactide (DL-LA) and 43.6g of PEG (1500) to a 250mL jacketed three-necked flask, raise the temperature to 130℃, vacuum and remove water for 1h, then add 0.2g of stannous chloride and continue the reaction for 3h. After the reaction is completed, precipitate with n-hexane and vacuum dry to obtain a block copolymer (PDLLA-PEG1500-PDLLA). Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 18.0g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 7.54g of DCC (dicyclohexylcarbodiimide) and 1.1g of DMAP (4-dimethylaminopyridine) and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and then placed in a vacuum oven for drying for 24 to 72 hours to obtain the final product I-PDLLA-PEG1500-PDLLA-I (hereinafter referred to as PEG1500-PDLLA-I).

[0059] The relative molecular weight of the polymer was calculated to be 2818 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the iodine mass content was 25% by iodine titration method.

[0060] According to the basic operation steps of Example 2, other block copolymers were obtained by using PEG with different molecular weights as initiators and polymerizing with different monomers. Different amounts of triiodobenzoic acid were further added to participate in the reaction to obtain iodine-containing block copolymers with different mass contents. The specific parameters are as shown in the following table:

[0061]

[0062] Take 0.50 g of any of the above iodinated copolymers, add 0.50 g of DMSO, and stir to dissolve at room temperature. The completely dissolved liquid embolic agent is packaged in a vial and sterilized to obtain an in-situ phase-change liquid embolic agent capable of long-term self-development.

[0063] The mechanical properties of the embolic agent and whether it has distal embolic ability were initially determined through rabbit ear embolization experiments; the mechanical property evaluation criteria were: whether the embolic material was lost from the rabbit ear; the distal embolization evaluation criteria were: whether it reached the distal end of the auricular artery. The average gray value of the development degree was the gray value of the development of the embolic agent under DSA and the original photos were saved, and the gray value of the development was detected by Image Pro Plus image analysis software (the smaller the gray value, the better the development effect), and compared with iodized oil (the average gray value of iodized oil development was 16).

[0064] Rabbit ear embolization: Since the thickness of the rabbit ear central artery is suitable for puncture and can be clearly seen in vitro, New Zealand white rabbits were used to evaluate the embolic effect of the embolic agent. Before surgery, the animal was anesthetized by intramuscular injection of an appropriate amount of anesthetic, and the rabbit ear hair was shaved with an electric shaver, and then the animal was laid flat on the operating table. After the proximal end of the ear root of the blood vessel was disinfected with 75% ethanol, the embolic agent was slowly infused from the proximal end to the distal end through the rabbit ear central artery with a 1mL syringe (about 6s), with a dose of 0.1mL / ear. After the injection, the needle was pulled out and the puncture site was immediately pressed with a sterile cotton ball to prevent the drug solution from extravasating. After 1 hour, it was placed under the DSA imaging device to evaluate the embolic and imaging effects. The results of different formulations are shown in the following table: The results show that the iodinated PDLLA liquid embolic agent has different embolic effects, and the mechanical properties of the embolic material can be further controlled by adjusting the hydrophilic and hydrophobic molecular weight of the block copolymer, so that the embolic material does not flow from the distal end.

[0065]

[0066] a The analysis of the grayscale values ​​of each sample was performed using the same range of intensity windows; b “+” represents greater than, and “-” represents less than.

[0067] It can be seen from the above experimental cases that in the PDLLA system, the iodine content and the segment ratio will comprehensively affect the performance of the embolic agent. The iodine content is optimally controlled between 21-26%, the molecular weight ratio of the hydrophilic segment PEG1000 and the hydrophobic segment PDLLA is 1.0~1.7:1; the molecular weight ratio of the hydrophilic segment PEG1500 and the hydrophobic segment PDLLA is 1.1~2.8:1.

[0068] Example 3: PLLA embolic agent system

[0069] (1) PLLA embolic agent 1 (PLLA-1)

[0070] Add 40g of L-lactide (L-LA) and 43.8g of PEG (1500) to a 250mL jacketed three-necked flask, raise the temperature to 130℃, vacuum and remove water for 1h, then add 0.2g of stannous chloride and continue the reaction for 3h. After the reaction is completed, precipitate with n-hexane and vacuum dry to obtain a block copolymer (PLLA-PEG1500-PLLA). Weigh 10g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 8.5g of triiodobenzoic acid and use 4mL of N, N-dimethylformamide, weigh 3.5g of DCC (dicyclohexylcarbodiimide) and 0.52g of DMAP (4-dimethylaminopyridine), and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and then placed in a vacuum oven for drying for 24 to 72 hours to obtain the final product I-PLLA-PEG1500-PLLA-I (hereinafter referred to as PEG1500-PLLA-I).

[0071] The relative molecular weight of the polymer was calculated to be 3446 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the iodine mass content was 22% by iodine titration method.

[0072] (2) PLLA embolic agent 2 (PLLA-2)

[0073] Add 40g of L-lactide (L-LA) and 29.8g of PEG (1500) to a 250mL jacketed three-necked flask, raise the temperature to 130℃, vacuum and remove water for 1h, then add 0.2g of stannous chloride and continue the reaction for 3h. After the reaction is completed, precipitate with n-hexane and vacuum dry to obtain a block copolymer (PLLA-PEG1500-PLLA). Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to dissolve it by stirring at room temperature, weigh 11.1g of triiodobenzoic acid and use 4mL of N, N-dimethylformamide, weigh 4.57g of DCC (dicyclohexylcarbodiimide) and 0.68g of DMAP (4-dimethylaminopyridine), dissolve them in 20mL of ultra-dry dichloromethane, and place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction is completed. The above-obtained product was further purified with n-hexane, and the precipitate was collected and then placed in a vacuum oven for drying for 24 to 72 hours to obtain the final product I-PLLA-PEG1500-PLLA-I (hereinafter referred to as PEG1500-PLLA-I).

[0074] The relative molecular weight of the polymer was calculated to be 3739 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the iodine mass content was 21% by iodine titration method.

[0075] According to the basic operation steps of Example 3, other block copolymers were obtained by using PEG with different molecular weights as initiators and polymerizing with different monomers. Different amounts of triiodobenzoic acid were further added to participate in the reaction to obtain iodine-containing block copolymers with different mass contents. The specific parameters are as shown in the following table:

[0076]

[0077] Take 0.40g of any of the above iodinated copolymers, add 0.60g of DMSO, and stir to dissolve at room temperature. The completely dissolved liquid embolic agent is encapsulated in a vial and sterilized to obtain an in-situ phase-change liquid embolic agent that can be self-developed for a long time. The average development gray value is the gray value of the embolic agent placed under DSA for development observation and preservation of the original photo, and the gray value of the development is detected by Image ProPlus image analysis software (the smaller the gray value, the better the development effect), and compared with iodized oil (the average gray value of iodized oil is 16).

[0078] The mechanical properties of the embolic agent and whether it has distal embolization ability were preliminarily determined through the rabbit ear embolization experiment; the mechanical property evaluation standard was whether the embolic material was lost from the rabbit ear; the distal embolization evaluation standard was whether it reached the distal end of the marginal auricular artery.

[0079] Rabbit ear embolization: Since the thickness of the rabbit ear central artery is suitable for puncture and can be clearly seen in vitro, New Zealand white rabbits are used to evaluate the embolic effect of the embolic agent. Before surgery, the animal was anesthetized by intramuscular injection of an appropriate amount of anesthetic, and the rabbit ear hair was shaved with an electric shaver, and then the animal was laid flat on the operating table. After disinfecting the proximal end of the blood vessel ear root with 75% ethanol, the embolic agent was slowly infused from the proximal end to the distal end through the rabbit ear central artery with a 1mL syringe (about 6s), with a dose of 0.1mL / ear. After the injection, the needle was pulled out and the puncture site was immediately pressed with a sterile cotton ball to prevent the drug solution from extravasating. After 1h, it was placed under the DSA imaging device to evaluate the embolic and imaging effects. The results of different formulations are shown in the following table: The results show that the iodinated PLLA liquid embolic agent has different embolic effects, and the mechanical properties of the embolic material can be further controlled by adjusting the hydrophilic and hydrophobic molecular weight of the block copolymer, so that the embolic material does not flow from the distal end.

[0080]

[0081] a The analysis of the grayscale values ​​of each sample was performed using the same range of intensity windows; b “+” represents greater than, and “-” represents less than.

[0082] From the above experimental cases, it can be seen that in the PLLA system, the iodine content and the segment ratio will comprehensively affect the performance of the embolic agent. The optimal iodine content is controlled between 21-26%, the molecular weight ratio of the hydrophilic segment PEG1000 and the hydrophobic segment PLLA is 0.8~1.2:1; the molecular weight ratio of the hydrophilic segment PEG1500 and the hydrophobic segment PLLA is 1.2~1.6:1.

[0083] Example 4: PCL embolic agent system

[0084] (1) PCL embolic agent 1 (PCL-1)

[0085] Add 60g of caprolactone and 51.6g of PEG (1000) to a 250mL jacketed three-necked flask, heat to 130℃, vacuum and remove water for 1h, then add 0.3g of stannous chloride and continue to react for 3h. After the reaction, precipitate with n-hexane and dry in vacuum to obtain a block copolymer (PCL-PEG1000-PCL). Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 12.0g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 5.0g of DCC (dicyclohexylcarbodiimide) and 0.74g of DMAP (4-dimethylaminopyridine) and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and dried in a vacuum oven for 24 to 72 hours to obtain the final product I-PCL-PEG1000-PCL-I (hereinafter referred to as PEG1000-PCL-I).

[0086] The relative molecular weight of the polymer was calculated to be 2997 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the iodine mass content was 19% by iodine titration method.

[0087] (2) PCL embolic agent 2 (PCL-2)

[0088] Add 60g of caprolactone and 25.8g of PEG (1000) to a 250mL jacketed three-necked flask, heat to 130℃, vacuum and remove water for 1h, then add 0.3g of stannous chloride and continue to react for 3h. After the reaction is completed, precipitate with n-hexane and vacuum dry to obtain a block copolymer (PCL-PEG1000-PCL). Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 7.7g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 3.18g of DCC (dicyclohexylcarbodiimide) and 0.47g of DMAP (4-dimethylaminopyridine) and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and dried in a vacuum oven for 24 to 72 hours to obtain the final product I-PCL-PEG1000-PCL-I (hereinafter referred to as PEG1000-PCL-I).

[0089] The relative molecular weight of the polymer was calculated to be 4438 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the iodine mass content was 18% by iodine titration method.

[0090] (3) PCL embolic agent 3 (PCL-3)

[0091] Add 60g of caprolactone and 103.2g of PEG (1500) to a 250mL jacketed three-necked flask, heat to 130℃, vacuum to remove water for 1h, then add 0.3g of stannous chloride and continue to react for 3h. After the reaction, precipitate with n-hexane and vacuum dry to obtain a block copolymer (PCL-PEG1500-PCL). Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 11.4g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 4.72g of DCC (dicyclohexylcarbodiimide) and 0.70g of DMAP (4-dimethylaminopyridine) and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and dried in a vacuum oven for 24 to 72 hours to obtain the final product I-PCL-PEG1500-PCL-I (hereinafter referred to as PEG1500-PCL-I).

[0092] The relative molecular weight of the polymer was calculated to be 3293 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the iodine mass content was 25% by iodine titration method.

[0093] (4) PCL embolic agent 4 (PCL-4)

[0094] Add 60g of caprolactone and 51.6g of PEG (1500) to a 250mL jacketed three-necked flask, heat to 130℃, vacuum and remove water for 1h, then add 0.3g of stannous chloride and continue to react for 3h. After the reaction is completed, precipitate with n-hexane and vacuum dry to obtain poly (ethylene glycol lactide) (PCL-PEG1500-PCL) polymer. Weigh 10.0g of the above polymer and add 80mL of ultra-dry dichloromethane to stir and dissolve at room temperature, weigh 8.0g of triiodobenzoic acid and dissolve it in 4mL of N, N-dimethylformamide, weigh 3.29g of DCC (dicyclohexylcarbodiimide) and 0.49g of DMAP (4-dimethylaminopyridine) and dissolve them in 20mL of ultra-dry dichloromethane. Place the above three solutions in a 250mL single-mouth bottle and mix and react for 24h. After the reaction, the product was further purified with n-hexane, and the precipitate was collected and dried in a vacuum oven for 24 to 72 hours to obtain the final product I-PCL-PEG1500-PCL-I (hereinafter referred to as PEG1500-PCL-I).

[0095] The relative molecular weight of the polymer was calculated to be 4400 by hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer, and the iodine mass content was 17% by iodine titration method.

[0096] According to the basic operation steps of Example 4, other block copolymers were obtained by using PEG with different molecular weights as initiators and polymerizing with different monomers. Different amounts of triiodobenzoic acid were further added to participate in the reaction to obtain iodine-containing block copolymers with different mass contents. The specific parameters are as shown in the following table:

[0097]

[0098] Take 0.40 g of any of the above iodinated copolymers, add 0.20 g of DMSO and 0.40 g of ethanol and stir to dissolve at room temperature. The completely dissolved liquid embolic agent is packaged in a vial and sterilized to obtain an in-situ phase-change liquid embolic agent capable of long-term self-development.

[0099] The mechanical properties of the embolic agent and whether it has distal embolic ability were initially determined through rabbit ear embolization experiments; the mechanical property evaluation criteria were: whether the embolic material was lost from the rabbit ear; the distal embolization evaluation criteria were: whether it reached the distal end of the auricular artery. The average gray value of the development degree was the gray value of the development of the embolic agent under DSA and the original photos were saved, and the gray value of the development was detected by Image Pro Plus image analysis software (the smaller the gray value, the better the development effect), and compared with iodized oil (the average gray value of iodized oil development was 16).

[0100] Rabbit ear embolization: Since the thickness of the rabbit ear central artery is suitable for puncture and can be clearly seen in vitro, New Zealand white rabbits were used to evaluate the embolic effect of the embolic agent. Before surgery, the animal was anesthetized by intramuscular injection of an appropriate amount of anesthetic, and the rabbit ear hair was shaved with an electric shaver, and then the animal was laid flat on the operating table. After disinfecting the proximal end of the ear root of the blood vessel with 75% ethanol, the embolic agent was slowly infused from the proximal end to the distal end through the rabbit ear central artery with a 1mL syringe (about 6s), with a dose of 0.1mL / ear. After the injection, the needle was pulled out and the puncture site was immediately pressed with a sterile cotton ball to prevent the drug solution from extravasating. After 1 hour, it was placed under the DSA imaging device to evaluate the embolic and imaging effects. The results of different formulations are shown in the following table: The results show that the iodinated PCL liquid embolic agent has different embolic effects, and the mechanical properties of the embolic material can be further controlled by adjusting the hydrophilic and hydrophobic molecular weight of the block copolymer, so that the embolic material does not flow from the distal end.

[0101]

[0102] a The analysis of the grayscale values ​​of each sample was performed using the same range of intensity windows; b “+” represents greater than, and “-” represents less than.

[0103] It can be seen from the above experimental cases that in the PCL system, the iodine content and the segment ratio will comprehensively affect the performance of the embolic agent. The iodine content is optimally controlled between 17-28%, and the molecular weight ratio of the hydrophilic segment PEG (1000) and the hydrophobic segment (PCL) is 0.4~0.7:1; the molecular weight ratio of the hydrophilic segment PEG (1500) and the hydrophobic segment (PCL) is 1.1~1.5:1.

[0104] Example 5

[0105] The rabbit renal artery embolization experiment was used to comprehensively judge the imaging properties of the embolic agents PDLLGA-5, PDLLA-3, PLLA-6 and PCL-12 and whether they have distal embolization ability.

[0106] At room temperature, take each of PDLLGA-5, PDLLA-3, PLLA-6, and PCL-12, add them to DMSO and ethanol, and stir to dissolve. The mass fraction of the embolic polymer is 40%. The completely dissolved liquid embolic agent is packaged in a vial and sterilized.

[0107] Rabbit renal artery embolization: The rabbit is fixed with a fixator, the hair on the ears, abdomen and groin is removed, the ear vein is sprayed with alcohol to dilate the ear vein, 10mL of the prepared urethane solution is injected, the rabbit leg skin is clamped with hemostatic forceps, and the rabbit anesthesia is fully confirmed. If there is still a reaction, continue to supplement the appropriate amount of urethane. After the rabbit is fully anesthetized, proceed to the next step; fix the rabbit in a supine position on the acrylic board. Wrap the limbs with masking tape and then fix them to the acrylic board. Touch the groin to find the arterial pulsation point. After confirming the pulsation point, a linear incision is made 2~3cm to the left along the groin direction. The femoral bundle including the femoral vein, femoral artery and nerve is separated by blunt separation, and the femoral artery is completely separated by surgical curved forceps. The femoral artery is threaded with a puncture needle, and the guide wire is inserted after the arterial blood flows out of the tube. After the introduction is successful, the catheter is inserted. After the catheter was observed to be inserted into the renal artery through the DSA operating table, contrast angiography was performed. After confirming that the catheter was successfully inserted, the catheter was flushed with normal saline. After flushing, 1 mL of embolic solution was injected. The material push rate was 1 mL / min. PEG300 was used to push the remaining embolic agent in the catheter into the blood vessel at 1 mL / min. After the injection was completed, wait for 30 minutes and inject contrast agent to observe the vascular embolism. The catheter was then removed, the blood vessels were ligated, and then layer-by-layer sutures were performed and disinfected with iodine. After the operation was completed, the rabbits were kept for 4 weeks and their health was closely observed.

[0108] The results showed that the liquid embolic agents PDLLGA-5, PDLLA-3, PLLA-6 and PCL-12 formed by compounding materials can achieve distal embolization, and the real-time imaging effect is good ( Figures 3 to 6 ); 4 weeks after PCL-12 embolic agent embolization, the renal blood vessels were not restored. The rabbits were immediately dissected and compared with the blank group (left kidney). After dissection, the right kidney was necrotic and atrophic ( Figure 7 ).

[0109] Although the embodiments of the present invention are disclosed for illustrative purposes, those skilled in the art will appreciate that various substitutions, changes and modifications are possible without departing from the spirit and scope of the present invention and the appended claims. Therefore, the scope of the present invention is not limited to the contents disclosed in the embodiments.

Claims

1. An embolic polymer, characterized in that: The copolymer is an iodinated copolymer, wherein the mass content of iodine is 17-28%; the copolymer comprises a PEG hydrophilic segment and a polyester hydrophobic segment; The polyester hydrophobic segment is PDLLGA, the molecular weight of the PEG hydrophilic segment is 1000, and the molecular weight ratio of the PEG hydrophilic segment to the polyester hydrophobic segment is 1.3-1.8:1; Or, the polyester hydrophobic segment is PDLLGA, the molecular weight of the PEG hydrophilic segment is 1500, and the molecular weight ratio of the PEG hydrophilic segment to the polyester hydrophobic segment is 1.9-3.9:1; Or, the polyester hydrophobic segment is PDLLA, the molecular weight of the PEG hydrophilic segment is 1000, and the molecular weight ratio of the PEG hydrophilic segment to the polyester hydrophobic segment is 1.0-1.7:1; Or, the polyester hydrophobic segment is PDLLA, the molecular weight of the PEG hydrophilic segment is 1500, and the molecular weight ratio of the PEG hydrophilic segment to the polyester hydrophobic segment is 1.1-2.8:1; Or, the polyester hydrophobic segment is PLLA, the molecular weight of the PEG hydrophilic segment is 1000, and the molecular weight ratio of the PEG hydrophilic segment to the polyester hydrophobic segment is 0.8-1.2:1; Or, the polyester hydrophobic segment is PLLA, the molecular weight of the PEG hydrophilic segment is 1500, and the molecular weight ratio of the PEG hydrophilic segment to the polyester hydrophobic segment is 1.2-1.6:1; Or, the polyester hydrophobic segment is PCL, the molecular weight of the PEG hydrophilic segment is 1000, and the molecular weight ratio of the PEG hydrophilic segment to the polyester hydrophobic segment is 0.45-0.7:1; Alternatively, the polyester hydrophobic segment is PCL, the molecular weight of the PEG hydrophilic segment is 1500, and the molecular weight ratio of the PEG hydrophilic segment to the polyester hydrophobic segment is 1.1~1.5:

1.

2. The method for preparing an embolic polymer according to claim 1, characterized in that: The hydrophobic monomers are copolymerized under the initiator PEG to obtain a block copolymer; the iodinated copolymer is obtained by bonding the iodine-containing small molecules to the block copolymer through covalent bonds.

3. The preparation method according to claim 2, characterized in that: The hydrophobic monomer is one or two of caprolactone, lactide, L-lactide or glycolide, and the copolymer segments formed therefrom are PDLLGA, PDLLA, PCL and PLLA segments.

4. A medical liquid embolic agent capable of long-term self-radiography, characterized in that: The method comprises dissolving the embolic polymer according to claim 1 in a non-protonic polar solvent, wherein the mass concentration of the embolic polymer is 30-50%.

5. The medical liquid embolic agent according to claim 4, characterized in that: The aprotic polar solvent is dimethyl sulfoxide, or a mixture of dimethyl sulfoxide and ethanol.

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