CN118755063B

CN118755063B - Embolic polymer, medical liquid embolic agent and application thereof

Info

Publication number: CN118755063B
Application number: CN202411244993.7A
Authority: CN
Inventors: 易立; 方超; 张静
Original assignee: Zhiyuan Baimai Hangzhou Technology Co ltd
Current assignee: Zhiyuan Baimai Hangzhou Technology Co ltd
Priority date: 2024-09-06
Filing date: 2024-09-06
Publication date: 2024-12-24
Anticipated expiration: 2044-09-06
Also published as: CN118755063A

Abstract

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 appliances. The embolic polymer is a hydrophobic and hydrophilic iodized block copolymer, and the phase change speed and strength of the embolic polymer are optimized through the regulation and control of the proportion of hydrophilic and hydrophobic chain segments and the iodine content. After the embolic polymer and the polar solvent are prepared into the embolic agent, the in-situ solid implant is spontaneously formed through the solvent exchange effect, so that not only can the effective embolism of the target vascular site be realized, but also the dual purposes of real-time development and long-term development can be achieved, the embolic agent is beneficial to postoperative review or further treatment, and has wide application prospect.

Description

Embolic polymer, medical liquid embolic agent and application thereof

Technical Field

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 appliances.

Background

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and intervention in various treatment methods of liver cancer is considered as the most common technique for liver cancer treatment, wherein TACE (chemoembolization via hepatic artery) accounts for more than 90%, and almost involves treatment of liver cancer in various stages. TACE is used to control bleeding, treat vascular diseases, treat tumor and eliminate lesion organs by injecting embolic material into lesion sites via artery or vein with the help of imaging equipment (such as X-ray) under the visual effect. Among these, embolic material is critical to the success of transcatheter embolization.

The conventional liver cancer vascular embolism materials comprise iodized oil, gelatin sponge, PVA particles, blank microspheres (c-TACE), drug-loaded microspheres (D-TACE) and the like. The embolic material has different properties and different applicable sites and conditions. The solid embolic agent is sized to limit the location of the embolic vessel. One of the unique properties of liquid embolic agents compared to solid embolic materials is that they are capable of filling a target vessel and inducing vascular occlusion by advancing with blood flow and going deep into the vascular bed to areas where solid embolic agents cannot reach, the degree of occlusion being higher than with solid embolic materials. The iodized oil is the most commonly used liquid embolic agent in the current liver cancer vascular embolism, can be developed under X rays, has good tissue compatibility, can reach end embolism, but is easy to be washed out by blood due to low viscosity in the use process, has weak embolic effect, and is easy to cause vascular recanalization.

In addition, other liquid embolic agents such as Onyx, n-butyl alpha-cyanoacrylate (NBCA glue) are commonly injected into the targeted site to immediately solidify, and are mainly used in the field of local embolic applications. Therefore, the development of the phase-change liquid embolic agent which not only can achieve distal embolism, but also has certain mechanical property and is not flushed away has good market application prospect. At present, temporary developing agents are mostly adopted for embolic materials used clinically, so that the problems that, for example, metal developing agents such as tantalum powder are incompletely embedded and the like, artifacts can be caused to influence the developing effect, iodine-containing nonionic developing agents such as iohexol are easy to metabolize in a short time after operation, and the embolic site needs to be subjected to angiographic diagnosis again during postoperative review exist.

Disclosure of Invention

The invention aims to provide a medical liquid embolic agent which can realize long-term self-development and distal embolism at the same time, and can be used for treating vascular diseases. The medical liquid embolic agent is prepared by dissolving embolic polymer in aprotic polar solvent. The embolic polymer combines an iodine-containing compound and a segmented copolymer in a covalent bond mode, and by regulating and controlling the proportion of the block and the mass content of iodine, the embolic agent can be developed, and simultaneously, by optimizing the phase change speed and strength, the embolic polymer spontaneously forms an in-situ solid implant through the solvent exchange effect after entering blood, so that the effective embolism of a target vascular site can be realized, and the dual purposes of real-time development and long-term development can be achieved.

According to the first aspect of the embodiment of the application, the embolic polymer body is a segmented copolymer obtained by copolymerizing hydrophobic monomers under the initiation of an initiator PEG, wherein the hydrophobic monomers form a hydrophobic segment, the PEG forms a hydrophilic segment, and the hydrophilic and hydrophobic properties of the copolymer are regulated by regulating and controlling the molecular weight of the initiator and the proportion of the segmented monomers, so that the phase change speed and strength of the copolymer in blood are changed. In the application, the hydrophobic monomer can be one or two of caprolactone, lactide, levorotatory lactide or glycolide, and the formed copolymer chain segment can be PDLLGA, PDLLA, PCL or PLLA segments. Further, the block copolymer is bonded by covalent bond and triiodobenzoic acid to obtain an iodinated copolymer, i.e., an embolic polymer. The strength and the phase change speed of the embolic agent are further optimized through the range regulation and control of the iodine content.

Wherein the iodine content is 17% -28%.

The preparation method comprises the steps of adding an initiator and a monomer into a 250mL jacketed three-necked flask, heating, vacuumizing and removing water for 1h, and then adding a catalyst for reaction. After the reaction, the mixture was precipitated with n-hexane and dried in vacuo to obtain a block copolymer. Weighing the block copolymer, adding ultra-dry dichloromethane, stirring at room temperature for dissolution, weighing tri-iodo benzoic acid, dissolving with N, N-dimethylformamide, weighing DCC (dicyclohexylcarbodiimide) and DMAP (4-dimethylaminopyridine), and dissolving with ultra-dry dichloromethane. The three solutions were mixed in a single-necked flask of 250mL to perform a reaction. After the reaction is finished, the obtained product is further purified by n-hexane, the precipitate is collected and then put into a vacuum oven for drying for 24-72 h, and the final product iodized copolymer (embolic polymer) is obtained.

Preferably, the comonomer is one or two of caprolactone, lactide, levorotatory lactide or glycolide, more preferably, the comonomer is caprolactone or levorotatory lactide.

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

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

Preferably, the molecular weight ratio of the hydrophilic chain segment PEG1000 to the hydrophobic chain segment PDLLA is 1.0-1.7:1, and the molecular weight ratio of the hydrophilic chain segment PEG1500 to the hydrophobic chain segment PDLLA is 1.1-2.8:1.

Preferably, the molecular weight ratio of the hydrophilic chain segment PEG1000 to the hydrophobic chain segment PLLA is 0.8-1.2:1, and the molecular weight ratio of the hydrophilic chain segment PEG1500 to the hydrophobic chain segment PLLA is 1.2-1.6:1.

Preferably, the molecular weight ratio of the hydrophilic chain segment PEG1000 to the hydrophobic chain segment PCL is 0.45-0.7:1, and the molecular weight ratio of the hydrophilic chain segment PEG1500 to the hydrophobic chain segment PCL is 1.1-1.5:1.

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

According to a second aspect of embodiments of the present application, there is provided a long term self-developed medical fluid embolic agent. The embolic polymer prepared by the method is solid and is dissolved in an aprotic polar solvent at room temperature, wherein the mass concentration of the embolic polymer is 30-50%, and the aprotic polar solvent is dimethyl sulfoxide or/and dimethyl sulfoxide and ethanol.

The invention relates to a preparation method of a phase-change controllable embolic agent, which comprises the following steps:

Under the room temperature environment, taking single iodized copolymer, adding aprotic polar solvent, stirring and dissolving, packaging the completely dissolved liquid embolic agent in a penicillin bottle, and sterilizing to obtain the in-situ phase change liquid embolic agent capable of long-term self-development.

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

The technical scheme provided by the embodiment of the application can have the following beneficial effects that the embolic polymer is an in-situ phase-change liquid embolic material, and after entering a human body, the embolic polymer spontaneously forms an in-situ solid implant with excellent mechanical property through the solvent exchange effect, so that long-term embolism of the vascular tip is realized, the dual effects of real-time imaging and embolic imaging can be achieved, and the embolic polymer is beneficial to postoperative review or further treatment.

Drawings

FIG. 1 (a) shows the effect of the embolic agent rabbit ear on PDLLGA-1 in the example of the present invention, and FIG. 1 (b) shows the effect of the embolic agent rabbit ear on PDLLA-1 in the example of the present invention;

FIG. 2 (a) shows an embolic agent rabbit ear embolic effect of PDLLGA-5 in an embodiment of the present invention, (b) in FIG. 2 shows an embolic agent rabbit ear embolic effect of PDLLA-3 in an embodiment of the present invention, (c) in FIG. 2 shows an embolic agent rabbit ear embolic effect of PLLA-6 in an embodiment of the present invention, and (d) in FIG. 2 shows an embolic agent rabbit ear embolic effect of PCL-12 in an embodiment of the present invention;

FIG. 3 (a) is a graph showing the effect of PDLLGA-5 embolic agent on rabbit kidney embolism in an embodiment of the present invention, and FIG. 3 (b) is a graph showing the effect of PDLLGA-5 embolic agent 30min later in an embodiment of the present invention;

FIG. 4 (a) is a graph showing the effect of PDLLA-3 embolic agent on rabbit kidney embolism in an embodiment of the present invention, and FIG. 4 (b) is a graph showing the effect of PDLLA-3 embolic agent after 30min in an embodiment of the present invention;

FIG. 5 (a) is a graph showing the effect of PDLLA-3 embolic agent on rabbit kidney embolism in an embodiment of the present invention, and FIG. 5 (b) is a graph showing the effect of PLLA-6 embolic agent in an embodiment of the present invention after 30 min;

FIG. 6 (a) is a graph showing the effect of PDLLA-3 embolic agent on rabbit kidney embolism in an embodiment of the present invention, and FIG. 6 (b) is a graph showing the effect of PCL-12 embolic agent in an embodiment of the present invention after 30 min;

FIG. 7 (a) is a review of the map after 4 weeks of renal embolism of PCL-12 embolic agent in the present example, and FIG. 7 (b) is a view of renal anatomy after 4 weeks of renal embolism of PCL-12 embolic agent in the present example.

Detailed Description

The following examples serve to further illustrate the invention and are intended to illustrate it and should not be construed as limiting its scope. Weight parts and weight percentages are used hereinafter unless otherwise indicated.

The raw materials used in the invention are conventional commercial products unless otherwise specified, and the methods used in the invention are conventional methods in the art unless otherwise specified.

PEG600, PEG1000, PEG1500, these being different molecular weight grades of polyethylene glycol (Polyethylene Glycol, PEG). PEG is a linear polymer consisting of repeating oxyethylene units. The numbers indicate molecular weights, e.g., PEG600, meaning that the average molecular weight of the PEG is about 600 daltons.

PDLLGA is a random copolymer obtained by ring-opening polymerization of two monomers, namely, racemic lactide (DL-LA) and Glycolide (GA), and is also called a poly-racemic lactide-glycolide copolymer. PCL refers to polycaprolactone. PDLLA refers to racemized polylactic acid, belongs to amorphous polymer, PLLA refers to levorotatory polylactic acid, and has certain crystallinity, wherein PLLA is obtained by ring-opening polymerization of levorotatory lactide, and PDLLA is obtained by ring-opening polymerization of racemized lactide.

EXAMPLE 1 PDLLGA embolic System

(1) PDLLGA embolic agent 1 (PDLLGA-1)

31.6G of DL-lactide (DL-LA), 8.4g of Glycolide (GA) and 0.05g of 1, 4-butanediol are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, vacuum is pumped to remove water for 1h, and then 0.2g of stannous chloride is added for continuous reaction for 3h. After the reaction, the polymer is precipitated with n-hexane and dried in vacuum to obtain the poly (glycolide) (PDLLGA) polymer. 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride under stirring at room temperature, 10.0g of triiodobenzoic acid was weighed and dissolved in 4mLN, N-dimethylformamide, 4.1g of DCC (dicyclohexylcarbodiimide) and 0.61g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, the obtained product is further purified by n-hexane, the precipitate is collected and then put into a vacuum oven for drying for 24-72 h, and the final product is poly (glycolide-lactide-iodine) (I-PDLLGA-I, which is abbreviated as PDLLGA-I hereinafter).

The mass content of iodine is 21% by iodine titration method, and the ratio of glycolide and lactide of the polymer is 76/24 and the relative molecular weight is 2545.

(2) PDLLGA embolic agent 2 (PDLLGA-2)

31.6G of DL-lactide (DL-LA), 8.4g of Glycolide (GA) and 30.0g of PEG (1500) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, vacuum is pumped to remove water for 1h, and then 0.2g of stannous chloride is added for continuous reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried in vacuo to give a block copolymer (PDLLGA-PEG 1500-PDLLGA). 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride under stirring at room temperature, 7.0g of triiodobenzoic acid was weighed and dissolved in 4mLN, N-dimethylformamide, 2.89g of DCC (dicyclohexylcarbodiimide) and 0.43g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, the obtained product is further purified by n-hexane, the precipitate is collected and then put into a vacuum oven for drying for 24-72 h, and the final product is I-PDLLGA-PEG1500-PDLLGA-I (hereinafter referred to as PEG 1500-PDLLGA-I).

The mass content of iodine is 17% by iodine titration method, and the hydrogen spectrum measured by nuclear magnetic resonance hydrogen spectrometer is used for calculating the glycolide-lactide ratio of the polymer to be 72/28 and the relative molecular weight to be 3348.

(3) PDLLGA embolic agent 3 (PDLLGA-3)

31.6G of DL-lactide (DL-LA), 8.4g of Glycolide (GA) and 54.4g of PEG (1500) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, vacuum is pumped to remove water for 1h, and then 0.2g of stannous chloride is added for continuous reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried in vacuo to give a block copolymer (PDLLGA-PEG 1500-PDLLGA). 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride at room temperature with stirring, 9.4g of triiodobenzoic acid was weighed and dissolved in 4mLN, N-dimethylformamide, 3.86g of DCC (dicyclohexylcarbodiimide) and 0.57g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, the obtained product is further purified by n-hexane, the precipitate is collected and then put into a vacuum oven for drying for 24-72 h, and the final product is I-PDLLGA-PEG1500-PDLLGA-I (hereinafter referred to as PEG 1500-PDLLGA-I).

The mass content of iodine is 21% by iodine titration method, and the ratio of glycolide and lactide of the polymer is 70/30 and the relative molecular weight is 2625.

According to the basic operation procedure of example 1, other block copolymers are obtained by polymerizing other PEG with different molecular weights as initiator and different monomers, and further adding tri-iodo benzoic acid with different contents to participate in the reaction, so as to obtain iodine-containing block copolymers with different mass contents, and specific parameters and the following table are shown in the specification:

taking 0.30g of any one of the iodized copolymers, adding 0.70g of DMSO, stirring and dissolving in a room temperature environment, packaging the completely dissolved liquid embolic agent in a penicillin bottle, and sterilizing to obtain the in-situ phase change liquid embolic agent capable of long-term self-development.

The mechanical property of the embolic agent and whether the embolic agent has distal embolic capability are preliminarily judged through a rabbit ear embolic experiment, the mechanical property evaluation standard is whether the embolic agent runs off from rabbit ears, and the distal embolic evaluation standard is whether the distal end of the auricular artery is reached. The average development gray value is obtained by observing and developing the embolic agent under DSA and storing the original photo, and the development gray value (the smaller the gray value, the better the development effect) is detected by using Image Pro Plus Image analysis software, and the contrast is carried out with the iodized oil (the average development gray value of the iodized oil is 16).

Rabbit ear embolism, since the thickness of central artery blood vessel of rabbit ear is suitable for puncture and is clearly visible in vitro, new Zealand white rabbits are used for evaluating the embolic effect of embolic agent. The animals were anesthetized by intramuscular injection of an appropriate amount of the anesthetic before surgery, the rabbit ear hair was shaved with an electric razor, and the animals were then placed flat on an operating table. After the proximal end of the vascular auricle is sterilized by 75% ethanol, the embolic agent is slowly infused (about 6 s) from the proximal end to the distal end by a 1mL syringe through the central artery of the rabbit ear, the dosage is 0.1 mL/ear, after the injection is finished, the needle head is pulled out, the puncture site is immediately pressed by a sterilized cotton ball to prevent the liquid medicine from extravasating, and after 1h, the embolic agent is placed under DSA imaging equipment to evaluate the embolic and developing effects. The results of different formulas are shown in the following table, and the result shows that the PDLLGA liquid embolic agent after iodination has different embolic effects, and the mechanical properties of the embolic agent can be further controlled by adjusting the hydrophilic and hydrophobic molecular weight of the block copolymer, so that the embolic agent does not run off from the distal end.

^a The developed gray value analysis of each sample takes the intensity window of the same range, ^b "+" represents greater than, "-" represents less than.

From the above experimental cases, it can be seen that the iodine content and the segment ratio will affect the properties of the embolic agent in a combined way, the addition of iodine may involve a change in the molecular structure of the polymer, a change in the phase change behavior, or affect the mechanical properties of the polymer molecule, for example, the iodination process may result in a change in the molecular structure of the PEG/polyester, and in particular the introduction of iodine atoms may increase intermolecular interactions such as hydrogen bonding or van der waals forces. The introduction of iodine may increase the intermolecular distance, thereby affecting the physical properties of the polymer, such as melting point and glass transition temperature (Tg), and as the iodine content increases, the material may become more rigid, reducing its flexibility. However, within a certain range, proper amounts of iodination may not significantly affect flexibility, but rather help maintain good mechanical properties. In a word, in PDLLGA system, iodine content is optimally controlled between 21-22%, the molecular weight ratio of the hydrophilic chain segment PEG1000 to the hydrophobic chain segment PDLLGA is 1.3-1.8:1, and the molecular weight ratio of the hydrophilic chain segment PEG1500 to the hydrophobic chain segment PDLLGA is 1.9-3.9:1.

EXAMPLE 2 PDLLA embolic agent System

(1) PDLLA embolic agent 1 (PDLLA-1)

60G of DL-lactide (DL-LA) and 21.8g of PEG (1500) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, the vacuum is pumped to remove water for 1h, and then 0.3g of stannous chloride is added for continuous reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried under vacuum to obtain a block copolymer (PDLLA-PEG 1500-PDLLA). 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride at room temperature with stirring, 9.85g of triiodobenzoic acid was weighed and dissolved in 4mLN g of N-dimethylformamide, 4.07g of DCC (dicyclohexylcarbodiimide) and 0.60g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, further purifying the obtained product by using normal hexane, collecting precipitate, and then placing the precipitate into a vacuum oven for drying for 24-72 h to obtain the final product which is I-PDLLA-PEG1500-PDLLA-I (hereinafter referred to as PEG 1500-PDLLA-I).

The relative molecular weight of the polymer is calculated to be 4005 by a hydrogen spectrum measured by a nuclear magnetic resonance hydrogen spectrometer, and the iodine content is 20% by mass through an iodine titration method.

(2) PDLLA embolic agent 2 (PDLLA-2)

60G of DL-lactide (DL-LA) and 32.7g of PEG (1500) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, the vacuum is pumped to remove water for 1h, and then 0.3g of stannous chloride is added for continuous reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried under vacuum to obtain a block copolymer (PDLLA-PEG 1500-PDLLA). 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride at room temperature with stirring, 13.71g of triiodobenzoic acid was weighed and dissolved in 4mLN g of N-dimethylformamide, 5.66g of DCC (dicyclohexylcarbodiimide) and 0.84g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, further purifying the obtained product by using normal hexane, collecting precipitate, and then placing the precipitate into a vacuum oven for drying for 24-72 h to obtain the final product which is I-PDLLA-PEG1500-PDLLA-I (hereinafter referred to as PEG 1500-PDLLA-I).

The relative molecular weight of the polymer is calculated to be 3451 by hydrogen spectrum measured by a nuclear magnetic resonance hydrogen spectrometer, and the iodine content is 22% by mass through an iodine titration method.

(3) PDLLA embolic agent 3 (PDLLA-3)

40G of DL-lactide (DL-LA) and 43.6g of PEG (1500) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, the vacuum is pumped to remove water for 1h, and then 0.2g of stannous chloride is added for continuous reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried under vacuum to obtain a block copolymer (PDLLA-PEG 1500-PDLLA). 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride at room temperature with stirring, 18.0g of triiodobenzoic acid was weighed and dissolved in 4mLN, N-dimethylformamide, 7.54g of DCC (dicyclohexylcarbodiimide) and 1.1g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, further purifying the obtained product by using normal hexane, collecting precipitate, and then placing the precipitate into a vacuum oven for drying for 24-72 h to obtain the final product which is I-PDLLA-PEG1500-PDLLA-I (hereinafter referred to as PEG 1500-PDLLA-I).

The relative molecular weight of the polymer is calculated to be 2818 by a hydrogen spectrum measured by a nuclear magnetic resonance hydrogen spectrometer, and the iodine content is 25% by an iodine titration method.

According to the basic operation procedure of example 2, other block copolymers are obtained by polymerizing other PEG with different molecular weights as initiator and different monomers, and further adding tri-iodo benzoic acid with different contents to participate in the reaction, so as to obtain iodine-containing block copolymers with different mass contents, and specific parameters and the following table are shown in the specification:

taking 0.50g of any one of the iodized copolymers, adding 0.50g of DMSO, stirring and dissolving in a room temperature environment, packaging the completely dissolved liquid embolic agent in a penicillin bottle, and sterilizing to obtain the in-situ phase change liquid embolic agent capable of long-term self-development.

Rabbit ear embolism, since the thickness of central artery blood vessel of rabbit ear is suitable for puncture and is clearly visible in vitro, new Zealand white rabbits are used for evaluating the embolic effect of embolic agent. The animals were anesthetized by intramuscular injection of an appropriate amount of the anesthetic before surgery, the rabbit ear hair was shaved with an electric razor, and the animals were then placed flat on an operating table. After the proximal end of the vascular auricle is sterilized by 75% ethanol, the embolic agent is slowly infused (about 6 s) from the proximal end to the distal end by a 1mL syringe through the central artery of the rabbit ear, the dosage is 0.1 mL/ear, after the injection is finished, the needle head is pulled out, the puncture site is immediately pressed by a sterilized cotton ball to prevent the liquid medicine from extravasating, and after 1h, the embolic agent is placed under DSA imaging equipment to evaluate the embolic and developing effects. The results of different formulas are shown in the following table, and the result shows that the iodinated PDLLA liquid embolic agent has different embolic effects, and the mechanical properties of the embolic agent can be further controlled by adjusting the hydrophilic and hydrophobic molecular weight of the block copolymer, so that the embolic agent does not run off from the far end.

From the experimental cases, the iodine content and the chain segment proportion in the PDLLA system comprehensively influence the performance of the embolic agent, the iodine content is optimally controlled to be 21-26%, the molecular weight proportion of the hydrophilic chain segment PEG1000 and the hydrophobic chain segment PDLLA is 1.0-1.7:1, and the molecular weight proportion of the hydrophilic chain segment PEG1500 and the hydrophobic chain segment PDLLA is 1.1-2.8:1.

EXAMPLE 3 PLLA embolic System

(1) PLLA embolic agent 1 (PLLA-1)

40G of L-lactide (L-LA) and 43.8g of PEG (1500) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, vacuum is pumped to remove water for 1h, and then 0.2g of stannous chloride is added for continuous reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried under vacuum to obtain a block copolymer (PLLA-PEG 1500-PLLA). 10g of the above polymer was weighed, 80mL of ultra-dry methylene chloride was added thereto, and the mixture was stirred at room temperature to dissolve, 8.5g of triiodobenzoic acid was weighed with 4mLN, N dimethylformamide, 3.5g of DCC (dicyclohexylcarbodiimide) and 0.52g of DMAP (4-dimethylaminopyridine) were weighed, and the mixture was dissolved with 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, further purifying the obtained product by using n-hexane, collecting precipitate, and then placing the precipitate into a vacuum oven for drying for 24-72 h to obtain the final product which is I-PLLA-PEG1500-PLLA-I (hereinafter referred to as PEG 1500-PLLA-I).

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

(2) PLLA embolic agent 2 (PLLA-2)

40G of L-lactide (L-LA) and 29.8g of PEG (1500) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, vacuum is pumped to remove water for 1h, and then 0.2g of stannous chloride is added for continuous reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried under vacuum to obtain a block copolymer (PLLA-PEG 1500-PLLA). 10.0g of the polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride under stirring at room temperature, 11.1g of triiodobenzoic acid was weighed and dissolved in 4. mLN mL of N-dimethylformamide, 4.57g of DCC (dicyclohexylcarbodiimide) and 0.68g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride, and the three solutions were placed in a single-necked flask and mixed and reacted for 24 hours in 250mL of water. After the reaction was completed. And further purifying the obtained product by using n-hexane, collecting precipitate, and then placing the precipitate into a vacuum oven for drying for 24-72 h to obtain the final product which is I-PLLA-PEG1500-PLLA-I (hereinafter referred to as PEG 1500-PLLA-I).

The relative molecular weight of the polymer is calculated to be 3739 by hydrogen spectrum measured by a nuclear magnetic resonance hydrogen spectrometer, and the iodine content is 21% by mass through an iodine titration method.

According to the basic operation procedure of example 3, other block copolymers are obtained by polymerizing other PEG with different molecular weights as initiator and different monomers, and further adding tri-iodo benzoic acid with different contents to participate in the reaction, to obtain iodine-containing block copolymers with different mass contents, the specific parameters and the following table are:

Taking 0.40g of any one of the iodized copolymers, adding 0.60g of DMSO, stirring and dissolving in a room temperature environment, packaging the completely dissolved liquid embolic agent in a penicillin bottle, and sterilizing to obtain the in-situ phase change liquid embolic agent capable of long-term self-development. The average development gray value is obtained by observing and developing the embolic agent under DSA and storing the original photo, and the development gray value (the smaller the gray value, the better the development effect) is detected by using Image Pro Plus Image analysis software, and the contrast is carried out with the iodized oil (the average development gray value of the iodized oil is 16).

The mechanical property of the embolic agent and whether the embolic agent has distal embolic capability are preliminarily judged through a rabbit ear embolic experiment, the mechanical property evaluation standard is whether the embolic agent runs off from rabbit ears, and the distal embolic evaluation standard is whether the distal end of the auricular artery is reached.

Rabbit ear embolism, since the thickness of central artery blood vessel of rabbit ear is suitable for puncture and is clearly visible in vitro, new Zealand white rabbits are used for evaluating the embolic effect of embolic agent. The animals were anesthetized by intramuscular injection of an appropriate amount of the anesthetic before surgery, the rabbit ear hair was shaved with an electric razor, and the animals were then placed flat on an operating table. After the proximal end of the vascular auricle is sterilized by 75% ethanol, the embolic agent is slowly infused (about 6 s) from the proximal end to the distal end by a 1mL syringe through the central artery of the rabbit ear, the dosage is 0.1 mL/ear, after the injection is finished, the needle head is pulled out, the puncture site is immediately pressed by a sterilized cotton ball to prevent the liquid medicine from extravasating, and after 1h, the embolic agent is placed under DSA imaging equipment to evaluate the embolic and developing effects. The results of different formulas are shown in the following table, and the results show that the PLLA liquid embolic agent after iodination has different embolic effects, and the mechanical properties of the embolic agent can be further controlled by adjusting the hydrophilic and hydrophobic molecular weight of the block copolymer, so that the embolic agent does not run off from the distal end.

From the experimental cases, the iodine content and the chain segment proportion in the PLLA system affect the performance of the embolic agent comprehensively, the iodine content is optimally controlled to be 21-26%, the molecular weight proportion of the hydrophilic chain segment PEG1000 and the hydrophobic chain segment PLLA is 0.8-1.2:1, and the molecular weight proportion of the hydrophilic chain segment PEG1500 and the hydrophobic chain segment PLLA is 1.2-1.6:1.

EXAMPLE 4 PCL embolic System

(1) PCL embolic agent 1 (PCL-1)

60G of caprolactone and 51.6g of PEG (1000) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, the vacuum is pumped out to remove water for 1h, and then 0.3g of stannous chloride is added to continue the reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried in vacuo to give a block copolymer (PCL-PEG 1000-PCL). 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride at room temperature with stirring, 12.0g of triiodobenzoic acid was weighed and dissolved in 4mLN g of N-dimethylformamide, 5.0g of DCC (dicyclohexylcarbodiimide) and 0.74g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, further purifying the obtained product by using n-hexane, collecting precipitate, and then placing the precipitate into a vacuum oven for drying for 24-72 h to obtain the final product which is I-PCL-PEG1000-PCL-I (hereinafter referred to as PEG 1000-PCL-I).

The relative molecular weight of the polymer is 2997 by calculating the hydrogen spectrum measured by a nuclear magnetic resonance hydrogen spectrometer, and the iodine content is 19% by iodine titration.

(2) PCL embolic agent 2 (PCL-2)

60G of caprolactone and 25.8g of PEG (1000) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, the vacuum is pumped out to remove water for 1h, and then 0.3g of stannous chloride is added to continue the reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried in vacuo to give a block copolymer (PCL-PEG 1000-PCL). 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride under stirring at room temperature, 7.7g of triiodobenzoic acid was weighed and dissolved in 4mLN, N-dimethylformamide, 3.18g of DCC (dicyclohexylcarbodiimide) and 0.47g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, further purifying the obtained product by using n-hexane, collecting precipitate, and then placing the precipitate into a vacuum oven for drying for 24-72 h to obtain the final product which is I-PCL-PEG1000-PCL-I (hereinafter referred to as PEG 1000-PCL-I).

The relative molecular weight of the polymer is calculated to be 4438 by a hydrogen spectrum measured by a nuclear magnetic resonance hydrogen spectrometer, and the iodine content is 18% by an iodine titration method.

(3) PCL embolic agent 3 (PCL-3)

60G of caprolactone and 103.2g of PEG (1500) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, the vacuum is pumped out to remove water for 1h, and then 0.3g of stannous chloride is added for continuous reaction for 3h. After the reaction, the mixture was precipitated with n-hexane and dried in vacuo to give a block copolymer (PCL-PEG 1500-PCL). 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride at room temperature with stirring, 11.4g of triiodobenzoic acid was weighed and dissolved in 4mLN, N-dimethylformamide, 4.72g of DCC (dicyclohexylcarbodiimide) and 0.70g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, further purifying the obtained product by using n-hexane, collecting precipitate, and then placing the precipitate into a vacuum oven for drying for 24-72 h to obtain the final product which is I-PCL-PEG1500-PCL-I (hereinafter referred to as PEG 1500-PCL-I).

The relative molecular weight of the polymer is calculated to be 3293 by a hydrogen spectrum measured by a nuclear magnetic resonance hydrogen spectrometer, and the iodine content is 25% by an iodine titration method.

(4) PCL embolic agent 4 (PCL-4)

60G of caprolactone and 51.6g of PEG (1500) are added into a 250mL jacketed three-necked flask, the temperature is raised to 130 ℃, the vacuum is pumped out to remove water for 1h, and then 0.3g of stannous chloride is added to continue the reaction for 3h. After the reaction, precipitating with n-hexane, and vacuum drying to obtain the poly (glycolide-lactide) (PCL-PEG 1500-PCL) polymer. 10.0g of the above polymer was weighed and dissolved in 80mL of ultra-dry methylene chloride at room temperature with stirring, 8.0g of triiodobenzoic acid was weighed and dissolved in 4mLN, N-dimethylformamide, 3.29g of DCC (dicyclohexylcarbodiimide) and 0.49g of DMAP (4-dimethylaminopyridine) were weighed and dissolved in 20mL of ultra-dry methylene chloride. The three solutions were placed in a single-necked flask of 250mL and reacted for 24h. After the reaction is finished, further purifying the obtained product by using n-hexane, collecting precipitate, and then placing the precipitate into a vacuum oven for drying for 24-72 h to obtain the final product which is I-PCL-PEG1500-PCL-I (hereinafter referred to as PEG 1500-PCL-I).

And calculating the relative molecular weight of the polymer to be 4400 according to a hydrogen spectrum measured by a nuclear magnetic resonance hydrogen spectrometer, and obtaining the iodine content of 17% by an iodine titration method.

According to the basic operation procedure of example 4, other block copolymers are obtained by polymerizing other PEG with different molecular weights as initiator with different monomers, and further adding tri-iodo benzoic acid with different contents to participate in the reaction, to obtain iodine-containing block copolymers with different mass contents, the specific parameters and the following table are:

Taking 0.40g of any one of the iodized copolymers, adding 0.20g of DMSO and 0.40g of ethanol, stirring and dissolving in room temperature environment, packaging the completely dissolved liquid embolic agent in a penicillin bottle, and sterilizing to obtain the in-situ phase change liquid embolic agent capable of long-term self-development.

Rabbit ear embolism, since the thickness of central artery blood vessel of rabbit ear is suitable for puncture and is clearly visible in vitro, new Zealand white rabbits are used for evaluating the embolic effect of embolic agent. The animals were anesthetized by intramuscular injection of an appropriate amount of the anesthetic before surgery, the rabbit ear hair was shaved with an electric razor, and the animals were then placed flat on an operating table. After the proximal end of the vascular auricle is sterilized by 75% ethanol, the embolic agent is slowly infused (about 6 s) from the proximal end to the distal end by a 1mL syringe through the central artery of the rabbit ear, the dosage is 0.1 mL/ear, after the injection is finished, the needle head is pulled out, the puncture site is immediately pressed by a sterilized cotton ball to prevent the liquid medicine from extravasating, and after 1h, the embolic agent is placed under DSA imaging equipment to evaluate the embolic and developing effects. The results of different formulas are shown in the following table, and the results show that the iodinated PCL liquid embolic agent has different embolic effects, and the mechanical properties of the embolic agent can be further controlled by adjusting the hydrophilic and hydrophobic molecular weight of the block copolymer, so that the embolic agent does not run off from the distal end.

From the experimental cases, the iodine content and the chain segment proportion in the PCL system affect the performance of the embolic agent comprehensively, the iodine content is optimally controlled to be 17-28%, the molecular weight proportion of the hydrophilic chain segment PEG (1000) and the hydrophobic chain segment (PCL) is 0.4-0.7:1, and the molecular weight proportion of the hydrophilic chain segment PEG (1500) and the hydrophobic chain segment (PCL) is 1.1-1.5:1.

Example 5

The imaging performance of the embolic agents PDLLGA, PDLLA-3, PLLA-6 and PCL-12 and whether the embolic agents have distal embolic capability are comprehensively judged through rabbit renal artery embolic experiments.

Under the room temperature environment, the preparation PDLLGA, PDLLA-3, PLLA-6 and PCL-12 are added into DMSO and ethanol, stirred and dissolved, the mass fraction of embolic polymer is 40%, and the completely dissolved liquid embolic agent is packaged in a penicillin bottle and sterilized.

And (3) rabbit renal artery embolism, namely fixing rabbits by a fixer, removing hairs at the ears, the abdomen and the groin, spraying alcohol at the veins at the edges of the ears, expanding the veins at the edges of the ears, injecting 10mL of prepared uratam solution, clamping the skin of the legs of the rabbits by using hemostats, and fully confirming the anesthesia of the rabbits, and if the reaction still exists, continuously supplementing a proper amount of uratam. After the rabbits are completely anesthetized, the next step is carried out, and the rabbits are fixed on an acrylic plate in a supine position. The limbs are wound by the masking tape and then fixed on the acrylic plate. Touching groin to find the arterial pulse moving point. After the pulsation point is confirmed, a linear incision is cut along the groin direction by 2-3 cm left. The femoral bundles including the femoral vein, femoral artery and nerve were separated by passive separation and the femoral artery was completely separated by surgical forceps. Femoral artery threading is carried out by using a puncture needle, the intervention of a guide wire is carried out after the arterial blood flows out of a tube orifice, and a catheter is inserted after the successful introduction. After the catheter is observed to be inserted into the renal artery through the DSA operation table, contrast agent radiography is carried out, after the success of the catheter insertion is confirmed, a flushing pipe is carried out by using physiological saline, 1mL of embolic solution is injected after the flushing pipe, the material injection speed is 1mL/min, the remaining embolic agent in the catheter is continuously pushed into a blood vessel at 1mL/min by using PEG300, after the injection is finished, the patient waits for 30min, and the vascular embolism condition is observed by injecting the contrast agent. The catheter is pulled out, the blood vessel ligation is carried out, and then the suture layer by layer is carried out, and the iodophor is sterilized. After the operation is finished, the rabbits are continuously kept for 4 weeks, and the health condition of the rabbits is closely observed.

The results show that the liquid embolic agents PDLLGA, PDLLA-3, PLLA-6 and PCL-12 formed by material compounding can realize distal embolism and have good real-time development effect (figures 3 to 6), and the PCL-12 embolic agent is rechecked after 4 weeks after embolism, the renal blood vessels are not recaptured, the rabbits are immediately dissected, and compared with a blank group (left kidney), and the right kidney is necrotized and atrophic after dissection (figure 7).

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

Claims

1. An embolic polymer is characterized by being an iodinated copolymer, wherein the mass content of iodine is 17-28%, and the copolymer comprises a PEG hydrophilic chain segment and a polyester hydrophobic chain segment;

The polyester hydrophobic chain segment is PDLLGA, the molecular weight of the PEG hydrophilic chain segment is 1000, and the molecular weight ratio of the PEG hydrophilic chain segment to the polyester hydrophobic chain segment is 1.3-1.8:1;

Or the polyester hydrophobic chain segment is PDLLGA, the molecular weight of the PEG hydrophilic chain segment is 1500, and the molecular weight ratio of the PEG hydrophilic chain segment to the polyester hydrophobic chain segment is 1.9-3.9:1;

Or the polyester hydrophobic chain segment is PDLLA, the molecular weight of the PEG hydrophilic chain segment is 1000, and the molecular weight ratio of the PEG hydrophilic chain segment to the polyester hydrophobic chain segment is 1.0-1.7:1;

or the polyester hydrophobic chain segment is PDLLA, the molecular weight of the PEG hydrophilic chain segment is 1500, and the molecular weight ratio of the PEG hydrophilic chain segment to the polyester hydrophobic chain segment is 1.1-2.8:1;

or the polyester hydrophobic chain segment is PLLA, the molecular weight of the PEG hydrophilic chain segment is 1000, and the molecular weight ratio of the PEG hydrophilic chain segment to the polyester hydrophobic chain segment is 0.8-1.2:1;

or the polyester hydrophobic chain segment is PLLA, the molecular weight of the PEG hydrophilic chain segment is 1500, and the molecular weight ratio of the PEG hydrophilic chain segment to the polyester hydrophobic chain segment is 1.2-1.6:1;

Or the polyester hydrophobic chain segment is PCL, the molecular weight of the PEG hydrophilic chain segment is 1000, and the molecular weight ratio of the PEG hydrophilic chain segment to the polyester hydrophobic chain segment is 0.45-0.7:1;

or the polyester hydrophobic chain segment is PCL, the molecular weight of the PEG hydrophilic chain segment is 1500, and the molecular weight ratio of the PEG hydrophilic chain segment to the polyester hydrophobic chain segment is 1.1-1.5:1.

2. The method for preparing the embolic polymer according to claim 1, wherein the hydrophobic monomer is copolymerized under the initiation of the initiator PEG to obtain a block copolymer, and the small molecule containing iodine is covalently bonded with the block copolymer to obtain the iodinated copolymer.

3. The method according to claim 2, wherein the hydrophobic monomer is one or two of caprolactone, lactide, levorotatory lactide or glycolide, and the copolymer segment formed by the hydrophobic monomer is PDLLGA, PDLLA, PCL, PLLA segments.

4. A medical liquid embolic agent capable of long-term self-development, which is characterized in that the embolic polymer in claim 1 is dissolved in an aprotic polar solvent, wherein the mass concentration of the embolic polymer is 30-50%.

5. The medical liquid embolic agent of claim 4, wherein the aprotic polar solvent is dimethylsulfoxide, or a mixture of dimethylsulfoxide and ethanol.