Copolymer and preparation method thereof, embolic agent solution and embolic agent system

Abstract

The invention relates to a copolymer and a preparation method thereof, an embolic agent solution and an embolic agent system. The copolymer comprises a hydrophilic chain segment and a hydrophobic chain segment, the hydrophilic chain segment comprises at least one of acrylic acid with a hydrophilic functional group and a derivative group thereof, the hydrophobic chain segment comprises at least one of acrylic acid with a hydrophobic functional group and a derivative group thereof, the hydrophilic functional group comprises at least one of carboxyl, hydroxyl, a sulfonic acid group and an amide group, and the hydrophobic functional group comprises at least one of acrylic acid and a derivative group thereof. The hydrophobic functional group includes a long-chain alkyl group. The hydrophilic chain segment not only can provide hydrophilic groups for the copolymer so as to enable the copolymer to have good water solubility, but also can change the solubility of the copolymer so as to change the rheological property of a copolymer solution. The hydrophobic unit can provide hydrophobic side groups for the copolymer, so that the molecular chain of the copolymer has certain hydrophobic characteristics. Therefore, when the copolymer is dissolved in a solvent, hydrophobic association can be generated among the hydrophobic side groups, so that necessary viscoelasticity is provided for a copolymer solution, and the copolymer solution is in a gel state.

Description

Technical Field

[0001] The present application relates to the technical field of embolic agents, and in particular to a copolymer and a preparation method thereof, an embolic agent solution and an embolic agent system. Background Art

[0002] Interventional embolization is a minimally invasive surgery. Compared with traditional open surgery, it has the advantages of less trauma, faster recovery, and fewer complications. In recent years, interventional embolization has played an increasingly important role in clinical medicine and is widely used in the clinical treatment of abnormal vascular lesions such as cerebral arteriovenous malformations (AVMs) and cerebral arteriovenous fistulas (DVFs). Interventional embolic agents are a type of reagent required for interventional embolization technology, mainly including solid embolic agents and liquid embolic agents.

[0003] However, in the related art, some existing liquid embolic agents have good fluidity, but their embolic effect is not ideal, while other liquid embolic agents can achieve a certain embolic effect, but their fluidity is poor, resulting in their peripheral embolic effect is not ideal, which leads to certain limitations in their application. Summary of the invention

[0004] The main technical problem solved by the present application is to provide a copolymer and a preparation method thereof, an embolic agent solution and an embolic agent system, so as to have both good fluidity and embolic effect.

[0005] In order to solve the above technical problems, a technical solution adopted in the present application is to provide a copolymer. The copolymer includes a hydrophilic segment and a hydrophobic segment, the hydrophilic segment includes at least one of acrylic acid and its derivative groups having a hydrophilic functional group, the hydrophobic segment includes at least one of acrylic acid and its derivative groups having a hydrophobic functional group, the hydrophilic functional group includes at least one of a carboxyl group, a hydroxyl group, a sulfonic acid group, and an amide group, and the hydrophobic functional group includes a long-chain alkyl group.

[0006] In some embodiments, the mass ratio of the hydrophilic segment to the hydrophobic segment is in the range of (80% to 95%): (5% to 20%).

[0007] In some embodiments, the weight average molecular weight of the copolymer is 10,000 g / mol to 50,000 g / mol.

[0008] In some embodiments, the monomer of the hydrophilic segment includes at least one of acrylic acid, methacrylic acid, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, 2-acrylamido-2-methyl-1-propane sulfonic acid, acrylamide, methacrylamide, N-isopropyl acrylamide, N-hydroxymethyl acrylamide, N,N-dimethylacrylamide, [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, and methoxy polyethylene glycol methacrylate.

[0009] In some embodiments, the monomer of the hydrophobic segment includes at least one of: dodecyl polyoxyethylene ether methacrylate, tetradecyl polyoxyethylene ether methacrylate, hexadecyl polyoxyethylene ether methacrylate, octadecyl polyoxyethylene ether methacrylate, behenyl polyoxyethylene ether methacrylate, hexadecyl dimethyl allyl ammonium chloride, octadecyl dimethyl allyl ammonium chloride, 2-acrylamide-2-methylbehenyl sodium sulfonate, 2-acrylamide tetradecane sodium sulfonate, and 2-acrylamide-2-methyldodecane sodium sulfonate.

[0010] In some embodiments, the copolymer has a structural formula as shown in formula (I):

[0011]

[0012] Wherein, X:Y:Z in formula (I) is (5-20):(40-85):(10-40); n is 20-30, and m is 11-21.

[0013] In order to solve the above technical problems, another technical solution adopted by the present application is to provide a method for preparing a copolymer. The preparation method comprises: copolymerizing at least one hydrophilic monomer and at least one hydrophobic monomer to form the copolymer, wherein the hydrophilic monomer comprises acrylic acid and its derivatives having a hydrophilic functional group, the hydrophobic monomer comprises acrylic acid and its derivatives having a hydrophobic functional group, the hydrophilic functional group comprises at least one of a carboxyl group, a hydroxyl group, a sulfonic acid group, and an amide group, and the hydrophobic functional group comprises a long-chain alkyl group.

[0014] In some embodiments, the mass ratio of the hydrophilic monomer to the hydrophobic monomer is: (80% to 95%): (5% to 20%).

[0015] In some embodiments, the copolymerization reaction further includes a chain transfer agent, and the chain transfer agent includes at least one of isopropanol, ethanol, and mercaptopropionic acid.

[0016] In some embodiments, the copolymerization reaction further includes an initiator, and the initiator includes at least one of an azo initiator, a photoinitiator, and a redox initiator.

[0017] In some embodiments, the azo initiator includes at least one of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride, azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, azobis(2-methylpropylimidazole) dihydrochloride, sodium azobiscyanovalerate, and azobis(2-methylpropylimidazole) dihydrochloride.

[0018] In some embodiments, the at least one hydrophilic monomer and the at least one hydrophobic monomer are copolymerized to form the copolymer, and the steps include: adding at least one hydrophilic monomer and at least one hydrophobic monomer into a reaction container, adding ultrapure water and a chain transfer agent, and stirring to dissolve; introducing a protective gas into the reaction system, adding an initiator to react to obtain a crude product, and purifying the crude product to obtain the copolymer.

[0019] In some embodiments, the at least one hydrophilic monomer and the at least one hydrophobic monomer are copolymerized to form the copolymer, comprising the steps of adding the at least one hydrophilic monomer and the at least one hydrophobic monomer into a reaction vessel equipped with a reflux condenser and a gas guide, adding ultrapure water and a chain transfer agent isopropanol, dissolving under stirring, introducing argon into the reaction system for 10 min to 30 min, adding an initiator 2,2'-azobis[2-(2-imidazoline-2-yl)propane] dihydrochloride, reacting at 50°C to 75°C under an argon atmosphere for 2 hours to 4 hours to obtain a crude product, washing it with at least one of methanol, ethanol, and acetone, and then drying it to obtain the copolymer.

[0020] To solve the above technical problems, another technical solution adopted by the present application is: providing an embolic solution. The embolic solution comprises a copolymer and a first solvent, wherein the copolymer is a copolymer as described in any of the above embodiments or a copolymer prepared by the method for preparing a copolymer as described in any of the above embodiments, and the first solvent comprises at least one of ethanol, 50% ethanol aqueous solution, dimethyl sulfoxide, and N-methylpyrrolidone.

[0021] In some embodiments, the concentration of the copolymer in the embolic agent solution is 5% to 10%.

[0022] In some embodiments, the shear viscosity of the embolic agent solution decreases as the shear stress increases.

[0023] To solve the above technical problems, another technical solution adopted by the present application is to provide an embolic agent system, which includes an embolic agent solution and a diluent, wherein the embolic agent solution is the embolic agent solution described in any of the above embodiments, and the diluent includes a developer, a second solvent and a functional component.

[0024] In some embodiments, the volume ratio of the embolic agent solution to the diluent is 1:(5-20).

[0025] In some embodiments, in the diluent, the mass fraction of the developer is 10% to 50%.

[0026] In some embodiments, the developer comprises at least one of iohexol, iopamidol, iodixanol, and iofluanidole, and / or the second solvent comprises at least one of water, saline, and glucose solution, and / or the functional component comprises an anticancer drug.

[0027] The beneficial effects of the present application are as follows: different from the prior art, the copolymer molecular structure provided by the present application contains a hydrophilic segment and a hydrophobic segment, and the hydrophilic segment is a monomer unit of a hydrophilic monomer, which can provide a hydrophilic group for the copolymer so that the copolymer has good water solubility. Further, the hydrophilic segment can also change the solubility of the copolymer to change the rheological properties of the copolymer solution. The hydrophobic unit is a monomer unit of a hydrophobic monomer, which can provide a hydrophobic side group for the copolymer so that the molecular chain of the copolymer has certain hydrophobic properties. In this way, when the copolymer is dissolved in a solvent, hydrophobic association can occur between each hydrophobic side group to form a spatial network structure, thereby providing the necessary viscoelasticity for the copolymer solution to make it in a gel state.

[0028] Furthermore, the embolic solution provided in the embodiment of the present application is a gel-state embolic solution formed by a hydrophobic associating copolymer and a first solvent. Since the gel of the hydrophobic associating copolymer has good biocompatibility and no cytotoxicity, and the gel-state embolic solution is slowly diluted and dissolved by the blood in the blood vessels, and is eventually metabolized and discharged by the human body. Even if a small amount of it refluxes or enters the venous circulation, the gel property of the embolic solution allows it to be diluted by the blood to a certain extent, reducing the risk of ectopic embolism, and the embolized blood vessels can be reopened under certain conditions, with good safety.

[0029] Furthermore, the embolic agent system provided in the embodiment of the present application includes an embolic agent solution in a gel state, and the gel-type embolic agent solution has good fluidity. When the embolic agent solution and the diluent are mixed to form the embolic agent system, the embolic agent system is also in a gel state and has fluidity, that is, the embolic agent system is a non-viscous injectable gel-type liquid embolic agent system, which has a shear thinning effect. Therefore, when the embolic agent system is pushed, due to its good fluidity, when the embolic agent system enters the blood vessel, it can adapt to different sizes and shapes, and can be evenly filled inside the blood vessel to achieve the purpose of blocking blood flow. In this way, the embolic agent system provided in the embodiment of the present application has both good fluidity and good embolic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is a rheological performance diagram of the embolic agent system in an embodiment of the present application;

[0031] Figure 2 It is a schematic diagram of the embolization experiment using the comparative embolic agent system, wherein a is the angiography immediately after the operation, and b is the angiography 4 days after the embolization.

[0032] Figure 3 Schematic diagram of embolization experiment using the embolic agent system in the embodiment of the present application, wherein a is angiography immediately after surgery, and b is angiography 4 days after embolization. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solution and effect of the present application clearer and more specific, the present application is further described in detail below with reference to the accompanying drawings and examples.

[0034] Hereinafter, the copolymer and its preparation method, embolic solution and embolic system of the present application are described in detail with appropriate reference to the drawings. However, there may be cases where unnecessary detailed descriptions are omitted. For example, there are cases where detailed descriptions of well-known matters and repeated descriptions of actually the same structure are omitted. This is to avoid the following description from becoming unnecessarily lengthy and to facilitate the understanding of those skilled in the art. In addition, the drawings and the following description are provided for those skilled in the art to fully understand the present application and are not intended to limit the subject matter described in the claims.

[0035] The "range" disclosed in the present application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range. For example, if a range of 60 to 120 and 80 to 110 is listed for a particular parameter, it is understood that a range of 60 to 110 and 80 to 120 is also expected. In addition, if the minimum range values ​​1 and 2 are listed, and if the maximum range values ​​3, 4 and 5 are listed, the following ranges can all be expected: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4 and 2 to 5. In the present application, unless otherwise specified, the numerical range "a to b" represents an abbreviation of any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" are listed in this document, and "0-5" is just an abbreviation of these numerical combinations. In addition, when a parameter is expressed as an integer ≥ 2, it is equivalent to disclosing that the parameter is, for example, an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0036] Unless otherwise specified, all embodiments and optional embodiments of the present application can be combined with each other to form a new technical solution.

[0037] Unless otherwise specified, all technical features and optional technical features of this application can be combined with each other to form a new technical solution.

[0038] Unless otherwise specified, all steps of the present application may be performed sequentially or randomly, preferably sequentially. For example, a method includes steps (a) and (b), which means that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially. For example, a method may also include step (c), which means that step (c) may be added to the method in any order, for example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0039] If there is no special explanation, the "include" and "comprising" mentioned in this application represent open-ended or closed-ended expressions. For example, "include" and "comprising" may represent that other components not listed may also be included or only listed components may be included or only listed components may be included.

[0040] If not specifically stated, in this application, the term "or" is inclusive. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, any of the following conditions satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0041] Interventional embolization is a minimally invasive surgery. Compared with traditional open surgery, it has the advantages of less trauma, faster recovery, and fewer complications. In recent years, interventional embolization has played an increasingly important role in clinical medicine and is widely used in the clinical treatment of abnormal vascular lesions such as cerebral arteriovenous malformations and cerebral arteriovenous fistulas. Interventional embolic agents are a type of reagent required for interventional embolization technology. They are agents that have the function of embolizing tumor blood vessels. They can form emboli in the lumen of tumor blood vessels, thereby blocking the lumen of the blood vessels, and ultimately achieving the purpose of ischemia and necrosis of the tumor, thereby achieving the purpose of treatment.

[0042] There are many types of interventional embolic agents. According to the physical properties of the embolic materials, the embolic materials used in interventional embolization therapy mainly include solid embolic agents and liquid embolic agents. Compared with solid embolic agents, liquid embolic agents have stronger fluidity. They can be directly injected into tumor tissue through thinner microcatheters and evenly fill the diseased blood vessels. They are completely suitable for tumors of different sizes and shapes, leaving no gaps between tumor tissue and embolic materials, thereby blocking the blood vessels, reducing the possibility of blood vessel recanalization, and achieving accurate and permanent embolism. Therefore, liquid embolic agents are a more ideal embolic material.

[0043] At present, the liquid embolic agents widely used in clinical practice mainly include two categories: adhesive liquid embolic agents and non-adhesive liquid embolic agents. Among them, cyanoacrylate embolic agents are a commonly used adhesive liquid embolic agent. This liquid embolic agent achieves the purpose of embolization by rapidly polymerizing cyanoacrylate under the catalytic action of anions in the blood after contact with blood. However, since cyanoacrylate embolic agents have strong adhesion, they are prone to adhesion to the catheter during treatment, and even the phenomenon of catheter sticking that cannot be removed may occur, causing certain risks.

[0044] Onyx liquid embolic agent is a new type of intravascular non-adhesive liquid embolic agent and one of the most commonly used non-adhesive liquid embolic agents. Onyx liquid embolic agent is a suspension formed by mixing ethylene-vinyl alcohol copolymer, dimethyl sulfoxide (DMSO) and micron-grade tantalum powder in a certain proportion. The working principle of Onyx liquid embolic agent is that ethylene-vinyl alcohol copolymer is non-water-soluble but soluble in DMSO, and nano-grade tantalum powder is used as a developer. When the liquid embolic agent comes into contact with an aqueous solution (such as blood), DMSO quickly diffuses into the aqueous solution, and ethylene-vinyl alcohol copolymer precipitates into a solid, which plays an embolic role. For example, it can block the blood vessels of intracranial lesions and achieve the purpose of blocking blood flow. The developer micron-grade tantalum powder can be developed under X-rays and then captured by the developed image, which is convenient for the treatment and diagnosis of diseases.

[0045] However, both cyanoacrylate embolic agents and Onyx liquid embolic agents have weak peripheral embolic effects and are not suitable for loading anticancer drugs.

[0046] In order to solve the contradiction between the fluidity and embolic properties of the existing liquid embolic agents in the related art, the purpose of the present application is to provide an embolic agent solution, which includes a copolymer and a first solvent, and the copolymer can be dissolved in the first solvent to form a hydrogel-type embolic agent solution. The embolic agent solution has good fluidity to play a peripheral embolic role, and can also stay in the blood vessel for a long time. Furthermore, the embolic agent solution also has a broad drug loading effect and can load most commonly used anticancer drugs.

[0047] The present invention is further described below in conjunction with specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the raw materials and reagents used in the embodiments of the present invention are conventionally purchased raw materials and reagents.

[0048] 1. Copolymers and their structural characteristics

[0049] The embodiment of the present application provides a copolymer, which is a hydrophobically associating polymer, such as a water-soluble hydrophobically associating polymer. Specifically, a hydrophobically associating polymer refers to a polymer in which an appropriate amount of hydrophobic segments are added to the long chain structure of the hydrophilic macromolecule of the polymer. In this way, in the molecular structure of the hydrophobically associating polymer, there are a large number of hydrophilic polar groups in parallel on the long chain and a small amount of hydrophobic non-polar groups with hydrophobic effects. Among them, the hydrophilic polar groups bring great viscosity to the polymer solution through hydration, and the hydrophobic non-polar groups enhance the aggregation between the long molecular chains of the polymer through the interaction of the non-polar groups in the polar atmosphere of the aqueous solution, thereby further increasing the viscosity of the polymer solution. In other words, this characteristic of the hydrophobically associating polymer enables it to dissolve in water and form a hydrophobically associating polymer solution, and the hydrophobically associating polymer solution is a gel with a shear-thinning effect. Therefore, the polymer solution formed by diluting the copolymer provided in the embodiment of the present application with water can form a gel with a shear-thinning effect.

[0050] Specifically, the copolymer includes a hydrophilic segment and a hydrophobic segment. Wherein, the hydrophilic segment includes at least one of acrylic acid and its derivative groups having a hydrophilic functional group, the hydrophobic segment includes at least one of acrylic acid and its derivative groups having a hydrophobic functional group, the hydrophilic functional group includes at least one of a carboxyl group, a hydroxyl group, a sulfonic acid group, and an amide group, and the hydrophobic functional group includes a long-chain alkyl group. Wherein, the hydrophilic segment is a monomer unit of a hydrophilic monomer, which can provide a hydrophilic group for the copolymer so that the copolymer has good water solubility. Further, the hydrophilic segment can also change the solubility of the copolymer to change the rheological properties of the copolymer solution. The hydrophobic unit is a monomer unit of a hydrophobic monomer, which can provide a hydrophobic side group for the copolymer so that the molecular chain of the copolymer has certain hydrophobic properties. In this way, when the copolymer is dissolved in a solvent, hydrophobic association can occur between each hydrophobic side group to form a spatial network structure, thereby providing the necessary viscoelasticity for the copolymer solution, making it in a gel state.

[0051] In some embodiments, the carbon atom number distribution of the long-chain alkyl group is twelve to twenty-two, for example, dodecyl (C12 alkyl), tetradecyl (C14 alkyl), hexadecyl (C16 alkyl), octadecyl (C18 alkyl), docosyl (C22 alkyl), etc.

[0052] The working principle of the copolymer provided in the embodiments of the present application being dissolved in a solvent to form a copolymer solution in a gel state is as follows.

[0053] In the molecular structure of the copolymer, a small amount of hydrophobic functional groups are carried on the hydrophilic macromolecular chain of the copolymer. When the copolymer is dissolved in a solvent to form a copolymer solution, the hydrophobic functional groups in the copolymer form an association structure in the aqueous solution through non-covalent bond interactions. Specifically, the hydrophobic functional groups in the copolymer aggregate in the solvent due to their hydrophobic effect to form a hydrophobic core, resulting in intramolecular and intermolecular associations between the molecular chains. That is, the hydrophobic core can serve as a physical crosslinking point to connect the copolymer molecular chains to form a three-dimensional network structure.

[0054] Furthermore, when the concentration of the copolymer solution is higher than the critical concentration (Critical Aggregation Concentration, CAC), the aggregation of the hydrophobic groups becomes significant enough, and the hydrophilic macromolecular chains aggregate through the action of hydrophobic association, thus forming a supramolecular structure dominated by intermolecular association, that is, forming an intermolecular association dynamic physical cross-linking network, which can increase the fluid mechanics volume and significantly increase the viscosity of the copolymer solution. In other words, when the concentration of the copolymer solution is higher than the critical concentration, the viscosity of the copolymer solution changes significantly, that is, it changes from a fluid liquid to a gel state. At the same time, the molecular dynamic physical cross-linking network can make the rheological properties of the hydrophobic associating copolymer manifest as shear thinning characteristics and thixotropy. That is, under the action of shear, the "cross-linking network" formed by the association of the hydrophobic associating copolymer is destroyed, and the viscosity of the copolymer solution decreases; when the shear action is eliminated, the "cross-linking network" formed by the association of the hydrophobic associating copolymer is re-formed, and the viscosity of the copolymer solution is restored.

[0055] Therefore, when the copolymer in the embodiment of the present application is dissolved in a solvent, the copolymer solution formed by the copolymer and the solvent undergoes a significant physical change, that is, from a fluid liquid to a gel state, due to the hydrophobic association between the copolymer molecular chains, so that the copolymer solution can form a hydrophobic association structure in the solvent. At the same time, the copolymer solution also has shear thinning properties and thixotropy.

[0056] In some embodiments, the long chain of the copolymer has parallel hydrophilic segments and hydrophobic segments, wherein the mass ratio of the hydrophilic segments to the hydrophobic segments is in the range of (80% to 95%): (5% to 20%). Preferably, 80%: 20%, 82%: 18%, 85%: 15%, 90%: 10%, 95%: 5%.

[0057] In some embodiments, the monomer of the hydrophilic segment includes at least one of acrylic acid, methacrylic acid, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, 2-acrylamido-2-methyl-1-propane sulfonic acid, acrylamide, methacrylamide, N-isopropylacrylamide, N-hydroxymethylacrylamide, N,N-dimethylacrylamide, [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl)ammonium hydroxide, and methoxy polyethylene glycol methacrylate. It is understood that the monomer of the hydrophilic segment is also referred to as a hydrophilic monomer.

[0058] In some embodiments, the monomer of the hydrophobic segment includes at least one of: dodecyl polyoxyethylene ether methacrylate, tetradecyl polyoxyethylene ether methacrylate, hexadecyl polyoxyethylene ether methacrylate, octadecyl polyoxyethylene ether methacrylate, behenyl polyoxyethylene ether methacrylate, hexadecyl dimethyl allyl ammonium chloride, octadecyl dimethyl allyl ammonium chloride, 2-acrylamide-2-methyl behenyl sodium sulfonate, 2-acrylamide tetradecane sodium sulfonate, and 2-acrylamide-2-methyl dodecane sodium sulfonate. It is understood that the monomer of the hydrophobic segment is also referred to as a hydrophobic monomer.

[0059] In some embodiments, the copolymer comprising a hydrophilic segment and a hydrophobic segment is a multi-block copolymer, and its structural formula is shown in formula (I):

[0060]

[0061] Among them, X:Y:Z in formula (I) is (5-20):(40-85):(10-40); n is 20-30, and m is 11-21. For example, n is 20, m is 21; n is 22, m is 18; n is 25, m is 17; n is 28, m is 12; n is 30, m is 11, etc.

[0062] In some embodiments, n may be 25, and m may be 17, that is, the structural formula of the copolymer is as shown in formula (II):

[0063]

[0064] Among them, X:Y:Z in formula (II) is (5-20):(40-85):(10-40).

[0065] For hydrophobic associating copolymer solution, the size of its weight average molecular weight is associated with its rheological properties. Specifically, the copolymer solution formed by the copolymer with a higher weight average molecular weight exhibits a higher zero shear viscosity at a low shear rate, which means that under static or low flow conditions, it has a higher internal resistance and is solid or close to a solid state; under shear, the viscosity of the copolymer solution decreases with the increase of the shear rate, showing obvious shear thinning behavior. In addition, the copolymer solution formed by the copolymer with a higher weight average molecular weight also has thixotropy, that is, when it is not sheared, its viscosity will return to a static level over time. In view of this, in order to ensure that the copolymer has ideal rheological properties while being able to be metabolized and discharged by the human body, by adjusting the polymerization conditions of the copolymer, the weight average molecular weight of the copolymer provided in the embodiment of the present application is 5000g / mol~100000g / mol, preferably 10000g / mol~50000g / mol.

[0066] 2. Preparation method of copolymer

[0067] The present application also provides a method for preparing a copolymer, which can be an aqueous solution polymerization method. That is, the copolymer provided in the embodiment of the present application can be obtained by copolymerization by aqueous solution polymerization. Specifically, the preparation method may include: at least one hydrophilic monomer and at least one hydrophobic monomer are copolymerized to form a copolymer. Wherein, the hydrophilic monomer includes acrylic acid and its derivatives having a hydrophilic functional group, the hydrophobic monomer includes acrylic acid and its derivatives having a hydrophobic functional group, the hydrophilic functional group includes at least one of a carboxyl group, a hydroxyl group, a sulfonic acid group, and an amide group, and the hydrophobic functional group includes a long-chain alkyl group. Wherein, the carbon chain carbon atom number of the long-chain alkyl group is distributed from twelve to twenty-two, for example, dodecyl (C12 alkyl), tetradecyl (C14 alkyl), hexadecyl (C16 alkyl), octadecyl (C18 alkyl), and docosyl (C22 alkyl).

[0068] In some embodiments, the preparation method comprises the following steps:

[0069] Step S10, adding at least one hydrophilic monomer and at least one hydrophobic monomer into a reaction container, adding ultrapure water and a chain transfer agent, and stirring to dissolve.

[0070] Specifically, in step S10, at least one hydrophilic monomer and at least one hydrophobic monomer are added to a reaction vessel equipped with a reflux condenser and a gas guide device according to the feed ratio of the hydrophilic monomer and the hydrophobic monomer. Further, ultrapure water and a chain transfer agent are added to the reaction vessel. The hydrophilic monomer and the chain transfer agent added to the reaction vessel are dissolved in the ultrapure water by a stirring device. The reaction vessel may be a three-necked flask. The stirring device may be a magnetic stirrer, for example, a magnetic stirrer provided with a heating component.

[0071] In some embodiments, the feed ratio of the hydrophilic monomer to the hydrophobic monomer may be a mass ratio of the hydrophilic monomer to the hydrophobic monomer, wherein the mass ratio of the two is: (80% to 95%): (5% to 20%). The hydrophilic monomer and the hydrophobic monomer are the same as described above.

[0072] In some embodiments, the mass ratio of ultrapure water to the mass ratio of the chain transfer agent is 4:1 to 5:1.

[0073] In some embodiments, the chain transfer agent can be any chain transfer agent known to those skilled in the art, without any particular limitation. Specifically, the chain transfer agent includes at least one of isopropanol, ethanol, and mercaptopropionic acid. Preferably, the chain transfer agent is isopropanol.

[0074] Specifically, in the preparation process of copolymers, on the one hand, chain transfer agents can be used to control the molecular weight of copolymers. That is, in the free radical polymerization reaction, the chain transfer agent provides a stable free radical, reacts with the end of the growing chain, transfers the free radical to the chain transfer agent, thereby terminating the growth of the current chain, and at the same time, the free radical on the chain transfer agent can trigger new monomer molecules to form new growing chains. Therefore, the chain transfer agent can both limit the growth of the copolymer molecular chain and form new growing chains, thereby effectively controlling the molecular weight of the copolymer. In other words, the molecular weight distribution of the copolymer can be adjusted by using a chain transfer agent. On the other hand, by controlling the amount of the chain transfer agent, the segment length of the copolymer can be accurately controlled, which helps to form a block copolymer with a specific structure.

[0075] In addition, during the preparation of the copolymer, the polymerization reaction can be continuously maintained through the chain transfer agent, and the activity of the reaction can be maintained even at a lower monomer concentration.

[0076] In some embodiments, the ultrapure water may be deionized water or distilled water.

[0077] It should be noted that in step S10, there is no particular order in which the hydrophilic monomer, the hydrophobic monomer, the ultrapure water, and the chain transfer agent are added. For example, the ultrapure water may be added first, and then the hydrophilic monomer, the hydrophobic monomer, and the chain transfer agent; or the hydrophilic monomer, the hydrophobic monomer, the ultrapure water, and the chain transfer agent may be added simultaneously. The specific order may be adjusted according to the actual application, and this application does not impose any specific limitation.

[0078] Step S20, introducing a protective gas into the reaction system, adding an initiator to react, obtaining a crude product, and purifying the crude product to obtain a copolymer.

[0079] Specifically, in step S20, a protective gas is introduced into the reaction system for 10 to 30 minutes, the reaction system is heated to an initiation temperature, and an initiator is added, so that the hydrophilic monomer, the hydrophobic monomer and the chain transfer agent added in step S10 are copolymerized under the protective gas atmosphere and at the initiation temperature to obtain a crude product. The crude product is a copolymer solution formed by the polymerization reaction, which is a high-viscosity liquid, so the crude product can also be called a copolymer colloid.

[0080] In some embodiments, the protective gas may be an inert gas such as argon.

[0081] In some embodiments, the amount of initiator added is 100 mg to 150 mg. The initiation temperature is 40° C. to 75° C., preferably 50° C. to 70° C. The polymerization reaction time is preferably 1 hour to 6 hours, preferably 2 hours to 4 hours.

[0082] In some embodiments, the initiator may be at least one of an azo initiator, a redox initiator system, and a photoinitiator. Among them, the azo initiator may include a water-soluble azo initiator. Specifically, the azo initiator may be selected from at least one of 2,2'-azobis[2-(2-imidazoline-2-yl)propane] dihydrochloride, azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, sodium azobiscyanovalerate, and azobis(2-methylpropylimidazole) dihydrochloride.

[0083] In some embodiments, the copolymerization reaction can be controlled to be completed according to the preset heating time. When the preset heating time is reached, the heating is stopped, and the reaction system is cooled to 20°C to 25°C to obtain a crude product. The preset heating time can be 2 to 4 hours, and of course the preset time can be adjusted according to actual needs. For example, the preset heating time can be 1.5 hours, 4.5 hours, 6 hours, etc. This application does not make specific restrictions, as long as the copolymer formed by the crude product can meet the required performance requirements.

[0084] After the copolymerization reaction is completed, the obtained crude product is purified using a poor solvent and dried to obtain a copolymer. Wherein, the purification method is a method well known to those skilled in the art. For example, the crude product can be washed with a poor solvent, for example, 2 to 4 times. The poor solvent is selected from at least one of methanol, ethanol, and acetone. Further, the washed crude product is placed in a drying device (such as an oven) for drying to remove residual solvent to obtain a copolymer. Wherein, the drying temperature is preferably 80°C to 95°C. The drying time is preferably 0.5 hours to 3 hours, preferably 1 hour to 2 hours. At this time, the copolymer is a white solid.

[0085] In step S20, by drying the washed crude product, the stability of the copolymer can be ensured and agglomeration of the copolymer in subsequent treatment can be reduced.

[0086] In the copolymer preparation method provided in the embodiment of the present application, an ABA type ternary block copolymer, a BAB type ternary block copolymer, an ABC type ternary block copolymer, an ACB type ternary block copolymer, or a BAC type ternary block copolymer can be formed through step S10 and step S20.

[0087] In some embodiments, the at least one hydrophilic monomer may include a hydrophilic monomer selected from acrylic acid, methacrylic acid, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, 2-acrylamido-2-methyl-1-propane sulfonic acid, acrylamide, methacrylamide, N-isopropylacrylamide, N-hydroxymethylacrylamide, N,N-dimethylacrylamide, [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, methoxy polyethylene glycol methacrylate; At least one hydrophobic monomer may include a hydrophobic monomer, for example, selected from dodecyl polyoxyethylene ether methacrylate, tetradecyl polyoxyethylene ether methacrylate, hexadecyl polyoxyethylene ether methacrylate, octadecyl polyoxyethylene ether methacrylate, behenyl polyoxyethylene methacrylate, hexadecyl dimethyl allyl ammonium chloride, octadecyl dimethyl allyl ammonium chloride, 2-acrylamide-2-methyl behenyl sodium sulfonate, 2-acrylamide tetradecane sodium sulfonate, 2-acrylamide-2-methyl dodecane sodium sulfonate. At this time, a hydrophilic monomer and a hydrophobic monomer are polymerized by aqueous solution polymerization under the initiation of an initiator, and the active chain end of one of the monomers is converted into an active center capable of initiating polymerization of another different monomer by a chain transfer agent to form a ternary block copolymer. That is, the copolymer is an ABA type ternary block copolymer or a BAB type ternary block copolymer.

[0088] In some embodiments, at least one hydrophilic monomer may include two different hydrophilic monomers, namely, two different hydrophilic monomers selected from acrylic acid, methacrylic acid, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, 2-acrylamido-2-methyl-1-propane sulfonic acid, acrylamide, methacrylamide, N-isopropylacrylamide, N-hydroxymethylacrylamide, N,N-dimethylacrylamide, [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, and methoxy polyethylene glycol methacrylate. For example, the two different hydrophilic monomers can be acrylic acid and hydroxypropyl methacrylate, or N-isopropylacrylamide and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl)ammonium hydroxide, or acrylic acid and hydroxyethyl acrylate, or acrylic acid and hydroxypropyl acrylate, or acrylic acid and hydroxyethyl methacrylate, or acrylic acid and methoxypolyethylene glycol methacrylate, or methacrylic acid and hydroxyethyl acrylate, or methacrylic acid and hydroxypropyl acrylate, or methacrylic acid and hydroxyethyl methacrylate, or methacrylic acid and methoxypolyethylene glycol methacrylate, or methacrylamide and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl)ammonium hydroxide; or N-hydroxymethylacrylamide and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl)ammonium hydroxide; the at least one hydrophobic monomer can include a hydrophobic monomer, which can also be selected from one of the above hydrophobic monomers. At this time, two hydrophilic monomers and one hydrophobic monomer are polymerized by aqueous solution polymerization under the initiation of an initiator, and at the same time, the active chain end of one of the monomers is converted into an active center capable of initiating polymerization of another different monomer by a chain transfer agent to form a ternary block copolymer. That is, the copolymer is one of an ABC type ternary block copolymer, an ACB type ternary block copolymer, or a BAC type ternary block copolymer.

[0089] In some embodiments, at least one hydrophilic monomer may include three different hydrophilic monomers, such as 2-acrylamido-2-methyl-1-propane sulfonic acid and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, and hydroxypropyl methacrylate; at least one hydrophobic monomer may include a hydrophobic monomer, which may also be selected from one of the above hydrophobic monomers. At this time, three different hydrophilic monomers and one hydrophobic monomer are polymerized by aqueous solution polymerization under the initiation of an initiator, and at the same time, the active chain end of one of the monomers is converted into an active center capable of initiating polymerization of another different monomer by a chain transfer agent to form a tetrablock copolymer. That is, the copolymer is one of a tetrablock copolymer such as an ABCD-type tetrablock copolymer, an ACBD-type tetrablock copolymer, and a CBDA-type tetrablock copolymer.

[0090] In the copolymer preparation method provided in the present application, a hydrophilic monomer and a hydrophobic monomer are polymerized in a chain transfer agent and an initiator by an aqueous solution polymerization method. During the polymerization process, by setting the feed ratio of the hydrophobic monomer and the hydrophilic monomer and adding a chain transfer agent, an appropriate amount of hydrophobic segments are added to the long chain structure of the hydrophilic macromolecule of the copolymer, thereby forming a multi-block hydrophobic associating copolymer. The structural characteristics of the copolymer are the same as described above, and the specific contents can be referred to.

[0091] 3. Embolic Solution

[0092] The present application also provides an embolic solution, comprising a copolymer and a first solvent. The copolymer is a copolymer as described in the above embodiment or a copolymer prepared by the method for preparing a copolymer as described in the above embodiment. The first solvent comprises at least one of ethanol, 50% ethanol aqueous solution, dimethyl sulfoxide, and N-methylpyrrolidone. Optionally, the embolic solution may also be referred to as an embolic stock solution or an embolic mother solution.

[0093] Specifically, the copolymer can be dissolved in the first solvent to form a flowing copolymer solution. When the first solvent is a 50% ethanol aqueous solution, the copolymer is dissolved in the 50% ethanol aqueous solution, and the aggregation degree of the hydrophobic functional groups in the copolymer, such as C18 alkyl, in the first solvent is lower than that in water, and it is difficult to form a hydrophobic core, and the degree of hydrophobic association is low. The formed solution is flowing, which is convenient for subsequent filling, and a gel with an embolic effect is formed by dilution with a second solvent (such as at least one of water, physiological saline, glucose solution, etc.).

[0094] When the first solvent is ethanol, the copolymer is dissolved in ethanol, and the degree of aggregation of the hydrophobic functional groups in the copolymer, such as C18 alkyl, in the first solvent is lower than that in water, and it is difficult to form a hydrophobic core. The degree of hydrophobic association is low, and the formed solution is fluid, which is convenient for subsequent filling, and a gel with embolic effect is formed by dilution with a second solvent (such as at least one of water, saline, and glucose solution).

[0095] When the first solvent is dimethyl sulfoxide or N-methylpyrrolidone, the process of dissolving the copolymer therein to form a copolymer solution is similar to that when the first solvent is ethanol, and the details can be referred to the above content.

[0096] In some embodiments, the gel-type hydrophobically associating copolymer solution has good biocompatibility and does not cause excessive adverse reactions when in contact with blood.

[0097] In some embodiments, the gel-type hydrophobically associating copolymer solution can also be loaded with anticancer drugs to achieve local controlled drug release and enhance the therapeutic effect.

[0098] Specifically, the mass ratio of the copolymer to the first solvent may be set to 1:9 to 19. That is, the concentration of the copolymer in the embolic agent solution is in the range of 5% to 10%.

[0099] 4. Embolic Agent System

[0100] The present application also provides an embolic agent system, comprising an embolic agent solution and a diluent, wherein the embolic agent solution is the embolic agent solution as described in any of the above embodiments, and the diluent may include a developer, a solvent, and a functional component.

[0101] In some embodiments, different anticancer drugs can be added to the diluent according to actual needs, and mixed with the embolic agent solution to form a drug-loaded embolic agent system to achieve a broad drug-loading effect.

[0102] In some embodiments, the volume ratio of the embolic solution to the diluent is 1:(5-20). Specifically, when measuring the rheological properties of the embolic system, the embolic solution can be diluted at a volume ratio of 1:5.

[0103] In some embodiments, in the diluent, the mass fraction of the developer is 10% to 50%.

[0104] In some embodiments, the developer includes at least one of iohexol, iopamidol, iodixanol, and iofluanidone, and / or the second solvent includes at least one of water, saline, and glucose solution, and / or the functional component includes an anticancer drug. Wherein, the second solvent can be selected according to the actual application needs. The anticancer drug can include at least one of doxorubicin, epirubicin, daunorubicin, irinotecan, topotecan, sorafenib, paclitaxel, vinorelbine, bleomycin, etc., which can be selected according to actual needs, and the application is not specifically limited.

[0105] The embolic agent system provided in the embodiment of the present application includes an embolic agent solution in a flowing state, and the embolic agent solution in a flowing state has good fluidity. When the embolic agent solution and the diluent are mixed to form the embolic agent system, the embolic agent system is transformed into a gel state, and exhibits fluidity under stress, that is, the embolic agent system is a non-viscous injectable gel-type liquid embolic agent system, which has a shear thinning effect. Therefore, when the embolic agent system is pushed, due to its good fluidity, when the embolic agent system enters the blood vessel, it can adapt to different sizes and shapes, and can be evenly filled inside the blood vessel to achieve the purpose of blocking blood flow. In this way, the embolic agent system provided in the embodiment of the present application has both good fluidity and good embolic effect.

[0106] The non-viscous injectable gel-type liquid embolic agent system has a shear-thinning property, that is, the gel-type liquid embolic agent system is close to a solid state when it is stationary. When it is subjected to shear force (such as injection by a syringe), the hydrophobic association between the copolymer chains is weakened, and the gel-type liquid embolic agent system exhibits a lower viscosity, has a certain fluidity, and is easy to flow. Therefore, when the embolic agent solution is mixed with the second solvent to form an embolic agent gel with a shear-thinning effect, after it is injected into a blood vessel to form an embolism, it can maintain a gel state for a long time to block blood flow. In other words, the embolic agent system provided in the embodiment of the present application has both good fluidity and good embolic effect.

[0107] Furthermore, due to the gel properties of the embolic agent system, it is injectable, that is, it can be directly injected into the target blood vessel through a microcatheter, deep into the blood vessel extremities, and achieve the effect of extremity embolization. In addition, due to the gel properties of the embolic agent system, it can be diluted by blood to a certain extent, reducing the risk of ectopic embolism, and the embolized blood vessels can be reopened under certain conditions.

[0108] Furthermore, the embolic agent system provided in the embodiment of the present application has good biocompatibility and no cytotoxicity. Therefore, while achieving the embolic effect, the embolic agent system also has good biocompatibility and no cytotoxicity, and it will be slowly diluted and dissolved by the blood in the blood vessels, and eventually be metabolized and discharged by the human body, and a small amount of reflux or entry into the venous circulation will not cause ectopic embolism, and has good safety.

[0109] In some embodiments, the hydrophobic associative properties of the copolymers provided in the embodiments of the present application can be regulated by changing the content of the hydrophobic segments in the main chain of the copolymer and the length of the hydrophobic microblocks, thereby optimizing the performance of the embolic agent system.

[0110] See also Figure 1 , Figure 1 is a rheological performance diagram of the embolic agent system in the embodiment of the present application. Figure 1 As shown in the figure, when the shear stress increases, the long-chain molecules in the embolic system are forced to arrange downstream, reducing internal friction and entanglement. In this way, the long-chain molecules in the copolymer gel are more likely to arrange downstream under shear, showing obvious shear thinning behavior, thereby reducing the viscosity of the embolic system. In other words, the shear viscosity of the embolic system decreases with increasing shear stress. On the rheological property curve, the shear thinning of the embolic system is manifested as a curve in which the viscosity decreases with increasing shear rate.

[0111] V. Examples of Copolymers and Embolic Agent Solutions

[0112] The present application will be described and explained below through several groups of specific experimental examples and comparative experimental examples, but they should not be used to limit the scope of the present application. The reagents used in the following examples are all commercially available.

[0113] Example 1

[0114] According to the feed ratio of hydrophobic monomer to hydrophilic monomer of 10%:90%, 35g of hydrophilic monomer acrylic acid and 10g of hydroxypropyl methacrylate and 5g of hydrophobic monomer octadecyl polyoxyethylene ether methacrylate were added to a reaction vessel equipped with a reflux condenser and a gas guide. Further, 125g of ultrapure water and 25g of chain transfer agent isopropanol were added and dissolved under magnetic stirring. Argon was introduced into the reaction system for 20 minutes, the reaction system was heated to 55°C, and 100mg of initiator 2,2'-azobis[2-(2-imidazoline-2-yl)propane] dihydrochloride was added to initiate the polymerization reaction. The reaction system was reacted at 55°C for 4 hours under an argon atmosphere to obtain a high-viscosity liquid.

[0115] Wash with ethanol three times and dry to obtain a white solid. After the copolymerization reaction is completed, purify the obtained crude product with poor solvent ethanol, for example, wash with ethanol three times. Put the washed crude product into an oven at a constant temperature of 90°C and dry it for 1 hour to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 1 is named Copolymer-1. The Copolymer-1 is formed by aqueous solution polymerization of two hydrophilic monomers and one hydrophobic monomer under the initiation of an initiator, so the Copolymer-1 is one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0116] The weight average molecular weight of Copolymer-1 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 28172 g / mol.

[0117] Copolymer-1 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-1 was dissolved in 9 g of ethanol to form an embolic solution.

[0118] The embolic solution obtained in Example 1 was diluted 5 times with ultrapure water to prepare a copolymer gel (also referred to as embolic gel). Further, the copolymer gel obtained in Example 1 was tested using a viscosity measuring device. At 25°C, 0.1s -1 The viscosity reaches 535000mPa·s at shear rate, 1000s -1 The viscosity under shear rate reaches 290 mPa·s. The viscosity measuring device can be one of an Ubbelohde viscometer, a rotational viscometer, a falling ball viscometer or a rheometer.

[0119] The process steps of Examples 2 to 21 are basically the same as those of Example 1, but some reaction conditions are different. Please refer to Table 1 for details. Table 1 shows the preparation conditions and performance parameters of the copolymers and embolic agent solutions in Examples 1-21 of the present application.

[0120] Example 2

[0121] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is changed to acrylamide, the hydrophobic monomer is still octadecyl polyoxyethylene ether methacrylate, and the feed ratio of the hydrophobic monomer to the hydrophilic monomer is changed to 20%:80%, that is, 40g of the hydrophilic monomer acrylamide and 10g of the hydrophobic monomer octadecyl polyoxyethylene ether methacrylate are added, and the amount of the chain transfer agent isopropanol is changed to 30g to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 2 is named Copolymer-2. In the polymerization process of Copolymer-2, a hydrophilic monomer and a hydrophobic monomer are polymerized by aqueous solution polymerization under the initiation of an initiator, and at the same time, the active chain end of one of the monomers is converted into an active center that can initiate the polymerization of another different monomer by the chain transfer agent isopropanol to form a ternary block copolymer. Therefore, the Copolymer-2 is an ABA type ternary block copolymer or a BAB type ternary block copolymer.

[0122] The weight average molecular weight of Copolymer-2 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 40993 g / mol.

[0123] Copolymer-2 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-2 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0124] The embolic solution obtained in Example 2 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 2 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity reaches 454000mPa·s at shear rate, 1000s -1 The viscosity under shear rate reaches 213mPa·s.

[0125] It should be noted that in Example 2, the hydrophilic monomer can be replaced by one of methacrylamide, N-isopropylacrylamide, N-hydroxymethylacrylamide, and N,N-dimethylacrylamide, and its preparation method and steps are basically the same as those described in Example 2, and the copolymer prepared thereby is also an ABA type ternary block copolymer or a BAB type ternary block copolymer.

[0126] Example 3 - Tetrablock Copolymer

[0127] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is changed to 2-acrylamido-2-methyl-1-propane sulfonic acid and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, and hydroxypropyl methacrylate, the hydrophobic monomer is changed to behenyl polyoxyethylene ether methacrylate, and the feed ratio of the hydrophobic monomer to the hydrophilic monomer is changed to 10%:100%, that is, 10g of the hydrophilic monomer 2-acrylamido-2-methyl-1-propane sulfonic acid, 30g of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, and 10g of hydroxypropyl methacrylate, 5g of the hydrophobic monomer behenyl polyoxyethylene ether methacrylate are added, and the amount of ultrapure water added is changed to 120g to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 3 is named Copolymer-3. The Copolymer-3 is formed by polymerizing three different hydrophilic monomers and one hydrophobic monomer through aqueous solution polymerization under the initiation of an initiator, and at the same time, the active chain end of one of the monomers is converted into an active center capable of initiating polymerization of another different monomer through a chain transfer agent. Therefore, the Copolymer-3 is one of the four-block copolymers such as ABCD-type four-block copolymer, ACBD-type four-block copolymer, and CBDA-type four-block copolymer.

[0128] The weight average molecular weight of Copolymer-3 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 23598 g / mol.

[0129] The Copolymer-3 was dissolved in the first solvent to prepare an embolic agent solution. Specifically, 1 g of the Copolymer-3 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic agent solution.

[0130] The embolic solution obtained in Example 3 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 3 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 240000mPa·s, 1000s -1 The viscosity reaches 454mPa·s at the shear rate.

[0131] Example 4

[0132] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is changed to N-isopropyl acrylamide and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, the hydrophobic monomer is changed to behenyl polyoxyethylene ether methacrylate, and the feed ratio of the hydrophobic monomer to the hydrophilic monomer is changed to 20%:80%, that is, 30g of the hydrophilic monomer N-isopropyl acrylamide and 10g of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide are added, and 10g of the hydrophobic monomer behenyl polyoxyethylene ether methacrylate is added to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 4 is named Copolymer-4. Similar to Copolymer-1, Copolymer-4 can also be one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0133] The weight average molecular weight of Copolymer-4 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 25325 g / mol.

[0134] The Copolymer-4 was dissolved in the first solvent to prepare an embolic solution. Specifically, 1 g of the Copolymer-4 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0135] The embolic solution obtained in Example 4 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 4 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 516000mPa·s, 1000s -1 The viscosity under shear rate reaches 403mPa·s.

[0136] Example 5

[0137] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomers are replaced with acrylic acid and hydroxyethyl acrylate to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 5 is named Copolymer-5. Similar to Copolymer-1, the Copolymer-5 can also be one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0138] The weight average molecular weight of Copolymer-5 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 38563 g / mol.

[0139] Copolymer-5 was dissolved in a first solvent to prepare an embolic agent solution. Specifically, 1 g of Copolymer-5 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic agent solution.

[0140] The embolic solution obtained in Example 5 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 5 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 339000mPa·s, 1000s -1 The viscosity under shear rate reaches 353mPa·s.

[0141] Example 6

[0142] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomers are replaced with acrylic acid and hydroxypropyl acrylate to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 6 is named Copolymer-6. Similar to Copolymer-1, Copolymer-6 can also be one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0143] The weight average molecular weight of Copolymer-6 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 32661 g / mol.

[0144] Copolymer-6 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-6 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0145] The embolic solution obtained in Example 6 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 6 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 229000mPa·s, 1000s -1 The viscosity under shear rate reaches 327mPa·s.

[0146] Example 7

[0147] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomers are replaced with acrylic acid and hydroxyethyl methacrylate to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 7 is named Copolymer-7. Similar to Copolymer-1, the Copolymer-7 can also be one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0148] The weight average molecular weight of Copolymer-7 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 43190 g / mol.

[0149] Copolymer-7 was dissolved in a first solvent to prepare an embolic agent solution. Specifically, 1 g of Copolymer-7 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic agent solution.

[0150] The embolic solution obtained in Example 7 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 7 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 385000mPa·s, 1000s -1 The viscosity under shear rate reaches 315mPa·s.

[0151] Example 8

[0152] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is replaced with acrylic acid and methoxy polyethylene glycol methacrylate to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 8 is named Copolymer-8. Similar to Copolymer-1, Copolymer-8 can also be one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0153] The weight average molecular weight of Copolymer-8 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 30575 g / mol.

[0154] Copolymer-8 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-8 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0155] The embolic solution obtained in Example 8 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 8 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 239000mPa·s, 1000s -1 The viscosity under shear rate reaches 418mPa·s.

[0156] Example 9

[0157] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomers are replaced with methacrylic acid and hydroxyethyl acrylate to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 9 is named Copolymer-9. Similar to Copolymer-1, Copolymer-9 can also be one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0158] The weight average molecular weight of Copolymer-9 was measured by gel permeation chromatography according to GB / T21963-2009, and was found to be 43329 g / mol.

[0159] Copolymer-9 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-9 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0160] The embolic solution obtained in Example 9 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 9 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 239000mPa·s, 1000s -1 The viscosity at the shear rate reached 323 mPa·s. Example 10

[0161] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is changed to methacrylic acid and hydroxypropyl acrylate, and the hydrophobic monomer is changed to dodecyl polyoxyethylene ether methacrylate, and the feed ratio of the two is still 10%:90%, to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 10 is named Copolymer-10. Similar to Copolymer-1, the Copolymer-10 can also be one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0162] The weight average molecular weight of Copolymer-10 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 32968 g / mol.

[0163] The Copolymer-10 was dissolved in the first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-10 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0164] The embolic solution obtained in Example 10 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 10 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 272000mPa·s, 1000s -1 The viscosity reaches 299mPa·s under shear rate.

[0165] Embodiment 11

[0166] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is changed to methacrylic acid and hydroxyethyl acrylate, and the hydrophobic monomer is changed to behenyl polyoxyethylene ether methacrylate, and the feed ratio of the two is still 10%:90%, to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 11 is named Copolymer-11. Similar to Copolymer-1, the Copolymer-11 can also be one of an ABC type ternary block copolymer, an ACB type ternary block copolymer, or a BAC type ternary block copolymer.

[0167] The weight average molecular weight of Copolymer-11 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 38750 g / mol.

[0168] Copolymer-11 was dissolved in a first solvent to prepare an embolic agent solution. Specifically, 1 g of Copolymer-11 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic agent solution.

[0169] The embolic solution obtained in Example 11 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 11 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 303000mPa·s, 1000s -1 The viscosity under shear rate reaches 270mPa·s.

[0170] Example 12

[0171] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is changed to methacrylic acid and methoxy polyethylene glycol methacrylate, and the hydrophobic monomer is changed to tetradecyl polyoxyethylene ether methacrylate, and the feed ratio of the two is still 10%:90%, to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 12 is named Copolymer-12. Similar to Copolymer-1, the Copolymer-12 can also be one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0172] The weight average molecular weight of Copolymer-12 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 37620 g / mol.

[0173] Copolymer-12 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-12 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0174] The embolic solution obtained in Example 12 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 12 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity reaches 441000mPa·s at shear rate, 1000s -1 The viscosity reaches 434 mPa·s at the shear rate.

[0175] Example 13 - Binary Block Copolymer

[0176] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is changed to methacrylamide and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, and the hydrophobic monomer is changed to hexadecyl polyoxyethylene ether methacrylate, and the feed ratio of the two is still 10%:90%, to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 13 is named Copolymer-13. Similar to Copolymer-1, the Copolymer-13 can also be one of an ABC-type ternary block copolymer, an ACB-type ternary block copolymer, or a BAC-type ternary block copolymer.

[0177] The weight average molecular weight of Copolymer-13 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 30408 ​​g / mol.

[0178] The Copolymer-13 was dissolved in the first solvent to prepare an embolic solution. Specifically, 1 g of the Copolymer-13 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0179] The embolic solution obtained in Example 13 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 13 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity reaches 491000mPa·s at shear rate, 1000s -1 The viscosity under shear rate reaches 228mPa·s.

[0180] Embodiment 14

[0181] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is changed to N-hydroxymethyl acrylamide and [2-(methacryloyloxy)ethyl] dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, and the hydrophobic monomer is changed to hexadecyl polyoxyethylene ether methacrylate, and the feed ratio of the two is still 10%:90%, to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 14 is named Copolymer-14. Similar to Copolymer-1, Copolymer-14 can also be one of an ABC type ternary block copolymer, an ACB type ternary block copolymer, or a BAC type ternary block copolymer.

[0182] The weight average molecular weight of Copolymer-14 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 43700 g / mol.

[0183] Copolymer-14 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-14 was dissolved in 9 g of ethanol to form an embolic solution.

[0184] The embolic solution obtained in Example 14 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 14 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 356000mPa·s, 1000s -1 The viscosity under shear rate reaches 403mPa·s.

[0185] Embodiment 15

[0186] According to the preparation method and steps of the copolymer in Example 1, the hydrophilic monomer is changed to N-hydroxymethyl acrylamide and [2-(methacryloyloxy)ethyl] dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, and the hydrophobic monomer is changed to 2-acrylamide-2-methyl dodecyl sodium sulfonate, and the feed ratio of the two is still 10%:90%, to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 15 is named Copolymer-15. Similar to Copolymer-1, Copolymer-15 can also be one of an ABC type ternary block copolymer, an ACB type ternary block copolymer, or a BAC type ternary block copolymer.

[0187] The weight average molecular weight of Copolymer-15 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 28531 g / mol.

[0188] Copolymer-15 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-15 was dissolved in 9 g of ethanol to form an embolic solution.

[0189] The embolic solution obtained in Example 15 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 15 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 293000mPa·s, 1000s -1 The viscosity under shear rate reaches 274mPa·s.

[0190] Example 16

[0191] According to the preparation method and steps of the copolymer in Example 1, the hydrophobic monomer is changed to sodium 2-acrylamido-2-methylbehenyl sulfonate, the hydrophilic monomer is still acrylic acid and hydroxypropyl methacrylate, and the feed ratio of the hydrophobic monomer to the hydrophilic monomer is still 10%:90%, to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 16 is named Copolymer-16. Similar to Copolymer-1, the Copolymer-16 can also be one of an ABC type ternary block copolymer, an ACB type ternary block copolymer, or a BAC type ternary block copolymer.

[0192] The weight average molecular weight of Copolymer-16 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 33396 g / mol.

[0193] Copolymer-16 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-16 was dissolved in 9 g of ethanol to form an embolic solution.

[0194] The embolic solution obtained in Example 16 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 16 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 254000mPa·s, 1000s -1 The viscosity under shear rate reaches 323mPa·s.

[0195] Embodiment 17

[0196] According to the preparation method and steps of the copolymer in Example 1, the feed ratio of the hydrophobic monomer to the hydrophilic monomer was changed to 5%:95% to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 17 is named Copolymer-17.

[0197] The weight average molecular weight of Copolymer--17 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 33400 g / mol.

[0198] Copolymer-17 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-17 was dissolved in 9 g of dimethyl sulfoxide to form an embolic solution.

[0199] The embolic solution obtained in Example 17 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 17 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 255000mPa·s, 1000s -1 The viscosity reaches 398mPa·s under shear rate.

[0200] Embodiment 18

[0201] According to the preparation method and steps of the copolymer in Example 1, the feed ratio of the hydrophobic monomer to the hydrophilic monomer was changed to 15%:85% to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 18 is named Copolymer-18.

[0202] The weight average molecular weight of Copolymer-18 was measured by gel permeation chromatography according to GB / T218183-2008, and was found to be 36043 g / mol.

[0203] Copolymer-18 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-18 was dissolved in 9 g of N-methylpyrrolidone to form an embolic solution.

[0204] The embolic solution obtained in Example 18 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 18 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 474000mPa·s, 1000s -1 The viscosity reaches 449 mPa·s at the shear rate.

[0205] Embodiment 19

[0206] According to the preparation method and steps of the copolymer in Example 1, the polymerization reaction conditions of the reaction system were changed to react at 45° C. for 4 hours under argon atmosphere to obtain a copolymer. For ease of description, the copolymer prepared in Example 19 is named Copolymer-19.

[0207] The weight average molecular weight of Copolymer-19 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 28673 g / mol.

[0208] The Copolymer-19 was dissolved in the first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-19 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0209] The embolic solution obtained in Example 19 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 19 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 432000mPa·s, 1000s -1 The viscosity under shear rate reaches 287mPa·s.

[0210] Embodiment 20

[0211] According to the preparation method and steps of the copolymer in Example 1, the polymerization reaction conditions of the reaction system were changed to 60° C. for 4 hours under argon atmosphere to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 20 is named Copolymer-20.

[0212] The weight average molecular weight of Copolymer-20 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 31790 g / mol.

[0213] Copolymer-20 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-20 was dissolved in 9 g of a 50% ethanol aqueous solution to form an embolic solution.

[0214] The embolic solution obtained in Example 20 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 20 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 291000mPa·s, 1000s -1 The viscosity under shear rate reaches 329mPa·s.

[0215] Embodiment 21

[0216] According to the preparation method and steps of the copolymer in Example 1, the polymerization reaction conditions of the reaction system were changed to 75° C. for 4 hours under argon atmosphere to obtain a copolymer. For the convenience of description, the copolymer prepared in Example 21 is named Copolymer-21.

[0217] The weight average molecular weight of Copolymer-21 was measured by gel permeation chromatography according to GB / T21863-2008, and was found to be 43323 g / mol.

[0218] Copolymer-21 was dissolved in a first solvent to prepare an embolic solution. Specifically, 1 g of Copolymer-21 was dissolved in 21 g of a 50% ethanol aqueous solution to form an embolic solution.

[0219] The embolic solution obtained in Example 21 was diluted 5 times with ultrapure water to prepare a copolymer gel. Further, the copolymer gel in Example 21 was tested according to the viscosity test method of the copolymer gel in Example 1. At 25°C, 0.1s -1 The viscosity at shear rate reaches 337000mPa·s, 1000s -1 The viscosity reaches 205 mPa·s at the shear rate.

[0220] Any one of the embolic agent solutions in Examples 1-21 above is selected for dilution to form an embolic agent system. For example, the embolic agent solution prepared in Example 3 is diluted and prepared into an embolic agent system with a diluent. Specifically, 1 part of the embolic agent solution, 2 parts of water for injection, and 2 parts of 320 mg / ml iodixanol are mixed evenly to form an embolic agent system, which is named as an experimental product.

[0221] Comparative Example

[0222] Poppy ethiodized oil and water for injection were mixed and emulsified at a ratio of 4:1 to form an embolic agent system, which was named the control sample.

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229] The results show that:

[0230] The embolic agent gels prepared from the copolymers in Examples 1 to 21 of the present application after being diluted with 5 times the second solvent (such as water) all exhibited obvious shear thinning behavior. Specifically, when the shear rate was 0.1s -1 When the viscosity of the embolic gel in each embodiment ranges from 2.29×10 5 mPa·s~5.35×10 5 mPa·s. That is, at a shear rate of 0.1s -1 When the shear rate increases to 1000s, the viscosity of the embolic system is on the order of 100,000. It can be understood by those skilled in the art that the embolic system is in a viscous state, that is, the embolic system is in a gel state. -1 When the shear rate is increased from 0.1s to 0.5s, the viscosity of the embolic agent system in each embodiment is greatly reduced, and the viscosity of the embolic agent system at this time is in the range of 205mPa·s to 454mPa·s. That is, those skilled in the art can understand that the embolic agent system is in a flowing state and has good fluidity. -1 Increase to 1000s -1 The viscosity of the embolic system decreased by 10 5 orders of magnitude, which makes the embolic agent system show obvious shear thinning behavior.

[0231] Therefore, when the shear stress increases, the long-chain molecules in the embolic agent system in the embodiment of the present application are forced to arrange downstream, reducing internal friction and entanglement. In this way, the long-chain molecules in the copolymer gel are more likely to arrange downstream under shear, showing obvious shear thinning behavior, thereby reducing the viscosity of the embolic agent system. In other words, the shear viscosity of the embolic agent system decreases with the increase of shear stress. Figure 1 In the rheological property curve of the embolic agent system, the shear thinning is manifested as a curve in which the viscosity decreases with increasing shear rate.

[0232] 6. Embolization effect test

[0233] The embolic performance test of the embolic agent system obtained in the above examples and comparative examples was carried out, and the test method was as follows:

[0234] Through the femoral artery, 6.4 mL of the experimental product was injected into the lower level of the left kidney with a 2.7 Fr microcatheter, and DSA angiography was performed immediately and 1 hour after surgery; 5.5 mL of the control product was injected into the lower level of the right kidney, and DSA angiography was performed immediately after surgery. After the animals were observed for 4 days, the femoral artery was accessed again, and DSA angiography was performed on both kidneys. 3.3 mL of the experimental product was injected into the upper level of the left kidney with a 2.7 Fr balloon occlusion microcatheter. After DSA angiography was performed immediately after surgery, the animals were killed and dissected.

[0235] See also Figure 2 and Figure 3 , Figure 2 It is a schematic diagram of the embolization experiment using the comparative embolic agent system, wherein a is the angiography immediately after the operation, and b is the angiography 4 days after the embolization. Figure 3 Schematic diagram of embolization experiment using the embolic agent system in the embodiment of the present application, wherein a is angiography immediately after surgery, and b is angiography 4 days after embolization.

[0236] like Figure 2 As shown in the comparative example, DSA angiography was performed 4 days later to observe that the blood vessels in the target area had basically been restored, and after dissection, it was observed that there was no abnormality in the target area, showing a new tissue state. Figure 3 As shown, DSA angiography was performed on the experimental sample 4 days later and it was observed that most of the blood vessels had been restored, and the peripheral blood vessels in the contour of the target area were still not stained. After dissection, obvious necrotic spots were observed on the surface of the target area. After longitudinal section, it was observed that the necrotic area was limited to the contour area, which was consistent with the DSA image, confirming that the embolic agent system provided in the embodiment of the present application has the effect of peripheral embolization and has a better embolic effect than iodized oil.

[0237] That is to say, the gel-type embolic agent system provided in the embodiment of the present application can form a continuous gel in the blood vessel and has good mechanical strength to achieve a good embolic effect.

[0238] In summary, the embolic agent system provided in the embodiment of the present application includes an embolic agent solution in a flowing state, and the embolic agent solution in a flowing state has good fluidity. When the embolic agent solution and the diluent are mixed to form the embolic agent system, the embolic agent system is transformed into a gel state, and exhibits fluidity under stress, that is, the embolic agent system is a non-viscous injectable gel-type liquid embolic agent system, which has a shear thinning effect. Therefore, when the embolic agent system is pushed, due to its good fluidity, when the embolic agent system enters the blood vessel, it can adapt to different sizes and shapes, and can be evenly filled inside the blood vessel to achieve the purpose of blocking blood flow. In this way, the embolic agent system provided in the embodiment of the present application has both good fluidity and good embolic effect.

[0239] Furthermore, the embolic agent system provided in the embodiment of the present application has good biocompatibility and no cytotoxicity. Therefore, while achieving the embolic effect, the embolic agent system also has good biocompatibility and no cytotoxicity, and it will be slowly diluted and dissolved by the blood in the blood vessels, and eventually be metabolized and excreted by the human body, and a small amount of reflux or entry into the venous circulation will not cause ectopic embolism, and has good safety.

[0240] The above description is only an implementation method of the present application, and does not limit the patent scope of the present application. Any equivalent structure or equivalent process transformation made using the contents of the present application specification and drawings, or directly or indirectly used in other related technical fields, are also included in the patent protection scope of the present application.

Claims

1. A copolymer, characterized in that The copolymer includes a hydrophilic segment and a hydrophobic segment, the hydrophilic segment includes at least one of acrylic acid and its derivative groups having a hydrophilic functional group, the hydrophobic segment includes at least one of acrylic acid and its derivative groups having a hydrophobic functional group, the hydrophilic functional group includes at least one of a carboxyl group, a hydroxyl group, a sulfonic acid group, and an amide group, and the hydrophobic functional group includes a long-chain alkyl group.

2. The copolymer according to claim 1, characterized in that The mass ratio of the hydrophilic segment to the hydrophobic segment is in the range of (80% to 95%): (5% to 20%).

3. The copolymer according to claim 1, characterized in that The weight average molecular weight of the copolymer is 10000 g / mol to 50000 g / mol.

4. The copolymer according to claim 1, characterized in that The monomer of the hydrophilic segment includes at least one of acrylic acid, methacrylic acid, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, 2-acrylamido-2-methyl-1-propane sulfonic acid, acrylamide, methacrylamide, N-isopropyl acrylamide, N-hydroxymethyl acrylamide, N,N-dimethylacrylamide, [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, and methoxy polyethylene glycol methacrylate.

5. The copolymer according to claim 1, characterized in that The monomer of the hydrophobic segment includes at least one of: dodecyl polyoxyethylene ether methacrylate, tetradecyl polyoxyethylene ether methacrylate, hexadecyl polyoxyethylene ether methacrylate, octadecyl polyoxyethylene ether methacrylate, behenyl polyoxyethylene ether methacrylate, hexadecyl dimethyl allyl ammonium chloride, octadecyl dimethyl allyl ammonium chloride, 2-acrylamide-2-methylbehenyl sodium sulfonate, 2-acrylamide tetradecane sodium sulfonate, and 2-acrylamide-2-methyldodecane sodium sulfonate.

6. The copolymer according to claim 1, characterized in that The copolymer according to any one of claims 1 to 5, characterized in that the structural formula of the copolymer is as shown in formula (I): Wherein, X:Y:Z in formula (I) is (5-20):(40-85):(10-40); n is 20-30, and m is 11-21.

7. A method for preparing a copolymer, characterized in that: include: At least one hydrophilic monomer and at least one hydrophobic monomer are copolymerized to form the copolymer, wherein the hydrophilic monomer includes acrylic acid and its derivatives having a hydrophilic functional group, the hydrophobic monomer includes acrylic acid and its derivatives having a hydrophobic functional group, the hydrophilic functional group includes at least one of a carboxyl group, a hydroxyl group, a sulfonic acid group, and an amide group, and the hydrophobic functional group includes a long-chain alkyl group.

8. The method for preparing a copolymer according to claim 7, characterized in that: The mass ratio of the hydrophilic monomer to the hydrophobic monomer is: (80% to 95%): (5% to 20%).

9. The method for preparing a copolymer according to claim 7, characterized in that: In the copolymerization reaction, a chain transfer agent is also included, and the chain transfer agent includes at least one of isopropanol, ethanol, and mercaptopropionic acid.

10. The method for preparing a copolymer according to claim 7, characterized in that: In the copolymerization reaction, an initiator is also included, and the initiator includes at least one of an azo initiator, a photoinitiator, and a redox initiator.

11. The method for preparing a copolymer according to claim 10, characterized in that: The azo initiator includes at least one of 2,2'-azobis[2-(2-imidazoline-2-yl)propane] dihydrochloride, azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, azobis(2-methylpropylimidazole) dihydrochloride, sodium azobiscyanovalerate, and azobis(2-methylpropylimidazole) dihydrochloride.

12. The method for preparing a copolymer according to claim 7, characterized in that: The step of copolymerizing the at least one hydrophilic monomer and the at least one hydrophobic monomer to form the copolymer comprises: Add at least one hydrophilic monomer and at least one hydrophobic monomer into a reaction container, add ultrapure water and a chain transfer agent, and stir to dissolve; A protective gas is introduced into the reaction system, an initiator is added to react to obtain a crude product, and the crude product is purified to obtain the copolymer.

13. The method for preparing a copolymer according to any one of claims 7 to 12, characterized in that: The step of copolymerizing the at least one hydrophilic monomer and the at least one hydrophobic monomer to form the copolymer comprises: The at least one hydrophilic monomer and the at least one hydrophobic monomer are added to a reaction container equipped with a reflux condenser and a gas guide device, ultrapure water and a chain transfer agent isopropanol are added, dissolved under stirring, argon is introduced into the reaction system for 10 minutes to 30 minutes, an initiator 2,2'-azobis[2-(2-imidazoline-2-yl)propane] dihydrochloride is added, and the reaction is carried out at 50°C to 75°C for 2 hours to 4 hours under an argon atmosphere to obtain a crude product, which is washed with at least one of methanol, ethanol and acetone, and then dried to obtain the copolymer.

14. An embolic solution, characterized in that: The method comprises a copolymer and a first solvent, wherein the copolymer is a copolymer as described in any one of claims 1 to 6 or a copolymer prepared by the method for preparing a copolymer as described in any one of claims 8 to 13, and the first solvent comprises at least one of ethanol, 50% ethanol aqueous solution, dimethyl sulfoxide, and N-methylpyrrolidone.

15. The embolic solution according to claim 14, characterized in that The concentration of the copolymer in the embolic agent solution is 5% to 10%.

16. The embolic solution according to claim 14 or 15, characterized in that: The shear viscosity of the embolic agent solution decreases with the increase of shear stress.

17. An embolic agent system, characterized in that: The invention comprises an embolic agent solution and a diluent, wherein the embolic agent solution is the embolic agent solution according to any one of claims 14 to 16, and the diluent comprises a developer, a second solvent and a functional component.

18. The embolic agent system according to claim 17, wherein: The volume ratio of the embolic solution to the diluent is 1:(5-20).

19. The embolic agent system according to claim 17, wherein: In the diluent, the mass fraction of the developer is 10% to 50%.

20. The embolic agent system according to any one of claims 17 to 19, characterized in that: The developer includes at least one of iohexol, iopamidol, iodixanol, and iofluanidol, and / or the second solvent includes at least one of water, saline, and glucose solution, and / or the functional component includes an anticancer drug.

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