Injectable amphiphilic block copolymer liquid embolic agent, preparation method thereof and interventional therapy preparation

Abstract

The invention relates to the technical field of embolism agents, in particular to an injectable amphiphilic block copolymer liquid embolism agent, a preparation method of the injectable amphiphilic block copolymer liquid embolism agent and an interventional therapy preparation, and the injectable amphiphilic block copolymer liquid embolism agent comprises an amphiphilic block copolymer, an organic solvent and at least one developable material; the amphiphilic block copolymer comprises a hydrophilic chain segment and a hydrophobic chain segment. The liquid embolism agent obtained by utilizing the amphiphilic block copolymer containing the hydrophilic chain segment and the hydrophobic chain segment, the organic solvent and the developable material can be self-assembled to form a lumen structure with a hydrophilic surface in the embolism process, the viscosity of the embolism agent is reduced by grafting the hydrophilic polymer chain segment, and the curing time is prolonged; therefore, the embolism of the blood vessel at the farther end is realized. The liquid embolism agent has controllable embolism property, the biomechanical property of the liquid embolism agent is relatively softer than that of a hydrophobic polymer, the flexibility is increased, and the liquid embolism agent is more suitable for embolism in blood vessels; and the embolism depth reaches the far-end capillary vessel, so that more branches are embolized.

Description

Technical Field

[0001] The invention relates to the technical field of embolic agents, and in particular to an injectable amphiphilic block copolymer liquid embolic agent and a preparation method thereof, and an interventional treatment preparation. Background Art

[0002] At present, the clinical liquid embolic agents available on the market are divided into adhesive liquid embolic agents with gel-like behavior and non-adhesive liquid embolic agents with lava-like behavior. Adhesive liquid embolic agents are mainly composed of cyanoacrylate, which does not have a development effect. They rapidly polymerize and coagulate by contact with anions in the blood. The tip of the microcatheter is easily coated with acrylic glue, causing occlusion. Non-adhesive liquid embolic agents are prepared by adding contrast agents to dimethyl sulfoxide (DMSO) solutions of ethylene vinyl alcohol (EVOH) copolymers.

[0003] Among them, Onyx (Medtronic, USA) is the most widely used in clinical practice and has obtained FDA and CE certification, making it available in Europe and the United States. Onyx is a dimethyl sulfoxide solution of ethylene vinyl alcohol copolymer with ultrafine tantalum powder added as a contrast agent. To ensure good visualization, Onyx needs to be shaken for a long time before use to form a suspension so that the tantalum powder is evenly distributed in the solution. At the same time, a DMSO-compatible catheter is required during operation. After injection into the vascular system, Onyx undergoes a phase transition, and the organic solvent (DMSO) in the EVOH polymer mixture diffuses and is replaced by the surrounding water environment, resulting in polymer precipitation to form an embolic mass to block the blood vessel and achieve the purpose of blocking blood flow. However, complications related to embolism include the risk of proximal vascular perforation, chronic inflammation or stroke, and the slow injection speed (<0.16mL / min) will still lead to problems with catheter removal once the reflux length exceeds a certain distance or exceeds several minutes, and the risk of catheter jam or rupture of the blood vessel after forced withdrawal.

[0004] Another liquid embolic agent, PHIL (MicroVention, Aliso Viejo, USA), is prepared from polylactic acid-co-glycolide, poly(hydroxyethyl methacrylate), triiodophenol and dimethyl sulfoxide. The covalently bound iodine improves the imaging effect and is suitable for long-term embolization; however, as a vascular implant material, its biosafety and potential toxicity remain crucial issues.

[0005] Therefore, the prior art still needs to be improved and developed. Summary of the invention

[0006] In view of the above-mentioned deficiencies in the prior art, the purpose of the present invention is to provide an injectable amphiphilic block copolymer liquid embolic agent and a preparation method and an interventional treatment preparation, aiming to solve the problems of uncontrollable curing time and embolic depth of the existing embolic agents.

[0007] The technical solution of the present invention is as follows:

[0008] An injectable amphiphilic block copolymer liquid embolic agent comprises an amphiphilic block copolymer, an organic solvent and at least one developable material; the amphiphilic block copolymer comprises a hydrophilic segment and a hydrophobic segment.

[0009] The injectable amphiphilic block copolymer liquid embolic agent comprises, by mass fraction, 2wt%-70wt% of amphiphilic block copolymer, 20%-99wt% of organic solvent, and 5%-80wt% of developable material.

[0010] The injectable amphiphilic block copolymer liquid embolic agent is polymerized from at least one hydrophilic segment and at least one hydrophobic segment.

[0011] The injectable amphiphilic block copolymer liquid embolic agent, wherein the hydrophilic segment is selected from one or more of gelatin, polyacrylic acid, polymethacrylic acid, polymethyl acrylate, polyacrylamine, polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyacrylamide, poly(N-isopropylacrylamide), polyglycerol ester, polyethyleneimine, polyglutamic acid, polyaspartic acid, polylysine, polyethylene glycol, polyoxyethylene, and polyvinylpyrrolidone.

[0012] The injectable amphiphilic block copolymer liquid embolic agent, wherein the hydrophobic segment is selected from one or more of ethylene-vinyl alcohol copolymer, polyethylene, polypropylene, polyisobutylene, polybutene, polyisoprene, polybutadiene, polybutenol, polybutenyl ester, polydimethylsiloxane, polyvinylidene fluoride, polyetheretherketone, polyethersulfone, polysiloxane, polytetrafluoroethylene, polyvinyl chloride, polynaphthol, polyphenanthrene ether, polyterephthalamide, polyterephthalimide, polyethylene terephthalate, polylactic acid, polylactic acid-glycolic acid copolymer, poly-ε-caprolactone, polybenzyl aspartic acid, polybenzyl glutamic acid, polystyrene, polyisopropyl acrylamide, and polyphenylene ether.

[0013] The injectable amphiphilic block copolymer liquid embolic agent, wherein the developable material comprises metal monomer powder, metal complex, and iodine-containing compound; the metal monomer powder is selected from one or more of gold powder, silver powder, platinum powder, tantalum powder, bismuth powder, tungsten powder, barium powder, iridium powder, cobalt powder, and chromium powder; the metal complex is a complex formed by a polymer and a polyoxometallic acid; the iodine-containing compound is selected from one or more of iohexol, iopamidol, iopromide, ioversol, iodic acid, iodixanol, diatrizoate, iodized oil, and a compound containing a 1,3,5-triiodophenyl group.

[0014] The injectable amphiphilic block copolymer liquid embolic agent, wherein the weight average molecular weight of the amphiphilic block copolymer is 1,000 to 1,000,000.

[0015] The injectable amphiphilic block copolymer liquid embolic agent, wherein the organic solvent is selected from at least one of dimethyl sulfoxide, N-vinyl pyrrolidone, N-methyl pyrrolidone, benzyl benzoate, acetone, toluene, dichloromethane, chloroform, ethanol, methanol, ethyl acetate, tetrahydrofuran, cyclohexane, cyclohexanone, diacetone alcohol, dimethylformamide, and methyl methacrylate.

[0016] A method for preparing an injectable amphiphilic block copolymer liquid embolic agent comprises the steps of:

[0017] mixing the amphiphilic block copolymer with an organic solvent to obtain a mixed solution;

[0018] The developable material is mixed with the mixed solution to obtain an injectable amphiphilic block copolymer liquid embolic agent.

[0019] An interventional treatment preparation comprises an injectable amphiphilic block copolymer liquid embolic agent.

[0020] Beneficial effects: The present invention provides an injectable amphiphilic block copolymer liquid embolic agent and a preparation method thereof, and an interventional treatment preparation. The injectable amphiphilic block copolymer liquid embolic agent comprises an amphiphilic block copolymer, an organic solvent, and at least one developable material; the amphiphilic block copolymer comprises a hydrophilic segment and a hydrophobic segment. The present invention utilizes an amphiphilic block copolymer containing a hydrophilic segment and a hydrophobic segment, an organic solvent, and a developable material to obtain a liquid embolic agent based on an amphiphilic polymer developable composite material. The liquid embolic agent can self-assemble to form a tubular structure with a hydrophilic surface during the embolization process, and the viscosity of the embolic agent is reduced by grafting a hydrophilic polymer segment, and the curing time is prolonged, thereby achieving embolization of more distal blood vessels. In addition, the liquid embolic agent has controllable embolic properties, and its biomechanical properties are relatively softer than those of hydrophobic polymers, and the increased flexibility makes it more suitable for embolization in blood vessels; and its embolization depth reaches the distal capillaries, embolizing more branches, and achieving an ideal therapeutic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a schematic diagram of the injectable amphiphilic block copolymer liquid embolic agent of the present invention self-assembling to form a tubular cavity structure with a hydrophilic surface;

[0022] Figure 2 This is a schematic diagram of the process for preparing an injectable amphiphilic block copolymer liquid embolic agent according to Example 1;

[0023] Figure 3Schematic diagram of the precipitation principle of the liquid embolic agent prepared in Example 1;

[0024] Figure 4 This is a state diagram of a liquid embolic agent containing tantalum powder in an aqueous solution;

[0025] Figure 5 This is a test diagram of the diffusion performance of the liquid embolic agent with PEG-PLGA as the main component in the decellularized liver;

[0026] Figure 6 This is a characterization diagram of the amphiphilic block copolymer liquid embolic agent embolized the portal vein of rat liver 7 days later;

[0027] Figure 7 This is a comparison of H&E staining of normal liver and rat liver 7 days after embolization;

[0028] Figure 8 is a state diagram of the PEG-PLGA block copolymer liquid embolic agent prepared in Example 2 in aqueous solution;

[0029] Fig. 9 The state diagram of the liquid embolic agent containing tantalum powder in aqueous solution in Example 2

[0030] Fig.10 is a state diagram of the PEG-PLGA block copolymer liquid embolic agent prepared in Example 3 in aqueous solution;

[0031] Fig.11 This is a state diagram of an aqueous solution of a PLGA-PEG-PLGA triblock copolymer at room temperature;

[0032] Fig.12 This is a state diagram of PLGA-PEG-PLGA triblock copolymer transforming into gel at 37°C;

[0033] Fig.13 This is the state diagram of the PLGA-PEG-PLGA triblock copolymer aqueous solution injected into 37°C water;

[0034] Fig.14 This is the state diagram of PLGA-PEG-PLGA triblock copolymer plus tantalum powder injected into 37℃ water;

[0035] Fig.15 This is a hydrophilicity test diagram;

[0036] Fig.16 This is a test diagram of the mechanical tensile properties of the liquid embolic agent after solidification and molding;

[0037] Fig.17 This is a comparative data chart of the viscosity of liquid embolic agents;

[0038] Fig.18The figure shows the sedimentation rate of the liquid embolic agent prepared in Example 1 in DMSO solutions with different concentration gradients;

[0039] Fig.19 is a graph showing the relationship between injection speed and the diameter of the solid embolic agent formed;

[0040] Fig. 20 The figure shows the effect of testing PLGA liquid embolic agent in decellularized liver. DETAILED DESCRIPTION

[0041] The present invention provides an injectable amphiphilic block copolymer liquid embolic agent and a preparation method thereof, and an interventional treatment preparation. To make the purpose, technical solution and effect of the present invention clearer and more specific, the present invention is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0042] It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as generally understood by those skilled in the art in the art to which the present invention belongs. It should also be understood that terms such as those defined in general dictionaries should be understood to have meanings consistent with the meanings in the context of the prior art, and will not be interpreted with idealized or overly formal meanings unless specifically defined as herein.

[0043] Arteriovenous malformation is a type of congenital vascular disease in which arteries and veins are abnormally connected, which may occur in soft tissues, bone tissues, internal organs and other parts of the body. The vascular network in the area of ​​arteriovenous malformation is dispersed and the vascular resistance is low, which recruits peripheral blood flow. At the same time, it also increases the risk of rupture and bleeding of the abnormal vascular mass under high pressure, which seriously threatens human health. Among them, the incidence of cerebral vascular malformation is increasing year by year. In 2022, the number of patients with cerebral vascular malformation bleeding in China reached 20,000, with a compound annual growth rate of 3.0%, and it is expected to reach 21,000 in 2023. Vascular embolization is minimally invasive, safe, effective, and has few side effects. It has become one of the preferred methods for the treatment of intracranial arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs). This treatment method mainly embolizes the abnormal vascular mass through blood vessels or percutaneously, blocks the blood flow of the distal capillary network, and prevents further development of the lesion area. At present, interventional embolic materials can be divided into solid embolic agents and liquid embolic agents according to their physical properties. Commonly used solid embolic agents include gelatin sponge, polyvinyl alcohol (PVA) particles, detachable balloons and spring coils. Granular embolic agents such as polyvinyl alcohol (PVA) are too large or too small to match the malformed blood vessels, and the recanalization rate of blood vessels after embolization is high. Spring coils are mostly used to assist embolization and cannot be used alone to treat arteriovenous malformations. Therefore, the embolization effect of solid embolic agents on irregular blood vessels is often not ideal, because microsphere aggregation may lead to catheter obstruction, proximal vessel obstruction and high recurrence rate. In contrast, liquid embolic agents (LEAs) have great advantages in embolizing smaller and irregular lesion vessels by using thinner microcatheters. A significant advantage of liquid embolic agents is that they can be precisely injected into lesion vessels to solidify and hinder blood flow without the need for direct surgery at the lesion site (such as hemangioma). This not only reduces surgical trauma, but also minimizes recovery time. The physicochemical transformation mechanisms of liquid embolic agents include polymerization, precipitation, or cross-linking processes such as activation of in situ gel formation by ion, pH or heat activation.

[0044] However, existing liquid embolic agents have defects in terms of controllable curing process and curing time, liquid viscosity, embolism depth and other related issues for vascular embolism. It is still necessary to further develop liquid embolic agents with superior performance for safe and effective intravascular embolism.

[0045] Based on this, the present invention provides an injectable amphiphilic block copolymer liquid embolic agent, comprising an amphiphilic block copolymer, an organic solvent, and at least one developable material; the amphiphilic block copolymer comprises a hydrophilic segment and a hydrophobic segment.

[0046] In this embodiment, after the developable material, the organic solvent and the amphiphilic block copolymer are mixed to form an injectable amphiphilic block copolymer liquid embolic agent, the developable material is physically and / or chemically bonded to the amphiphilic block copolymer to form an amphiphilic polymer developable composite material. The liquid embolic agent can be injected through a catheter to evenly fill the diseased blood vessels, and the polymer precipitates after contacting the blood, and completely embolizes the blood vessels after solidification, achieving precise treatment to avoid recanalization of the blood vessels; and the liquid embolic agent has the advantages of good development effect, not easy to block the microcatheter, prolonged in vivo solidification time, and can embolize more distal blood vessels and embolize completely, and has broad application prospects.

[0047] Specifically, the controllable liquid embolic agent based on the amphiphilic block copolymer of the present invention can self-assemble to form a tubular structure with a hydrophilic surface (such as Figure 1 As shown in the figure, the viscosity of the embolic agent is reduced by grafting hydrophilic polymer segments, and the curing time is prolonged, thereby achieving embolization of more distal blood vessels; at the same time, the developable material is developed under X-rays as a contrast agent, and the real-time position can be detected after injection into the body. The liquid embolic agent composed of amphiphilic block copolymers, organic solvents and at least one developable material has controllable embolic properties, and its biomechanical properties are relatively softer and more flexible than hydrophobic polymers, making it more suitable for intravascular embolism. At the same time, its embolism depth reaches the distal capillaries, embolizing more branches and achieving ideal therapeutic effects. The injectable amphiphilic block copolymer liquid embolic agent has multi-purpose characteristics, biosafety and the potential to treat various vascular diseases, and has great application prospects as an intravascular liquid embolic agent in the future clinic.

[0048] In some embodiments, the injectable amphiphilic block copolymer liquid embolic agent comprises, by mass fraction, 2wt%-70wt% of amphiphilic block copolymer, 20%-99wt% of organic solvent, and 5%-80wt% of developable material. By controlling the composition of the injectable amphiphilic block copolymer liquid embolic agent by mass fraction within the above range, the embolic agent can have the effects of good development effect, not easy to block the microcatheter, prolonged in vivo solidification time, and embolization of more distal blood vessels and complete embolization.

[0049] In a preferred embodiment, the injectable amphiphilic block copolymer liquid embolic agent comprises, by mass fraction, 5wt%-65wt% of amphiphilic block copolymer, 35%-95wt% of organic solvent, and 5%-65wt% of developable material.

[0050] In a more preferred embodiment, the injectable amphiphilic block copolymer liquid embolic agent comprises, by mass fraction, 6.67 wt % of amphiphilic block copolymer, 60 wt % of organic solvent, and 33.33 wt % of developable material.

[0051] In some embodiments, the amphiphilic block copolymer is polymerized by at least one hydrophilic segment and at least one hydrophobic segment. As an example, the hydrophilic segment is represented by A, and the hydrophobic segment is represented by B. The amphiphilic block copolymer may include but is not limited to AB, BA, ABA, BAB, ABAB, BABA, ABABA, etc., and the triblock hydrophilic-hydrophobic-hydrophilic copolymer of ABA structure includes such as poloxamer (PEO-PPO-PEO), PEG-PLA-PEG, PLGA-PEG-PLGA, etc. And the amphiphilic block copolymer may be one or at least two of the above copolymers.

[0052] Specifically, the amphiphilic block copolymer can be polymerized by a hydrophilic segment and a hydrophobic segment; it can also be polymerized by at least two different or the same hydrophilic segments and at least two different or the same hydrophobic segments; or, at least two different or the same hydrophilic segments and a hydrophobic segment are polymerized; or, a hydrophilic segment and at least two different or the same hydrophobic segments are polymerized. And the amphiphilic block copolymer is not limited to a single component, and can be a mixture of amphiphilic block copolymers of different compositions. Suitable amphiphilic block copolymers can be selected according to actual needs. The component content of the hydrophilic segment and the hydrophobic segment in the amphiphilic block copolymer directly affects the precipitation time and curing rate of the liquid embolic agent. By adjusting the ratio of the hydrophilic segment and the hydrophobic segment, the curing rate of the liquid embolic agent in the body can be adjusted.

[0053] In some embodiments, the molar ratio of the hydrophilic segment to the hydrophobic segment in the amphiphilic block copolymer is 0.1%-70%.

[0054] In some embodiments, the hydrophilic segment is selected from but not limited to one or more of methacrylated gelatin (Ge1MA), polyacrylic acid (PAA), polymethacrylic acid, polymethyl acrylate, polyacrylamine, polyhydroxyethyl acrylate (PHEA), polyhydroxyethyl methacrylate, polyacrylamide (PAM), poly(N-isopropylacrylamide) (PNIAM), polyglycerol esters, polyethyleneimine (PEI), polyglutamic acid, polyaspartic acid, polylysine, polyethylene glycol (PEG), polyoxyethylene (PEO), and polyvinylpyrrolidone (PVP). The above hydrophilic segments can be used to increase the hydrophilicity of the amphiphilic block copolymer.

[0055] In some embodiments, the hydrophobic segment is selected from but not limited to ethylene-vinyl alcohol copolymer (EVOH), polyethylene (PE), polypropylene (PP), polyisobutylene (PIB), polybutene (PB), polyisoprene (PI), polybutadiene (PBD), polybutene alcohol (PBA), polybutene ester (PBE), polydimethylsiloxane (PDMS), polyvinylidene fluoride (PVDF), polyetheretherketone, polyethersulfone (PES), polysiloxane, polytetrafluoroethylene (PTFE), polyvinyl chloride, polynaphthol, polyphenanthrene ether, polyterephthalamide (PA66), polyterephthalimide (PI), polyethylene terephthalate (PET), polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), poly-ε-caprolactone (PCL), polybenzyl aspartic acid (PBLA), polybenzyl glutamic acid (PBLG), polystyrene (PS), polyisopropylacrylamide (PIPAA), polyphenylene ether (PPO) One or more.

[0056] In some embodiments, the developable material includes metal monomer powder, metal complex, and iodine-containing compound; the metal monomer powder is selected from one or more of gold powder, silver powder, platinum powder, tantalum powder, bismuth powder, tungsten powder, barium powder, iridium powder, cobalt powder, and chromium powder; the metal complex is a complex formed by a polymer and a polyoxometalate; the iodine-containing compound is selected from one or more of iohexol, iopamidol, iopromide, ioversol, iodine acid, iodixanol, diatrizoate, and iodized oil. The above-mentioned developable material can be used as a contrast agent for development under X-rays, and the real-time position can be detected after injection into the body.

[0057] In some embodiments, the particle size of the developable material is ≤ 5 μm.

[0058] In some embodiments, the weight average molecular weight of the amphiphilic block copolymer is 1,000 to 1,000,000. By controlling the weight average molecular weight of the amphiphilic block copolymer within the above range, the biomechanical properties of the liquid embolic agent can be relatively softer than those of the hydrophobic polymer and the flexibility can be increased, making it more suitable for intravascular embolism. At the same time, the embolism depth can reach the distal capillaries and embolize more branches.

[0059] In some embodiments, the organic solvent is selected from at least one of dimethyl sulfoxide (DMSO), N-vinyl pyrrolidone (NVP), N-methyl pyrrolidone (NMP), benzyl benzoate (BB), acetone, toluene, dichloromethane, chloroform, ethanol, methanol, ethyl acetate (EAC), tetrahydrofuran (THF), cyclohexane (CYH), cyclohexanone (CYC), diacetone alcohol (DAA), dimethylformamide (DMF), and methyl methacrylate (MMA). The above organic solvent can dissolve the amphiphilic block copolymer.

[0060] In addition, the present invention also provides a method for preparing an injectable amphiphilic block copolymer liquid embolic agent, comprising the steps of:

[0061] Step S10: mixing an amphiphilic block copolymer (formed by polymerization of a hydrophilic segment and a hydrophobic segment) with an organic solvent to obtain a mixed solution;

[0062] Step S20: mixing the developable material with the mixed solution to obtain an injectable amphiphilic block copolymer liquid embolic agent.

[0063] In this embodiment, an injectable amphiphilic block copolymer liquid embolic agent can be prepared by a simple mixing method, wherein after the developable material is mixed with the mixed solution, the developable material is physically and / or chemically bonded to the amphiphilic block copolymer to form an amphiphilic polymer developable composite material. The liquid embolic agent can be injected through a catheter to evenly fill the diseased blood vessels, and the polymer precipitates after contacting the blood, and completely embolizes the blood vessels after solidification, achieving precise treatment to avoid recanalization of the blood vessels; and the liquid embolic agent has the advantages of good development effect, not easy to block the microcatheter, prolonged in vivo solidification time, and can embolize more distal blood vessels and embolize completely.

[0064] In addition, the present invention also provides an interventional treatment preparation, comprising the injectable amphiphilic block copolymer liquid embolic agent.

[0065] In some embodiments, the interventional therapeutic preparation can be used for various vascular diseases. The interventional therapeutic preparation can self-assemble to form a tubular structure with a hydrophilic surface during the embolization process. The viscosity of the embolic agent is reduced by grafting hydrophilic polymer segments, and the curing time is prolonged, thereby achieving embolization of more distal blood vessels. At the same time, the developable material is developed under X-rays as a contrast agent, and the real-time position can be detected after injection into the body.

[0066] The following examples are further given to illustrate the present invention in detail. It should also be understood that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention belong to the scope of protection of the present invention.

[0067] Example 1

[0068] This embodiment provides an injectable diblock amphiphilic block copolymer liquid embolic agent, such as Figure 2 As shown, the preparation steps include:

[0069] Poly(lactide-co-glycolide) (PLGA) and polyethylene glycol (PEG) are FDA-approved polymers that are widely used in the field of biomaterials and drug delivery due to their biocompatibility. Poly(ethylene glycol) (PEG) is a hydrophilic polymer that reduces its interaction with blood components. The ratio of poly(lactic acid) (PLA) and poly(glycolic acid) (PGA) in poly(lactic-co-glycolic acid) (PLGA) can also be used to control the degradation rate or drug release rate during controlled release from PLGA, such as 50 / 50, 75 / 25, 25 / 75, 90 / 10, 10 / 90, etc.

[0070] Step 1: The diblock amphiphilic block copolymer (PEG-PLGA) formed by grafting polyethylene glycol on poly(lactic acid-co-glycolic acid) (PLGA) was dissolved in an organic solvent dimethyl sulfoxide (DMSO) to obtain a uniform solution, wherein the content of PEG-PLGA was 10 wt%.

[0071] Step 2: Add tantalum powder (particle size ≤ 5 μm), a developable contrast agent, to the solution obtained in step 1, wherein the weight proportions are 6.67 parts of PEG-PLGA, 33.33 parts of tantalum powder, and 60 parts of DMSO, and mix thoroughly to obtain a liquid embolic agent.

[0072] Step 3: The liquid embolic agent obtained in step 2 is added to water or injected into a blood vessel through a microcatheter to solidify, thereby embolizing the blood vessels in the lesion area.

[0073] In this embodiment, during the solidification process of the liquid embolic agent, DMSO in the liquid embolic agent diffuses into water, and the high molecular polymer solidifies and precipitates through solvent exchange. The schematic diagram of the principle is shown in FIG. Figure 3 shown.

[0074] In this embodiment, the liquid embolic agent is solidified in water and then formed into a state as follows Figure 4 shown.

[0075] In this embodiment, the liquid embolic agent was solidified and formed in the decellularized liver in vitro model. Figure 5 As shown, the liquid embolic agent can be smoothly injected into the terminal blood vessels and solidify in the proximal and distal blood vessels to achieve an embolic effect.

[0076] In this example, the liquid embolic agent was solidified and formed in the rat liver model. Figure 6 shown.

[0077] In this embodiment, after the liquid embolic agent is solidified in the rat liver model, the slices are shown in FIG. Figure 7 The embolic agent was injected into the portal vein of rat liver by syringe and the embolized liver was characterized 7 days later (as shown in Figure 7Liquid embolic agents have good imaging effects. The embolic position can be monitored under Micro-CT, and the embolic agent reaches the end of the blood vessel. Figure 7 Comparison of the H&E staining of normal liver and rat liver 7 days after embolization shows that the material did not shift 7 days after embolization, and the embolized liver lobe was necrotic. H&E staining of liver tissue sections showed that the nuclei of the hepatocytes around the embolized blood vessels were dissolved and the nuclei of the hepatocytes could no longer be observed.

[0078] Example 2

[0079] The preparation method of the liquid embolic agent of this embodiment is basically the same as that of embodiment 1, except that: in this embodiment, a polymer with a weight average molecular weight of 103 kDa PEG 5k-PLGA75 / 25 is used, which is calculated by weight as 10 parts of PEG-PLGA and 90 parts of DMSO. After fully mixing, a polymer liquid is obtained and the solution is injected into water. By solvent exchange, Figure 8 Medium and high molecular weight polymer solidification precipitation. Fig. 9 In the method, PEG-PLGA 6 parts, tantalum powder 34 parts, DMSO 60 parts are used as the raw materials, and the mixture is fully mixed to obtain a liquid embolic agent and a state of the liquid embolic agent after solidification in water.

[0080] Example 3

[0081] The preparation method of the liquid embolic agent of this embodiment is basically the same as that of the embodiment 1, except that: the polymer material is changed to 20 parts by mass of PEG 5k-PLGA50 / 50 with a weight average molecular weight of 20 kDa and 80 parts by mass of DMSO, which are fully mixed to obtain a polymer liquid and the solution is injected into water, and then the solvent is exchanged. Fig.10 The solidification and precipitation state of the polymer was demonstrated, indicating that the amphiphilic block polymer material can also be used to prepare liquid embolic agents and solidify and precipitate in water after the weight-average molecular weight and mass fraction are changed.

[0082] Example 4

[0083] The preparation method of the liquid embolic agent in this example is basically the same as that in Example 1, except that a triblock amphiphilic block copolymer (PLGA-PEG-PLGA) is used in this example.

[0084] Fig.11 The state of aqueous solution of PLGA-PEG-PLGA triblock copolymer at room temperature is shown; Fig.12 It was demonstrated that PLGA-PEG-PLGA triblock copolymers transform into gels at 37°C; Fig.13 The PLGA-PEG-PLGA triblock copolymer aqueous solution was injected into 37°C water to solidify and form; Fig.14 The curing and molding of PLGA-PEG-PLGA triblock copolymer plus tantalum powder injected into 37°C water was demonstrated.

[0085] Example 5

[0086] The preparation method of the liquid embolic agent in this embodiment is substantially the same as that in Embodiment 1, except that a hydrophobic polymer (PLGA) is used in this embodiment.

[0087] Under the same molecular weight (weight average molecular weight of 79kDa), the hydrophilicity test results of the amphiphilic block copolymer (PEG-PLGA) and the hydrophobic polymer (PLGA) showed that the contact angle of PEG-PLGA was significantly smaller than that of PLGA, indicating that PEG-PLGA has better hydrophilicity (such as Fig.15 shown).

[0088] Furthermore, under the condition of equal molecular weight (weight average molecular weight of 79 kDa), the results of mechanical property test after curing of amphiphilic block copolymer (PEG-PLGA) and hydrophobic polymer (PLGA) showed that the Young's modulus of PEG-PLGA was significantly smaller than that of PLGA, indicating that the mechanical properties of the embolic agent prepared by PEG-PLGA were relatively softer than those of the hydrophobic PLGA embolic agent, and the flexibility was increased (e.g. Fig.16 shown).

[0089] Furthermore, the viscosity test results of the liquid embolic agent showed that Fig.17 As shown in the figure, the viscosity of PEG-PLGA liquid embolic agent was significantly lower than that of PLGA group.

[0090] Furthermore, the liquid embolic agents were injected into DMSO solutions with different concentration gradients to observe the precipitation and their solidification in DMSO-water mixed solvents (e.g. Fig.18 PLGA begins to form in a solvent with a DMSO volume fraction of 40%, and PEG-PLGA begins to form in a solvent with a DMSO volume fraction of 30%. This shows that compared with PLGA, PEG-PLGA begins to form in a solvent with a lower DMSO content, proving that the curing time of PEG-PLGA is longer and slower.

[0091] Furthermore, the relationship between injection speed and the diameter of the solid embolic agent is that the diameter of the solid embolic agent formed increases with increasing injection speed. The diameter of the solid embolic agent formed by the PEG-PLGA liquid embolic agent at different injection rates is smaller than that of the PLGA liquid embolic agent (e.g. Fig.19 shown).

[0092] Furthermore, the embolization effect was tested in decellularized liver. Fig. 20When the PLGA liquid embolic agent is injected into the blood vessel, it precipitates quickly, causing a large amount of blockage in the main blood vessel, resulting in vascular rupture, failure to reach the terminal blood vessel, and incomplete embolization. Fig. 20 Compared with PLGA liquid embolic agents, Figure 5 The PEG-PLGA liquid embolic agent can reach the peripheral blood vessels smoothly, showing a more superior embolic performance.

[0093] Example 6

[0094] This embodiment lists liquid embolic agents with different mass percentage compositions, and the developable material, the amphiphilic block copolymer, and the organic solvent are mixed in different mass percentages, as shown in Table 1:

[0095] Table 1

[0096] Developable material (wt%) Amphiphilic block copolymer (wt%) Organic solvent (wt%) 5 10 85 10 9 81 15 8.5 76.5 20 8 72 34 6.6 59.4 40 6 54 60 4 36 80 2 18

[0097] The liquid embolic agent is prepared according to Table 1, so that the liquid embolic agent has controllable embolic properties. Its biomechanical properties are relatively softer than those of hydrophobic polymers, and its increased flexibility makes it more suitable for intravascular embolism. Moreover, its embolic depth reaches the distal capillaries, embolizing more branches and achieving an ideal therapeutic effect.

[0098] By mass percentage, the mass percentage of the developable material was set at 50wt%, and the ratio of the amphiphilic block copolymer to the organic solvent was controlled. The solidification of the obtained liquid embolic agent in water is shown in Table 2:

[0099] Table 2

[0100]

[0101] Wherein, *, √, and × represent -half, -complete, and -no precipitation in water, respectively.

[0102] It can be seen that by controlling the composition of the injectable amphiphilic block copolymer liquid embolic agent in the above-mentioned mass fraction range, a liquid embolic agent with good imaging effect, not easy to block the microcatheter, prolonged in vivo solidification time, and the ability to embolize more distal blood vessels and complete embolization can be prepared.

[0103] Example 7

[0104] The preparation method of the liquid embolic agent of this embodiment is basically the same as that of Example 1, except that: in this embodiment, the developer used is iohexol, which is recorded as 10 parts of PEG-PLGA, 30 parts of iohexol, and 60 parts of DMSO by mass. The liquid embolic agent is obtained after sufficient mixing. The normal liver blood vessels of rats are embolized through a microcatheter. The embolic agent solidifies in the blood vessels and can be embolized to the end of the blood vessels. The embolic agent can be continuously developed in vivo, and ischemic cell necrosis occurs around the embolized blood vessel area.

[0105] In summary, the present invention provides an injectable amphiphilic block copolymer liquid embolic agent and its preparation method and interventional treatment preparation. The injectable amphiphilic block copolymer liquid embolic agent includes an amphiphilic block copolymer, an organic solvent, and at least one developable material; the amphiphilic block copolymer includes a hydrophilic segment and a hydrophobic segment. The present invention uses an amphiphilic block copolymer containing a hydrophilic segment and a hydrophobic segment with an organic solvent and a developable material to obtain a liquid embolic agent based on an amphiphilic polymer developable composite material. The liquid embolic agent can self-assemble to form a tubular structure with a hydrophilic surface during the embolization process. The viscosity of the embolic agent is reduced by grafting a hydrophilic polymer segment, and the curing time is prolonged, thereby achieving embolization of more distal blood vessels. In addition, the liquid embolic agent has controllable embolic properties, and its biomechanical properties are relatively softer than those of hydrophobic polymers, and the increased flexibility is more suitable for embolism in blood vessels; and its embolism depth reaches the distal capillaries, embolizing more branches, and achieving an ideal therapeutic effect.

[0106] It should be understood that the application of the present invention is not limited to the above examples. For ordinary technicians in this field, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. An injectable amphiphilic block copolymer liquid embolic agent, characterized in that: The invention comprises an amphiphilic block copolymer, an organic solvent and at least one developable material; the amphiphilic block copolymer comprises a hydrophilic segment and a hydrophobic segment.

2. The injectable amphiphilic block copolymer liquid embolic agent according to claim 1, characterized in that: The injectable amphiphilic block copolymer liquid embolic agent comprises, by mass fraction, 2wt%-70wt% of the amphiphilic block copolymer, 20%-99wt% of the organic solvent, and 5%-80wt% of the developable material.

3. The injectable amphiphilic block copolymer liquid embolic agent according to claim 1 or 2, characterized in that: The amphiphilic block copolymer comprises at least one hydrophilic segment and at least one hydrophobic segment.

4. The injectable amphiphilic block copolymer liquid embolic agent according to claim 1 or 2, characterized in that: The hydrophilic segment is selected from one or more of gelatin, polyacrylic acid, polymethacrylic acid, polymethyl acrylate, polyacrylamine, polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyacrylamide, poly(N-isopropylacrylamide), polyglycerol ester, polyethyleneimine, polyglutamic acid, polyaspartic acid, polylysine, polyethylene glycol, polyoxyethylene, and polyvinylpyrrolidone.

5. The injectable amphiphilic block copolymer liquid embolic agent according to claim 1 or 2, characterized in that: The hydrophobic segment is selected from one or more of ethylene-vinyl alcohol copolymer, polyethylene, polypropylene, polyisobutylene, polybutene, polyisoprene, polybutadiene, polybutenol, polybutenyl ester, polydimethylsiloxane, polyvinylidene fluoride, polyetheretherketone, polyethersulfone, polysiloxane, polytetrafluoroethylene, polyvinyl chloride, polynaphthol, polyphenanthrene ether, polyterephthalamide, polyterephthalimide, polyethylene terephthalate, polylactic acid, polylactic acid-glycolic acid copolymer, poly-ε-caprolactone, polybenzyl aspartic acid, polybenzyl glutamic acid, polystyrene, polyisopropyl acrylamide, and polyphenylene ether.

6. The injectable amphiphilic block copolymer liquid embolic agent according to claim 1, characterized in that: The developable material includes metal monomer powder, metal complex, and iodine-containing compound; the metal monomer powder is selected from one or more of gold powder, silver powder, platinum powder, tantalum powder, bismuth powder, tungsten powder, barium powder, iridium powder, cobalt powder, and chromium powder; the metal complex is a complex formed by a polymer and a polyoxometalate; the iodine-containing compound is selected from one or more of iohexol, iopamidol, iopromide, ioversol, iodine acid, iodixanol, diatrizoate, iodized oil, and a compound containing a 1,3,5-triiodophenyl group.

7. The injectable amphiphilic block copolymer liquid embolic agent according to claim 1, characterized in that: The weight average molecular weight of the amphiphilic block copolymer is 1,000 to 1,000,000.

8. The injectable amphiphilic block copolymer liquid embolic agent according to claim 1, characterized in that: The organic solvent is selected from at least one of dimethyl sulfoxide, N-vinyl pyrrolidone, N-methyl pyrrolidone, benzyl benzoate, acetone, toluene, dichloromethane, chloroform, ethanol, methanol, ethyl acetate, tetrahydrofuran, cyclohexane, cyclohexanone, diacetone alcohol, dimethylformamide, and methyl methacrylate.

9. A method for preparing the injectable amphiphilic block copolymer liquid embolic agent according to any one of claims 1 to 8, characterized in that: Includes steps: mixing the amphiphilic block copolymer with an organic solvent to obtain a mixed solution; The developable material is mixed with the mixed solution to obtain an injectable amphiphilic block copolymer liquid embolic agent.

10. An interventional therapy preparation, characterized in that: The invention comprises the injectable amphiphilic block copolymer liquid embolic agent according to any one of claims 1 to 8.

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