Soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolism microsphere and preparation method thereof

Abstract

The invention provides a soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolism microsphere and a preparation method thereof, the microsphere takes polyurethane as a matrix, magnetic particles, a developing agent and an anti-tumor hydrophobic drug are compounded through a microfluidic method, and the microsphere has good soft elasticity. The blood vessel embolism microsphere provided by the invention has good biocompatibility and safety, controllable particle size, uniform size and soft elasticity, can enter blood vessels with different diameters and embolism tumor peripheral blood vessels, is higher in filling rate and more complete in embolism, meets the requirement of stable embolism, and has a good application prospect. According to the preparation method, efficient loading and long-acting slow release of anti-tumor hydrophobic drugs can be effectively achieved, developing and precise positioning can be achieved, and the magnetic-thermal therapy and targeted drug use can be achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations characterized by special physical shapes, and particularly relates to a soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolization microsphere and a preparation method thereof. Background Art

[0002] Cancer cells rely on a continuous blood supply for nutrients and oxygen to proliferate rapidly. They secrete angiogenic factors (such as VEGF) to induce angiogenesis. Studies have found that approximately 90% of solid tumors receive their blood supply from specific arteries (such as the hepatic artery in liver cancer), providing a breakthrough for targeted blood supply disruption.

[0003] Vascular embolic agents are precisely injected into the tumor's blood supply arteries through interventional techniques. They block blood flow with physical embolism or drug-loaded microspheres, causing cancer cells to become hypoxic and necrotic, while suppressing pro-angiogenic signals in the tumor microenvironment. For example, in the treatment of liver cancer, transcatheter embolization (TACE), combining embolization with local chemotherapy, can increase drug concentrations in the tumor area by 20-40 times. This dual mechanism has resulted in an objective response rate exceeding 50% and a median survival of over 19 months. This strategy, combining precise blood occlusion with efficient tumor control, has become an important treatment for advanced cancers.

[0004] Currently, polymer microspheres are generally used as embolic agents, mainly polyvinyl alcohol microspheres and gelatin microspheres. Polyvinyl alcohol microspheres are often prepared by suspension polymerization, where linear polyvinyl alcohol or functional branched polyvinyl alcohol molecules are dissolved in the aqueous phase, and initiators, cross-linking agents, etc. are dissolved in the oil phase. This process has poor stability, low reaction controllability, and a wide distribution of microsphere particle size. Microspheres of the target particle size need to be screened through a sieve, and the product utilization rate is low. Gelatin microspheres are prepared by the oil-in-water method, which has higher process stability, but their drug loading method is similar to that of polyvinyl alcohol microspheres. The microspheres need to be soaked in a drug solution for a period of time before use, which is cumbersome to operate, and the aqueous phase microspheres often only have a good affinity for hydrophilic drugs. However, most anti-tumor drugs are hydrophobic, and the hydrophilicity of polyvinyl alcohol and gelatin aqueous phase microspheres in the prior art greatly limits their loading of hydrophobic drugs.

[0005] The visualization of embolic microspheres is crucial for intraoperative accuracy and postoperative follow-up evaluation. Currently, the microspheres used in clinical practice cannot be developed under X-ray or magnetic resonance imaging. CN118649277A discloses a radioactive iodine-loaded manganese-based metal organic framework-containing degradable embolic microsphere and its preparation method. First, a hollow porous manganese-based metal framework is combined with radioactive iodine-131, and polyurethane microspheres are prepared by emulsion dispersion polymerization. Then, the iodine-loaded metal organic framework is coated on the surface of the microsphere by polydopamine coating to achieve X-ray development. However, the developer in the microsphere is only present on the surface of the microsphere, the coating amount is small, and the stability is limited. CN115590824A discloses a polyvinyl alcohol embolic microsphere with a developer and its preparation method and application. First, a cross-linking agent with a developing element is prepared, and then the polyvinyl alcohol microspheres are prepared by emulsion polymerization or microfluidics. The embolic microspheres are stable in development, but the modification and synthesis process of the cross-linking agent is complicated. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to address the above-mentioned deficiencies in the prior art and provide a soft elastic polyurethane-based developable magnetic vascular embolization microsphere loaded with hydrophobic drugs and a preparation method thereof. The particle size of the microspheres can be precisely controlled, the hydrophobic drugs can be conveniently and effectively loaded, and they have X-ray developability and soft elasticity, making them suitable for tumor embolization treatment. The preparation method has a stable reaction process.

[0007] In order to solve the above technical problems, the technical solution provided by the present invention is: Provided are soft elastic polyurethane-based developable magnetic vascular embolization microspheres loaded with hydrophobic drugs. The microspheres use polyurethane as a matrix and are composited with magnetic particles, a developer and an anti-tumor hydrophobic drug by a microfluidic method. The microspheres have good soft elasticity.

[0008] According to the above scheme, the particle size of the developable magnetic vascular embolization microspheres can be adjusted within the range of 50 to 1000 μm, and the particle size is uniform.

[0009] According to the above scheme, the polyurethane is obtained by cross-linking polyurethane terminated by carbon-carbon double bonds.

[0010] According to the above solution, the magnetic particles are at least one of ferroferric oxide, zinc ferrite, cobalt ferrite, manganese ferrite, and γ-ferric oxide, and the particle size is 5 to 500 nm.

[0011] According to the above solution, the developer is at least one of iodized oil, iodophenyl ester, and barium sulfate. The developer is used for X-ray imaging.

[0012] According to the above scheme, the anti-tumor hydrophobic drug is one or more of platinum drugs (cisplatin, carboplatin, oxaliplatin, lobaplatin, nedaplatin), anthracycline drugs (doxorubicin, pirarubicin, daunorubicin, epirubicin), taxane drugs (paclitaxel, docetaxel), vinca alkaloids (vinblastine, vincristine, vindesine, vinorelbine), camptothecin drugs (camptothecin, irinotecan, topotecan, rubitecan), nitrosourea drugs (carmustine, lomustine, semustine, nimustine), targeted anticancer drugs (sorafenib, erlotinib, apatinib, sunitinib).

[0013] According to the above solution, the mass of the magnetic particles is 1-50 wt% of the polyurethane, the mass of the developer is 5-100 wt% of the polyurethane, and the mass of the hydrophobic drug is 1-50 wt% of the polyurethane.

[0014] The present invention also includes a method for preparing the above-mentioned soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolization microspheres: polyurethane terminated with carbon-carbon double bonds, magnetic particles, a developer, an anti-tumor hydrophobic drug, and an initiator are mixed uniformly as a single dispersed phase or separately as a multi-component dispersed phase (oil phase) in an organic solvent as needed, a polyvinyl alcohol solution is used as a mobile phase (aqueous phase), a microsphere emulsion is prepared by a microfluidic method, the polyurethane in the microsphere emulsion is polymerized by the initiator, and the organic solvent is removed by rotary evaporation to obtain soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolization microspheres.

[0015] According to the above scheme, the preparation method of the carbon-carbon double bond terminated polyurethane includes the following steps: dissolving the first polyol, the second polyol, the diisocyanate, and the catalyst in a solvent, reacting at 70-90°C for 2-5 hours under the protection of an inert gas for prepolymerization, then cooling to 60-65°C, adding a capping agent and continuing the reaction for 1-3 hours, and post-processing to obtain the carbon-carbon double bond terminated polyurethane.

[0016] According to the above scheme, the solvent is any one of toluene, acetone, N,N-dimethylformamide, and dimethyl sulfoxide; the total mass of the first polyol and the second polyol to the solvent volume ratio is 0.1 to 1 g / mL; the first polyol is any one of polyethylene glycol and polypropylene glycol, with a number average molecular weight of 400 to 4000, providing softness; the second polyol is any one of polycaprolactone diol, polylactic acid diol, and poly (lactic acid-caprolactone) diol, with a number average molecular weight of 1000 to 10000, providing degradability; the diisocyanate is isophorone diol. The polyurethane microspheres are preferably selected from the group consisting of isocyanate, hexamethylene diisocyanate, and 4,4-diisocyanatodicyclohexylmethane; the catalyst is an organometallic catalyst, including an organotin catalyst or an organobismuth catalyst; the inert gas is selected from the group consisting of argon, nitrogen, and helium; and the capping agent is a small molecule containing a hydroxyl group and a carbon-carbon double bond, selected from the group consisting of hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, allyl alcohol, 3-methylallyl alcohol, ethyl 4-hydroxycrotonate, 2-hydroxycyclohexyl acrylate, and 3-butene-1-ol. The introduction of capped carbon-carbon double bonds allows for further crosslinking of the polyurethane, imparting elasticity to the microspheres. The polyurethane's flexibility allows for easy deformation, facilitating passage through microcatheters into vessels of varying diameters, enabling embolization of smaller peripheral tumor vessels and improving embolization efficiency.

[0017] Preferably, the molar ratio of the first polyol to the second polyol is 1:0.05-2, the molar ratio of the total molar amount of the first polyol and the second polyol to the diisocyanate is 1:1.05-2, and the molar ratio of the total molar amount of the first polyol and the second polyol to the capping agent is 1:0.1-2. Furthermore, the molar ratio of the total hydroxyl groups in the first polyol, the second polyol, and the capping agent to the isocyanate groups in the diisocyanate is 1:1, and the mass of the catalyst is 0.01-0.5% of the total mass of the first polyol, the second polyol, the diisocyanate, and the capping agent. If the capping agent content is too low, the microspheres have low elasticity and are difficult to recover from deformation. If the capping agent content is too high, the microspheres have high hardness and are difficult to deform.

[0018] According to the above scheme, the initiator is a thermal initiator and / or photoinitiator for initiating carbon-carbon double bond polymerization, specifically azobisisobutyronitrile, azobisisovaleronitrile, azobiscyclohexanenitrile, azobisisoheptonitrile, benzoyl peroxide, tert-butyl peroxide, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (CAS No. 106797-53-9), 2-hydroxy-2-methylpropiophenone (CAS No. 7473-98-5), 2,2-dimethoxy-2-phenylacetophenone (CAS No. 2 4650-42-8), 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (CAS No. 71868-10-5), ethyl 2,4,6-trimethylbenzoylphenylphosphonate (CAS No. 84434-11-7), diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide (CAS No. 75980-60-8), phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide (CAS No. 162881-26-7), and camphorquinone.

[0019] According to the above scheme, the organic solvent is obtained by mixing a main solvent and a co-solvent, the main solvent is any one of dichloromethane or chloroform or a mixture of the two in any proportion, the co-solvent is a low-boiling point solvent that can dissolve anti-tumor hydrophobic drugs, specifically any one of acetone, tetrahydrofuran, ethyl acetate, methanol, ethanol, ether, n-hexane, isopropanol, acetonitrile, and chloroform or a mixture of several thereof, and the volume ratio of the main solvent to the co-solvent is 1 to 9:1.

[0020] According to the above scheme, the concentration of the carbon-carbon double bond terminated polyurethane in the dispersed phase is 0.005-0.2 g / mL, the mass ratio of the anti-tumor hydrophobic drug to the carbon-carbon double bond terminated polyurethane is 0.01-0.2:1, the mass ratio of the magnetic particles to the carbon-carbon double bond terminated polyurethane is 0.02-0.2:1, the mass ratio of the developer to the carbon-carbon double bond terminated polyurethane is 0.1-2:1, and the mass ratio of the initiator to the carbon-carbon double bond terminated polyurethane is 0.0001-0.01:1.

[0021] According to the above scheme, the polyvinyl alcohol solution is obtained by dissolving polyvinyl alcohol 1788 in water, with a concentration of 0.5 to 5 wt%.

[0022] According to the above scheme, the microfluidic method for preparing microsphere emulsion includes the following steps: connecting the mobile phase to the silicone hose through a syringe, connecting the dispersed phase to the silicone hose through a single-component or multi-component syringe with a flat needle, and then using a dual-channel syringe pump to push the mobile phase and dispersed phase at a constant speed to form a microsphere emulsion.

[0023] According to the above scheme, the inner diameter of the silicone hose is 0.5 to 2 mm, the size of the flat-end needle is 18 to 32 gauge, and the outer diameter of the flat-end needle is smaller than the inner diameter of the silicone hose; the dispersed phase flow rate is 0.05 to 80 mL / h, and the flow rate ratio of the mobile phase to the dispersed phase is 5 to 200:1. When multiple components in the dispersed phase, such as anti-tumor hydrophobic drugs, magnetic particles, and imaging agents, are difficult to stabilize in the solvent due to mutual incompatibility, the incompatible components can be separated into two or more sub-channels and injected separately, that is, using a multi-channel microfluidic method, which effectively solves the stability problem and produces a uniform and stable microsphere emulsion and microspheres.

[0024] According to the above scheme, the initiator triggers the polymerization reaction of polyurethane in the microsphere emulsion in a manner including thermal initiation or photoinitiation, the thermal initiation temperature is 30-80°C, the photoinitiation light source wavelength is 365nm or 405nm, and the polymerization reaction time is 5-180min.

[0025] According to the above scheme, the rotary evaporation speed is 20-100 rpm, the pressure is 50-1013 mbar, and the temperature is 20-80° C. If the speed is too low, the solvent evaporates slowly and the droplets are prone to adhesion. If the speed is too high, the microspheres are prone to deformation.

[0026] The present invention also provides the use of the above-mentioned soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolization microspheres in the preparation of vascular embolization drugs for treating tumors.

[0027] The vascular embolic microspheres described in this invention utilize a polyurethane matrix loaded with a hydrophobic anti-tumor drug and are combined with a developer and magnetic particles. Microfluidics allows for the controlled preparation of the composite microspheres, resulting in vascular embolic microspheres with uniform X-ray development. By using polyurethane terminated with carbon-carbon double bonds as the raw material, elastic vascular embolic microspheres can be obtained. By optimizing the molecular weights and ratios of the first polyol, second polyol, diisocyanate, and end-capping agent in the polyurethane raw material, soft, elastic polyurethane microspheres can be obtained.

[0028] The beneficial effects of the present invention are as follows: 1. The vascular embolic microspheres provided by the present invention have excellent biocompatibility and safety, controllable and uniform particle size, and soft elasticity. They can enter blood vessels of varying diameters and embolize peripheral tumor vessels, achieving a higher filling rate and more complete embolization, meeting the requirements for stable embolization. They can effectively achieve efficient loading and long-term sustained release of anti-tumor hydrophobic drugs, are imageable and precisely targeted, and possess magnetic properties, enabling magnetic thermal therapy and targeted medication. 2. The preparation method of the present invention is simple, highly controllable, and amenable to large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the polyurethane prepared in step (1) of Example 1 of the present invention; Figure 2This is a photo of the vascular embolic microspheres prepared in Example 1 under an optical microscope; Figure 3 This is a graph showing the magnetothermal temperature rise curve of the vascular embolization microspheres prepared in Example 1; Figure 4 This is a drug release curve of the vascular embolization microspheres prepared in Example 1; Figure 5 The images of the vascular embolic microspheres prepared in Example 1 and Example 2 under X-ray development; Figure 6 The rheological test graphs of the vascular embolic microspheres prepared in Example 1 and Example 2; Figure 7 This is a graph showing the deformation recovery of the vascular embolic microspheres prepared in Example 3 after being compressed; Figure 8 This is the pressure-strain diagram of the vascular embolic microspheres prepared in Example 3. DETAILED DESCRIPTION

[0030] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is further described in detail below with reference to the accompanying drawings.

[0031] The magnetic particles used in the embodiment of the present invention are ferroferric oxide magnetic particles, and the specific preparation method is as follows: the ferroferric oxide magnetic particles are prepared by a high-temperature pyrolysis method. First, 2 mmol of ferric acetylacetonate, 3.8 mmol of oleic acid, and 20 mL of dibenzyl ether were weighed and mixed in a 100 mL three-necked flask. The raw materials were completely dissolved by ultrasonication for 5 minutes to obtain a mixed solution. Then, the air in the flask was vacuum-evacuated and replaced with argon. The vacuum-evacuation and replacement were repeated three times to completely remove the air in the flask. Subsequently, under the protection of argon, the mixed solution was heated to 120°C and kept warm for half an hour to remove all water in the solution. Thereafter, it was further heated to 200°C and kept warm for 2 hours to allow the metal salt to fully decompose and form small crystal nuclei. The temperature was then rapidly increased to 290°C at a rate of 25°C / min and kept warm for half an hour to allow the crystal nuclei to gradually grow into nanoparticles. Finally, heating was stopped. After the solution was naturally cooled to room temperature, the obtained magnetic nanoparticles were separated by a magnet and the product was washed alternately with anhydrous ethanol and n-hexane. The washing process was repeated three times. The product was then vacuum-dried for 24 hours to obtain ferroferric oxide magnetic particles (with a hydrodynamic diameter of about 100 nm and monodispersity).

[0032] Example 1 A soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolization microsphere, the preparation method of which is as follows: (1) Preparation of polyurethane terminated with carbon-carbon double bonds: 1.5 g polyethylene glycol 800 (1.87 mmol) and 0.94 g polycaprolactone diol 2000 (0.47 mmol) were added to a 100 mL three-necked round-bottom flask, dried under vacuum at 100 °C overnight, and the mixture was evacuated and replaced with inert gas argon three times. Then, toluene solvent treated with 10 mL molecular sieves to remove water was added. After mechanical stirring and dissolution, 0.625 g isophorone diisocyanate (2.81 mmol) and 3 μL dibutyltin dilaurate were added. The mixture was stirred and reacted at 75 °C for 3 hours under argon protection, and then cooled to 60 °C. 0.11 g hydroxyethyl acrylate (0.94 mmol) was added and the reaction was continued for 2 hours. After the reaction, the product was precipitated and washed three times in n-hexane. After vacuum drying at room temperature, the obtained solid product (about 3 g) was stored at 4 °C in the dark. (2) Preparation of microsphere emulsion: Prepare the mobile phase (aqueous phase): Weigh polyvinyl alcohol 1788 and dissolve it in deionized water and filter it to obtain a polyvinyl alcohol concentration of 1 wt %. Preparation of dispersed phase (oil phase): The dispersed phase is divided into component A and component B. Component A: 2 mg of sorafenib (hydrophobic drug) is weighed and dissolved in 0.2 mL of acetone, 10 mg of the carbon-carbon double bond-terminated polyurethane prepared in step (1) and 0.1 mg of azobisisobutyronitrile (polymerization initiator) are weighed and dissolved in 0.8 mL of dichloromethane, the two are mixed and then 20 mg of iodized oil (developer) is added; Component B: 2 mg of ferrosoferric oxide magnetic particles are weighed and dispersed in 1 mL of dichloromethane, and then 10 mg of the carbon-carbon double bond-terminated polyurethane prepared in step (1) and 0.1 mg of azobisisobutyronitrile are weighed and dissolved therein; The dispersed phase components A and B were placed in two separate chambers of a two-component syringe with a flat-point needle. The 26G flat-point needle was connected to a silicone hose with an inner diameter of 1 mm. The mobile phase was also connected to the silicone hose via a syringe. The dispersed phase and mobile phase were introduced at a constant rate via a dual-channel syringe pump. The dispersed phase flow rate was 4 mL / h, and the mobile phase flow rate was 80 mL / h, to form a microsphere emulsion. (3) Preparation of vascular embolic microspheres: 1 mL of the microsphere emulsion obtained in step (2) was transferred to a rotary evaporator. The solvent was initially removed by rotary evaporation at a speed of 30 rpm, a pressure of 300 mbar, and a temperature of 30°C for 10 minutes until no dense small bubbles were generated. The temperature was then raised to 60°C and the rotation was continued for 50 minutes to fully allow the cross-linking reaction to proceed. Finally, the microspheres were repeatedly washed with deionized water to remove the residual polyvinyl alcohol on the surface to obtain vascular embolic microspheres.

[0033] Characterization of polyurethane molecular structure: Weigh 10 mg of the product obtained in step (1), dissolve it in 0.6 mL of deuterated dimethyl sulfoxide, and use a nuclear magnetic resonance spectrometer (AMX-500, Bruker, Germany) to measure the nuclear magnetic resonance hydrogen spectrum of the sample. The results are as follows Figure 1 As shown in the figure, it can be seen that the proton peak appearing at the chemical shift of 4.86 ppm comes from the hydrogen on the carbon-carbon double bond, indicating that the carbon-carbon double bond was successfully introduced in the last step of the end-capping reaction.

[0034] Microsphere morphology characterization: The vascular embolization microspheres prepared in this example were placed under an optical microscope (IX71, Olympus, Japan) and the morphology of the microspheres was observed and photographed. Figure 2 As shown in the figure, the microspheres are opaque black-brown under a microscope, do not agglomerate, have good dispersion, high roundness, and uniform particle size, with an average particle size of 132 μm.

[0035] Microsphere magnetothermal heating performance test: 10 mg of the vascular embolization microspheres prepared in this example were weighed and placed in a high-frequency induction heating machine (300 kHz, WRJ-CGP06A, WanRuiJie, China) for 5 minutes. The temperature of the microspheres was recorded at 30-second intervals. The results are shown in the figure. Figure 3 As shown in the figure, within five minutes, the temperature of the microspheres can rise from 22°C to 63°C, with a net temperature increase of 41°C, which has efficient magnetothermal heating characteristics.

[0036] Microsphere drug release rate test: First, 0.01 M phosphate buffer (pH 7.4) containing 1 wt% Tween 80 was prepared as a release medium. 10 mg of the vascular embolic microspheres prepared in this example was weighed and added to a centrifuge tube containing 4 mL of the release medium. The tube was placed in a constant temperature oscillator at 37°C. At the set time points (1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 192 h, 240 h, 288 h, 336 h), 1 mL of the supernatant was removed and added with 1 mL of the release medium. The absorbance of the sample at 264 nm was measured using a high performance liquid chromatography (Acquity, Waters, USA) (chromatographic column: Agilent C18, 5 μm, 4.6 × 250 mm). The drug concentration in the sample was calculated based on the measured sorafenib drug standard curve. Finally, the drug release curve was calculated and plotted. The results are shown in Figure 2. Figure 4 As shown in the figure, the drug release rate is fast in the first two days, and the cumulative drug release in two days is 17μg / mg. The subsequent drug release rate slows down, and the cumulative drug release in 14 days is 31μg / mg. The sustained release time can be as long as two weeks.

[0037] Example 2 A vascular embolic microsphere, the preparation method of which differs from that of Example 1 in that: In step (2), iodized oil was not added, and the other conditions remained unchanged.

[0038] Characterization of microsphere development: 10 mg of the vascular embolic microspheres prepared in Example 1 and this example were weighed and placed in a centrifuge tube. The microspheres were then imaged under X-rays on a micro-CT imaging system (SkyScan 1276, Bruker, USA) and compared with iodized oil. The results are shown in Figure 2. Figure 5 As shown in the figure, it can be seen that the vascular embolic microspheres prepared in Example 1 are similar to simple iodized oil, are not X-ray transparent, and can be clearly imaged under X-rays. The microspheres prepared in this example without adding iodized oil are invisible under X-rays.

[0039] Microsphere modulus characterization: The vascular embolic microspheres prepared in Example 1 and this example were spread on the test bench of a rheometer (MCR302e, Anton Paar, Austria) respectively. The storage modulus (G') and loss modulus (G") were measured at 25°C with an angular frequency of 0.1 to 100 rad / s. The modulus was also tested at a fixed strain (1%). The results are shown in Figure 2. Figure 6 As shown in the figure, it can be seen that G' of the two microspheres is always greater than G", indicating that they are solid elastic. In addition, it can be observed that G' of the microspheres obtained in Example 2 is higher than that in Example 1. The reason is that iodized oil is added in Example 1, which can play the role of plasticization, dilution and lubrication, and can increase the softness of the microspheres, making the microspheres more easily deformable.

[0040] Example 3 A method for preparing vascular embolic microspheres differs from that of Example 1 in that, in step (2), the concentration of polyurethane is increased to 10 times. Increasing the concentration of polyurethane produces microspheres with larger particle sizes (average particle size 600 μm), facilitating testing of their macroscopic soft elasticity. The specific steps for preparing the microsphere emulsion in step (2) are as follows: Prepare the mobile phase (aqueous phase): Weigh polyvinyl alcohol 1788 and dissolve it in deionized water and filter it to obtain a polyvinyl alcohol concentration of 1 wt %. Preparation of dispersed phase (oil phase): The dispersed phase is divided into component A and component B. Component A: 2 mg of sorafenib is weighed and dissolved in 0.2 mL of acetone, 100 mg of the carbon-carbon double bond-terminated polyurethane prepared in step (1) and 1 mg of azobisisobutyronitrile are weighed and dissolved in 0.8 mL of dichloromethane, the two are mixed and then 20 mg of iodized oil is added; Component B: 2 mg of ferroferric oxide magnetic particles are weighed and dispersed in 1 mL of dichloromethane, and then 100 mg of the carbon-carbon double bond-terminated polyurethane prepared in step (1) and 1 mg of azobisisobutyronitrile are weighed and dissolved therein; The obtained dispersed phase component A and component B were respectively placed in two independent chambers of a two-component syringe with a flat needle. The 26G flat needle was connected to a silicone hose with an inner diameter of 1 mm. The mobile phase was also connected to the silicone hose through a syringe. The dispersed phase and the mobile phase were pushed out at a constant speed through a dual-channel syringe pump. The flow rate of the dispersed phase was 4 mL / h and the flow rate of the mobile phase was 80 mL / h to form a microsphere emulsion.

[0041] Macroscopic characterization of the soft elasticity of microspheres: The vascular embolic microspheres prepared in this example were placed under a digital microscope (AD106S, Anton Star, China). The microspheres were clamped with stainless steel ophthalmic straight forceps and compressed. When the compression deformation reached about 50%, the forceps were released and the deformation recovery of the microspheres was observed and recorded. The results are shown in Figure 2. Figure 7 As shown in the figure, the microsphere can be easily compressed to 50% of its diameter under the action of ophthalmic forceps. Within 2 seconds after releasing the forceps, the microsphere can quickly recover to its original diameter, indicating that the vascular embolization microsphere has good mechanical compression performance. The compression deformation can reach more than 50%, and the deformation can be quickly recovered, indicating that the microsphere has good soft elasticity. In addition, a single embolic microsphere prepared in this example was placed on a universal mechanical testing machine (YH-9002, Yuhong Optoelectronics, China) and equipped with a micro pressure sensor (JLBS-M2-500g) to test the pressure changes of the microsphere under different deformations. The results are shown in Figure 1. Figure 8 As shown in the figure, when the deformation is 50%, the pressure is only 0.06N, and when the deformation is as high as 80%, the pressure is only 1.6N, which shows that the microspheres are soft.

[0042] Example 4 A vascular embolic microsphere, the preparation method of which differs from that of Example 1 in that: In step (2), the oil phase did not contain ferroferric oxide magnetic particles or sorafenib. Instead, it contained only one component: 100 mg of carbon-carbon double-bond terminated polyurethane and 1 mg of azobisisobutyronitrile were dissolved in 1 mL of dichloromethane, and 20 mg of iodized oil was added. The resulting microspheres had the same particle size as those in Example 1, but lacked magnetocaloric properties and were unable to release the drug.

[0043] Example 5 A vascular embolic microsphere, the preparation method of which differs from that of Example 1 in that: In step (2), the concentration of polyurethane in the dispersed phase is 5 wt %, i.e., 50 mg of carbon-carbon double-bond terminated polyurethane is dissolved in 1 mL of dichloromethane. Increasing the polyurethane concentration increases the diameter of the droplets in the microsphere emulsion, and the diameter of the resulting microspheres also increases accordingly. In this example, the particle size of the microspheres obtained is 300 μm.

[0044] Example 6 A vascular embolic microsphere, the preparation method of which differs from that of Example 1 in that: In step (2), the polymerization initiator is adjusted to an equal mass of phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide. After the microsphere emulsion is prepared, the microsphere emulsion is irradiated with 405 nm blue-violet light for 10 minutes to initiate polymerization.

[0045] In step (3), the microspheres were first rotated and volatilized at a speed of 30 rpm, a pressure of 300 mbar, and a temperature of 30°C for 10 minutes, and then the pressure was adjusted to 100 mbar and the rotation was continued for 50 minutes to fully remove the solvent. Finally, the microspheres were repeatedly washed with deionized water to remove the residual polyvinyl alcohol on the surface.

[0046] The particle size, soft elasticity, etc. of the obtained microspheres are the same as those in Example 1. That is, the target microspheres can also be obtained by changing the thermal initiation to light initiation.

[0047] Example 7 A vascular embolic microsphere, the preparation method of which differs from that of Example 1 in that: In step (2), the dispersed phase flow rate is 1 mL / h, the mobile phase flow rate is 80 mL / h, and the diameter of the resulting microspheres is 100 μm. In other words, increasing the flow rate ratio of the mobile phase to the dispersed phase can reduce the particle size of the microspheres.

[0048] It should be understood that those skilled in the art can make improvements or changes based on the above description, and all such improvements and changes should fall within the scope of protection of the appended claims of the present invention.

Claims

1. A soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolization microsphere, characterized in that: The microspheres are based on polyurethane and are composited with magnetic particles, a developer and an anti-tumor hydrophobic drug by a microfluidic method, and have good soft elasticity.

2. The developable magnetic vascular embolic microspheres containing hydrophobic drugs and soft elastic polyurethane as claimed in claim 1, characterized in that: The particle size of the developable magnetic vascular embolization microspheres is adjustable within the range of 50 to 1000 μm and is uniform.

3. The developable magnetic vascular embolic microspheres containing hydrophobic drugs and soft elastic polyurethane as claimed in claim 1, characterized in that: The polyurethane is obtained by cross-linking polyurethane terminated with carbon-carbon double bonds; the magnetic particles are at least one of ferroferric oxide, zinc ferrite, cobalt ferrite, manganese ferrite, and γ-ferric oxide, and have a particle size of 5 to 500 nm; the developer is at least one of iodized oil, iodophenyl ester, and barium sulfate; and the anti-tumor hydrophobic drug is one or more of a platinum drug, anthracycline drug, taxane drug, vinblastine drug, camptothecin drug, nitrosourea drug, and targeted anticancer drug.

4. The developable magnetic vascular embolic microspheres containing hydrophobic drugs and soft elastic polyurethane as claimed in claim 1, characterized in that: The mass of the magnetic particles is 1 to 50 wt % of the polyurethane, the mass of the developer is 5 to 100 wt % of the polyurethane, and the mass of the hydrophobic drug is 1 to 50 wt % of the polyurethane.

5. A method for preparing the developable magnetic vascular embolic microspheres loaded with hydrophobic drugs and soft elastic polyurethane as claimed in any one of claims 1 to 4, characterized in that: Carbon-carbon double bond-terminated polyurethane, magnetic particles, developer, anti-tumor hydrophobic drug, and initiator are mixed uniformly as a single dispersed phase or separately as a multi-component dispersed phase in an organic solvent as needed. Polyvinyl alcohol solution is used as the mobile phase. Microsphere emulsion is prepared by microfluidics. The polyurethane in the microsphere emulsion undergoes polymerization reaction initiated by the initiator, and the organic solvent is removed by rotary evaporation to obtain soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolization microspheres.

6. The method for preparing the developable magnetic vascular embolic microspheres loaded with hydrophobic drugs based on soft elastic polyurethane according to claim 5, characterized in that: The preparation method of carbon-carbon double bond terminated polyurethane comprises the following steps: dissolving a first polyol, a second polyol, a diisocyanate and a catalyst in a solvent, reacting at 70-90° C. for 2-5 hours under inert gas protection for prepolymerization, then cooling to 60-65° C., adding a capping agent and continuing the reaction for 1-3 hours, and post-treating to obtain carbon-carbon double bond terminated polyurethane.

7. The method for preparing the developable magnetic vascular embolic microspheres loaded with hydrophobic drugs based on soft elastic polyurethane according to claim 6, characterized in that: The solvent is any one of toluene, acetone, N,N-dimethylformamide, and dimethyl sulfoxide; the total mass of the first polyol and the second polyol to the solvent volume ratio is 0.1 to 1 g / mL; the first polyol is any one of polyethylene glycol and polypropylene glycol, and the number average molecular weight is 400 to 4000; the second polyol is any one of polycaprolactone diol, polylactic acid diol, and poly (lactic acid-caprolactone) diol, and the number average molecular weight is 1000 to 10000; the diisocyanate The acid ester is any one of isophorone diisocyanate, hexamethylene diisocyanate, and 4,4-diisocyanate dicyclohexylmethane; the catalyst is an organic metal catalyst; the inert gas is any one of argon, nitrogen, and helium; and the end-capping agent is any one of hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, allyl alcohol, 3-methylallyl alcohol, 4-hydroxycrotonate ethyl ester, 2-hydroxycyclohexyl acrylate, and 3-butene-1-ol.

8. The method for preparing the developable magnetic vascular embolic microspheres loaded with hydrophobic drugs based on soft elastic polyurethane according to claim 5, characterized in that: The initiator is a thermal initiator and / or photoinitiator for initiating carbon-carbon double bond polymerization; the organic solvent is obtained by mixing a main solvent and a cosolvent, the main solvent is any one of dichloromethane or chloroform or a mixture of the two in any proportion, the cosolvent is any one of acetone, tetrahydrofuran, ethyl acetate, methanol, ethanol, ether, n-hexane, isopropanol, acetonitrile, and chloroform or a mixture of several thereof, and the volume ratio of the main solvent to the cosolvent is 1 to 9:1; the concentration of the carbon-carbon double bond terminated polyurethane in the dispersed phase is 0. 005-0.2 g / mL, the mass ratio of the anti-tumor hydrophobic drug to the carbon-carbon double bond-terminated polyurethane is 0.01-0.2:1, the mass ratio of the magnetic particles to the carbon-carbon double bond-terminated polyurethane is 0.02-0.2:1, the mass ratio of the developer to the carbon-carbon double bond-terminated polyurethane is 0.1-2:1, and the mass ratio of the initiator to the carbon-carbon double bond-terminated polyurethane is 0.0001-0.01:1; the polyvinyl alcohol solution is obtained by dissolving polyvinyl alcohol 1788 in water, and the concentration is 0.5-5wt%.

9. The method for preparing the developable magnetic vascular embolic microspheres loaded with hydrophobic drugs based on soft elastic polyurethane according to claim 5, characterized in that: The microfluidic method for preparing a microsphere emulsion comprises the following steps: connecting a mobile phase to a silicone hose via a syringe, connecting a dispersed phase to the silicone hose via a single-component or multi-component syringe with a flat-end needle, and then using a dual-channel syringe pump to push out the mobile phase and dispersed phase at a constant speed to form a microsphere emulsion; the inner diameter of the silicone hose is 0.5-2 mm, the size of the flat-end needle is 18-32G, and the outer diameter of the flat-end needle is smaller than the inner diameter of the silicone hose; the dispersed phase flow rate is 0.05-80 mL / h, and the flow rate ratio of the mobile phase to the dispersed phase is 5-200:1; the initiator initiates a polymerization reaction of polyurethane in the microsphere emulsion in a manner including thermal initiation or photoinitiation, the thermal initiation temperature is 30-80° C., the wavelength of the photoinitiation light source is 365 nm or 405 nm, and the polymerization reaction time is 5-180 min; the rotary evaporation speed is 20-100 rpm, the pressure is 50-1013 mbar, and the temperature is 20-80° C.

10. Use of the soft elastic polyurethane-based hydrophobic drug-loaded developable magnetic vascular embolic microspheres according to any one of claims 1 to 4 in the preparation of vascular embolic drugs for treating tumors.

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