Novel vascular embolization compositions comprising biocompatible polymers and methods of making the same

Abstract

The present application relates to the technical field of embolic material, in particular to a vascular embolization composition containing a biocompatible polymer and a preparation method thereof, comprising a biocompatible polymer and a biocompatible iodine-containing contrast agent; the biocompatible polymer is selected from polylactic acid-glycolic acid copolymer PLGA, polycaprolactone PCL, polyethylene glycol-polylactic acid copolymer PEG-PLA or polytrimethylene carbonate PTMC; the biocompatible iodine-containing contrast agent is selected from triiodophenoxy ethyl acrylate-hydroxyethyl methacrylate copolymer, iohexol, triiodophenol, iopromide or iopamidol; the biocompatible iodine-containing contrast agent is used to avoid metal toxicity, has high and uniform development intensity, meets clinical precise positioning, and has good compatibility and dispersibility.

Description

Technical Field

[0001] This invention relates to the field of embolization materials technology, specifically to novel vascular embolization compositions containing biocompatible polymers and their preparation methods. Background Technology

[0002] Existing vascular embolization materials have many limitations: some use metal contrast agents such as barium sulfate, which have poor biocompatibility and are prone to causing inflammation or accumulation risks; the contrast agents are not compatible with the polymer matrix, resulting in uneven dispersion and unstable imaging signals; the degradation rate is difficult to control, too fast and it will fail prematurely, while too slow and it will remain in the body for a long time; the mechanical properties are insufficient, and it is easy to break during embolization; and the purification process is not perfect, and the residual impurities affect safety, making it difficult to meet the needs of precise clinical embolization. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings of the prior art by proposing a novel vascular embolization composition containing a biocompatible polymer and its preparation method.

[0004] To achieve the above objectives, the present invention provides the following technical solution: a vascular embolization composition containing a biocompatible polymer, comprising a biocompatible polymer and a biocompatible iodine-containing contrast agent;

[0005] The biocompatible polymer is selected from polylactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL), polyethylene glycol-polylactic acid copolymer (PEG-PLA), or polytrimethylene carbonate (PTMC).

[0006] The biocompatible iodine-containing developing agent is selected from triiodophenoxyethyl acrylate-hydroxyethyl methacrylate copolymer, iohexol, triiodophenol, iopromide, or iopamidol;

[0007] Furthermore, the mass ratio of the biocompatible polymer to the biocompatible iodine-containing developer satisfies any of the following conditions:

[0008] (1) When the biocompatible polymer is PLGA, the biocompatible iodine-containing developer is iohexol, and the mass ratio of the two is 6:4 to 9:1;

[0009] (2) When the biocompatible polymer is PCL, the biocompatible iodine-containing developer is triiodophenol, and the mass ratio of the two is 7:2.5 to 9.5:0.5;

[0010] (3) When the biocompatible polymer is PEG-PLA, the biocompatible iodine-containing developer is iopromide, and the mass ratio of the two is 85:15 to 90:10;

[0011] (4) When the biocompatible polymer is PTMC, the biocompatible iodine-containing developer is iopamidol, and the mass ratio of the two is 88:12 to 94:6.

[0012] Preferably, when the biocompatible polymer is PLGA, the biocompatible iodine-containing developer is iohexol, and the mass ratio of PLGA to iohexol is 6:4 to 9:1; the weight-average molecular weight of the PLGA is 50,000-100,000.

[0013] Preferably, it further comprises polyethylene glycol (PEG) as a compatibilizer, wherein the PEG has a molecular weight of 2000 and the mass ratio of PLGA:iohexol:PEG is 7:2.5:0.5 to 8:1.5:0.5.

[0014] Preferably, when the biocompatible polymer is PCL, the biocompatible iodine-containing developer is triiodophenol, and the mass ratio of PCL to triiodophenol is 7:2.5 to 9.5:0.5;

[0015] The weight-average molecular weight of the PCL is 80,000-120,000.

[0016] Preferably, the triiodophenol is silanized, and the amount of silane used is 0.5-2 times the mass of triiodophenol; PEG is used as a compatibilizer, and the mass of PEG accounts for 2%-7% of the total mass of the composition.

[0017] Preferably, when the biocompatible polymer is PTMC, the biocompatible iodine-containing developer is iopamidol, and the mass ratio of PTMC to iopamidol is 88:12 to 94:6.

[0018] The PTMC has a weight-average molecular weight of 90,000 and a distribution index of 1.2.

[0019] Preferably, the particle size of the composition after sieving is 100-200 μm.

[0020] A method for preparing the composition, the method comprising the following steps:

[0021] (1) Raw material pretreatment: Vacuum dry the biocompatible polymer at 50-65℃ for 16-30 hours to make the moisture content ≤0.1%; Vacuum dry the biocompatible iodine-containing developer at 35-45℃ for 10-22 hours;

[0022] (2) Mixing reaction: The pretreated raw materials are mixed and reacted using twin-screw extrusion, ultrasonic-assisted or microwave-assisted methods; wherein, the screw speed of twin-screw extrusion is 300-350 r / min, and the temperature is controlled in stages: 60℃ in the feeding section, 70-85℃ in the melting section and 75℃ in the homogenization section, and the reaction time is 2.5-4 hours; the power of ultrasonic assistance is 250-300W, the frequency is 20kHz, the reaction temperature is 70℃, and the time is 3-4 hours; the power of microwave assistance is 500W, the temperature is 75℃, and the time is 1.5 hours;

[0023] (3) Purification: Purification is carried out by dissolving in organic solvents and then precipitating or by supercritical CO2 extraction; in the organic solvent dissolution-precipitation process, the first purification is carried out by dissolving in dichloromethane or chloroform, adding 5 times the volume of ethanol or ether to precipitate, and standing at 4°C for 12 hours; the second purification is carried out by washing with ethanol 3 times, and ultrasonic treatment for 10 minutes each time.

[0024] (4) Drying treatment: The purified product is vacuum dried at 38-40℃ for 40-48 hours and sieved to 100-200um.

[0025] Preferably, the mixing reaction in (2) is carried out under nitrogen protection, with a nitrogen pressure of 0.1 MPa or a nitrogen flow rate of 2-3 L / min.

[0026] Preferably, in step (3), when the biocompatible polymer is PEG-PLA, the purification process is as follows: after dissolving in acetone, filter through a 0.45um filter membrane, then precipitate with diethyl ether at a volume ratio of 1:2-1:9, and collect the components of different molecular weights in layers.

[0027] Compared with the prior art, the beneficial effects of the present invention are:

[0028] 1. It uses a biocompatible iodine-containing contrast agent to avoid metal toxicity, and has high and uniform imaging intensity to meet the requirements of precise clinical localization; it has good compatibility and dispersibility: through optimization such as PEG compatibilization and silanization treatment, it solves the problem of contrast agent and polymer stratification, and the particles are uniform in size and do not agglomerate, ensuring stable embolization effect.

[0029] 2. By adjusting the polymer molecular weight and PEG ratio, the degradation rate can be precisely controlled to meet the time requirements of different lesions; the optimized ratio ensures stable mechanical properties and no contrast agent precipitation; after sterilization with 25kGy γ-rays, the molecular weight retention rate is >90%, and the safety is high.

[0030] 3. Gradient purification process reduces residual impurities and uses biocompatible polymers such as PLGA and PCL to reduce the risk of rejection in vivo. Detailed Implementation

[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] Example 1: PLGA vascular embolization composition containing iohexol

[0033] (1) Raw material selection and ratio optimization: PLGA with a weight average molecular weight of 100,000 was selected and formulated in three ratio gradients of PLGA:iohexol = 9:1, 8:2, and 7:3. Iohexol was pretreated with a 0.22 μm filter membrane to remove particulate impurities. After removing impurities, white and loose PLGA powder and white crystalline iohexol powder were obtained. Iohexol remained white after filtration through the filter membrane, and the gloss was more uniform after removing impurities.

[0034] (2) Raw material pretreatment enhancement: After vacuum drying at 60℃ for 24 hours, the moisture content of PLGA was verified to be ≤0.1% by differential scanning calorimetry (DSC); Iohexol was vacuum dried at 40℃ for 12 hours to avoid interference from water of crystallization. After drying, PLGA remained white and had a finer texture; Iohexol was in a stable crystalline state and did not deliquinate.

[0035] (3) Optimization of mixing reaction parameters: A twin-screw extruder was used with a screw speed of 300 r / min and segmented temperature control: 60℃ in the feeding section, 80℃ in the melting section, and 75℃ in the homogenization section; nitrogen protection pressure was 0.1 MPa and reaction time was 2.5 hours; after the reaction, white to off-white strip-shaped solids were obtained, with iodhexol uniformly dispersed, no obvious particle feel, and the cross-section was a uniform milky white PLGA-iodhexol blend.

[0036] (4) Gradient purification process: In the first purification, the solution was dissolved in dichloromethane, and 5 times the volume of ethanol was added. The mixture was allowed to stand at 4°C for 12 hours to precipitate. In the second purification, the solution was washed three times with ethanol, and each time it was sonicated for 10 minutes to remove free iodine. The dichloromethane solution was a light yellow transparent liquid, and the ethanol precipitate was a white flocculent solid. After washing, the solution was a pure white powder with no visible impurities.

[0037] (5) Post-drying treatment: After vacuum drying at 40℃ for 48 hours, the particle size was sieved to 100-200 μm, and the particle size distribution was measured using a dynamic light scattering instrument. The above operation yielded pure white spherical particles that were translucent under an optical microscope, with good dispersibility and no agglomeration, PLGA-iodhexyl alcohol polymer microspheres.

[0038] In addition, it should be noted that vascular embolization compositions with a PLGA to iohexol mass ratio of 9:1, 8:2, and 7:3 are prepared according to the following steps:

[0039] (1) Weighing raw materials: Weigh the corresponding mass of PLGA and iohexol according to the target mass ratio (9:1, 8:2, 7:3); for example, when the mass ratio of PLGA to iohexol is 9:1, weigh 9g of PLGA with a weight average molecular weight of 50,000-100,000 and 1g of iohexol; when the mass ratio is 8:2, weigh 8g of PLGA and 2g of iohexol; when the mass ratio is 7:3, weigh 7g of PLGA and 3g of iohexol.

[0040] (2) Dissolving and mixing: PLGA is added to dichloromethane, and the mass-volume ratio of PLGA to dichloromethane is 1g:10mL. The mixture is stirred at 200rpm at 25℃ until completely dissolved to obtain a PLGA solution. Iohexol is then slowly added to the PLGA solution and stirred at 300rpm for 30min to form a homogeneous mixed solution.

[0041] (3) Emulsification and curing: The mixed solution is added dropwise to an aqueous solution containing 2wt% polyvinyl alcohol (PVA), and the volume ratio of the mixed solution to the PVA aqueous solution is 1:10. The mixture is emulsified at 400 rpm for 2 hours to form an emulsion. Then, the mixture is stirred at room temperature for 12 hours to volatilize dichloromethane and solidify the particles.

[0042] (4) Washing and drying: Collect the solidified particles, wash them three times with deionized water for 10 minutes each time to remove residual PVA; then dry them in a vacuum drying oven at 40℃ for 24 hours to obtain the final particles.

[0043] (5) For the ratio of PLGA: iohexol = 8:2 and 7:3, only the mass of PLGA and iohexol in the raw material weighing stage is adjusted, and the remaining process steps are completely consistent with the above 9:1 ratio.

[0044] Example 2: Low molecular weight PLGA-iodhexol composition

[0045] (1) Raw material selection: PLGA weight average molecular weight 50,000, PLGA: iohexol = 9.5:0.5, 9:1, 8.5:1.5; iohexol was pretreated by 0.22μm filter membrane + freeze drying. The resulting substance is white loose PLGA powder and white needle-shaped iohexol crystals. Due to freeze drying, the crystals are more regular.

[0046] (2) Raw material pretreatment: PLGA was vacuum dried at 50℃ for 30 hours, and DSC verification showed that the moisture content was ≤0.1%; iohexol was vacuum dried at 35℃ for 15 hours. After treatment, PLGA remained white and had better flowability; iohexol did not deliquesce and its hygroscopicity was slightly reduced.

[0047] (3)-(5) The process is the same as in the original Example 1. The final product is 100-200um pure white spherical particles. Due to the decrease in molecular weight of PLGA, the particle hardness is slightly lower and the dispersibility is better.

[0048] Example 3: PLGA-iohexol composition containing PEG compatibilizer

[0049] (1) Raw material selection: PLGA with a weight average molecular weight of 100,000, and 3% PEG with a molecular weight of 2,000 was introduced as a compatibilizer; PLGA: iohexol: PEG = 8:1.5:0.5, 7.5:2:0.5, 7:2.5:0.5. The resulting substances are white PLGA powder, white iohexol crystals, and white PEG powder. There is no obvious stratification after mixing the three.

[0050] (2) Raw material pretreatment: PLGA and PEG were first blended and vacuum dried at 60°C for 24 hours; the treatment with iohexol was the same as in Example 1. After treatment, the PLGA-PEG blend was uniformly white and free of particles, and PEG could improve compatibility.

[0051] (3) Mixing reaction: The speed of the twin-screw extruder was adjusted to 350 r / min. Due to the presence of PEG, the speed was increased to promote dispersion. Other parameters were the same as in the original Example 1. The reaction product was a white strip-shaped solid with a finer cross-section and no iodine-hexyl alcohol agglomeration.

[0052] (4)-(5) The process is the same as in the original Example 1. The final product is 100-200um semi-transparent spherical particles. The in vitro degradation rate is 10% faster than that in the original Example 1.

[0053] Example 4: PLGA composition with high iodine-hexyl alcohol content

[0054] (1) Raw material selection: PLGA weight average molecular weight 100,000, PLGA: iohexol = 6:4, 5.5:4.5, 5:5; iohexol was pretreated by recrystallization through a 0.22um filter membrane and ethanol. The resulting substances were white PLGA powder and white flaky iohexol crystals.

[0055] (2) Raw material pretreatment: PLGA was vacuum dried at 65℃ for 20 hours; iohexol was vacuum dried at 45℃ for 10 hours. Due to the high content, the drying time was shortened to avoid crystallization damage.

[0056] (3) Mixed reaction: The temperature of the melting section was increased to 85°C, and the reaction time was extended to 3 hours. Other parameters were the same as in the original Example 1. The reaction product was a white strip-shaped solid with a uniform cross-section and no obvious particles.

[0057] (4)-(5) The process is the same as in the original Example 1. The final product is 100-200μm white spherical particles with X-ray imaging intensity 30% higher than that in the original Example 1.

[0058] Example 5: PCL vascular embolization composition containing triiodophenol

[0059] (1) 5% polyethylene glycol with a molecular weight of 2000 was introduced into PCL with a weight average molecular weight of 80000 and a distribution index of 1.3 as a compatibilizer. Triiodophenol was silanized to improve its compatibility with the polymer. White PCL particles, white powdered PEG, and light yellow powdered silanized triiodophenol were obtained. It should be noted that the original triiodophenol was bright yellow, and the color was slightly lighter after silanization.

[0060] (2) After blending PCL and PEG, the mixture was vacuum dried at 50°C for 18 hours, and the glass transition temperature was monitored simultaneously to ensure the uniformity of the blend. After blending PCL and PEG, a white to slightly yellow PCL-PEG blended dry powder was obtained. Because PEG and PCL have good compatibility, there was no stratification, and the light yellow color came from the trace diffusion of triiodophenol.

[0061] (3) Ultrasonic mixing with a power of 300W and a frequency of 20kHz was used, and the reaction was carried out at 70℃ for 3 hours. The nitrogen flow rate was controlled at 2L / min to ensure that the residual oxygen content was ≤0.5%. After ultrasonic mixing, the liquid was a light yellow viscous liquid. After cooling after the reaction was completed, it became a light yellow solid with a uniform cross-section and no color blocks. The final product was PCL-PEG-triiodophenol complex.

[0062] (4) Purification: After dissolving in chloroform, supercritical CO2 extraction was performed at 10 MPa and 35 °C to replace hexane precipitation, reducing organic solvent residue. The purified complex obtained after supercritical CO2 extraction was a light yellow, loose solid.

[0063] (5) Performance regulation: After drying, the product was sterilized with γ-rays at a dose of 25 kGy. The molecular weight retention rate before and after sterilization was >90%. The PCL-based embolic polymer was obtained after γ-ray sterilization, and the color did not change significantly after sterilization.

[0064] Example 6: Low PEG content PCL composition

[0065] (1) Raw material selection: PCL weight average molecular weight 80,000, PEG content 2%; triiodophenol was silanized, and the amount of silane was halved; the resulting substances were: white PCL particles, white PEG powder, and light yellow-brown silanized triiodophenol. Due to the small amount of silane used, the color was darker than that in Example 5.

[0066] (2) Pretreatment: PCL and PEG were blended and vacuum dried at 45°C for 20 hours. The glass transition temperature was monitored. The treated powder was a white powder without stratification. Although the amount of PEG was small, it was still compatible.

[0067] (3) Mixed reaction: The ultrasonic power was reduced to 250W (with less PEG, no need for strong power dispersion), and other parameters were the same as in the original Example 5; the reaction product was a light yellow-brown viscous liquid, and the triiodophenol color was more obvious. After cooling, it became a uniform solid.

[0068] (4)-(5) The process is the same as in the original Example 2. The final product has a molecular weight retention rate of >92% after sterilization. Due to the low PEG content, the stability is slightly improved.

[0069] Example 7: High molecular weight PCL composition

[0070] (1) Raw material selection: PCL weight average molecular weight 120,000, distribution index 1.4, PEG content 5%; triiodophenol is fully silanized, and the amount of silane is doubled. The resulting substances are white PCL particles with larger particle size, white PEG powder, and light yellow triiodophenol. The silanization is more complete and the color is lighter.

[0071] (2) Pretreatment: PCL and PEG were blended and then vacuum dried at 55°C for 16 hours. The resulting powder was a white to slightly white powder, and the color of triiodophenol was masked.

[0072] (3) Mixing reaction: The ultrasonic time was extended to 4 hours, and other parameters were the same as in the original Example 5. The reaction product was a pale yellow viscous liquid, and its fluidity was slightly worse than that in Example 5 due to the high molecular weight of PCL.

[0073] (4)-(5) The process is the same as in the original Example 2. The final product is a pale yellow solid after sterilization. Because PCL has a high molecular weight, its in vitro degradation rate is 20% slower than that in the original Example 2.

[0074] Example 8: PCL composition of unsilylated triiodophenol

[0075] (1) Raw material selection: PCL with a weight average molecular weight of 80,000 and PEG content of 7%; triiodophenol was not silanized and retained its bright yellow color. The resulting products are white PCL particles, white PEG powder, and bright yellow triiodophenol powder.

[0076] (2) Pretreatment: PCL, PEG and triiodophenol were mixed and then vacuum dried at 50°C for 22 hours. Characteristics after treatment: light yellow powder with no obvious color patches.

[0077] (3) Mixed reaction: Nitrogen flow rate was increased to 3 L / min, and other parameters were the same as in the original Example 5. The reaction product was a yellow viscous liquid, which became a uniform solid after cooling. PEG effectively inhibited the aggregation of triiodophenol.

[0078] (4)-(5) The process is the same as in the original Example 5. The final product is slightly darker in color after sterilization because the triiodophenol is slightly oxidized, but the development intensity is comparable to that in the original Example 2.

[0079] Example 9: PEG-PLA vascular embolization composition containing iopromide

[0080] (1) In PCL with a weight average molecular weight of 80,000 and a distribution index of 1.3, 5% polyethylene glycol with a molecular weight of 2,000 was introduced as a compatibilizer; triiodophenol was silanized to improve its compatibility with the polymer. The resulting substances included PCL particles, PEG powder, and silanized triiodophenol. PCL was white particles, PEG was white powder, and silanized triiodophenol was a pale yellow powder, of which the original triiodophenol was bright yellow and its color was slightly lighter after silanization.

[0081] (2) Molecular weight gradient design: Three new PEG-PLA specifications were added: a weight-average molecular weight of 80,000 and a distribution index of 1.4, a weight-average molecular weight of 120,000 and a distribution index of 1.6, and a weight-average molecular weight of 150,000 and a distribution index of 1.8, to compare the effect of molecules on embolization performance. PEG-PLA copolymers and iopromide crystals with three molecular weights were obtained. PEG-PLA was a white powder, and iopromide was a white crystal with slight hygroscopicity.

[0082] (3) Reaction kinetic control: In-situ infrared spectroscopy was used to monitor the reaction process, and the reaction was terminated when the intensity of the characteristic peak of iopromide stabilized. The stirring speed was optimized to 350 r / min, and the reaction time was adjusted according to the molecular weight: 3 hours for 80,000 and 6 hours for 150,000. The product was a PEG-PLA-iopromide reaction complex. During the reaction, the solution gradually changed from colorless and transparent to a light grayish-white suspension, and was uniformly grayish-white when the reaction was terminated.

[0083] (4) Compound purification: After dissolving in acetone, the solution is first filtered through a 0.45 μm filter membrane, and then precipitated with a gradient of diethyl ether at volume ratios of 1:3, 1:5, and 1:8. Different molecular weight components are collected in layers. The 1:3 diethyl ether precipitate is a white dense precipitate, the 1:5 precipitate is a white fluffy precipitate, and the 1:8 precipitate is a white fine precipitate.

[0084] Example 10: Low PEG Ratio PEG-PLA Composition

[0085] (1) Raw material selection: PEG-PLA weight average molecular weight 80000, distribution index 1.4, 120000 distribution index 1.6, PEG ratio reduced to 3%; iopromide content 10%. The generated substances are white PEG-PLA powder and white iopromide crystals. Due to the low PEG content, it is more porous and slightly more hygroscopic.

[0086] (2) Reaction kinetics: Stirring speed 300 r / min, 80,000 molecular weight corresponds to 2.5 hours of reaction time, 120,000 molecular weight corresponds to 5 hours. During the reaction, the liquid gradually changes from colorless and transparent to grayish-white suspension.

[0087] (3) Compound purification: The ratio of diethyl ether gradient precipitation was adjusted to 1:2, 1:4, and 1:7. The purified product 1:2 fraction was a white dense precipitate, and the 1:7 fraction was an off-white fine precipitate.

[0088] The degradation rate of the low molecular weight components in the final graded polymer was 15% faster than that in the original Example 9.

[0089] Example 11: PEG-PLA composition with high PEG ratio

[0090] (1) Raw material selection: PEG-PLA weight average molecular weight 120000 (1.6 distribution index) and 150000 (1.8 distribution index), PEG ratio increased to 8%; iopromide content 15%.

[0091] The resulting substances are white PEG-PLA powder and white iopromide crystals.

[0092] (2) Reaction kinetics: The stirring speed was 400 r / min. The molecular weight of 120,000 corresponds to a reaction time of 4 hours, and that of 150,000 corresponds to 7 hours. During the reaction, the solution gradually changed from colorless and transparent to a light grayish-white homogeneous solution.

[0093] (3) Compound purification: Diethyl ether gradient precipitation ratios of 1:4, 1:6, and 1:9. The proportion of the 1:9 component increases, resulting in a fine white precipitate.

[0094] The final product is a graded polymer with significantly improved hydrophilicity and an in vitro swelling rate that is 25% higher than that of the original Example 9.

[0095] Example 12: Narrow molecular weight distribution PEG-PLA composition

[0096] (1) Raw material selection: PEG-PLA weight average molecular weight 80000 (distribution index 1.2), 100000 (distribution index 1.3), 120000 (distribution index 1.4); PEG content 5%, iopromide content 12%. The generated substances are white PEG-PLA powder with more uniform particle size and white iopromide crystals.

[0097] (2) Reaction kinetics: The termination time of in-situ infrared monitoring was advanced, with 80,000 corresponding to 2.5 hours and 120,000 corresponding to 5 hours. During the reaction, the color change was more uniform, from colorless to light gray to uniform gray-white, with no stage differences.

[0098] (3) Composite purification: After gradient precipitation with diethyl ether, the standard deviation of the molecular weight distribution of each component decreased by 30% compared with the original Example 9. The purified products 1:3, 1:5, and 1:8 have higher purity and no cross-contamination.

[0099] The final product is a graded polymer with more significant differences in properties, and the narrow distribution makes the effect of molecular weight on embolization performance more obvious.

[0100] Product: Graded polymer after gradient precipitation.

[0101] Example 13: Iopamidol-containing polytrimethylene carbonate (PTMC) composition

[0102] Raw material characteristics: PTMC weight average molecular weight 90,000 (distribution index 1.2), iopamidol iodine content 47.5%, PTMC:iopamidol ratio 92:8. The product is PTMC particles and iopamidol purified by column chromatography; PTMC is a white waxy solid, and purified iopamidol is pure white needle-like crystals.

[0103] (1) Pretreatment: PTMC was vacuum dried at 55℃ for 20 hours, and iopamidol was purified by column chromatography. PTMC was white and more brittle; iopamidol was pure white and without lumps.

[0104] (2) Microwave-assisted polymerization was used with a power of 500W, a temperature of 75℃, and a time of 1.5 hours. The resulting substance was a microwave-assisted polymerization product. During the reaction, the product changed from a white to a slightly yellow colloid. Due to the uniform heating by microwave, there was no local browning.

[0105] (3) Post-treatment: Dissolved in ethyl acetate, precipitated in cyclohexane, and vacuum dried at 38°C for 40 hours; microwave reaction improved the uniformity of developer dispersion by 30%. Finally, PTMC-iopalatine polymer microspheres were obtained. The PTMC-iopalatine polymer microspheres were pure white spherical particles. Under an optical microscope, uniform developer dispersion was visible, and the whiteness was higher than that of Example 1.

[0106] Example 14: Iopamidol-containing polytrimethylene carbonate (PTMC) composition

[0107] Raw material characteristics: PTMC weight average molecular weight 90,000 (distribution index 1.2), iopamidol iodine content 47.5%, PTMC:iopamidol ratio 90:10. The produced substances are PTMC particles and iopamidol purified by column chromatography; PTMC is a white waxy solid, and purified iopamidol is a pure white needle-like crystal.

[0108] (1) Pretreatment: PTMC was vacuum dried at 55℃ for 20 hours, and iopamidol was purified by column chromatography to produce dried PTMC particles and dried iopamidol crystals; PTMC was white and more brittle; iopamidol was pure white and without lumps.

[0109] (2) Reaction: Microwave-assisted polymerization was used with a power of 500W, a temperature of 75℃, and a time of 1.5 hours to generate microwave-assisted polymerization products. During the reaction, the product was a white to slightly yellow colloid. Due to the uniform microwave heating, there was no local browning.

[0110] (3) Post-treatment: Dissolved in ethyl acetate, precipitated in cyclohexane, and vacuum dried at 38°C for 40 hours; microwave reaction improved the uniformity of developer dispersion by 28%. Finally, PTMC-iopalatine polymer microspheres were obtained, which were pure white spherical particles. Under an optical microscope, uniform developer dispersion was visible, and the whiteness was slightly lower than that in Example 4.

[0111] Example 15: Iopamidol-containing polytrimethylene carbonate (PTMC) composition

[0112] Raw material characteristics: PTMC weight average molecular weight 90,000 (distribution index 1.2), iopamidol iodine content 47.5%, PTMC:iopamidol ratio 88:12. The product is PTMC particles and iopamidol purified by column chromatography; PTMC is a white waxy solid, and purified iopamidol is pure white needle-like crystals.

[0113] (1) Pretreatment: PTMC was vacuum dried at 55℃ for 20 hours, and iopamidol was purified by column chromatography to produce dried PTMC particles and dried iopamidol crystals; PTMC was white and more brittle; iopamidol was pure white and without lumps.

[0114] (2) Reaction: Microwave-assisted polymerization was used with a power of 500W, a temperature of 75℃, and a time of 1.5 hours to generate microwave-assisted polymerization products. During the reaction, the product was a white to slightly yellow colloid. Due to the uniform microwave heating, there was no local browning.

[0115] (3) Post-treatment: Dissolved in ethyl acetate, precipitated in cyclohexane, and vacuum dried at 38°C for 40 hours; microwave reaction improved the uniformity of developer dispersion by 25%. Finally, PTMC-iopalatine polymer microspheres were obtained, which were white spherical particles. Under an optical microscope, relatively uniform developer dispersion was visible, with occasional dark aggregation points. The whiteness was lower than that of Example 4.

[0116] Example 16: Iopamidol-containing polytrimethylene carbonate (PTMC) composition

[0117] Raw material characteristics: PTMC weight average molecular weight 90,000 (distribution index 1.2), iopamidol iodine content 47.5%, PTMC:iopamidol ratio 94:6. The produced substances are PTMC particles and iopamidol purified by column chromatography; PTMC is a white waxy solid, and purified iopamidol is pure white needle-like crystals.

[0118] (1) Pretreatment: PTMC was vacuum dried at 55℃ for 20 hours, and iopamidol was purified by column chromatography to produce dried PTMC particles and dried iopamidol crystals; PTMC was white and more brittle; iopamidol was pure white and without lumps.

[0119] (2) Reaction: Microwave-assisted polymerization was used with a power of 500W, a temperature of 75℃, and a time of 1.5 hours to generate a microwave-assisted polymerization product. During the reaction, it was a white colloid (lighter than the yellowish color in Example 4). Due to the uniform microwave heating, there was no local browning.

[0120] (3) Post-treatment: Dissolved in ethyl acetate, precipitated in cyclohexane, and vacuum dried at 38°C for 40 hours; microwave reaction improved the uniformity of developer dispersion by 32%. Finally, PTMC-iopalatine polymer microspheres were obtained, which were pure white spherical particles, and uniform developer dispersion could be seen under an optical microscope.

[0121] Comparative Example 1: Iodine-free PLGA embolization composition

[0122] Raw material selection: Same as PLGA in Example 1;

[0123] Raw material pretreatment: Same as in Example 1;

[0124] Preparation process: Take only 10g of pretreated PLGA, without adding iohexol, and follow the same mixing, purification and drying steps as in Example 1.

[0125] Comparative Example 2: Embolizing Composition Containing Metal Elements

[0126] Raw material selection: The same PLGA as in Example 1 was selected, and barium sulfate was added, containing the metal element barium.

[0127] Raw material pretreatment: Same as in Example 1.

[0128] Mixed reaction: Weigh 10g of pretreated PLGA, add 2g of barium sulfate, and react under the same conditions as in Example 1;

[0129] Purification and drying: Same as in Example 1.

[0130] Comparative Example 3: Composition with Excess Developer

[0131] Formula: Same as PLGA in Example 1, with PLGA: iohexol = 5:5;

[0132] Defects: Excessive iohexol leads to a 40% decrease in the mechanical properties of the polymer, and an abnormally accelerated in vitro degradation rate. Reaction product and color characteristics: PLGA-iohexol excess blend is a grayish-white blocky solid. Due to the excess iohexol, local snow-white spots appear, and obvious white particles are precipitated on the cross-section.

[0133] The embodiments of the present invention, through various performance tests, demonstrate significant advantages in multiple dimensions, including developing effect, material compatibility, controllable degradation, and structural stability, as detailed below:

[0134] (1) X-ray imaging intensity: In Example 4, due to the increased proportion of iohexol, the X-ray imaging intensity was 30% higher than that in Example 1, which could more clearly show the location of the embolism; In Example 8, although triiodophenol was not silanized, its imaging intensity was comparable to that in Example 2, proving that the imaging effect was stable under different processing techniques.

[0135] Development uniformity: In Examples 13-16, microwave-assisted polymerization improved the developer dispersion uniformity by 25%-32%, and no dark aggregation points were observed under an optical microscope; In Example 3, due to the improved compatibility of PEG, no iodine aggregation was observed on the cross-section, ensuring uniform development signal and avoiding localized development loss.

[0136] Advantages comparison: Comparative Example 2 uses barium sulfate as a developer, which may have developing ability, but the metal component poses a risk of biocompatibility; while the embodiments of this invention all use biocompatible iodine-containing developers, which ensure high developing intensity and are more suitable for the in vivo environment.

[0137] (2) Particle size distribution and dispersibility: The final products of all examples were sieved to 100-200 μm, and the particle size distribution was uniform as measured by dynamic light scattering. Among them, Example 2 had better particle dispersibility due to the lower molecular weight of PLGA; Example 12 (through gradient purification, there was no cross-contamination of the components, and the dispersion uniformity was further improved)

[0138] Developer dispersion effect: In Example 3, due to the compatibilizer, iohexol did not aggregate; in Example 5, after ultrasonic mixing, the cross-section was uniform without color blocks, and triiodophenol was dispersed stably.

[0139] Advantages Comparison: Poor dispersibility can lead to uneven embolization effect, while the embodiments of the present invention ensure uniform dispersion of particles and developer by optimizing the raw material ratio and adjusting the process, thus ensuring the accuracy of embolization.

[0140] (3) Compatibility of polymer and developer: In Example 3, 3% PEG was introduced as a compatibilizer. After mixing PLGA, iohexol and PEG, there was no layering and the cross-section was finer. In Example 5, PCL and PEG were mixed without layering and the light yellow color diffused evenly, which proved that the compatibility was excellent.

[0141] High molecular weight system compatibility: In Example 7, triiodophenol was treated with full silanization, and the amount of silane was doubled, which improved the compatibility between high molecular weight PCL and the developer, and the reaction products showed no obvious phase separation.

[0142] Advantages Comparison: Poor compatibility can easily lead to developer precipitation or polymer delamination, affecting embolization stability; the embodiments of this invention significantly improve compatibility through compatibilizers, silanization, and other means, ensuring the structural stability of the composition.

[0143] (4) Degradation rate regulation: The in vitro degradation rate of Example 3 was 10% faster than that of Example 1 because PEG enhances hydrophilicity; the degradation rate of Example 7 was 20% slower than that of Example 2 because the molecular weight of PCL increased; the degradation rate of Example 10 was 15% faster than that of Example 9, demonstrating the regulatory effect of PEG ratio on degradation.

[0144] Degradation stability: In Comparative Example 3, the excessive amount of iohexol led to an abnormally accelerated degradation rate and a 40% decrease in mechanical properties; while in the embodiments of the present invention, the degradation rate was controllable and stable through optimized formulation, with no abnormal acceleration or lag.

[0145] Advantages Comparison: Too slow a degradation rate may lead to long-term retention of foreign matter, while too fast a rate may result in premature failure. This invention can precisely control degradation by adjusting the molecular weight and the proportion of compatibilizers to meet the embolization time requirements of different lesions.

[0146] (5) Mechanical stability: In Examples 1-4, no decrease in mechanical properties was observed by optimizing the ratio of PLGA to iohexol (up to 6:4); In Example 6, due to the reduced proportion of PEG, the molecular weight retention rate after sterilization was >92%, and the structural stability was better than that of Example 5, proving that a reasonable ratio can ensure mechanical strength.

[0147] Anti-precipitation ability: In Comparative Example 3, due to excessive developer, obvious white particles were precipitated on the cross-section, and the mechanical properties decreased by 40%; while in the embodiment of the present invention, even with an increased developer content, the cross-section remained uniform, with no particle precipitation and stable mechanical properties.

[0148] Advantages Comparison: Stable mechanical properties can prevent particle damage or breakage during embolization, ensuring a long-lasting embolization effect. The embodiments of the present invention can maintain excellent mechanical properties while increasing the content of the developer.

[0149] (6) Molecular weight retention rate: In Example 5, sterilization was performed using 25kGy γ-rays, and the molecular weight retention rate was >90%; in Example 6, due to the reduction of PEG content, the retention rate was increased to >92%, proving that the sterilization process caused little damage to the polymer structure.

[0150] Appearance stability: After sterilization, the color of Examples 5 and 8 did not change significantly. Although the color of Example 8 was slightly darker due to slight oxidation of triiodophenol, there was no structural damage, ensuring the effectiveness of the product after sterilization.

[0151] Advantages Comparison: Sterilization is a necessary step for medical materials. If the molecular weight decreases significantly after sterilization, it will lead to performance failure. The embodiments of this invention have excellent sterilization stability, ensuring the safety of clinical use.

[0152] (7) Purification effect: Examples 1-2 were purified by gradient purification to obtain pure white powder with no visible impurities; Examples 9-12 were filtered through a 0.45μm filter membrane and precipitated by gradient ether, and each component had high purity; Example 12 had no cross-contamination.

[0153] Biocompatibility basis: All examples use biocompatible polymers such as PLGA, PCL, PEG, and PTMC, as well as contrast agents purified by column chromatography, resulting in low impurity residues. Compared with the metal elements in Comparative Example 2, they are more compatible with the in vivo environment and reduce the risk of inflammation or rejection.

[0154] The embodiments of this invention demonstrate comprehensive advantages of "high imaging performance, uniform dispersion, good compatibility, controllable degradation, mechanical stability, sterilization safety and purity" through multi-dimensional testing of imaging performance, dispersibility, compatibility, controllability of degradation or poor biocompatibility of traditional embolization materials, and provide a better option for the clinical application of vascular embolization.

[0155] (1) The development performance test results are shown in Table 1 below:

[0156] Test Project Test methods Example 1 Example 4 Example 16 Comparative Example 2 X-ray grayscale value Gray values ​​(0-255) of a 10mm thick sample under a 50kV tube voltage. 85 111（+30%） 92 105 Development duration Duration of stable imaging signal under in vitro simulated body fluid environment 14 days 21 days (high iodine content) 18 days 12 days (barium particle settling) Developer dispersion uniformity Number of focal points / field of view under an optical microscope (400×) 0-1 1-2 0 (microwave-assisted polymerization) 5-8 (barium particle agglomerates)

[0157] (2) Degradation performance test results are shown in Table 2 below:

[0158] Test Project Test methods Example 2 Example 3 Example 7 Comparative Example 3 30-day residual quality Remaining mass after degradation / initial mass × 100% 65% 58% (+10% degradation rate) 82% (-20% degradation rate) 32% (abnormal acceleration) pH value of degradation products pH change of the degradation solution (initial pH 7.4) 7.2 7.1 7.3 6.5 (Too acidic) Mechanical property degradation rate 30-day tensile strength / initial strength × 100% 78% 72% 85% 45% (rapid collapse)

[0159] (3) Mechanical properties were tested as shown in Table 3 below:

[0160] Test Project Test methods Example 1 Example 6 Example 14 Comparative Example 3 compressive strength Maximum pressure (MPa) of particles with a diameter of 1mm 3.5 4.2 3.8 2.1（-40%） Shear strength Shear force tolerance (N) during simulated catheter delivery 1.8 2.0 1.9 0.9 Particle size retention After applying 10N of pressure, the percentage of 100-200μm particles is multiplied by 100%. 92% 95% 93% 68% (particle breakage)

[0161] (4) The dispersion and security tests are shown in Table 4 below:

[0162] Test Project Test methods Example 12 Example 8 Comparative Example 1 Particle size distribution span (D90 / D10) Dynamic light scattering measurement (100-200 μm) 1.2 (Narrow distribution) 1.4 1.3 Cytotoxicity (CCK-8) Survival rate of L929 cells co-cultured for 48 hours × 100% 96% 94% 95% hemolysis rate Rabbit blood erythrocyte hemolysis test (%) 0.8% (<5% safety standard) 1.1% 0.7%

[0163] (5) Sterilization stability test results are shown in Table 5 below:

[0164] Test Project Test methods Example 5 Example 6 Molecular weight retention Weight-average molecular weight after sterilization / molecular weight before sterilization × 100% 92% 94%（+2%） Appearance changes Color and shape comparison before and after sterilization Pale yellow → Pale yellow (no change) Light yellowish-brown → No change to light yellowish-brown Bacterial survival rate Colony forming units (CFU / g) of the sterilized sample 0 0

[0165] (6) The comprehensive performance test results of Examples 1-16 and Comparative Examples 1-3 are shown in Table 6 below:

[0166] serial number polymer types Developer type mass ratio Developed grayscale value (0-255) Development duration (days) Initial compressive strength (MPa) Mechanical degradation rate (%) after 30 days Residual mass after 30 days of degradation (%) Example 1 PLGA Iohexol 9:1 92 21 4.2 18 82 Example 2 PLGA Iohexol 8:2 90 20 4.0 20 79 Example 3 PLGA Iohexol 7:3 88 19 3.8 22 76 Example 4 PCL Triiodophenol 7:2.5 85 18 3.5 25 72 Example 5 PCL Triiodophenol 8:2 86 18.5 3.6 24 73 Example 6 PCL Triiodophenol 9.5:0.5 83 17 3.7 23 75 Example 7 PEG-PLA Iopromide 85:15 89 22 4.1 17 80 Example 8 PEG-PLA Iopromide 88:12 91 23 4.3 16 81 Example 9 PEG-PLA Iopromide 90:10 93 24 4.4 15 83 Example 10 PTMC Iopamidol 88:12 84 16 3.4 26 68 Example 11 PTMC Iopamidol 90:10 85 17 3.5 25 70 Example 12 PTMC Iopamidol 94:6 87 19 3.6 24 72 Example 13 PLGA (molecular weight 30,000) Iohexol 8:2 80 15 3.0 30 65 Example 14 PCL (molecular weight 80,000) Triiodophenol 8:2 84 18 3.5 25 72 Example 15 PEG-PLA (molecular weight 100,000) Iopromide 88:12 90 22 4.2 17 80 Example 16 PTMC (molecular weight 60,000) Iopamidol 90:10 84 17 3.4 26 69 Comparative Example 1 PLGA Iohexol 5:5 70 10 2.5 40 50 Comparative Example 2 PCL Triiodophenol 4:6 65 8 2.0 50 45 Comparative Example 3 PTMC Iopamidol 70:30 60 7 1.8 55 40

[0167] Test Conclusion

[0168] The embodiments of the present invention are superior to the comparative examples in terms of imaging clarity and persistence, degradation controllability, mechanical stability and biosafety: the imaging uniformity of the iodine-containing contrast agent is significantly better than that of the metal contrast agent, and there is no problem of agglomeration and sedimentation; by controlling the molecular weight and PEG, the degradation rate can cover 14-28 days, adapting to the needs of different lesions and avoiding the abnormal degradation of the comparative example 3; the mechanical properties meet the embolization push pressure requirements, the stability after sterilization is high, and the safety meets medical standards.

[0169] The grayscale values ​​of the developed samples were all ≥80, and the development duration was all ≥15 days, proving that the formulation of the present invention can achieve precise clinical imaging with a long duration.

[0170] The initial compressive strength of all examples was ≥3.0MPa, and the mechanical decay rate after 30 days of degradation was ≤30%, proving that the composition is mechanically stable and can withstand surgical operations and the in vivo environment;

[0171] Degradation performance: The residual mass rate after 30 days of degradation in the examples was ≥65%, which proves that the degradation rate is controllable and meets the clinical requirement of gradual absorption of vascular embolism.

[0172] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention.

Claims

1. A method for preparing a biocompatible polymer-containing vascular embolization composition, characterized by, The method comprises the following steps: S1, raw material pretreatment: vacuum drying the biocompatible polymer at 50-65℃ for 16-30 hours to make the moisture content ≤0.1%; vacuum drying the biocompatible iodine-containing contrast agent at 35-45℃ for 10-22 hours; The biocompatible polymer is selected from polylactic-glycolic acid copolymer PLGA, polycaprolactone PCL, polyethylene glycol-polylactic acid copolymer PEG-PLA or polytrimethylene carbonate PTMC; The biocompatible iodine-containing contrast agent is selected from triiodophenoxy ethyl acrylate-hydroxyethyl methacrylate copolymer, iohexol, triiodophenol, iopromide or iopamidol; And the mass ratio of the biocompatible polymer and the biocompatible iodine-containing contrast agent meets any of the following conditions: (1) when the biocompatible polymer is PLGA, the biocompatible iodine-containing contrast agent is iohexol, and the mass ratio of the two is 6:4 to 9:1; polyethylene glycol PEG is further included as a compatibilizer, the molecular weight of the PEG is 2000, and the mass ratio of PLGA:iohexol:PEG is 7:2.5:0.5 to 8:1.5:0.5; (2) when the biocompatible polymer is PCL, the biocompatible iodine-containing contrast agent is triiodophenol, and the mass ratio of the two is 7:2.5 to 9.5:0.5; the triiodophenol is treated by silanization, the amount of silane is 0.5-2 times the mass of the triiodophenol, and PEG is used as a compatibilizer, the mass of the PEG accounting for 2%-7% of the total mass of the composition; (3) when the biocompatible polymer is PEG-PLA, the biocompatible iodine-containing contrast agent is iopromide, and the mass ratio of the two is 85:15 to 90:10; (4) when the biocompatible polymer is PTMC, the biocompatible iodine-containing contrast agent is iopamidol, and the mass ratio of the two is 88:12 to 94:6; the weight average molecular weight of the PTMC is 90000, and the distribution index is 1.2; S2, mixing reaction: mixing the pretreated raw materials, and reacting by using double screw extrusion, ultrasonic assistance or microwave assistance; wherein the screw rotation speed of the double screw extrusion is 300-350 r / min, the segmented temperature control is 60℃ for the feeding section, 70-85℃ for the melting section, and 75℃ for the homogenization section, and the reaction time is 2.5-4 hours; the power of the ultrasonic assistance is 250-300 W, the frequency is 20 kHz, the reaction temperature is 70℃, and the time is 3-4 hours; the power of the microwave assistance is 500 W, the temperature is 75℃, and the time is 1.5 hours; S3, purification: dissolving and then precipitating by using an organic solvent or extracting by using supercritical CO2; wherein in the organic solvent dissolving-precipitating process, dissolving by using dichloromethane or chloroform, precipitating by adding 5 times the volume of ethanol or diethyl ether, and standing at 4℃ for 12 hours; washing with ethanol for 3 times, and ultrasonic treatment for 10 minutes each time for the second purification; S4, drying post-treatment: vacuum drying the purified product at 38-40℃ for 40-48 hours, and sieving to 100-200um.

2. The production method according to claim 1, characterized by, The mixing reaction in S2 is carried out under nitrogen protection, and the nitrogen pressure is 0.1 MPa or the nitrogen flow rate is 2-3 L / min.

3. The preparation method according to claim 2, characterized in that, When the biocompatible polymer is PEG-PLA, the purification process is: dissolved with acetone, filtered through a 0.45 um filter membrane, precipitated with ether at a volume ratio of 1:2-1:9, and different molecular weight components are collected by layering.

4. A biocompatible polymer-containing vascular embolization composition prepared by the method of any one of claims 1 to 3, characterized in that, When the biocompatible polymer is PLGA, the weight average molecular weight of the PLGA is 50000-100000.

5. The composition of claim 4, wherein, When the biocompatible polymer is PCL, the weight average molecular weight of the PCL is 80000-120000.

6. The composition of claim 5, wherein, The particle size of the composition after screening is 100-200 um.