Gelatin-based embolic gel microspheres and methods of making the same

Abstract

The application provides a gelatin-based embolism gel microsphere and a preparation method thereof. The gelatin-based embolism gel microsphere is prepared from at least the following: an aqueous phase solution including 8-14% of gelatin in mass fraction, 0.2-0.4% of a photoinitiator in mass fraction, a zwitterionic monomer and a hydrogen-bondable monomer; the molar ratio of the zwitterionic monomer to the hydrogen-bondable monomer is 0.5-1.5; the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bondable monomer is 6-10%; an oil phase solution including an organic oil with a dynamic viscosity of 110-300 mPa*s (20 DEG C); the volume ratio of the oil phase solution to the aqueous phase solution is (5-10):1. The gelatin-based embolism gel microsphere has the advantages of high toughness, moderate swelling degree, self-healing after damage, longer degradation stability period, and the ability to simultaneously load more cationic drugs and anionic drugs.

Description

Technical Field

[0001] The present application relates to the technical field of embolic gel microspheres, and in particular to gelatin-based embolic gel microspheres and a preparation method thereof. Background Art

[0002] Malignant tumors (cancer) are one of the most common causes of death. Cancer treatment remains a major challenge worldwide, especially for certain diseases such as liver cancer, where early symptoms are subtle. Most patients are diagnosed in the advanced stages, making surgical resection difficult and the treatment and prognosis relatively poor. Transarterial chemoembolization (TACE) is a minimally invasive technique that selectively injects an embolic agent or anticancer drug combined with microparticles to occlude the tumor's blood supply arteries. It is a type of interventional vascular therapy. Its advantages include: first, embolizing the tumor's blood supply arteries, causing ischemia, hypoxia, and necrosis; second, increasing local drug concentration and prolonging drug contact time with the tumor tissue, significantly improving efficacy compared to simple perfusion chemotherapy and embolization alone. TACE is suitable for both palliative and relatively radical treatment of liver cancer, kidney cancer, pancreatic cancer, lung cancer, and pelvic malignancies, as well as radical treatment of hepatic hemangiomas.

[0003] The effectiveness of TACE therapy depends largely on the performance and characteristics of the embolic agent. Traditional embolic agents are mostly liquid, which have the problem of high fluidity. Newer solid embolic agents often cannot effectively load both anionic and cationic drugs simultaneously, and they also suffer from problems such as low drug loading, short degradation time, and low strength. Summary of the Invention

[0004] In view of this, the purpose of this application is to provide a gelatin-based embolic gel microsphere and a preparation method thereof.

[0005] Based on the above objectives, the present application provides a gelatin-based embolic gel microsphere, which is prepared from at least the following substances:

[0006] Aqueous phase solution: comprising 8%-14% gelatin by mass, 0.1%-1% photoinitiator by mass, zwitterionic monomer and hydrogen-bonding monomer; wherein the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer is 0.5-1.5; and the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer is 6-10%;

[0007] Oil phase solution: comprising an organic oil having a dynamic viscosity of 110-300 mPa*s (20°C);

[0008] Wherein, the volume ratio of the oil phase solution to the water phase solution is (1-20):1, preferably (5-10):1.

[0009] In some embodiments, the zwitterionic monomer is selected from at least one of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, 3-(dimethyl(4-vinylbenzylammonium)propyl sulfonate and 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate; and / or

[0010] The hydrogen-bonding monomer is selected from monomers having a carbon-carbon double bond and an amide group.

[0011] In some embodiments, the hydrogen-bonding monomer is selected from at least one of N-hydroxyethyl acrylamide, N,N-dimethyl acrylamide, 2-methyl acrylamide, 2-acrylamido-2-methylpropanesulfonic acid, tert-butyl acrylamidesulfonic acid, N-isopropyl acrylamide and N-(pyridin-2-yl) acrylamide.

[0012] In some embodiments, in the aqueous solution, the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer is 0.7-1.5; the mass fraction of the gelatin is 8%-13%; the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer is 7.2-9.2%; and / or

[0013] The volumes of the oil phase solution and the water phase solution are (6-8):1.

[0014] In some embodiments, the anionic drug loading capacity of the gelatin-based embolic gel microspheres is 0.1-48.5 mg / mL, and the cationic drug loading capacity is 0.1-32.5 mg / mL, calculated based on the volume of the microspheres.

[0015] In some embodiments, the anionic drug loading capacity of the gelatin-based embolic gel microspheres is 37.5-46.5 mg / mL, and the cationic drug loading capacity is 22.4-31.4 mg / mL, calculated based on the volume of the microspheres; and / or

[0016] The internal pore size of the gelatin-based embolic gel microspheres is 1-100 μm, and the pore volume is 0.15-0.6 cm 3 / g; and / or

[0017] The gelatin-based embolic gel microspheres can withstand a compression deformation of 60-90%, and a compression recovery time of 5-30 seconds.

[0018] In some embodiments, the gelatin-based embolic gel microspheres have an internal pore size of 20-100 μm and a pore volume of 0.37-0.44 cm 3 / g; and / or

[0019] The gelatin-based embolic gel microspheres can withstand a compression deformation of 76-87% and a compression recovery time of 7-14 seconds; and / or

[0020] The equilibrium swelling rate of the gel microspheres is 50%-80% based on the mass ratio of swelling water to dry microspheres, and the volume increase rate after swelling is less than 15%.

[0021] In some embodiments, the organic oil is selected from at least one of liquid paraffin, n-hexane, mineral oil and silicone oil; and / or

[0022] The photoinitiator is selected from at least one of 2-hydroxy-2-methylpropiophenone, Omnirad 500 and photoinitiator 2959.

[0023] The present application also provides a method for preparing gelatin-based embolic gel microspheres, comprising:

[0024] Providing an aqueous solution; the aqueous solution comprises 8% to 14% by mass of gelatin, 0.2% to 0.4% by mass of a photoinitiator, a zwitterionic monomer, and a hydrogen-bonding monomer; wherein the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer is 0.5 to 1.5; and the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer is 6 to 10%;

[0025] Providing an oil phase solution; the oil phase solution comprises an organic oil having a dynamic viscosity of 110-300 mPa*s (20° C.);

[0026] Exposing the oil phase solution to an initiation wavelength corresponding to the photoinitiator, adding the aqueous phase solution dropwise to the oil phase solution under stirring at a first temperature for a first period of time; and performing a polymerization reaction at a second temperature for a second period of time;

[0027] The product obtained by the polymerization reaction is washed with isopropyl alcohol, purified with deionized water, sieved, dried and soaked in physiological saline to obtain the gelatin-based embolic gel microspheres.

[0028] In some embodiments, the first temperature is room temperature, the first time period is 15-30 minutes, the second temperature is 0°C-10°C, and the second time period is 6-12 hours.

[0029] As can be seen from the above, the gelatin-based embolic gel microspheres and their preparation method provided in this application, through the copolymerization reaction of gelatin, zwitterionic monomers and hydrogen-bonding monomers, obtain a dual network structure capable of simultaneously loading two different types of drugs, cationic drugs and anionic drugs; the dual network system formed by combining the rigid network of the gelatin helical structure with the flexible network formed by the polymerization of zwitterionic monomers and hydrogen-bonding monomers facilitates energy dissipation, while the hydrogen-bonding monomers can form reversible hydrogen bonds with each other and with gelatin, and the zwitterionic monomers can form reversible ionic bonds, which together achieve high energy dissipation and strong compressive resistance of the gelatin-based embolic gel microspheres; at the same time, the interaction between the zwitterionic and hydrogen-bonding structures and the gelatin is strengthened, thereby delaying the degradation time of the gelatin and improving the reliability of the embolization. At the same time, when the gelatin-based embolic gel microspheres rupture, they can achieve self-healing without significantly decreasing performance through reversible dynamic hydrogen bonding and ionic interactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions in this application or related technologies, the following briefly introduces the drawings required for use in the embodiments or related technical descriptions. Obviously, the drawings described below are merely embodiments of this application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0031] Figure 1 Schematic diagram of the preparation process of gelatin-based embolic gel microspheres according to an embodiment of the present application. DETAILED DESCRIPTION

[0032] In order to make the objectives, technical solutions and advantages of this application more clear, this application is further described in detail below in combination with specific embodiments and with reference to the accompanying drawings.

[0033] It should be noted that, unless otherwise defined, the technical terms or scientific terms used in the embodiments of the present application should have the usual meanings understood by people with ordinary skills in the field to which this application belongs. The "first", "second" and similar words used in the embodiments of the present application do not indicate any order, quantity or importance, but are only used to distinguish different components. "Include" or "comprising" and similar words mean that the elements or objects appearing before the word include the elements or objects listed after the word and their equivalents, without excluding other elements or objects.

[0034] Traditional embolic agents are liquid mixtures of iodized oil and chemotherapy drugs. Their fluidity can reduce drug efficacy and cause systemic toxicity. Solid embolic agents, including gelatin sponges, polyvinyl alcohol particles, and microspheres, offer improved anchoring within blood vessels, are non-toxic, and offer improved therapeutic efficacy compared to traditional embolic agents. However, facing the complex and diverse patient and surgical scenarios, current embolic agents still have numerous shortcomings. These include low loading efficiency when simultaneously loading cationic and anionic drugs; low strength; rapid degradation, which can lead to insecure embolization if damaged; poor vascular compatibility; or a single performance excelling but poor overall performance. These issues severely impact embolic and therapeutic efficacy. To further improve therapeutic outcomes, the development of novel embolic agents with superior performance that meet diverse clinical requirements remains an urgent task.

[0035] Based on this, the embodiments of the present application provide a gelatin-based embolic gel microsphere and a preparation method thereof. Through the polymerization of gelatin, zwitterionic monomers and hydrogen-bonding monomers, supplemented by a mixing process of an aqueous solution and an oily solution, the oil-water phase is stirred into balls and then photocured and cross-linked to achieve high strength and toughness, moderate swelling, self-healing after damage, and a longer degradation stability period. To a certain extent, it can solve the problems of low loading efficiency, short degradation time and low strength of solid embolic agents when simultaneously loading cationic and anionic drugs.

[0036] The present invention provides a gelatin-based embolic gel microsphere, which is prepared from at least the following substances:

[0037] Aqueous solution: comprising 8%-14% gelatin by mass, 0.2%-0.4% photoinitiator by mass, zwitterionic monomer, and hydrogen-bonding monomer; wherein the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer is 0.5-1.5; and the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer is 6-10%;

[0038] Oil phase solution: comprising an organic oil having a dynamic viscosity of 110-300 mPa*s (20°C);

[0039] Wherein, the volumes of the oil phase solution and the water phase solution are (5-10):1.

[0040] Gelatin, a natural polymer derived from the hydrolysis of collagen, boasts excellent biocompatibility, ease of availability, swellability upon water absorption, biodegradability, and non-toxicity. Gelatin-based embolic gel microspheres, made by cross-linking gelatin with zwitterionic monomers and hydrogen-bonding monomers, are smooth and spherical in appearance, allowing for better conformity to blood vessels. After absorbing water, the gelatin-based embolic gel microspheres exhibit elasticity, achieving a superior embolic effect. They are also biodegradable in vivo and exhibit excellent recanalization properties.

[0041] In some embodiments, the photoinitiator can be a water-soluble photoinitiator selected from 2-hydroxy-2-methylpropiophenone (photoinitiator 1173), photoinitiator 500 (Omnirad 500), and photoinitiator 2959. Photoinitiator 500 is a liquid mixture of two photoinitiators, the active ingredients of which include photoinitiator 184 (1-hydroxycyclohexylphenyl ketone) and photoinitiator BP (benzophenone, also known as benzophenone, benzophenone, benzophenone, benzoylphenyl, benzoylphenyl, or benzoylphenyl). Photoinitiator 2959 is 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone. The mass fraction of the photoinitiator in the aqueous solution can be 0.3%. Among them, the zwitterionic monomer can be selected from at least one of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide and 3-(dimethyl (4-vinylbenzylammonium) propyl sulfonate. [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, the structural formula is The structural formula of 3-(dimethyl(4-vinylbenzylammonium)propylsulfonate is .

[0042] Wherein, the hydrogen-bonding monomer is selected from monomers having a carbon-carbon double bond and an amide group. The hydrogen-bonding in the hydrogen-bonding monomer can be understood as generating a mutual hydrogen-bonding between the N and H atoms in the monomer or generating a hydrogen-bonding between the N and H atoms in the monomer and the H atoms in gelatin. In certain embodiments, the hydrogen-bonding monomer is selected from at least one of N-hydroxyethyl acrylamide, N,N-dimethyl acrylamide, 2-methyl acrylamide, N-isopropyl acrylamide and N-(pyridin-2-yl) acrylamide. After the polymerization reaction is initiated by a photoinitiator, the zwitterionic monomer and the hydrogen-bonding monomer can be polymerized through a double bond reaction to form a zwitterionic polymer, a hydrogen-bonding polymer, and a random copolymer network of the zwitterionic polymer and the hydrogen-bonding polymer.

[0043] In some embodiments, in the aqueous solution, the mass fraction of the gelatin is 8%-13%; the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer can be (0.7-1.5):1; and the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer can be 7.2-9.2%.

[0044] In some embodiments, the organic oil may be selected from at least one of liquid paraffin, n-hexane, mineral oil, and silicone oil. The volume ratio of the oil phase solution to the aqueous phase solution may be (6-8):1.

[0045] In some embodiments, the gelatin-based embolic gel microspheres have an anionic drug loading of 0.1-48.5 mg / mL, calculated by microsphere volume, and a cationic drug loading of 0.1-32.5 mg / mL, calculated by microsphere volume. The cationic drug may be at least one of doxorubicin, pirarubicin, and epirubicin. The anionic drug may be at least one of ketoprofen and suprofen.

[0046] In some embodiments, the anionic drug loading capacity of the gelatin-based embolic gel microspheres is 37.5-46.5 mg / mL, and the cationic drug loading capacity is 22.4-31.4 mg / mL, calculated based on the volume of the microspheres.

[0047] In some embodiments, the gelatin-based embolic gel microspheres have an internal pore size of 1-100 μm and a pore volume of 0.15-0.6 cm 3 / g. Furthermore, the internal pore size of the gelatin-based embolic gel microspheres is 20-100 μm, and the pore volume is 0.37-0.44 cm 3 / g.

[0048] In some embodiments, the gelatin-based embolic gel microspheres can withstand a compression deformation of 60-90% and a compression recovery time of 5-30 seconds. The gelatin-based embolic gel microspheres can withstand a compression deformation of 76-87% and a compression recovery time of 7-14 seconds.

[0049] In some embodiments, the gelatin-based embolic gel microspheres exhibit an equilibrium swelling ratio of 50%-80% based on the mass ratio of swelling water to dry spheres, and a volume increase rate of less than 15% after swelling. The gelatin component in the gelatin-based embolic gel microspheres degrades within 30-90 days, while the remaining components are metabolized, presenting no toxic effects on human health.

[0050] In some embodiments, the gel microspheres can be used for vascular intervention via a microcatheter, with sizes including but not limited to 1.8F, 2.0F, 2.2F, 2.5F, and 2.7F. In some embodiments, the gel microspheres are used for transarterial chemoembolization to treat malignant tumors, where the microspheres are injected into tumor blood vessels via a microcatheter to form an embolization. Specifically, after being loaded with drugs, the gel microspheres can achieve malignant tumor treatment by releasing the drugs.

[0051] Based on the same inventive concept, corresponding to the gelatin-based embolic gel microspheres of any of the above embodiments, the embodiments of the present application further provide a method for preparing gelatin-based embolic gel microspheres.

[0052] like Figure 1 As shown, the preparation method of the gelatin-based embolic gel microspheres provided in the embodiments of the present application may include:

[0053] S100, providing an aqueous solution; the aqueous solution comprising 8%-14% by mass of gelatin, 0.2%-0.4% by mass of a photoinitiator, a zwitterionic monomer, and a hydrogen-bonding monomer; wherein the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer is 0.5-1.5; and the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer is 6-10%;

[0054] S200, providing an oil phase solution; the oil phase solution includes an organic oil having a dynamic viscosity of 110-300 mPa*s (20° C.);

[0055] S300, exposing the oil phase solution to an initiation wavelength corresponding to the photoinitiator, adding the aqueous phase solution dropwise to the oil phase solution under stirring at a first temperature for a first time, and performing polymerization at a second temperature for a second time;

[0056] S400, washing the product obtained from the polymerization reaction with isopropyl alcohol, purifying it with deionized water, sieving it, drying it, and soaking it in physiological saline to obtain the gelatin-based embolic gel microspheres.

[0057] In step S100, the gelatin with a mass fraction of 8%-14% can be prepared by the following method: measuring a certain volume of deionized water, weighing a corresponding mass of gelatin powder, and preparing a gelatin solution with a mass fraction of 8-14%.

[0058] Specifically, weigh the corresponding volume of water and the corresponding mass of gelatin powder based on the desired gelatin mass fraction in the gelatin solution. Then, add the weighed gelatin powder to a beaker filled with deionized water. Seal the beaker and transfer it to a constant temperature water bath at 40°C to 60°C to allow it to completely dissolve. Allow it to stand for defoaming to obtain the gelatin solution.

[0059] The aqueous solution can be prepared by adding corresponding masses of photoinitiator, zwitterionic monomer and hydrogen-bonding monomer to gelatin solution and stirring uniformly at a temperature of 50°C.

[0060] In some embodiments, the photoinitiator is selected from at least one of 2-hydroxy-2-methylpropiophenone, photoinitiator 500 and photoinitiator 2959.

[0061] In some embodiments, the zwitterionic monomer is selected from at least one of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide and 3-(dimethyl(4-vinylbenzylammonium)propyl sulfonate); and / or the hydrogen-bonding monomer is selected from monomers having a carbon-carbon double bond and an amide group.

[0062] In some embodiments, the hydrogen-bonding monomer is selected from at least one of N-hydroxyethyl acrylamide, N,N-dimethyl acrylamide, 2-methyl acrylamide, N-isopropyl acrylamide, and N-(pyridin-2-yl) acrylamide.

[0063] In some embodiments, in the aqueous solution, the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer is 0.7-1.5; the mass fraction of the gelatin is 8%-13%; and the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer is 7.2-9.2%.

[0064] In step S200, the organic oil may be selected from at least one of liquid paraffin, n-hexane, mineral oil and silicone oil.

[0065] In step S300, the initiation wavelength can be the wavelength at which the photoinitiator has the highest efficiency. For example, the absorption wavelength of photoinitiator 1173 is 331 nm. The first temperature can be room temperature, and the first duration can be 15-30 minutes. For example, the oil phase can be added to a reactor exposed to the wavelength at which the photoinitiator has the highest efficiency, stirred, and then the aqueous solution can be slowly added dropwise. The volume ratio of the oil phase solution to the aqueous solution can be (6-8):1.

[0066] In some embodiments, the second temperature can be 0°C-10°C, and the second duration can be 6-12 hours. The second temperature can be controlled by a low-temperature cooling water circulation pump. Stirring can be performed to thoroughly mix the aqueous and oil phases, followed by a second period of time to allow polymerization to proceed, yielding preliminarily formed spherical particles. After polymerization, a network can form within the gel microspheres, with the gelatin helical structure serving as the backbone and zwitterionic polymers and hydrogen-bonding polymers crosslinked. Interactions within the system include anionic and cationic interactions between the zwitterionic polymers and gelatin, as well as hydrogen bonding interactions between the various substances. The cut or damaged surface of the microspheres can completely heal within 2-6 hours after bonding through hydrogen bonding and ionic forces, indicating that their self-healing properties stem from dynamic ionic and hydrogen bonding interactions. The mechanical properties of the healed microspheres do not degrade by more than 10% compared to the original microspheres. The gelatin-based embolic gel microspheres can withstand compression deformation of 60-90%, with a compression recovery time of 5-30 seconds.

[0067] In step S400, the oil phase of the microspheres can be washed with isopropyl alcohol to initially obtain gelatin-based embolic gel microspheres A. The isopropyl alcohol can be replaced multiple times for multiple washings. During deionized water purification, the deionized water can be replaced multiple times for multiple purifications to obtain gelatin-based embolic gel microspheres B.

[0068] In some embodiments, sieving can include placing standard sieves of varying pore sizes in descending order from top to bottom, then slowly pouring the prepared microspheres into the topmost standard sieve, followed by slowly rinsing with deionized water from top to bottom to remove particles smaller than the pore size of the standard sieves, thereby ensuring that the particle size of each standard sieve is greater than or equal to the pore size of the standard sieve. In this manner, gelatin-based embolic gel microspheres C of varying particle sizes can be obtained. The deionized water rinses can be repeated multiple times.

[0069] In some embodiments, the pore sizes of the standard sieves are, from top to bottom, 70µm, 100µm, 300µm, 500µm, 700µm, 900µm, 1200µm, 1500µm, and 2000µm, and the corresponding gelatin-based embolic gel microspheres have a size range of 100-300µm, 300-500µm, 500-700µm, 700-900µm, 900-1200µm, 1200-1500µm, and 1500-2000µm. The internal pore size of the prepared gel microspheres is between 1-100µm, and the pore volume is between 0.15-0.6cm 3 / g.

[0070] In some embodiments, gelatin-based embolic gel microspheres of varying particle sizes can be placed in anhydrous ethanol, stirred, and filtered; then dried in a forced-air drying oven at 50°C-60°C for 18-30 hours, and the oven temperature can be raised to 120°C-140°C to remove residual ethanol and solvent, thereby obtaining dried gelatin-based embolic gel microspheres D. The filtration can be repeated three times, with the anhydrous ethanol replaced each time.

[0071] In some embodiments, the saline soaking step can include placing the gelatin-based embolic gel microspheres D into an excess of saline to allow them to absorb water, thereby obtaining injectable gelatin-based embolic gel microspheres. The gel microspheres have an equilibrium swelling ratio, calculated as the mass ratio of swelling water to dry microspheres, of between 50% and 80%, and a volume increase rate of less than 15% after swelling.

[0072] In some embodiments, the gelatin component in the gel microspheres will be degraded within 30-90 days, and the remaining components will be metabolized without toxic effects on human health.

[0073] In some embodiments, the gel microspheres can be used for vascular intervention via a microcatheter, and the sizes of the microcatheter include but are not limited to 1.8F, 2.0F, 2.2F, 2.5F or 2.7F.

[0074] In some embodiments, the gel microspheres are used for transarterial chemoembolization to treat malignant tumors, and the microspheres are injected into tumor blood vessels through a microcatheter to form embolism.

[0075] In some embodiments, the gel microspheres, after being loaded with drugs, can achieve the treatment of malignant tumors by releasing drugs.

[0076] The technical solution of the present invention is further described below with reference to specific implementation methods.

[0077] The experimental methods in the following examples are conventional methods unless otherwise specified.

[0078] Unless otherwise specified, the test materials used in the following examples were purchased from conventional biochemical reagent stores.

[0079] Example 1

[0080] 1) Preparation of gelatin-based embolic gel microspheres:

[0081] S1: Preparation of Gelatin Solution: Prepare a 10% gelatin solution by weight using a certain amount of deionized water and gelatin powder. Add the weighed gelatin powder to a beaker filled with deionized water. Seal the beaker and transfer it to a 50°C constant temperature water bath to completely dissolve the gelatin powder. Allow to stand for defoaming to obtain the gelatin solution.

[0082] S2: Add [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide, N-hydroxyethyl acrylamide, and photoinitiator 1173 to the gelatin aqueous solution and stir evenly at 50°C to form an aqueous phase solution. The total mass fraction of the two monomers in the aqueous phase solution is 8%, the molar ratio of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide and N-hydroxyethyl acrylamide is 1.2, and the mass fraction of photoinitiator 1173 in the aqueous phase is 0.3%.

[0083] S3: Preparation of oil phase solution: Add an appropriate amount of liquid paraffin to a beaker, seal it and place it in a constant temperature water bath at 45°C for 1.5 hours to obtain the oil phase solution.

[0084] S4: Preparation of microspheres: At room temperature, add the oil phase to a reactor exposed to 335nm wavelength ultraviolet light, put it in a mechanical stirring state with a stirring rate of 150rmp, slowly add the aqueous phase solution dropwise to the oil solution, stir at room temperature for 25 minutes, immediately start the low-temperature cooling water circulation pump, control the reaction temperature to 5°C, stir for 60 minutes, and then let it stand for 8 hours to obtain well-formed spherical particles; the volume of the oil phase is 6 times the volume of the aqueous phase.

[0085] S5: Oil phase washing of microspheres: Add 6°C isopropanol to the reaction device, stir mechanically for 2.5 minutes at a stirring rate of 80 rpm, let it stand for 1.5 minutes, pour out the upper oil phase solution, and then transfer the particles to a clean container. Add 2.5 times the volume of 6°C isopropanol to the container. After sealing, place the container on a constant temperature magnetic stirrer and stir at a speed of 50-100 rpm. Replace the 6°C isopropanol every 10 minutes. Repeat the operation 3-5 times. After the last washing with isopropanol, pour the particles into the filtration device, connect and open the circulating water vacuum pump for filtration to obtain microspheres A.

[0086] S6: Purification of microspheres: Add 9 times the volume of deionized water as that of microsphere A into the container. After sealing, place the container on a constant temperature magnetic stirrer and stir at 80 rpm at room temperature. Filter and replace the deionized water every 30 minutes. Repeat the filtration and washing for 5 times. After the deionized water washing is completed, the microsphere product B is obtained.

[0087] S7: Screening of microspheres: Place standard sieves of different pore sizes in descending order from top to bottom, slowly pour the prepared microspheres into the top standard sieve, and then slowly rinse with deionized water from top to bottom. Repeat the rinse several times to ensure that the particle size of each standard sieve is ≥ the pore size of the standard sieve, thus obtaining microsphere products C of different particle sizes.

[0088] S8: Place microsphere product C of different particle sizes in 2.5 times its volume of anhydrous ethanol, stir at 80 rpm, filter and replace anhydrous ethanol every 30 minutes, repeat the operation three times, after cleaning and filtering with anhydrous ethanol, dry the microsphere product C in a 55°C forced air drying oven for 24 hours, then increase the oven temperature to 135°C to remove residual ethanol and solvent to obtain the final dried microsphere D, which is then stored in a dry environment.

[0089] S9: The dried microspheres D are placed into excess physiological saline and soaked until they are fully absorbed with water, thereby obtaining the final injectable gel microspheres.

[0090] The gel microspheres are used for transarterial chemoembolization to treat malignant tumors, and the microspheres are injected into tumor blood vessels through a microcatheter to form embolism.

[0091] After being loaded with drugs, the gel microspheres can achieve the treatment of malignant tumors by releasing the drugs.

[0092] 2) Detection method:

[0093] The internal pore size of the drug-loaded embolic gel microspheres can be obtained by microscopic observation after freeze-drying, and the pore volume of the microspheres can be obtained by mercury exclusion method.

[0094] The compression deformation of the drug-loaded embolic gel microspheres was tested using a universal mechanical testing machine in compression mode, and the compression recovery time was obtained by observation.

[0095] The equilibrium swelling ratio is calculated by the ratio of the mass of the swelling water absorbed by the swelling to the mass of the dry bulb before swelling.

[0096] The concentration difference of the drug solution before and after absorption was tested by the UV spectral characteristic peak method to obtain the drug loading concentration of the drug-loaded embolic gel microspheres.

[0097] The microspheres were placed in physiological saline to observe their morphology and the presence of flocculent degradation products in the saline to determine whether the gel had begun to degrade.

[0098] 3) Test results: The internal pore diameter of the gel microspheres is between 20-100 μm, and the pore volume is 0.42 cm 3 / g.

[0099] After the gel microspheres were cut open, the cut surfaces were fitted together, and the cut surfaces were completely healed within 4.5 hours. After healing, the mechanical properties of the microspheres decreased by about 7% compared with the original microspheres.

[0100] The pore sizes of the standard sieves from top to bottom are: 70µm, 100µm, 300µm, 500µm, 700µm, 900µm, 1200µm, 1500µm, 2000µm, and the corresponding microsphere size ranges are: 100~300µm, 300~500µm, 500~700µm, 700~900µm, 900~1200µm, 1200~1500µm, 1500~2000µm.

[0101] The gel microspheres can withstand a compression deformation of 76%, and the compression recovery time is 7s.

[0102] The equilibrium swelling rate of the gel microspheres is 78% calculated based on the mass ratio of swelling water to dry microspheres, and the volume increase rate after swelling is 12%.

[0103] The anionic drug methotrexate disodium drug loading amount of the gel microspheres can reach 44.3 mg / mL based on the volume of the microspheres, and the cationic drug doxorubicin drug loading amount can reach 26.5 mg / mL based on the volume of the microspheres.

[0104] The gelatin component in the gel microspheres will begin to degrade in physiological saline on the 46th day and will be completely degraded on the 86th day.

[0105] The gel microspheres can be used for vascular intervention via a microcatheter, and the sizes of the microcatheter include but are not limited to 1.8F, 2.0F, 2.2F, 2.5F, 2.7F, etc.

[0106] Example 2

[0107] 1) Preparation of gelatin-based embolic gel microspheres:

[0108] S1: Preparation of Gelatin Solution: Prepare a 12% gelatin solution by weight using a certain amount of deionized water and gelatin powder. Add the weighed gelatin powder to a beaker filled with deionized water. Seal the beaker and transfer it to a 55°C constant temperature water bath to completely dissolve the gelatin powder. Allow to stand for defoaming to obtain the gelatin solution.

[0109] S2: Add 3-(dimethyl(4-vinylbenzylammonium)propylsulfonate), 2-methylacrylamide, and photoinitiator 2959 to the gelatin aqueous solution and stir evenly at 60°C to form an aqueous phase solution. The total mass fraction of the two monomers in the aqueous phase solution is 7.2%, the molar ratio of 3-(dimethyl(4-vinylbenzylammonium)propylsulfonate to 2-methylacrylamide is 0.7, and the mass fraction of photoinitiator 2959 in the aqueous phase is 0.3%.

[0110] S3: Preparation of oil phase solution: Add an appropriate amount of n-hexane to a beaker, seal it, and place it in a constant temperature water bath at 45°C for 1.5 hours to obtain an oil phase solution.

[0111] S4: Preparation of microspheres: At room temperature, the oil phase was added to a reactor exposed to 276 nm ultraviolet light and mechanically stirred at a rate of 200 rpm. The aqueous phase solution was slowly added dropwise to the oil solution and stirred at room temperature for 20 minutes. The reaction temperature was immediately controlled to 5°C by turning on the low-temperature cooling water circulation pump. The reaction mixture was stirred for 80 minutes and then allowed to stand for 8 hours to obtain well-formed spherical particles. The volume of the oil phase was 7 times that of the aqueous phase.

[0112] S5: Oil phase washing of microspheres: add 8°C isopropanol to the reaction apparatus, stir mechanically for 2.5 minutes at a stirring rate of 80 rpm, let it stand for 1.5 minutes, pour out the upper oil phase solution, and then transfer the particles to a clean container. Add 2.5 times the volume of 8°C isopropanol to the container, seal it, place it on a constant temperature magnetic stirrer, stir at a speed of 100 rpm, replace 8°C isopropanol every 10 minutes, repeat this operation 4 times, and after the last washing with isopropanol, pour the particles into a filtration device, connect and open a circulating water vacuum pump for filtration to obtain microspheres A;

[0113] S6: Purification of microspheres: Add 8 times the volume of deionized water as that of microspheres A to the container, seal it, and place it on a thermostatic magnetic stirrer. Stir at 90 rpm at room temperature. Filter and replace the deionized water every 30 minutes. Repeat the filtration and washing six times. After the deionized water washing is completed, microsphere product B is obtained.

[0114] S7: Sieving of microspheres: Place standard sieves of different pore sizes in descending order from top to bottom, slowly pour the prepared microspheres into the top standard sieve, and then slowly rinse with deionized water from top to bottom. Repeat the rinse several times to ensure that the particle size of each standard sieve is ≥ the pore size of the standard sieve, thus obtaining microsphere products C of different particle sizes;

[0115] S8: Place microsphere product C of different particle sizes in 2.5 times its volume of anhydrous ethanol, stir at 90 rpm, filter and replace anhydrous ethanol every 30 minutes, repeat this operation three times, after washing and filtering with anhydrous ethanol, dry the microsphere product C in a 50°C forced air drying oven for 20 hours, then increase the oven temperature to 140°C to remove residual ethanol and solvent to obtain the final dried microsphere D, which is then stored in a dry environment;

[0116] S9: The dried microspheres D are placed into excess physiological saline and soaked until they are fully absorbed with water, thereby obtaining the final injectable gel microspheres.

[0117] The gel microspheres are used for transarterial chemoembolization to treat malignant tumors, and the microspheres are injected into tumor blood vessels through a microcatheter to form embolism.

[0118] After being loaded with drugs, the gel microspheres can achieve the treatment of malignant tumors by releasing the drugs.

[0119] 2) Detection method:

[0120] The internal pore size of the drug-loaded embolic gel microspheres can be obtained by microscopic observation after freeze-drying, and the pore volume of the microspheres can be obtained by mercury exclusion method.

[0121] The compression deformation of the drug-loaded embolic gel microspheres was tested using a universal mechanical testing machine in compression mode, and the compression recovery time was obtained by observation.

[0122] The equilibrium swelling ratio is calculated by the ratio of the mass of the swelling water absorbed by the swelling to the mass of the dry bulb before swelling.

[0123] The concentration difference of the drug solution before and after absorption was tested by the UV spectral characteristic peak method to obtain the drug loading concentration of the drug-loaded embolic gel microspheres.

[0124] The microspheres were placed in physiological saline to observe their morphology and the presence of flocculent degradation products in the saline to determine whether the gel had begun to degrade.

[0125] 3) Test results:

[0126] The internal pore diameter of the gel microspheres is between 20 and 80 μm, and the pore volume is 0.37 cm 3 / g.

[0127] After the gel microspheres were cut open, the cut surfaces were fitted together, and the cut surfaces were completely healed in 5.4 hours. After healing, the mechanical properties of the microspheres decreased by about 8.5% compared with the original microspheres.

[0128] The pore sizes of the standard sieves from top to bottom are: 70µm, 100µm, 300µm, 500µm, 700µm, 900µm, 1200µm, 1500µm, 2000µm, and the corresponding microsphere size ranges are: 100~300µm, 300~500µm, 500~700µm, 700~900µm, 900~1200µm, 1200~1500µm, 1500~2000µm.

[0129] The gel microspheres can withstand a compression deformation of 82%, and the compression recovery time is between 7.5s.

[0130] The equilibrium swelling rate of the gel microspheres is 62.5% calculated based on the mass ratio of swelling water to dry microspheres, and the volume increase rate after swelling is 7.6%.

[0131] The maximum drug loading capacity of the anionic drug methotrexate disodium of the gel microspheres is 37.5 mg / mL, calculated based on the volume of the microspheres, and the maximum drug loading capacity of the cationic drug doxorubicin is 22.4 mg / mL, calculated based on the volume of the microspheres.

[0132] The gelatin component in the gel microspheres will begin to degrade in physiological saline on the 54th day and will be completely degraded on the 92nd day.

[0133] The gel microspheres can be used for vascular intervention via a microcatheter, and the sizes of the microcatheter include but are not limited to 1.8F, 2.0F, 2.2F, 2.5F, 2.7F, etc.

[0134] Example 3

[0135] 1) Preparation of gelatin-based embolic gel microspheres:

[0136] S1: Preparation of Gelatin Solution: Prepare a 13% gelatin solution by weight using a certain amount of deionized water and gelatin powder. Add the weighed gelatin powder to a beaker filled with deionized water. Seal the beaker and transfer it to a 60°C constant temperature water bath to completely dissolve the gelatin powder. Allow to stand for defoaming to obtain the gelatin solution.

[0137] S2: 3-(Dimethyl(4-vinylbenzylammonium)propylsulfonate), N,N-dimethylacrylamide, and photoinitiator Omnirad 500 were added to the gelatin aqueous solution and stirred at 50°C to form an aqueous phase solution. The total mass fraction of the two monomers in the aqueous phase solution was 9.2%, the molar ratio of 3-(dimethyl(4-vinylbenzylammonium)propylsulfonate to 2-methylacrylamide was 1.5, and the mass fraction of the photoinitiator Omnirad 500 in the aqueous phase was 0.3%.

[0138] S3: Preparation of oil phase solution: Add an appropriate amount of n-hexane to a beaker, seal it, and place it in a constant temperature water bath at 50°C for 2 hours to obtain an oil phase solution.

[0139] S4: Preparation of microspheres: At room temperature, add the oil phase to a reactor exposed to 250nm ultraviolet light and place it in a mechanically stirred state at a stirring rate of 250rpm. Slowly add the aqueous phase solution dropwise to the oil solution and stir at room temperature for 25 minutes. Immediately start the low-temperature cooling water circulation pump and control the reaction temperature to 0°C. Stir for 60 minutes and then let it stand for 10 hours to obtain well-formed spherical particles. The volume of the oil phase is 8 times that of the aqueous phase.

[0140] S5: Oil phase washing of microspheres: add 10°C isopropanol to the reaction apparatus, stir mechanically for 2.5 minutes at a stirring rate of 100 rpm, let it stand for 1.5 minutes, pour out the upper oil phase solution, and then transfer the particles to a clean container. Add 2.5 times the volume of 10°C isopropanol to the container, seal it, place it on a constant temperature magnetic stirrer, stir at a speed of 100 rpm, replace the 10°C isopropanol every 8 minutes, repeat this operation 5 times, and after the last washing with isopropanol, pour the particles into a filtration device, connect and open a circulating water vacuum pump for filtration to obtain microspheres A;

[0141] S6: Purification of microspheres: Add 10 times the volume of deionized water as that of microspheres A to the container, seal it, place it on a thermostatic magnetic stirrer, and stir it at 100 rpm at room temperature. Filter and replace the deionized water every 35 minutes, repeat the filtration and washing five times, and obtain microsphere product B after the deionized water washing is completed;

[0142] S7: Sieving of microspheres: Place standard sieves of different pore sizes in descending order from top to bottom, slowly pour the prepared microspheres into the top standard sieve, and then slowly rinse with deionized water from top to bottom. Repeat the rinse several times to ensure that the particle size of each standard sieve is ≥ the pore size of the standard sieve, thus obtaining microsphere products C of different particle sizes;

[0143] S8: Place microsphere product C of different particle sizes in 2.5 times its volume of anhydrous ethanol, stir at 100 rpm, filter and replace anhydrous ethanol every 35 minutes, repeat this operation three times, after washing and filtering with anhydrous ethanol, dry microsphere product C in a 55°C forced air drying oven for 24 hours, then increase the oven temperature to 140°C to remove residual ethanol and solvent to obtain the final dried microsphere D, which is then stored in a dry environment;

[0144] S9: The dried microspheres D are placed into excess physiological saline and soaked until they are fully absorbed with water, thereby obtaining the final injectable gel microspheres.

[0145] The gel microspheres are used for transarterial chemoembolization to treat malignant tumors, and the microspheres are injected into tumor blood vessels through a microcatheter to form embolism.

[0146] After being loaded with drugs, the gel microspheres can achieve the treatment of malignant tumors by releasing the drugs.

[0147] 2) Detection method:

[0148] The internal pore size of the drug-loaded embolic gel microspheres can be obtained by microscopic observation after freeze-drying, and the pore volume of the microspheres can be obtained by mercury exclusion method.

[0149] The compression deformation of the drug-loaded embolic gel microspheres was tested using a universal mechanical testing machine in compression mode, and the compression recovery time was obtained by observation.

[0150] The equilibrium swelling ratio is calculated by the ratio of the mass of the swelling water absorbed by the swelling to the mass of the dry bulb before swelling.

[0151] The concentration difference of the drug solution before and after absorption was tested by the UV spectral characteristic peak method to obtain the drug loading concentration of the drug-loaded embolic gel microspheres.

[0152] The microspheres were placed in physiological saline to observe their morphology and the presence of flocculent degradation products in the saline to determine whether the gel had begun to degrade.

[0153] 3) Test results:

[0154] The internal pore diameter of the gel microspheres is between 30-90 μm, and the pore volume is 0.44 cm 3 / g.

[0155] After the gel microspheres were cut open and the cut surfaces were fitted together, the cut surfaces were completely healed within 3.6 hours. After healing, the mechanical properties of the microspheres decreased by approximately 5.4% compared to the original microspheres.

[0156] The pore sizes of the standard sieves from top to bottom are: 70µm, 100µm, 300µm, 500µm, 700µm, 900µm, 1200µm, 1500µm, 2000µm, and the corresponding microsphere size ranges are: 100~300µm, 300~500µm, 500~700µm, 700~900µm, 900~1200µm, 1200~1500µm, 1500~2000µm.

[0157] The gel microspheres can withstand a compression deformation of 87%, and the compression recovery time is between 14 seconds.

[0158] The equilibrium swelling rate of the gel microspheres is 64% calculated based on the mass ratio of swelling water to dry microspheres, and the volume increase rate after swelling is 7.8%.

[0159] The maximum anionic drug methotrexate disodium loading of the gel microspheres is 46.5 mg / mL, calculated based on the volume of the microspheres, and the maximum cationic drug doxorubicin loading is 31.4 mg / mL, calculated based on the volume of the microspheres.

[0160] The gelatin component in the gel microspheres will begin to degrade in physiological saline on the 48th day and will be completely degraded on the 85th day.

[0161] The gel microspheres can be used for vascular intervention via a microcatheter, and the sizes of the microcatheter include but are not limited to 1.8F, 2.0F, 2.2F, 2.5F, 2.7F, etc.

[0162] Comparative Example 1

[0163] The only difference from Example 3 is that the hydrogen-bonding monomer in Example 3 is not included.

[0164] Test results: After the gel microspheres were cut open and the cut surfaces were fitted together, the cut surfaces could be completely healed within 12 hours. After healing, the mechanical properties of the microspheres decreased by about 54.6% compared with the original microspheres.

[0165] The gel microspheres can withstand a compression deformation of 34.5%, a compression recovery time of 26 seconds, and a deformation recovery of 77.6% at equilibrium.

[0166] The equilibrium swelling rate of the gel microspheres is 82% calculated based on the mass ratio of swelling water to dry microspheres, and the volume increase rate after swelling is 18.6%.

[0167] The maximum drug loading capacity of the anionic drug methotrexate disodium of the gel microspheres is 44.2 mg / mL, calculated based on the volume of the microspheres, and the maximum drug loading capacity of the cationic drug doxorubicin is 25.6 mg / mL, calculated based on the volume of the microspheres.

[0168] The gelatin component in the gel microspheres will begin to degrade in physiological saline on the 32nd day and will be completely degraded in about 60 days.

[0169] The gel microspheres can be used for vascular intervention via a microcatheter, and the sizes of the microcatheter include but are not limited to 1.8F, 2.0F, 2.2F, 2.5F, 2.7F, etc.

[0170] Comparative Example 2

[0171] The only difference from Example 3 is that the 3-(dimethyl(4-vinylbenzylammonium)propylsulfonate in Example 3 is replaced by dimethacrylate ethyl quaternary ammonium propanesulfonic acid inner salt.

[0172] Results: The gel microspheres were cut and the cut surfaces were fitted together. The cut surfaces healed completely within 3.5 hours. After healing, the mechanical properties of the microspheres decreased by about 32.2% compared with the original microspheres.

[0173] The gel microspheres can withstand a compression deformation of 44.2%, and the compression recovery time is between 16 seconds.

[0174] The equilibrium swelling rate of the gel microspheres is 82% calculated based on the mass ratio of swelling water to dry microspheres, and the volume increase rate after swelling is 16.7%.

[0175] The maximum drug loading capacity of the anionic drug methotrexate disodium of the gel microspheres is 40.8 mg / mL, calculated based on the volume of the microspheres, and the maximum drug loading capacity of the cationic drug doxorubicin is 27.5 mg / mL, calculated based on the volume of the microspheres.

[0176] The gelatin component in the gel microspheres will begin to degrade in physiological saline on the 42nd day and will be completely degraded on the 74th day.

[0177] The gel microspheres can be used for vascular intervention via a microcatheter, and the sizes of the microcatheter include but are not limited to 1.8F, 2.0F, 2.2F, 2.5F, 2.7F, etc.

[0178] Comparative Example 3

[0179] Compared with Example 3, the only difference is that the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer in Example 3 is replaced with 0.2.

[0180] Results: The gel microspheres were cut open and the cut surfaces were fitted together. The cut surfaces healed completely within 2.5 hours. After healing, the mechanical properties of the microspheres decreased by about 8.2% compared with the original microspheres.

[0181] The compressive deformation that the gel microspheres can withstand is 82.5%, and the compression recovery time is between 6 seconds.

[0182] The equilibrium swelling rate of the gel microspheres is 68% calculated based on the mass ratio of swelling water to dry microspheres, and the volume increase rate after swelling is 9.2%.

[0183] The maximum drug loading capacity of the anionic drug methotrexate disodium of the gel microspheres is 10.8 mg / mL, calculated based on the volume of the microspheres, and the maximum drug loading capacity of the cationic drug doxorubicin is 8.7 mg / mL, calculated based on the volume of the microspheres.

[0184] The gelatin component in the gel microspheres will begin to degrade in physiological saline on the 45th day and will be completely degraded on the 82nd day.

[0185] The gel microspheres can be used for vascular intervention via a microcatheter, and the sizes of the microcatheter include but are not limited to 1.8F, 2.0F, 2.2F, 2.5F, 2.7F, etc.

[0186] Comparative Example 4

[0187] Compared with Example 3, the only difference is that the ratio of the zwitterionic monomer to the hydrogen-bonding monomer in Example 3 is replaced with 2.0.

[0188] Test results: After the gel microspheres were cut open and the cut surfaces were fitted together, the cut surfaces could be completely healed in 7.5 hours. After healing, the mechanical properties of the microspheres decreased by about 41.4% compared with the original microspheres.

[0189] The gel microspheres can withstand a compression deformation of 42.5%, a compression recovery time of 19 seconds, and a deformation recovery of 84.2% at equilibrium.

[0190] The equilibrium swelling rate of the gel microspheres is 78% calculated based on the mass ratio of swelling water to dry microspheres, and the volume increase rate after swelling is 17.9%.

[0191] The maximum drug loading capacity of the anionic drug methotrexate disodium of the gel microspheres is 41.8 mg / mL, calculated based on the volume of the microspheres, and the maximum drug loading capacity of the cationic drug doxorubicin is 24.3 mg / mL, calculated based on the volume of the microspheres.

[0192] The gelatin component in the gel microspheres will begin to degrade in physiological saline on the 36th day and will be completely degraded on the 64th day.

[0193] The gel microspheres can be used for vascular intervention via a microcatheter, and the sizes of the microcatheter include but are not limited to 1.8F, 2.0F, 2.2F, 2.5F, 2.7F, etc.

[0194] As can be seen, the gelatin-based embolic gel microspheres prepared in Examples 1 to 3 simultaneously loaded cationic and anionic drugs at high loading levels, exhibited excellent self-healing properties in the event of rupture, exhibited excellent swelling rate and compressibility, and were able to delay degradation, thereby improving embolic reliability. Comparing Example 2 with Example 1, it can be seen that reducing the amount of zwitterionic monomer reduced the drug concentration and swelling rate, but increased compressibility (i.e., strength). Comparing Example 3 with Examples 1 and 2, increasing the amount of zwitterionic monomer, changing the type of hydrogen-bonding monomer, and increasing the gelatin concentration increased the drug concentration, further enhancing strength, and strengthening the self-healing ability.

[0195] Comparing each embodiment with Comparative Example 1, it can be seen that when the hydrogen-bonding monomers in the embodiments of the present application are omitted, although the drug loading is increased, the self-healing property of the gelatin-based embolic gel microspheres is greatly reduced, the mechanical properties recovery deteriorates, and complete recovery cannot be achieved after compression. Comparing each embodiment with Comparative Example 2, when the type of zwitterionic monomers in the embodiments of the present application is changed, the compression resistance of the microspheres is significantly reduced, and the strength after self-healing decreases significantly. Comparing each embodiment with Comparative Example 3, it can be seen that when the ratio of zwitterionic monomers to hydrogen-bonding monomers is lower than the set range of the present application, the drug loading of the prepared gelatin-based embolic gel microspheres is greatly reduced. Comparing each embodiment with Comparative Example 4, it can be seen that when the ratio of zwitterionic monomers to hydrogen-bonding monomers exceeds the set range of the present application, the self-healing property of the prepared gelatin-based embolic gel microspheres is reduced, and the compressive strength and recovery after compression are reduced.

[0196] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present disclosure (including the claims) is limited to these examples. Within the scope of the present disclosure, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the embodiments of the present disclosure as described above, which are not provided in detail for the sake of simplicity.

[0197] While the disclosure has been described in conjunction with specific embodiments thereof, many alternatives, modifications and variations of these embodiments will be apparent to those skilled in the art in light of the foregoing description.

[0198] The embodiments of the present disclosure are intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the embodiments of the present disclosure should be included in the scope of protection of the present disclosure.

Claims

1. A gelatin-based embolic gel microsphere, characterized in that: Prepared from at least the following substances: An aqueous solution comprising a zwitterionic monomer, a hydrogen-bonding monomer, 8% to 14% by mass of gelatin, and 0.1% to 1% by mass of a photoinitiator; wherein the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer is 0.5 to 1.5; and the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer is 6 to 10%; and Oil phase solution; wherein the volume ratio of the oil phase solution to the aqueous phase solution is (5-10):1; The zwitterionic monomer is selected from at least one of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl) ammonium hydroxide and 3-(dimethyl(4-vinylbenzylammonium)propyl sulfonate; The hydrogen-bonding monomer is selected from monomers having a carbon-carbon double bond and an amide group.

2. The gelatin-based embolic gel microspheres according to claim 1, characterized in that: The hydrogen-bonding monomer is selected from at least one of N-hydroxyethyl acrylamide, N,N-dimethyl acrylamide, 2-methyl acrylamide, 2-acrylamido-2-methylpropanesulfonic acid, tert-butyl acrylamidesulfonic acid, N-isopropyl acrylamide and N-(pyridin-2-yl) acrylamide.

3. The gelatin-based embolic gel microspheres according to claim 1, characterized in that: In the aqueous solution, the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer is 0.7-1.5; the mass fraction of the gelatin is 8%-13%; and the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer is 7.2-9.2%.

4. The gelatin-based embolic gel microspheres according to claim 1, characterized in that: The volume ratio of the oil phase solution to the water phase solution is (6-8):

1.

5. The gelatin-based embolic gel microspheres according to claim 1, characterized in that: The oil phase solution is selected from at least one of liquid paraffin, n-hexane, mineral oil and silicone oil.

6. The gelatin-based embolic gel microspheres according to claim 1, characterized in that: The photoinitiator is selected from at least one of 2-hydroxy-2-methylpropiophenone, photoinitiator 500 and photoinitiator 2959.

7. A method for preparing the gelatin-based embolic gel microspheres according to any one of claims 1 to 6, characterized in that: include: providing an aqueous solution; The aqueous solution comprises 8% to 14% gelatin by mass, 0.2% to 0.4% photoinitiator by mass, zwitterionic monomer, and hydrogen-bonding monomer by mass; wherein the molar ratio of the zwitterionic monomer to the hydrogen-bonding monomer is 0.5 to 1.5; and the sum of the mass fractions of the zwitterionic monomer and the hydrogen-bonding monomer is 6 to 10%; providing an oil phase solution; Exposing the oil phase solution to an initiation wavelength corresponding to the photoinitiator, adding the aqueous phase solution dropwise to the oil phase solution under stirring at a first temperature for a first period of time; and performing a polymerization reaction at a second temperature for a second period of time; The product obtained by the polymerization reaction is washed, purified, sieved, dried and soaked to obtain the gelatin-based embolic gel microspheres.

8. The method for preparing gelatin-based embolic gel microspheres according to claim 7, characterized in that: The first temperature is room temperature, and the first duration is 15-30 minutes; and / or The second temperature is 0°C-10°C, and the second time period is 6-12 hours.

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