Gelatin-based embolism gel microsphere and preparation method thereof

Abstract

The invention provides gelatin-based embolism gel microspheres and a preparation method thereof. The gelatin-based embolism gel microspheres are at least prepared from the following substances: an aqueous phase solution which comprises gelatin with the mass fraction of 8%-14%, a photoinitiator with the mass fraction of 0.2%-0.4%, a zwitterionic monomer and a monomer capable of realizing hydrogen-bond interaction; wherein the molar ratio of the zwitterionic monomer to the monomer capable of realizing hydrogen-bond interaction is 0.5-1.5; the sum of the mass fractions of the zwitterionic monomer and the monomer capable of realizing hydrogen-bond interaction is 6-10%; the oil phase solution comprises organic oil with the dynamic viscosity of 110 to 300 mPa * s (20 DEG C); wherein the volume ratio of the oil phase solution to the water phase solution is (5-10): 1. The self-healing hydrogel has the advantages of being high in toughness, moderate in swelling degree, capable of self-healing after being damaged, longer in degradation stable period, capable of loading more cationic drugs and anionic drugs at the same time and the like.

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. The treatment of cancer is still a major global problem, especially for certain specific diseases such as liver cancer. The early symptoms are hidden. Usually, most patients are diagnosed in the middle and late stages. At this time, surgical resection is difficult, and the treatment and prognosis are relatively poor. Transarterial chemoembolization (TACE) is a minimally invasive technology that selectively injects embolic agents or anticancer drugs combined with microparticles and embolizes the tumor blood supply artery. It is a type of interventional vascular treatment technology. Its advantages are: on the one hand, embolizing the tumor blood supply artery causes ischemia, hypoxia and necrosis of the tumor tissue; on the other hand, it increases the local drug concentration and prolongs the contact time between the drug and the tumor tissue, and the efficacy is significantly improved compared with simple perfusion chemotherapy and simple embolization. TACE is suitable for palliative treatment and relatively radical treatment of liver cancer, kidney cancer, pancreatic cancer, lung cancer, pelvic malignant tumors, etc., and radical treatment of hepatic hemangioma.

[0003] The therapeutic effect of TACE depends largely on the performance and characteristics of embolic agents. Traditional embolic agents are mostly liquid embolic agents, which have the problem of strong fluidity. New solid embolic agents often cannot achieve efficient loading of both anionic and cationic drugs at the same time, and have problems such as small drug loading, short degradation time and low strength. Summary of the invention

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

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

[0006] Aqueous phase solution: comprising gelatin with a mass fraction of 8%-14%, a photoinitiator with a mass fraction of 0.1%-1%, 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%;

[0007] Oil phase solution: comprising organic oil with 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 of the 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-methylpropane sulfonic acid, tert-butyl acrylamide sulfonic 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 of the embodiments, the anionic drug loading of the gelatin-based embolic gel microspheres is 0.1-48.5 mg / mL, and the cationic drug loading is 0.1-32.5 mg / mL, calculated based on the volume of the microspheres.

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

[0016] The gelatin-based embolic gel microspheres have an internal pore size of 1-100 μm and a pore volume of 0.15-0.6 cm3 / 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 cm3 / g; and / or

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

[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, dropping the water phase solution into the oil phase solution under stirring at a first temperature, stirring for a first time; and polymerizing at a second temperature for a second time;

[0027] The product obtained by the polymerization reaction is washed with isopropanol, 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, and 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 methods provided by the present application, through the copolymerization of gelatin, zwitterionic monomers and hydrogen-bonding monomers, obtain a double network structure capable of simultaneously loading two different types of drugs, cationic drugs and anionic drugs; the double 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 is conducive to the dissipation of energy, and 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 work together to 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 gelatin is strengthened, thereby delaying the degradation time of gelatin and improving the reliability of embolism. At the same time, when the gelatin-based embolic gel microspheres are ruptured, self-healing can be achieved without significant performance degradation through reversible dynamic hydrogen bonds and ionic effects. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0031] Figure 1 This is a schematic diagram of the preparation process of the 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 the present application more clearly understood, the present 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 be understood by people with ordinary skills in the field to which the present 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 cover the elements or objects listed after the word and their equivalents, without excluding other elements or objects.

[0034] Traditional embolic agents are liquid reagents mixed with iodized oil / chemotherapeutic drugs. Due to their fluidity, they can easily reduce the efficacy of drugs and cause systemic toxicity. Solid embolic agents include gelatin sponges, polyvinyl alcohol particles and microspheres, which can be better fixed in blood vessels, have no toxic side effects, and have improved therapeutic effects compared to traditional embolic agents. However, facing complex and diverse patients and surgical conditions, current embolic agents still have many shortcomings. For example, when loading cationic drugs and anionic drugs at the same time, it is easy to have low loading efficiency of cationic drugs and anionic drugs; low strength; fast degradation rate, once the blood vessels are damaged, it is easy to cause embolism to be weak; low compatibility with blood vessels or outstanding performance in one performance but poor overall performance, etc., which seriously affect the embolism and treatment effects. In order to further improve the treatment effect, the development of new embolic agents that meet various clinical requirements and have excellent performance is still an urgent problem to be solved.

[0035] Based on this, the embodiment of the present application provides a gelatin-based embolic gel microsphere and a preparation method thereof, which is achieved by polymerization of gelatin, zwitterionic monomers and hydrogen-bonding monomers, assisted by a mixing process of an aqueous solution and an oily solution, and light-curing and cross-linking molding after oil-water phase stirring into balls to achieve high strength and toughness, moderate swelling, self-healing after destruction, and a longer degradation stability period. It can to a certain extent 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 application provides a gelatin-based embolic gel microsphere, which is prepared from at least the following substances:

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

[0038] Oil phase solution: comprising organic oil with 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] Among them, gelatin is a natural polymer material obtained by hydrolysis of collagen, which has the advantages of good biocompatibility, easy availability, easy swelling after water absorption, biodegradability, non-toxicity, harmlessness, etc. The gelatin-based embolic gel microspheres made by cross-linking gelatin with zwitterionic monomers and hydrogen-bonding monomers have a smooth spherical appearance and can better fit the blood vessels; the gelatin-based embolic gel microspheres are elastic after absorbing water and can achieve a better embolic effect; the gelatin-based embolic gel microspheres can be biodegraded in the body and have good recanalization performance.

[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. Among them, photoinitiator 500 is a liquid mixture of two photoinitiators, and the active ingredients include photoinitiator 184 (1-hydroxycyclohexyl phenyl ketone) and photoinitiator BP (benzophenone, also known as benzophenone, benzophenone, benzophenone, benzoylbenzene, benzoylbenzene or benzoylbenzene). Photoinitiator 2959 is 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone. In the aqueous phase solution, the mass fraction of the photoinitiator 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 SBMA: The structural formula of 3-(dimethyl(4-vinylbenzylammonium)propylsulfonate is DVBAPS:

[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 a mutual hydrogen-bonding between the N and H atoms in the monomer or a hydrogen-bonding between the N and H atoms in the monomer and the H atoms in gelatin. 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. After the polymerization reaction is initiated by a photoinitiator, the zwitterionic monomer and the hydrogen-bonding monomer can be polymerized by double bond reaction to form a zwitterionic polymer, a hydrogen-bonding polymer, and a random copolymer network of zwitterionic polymers and hydrogen-bonding polymers.

[0043] In some of the 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; 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 can 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 water phase solution can be (6-8):1.

[0045] In some embodiments, the anionic drug loading of the gelatin-based embolic gel microspheres is 0.1-48.5 mg / mL, and the cationic drug loading is 0.1-32.5 mg / mL, calculated by the volume of the microspheres. 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 of the embodiments, the anionic drug loading of the gelatin-based embolic gel microspheres is 37.5-46.5 mg / mL, calculated by the volume of the microspheres, and the cationic drug loading is 22.4-31.4 mg / mL, calculated by 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 shape of 60-90%, and a compression recovery time of 5-30 seconds. The gelatin-based embolic gel microspheres can withstand a compression shape of 76-87%, and a compression recovery time of 7-14 seconds.

[0049] In some embodiments, the equilibrium swelling rate of the gelatin-based embolic gel microspheres is 50%-80% based on the mass ratio of swelling water to dry ball, and the volume increase rate after swelling is less than 15%. The gelatin component in the gelatin-based embolic gel microspheres will be degraded within 30-90 days, and the remaining components will enter metabolism, which has no toxic effect on human health.

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

[0051] Based on the same inventive concept, corresponding to the gelatin-based embolic gel microspheres of any of the above embodiments, the embodiment of the present application further provides 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 embodiment of the present application may include:

[0053] S100, providing an aqueous solution; the aqueous solution comprises 8%-14% gelatin by mass, 0.2%-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 0.5-1.5; 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 comprises 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, dropping the aqueous phase solution into the oil phase solution under stirring at a first temperature, stirring for a first time, and performing polymerization reaction at a second temperature for a second time;

[0056] S400, washing the product obtained by the polymerization reaction with isopropanol, purifying with deionized water, sieving, drying and soaking with 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, the corresponding volume of water and the corresponding mass of gelatin powder can be weighed according to the mass fraction of gelatin in the gelatin solution to be configured. Then the weighed gelatin powder is added to a beaker filled with deionized water, the beaker is sealed and transferred to a constant temperature water bath at 40°C to 60°C to wait for it to be completely dissolved, and the gelatin solution can be obtained after standing and defoaming.

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

[0060] In some of the 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 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 may be the initiation wavelength with the highest efficiency of the corresponding photoinitiator. For example, the absorption wavelength of the photoinitiator 1173 is 331 nm. The first temperature may be room temperature, and the first time duration may be 15-30 min. For example, the oil phase may be added to a reactor exposed to the initiation wavelength with the highest efficiency of the corresponding photoinitiator, and the oil phase may be in a stirring state, and then the aqueous phase solution may be slowly added dropwise. The volume ratio of the oil phase solution to the aqueous phase solution may be (6-8):1.

[0066] In some embodiments, the second temperature can be 0°C-10°C, and the second time can be 6-12h. Among them, the temperature can be controlled to the second temperature by a low-temperature cooling water circulation pump. Stirring can be performed first to fully mix the water phase and the oil phase, and then placed for a second time to fully perform the polymerization reaction to obtain initially formed spherical particles. After the polymerization reaction, a network form can be formed inside the gel microsphere with a gelatin spiral structure as the skeleton, and zwitterionic polymers and hydrogen-bonded polymers cross-linked; at the same time, the interaction within the system includes anionic and cationic interactions between zwitterionic polymers and gelatin and hydrogen bonding interactions between multiple substances. The cut surface or broken surface of the microsphere can be completely healed within 2-6h after bonding through hydrogen bonding forces and ionic forces, that is, its self-healing property comes from dynamic ionic interactions and hydrogen bonding, etc. The mechanical properties of the microsphere after self-healing are no more than 10% lower than those of the original microsphere. The gelatin-based embolic gel microsphere can withstand a compression shape of 60-90%, and the compression recovery time can be 5-30s.

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

[0068] In some embodiments, the sieving may include placing standard sieves of different apertures in descending order from top to bottom, then slowly pouring the prepared microspheres into the topmost standard sieve, and then slowly rinsing with deionized water from top to bottom to wash away particles smaller than the aperture of the standard sieve from the standard sieve, so that the particle size in each standard sieve is greater than or equal to the aperture of the standard sieve. In this way, gelatin-based embolic gel microspheres C of different particle sizes can be obtained. The number of times of rinsing with deionized water can be multiple times.

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

[0070] In some embodiments, gelatin-based embolic gel microspheres of different particle sizes can be placed in anhydrous ethanol, stirred and filtered, and then dried in a 50°C-60°C forced air drying oven for 18-30 hours, and then the oven temperature is increased to 120°C-140°C to remove residual ethanol and solvent to obtain dried gelatin-based embolic gel microspheres D. The number of filtrations can be three times, and the anhydrous ethanol can be replaced each time the filtrations are performed.

[0071] In some embodiments, the physiological saline soaking can be specifically to put the gelatin-based embolic gel microspheres D into an excess of physiological saline, soak and absorb water, and then obtain injectable gelatin-based embolic gel microspheres. The equilibrium swelling rate of the gel microspheres is between 50% and 80% calculated by the mass ratio of swelling water to dry balls, and the volume increase rate after swelling is less than 15%.

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

[0073] In some of the 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 of the 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 of the embodiments, the gel microspheres, after being loaded with drugs, can achieve the treatment of malignant tumors by releasing the drugs.

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

[0077] The experimental methods in the following examples are all 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 aqueous solution: Take a certain amount of deionized water and gelatin powder to prepare a 10% mass fraction gelatin solution. Add the weighed gelatin powder into a beaker filled with deionized water, seal the beaker and transfer it to a constant temperature water bath at 50°C to wait for it to completely dissolve, and then stand it to defoam to obtain a 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%, of which 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 into 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.

[0084] S4: Preparation of microspheres: At room temperature, add the oil phase into a reactor exposed to 335nm wavelength ultraviolet light, put it in a mechanical stirring state, and the stirring rate is 150rmp. Slowly add the aqueous solution dropwise to the oil solution, stir at room temperature for 25min, immediately start the low-temperature cooling water circulation pump, control the reaction temperature to 5℃, stir for 60min, and then let it stand for 8h 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 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 6°C isopropanol every 10 minutes, repeat the operation 3-5 times, and 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 of microsphere A into the container, seal it, place the container on a constant temperature magnetic stirrer, stir at 80 rpm at room temperature, filter and replace the deionized water every 30 minutes, repeat the filtration and washing for 5 times, and obtain microsphere product B after washing with deionized water.

[0087] S7: Screening of microspheres: Arrange standard sieves of different apertures from top to bottom in descending order, slowly pour the prepared microspheres into the top standard sieve, and then slowly rinse with deionized water from top to bottom, repeatedly rinse several times to ensure that the particle size in each standard sieve is ≥ the aperture size of the standard sieve, so as to obtain microsphere products C of different particle sizes.

[0088] S8: Place microsphere product C with 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: Pour the dried microspheres D into excess physiological saline and, after being fully soaked and absorbed, obtain 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 by the compression mode of the universal mechanical testing machine, and the compression recovery time was obtained by observation.

[0095] The equilibrium swelling ratio is calculated by the ratio of the mass of 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 characteristic peak method of ultraviolet spectrum to obtain the drug loading concentration of the drug-loaded embolic gel microspheres.

[0097] The microspheres were placed in physiological saline and observed for 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 size of the gel microspheres is between 20-100 μm, and the pore volume is 0.42 cm 3 / g.

[0099] After the gel microspheres are cut open, the cut surfaces are fitted together, and the cut surfaces can be completely healed in 4.5 hours. After healing, the mechanical properties thereof decrease by about 7% compared with the original microspheres.

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

[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 of the gel microspheres can reach 44.3 mg / mL calculated by the volume of the microspheres, and the cationic drug doxorubicin drug loading can reach 26.5 mg / mL calculated by the volume of the microspheres.

[0104] The gelatin component in the gel microspheres will begin to degrade on the 46th day in physiological saline 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 aqueous solution: Take a certain amount of deionized water and gelatin powder to prepare a 12% mass fraction gelatin solution. Add the weighed gelatin powder into a beaker filled with deionized water, seal the beaker and transfer it to a constant temperature water bath at 55°C to wait for it to completely dissolve, and then stand it to defoam to obtain a gelatin solution.

[0109] S2: Add 3-(dimethyl(4-vinylbenzylammonium)propyl sulfonate, 2-methylacrylamide and photoinitiator 2959 to the gelatin aqueous solution, stir evenly at 60°C to form an aqueous solution, the total mass fraction of the two monomers in the aqueous solution is 7.2%, the molar ratio of 3-(dimethyl(4-vinylbenzylammonium)propyl sulfonate and 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, add the oil phase into a reactor exposed to 276nm wavelength ultraviolet light, and put it in a mechanical stirring state at a stirring rate of 200rmp. Slowly add the aqueous phase solution to the oil solution, stir at room temperature for 20min, immediately start the low-temperature cooling water circulation pump, control the reaction temperature to 5℃, stir for 80min, and then leave it for 8h to obtain well-formed spherical particles; the volume of the oil phase is 7 times the volume of the aqueous phase;

[0112] S5: Oil phase washing of microspheres: add 8°C isopropanol to the reaction device, stir mechanically for 2.5 min at a stirring rate of 80 rpm, let stand for 1.5 min, 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 the container on a constant temperature magnetic stirrer, stir at a speed of 100 rpm, replace 8°C isopropanol every 10 min, repeat the operation 4 times, and after the last washing with isopropanol, pour the particles into a suction filtration device, connect and open a circulating water vacuum pump for suction filtration to obtain microspheres A;

[0113] S6: Purification of microspheres: Add 8 times the volume of deionized water of microsphere A into the container, seal it, place the container on a constant temperature magnetic stirrer, stir at 90 rpm at room temperature, filter and replace deionized water every 30 minutes, repeat the filtration and washing for 6 times, and obtain microsphere product B after washing with deionized water;

[0114] S7: Sieving of microspheres: Place standard sieves of different apertures 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, repeatedly rinse several times to ensure that the particle size in each standard sieve is ≥ the aperture of the standard sieve, that is, obtain 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 the operation three times, after the anhydrous ethanol is washed and filtered, 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, and obtain the final dried microsphere D, which is then stored in a dry environment;

[0116] S9: Pour the dried microspheres D into excess physiological saline and, after being fully soaked and absorbed, obtain 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 by the compression mode of the universal mechanical testing machine, and the compression recovery time was obtained by observation.

[0122] The equilibrium swelling ratio is calculated by the ratio of the mass of 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 characteristic peak method of ultraviolet spectrum to obtain the drug loading concentration of the drug-loaded embolic gel microspheres.

[0124] The microspheres were placed in physiological saline and observed for 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 size 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 could be 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 are 70 μm, 100 μm, 300 μm, 500 μm, 700 μm, 900 μm, 1200 μm, 1500 μm and 2000 μm from top to bottom, and the corresponding microsphere size ranges are 100-300 μm, 300-500 μm, 500-700 μm, 700-900 μm, 900-1200 μm, 1200-1500 μm and 1500-2000 μm.

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

[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 amount of anionic drug methotrexate disodium of the gel microspheres is 37.5 mg / mL calculated by the volume of the microspheres, and the maximum drug loading amount of cationic drug doxorubicin is 22.4 mg / mL calculated by the volume of the microspheres.

[0132] The gelatin component in the gel microspheres will begin to degrade on the 54th day in physiological saline 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 aqueous solution: Take a certain amount of deionized water and gelatin powder to prepare a gelatin solution with a mass fraction of 13%. Add the weighed gelatin powder into a beaker filled with deionized water, seal the beaker and transfer it to a constant temperature water bath at 60°C to wait for it to completely dissolve, and then stand it to defoam to obtain a gelatin solution.

[0137] S2: 3-(dimethyl(4-vinylbenzylammonium)propylsulfonate, N,N-dimethylacrylamide and photoinitiator Omnirad 500 are 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 is 9.2%, wherein the molar ratio of 3-(dimethyl(4-vinylbenzylammonium)propylsulfonate to 2-methylacrylamide is 1.5, and the mass fraction of the photoinitiator Omnirad 500 in the aqueous phase is 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 wavelength ultraviolet light, and put it in a mechanical stirring state at a stirring rate of 250rmp. Slowly add the aqueous phase solution to the oil solution, stir at room temperature for 25min, immediately start the low-temperature cooling water circulation pump, control the reaction temperature to 0℃, stir for 60min, and then leave it for 10h to obtain well-formed spherical particles; the volume of the oil phase is 8 times the volume of the aqueous phase;

[0140] S5: Oil phase washing of microspheres: add 10°C isopropanol to the reaction device, stir mechanically for 2.5 min at a stirring rate of 100 rpm, let stand for 1.5 min, 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 the container on a constant temperature magnetic stirrer, stir at a speed of 100 rpm, replace 10°C isopropanol every 8 min, repeat the operation 5 times, and after the last washing with isopropanol, pour the particles into a suction filtration device, connect and open a circulating water vacuum pump for suction filtration to obtain microspheres A;

[0141] S6: Purification of microspheres: Add 10 times the volume of deionized water of microsphere A into the container, seal it, place the container on a constant temperature magnetic stirrer, stir at 100 rpm at room temperature, replace deionized water by suction every 35 minutes, repeat the suction filtration and washing for 5 times, and obtain microsphere product B after washing with deionized water;

[0142] S7: Sieving of microspheres: Place standard sieves of different apertures 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, repeatedly rinse several times to ensure that the particle size in each standard sieve is ≥ the aperture of the standard sieve, that is, obtain microsphere products C of different particle sizes;

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

[0144] S9: Pour the dried microspheres D into excess physiological saline and, after being fully soaked and absorbed, obtain 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 by the compression mode of the universal mechanical testing machine, and the compression recovery time was obtained by observation.

[0150] The equilibrium swelling ratio is calculated by the ratio of the mass of 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 characteristic peak method of ultraviolet spectrum to obtain the drug loading concentration of the drug-loaded embolic gel microspheres.

[0152] The microspheres were placed in physiological saline and observed for 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 size of the gel microspheres is between 30 and 90 μm, and the pore volume is 0.44 cm 3 / g.

[0155] After the gel microspheres were cut open, the cut surfaces were fitted together, and the cut surfaces could be completely healed in 3.6 hours. After healing, the mechanical properties of the microspheres decreased by about 5.4% compared with the original microspheres.

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

[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 on the 48th day in physiological saline 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 after 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 anionic drug methotrexate disodium of the gel microspheres is 44.2 mg / mL calculated by the volume of the microspheres, and the maximum drug loading capacity of cationic drug doxorubicin is 25.6 mg / mL calculated by 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: After the gel microspheres were cut open, the cut surfaces were fitted together and the cut surfaces were completely healed in 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 amount of anionic drug methotrexate disodium of the gel microspheres is 40.8 mg / mL calculated by the volume of the microspheres, and the maximum drug loading amount of cationic drug doxorubicin is 27.5 mg / mL calculated by 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 in about 74 days.

[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 to 0.2.

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

[0181] After the gel microspheres are cut open, the cut surfaces are fitted together, and the cut surfaces can be completely healed in 2.5 hours. After healing, the mechanical properties thereof decrease by about 8.2% compared with the original microspheres.

[0182] The compressive deformation that the gel microspheres can withstand is 82.5%, and the compression recovery time is between 6 seconds.

[0183] 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%.

[0184] The maximum drug loading capacity of anionic drug methotrexate disodium of the gel microspheres is 10.8 mg / mL calculated by the volume of the microspheres, and the maximum drug loading capacity of cationic drug doxorubicin is 8.7 mg / mL calculated by the volume of the microspheres.

[0185] The gelatin component in the gel microspheres will begin to degrade on the 45th day in physiological saline and will be completely degraded on the 82nd day.

[0186] 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.

[0187] Comparative Example 4

[0188] 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.

[0189] 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.

[0190] After the gel microspheres were cut open, the cut surfaces were fitted together, and 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.

[0191] 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.

[0192] 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%.

[0193] The maximum drug loading amount of anionic drug methotrexate disodium of the gel microspheres is 41.8 mg / mL calculated by the volume of the microspheres, and the maximum drug loading amount of cationic drug doxorubicin is 24.3 mg / mL calculated by the volume of the microspheres.

[0194] The gelatin component in the gel microspheres will begin to degrade on the 36th day in physiological saline and will be completely degraded on the 64th day.

[0195] 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.

[0196] It can be seen that the gelatin-based embolic gel microspheres prepared in Examples 1 to 3 have a good loading capacity of cationic and anionic drugs, and have good self-healing properties when rupture occurs. They have excellent swelling rate and compressible properties, and can delay degradation time, improve the reliability of embolism, etc. Comparing Example 2 with Example 1, it can be seen that after reducing the amount of zwitterionic monomers, the drug concentration is reduced, the swelling rate is reduced, but the compressible properties (i.e., strength) are increased. Comparing Example 3 with Examples 1 and 2, after increasing the amount of zwitterionic monomers, the type of monomers that can hydrogen bond is changed, the gelatin concentration is increased, and the drug concentration is increased; the strength is further increased, and the self-healing ability is enhanced.

[0197] Comparing each embodiment with Comparative Example 1, it can be seen that when the hydrogen-bonding monomer in the embodiment of the present application is omitted, although the drug loading is increased, the self-healing property of the gelatin-based embolic gel microspheres is greatly reduced, the mechanical properties are poor in resilience, and full recovery cannot be achieved after compression. Comparing each embodiment with Comparative Example 2, when the type of zwitterionic monomer in the embodiment of the present application is changed, the compression resistance of the microspheres is significantly reduced, and the strength decreases significantly after self-healing. 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 compression strength and resilience after compression are reduced.

[0198] 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. Based on the concept 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.

[0199] 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.

[0200] 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: Aqueous phase solution: comprising a zwitterionic monomer, a hydrogen-bonding monomer, 8%-14% gelatin by mass, and 0.1%-1% photoinitiator by mass; 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%; and Oil phase solution; wherein the volume ratio of the oil phase solution to the water phase solution is (5-10):

1.

2. The gelatin-based embolic gel microspheres according to claim 1, characterized in that: 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.

3. The gelatin-based embolic gel microspheres according to claim 1, characterized in that: The hydrogen-bonding monomer is selected from monomers having a carbon-carbon double bond and an amide group.

4. The gelatin-based embolic gel microspheres according to claim 3, 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.

5. The gelatin-based embolic gel microspheres according to claim 1, characterized in that: In the aqueous phase 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%.

6. 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.

7. 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.

8. 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.

9. A method for preparing gelatin-based embolic gel microspheres, characterized in that: include: providing an aqueous solution; The aqueous solution comprises gelatin with a mass fraction of 8%-14%, a photoinitiator with a mass fraction of 0.2%-0.4%, 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%; providing an oil phase solution; Exposing the oil phase solution to an initiation wavelength corresponding to the photoinitiator, dropping the water phase solution into the oil phase solution under stirring at a first temperature, stirring for a first time; and polymerizing at a second temperature for a second time; The product obtained by the polymerization reaction is washed, purified, sieved, dried and soaked to obtain the gelatin-based embolic gel microspheres.

10. The method for preparing gelatin-based embolic gel microspheres according to claim 9, 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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