Gelatin sponge particle synthesis method

Abstract

The invention discloses a synthetic method of gelatin sponge particles. The synthetic method comprises the following steps: preparing a gelatin solution; adding a water-soluble developing agent, and uniformly stirring to obtain gelatin gel; drying and crushing to obtain pretreated gelatin powder; putting the pretreated gelatin powder and water into a high-pressure reaction kettle together, and uniformly stirring to obtain gelatin dispersion liquid; adding a cross-linking agent and a physical foaming agent into the gelatin dispersion liquid to increase the pressure in the reaction kettle to a first pressure; stopping stirring and releasing the pressure in the high-pressure reaction kettle to prepare the gelatin sponge particles. According to the method provided by the invention, firstly, gelatin gel with a developing effect is prepared, and then the gelatin gel is dried and crushed to obtain pretreated gelatin powder with uniform particles, so that the gelatin powder, a cross-linking agent and a physical foaming agent are mixed in water and then cross-linked to form developable gelatin sponge particles with relatively uniform particle sizes; the problems that in the background technology, foam structures are prone to being damaged, and the particle morphology is uncontrollable when gelatin sponge particles are manufactured are solved.

Description

Technical Field

[0001] The present invention relates to the technical field of gelatin sponges, and particularly to a method for synthesizing gelatin sponge particles. Background Art

[0002] Gelatin sponge particles are generally used in embolization. Embolization is a procedure in which some artificial embolization materials are controllably injected into the supply blood vessels of a lesion or organ, or into the diseased blood vessels, so that they are occluded and blood supply is interrupted, in order to achieve the effects of controlling bleeding, treating vascular diseases and tumors, and eliminating the functions of diseased organs.

[0003] Since gelatin is a natural, non-toxic and harmless polymer compound, which has good biocompatibility, low price, strong water absorption, etc., and the gelatin sponge can be degraded and absorbed in the human body in about two weeks, the blood circulation can be restored after embolization, avoiding the pain of the patient during the restoration of the blood circulation in the operation, so it is widely used in vascular embolization surgery.

[0004] Most of the existing gelatin sponge particles are relatively large in size and do not have a radiopaque function. If they need to be made into sponge particles, they need to be crushed, so it is easy to cause damage to the pore structure and the particle morphology is uncontrollable. Summary of the Invention

[0005] In order to solve the above technical problems, the present invention provides a method for synthesizing gelatin sponge particles. The specific technical solution is as follows: A method for synthesizing gelatin sponge particles, comprising the following steps: S1: Place gelatin in water, swell it and then heat it to dissolve to obtain a gelatin solution; S2: Add a water-soluble radiopaque agent to the gelatin solution obtained in step S1 and stir evenly, and then cool it to obtain a gelatin gel; S3: Dry the gelatin gel obtained in step S2, and crush the dried gelatin gel to obtain pretreated gelatin powder; S4: Place the pretreated gelatin powder obtained in step S3 and water together in a high-pressure reactor, stir evenly to obtain a gelatin dispersion; S5: Add a crosslinking agent to the gelatin dispersion obtained in step S4 and continue to stir; and add a physical foaming agent to the high-pressure reactor to increase the pressure in the reactor to a first pressure; S6: Stop stirring after a first time interval, and release the pressure in the high-pressure reactor to obtain gelatin sponge particles.

[0006] Preferably, the drying of the gelatin gel obtained in step S2 specifically includes: Drying the gelatin gel by baking or freeze-drying; If the gelatin gel is dried, control the drying temperature at 30°C - 60°C; if the gelatin gel is freeze-dried, control the freeze-drying temperature at -50°C to -10°C.

[0007] Preferably, the preparation of the pretreated gelatin powder by crushing the dried gelatin gel specifically includes: Crushing the dried gelatin gel to obtain the first gelatin powder; Sieving the first gelatin powder into the second gelatin powder with a particle size of 10μm to 700μm; Among them, the pretreated gelatin powder is the second gelatin powder.

[0008] Preferably, the temperature of the water in step S4 is controlled at 10°C to 30°C.

[0009] Preferably, the stirring speed in step S5 is controlled at 100 rpm to 500 rpm.

[0010] Preferably, the mass of the cross-linking agent added in step S5 accounts for 1% to 20% of the mass of the pretreated gelatin powder.

[0011] Preferably, the first pressure is 1 MPa to 8 MPa.

[0012] Preferably, the first time interval is 10 min to 120 min.

[0013] Preferably, the water in steps S1 and S4 is sterile water.

[0014] Preferably, the heating temperature in step S1 is controlled at 45°C to 55°C.

[0015] A method for synthesizing gelatin sponge particles provided by the present invention, by first dissolving gelatin and mixing it with a water-soluble developer, then cooling the mixture to obtain a gelatin gel with a developing effect, and then drying and crushing the gelatin gel to obtain pretreated gelatin powder with uniform particles, so that the gelatin powder, cross-linking agent and physical foaming agent are mixed in water and cross-linked to form developable gelatin sponge particles with relatively uniform particle sizes, solving the problems that the production of gelatin sponge particles in the background technology is likely to cause damage to the pore structure and uncontrollable particle morphology. Detailed implementation mode

[0016] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be described in detail below. The description of this part is only exemplary and explanatory, and should not have any limiting effect on the protection scope of the present invention.

[0017] This embodiment provides a method for synthesizing gelatin sponge particles, including the following steps: Step 1: Place gelatin in water, swell it, and then heat to dissolve it to obtain a gelatin solution.

[0018] Step 2: Add a water-soluble developer to the gelatin solution obtained in Step 1 and stir evenly. After cooling, obtain a gelatin gel.

[0019] Step 3: Dry the gelatin gel obtained in Step 2, and then crush the dried gelatin gel to obtain pretreated gelatin powder.

[0020] Step 4: Place the pretreated gelatin powder obtained in Step 3 and water together in a high-pressure reactor, stir evenly to obtain a gelatin dispersion.

[0021] Step 5: Add a crosslinking agent to the gelatin dispersion obtained in Step 4 and continue stirring; add a physical foaming agent to the high-pressure reactor to increase the pressure in the reactor to a first pressure.

[0022] Step 6: After a first time interval, stop stirring and release the pressure in the high-pressure reactor to obtain gelatin sponge particles.

[0023] Specifically, in step 1, the gelatin can be gelatin powder or gelatin granules. After the gelatin is placed in water, it will absorb water and swell. After heating, the gelatin dissolves to form a gelatin solution. In step 2, a water-soluble developer such as iohexol or iotrolan is added to the gelatin solution. Stirring evenly can make the developer and gelatin fully blend together. When cooled to 35°C to 40°C or below, it condenses to form a gelatin gel. In step 3, the gelatin gel is dried and crushed to make gel powder. At this time, the particle size of the powder is uneven, and the gel powder can be screened through a sieve or the like to obtain the gel powder with the required particle size. In step 4, the gel powder with the required particle size and water are stirred together in a high-pressure reactor to disperse the gel powder in water. It should be noted that in order to prevent the gel powder from dissolving in water, the water temperature at this time needs to be below the dissolution temperature of the gel, usually below 45°C to 55°C. In step 5, a cross-linking agent and a physical foaming agent are added to the reactor together, and the gelatin dispersion is continuously stirred to make the gelatin powder continue to be suspended and dispersed. It should be noted that in this embodiment, the physical foaming agent added is a gas. After adding the physical foaming agent, the air pressure in the high-pressure reactor rises. Under the continuous stirring action and high pressure, the cross-linking agent and the physical foaming agent uniformly and quickly penetrate into the pretreated gelatin powder, and gradually cause the gelatin powder to undergo a cross-linking reaction. The mechanical strength of the gelatin powder is increased to prevent it from further swelling, and a certain particle size and morphology are maintained. In step 6, when the infiltration reaches the appropriate time, by releasing the pressure in the high-pressure reactor, the physical foaming agent in the gelatin powder expands, thereby obtaining gelatin sponge particles in a pore state. The speed of pressure release can be adjusted to obtain open-cell or closed-cell sponge particles with a uniform pore state. Since the pretreated gelatin powder is the sieved gelatin powder and the particle size is relatively uniform, the particle size of the finally prepared gelatin sponge particles is also relatively uniform.

[0024] A method for synthesizing gelatin sponge particles provided by this embodiment first dissolves gelatin and then mixes it with a water-soluble developer. After cooling the mixture, a gelatin gel with a developing effect is obtained. Then, after drying and crushing the gelatin gel, pretreated gelatin powder with uniform particles is obtained. By mixing the gelatin powder with a cross-linking agent and a physical foaming agent in water and cross-linking, developable gelatin sponge particles with relatively uniform particle sizes are formed, solving the problems in the background technology that the production of gelatin sponge particles is likely to cause damage to the pore structure and uncontrollable particle morphology.

[0025] Further, the drying method of the gelatin gel specifically includes drying or freeze-drying.

[0026] If the gelatin gel is dried, the drying temperature needs to be controlled at 30°C - 60°C; if the gelatin gel is freeze-dried, the freeze-drying temperature needs to be controlled at -50°C to -10°C.

[0027] Further, the crushing of the dried gelatin gel specifically includes the following steps: Step 1: The dried gelatin gel is crushed to obtain the first gelatin powder.

[0028] Step 2: The first gelatin powder is sieved into the second gelatin powder with a particle size of 10 μm to 700 μm.

[0029] Among them, the pretreated gelatin powder is the second gelatin powder.

[0030] Specifically, the particle sizes of the dried and crushed gelatin powder are uneven. Through structures such as sieves, the required particle size of the gelatin powder can be first sieved out, and then the sieved gelatin powder is used to prepare gelatin sponge particles, so as to obtain gelatin sponge particles with uniform particle sizes and the required particle sizes.

[0031] Among them, since the physical blowing agent will expand and push the pretreated gelatin powder to expand and become larger after the pressure in the high-pressure reactor is released, when the particle size of the gelatin powder expands, the content of the physical blowing agent that can be accommodated also increases. However, since the foaming ratio of the physical blowing agent is affected by various factors such as pressure and foaming time, the magnification of the particle size of the gelatin sponge particles relative to the particle size of the pretreated gelatin powder is not fixed. In the examples provided in this embodiment, the particle size of the pretreated gelatin powder is 10 μm to 700 μm, and the particle size of the prepared gelatin sponge particles is 11 μm to 3000 μm, that is, the growth range of the particle size of the gelatin sponge particles is approximately 1.1 to 4.3 times the size of the pretreated gelatin powder.

[0032] Further, the temperature of the water in Step 4 is controlled at 10°C to 30°C to prevent the gelatin powder from dissolving in water.

[0033] Further, the stirring speed in Step 5 is controlled at 100 rpm to 500 rpm to facilitate the suspension and dispersion of the gelatin powder, and at the same time facilitate the immersion of the cross-linking agent and the physical blowing agent into the pretreated gelatin powder.

[0034] Further, the mass of the cross-linking agent added in Step 5 accounts for 1% to 20% of the mass of the pretreated gelatin powder.

[0035] Among them, since the cross-linking agent is used for the curing and shaping of gelatin and can affect the mechanical properties of the gelatin sponge particles, the dosage of the cross-linking agent can be adjusted according to needs.

[0036] Further, the first pressure is 1 MPa to 8 MPa.

[0037] Among them, since the physical blowing agent expands after the pressure is released after pressurization, the physical blowing agent inside the gelatin powder thus expands it. The magnitude of the first pressure can affect the expansion ratio of the physical blowing agent, thereby changing the size of the gelatin sponge particles and the water absorption effect of the gelatin sponge particles. Therefore, the magnitude of the first pressure can be adjusted according to needs.

[0038] Furthermore, the first time interval is from 10 min to 120 min.

[0039] Among them, the stirring time can affect the degree of infiltration of the crosslinking agent and the physical foaming agent into the gelatin powder, thereby changing the size of the prepared gelatin sponge particles, and the length of the first time can be adjusted according to requirements.

[0040] Furthermore, the water in Steps 1 and 4 is sterile water to avoid contamination of the prepared gelatin sponge particles.

[0041] Furthermore, the heating temperature in Step 1 is controlled at 45°C to 55°C to fully dissolve the gelatin.

[0042] Two specific embodiments are provided below. The provided embodiments can enable those skilled in the art to more comprehensively understand the present invention, but do not limit the present invention in any way.

[0043] Embodiment 1: Animal-derived gelatin is swollen in water, heated and stirred to dissolve, iopamidol is added as a water-soluble contrast agent and stirred evenly, cooled to gel, the gelatin gel with the water-soluble contrast agent is dried at 50°C and then pulverized, screened into pretreated gelatin powder with a particle size of 50 μm to 100 μm, the pretreated gelatin powder is put into a high-pressure reactor filled with water and stirred to disperse, the water temperature is controlled at 20°C, the stirring speed is 200 rpm, 5% of the mass of the pretreated gelatin powder of glutaraldehyde is added as a crosslinking agent, CO2 gas is introduced as a physical foaming agent, the pressure in the high-pressure reactor is increased to 1 MPa, after 30 min, the pressure is released, and developable gelatin sponge particles with a particle size of 55 μm to 110 μm are prepared.

[0044] Embodiment 2: Animal-derived gelatin is swollen in water, heated and stirred to dissolve, iopamidol is added as a water-soluble contrast agent and stirred evenly, cooled to gel, the gelatin gel with the water-soluble contrast agent is dried at 50°C and then pulverized, screened into pretreated gelatin powder with a particle size of 650 μm to 700 μm, the pretreated gelatin powder is put into a high-pressure reactor filled with water and stirred to disperse, the water temperature is controlled at 25°C, the stirring speed is 300 rpm, 10% of the mass of the pretreated gelatin powder of glutaraldehyde is added as a crosslinking agent, CO2 gas is introduced as a physical foaming agent, the pressure in the high-pressure reactor is increased to 8 MPa, after 100 min, the pressure is released, and developable gelatin sponge particles with a particle size of 2800 μm to 3000 μm are prepared.

[0045] Working principle: After placing gelatin in water, the gelatin will absorb water and swell. After heating, the gelatin dissolves to form a gelatin solution. A water-soluble developer, such as iohexol, iotrolan, etc., is added to the gelatin solution, and stirring evenly can make the developer and gelatin fully blend together. When cooled to 35°C to 40°C or below, it condenses to form a gelatin gel. The gelatin gel is dried and crushed to make gel powder. At this time, the particle size of the powder is uneven, and the gel powder can be screened through a sieve or the like to obtain the gel powder with the required particle size. The gel powder with the required particle size and water are stirred together in a high-pressure reactor to disperse the gel powder in water. To avoid the gel powder dissolving in water, the water temperature at this time needs to be below the dissolution temperature of the gel, usually below 45°C to 55°C. A cross-linking agent and a physical foaming agent are added to the reactor together, and the gelatin dispersion is continuously stirred to keep the gelatin powder suspended and dispersed. Among them, the added physical foaming agent is a gas. After adding the physical foaming agent, the air pressure in the high-pressure reactor rises. Under the continuous stirring action and high pressure, the cross-linking agent and the physical foaming agent uniformly and quickly penetrate into the pretreated gelatin powder, and gradually cause the gelatin powder to undergo a cross-linking reaction. The mechanical strength of the gelatin powder is increased to prevent its further swelling and maintain a certain particle size and morphology. When the infiltration reaches the appropriate time, by releasing the pressure in the high-pressure reactor, the physical foaming agent in the gelatin powder expands, thereby obtaining gelatin sponge particles in a pore state. The rate of pressure release can be adjusted to obtain open-cell or closed-cell sponge particles with a uniform pore state. Since the pretreated gelatin powder is the sieved gelatin powder and the particle size is relatively uniform, the particle size of the finally prepared gelatin sponge particles is also relatively uniform.

[0046] It should be noted that in this text, the term "including", "comprising" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements not only includes those elements, but also includes other elements not expressly listed, or also includes elements inherent to such process, method, article or device.

[0047] Specific examples are used in this article to elaborate on the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method and its core idea of the present invention. The above are only the preferred embodiments of the present invention. For those of ordinary skill in the art, without departing from the principle of the present invention, several improvements, refinements or changes can be made, or the above technical features can be combined in an appropriate manner; these improvements, refinements, changes or combinations, or directly applying the concept and technical solution of the invention to other occasions without improvement, should all be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing gelatin sponge particles, characterized in that, It includes the following steps: S1: Place gelatin in water, let it swell and then heat to dissolve to obtain a gelatin solution; S2: Add a water-soluble developer to the gelatin solution obtained in step S1 and stir evenly, then cool to obtain a gelatin gel; S3: Dry the gelatin gel obtained in step S2, and crush the dried gelatin gel to obtain pretreated gelatin powder; S4: Place the pretreated gelatin powder obtained in step S3 and water together in a high-pressure reactor, stir evenly to obtain a gelatin dispersion; S5: Add a crosslinking agent to the gelatin dispersion obtained in step S4 and continue stirring; and add a physical foaming agent to the high-pressure reactor to raise the pressure in the reactor to a first pressure; S6: Stop stirring after a first time interval, and release the pressure in the high-pressure reactor to obtain gelatin sponge particles.

2. The method according to claim 1, wherein The drying of the gelatin gel obtained in step S2 specifically includes: Drying the gelatin gel by baking or freeze-drying; If the gelatin gel is dried by baking, control the baking temperature at 30°C - 60°C; if the gelatin gel is freeze-dried, control the freeze-drying temperature at -50°C to -10°C.

3. The method according to claim 1, wherein The crushing of the dried gelatin gel to obtain pretreated gelatin powder specifically includes: Crush the dried gelatin gel to obtain a first gelatin powder; Sieve the first gelatin powder into a second gelatin powder with a particle size of 10μm to 700μm; Wherein, the pretreated gelatin powder is the second gelatin powder.

4. The method according to claim 1, characterized in that, The temperature of water in step S4 is controlled at 10°C to 30°C.

5. The method according to claim 1, wherein The stirring speed in step S5 is controlled at 100rpm to 500rpm.

6. The method according to claim 1, characterized in that The mass of the crosslinking agent added in step S5 accounts for 1% to 20% of the mass of the pretreated gelatin powder.

7. The method according to claim 1, wherein The first pressure is 1MPa to 8MPa.

8. The method according to claim 1, characterized in that, The first time interval is 10min to 120min.

9. The method according to any one of claims 1 to 8, characterized in that The water in steps S1 and S4 is sterile water.

10. The method according to any one of claims 1 to 8, characterized in that The heating temperature in step S1 is controlled at 45°C to 55°C.