CN110876812A - Gelatin sponge suppository, preparation method and application thereof, and medicine for treating vascular diseases or tumors - Google Patents
Gelatin sponge suppository, preparation method and application thereof, and medicine for treating vascular diseases or tumors Download PDFInfo
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- CN110876812A CN110876812A CN201911244616.2A CN201911244616A CN110876812A CN 110876812 A CN110876812 A CN 110876812A CN 201911244616 A CN201911244616 A CN 201911244616A CN 110876812 A CN110876812 A CN 110876812A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0036—Porous materials, e.g. foams or sponges
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/104—Gelatin
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/36—After-treatment
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2389/00—Characterised by the use of proteins; Derivatives thereof
Abstract
The invention relates to the field of medicinal embolism, and particularly provides a gelatin sponge embolism agent, a preparation method and application thereof, and a medicament for treating vascular diseases or tumors. The preparation method of the gelatin sponge embolic agent comprises the following steps: sequentially stirring and/or bubbling the gelatin aqueous solution, drying to obtain gelatin sponge, and then sequentially physically crosslinking and post-treating the gelatin sponge to obtain a gelatin sponge embolic agent; the physical crosslinking mode comprises the following steps: high-temperature crosslinking or gamma-ray irradiation crosslinking, wherein the temperature of the high-temperature crosslinking is 100-180 ℃. The method has scientific process, does not introduce chemical cross-linking agents such as formaldehyde or glutaraldehyde and the like, has good biocompatibility, is safe and nontoxic, and has the advantages of low cost and suitability for large-scale production.
Description
Technical Field
The invention relates to the field of medicinal embolism, in particular to a gelatin sponge embolism agent, a preparation method and application thereof, and a medicament for treating vascular diseases or tumors.
Background
Embolization is the controlled injection of artificial embolizing material into the supply or diseased vessel of a disease or organ to occlude and interrupt the blood supply for the purpose of controlling bleeding, treating vascular lesions, tumors, and eliminating the function of the diseased organ. The excellent embolism material has the characteristics of good biocompatibility, no toxicity, selectable particle size, controllable in-vivo degradation rate, weak antigenicity and the like.
The embolization materials in the current market mainly comprise polyvinyl alcohol materials, gelatin materials, platinum microcoils and liquid embolization agents, and the materials have some defects. For example: the polyvinyl alcohol material and the platinum microcoil material are nondegradable and expensive after being embolized. Liquid embolic agents such as cyanoacrylate (cyanoacrylic acid), dehydrated ethanol, iodized oil and the like are easy to cause false embolism in clinical operation, and have great operation difficulty. Gelatin is a natural, non-toxic and harmless high molecular compound, has the characteristics of good biocompatibility, low price, strong water absorption and the like, but is easy to dissolve at physiological temperature; the gelatin material is used for embolism and is required to be crosslinked, so that the gelatin material is insoluble at physiological temperature, is degraded and absorbed after being embolized in a body, realizes blood passage recanalization after embolization, and avoids the pain of operative blood passage recanalization of a patient.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a preparation method of a gelatin sponge embolic agent, which has the advantages of scientific process, no introduction of chemical cross-linking agents such as formaldehyde or glutaraldehyde and the like, good biocompatibility, safety, no toxicity, low cost and suitability for large-scale production.
The second purpose of the invention is to provide a gelatin sponge embolic agent.
The third purpose of the invention is to provide the application of the gelatin sponge embolic agent.
The fourth purpose of the invention is to provide a medicine for treating vascular diseases or tumors.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
in a first aspect, the invention provides a preparation method of a gelatin sponge embolic agent, which comprises the following steps: sequentially stirring and/or bubbling the gelatin aqueous solution, drying to obtain gelatin sponge, and then sequentially physically crosslinking and post-treating the gelatin sponge to obtain a gelatin sponge embolic agent; the physical crosslinking mode comprises the following steps: high-temperature crosslinking or gamma-ray irradiation crosslinking, wherein the temperature of the high-temperature crosslinking is 100-180 ℃.
As a further preferred embodiment, the concentration of the aqueous gelatin solution is 4 to 15 wt%, preferably 5 to 10 wt%.
As a further preferable technical proposal, the stirring time is 10-60min, and/or the stirring speed is 800-1200 r/min;
preferably, the drying comprises freeze-drying;
preferably, the temperature of the freeze drying is-50 to-10 ℃, and/or the time of the freeze drying is 20 to 60 hours.
As a further preferred technical scheme, the temperature of high-temperature crosslinking is 120-160 ℃;
preferably, the high-temperature crosslinking time is 1-5h, preferably 3-5 h;
preferably, the high temperature crosslinking is carried out under standard atmospheric or vacuum conditions;
preferably, the time for gamma ray irradiation for crosslinking is 15-30h, and/or the irradiation dose is 15-30K.
As a further preferred technical solution, the post-treatment comprises: the gelatin sponge after physical cross-linking is sequentially crushed, screened and sterilized to obtain the gelatin sponge embolic agent.
As a further preferred solution, the screening comprises at least one of water screening, air flow screening or ultrasonic screening.
As a further preferred technical scheme, the screening comprises primary screening and secondary screening which are sequentially carried out;
preferably, the screening comprises: adopting 10-100 mesh screens to perform primary screening on the crushed gelatin sponge to obtain gelatin sponge particles with the particle size of 10-100 meshes, and then adopting 10-100 mesh screens to perform secondary screening on the gelatin sponge particles with the particle size of 10-100 meshes to obtain gelatin sponge particles with different particle sizes;
preferably, the primary screening comprises underwater screening and the secondary screening comprises ultrasonic screening.
In a second aspect, the invention provides a gelatin sponge embolic agent obtained by the above preparation method.
In a third aspect, the invention provides an application of the gelatin sponge embolic agent in preparing a medicament for treating vascular diseases or tumors.
In a fourth aspect, the invention provides a medicament for treating vascular diseases or tumors, which comprises the gelatin sponge embolic agent.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the gelatin sponge embolic agent provided by the invention comprises the steps of firstly stirring and/or bubbling gelatin water solution, and drying to obtain gelatin sponge (or called as uncrosslinked gelatin material), wherein the gelatin sponge does not contain chemical crosslinking agents such as formaldehyde or glutaraldehyde and is in a sponge shape and contains a large amount of pores; then the gelatin sponge realizes crosslinking through a physical crosslinking mode, which comprises high-temperature crosslinking at a specific temperature or gamma-ray irradiation crosslinking, the crosslinked gelatin material is insoluble at a physiological temperature, in addition, chemical crosslinking agents such as formaldehyde or glutaraldehyde and the like are not introduced into the physical crosslinking mode, the step of removing the chemical crosslinking agents is not needed, the chemical crosslinking agent residue can not occur in a human body, the biocompatibility is good, the gelatin sponge suppository is safe and nontoxic, and finally the gelatin sponge suppository is obtained through post-treatment. In addition, the method also has the advantages of low cost and suitability for large-scale production.
The high-temperature crosslinking temperature is 100-180 ℃, the crosslinking effect is good, if the temperature is too low, the in vivo (at physiological temperature) degradation is too fast, and the expected embolization effect cannot be achieved; if the temperature is too high, the crosslinking is excessive, the liquid absorptivity is small, the hardness is higher, the tube is easily blocked in the process of pushing and injecting, and the degradation period is too long, so that the vessel recanalization is not facilitated.
Drawings
FIG. 1 is a pathological section of an implantation test of the gelatin sponge embolization agent obtained in example 20.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer.
According to one aspect of the present invention, there is provided a method for preparing a gelatin sponge embolic agent, comprising the steps of: sequentially stirring and/or bubbling the gelatin aqueous solution, drying to obtain gelatin sponge, and then sequentially physically crosslinking and post-treating the gelatin sponge to obtain a gelatin sponge embolic agent; the physical crosslinking mode comprises the following steps: high-temperature crosslinking or gamma-ray irradiation crosslinking, wherein the temperature of the high-temperature crosslinking is 100-180 ℃.
The preparation method of the gelatin sponge embolic agent comprises the steps of firstly stirring and/or bubbling gelatin aqueous solution, and drying to obtain gelatin sponge (or called as uncrosslinked gelatin material), wherein the gelatin sponge does not contain chemical crosslinking agents such as formaldehyde or glutaraldehyde and is in a sponge shape and contains a large number of pores; then the gelatin sponge realizes crosslinking through a physical crosslinking mode, which comprises high-temperature crosslinking at a specific temperature or gamma-ray irradiation crosslinking, the crosslinked gelatin material is insoluble at a physiological temperature, in addition, chemical crosslinking agents such as formaldehyde or glutaraldehyde and the like are not introduced into the physical crosslinking mode, the step of removing the chemical crosslinking agents is not needed, the chemical crosslinking agent residue can not occur in a human body, the biocompatibility is good, the gelatin sponge suppository is safe and nontoxic, and finally the gelatin sponge suppository is obtained through post-treatment. In addition, the method also has the advantages of low cost and suitability for large-scale production.
The high-temperature crosslinking temperature is 100-180 ℃, the crosslinking effect is good, if the temperature is too low, the in vivo (at physiological temperature) degradation is too fast, and the expected embolization effect cannot be achieved; if the temperature is too high, the crosslinking is excessive, the liquid absorptivity is small, the hardness is higher, the tube is easily blocked in the process of pushing and injecting, and the degradation period is too long, so that the vessel recanalization is not facilitated.
It should be noted that:
the above-mentioned "stirring and/or bubbling of the aqueous gelatin solution in sequence, and drying" includes the following cases: (1) sequentially stirring and drying the gelatin water solution; (2) bubbling and drying the gelatin water solution in sequence; (3) sequentially stirring, bubbling and drying the gelatin water solution; (4) bubbling, stirring and drying the gelatin water solution in sequence; (5) the aqueous gelatin solution is first bubbled and stirred, while bubbling and stirring are simultaneously performed, and then dried.
In a preferred embodiment, the concentration of the aqueous gelatin solution is 4 to 15 wt.%, preferably 5 to 10 wt.%. Such concentrations are typically, but not limited to, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 wt%. When the concentration of the gelatin aqueous solution is within the above range, the stirring of the aqueous solution is more easily performed, and more bubbles can be formed. If the concentration is too low, the foam amount is too small, pores in the foam are too small, and the density of the dried gelatin sponge is too high; if the concentration is too high, the gelatin content is too low, the water content is too high, and the subsequent drying time is too long.
Alternatively, the method of preparing the aqueous gelatin solution comprises: putting gelatin into water, and heating to obtain gelatin water solution.
Optionally, the temperature of heating is 20-70 ℃. The above temperatures are typically, but not limited to, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 or 70 ℃.
Optionally, the heating means comprises water bath heating. The water bath heating is mild, the materials can be uniformly heated, and the dissolving process of the gelatin is uniform and controllable.
In a preferred embodiment, the stirring time is 10-60min, and/or the stirring speed is 800-. The above stirring time is typically, but not limited to, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 min. The stirring speed is typically, but not limited to, 800, 850, 900, 950, 1000, 1050, 1100, 1150 or 1200 r/min. When the stirring time and the stirring speed are within the above ranges, the aqueous gelatin solution can be completely converted into a foam, and if the stirring time and the stirring speed are too short or too slow, a part of gelatin which is not converted into a foam may be present, and if the stirring time and the stirring speed are too long or too fast, unnecessary production costs may be increased.
Preferably, the drying comprises freeze-drying. The foamed gelatin is freeze dried to form a solid gelatin sponge product.
Preferably, the temperature of the freeze drying is-50 to-10 ℃, and/or the time of the freeze drying is 20 to 60 hours. The temperature of the above-mentioned freeze-drying is typically, but not limited to, -50, -45, -40, -35, -30, -25, -20, -15 or-10 ℃; the freeze-drying time is typically, but not limited to, 20, 25, 30, 35, 40, 45, 50, 55 or 60 hours. The temperature and time of the freeze drying are more scientific, and the foamed gelatin can be quickly and completely dried to form the gelatin sponge.
In a preferred embodiment, the temperature for high temperature crosslinking is 120-160 ℃. The high temperature crosslinking temperature is typically, but not limited to, 120, 125, 130, 135, 140, 145, 150, 155, or 160 ℃. By further optimizing the high-temperature crosslinking temperature, the high-temperature crosslinking efficiency is higher, the crosslinking effect is better, and the connection between gelatin molecules is tighter.
Preferably, the high temperature crosslinking time is 1 to 5 hours, preferably 3 to 5 hours. The high temperature crosslinking time is typically, but not limited to, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 hours. The high-temperature crosslinking time is not short enough, the crosslinking is incomplete due to the short time, the quality of the obtained product is not high enough, and the gelatin is easy to age and even inactivate due to the long crosslinking time.
Preferably, the high temperature crosslinking is performed under standard atmospheric or vacuum conditions.
Preferably, the time for gamma ray irradiation for crosslinking is 15-30h, and/or the irradiation dose is 15-30K. The time is typically, but not limited to, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 h. The radiation dose is typically, but not limited to, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28 or 30K. Similar to high-temperature crosslinking time and high-temperature crosslinking temperature, the gamma-ray irradiation crosslinking time and the irradiation dose are more scientific, so that complete crosslinking can be ensured, and the product quality is not reduced.
In a preferred embodiment, the post-treatment comprises: the gelatin sponge after physical cross-linking is sequentially crushed, screened and sterilized to obtain the gelatin sponge embolic agent. The gelatin sponge after physical crosslinking is still in a large and hard block shape and cannot be directly applied, and the gelatin sponge embolic agent which is directly applied and can be selected in particle size can be obtained after the specific post-treatment process.
Preferably, the screening comprises at least one of water screening, air flow screening or ultrasonic screening.
Screening in water means that the sieve and the material are screened in water. The air flow screening is a screening method which utilizes high-speed air flow as a carrier to spray fully dispersed materials to a screen, so that rapid grading is realized. Ultrasonic screening refers to a method for screening materials by using ultrasonic waves, and compared with common vibration screening, the screening efficiency and the net cleaning efficiency are higher.
Alternatively, the screening may comprise underwater screening, air flow screening, ultrasonic screening, a combination of underwater screening and air flow screening, a combination of underwater screening and ultrasonic screening, or a combination of air flow screening and ultrasonic screening, or the like.
Preferably, the sieving comprises a primary sieving and a secondary sieving performed in sequence. Through twice screening, the different classification of the crushed gelatin sponge is realized, and gelatin sponge particles with different particle size specifications are obtained.
Preferably, the screening comprises: and (3) screening the crushed gelatin sponge by using screens of 10 meshes and 100 meshes for the first time to obtain gelatin sponge particles with the particle size of 10-100 meshes, and screening the gelatin sponge particles with the particle size of 10-100 meshes for the second time by using screens with different meshes within the range of 10-100 meshes to obtain the gelatin sponge particles with different particle sizes. After the specific primary screening and the secondary screening, the gelatin sponge particles with different particle size specifications can be obtained, and the gelatin sponge particles with the specific particle size specifications are selected according to actual use requirements.
Optionally, the mesh number of the screen in the secondary screening includes at least one of 10 mesh, 14 mesh, 18 mesh, 26 mesh, 32 mesh, 50 mesh, or 100 mesh.
Preferably, the primary screening comprises underwater screening and the secondary screening comprises ultrasonic screening.
It will be appreciated that after the selection of the mode of sieving in water, the product obtained by sieving must also be dried to ensure that the product is dry and that possible subsequent sieving is possible.
Optionally, the sterilization mode comprises irradiation sterilization, the irradiation mode can be electron beam irradiation or gamma ray irradiation, and the irradiation dose can be 15-30K.
According to another aspect of the present invention, there is provided a gelatin sponge embolic agent obtained by the above-mentioned preparation method. The gelatin sponge embolic agent is obtained by the preparation method, so the gelatin sponge embolic agent has the advantages of no chemical cross-linking agent, good biocompatibility, safety, no toxicity, degradability in vivo and low cost.
The following table shows the relevant detection results of the gelatin sponge embolic agent prepared by the method:
TABLE 1
According to another aspect of the present invention, there is provided a use of the above gelatin sponge embolization agent for the preparation of a medicament for the treatment of vascular diseases or tumors. The gelatin sponge suppository is applied to the preparation of the medicine for treating vascular diseases or tumors, and can improve the biocompatibility, reduce the toxicity, avoid generating larger side effects and reduce the cost while ensuring the treatment effect of the medicine on related diseases.
According to another aspect of the present invention, there is provided a medicament for treating vascular diseases or tumors, comprising the above-mentioned gelatin sponge embolic agent. The medicine comprises the gelatin sponge embolic agent, so the medicine at least has the advantages of good biocompatibility, safety, no toxicity and low cost.
The present invention will be described in further detail with reference to examples and comparative examples.
Example 1
A preparation method of a gelatin sponge embolic agent comprises the following steps:
(a) sequentially stirring and drying the gelatin water solution with the concentration of 20 wt% to obtain gelatin sponge, stirring for 70min, and vacuum drying at 5 ℃ for 65 h;
(b) physically crosslinking the gelatin sponge in a manner of high temperature crosslinking at 180 ℃ for 0.5h under standard atmospheric pressure;
(c) sequentially crushing, screening and sterilizing the gelatin sponge after physical crosslinking, wherein the screening comprises the following steps: and (3) screening the crushed gelatin sponge by using screens of 10 meshes and 100 meshes in water to obtain gelatin sponge particles with the particle size of 10-100 meshes, and drying the gelatin sponge particles with the particle size of 10-100 meshes, and ultrasonically screening the gelatin sponge particles with the particle size of 10-100 meshes by using screens of 10 meshes, 14 meshes, 18 meshes, 26 meshes, 32 meshes, 50 meshes and 100 meshes to obtain the gelatin sponge embolic agents with different particle size specifications.
Examples 2 to 4
A method for preparing a gelatin sponge embolization agent, which is different from example 1, in examples 2-4, the high temperature cross-linking temperature is 100, 120 and 160 ℃.
The temperature for high temperature crosslinking in examples 3-4 is within the preferred range of the present invention.
Examples 5 to 7
A method for preparing a gelatin sponge suppository, which is different from the embodiment 4, in the embodiments 5-7, the high temperature cross-linking time is 1, 3 and 5h respectively.
The time for high temperature crosslinking in examples 5-7 is within the preferred range of the present invention.
Examples 8 to 11
A method for preparing a gelatin sponge embolization agent, which is different from example 7, in examples 8-11, the concentrations of the gelatin aqueous solutions were 4, 15, 5 and 10 wt%, respectively.
The concentrations of the aqueous solutions of gelatin in examples 8-11 were within the preferred range of the present invention, and the concentrations of the aqueous solutions of gelatin in examples 10-11 were within the further preferred range of the present invention.
Examples 12 to 14
A method for preparing a gelatin sponge suppository, which is different from the gelatin sponge suppository prepared in the embodiment 11, the stirring time is 10 min, 30 min and 60min respectively in the embodiment 12 to 14.
The stirring times in examples 12-14 are all within the preferred range of the present invention.
Examples 15 to 17
A method for preparing a gelatin sponge embolic agent, which is different from the embodiment 14, in the embodiment 15-17, the drying mode in the step (a) is freeze drying, the temperature of the freeze drying is-50, -30 and-20 ℃, and the drying time is 60, 40 and 20h respectively.
The drying manner, drying temperature and drying time in examples 15 to 17 were within the preferable ranges of the present invention.
Example 18
Different from example 17, the preparation method of the gelatin sponge embolic agent in this example is that the physical crosslinking mode is gamma ray irradiation crosslinking, and the crosslinking time is 25 h.
Example 19
A preparation method of a gelatin sponge embolic agent comprises the following steps:
(a) weighing 140g of gelatin in a 10L reaction kettle, adding 2000mL of injection water, and stirring in a water bath at 60 ℃ until the gelatin is completely dissolved to form a uniform and transparent solution;
cooling the solution to 40 ℃, rapidly stirring for 20 minutes, when the solution is uniform and fine foam, the volume of the foam is 5-8 times of the volume of the original solution, and rapidly transferring the solution to a pre-cooled (1 hour at 0 ℃); transferring the formed foam into a freeze dryer for freeze drying at-50 ℃ for 1h, starting vacuum, and carrying out programmed temperature rise for 48h to obtain a white gelatin sponge product;
(b) placing the gelatin sponge at 150 ℃ and under standard atmospheric pressure for crosslinking for 4h to obtain a hardened yellowish gelatin sponge product;
(c) placing the hardened gelatin sponge in a centrifugal grinder to be ground to obtain a gelatin sponge particle product;
placing the gelatin sponge particles in injection water under a ten thousand-level environment, screening by using a 100-mesh and 10-mesh screen, removing small particles and oversize particles, collecting products between 10 meshes and 100 meshes, dehydrating and freeze-drying to obtain dry gelatin sponge particle products;
and (3) dry screening: under a ten thousand-level environment, ultrasonically screening the dried gelatin sponge particles respectively under 10 meshes, 14 meshes, 18 meshes, 26 meshes, 32 meshes, 50 meshes and 100 meshes, and controlling the granularity of each interval to be more than 80 percent to obtain the gelatin sponge particles with various specifications;
and (3) subpackaging the gelatin sponge particles with various specifications into penicillin bottles in a hundred-grade environment, sealing by a gland, sterilizing by using electron beam irradiation, and obtaining gelatin sponge particle embolic agent products with different particle sizes by using 25K of irradiation dose.
Example 20
A preparation method of a gelatin sponge embolic agent comprises the following steps:
(a) weighing 200g of gelatin in a 30L reaction kettle, adding 4000mL of injection water, and stirring in a water bath at 70 ℃ until the gelatin is completely dissolved to form a uniform and transparent solution;
cooling the solution to 40 ℃, rapidly stirring for 20 minutes, when the solution is uniform and fine foam, the volume of the foam is 5-8 times of the volume of the original solution, and rapidly transferring the solution to a pre-cooled (1 hour at 0 ℃); transferring the formed foam into a freeze dryer for freeze drying at-50 ℃ for 1h, starting vacuum, and carrying out temperature programming for 60h to obtain a white gelatin sponge product;
(b) placing the gelatin sponge at 160 ℃ and under atmospheric pressure for crosslinking for 3h to obtain a hardened yellowish gelatin sponge product;
(c) placing the hardened gelatin sponge in a centrifugal grinder to be ground to obtain a gelatin sponge particle product;
placing the gelatin sponge particles in injection water under a ten thousand-level environment, screening by using a 100-mesh and 10-mesh screen, removing small particles and oversize particles, collecting products between 10 meshes and 100 meshes, dehydrating and freeze-drying to obtain dry gelatin sponge particle products;
and (3) dry screening: under a ten thousand-level environment, ultrasonically screening the dried gelatin sponge particles respectively under 10 meshes, 14 meshes, 18 meshes, 26 meshes, 32 meshes, 50 meshes and 100 meshes, and controlling the granularity of each interval to be more than 80 percent to obtain the gelatin sponge particles with various specifications;
and (3) subpackaging the gelatin sponge particles with various specifications into penicillin bottles in a hundred-grade environment, sealing by a gland, sterilizing by using electron beam irradiation, and obtaining gelatin sponge particle embolic agent products with different particle sizes by using 25K of irradiation dose.
Example 21
A preparation method of a gelatin sponge embolic agent comprises the following steps:
(a) weighing 200g of gelatin in a 30L reaction kettle, adding 4000mL of injection water, and stirring in a water bath at 70 ℃ until the gelatin is completely dissolved to form a uniform and transparent solution;
cooling the solution to 40 ℃, rapidly stirring for 10 minutes, when the solution is uniform and fine foam, the volume of the foam is 5-8 times of the volume of the original solution, and rapidly transferring the solution to a pre-cooled (1 hour at 0 ℃); transferring the formed foam into a freeze dryer for freeze drying, pre-freezing for 3h at-40 ℃, starting vacuum, and carrying out temperature programming for 60h to obtain a white gelatin sponge product;
(b) placing the gelatin sponge at 120 ℃, and crosslinking for 3h under vacuum to obtain a hardened yellowish gelatin sponge product;
(c) placing the hardened gelatin sponge in a centrifugal grinder to be ground to obtain a gelatin sponge particle product;
placing the gelatin sponge particles in injection water under a ten thousand-level environment, screening by using a 100-mesh and 10-mesh screen, removing small particles and oversize particles, collecting products between 10 meshes and 100 meshes, dehydrating and freeze-drying to obtain dry gelatin sponge particle products;
and (3) dry screening: under a ten thousand-level environment, ultrasonically screening the dried gelatin sponge particles respectively under 10 meshes, 14 meshes, 18 meshes, 26 meshes, 32 meshes, 50 meshes and 100 meshes, and controlling the granularity of each interval to be more than 80 percent to obtain the gelatin sponge particles with various specifications;
and (3) subpackaging the gelatin sponge particles of various specifications into pre-filled syringes in hundred-grade environment, and performing gamma-ray irradiation sterilization with irradiation dose of 20K for 20h to obtain gelatin sponge particle embolic agent products of different particle sizes.
Example 22
A preparation method of a gelatin sponge embolic agent comprises the following steps:
(a) weighing 200g of gelatin in a 30L reaction kettle, adding 4000mL of injection water, and stirring in a water bath at 70 ℃ until the gelatin is completely dissolved to form a uniform and transparent solution;
cooling the solution to 40 ℃, rapidly stirring for 10 minutes, when the solution is uniform and fine foam, the volume of the foam is 5-8 times of the volume of the original solution, and rapidly transferring the solution to a pre-cooled (1 hour at 0 ℃); transferring the formed foam into a freeze dryer for freeze drying, pre-freezing for 3h at-40 ℃, starting vacuum, and carrying out temperature programming for 60h to obtain a white gelatin sponge product;
(b) placing the gelatin sponge under gamma rays for irradiation crosslinking for 25h to obtain a hardened gelatin sponge product;
(c) placing the hardened gelatin sponge in a centrifugal grinder to be ground to obtain a gelatin sponge particle product;
placing the gelatin sponge particles in injection water under ten thousand-level environment, screening under 10 meshes, 14 meshes, 18 meshes, 26 meshes, 32 meshes, 50 meshes and 100 meshes, respectively collecting products in each interval, dehydrating and freeze-drying to obtain dry gelatin sponge particle products;
and (3) dry screening: in a ten thousand-level environment, the dried gelatin sponge particles in each interval are respectively screened by airflow under 10 meshes, 14 meshes, 18 meshes, 26 meshes, 32 meshes, 50 meshes and 100 meshes, and the granularity of each interval is controlled to be more than 80 percent to obtain the gelatin sponge particles with various specifications;
and (3) subpackaging the gelatin sponge particles of various specifications into pre-filled syringes in hundred-grade environment, and performing gamma-ray irradiation sterilization with irradiation dose of 20K for 20h to obtain gelatin sponge particle embolic agent products of different particle sizes.
Comparative examples 1 to 2
A method for preparing a gelatin sponge embolization agent, which is different from example 1, the high temperature cross-linking temperature is 95 ℃ and 185 ℃.
The temperature for high temperature crosslinking in comparative examples 1-2 is outside the range provided by the present invention.
Comparative example 3
The gelatin sponge embolic agent was prepared by the method of example 1 in patent CN 101161298A.
Performance detection
The performance of the intermediate gelatin sponge and the gelatin sponge particle embolic agent obtained in the above examples and various proportions are respectively tested:
the method for detecting the compression modulus of the gelatin sponge comprises the following steps:
taking a gelatin sponge sample, and compressing at a compression rate of 0.5mm/s, wherein the compression modulus is the slope of a linear strain area on a stress-strain curve; the results are as follows:
TABLE 2
The liquid absorbability test method of the gelatin sponge particle embolic agent comprises the following steps:
sample 0.1g (m)0) 5.0g (m) are added1) Fully absorbing water in water until water absorption is saturated, filtering, and collecting residual water (m)2) The liquid absorbency was calculated.
Liquid absorbency (m)1-m2)/m0
Method for determining the digestibility of a gelfoam particle embolic agent:
the sample was taken, immersed in water until saturated, taken out, freed of excess water, placed in a stoppered flask containing a 37 ℃ solution of 1% (w/w) pepsin in hydrochloric acid, shaken at 37 ± 1 ℃ until complete digestion, and the digestion time was recorded.
TABLE 3
Sub-chronic systemic toxicity test:
the test gelatin sponge particle embolic agent is implanted subcutaneously in the back of the animals of the test group, and the animals of the control group are treated with a sham operation. After implantation, all animals were clinically observed daily and weighed weekly. After 90 days, blood was taken for clinical pathology (hematology and clinical biochemistry) examination, and histopathological examination. The body weight data, hematology and blood biochemistry data and relative weight (specific weight) of organs of the test group and the control group are subjected to a statistical analysis test process; no obvious abnormal expression appears in the clinical observation of the animals of the test group and the control group. Compared with the control group, the test group has no significant difference related to the toxicity of the sample in the aspects of body weight data, clinical and pathological indexes, relative weight of organs and the like. Compared with the control group, the test group has no pathological changes related to the toxicity of the sample in gross and histopathological examination, and the gelatin sponge particle embolic agent has no systemic toxicity reaction.
Local tissue reaction after implantation:
the gelatin sponge particle embolic agent and a control sample (high-density polyethylene) are respectively implanted into muscle tissues at two sides of the back of a rabbit, the materials are obtained at 1 week, 4 weeks, 8 weeks and 13 weeks of implantation, HE staining is carried out, and inflammatory reaction around the sample, formation and degradation of a sac cavity and a sac wall are observed under a light microscope. The tissue structure of the muscle implantation part of the test gelatin sponge particle embolic agent sample and the control sample is not abnormal by visual observation (see the pathological section in the following figure). Histopathological examination showed no irritation in the test samples compared to the control samples at 1 week, 4 weeks, 8 weeks, and 13 weeks (scores in tables 4-7).
The above test gel sponge particle embolization agents are all referred to the gelatin sponge embolization agents obtained in example 20.
TABLE 4 local response score after muscle Implantation (Implantation period: 1 week)
TABLE 5 local response score after muscle Implantation (Implantation period: 4 weeks)
TABLE 6 local response score after muscle Implantation (Implantation period: 8 weeks)
TABLE 7 local response score after muscle Implantation (Implantation period: 13 weeks)
Note: no stimulation: 0.0 to 2.9; slight stimulation: 3.0 to 8.9; toxic stimulation: 9.0 to 15.0; severe stimulation > 15. Fig. 1 is a pathological section of an implantation test of the gelatin sponge embolic agent obtained in example 20, and it can be seen from the pathological section that samples in tissues at the implantation position are completely degraded, and infiltration of fat tissues, generation of fibrous connective tissues and regeneration of muscle fibers at the implantation position can be observed, thereby illustrating that the gelatin sponge embolic agent provided by the invention can be completely degraded in vivo, and blood passage recanalization at the embolism position (or referred to as the implantation position) is realized.
Animal experiments:
gelatin sponge particle microsphere embolization to Beagle canine renal artery embolization test: the Beagle dog had DSA examination immediately after embolization of one side of the renal artery, and the embolization of the renal artery was observed, and the results showed: after 4 groups of animals are subjected to embolism, the blood vessels at all levels below the main trunk of the renal artery are subjected to angiography and recheck, and the renal blood flow is interrupted. Over time, the volume of the kidney on the side of the embolism becomes smaller and smaller, and the shape becomes irregular. The volume of the embolized side kidney was reduced to about 1/4, 1/10-1/4, 1/5-1/2, and 1/3-1/2, respectively, of the protonephron at 13 weeks.
Safety: animals were all alive and no obvious abnormalities were found.
The embolization agent used in the above animal experiments was the gelatin sponge embolization agent of example 20.
While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (10)
1. A preparation method of a gelatin sponge embolic agent is characterized by comprising the following steps: sequentially stirring and/or bubbling the gelatin aqueous solution, drying to obtain gelatin sponge, and then sequentially physically crosslinking and post-treating the gelatin sponge to obtain a gelatin sponge embolic agent; the physical crosslinking mode comprises the following steps: high-temperature crosslinking or gamma-ray irradiation crosslinking, wherein the temperature of the high-temperature crosslinking is 100-180 ℃.
2. The method for preparing a gelatin sponge embolization agent according to claim 1, wherein the concentration of the gelatin aqueous solution is 4-15 wt%, preferably 5-10 wt%.
3. The method for preparing a gelatin sponge embolization agent according to claim 1, wherein the stirring time is 10-60min, and/or the stirring speed is 800-;
preferably, the drying comprises freeze-drying;
preferably, the temperature of the freeze drying is-50 to-10 ℃, and/or the time of the freeze drying is 20 to 60 hours.
4. The method for preparing a gelatin sponge embolic agent as claimed in claim 1, wherein the temperature of high temperature cross-linking is 120-160 ℃;
preferably, the high-temperature crosslinking time is 1-5h, preferably 3-5 h;
preferably, the high temperature crosslinking is carried out under standard atmospheric or vacuum conditions;
preferably, the time for gamma ray irradiation for crosslinking is 15-30h, and/or the irradiation dose is 15-30K.
5. A method of preparing a gelatin sponge embolic agent as in any of claims 1 to 4, wherein the post-treatment comprises: the gelatin sponge after physical cross-linking is sequentially crushed, screened and sterilized to obtain the gelatin sponge embolic agent.
6. The method of claim 5, wherein the sieving comprises at least one of water sieving, air sieving, or ultrasonic sieving.
7. The method for preparing a gelatin sponge embolization agent according to claim 5, wherein the sieving comprises a primary sieving and a secondary sieving in this order;
preferably, the screening comprises: adopting 10-100 mesh screens to perform primary screening on the crushed gelatin sponge to obtain gelatin sponge particles with the particle size of 10-100 meshes, and then adopting 10-100 mesh screens to perform secondary screening on the gelatin sponge particles with the particle size of 10-100 meshes to obtain gelatin sponge particles with different particle sizes;
preferably, the primary screening comprises underwater screening and the secondary screening comprises ultrasonic screening.
8. A gelatin sponge embolic agent obtained by the manufacturing method of any of claims 1 to 7.
9. Use of the gelatin sponge embolic agent of claim 8 for the manufacture of a medicament for the treatment of vascular disease or tumor.
10. A medicament for the treatment of vascular disease or tumor comprising the gelatin sponge embolic agent of claim 8.
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